Who Classification of Head & Neck Tumors - 2017

.~World Health Organization Classification of Tl.lmours Delellis HA. Lloyd R.V., Heítz P.U., Eng C. (Eds): World Health Organization Classification of Tumours. Pathology ard Genetics of Tumours of Endocrine Orga.ns (3rd ed:ion). IARC p,ass: ryo·i 2004. ISBN 978·92·832·2416-7

Lakhani S.fi., Eilis 10., Schnitt S J. T2n P.H, var. de Vijver M.J, (Eds) WHO Classmc2íicn of Tumours of the Breast (4th editior). IARC: Lyon 2012. ISBN 978-92-832-2,]33-4

Mooh H., Hucnphrey PA, e! bright T.M., Reuter V.E. (Eds): WHO C1assificator: ot Tumo:.rs ot the Ur,nary Systerc 2nd Male Ger:ital Organs (4th edition). IARC Lyon 2016. '.SBN 978-92-832-2437-2

LeBoit P.E., Burg G , Weedon D .. Sarasin A. (Eds): World Health

Hetcher C.O.M., Bridge J.A,

Organiz::1.ticn Class'ticalion o"'

(Eas): \/JHO Ciassification of Twnours of Soft T:ssue and Bone (4th edition). iARC: Lyon 2013. iSBN 978-92·832-2434-1

Louis D.N , Ohgaki ½.. W.est!er O.O., Cavenee \/íJ.f<. WHO Classiticatíon of TJmcurs of the

Tumours. Patt1ology a:1d Genetics of Skin Tumours (3rd edltlor). IARC Press: Lyon 2006. ISBN 978\)2·832·2414-0

Swerdlow S.H., Campo S., Harris NL, Jaffe E.S., Pile<' S.A., Stein H., Thieie J., Vardiman r.W. (Eds): WH:J Classification of Tumours of Haematopoletic and Lymphoid

Tissues (4th ed:tíon). IARC: Lyor 2008. ISBN 978-92·832-243!-J

Hogendoom P,C.W., fv'ler:ens F.

Kurmar RJ . Carcangiu M L., Herr cgton C S, Young R.H. (Eds): WHO C:assifícat:or: of TuGours of Fema:e Rep:oductive Organs (4:h edition). IARC: Lyon 2014. ISBN 978-92-832-2435-8

Bosman F.T., C:srneiro F..

Trav's W.D., Brambília E..

Hruban R.H., Theiss ND. WHO Class 1ficatim·cf Tumours o: tne Oigest:ve System ( 4th edífon). IARC: Lyon 2010. ISBN 978-92-832-2432-7

Buri,;e A.P .. Marx A .. Nícho'son A.G. WHO Classiicatíon of TJrrours ot tre Lung, ?leura, Thymus & Heact (4th ed:tion). IARC· Lyon 20' 5. ISBN 978-92-832-2436-5

Centrai Nervous System (Rev:sed 4t1 edltion). IARC: Lycn 2016. ISBN 978·92 832-4492-9

Ei-Naggar AK, Chan J.K.C .. Grandis J.R, Takata ,., Slo:,tweg .:>J. (Eds): WHO Classlfication af Heaa and Neck Tumours (.!t\¡ editio;1). :ARC: Lyon 2017 iSBN 978-92 832-2438-9

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World Health Organization Classification of Tumours WHO

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lnternational Agency for Research on Cancer (IARC)

4th Edition

WHO Classification of Head and Neck Tumours

Edited by

Adel K. EI-Naggar John K.C. Chan Jennifer R. Grandis Takashi Takata Pieter J. Slootweg

lnternational Agency for Research on Cancer Lyon, 2017

World Health Organization Classification of Tumours Series Editors

Fred T. Bosman, MD PhD Elaine S. Jaffe, MD Sunil R. Lakhani, MD FRCPath Hiroko Ohgaki, PhD

WHO Classification of Head and Neck Tumours Editors

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Adel K. El-Naggar, MD, PhD John K.C. Chan, MBBS Jennifer R. Grandis, MD Takashi Takata, DOS, PhD Pieter J. Slootweg, MD, DMD, PhD Asiedua Asante Anne-Sophie Hameau Jessica Cox. Alberto Machado Delphine Nicolas Julia Brinkmann Maestro 38330 Saint-lsmíer, France lnternational Agency for Research on Cancer (lARC) 69372 Lyon Cedex 08, France

The WHO Classification of Head and Neck Tumours presented in this book reflects the views of a Working Group that convened for a Consensus and Editorial Meeting at the lnternational Agency for Research on Cancer, Lyon, 14-16 January 2016.

Members of the Working Group are indicated in the list of contributors on pages 285-292.

Published by the lnternational Agency for Research on Cancer (IARC), 150 Cours Albert Thomas, 69372 Lyon Cedex 08, France

© /nternational Agency far Research on Cancer, 2017 Distributed by WHO Press, World Health Organization, 20 Avenue Appia, 1211 Geneva 27, Swítzerland Tel.: +4122791 3264; Fax: +4122791 4857; email: [email protected] Publications of the World Health Organization enjoy copyright protection in accordance with the provisions of Protocol 2 of the Universal Copyright Convention. AII rights reserved. The designations employed and the presentation of the material in this publication do not imply the expression of any opinion whatsoever on the part of the Secretariat of the World Health Organization concerning the legal status of any country, territory, city, or area or of its authorities, or concerning the delimitation of its frontiers or boundaries. The mention of specific companies or of certain manufacturers' products does not imply that they are endorsed or recommended by the World Health Organization in preference to others of a similar nature that are not mentioned. Errors and omissions excepted, the names of proprietary products are distinguished by initial capital letters. The authors alone are responsible for the views expressed in this publication. The copyright of figures and tables remains with the authors. (See Sources offigures and tables, pages 294-297.) First print run (10 000 copies)

Formal for bibliographic citations: EI-Naggar A.K., Chan J.K.C., Grandis J.R., Takata T., Slootweg P.J. (Eds): WHO Classification of Head and Neck Tumours (4th edition). IARC: Lyon 2017

IARC Library Cataloguing in Publication Data WHO classification of head and neck tumours / edited by Adel K. EI-Naggar, John K.C. Chan, Jennifer R. Grand is, Takashi Takata, Pieter J. Slootweg. - 4th edition. (World Health Organization classification of tumours) 1. Head and neck neoplasms - genetics 3. Odontogenic tumours - genetics

2. Head and neck neoplasms - pathÓlogy 4. Odontogenic tumours - pathology

l. EI-Naggar, Adel K. 11. Series

ISBN 978-92-832-2438-9

(NLM Classification: WE 707)

Contents Tumours of the nasal cavity, paranasal sinuses and skull base

11

WHO and TNM classifications lntroduction Carcínomas Keratinizing squamous cell carcinoma Non-keratinizing squamous cell carcinoma Spindle cell (sarcomatoid) squamous cell carcinoma Lymphoepithelial carcinoma Sinonasal undifferentiated carcinoma NUT carcinoma Neuroendocrine carcinoma Adenocarcinoma lntestinal-type adenocarcinoma Non-intestinal-type adenocarcinoma Teratocarcinosarcoma Sinonasal papillomas Sinonasal papilloma, inverted type Sinonasal papilloma, oncocytic type Sinonasal papilloma, exophytic type Respiratory epithelial lesions Respiratory epithelial adenomatoid hamartoma Seromucinous hamartoma Salivary gland tumours Pleomorphic adenoma Malignant soft tissue tumours Fibrosarcoma Undifferentiated pleomorphic sarcoma Leiomyosarcoma Rhabdomyosarcoma Angiosarcoma Malignant peripheral nerve sheath tumour Biphenotypic sínonasal sarcoma Synovial sarcoma Borderline / low-grade malignant soft tissue tumours Desmoid-type fibromatosis Sinonasal glomangiopericytoma Solitary fibrous tumour Epithelioid haemangioendothelioma Benign soft tissue tumours Leíomyoma Haemangioma Schwannoma Neurofibroma Other tumours Meningioma Sinonasal ameloblastoma Chondromesenchymal hamartoma Haematolymphoid tumours Overview Extranodal NK/T-cell lymphoma Extraosseous plasmacytoma Neuroectodermal /melanocytic tumours Ewing sarcoma/primitive neuroectodermal tumours Olfactory neuroblastoma Mucosa! melanoma

12 14 14 14 15 17 18 18 20 21 23 23 24 26 28 28 29 30 31 31 32 33 33 34 34 35 35 36 38 39 40 41 43 43 44 45 46 47 47 47 48 49 50 50 51 51 52 52 52 54 56 56 57 60

2 Tumours of the nasopharynx WHO and TNM classifications

63 64

lntroduction Nasopharyngeal carcinoma Nasopharyngeal papillary adenocarcinoma Salivary gland tumours Adenoid cystic carcinoma Salivary gland anlage tumour Benign and borderline lesions Hairy polyp Ectopic pituitary adenoma Craniopharyngioma Soft tissue tumours Nasopharyngeal angiofibroma Haematolymphoid tumours Notochordal tumours Chordoma

3 Tumours of the hypopharynx, larynx, trachea and parapharyngeal space WHO and TNM classifications lntroductíon Malignant surface epithelial tumours Conventional squamous cell carcinoma Verrucous squamous cell carcinoma Basaloid squamous cell carcinoma Papillary squamous cell carcinoma Spindle cell squamous cell carcinoma Adenosquamous carcinoma Lymphoepithelial carcinoma Precursor lesions Dysplasia Squamous cell papilloma & squamous cell papillomatosis Neuroendocrine tumours Well-differentiated neuroendocrine carcinoma Moderately differentiated neuroendocrine carcinoma Poorly differentiated neuroendocrine carcinoma Salivary gland tumours Adenoid cystic carcinoma Pleomorphic adenoma Oncocytic papillary cystadenoma Soft tissue tumours Granular cell tumour Liposarcoma lnflammatory myofibroblastic tumour Cartilage tumours Chondroma and chondrosarcoma Haematolymphoid tumours

65 65 70 71 71 71 72 72 72 73 74 74 75 76 76 77

78 81 81 81 84 85 87 87 89 90 91 91 93 95 95 96 97 99 99 99 99 100 100 100 101 102 102 104

105 4 Tumours of the oral cavity and mobile tengue 106 WHO and TNM classifications 108 lntroduction 109 Malignant surface epithelial tumours 109 Squamous cell carcinoma Oral p9tentially malignant disorders & oral epithelial dysplasia 112 112 Oral potentially malignant disorders 112 Oral epithelial dysplasia 113 Proliferative verrucous leukoplakia 115 Papillomas 115 Squamous cell papilloma 116 Condyloma acuminatum

Verruca vulgaris Multifocal epithelial hyperplasia Tumours of uncertain histogenesis Congenital granular cell epulis Ectomesenchymal chondromyxoid tumour Soft tissue and neural tumours Granular cell tumour Rhabdomyoma Lymphangioma Haemangioma Schwannoma and neurofibroma Kaposi sarcoma Myofibroblastic sarcoma Oral mucosa! melanoma Salivary type tumours Mucoepidermoid carcinoma Pleomorphic adenoma Haematolymphoid tumours Overview CD30-positive T-cell lymphoproliferative disorder Plasmablastic lymphoma Langerhans cell histiocytosis Extramedullary myeloid sarcoma 5 Tumours of the oropharynx

117 117 119 119 119 121 121 122 122 123 123 124 125 126 127 127 127 128 128 129 129 130 131 133

(base of tangue, tonsils, adenoids) WHO and TNM classifications lntroduction Squamous cell carcinoma Squamous cell carcinoma, HPV-positive Squamous cell carcinoma, HPV-negative Salivary gland tumours Pleomorphic adenoma Adenoid cystic carcinoma Polymorphous adenocarcinoma Haematolymphoid tumours lntroduction Hodgkin lymphoma Burkitt lymphoma Follicular lymphoma Mantle cell lymphoma T-lymphoblastic leukaemia/lymphoma Follicular dendritic cell sarcoma 6 Tumours and tumour~like lesions

134 136 136 136 138 139 139 139 140 141 141 141 142 143 144 144 145 147

of the neck and lymph nodes WHO classification lntroduction Tumours of unknown origin Carcinoma of unknown primary Merkel cell carcinoma Heterotopia-associated carcinoma Haematolymphoid tumours Cysts and cyst-like lesions Branchial cleft cyst Thyroglossal duct cyst Ranula Dermoid and teratoid cysts 7 Tumours of salivary glands WHO and TNM classifications

148 148 150 150 151 152 154 155 155 156 156 157 159 160

lntroduction Malignant tumours Mucoepidermoid carcinoma Adenoid cystic carcinoma Acinic cell carcinoma Polymorphous adenocarcinoma Clear cell carcinoma Basal cell adenocarcinoma lntraductal carcinoma Adenocarcinoma, NOS Salivary duct carcinoma Myoepithelial carcinoma Epithelial-myoepithelial carcinoma Carcinoma ex pleomorphic adenoma Secretory carcinoma Sebaceous adenocarcinoma Carcinosarcoma Poorly differentiated carcinoma Lymphoepithelial carcinoma Squamous cell carcinoma Oncocytic carcinoma Sialoblastoma Benign tumours Pleomorphic adenoma Myoepithelioma Basal cell adenoma Warthin tumour Oncocytoma Lymphadenoma Cystadenoma Sialadenoma papilliferum Ductal papillomas Sebaceous adenoma Canalicular adenoma and other ductal adenomas Non-neoplastic epithelial lesions Sclerosing polycystic adenosis Nodular oncocytic hyperplasia L1/mphoepithelial sialadenitis lntercalated duct hyperplasia Benign soft tissue lesions Haemangioma Lipoma/sialolipoma Nodular fasciitis Haematolymphoid tumours Extranodal marginal zone lymphoma of mucosaassociated tymphoid tissue (MALT lymphoma)

8 Odontogenic and maxillofacial bone tumours WHO classification lntroduction Odontogenic carcinomas Ameloblastic carcinoma Primary intraosseous carcinoma, NOS Sclerosing odontogenic carcinoma CJear cell odontogenic carcinoma Ghost cell odontogenic carcinoma Odontogenic carcinosarcoma Odontogenic sarcomas Benign epithelial odontogenic tumours Ameloblastoma Ameloblastoma, unicystic type

162 163 163 164 166 167 168 169 170 171 173 174 175 176 177 178 179 180 181 182 182 183 185 185 186 187 188 189 190 191 192 192 193 194 195 195 195 196 197 198 198 198 199 200 201 203 204 205 206 206 207 209 210 211 213 214 215 215 217

Ameloblastoma, extraosseous/peripheral type Metastasizing ameloblastoma Squamous odontogenic tumour Calcifying epithelial odontogenic tumour Adenomatoid odontogenic tumour Benign mixed epithelial & mesenchymal odontogenic tumours Ameloblastic fibroma Primordial odontogenic tumour Odontoma Dentinogenic ghost cell tumour Benign mesenchymal odontogenic tumours Odontogenic fibroma Odontogenic myxoma/myxofibroma Cementoblastoma Cemento-ossifying fibroma Odontogenic cysts of inflammatory origin Radicular cyst lnflammatory collateral cysts Odontogenic and non-odontogenic developmental cysts Dentigerous cyst Odontogenic keratocyst Lateral periodontal cyst and botryoid odontogenic cyst Gingival cysts Glandular odontogenic cyst Calcifying odontogenic cyst Orthokeratinized odontogenic cyst Nasopalatine duct cyst Malignant maxillofacial bone and cartilage tumours Chondrosarcoma Mesenchymal chondrosarcoma Osteosarcoma Benign maxillofacial bone and cartilage tumours Chondroma Osteoma Melanotic neuroectodermal tumour of infancy Chondroblastoma Chondromyxoid fibroma Osteoid osteoma Osteoblastoma Desmoplastic fibroma Fibro-osseous and osteochondromatous lesions Ossifying fibroma Familia! gigantiform cementoma Fibrous dysplasia Cemento-osseous dysplasia Osteochondroma Giant cell lesions and simple bone cyst Central giant cell granuloma Peripheral giant cell granuloma Cherubism Aneurysmal bone cyst Simple bone cyst Haematolymphoid tumours Solitary plasmacytoma of bone

218 218 219 220 221 222 222 223 224 226 228 228 229 230 231 232

232 233 234 234 235

236 238 238 239

9 Tumours of the ear WHO classification lntroduction Tumours of the external auditory canal Squamous cell carcinoma Ceruminous adenocarcinoma Ceruminous adenoma Tumours of the middle and inner ear Squamous cell carcinoma Aggressive papillary tumour Endolymphatic sac tumour Otosclerosis Cholesteatoma Vestibular schwannoma Meningioma Middle ear adenoma

10 Paraganglion tumours WHO classification lntroduction Carotid body paraganglioma Laryngeal paraganglioma Middle ear paraganglioma Vagal paraganglioma

241

Contributors

241 243

Declaration of interests

243

IARC/WHO Committee for ICD-0

244

Sources of figures

244

Sources of tables

246

References

246

Subject index

246

247 248 249

249 249

250 251

251 253

253 254 255

256 256 257

257 258 259

260 260

List of abbreviations

261 262 263 263

263 264_ 265 266

266 266 267 268

269 270 271 272

275 276

276 277 281 282

283 285 292 293 294 297 298 340 347

CHAPTER 1 Tumours of the nasal cavity, paranasal sinuses and skull base

Squamous cell carcinomas Lymphoepithelial carcinoma NUT carcinoma Neuroendocrina carcinomas Adenocarcinomas Teratocarcinosarcoma Sinonasal papillomas Respiratory epithelial lesions Salivary gland tumours Malignant soft tissue tumours Borderline / low-grade malignant soft tissue tumours Benign soft tissue tumours Haematolymphoid tumours Neuroectodermal / melanocytic tumours

WHO classification of tumours of the nasal cavity, paranasal sinuses and skull base

Carcinomas

Borderline/low-grade malignant soft tissue tumours

Keratinizing squamous cell carcinoma Non-keratinizing squamous cell carcinoma Spindle cell squamous cell carcinoma Lymphoepithelial carcinoma Sinonasal undifferentiated carcinoma NUT carcinoma Neuroendocrine carcinomas Small cell neuroendocrine carcinoma Large cell neuroendocrine carcinoma Adenocarcinomas lntestinal-type adenocarcinoma Non-intestinal-type adenocarcinoma

8071/3 8072/3 8074/3 8082/3 8020/3 8023/3*

Teratocarcinosarcoma

9081/3

8041/3 8013/3 814 4/3 8140/3

Desmoid-type fibromatosis Sinonasal glomangiopericytoma Solitary fibrous tumour Epithelioid haemangioendothelioma

8821 /1 9 150/ 1 8815/1 9133/3

Benign soft tissue tumours Leiomyoma Haemangioma Schwannoma Neurofibroma

8890/0 9120/0 9560/0 9540/0

Other tumours Meningioma Sinonasal ameloblastoma Chondromesenchymal hamartoma

9530/0 9310/0

Sinonasal papillomas Sinonasal papilloma, inverted type Sinonasal papilloma, oncocytic type Sinonasal papilloma, exophytic type

8121 /1 8121 /1 8121/0

Haematolymphoid tumours Extranodal NK/T-cell lymphoma Extraosseous plasmacytoma

Respiratory epithelial lesions

Neuroectodermal / melanocytic tumours

Respiratory epithelial adenomatoid hamartoma Seromucinous hamartoma

Ewing sarcoma/ primitive neuroectodermal tumour Olfactory neuroblastoma Mucosa! melanoma

Salivary gland tumours Pleomorphic adenoma

9719/3 9734/3

9364/3 9522/3 8720/3

8940/0

Malignant soft tissue tumours Fibrosarcoma Undifferentiated pleomorphic sarcoma Leiomyosarcoma Rhabdomyosarcoma, NOS Embryonal rhabdomyosarcoma Alveolar rhabdomyosarcoma Pleomorphic rhabdomyosarcoma, adult type Spindle cell rhabdomyosarcoma Angiosarcoma Malignan! peripheral nerve sheath tumour Biphenotypic sinonasal sarcoma Synovial sarcoma

12

8810/3 8802/3 8890/3 8900/3 8910/3 8920/3 8901/3 8912/3 9120/3 9540/3 9045/3* 9040/3

The morphology codes are from the lnternational Classification of Diseases for Oncology (ICD-0) 1776AJ. Behaviour is coded /O for benign tumours; /1 for unspecified, borderline, or uncertain behaviour; /2 for carcinoma in situ and grade 111 intraepithelial neoplasia; and /3 for malignan! tumours. The classification is modified from the previous WHO classification , taking into account changes in our understanding of these lesions. 'These new codes were approved by the IARC/WHO Committee for ICD-0.

Tumours of the nasal cavity, paranasal sinuses and skull base

TNM classification of carcinomas of the nasal cavity and paranasal sinuses

TNM classificationª·" T - Primary tumour TX Primary tumour cannot be assessed TO No evidence of primary tumour Tis Carcinoma in situ Maxillary sinus Tumour limited to the antral mucosa. with no erosion or destruction of bone T2 Tumour causing bone erosion or destruction, including extension into hard palate and/or middle nasal meatus, except extension to posterior wall of maxillary sinus and pterygoid plates T3 Tumour invades any of the following: bone of posterior wall of maxillary sinus, subcutaneous tissues, !loor or medial wall of orbit, pterygoid fossa, ethmoid sinuses T4a Tumour invades any ot the following: anterior orbital contents, skin of cheek, pterygoid plates, infratemporal fossa, cribriform plate, sphenoid or frontal sinuses T4b Tumour invades any of the following: orbital apex, dura, brain, middle cranial fossa, cranial nerves other than maxillary division of trigeminal nerve (V2), nasopharynx, clivus T1

Nasal cavity and ethmoid sinus T1 Tumour limited to one subsite of nasal cavity or ethmoid sinus, with or without bony invasion T2 Tumour involves two subsites in a single site or extends to involve an adjacent site within the nasoethmoidal complex, with or without bony invasion T3 Tumour extends to invade the medial wall or !loor of the orbit, maxillary sinus, palate, or cribriform plate T4a Tumour invades any of the following: anterior orbital contents, skin of nose or cheek, minimal extension to anterior cranial fossa, pterygoid plates, sphenoid or frontal sinuses T4b Tumour invades any of the following: orbital apex, dura, brain, middle cranial fossa, cranial nerves other than V2, nasopharynx, clivus

N - Regional lymph nodes (i.e. the cervical nodes) NX Regional lymph nades cannot be assessed NO No regional lymph node metastasis N1 Metastasis in a single ipsilateral lymph node, s; 3 cm in g reatest dimension N2 Metastasis as specified in N2a, N2b, or N2c below N2a Metastasis in a single ipsilateral lymph nade, > 3 cm but s; 6 cm in greatest dimension N2b Metastasis in multiple ipsilateral lymph nodes, all s; 6 cm in greatest dimension N2c Metastasis in bilateral or contralateral lymph nades, ali s; 6 cm in greatest dimension N3 Metastasis in a lymph nade > 6 cm in greatest dimension Note: Midline nodes are considered ipsilateral nodes.

M - Distant metastasis MO No distan! metastasis M1 Distan! metastasis Stage grouping Stage O Tis Stage 1 T1 Stage 11 T2 T1 - 2 Stage 111 T3 Stage IVA T1 - 3 T4a Stage IVB T4b AnyT Stage IVC AnyT

NO NO NO N1 N0-1 N2 N0-2 Any N N3 Any N

MO MO MO MO MO MO MO MO MO M1

ªAdapted from Edge et al. [625AI - used with permission of the American Joint Committee on Cancer (AJCC), Chicago, lllinois; the original and primary source for this information is the AJCC Cancer Staging Manual, Seventh Edition (2010) published by Springer Science+Business Media - and Sobin et al. [2228A) . ºA help desk for specific questions about TNM classification is available at http://www.uicc.org/resources/tnm/helpdesk.

TNM classification of carcinomas of th e nasal cavity and paranasal sinuses

13


lntroduction Slootweg P.J . Chan J.K.C. Stelow E.B. Thompson L.D. R.

The sinonasal tract (i.e. the nasal cavity and associated paranasal sinuses) is the site of origin for a wide variety of neoplasms. The entities included in th is chapter meet one of three inclusion criteria: (1) they occur exclusively in the sinonasal tract , (2) they occur at other head and neck sites but show a predilection for the sinonasal tract, or (3) they are important in the sinonasal tract for differential diagnostic reaso ns. Th e first group is discussed extensively and the other two more concisely, with the reader referred to other chapters for additional information. This edition includes NUT carcinoma and biphenotypic sinonasal sarcoma as well-defi ned new entities. HPV-related

carcinoma with adenoid cystic-like features is provisionally listed as a subtype of non-keratinizing squamous cell carcinoma, with additional data needed to justify ful l recognition as a unique entity. Tumours of bone and cartilage, which were included in both the jaw and sinonasal tract chapters in the previous edition, are in this edition discussed exclusively in Chapter 8 (Odontogenic and maxillofacial bone tumours, p. 203) - a more appropriate approach given their morphological overlap with sorne odontogenic tumours. The role of immunohistochemical and genetic features in tumour characterization is reported with a balance between worldwide global application and the use of more expensive diagnostic methods not everywhere available, in an effort to ensure a more universal applicability of the classification . lt is noted that sorne tumours may constitute a spectrum of entities, such as highgrade non-intestinal-type adenocarcinoma and sinonasal undifferentiated

Carcinomas Keratinizing squamous ce// carcinoma

Synonym Epidermoid carcinoma

Bishop J.A. Bell D. Westra W.H ..

Epidemiology Sinonasal KSCCs are rare, and the sinonasal tract is the least common head and neck subsite involved by squamous cell carcinoma (SCC) {82}. KSCC most often affects patients in their sixth to seventh decades of life, and men are affected twice as often as women (82,2065,.2438}.

Detinition Sinonasal keratinizing squamous cell carcinoma (KSCC) is a malignant epithelial neoplasm arising from the surface epithelium lining the nasal cavity and paranasal sinuses and exhibiting squamous differentiation. ICD-0 code 14

8071/3

Etiology Cigarette smoking increases risk, although less dramatically than in other head and neck sites {271,960,1458, 2688}. Wood dust, leather dust, and other


carcinoma, and that there may be sorne overlap between tumours, such as between sorne sinonasal undifferentiated carcinomas and high-grade neuroendocrine carcinomas. More data are needed befare recommendations can be made on how best to classify tumours within these categories. In the meantime, we have tried to remain consistent with previous classification systems of tumours both at this site and at others (e.g. the classification of high-grade neuroendocrine carcinomas of the lung). Within the sinonasal trae!, CT is primarily used to evaluate mass effect on adjacent osseous structures, whereas MRI is better for disti nguishing mucosa! thickening and fluid resulting from a pathological mass process. Thus, these imaging modalities are complementary techniques. However, in general, cross-sectional imaging findi ngs are not unique or tumourspecific; therefore, information regarding imaging findings is included only when it is of specific diagnostic value.

industrial exposures are linked to sinonasal KSCC, although the association is not as strong as with intestinal-type adenocarcinoma {940,1490,1627). High-risk HPV is most frequently associated with non-keratinizing squamous cell carcinoma (see Non-keratínizing squamous ce// carcinoma, p. 15) (199,636,1335}. Sorne sinonasal papillomas (2-10%) undergo malignant transformation, usually into KSCC and less frequently into nonkeratinizing squamous cell carcinoma (1 750}.

Localization The maxillary sinus is most frequently affected, followed by the nasal cavity and ethmoid sinus. Primary carcinomas of the sphenoid and frontal sinuses are rare {82, 1999,2065,2342, 2438}.

Cl inical features Presenting symptoms are generally nonspecific and include nasal obstruction, epistaxis, and rhinorrhoea. Facial pain and/or paralysis, diplopía, and proptosis are indicative of more-advanced tumour growth {1458}. lmaging determines extent of disease.

Macroscopy The tumour is exophytic or endophytic, with various degrees of ulceration, necrosis, and haemorrhage.

Cytology Aspirates of metastases are cellular, with sheets and small clusters of malignant squamous cells with intracellular and extracellular keratinization. Mixed inflammation and necrosis can be present.

Histopathology KSCC exhibits histological features identical to those of conventional squamous cell carcinoma of other head and neck sites, with irregular nests and cords of eosinophilic cells demonstrating keratinization . and inducing a desmoplastic stromal reaction. Grades include well, moderately, and poorly differentiated. See Chapter 3 ( Tumours of the hypopharynx, /arynx, trachea and parapharyngeal space, p. 77) for further detail.

Genetic profile The genetic profile is similar to that of KSCC of other upper aerodigestive tract sites, whereas the genetic profile of nonkeratinizing squamous cell carcinoma is

~

Fig. 1.02 Sinonasal non-keratinizing squamous cell carcinoma. A lnterconnecting squamous ribbons invading the stroma with a broad, pushing border. B lnvasion takes the form of thick, anastomosing ribbons of tumour cells with a smooth stromal interface and no desmoplastic reaction. C Non-keratinizing squamoid cells with nuclear atypia, numerous mitotic figures, and peripheral palisading of tumour nuclei.

similar to that of its counterpart in the oropharynx (447,1458,1474}.

Non-keratinizing squamous ce// carcinoma

Prognosis and predictive factors

Bishop J.A. Brandwein-Gensler M. Nicolai P. Steens S. Syrjanen S. Westra W.H.

The 5-year overall survival rate for sinonasal squamous cell carcinoma is approximately 50-60%, and is stage-dependent (2065,2397,2438) Carcinomas of the nasal cavity have a better prognosis than carcinomas arising in the paranasal sinuses {82,617,2397,2438]. This difference is likely in part because sinus carcinomas present later and at higher stage; it is unclear whether there is a stage-forstage survival difference. Regional lymph node metastasis is uncommon (1458).

Definition Non-keratinizing squamous cell carcinoma (NKSCC) is a squamous cell carcinoma (SCC) characterized by a distinctive ribbon-like growth pattern with absent to limited maturation.

Carcinomas

15

ICD-0 code

8072/3

Synonyms Schneiderian carcinoma; transitional cell carcinoma; cylindrical cell carcinoma Epidemiology NKSCC accounts for approximately 1027% of sinonasal SCC. lt affects adults in their sixth to seventh decades of lite, and men more frequently than women {199, 636,1784,1999}. Etiology In general, NKSCC has similar risk factors to keratinizing squamous cell carcinoma, but 30-50% of cases harbour transcriptionally active high-risk HPV {199,636,1335). Sorne sinonasal papillomas (2-10%) undergo malignan! transformation. usually into keratinizing squamous cell carcinoma and less frequently into NKSCC {1750). Localization NKSCC arises most frequently from the maxillary sinus or nasal cavity {82,1402, 2065,24381.

16

Clinical features Presenting signs and symptoms include nasal obstruction, discharge, epistaxis, facial pain or fullness, nasal mass or ulcer, and eye-related symptoms in advanced cases {1 458). Patients with paranasal sinus neoplasms present later and at a higher stage than do patients with nasal cavity carcinomas {82,2438). lmaging determines extent of disease. Macroscopy The tumours are variably exophytic and/ or inverted in growth, and often friable, with necrosis and/or haemorrhage. Cytology Aspirates of metastases are cellular, with clusters of basaloid cells showing cytological features typical of malignancy, with nuclear atypia and increased mitotic figures . Mixed inflammation and necrosis can be present. • Histopathology NKSCC characteristi cally grows as expanding nests or anastomosing ribbons of cells in the submucosa, with a smooth stromal interface and a pushing border eliciting minimal or no desmoplasia. This


pattern is reminiscent of urothelial carcinoma (hence the synonym "transitional cell carcinoma") and may be difficult to recognize as invasive, particularly in small biopsies. Papillary features can be seen within the tumour or at the mucosa! surface . NKSCC has an immature appearance, with minimal or no keratinization; tumour nuclei are oval and the N:C ratio is high. Basal/superfic ial cellular polarity is often apparent: basaltype cells often demonstrate peripheral palisading, whereas superficial cells are more flattened. Scattered mucinous cells are occasionally present. The degree of nuclear atypia varíes, but mitotic figures are typically numerous, and necrosis is common. There is no established role for tumour grading in this variant. There is a broad differential diagnosis·; the growth pattern of NKSCC can mimic that of a sinonasal papilloma with malignant transformation. However, this would require confirmation of metachronous or synchronous sinonasal papilloma. Sinonasal undifferentiated carcinoma, neuroendocrine carcinoma, the salid variant of adenoid cystic carcinoma, and SMARCB1-deficient carcinomas should be considered in the differential

diagnosis. The presence of so-called abrupt keratinization should raise the possibility of NUT carcinoma. NKSCC is diffusely positive for cytokeratins (including high-molecular-weight forms such as CK5/6) and for p63 and p40. lt retains nuclear expression of SMARCB1 (INl1) and is negative for neuroendocrine markers, S100, and NUT1. HPV-related SCCs are diffuse ly p16positive by immunohistochemistry and positive for HPV by in situ hybridization and PCR.

Genetic profile The distinctive mutational profiles of HPV-positive and HPV-negative sinonasal SCC are similar to those of their coun terparts in other head and neck sites, such as the oropharynx [447,1458,1474).

Prognosis and predictive factors The 5-year overall survival rate of sinonasal SCCs as a group is approximately 60%; it is unclear whether the survival rate of NKSee differs from that of keratinizing squamous cell carcinoma {82,1999, 2065,2397,2438). HPV positivity may be associated with improved survival, although the prognostic signif icance is not as clearly defined as it is in the oropharynx {199,1335). Sorne studies have demonstrated improved survival in sinonasal sce harbouring high-risk HPV or overexpressing EGFR [199,1335,2342}. The newly recognized sinonasal tract HPV-related carcinoma with adenoid cystic-like features is a distinctive HPVrelated carcinoma of the sinonasal tract, with histological and immunophenotypic features of both surface-derived and salivary gland carcinoma - the latter showing the appearance of a high -grade adenoid cystic carcinoma. Among the few cases of HPV-related carcinoma with adenoid cystic- like features that have been reported to date, the female-to-male ratio is 7:2 and the patient age range is 4075 years {199,202,1065). The presence of a high-risk HPV type suggests a viral etiology [202,1065). Most cases present with nasal obstruction and/or epistaxis, with a tan-white, fleshy mass undermining normal-looking mucosa. The tumour consists of highly cellular proliferations of basaloid cells growing in various sizes, separated by thin collagenized fibrous bands. The growth pattern is predominantly salid, but cribriform structures are frequently encountered . The basaloid

cells align around cylindromatous microcystic spaces and have hyperchromatic and slightly angu lated nuclei with a high N:e ratio. In contrast to typical NKSCe, true ductal cells are also present (although less conspicuous), often surrounded by a peripheral layer of basaloid to clear myoepithelial cells. When this bilayered pattern is well developed, it imparts an appearance like th at of epithelial-myoepithelial carcinoma. Although overt squamous differentiation is not typically present in the invasive component, the surface epithelium may show various degrees of dysplasia. Mitotic rates are usually high, and necrosis may be seen. The basaloid cells show myoepithelial differentiation (e.g. S100, calponin , p63, and actin), and the ductal cells are KITpositive. Cytokeratins tend to be more strongly expressed in the ductal rather than myoepithelial cells . Both cell types are p16-positive and harbour high-risk HPV as detected by in situ hybridization. No MYB translocations (typically seen in about 50% of adenoid cystic carcinomas) have been identified [202} . To date, with only a limited number of cases reported, local recurrence has been seen, but no regional or distant metastases or tumourrelated deaths {202).

Etiology sesee is associated with smoking and radiation exposure {1398 ,2396 }. HPV has been negative in the few cases tested {199).

Localization sesee arises in the nasal cavity and/ or maxillary or frontal sinuses [787,912, 1032,1035).

Clinical features Patients present with nasal obstruction, epistaxis, and/or facial swelling, with masses apparent on e T or MR I {787,896, 912,1032,1035}.

Macroscopy

Spmdmcell(sarcomawid) squamous cell carcinoma

Sorne SCSCCs grow as a polypoid mass with an ulcerated surface, similar to the more common laryngeal examples {896, 912).

Bishop J.A. Lewis J.S .

Cytology Definition

See Spindle ce!/ squamous ce!/ carcinoma section (p. 87) in Chapter 3.

Spindle cell squamous cell carcinoma (SCSCe) is a variant of squamous cell carcinoma characterized by predominan\ malignan! spind le and/or pleomorphic cells.

For histology and diffe rential diagnosis, see Spindle ce// squamous ce!! carcinoma section (p. 87) in Chapter 3.

ICD-0 code

Prognosis and predictiva factors

8074/3

Synonym

Histopathology

No specific features are described for the sinonasal tract regían.

Sarcomatoid carcinoma

Epidemiology sesee presents most commr;mly in elderly men {156,1330,2396}. This variant is rare in the sinonasal tract, accounting for < 5% of sinonasal squamous cell carcinomas {199,787,896,912,1032,1035}.

Carcinomas

17

Lymphoepithelial carcinoma

Clinical features

Bishop J.A. Gaulard P. Gillison M.

Patients present with nasal obstruction, nasal discharge, and/or epistaxis. Patients may also have eye symptoms or cranial nerve palsies as a result of local tumour invasion {1125,2034,2584,2733}.

Definition

Macroscopy

Lymphoepithelial carcinoma (LEC) is a squamous cell carcinoma morphologically similar to non-keratinizing nasopharyngeal carcinoma, undifferentiated subtype.

The tumours are irregular or polypoid, tan-white, bulky masses that may be haemorrhagic {1155,2034,2347).

!CD-O code

8082/3

Synonym

Cytology The cytological findings are the same as those far non-keratinizing nasopharyngeal carcinoma, undifferentiated subtype (see Nasopharyngeal carcinoma, p. 65.)

Lymphoepithelioma-like carcinoma

< 60 years, and of White ethnicity have significantly improved survival {38 1). Sinonasal LEC metastasizes to regional lymph nades less frequently than does nasopharyngeal carcinoma, and tends to be radiosensitive even in the presence of nada! disease {381,1125,2034,2584, 2733).

Sinonasal undifferentiated carcinoma Lewis J.S. Bishop J.A Gill ison M. Westra W.H. Yarbrough W.G.

H istopathology Epidemiology Sinonasal LEC is rare, with only about 40 reported cases {1125,2034,2584,2733). lt most frequently affects men in th eir fifth to seventh decades of life (median patient age: 58 years) {381 ,11 25,2034, 2584,2733). Most reported cases have been in patients from Asia, where EBVrelated malignancies are endemic.

Etiology In the sinonasal tract, most cases (> 90%) of LEC harbour EBV {11 25,1392, 2034,2584,2733}.

Localization Sinonasal LEC arises in th e nasal cavity more frequently than in the paranasal sinuses (2034,2584,2733}. For an LEC to be considered truly primary to the sinonasal reg ion, spread from a nearby nasopharyngeal carcinoma must be excluded on clinical, radiograph ical, and/or pathological grounds. 18

LEC is defined by its resemb lañce to non-keratinizing nasopharyngeal carcinoma, undifferentiated subtype (see Nasopharyngeal carcinoma, p. 65). By immunohistochemistry, LEC is diffusely positive far pancytokeratin, CK5/6, p63, and p40, and is negative for lymphoid and melanocytic markers. Sinonasal LEC is usually positive far EBVencoded small RNA (EBER) by in situ hybridization. Sinonasal LEC must be distinguished from lymphoma and melanoma (potential mimics), as well as from sinonasal undifferentiated carcinoma, a neoplasm that lacks th e syncytial growth pattern of LEC, is consistently EBER-negative, and lacks CK5/6, with limited to absent p63 .

Definition Sinonasal undifferentiated carcinoma (SNUC) is undifferentiated carcinoma of the sinonasal tract without glandular or squamous features and not otherwise classifiable . Table 1.01 Differential diagnosis of sinonasal undifferentiated carcinoma Lymphoma Non-keratinizing squamous cell carcinoma (including HPV-related carcinoma with adenoid cystic- like features) Basaloid squamous ce!! carcinoma High-grade neuroendocrina carcinoma Olfactory neuroblastoma NUT carcinoma


Alveolar rhabdomyosarcoma

According to the SEER database, sinonasal LEC has a 5-year disease-specific survival rate of approximately 50%; patients with localized disease, aged

Adenoid cystic carcinoma, solld-type (grade 111)


Ewing sarcoma / primitiva neuroectodermal tumour

Melanoma

other visual symptoms (2656). Proptosis and periorbital swelling can be seen as well, features reflecting frequent orbital involvement.

Macroscopy Tumours are usually large (> 4 cm) at presentation, with a fungating endoscopic appearance and poorly defined margins radiographically {1883).

Cytology Aspirates of metastatic SNUC are cellular, with cohesive groups, single large malignant cells, and background necrotic debris. Numerous mitotic figures and apoptotic bodies can be seen. Neuroendocrine features are typically not prominent, and squamous or glandular features are not seen.

Histopathology

ICD-0 code

8020/3

be questioned {199,365,885,2518}.

Epidemiology

Localization

SNUC is rare, with about 0.02 cases per 100 000 people, accounting for only about 3-5% of ali sinonasal carcinomas (1458}. lt occurs in patients of a wide range of ages, from teenagers to the elderly (average patient age: 50-60 years). App roximately 60- 70% of patients are Caucasian males {371,1974}.

Etiology

Tumours arise most frequently in the nasal cavity and ethmoid sin uses, and most present as very large masses involving multiple sites. As many as 60% of cases have spread beyond the sinonasal trae! to adjacent sites such as the orbital apex, skull base, and brain {1974). Nodal metastases are relatively uncommon (occurring in 10-15% of cases) despite large primary tumour size {416,885,1974}.

No consistent etiology of SNUC has been identified. Sorne patients are smokers but many are not {365). lf EBV or HPV is detected, the diagnosis of SNUC should

Patients present with nasal obstruction, epistaxis, headache, and diplopía or

Clinical features

SNUC consists of sheets, lobules, and trabeculae of overtly malignant cells with moderately large round nuclei, varying amounts of cytoplasm, and well-defined cell borders. Nuclei vary from hyperchromatic to vesicular, but most tumours have open chromatin with prominent nucleoli. Apoptosis, mitoses, and necrosis are frequent. Despite their high-grade appearance, SNUCs characteristically have tumour nuclei of relatively consisten! size and lack of pleomorphism. By definition, there is no squamous or glandular differentiation, although adjacent carcinoma in situ has been described. By immunohistochemistry, the tumour is positive for pancytokeratin (AE1/AE3) and simple cytokeratins such as CK7, CK8, and CK18, but is negative for CK5/6. The tumour cells are variably positive for p63, but consistently negative for its more squamous-specifi c isoform, p40 {2186}. The cells are consistently positive for neuron-specific enolase. Very focal, patchy staining for chromogranin and synaptophysin may be seen {365,416}, but does not qualify a tumour as a neuroendocrine carcinoma in the absence of supporting histological features. The tumours are negative for carcinoembryonic antigen, S100, CD45, and calretinin {2635). The tumours are consistently p16-positive, regardless of HPV status {885,2518}. The differential diagnosis is lengthy (Table 1.1), but most importantly includes lymphoma, non-ke ratinizing squamous cell carcinoma, basaloid squamous cell Carcinomas

19

carcinoma, and neuroendocrine carcinoma. Squamous cell carc inoma has areas of histological squamous differentiation and is consistently positive for CK5/6, p63, and p40. Neuroendocrine carcinomas have speckled chromatin and other histological features such as rosette formation and palisading, and are con sistently reactive with neuroendocrine marl
Genetic profile No specif ic genetic alterations have been identified in SNUC {819). The S0X2gene is amplified in one third of tumours {2102}. KIT (CD117) is frequently strongly expressed, but no activating mutations or gene amplifications have been identified {416).

-

-

Fig. 1.09 NUT carcinoma. A Sheets of moderate-sized monomorphic poorly differentiated epithelioid cells have pale to clear glycogenated cytoplasm; the intervening stroma is sean!, and necrosis and mitoses are invariably present. B Abrupt keratinization can appear as a discrete island within a sea of poorly differentiated cells. C FISH demonstrates NUT rearrangement when red and green probes flanking the NUT Jocus are split apart; the red and green signals together are the normal NUT allele. D Diffuse, nuclear immunohistochemical staining with the NUT antibody is diagnostic of NUT carcinoma; the speckled pattern is characteristic but not always this distinct.

ICD-0 code

8023/3


Synonyms

The prognosis of SNUC is poor, although it seems to have improved in recent years, likely dueto the use of aggressive trimodality therapy {371}. Systemic chemotherapy is associated with particularly high response rates (243}. A large analysis of SEER data showed a median overall survival of 22.1 months and 3-, 5-, and 10-year survival rates of 44.3%, 34.9%, and 31.3%, respectively (371]. A recent meta-analysis had similarfindings {1974). Patient survival is significantly better with primary surgical resection [1974,2685) .

NUT midline carcinoma; t(15;19) carci noma; midline carcinoma of children and young adults with NUT rearrangement

Epidemiology NUT carcinoma is a rare tumour in the upper aerodigestive tract {t59,393, 2234}. Dueto its rarity, the true incidence is unknown. In the largest series reported (n = 40), the median patient age was 21 .9 years , but people of all ages were affected (range: 0.1- 82 years). A slight predominance of females was seen, with 55% of the cases occurring in females {393).

NUT carcinoma

Clinical features NUT carcinoma presents with nonspecific symptoms caused by a rap idly growing mass. In the sinonasal tract, this manifests as nasal obstruction, pain, epistaxis, nasal discharge, and frequently eye-related symptoms such as proptosis {205,692). lmag ing studies reveal extensive local invasion into neighbouring structures such as the orbit or brain (205 ,692}. In approximately 50% of cases, NUT carcinoma presents with lymph nade involve ment or distant metastatic disease {159}.

Macroscopy Few tumours are resected, due to early disease spread. No consistent macroscopic features have been described .

Etiology French C.A. Bishop J.A. Lewis J.S. Muller S. Westra W.H.

Definition NUT carcinoma is a poorly differentiated carcinoma (often with evidence of squamous differentiation) defined by the presence of nuclear protein in testis (NUT) gene (NUTM1) rearrangement. 20

The etiology is unknown . There is no association with HPV, EBV, other viral infection; smoking; or other environmental factors .

Cytology

Localization

Aspirates of metastases are cellular, with variably sized clusters of malignant cells and single malignant cells. Mitotic figu res and apoptotic bodies are seen. Squamous differentiation may be observed.

Most cases (65%) in the head and neck are in the nasal cavity and paranasal sinuses, but rare cases involve the orbital region, nasopharynx, oropharynx, larynx, epiglottis, and majar salivary glands {159,508,763,2032}. The tumours are generally midline.

The diagnosis of NUT carcinoma is estab lished by demonstration of NUT rearrangement, rather than by histology. An unequivocal diagnosis can be made by demonstration of diffuse (> 50%)


Histopathology

Chromosome 15q14 BRD4

N

BRD3

N

. ,_¡- -...............- -L.IJi._,¡,__ . i _ _ _ _ __

Chromosome 19pl3. l

¡_,¡- -.....

Chromosome 9q34.2

=---'- -L.1Ji...._f _.

Chromosome Bpll.23

Neuroendocrine carcinomas Thompson L.D.R. Bell D. Bishop J .A.

Definition NSD3°NUT

N

.__.-....--~:::a:::::::.J• l.:;~=:;¡¡¡¡¡¡¡¡¡¡....¡.1u;;.:,•.;;:¡¡

PWWP

1 -

1

Acidic doma in 2

PHD

NLS

1111

SET C/H rlch Ac!dlc domainl

Sinonasal neuroendocrine carcinoma is a high-grade carcinoma with morphological and immunohistochemical features of neuroendoc rine differentiation.

-

ICD-0 codes

NES Bromo ET

Fig. 1.10 NUT carcinoma. Schematic illustration of the various translocations that occur in NUT carcinoma between NUTgenes and BRD4, BRD3, and WHSC1L1 (also called NSD3); the arrows indicate breakpoints. Nearly the entire NUT transcript is preserved in every known translocation. PWWP, PWWP domain; PHD, plant homeodomain; SET, SET domain; C/H rich, Cys/His-rich domain; NLS, nuclear Jocalization signal sequence; NES, nuclear export signal sequence; Bromo, bromodomain; ET, extraterminal domain.

nuclear staining with the NUT monoclonal antibody C52, which has a sensitivity of 87% (916}. Other diagnostic tools include FISH, RT-PCR, conventional cytogenetics, and targeted next-generation sequencing approaches . The histology is that of an undifferentiated carcinoma or poorly differentiated squamous cell carcinoma. NUT carcinoma consists of sheets of cells with moderately large, round to oval nuclei. The chromatin is vesicu lar with distinct nucleoli. Cytoplasm varíes from scant to moderate, and can be clear. Mitotic activity is brisk and necrosis is often present. Hallmark features include monomorphism and the presence of so-called abru pt foci of keratinization. Occasional tumours have more extensive squamous differentiation (764). lntratumoural acute inflammation can be brisk and is frequently present. Glandular and mesenchymal differentiation, although described, is infrequent (566) . Markers other !han NUT that are commonly positive include p63, p40, and cytokeratins (2265). NUT carcinoma occasionally (in 55% of cases) expresses CD34 {764). Occasional positivity for neuroendocrine markers, p16, and TTF1 has also been described. Due to the non-specific, poorly differentiated nature of NUT carcinoma, it is often confused with poorly differentiated squamous cel l carcinoma, Ewing sarcoma, sinonasal undifferentiated carcinoma, leukaemia, germ cell tumour, and even olfactory neuroblastoma (763). A provi sionally defined entity included in the differential diagnosis is SMARCB1-deficient

carcinoma. However, unlike NUT carci nomas, SMARCB1 -deficient sinonasal carc inomas do not exhibit focal keratinization. lnstead, the basaloid cells demonstrate various degrees of rhabdoid or plasmacytoid features. Because SMARCB1-deficient sinonasal carcinomas have biallelic inactivation of SMARCB1 (IN/1), immunohistochemical staining for SMARCB1 consistently demonstrates loss of nuclear expression, an importan! fi nding for distinguishing SMARCB1 -deficient carcinoma from NUT carcinoma.

Genetic profile NUT carcinoma is genetically defi ned by rearrangements of the nuclear protein in testis (NUTJ gene (NUTM1). In most NUT carcinomas, most of the codi ng sequence of NUTM1 on chromosome 15q14 is fused with BRD4 (in 70% of cases), BRD3 (in 6%), or WHSC1L1 (also called NS03), creating chimeric genes that encade NUT fusion proteins (159, 764,765,766,767,2318}. In the re maining cases, referred to as NUT-variant carcinoma, NUTM1 is fused toan unknown partner gene. To date, no other oncogenic mutations have been identified in NUT carcinoma.

Prognosis and predictive fact9rs Prognosis is poor, with a median overall survival of 9.8 months {393}. Sorne evidence suggests that patients with NUTvariant carc inoma may have a longer survival than do BRD-NUT carcinoma patients {159,763 }.

Small cell neuroendocrine carcinoma (SmCC) Large cell neuroendocrine carcinoma (LCNEC)

8041/3 8013/3

Synonyms Poorly differentiated neuroendocrine carcinoma; high-grade neuroendocrine carcinoma

Epidemiology Sinonasal neuroendocrine carc inomas are rare, accounting for about 3% of sinonasal tumours, but are more common in middle-aged to older men . The mean patient ages are 49-65 years for LCNEC and 40-55 years for SmCC (370, 1831,1853,2222}.

Etiology There is rare association with transcrip tionally active high-risk HPV (199,1323} and previous irradiation (2535). but no strong smoki ng association {2296}.

Localization The most common location is the ethmoid sinus, followed by the nasal cavity and the maxillary and sphenoid sinuses (1631,2222,2296}.

Clinical features Many patients present with non-specific symptoms (e.g. nasal obstruction, discharge, and sinusitis) and have advanced local disease (pT3 or T4), with regional or distan! metastases (to lung, liver, or bone) (11 4,1428,1631,1853}. Rarely, paraneoplastic syndromes are reported {114,1207,2018,2482}.

Macroscopy The tumours are large and destructive, with haemorrhage and necrosis.

Carcinomas

21

~

--

-

Fig. 1.11 Sinonasal neuroendocrine carcinoma. A Coronal CT demonstrates a midline destructive mass. B Small cells with nuclear moulding, even chromatin distribution, and inconspicuous nucleoli are characteristic for a small cell neuroendocrine carcinoma; apoptotic figures and mitoses are apparent. C The neoplastic cells are large and have a high N:C ratio, with small nucleoli and salt-and-pepper nuclear chromatin distribution in a large cell neuroendocrine carcinoma. DA strong and diffuse, cytoplasmic dot-like (perinuclear) reaction with pancytokeratin in a small cell neuroendocrine carcinoma.

Cytology Aspirates of metastases are identical to those of SmCC and LCNEC sampled elsewhere. Malignant cells show less cohesion than seen in other epithelial malignancies and are more fragile, displaying more crush artefact. Mitotic figures and apoptotic bodies are frequent. Histopathology Sinonasal neuroendocrine carcinoma is histologically identical to its counterparts in lung and other head and neck sites; for a detailed description, see Poorly differentiated neuroendocrine carcinoma (p. 97). The tumours are highly infiltrative, with frequent perineural and lymphovascular invasion (1853,2222). LCNEC contains large cells that show light microscopic neuroendocrine features; for a detailed description of these features , see Poorly differentiated neuroendocrine carcinoma (p. 97). SmCC and LCNEC are strongly immunopositive for cytokeratins (e.g. CAM5.2 and AE1/AE3) and EMA, frequently showing a perinuclear or dot-like pattern (1587). Neuroendocrine differentiation can be confirmed by staining with at least one neuroendocrine marker, such as synaptophysin (most sensitive and specific), 22

chromogranin, neuron-specific enolase, or CD56 (least specific) {486}. although neuron-specific enolase is less common in LCNEC (114,2568}. In SmCC, S100 protein staining (when positive) is diffuse rather than sustentacular {2222} . SmCC and LCNEC are positive far p16 (which is negative in sinonasal undifferentiated carcinoma); focally, they may be weakly positive for p63. The tumours are rarely reactive with calretinin and are consistently negative far CK5/6, EBV-encoded small RNA (EBER), and CK20 {378,390, 2635). ASCL1 (also called hASH1), which is a master gene for neuroendocrine differentiation, shows a higher degree of expression in SmCC and LCNEC than in olfactory neuroblastoma or rhabdomyosarcoma (486,2331). Nuclear immunohistochemistry for p53 correlates with TP53 mutations {758). Rare examples of sinonasal neuroendocrine carcinoma combined with either squamous cell carcinoma (in situ or invasive) or adenocarcinoma ha'{e been reported (1 14,758 ;1320}. However, squamous cell carcinoma or adenocarcinoma should not be regarded as sinonasal neuroendocrine carcinoma based solely on the presence of focal neuroendocrine immunoreactivity in the absence of


light-microscopic features of neuroendocrine differentiation. The differential diagnosis frequently ineludes olfactory neuroblastoma, sinonasal undifferentiated carcinoma, and NUT carcinoma. High-grade olfactory neuroblastoma may retain a focal lobular architecture with a variable presence of peripheral sustentacular cells demonstrated by immunohistochemistry; cytokeratins, if expressed, tend to be focal rather than diffuse. Sinonasal undifferentiated carcinomas occasionally express neuroendocrine markers, but lack the morphological features of LCNEC [773, 1034,2568}. NUT carcinoma does not show neuroendocrine differentiation, and typically shows diffuse expression of CK5/6 and p63 (692).

Prognosis and predictiva factors The 5-year disease-free survival rate is about 50-65% overall, and is better for sphenoid sinus tumours (-80%) than for maxillary or ethmoid sinus tumours (-33%), in particular when managed by combination surgery and/or neoadjuvant, concurrent, or adjuvant chemoradiotherapy, with neoadjuvant therapy possibly yielding a better outcome (especially for LCNEC) (770,1428,1631,1831,2462).

Epidemiology Sinonasal ITACs are uncommon, with an overall incidence of < 1 case per 1 million person-years. However, incidence varíes drastically across populations, and the tumours are as much as 500 times as prevalent among people who work for prolonged periods in wood or leather-working industries as they are in the general population {9). Men are 3 - 4 times as likely to develop these tumours as women, which is thought to be due to differences in occupational exposure rates (139,1238,2063}. Although the patient age range is reportedly wide, most patients are older, with mean and median reported patient ages at diagnosis in the sixth to seventh decades of lite.

Data are limited, but LCNECs tend to have a better prognosis than do SmCCs {1587, 1631, 2016 ,2462}. Advanced-stage disease is associated with poor prognosis {1831).

Jntestinal-type adenocarcinoma Stelow E.B. Franchi A. Wenig B.M.

Definition Sinonasal intestinal-type adenocarcinoma (ITAC) is an adenocarcinoma of the sinonasal tract morphologically similar to adenocarcinomas primary to the intestines. ICD-0 code

Etiology Many ITACs are secondary to wood dust or leather dust exposure {9,10,9 18,1238). Formaldehyde and textile dust exposures may also increase the risk of these tumours {1490).

8144/3

Synonyms Colloid-type adenocarcinoma; colonictype adenocarcinoma; enteric-type adenocarcinoma

,l

Clinical features Patients with ITACs typically present with unilateral nasal obstruction, epistaxis, and/or rhi norrhoea {139,2063}. Less common symptoms include pain, facial contour changes, and diplopía. The tumours present as soft tissue densities within the sinonasal tract {139}. Destruction of surrounding bone occurs in nearly half of ali patients. Patients most often present with multiple sites of involvement {139}. Osseous destruction with local spread into surrounding tissues, including the orbit and brain, is frequently seen. Macroscopy In vivo, ITACs are polypoid, papillary, nodular, and fungating {139,2063). Th ey are usually friable, sometimes ulcerated or haemorrhagic, and uncommonly gelatinous or mucoid.

Localization ITACs typically develop near the lateral

- ;,.... \

nasal wall, near the middle turbinate {139, 2063). lt is estimated that 40% of cases develop in the ethmoid sinuses, 28% in the nasal cavity, and 23% in the maxillary sinus.

1

,...1

1

'

-

•

Fig. 1.12 Sinonasal intestinal-type adenocarcinoma. A This well-differentíated tumour shows papillary growth with numerous goblet and Paneth cells. B This tumour is moderately differentiated, with cribriform growth and areas of necrosis. C This tumour is composed of abundan! extracellular mucus with occasional strips of malignan! epithelium. D Sorne tumours are composed of signet-ring cells.

Carcinomas

23

Cytology Aspirates of rare metastatic lesions show findings identical to those seen with colorectal adenocarcinomas. Histopathology ITACs show a morphological spectrum similar to that of adenocarcinomas of the intestines {139,1238,2063}. They are often exophytic with a papillary and tubular growth (in approximately 75% of cases) or may be mucinous or composed predominantly of signe! ring cells. The degree of differentiation varies from extremely well differentiated to poorly differentiated. Papillae and tubules are lined by a single !ayer of columnar epithelial cells that show differentiation and cytological features similar to !hose seen in intestinal adenocarcinomas . Most cells appear columnar with eosinophilic, mucinous cytoplasm. Paneth cells, goblet cells, and endocri ne cells are typically also present in variable proportions. Although atypia may be difficult to appreciate, nuclear changes that appear at least adenomatous are the rule. Thus, nuctei are cigar-shaped, hyperchromatic, and enlarged, and lose basement membrane localization. Mitotic figures are frequent. Necrosis is usually present, typically within the tubular and folded spaces, similar to what is seen in intestinal adenocarcinomas. As these tumours become more poorly differentiated, tubular and papillary structures are replaced by nested, cribriform , and salid growth patterns. A minority of cases show abundan! mucus production (139,1238). These cases are similar to sorne primary intestinal adenocarcinomas and consi st of small to medium-sized cystic spaces (alveoli) partially lined by (and containing strips of) attenuated neoplastic epithelium rich in goblet cells. The strips often float like ribbons within mucus lakes and sometimes form small cribriform structures. The individual neoplastic cells have atypical and hyperchromatic nuclei and abundant mucinous cytoplasm. Less commonly, the neoplastic cells are mostly single , with a large amount of intracytoplasmic mucus that compresses the nucleus (signet ring cells). Finally, sorne tumours have a mixed pattern of growth, appearing papillary and tubular in sorne areas and more mucinous in others. ITACs are invasive (often extensively infiltrating the submucosa) and may show perineural and osseous invasion {139}. 24

Stromal tissues are loase and fibrovascular, often containing abundant chronic inflammatory cells. Histological similarity to primary gastrointestinal trae! tumours necessitates exclusion of a metastatic tumour. Proposed grading schemas are rather complicated, given the rarity of these tumours {139,1238). Tumours that are predominately papillary can be graded as well, moderately, or poorly differentiated (papillary tubular cylinder cell 1, 11, and 111; or papillary, colonic, and salid). Mucinous tumours are either moderately differentiated (alveolar) or poorly differentiated (signet ring cell). Mixed tumours are typically well to moderately differentiated. Overall survival rates at 3 years have been shown to vary depending on grade. Histochemical staining shows intracytoplasmic, intraluminal, and/or extracellular material that is mucicarmine-positive and gives a diastase-resistant positive periodic acid-Schiff (PAS) reaction {139}. Neoplastic cells express pancytokeratins, are variably reactive with CK7 and carcinoembryonic antigen, and are mostly CK20-positive {1 213,1573}. Most tumours also express the markers CDX2, MUC2, and vi llin (358,1213}. There may be variable expression of neuroendocrine markers {1 573,1928}. Genetic profile KRAS mutations occur in 6-40% of cases, whereas BRAF mutations occur in < 10% {755 ,1926,2037,2327). 1 umours are microsatellite-stable and do not lose expression of mismatch repair proteins {1 546,1854). EGFR mutations are infrequent and amplifications are uncommon {755,1926}. Expression of p53 is aberrant in more than half of ali cases, and 41% have been shown to have TP53 mutations {757). CDKN2A (also called P16) is frequently altered , due either to promoter methylation or to loss of heterozygosity at 9p21 {1857). Variable betacatenin expression has been reported , with sorne studies showing > 30% of cases with aberrant nuclear expression {757,1854}.

Prognosis and predictive fact9rs The grading systems described above predict survival and recurrence, althoug h results have not been universal {1 39,754, 760,1238}. Low-grade papillary tumours have the best outcomes, with > 80% of patients surviving 3 years and > 60% of


patients being disease-free at 5 years. Grade 2 and 3 papillary tumours have 3-year survival rates of 54% and 36%, respectively. Mucinous tumours with alveolar growth and mixed or transitional tumours have prognoses similar to that of grade 2 papillary tumours, whereas tumours showing signet ring morphology behave the most aggressively. Locally advanced tumours that invade into the orbit, skin, sphenoid or frontal sinuses, or brain have a significantly worse prognosis. Local disease is the most common cause of mortality. About 8% of patients have lymph nade metastases and 13% have distan! metastases {139}.

Non-intestínal-type adenocarcínoma Stelow E.B. Brandwein-Gensler M. Franchi A. Nicolai P. Wenig B.M.

Definition Sinonasal non-intestinal-type adenocarcinoma (non-lTAC) is an adenocarcinoma of the sinonasal tract that does not show the features of a salivary gland neoplasia and does not have an intestinal phenotype. Although these tumours are morphologically heterogeneous, this category may include sorne specific entities that are morphologically unique (e.g. renal cell-like carcinoma). ICD-0 code

8140/3

Synonyms Terminal tubulus adenocarcinoma; tubulopapillary low-grade adenocarcinoma; low-grade adenocarcinoma; seromucinous adenocarcinoma; renal cell- like carcinoma Epidemiology Sinonasal low-grade non-intestinal-type adenocarcinomas (LG non-lTACs) are very uncommon. There is no sex predilection {967,1139,1721). Patients have ranged in age from 9 to 89 years, with a mean age at presentation in the sixth decade of life. High-grade non-intestinaltype adenocarcinomas (HG non-lTACs) are rare, affect men more frequently, and occur over a wide age range, with a

mean patient age at presentation in the sixth decade of lite {967,2266}.

Etiology There is no known etiology for LG nonlTACs or HG non-lTACs. Rare HG nonlTACs have been associated with highrisk HPV or sinonasal papillomas (2266).

Localization Most LG non-lTACs (64%) arise in the nasal cavities (frequently the middle turbinate), and 20% arise in the ethmoid sinuses (967,1139). The remaining tumours involve the other sinuses or multiple locations throughout the sinonasal tract. Approximately half of ali HG non-lTAC cases are locally advanced at presentation and involve both the sinuses and the nasal cavity {967,2266 }. Approximately one third involve the nasal cavity only.

Fig. 1.13 Sinonasal low-grade non-intestinal-type adenocarcinoma. Endoscopic view of the right nasal fossa (A) and coronal turbo spin echo T2-weighted MRI (B). The tumour (T) is centred on the superior meatus and laterally displaces the ethmoidal complex (asterisks); the point of origin was on the upper part of the septum. LW, lateral wall; MT, middle turbinate; NS, nasal septum.

Clínica! features Most patients with LG non-lTACs present with obstruction (1721,2193}. Other symptoms include epistaxis and pain. Patients with HG non-lTACs present with obstruction, epistaxis, pain, deformity, and proptosis {967}. On imaging, LG non-lTACs present as solid masses, filling the nasal cavity or sinuses. HG non-lTACs show more destructive growth, with osseous involvement and invasion into surrounding structures (e.g . the orbit).

Macroscopy Low-grade non-lTACs may appear red and polypoid or raspberry-like and firm (1237).

Histopathology Low-grade non-lTACs have predominately papillary and/or tubular (glandular) features with complex growth, including back-to-back glands (cribriform) with little intervening stroma {967,1139,1237). A single layer of uniform mucinous cuboidal to columnar epithelial cells lines the structures. These cells have eosinophilic cytoplasm and uniform, basally located nuclei. Mitotic figu res are rare and necrosis is not seen. lnvasive growth, including within the submucosa as well as into bone, may be present. Calcispherules are rarely seen (967). Occasional tumours have more dilated glands (1237, 1721). HG non-lTACs show much more diversity in their histology {967,2266). Many have a predominately solid growth with

occasional glandular structures and/ or individual mucocytes . Sorne have a nested growth and are infiltrative. Numerous mitotic figures are seen with necrosis (individual-cel l and confluent), as well as infiltrative growth with tissue destruction and osseous invasion. Occasional cases are composed predominately of clear cells, reminiscent of metastatic renal cell carcinoma {2287) . These tumours have been referred to as sinonasal renal cell-like carcinomas. The tumours are composed of

monomorphous cuboidal to columnar glycogen-rich clear cells that lack mucin production . The cellular cytoplasm may be crystal clear or slight ly eosinophilic. Perineural invasion, lymphovascular invasion, necrosis, and severe pleomorphism are absent, and the overall histological impression is that of a low-grade neoplasm. In most LG non-lTACs and HG nonlTACs, intraluminal mucin or material that gives a diastase-resistant positive reaction with periodic acid-Schiff (PAS) Carcinomas

25

B This tumour is

can be identified. In HG non-lTAC, cells with intracytoplasmic mucin or diastaseresistant PAS positivity may be present. The tumours express cytokeratins (typically CK7 and infrequently limited CK20) {2266}. Squamous antigens, such as p63, are typically not expressed orare expressed only focally (2193}. Markers of intestinal differentiation, such as CDX2 and MUC2, are also not expressed or are expressed only focally {358,2266}. Sorne authors have reported expression of D0G1, SOX10, and S100 (1933). HG non- lTACs can focally express

neuroendocrine antigens (2266). Renal cell- like carcinomas express CAIX and CD1 0, but do not express PAX8 or renal cell carcinoma marker (2156}. Beta-catenin and mismatch repair protein expression is wildtype {2679). Overexpression of p53 may occur as well (2193}.

Genetic profile Only rare LG non-lTACs have been studied fo r molecular abnormalities. RAS mutations are not seen (755). Rare BRAF mutations have been found (755).


Definition Sinonasal teratocarcinosarcoma is a malignant sinonasal neoplasm with combined histological features of teratoma and carcinosarcoma, lacking malignant germ cell components. ICD-0 code

9081/3

Synonyms Malignant teratoma; blastoma; teratocarc inoma; teratoid carcinosarcoma Epidemiology Teratocarcinosarcoma is a rare tumour affecting adults (median patient age: 60 years), with a strong male predilection. Localization The tumour most commonly involves the 26

nasal cavity, followed by the ethmoid sinus and the maxillary sinus {1628). lntracranial extension occurs in approximately 20% of cases (1628).

Clinical features The most common presenting symptoms are nasal obstruction and epistaxis. lmaging studies show a nasal cavity mass with opacification of paranasal sinuses and frequent bone destruction. Macroscopy Tumour tissue is firm to friable, with a variegated reddish-purple to browri appearance. When present, the surface mucosa is often ulcerated, and areas of necrosis and haemorrhage are evident at the cut surface.


Prognosis and predictive factors Approximately 25% of LG non- lTACs recur, and only 6% of patients die from their tumours, usually as a result of loss of local control {967,1139,1721). Patients with HG non-lTAC tare much worse {967}; most die from the disease within 5 years of diagnosis. Occasional HG non-lTACs metastasize locally and distally. The reported cases of renal cell- like carcinoma have neither recu rred nor metastasized (2156).

Franchi A. Wenig B.M.

Histopathology Teratocarcinosarcoma is composed of an admixture of epithelial, mesenchymal, and neuroep ithelial elements. The epithelial components include keratinizing and non-keratinizing squamous epithelium, pseudostratified columnar ciliated epithelium, and glandular/ductal structu res. An importan! diagnostic feature is the presence of nests of immature squamous epithelium with clear so-called fetal-appearing cells {966}. The most-represented mesenchymal elements are spindle cells with features of f ibroblasts or myofibroblasts, but areas with rhabdomyoblastic, cartilaginous, osteoblastic, smooth-muscle, or adipocytic differentiation can be seen, with appearances ranging from benign to frankly malignant. The neuroepithelial component

consists of a proliferation of immature round to oval cells either in solid nests or within a neurofibrillary background, sometimes with rosette formation. The immunohistochemical profile matches that of the tumour components, including epithelial, mesenchymal, and neuroepithelial components. PLAP, alpha-fetoprotein, hCG, and CD30 are negative. Cell of origin The favoured hypothesis is origin from somatic pluripotent stem cells of the

neuroepithelium related to the olfactory membrane {1801,2054). Genetic profile There are limited reports in the literature on the cytogenetic abnormalities. These abnormalities include extra copies of chromosome 12p in a subpopulation of neoplastic cells in a hybrid case that also exhibited foci of yolk sac elements {2380) in addition to teratocarcinosarcoma features, thus not completely meeting the definition that excludes malignan! germ

cell components, and the presence of trisomy 12 wit h a subclone of cells showing loss of 1p in one case {2516). In another study, no amplification of 12p was found in any of 3 cases {2054). Prognosis and predictive factors Teratocarcinosarcoma is an aggressive tumour, with frequent lymph node and distan! metastasis. Reported survival rates range from 50% to 70% in different series, with an average follow-up of 40 months {1628).


27

Sinonasal papillomas

Sinonasal papilloma, inverted type

has been reported in 1.9- 27% of cases in different series; most malignancies were synchronous tumours (1750).

Hunt JL Bell D. Sarioglu S.

Etiology

Definition Sinonasal inverted papilloma is a surface mucosa! lesion of the sinonasal tract that usually shows inverted growth and has multi layered epithelium with mucocytes and transmigrating neutroph ils.

ICD-0 code

8121/1

Synonyms lnverting papilloma; inverted Schneiderian papil loma; Schneiderian papilloma, inverted type

Epidemiology lnverted papillomas are the most frequent papillomas of the sinonasal region, arising from the sinonasal epithelial lining. An estimated 0.74- 2.3 new cases may be expected per 100 000 population annually (294,1750). The tumour is most frequent in the fifth and sixth decades of lite (patient age range: 6- 84 years) and is 2.5-3 times as common in males as in females {141,1224,251 1). Recurrences are frequent and malignant transformation

28

Exposure to organic solvents seems to be a risk factor for inverted papilloma development {505), whereas no such association far smoking or alcohol consumption has been shown . Varying rates of HPV detection have been reported. In a metaanalysis including 760 inverted papilloma cases, 38.5% of the cases were HPVpositive by either in situ hybridization or PCR {2323). Low-risk HPV (HPV 6 and 11) is 2.8 times as frequent as high-risk HPV (HPV 16 and 18) in inverted papilloma. However, high-risk HPV is more frequent in cases with high-grade dysplasia and carcinoma (1352). E6 and E7 mRNAs, associated with transcriptionally active high-risk HPV infection, were detected in ali cases in a series of 19 inverted papillomas; however, this expression was seen in only 1% of the tumour cells in 58% of the cases, and HPV DNA was positive in only 2 cases. Expression of p16, which is an accepted surrogate biomarker for high-risk HPV infection in oropharyngeal carcinoma, is controversia! in inverted papilloma; in sorne series, no correlation between p16 and HPV was seen {420,2283}.

Tumours of the nasal cavi ty, paranasal sinuses and skull base

Localization The nasal cavity and the maxillary sinus are the most common locations of inverted papilloma, with the medial wall being the most common site of origin in t he maxillary sinus. Other locations as site of primary origin are more rare, including the ethmoid sinus, frontal sinus, and nasal septum. About 30% of cases originate from multiple sites. lnverted papilloma may rarely be bilateral and may originate from multiple extrasinonasal siles, including the nasopharynx, pharynx, lacrimal sac, middle ear, temporal bone, and neck (75,1224,2147).

Clinical features Patients may present with non-specific symptoms such as nasal obstruction, polyp s, epistaxis, rhinorrhoea, hyposmia, and headache of long duration . Rarely, sensorineural and auditory symptoms are described. Both CT and MRI are valuable; CT may provide information about the site of origin of the tumour, and MR I shows the extent of the disease. On MRI, the lesi on characteristically has a septate striated appearance (75). Several staging systems have been proposed for inverted papilloma (75,1224). One commonly used staging system {1283} depends on the extent of disease, considering both rad iological and endoscopic findings. The American Joint Committee on

Cancer (AJCC) staging system is also commonly used.

Macroscopy lnverted papilloma is covered with a grey, undulating surface resembling a mulberry. Because of their cellular density, the lesions do not transilluminate. Histopathology Multiple inversions of the surface epithelium into the underlying stroma, composed of squamous and/or respiratory cells and lined by a distinct and intact, continuous basement membrane, is the typical morphology of inverted papilloma. Non-keratinizing squamous or transitional epithelium, 5-30 cells thick, frequently predominates, and is covered by a layer of ciliated columnar cells. lnfiltration of the epithelium by neutrophils (so-called transmigrating neutrophils) is frequently seen. Mitoses are sparse and confined to the basal layers {141,2002,2075). There is usually a loss of underlying seromucinous glands (2075}. The stroma may be either loase or dense, and may be inflamed. Cells showing squamous and columnar differentiation are positive far cytokeratins (e.g. CK10, CK10/13, and CK1/2/10/1 1) {2106}. Premalignant and malignant features, dysplasia, carcinoma in situ, and invasive carcinoma can be seen arising in inverted papilloma. Sampling should be thorough, and evidence of malignan! transformation should be sought during histopathological evaluation. There is no consensus about the grading of dysplasia in inverted papilloma, and the diagnosis of malignan! transformation may be challenging. Keratinizing squamous cell carcinoma, non-keratinizing squamous

cell carcinoma, mucoepidermoid carcinoma, sinonasal undifferentiated carcinoma, and verrucous squamous cell carcinoma can ali be seen in malignan! transformation. Lymphovascular invasion, atypical mitoses, desmoplasia, bone invasion, decreased transmigrating neutrophils, paradoxical maturation, dyskeratosis, increased Ki-67 expression, and p53 expression in > 25% of cells are among the most importan! features of malignancy (1750}.

Genetic profile lnverted papillomas are neoplastic and monoclonal proliferations, as shown by X chromosome analysis. However, the chromosomal LOHs at arms 3p, 9p21, 11q13, 13q11, and 17p13 that occur frequently during neoplastic transformation of the upper respiratory tract have not been detected {315). In one small series of 7 cases, at least one epigenetic event of aberrant DNA hypermethylation was observed, suggesting a role of epigenetics in inverted papilloma development (2276). Furthermore, from a small number of cases studied, it appears that activating mutations in the EGFR gene have a high prevalence in inverted papillomas and in concurrent squamous cell carcinomas arising from inverted papilloma {2442A). Prognosis and predictive factors In one large series, cases originating from the nasal cavity had a significantly lower recurrence rate {1224). The ratio of lowrisk HPV (HPV 6 and 11) to high-risk HPV (HPV 16 and 18) was 1.1:1 in inverted papilloma with high-grade dysplasia, versus 4.8:1 in the rest of the cases, suggesting an association between high-risk HPV and

malignan! transformation {1352). However, no correlation was found between E6/E7 transcriptional activity and progression, recurrence, or malignan! transformation (2283). In one series, malignant transformation in inverted papilloma was identified more frequently in smokers (in 24.6% of cases) !han in non-smokers (in 2.8%), and the odds ratio of malignancy for smoking was 12.7 (1020). Type of surger.y is also an importan! prognostic factor for recurrence {962).

Sinonasal papilloma, oncocytic type Hunt J.L. Chiosea S. Sarioglu S.

Definition Sinonasal oncocytic papilloma is a papilloma derived from the sinonasal epithelium composed of both exophytic fronds and endophytic invaginations lined by multiple layers of columnar cells with oncocytic features. lntraepithelial microcysts containing mucin and neutrophils are characteristic. ICD-0 code

8121/1

Synonyms Oncocytic Schneiderian papilloma; cylindrical cell papilloma; columnar cell papilloma Epidemiology Oncocytic papilloma is equally distributed between the sexes, and most patients are aged > 50 years (2511 ).

Sinonasal papillomas

29

Etiology Unlike in exophytic and inverted papillomas, HPV has not been identified in oncocytic papillomas (792}. Localization Oncocytic papilloma almost always occurs unilaterally on the lateral nasal wall or in the paranasal sinuses (usually the maxillary or ethmoid). lt may remain localized, involve both areas, or (if neglected) extend into contiguous areas. Clinical features Patients present with nasal obstruction and/or intermittent epistaxis. Macroscopy Oncocytic papilloma is a fleshy, pink, tan, or reddish-brown polypoid growth. Histopathology Oncocytic pap liorna exhibits both exophytic and endophytic growth. The epithelium is multilayered, 2-8 cells thick, and composed of columnar cells with swollen, finely granular cytoplasm. The high content of cytochrome c oxidase and ultrastructural presence of numerous mitochondria establish the papilloma's oncocytic nature {145). The nuclei are either small, dark, and uniform or slightly vesicular with barely discernible nucleoli . Cilia in various stages of regression may be observed in the outermost cells. The epithelium usually contains small cysts tilled with mucin or neutrophils (microabscesses). These cysts are not present in the stroma, which helps distinguish this lesion from rhinosporidiosis. The stroma varíes from oedematous to fibrous, and may contain modest numbers of lymphocytes, plasma cells, and neutrophils, but few eosinophils. Seromucinous glands are sparse to absent. Oncocytic papilloma may rarely undergo malignant transformation. lt is also occasionally confused with low-grade papillary adenocarcinoma {1403). The presence of intact basement membranes and absence of infiltrative growth are features that indicate a benign lesion. In addition, the presence of intraepithelial mucin-filled cysts and microabscesses and the stratified oncocytic epithelium of a papilloma are rarely seen in low-grade adenocarcinoma.

inverted papilloma. lf inadequately exc ised, especially using mucosa! stripping, at least 25- 35% of cases recur, usually within 5 years {962). Smaller tumours can be resected endoscopically. About 4-17% of all oncocytic papillomas harbour a carcinoma {1201,1441,2511 ). Most of these are squamous, but mucoepidermoid, small cell, and sinonasal undifferentiated carcinomas have also been described {2370,2511 }. Prognosis depends on the histological type, the degree of invasion, and the extent of tumour. In sorne instances, the carcinoma is in situ and of little consequence to the patient, whereas other cases are locally aggressive and may metastasize.

Sinonasal papilloma, exophytic type Hunt J.L. Lewis J.S. Richardson M. Sarioglu S. Syrjanen S.

Definition Sinonasal exophytic papilloma is a papilloma derived from the sinonasal mucosa, composed of papillary fronds with delicate fibrovascular cores covered by multilayered epithelium. ICD-0 code

Synonyms Schneiderian papilloma, exophytic type; fungiform papilloma; everted papilloma; transitional cell papilloma; septal papilloma; Ringertz tumour

Prognosis and predictive factors The clinical behaviour parallels that of 30

8121/0


Epidemiology Exophytic papillomas are 2-1O times as common in men as in women, and typically occur in individuals aged 20- 50 years (reported range: 2-87 years) (441}. Etiology Theré is increasing evidence to suggest that exophytic papillomas may be etiologically related to HPV. In a large metaanalysis, exophytic papil lomas were associated with HPV in 63.5% of cases, pre dominantly with the low-risk types 6 and 11 , and rarely with types 16 and 57b {2323). Localization Exophytic papillomas usually arise on the lower anterior nasal septum. As they enlarge, they may secondarily involve the lateral nasal wall, but only intrequently originate from this location . lnvolvement of the paranasal sinuses is practically non-existent. Bilateral lesions are exceptional. Benign keratinizing cutaneous tumours of nasal vestibule origin do not constitute sinonasal exophytic papilloma. Clinical features The typical presenting symptoms are epistaxis, unilateral nasal obstruction, and the presence of an asymptomatic mass. Macroscopy Th e lesions present as papillary or warty; grey, pink, or tan; non-translucent growths attached to the nasal septum by a relatively broad base. Histopathology Exophytic papillomas are typically as large as about 2.0 cm. Microscopically,

Exophytic growth pattern with thickened epithelium and focal mucocytes.

they are composed ot papillary fronds with fibrovascular cores covered by a multilayered epithelium that is 5-20 cells thick. The epithelium varíes trom squamous to ciliated pseudostratified columnar (respiratory), or may be transitional between the two. Scattered mucocytes are common. Surface keratinization is absent or scant, unless the lesion has been irritated by trauma or exposure to the drying effects ot air. Mitoses are rare and are not usually atypical. Unless infected or irritated, the stroma contains few inflammatory cells.

Malignant change in exophytic papilloma is extremely rare {157,441}. Exophytic papillomas must be distinguished from keratinizing cutaneous squamous cell papillomas, which are much more common in the nasal vestibule. The absence ot extensive surface keratinization, presence of mucocytes, and presence ot cil iated and/or transitional epithelium help to contirm t he diagnosis ot exophytic papilloma. The presence ot seromucinous glands and septal cartilage turther indicate that the lesion is ot mucosa! rather than cutaneous origin.

Prognosis and predictive factors Complete surgical excision is the treatment of choice. lnadequate excision (rather than multiplicity of lesions) probably accounts for th e local recurrence rate of 22- 50% {441}. Exceptionally, carcinomas have been seen arising in exophytic papillomas, with reported cases including squamous cell carcinoma; mucoepidermoid carcinoma (1750}; and low-grade non-intestinal, non-salivary gland adenocarcinoma {220). HPV status has not been clearly shown to correlate with recurrence risk or carcinoma development.

Respiratory epithelial lesions Respiratory epithelial adenomatoid hamartoma Wenig B.M. Franchi A. Ro JY.

Definition Sinonasal respiratory epithelial adenomatoid hamartoma (REAH) is a benign acquired overgrowth ot indigenous glands of the sinonasal tract arising trom the surtace epithelium.

age from the third to ninth decades ot lite, with a median patient age in the sixth decade !1367,2588).

Localization The majority occur in the nasal cavity, in particular the posterior nasal septum {2588} . lnvolvement of other intranasal sites occurs less often, and may be identified along the lateral nasal wall, middle meatus, and inferior turbinate. Uncommonly, the lesions may occur in the nasopharynx, ethmoid sinus, and frontal sinus. Most lesions are unilateral but sorne are bilateral {2588) .

Synonym Glandular hamartoma

Epidemiology The lesions predominantly occur in adult patients, with a distinct male predominance {1367,2588}. Patients range in

Clinical features Patients present with nasal obstruction, stuffiness, epistaxis, and chron ic (recurrent) rhinosinusitis occurring over the course of months to years {2588}.

Macroscopy REAHs are polypoid or exophytic lesions with a rubbery consistency. They are tanwhite to reddish-brown and measure as much as 6 cm in greatest dimension .

Histopathology Histopathology shows a glandular proliferation composed of widely spaced, small to medium-sized glands separated by stromal tissue. The glands arise in direct contin uity with the surface epithelium , which invaginates downwards into the submucosa {1 852,2588}. The glands are round to oval and composed of multilayered c iliated respiratory epithelium, often with admixed mucin-secreting (goblet) cells; glandular dilatation distended with mucus can be seen. A characteristic finding is the presence of envelopment of the glands by a thickened, eosinophilic basement membrane {2588). Atrophic

Respiratory epithelial lesions

31

glandular alterations may be present, lined by a single !ayer of flattened to cuboidal-appearing epithelium. Small reactive-appearing seromucinous glands are present among the glandular proliferation. Addítíonal coexisting findings may include sinonasal inflammatory polyps, surface epithelial hyperplasia and/ or squamous metaplasia, and osseous and/or chondroid metaplasia. Rarely, the lesions may be associated with sinonasal inverted papilloma or solitary fibrous tumour {2588}. The occasional presence of both REAH and seromucinous hamartoma suggests a spectrum from pure REAH to seromucinous hamartoma {1218). The glands are immunoreactive for cytokeratins such as AE1/AE3, CAM5.2, and CK7 but negative for CK20 and CDX2. Myoepithelial/basal cell markers (including p63) are typically present but may be absent; the absence of markers for myoepithelial/basal cells does not confer a diagnosis of adenocarcinoma {1 794).

Seromucinous hamsrtoms Ro J.Y. Franchi A.

Histopathology Definition Sinonasal seromucinous hamartoma (SH) is a benign overgrowth of indigenous seromucinous glands of the nasal cavity and paranasal sinuses.

Synonyms Epithelial hamartoma; glandular hamartoma; microglandular adenosis of nose {445)

Epidemiology SHs are extremely rare (1218). They occur predominantly in adults, with a maleto-female ratio 3:2. The patient age range is 14-85 years (mean: 56 years).

Etiology SH has no association with any specific etiological agent, but it often arises in the setting of inflammatory polyps.

Genetic profile

Localization

The reported increased fractional allelic loss of 31 % is unusually high for a nonneoplastic entity, raising the possibility that REAH may in fact be a benign neoplasm rather than a hamartoma {1796}.

SH usually occurs at the posterior nasal septum or nasopharynx, and is rarely described on the lateral nasal wall or in the paranasal sinuses (2567).

Clinical features Prognosis and predictive factors Complete surgical excision is curative.

The typical symptoms are nasal obstruction and epistaxis. The lesions are often found incidentally, and are sometimes associated with other medica! cond itions, such as rheumatoid arthritis, Parkinson disease, and chronic sinl!sitis. Physical examination reveals a polypoid mass without other aggressive features.

Macroscopy SHs are typically polypoid or exophytic, typical ly with a rubbery consistency and 32

a tan-white to reddish-brown appearance. They measure 0.6-6 cm in greaWWtest dimension.

Tumours of the nasal cavity, paranasal sínuses and skull base

SH is a polypoid mass covered by respiratory epithelium, and contains small to large glands and ducts lined by a single layer of cuboidal or flattened epithelíal cells with bland, oval to round nuclei and amphophilic to eosinophílíc cytoplasm. Mitoses are absent. The surrounding fibrous stroma often contains a lymphoplasmacytic infiltrate (125,1044). Eosinophilic secretion can be seen in the lumen, and goblet or clear cells may be observed. The tubular glands may be encircled by thick basement membrane material. The proliferating tubules intermíngle with the pre-existing seromucínous acini or invaginated respiratory epithelium forming glands or cysts, similar to features of respiratory epithelial adenomatoid hamartoma, supporting the possibility that SH and respiratory epithelial adenomatoid hamartoma constitute a spectrum of lesíons, often seen together {2565,2567). lmmunohistochemistry shows positivity for CK17, CK19, EMA, lysozyme, and S100, with an absence of myoepíthelial (basal) cells around the seromucinous glands (731). The stroma around tubules is posítive for calponín, SMA, and desmín, indicating myofibroblastíc / smooth muscle differentiatíon {1564}.

Prognosis and predictiva factors Conservative but complete surgical exc isíon is curative. With follow-up available from 4 months to 10 years (mean: 6 years), ali patients are alive and well after surgical removal, with no documented cases of metastasis and only one report of recurrence (731}.

Salivary gland tumours

Bell D. Bullerdiek J. Gnepp D.R. Hunt J.L.

P/eomorphic adenoma Definition Pleomorphic adenoma (PA) is a benign tumour with variable cytomorphological and architectural manifestations. The identification of epithelial and myoepithelial/stromal components is essential for the diagnosis of PA. See also the Pleomorphic adenoma section (p. 185) in Chapter 7 (Tumours of sa/ivary glands).

ICD-0 code

8940/0

Synonym Benign mixed tumour

Epidemiology Most intranasal PAs present in the third to sixth decades of lite, with a slight female preponderance (8,477,2109,2257f.

. '...; • ~"

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Localization The tumour generally (in about 80% of cases) arises in the nasal septal mucosa, despite the fact that the seromucinous glands are mainly located in the lateral wall and turbinates (8,1286,2109}.

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Clinical features The most common presenting symptom is unilateral nasal obstruction. Epistaxis and sinusitis can occur secondary to extension into the maxillary sinus {2109}. Affected patients present within 1 year of the onset of symptoms {2109}.

Macroscopy The range of tumour size is 0.5- 7 cm, and the tumours are descri bed as exophytic or polyp oid (with a broad base), oval, dome-shaped, firm, and grey (8,2109}. No destruction of surrounding tissue is seen .

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Histopathology


In the nasal cavity, these neoplasms display a more dom inant epithelial componen! (vs stromal components) th an is seen in PAs of the major salivary glands {8,2109}.

Complete surgical excision is the treatment of choice. The recurrence rate is lower than that of parotid PA. Malignan! transformation of PA of the nasal cavity has been reported in 2.4-10% of cases {8,451,2109).


33

Malignant soft tissue tumours

Fibrosarcoma Franchi A. Flucke U. Thompson L. D.R.

Definition Fibrosarcoma is a malignant spindle cell tumour with fascicular architecture and variable collagen matrix production, showing fibroblastic/myofibroblastic differentiation. lt is a diagnosis of exclusion. ICD-Ocode

8810/3

Synonym Adult-type fibrosarcoma Epidemiology Sinonasal fibrosarcoma is a rare tumour (accounting for < 3% of ali non-epithelial tumours), but is the second most common head and neck sarcoma. lt affects adults (mean age: 55 years), with no significan! sex predilection {1829). Etiology The etiology is uncertain, but sinonasal radiation-induced fibrosarcomas have been reported {314}. Localization The maxillary sinus is the most common site of involvement, followed by the nasal cavity {1829). Clinical features The most common presentations are nasal obstruction, epistaxis, and a nasal mass, usually with short symptom duration {780}. Macroscopy The tumour presents as a polypoid, poorly circumscribed, white, firm, and pedunculated or fungating mass projecting into the lumen, with frequent infiltration of the adjacent bone. Haemorrhage and necrosis are present in high-grade examples.

34

Histopathology Fibrosarcomas are moderately to highly cellular proliferations of spindle cells, arranged in intersecting fascicles, often w ith a herringbone or chevron pattern, and with a variable amount of co llagen production. There is moderate cel lular atypia, but profound pleomorphism is usually lacking. Tumours with significan! pleomorphi sm and storiform areas are b etter categorized as undifferentiated pleomorph ic sarcoma. Mitotic a.ctivity is variable. Th e tumour borders are poorly defined and there is invasion of the sinonasal mucosa and bone. Histological grading, w ith distinction of lowgrade and high-grade tumours, is performed on the basis of cellularity, atypia, mitotic activity, and tumour necrosis. Because the histological appearance of th e tumour is non-specif ic, diagnosis requ ires the exclusion of other entities, including sarcomatoid carcinoma, synovial sarcoma, leiomyosarcoma, spindle cell rhabdomyosarcoma, spindle cell melanoma, malignan! peripheral nerve sheath tumour, biphenotypic sinonasal sarcoma, glomangiopericytoma, desmoid f ibromatosis, and fibroblastic osteosarcoma. An appropriate immunohistochemical panel is necessary to rule out these other neoplasms, with the addition of selected molecular studies as necessary. By convention, the tumour is reactive with vimentin and


occasionally with actins, but negative for epithelial markers, S100 protein, S0X10, HMB45, beta-catenin, desmin, myogenin, and CD34. Electron microscopy can confirm the fibroblastic differentiation of the tumour, demonstrating the presence of abundant cytoplasmic rough endoplasmic reticulum cisternae and excluding the presence of epithelial, muscle, and melanocytic differe ntiation.

Genetic profile The genetic profile of sinonasal fi brosarcoma has not been specifical ly investigated, but soft tissue fibrosarcomas in general show a complex karyotype, with several numerical and structural chromosomal abnormalities. Prognosis and predictive factors The disease-specific survival rate is about 75%, with better survival among patients treated with surgery (with or without adjuvant radiotherapy) than among those treated w ith radiotherapy alone {1829). The rate of recurrence is high (-60%), and recurrence is usually identified befare metastatic disease (to lung or bone), which occurs in about 15% of patients. The prognosis is worse far male patients, and in cases of large tumours, multisite involvement, high histological grade, and positive margins {156,780,965,1263}.

Undifferentiated pleomorphic sarcoma

Clinical features There are non-specific signs and symptoms, including a painless mass, nasal obstruction, proptosis, diplopía, and epistaxis. Very rarely, undifferentiated p leomorp hic sarcoma presents with regional or d istan! metastasis {2294).

Flucke U. Franchi A. Thompson L.D.R.

and p leomorphic liposarcoma , and highgrade myxofibrosarcoma) {902l.

Genetic profile There are com plex genetic aberrations {902).

Prognosis and predictive factors Definition

Macroscopy

Undifferentiated pleomorphic sarcoma is a high-grade soft tissue sarcoma with no line of differentiation. lt is a d iagnosis of exclusion .

The tumours consist of a multilob ulated greyish-white fl eshy mass. Cut surface often shows haemorrhagic, myxoid, and/ or necrotic changes. Most neoplasms appear circumscribed. but extension into adjacent structures may be seen {2578).

ICD-0 code

8802/3

Synonym

Histopathology

Malignant fibrous histiocytoma

The tumour is composed of an admixture of spindle and pl eomorphic cells set in a variably collagenized extracellular matrix. Cellularity varíes. Pleomorphism, numerous mitoses, atyp ical mitoses. areas of tumour necrosis, histiocyte-like cells, and foamy cells, as well as giant tumour cells with enlarged, polylobulated nuclei are commonly observed. lmmunohistochemically, there are sorn e limited foci of SMA reactivity, whereas h-caldesmon, desmin, S100 protein, and epithelial markers are usually not expressed. Histiocytic antigens are of no utility. Ultrastructurally, many tumour cells show features of f ibroblasts, myofi broblasts, or histiocytes. Undiffe rentiated pleomorphic sarcoma is a diagnosis of exclusion. Other potential mimics must be ru led out, including carcinomas, melanoma, lymp homa, and sarcomas (including rhabdomyosarcoma, leiomyosarcoma, malignan! peripheral nerve sheath tumo ur, dedifferentiated

Epidemiology This sarcoma occurs in adults, and sinonasal examples are rare. However, undifferentiated pleomorphic sarcoma is the third most frequently reported histotype in !he sinonasal tract, after rhabdomyosarcomas and fibrosarcomas (2326, 2534).

Etiology Radiation therapy contributes to the risk of developing an undifferentiated pleomorphic sarcoma {2294,2534).

Localization Lesions are generally evenly distributed among the sinonasal tract (i.e. maxillary sinus, nasop harynx, and nasal cavity), upper aerodigestive system, and parotid reg ion (2294,2326,2534}. The mass is usually subcutaneous or submucosal in location, regardless of the affected site, but may also arise in bone (2294).

The 5-year survival rate is 60-70% {2326,2529). Surgery seems to be essential regardless of the margin status, and radiation therapy seems to be necessary for local control {2326). Previous radiation has been reported as an adverse prognostic factor for d isease-free survival {2534l.

Leiomyosarcoma Flucke U. Franchi A.

Definition Leiomyosarcoma is defined as sarcoma with smooth muscle d ifferentiation.

ICD-Ocode

8890/3

Epidemiology Smooth muscle tumours of the sinonasal tract are very rare. Most cases arise in adults. Children are rarely affected (538,606,902,1047).

Etiology Radiation therapy contrib utes to the risk of developing a leiomyosarcoma {778).

Localization The nasal cavities, nasopharynx, and paranasal sinuses may be involved {778,1312,2326). Tumours can also arise in the oral cavity or perioral reg ion (606,2104).

Clinical features The tumou rs present as a polypoid soft tissue mass. Symptoms depend on the site of involvement and include pain, nasal obstruction, and epistaxis. The lesions can also affect the c raniofacial bone, either p rimarily or secondarily. Leiomyosarcomas metastasize to the lung, liver, brain, other soft tissue sites, or bone. Lymph nade metastases are rarely reported {606,778,1312,2326,2664}. Metastasis from other siles (e.g . the uterus) should be excluded {606,2104l . Malignant soft tissue tumours

35

Pleomorphic rhabdomyosarcoma , adult type 8901/3 Spindle cel l rhabdomyosarcoma 8912/3

Synonyms Rhabdosarcoma; myosarcoma; malignant rhabdomyoma

Epidemiology Sinonasal rhabdomyosarcoma is a ra re tumour, with an overall annual incidence of 0.034 cases per 100 000 population {2066}. lt is the most common sinonasal sarcoma in both children and adults (317,983,2326}. The peak incidence is in patients in the first decade of life, with no significan! sex predilection (2066) .

Macroscopy The tumours are polypoid , fi rm , and either poorly defined or well circumscribed b ut unencapsulated. On sectioning, they are whorled and whitish or tan-grey, with areas of haemorrhage, cystic degeneration, and necrosis {538,778,1590).

Histopathology The tumours show infiltrative growth or sharply demarcated borders. They are composed of spindle cells arran ged in interlacing fascicles. Storiform architecture can be focally present. The tumour cel l nuclei are oval to elongate and frequently blunt-ended. There is variable atypia, with enlarged nuclei and hyperchro masia. Nucleoli are sometimes obvious. The eosinophilic cytoplasm often shows small perinuclear vacuoles. Epithelioid cytomorphology is rarely seen . Osteoclastic and pleomorphic giant cells may occur. Tumours with a myxoid background must not be confused with spind le cell myoepithelioma. Scattered inflammatory cells are seen in sorne cases. Rarely, dystrophic or psammomatous calcification has been reported . The French Fédération Nationale des Centres de Lutte Contre le Cancer (FNCLCC) grading criteria depend on mitotic activity, necrosis, and resemblance to normal tissue {467,538, 606,902,1312,1590,1607}. lmmunohistochemically, smooth muscle differentiation is demonstrated by diffuse staining for desmin, h-caldesmon, SMA, and MSA, with positivity for at least two of these markers {467,1312,1607).

pathobiology of leiomyosarcomas, including TP53, FANCA, ATM, RB1, CDK2NA. PTEN, MYOCO, ROR2, and MED12 {9 02,1607,1961}.


Localization

Clinical behaviour depends mainly on tumour location, with sinonasal tumours being more aggressive d ueto th eir clase proximity to both orbital and cerebral cavities. Surgery is the treatment of choice, but wide resection is often impossible. Radiotherapy can be given. One third of ali patients d ie of their tumour, as a result of either distant metastases or uncontro lled local recurrence involving vital head and neck structures. Complete surgical excision seems to be an important predictor of disease-free survival. 'Morphologically high-grade sarcomas seem to be more aggressive {467,606 ,778,902, 1607,2294,2326}.

The most com monly involved siles are the paranasal sinuses, followed by the nasal cavity (2066}.

Rhabdomyosarcoma

Definition Rhabdomyosarcoma is a malignant mesenchymal tum our with skeletal muscle differentiation. Embryonal, alveolar, pleomorphic, and spindle-cell subtypes are recognized .

There is a complex genomic profile, with a variety of genes involved in the 36

Rhabdomyosarcoma, NOS Embryonal rhabdomyosarcoma Alveolar rhabdomyosarcoma


Clinical features Symptoms include nasal obstruction, pain, facial swelling, proptosis, and epistaxis (317,779}.

Macroscopy Most lesions present as polypo id, poorly c ircumscribed masses with smooth surfaces, often extending into the adjacent structures . They are fle shy, gelatinous lesions with a tan to g rey cut surface. Botryoid rhabdomyosarcoma presents with multiple g rape-like polypo id masses. The spindle-cell variant is tan-white with a f irm cons istency.

Histopathology

Franchi A. Flucke U. Thompson L.D.R .

ICD-0 codes Genetic profile

Etiology Rare examples of rad iation-induced sinonasal rhabdomyosarcoma have been reported {1191}.

8900/3 8910/3 8920/3

In th e sinonasal tract. embryonal rhabdomyosarcoma (including the botryoid variant) is the most frequent histological subtype in young patients. lt consists of primitive round to spin dle cells, with scant cytoplasm and hyperchromatic nuclei. Scattered rhabdomyob lasts with brig htly eosinophilic eccentric cytoplasm are observed. Their number increases in tumours treated with chemotherapy. Botryoid rhabdomyosarcoma typically has a polypoid arch itecture, and presents linear aggregates of tumour ce lls clase to the surface epithelium (cambium layer), yielding a gradient of cellularity.

Sinonasal alveolar rhabdomyosarcoma is more frequent in the adult population (2326}, and typically presents f ibrovascular septa separating nests of round, small to medium-sized neoplastic cells, which tend to coalesce in the centre with dyscohesion at the periphery. Giant cells with multiple peripheral nuclei may be present. The salid variant of alveolar rhabdomyosarcoma lacks the fib rovas cular septa, and the tumour cells grow in sheets. The spindle-cell subtype is very rarely observed in the sinonasal region {1707); it consists of a fasciculated proliferation of spindle cells with elongated nuclei and pale indistinct cytoplasm, with interspersed spindled or polygonal rhabdomyoblasts with abundan!, brightly eosinophilic cytoplasm. lmmunohistochemically, the most usefu l myogenic markers are desmin and MYF4 (myogenin), which are expressed in all tumours. Compared with alveolar rhabdomyosarcomas, in which there is MYF4 staining in almos! 100% of the nuclei, embryonal rhabdomyosarcomas stain for MYF4 in a more heterogeneous

fashion, which provides a clue as to their subclassification (1819). MYOD1, tasi myosin, myoglobin, and MSA are also positive, but less specific. SMA is positive in about 10% of cases {983). Rh abdomyosarcoma, in particular the alveolar subtype, may coexpress non-myogenic markers, including cytokeratins (in 5- 8% of cases), EMA , CD56, chromogranin, synaptophysin, CD20, and CD99, and this may be a source of diagnostic confus ion with carcinomas, neuroendocrine tumours, and haematolymphoid tumours {1707,2671). Ultrastructurally, rud imentary sarcomeric structures, consisting of alternating thin and thick filaments with Z bandlike structures, are recognized in the cytoplasm.

Genetic profile Most alveolar rhabdomyosarcomas (7080%) harbour a PAX3-FOX01 fusion, and the PAX7-FOX01 fusion is less frequently detected. ldentification of these gene fusions is particularly useful for the diagnosis of tumours arising in unusual

clinical settings (e.g. in older adults) and/ or with atypical morphology and immunohistochemical profiles {2671). To date, no specific recurren! genetic abnorma lity has been identified in embryonal rhabdomyosarcoma. Most of these tumours have allelic losses in various chromosome 11 loci. Paediatric spindle cell rhabdomyosarcoma shows a consisten! NCOA 2 rearrangement (1661 ).

Genetic susceptibility Rhabdomyosarcoma can arise in children affected by genetic syndromes, including Li- Fraumeni syndrome (associated with an inactivating mutation of TP53), Costello syndrome (also called fac iocutaneoskeletal syndrome; HRAS mutation), neurofibromatosis type 1 (inactivating mutation of one allele of the NF1 gene), and Beckwith-Wiedemann syndrome (mutation or deletion of the 11 p15.5 chromosomal region) {506).

Prognosis and predictiva factors Overall , rhabdomyosarcoma carries a relatively poor prognosis among sinonasal Malignan! soft tissue tumours

37

sarcomas, with a 5-year survival rate of 40-45% (2326,2645,2648}. Patient age < 18 years and female sex are associated with better survival (2066,2381). Patients with alveolar rhabdomyosarcomas present more often with regional and distant metastases and have a higher recurrence rate and poorer survival {2381) th an do patients with the embryonal or botryoid subtype. lnfiltration of the skull base and the presence of a residual tumour after primary therapy have also been associated with an unfavourable clinical course (2648).

Angiosarcoma Bullerdiek J. Flucke U. Franchi A. Thompson L.D.R.

Definition Angiosarcoma is a malignant neoplasm of vascular origin. ICD-0 code

9120/3

Synonyms Epithelioid haemangioendothelioma; malignant haemangioendothelioma; malignant angioendothelioma; haemangiosarcoma; haemangioblastoma The use of these synonyms is discouraged, particularly given that epithelioid haemangioendothelioma is a unique entity. Epidemiology Nearly 50% of cases develop in the skin and superficial soft tissues of the head

38

and neck, but sinonasal angiosarcoma accounts for < 0.1 % of ali head and neck malignancies and < 1% of all sinonasal malignancies (107,1540,1706,1718}. Sinonasal angiosarcomas can develop in patients of any age (reported range: 8-82 years), with peak incidence in the fifth decade of life (mean patient age: 47 years), younger than the co rresponding age for skin and soft tissue angiosarcomas of the head and neck {107,1508,1540). There is a male predilection, with a male-to-female ratio of 3:2 (777,1718,2419,2613,2626}.

1 .

'~'

6.. ' ·~ --.- ......._............_

'

Fig. 1.29 Sinonasal angiosarcoma. Neolumen formation is seen within this angiosarcoma, where there is only mild nuclear pleomorphism; vascular channels are apparent throughout.

Etiology Environmental exposure to rad iation (1472,1508,1706}, vinyl chloride (2613), and coal dust are rarely reported risk factors.

facilitating pre-surgical embolization (1718,241 9}. Staging is not applied to sinonasal angiosarcoma, but lymph node and distant metastasis are not common at initial presentation.

Localization A single site of involvement within the sinonasal tract is more common than multiple sites ; the nasal cavity and maxillary sinus are most frequently affected (777,1718,241 9,2613,2626}.

Macroscopy The tumours can be as large as 8 cm (mean: 3.9 cm); paranasal sinus tumours are typically larger than sinonasal cavity tumours (6.8 vs 2.2 cm). The tumours are nodular to polypoid , soft, friable, purple to red, and often ulcerated, with associated haemorrhage and necrosis (777,1718,2419,2613,2626}.

Clinical features The presenting signs and symptoms, which are non-specific and usually of short duration (mean: 9.8 months), are most commonly recurrent epistaxi s and obstruction (1718} along with nasal discharge, enlarging mass, sinusitis, epiphora, pain, diplopía, and headaches. Sinonasal angiosarcomas are infi ltrative tumours, often associated with bone erosion. The tumours show contrast enhancement or a bright signal on T2weighted MRI. Angiography reveals tumour extent and feeder vessel(s),


Histopathology The tumours develop below an intact, uninvolved epithelium, with vasoformative neoplastic cells expanding into soft tissue and bone, frequently accompanied by necrosis and haemorrhage. The tortuous, irregu lar, freely anastomosing vascular channels create cleft-like spaces, rudimentary vessels, capillary-sized vessels, and/or large cavernous spaces filled with erythrocytes and lined by plump, enlarged, atypical, spindled or epithelioid endothelial ce lls protruding into the vascular spaces in multiple layers or papillae. lntracytoplasmic lumina (often containing erythrocytes) are pathognomonic. Enlarged pleomorphic nuclei show coarse, heavy nuclear chromatin distribution, irregular nuclear contours, and prominent nucleoli. Mitotic figu res, including atypical forms , are easily identifi ed throughout (1718,2419,2613,2626). The tumours are diffusely immunoreactive with vimentin, CD34, CD31, claudin 5, ERG, FLl 1, 02-40, and factor Vlll-related antigen, and focally reactive with keratin (in particular the epithelioid variant) and actin {1609,1718,2626}. Grading is not applied to sinonasal angiosarcoma.

Genetic profile

Histopathology

There are no specific cytogenetic findings {2626}.

MPNSTs are usually unencapsulated, highly infiltrative tumours with a range of cell morphologies (including spindle, epithelioid, pleomorphic, and small round cel l). Common growth patterns include a marbled effect with alternating cellular and myxoid areas, perivascular cuffs, poorly defined nuclear palisading, and neuroid whorls. A rosette-like appearance with hyaline bands is less common . Tumours often show multiple patterns with in the same lesion , including pleomorphic or small-cel l areas. Spindle cell MPNSTs are often arranged in long fascicles or a herringbone pattern. The cells have elongated , tapered, buckled, or wavy nuclei and scant amphophilic cytoplasm. The nuclei may be hyp erchromatic or may be vesicular with coarse chromatin. Mitoses, haemorrhage, and necrosis are frequent. Heterologous (e.g. osteoid, cartilage, striated muscle, orangiosarcoma) elements are seen in about 15% of cases {613,965,2005,2398}. Malignan! triton tumour shows MPNST with rhabdomyosarcoma {965}. Glandular MPNST may have goblet cells, with benign or malignant glands present. The tumours are c lassified as low-grade or high-grade on the basis of mitotic index, atypical mitoses, pleomorphism, and necrosis {2005,2398}. There is no diagnostic immunoprofile, but neoplasti c cells show nuclear and cytoplasmic S100 protein and nuclear S0X10 immunoreactivity {1608}. Epithelioid MPNSTs show strong S100 protein expression and loss of SMARCB1 (INl1) (in 70% of c ases), whereas only scattered cells are reactive with S100 protein

Prognosis and predictive factors Although recu rrences are common (occurring in -40% of cases), the overall survival rate far angiosarcoma is still approximately 60% {7?7,1706,1718,2419,2613,2626}. Metastatic disease occurs most commonly to the lung, liver, spleen, and bone (marrow) {171 8} . Specific etiological factors are associated with shorter survival {2613,2675}.

Malignant peripheral nerve sheath tumour

Fig. 1.30 Sinonasal malignan! peripheral nerve sheath tumour. Coronal T2-weighted MRI demonstrates a large, heterogeneously enhancing mass filling the maxillary sinus.

Localization

Flucke U. Franchi A. Thompson L.D. R.

Cranial nerves are involved, with the vestibular and vagal nerves being most com monly atfected (613,1626).

Definition

The tumours arise de novo, commonly in a majar nerve trunk or from a pre-existing neurofibroma, and rarely from schwannoma. Patients may present with a painful and/or rapidly enlarging mass, with asso ciated neurological deficits {2398}.

Clinical features Malignant peripheral nerve sheath tumours (MPNSTs) are malignant soft tissue neoplasms that arise fro m peripheral nerves or benign nerve sheath tumours with variable differentiation towards one of the cellular components of the nerve sheath (i.e. Schwann cells, fibroblasts, or perineurial cells).

ICD-0 code

9540/3

Synonyms Malignant schwannoma; neurofibrosarcoma; malignant neurilemmoma

Macroscopy The tumours may be within or attached to a nerve trunk or neurofibroma with a fusiform appearance. They tend to be white, salid, and fleshy, sometimes with myxoid change and frequent necrosis and haemorrhage {965,2398}.

Epidemiology About 20% of all MPNSTs develop in the head and neck, with 25~30% of cases associated with neurofibromatosis type 1 (NF1). MPNSTs occur mainly in adults, with a wide patient age range and a mean patient age in the fifth decade of life {965,972}. Cases associated with NF1 tend to occur in younger patients, with a mean patient age in the third to fourth decade {613}. More rarely, MPNSTs develop during childhood (2398).

Etiology MPNST develops in the setting of NF1 and infrequently in patients who have been irradiated (2005}.

Malignant soft tissue tumours

39

in spindle cell MPNSTs in which INl1 is retained. Nestin shows strong cytoplasmic staining and is useful in combination with other markers. Cytokeratins, EMA, and C034 may be positive, but their expression has not b een described in the epithelio id variant (1138,2398}. Genetic profile The most frequent gene alterations inelude loss of NF1 on 17q1 1 and of TP53on 17q13. lnactivation of the N F1 tumour suppressor gene can occur both in sporadic cases and in patients with NF1 {2398}. Genetic susceptibility The tumours are associated with NF1.

most frequently characterized by a recurrent PAX3-MAML3 gene fusion. ICD-0 code

Epidemiology BSNS predominantly affects females, with a female-to -male ratio of 2:1. The reported patient age range is 24-85 years (mean: 52 years) {1051,1409,1913}. Localization BSNS typically involves multiple siles in the sinonasal tract, in particu lar the

Biphenotypic sinonasal sarcoma Lewis J.E. Oliveira A. M.

Definition Biphenotypic sinonasal sarcoma (BSNS) is a low-grade spindle cell sarcoma with distinctive histological, immunohistoc hemical, and molecular features . lt is

40

9045/3

Synonym Low-grade sinonasal sarcoma with neural and myogenic features

Prognosis and predictive factors MPNSTs are aggressive tumours. Worse prognosis is associated with large tumours (> 5 cm), NF1 association, high tumour grade, trunca! location, high mitotic index (> 6 mitoses per 1O high-power fields), and incomplete resection. The recurrence rate is as high as 40%, and ap proximately two thi rd of cases metastasize, usually haematogenously to the lungs and bone {965,972,2398}.


superior aspect of the nasal cavity and ethmoid sinus. Tumour may also extend to the orbit or cribrifo rm plate. Clinical features The symptoms, whic h are relatively nonspecific and reflect the presence of a sinonasal mass, include difficulty breathing through the nose, facial pressure, and co ngestion. Macroscopy The gross specimen usually presents as multiple polypoid fragments of somewhat firm, reddish-pink to tan or grey tissue, as large as approximately 4 cm in greatest aggregate dimension.

Histopathology The tumour is characterized by a cellular submucosal spindle-ce ll proliferation, composed of elongated spindle cells arranged in medium-length to long intersecting fascicles. A herringbone pattern, which resembles the histology of synovial sarcoma, is frequently seen. Tumours are unencapsulated and infiltrative, including into bone. There is a scant. delicate collagen matrix. Nuclei are slender and relatively uniform in appearance, without significant pleomorphism or hyperchromasia. Mitotic activity is sparse (1051 ,1409,1913}. Most tumours show a striking concomitant proliferation of the covering epithelium, the invaginations of which are intimately admixed with neoplastic spindle cells. Squamous or oncocytic metaplasia of the epithelial proliferation can resemble that seen in sinonasal papillomas. Other frequent findings include haemangiopericytomatous vascular pattern and the presence of scattered small lymphocytes. A minority of cases (11%) show focal rhabdomyoblastic differentiation, a histological feature that may be associated with an alternate fusion partner {1051). lmmunohistochemical features are also distinctive. Ali tumours show at least focal positivity for S100 and most (96%) also stain with either SMA or MSA. S100 zand actin staining patterns may be focal, patchy, or diffuse. Focal and/or weak reactivity for CD34, desmin, MYOD1 , myogenin, EMA , and cytokeratin has been noted in severa! cases (1051,1409}.

Genetic profile At the cytogenetic and molecular levels, BSNS is characterized by the chromosomal translocation t(2;4)(q35;q31.1), which results in an in-trame fusion of exon 7 of the transcription factor PAX3 to exon 2 of MAML3, a coactivator of the Notch signalling pathway. The fusion transcript is highly expressed and may contribute to the unusual phenotype of this tumour {2545}. PAX3-MAML3 is found in most examples, but a subset of cases harbour alternate PAX3 or MAML3 fusion genes, including PAX3-FOX01 and PAX3-NCOA 1, the same fusion transcripts found in alveolar rhabdomyosarcoma (1051,2305,2628}.

B

A

PAX3

MAML3

PAX3-MAML3

• •1 1l l1 1 1 1 1i 1 • • 1 1 j 1 !

PAX3

1 • 1

N

•• ,H!-lJ--- ••

''-111\111-H j MA~L3 j

' "PAXJ-MAML:J !!!!

•-1._._I•-.l_.1 ._______.1-,

•

,1 .

60

!!

e

D

f"g

¡

-' 40

~e ~ 20

1u ~

Control

PAX3·

MAML3

PAX3

PAX3-

FOX01

Fig. 1.34 Biphenotypic sinonasal sarcoma. Structure and transactivation potential of the PAX3-MAML3 fusion protein. A,B The t(2;4) translocation /uses exons 1-7 of PAX3 to exons 2-5 of MAML3 to create a novel PAX3-MAML3 fusion protein that retains the DNA-binding domains of PAX3 but lacks the Notch-binding site of MAML3; the arrows along the chromosomes indicate the transcription orientation of PAX3, MAML3, and PAX3-MAML3. C Fusion-signal FISH shows the juxtaposition of the 5' PAX3 (red) locus to the 3' MAML3 (green) locus; the location of these probes is shown in panel A. D Transient transcription assays demonstrate the poten! transactivation potential of PAX3-MAML3. PD, paired domain; HD, homeodomain; TAO, transactivation domain. Reprinted from Wang X et al. {2545}.

invasion of local structures. Nearly 50% of patients with follow-up in the original series experienced local recurrence, as long as 9 years after initial treatment. Neither metastatic disease nor death from disease has been reported {1409}. Specific predictive factors have not been defined.

Synovial sarcoma

sarcomas in children, adolescents, and young adults, with a mean patient age at first diagnosis in the third to fo urth decade of life {121 5).

Etiology Synovial sarcomas are exceptionally associated with prior radiotherapy {568 ,629,2459).

Localization The sinonasal tract and skull are rare localizations.

Bullerdiek J. Bell D.

Clinical features Definition Synovial sarcoma is a mesenchymal tumour that displays a variable degree of epithelial differentiation, including gland formation, and has a specific chromosomal translocation t(X;1 B)(p11 ;q11) that leads to formation of an SS18-SSX fusion gene (735).

ICD-0 code

9040/3

Synonyms Synovial cell sarcoma; synovioma


Epidemiology

The natural history of BSNS is characterized by slowly progressive growth with

Synovial sarcomas are the most common non-rhabdomyosarcoma soft tissue

There are palpable, deep-seated swellings, with or without associated pain or tenderness.

Macroscopy Lesions are yellow or grey to white, and well circumscribed when slow-growing.

Histopathology Severa! monophasic subtypes (i.e. spindle-cell, calcifying/ossifying, myxoid, and poorly differentiated) and biphasic subtypes with glandular or solid epithelial cells can be distinguished. Poorly differentiated tumours may contain areas with frequent mitoses and necrosis {726,2399}. There is TLE1 nuclear immunoreactivity in as many as 95% of cases; Malignant soft tissue tumours

41

variable positivity for CD99, BCL2, and CD56; and patchy to focal reactivity with epithelial markers (EMA), cytokeratins (CK7), and BerEP4. The tumours are usually negative for S100 and WT1.

Genetic profile The chromosomal translocation t(X;18) (p11 ;q11), likely acting as driver mutation, is a specific genetic alteration in synovial sarcomas (2436), and is also described among skull base and sinonasal tract tumours {181,450,835,2299}. lt results in a gene fusion between SS18 (also called SYT) and one of three SSX genes (454). The fusion can be detected by classic cytogenetics, quantitative RT-PCR {903}, or FISH {827) . Variant translocations exist, and a considerable percentage of synovial sarcomas do not show these aberrations.

Prognosis and predictive factors The prognosis varíes depending on staging, grading, resectab ility, use of radiation therapy, site of primary tumour, and presence of metastases {2507). Clinically aggressive behaviour, apparently determined early during tumorigenesis, is associated with more-complex genomes and upregulation of AURKA and KIF18A {1930).

42

Fig. 1.36 Biphasic synovial sarcoma. A lmmunoreactivity with a pancytokeratin cocktail. B Nuclear immunoreactivity with TLE1 .


Borderline / low-grade malignant soft tissue tumours

Desmoid-type fibromatosis

Localization Soft tissues of the neck are most commonly affected {155,551}. whereas the maxillary sinus, nasopharynx, and oral cavity are infrequently involved {753,780,856}. Multifocality may be seen in syndromic cases.

Wenig B. M. Flucke U. Thompson L.D. R.

Definition Oesmoid-type fibromatosis is a locally infiltrative, non-metastasizing, cytologically bland (myo)fibroblastic neoplasm.

ICD-0 code

8821/1

Clinical features Symptoms include an enlarging painless neck mass, as well as nasal obstruction and epistaxis in the sinonasal tract. Facial deformity, proptosís, and dysphagia may occur with disease progression.

Epidemiology About 10-15% of cases occur in the head and neck {528,1556,2532). As many as 30% of cases occur in children (551,738,1018,1847). There is no sex predilection.

Etiology There is an association with Gardner syndrome (familia! colorectal polyposis) {463), including familia! adenomatous polyposis (472,2094). Surgery-rel ated trauma may be a contributory factor.

Genetic profile

Desmoid-type fíbromatosis presents as a fí rm , tan-white, poorly delineated or infiltratíng lesíon of variable size, wíth a trabecu lar or whorled appearance on cut section.

Cytogenetic abnormalities on chromosomes 8 and 20 support a monoclonal neoplastic nature (269). Germline mutations of the APC gene are primarily identified in the setting of Gardner-type familia! adenomatous polyposis, whereas mutations in the beta-catenin gene (CTNNB1) are identified in as many as 85% of sporadic cases (738,1059, 1355). with T41A, S45F, and S45P mutations being the most frequent {1 059,1355).

Histopathology

Genetic susceptibility

Histopathology shows a poorly circu mscribed, infiltrative (to muscle and/or bone), fascicular growth of moderate cellularity composed of spindle-shaped cells with tapering to plump _vesicular nuclei, small nucleoli, and indistinct cytoplasm, separated by abundant collagen. Mild nuclear pleomorphism and rare mitotic figures may be identified; atypical mítoses and necrosis are absent. The stroma is variably collagenized, may

Patients with Gardner syndrome {463} or Gardner-type familia! adenomatous polyposis are at increased rísk {472,2094).

Synonyms Desmoid tumour; aggressive fibromatosis; infantile fibromatosis (desmoid variant)

focally be myxoid or mucoid-appearing, and may be characterized by keloid-like collagen. Vascularity varies, consisting of compressed vessels that tend to be evenly spaced. Lesiona! cells are reactive for vimentín, nuclear beta-caten in (in 70-75% of cases), actins, and occasionally desmin {184,335,1818,2400).

Macroscopy

Prognosis and predictiva factors In general, the prognosis is good (1 193}, with positíve surgical margins associated with recurrence, usually < 2 years after surgery (1050}. Young patient age and CTNNB1 S45F mutatíon may be independent risk factors for recurrence (473,2457).

Borderline/low-grade malignan! soft tíssue tumours

43

Sinonasal glomangiopericytoma

Macroscopy The tumours are generally polypoid, nontranslucent, beefy red to pink, soft, and fleshy to friable, with an average size of 3.0cm.

Thompson L.O.R. Flucke U. Wenig B.M.

Definition Sinonasal glomangioperi cytoma is a sinonasal tumour demonstrating a perivascu lar myoid phenotype. ICD-Ocode

9150/1

Synonym Sinonasal haemangiopericytoma- like tumour Epidemiology Glomangiopericytomas account for < 0.5% of all sinonasal tract neoplasms {356,476,2389). with a slight female predilection and a peak incidence in the seventh decade of lite, although individuals of any age may be affected. Localization The tumour is nearly always unilateral (only 5% are bilateral), affecting the nasal cavity alone and frequently extending into paranasal sinuses. lsolated paranasal sinus involvement has also been reported {189,356,476,640,2389]. Clinical features Most patients present with nasal obstruction and epistaxis, with other non-specific fi ndings present for an average duration of < 1 year {2389}. Associated severe oncogenic osteomalacia has been reported {257,356).

Histopathology Th e unencapsulated tumour is identified below an intact epithelium , although friction surface erosion may be seen in large tumours. There is a so-called patternless diffuse architecture, frequently effacing or enveloping normal tissue. The cells may be arranged in short fascicles; in storiform, whorled, meningothelial, or reticular arrangements; or in short palisades of closely packed cells. The cells are separated by a vascular plexus ranging from capillaries to large patulous spaces. Prominent, thick, acellular, peritheliomatous hyalinization is a characteristic feature. There is a syncytial architecture to the c losely packed, uniform, oval to elongate cells, with indistinct cell borders. The nuclei are oval to spindle-shaped, vesicular to hyperchromatic, and surrounded by nondescript cytoplasm. Mitoses are limited (< 3 per 10 high-power fields), and nuclear pleomorphism is absent to mild. Mast cells, eosinophils, and extravasated erythrocytes are variably present. Tumour giant cells are rarely identified, but an aggregation of degenerating tumour cells, similar to those of symplastic glomus tumour, may be seen {657). lnfrequently, fibrosis or myxoid change may be identified . Rarely, glom·angiopericytoma may contain mature adipose tissue (lipomatous) or extramedullary haematopoiesis {742,904,1732,2389}. Concurrent collision tumours, most often solitary fibrous tumours, have been reported {17,822,2389). Malignant

show proglomangiopericytomas found pleomorphism, necrosis, and increased mitoses {2389). By immunohistochemical analysis, glomangiopericytomas usually show diffuse reactivity with actins (SMA > MSA), nuclear betacatenin, cycl in 01 , factor Xllla, 1 and vimentin, and lack significan! expression of CD34, CD31, CD11 7, STAT6, BCL2, cytokeratin, EMA, desmin, or S100 protein {17,356,630,1274,1339,2389}. Genetic profile Somatic, single-nucleotide-substitution, heterozygous mutations in the betacatenin gene (CTNNB1), specifically in the GSK3beta region (codons 32, 33, 37, 41 , and 45 encoded by exon 3) have been identified in glomangiopericytoma {923,1339]. Accumu lation of beta-catenin results in nuclear translocation, which has been shown to upregulate cyclin 01 and lead to its oncogenic activation. Activation of beta-catenin and the resulting cyclin 01 overexpression are important pathogenetic events {1339}. In the differential diagnosis it is importan! to note that NAB2-STAT6 gene fusion in solitary fibrous tumours {603}. MIR143-NOTCH fusion in glomus tumours {1 660} and

, I a ..a,Ullll.:.lll.- _ _.L_ _ __ ,._ Fig. 1.38 Nasal glomangiopericytoma. A The surface respiratory epithelium is uninvolved by !he patternless proliferation of spindled neoplastic cells; there is well-developed peritheliomatous hyalinízation. B Spindled cells with ovoid nuclei in a syncytial arrangement; numerous eosínophils and mast cells are apparent.

t..._.

44


ACTB-GL/1 fusion in pericytoma (514} are not seen in glomangiopericytoma.

Prognosis and predictiva factors Glomangiopericytoma is an indolent tumour with an excellent survival rate. Recurrence (which occurs in as many as 40% of cases) is usually a resu lt of inadequate surgery {356,640,2389}. Aggressive (malignan!) behaviour is suggested by tumour size > 5 cm, bone invasion, profound nuclear pleomorphism, high mitotic rate (> 4 mitoses per 10 high-power fields), and necrosis {356,476,1274,2389}.

Solitsry fibrous tumour Flucke U. Thompson L.D.R. Wenig B.M.

Definition Solitary fibrous tumour is a fusion geneassociated tumour of fibroblastic phenotype, with a branching vasculature.

ICD-0 code

8815/1

Synonyms Haemangiopericytoma; giant cell angiofibroma

Epidemiology Solitary fi brous tumours are rare , accounting for < 0.1% of ali sinonasal neoplasms (1 51). Adults are mainly affected, with no sex predilection (17,564,861,2620,2735}.

Localization Tumours affect the nasal cavity (2620, 2735}.

Clinical features Patients experience nasal obstruction and epistaxis, among other non-specific findings (1 51,2620,2735}.

Macroscopy Tumours are polypoid, firm, and white, and are usually small due to the confined space of the sinonasal tract (151,2620,2735}.

Fig. 1.40 Solitary fibrous tumour. A Note the pattemless architecture of the fibroblastic cells; there is a collagenous background, and sinonasal mucosa is seen in the upper part of the field. B Nuclear STAT6 expression is !he most specific immunohistochemical marker.

Histopathology Tumours are submucosal, pseudoencapsulated, and variably cellular, consisting of bland spindle-shaped cells arranged in a haphazard architecture. Multinucleated giant cells may be present. The vessels are stellate to staghorn-like in shape. There is a variable collagenous background that includes ropey, keloidal, or amianthoid collagen bundles. lmmunohistochemically, the cells show a specific reaction with STAT6 (nuclear) and CD34, but are non-reactive with desmin, S100 protein, actins, and nuclear beta-catenin (489,563,603,923, 2620,2683,2735}.

Genetic profile NAB2-STAT6 gene fusion seems to be specific {33,511,565,1634].

Prognosis and predictive factors Complete surgical resection is usually curative. Patient age > 55 years, tumour size > 15 cm, necrosis, and > 4 mitoses per 10 high-power fields probably suggest more aggressive behaviour {564,1297,2659).

Borderline/low-grade malignan! soft tissue tumours

45

Epithelioid haemangioendothelioma Flucke U. Franchi A.

Definition A malignant neoplasm of low- to intermediate-grade, composed of neoplastic cells that have an endothelial phenotype, epithelioid morphology, and a hyalinized, chondroid, or basophilic stroma.

ICD-0 code

9133/3

Epidemiology There is a wide patient age distribution, with children rarely being affected (280,2579).

Localization Occurrence in the head and neck is rare. Epithelioid haemangioendothelioma may arise in soft tissue, skin, and bone. The neck, oral cavity, salivary glands, and jawbones may be affected . Very rarely, a lymph node may be the primary site (422,662,739,1886}.

Clinical features Epithelioid haemangioendotheliomas are classically slow-growing, infiltrative, and (rarely) metastasizing lesions (280). Symptoms are mostly non-specific. Pain and tend erness may be present {1589,2579). There is a propensity for lymph node metastasis (739).

Macroscopy The (multi)nodular mass typically shows a pale, solid cut surface, sometimes with sorne haemorrhage {280}.

Histopathology The epithelioid- and histiocytoid-appearing endothelial cells are arranged in short cords and strands in a myxohyaline stroma. They show subtle intracytoplasmic lumina and an abundant hyaline cytoplasm. Striking nuclear atypia is seen in approximately 30% of cases. Mitotic activity is usually low. Multicellular vascular channels are present in individual cases {574,739,1589,2579}.

46

Endothelial markers are expressed, with CD31, ERG, and FLl1 being the most sensitive. Cytokeratin expression is seen in about 30% of cases, which may as a result b e confused with carcinomas or myoepithelial tumours (739,1589}. There is nuclear positivity for CAMTA1 in cases with WWTR1-CAMTA1 fusion . There is nuclear expression of TFE3 in cases with YAP1-TFE3 fusion, but this marker should be used with caution due to the possibility of unspecific staining (662,739,2161).

Genetic profile WWTR1-CAMTA1 fusion is present in most of the cases. A small subset of tumours harbour a YAP1-TFE:J fusion (85,662,739,2351}.


Prognosis and predictive factors Most cases behave in an indolent manner. A progressive clinical course with tumour-related fatality has been documented in sorne instances {574,1589,2579). A proposal for ri sk stratification showed that > 3 mitoses per 50 high-power fields and tumour size > 3 cm are associated with higher mortality, irrespective of localization , atypia, cell spindling, or necrosis (574).

Benign soft tissue tumours

Thompson L.D.R . Bullerdiek J. Flucke U. Franchi A.

Leiomyoma

Haemangioma

Definition Leiomyomas are benign tumours with smooth muscle differentiation (and vascular differentiation in the case of angioleiomyoma). ICD-0 code

8890/0

Epidemiology Leiomyomas are extremely rare in the head and neck reg ion, accounting for < 1% of all leiomyomas (2488}. Adults are rnost commonly affected, with an equal sex distribution {1047,2488). lt seems that most sinonasal tract examples are angioleiomyomas {20,1047,1607}. Localization The most common site of leiomyoma in the head and neck region is the lips, followed by the tangue, cheeks, palate, gingiva, and mandible (2488}. The tumours are extraordinarily rare in the sinonasal tract, with involvement of the nasal cavity in most of the cases and more rarely of the paranasal sinuses (20, 778,1047). Clinical features The tumours are clinically indistinct and present as longstanding polypoid rnasses with nasal obstruction, epistaxis, and pain (20,778,1047,2488).

Macroscopy Lesions are polypoid, nodular, and usually sharply demarcated, with a white to tan trabecular cut surface {20,1047,2488). Histopathology Tumours are subepithelial with infrequent mucosa! ulceration. Spindled tumour cells are arranged in intersecting fascicles. The nuclei are oval to elongate and cigar-shaped, without atypia. There is eosinophilic fibrillary cytoplasm. Unlike in leiomyosarcoma, mitotic figures are absent. Angioleiomyoma, the most common smooth muscle tumour in this reg ion, shows a prominent vasculature surrounded by smooth muscle cells with which the vessels are intimately associated. Calcification, ossification, fatty metaplasia, or myxohyaline degeneration may be seen and may suggest regression in longstanding lesions {20,606,778,1047, 1606). A fatty componen! is more common in males and older patients {20). lmmunohistochemically, lesions express smooth muscle markers (alpha-SMA, MSA, desmin, and caldesmon) but are negative far HMB45, S0X10, and S100 (20,1047,1606}. Genetic profile Angioleiomyomas show loss of 22q1 1.2 and low-level amplification of Xq {1741). Prognosis and predictive factors The prognosis is excellent {20,1047}.

Definition Haemangioma is a benign neoplasm of vascular phenotype. ICD-0 code

9120/0

Synonyms Lobular capillary haemangioma; pyogenic granuloma; capillary haemangioma; cavernous haemangioma Epidemiology Mucosa! haemangiomas account for about 10% of head and neck haemangiomas and about 25% of non-epithelial sinonasal tract neoplasms {777,1620, 1936,2221). Haemangiomas occur in patients of all ages (median: 40 years). There are incidence peaks among boys and adolescent males and among pregnant women, with an equal sex distribution in patients aged > 40 years {644, 777,963,1174, 1620,2221J. Etiology Lobular capillary haernangioma is associated with injury, hormonal factors (pregnancy and oral contraceptive use) (559,1292, 1936). and drugs (vemurafenib) {2061). Localization The anterior septum is most frequently affected, followed by turbinates and sinuses (644,1620,1936,2221}.


47

A Fig. 1.43 Lobular capillary haemangioma. surrounding a central penetraling vessel.

Clinical features Presenting symptoms include epistaxis and obstruction, usually of short duration (559,1620,1936,2221). lmaging studies show an intensely enhancing tumour surrounded by a hypoattenuated peripheral rim, often with bony remodelling (1 174, 1360,2669}. Macroscopy The mean size is < 1.0 cm, but examples as large as 8 cm have been reported {1936,2221). The gross appearance ranges from that of a diffuse, flat mass to that of a bulging, polypoid nodule. The lesions are soft and usually have surface epithelial ulceration {644,777,963,11 74, 1620). Histopathology Haemangiomas in the sinonasal tract are divided primarily into capillary and cavernous types {1174,1620,1936,1956, 2221}. Other variants are repo rted rarely. Lobular capillary haemangioma is a circumscribed proliferation of capillaries with plump endothelial cells surrounded by pericytes in a fibromyxoid stroma, arranged in one or more lobules (which may show high cellularity). Each lobule has a large central vein surrounded by small capillaries, with an overlying collarette of epithelium (often ulcerated or atrophic). Mitoses are often identified, without atypical forms. Cavernous haemangiomas are composed of multiple, large, cystic, thin-walled, blood -filled spaces lined by endothelial cells and separated by scant connective tissue stroma. The neoplastic cells react with FLl1, CD34, CD31, and factor Vl ll-related antigen, with variable

48

expression of estrogen and progesterone receptors. Genetic profile A single case had a clonal del(21) (q21. 2q22.12) {2425¡. Genetic susceptibility Associations with Sturge- Weber syndrome (encephalotrigeminal angiomatosis) and von Hippel-Lindau disease have been reported. Prognosis and predictive factors Recurrences, which occur in as many as 42% of cases, are usually identifi ed in older patients. Pregnancy-relate d regression occurs after parturiti<5n {134, 559,1936,2221). Angiosarcomas arise de novo {1718).

Schwannoma Definition Schwannoma is a benign tumour of Schwann-cell phenotype. ICD-0 code

9560/0

Synonyms Neurilemmoma; benign peripheral nerve sheath tumour Epide miology Less than 4% of schwannomas involve the nasal cavity and paranasal sinuses (929, 952,994,2170). developing in middleaged adults (mean patient age: 50 years; range: 17-81 years) with an equal sex distribution {747,1594,2170,2314).


Localization Sinonasal schwannomas arise from the branches of the cranial nerves (V and IXXII) and autonomic nervous system, affecting (in descending arder of frequen cy) the ethmoid and maxillary sinuses, nasal cavity, and sphenoid and frontal sinuses {952,994,1866,2170,2314). Clinical features The most common presenting symp toms are headache, nasal obstruction, facial pain, and Horner syndrome (ocu losympathetic palsy), followed by other non-specific findings {929,1866,2 170, 2314). lmaging shows an inhomogeneous, low-density soft tissue mass, with bone erosion occasionall y noted {1230, 1866,2170,2314). Tumours may expand into the orbit, nasopharynx, and cranial cavity (1866,2170). Macroscopy Sinonasal schwannomas can reach 7 cm in size (mean: 2.5 cm). They are wellcircumscribed , globular, firm to rubbery, yellowish-tan tumours with a solid to myxoid and cystic cut su rface, frequently with haemorrhage. Histopathology Schwannomas are unencapsulated tumours composed of Antoni A cellular areas with nuclear palisad ing alternating with hypocellular, myxoid Antoni B areas. The tumour cells are fusiform with elongated cytoplasmic extensions imparting a wavy to spindled appearance. The nuclei are wavy and tapered , with heterochromatin. In Antoni B areas, a perivascular hyali nization is characteristic. Mitoses are

scant and necrosis is absent. Extensive degeneration may result in a narrow rim of recogn izable tumour at the periphery (300,952}. Epithelioid variants and hybrid tumours (i.e . neurofibroma and perineurioma) are rare in the sinonasal tract {109). Jmmunophenotype The neoplastic cells are strongly and diffusely reactive with S100 protein and SOX10, with CD34-positive fibroblasts in the Antoni B areas. Focal GFAP and AE1/AE3 immunoreactivity has been described, but neurofilament protein (NFP) and actin are negative {1608}. Prognosis and predictive factors Schwannomas exceptionally undergo malignan! transformation {972,1575,1626, 2422). but otherwise have a very low recurrence potential.

Neurofibroma

the maxillary sinus {1 09,281); the majority are unilateral {211 ,1308}.

Definition Neurofibroma is a benign peripheral nerve sheath tumour composed of mixed Schwann cells, perineu ral-like cells, and intraneural fibroblasts.

Clinical features Non-specific symptoms include a mass, obstruction, epistaxis, and pain {81,109, 1866).

9540/0

Macroscopy Tumours are firm, glistening, fusiform , and sometimes polypoid, with a mean size of 3.1 cm (81,109,998).

Epidemiology Neurofibromas are exceptional in the sinonasal tract. They show no sex predilection. The mean patient age is in the fifth decade of life overall, and ·35 years among patients with neurofibromatosis type 1 {109}.

Histopathology Neurofibromas are unencapsulated tumours intimately associated with nerve twigs. Lesiona! cells (modified Schwann cells, intraneural fibroblasts, and perineurial hybrid ce lls) intermix with coarse collagen bundles and mast cel ls within a mucopolysaccharide-rich stroma. There are ovoid to spindled cells with undulating, pointy nuclei with thin cytoplasmic processes extending into the stroma, often

ICD-0 code Synonym Fibroneuroma

Localization Sinonasal neurofibromas arise most commonly at the nasal vestibu le, followed by

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Fig. 1.45 Nasal neurofibroma. A An intact squamous mucosa overlies a proliferation of Schwann cells, perineurial cells, and fibroblasts blended with collagen libres. B Nerve fibre twigs are interspersed among Schwann cells, perineurial cells, and collagen fibres; mast cells are also present.


49

with a centripetal gradient of cellularity. lncreased cellularity, a storiform growth pattern, and pleomorphism may be seen, but fascicular growth or increased mitoses (in particular atypical mitoses) sug gest malignan! change {109,994,1866). Plexiform neurofibroma and composite tumours (i.e. schwannoma and perineurioma) are exceptional {109,1026,1308), and the diffuse type has not been reported. The subpopulations of neurofibroma

are highlighted with S100 protein, GFAP, CD34, and BCL2, with S0X10, NFP, and calretinin highlighting the axons specifically (109,719}.

Genetic susceptibility About 10% of sinonasal neurofibromas arise within neurofibromatosis type 1 {109,2001,2453).

Geneti c profile Neurofibromatosis type 1- related neurofi bromas have associated biallelic inactivation by germline mutations of the NF1 gene (17q11 .2) {6,1836).

Prognosis and predictive factors Neurofibromas are benign, with a 5% recurrence rate due to incomplete excision {1866,2001 }. Malignan! transformation is exceptional {1866).

is much more common, with 20% of meningiomas showing extracranial extension {772,1867,2029,2388). By consensus, a diagnosis of primary sinonasal meningioma should not be rendered when a detectable intracranial mass is present {1666,2029). Sinonasal mening iomas affect women and men equally (with a ratio of 1:1), and have a mean patient age of 48 years (range: 13- 88 years) {2160, 2388).

Clinical features Symptoms are non-specific, present for a long duration (mean: 4 years), and most commonly include a mass or p olyp and nasal obstruction {772,823,1006,1867, 2388). The imag ing fi ndings are nonspecific, revealing opacification, sornetimes with bone erosion or hyperostosis . In most cases, direct extension by permeative growth from an intracranial primary can be documented; the intracranial primary may be a small en plaque meningioma \1666,2388).

Other tumours Meningioma Ro J.Y. Bell D. Nicolai P. Thompson L.D.R.

Definition Meningioma is a neoplasm composed of meningothelial cells. ICD-0 code

9530/0

Synonym Sinonasal trae! meningioma

Etiology Radiation exposure and sex hormones are unproven etiological factors {772, 1006,1039).

Epidemiology Primary extracranial (i.e. ectopic or extracalvarial) meningiomas of the sinonasal tract are rare, accounting for 0 .1 % of primary sinonasal neoplasms, 2% of all meningiomas, and 24% of all primary extracranial meningiomas. Direct extension

Localization Sinonasal meningiomas involve the nasal cavity most commonly, followed by the paranasal sinuses (most commonly the frontal sinus), with multiple siles frequently affected . Most tumours are left-sided {772,1006,1867,2029,2388}.

50


Macroscopy The tumours are often polypoid , covered by an intact epithelium, and expanding into bone. They can reach 8.0 cm in size (mean: 3 cm). Histopathology Sinonasal meningiomas, often blended with surface squamous or respiratory epithelium, are arranged in lobules of

whorled syncytial meningothelial cells. Nuclei are bland and round to oval, with small nucleoli and occasional intranuclear cytoplasmic inclusions {2388}. Psammoma bodies are occasionally present. ot the i 5 histological types of meningioma, the most common in the sinonasal trae! are meningothelial , transitional, metaplastic, and psammomatous, and most are grade i tumours {i858,i859}. Grade 2 and 3 meningiomas are rare {2388}. Meningiomas typically react with EMA, CK18, and vi mentin. Rare tumours may react with pancytokeratin and CK? (in a pre-psammomatous pattern), CD34 (fibrous and atyp ical types), and SiOO protein (fibrous type), whereas GFAP, STAT6, and SMA are non-reactive {2160). Progesterone and estrogen receptor reactivity is present {2388l.

Genetic susceptibility Neurofibromatosis type 2 association is not significan! in sinonasal meningiomas. Prognosis and predictive factors The prognosis of sinonasal meningiomas is good . Although recurrences develop in about 30% of cases (due to incompletely excised tumours), metastasis and malignan! transformation have not been reported [i006,i858,1867,2388).

Sinonasal ame/oblastoma Wenig B.M.

Definition Sinonasal ameloblastoma is a locally aggressive, primarily gnathic (jaw) tumour with a high propensity for recurrence. lt originales wholly within the sinonasal trae!, without connection to gnathic siles, arising from sinonasal epithelium and showing histological features identical to !hose of its counterpart originating in the jaw. ICD-0 code

ameloblastoma occurring in the jaws) {2090}.

Localization The tumours may involve the nasal cavity only, the paranasal sinuses only, or both the nasal cavity and the paranasal sinuses {2090}. Clinical features Patients usually present with a mass lesion and nasal obstruction; symptom duration ranges from 1 month to severa! years {2090}. Unlike gnathic ameloblastomas, which have a characteri stic multilocular and radiolucent presentation, sinonasal ameloblastomas are described radiograph ically as salid ma:sses or opacifications {2090l. Bone destruction, erosion , and remodelling (with remnant of bony shell delimiting the lesion as it grows) may be present {2090). Histopathology Histologically, sinonasal ameloblastomas are similar in appearance to their gnathic counterparts. In the sinonasal trae!, ameloblastomatous proliferation can be seen arising in direct continuity with the intact sinonasal surface mucosa! epithelium, a finding th at in conjunction with the absence of continuity with gnathic sites confirm s primary sinonasal origin.

93i0/0

Epidemiology Sinonasal ameloblastomas are uncommon tumours. There is a decided male predilection and the mean palien! age at presentation is 59.7 years (approximately 15-25 years older than far

Prognosis and predictive factors Overall treatment success correiates with complete surgical eradication performed in conjunction with thoroughly detailed rad iographical imaging. The tumour may recur, which generally happens within 1-2 years of the initial

procedure but may occur years after the surgery {2090}. No tumour deaths, metastases, or instances of malignan! transtormation have been reported.

Chondromesenchymal hamartoma Toner M. Hunt J.L.

Definition Chondromesenchymal hamartoma is a benign, locally destructive, tumour-like growth containing mixed mesenchymal elements. Synonyms Nasal chon dromesenchymal hamartoma; mesenchymoma Epidemiology This rare lesion occurs predominantly in infants, but occasionally in older ch ildren and adults, with amale predominance. Localization The most common sites are the paranasal sinuses, nasal cavity, and orbit. lntracranial and skull base extension may occur [1568}. Clinical features This is a slow-growing expansile lesion that can be locally destructive. Patients may present with nasal congestion or symptoms related to a polypoid mass. Radiological tindings may appear deceptively aggressive, with bone erosion and intracranial extension. Other tumours

5i

Macroscopy The tissue is typically firm and white, resembling cartilage.

Histopathology Histopathology shows a fabular proliferation of mature and immature hyaline cartilage in a variably ce llular fibrous background {1568). The stromal component may be highly cellular, and mitoses may be present. The stromal and carti laginous elements may be admixed with bony trabeculae or may surround bony islands {1795). The cartilaginous areas are S100positive; the stromal cells are SMA-posi tive and cytokeratin-negative {1795).

Genetic susceptibility There is an association with the pleuropulmonary blastoma-associated O!CER1 familia! tumour susceptibility syndrome,

..

Fig. 1.48 Chondromesenchymal hamartoma. Fibrovascular stroma with cellular lobules of cartilage that surround bony trabeculae.

in which chondromesenchymal hamartoma may be the presenting lesion (2281).

Prognosis and predictive factors After surgical removal, the recurrence rate is generally low (1554).

Haematolymphoid tumours Overview

9% between 2000 and 2011 (607}.

Chuang S.-S. Ferry J.A.

Localization

Definition Nearly ali haematolymphoid tumours arising from the nasal cavity or paranasal sinuses are non-H odgkin lymphomas, although extramedullary plasmacytomas and rare myeloid and histiocytic neop lasms also occur {116,1027,1830,1888}.

Epidemiology Sinonasal lymphoma accounts for 1215% of ali head and neck cancers. lt is the third most common sinonasal malignancy, after squamous cell carcinoma and adenocarcinoma {484,1012}. In the USA, the frequency decreased in the early 21st century, probably reflecting a reduction in HIV-associated lymphomas due to antiretroviral therapy {484). However, extranodal NK/T-cell lymphoma, nasal-type (ENKTL), which has a predilection for East Asians and Latín Americans {86,446,607,1349), is increasing in the USA, with an average annual increase in incidence of approximately 52

myeloid sarcoma, and histiocytic neoplasm (484,500,1012).

ENKTL has a predilection for the nasal cavity and may also arise from paranasal sinuses (86,446,607,1349}. Diffuse large B-cell lymphoma (DLBCL) most • com monly arises from the paranasal sinuses but may arise from the nasal cavity (1169).

Modern therapies have significantly improved the prog nosis of sinonasal DLBCL. lnvolvement of multiple sinuses is a negative prognostic indicator (11 69).

Clinical features

Extranoda/NK/T-celllymphoma

Patients with nasal tumours present with nasal obstruction, epistaxis, and/or a destructive mass involving nose, nasal septum, palate, orbit, or facial skin. Patients with paranasal tumours present with symptoms of chronic paranasal sinusitis and soft tissue or bony destruction. B symptoms (e.g. fever, night sweats, and weight loss) occur in about 20% and 10% of patients, respectively, with sinonasal ENKTL and DLBCL.


Chuang S.-S. Gaulard P. Jaffe E.S. Ko Y. -H.

Definition Extranodal NK/T-cell lym phoma, nasaltype (EN KTL) is an extranodal lymphoma with a cytotoxic phenotype and a universal association with EBV.

Histopathology In addition to DLBCL and ENKTL" there have been rare cases of other sinonasal haematolymphoid tumours , such as sinonasal Burkitt lymphoma, peripheral T-cell lymphoma, MALT lymphoma, extraosseous plasmacytoma, extramedullary


ICD-0 code

9719/3

Synonyms Angiocentric lymphoma; lethal midline granuloma; malignan! midline reticu losis; polymorphic reticulosis

fig. 1.49 Extranodal NK/T-cell lymphoma, nasal-type. A Right nasal tumour with obstruction, ecchymosis of the nasal side wall and facial skin, and invasion to the right nasal ala with tumour formation. B Postcontrast CT of the same case shows a homogeneously enhancing soft tissue mass in !he right nasal cavity involving the right nostril, nasal ala, and perinasal facial skin, and destruction of !he anterior lower aspee! of the nasal septum.

Epidemiology

Clinical features

Extranodal NK/T-cell lymphoma is more prevalent among East Asians and the indigenous populations of Mexico and Central and South America than in other populations {86,446,1349,19401.

Patients with nasal tumours present with nasal obstruction and/or epistaxis. Nasal tumours may cause perforation of the nasal septum or palate and may spread to the skin or orbit with ecchymosis or ulcerative tumours. Paranasal tumours may mimic chronic paranasal sinusitis. Most cases present with stage I or 11 disease, with as many as 10- 20% of cases spreading to skin, gastrointestinal tract, testis, or distan! nodal regions.

Etiology The precise etiology is unknown, although EBV is crucial in pathogenesis. Lifestyle and environmental factors such as being a farmer, pesticide use, and living near incinerators might be risk factors (2657).

Localization ENKTL occurs most commonly in the upper aerodigestive tract (in 70- 85% of cases), mainly in the nasal cavity, paranasal sinuses, and Waldeyer ring (pharyngeal lymphoid ring), with sorne cases occurring in the skin, gastrointestinal tract, soft tissue, and other extranodal siles {1132,1229,1909,2317}.

Histopathology ENKTL infiltrates nasal tissue in a diffuse pattern, frequently with an angiocentric/ angioinvasive growth pattern, leading to geographical tumour necrosis. In rare instances, multiple biopsies might be needed to identify tumours showing extensive necrosis with few viable cells. The neoplastic cells vary in size and have irregularly folded nuclei, granular chromatin, and small nucleoli. Small cells might

mimic a benign infiltrate but exh ibit cellular atypia such as irregular nuclear contours and mitoses. lmmunohistochemically, the tumour cells express CD3, cytotoxic markers (i.e. TIA1, granzyme B, or perforin), and frequently CD56 (1132,19091. They rarely express CD4,·CD5, or CDS. Examples with largecell morphology often express CD30. CD57 is nearly always negative (11 32}. The tumours are mainly derived from NK cells, with a minority (10-40%) having T-cell lineage (gamma delta or more rarely alpha beta) {102,1132,1418,19091. CD56 is more frequently expressed in tumours of NK-cell origin, whereas CD5 expression usually indicates a T-cell lineage {1132,19091. EN KTL is positive for EBV-encoded small RNA (EBER) in the majority of cells by in situ hybridization {443,444,2322) . LMP1 is usually weak or negative. Cases showing a similar phenotype but EBV negativity are considered peripheral T-cell lymphoma, NOS {1108,2322).

Genetic profile ENKTL shows complex genetic alterations, with numerous chromosomal gains and losses {1695). The commonly deleted chromosomal region at 6q21-23 contains severa! candidate tumour suppressor genes, including PRDM1, ATG5, AIM1, HACE1, and FOX03 {1091,1189, 1289}. ENKTL has a distinctive genetic signature shared by cases with NK-cell and T-cell origin (1053). The JAK/STAT pathway is activated in most cases, by genetic alterations of JAK3, STAT3, or PTPRK {406,485,1053,1272,1370}. Recurrent mutations are frequent in tumour suppressor genes, including TP53 (in 20- 60% of cases) {1941) and DDX3X (in 20% of cases) (1134). EBV infection

Haematolymphoid tumours

53

severely deregulates host microRNA profi les; downregulation of miR-146a and miR-15a promotes cell proliferation and predicts poor prognosis in ENKTL {1266, 1802].

Genetic susceptibility The strong EBV association and ethnic predisposition suggest a genetic defect in the host immune response to EBV infection [534,535}. The lymphotoxin alpha gene (LTA) +252 (AG) polymorphism is associated with increased risk of ENKTL (409}. Prognosis and predictiva factors Prognostication of ENKTL traditionally depends on clinicopathological parameters, including stage (1364,2431). However, the amount of EBV DNA in plasma is a surrogate biomarker of lymphoma load, with diagnostic and prognostic

significance (1221,1319,2431). EBV DNA and PET findings have been integrated into prognostic algorithms {1226). With curren! regimens, durable re mission can be achieved in 70-80% of stage 1/11 cases, and as many as 50% of stage 111/IV cases (1318,2431 }.

Extraosseous plasmacytoma Feldman A.L. Ott G.

Definition Extraosseous plasmacytoma is a massforming proliferation of monoclonal plasma cells with extraosseous (extramedullary) presentation, in the absence of underlying multiple myeloma. Extraosseous plasmacytomas in the nasopharynx

and other soft tissues in th e head and neck must be distinguished from 8-cell lymphomas with plasmacytic/plasmablastic differentiation, in particular MALT lymphoma and plasmablastic lymphoma.

ICD-0 code

9734/3

Synonyms Extramedullary plasmacytoma; plasmacytoma Epidemiology The median patient age is 60 years and there is a male predominance, with a male-to-female ratio of 3- 4: 1 [46,1 617). Localization About 80% of extraosseous plasmacytomas involve the upper respiratory tract, most commonly the nasal cavity and paranasal sinuses, followed by the nasopharynx, oropharynx, and larynx (46, 1617). Less common primary sites in the head and neck include the hypopharynx, salivary and thyroid glands, cervical lymph nodes, !rachea, and oesophagus. Cervical lymph nades are involved secondarily in about 15% of cases [1586). Clinical features Extraosseous plasmacytomas are typically solitary, and examples occurring in the head and neck most commonly (in 80% of cases) presentas a mass {1617). Add itional fin dings at presentation inelude airway obstruction, epistaxis, local pain, proptosis, rhinorrhoea, cervical lymphadenopathy, and cranial nerve palsies. A minority of patients (< 25%) have a monoclonal serum paraprotein (M protein), typically of lgA type {2245). By definition, diagnostic features of plasma cell myeloma are absent {1476). H istopathology Microscopic evaluation typically shows

54


j¡

Fig. 1.54 Plasmacytoma. Monotonous infiltrate of plasma cells.

(1278). Monotypic immunoglobulin light chains can typically be demonstrated by immunohistochemistry or in situ hybri dization. Staining fo r heavy chains may reveal expression of lgA or lgG, whereas staining for lgM should raise suspicion for B-cell lymphoma. EBV has been reported to be positive in 15% of cases {26), but the presence of EBV should also prompt consideration of plasmablastic lymphoma.

Genetic profile diffuse infiltration by sheets of plasma cells, which may be well, moderately, or poorly differentiated {1617,2316}. Amyloid deposits may be present {2316, 2616). Moderately and well-differentiated extraosseous plasmacytomas mus! be distinguished from B-cell Jymphoma, in particular from MALT lymphoma with extensive plasmacytic differentiation (584, 1062). Poorly differentiated extraosseous plasmacytomas must be distinguished from plasmablastic lymphoma (2316}; sorne cases may be anaplastic to the point that plasma-cell differentiation is not apparent, prompting consideration of

poorly differentiated non-haematological neoplasms {1172).

lmmunophenotype The neoplastic cells often express markers of plasmacytic differentiation, such as C0138, C038, VS38, and MUM1/IRF4 {232} . They variably express C079a, only rarely express C020, and are typically negative for PAX5. Extraosseous plasmacytomas may express EMA. Cyclin 0 1 has been reported to be negative. C056 is expressed less frequently than in plasma cell myeloma, and the Ki-67 index is lower !han in plasma cell myeloma

Sorne genetic features are similar to !hose of plasma cell myeloma (232}, but diffe rences have been reported, in particular different IGH translocation partners {1 93}.

Prognosis and predictive factors The prognosis of extraosseous plasmacytoma is much better than that of plasma cell myeloma, and most patients are treated with local radiation therapy {504, 583). Regional recurrence or spread to other extraosseous siles may occur, and about 15% of patients develop multiple myeloma {46}.


55


Ewing sarcoma/primitive neuroectodermaltumour

2617l; older patients may occasionally be affected {921,2617}.

Wenig B.M. Flucke U. Thompson L.D.R .

Localization The most common head and neck sites include the skull and jaws (49,2601}; less common siles include the sinonasal trae\ (most commonly the maxillary sinus or nasal fossa) {921,1036,1331,2617}, orbit, and various mucosa! sites . Extension to dura, orbit, or brain may be present (921).

Definition Ewing sarcoma / primitive (peripheral) neuroectodermal tumours are high-grade pri mitive small round cell sarcomas with variable neuroectodermal differentiation, characterized by the presence of translocations between the EWSR1 gene on chromosome 22 and a member of the ETS family of transcription factors. ICD-0 code

9364/3

Synonyms Peri pheral neuroectodermal tumour; peripheral neuroepithelioma; peripheral neuroblastoma; adult neuroblastoma Epidemiology Ewing sarcoma and primitive neuroectodermal tumour primarily occur in nonhead and neck sites, with only 2-10% developing in th e head and neck {49). The tumours are slightly more common in males {49,921}, and occur predominantly (but not exclusively) in children and young adults {921,1017,1036,1331,2601,

Clinical features Symptoms include pain, mass lesion, and nasal obstruction, which often develop rapidly (within months) (261 7). Macroscopy Sinonasal tract tumours may appear polypoid or multilobular, greyish-white, and glistening, with associated haemorrhage; ulceration is often present. Histopathology The tumour is markedly cellular with diffuse (sheet-like) or lobular growth; the appearance may occasionally be trabecular or cord-like. The tumour is composed of uniform small cells with round to oval nuclei, fine-appearing (powdery) nuclear chromatin , a distinct nuclear membrane, inconspicuous to small nucleoli, sean\ pale to vacuolated (clear) cytoplasm, and indistinct cell borders. Mitotic activity is

variable, with 5-10 mitoses per 10 highpower f ields. Prominent intratumoural thin-walled vessels are present, which may be compressed and obscured by the cellular proliferation . A minimal stromal componen! is present, which may include thin fibrous strands separating tumour lobules. Pseudorosettes (Homer Wright rosettes) are present in most cases; less often, true neural rosettes (Flexner-Wintersteiner rosettes) may be identifi ed . Histological variants include atypical or large-cell, clear-cell, haemangioendothelioma-like, adamantinomalike, spindled , and sclerosing forms (197, 743}. lntracytoplasmic material that gives a diastase-sensitive positi ve reaction with periodic acid-Schiff (PAS) is present. Neoplastic cells strongly and diffusely express membranous C099 in nearly ali cases. Nuclear FLl1 is seen in a large percentage of cases; those with EWSR1FL/1 fusion show strong nuclear reactions with the C-terminus of FL/1 (1506,2411, 2544). Vimentin is positive. Cytokeratins show stro ng, focal to diffuse staining with a dot-like pattern in as many as one third of cases, and in particular in adamantinoma-like tumours {197,894,921 }. There is reactivity for at least one neural marker (e.g. neuron-specific enolase, S100 protein, synaptophysin, c hromogranin, NFP, or GFAP). KIT (CD 11 7) expression is

A.. ....t::~ :Mlllla:-.J.:aá:'l.i¡:. • - ~ ,. ... •• ....,,-.;~ • '.!:l. . . . ._.;..:...; ~ .lii--J.::!ll~-Eo,,;,;~olCL-:=...,.,;¡¡=1-Fig. 1.56 Sinonasal Ewing sarcoma / primitive neuroectodermal tumour. A Hypercellular neoplasm with diffuse growth composed of uniform small cells with round to oval nuclei, fine-appearing nuclear chromatin, and pale to vacuolated cytoplasm. B Neoplastic cells show diffuse and strong membranous CD99 staining in nearly all cases; CD99 is sensitive bul not specific for the diagnosis of Ewing sarcoma I primitive neuroectodermal tumour.

56


0/fsctory neuroblastoma Bell D. Franchi A. Gillison M. Thompson L.D.R. Wenig B.M.

Definition Olfactory neuroblastoma (ONB) is a malignan! neuroectodermal neoplasm with neuroblastic differentiation, most often localized in the superior nasal cavity. Fig. 1.57 Ewing sarcoma/ primitive neuroectodermal tumour. On EWSR1 dual-colour break-apart FISH, Ewing sarcoma cells that have the chromosomal rearrangement show a red signa! distanced from a green signa!, indicating a translocation involving one EWSR1 allele, whereas the second allele is intact, as shown by red and green signals that overlap.

present in approximately 25% of cases (743). Rarely, desmin staining is present, but myogenic and haematolym phoid markers are typical ly absent.

Genetic profile There is consisten! rec iproca! translocation between chromosome 11 and chromosome 22 (present in 90- 95% of cases). The most common translocation involves the EWSR1 gene (on chromosome 22) and the FL/1 gene (on chromosome 11), resulting in an EWSR1-FLl1 fusion transcript. C/C-DUX4 fusion, a result of a t(4;19) or t(10;19) translocation, may be identified in EWSR1 fusion- negative cases (1101}. CIC-DUX4 fusion-positive tumours occur mainly in young adult men, most frequently in the soft tissues of extremities. They show a higher degree of heterogeneity in nuclear morphology and have vari able CD99 expression (membranous, not diffuse) than do EWSR1 fusion-positive cases, raising the possibility that CIC-DUX4 fusion tumour may be outside the scope of Ewing sarcoma (2246).

Genetic susceptibility Heritable retinoblastoma may predispose patients to Ewing sarcoma and perhaps to a subset of poorly differentiated neuroectodermal tumours in the sinonasal region that may be re lated to olfactory neuroblastoma (1236).

Prognosis and predictive factors The 5-year survival rate for sinonasal Ewing sarcoma/ primitive neuroectodermal tumour is 50-75%, reflecting a better overall prognosis at this site compared with cases at other siles (49,921}. The 5-year survival rate for patients with advanced disease is < 25% (2617}. Local recurrence and distan! metastases may occur within 2 years, even in patients with localized disease. When metastases occur, the most common sites include the lungs and bone; lymph nade metastasis is less common, occurring in approximately 20% of cases. Prognosis has been found to be linked to tumour stage as determinea by the lntergroup Rhabdomyosarcoma Study Group (IRSG) staging system (126}. tumour size (with size > 8 cm associated with adverse behaviour) (127,2601}, TP53 alteration (which appears to define a cli nical subset with a markedly poorer outcome) {1592}, the presence of the type 1 EWSR1 -FLl1 fusion transcript (thought to suggest a better prognosis !han other fusion transcripts) (542}, and poor histological or radiological response at the site of primary tumour and incomplete radiological remission of lung metastases alter primary chemotherapy (associated with adverse behaviour) (31,49,127}. There is an increased incidence of radiation-induced sarcomas later in life among surviving patients (1838} .

ICD-0 code

9522/3

Synonyms Aesthesioneuroblastoma; aesthesioneurocytoma; aesthesioneuroepithelioma; olfactory placode tumour

Epidemiology ONB has an estimated annual incidence of 4 cases per 10 million population, and accounts for approximately 3% of all sinonasal tumours (273). Patients range in age from 2 to 90 years. Althoug h a bimodal age distribution was initially reported, recen! data support an even distri bution across ali ages, with a peak in the fifth and sixth decades of life (273 , 1130,1903}. Males are affected slightly more often than females (male-to-female ratio: 1.2:1 ). There is no reported ethnic or fami lia! predilection.

Localization The anatomical distribution of ONB is confined to the cribriform p late, the superior turbinate (nasal concha), and the superior half of the nasal septum. The vomeronasal organ (also called Jacobson's organ), sphenopalatine ganglion, olfactory placode, and the term inal nerve (also called the ganglion of Loci) are included in the areas of proposed origin. Ectopic tumours within the paranasal sinuses (other than the ethmoid sinuses) are vanishingly rare (except in recurrent cases), and the diagnosis of ONB with no invo lvement of the cribriform p late is a diagnosis of exclusion (1619,2383}.


57

Fig. 1.58 Olfactory neuroblastoma. lmaging studies show a dumbbell-shaped tumour.

Fig. 1.59 Olfactory neuroblastoma. The gross appearance is that of a polypoid reddish-grey mass, with hypervascular cut surface.

Clinical features Clinically, ONBs often have a subtle presentation mimicking that of benign inflammatory/infectious diseases, and delay in diagnosis is frequent. Nasal obstruction and epistaxis are typical early manifestations; headaches, pain, excessive lacrimation, rhinorrhoea, and visual disturbances are uncommon. Anosm ia occurs in < 5% of patients. Paraneoplastic syndromes (i.e. ectopic adrenocorticotropic hormone syndrome or syndrome of inappropriate antidiuretic hormone secretion) are detected in about 2% of patients (789}. Physical examination and flexible fi bre-optic endoscopic evaluation, complemented with CT and MRI, are useful in the diagnostic work-up. The classic imaging findings include a dumbbell-shaped mass extending across the cribriform plate, with the waist at the cribritorm plate. MRI better delineates sinonasal and intraorbital or intracerebral extension . ONB is T1-hypointense and T2-isointense or T2-hyperintense to grey matter, with avid homogeneous enhancement with contrast. Bone erosion is better demonstrated by CT, with careful evaluation for erosion of the lamina papyracea, cribritorm plate, and fovea ethmoidalis. Peripheral tumour cysts and 58

speckled calcifications are characteristic of ONB. Severa! staging systems have been proposed, with no single system universally accepted. The first staging system proposed, and the one most commonly applied, is that of Kadish (1162), which stages local disease only; it distinguishes tumours that involve the nasal cavity only (Kadish stage A), from those that extend into the paranasal sinuses (Kadish stage B), and those that extend beyond the paranasal sinuses (Kadish stage C) {11 62}. Morita (1650} modified the Kadish system by adding a stage D, defined by the presence of metastases (either regional nodal disease or distan! metastasis). The TNM staging system for paranasal sinus tumours can potentially be applied (626}; however, the Kadish system and Morita modification are more applicable, due to the biologically unique behaviour of ONB compared with other sinonasal tumours.

Macroscopy The tumours are usua\ly unilateral, polypoid, glistening, soft, reddish-grey masses with an intact mucosa; the cut surface appears greyish-tan to pinkish-red and hypervascularized. The tumours range from < 1 cm in size to large masses involving the nasal cavity and intracrar1ial region. They frequently expand into the adjacent paranasal sinuses, orbit, and cranial vault (2383).

Cytology Aspirates of metastatic lesions show cytological fi ndings most similar to those seen in low-grade neuroendocrine carcinoma aspirates, with nests of somewhat monomorphic, fragile epithelioid cells with delicate chromatin and cytoplasm. Aspirates of high-grade tumours may show features similar to !hose seen

Tumours of t11e nasal cavity, paranasal sinuses and skull base

Table 1.02 Olfactory neuroblastoma staging systems proposed by Kadish and Merita; reprinted from Ow TJ et al. {1789)

Kadish stage A

Tumour confined to the nasal cavity

B

Tumour involvement of the nasal cavity and paranasal sinuses

e

Tumour extends beyond the nasal cavity and paranasal sinuses

Morlta modiflcatlon A

Tumour confined to the nasal cavity

B

Tumour involvement of the nasal cavity and paranasal sinuses

e

Tumour extends beyond the nasal cavity and paranasal sinuses

D

Presence of metastases (regional or distan!)

in small cell neuroendocrine carcinoma aspira tes.

Histopathology Low-grade ONBs form submucosal, sharply demarcated nests, lobules, or sheets ot cells, often separated by richly vascular or hyalinized fi brous stroma. Pseudorosettes (Homer Wright rosettes), with neoplastic cells palisading or cuffed around the central delicate fibri llar neural matrix, may be seen. The cells are often uniform, with sparse cytoplasm and round or ovoid nuclei with punctate salt-and-pepper chromatin and nucleoli that are either small or absent. ONB is characterized by fibrillary cytoplasm and interdigitating neuronal processes (neuropil), created by a syncytium ot cells. Higher-grade tumours show tumour necrosis, pleomorphism, increased mitoses, decreased to absent neuropil, and a less overt lobular growth pattern. The cells can be arranged in gland-like rings or ti ght annular formations with a true lumen (Flexner-Wintersteiner rosettes).

Table 1.03 Olfactory neuroblastoma staging systems. Key features and criteria for Hyams grades 1-IV and corresponding hístopathological H&E slides Hyams grade

Key feature/crlterlon 11

111

IV

Lobular

Variable

Variable

Present

Prominent

Marked

Moderate

Prominent

Marked

Architecture

Lobular

Mitotic activity

Absent

Nuclear polymorphism

Absent

Prominent

Present

Minimal

Absent

Rosettes

Homer Wright rosettes

Homer Wright reselles

Flexner-Wintersteiner rosettes

Flexner-Wintersteiner rosettes

Necrosis

Absent

Absent

+/- present

Common

- - --

- - - - t - - - - ------+-- -- - - - - --t-______ _._____

Fibrillary matrix

- - - - -- - 1 - -- - - - - - -- + - - - - - - - - - - - 1 - -- - - -- - -- -1- -- - - - - - ----j

H&E

Rosettes alone are not diagnostic of ONB, although the Homer Wright rosettes are nearly pathognomonic in the nasal cavity when containing true neuropil. Perivascular pseudorosettes (like those seen in ependymomas) are non-specific. The mitotic rate is variable, but is usually low, especially in lower-grade tumours. Calcifications (concretion-like or psammomatous) may be seen, less frequently as the grade increases. Melanin pigment, ganglion cells, rhabdomyoblasts, divergen! differentiation as islands of true epithelium (squamous pearls or gland formation), and clear-cell change may occasionally be encountered in ONB [149,694,1457,1632}. The most widely used gradi ng system for ONB was developed by Hyams et al. {950). This system divides the spectrum of ONB maturation into tour grades, ranging from most differentiated (grade 1) to least differentiated (grade IV), on the basis of tumour architecture, mitotic activity, nuclear pleomorphism, fibrillary matrix and rosettes, necrosis, gland proliferation, and calcifications. This grading scheme has been independently validated in relation to prognosis {802,1203, 2036, 2336}. The typical immunohistochemical profile includes diffuse staining for neuronspecific enolase [2424}, synaptophysin, chromogranin A, CD56 (NCAM) and

beta-tubulin, as well as variable S100 protein reactivity, which is typically in a sustentacular cell pattern highlighting only cells at the periphery of the nests, often limited in higher-grade tumours. Sustentacular cells may also be positive for GFAP. Calretinin staining (nuclear and cytoplasmic) has been reported in ONB {2635) but can also be seen in other sinonasal tumours. As many as one third of ONBs may also stain focally far cytokeratin (CAM5.2, CK18) {1014,1619). Negative markers include C045RB, CD99, p63, and FLl 1. Proliferation marker studies reveal a variable Ki: 67 proliferation index (2- 50%) {1619,2383}, and BCL2 expression increases with tumour grade. Rare desmin or myogenin reactivity is seen in ONB with rhabdomyoblastic differentiation (203).

Genetic protile ONB demonstrates numerous chromosomal aberrations, deletions, and gains, but with no consistent pattern {221,907, 1015,1983}. In one study, a specific deletion on chromosome 11 and gain on chromosome 1p were associated with metastasis anda worse prognosis {221 }. Gains have been shown to be more freq uent than losses, and high-stage ONBs show more alterations than low-stage_tumours. Gains in 20q and 13q may be importan! in the progression of this neoplasm;

these regions may harbour genes with functional relevance in ONB. The detection of PTCH1, GL/1, and GL/2 in 70%, 70%, and 65% , res pectively, of human ONB specimens suggests that the SHH signalling pathway may be involved in the pathogenesis of this neoplasm {1534}. The OMP and RICBB genes have been found to be expressed in ONBs {875}.

Prognosis and predictive factors In addition to staging, histological grade is usefu l in prognostication and management of ONB {174,1203,1519,2468}. Highgrade tumours tend to have a poorer outcome {174,616,1130,1 519}. A single institutional retrospective review found that high tumour grade was significantly associated with poor outcome, but advanced stage was not {174). Metastatic ONB is associated with significantly worse overall survival, and high-grade ONB with significantly worse disease-free survival. High Hyams grade (111/IV) is associated with more aggressive locoregional disease {1519} and is a predictor of worse disease-free survival (174). lt is yet to be determined whether histopathological grading alone is a sufficient stratification tool and an independent predictor of overall survival {616,802,1203,2036, 2336,2468).


59

Mucosa/ melanoma Williams M.O. Speight P. Wenig B.M.

Definition Mucosal melanoma is a malignant neoplasm arising from melanocytes in the mucosa.

ICD-0 code

8720/3

'>

Fig. 1.61 Sinonasal mucosa! melanoma. T2-weighted axial MRI of sinonasal mucosa! melanoma of the nasal septum (arrow).

pigmented (black) and friable to tan or grey and firm.

Epidemiology

Localization

Sinonasal mucosal melanomas constitute 1% of all melanomas and about 4% of ali sinonasal tumours (796,1645). There is a wide patient age range, with an incidence peak in the seventh decade of lite (2395). There is no sex predilection (2395}.

Sinonasal mucosa! melanomas most frequently arise in the nasal cavity or septum, and rarely in the nasopharynx or maxillary sinuses (1645,2395).

Etiology Mucosal melanomas are biologically distinct from cutaneous melanomas. Etiological factors, including melanocytosis, remain speculative.

Fig. 1.62 Sinonasal mucosa! melanoma. A polypoid slightly pigmentad mass distends the submucosa.

Clinical features Patients may present with non-specific symptoms of epistaxis or sinonasal congestion.

Cytology Asp irates of metastatic lesions show the diversity of featu res discussed within the histopathology section below, similar to the features seen in aspirates of metastatic dermal melanoma. The diagnosis must be considered within the differential for any aspirate showing a malignancy that is not obviously epithelial.

Macroscopy Sinonasal mucosal melanomas are often polypoid, and range from deeply

.

Histopathology Solid sheets or nests of epithelioid cel ls

:J. ''

.

Fig. 1.63 Sinonasal mucosa! melanoma. The histological features vary from (A) clear, non-pigmented, slightly spindled cells to (B) pigmented epithelioid cells with prominent nucleoli. The histological spectrum of melanoma includes (C) spindled, fasciculated growth pattern and (D) rhabdoid proliferation.

60


with variable N:C ratios infiltrate the submucosa. Surface ulceration is often present, but with intact surface epithelium , pagetoid and/or surface spread may be present. Variable cellular morphology is present from case to case and within individual cases, ranging from epithelioid/undifferentiated cells to spindled, plasmacytoid, and rhabdoid cells, with or without prominent nucleoli. In neoplasms with a prominent spindlecell componen!, fascicu lar to storiform growth can be seen. Mitoses are readily identified and atypical forms are often present. Discohesion leads to cuffing of endothelial cells (resulting in a pseudopapillary or peritheliomatous pattern). As many as 50% of lesions are amelanotic, resulting in a broader differential diagnosis at this site, including small blue cell tumours (olfactory neuroblastoma and rhabdomyosarcoma), high-grade carcinomas (sinonasal undifferentiated carcinoma, poorly differentiated squamous

cell carcinoma, NUT carcinoma, and SMARCB1 -deficient carcinoma), neuroendocrine carcinomas, diffuse large 8-cell lymphoma, and Ewing sarcoma/ primitive neuroectodermal tumour. lmmunohistochemical evaluation is necessary, particularly in amelanotic tumours. S100 protein and melanocytic markers (HMB45, tyrosinase, melan-A, MITF, and S0X10) show variable sensitivity depending on morphological type. S100 protein highlights > 95% of epithelioid/undifferentiated melanomas, versus 85% of spindled mucosal melanomas (1917,2395). Similar variability has been noted far melanocytic markers, which highlight 75- 80% of melanomas with epithelioid morphology versus 65-70% of spindle cell melanomas (2395). Genetic profile The molecular profile is distinct from those of cutaneous and uveal melanomas, with higher rates of K/Tmutations, followed by

Table 1.04 Molecular alterations in melanomas vary by site of origin

Frequency by site of orlgln Molecular alteration

Mucosa! {2708}

Cutaneous {1}

Ocular (uveal) {2467}

<6%

50%

0%

15-20%

30%

<5%

25% (10-37%)

6- 8%

< 1%

Unknown

3%

50% (metastases) 50%

BRAF mutationsª NRAS K/Tmutationl amplificationb BAP1 mutation GNAQ

0%

2%

GNA11

Rare

4%

NRAS mutations and rare BRAF mutations (Table 1.04) (1,2467,2708}. Genetic susceptibility Sinonasal mucosal melanomas have a possible association with melanocytosis, which is strongly associated with uveal melanomas. Prognosis and predictive factors Distinguishing mucosa! from cutaneous origin and excluding metastasis to the sinonasal region are importan! for staging and prognosis. The seventh edition of the American Joint Committee on Cancer (AJCC) cancer staging manual added head and neck mucosa! melanoma stag ing: ali tumours are T3- 4, associated with poor overall survival (< 30%) at 5 years {1 17,530,1495}. Metastatic disease (stage IV) and advanced patient age are the most importan! prognostic factors. K/T-mutant tumours have shown response to KIT inhibitor therapy; however, the response is not durable (1009,2439}. Future therapeutic development requires trials specifically evaluating mucosa! melanomas; findings in cutaneous melanomas may not be applicable, due to the different genetic profile {1354). Cutaneous melanoma prognostic factors (e.g. Clark level of invasion and Breslow tumour thickness) do not apply.

36°/.o Monosomy of chromosome

Treatment and clinical trials are on-golng for: ªBRAF inhibitors (cutaneous) and blmatinib (mucosa!; most patients develop resistance). lmmunotherapy trials are also underway; evaluation in all subsites will be critica! for determining efficacy.

Neuroectodermal/melanocytic tumours

61

CHAPTER 2 Tumours of the nasopharynx

Nasopharyngeal carcinoma Nasopharyngeal papillary adenocarcinoma Salivary gland tumours Benign and borderline lesions Soft tissue tumours Haematolymphoid turnours Notochordal tumours

WHO classification of tumours of the nasopharynx Carcinomas Nasopharyngeal carcinoma Non-keratinizing squamous cell carcinoma Keratinizing squamous cell carcinoma Basaloid squamous cell carcinoma Nasopharyngeal papillary adenocarcinoma Salivary gland tumours Adenoid cystic carcinoma Salivary gland anlage tumour Benign and borderline lesions Hairy polyp Ectopic pituitary adenoma Craniopharyngioma

8072/3 8071/3 8083/3 8260/3 8200/3

Soft tissue tumours Nasopharyngeal angiofibroma

9160/0

Haematolymphoid tumours Diffuse large B-cell lymphoma Extraosseous plasmacytoma Extramedullary myeloid sarcoma

9680/3 9734/3 9930/3

Notochordal tumours Chordoma

9370/3

The morphology codes are from the lnternational Classification of Diseases for Oncology (ICD-0) 1776A}. Behaviour is coded /0 for benign tumours: /1 for unspecified, borderline, or uncertain behaviour; /2 far carcinoma in situ and grade 111 intraepithelial neoplasia; and /3 for malignant tumours. The classification is modilied from the previous WHO classification, taking into account changes in our understanding of these lesions.

8272/0 9350/1

TNM classification of carcinomas of the nasopharynx TNM classification•,b

M - Distant metastasis

T - Primary tumour

MO M1

TX TO Tis T1 T2 T3 T4

Primary tumour cannot be assessed No evidence of primary tumour Carcinoma in situ Tumour confined to nasopharynx, or extends to oropharynx and/or nasal cavity Tumour with parapharyngeal extension (which denotes posterolateral infiltration of tumour) Tumour invades bony structures of skull base and/or paranasal sinuses Tumour with intracranial extension and/or involvement of cranial nerves, infratemporal fossa, hypopharynx, orbit, or masticator space

N - Regional lymph nodes (i.e. the cervical nodes) NX NO N1

N2 N3 N3a N3b

Regional lymph nades cannot be assessed No regional lymph nade metastasis Unilateral metastasis in cervical lymph node(s), and/ or unilateral or bilateral metastasis in retropharyngeal lymph nades, s: 6 cm in greatest dimension, above the supraclavicular fossa Bilateral metastasis in cervical lymph node(s), s: 6 cm in greatest dimension, above the supraclavicular fossa Metastasis in cervical lymph node(s), > 6 cm and/or in the supraclavicular fossa > 6 cm in greatest dimension In the supraclavicular fossaº

Stage grouping Stage O Stage 1 Stage 11 Stage 111 Stage IVA Stage IVB Stage IVC

Tis T1 T1 12 T1-2 T3 T4 AnyT AnyT

NO NO N1 N0-1 N2 N0-2 N0-2 N3 Any N

MD MD MO MD MO MO MO MO M1

'Adapted from Edge et al. {625A} - used with permission of the American Joint Committee on Cancer (AJCC), Chicago, lllinois; the original and prima ry source for this information is the AJCC Cancer Staging Manual, Seventh Edition {2010) published by Springer Science+Business Media - and Sobin et al. {2228A). "A help desk for specific questions about TNM classification is available at http://www.uicc.org/resources/tnm/helpdesk. ºThe supraclavicular fossa is !he triangular region defined by three points: (1) !he superior margin of the sternal end of the clavicle, (2) the superior mar gin of the lateral end of the clavicle, and (3) !he point where the neck meets the shoulder; this includes caudal portions of levels IV and V.

Note: Midline nades are considered ipsilateral nades.

64

No distan! metastasis Distan! metastasis

WHO and TNM classification of tumours of the nasopharynx

lntroduction

Chan J.K.C. Slootweg P.J.

A broad range of neoplasms can arise in tl1e nasopharynx, from epithelial to mesenchymal, lymphoid, and neuroectodermal. The most common is nasopharyngeal carcinoma, which shows remarkable geographical differences in incidence. In this chapter, only the more

common tumour types and site-specific tumour types are described in detail. Other tumour types that can occur in the nasopharynx are covered in other chap ters, including Chapter 1 (Tumours of the nasal cavity, paranasal sinuses and sku/1 base, p. 11 ), Chapter 3 (Tumours

Nasopharyngeal carcinoma

Definition Nasopharyngeal carcinoma (NPC) is a carcinoma arising in the nasopharyngeal mucosa that shows light microscopic or ultrastructural evidence of squamous d ifferentiation . The term encompasses nonkeratinizing, keratinizing, and basalo id squamous cell carcinoma.

ICD-0 codes Non-keratinizing squamous cell carcinoma Keratinizing squamous cell carcinoma Basaloid squamous cell carcinoma

8072/3 8071/3 8083/3

Synonyms Lymphoepithelial carcinoma; undifferentiated carcinoma with lymphoid stro ma; squamous cell carcinoma (WHO grade 1); non-keratinizing carcinoma (WHO grade 2); undifferentiated carcinoma (WHO grade 3)

including the lnuit, Northern Africans, and Chinese from south-eastern Asia. Sorne of the highest incidences of NPC have been observed in Hong Kong SAR, China, with 2012 age-standardized incidences of 12.5 cases and 4.1 cases per 100 000 males and females, respective ly {363}. The annual incidence of NPC in southern China is 15-50 cases per 100 000 population {1004}. The rates in menare commonly double or trip le those in women. NPC affects predominantly adults, but rare cases are seen in the paediatric population . In high-ri sk populations, NPC incidence rises alter the age of 30 years, peaks at 40- 60 years, and then declines {1822} In Chinese who migrate to North America, the incidence of NPC declines, but remains significantly higher than in th e general North American population {296}. The age-standardized incidences of NPC have decreased over the past decades, particularly among Ch inese in Hong Kong SAR {826,2693).

Epidemiology NPC is an uncommon tumour among Caucasians, with an age-adjusted annual incidence of less than 1 case per 100 000 population. The annual incidence in North America is 0.3-0.7 cases per 100 000 population {1 124). NPC is common among sorne ethnic groups,

Etiology Causative carcinogens have not yet been definitively identified , but tobacco smoking and alcohol consumption are likely contributing factors for keratinizing NPC (K-NPC); and a high consumption of salted and fermented foods with

of the hypopharynx, /arynx, trachea and parapharyngea/ space, p. 77), Chapter 4 (Tumours of the oral cavity and mobile tangue, p. 105), and Chapter 5 (Tumours of the oropharynx, p. 133).

Pete rsson B.F. Bel! D. EI-Mofty S.K. Gillison M.

Lewis J .S. Nadal A. Nicolai P. Wenig B.M.

Table 2.01 Structures involved by local infiltration of nasopharyngeal carcinoma; MRI data of 308 patients , Pamela Youde Nethersole Eastern Hospital, Hong Kong. Structures involved

Frequency

Adjacent soft tissues Nasal cavity

87%

Oropharyngeal wall, soft palate

21 %

Parapharyngeal space, carotid space

68%

Pterygoid muscle (medial, lateral)

48%

Prevertebral muscle

19%

Bony erosion / paranasal sinus Nasal septum Pterygoid plate(s), pterygomaxillary fissure, pterygopalatine fossa

3% 27%

Maxillary antrum

4%

Ethmoid sinus

6%

Sphenoid sinus; sphenoid bone; foramina lacerum, ovale, and rotundum

38%

Clivus

41%

Petrous bone, petro-occipital fissure

19%

Jugular foramen, hypoglossal canal

4%

Pituitary fossa/gland

3%

Extensive/intracraniat extension Cavernous sinus

16%

Cerebrum, meninges, cisterns

4%

lnfratemporal fossa

9%

Orbit, orbital fissure(s)

4%

Hypopharynx

2%


65

generally absent in K-NPC, especially in non-endemic regions (1542,1731). EBV infection is necessary but not sufficient for tumorigenesis. Oncogenic (h igh-risk) HPV types may play a role in a subset of NPCs, especially in non-endemic regions. Like in the oropharynx, HPV-related NPCs most frequently show non-keratinizing histology {2000,2273).

Localization The pharyngeal recess (fossa of Rosenmüller) is the most common site of origin {1010,1011). The next most common site is the superior posterior wall of the nasopharynx.

Clinical features

1984

l9S6

l98S

1990

1992

199~

1996

199S

2000

Year Fig. 2.01 Age-standardized incidence rates (per 100 000 population} of malignan! neoplasm of nasopharynx by sex in Hong Kong SAR, China, 1983-2000; compiled based on the World Standard Population specified by Ahmad 08 et al. {29). Note: Data from 1996 onwards are based on population estimates using the resident population approach rather than the extended de facto approach. The Hong Kong Population Census conducted in June to August 2011 provides a benchmark for revising population figures compiled since the 2006 Hong Kong Population By-census. Classification of diseases and causes of death is based on the lnternational Statistical Classification of Diseases and Related Health Problems, 10th Revision (ICD-1O) from 2001 onwards; figures from 2001 onwards may not be comparable with figures for previous years, which were compilad based on ICD-9. Reprinted from Hong Kong Cancer Registry {363).

Table 2.02 Common presenting symptoms and signs of nasopharyngeal carcinoma; data from 722 consecutiva patients treated at Pamela Youde Nethersole Eastern Hospital, Hong Kong SAR, China, in 1994-2001. Presenting features

Frequency

Symptoms Neck mass

42%

Nasal (postnasal drip, discharge, bleeding, obstruction)

46%

Aura! (tinnitus, discharge, earache, deafness)

42%

Headache

16%

Double vision, squint, blindness

6%

Facial numbness

5%

Speech/swallowing problem

2%

Weight loss

4%

Physical signs Enlarged neck node(s}

72%

Bilateral neck nades

35%

Neck nodes extending to supraclavicular fossa

12%

Cranial nerve palsy

10%

Deafness

3%

Dermatomyositis

1%

66

Tumours of the nasopharynx

high nitrosamine content has been implicated in non-keratinizing NPC (NKNPC) in populations where that histological subtype is endemic. NK-NPC has a multifactorial etiology, including genetic susceptibility, EBV infection, and possibly consumption of salted fish {96,97, 1003, 1005,1740,2693,2694,2695,2696). Salted fish contains volatile carcinogenic nitrosamines or their precursors, as well as EBV-activating substances [1045, 1046,2144,2734}. The importance of exposure in early life is indicated by studies showing that low-risk ethnic groups born in high-risk areas have higher risk of NPC {1120,1121). In low-incidence regions like northern China, the consumption of salted fish still carries an adjusted relative risk as high as 5.6 {295}. Other envi ronmental factors, such as occupational exposure to wood dust, formaldehyde, heat, smoke, dust, and chemica[ fumes have also been proposed as possible contributing or causative factors {98, 1740,2693). Most studies show that NK-NPC has a strong association with EBV, especially in endemic reg ions; conversely, EBV is

Most patients present with locoregionally advanced disease, commonly with cervical lymph node metastases (1040,2508) The presenting symptoms are related to the presence of a mass in the nasopharynx (e.g. epistaxis, obstruction, and blood-stained postnasal drip), Eustachian tube dysfunction (e.g. hearing impairment, tinnitus, and serous otitis media), skull base involvement with impairment of the fifth and sixth cranial nerves (e.g. headache, diplopía, facial pain, numbness, and paraesthesia), and painless neck mass dueto lymph node metastasis (1358). Distant metastasis at presentation has been reported in approximately 5% of patients {2368}, and 10% of patients with NPC are asymptomatic . In endemic areas, 12% of patients with dermatomyositis

Fig. 2.02 MRI of nasopharyngeal carcinoma (NPC}. A 40-year-old woman presented wilh a 2-month history of tinnitus, followed by neck masses, nasal symptoms, headache, and diplopia. Physical examination revealed left sixth nerve palsy and bilateral upper-middle cervical lymph nades. Endoscopy revealed tumour in the nasopharynx extending to the posterior nasal cavity. Biopsy confirmad undifferentiated carcinoma. MRI showed NPC with extensiva local infiltration of adjacent soft tissues, erosion of skull base/ paranasal sinuses, and intracranial extension, together with bilateral retropharyngeal and cervical nodes.

have NPC as an underlying malignancy [1848). whereas only 1% of patients with NPC have dermatomyositis (2367). Tumour spread NPC is notorious for its highly malignan! behaviour, with extensive locoregional infiltration and early lymphatic spread, erosion of skull base and paranasal sinuses, intracranial spread, infiltration of cranial nerves, and extension to adjacent structures (e.g. infratemporal fossa, orbit, and hypopharynx). Given the rich lymphatic plexus in the nasopharynx, lymphatic spread occurs early in the course of disease. In cases staged by imaging, about 20% of patients have no enlarged nodes, and about half have retropharyngeal node involvement {21 40}. The jugulodigastric node is the most commonly pal pable node at presentation, and involvement of the posterior cervica l chain is more frequent than with other head and neck cancers. The most common sites of distan! metastasis (in descending arder of frequency) are bone, lung, liver, and distan! nades {2369).

TNMstaging The main differences between the sixth and seventh editions of the AJCC cancer staging manual are that (1) tumours classified in the sixth edition as T2a (i.e. tumour extending to oropharynx and/or nasal cavity without parapharyngeal extension) are classified in the seventh edition as T1 and (2) retropharyngeal lymph node(s). regardless of unilateral or bilateral location, are conside red N1 in the seventh edition. Serology EBV serology is positive in most patients with NK-NPC (917). lgA antibody against EBV viral capsid antigen and lgG/ lgA against EBV early antigens are the most extensively used diagnostic tools, with detection rates of 69-93% {383,525). Another approach is to test for elevated levels of circulating EBV DNA or RNA, using techniques for detecting the BamHI-W region of the EBV genome, EBV-encoded small RNAs (EBERs), or EBNA1 in the plasma or serum, with reported sensitivity in NPC as high as 96% {382,1433,1463,2 168).

Macroscopy The tumour can present as a smooth bulge in the mucosa, a discrete raised nodule with or without surface ulceration, or a frankly infiltrative fungating mass. In sorne cases, there is no grossly visible lesion (1468}.

Cytology Aspirates of metastatic K-NPCs and NKNPCs show findings similar to those at other sites. Aspirates often show a background of lymphocytes and plasma cells, with irregu lar clusters of large cells with overlapping vesicular nuclei and large nucleoli (384,1265). The cytoplasm of these cells is often frag ile and barely visib le. There are commonly many naked nuclei (1636} The diagnosis can be read ily confirmed by immunostaining for cytokeratin and in situ hybridization for EBER.

Histopathology Non-keratinizing squamous ce// carcinoma NK-NPC exhibits a variety of architectural patterns, frequently mixed within the


67

same tumour mass, ranging from solid sheets to irregular islands, trabeculae, and discohesive sheets of malignant cells intimately intermi ngled with variable numbers of lymphocytes and plasma cells. The undifferentiated subtype, which is more common, is characterized by large tumour cells with a syncytial appearance, round to oval vesicular nuclei, and large central nucleoli. The nuclei can be chromatin-rich rather than vesicular and the neoplastic cells generally have scant amphophilic or eosinophilic cytoplasm. The malignant cells can assume spindle-cell features in fascicular arrangements. The differentiated subtype exhibits cellular stratification and pavementing, o/ten with plexiform growth; occasional keratinized cells may be present. Compared with those in the undifferentiated subtype, the neoplastic cells are often slightly smaller, the N:C ratio is lower, the nuclei are o/ten more chromatin -rich, and the nucleoli are usually less prominent. Focally, intercellular bridges may be present. However, subclassification into undifferentiated and differentiated subtypes has no clinical or prognostic value. The density of lymphocytes and plasma cells within the tumour cell aggregates is 68


highly variable. When abundant, the inflammatory cells break up the tumour into tiny clusters or single cells, making it difficult to recognize the epithelial nature of the neoplasm. Sorne cases may demonstrate abundant eosinophils, neutrophils, or epithelioid granulomas {399,781,1379, 1471). A desmoplastic stromal reaction is uncommon. lsolated or scattered groups of tumour cells may appear shrunken, with smudged nuclei and dense amphophilic or eosinophilic cytoplasm. In as many as 10% of cases, there are interspersed intra- or extracellular small spherical amyloid globules {1919]. Uncommon features include papillary frond formation, clearcell change, accumulation of extracellular

oedema fluid or mucosubstances, and presence of intracytoplasmic mucin in very rare cells {11 09,1302). In cervical lymph node metastases, malignant cells within the lymph nodes may be arranged in various patterns. In particular, neoplastic cells may display Reed- Sternberg cell-like features in a mixed inflammatory background, mimicking Hodgkin lymphoma (329,1384). Epithelioid granulomas (sometimes necrotizing) are present in approximately 20% of cases (1384). A cystic appearance of NK-NPC metastases to lymph nodes may simulate a metastasis from the oropharynx. Keratinizing squamous ce// carcinoma K-NPCs are a group of invasive carcinomas showing obvious squamous differentiation at the light microscopic leve!, in the form of intercellular bridges and/or various degrees of keratinization, accompanied by a desmoplastic stroma, akin to that seen in squamous cell carcinoma at other head and neck sites. K-NPC can arise de novo or (more rarely) secondary to radiotherapy {398). Basaloid squamous ce// carcinoma This tumour is morph0logically identical to analogous tumours more commonlY

occurring in other head and neck sites, and has infrequently been reported to occur as a p ri mary tumour of the nasopharynx (132,133,1672,1839,2528}. EBV may be positive, especially in high-incidence ethnic groups (1672,2528}.

(1056). Genomic sequencing reveals a distinctive mutational signature, with nine significantly mutated genes (1431}. The significance of these genes in p athogenesis, prognosis, and response to therapy has yet to be determined.

/mmunohistochemistry

NK-N PC is associated with EBV in almost ali cases. The most reliable way to demonstrate EBV is in situ hybridization far EBER {1037,1066,1085,1904,2428}. This test is helpful in the evaluation of cervical lymph nades harbouri ng undifferen tiated ar poorly differentiated squamous cell carcinoma of unknown arigin, with a positive result strongly suggesting the possibility of NPC. lmmunostaining for LMP 1 is not a sensitive ar reliable method far demonstrating lhe presence of EBV {908,1833,1904). PCR far EBV is not rel iable either, because even a few bystander EBV-positive lymphocytes can give rise to a positive result {2428).

Genetic susceptibility The risk of developing NPC is linked to genes coding far certain tissue antigens (i.e. HLA genes). In Chinese populat ions, HLA-A*02 alleles and HLA-8*46 alleles are associated with a high risk of NPC (864,1042). High-resolution genotyping has shown a consisten! association be tween NPC and the HLA-A*0207 allele, which is common in Chinese popu lations {990]. Genetic polymorph isms in genes coding for metabolic enzymes· (CYP2E1 and GSTM1) and DN A repai r enzymes (OGG1 and XRCC1) have also been associated with increased risk of NPC {989, 991). Linkage studies have suggested that susceptibility loci for NPC are present on chromosomes 3, 4, and 14 {700, 2654). Familia! clustering of NPC is well reported (1003,1 133,1157,2609}. The relative risk in fi rst-degree relatives of patients with NPC varíes from 6.3 to 21.3 {397,1362,2692,2722} . There are no clinical characteristics that sep arate sporadic from fami lia! cases.

Genetic profile Deletions on 3p and 9p are early events in NPC (442), and the chromosomal regions that most frequent show gain and loss are on chromosome 12 and 3p. Array comparative genomic hybridization studies have identified frequent copynumber gains of MYCL (1p34.3), TERC (3q26.3), ESR1 (6q25.1), and PIK3CA

Prognosis and predictive factors The most powerful prognostic factor of NPC is stage at presentation. A study using the 2002 TNM staging system found that the 5-year disease-specific survival rate for stage I disease was 98%; for stage IIA- B, 95%; far stage 111, 86% ; and for stage IVA-B, 73%. lncreasing tumour volume is a negative prognostic factor,

NPC stains strongly far p63, pancytokeratin, and high-molecular-weight cytokeratins, with often patchy expression of low-molecular-weight cytokeratins and EMA. CK7 and CK20 are negative (756}.

EBV detection

with an estimated 1% increase in risk of local failure per 1 cm 3 increase in volume (386,2330). Circulating plasma/serum levels of EBV DNA are substantially elevated in patients with active disease (in particular distan! metastasis); drop to very low l itres upan rem ission (374,1462, 1728,2168}; and correlate with advanced stage {1463} and survival {374,1462}. Other unfavourable prognostic factors are fixation of involved neck nades, male sex, patient age > 40 years, cranial nerve palsy, and ear symptoms at presentation (1851,2139,2368). The issue of histopathological type (keratin izing vs non-keratinizing) in relation to prognosis is complex. Compared with NK-NPC, K-NPC shows a greater propensity far locally advanced tumour growth (which occurs in 76% vs 55% of cases, respectively) (1966} and a lower propens ity for lymph nade metastasis (which occurs in 29% vs 70% of cases, respectively) (1715). Sorne studies have suggested that K-NPC is less responsive to radiation therapy and has a worse prognosis than NK-NPC {1023,1715, 1966,2142}, but other studies have not found any differences in biological behaviour (375,737}. The significance of the presence of highrisk HPV is not wel l established. Severa! studies have suggested that HPV-related tumours have a worse prognosis than do EBV-related cases, but perhaps a better outcome than do cases negative far both viruses {592,1435,1460,1561,2000, 2273}. With improved treatment protocols, the development of a second malignan! tumour becomes significan!. Squamous cell carcinoma and various sarcomas Nasopharyngeal carcinoma

69

are most common. The annual incidence of postradiation squamous cell carcinoma has been reported to be 0.55-1 % {1270,2531}; in one study, the mean latency period was 10.5 years (range:

6.4- 15.8 years) {380). Postradiation squamous cell carcinoma may occur at uncommon siles, such as the externa! auditory canal, middle ear, and temporal bone {1430,1461,1752,2364}.

Nasopharyngeal papillary adenocarcinoma Definition

Macroscopy

Nasopharyngeal papillary adenocarcinoma is a low-grade adenocarcinoma with predominately papillary architecture, found in the nasopharynx.

Nasopharyngeal papillary adenocarcinomas are exophytic and appear papillary, polypoid, or nodular. They may be soft or gritty (2590}.

ICD-0 code

8260/3

Synonym Thyroid -like low-grade nasopharyngeal papillary adenocarcinoma

Epidemiology Nasopharyngeal papillary adenocarcinomas account tor < 1% of nasopharyngeal malignancies. They can occur in patients of any age (reported range: 9- 64 years) {1894,2590). No sex predilection has been shown.

Localization Nasopharyngeal papillary adenocarcinomas can involve any part of the nasopharynx {2590).

Clinical features Patients typically present with nasal obstruction (1894,2590}. Subsets of patients present with rhinorrhoea, epistaxis, otitis media, or hearing problems.

70


Many prognostic molecular and immunohistochemical markers have been studied, but only that of plasma/serum levels of EBV DNA {2717} has been incorporated into clinical practice.

Stelow E.B. Bell O. Wenig B.M.

Histopathology Nasopharyngeal papillary adenocarcinomas are composed of complex, arborizing papillae with hyalinized fibrovascular cores and glands {1894,2590] . The lesions are invasive and typically involve the surface epithelium, tocally merging with non-neoplastic epithelium. Papillae are lined by a single layer of cuboidal to co lumnar cells that have a moderate amount of eosinophilic cytoplasm. Similar to those seen in papillary thyroid carcinomas, the nuclei vary trom round to oval and have moderate membrane irregularity with vesicular to clear c hromatin. Psammomatoid calcifications are seen in about one third of cases. Mitotic figu res are uncommon and necrosis is rare. Perineural and angiolymphatic invasion are not seen. The tumours express EMA, CK5/6, and often CK7 {1894,2590}. The subset of cases positive for CK19 and TTF1 {342} has been referred to as thyroid-like

low-grade nasopharyngeal papillary adenocarcinoma, but thyroglobulin is negative. S100 protein expression is seen fo cally in many cases.

Genetic profile BRAF mutations have not been identified (1768,1870).

Prognosis and predictiva factors Most patients with nasopharyngeal papillary adenocarcinoma have been treated with surgery alone, although sorne have also received radiation therapy {1894, 2590}. No patients have developed rec urrences or metastases.

Salivary gland tumours Adenoid cystic carcinoma Stelow E.B. Bell D. Seethala R. Stenman G.

findings 'are similar to those fo r adenoid cystic carcinomas found elsewhere (2391). They are described in detail in the Adenoid cystic carcinoma section in Chapter 7, p. 164. The tumours are mostly submucosal, but sorne may show mucosa! extension.

Definition

Genetic profile

Adenoid cystic carcinoma is a slowgrowing and relentless salivary gland malignancy composed of epithelial and myoepithelial neoplastic cells that form various patterns, including tubular, c ribriform , and solid forms.

The adenoid cystic carcinoma- specific 1(6;9) chromosomal translocation, resulting in a MYB-NF/8 gene fusion, has been detected in tumours at this site (987,1862, 2391).

ICD-0 code

The reported 5-year disease-free and overall survival rates are 30-65% and 5 4-70%, respectively {325,1447).

Prognosis and predictiva factors 8200/3

Epidemiology Approximately 2-8% of adenoid cystic carcinomas involve the nasopharynx (1709,1864). The tumours are the most common salivary gland malignancy affecting the area and account for almos! one quarter of ali adenocarcinomas found at the site {1894). The mean patient age at presentation is 45 years, and men and women are equally affected {1894,2391).

Salivary g/and anlage tumour Chiosea S. Seethala R. Skálová A.

Definition Localization Adenoid cystic carcinoma can involve the nasopharynx either in isolation or through spread from !he sinonasal trae!.

Salivary gland anlage tumour is a midline nasopharyngeal lesion with biphasic epithelial and myoepithelial components (979).

Clinical features

Synonym

Patients most often present with epistaxis, nasal obstruction, and tinnitus {1447). Most patients present with advanced stage disease {325,2391).

Congenital pleomorphic adenoma {554, 937)

Histopathology The histological and immunohistochemical

2406,2516). The affected patients are infants (diagnosed by 3 months of age), and there is a male predilection. A case suspected to have developed in utero has been reported {1945).

Localization Salivary gland anlage tumours occur in the posterior nasal septum or the posterio r nasopharyngeal wall.

Clinical features Patients present with respiratory distress due to nasal airway obstruction {979). Before birth, salivary gland anlage tumour may be associated with polyhydramnios {1945).

Macroscopy The typical appearance is that of a polypoid to peduncu lated smooth tan -brown mass with solid to microcystic cut surtace (979).

Histopathology Salivary gland anlage tumours display a complex polypoid configuration, with a submucosal network of tu bules and ducts with variable keratinization that are continuous with the surface squamous epithelium. The spindle ce ll componen! varíes from hypocell ular to more cellu lar myoepithelial nodules in the centre of the polyp. Cellular atypia and mitoses are absent {979). The epithelial components are positive for cytokeratins and EMA, and the myoepithelial nodules express SMA and cytokeratins .

Epidemiology


Approximately 35 examples of salivary gland anlage tumour have been reported {554,8 16,978,979, 1537,1633, 1945,2282,

No recurrences alter excision have been reported.

Fig. 2.1 O Salivary gland anlage tumour. "stroma".


71

Benign and borderline lesions

Hairypolyp

Ectopic pituitary adenoma

Katabi N. Hunt J.L. Thompson L.D.R. Wenig B.M.

Definition

Definition

Hairy polyp is a benign polypoid lesion with a suspected developmental orígin, composed of ectoderm and mesoderm.

Ectopic pituitary adenoma is a benign anterior pituitary gland neoplasm that does not involve the sella turcica.

Synonyms

ICD-0 code

8272/0

Teratoid polyp; dermoid polyp

Synonyms Epidemiology Haíry polyp occurs primaríly in neonates and older ínfants, and extremely rarely in adults {364,888}. There is a femare predominance, wíth a female-to-male ratio of 6:1 (89,622,1210).

Localization The most common locatíon is the lateral wall of the nasopharynx (accounting for 60% ot cases), but hairy polyp may also occur in the oropharynx, palate, tonsil, tangue, lip, and middle ear (622,1210,1223].

Extrasellar pituitary adenoma; extracranial pituitary adenoma

Epidemiology Pituitary adenomas account for < 3% ot tumours ot the sphenoid sinus or nasopharynx (683,1782,2392} . Palien! age at presentation varíes widely (range: 2-84 years; mean: 54 years). Females are affected slightly more than males, with a female-to-male ratio of 1.3:1 (2392} .

Localization Clinical features The presentatíon includes a pedunculated mass that may be assocíated wíth cough , dyspnoea, vomiting, and difficulty in swallowing . Rarely, it is associated with other congenital malformations, such as cleft palate or Dandy- Walker syndrome {106,2359}.

Ectopic pítuitary adenomas occur most trequently in the sphenoid sinus/bone {301,1459,1959,2392,2417). followed by the nasopharynx, with rare cases reported in the nasal cavity, ethmoid sinus, temporal bone, and nasal bridge (87, 1959).

Clinical features Macroscopy The polyp has a skin-like surface and can be as large as 6 cm in greatest dimension, with an attachment to the lateral wall of the nasopharynx {1623}.

Histopathology The polyp is covered by keratinized squamous epithelium containing pilosebaceous units. The core consists of fibroadipose tissue. Skeletal muscle, carti lage, and bone may be present. Meningothelial remnants have been identified {1770). Hairy polyp is differentiated from teratoma by a lack of endodermal components.

Prognosis and predictive factors Surgical excision is curative {23591. 72


Symptoms include obstruction, sinusitis, rhinorrhoea, discharge, headache, and pain. Visual disturbances and nerve changes are uncommon (2392) . Sorne patients present with endocrinopathic manifestations, such as Cushing syndrome (hypercortisolism), acromegaly, amenorrhoea, or galactorrhoea (468,483,1030,1932,2175). Asymptomatic presentation occurs in about 10% of cases. lmaging studies are required to exclude direct extension from the sella. Bone destruction is often present (873,958,2207,2668).

Macroscopy Macroscopically, ectopic pituitary adenomas are polypoid tumours measuring 0.8-8 cm (mean: 3.4 cm) (1459,21661.

Histopathology Ectopic pituitary adenoma is a submucosal epithe lioid neoplasm with solid, organoid, and trabecular growth patterns. The epithelioid cells have round nuclei, with a dispersed chromatin pattern and granular eosinophilic cytoplasm. Plasmacytoid-appearing cells may be present. Gland-like spaces may be seen, but there is no squamous differentiation. There is mild to moderate nuclear variation (so-called endocrine atypia). Scattered mitotic figures may be present, but not atypical mitoses or necrosis. Caicifications and psammoma-like bodies may be identified [1459,1493,2166). The stroma is usually richly vascularized and often heavíly collagenized. The tumour cel ls express cytokeratins (often in a perinuclear dot-li ke pattern) and neuroendocrine markers (e.g . synaptophysin, CD56, and chromogran in). S100 protein may be positive, but the sustentacular pattern of oltactory neuroblastoma ís absent. Reactivity with two or more pi tuitary hormones is seen in as many as 50% of cases. About one third of ali cases express a single hormone, most commonly prolactin. Approximately 20% of ectopic pituitary adenomas are null cell adenomas - lacking expression of any hormone marker. The diagnosis of null cell adenoma is preferably supported by the demonstration of pituitary transcription factors (e.g. PIT1 , TPIT, SF1, ER-alpha, GATA2, and alpha subunits)

.

Fig. 2.11 Ectopic pituitary adenoma. Strong and diffuse granular cytoplasmic immunoreactivity for prolaclin, one of the peptides mas! commonly identified in ectopic pituitary adenoma.

.,._,,

\

Fig. 2.1 2 Ectopic pituitary adenoma. A Organoid growth pattern with rich vascularity. B Marked sclerosing fibrosis associated with compressed neoplastic cells. e Rosettes and pseudorosettes. D Profound nuclear pleomorphism can frequently be seen in pituitary adenoma; there is a spicule of bone noted, as bone destruction may be seen.

[87,1459). Ectopic pituitary adenoma must be distinguished from other neuroendocrine neoplasms.

Prognosis and predictive factors Surgical resection can be curative, but recurrences are not uncommon.

Localization Craniopharyngioma can occur extrac ranially in the nasopharynx 11622). and exceptionally in the sinonasal tract 11064, 1748,2716).

Craniopharyngioma

Clinical features Nasopharyngeal involvement is associated with headache, impaired vision, and nasal obstruction.

Definition Craniopharyngioma is a benign epithelial tumour thought to derive from the Rathke cleft.

Macroscopy Most craniopharyngiomas have a cystic component containing brown (so called machine-oil) fluid {2697).

ICD-0 code

H istopathology The adamantinomatous type shows cords of basaloid cells with peripheral palisading surrounding loose stellate-

Synonym Pituitary adamantinoma

9350/1

type cells. In addition, so-called wet keratin (composed of eosinophilic keratinized ce lls with ghost nuclei) and associated calcifi cation is present. The papillary type includes sheets of dyscohesive squamous epithelium that form pseudopapillae with anastomosing fibrovascu lar stroma {1 905,2333}.

Genetic profile The adamantinomatous type harbours CTNNB1 (b eta-catenin) mutations and the papillary type harbours BRAFV600E mutations {263,1547). Prognosis and predictive factors Treatment includes surgery with or without radiation 12697}. Craniopharyngioma may be associated with long-term morbidity and recurrence {1948).

Benign and borderline lesions

73

Soft tissue tumours

Prasad M.L. Franchi A. Thompson L.D.R.

Nasopharyngeal angiofibroma Definition Nasopharyngeal angiofibroma is a locally aggressive, variably cellular fibrovascular neoplasm arising in the nasopharynx of young males. 9160/0

ICD-0 code

Synonyms Angiofibroma; juvenile angiofibroma; juvenile nasopharyngeal angiofibroma Epidemiology Nasopharyngeal angiofibroma is rare, constituting < 0.5% of ali head and neck tumours {230,2700). lts incidence is 0.4 cases per million in the general popu lation and 3.7 per million in the at-risk population (i.e. 1O- to 24-year-old males) {845). The tumour develops almost exclu sively in adolescent and young males (av erage patient age: 17 years) (230,1716, 2621). Female patients should be evalu ated for underlying testicular feminization. Etiology There is evidence of hormonal depend ency of nasopharyngeal angiofibroma. Tumour growth is associated with pu berty in boys, and tumour cells frequently express androgen receptor (1063,1716, 2621).

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of CT angiography of a 15-year-old boy with a hypervascular left nasal mass centred in the sphenopalatine foramen and extending into the pterygopalatine fossa, with supply from an enlarged left interna! maxillary artery (arrow), which is a branch of the externa! carotid artery (arrowhead). 74


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Fig. 2.14 Nasopharyngeal angiofibroma. A A richly vascular tumour underlying the nasopharyngeal respiratory-type mucosa, showing variously sized blood vessels in a cellular fibroblastic stroma. The vascular componen! ranges from capillaries to large dilated vessels. B The vascular componen! is variable, ranging from thin, slit-like branching capillaries supported only by endothelial cells to dilated vessels; the stroma shows dense collagen with spindled to stellate fibroblasts. C In this area, the stroma is loose and myxoid, and contains stellate fibroblasts. The blood vessel walls range from !hin (supported only by endothelium) to unevenly thick, due to !he variable mural smooth muscle content. D Nuclear localization of beta-catenin is seen in stromal cells only; in endothelial cells, the expression remains membranous and cytoplasmic.

Localization Nasopharyngeal angiofibroma arises in the nasopharynx or posterolateral nasal cavity wall (230,1716,2700}. Clínica! features Patients present with the classic triad of nasal obstruction, epistaxis, and na sopharyngeal mass (230,1222). Other symptoms include nasal discharge, si nusitis, facial deformity, deafness, otitis, diplopía, proptosis, headache, and pain {1716,2700}. Radiological imaging fre quently shows a tumour in the nasophar ynx and nasal cavity with sinus opacity and bone destruction. Anterior bowing of the posterior wall of the maxillary antrum (called the Holman-Miller sign or the an tral sign) is typical {1716,2700}. Large tu mours can extend into maxillary, ethmoid, and sphenoid sinuses; pterygopalatine and infratemporal fossa; and orbit. lntrac ranial extension (usually into the middle

cranial fossa) is seen in 10-30% of cases {230,1388,1559,1716}. Angiography is diagnostic, identifies the feeding vessel (usually the interna! maxillary artery), and is essential for pre-surgical embolization {219). Due to the characteristic imaging appearance, diagnostic biopsy (which carries a risk of life-threatening haemor rhage) is often unnecessary. Macroscopy The average tumour size is 4 cm, but tu mours as large as 22 cm have been re ported. The neoplasm is polypoid and lobulated and often takes the shape of surrounding structures. Histopathology The tumour has two components: vascu lar and stromal. The blood vessels are of various sizes, shapes, and thicknesses, ranging from slit-like capillaries to ir regularly dilated and branching vessels.

The vessel walls may be thin (supported only by endothelial cells) or may be ensheathed focally or continuously by smooth muscle of varying thickness. No elastic tissue is identified except in feeding arteries. The stroma consists of bipolar or stellate fibroblastic cells with plump, vesicular, spindled nuclei, and the cells may appear to be arranged around the blood vessels. Nucleoli are indistinct and mitoses are usually absent. Scattered multinucleated stellate stromal giant cells may be seen. The stroma varies from loose, oedematous, and cellular to densely collagenous and paucicellular; mast cells are frequently present. Tumours treated with embolization show areas of necrosis and intravascular foreign material. Tumours treated with the androgen receptor blocker flutamide are hypocellular, with increased stromal collagen {815}. CD31 and CD34 immunohistochemistry

highlights the endothelium of blood vesseis, and SMA highlights the smooth muscle in the vessels. The stromal cells show nuclear expression of androgen receptor and beta-catenin - the latter in > 90% of tumours 15,1063}. The stromal cells occasionally express SMA, especially at the periphery of the tumour, but are negative for desmin and S100 protein. Expression of estrogen receptor, progesterone receptor, and KIT (CD117) has been reported 11452,1641 ,1978}.

Genetic profile Nasopharyngeal angiofibroma is characterized by chromosomal gains 1282}. Loss of the Y chromosome with gain of the X chromosome is frequently documented 12092}. Somatic mutation in exon 3 of the beta-catenin gene (CTNNB1) is seen in 75% of the tumours, although nuclear localization of beta-catenin is seen in > 90% of cases {5}.

Haematolymphoid tumours Definltion Haematolymphoid tumours of the nasopharynx are neoplasms of lymphoid, plasma cell, or myeloid origin arising in the nasopharynx.

ICD-0 codas Extraosseous plasmacytoma 9734/3 Extramedullary myeloid sarcoma 9930/3 Diffuse large B-cell lymphoma 9680/3

Epidemiology Nasopharyngeal lymphomas account for about 15% {37,666,934} of all head and neck lymphomas and for 9% {1372} to 35% {682} of Waldeyer ring (pharyngeal lymphoid ring) lymphomas. Oiffuse large 8-cell lymphoma is the most common type {37,50,682,2652}. NK-cell and T-cell lymphomas occur more trequently in Asia than in western countries {1054}. Adults and (rarely) children are affected {50,432,1635}. The average patient age and male-to-female ratio vary by type of lymphoma. For example, extranodal NK/ T-cell lymphoma (see Extranodal NK!Tce/1 /ymphoma, p.52) {1108,23221 affects

slightly younger patients, with a higher male-to-female ratio, than does diffuse large 8-cell lymphoma (see Diffuse large 8-cell lymphoma) {2652}. Burkitt lymphoma is a common type among children 12642}. Nasopharyngeal extraosseous plasmacytoma accounts for 10-16% of ali head and neck extraosseous plasmacytomas {116,494,2078}. Nasopharyngeal myeloid sarcoma is rare {433,1957).

Genetic susceptibility There have been isolated reports of nasopharyngeal angiof1broma arising in association with familial adenomatous polyposis 1712,832,2454). No germline mutations of APC, C TNN81, or any other gene have been reported in sporadic nasopharyngeal angiofibroma.

Prognosis and predictiva factors One or more recurrences occur in 5- 25% of patients {230,1222,1388}. Prognosis depends on the size and extent of the tumour, the presence of multiple feeding vessels (including bilateral vascularity), and the completeness of surgical resection {1559,2227}. Sarcomatous transformation has been reported in association with radiotherapy, as has metastasis {2621 }. Spontaneous regression after puberty can rarely occur {2621}.

Ferry J.A. Ko Y.-H.

cervical lymph nodes at presentation, and more-distant spread is not uncommon {37,50,432,1054,1635}.

Clinical features Patients present with nasal obstruction, epistaxis, hearing loss, headache, dyspnoea, and/or cervical lymphadenopathy. A minority have constitutional symptoms {50,1054,2228,2652}.

Histopathology Etiology Most lymphomas, plasmacytomas, and myeloid sarcomas arise sporadically. EBV contributes to the pathogenesis of NK/T-cell lymphoma. Sorne patients with high-grade 8-cell lymphoma or classical Hodgkin lymphoma are immunocompromised {1939,2228}.

Localization Lymphoma forms an often bulky, usually symmetrical lesion, commonly with invasion of adjacent structures {432,2652). Stage at presentation varíes by type of lymphoma, but most lymphomas involve

Diffuse large B-cell lymphoma is most common, followed by NK/T-cell lymphoma and peripheral T-cell lymphoma, NOS {50,432,1054,1372,2652}. Other lymphomas include MALT lymphoma {50,1372,2652). follicular lymphoma {50,432,1372). Burkitt lymphoma {2228, 2652}, and mantle cell lymphoma {2652}, as well as the rare anaplastic large cell lymphoma {1054,2652), 8and T-lymphoblastic lymphomas {1054, 1473), and classical Hodgkin lymphoma {1143,1939).


75

Scanned by CamScanner

Notochordal tumours

Baumhoer D. Bullerdiek J . Nicolai P.

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... • ..O ' -141,~ . Fig. 2.15 Chordoma. A Nests of epilhelioid cells with eosinophilic and vacuolated cytoplasm showing osteodestructive growth. B lmmunohistochemical double-stain with CK19 (red, staining of cytoplasm) and brachyury (brown, staining of nuclei). • _,.,. .

Chordoma

primary occurrence at these sites is exceedingly rare {2665).

Definition Chordoma is a malignant tumour with notochordal differentiation.

ICD-0 code

9370/3

Clinical features Chordomas p resent with headache, eranial nerve palsy, or brain stem compression, depending on the anatomical structures comprom ised.

Epidemiology The annual incidence of chordoma is 0.8 cases per 100 000 population, with 32- 42% arising in cranial sites, mainly in the base of the skull. There is a male predominance, with a male-to-female ratio of 1.6:1. lndividuals of any age can be affected , although chordoma is rare in chi ldhood (372, 2224).

Localization The clivus is most commonly involved. The nasopharynx and nasal cavity can be involved by local extension, but

76


Macroscopy The tumours generally show bone-destructive growth; the cut surface is gelatinous or cartilage-like.

variable pleomorphism . Necrosis is frequently present. Chordoma typically shows expression of cytokeratins, EMA, S100, and brachyury {1610,2517). Variants include chondroid chordoma, which shows matrix rem iniscent of hyaline cartilage, and dedifferentiated chordoma, which is a biphasic tumour with classic chordoma juxtaposed to high-grade und iffe rentiated sarcoma.


Histopathology

In rare familia! cases, a duplication of the T (brachyury) gene can be found (2670}.

Chordomas consist of cords and lobules of cells in a myxoid stroma, separated by thin fibrous sepia. The characteristic ce lls are physaliphorous, with abundant and highly vacuolated (bubbly) cytoplasm, but many tumour cells are nondescriptly epithelioid in appearance. The nuclei are uniform and round, with

The most importan! prognostic factor is comp lete surgical resection, which can be achieved only rarely in cranial sites {2259 }. The 3-, 5 -, an d 10-year overall survival rates are 80.9%, 73 .5%, and 58.7%, respectively {372}.


CHAPTER 3 Tumours of the hypopharynx, larynx, trachea and parapharyngeal space

Malignant surface epithelial tumours Precursor lesions Neuroendocrine tumours Salivary gland tumours Soft tissue tumours Cartilage tumours Haematolymphoid tumours

WHO classification of tumours of the hypopharynx, larynx, trachea and parapharyngeal space Salivary gland tumours

Malignant surface epithelial tumours Conventional squamous cell carcinoma Verrucous squamous cell carcinoma Basaloid squamous cell carcinoma Papillary squamous cell carcinoma Spindle cell squamous cell carcinoma Adenosquamous carcinoma Lymphoepithelial carcinoma

8070/3 8051/3 8083/3 8052/3 8074/3 8560/3 8082/3

Adenoid cystic carcinoma Pleomorphic adenoma Oncocytic papillary cystadenoma

8077/0 8077/2 8052/0 8060/0

Cartilage tumours

8240/3


8200/3 8940/0 8290/0

Soft tissue tumours Granular cell tumour Liposarcoma lnfl ammatory myofibroblastic tumour

9580/0 8850/3 8825/1

Precursor lesions Dysplasia, low grade Dysplasia, high grade Squamous cell papilloma Squamous cell papillomatosis

Chondroma Chondrosarcoma Chondrosarcoma, grade 1 Chondrosarcoma, grade 2/3

9220/0 9220/3 9222/1 9220/3

Neuroendocrine tumours Well-differentiated neuroendocrine carcinoma Moderately differentiated neuroendocrine carcinoma Poorly differentiated neuroendocrine carcinoma Small cell neuroendocrine carcinoma Large cell neuroendocrine carcinoma

78

8249/3 8041/3 8013/3

The morphology codes are from the lnternational Classification of Diseases for Oncology (ICD-0) {776A}. Behaviour is coded /Ofor benign tumours: /1 for unspecified, borderline, or uncertain behaviour; /2 for carcinoma in situ and grade 111 intraepithelial neoplasia; and /3 for malignant tumours. The classification is modified from the previous WHO classification, taking into account changes in our understanding of these lesions.

WHO classification of tumours of the hypopharynx, larynx, trachea and parapharyngeal space

TNM classification of carcinomas of the larynx

TNM classification•,b

T3 T4a

T - Primary tumour TX TO Tis

Primary tumour cannot be assessed No evidence of primary tumour Carcinoma in situ T4b

Supraglottis T1 T2

T3

T4a

T4b

Tumour limited to one subsite of supraglottis, with normal vocal cord mobility Tumour invades mucosa of more than one adjacent subsite of supraglottis or glottis or region outside the supraglottis (e.g. mucosa of base of tongue , vallecula, or medial wall of pyriform sinus), without fixation of the larynx Tumour limited to larynx with vocal cord fixation and/or invades any of the following: postcricoid area, pre-epiglottic space, paraglottic space, inner cortex of thyroid cartilage Tumour invades through the thyroid cartilage and/or invades tissues beyond the larynx; for example, !rachea, soft tissues of neck including deep/extrinsic muscle of tongue (genioglossus, hyoglossus, palatoglossus, and styloglossus), strap muscles, thyroid , oesophagus Tumour invades prevertebral space or mediastinal structures, or encases carotid artery

T1a T1 b T2 T3

T4a

T4b

Tumour limited to vocal cord(s) (may involve anterior or posterior commissure), with normal vocal cord mobility Tumour limited to one vocal cord Tumour involves both vocal cords Tumour extends to supraglottis and/or subglottis, and/or with impaired vocal cord mobility Tumour limited to larynx with vocal cord fixation and/or invades paraglottic space and/or inner cortex of the thyroid cartilage Tumour invades through the outer cortex of the thyroid cartilage and/or invades tissues beyond the larynx; for example, trachea, soft tissues of neck including deep/ extrinsic muscle of tongue (genioglossus, hyoglossus, palatoglossus, and styloglossus), strap muscles, thyroid, oesophagus Tumour invades prevertebral space or mediastinal structures, or encases carotid artery

Subglottis T1 T2

N - Regional lymph nodes (i.e. the cervical nades) NX NO N1 N2 N2a N2b N2c N3

Regional lymph nades cannot be assessed No regional lymph node metastasis Metastasis in a single ipsilateral lymph node,;::; 3 cm in greatest dimension Metastasis as specified in N2a, N2b, or N2c below Metastasis in a single ipsilateral lymph node, > 3 cm but ;::; 6 cm in greatest dimension Metastasis in multiple ipsilateral lymph nodes, all ;::; 6 cm in greatest dimension Metastasis in bilateral or contralateral lymph nodes, all;::; 6 cm in greatest dimension Metastasis in a lymph node > 6 cm in greatest dimension

Note: Midline nodes are considered ipsilateral nodes.

M - Distant metastasis

Glottis T1

Tumour limited to larynx, with vocal cord fixation Tumour invades cricoid or thyroid cartilage and/or invades tissues beyond the larynx; for example, trachea, soft tissues of neck including deep/extrinsic muscle of tongue (genioglossus, hyoglossus, palatoglossus, and styloglossus), strap muscles, thyroid, oesophagus Tumour invades prevertebral space or mediastinal structures, or encases carotid artery

Tumour limited to subglottis Tumour extends to vocal cord(s), with normal or impaired mobility

MO M1


Stage grouping StageO Stage 1 Stage 11 Stage 11 1 Stage IVA Stage IVB Stage IVC

Tis T1 T2 T1-2 T3 T1-3 T4a T4b AnyT AnyT

NO NO NO N1 N0-1 N2 N0-2 AnyN N3 AnyN


'Adapted from Edge et al. (625A} - used with permission of the American Joint Committee on Cancer (AJCC), Chicago, lllinois; the original and primary source for this information is the AJCC Cancer Staging Manual, Seventh Edition (2010) published by Springer Science+Business Med ia - and Sobin et al. (2228A}. "A help desk for specific questions about TNM classification is available at http://www.uicc.org/resources/tnm/helpdesk.

TNM c lassification of carcinomas of the larynx

79

TNM classification of carcinomas of the hypopharynx

TNM classification•,b T - Primary tumour TX Primary tumour cannot be assessed TO No evidence of primary tumour Tis Carcinoma in situ T1 Tumour limited to one subsite of hypopharynx and/or s 2 cm in greatest dimension T2 Tumour invades more than one subsite of hypopharynx or an adjacent site, or measures > 2 cm but s 4 cm in greatest dimension, without fixation of hemilarynx T3 Tumour > 4 cm in greatest dimension, or with tixation of hemilarynx or extension to oesophagus T4a Tumour invades any of the foliowing: thyroid/cricoid cartilage, hyoid bone, thyroid gland, oesophagus, central compartment soft tissue (which includes prelaryngeal strap muscles and subcutaneous fat) Tumour invades prevertebral fascia, encases carotid T4b artery, or invades mediastinal structures N - Regional lymph nodes (i.e. the cervical nodes) NX Regional lymph nades cannot be assessed NO No regional lymph node metastasis N1 Metastasis in a single ipsilateral lymph nade, s 3 cm in greatest dimension N2 Metastasis as specitied in N2a, N2b, or N2c below N2a Metastasis in a single ipsilateral lymph node, > 3 cm but s 6 cm in greatest dimension N2b Metastasis in multiple ipsilateral lymph nodes, ali s 6 cm in greatest dimension N2c Metastasis in bilateral or contralateral lymph nodes, ali s 6 cm in greatest dimension N3 Metastasis in a lymph nade > 6 cm in greatest dimension Note: Midline nades are considered ipsilateral nades.

80

M - Distant metastasis MO No distan! metastasis M1 Distan! metastasis Stage grouping Stage O Stage 1 Stage 11 Stage 111 Stage IVA Stage IVB Stage IVC

Tis T1 T2 T1 -2 T3 T1-3 T4a T4b AnyT AnyT

NO NO NO N1 N0--1 N2 N0--2 Any N N3 Any N


ªAdapted from Edge et al. {625AJ - used with permission of the American Joint Committee on Cancer (AJCC), Chicago, lllinois; the original and primary source for this information is the AJCC Cancer Staging Manual , Sevent11 Edition (201 O) published by Springer Science+Business Media - and Sobin et al. {2228AJ. bA help desk for specific questions about TNM classification is available at http://www.uicc.org/resources/tnm/helpdesk.

Tumours of the hypopharynx, larynx, trachea and parapharyngeal space


Slootweg P.J. Grandis J.R.

/ntroduction

accepted distinction between low-, intermediate-, and high-grade carcinoma has been used, in line with the nomenclature for histologically similar lesions at other body siles. Discussion of soft tissue and salivary gland lesions, as well as haematolymphoid tumours, has been limited to the specific entities that are often faund in the laryngohypopharynx or that have an importan! differential diagnostic role al this site.

Laryngeal and hypopharyngeal pathology mainly encompasses lesions of the covering mucous membrane, with underlying soft tissues, salivary gland tissue, and cartilage playing a minar role. Therefore, this chapter emphasizes lesions that arise from the mucosa! lining. The main difference from the previous edition is in the discussion of mucosa! premalignancies, about which the aim

was to achieve a universally accepted consensus in arder to put an end to the confusion that can arise from the use of severa! difieren! classification systems. Currently, a two-tiered classification (consisting of low-grade and high-grade dysplasia) is recommended, to which guidelines have been added on how to recognize carcinoma in situ within the high-grade dysplasia group in case a three-tiered system is preferred. For neuroendocrine carcinomas, the widely

Malignant surface epithelial tumours Convenüonalsquamous ce// carcinoma Zidar N. Brandwein-Gensler M. Cardesa A. Helliwell T. Hille J. Nadal A.

Definition Conventional squamous cell carcinoma (SCC) is a malignant epithelial tumour with evidence of squamous differentiation. ICD-0 code

8070/3

Synonym Epidermoid carcinoma

Epidemiology SCC of the larynx and hypopharynx is the second most common respiratory tract cancer, after lung cancer (359]. lt accounts for 1.6-2% of ali malignant tumours in men and 0.2- 0.4% in women (238}. There is marked geographical variation in the frequency of SCC, both between countries and in different parts of the same country. lt occurs most frequently in the sixth and seventh decades of lite. Rare cases have

Fig. 3.01 Macroscopic appearance of conventional squamous cell carcinoma. A Supraglottic carcinoma of the larynx: an ulcerated tumour with raised edges at the base of the epiglottis. B Subglottic carcinoma of the larynx: a partially flat and partially exophytic nodular tumour of the subglottis, extending to the anterior commissure. C Hypopharyngeal carcinoma of the piriform sinus: a large, ulcerated tumour with raised edges in the piriform sinus, extending to the aryepiglottic fold.

been described in children (137,1766}. The tumours are more common in men (359,1947). although the male-to-female ratio is decreasing in sorne countries, possibly due to increased incidence of smoking among women over the past two decades (569). Tracheal carcinoma is rare, with approximately 1 tracheal carcin.oma far every 75 laryngeal cases; it accounts far < 0.1% of cancer deaths. SCC accounts far 55-73% of all tracheal carcinomas (143,820) .

Etiology Cigarette smoking and (to a lesser extent) alcohol consumption are the most important risk factors far laryngeal and hypopharyngeal SCC (953). Eliminating smoking and alcohol consumption could prevent as many as 90% of laryngeal cancers {695). Other factors, such as gastro-oesophageal reflux, diet, nutritional factors, and socioeconomic status, have been linked to increased risk of laryngeal cancer, particularly in patients who lack the majar risk factors (480,665, 762,1333}.

Malignan! surface epithelial tumours

81

HPVs play a limited role in the pathogenesis of SCC of the larynx. In recent studies, transcriptionally active HPVs were detected in 4-15% of cases {417,922, 1408,2095). Unlike in the oropharynx, the morphology of laryngeal SCC does not predict viral etiology {1408). Localization There are geographical differences in the topographical distri bution of laryngeal SCC. The most common location for laryngeal SCC is the supraglottis in sorne countries (e.g. France, Spain , ltaly, Finland, and the Netherlands) and the glottis in others (e.g. the USA, Canada, the United Kingdom, and Sweden) [143). The rarest localization of laryngeal cancer is the subglottis {2067). Hypopharyngeal SCC occurs most frequently in the piriform sinus (60-85% of cases) and rarely in other localizations, such as the posterior pharyngeal wall (10- 20%) and postcricoid area (5-15%) {971 ,2449). Tracheal SCC is usually located in the lower third of the trachea (> 50% of cases) and less frequently in the upper or middle third {820). Clinical features The most common early symptoms of laryngeal SCC are hoarseness (with glottic and supraglottic SCC) and dyspnoea and stridor (with subglottic SCC). Other symptoms include dysphagia, change in the quality of voice, sensation of a foreign body in the throat, haemoptysis, and odynophagia {707,1949). The most frequent symptoms of hypopharyngeal SCC are odynophagia, dysphagia, and neck mass. Other symptoms include voice changes, otalgia, and constitutional symptoms {2449). Tracheal SCC usually presents with dyspnoea, wheezing or stridor, acute respiratory failure, cough, haemoptysis, and hoarseness {1970). Laryngeal, hypopharyngeal, and tracheal SCCs can spread directly to con tiguous structures or via lymphatic and blood vessels, giving rise to lymph node and distant metastases. These tumours have a strong tendency to metastasize to the regional lymph nades. The localization and frequency of lymph node metastases depend on the site of the primary tumou r. Haematog enous metastases are infrequent, but may occur in late stages of the disease, most frequently to the

82

lung, liver, and bones (2248); intracranial metastases have also been reported {544,2418). The TNM staging system is widely used for SCC. lt is presented in the text on pages 79 and 80. Macroscopy Laryngeal and hypopharyngeal SCC may present as an exophytic, flat, or nodular tumour with raised edges; as a polypoid lesion; or as a depressed, endophytic lesion. Central ulceration is frequently present. Tracheal SCC usually presents as a polypoid mass projecting into the lumen. Rarely, it grows as a circumferential mass. Cytology Aspirates of metastases are cellular, with sheets and small cl usters of malig nan! squamous cells with intracellular and extracellular keratinization. Mixed inflammation and necrosis can b e present. Histopathology The main histological features of SCC are sq uamous differentiation and invasion. Squamous differentiation is characterized by keratinization (with or without keratin pearl fo rmation) and/or intercellular bridges. lnvasion manifests as interruption of the basement membrane of the surface epithelium and the downwards growth of tumour islands, cords, or isolated tumour cells in the underlying tissue. lnvasion is almost always accompanied by a desmoplastic stromal reaction, which consists of proliferation of myofibroblasts, excessive deposition of an extracellular matrix, and neovascularization [2728,2729}. Tumour cells may invade the lymphatic and blood vessels or spread in the perineural plane or along nerves. SCCs are traditionally graded as well , moderately, or poorly differentiated, according to th e deg ree of differentiation, cellular pleomorphism, and mitotic activity. Well-differentiated SCC c losely resembles normal squamous epithelium and contains large, differentiated, keratinocyte-like squamous ce lls and small basal-type cells, which are usually located at the periphery of the tumour islands. There are intercellular bridges and typically full keratinization; mitoses are scarce. Moderately differentiated SCC exhibits more nuclear pleomorphism and

Tumours of the hypopharynx, larynx, !rachea and parapharyngeal space

more mitoses, including abnormal mitoses; there is usually less keratinization. In poorly differentiated SCC, basal-type cells predominate, with frequent mitoses (includ ing abnormal mitoses), b arely discernible intercellular bridges, and minimal or no keratinization. Although keratinization is more likely to be present in well - or moderately differentiated SCC, it should not be cons idered an important histological criterion in grading SCC . Often, in the presence of an intact surface epithe lium, intraepithelial dysplasia may be seen in direct continu ity with the SCC. Tumour growth at the invasive front can show an expansive or cohesive pattern (characterized by large tumour islands with well-defined pushing margins) and an infiltrative pattern (characterized by scattered small irregular cords or single tumour cells, with poorly defined infiltrating marg ins). lmmunophenotype SCC expresses various epithelial markers (e.g. cytokeratins, p63, and EMA). Well-differentiated SCC expresses medium/high-molecular-weight cytokeratins (e.g. CK5/6) but not low-molecularweight cytokeratins (e.g. CK8 and CK18), similar to normal squamous epithelium. Poorly differentiated SCC tends to lose expression of medium/high -molecularweight cytokeratins , and expresses lowmolecular-weight cytokeratins {1518} and vimentin {2474). Differentia/ diagnosis We ll-differentiated SCC must be distinguished from verrucous and papillary carcinomas, as well as fro m benign conditions such as p seudoepitheliomatous hyperplasia. Verrucous carcinoma lacks atypia, which is always present in SCC. Papillae formation and the absence of keratinization characterize papillary SCC, distinguishing it from SCC . Pseudoepitheliomatous hyperplasia is a benign condition that consists of deep, irregular tangues of epithelium that lack the atypia and abnormal mitoses seen in SCC. Poorly diffe rentiated SCC must be differentiated from melanoma, lymphoma, and neuroendocrine carcinoma. The corree! diagnosis is best determined by the use of appropriate immunohistochemistry and special stains fo r demonstration of mucin production. Melanoma is distinguished from SCC by its expression of S100, HMB45, melan A and other

melanocytic markers. Neuroendocrine carcinoma expresses neuroendocri ne markers (e.g. synaptophysin and chromogranin) but typically lacks p63 expression and does not show significant squamous differentiation. whereas SCC does not express neuroendocri ne markers. Lymphoma is distinguished from SCC by the presence of CD45 (leukocyte common antigen) and markers of 8 -cell or T-cell differentiation.

metalloproteinases {360,1515). Specific tumour suppressor microRNAs (the let-7 family, miR-7, and miR-206) are downregulated {2627).

impact on the outcome of SCC include patient age at presentation {425,2184), comorbidity (concurrent diseases) {395}, and performance status (425).

Prognosis and predictive factors The overall 5-year survival rate is 8085% for glottic SCC, 65- 75% for supraglottic SCC, about 40% for subglottic SCC {1431, 62.5% for hypopharyngeal SCC {2247). and 25- 47% for tracheal scc {820,1970}.

Genetic profile Laryngeal and hypopharyngeal SCCs develop as a result of multiple genetic abnormalities and the development of aneuploidy {478,846). LOH and comparative genomic hyb ridization studies have shown gains of 3q, 5p, 8q, 11q13, and 18p with losses at 3p, 5q, 8p, 9p, 11 q23-24, 13q, and 18q {1117,2100, 2310). Loss of multiple tumour suppressors is common. with the most commonly affected genes including CDKN2A and TP53. Amplified and mutated oncogenes include EGFR, VEGFA (previously called VEGF), PTGS2, PIK3CA, and matrix

Other factors that may have a significan!

Clinical prognostic factors

Stage remains the most significan! predictor of survival, and is discussed in detail elsewhere. Depth of invasion and the presence of reg ional and distant metastases are independent predictors of survival.

Localization is an important prognostic factor {143}. The best prognosis has been reported for glottic SCC, and the worst prognosis for subglottic and tracheal SCC.

Histopatho/ogical prognostic factors

Differentiation. The reports on the prognostic significance of traditional grading into well-, moderately, and poorly differentiated SCC are conflicting. Sorne investigators have suggested that the grading system has a significan! association with survival {1896,2134,2607}. whereas others have not confirmed this observation {425,1113). The main criticism of this widely used system of grading is related to its subjective nature and lack of objective criteria.

Invasiva front. lt has been shown that the histological features at the invasive front are prognostically much more important than those in the central and superficial parts of the tumour {284,285, 2677). A simple grading system has


83

been proposed for evaluation of the invasive front, which correlates closely with prognosis. Four histological features are evaluated: degree of keratinization, nuclear polymorphism, pattern of growth, and inflammatory response. The score for each parameter is summarized as a total malignancy score, with a high score indicating poor prognosis {284,285}. Pattern of invasion also features prominently in a multiparameter risk model for see {258}. Vascular and perineural invasion. The penetration of tumour cells in the lymphatic and/or blood vessels is associated with a high probability of lymph node and/or distant metastases. Vascular invasion tends to occur in aggressive see and is associated with recurrence and poor survival (2678}. Similarly, perineural invasion is associated with an increased risk of local recurrence, regional lymph node metastases, and poorer survival {258,684,2134,2241,2678}. Extracapsular spread in lymph node metastases. Metastases in the lymph nodes are the single most adverse prognostic factor in head and neck see (710, 1353}. The presence of extracapsu lar spread in lymph nodes is also prognostically important and is strongly associated with both regional recurrence and the development of distant metastases, resulting in poorer survival (262,710,996, 2315). However, sorne studies have failed to confirm the independent prognostic significance of extracapsular spread (1520,1896}.

Verrucous squamous ce// carcinoma Zidar N. Cardesa A. Gillison M. Helliwell T. Hille J. Nadal A.

Definition Verrucous squamous cell carcinoma (VC) is a variant of wel l-differentiated squamous cell carcinoma (SeC) that lacks the cytological features of malignancy, grows slowly, and is locally invasive but does not metastasize. ICD-0 code

8051/3

Synonym Ackerman tumour (453} Epidemiology ve is a rare tumour; in the USA, the incidence between 2000 and 201 1 was 0.024 cases per 100 000 population . Most cases present in older males, in their sixth or seventh decades of life (610, 1565}.

Fig. 3.03 Laryngeal verrucous carcinoma. A broadbased exophytic tumour with a warty surface.

Etiology ve has been etiologically linked to tobacco smoking (1255,1565,1783,2252}. Recent studies using highly sensitive and specific molecular methods suggest that ve is not associated with HPV infection (557,1760,1825). Localization The larynx is the second most common site of occurrence of ve in the head and neck, after the oral cavity (1255}. Most cases arise from the true vocal cords, but ve may also occur in the supraglottis and subglottis (610,1 255,1565}, hypopharynx {1255}, and !rachea {2278).

Resection margins. Resection margins clear of tumour are associated with a lower recurrence rate and better survival (1148,2211}. Margins are considered clear if there is no invasive see, see in situ, or dysplasia. An adequate margin of resection has not been precisely defined, but a margin of 5 mm is generally believed to be adequate (995}. Sorne studies have shown that even margins of 1-2 mm are adequate, particularly in glottic cancer (1698). Molecular factors. A systematic review failed to show any prognostic value of p53 expression in laryngeal carcinomas (1679,2353}. Fig. 3.04 Verrucous carcinoma. Fu\1-thickness view showing hyperkeratotic surface and projections and invaginations of well-differentiated squamous epithelium, invading the stroma with well-defined pushing margins.

84


Clinical features The symptoms and signs of ve are similar to those of conventional sce, with hoarseness as the most common presenting symptom. Other symptoms inelude airway obstruction, weight loss, dysphagia, and throat pain {1565,1783}.

Macroscopy ve presents as a large, tan to white, broad-based exophytic tumour with a warty surface. On cut surface, it is usually firm, with sharply defined margins.

Histopathology VC consists of thickened, club-shaped projections and invaginations of well-difterentiated squamous epithelium, composed of one to several layers of basal cells and an expanded layer of spinous cells that lack cytological atypia . There is marked surface keratinization (so-called church-spire ke ratosis). Mitoses are rare and contined to the basal ce ll layer, and there are no abnormal mitoses. VC invades the stroma with a well-defined pushing border, and invasion below the level of adjacent epithelium may be difficult to demonstrate in small biopsies unless the edge of the carcinoma is included . Lymphoplasmacytic inflammation is common. lntraepithelial microabscesses may be present in association with Gandida species superinfection. Ves that contain foci of conventional

see are considered hybrid (mixed) tumours {158}. The diagnosis of ve requires careful clinical and pathological correlation because the histological features have a wide differential diagnosis, including epithelial hyperplasia, squamous cell papilloma, well-differentiated conventional see, papillary see, and hybrid carcinoma (in vasive see and VC). lnvasion below the basal cell layer of the neighbouring normal epithelium differentiates VG from verrucous hyperplasia, but these diseases may occur concurrently, with a confluent interface. Squamous cell papilloma has thin, well-formed papillary fronds and is less keratinized. The lack of cytological atypia in ve distinguishes it from conventional see, papillary see, and hybrid carcinoma {330}. An apparent discrepancy between the clinical impression of malignancy and benign-looking morphology should raise the suspicion of ve. There is no specific immunohistochemical marker for ve {1759,1761}.

Prognosis and predictive factors ve is locally invasive and can cause extensive destruction if left untreated. lt does not metastasize to regional lymph nades or distant organs. lt has a better prognosis than does conventional see; the repo rted 5-year survival rate far laryngeal ve is 85-95% [610,1255}. The most important prognostic factor is stage at diagnosis; treatment is by surgery or radiotherapy (1052). Hybrid carcinoma has the potential for metastasis and should be treated as conventional see (1783}.

Basa/oíd squamous ce// carcinoma Lewis J.S. Gillison M. Westra W.H . Zidar N.

Definition Genetic profile Molecular studies on ve are limited, and the genetic profile of laryngeal ve is largely unknown. The pattern of expression of microRNAs in ve differs from that in conventional see; the importance of this finding in the pathogenesis and diagnosis of ve remains to be determ ined (1 758,1759}.

Basaloid squamous cell carcinoma (BSee) is a clinically unfavourable variant of squamous cell carcinoma (SeC) composed of a prominent basaloid component and with evidence of squamous ce ll differentiation.

ICD-0 code

Malignant surface epithelial tumours

8083/3

85

Epidemiology

Approximately 80% of patients with BSCC are White men in their mid-60s.

discern. Necrosis and mixed inflammation are often present. Histopathology

Etiology

Laryngeal and hypopharyngeal BSCC is strongly linked to tobacco use (reported in 80-90% of patients) and alcohol con sumption {658]. Transcriptionally active high-risk HPV, an established etiological factor at other sites, is consistently absent in BSCC arising at these anatomical subsites {171,415}. Localization

The larynx is a common site for BSCC, with a predilection far the supraglottis . The tumours also occur in the hypopharynx (pirifo rm sinus) {658,775) and rarely in the trachea (11 52). Clinical features

The symptoms and signs vary according to the site of origin, but usually include dysphagia, hoarseness, weight loss, sore throat, cough, haemoptysis, and neck mass. BSCC usually presents at an advanced stage at the time of initial diagnosis, with lymph node metastases and occasionally distant metastases {658). Macroscopy

There is no characteristic gross appearance. The tumour usually appears as a flat or slightly elevated lesion with central ulceration and poorly defined borders. Rarely, it presents as a polypoid tumour {658). Cytology

Aspirates of metastatic BSCC are cellular, with variably sized basaloid clusters of malignant cells exhibiting numerous mitotic figures and apoptotic bodies. Keratinization and definitive squamous differentiation may be rare and difficult to 86

BSCC consists of basaloid and conventional squamous components {2521). The tumours are submucosal, with rounded nests with smooth borders and peripheral palisading. Th ey tend to be closely apposed, with thin lines of hyalinized stroma between them, as if they are moulding together in a jigsaw-puzzle pattern. There is frequent comedonecrosis, and the tumour cells are round to oval and hyperchromatic. Nucleoli are usually lacking but occasionally prominent. Gland-like foci with basophilic myxoid or mucoid material are common and mimic true gland formation. A variable degree of nuclear pleomorphism is present, and high mitotic activity, apoptosis, and necrosis are common. Stromal hyalinization is characteristic; it can be linear between and around nests and nodular within nests. The conventional componen! may include abrupt keratinization adjacent to basaloid cells , dysplastic changes in the squamous epithelium, and conventional SCC. lmmunohistochemistry is strongly positive for high-molecular-weight cytokeratins, p63, and p40 (in a diffuse pattern). BSCC is negative for synaptophysin and chromogranin {1649,2129}. The differential diagnosis includes adenoid cystic carcinoma - which lacks squamous differentiation and shows partial p63 reactivity {655) and small cell neuroendocrine carcinoma - which has angulated nuclei with speckled chromatin, is positive for neuroendocrine markers, shows punctate perinuclear reactivity for cytokeratin (CAM5.2), and usually lacks reactivity for high-molecular-weight cytokeratins {2129}. The diagnosis of BSCC can still be made for tumours with all of the basaloid features even if they lack any


overt histological evidence of squamous differentiation. However, there must be definitive immunohistochemical evidence of squamous differenti ation, and adenoid cystic carcinoma and neuroendocrine carcinoma must be ruled out. Prognosis and predictive factors

lt has been debated whether BSCC has a worse prognosis than conventional SCC. Most investigators have found laryngeal/hypopharyngeal BSCC to be more aggressive than conventional SCC {776) . Patients with laryngeal BSCC have higher rates of nodal metastasis (-5070%) (658), significantly higher rates of distant metastasis, and poorer prognosis than do patients with conventional SCC {133,776,1439,2618). Active smokers and patients with nodal metastases at presentation have worse prognosis. Given the relative rarity of laryngeal and hypopharyngeal BSCC, no predictive markers of proven clinical significance have been developed. Because HPVrelated oropharyngeal basaloid carcinomas can be otherwise indistinguishable from laryngeal/hypopharyngeal BSCC, any tumour that appears to arise in the larynx/hypopharynx but involves the oropharynx should be tested for p16 and/ or high-risk HPV. This allows far the dist inction of aggressive BSCC from more prognostically favourable HPV-related oropharyngeal carcinomas that are histologically similar.

Papil/ary squamous ce// carcinoma

site in the upper aerodigestive tract {587, 1140,1 580,2030,2298,2394).

Clinical features

EI-Mofty S.K. Cardesa A . Helliwell T. HilleJ . Nada! A.

Definition Papillary squamous cell carcinoma (PSCC) is characterized by a papillary growth pattern, with thin fibrovascu lar cores covered by severely dysplastic epithelial cells or immature basaloid cells with minimal or no maturation.

ICD-0 code

The lesions are described as exophytic growths that may be painless or painful. They can be pink, white, or both pink and white. Laryngeal tumours are associated with hoarseness and airway obstruction. Nodal metastasis is uncommon, and distan! metastasis is rare (587,623,2030, 2298,2394).

Macroscopy Grossly, the lesion is papillary, friable, and soft, with a pinkish -grey colour. Tumour size ranges from 0.2 to 4.0 cm {2298,2394).

Prognosis and predictive factors PSCC has a better prognosis than conventional squamous cel l carcinoma, primarily due to low-stage presentation, with a low metastatic potential {587,623, 1580,2030,2394). HPV-related PSCCs of the oropharynx show a trend towards better patient survival than is associated with HPV-negative PSCC {1580).

Spindle ce// squamous ce// carcinoma Bishop J.A. Cardesa A. Helliwell T. Hille J. Nada! A.

8052/3

Cytology Epidemiology PSCC is uncommon; its exact prevalence in the head and neck is unknown . lt is more common in male patients, with a male-to-female ratio of 2-3:1 (623,1140, 2030,2298, 2394). In one study, PSCC constituted 0.5% of all laryngeal cancers (623). The average patient age is reported as mid-60s, with a slightly older average age among patients with oral PSCC {587,728,2030,2298).

Etiology Etiological factors inc lude tobacco use and alcohol consumption {728,2030, 2394), and HPV has recently been shown to be an etiological agent in a subset of PSCCs, particularly in the oropharynx and sinonasal tract {1140 ,1580, 2298).

Localization PSCC has been reported in almost every

Aspirates of metastatic lesions show features of keratin izing or non-keratinizing squamous cell carcinoma.

Histopathology A significan! componen! of PSCC is composed of papillary projections with central fibrovascular cores. lnvasion may be difficult to establish morphologically, but is implied by metastatic potential. The papillae are cove red with malignant epithelial cells with little ar no keratinization. Two types of surface epithelium are described: one resembles high-grade keratinizing epithelial dysplasia, and in the other, the epithelial cells are immature and basaloid, with no evidence of maturation or keratinization. Laryngeal tumours are not frequently HPV-associated, whereas oropharyngeal tumours are typically strongly positive for p16 and are HPV-related [1580, 2298).

Definition Spindle cell squamous cell carcinoma (SCSCC) is a variant of squamous cell carcinoma (SCC) characterized by predominan! malignan! spindle and/or pleomorphic cells.

ICD-0 code

8074/3

Fig. 3.08 Laryngeal spindle cell squamous cell carcinoma. A polypoid mass involving the larynx.


87

Synonyms

Macroscopy

Sarcomatoid carcinoma; carcinosarcoma

sesee is usually a polypoid mass protruding into the airway, often with an ulcerated surface mucosa {1 398,2396, 2506).

Epidemiology sesee is rare, accounting for < 1% of all laryngeal malignancies {608,2396). lt generally affects elderly patients, and has a male predilection {608,2396,2506).

Etiology sesee is linked to cigarette smoking and alcohol consumption. A subset of sesees may be radiation-induced. sesees of the larynx and hypopharynx are almost always negative for HPV {201, 2396,2555).

Localization The larynx, especially the glottis, is the most frequently involved site. The hypopharynx is infrequently affected {608, 1398,1749,2396).

Clinical features Patients present with airway obstru ction and/or hoarseness (1398,2396) .

88

Cytology Aspirates of metastatic sesee often show at leas! focal keratinizing see, but a malignan! spindle cel l componen! 'Tlay be all that is observed in sorne cases.

logous mesenchymal differentiation in the form of malignan! bone, cartilage, or skeletal muscle {1398,2396,2702). sesee is usually overtly malignant, with hypercellularity, necrosis, atypical mitotic figures, and hyperchromatic nuclei demonstrating marked nuclear pleomorphism. However, a subset of sesees are deceptively bland in areas, with or without prominent areas of hyalinization, mimicking reactive myofibroblastic proliferation or granulation tissue. The d iagnosis of sesee rests Oíl demonstrating epithelial differentiation, either on routine morphology (i.e. squamous dysplasia of residual surface epithelium or foci of conventional see mixed with sarcomatoid tumour) or by immunohistochemistry for cytokeratins (e.g. AE1 /AE3), EMA, p63, or p40 {1406,1749). However, as many as one third of sesees are purely spindled , and a significant subset is negative for epithelial markers {1398, 1749,2396,2506). True sarcomas of the larynx/hypopharynx are rare, and a malignant spindle cell neoplasm arising at these sites is best cons idered an sesee until proven otherwise.

Genetic profile Histopathology sesee is derived from the squamous epithelium and demonstrates divergen! differentiation by epithelial- mesenchymal transition {437,1259,1749,27271. lt c haracteristically grows as an exophytic mass with a predominantly ulcerated surface, sometimes containing remnants of dysplastic squamous epithelium and frequently showing areas of transition tomalignant spindled or pleomorphic tumour cells. Most sesees demonstrate a haphazard growth pattern of the spindled ce lls, and 7- 15% of cases exhibit hetera-


sesee harbours complex genetic alterations, similar to poorly differentiated sees {436,437).

Prognosis and predictive factors Despite its poorly differentiated appearance, sesee of the larynx/hypopharynx (in particular the true vocal co rd) tends to present at a low stage and, stage-forstage, has a prognosis similar to that of conventi onal see {187,608,1398,2396, 2506}. Exophytic sesees are more easily resected and have the best prognosis (2396).

Adenosquamous carcinoma Prasad M.L. Cardesa A. Helliwell T. HilleJ. Nadal A.

Definition Adenosquamous carcinoma (ASC) is a malignan! tumour that arises from the surface epithelium and shows both squamous and glandular differentiation.

ICD-0 code

8560/3

Epidemiology ASC is rare. lt has a male predisposition and usually develops in the sixth or seventh decade of life (patient age range: 34- 81 years) /1209).

Etiology As with squamous cell carcinoma (SCC), smoking and alcohol consumption are likely predisposing factors {1209). No association with HPV has been reported in ASC from the larynx and hypopharynx /1553).

Localization The larynx is a frequently affected site in the head and neck /60,1194,1209). A few cases in the hypopharynx have been reported /1314,1548,1553,2093}.

Clinical features Patients may present with hoarseness, sore throat, dysphagia, haemoptysis, or neck mass (1209).

Macroscopy ASC may present as an exophytic or polypoid mass (median size: 4 cm) or as mucosal induration or ulceration, similar to SCC /825,1209}.

Cytology Aspirates of metastases show features of keratinizing SCC. Malignan! glandular components, including cells with intracytoplasmic mucin, can be seen.

. .. ,.:

Fig. 3.11 Laryngeal adenosquamous carcinoma. A blending of the squamous and glandular components.

in close proximity, an important diagnostic feature. The adenocarcinoma consists of cribriform and tubuloglandular structures and tends to occur in the deeper parts of the tumour /1209). lntraluminal (or rarely, intracytoplasmic) mucin may be demonstrated by special stains, such as periodie acid-Schiff (PAS), Alcian blue, and mucicarmine. The tumour shows necrosis, mitoses, and vascular and perineural invasion consisten! with its high-grade nature. Metastatic ASC may display only one componen!. lmmunohistochemistry shows the expression of p63 in the squamous componen!; carc inoembryonic antigen, low-molecular-weight cytokeratin (CAM5.2), and CK7 in the adenocarcinomatous componen!; and high-molecular-weight cytokeratin in both components /1314,1548}. • CK20 is usually negative {1509}. The differential d iagnosis includes mucoepidermoid carcinoma, adenoid SCC, and conventional SCC invading the seromucinous glands. Distinction from mucoepidermoid carcinoma is importan! because ASC has a worse prognosis (Table

Prognosis and predictiva factors ASC is more aggressive than conventional SCC, with a propensity far recurrence and dissemination {60,703}. Reg ional lymph node metastases occur in about 75% of patients, and nearly 25% of patients develop distant metastases, most co mmonly to lung /1 209}. C linical stage al presentation seems to co rrelate with prognosis. The 5-year survival rate is approximately 13- 50% {1194,1209,2093}.

Table 3.01 Differences between adenosquamous and mucoepidermoid carcinoma

Adenosquamous carcinoma

Mucoepidermoid carcinoma

Evidence of origin from overlying squamous epithelium (e.g. dysplasia)

No evidence of origin from overlying squamous epithelium

Keratinization in squamous cells, keratin pearls

No keratinization or keratin pearls

lnfiltrative glands al deeper parts

Glands widespread with lobular arrangement

Squamous and adenocarcinoma adjacent to each other

Epidermoid and glandular cells closely intermingled within lobules of tumour

Secondary invasion of submucosal glands·

Arising from submucosal glands

No intermediate cells

lntermediate cells present

No MAML2 translocation

Usually associated with MAML2 translocationª

Histopathology ASC has a biphasic morphology, with squamous and glandular differentiation. Origin from surface epithelium is supported by the presence of squamous dysplasia. The squamous and adenocarcinomatous components are distinct but located

3.01). Demonstration of mucin and carcinoembryon ic antigen helps to distinguish ASC from adenoid SCC. Conventional SCC invading or entrapping seromucinous glands is d ifferentiated by its lobular architecture and the benign cytomorphology of its g landular cells /1209). Necrotizing sialometaplasia, wh ich is rare in the larynx, is characterized by the retention of the lobular architecture of the seromucous glands (despite being replaced by squamous metaplasia), ischaemic necrosis of the acini, chronic inflammation, and pseudoepitheliomatous hyperplasia of the overlying squamous epithelium (1962}.

8The presence of MAML2 lranslocalíon rules out adenosquamous carcinoma, bul MAML2 lranslocalíon is sornelimes absenl in mucoepidermoíd carcinoma {1194}.

Malignan! surface epithelial tumou rs

89

Lymphoepithelial carcinoma Bishop J.A. Gaulard P. Gillison M.

Definition Lymphoepithelial carcinoma (LEC) is a squamous cell carci noma morphologically similar to non-keratinizing nasopharyngeal carcinoma, undifferentiated subtype. ICD-0 code

8082/3

Synonym Lymphoepithelioma-like carcinoma Epidemiology LEC of the larynx, hypopharynx, and !rachea is rare, with only about 40 reported cases. lt affects older patients (mean pal ien! age: 62 years), and there is a male predominance. Unlike nasopharyngeal carcinoma, which most frequently affects Asían patients, LEC in the larynx usually occurs in White patients {381,1507,2584, 2706}.

Localization LEC occurs more frequently in the larynx than in the hypopharynx. Rare cases have arisen in the !rachea (1363,1777, 2340).

Etiology There is an association with smoking and alcohol consumption {604,1507,25841. There is also an association with EBV, although not as strong an association as in nasopharyngeal cases (1214,2584,2706).

Cytology As pirates of metastases show findings similar to those seen in aspirates of nonkeratinizing undifferentiated nasopharyngeal carcinoma.

90

Clinical features Patients present with hoarseness, neck mass, dysphonia, dysphagia, neck pain, and/or haemoptysis (604,1507,2584}.

Tumours of the hypopharynx, larynx. !rachea and parapharyngeal space

Histopathology LEC is defined by its resemblance to non-keratinizing und ifferentiated nasopharyngeal carcinoma (see Nasop haryngeal carcinoma, p. 65, Chapter 2). Unlike in the nasopharynx, LEC uncommonly harbours EBV in the larynx. Prognosis and predictiva factors Accord ing to SEER data, laryngeal LEC has a 5 -year disease-specific survival rate of approximately 60% (381 }. Regional lymph node metastasis occurs in approximately 75% of cases, with distan! metastasis in approximately 25% (1507).

Precursor lesions Table 3.02 Morphological critaria far tha classification of laryngeal precursor lesions {797)

Dysplasia

Low-grade dysplasia (including previous category of mild dysplasia): Low malignan! potantial; a spactrum of morphological changas ranging from squamous hyperplasia toan augmentation of basal and parabasal calls occupying as much as the lower half of the epithelium, while the upper portian ratains maturation

Gale N. Hille J. Jordan R.C. Nadal A . Williams M.O.

Stratification is preserved: transition of basal cells ar augmented basal/parabasal cell layer with perpendicular orientation to tha basement membrane to prickle cells horizontally oriented in the upper part

Architectural criteria

Definition Dysplasia at this body site constitutes a spectrum of architectural and cytological epithelial changes of the upper aerodigestive tract, caused by an accumulation of genetic changes that can be associated with an increased likelihood of progression to squamous cell carcinoma.

Spinous layer: spectrum of changes ranging from increased spinous layer in the whola thickness up to changas in which prickle cells are seen only in the upper epithalial hall Basal/parabasal layer: spectrum of changes, from 2-3 unchanged layers to augmentation of basal and parabasal cells in the lower half of the epithelium At most minimal cellular atypia

Cytological criteria

Parabasal cells: slightly incraased cytoplasm comparad to basal cells, enlarged nuclai, uniformly distributed chromatin, no intercellular bridges Rare regular mitoses in or near basal layer Few dyskeratotic cells present

ICD-0 codes Dysplasia, low grade Dysplasia, high grade

8077/0 8077/2

High-grade dysplasia (including previous categories of moderate dysplasia, severe dysplasia, and carcinoma in situ): A premalignant lesion; a spectrum of changes including immature epithelial cells occupying al leas! the lower half of the epithelium and as much as the whole epithelial thickness

Synonyms

Abnormal maturation

Squamous intraepithelial lesions; squamous intraepithelial neoplasia

Variable degrees of disordered stratification and polarity in as much as the whole epithelium

Epidemiology Dysplasia is seen mostly in adults and affects men more often than women, with a male-to-female ratio as high as 4.6:1 {799}. This disparity is especially evident alter the sixth decade of life. Epidemiological studies of laryngeal dysplasia are scarce. The annual incidence of laryngeal precancerous mucosal changes in the USA is 10.2 and 2 .1 lesions per 100 000 males and females, respectively (245}.

Etiology Cigarette smoking has been established as the princ ipal risk facto r in laryng eal carcinogenesis, especially in combination with alcohol abuse. The increased risk is linked to age at the start of smoking, duration of smoking, and quality of tobacco (2039,2451 }. Gastro-oesophageal reflux disease is also considered to be a possible risk factor {1395,2128}. High-risk HPV infection plays a minor role in dysplasia development {62 1,803,1644, 1799 }. Only integrated and transcriptionally active HPV can play a significan! role in carcinogenesis, and HPV 16 is the most freq uent genotype (922,1408}. Th e overall prevalence of HPV in dysplasia

Architectural criteriaª

Altered epithelial cells usually occupying from half to the entire epithelial thickness Two subtypes: keratinizing (spinous-cell type) and non-keratinizing (basal-cell type) Variable degree of irregularly shaped rete (bulbous, downwardly extending), with an intact basement membrane No stromal alterations Easily identified to conspicuous cellular and nuclear atypia, including marked variation in size and shape, marked variation in staining intensity with fraquent hyperchromasia, nucleoli increased in number and size

Cytological criteriaª

lncreased N:C ratio lncreased mitoses at or above the suprabasal level, with or without atypical forms Dyskeratotic and apoptotic cells are frequent throughout the entire epithelium

ªComplete loss of stratification and polarity and/or severe cytological atypia and atypical mitoses qualifies as carcinoma in situ if a three-liered system is used.

studies published since 2005 is 12% (range: 0- 38%) (621,803,1644,1799}.

Voice change, hoarseness, sore throat, and chronic cough are most common.

Localization

Macroscopy

Dysplasia can occur anywhere in the larynx, but it occurs most frequently along one vocal cord and less frequently along both vocal cords. The commissures as well as hypopharyngeal and. tracheal regions are rarely involved {801,1158, 2349).

Dysplasias are clinically identified as leukoplakias (white patches), erythroplakias (red patches), erythroleukoplakias (red and white patches), or chronic laryngitis. They present as small or large patches that are localized or diffuse , or as flat or exophytic and papillary lesions. Macroscopic appearance does not have any specific connotations fo r microscopy, which must always be determined histologically (247,80 1}.

Clinical features The symptoms and signs vary according to the location and size of the lesion.

Precursor lesions

91

Table 3.03 Terminology and grading systems used for dysplasia I squamous intraepithelial lesion (SIL) Level of abnormal maturation (WH02005) ¡'

Lower 113

1

Squamous hyperplasia

Moderate dysplasia

Upper 112 to 314

Moderate dysplasia

Full thickness

-

Í 1

Í 1

Mild dysplasia

113 to 112

Severe dysplasia

Ljubljana classification {799}

SIN classification {850}

WH02005 {146}

Squamous hyperplasia

l

Squam~os hyperplasia

Basal/parabasal hyperplasia

SIN 1

1

1

Amended Ljubljana classificalion {797}

Low-grade SIL

WH02017

Low-grade dysplasia

ISIN 1 or SIN 2

l

Atypical hyperplasia

High-grade SIL

SIN 2

High-grade dysplasia*

,___

Carcinoma in situ

Carcinoma in situ

Carcinoma in situ

*lf a three-tiered system is used, carcinoma in situ is separated from high-grade dysplasia. SIN, squamous intraepithelial neoplasia.

epithelial changes in arder to determine the appropriate treatment {733,1574, 2076). A review of the currently used histological grading systems and their approximate relationship is presented in Table 3.03 {2592). In an effort to harmonize the various concepts of the listed classifications, with their various morphological criteria and different terminology, a unified, two-grade system is proposed, with clear morphological criteria far defining the prognostic groups: low-grade (mild dysplasia) and high-grade (moderate and severe dysplasia / carcinoma in situ) {797). lf a three-tiered system is preferred far treatment purposes, the high-grade category can be further separated into high-grade dysplasia and carc inoma in situ {797}. Far a morphological description of each grade of dysplasia, see Table 3.02. Ancil lary studies (e.g. p53, p16, Ki-67, and EGFR) are currently not recommended for dysplasia classification. Genetic profile

Fig. 3.13 Leukoplakia of the left vocal cord. The anterior part of the left vocal cord is irregularly thickened and covered by whitish plaques.

Fig. 3.14 Low-grade dysplasia. Hyperplastic squamous epithelium shows augmented parabasal cells extending up to one third of the epithelium thickness; the upper half of the epithelium is unchanged.

Histopathology

Although the grading of upper aerodigestive tract dysplasia is to a certain degree a subjective process, grade is the most important prognostic factor far the biological behaviour of disease, because clinicians need a descriptor of the

Several classification systems have been devised to represent the spectrum of histological changes and their relation to biological behaviour, especially malignant progression {732,797,1291,2582).

92


Accumulation of genetic alterations produces aneuploidy in preneoplastic cells (2072,2680). Laryngeal dysplastic lesions show freq uent chromosomal changes/LOH al 9p21, 17p13, 3p26, and 3p14, with alterations al 9p21 being the earliest and most frequent, suggesting the implication of the CDKN2A gene in the early phases of neoplastic transfarmation. The most likely target of 17p13 LOH is TP53 {1679). Other molecular alterations consistently detected in premalignant laryngeal lesions include cyclin D1 overexpression (1814) and telomerase activity reactivation (1451 ,1496,

"')

Fig. 3.16 High-grade dysplasia / carcinoma in situ. Prominent architectural disorder; epithelial cells show severe cellular and nuclear atypia, mitoses are present, the basement membrana is intact, and a thick parakeratotic !ayer is evident on the surface (see Table 3.02, p. 91 ).

1497). None of these find ings are currently of diagnostic or prognostic utility.

Squamous ce// papílloma and squamous ce// papíllomatosís


Richardson M. Gale N. HilleJ. Zidar N.

A retrospective follow-up study found a highly significan! difference in the risk of malignan! progression between lowand high-grade lesions, at 1.6% and 12.5%, respectively (797,1184). Certain high-grade dysplasias (i.e. carcinomas in situ) are associated with higher risk of progression to invasive growth (occurring in 40% of cases) and may require more extensive surgery or rad iation th erapy, depending on the specific site (e.g. anterior commissure) and contributing risk factors (e.g. alcohol consumption and tobacco use) {2710).

Definition Squamous cell papilloma and squamous cell papillomatosis are benign exophytic squamous epithelial tumours cbmposed of branching fibrovascular cores, usually associated with HPV infection (genotypes 6 and 11).

ICD-0 codes Squamous cell papilloma Squamous cell papillomatosis

8052/0 8060/0

Synonyms Recurrent resp iratory papillomatosis; laryngeal papillomatosis; juvenile papillomatosis; adult papillomatosis

Epidemiology Squamous cell papilloma is the most common benign epithelial tumour of the larynx. Recurren! respiratory papillomatosi s (RRP) is characterized by multiple contiguous, locally recurren! squamous cell papillomas, although solitary lesions present infrequently. RRP is a rare disease involving the respi ratory tract that

occurs in both children and adults. The true incidence and prevalence of RRP are uncertain. The best projected estimates of annual incidence are 4.3 cases per 100 000 c hildren and approximately 1.8 cases per 100 000 adults {331 ,570}. The bimodal age distribution demonstrates the first peak in children aged < 5 years (juvenile cases) and the second peak in patients aged 20-40 years (adult cases) {331,1257). RRP is more common in children and is the most aggressive form of the disease, with 25% of cases presenting during infancy {1969, 2604). There is no sex predominance in children, but in adult patients there is a male-to-female ratio of 3:2 {570,602, 1774). Although the disease is rare, morbidity is notoriously high, compromising functions such as vocalization, swallowing, and breathing {821, 2605).

Etiology HPV 6 and 11 are the most frequent genotypes (seen in 90% of cases) associated with RRP as well as solitary papillomas {800,2605). A minority of cases (4- 5%) have coinfection with genotypes HPV 6 and 11, and fewer cases (3- 4%) with other HPV genotypes (e.g. 16, 31, 33, 35, and 39) (260 5). The modes of HPV transmission include sexual contact, non-sexual contact, and maternal contact (direct or indirect) (1324). Most neonatal HPV infection occurs by vertical transmission at birth {2325). A triad of factors (first-born child, vaginal delivery, and maternal age < 20 years) has been noted to correlate with RRP in children {1192). Caesarean section provides a lower risk of transmission but is not completely protective against infection. In contras!, active maternal genital HPV infection at the time of delivery increases exposure to a significan! viral load, with a high risk for transmitting infection {1324,2325). In adults, the mode of viral transmission remains unclear; transmission during sexual contact and reactivation of a slow-progressing latent infection from childhood have been suggested (1 199,1775,2028}. The unpredictable c linical course of RRP suggests possible host-specific genetic and immunological factors. Differences in HPV-specific immune response have been demonstrated between patients with RRP and controls {234,331,1742, 2003}.

Precursor lesions

93

features are seen in the upper layers of the epithelium. Mitotic features are seen along the basal to medial aspee! of the epith elium. Premature keratinization of individual epithelial cells contributes to a disorganized appearance. Surface keratinization is mínima!. Premalignant features are infrequent but should be reported if present. HPV genotype and variants can be dete rmined using sensitive conve ntional or real-time PCR (1774}. A lthough far less sensitive, and unable to detect H PV variants, in situ hybridization has also been used. Failu re to detect HPV by in situ hyb ridization is considered cons istent with a low copy numb er of HPV, below the detection sensitivity threshold of the in situ hybridization technique. However, specific patterns of in situ hybridization signals indicate that the viral status is either episomal (a diffuse signa! pattern) or integrate d (a punctate signa! pattern). The mechanism of squamous cel l papi lloma recurrence in juveniles may be more altributable to HPV integration (274} .

Localization The p apillomas usually involve th e vocal cords and ventricles, followed by transm ission to the false cords, epig lottis, subglottic area, hypopharynx, and nasopharynx. Rarely (in 1-3% of cases), the papillomas may extend to the lower respiratory trae!, which is associated with high mortality {821 ,1742,2325}. The d istribution of RRP follows a predictable pattern, with the tumours occurring at siles where c iliated and squamous epithe lium is juxtaposed.

Clinical features The presentation includes progressive hoarseness and stridor associated with growths of exophytic lesions within the larynx.

Macroscopy The proliferative luminal growths are exophytic, sessile, or pedunculated masses with bosselated surfaces. The papil lamas often g row as a friable cluster and bleed easily w ith minar trauma.

Histopathology


Squamous cell papillomas have a core composed of an arborizing fibrovascular network covered by squamous epithelium. Parabasal cell hyperplasia is often seen involving the lower half of the epithelium. Pronounced to subtle koi locyti c

The c li nical course of RRP is unpredictable and ranges from complete remission, to relatively stable lesions, to an aggressive c linical course of rapid progressive recurrences requiring surg ical interven tion, and potentially life-threatening resp iratory obstruction {570,1522,2325}. The clinical significance of variants of the H PV 6 and 11 genotypes in patients with RRP is unknown {1522}. Sorne studies have found the HPV 11 genotype to be the most importan! risk factor for aggressive c linical course, but this finding has not been consistently replicated (1774, 2605}. Other studies suggest that pati ent age at onset is im portan! (286}. Children diagnosed at < 3 years of age are 3.6 times as likely to have more than tour surgeries per year as are child ren diagnosed at an older age (1 774, 1969}. HPV 11 is more closely associated with a younger age at diagnosis, and in sorne studies it is associated with an aggressive clinical course (2605}. In adults, both HPV 11 and an observation time > 1O years have been found to be associated with aggressive clinical course (1774). These data suggest that there are factors other !han HPV typ e and patient age that determine disease course (286). A retrospective sequence analysis of HPV in RRP showed no evidence of

Fig. 3.17 Laryngeal papillomatosis. A Recurren! res-

piratory papillomatosis fills the endolaryngeal space. B Endoscopic view of multicoated clusters of papillomas within a larynx.

~ili---~..;...:;.-..i. Laryngeal papillomatosis. Florid papillomas line the endolarynx in this case of recurren! respiratory papillomatosis. Fig. 3.18

94

Tumours of the hypopharynx, larynx , !rachea and parapharyngeal space

Scanned by CamScanner

Moderately differentiated neuroendocrine carcinoma Perez-Ordonez B. Bishop J.A. Gnepp D.R. Hunt J. L. Thompson L.D. R.

Definition Moderately differentiated neuroendocrine carcinoma is an epithelial neoplasm demonstrating neuroendocrine differentiation with a histological grade between well-differentiated and poorly differentiated neuroendocrine carcinoma.

Clinical features Patients present with hoarseness, dysphagia, and airway obstruction {639, 2463). Rarely, a paraneoplastic syndrome (due to aberran! hormone production by the tumour) may be identified (218 ,709,2463,2586].

Macroscopy The tumours present as submucosal fleshy polypoid or sessile masses, 0.5~3 cm in size (2586).

10 high-power fields), and necrosis is absent. The tumour stroma is often fibrotic and highly vascular. The neoplastic cells are positive for cytokeratins, EMA, and al least one neuroendocrine marker (e.g. synaptophysin, chromogranin, or CD56). Peptides (e.g. serotonin, calcitonin, and somatostatin) may be positive, and TTF1 is variably positive. Ki-67 immunohistochem istry is not used in the grading of neuroendocrine tumours.

Histopathology


The tum:Jur cells grow in nests, cords, sheets, rnd trabeculae of round to slightly spindled cells with ample amphophilic to eosinophilic granular (sometimes oncocytic) cytoplasm . Gland-like structures or rosettes may be seen, exceptionally containing mucin vacuoles. The tumour nuclei exhibit stippled, evenly dispersed chromatin in a salt-and -pepper pattern . Minimal nuclear atypia is seen, mitotic rates are low (< 2 mitoses per 2 mm? or

The prognosis is difficult to determine due to the rarity of this tumour, but seems to be good alter surgery or laser resection. Recurrence and metastasis rates as high as 30% have been reported : with a 5-year survival rate of approximately 80% {639,2463). Older studies reported a more aggressive behaviour, due to the inclusion of moderately differentiated neuroendocrine carcinomas {2229,2230, 2463).

96

Tumours of the hypopharynx. larynx. !rachea and parapharyngeal space

ICD-0 code

8249/3

Synonyms Atypical carcinoid; neuroendocrine carcinoma, grade 11

Epidemiology These are the most common neuroendocrine carcinomas of the larynx (2463, 2586,2631). They occur more frequently in men, with a male-to-female ratio of 2.4:1, and have a peak incidence in the sixth and seventh decades of life (mean patient age: 63 years) {2463,2586,2589).

Etiology Most patients are heavy tobacco users (2463,2589}.

Local ization More than 90% of cases occur in the sup raglottic reg ion {2463,2589).

Poorly differentiated neuroendocrine carcinoma Perez-Ordonez B. Bishop J.A. Gnepp D'. R. Hunt J.L. Thompson L.D.R.

Definition

Clinical features Patients present with hoarseness, dysphagia, sore throat, and occasion ally haemoptysis {2586,2589}. Rarely, a paraneoplastic syndrome (due to aberran! hormone production by the tumour) may be identified {709,2463).

Macroscopy The tumours are tan-pink polypoid submucosal masses, 0.2- 4 cm in size, and often cove red by an ulcerated surface mucosa (2586,2589}.

Histopathology The tumour cells grow in nests, cords, sheets, and trabeculae of round to slightly spindled cells with ample amphophilic to eosinophilic granular cytoplasm. Gland-like structures or rosettes may be seen. The tumour nuclei may exhibit stippled, evenly dispersed chromatin or may show more nuclear atypia with prominent nucleoli. The defining featu res are necrosis and/or 2-1O mitoses per 2 mm 2 or iO high-power fields. Sorne tumours demonstrate oncocytic cytoplasm or stromal amyloid deposition . The neoplastic cells are positive for cytokeratins and at leas! one neuroendocrine marker (e .g. synaptophysin, chromogranin, or CD56). TTF1 is variably expressed. These tumours are frequently positive for calcitonin, which creates a potential diagnostic pitfal l, particularly in a lymph nade metastasis, where the tumour can be mistaken for medullary thyroid carcinoma.

Poorly differentiated neuroendoc rine carcinoma is a high-grade malignan! epithelial neoplasm with evidence of neuroendocrine differentiation. Two subtypes are recogn ized: small cell neuroendocrine carcinoma (SmCC) and large cell neuroendocrine carcinoma (LCNEC).

!CD-O codes Small cell neuroendocrine carcinoma 8041/3 Large cell neuroendocrine carcinoma 8013/3

Synonyms Small cell carcinoma, neuroendocrine type; oat cell carcinoma; neuroendocrine carcinoma, grade 111

Epidemiology lt is th e second most common neuroendocrine carcinoma of the larynx, tends to arise in older men (median patient age: 60 years), and has a male-to-female ratio of 2.3-4.3:1 {848 ,855,"1407,2463).

Etiology More than 90% of patients are cigarette smokers {"1407,2463). An association with HPV has been identified, but may not be as significan! as the association of HPV with oropharynx or sinonasal tract tumours {2382).

Localization Within the larynx, the re is a predilection for the supraglottic larynx, followed by the subglottis {848,855,2463).

Clinical features Patients present with non-specific symptoms, including hoarseness and/or dysphagia {848,855,1407,2463}. Many patients have regional or distan! metastases al presentation ["1612). Rarely, paraneoplastic syndromes are reported {709).

Macroscopy The tumour is a fleshy, ulcerated submucosal mass {848,1404f.

Histopathology SmCC grows in nests, sheets, and trabeculae of cells, with occasional nuclear palisading or rosette -like structures. lt is highly infiltrative, with frequent perineural and lymphovascular invasion. The tumour is composed of small to mediumsized cells with hyperchromatic nuclei, finely granular chromatin, and indistinct nucleoli with scant cytoplasm. Nuclear moulding, prominent crush artefact, necrosis, apoptosis, and DNA coating of vessel walls (the Azzopardi phenome non) are classic features , accompanied by a high mitotic rate (> 1O mitoses per 2 mm 2 or 10 high-power fields) LCNEC shows organoid nesting, palisading, rosettes , and/or trabeculae. lt is composed of medium-sized to large cells with abundan! cytoplasm. The nuclei have coarse chromatin (sometimes with a speckled, salt-and-pepper quality) and usually have a single prominent nucleolus. The tumour exhibits comedonecrosis and a high mitotic rate (> 10 mitoses per 2 mm 2 or 1O high-power fields).

Prognosis and predictive factors Approximately 30% of patients present with advanced disease, with a recurrence rate of about 60% and a 5-year survival rate of 50% {2463,2589,2632). There are no specific histological features that p redict outcome.

Neuroendocrine tu mours

97

Rare examples of SmCC and LCNEC harbour a component of squamous cell carcinoma, either within the invasive tumour or within the overlying mucosa (i.e. squamous cell carcinoma in situ). Combined SmCC- LCNEC cases are rarely seen (2631). Both SmCC and LCNEC are positive for cytokeratins (in particular low-molecular-weight cytokeratins) by immunohistochemistry, and SmCC may exhibit a perinuclear or dot-like pattern. Neuroendocrine differentiation is confirmed by staining with at least one neuroendocrine

98


marker (e.g. synaptophysin, chromogranin , or C056). TTF1 immunoexpression is variable. SmCC and LCNEC are negative or only weakly positive for p63 and are consistently negative for CK5/6. Prognosis and predictive factors These highly aggressive malignancies have high rates of regional and distan! metastasis, with about 70% of patients presenting with advanced disease, and 5-year survival rates of 5- 20% (708,848, 1170,2463}.


Adenoid cystic carcinoma Stenman G . Gnepp D.R. Wenig B.M.

Definition Adenoid cystic carcinoma (ACC) is a slow-growing and relentless salivary gland malignancy composed of epithelial and myoepithelial neoplastic cel ls that form various patterns , including tubular, cribriform, and solid forms. See also the Adenoid cystic carcinoma section (p. 164) in Chapter 7.


Prognosis and pred ictiva factors

Tracheal ACC o/ten presents at an advanced stage (2300). More than 50% of patients have metastases, frequently to the lungs {631 ). The 10-year survival rate is influenced by margin status {2319). In one study, most patients with laryngeal ACC had T4 lesions at initial diagnosis, although 87.9% had NO disease and only 6.1% had distant metastasis. The 5-year disease specif ic survival rate was higher among patients with laryngeal ACC who underwent surgery versus !hose who did not {609).

Complete resection is curative. Recurren! lesions are associated with an unfavourable clinical course.

Oncocytic papillary cystadenoma is a cystic lesion lined by oncocytic epithelium, with occasional luminal papillary projections.

8200/3

Epidemiology ACC is uncommon at these siles, but is the most common salivary gland malignancy in this location {318,426,609,704, 795,1058,1734,2371,2557]. There is no sex predilection and the tumours occur over a wide patient age range , but are most common in the sixth to eighth decades of life.

Localization Most laryngeal tumours are subglottic, with the supraglottis being the next most common location {609,1665,1734,2371, 2699).

Bloemena E. Bel! D. Hunt JL

Defin ition

Pleomorphic adenoma ICD-0 code

Oncocytic papillary cystadenoma

Bel! O. Bullerdiek J. Hunt J.L.

ICD-0 code

8290/0

Synonyms Definition Pleomorphic adenoma (PA) is a benign tumour with variable cytomorphological and architectural manifestations. The identification of epithelial and myoepithelial/stromal components is essential far the diagnosis of PA. See also the P!eomorphic adenoma section (p . 185) in Chapter 7 (Tumours of sa!ivary glands) .

ICD-0 code

8940/0

Oncocytic cyst; oncocytic papillary cystadenomatosis; oncocytic adenomatous hyperplasia; oxyphilic adenoma; oncocytoma; adenoma in laryngocoele

Epidemiology The tumour affects elderly patients, in the sixth and seventh decades of life {253}.

Localization The tumour occurs in the larynx, typically in the supraglottis {1382,2274).

Clinical features Symptoms include airway obstruction, dysphagia, dyspnoea, cough, hoarseness, sore throat, haemoptysis, and pain {1058,2557,2673) . Tracheal tumours may present with specific and asthma-mimicking symptoms {1022) .

Synonym

Clinical features

Benign mixed tumour

The symptoms are hoarseness, dysphonia, and rarely, airway obstruction {175, 2274).

Localization

Macroscopy

Only a few examples of PA in the larynx and hypopharynx have been reported in the literature (612,2085). They are typically located in the epiglottis or aryepiglottic folds.

The tumour is a submucosal mass with or without surface ulceration .

Clinical features

Histopathology

The common clinical presentatión of PA is that of a slow-growing, p ainless mass.

The histology is similar to that seen in ACCs found in the majar and other minar salivary gland siles; see the Adenoid cystic carcinoma section (p . 164).

Histopathology See the Pleomorphic adenoma section (p. 185) in Chapter 7. Salivary gland tumours

99

Histopathology The tumour consists of unilocular or multilocular cysts lined by oncocytic epithelium, with occasional intraluminal papillary projections. The lesion can be multifocal. Hyperplastic cellu lar formation may result in more-solid nests of oncocytic cells {1382,2274). Cell of origin The cell of origin is the minor salivary gland duct cell {1382,2274). Prognosis and predictive factors These lesions show benign behaviour but may recur. An association with squamous cell carcino ma has been describ ed in a case report (2274).

Soft tissue tumours Granular ce// tumour

Localization Laryngeal granular cell tumours most com monly involve the posterior third of the true vocal fold; tracheal granular cell tumours usually affect the cervical portian {2602].

Allen C.M. Gnepp D.R . Wen ig B.M.

Definition Granular cell tumour is an uncommon benign tumour of Schwann-cell differentiation characterized by poorly demarcated accumulations of plump granular ce lls {2458). See also the Granular ce!! tumoursection (p. 121) in Chapter 4.

Clinical features Laryngeal granular cel l tumours usually present with hoarseness. ·Tracheal granular cell tumours may cause stridor, cough, or haemoptysis {11 53). Other symptoms include sensation of a mass and dysphagia. As many as 10% of cases involve two or more tumours {2602).

ICD-0 code

Macroscopy Granular ce ll tumours present as sessile nodules measuring < 2 cm in diameter (92). On cut surface, the tumours are pale tan to yellowish-white.

9580/0

Synonyms Granular cell myoblastoma; granular cell schwannoma; granular cell neurofibroma; Abrikossoff tumour Epidemiology Granular cell tumou rs most trequently occur in the third to fifth decades of lite {1057). No sex predilection has been noted far laryngeal granular cell tumour, but tracheal granular cell tumour has a female predilection. Black populations appear to be disproportionately affected compared with other ethnic groups.

100

Histopathology The tumour shows submucosal unencapsulated or poorly circumscrib ed cellular p roliferation with syncytial, trabec ular, or nested growth, composed of cells with round to oval nuclei and abundant coarsely granular eosinophilic cytoplasm. There is usually minimal nuclear pleomorphism and mitotic activity. Pseudoepitheliomatous hyperplasia of the overlying epithelium may also be seen in


a substantial proportion of these lesions, and care should be taken when evaluating a superficial biopsy sample to prevent an overdiagnosis of squamou s cell carcinoma, because occasional tumours may be associated with mild to moderate cytological atypia in the pseudoepitheliomatous hyperplasic component. The granular cells are often intimately associated with nerves . The cytop lasmic granules give a diastase-resistant positive periodic acid-Schiff (PAS) reaction. The tu mour cells express 8 100 protein, CD57, an d S0X10 {72}, as well as CD68. Prognosis and predictive factors Surgical excision is curative. The risk of recurrence is low (< 10%).

Líposarcoma Flucke U. Franchi A. Thompson L.D.R.

Definition Li posarcoma is a malignant neoplasrn recapitulating fat. Three b iologically distinct categories are recognized: welldifferentiated/dedifferentiated (the most common), myxoid, and pleomorphic.

infiltrate of plasma cells, lymphocytes, and/or eosinophils.

ICD-0 code

8825/1

Synonyms lnflammatory pseudotumour; plasma cell granuloma

Epidemiology lnflammatory myofibroblastic tumours of the head and neck tend to occur in men and are most common in adults, although they can occur in children {462,2004).

Localization

ICD-0 code

8850/3

sarcoma shows 12q13-15 amplification, including MDM2 and COK4 {192).

Synonym Well-differentiated liposarcoma: atypical lipomatous tumour

Epidemiology These rare t1..1mours predominantly affect older males (mean patient age: 60 years) (691,867}.

Localization The tumours occur in the pharynx, mouth, larynx, and neck. The tangue is a common intraoral location {55,691,867}.

Clinical features The tumour is a slow-growing, painless mass causing dysphagia and airway obstruction {867,1708).

Prognosis and predictiva factors Multiple recurrences of lipoma-like/welldifferentiated lesions may occur alter surgical treatment, with late dedifferentiation. Tumour site and grade seem to influence prognosis, with laryngeal liposarcoma having a better outcome than oral tumours, possibly due to earlier recognition {867).

lnflammatory myofibroblastic tumour Wenig B.M. Flucke U. Franchi A.

Histopathology The most common lipoma-like subtype shows variation in ad ipocyte size, with hyperchromatic, enlarged nuclei. The irregu lar fibrous septa have atypical stromal cells {1708). Dedifferentiated nonlipogenic areas can exhibit a wide variety of growth patterns and cytomorphology (e.g. spindle-cell, pleomorphic, giantcell, round-cel l, and meningothelial-like). Heterologous elements (e.g. cartilage and bone) are rare {1538). MDM2 and CDK4 are positive in > 90% of the tumours {192,1538}.

Clinical features Laryngeal inflammatory myofibroblastic tumours present with hoarseness, stridor, dysphonia, ora foreign body sensation in the throat (194,2509,2585). In other sites, symptoms include obstruction, epistaxis, headaches, and dysphagia.

Macroscopy The tumour is a polypoid, pedunculated or nodular firm lesion with a smooth appearance and a fleshy to fi rm consistency, measuring 0.4- 3 cm in greatest dimension.

Histopathology

Macroscopy The tumou rs present as submucosal, wellcircumscribed, fatty- fibrous nodules (1708).

Laryngeal inflammatory myofibroblastic tumours primarily arise in the glottic regían {194,2509,2585). Non-Jaryngeal sites include the oral cavity, sinonasal tract, pharynx, tonsils, parapharyngeal space, salivary glands, and trachea {404,405,573,961,1776).

Definition lnflammatory myofibroblastic tumour is a distinctive neoplasm composed of myofibroblastic and fibroblastic spindle cells accompanied by an inflammatory

The tumour is a submucosal storiform to fascicular loosely cellular proliferation composed of spindle-shaped, stellate, epithelioid, and/or axonal (spider- like) cells with enlarged round to oval nuclei,

Genetic profile Well -differentiated/ded ifferentiated lipoSoft tissue tumours

101

inapparent to prominent nucleoli, and abundant fibrillar-looking cytoplasm . lntranuclear inclusions may be present in epithelioid cells. Mitotic figures may be numerous but atypical mitoses are not seen. There is a variable admixture of lymphocytes, plasma cells, and/or eosinophils. lnflammatory myofibroblastic tumours are immunoreactive for actins (focally to diffusely). Staining for desmin and cytokeratin is reported in 33% {464) to 77% {1581) of cases . ALK expression is seen in 36-60% of cases {366,376, 481). Distinction from spindle cell squamous cell carcinoma is critica!; areas of squamous dysplasia or differentiation are helpful in this differential diagnosis (see Spind!e ce// squamous ce!/ carcinoma,

p. 87) .

Genetic profile About 50-70% of cases (mainly in children) have clona! rearrangements involving chromosome band 2p23 that fuse the 3' kinase region of the ALK gene {890). Fusion partners include TPM3, TPM4, CLTC, RANBP2, and ATIC/268,481,1351, 1416,1808}.

...~-' .

~

Fig. 3.30 lnfiammatory myofibroblastic tumour. A The myofibroblasts may also appear epithelioid or histiocytoid, characterized by round to oval nuclei, enlarged nucleoli, and ample basophillc to eosinophilic granular cytoplasm; an inflammatory cell infiltrate is present. B The myofibroblasts include spindle-shaped to stellate cells with enlarged round to oblong nuclei and abundan! basophilic-appearing fibrillar cytoplasm; cells with long cytoplasmic extensions are seen. C lmmunohistochemical expression of ALK, including cytoplasmic staining as well as staining of the intranuclear inclusions.

Prognosis and predictive factors For laryngeal inflammatory myofibroblastic tumour, surgical resection is usually curative {573,901 ,2004,2585), but recurrence can rarely occur {901 ,2004, 2585). Rare examples of extrapulmonary

(non-head and neck) inflammatory myofib roblastic tumour metastasize and may be associated with the presence of RANBP2 and round cel l morphology {402,1539}. ALK reactivity may be

a favou rable prognostic indicator {462). ALK-negative cases may carry higher ris k of metastasis and death from disease {462).

Cartilage tumours Chondroma and chondrosarcoma

Chondrosarcoma, grade 1 Chondrosarcoma, grade 2/3

Epidemiology

Gale N. Hunt J.L. Lewis J.S. Thompson L.D.R.

Definition Chondroma is a benign mesenchymal tumour of larynx hyaline carti lage. Chondrosarcoma is a malignan! mesenchymal tumour of larynx hyaline cartilage.

ICD-0 codes Chondroma Chondrosarcoma 102

9222/1 9220/3

9220/0 9220/3

Cartilaginous tumours account for < 0.2% of ali laryngeal tumours, but are the most common non-epithelial tumours, with chondrosarcomas being much more common than chondromas {347,460,711,1397}. Chondromas occur across a wide patient age range, of 24-7 9 years (mean: 56 years), with a male-to-female ratio of 2:1 {1397). • Chondrosarcomas tend to occur in slightly older patients, with a patient age range of 25- 91 years (mean: 63 years), and have a male-to-female rati o of 3.2:1 {611,1397,2387). Chondrosarcomas are


Fig. 3.31 Laryngeal chondrosarcoma. Cut section of a chondrosarcoma arising from the cricoid cartilage and showing a solid, focally lobular and glistening greyishblue surface.

significantly more common in Whites than in Blacks, al a ratio of 7:1 (112).

Etiology The etiology remains unclear, although severa! hypotheses have been proposed. Disordered ossification, which is found only in hyaline cartilage (cricoid and rarely thyroid cartilage) in older patients and whlch occurs in areas of muscle insertion, may serve as a nidus for tumour development (112). lschaemic changes in chondroma may be a predisposing factor (2387}. Other possible predisposing factors are radiotherapy, polytetrafluoroethylene (Te/Ion) injection, and repeated laryngeal trauma (1773). Localization The most common site for laryngeal chondromas is the cricoid cartilage (accounting for -70% of cases), followed by the thyroid, arytenoid, and tracheal cartilages, in decreasing order of frequency {112,1361,1397}. Chondrosarcomas develop in the same locations, specifically along the anterior surface of !he posterior lamina of the cricoid cartilage {112,1773, 2387}. Rare tumours arise in the epiglottis (2387}. Clinical features Both tumours grow slowly, commonly as endolaryngeal masses. The symptoms of chondroma and chondrosarcoma are similar and depend on tumour size and location. Slowly progressive hoarseness, dyspnoea, dysphagia, and stridor are usually present. lf the tumour is located in the thyroid cartilage, the palien! may present with a palpable neck mass {112, 1773,2387). MRI may help in delineating

•

.

\

•.

~ - -"

. . . .,

··\

,1,-

,:-.

',

.., ' f

Fig. 3.32 Chondroma. Well-circumscribed tumour composed of hyaline cartilage, with low cellularity, lack of nuclear atypia of chondrocytes, and a single nucleus within a lacuna.

tumour extent (112) CT reveals a hypodense, well-defined tumour with interna! calcifications, cartilage destruction, and structural distortion {166,25 41 ,2619). FDG -PET may help with tumour grading, metastasis detection, and local recurrence assessment (1773).

Macroscopy Both tumours present as smooth, lobulated, submucosal masses covered by normal mucosa. On cut surface, the lesions are glassy, firm , white, or grey. Chondromas are usually < 2 cm in diameter, whereas chondrosarcomas can be as large as 12 cm (mean diameter: 3.5 cm. Dedifferentiated chondrosarcomas have foci with a fleshy appearance {347,809, 1397,2387}.

H istopathology Chondromas are composed of mature hyaline cartilage histologically resembling normal cartilage. Hypocellular areas contain evenly distributed, bland-looking chondrocytes in an abundan! basophilic matrix. Chondrocytes have small, uniform ,

~

, . B •,'P. 'f

...

single nuclei surrounded by eosinophilic cytoplasm and there is usually only one cell per !acuna. Cellular pleomorphism, mitoses, and binucleated chondrocytes are absent. Scattered foci of calcification and ossification may be seen. Chondrosarcomas show variably increas.ed cellularity, pleomorp hism, multinucleation, and mitoses, features useful in tumour grading. Most laryngeal chon drosarcomas are low-grade (grade 1), showing a pattern of lobular disarray and destructive invasion o/ native carti lage and bone. Chondrosarcomas have higher cellularity !han chondromas, binucleation in !he !acunar spaces , slight nuclear pleomorphism, and nuclear hyperchromasia. Moderately differentiated (grade 2) tumours show a higher degree of cellularity and nuclear pleomorphism than do grade 1 tumours, and may have scattered mitoses. High-grade (grade 3) tumours have high cellularity; significan! multinucleation, nuclear pleomorphism, and hyperchromasia; necrosis; and increased mitoses. Ossification and calci fication can be seen in ali grades (112, 1397,2387).

Rare cases of laryngeal clear cell chondrosarcoma have also been described, characterized by a sharp transition of conventional chondrosarcoma to a population of large clear cells with distinct cellular membranes but lacking typical, dense chondroid matrix (45). High-grade chondrosarcomas are rare, accounting for only about 5% o/ ali laryngeal chondrosarcomas {2387). Dedifferenti ated laryngeal chondrosarcomas are exceedingly rare; they show a biphasic appearance with well-differentiated chondrosarcoma juxtaposed with a high-grade

tr '

•

,.,

- -

-

. . - .-

Fig. 3.33 Chondrosarcoma. A Neoplastic proliferation with increased cellularity, chondrocytes showing mild nuclear and cellular pleomorphism and hyperchromasia, and invasion of the ossified region of the cricoid cartilage. B Moderately differentiated chondrosarcoma, grade 2. Remarkable cellularity, frequent binucleation in the !acunar spaces, and more pronounced nuclear and cellular pleomorphism.

Cartilage tumours

103

Wmacytomas constitute 5- 6% of extraosseous plasmacytomas of the head and neck (1 16,2078); nearly ali patients are adults. Extramedullary myeloid sarcoma and mast cell neoplasms are very rare (1028}. Among patients with widespread lymphoma or leukaemia , subtle laryngeal involvement is common {1028).

Localization Lymphoma and plasmacytoma involve the larynx more often than the trachea. Lymphoma involves the supraglottic larynx more often than the subglottic larynx. Primary parapharyngeal or hypopharyngeal origin of haematolymphoid neoplasms is very rare. Lymphomas (545, 1028,1300,1444) and plasmacytomas {1 483,2143,2304) are usually localized; sorne MALT lymphomas involve multiple mucosa-associated lymphoid tissue siles (997). Clinical features Patients present with coug h, dyspnoea, and hoarseness (1300,1 444,2304 ,2718]. Macroscopy Lymphomas and extraosseous plasmacytomas are usually smooth-su rfaced, raised or polypoid lesions {1028,1300, 2718). Lymphomas may be multinodular and/or circumferential (586,2701 }. 1 -

Fig. 3.35 MALT lymphoma arising in the larynx. There is a dense, diffuse infiltrate of marginal zone cells; neoplastic cells invade a submucosal gland to form a lymphoepithelial lesion.

non-cartilaginous sarcoma {809,2387). lmmunohistochemistry is rarely necessary, but the chondroid cells are immunoreactive with S100 protein and D2-40.

Prognosis and predictive factors The 1-year, 5-year, and 10-year diseasespecific survival rates for chondrosarcoma are 96.5%, 88.6%, and 84.8%, respectively, although the local recurrence rate is relatively high (18-50%), usually dueto incomplete resection (611,2387). Tumour grade and tumour subtype do not seem to influence outcome (other than possibly for dedifferentiated tumours) (1992), which encourages conservative, function-preserving surgery (including laser therapy) as primary treatment (347, 2387]. Distant metastases are exceedingly rare {460) .

104

Haematolymphoid tumours Ferry J. A. Chuang S.-S.

Definition Haematolymphoid tumours are primary malignan! neoplasms of lymphoid, plasma cell, or myeloid origin . Epidemiology Lymphomas arising in the larynx and trachea are rare, accounting fo r < 1% of neoplasms at these sites {717,1028, 1541]. Approximately 4% of head and neck lymphomas arise in the larynx; tracheal lymphomas are even less common (934). Lymphomas affect women more often th an men. Laryngeal plas


Histopathology The most common primary lymphoma at this body site is MALT lymphoma (586, 1300,1 444,2343,2718], but rare cases of diffuse large B-cell lymphoma (1028), extranodal NK/T-cell lymphoma (1 637}, anaplastic large cell lymphoma (1220), and other lymphomas have also been repo rted. Laryngeal extraosseous plasmacytoma is sometimes associated with laryngeal amyloidosis (1483). Prognosis and predictive factors The prognoses of lymphomas at this body site are similar to those of their counterparts in other sites. Extraosseous plasmacytoma has a favourable prognosis (1 028). al though patients may develop recurrences and a mi nority of cases progress to plasma cell myeloma (116, 2078).

j

•

CHAPTER 4 Tumours of the oral cavity and mobile tongue

•

Malignant surface epithelial tumours Oral potentially malignant disorders and oral epithelial dysplasia Papillomas Tumours of uncertain histogenesis

•

Soft tissue and neural tumours Oral mucosal melanóma Salivary type tumours Haematolymphoid tumours

r

WHO classification of tumours of the oral cavity and mobile tongue Epithelial tumours and lesions Squamous cell carcinoma Oral epithelial dysplasia Low grade High grade Proliferative verrucous leukoplakia

8070/3 8077/0 8077/2

Neurofibroma Kaposi sarcoma Myofibroblastic sarcoma

9540/0 9 140/3 8825/3

Oral mucosa! melanoma

8720/3

Salivary type tumours Papillomas Squamous cell papilloma Condyloma acuminatum Verruca vulgaris Multifocal epithelial hyperplasia

8052/0

8430/3 8940/0


Tumours of uncertain histogenesis Congenital granular cell epulis Ectomesenchymal chondromyxoid tumour

Mucoepidermoid carcinoma Pleomorphic adenoma

8982/0

CD30-positive T-cell lymphoproliferative disorder Plasmablastic lymphoma Langerhans cell histiocytosis Extramedullary myeloid sarcoma

9718/3 9735/3 9751/3 9930/3

Soft tissue and neural tumours Granular ce ll tumour Rhabdomyoma Lymphangioma Haemangioma Schwannoma

106

9580/0 8900/0 9170/0 9120/0 9560/0

Tumours of the oral cavity and mobile tongue

The morphology codes are lrom the lnternational Classilication ol Diseases lar Oncology (!CD-O) (776A}. Behaviour is coded /0 far benign tumours; /1 far unspecified, borderline, or uncertain behaviour; /2 far carcinoma in situ and grade 111 intraepithelial neoplasia; and /3 lar malignan! tumours. The classification is modified from the previous WHO classilication, taking into account changes in our understanding of these lesions.

TNM classification of carcinomas of the lip and oral cavity

TNM classification of carcinomas of the lip and oral cavity•,b

N2b

T - Primary tumour

N2c

TX

Primary tumour cannot be assessed TO No evidence of primary tumour Tis Carcinoma in situ T1 Tumour s 2 cm in greatest dimension T2 Tumour > 2 cm but s 4 cm in greatest dimension T3 Tumour > 4 cm in greatest dimension T4a (lip) Tumour invades through cortical bone, inferior alveolar nerve, !loor of mouth, or skin (of chin or nose) T4a (oral cavity) Tumour invades through cortical bone, into deep/extrinsic muscle of tangue (genioglossus, hyoglossus, palatoglossus, and styloglossus), maxillary sinus, or skin of tace T4b (lip and oral cavity) Tumour invades masticator space, pterygoid platas, or skull base; or encases interna! carotid artery Note: Superficial erosion alone of bone / tooth socket by gingival primary is no! sufficient to classify a tumour as T4.

N3

Metastasis in multíple ipsilateral lymph nodes, ali s 6 cm in greatest dimension Metastasis in bilateral or contralateral lymph nodes, ali s 6 cm in greatest dimension Metastasis in a lymph node > 6 cm in greatest dimension

Note: Midline nades are considered ipsilateral nodes.

M - Distant metastasis MO M1


Stage grouping StageO Stage 1 Stage 11 Stage 111 Stage IVA Stage IVB Stage IVC

Tis T1 T2 T1-2 T3 T1-3 T4a AnyT T4b AnyT

NO NO NO N1 N0-1 N2 N0-2 N3 Any N Any N


N - Regional lymph nodes (i.e. the cervical nodes) NX NO N1 N2 N2a

Regional lymph nodes cannot be assessed No regional lymph node metastasis Metastasis in a single ipsilateral lymph node, s 3 cm in greatest dimension Metastasis as specified in N2a, N2b, or N2c below Metastasis in a single ipsilateral lymph node, > 3 cm but s 6 cm in greatest dimension

ªAdapted from Edge et al. (625A} - used with permission of the American Joint Committee on Cancer (AJCC), Chicago, lllinois; the original and primary source for this information is the AJCC Cancer Staging Manual, Seventh Edition {201 O) published by Springer Science+Business Media - and Sobin et al. (2228AI. hA help desk for specific questions about TNM classification is available at http://www.uicc.org/resources/tnm/helpdesk.

TNM classification of carcinomas of the lip and oral cavity

107


Takata T. Slootweg P.J.

lntroductíon

grading system and a binary system are described . For other grading systems and related terminology used for dysplasia/ squamous intraep ithelial lesion, refer to the corresponding sections in Chapter 3 (Tumours of the hypopharynx, larynx, trachea and parapharyngeal space, p . 77). Although the cause of oral SCC is multifactorial, accumulated information on etiological and genetic factors in oral SCC and related precursor lesions supports targeted diagnosis and therapy of oral SCC. The content of th is chapter reflects the increase in knowledge on oral diseases and its practica! application in diagnosis and treatment. Hitherto unrecognized new entities deserving to be listed as such in this chapter have not been identified.

In the previous edition, tumours of the oral cavity and oropharynx were discussed together in one chapter. Now, diseases of these two anatomical reg ions are the subjects of two separate chapters; this chapter being devoted to the oral cavity and Chapter 5 (p. 133) to the oropharynx. Furthermore, as in other chapters, in an effort to minimize overlap, only selected non-epithelial and soft tissue tumours, salivary neoplasms and haematolymphoid tumours are highlighted . The outcome of this approach is that the content of this chapter is much reduced in comparison with the previous edition. Lesions that deserve prime attention in this chapter are the mucosa! diseases. The most pivotal malignancy of the oral

108

cavity and mobile tongue is squamous cell carcinoma (SCC) arising from the mucosa! epithelium . More than 90% of oral cancers are SCC. Most cases of oral SCC are moderately to well differentiated. For more detailed information on subtypes of SCC, see the corresponding sections in Chapter 3 (Tumours of the hypopharynx, /arynx, trachea and parapharyngeal space, p . 77). Oral potentially malignant disorders, cl inical presentations carrying a risk of cancer development. and oral epithelial dysplasia, a spectrum of histological and cytological changes with an increased risk of progression to SCC, are also importan! lesions for secondary prevention of oral SCCs. There are difieren! kinds of grading systems for epithelial dysplasia. In this chapter, a traditional three-tiered


Malignant surface epithelial tumours

Sloan P. Gale N. Hunter K. Lingen M.

Nylander K Reibel J. Salo T. Zain R.B .

Boll'IHAH

Squamous ce// carcinoma oefinition oral squamous cell carcinoma (OSCC) is a carcinoma with squamous differentiation arising from the mucosal epithelium. The proportion of cases that arise in clini cally evident oral potentially malignan! disorders is unknown. lt is most frequent in the fifth and sixth decades of lite and is typically associated with risk factors such as smoking, alcohol consumption, and betel-quid chewing.

ICD-0 code

C•noe1 ofthf' 1/p and 01111»1ity

-

5.1•

-

3.8-5.1

1:1 2.5-3.S

D

u -2_5

D

<1_9

8070/3

Epidemiology More than 90% of cancers in the oral cavity are OSCCs. With respect to the epidemiology of oral cancer, specific geographical regions must be considered separately, because there is marked variation in incidence. Overall, oral cancer (when oropharyngeal siles are included) is the sixth most common cancer in the world [2548). The GLOBOCAN project estimated 300 373 new cases in 2012, with a global age-standardized incidence rate of 4.0 cases per 100 000 population per year and a global mortality rate of 1.9 deaths per 100 000 population per year [702). High incidence of oral cancer is found in southern Asia (e.g . India; Pakistan; Sri Lanka; and Taiwan, China), with age-standardized incidence rates of > 10 cases per 100 000 population per year in parts ot India and Pakistan (702). lncidence is also high in eastern and western Europe (e.g. Hungary, Slovakia, Slovenia, and France), Latin America and the Caribbean (e.g. Brazil , Uruguay, and Puerto Rico), and Melanesia (e.g. Papua New Guinea) (702). Worldwide, oral cancer incidence is higher among males (5.5 cases per 100 000 population per year) than temales (2.5 cases per 100 000). However, the rat io is the reverse in India and Thailand, where the reported male-to -temale ratios are 1:2 and U .56, respectively (1 280). Most oral cance rs occur in patients aged 5070 years . As smoking rates decline, the

A BOl~ H XU

Csnc:e-r ol the lip 111'\d 0
-

2 .2•

-

l.&-2.2

•

1,1.1 .c

C)

0 .07-1 .1

D

.

B Fig. 4.01 Worldwide age-standardized rate (ASR) of (A) incidence and (B) mortality per 100 000 population per year, both sexes, of lip and oral cavity cancer. Reprinted from GLOBOCAN 2012, Ferlay J et al. {702}.

incidence of intraoral cancer is decreasing in sorne countries, whereas slight increases among younger patients have been reported in other countries (1456, 2159).

Etiology Smoking is by far the most importan! cause ot oral cancer. There is a dosedependent increase in risk, and. risk decreases after smoking cessation {1071, 2550). Alcohol consumption interacts synergistica lly with smoking, resulting in a more than additive risk [121, 865,1073). Smokeless tobacco is used orally in most parts ot the world, by chewing (chewing

tobacco) or dipping (snuff). Smokeless tobacco in chewing or dipping torms causes oral cancer; however, sorne studies (in particular studies ot Swedish snuft) show negligible risk {229,1072). Areca nut and/or tobacco can be mixed with other substances (e.g. slaked lime, betel inflorescence, condiments, sweetening agents, and spices) to create b etel quid. Betel- quid chewing increases the risk of oral cancer whether or not tobacco is added (900). HPV, in particu lar type 16, is a recogn ized etiological factor in oropharyngeal cancer but is only seen in a small minority (3%) of osees (515, 840,1438,2135). Exposure to sunlight is

Malignan! surtace epithelial tumours

109

an established risk factor fo r lip cancer. In Western Australia, lip cancer accounts for as many cases as ali intraoral sites together {7) . Poor oral health is associated with oral cancer {591,899) but has not been proven an independent risk factor {2547}. A diet rich in fruits and vegetables seems to have sorne protective effect against oral cancer {264,1503}.

Table 4.01

Subtypes of squamous cell carcinoma (SCC) of the oral cavity and mobile tongue

Oral SCC subtype

Features

References

Basaloid SCC

High-grade carcinoma, more-frequent metastasis but overall prognosis comparable to that of conventional SCC

{774,2653)

Spindle cell SCC

Worse prognosis than conventional SCC in oral cavity and mobile tongue; typically occurs as postradiation recurrence or second primary

{187,824}

Adenosquamous carcinoma

Highly infiltrative and aggressive, frequent metastasis, worse prognosis than conventional SCC

(1194,1553,2113)

Carcinoma cuniculatum

Well differentiated, usually on mucoperiosteum, locally destructive deep burrowing pattern, metastasis rare, recurs locally but rarely if ever metastasizes

(2312)

Verrucous SCC

Well-differentiated non-metastatic variant with pushingsuperficial invasion, exophytic, lacks atypia, good prognosis; may progress to invasiva conventional SCC

{1517,1759,2060)

Lymphoepithelial carcinoma

Rare, present at high stage, 70% associated with regional lymph nade metastasis; not ali are EBV-positive

(2034)

Papillary SCC

Keratinizing and non-keratinizing types, often arises on gingivae; better prognosis than conventional SCC

{1517,2060}

Acantholytic SCC

High-risk cutaneous variant that may occur on the lip; acantholysis can result in an adenoid appearance inpoorly differentiated intraoral

{605,807,2730}

Localization Oral cancer can affect any area of the oral mucosa. The most common siles for intraoral cance r in many populations are the tongue, floor of the mouth, and gingiva, accounting for more than half of all oral cancers (1337,1544,2423}. However, site distribution varies depending on the prevailing risk factors. Among many Asian populations, osee most common ly affects the buccal mucosa, due to tobacco chewing and betel-quid chewing.

Clinical features Oral cancers can be detected by visual inspection and palpation followed by biopsy and histopathological examination. Evaluation of the neck is also importan!. Small cancers may be asymptomatic, whereas advanced tumours give rise to various symptoms and signs such as discomfort, pain, reduced mobility of the tongue, and irritation from wearing dentures. The clinical presentation is that of variably white, erythematous, mixed, nodular, and ulcerated changes; when present, ulcerated changes often have raised margins {120}. Non-healing ulceration is a feature suggestive of malignancy; however, in a recent study, ulceration in osee (including its variants) was seen in slightly less than hall of the cases (56). eancer of the lower lip typically presents as a crusting lesion, often preceded by actinic cheilitis. An essential part of the diagnostic procedure for oral cancer is palpation of the lesion, typical ly revealing induration. Untortunately, small cancers are often unapparent to both patients and health professionals, resu lting in diagnostic delay (872). One reason is that small cancers can mimic other lesions commonly seen in the oral cavity.

scc

Cytology lntraoral tumours are usually evaluated by surgical biopsy. Meta-analys is shows that adjunctive tests cannot replace scalpel biopsy and histological assessment for oral cancer diagnosis {1985}. Fineneedle aspiration is useful for the detection of lymph node metastasis. Aspirates are cellu lar, with sheets and small clusters of malignan! squamous ce lls with intracellular and extracellu lar keratinization. Mixed inflammation and necrosis can be present.

Histopathology Most cancers of the oral cavity and mobile tang ue are moderately or well

- ---

--

differentiated; poorly differentiated squamous cell carc inoma is less freq uent. Well-differentiated osee is characterized by nests, cords, and islands of large cells with pink cytoplasm, prominent intercellular brid ges, and round nuc lei, which may not be obviously hyperchromatic. Dyskeratotic cells and squamous pearls are prominent. Cellular and nuclear pleomorphism , nuclear hyperchromasia, and mitotic figures (including atypical forms) increase with tumour grade. Grading alone does not correlate well with p rognosis. In poorly differentiated osee, features of squamous differentiation are minimal or absent, requiring immunohistochemical confirmation; AE1 /AE3, e K5/6, p 63, and

Macroscopy Squamous cell carcinomas are firm infi ltrative tumours, with a tan or wh ite cut surface .

,•. ,. Fig. 4.02 Conventional, moderately differentiated oral squamous cell carcinoma showing keratin pearl formation.

110


Genetic susceptibility The evidence of inherited genetic susceptibility for the development of osee is limited. osee may arise as part of a more general cancer syndrome, such as in patients with Li-Frau meni syndrome (1924] or Fanconi anaemia (223} .


__

;__...

Fig. 4.03 Oral squamous cell carcinoma of mobile tongue showing an adverse pattern of infiltration.

p40 are useful markers. Well-differentiated tumours tend to invade in large islands, whereas less-differentiated tumours tend to have jagged or finger-like projections or small islands and dispersed ind ividual cells at the invasive front. Significan! desmoplastic stroma with inflammatory host response can be found around nests of invading tumour cells. Adjacent mucosa frequently shows various grades of epithelial dysplasia. Perineural and lymphovascular invasion are seen, more frequently in poorly differentiated tumours {258,297,1424,2494).

Genetic profile Most osees are genetically unstable (183,1885,2070). with chromosomal loss at 3p, 8p, 9p, 17p and gains at 3q and 11q {396,2375}. These changes may extend for sorne distance from the clinical lesion, underpinning the clinical phenomenon of f ield cancerization (249). Genes reported to have a role in osee (e.g. TP53, CDKN2A , PTEN, HRAS, and PIK3CA) are mutated with sufficient frequency to support their potential role as drivers in cancer development {818, 1492,1712,1885,2288,2375}.

eonventional osee is aggressive, with a propensity for local invasion and early lymph node metastasis. The most significan! prognostic factors are tumour size, nodal status, and distan! metastasis. eonventional histological grading correlates poorly with clinical outcomes (259). Histological risk factors associated with a worse prognosis include a non-cohesive pattern of invasion {1424). perineural and lymphovascular invasion {2636,2640). bone invasion {625], and thickness > 4 mm {57}. Margins from the resection specimen predict local control better than margins from the tumour bed {1562}. High-grade dysplasia at a mucosa! margin correlates with local recurrence and second primary tumours (1424,2561). Extracapsular spread f rom metastasis in the neck, two or more positive nodes, and involvement of levels IV and V correlate with adverse outcome.


11 1

Oral potentially malignant disorders and oral epithelial dysplasia

Reibel J . Gale N. HilleJ. Hunt J .L. U ngen M . Muller S. Sloan P

Oral potentially malignant disorders

{1567,2629), and whether it plays a role in transformation has yet to be determ ined.

Oral epithelial dysplasia

Definition

Localization

Oral potentially m alignant d isorders (OPMDs) are c linical presentations that carry a risk of cancer development in the oral c avity, whethe r in a clinically definable precursor lesion or in clinically normal oral mucosa.

OPMDs can involve any intraoral site. Their distri bution varíes by specific d isorder, with etiological factors, and to a certain extent patient age and sex {1704}. Erythrop lakia is most frequently seen on the soft palate, floor of the mouth, and bucea! mucosa {1972).

Definition

Epidemiology In western countries, the reported prevalence of leukoplakia generally ranges from 1% to 4%. Higher prevalence rates are reported in parts of south-eastern Asia {1704}. The g lobal prevalence of leukoplakia is 2- 3% {1871}. In contras\, oral erythroplakia is a rare lesio n, w ith prevalence between 0.02% and 0.83% {1972} . Men are affected m uch more commonly than women. Other O PMDs can be common, but have much lower transformation rates.

Etiology OPMDs have different causes. Tobacco use (smoking and/or chewing) and alcoho l consumption are associated with sorne leukoplakias {1704). The use of areca nut, w ith o r without tobacco, causes oral submucous fibrosis {2404). For many cases of OPMDs, no etiological factors are known . High-risk HPV infection is only very rarely present in OPMDs

Table 4.02 Oral potentially malignan! disorders

Clinical features Most high-risk OPMDs form red, wh ite, or sp eckled oral lesions. "Leukoplakia" is a clinical term used to describe white plaques of q uestionable risk, once other specific con ditions and other OPMDs have b een ruled out {2551}, which normally requ ires biopsy. Leukopl akias can be homogeneously white or predominantly white with nodular, verrucous , or red areas . Predominantly wh ite examples with red areas are called erythroleukoplakias (speckled leukoplakias). Oral erythroplakia is defi ned equivalently, but as a red patch. Specifically defined OPMDs have characteristic presentations, and epithelial dysplasia may or may not be present. Other OPMDs have been reviewed elsewhere {2475).

Genetic susceptibility OPMDs are seen in the rare disorders Fanconi anaemia {889) and dyskeratosis congenita {932), but no genetic predisposition is present in most cases.

Erythroplakia Erythroleukoplakia Leukoplakia Oral submucous fibrosis Dyskeratosis congenita Smokeless tobacco keratosis Palatal lesions associated with reverse smoking Chronic candidiasis Lichen planus Discoid lupus erythematosus Syphilitic glossitis Actinic keratosis (lip only)

112

Tilakaratne W.M. Westra W.H . Williams M.O. Vigneswaran N. Fatani H A Odell E.W. Zain R.B.

Prognosis and predictive factors The transformation risk in many OPMDs is low, and many regress (1307}. For leukoplakia, a mean global transformation rate of 1- 2% has been estimated {1871}. A meta-analysis of cases with oral epithelial dysplasia found a transformation rate of 12% (1579). Presence of oral epitrielial dysplasia is the most important prognostic factor for malignant transformation, but clinical characteristics such as appearance (homogeneous vs. non-homogeneous), size, and site also have implications for clinical management {1704}.

Tumours of the oral cavity and mobile tangue

Oral epithelial dysplasia (OED) is a spectrum of architectural and cytolog ical epithelial changes caused by accumulation of genetic changes , associated w ith an increased risk of progression to squamous cel l carcinoma.

ICD-0 codes Low grade High grade

8077/0 8077/2

Synonyms Epithelial precursor lesions; intraepithelial neoplasia; squamous intraepithelial lesions

Histopathology OED includes abnormal proliferation, maturation , and differentiation of epithelial cells. The epithelium may be atrophic, acanthotic, keratinized, or non-keratinized. Dysplasia is present in a minority of leukoplakias but is a consisten! finding in erythroplakia and erythroleukoplakia. Tab le 4.03 lists the architectural and cytological disturbances that are used to diagnose OED. The number and combination of featu res vary between lesions. There is no good evidence to indicate how the presence of individual features cou ld be translated into a grade of dysplasia . No specific combination of features reliably distinguishes hyperplasia from mild dysplasia. OED may be diagnosed on the basis of architectural or cytological features alone. Traditio nally, OED is divided into th ree grades of severity. Judging the number of thirds of the epithelium affected is one factor in defining a grade. Mild dysplasia can be defined by cytological atypia limited to the basal third, moderate dysplasia by extension into the middle third , and severe dysplasia by extension into the upper third. However, arch itectural and cytological atypia and the architecture of the connective tissue interface should increase the grade. Marked atypia in the basal third of the epithelium may be sufficient for a diagnosis of severe dysplasi a. Carcinoma in

{316,2017) in combination with two additional markers at 4q and 17p {2712}.

Table 4.03 Diagnostic criteria for epithelial dysplasia; adapted from Barnes Letal. {146) Architectural changas

_____

Cytological changes

Irregular epithelíal stratification

Abnormal variation in nuclear size

Loss of polarity of basal cells

Abnormal variation in nuclear shape

Drop-shaped rete ridges

Abnormal variation in cell size

lncreased number of mitotic figures

Abnormal variation in cell shape

Abnormally superficial mitotic figures

lncreased N:C ratio

Premature keratinization in single cells

Atypical mitotic figures

Keratin pearls within rete ridges

lncreased number and size of nucleolí

Loss of epit11elíal cell cohesion

Hyperchromasia


Table 4.04 Grading systems for epithelíal dysplasia WHO dysplasia grade

Binary system

Mild dysplasia

Low-grade dysplasia -

Moderate dysplasia

-

High-grade dysplasia

e --

Severe dysplasia ~

The cut-off point betweenlow-grade and high-grade dysplasia, as suggested by Kujan O et al. {1291), is tour architectural and five cytological changes (see Table 4.03}, irrespective of the level within the epithelium. According to Nankivell P et al. {1702), a cut-off point of tour architectural and four cytological changes may improve prognostication.

situ in the oral cavity is considered synonymous with severe dysplasia. Dysplasia grading is poorly reproducible between observers. Sorne studies show good prognostic value (2250). but others find a poor association with outcome {721, 1505) . Consensus grading after review by more than one pathologist may enhance diagnostic reliabil ity (733,2249,2250). To improve reproducibility, sorne authors advocate a binary system (1291 ,1702,2553}, in line with proposals for laryngeal lesions (798), but binary scoring requires validation befare it can be routinely applied in the oral cavity. An unusual subset of OEDs positive for

HPV has been described, histologically characterized by epithelial hyperplasia and marked karyorrhexis and apoptosis throughout the epithelium {2629). According to conventional criteria, these qualify as severe dysplasia, but the risk of transformation has yet to be determined . lmmunostaining far p16 alone cannot be used as a surrogate marker for HPV infection in OED.

Genetic profile Prognostic genetic and molecular markers for malignan! transformation have been reported {1902,1971). most notably LOH at chromosomal arms 3p and 9p

Although the presence of dysplasia corre lates with the development of squamous cell carcinoma, most OEDs never progress to carc inoma. A metaanalysis of lesions with OED showed a transformation rate of 12% [1579). Generally, the more advanced the degree of dysplasia, the higher the likelihood of developing squamous cell carc inoma {1366,1579,2176,2552}. The 15-year mal ignan! transformation rates of mild, moderate, and severe dysplasia (as defined by the traditional three-grade system) are approximately 6%, 18% , and 39%, respectively, and the presence of dysplasia indicates long-term risk {2250) . The general problem of low reproducibility of curren! diagnostic c riteria underlies the poor correlation with transformation found in sorne studies {276,601,1016).

Prolíferative verrucous leukoplakia Definition Proliferative verrucous leukoplakia (PVL) is a distinct and aggressive form of oral potenti ally malignan\ disorder {2551). lt is multifocal, has a progressive course, and is associated with high recurrence and malignan! transformation rates {2,839,936).

Epidemiology PVL is rare in comparison with conventional oral leukoplakia. lt occurs in older

Table 4.05 Selected recen! reports on malignan! transformation of oral leukoplakia; in part adapted from Warnakulasuriya S and Ariyawardana A {2549)

Country

Cases

Notes

Observation period (years)

Frequency of malignan! transformatlon

Japan

142

a, b

4 (0.6-16)

6.3%

Denmark

254

a, b

6 (1.1-20.2)

6.7%

Warnakulasuriya Set al. 2011 {2552); Sperandio M etal. 2013 {2250)

United Kingdom

335

a,b

9

6.9%

Ho MW et al. 2012 {1007)

United Kingdom

83

a,c

China

320

a, c

Authors/year

Saito T et al. 2001 {2046) ~

lmstrup P et al. 2006 {1016)

--

Liu W et al. 2012 {1450) Brouns E et al. 2014 {276) Dos! F et al. 2013 {600) Mehanna HM et al. 2009 {1579)

Netherlands

144

Auslralia

368

Meta-analysis

992

-

·-

5

24.1%

5.1 (1-20)

17.8%

a,b

4.7 (1-14.9)

11.0%

a,c,d

Not available

7.1%·

Not applicable

12.1%

1----

c, d

>-

-

"rreated and untreated cases. bWith and without dysplasia. coysplasias only. dlncludes clinical diagnoses other !han leukoplakia. "Annual transformation rate: 1%.

Oral potentially malignan! disorders and oral epithelial dysplasia

113

exophytic growth resulting in a warty (verrucoid) surface with focal erythematous areas, and (4) development of verrucous or squamous cell carcinoma {839}. However, not every PVL goes through these clinical stages, and development of carcinoma has been noted in PVL clinically presenting as multifocal flat patches.

Histopathology Fig. 4.04 Proliferative verrucous leukoplakia. A61-year-old woman presented with an advanced proliferative verrucous leukoplakia involving the dorsal (A) and ventral surfaces of the tongue and palate (B). The patient had undergone multiple biopsies and surgeries during the previous 4 years, which had resulted in diagnoses of invasive and in situ squamous cell carcinomas.

patients (aged > 60 years), with a femaleto-male ratio of 4:1 {2,311}.

Etiology The etiology is unknown. In Europe and North America, PVL is not associated with known risk factors of oral cancers (i.e. tobacco use and alcohol consump tion). Neither HPV nor any other virus is associated with the development of PVL (81 1).

Localization PVL frequently involves gingiva, alveolar mucosa, and palate {839). The lateral and ventral surfaces of the tangue and floor of the mouth are rarely involved during the early stages of PVL.

Clinical features PVL exhibits varied clinical features in four clinical stages: (1) focal flat white keratosis, (2) diffuse and multifocal white patches, (3) slowly progressive horizontal and

Histopathology corresponds to the varied clinical features of PVL: localized flat or verrucous hyperorthokeratosis with minimal or no dysplasia, resulting in the underestimation of risk of malignan! transformation of these lesions during their early stages. Dysplasia develops only during th e late stages of PVL, before progressing into either verrucous or squamous cell carcinoma (839). Definitive diagnosis of PVL requires clinical and histopathological correlation. PVL frequently shows interface mucositis characterized by a band-like, lymphohistiocytic infiltrate subjacent to the basal cells; therefore, it may be misdiagnosed as lichen planus in early stages {311,839}. However, the

.

•~~·,

f'l'\,~ ·f l::.~

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Fig. 4.05 Oral epithelial dysplasia. A Hyperkeratosis with normal architecture and cytology. B Mild dysplasia: lack of polarization of basal cells, abnormal variation in nuclear size, shape, and stainability (hyperchromasia), and increased number of mitotic figures. Changes are confined to the basal third of the epithelium. C Moderate dysplasia: drop-shaped rete ridges, mild abnormal variation in nuclear size and stainability (hyperchromatism), increased nuclear/cytoplasmic ratio, and atypical mitotic figures in the basal/parabasal area. Changes extend to the mid-third of the epithelium.

114


presence of any dysplasia precludes the diagnosis of lichen planus. Diagnosis also requires the distinction of PVL from other white oral lesions by correlating the clin ical and microscopic presentations both retrospectively and prospectively through clase surveillance.

suppressor proteins p16 (p161NK4a) and p14ARF, is more frequent in PVL {1279} than in other oral potentially malignan! disorders. Like other oral potentially malignan! disorders, PVLs also develop chromosomal instability, and DNA aneuploidy can predict their risk of developing into carcinoma {1234).

rate of 30-40% (2,311 ). Carcinomas arising from PVL have better prognosis and long -term survival !han do conventional oral cancers. The development of multiple primaries at different locations is not uncommon in patients with PVL {36).

Genetic profile lnactivation (by homozygous deletion) of COKN2A (also called P16/NK4a and P14ARF), which codes for the tumour

Prognosis and predictiva factors As many as 70% of PVLs develop into invasive cancer, resulting in a mortality

Papillomas Squamous ce// papilloma

Etiology HPV infection has been reported, with the most common types being 6 and 11 (886,1168,1668,2324}. Reported prevalence rates of HPV DNA in oral squamous cell papillomas range from 0% to 100% (average: 34%) {1168,1668). This considerable variation may be due to differences in the HPV detection techniques used .

Muller S. Gale N. Odell E.W. Richardson M. Syrjanen S.

Definition Squamous cell papilloma is a benign hyperplastic exophytic localized proliferation with a verrucous or cau liflower-like morphology [2284l.

ICD-0 code

8052/0

dome-shaped and have a more nodular, papillary, ar verrucous surface (1925, 2284). Most squamous cell papillomas are solitary and grow rapidly to about 0.5 cm. Clinically distinguishing oral squamous cel l papilloma from verruca vulgaris, condyloma acuminatum, and multifocal epithelial hyperplasia is difficult [2325). Multiple papillomas can be seen in the setting of solid organ transplant and HIV infection .

Localization Any oral site can be involved, but the most common sites are the soft palate, tangue, lips, and gingiva (1914,1925, 2284).

Epidemiology

Clinical features

Squamous cell papillomas are common and can occur in patients of any age, although they occur more frequently in the third to fifth decades of lite {1914,1925,2284) . There is an equal sex distribution.

Squamous cell papillomas may" be pedunculated or sessile. The pedunculated lesions are composed of a cluster of finger-like fronds and may be white or mucosa! in colour, depending on the degree of keratinization. The sessile lesions are

Histopathology The lesions are exophytic, composed of papillary proliferations of hyperplastic stratified epithelium that are either covered by a layer of parakeratin or orthokeratin of variab le thickness or are non-keratinized (2284} . The finger-like epithel ial projections extend from a narrow base, supported by fibrovascular cores containing dilated capillaries. The stroma may be oedematous or hyalinized. Koilocytes are infrequent and Papillomas

115

mitotic activity unusual, except in the setting of trauma or inflammation [2284).

Prognosis and predictiva factors Treatment is simple excision, and recurrence is unusual {1914). There have been no reports of malignan! transformation or dissemination.

Etiology

Histopathology

HPV type 6 or 11 is identified in most cases. Neither histological appearance nor HPV type is an accurate indicator of genital origin, and non-sexual transmission is possible {2325}.

Histopathology shows a hyperplastic squamous proliferation associated with fibrovascular cores, exophytic growth, and a broad base. Basilar nuclear enlargement may be present, but keratinocyte maturation is maintairied, typically without the keratinizati on seen in verruca vulgaris. Compared with squamous cell papillomas, CAs have broader papillae, wh ich are o/ten blunted. The rete processes are bulbous, short, and straighter than those seen in papillomas, and koilocytes are more readily identified [77). In situ DNA hybridization or PCR amplification studies may be required far detection and typing of HPV to distinguish these lesions from other exophytic growths, including verrucous squamous ce ll carcinoma.

Localization CAs most o/ten occur on the labial mucosa, soft palate, and frenulum {2284}.

Condyloma acuminatum Clinical features Vigneswaran N. Lippman S. Muller S. Williams M.O.

Definition Oral condyloma acuminatum (CA) is the oral equivalent to anogenital CA.

Clinically, CA presents as a single or cluster of asymptomatic, painless sessile masses with an exophytic growth pattern. The surface is finely nodular, pink to slightly red , and tlatter than that of verruca vulgaris. The lesions are larger than squamous cell papillomas; reaching 15 mm in diameter {976,2284).

Prognosis and pred ictiva factors Recurrence after excision is common and more frequent than in squamous cell papillomas. Malignant transformation has not been reported in oral CA. HPV vaccines that protect against types 6 and 11 could also help to prevent associated CA {993}.

Synonym Venereal condyloma

Epidemiology Oral CAs are frequently transmitted sexually, with a peak incidence in young adults and a male predominance {1258, 2284). Autoinocu lation in patients with genital CA has been reported. Occurrence in children may be associated with sexual abuse {2284). Multiple CAs may indicate immunodeficiency.

116

Fig. 4.09 Condyloma acuminatum. Clinically, a sessile, flnely nodular, pink mass is identifled on the frenulum of the tangue.

Tumours of the oral cavity and mobile tang ue

Verruca vulgaris Muller S. Lippman S. Wil liams M.O.

The elongated rete ridges converge towards the centre. A prominent granular cell layer with keratohyalin granules often shows koilocytic changes.

Prognosis and predictive factors Definition Verruca vu lgaris (VV) is a benign virusinduced hyperplastic localizad pro liferation w ith a verrucous or caulif lower-like morphology {2284).

Spontaneous regression is seen, particu larly in ch ildren. Treatment is simple excision, and recurrence can occur (886, 1455,1925).

Mulüfocalepfthellalhyperplasia Vigneswaran N. Carlos R. Lippman S. Mosqueda-Taylor A. Muller S. Williams M.O.

Etiology Commonly reported HPV types include 2, 4, 40, and 57 {541,1455,2284).

Localization The most common ly reported oral sites are the lips, hard palate, anterior tongue, and gingiva.

Definition Multifocal benign squamous epithelial proliferation exclusively affecting oral mucosa, caused by human papilloma virus (HPV) {1965,2042).

Synonyms Heck disease; focal epithelial hyperplasia

Clinical features VV is asymptomatic. lt may be pedunculated or sessile with a rough pebbly or papillary white surface {1455,1925,2284). VVs grow rapidly (to a maximum size of < 5 mm), and multiple or cluste red lesions can occur.

HPV types 13 and 32 are implicated. However, other genotypes such as 1, 6, 11 , 16, 18 and 55 have also been detected {974,2042}. MFEH in o lder patients is mainly caused by HPV 32 (2042). Low socioeconomic status, malnutrition and c rowded living conditions are thought to be contributing factors. These probably explain the striking epidemio logical d ifferences between developed and developing countries . HIV patients have increased risk for MFEH (2042,1 233}.

Localization The most common locations for MFEH are the lips, buccal mucosa, and borders of the tongue. Hard palate and g ingiva are rare ly affected {2042}. The lowe r lip is characteristically more affected than the upper lip, and most lesions in the buccal mucosa are located along the occlusal plane.

Clinical features

Histopathology VVs are exophytic, composed of papillary proliferations of hyperplastic stratified epithelium that are covered by a thick layer of orthokerati n ¡1925,2284).

M ultifocal epithelia l hyperplasia (MFEH) is more prevalen! in ch ildren and adolescents with a female predominance as high as 5:1 {1965,2042). First reported in Native Americans and Eskimo peoples, it is panracial, documented in a lmost every ethnic group and geographical reg ion {2042).

Etiology

Epidemiology VV is the most common HPV-related lesion of the skin, but can also occur in the oral mucosa, perhaps as a result of autoinoculation {886,1925). Oral VV is most common in the third to fourth decade of life, w ith a slight male pred ilection.

Epidemiology

Fig. 4.11 Multiple papules in the lower lip mucosa of a 15-year-old boy.

MFEH presents as multiple papules similar in colour to the adjacent mucosa, measuring up to 5-10 mm. They may coalesce, forming plaques that may become secondarily ke ratinized. The most common appearance is a papulonodula r form w ith a smooth surface that occurs in the non-keratinized mucosa. Papillomas

117

functional inactivation of the RB gene and hence p16 immunohistochemistry has no diagnosti c role.

Genetic susceptibility Familia! transmission of MFEH is linked to the presence of HLA-DRB1*0404 (810). Prognosis and predictive factors Most lesions in children spontaneously disappear al puberty or with improved living conditions.

Fig. 4.12 Focal epithelial hyperplasia, viral change and mitosoid body (inset).

Histopathology MFEH shows mild hyperkeratosis and prominent acanthosis, with preservation of normal cell maturation {2042). Occasional koilocytes and "mitosoid" figures composed of cells with karyorrhectic nuclei that may mimic mitoses,

118

representing a cytopathic nuclear viral damage, are noted within ali epithelial layers {2042). The mitosoid figures are the most importan! feature of this entity; they are not present or are extremely rare in other HPV-related lesions. HPV subtypes implicated in MFEH do not cause


Tumours of uncertain histogenesis

congenital granular ce// epulis Allen C.M . Bullerdiek J. RoJY

Definition Congenital granular cell epulis is a rare benign tumour that affects the alveolar processes of newborns and is composed of sheets and nests of cells with abundan! granular cytoplasm {479).

Fig. 4.14 Congenital granular cell epulis of the maxilla.

overlying surface epithelium is usually attenuated, and pseudoepitheliomatous hyperplasia is not a feature. The tumour nuclei are typically small, uniform, and pale-staining, with no evidence of mitotic activity {428). In most cases , numerous small, thin-walled blood vessels are uniformly distributed throughout the lesion . Unlike the lesiona! cells of granular cell tumour of the tangue, those of congenital granular cell epulis show no reactivity for S100 protein.

Prognosis and predictiva factors Synonyms Congenital epulis; congenital epulis of the newborn; congenital gingival granular cell tumour; Neumann tumour

Epidemiology Congenital granular cell epulis affects newborns. Most series identify a striking female predilection {2698).

Fig. 4.15 Congenital granular cell epulis. Lesiona! cells with small, uniform nuclei and abundan! granular cytoplasm.

Localization Most cases develop on the maxillary anterior alveolar process, although the mandibular anterior alveolar process can also be affected {428}.

from < 1 cm to severa! centimetres in diameter {1293).

Histopathology Congenital granular cell epulis is characterized by sheets and nests of larg e polygonal cells with demarc ated cell membranes and granular cytoplasm . The

Clinical features Congenital granular cell epulis typically presents as a pedunculated soft tissue mass of normal mucosa! colour, ranging

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• ~ 4 1' I • • ,. '¡ • • 1 ~ ~ ~~ '1 ' . . . 4(1' ., • " _.. • , ~ • ,# ., ' ~"i ..,,.._ • • , ..... . • •• . .,. • .. . ~ ;. ~ .. , . ~ ¿ .... ., . " . ' ~ ~ ~·- .. - .... ' Fig. 4.13 Congenltal granular cell epulis. Bland, attenuated surface oral epithelium and underlying sheets of uniformly distributed lesiona! cells with scattered delicate blood vessels.

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Definition Ectomesenchymal chondromyxoid tumour (EMCMT) is a benign mesenchymal neoplasm composed of cells phenotypically resembling myoepith elial cells.

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Bishop J. A. Gnepp D.R. Ro J.Y.

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Conservative excision is the treatment of choice, particularly if the lesion interferes with eating or breathing !1304). Excisional biopsy may also be indicated if the clinical diagnosis is uncertain. For smaller lesions, observation may be appropriate, because spontaneous regression has been noted occasionally. Recurrence is not seen.

Epidemiology About 60 cases of EMCMT have been reported, affecting a wide patient age range (7- 78 years), with a mean patient age of 37 years. No sex predilection is apparent (44,2218}.

Tumours of uncertain histogenesis

119

Localization

Histopathology

In the oral cavity, EMCMT arises almos! exclusively in the dorsum of the anterior tangue. Rare cases have been reported in the posterior tangue and hard palate {44,1735).

EMCMT is an unencapsulated but generally well-circumscribed neoplasm within the tangue submucosa. Entrapment of skeletal muscle fi bres may be seen. At low power, EMCMT grows as lobules of cells separated by fibrous bands, with freq uent slit-like clefts within the tumour. The tumour cells are round, fusiform, or spindled cells arranged in cords, sheets , or a reticulated pattern within a myxoid or chondromyxoid stroma. Tumour cells have moderate amounts of eosinophilic to amphophilic cytoplasm, indistinct cel l borders, and nuclei with irregular membranes (e.g. with indentations or pseudoinclusions). Hyperchromatic nuclei and nuclear enlargement or multinucleation may be encountered . Mitotic figures are rare. Plasmacytoid cells and ductal structures are not encountered. •

Clinical features EMCMT presents as a longstanding (present fo r months or even years), painless, submucosal tangue mass without ulceration.

Macroscopy EMCMTs are generally small (< 2 cm), circumscribed, tan-g rey nodules with a gelatinous gross appearance.

Cytology Cytology shows cellu lar smears with myxoid to thick fibrillary tissue fragments, with clusters of oval, polygo nal, or spindled cells with uniform nuclei [440).

120


EMCMT is consistently immunoreactive fa r GFAP and usually immunoreactive far S100 protein and CD57. lmmu nostaining far cytoke ratins, EMA, actin, and p63 is variable [44,2218).

Cell of origin The cell of orig in is unknown . EMCMT may arise from undifferentiated ectomesenchymal cells from the embryonic neural crest mesenchyme of the first b ranchial arch [2218). Minar salivary gland origin is less likely, given th e inconsistent cytokeratin immunostaining and absence of minor salivary glands in the dorsal anterior tangue {880}.

Prognosis and predictive factors The prognosis is excellent, with a low risk of recurrence.

Soft tissue and neural tumours

Granular ce// tumour Allen C.M. Gnepp D.R. Ro J.Y.

Definition Granular cell tumour is an uncommon benign tumour of Schwann-cell differentiation characterized by poorly demarcated accumulations of plump granular cells (2458).

ICD-0 code

9580/0

Synonyms Granular cell myoblastoma; granular cell schwannoma; granular cell neurofibroma; Abrikossoff tumour (ali obsolete)

Epidemiology Most granular cell tumours are diagnosed duri ng the third to fifth decades of lite, although they may occur in patients of any age. Most reports describe a female-to-male ratio of 2:1, anda higher incidence in Black populations has been noted .

Localization Although granular cell tumour can affect any subcutaneous ar submucosal site, approximately 30-40% of cases occur on the tangue. The buccal mucosa is the second most common intraoral site.

Clinical features Granular cell tumour presents as a nontender, rubbery-firm, slow-growing, sessile, submucosal mass. On palpation, the tumour often feels demarcated, but not encapsulated. lf the tumour is near the surface, a yellowish to creamy-white colour is afien apparent. Most granular cell tumours are solitary, but multiple tumours have infrequently been reported (2074).

Macroscopy On cut surface, the tumour is a pale tan to yellowish-white submucosal nodule.

Histopathology

Fig. 4.17 Granular cell tumour. Sessile nodule of the dorsal tangue showing intact surface mucosa that is stretched by the underlying tumour.

This unencapsulated submucosal tumour intermingles with the adjacent normal tissue. The lesiona! cells usually appear polygonal and exhibit abundan! eosinophilic granular cytoplasm . The tumóur nuclei may be centrally or eccentrically located and are typically uniformly small, round, and pale-staining . The granular cells are often intimately associated with adjacent muscle fascicles or nerves. Sorne

granular cell tumours have a significan! degree of background fibrosis, with relatively few lesiona! cells. The cytoplasmic granules give a diastase-resistant positive peri odic acid-Schiff (PAS) reaction. lmmunohistochemistry is positive for S100 protein, CD57, and SOX10 {72). CD68 antibodies also label th e cytoplasmic granules . Pseudoepitheliomatous hyperp lasia overlies a substantial proportion (30- 50%) of these lesions; therefore, care should be taken when evaluating a superficial biopsy sample to preven! an erroneous diagnosis of squamous cell carcinoma. Rare cases of granular cell tumour with concurren! squamous cell carcinoma have been reported, so care ful and thorough evaluation of sections is necessary {1 68l. Rare examples of malignant granular cell tumour (characterized by pleomorphism , mitotic activity, spindle-shaped lesiona! cells, and necrosis) have also been described (2458).

Soft tissue and neuml tumours

121

Cell of origin lmmunohistochemical studies suggest differentiation consistent with an origin from Schwann cells {1976}. Prognosis and predictive factors Although recurrence is possible, the likelihood seems to be low, even when lesiona! tissue appears to have been transected at the margins {2458}.

Bullerdiek J. Ro J .Y. Thompson L.D.R.

Definition Rhabdomyoma is a benign tumour with skeletal muscle differentiation.

8900/0

Epidemiology Rhabdomyoma is divided into fetal, juvenile, and adult subtypes on the basis of histology rather than patient age. For adult rhabdomyoma, patient age varíes broadly (with a median age in the sixth decade of life {457)). Fetal rhabdomyoma usually occurs in newborns and during early childhood . There is a male predominan ce. Localization Rh abdomyomas occur predominantly in the head and neck. About 15% of patients with adult rhabdomyoma present with multifocal disease (1427}. Common localizations are the parapharyngeal

122

Genetic profile Aberrations of the PTCH1 locus have been reported in fetal rhabdomyomas {982\, which may be associated with naevoid basal cell carcinoma syndrome.

Clinical features The tumours present as soft, painless and non-tender masses.

Prognosis and predictive factors Recurrences are uncommon after surgical excision. Malignant transformation does not occur.

Macroscopy Rhabdomyoma presents as a well-delineated, rounded or coarsely lobulated, sessile or pedunculated smooth submucosal mass that is greyish-yellow to reddish-brown on cut surface. The tumours can be 0.5-10 cm, with most examples measuring 1-3 cm . There is no haemorrhage or necrosis.

Rhabdomyoms

ICD-0 code

space (affected in 36% of cases), larynx (15%), submandibular (14%), paratracheal region adjacent to the thyroid gland (12%), tangue (11 %), and floor of the mouth (9%) {540).

Histopathology The adult type is composed of variably sized, deeply eosinophilic polygonal cells and cells with vacuolated cytoplasm (spider cells). Rod-shaped cytoplasmic crystals (so-called jackstraws) or cross striations may be seen. Necrosis and mitoses are absent. The fetal type is composed of an intimate, haphazard-looking mixture of round or spindled mesenchymal cells and differentiated cells with myofibrils within an occasionally myxoid mucopolysaccharide-rich matrix . There is a gradient of cellularity or maturation towards the periphery. Strap cells with eosinophilic cytoplasm, occasionally with cross striations, may be seen. 'íhere is immunopositivity for SMA, desmin, myoglobin, and MYOD1; fetal myosin may be seen in th e fetal type. S100 protein and GFAP may be focally expressed .


Lymphangioma Bullerdiek J. Flucke U.

Definition Lymphangioma is a congenital malformation of lymphatic vessels. ICD-0 code

9170/0

Synonyms Lymphangioepithelioma (obsolete); lymphangiomatous polyp Epidemiology Lymphangiomas are rel atively uncommon. They are usually diagnosed in infancy or early childhood. Localization The skin and subcutaneous tissue of the head and neck region is the most common localization far lymphangiomas, but they are only occasionally re ported in the oral cavity. lntraoral lymphan giomas arise most commonly on the dorsum of the tangue, followed by the palate, bucea! mucosa, gingiva, and lips {2450}.

pericytes. The lumina may be subtle or d ilated, especially in infantile haemangiomas {280,1 141). Cavernous haemangiomas show larger dilated vascular spaces lined by endothelial cells. The endothelial cells are positive for CD34, CD31 , and ERG {280,1611). GLUT1 is positive in infantile haemangioma but negative in pyogenic granuloma, vascular ectasias, and congenital haemangioma {280, 1141,1746). Haemangiomas must be distinguished from pyogenic granulomas, which are ulcerated reactive lesions frequently arising on the g ingiva and characterized by lobular accumulations of maturing vascular granulation tissue.

Clinical features Clinical behaviour varíes, with erratic growth, progression, or even spontaneous regression during the first two decades of lile. Symptoms are related to size and perturbation of structure {280,2450). The lesions can be pedunculated or sessile.

Histopathology The malformations consist of variably sized, irregular, thin-walled fluid-fil led spaces lined by lymphatic endothelium surrounded by a stroma of fibrous, smooth-muscle, and adipose tissue, along with lymphocytes {280}. The vascular endothelial cells are immunopositive for CD31 or CD34 {1186), podoplanin (as recognized by 0 2-40), PROX1, and VEGFR3. Lymphatic endothelial cells stain for LYVE1 {280,1163,1536}. The wal ls of the lymphatic vessels stain positively for SMA (1186,1977}.

Genetic susceptibility Like other vascular anomalies, malformations of lymphatic vessels are com mon in Proteus syndrome {465}, wh ich is caused by a somatic activating mutation in AKT1 {1437). Other genetic disorders associated with lymphang ioma include Turner syndrome {45,X syndrome) and trisomy 21 {280}.

Haemangioma

Genetic susceptibility Haemangiomas have been described in carriers of various chromosomal abnormalities {39,2425,2484) and are frequently associated with full or partial polysomy 13 {108,1443,2007] .

Bullerdiek J. Flucke U.

Definition Oral haemangiomas are benign vascu lar hamartomas affecting the mucosa. They are distinct from vascular ectasias, vascu lar malformations, and s (also called lobular capillary haemangiomas).

ICD-0 code

9120/0

Recurrences may occur alter surgical resection {280}.

lnfantile haemangiomas initially grow rapidly, but most subsequently involute and require no intervention. Successful treatment options are beta blockers, steroid injection, endovascular sclerotherapy, and surgery {15,1669,2577).

Epidemiology Haemangiomas are frequent childhood tumours with a female predominance. They occur commonly in the head and neck region in both children and adults, but only rarely in the oral cavity (including the tangue) {11,235,1290). However, haemangioma (infantile haemangioma) is the most common benign tumour of the oral cavity and mobile tongue in the paediatric population {1502,2080)

Localization In the oral cavity, haemangioma can arise in the tongue, lips, buccal mucosa, gingiva, and palate {1502,1669,2682}.

Clinical features Prognosis and predictiva factors


The tumours present as smooth reddishpurple polypoid or pedunculated masses, often with increasing size and occasional bleeding.

Schwannoma and neurofibroma Flucke U. Wenig B.M.

Definition Schwannoma and neurofibroma are benign peripheral nerve sheath tumours. Schwannoma consists of Schwann cells, and neurofibroma consists of an admixture of Schwann cells, fibroblasts, perineurial-like cells, and axons.

ICD-0 codes Schwannoma Neurofibroma

9560/0 9540/0

Synonyms Schwannoma: neurilemmoma; neurinoma

Histopathology

Epidemiology

Capillary haemangiomas consist of multilobular arrangements of proliferating endothelial cells and capillaries of various shapes and sizes surrounded by

Schwannomas usually occur in adults. Neurofibromas are the most common benign peripheral nerve sheath tumour affecting infants, ch ildren , adolescents, Soft tissue and neural tumours

123

and adults {357,933,2005) .

Etiology Most lesions occur sporadically (933, 2005).

Localization lntraorally, the tangue is the most cornmon site, followed by the palate, bucea! mucosa, floor of the mouth, lips, gingiva, and jaws {656,933,1311,1440,1499}.

Clinical features Patients present with a slow-growing, sometimes painful, submucosal mass. Multiple neurofibromas are associated with neurofibromatosis type 1 {357,933, 952).

random rearrangement of spind le cells in a collagenous to myxoid stroma. The nuclei are wavy and the cytoplasm inconspicuous. Mitotic figures are usually absent. The collagen bundles typically have a so-called shredded-carrots appearance {2005}. Schwannomas show strong and diffuse nuclear and cytoplasmic S100 protein expression, as we ll as nuclear S0X10 reactivity. Scattered CD34-positive cells may be seen. In contras!, neurofibromas show heterogeneous expression of these markers (357,952,1183,1797,2005}.

Kaposi sarcoma Thompson L.D.R. Ro J.Y. Wenig B.M.

Definition Kaposi sarcoma is a locally aggressive vascular neoplasm of intermediate type, uniform ly associated with HHV8.

ICD-0 code

Genetic profile

Synonym Kaposi disease

Macroscopy

Schwan nomas are characterized by loss of chromosome 22 and inactivating mutations in NF2 {2267}. Neurofibromas are characterized by inactivation of NF1 {357}.

Both lesions are nodular with a tanwhite, glistening cut surface. An associated nerve can occasionally be identified {357,2005).

Neurofibroma is associated with neurofibromatosis type 1 (357,2005}.

Histopathology


In mucosal sites, schwannomas are typically submucosal and circumscribed but unencapsulated. They are composed of a spindle-cell proliferation arranged in alternating cellular Antoni A and hypocellular Antoni B areas. The spindle cells have oval, tapered, or buckled nuclei with poorly defined eosinophilic cytoplasm. Nuclear palisading is a frequent feature, occasionally with Verocay body formation. Degenerative nuclear atypia and mitotic figures should not be interpreted as ominous signs. Associated hyalinized blood vessels and foamy histiocytes are common. Haemorrhage and lymphocytes may be present {952,2005). Neurofibromas are characterized by

Both tumours follow a benign clinical course. Neurofibromas have the potential for malignan! transformation, especially in patients with neurofibromatosis type 1 (357,933,952,2005,2069}.

124



9140/3

Epidemiology Kaposi sarcoma is separated into tour distinct epidemiological categories (Table 4. 06); of these, only the AIDS-related (HIV-1-related) type is associated with oral manifestations {697,1812,1897). As many as 20% of individuals with HIV-1 infection develop oral Kaposi sarcoma, usuall y in the fou rth to fifth decades of lite. In industrialized countries, it is most common in horno- and bisexual HIV-1infected men, whereas there is no sex difference in developing countries {1811, 2538).

Etiology Kaposi sarcoma is always associated with the gamma-2 herpesvirus HHV8 (also called Kaposi sarcoma- associated herpesvirus; KSHV). The neoplasm develops in a complex dynamic with HIV-induced immunosuppression and environmental and genetic factors alter exposure to HHV8 in saliva or blood (122, 1347}.

Table 4.06 Clinical and epidemiological forms of Kaposi sarcoma. Adapted from Barnes Letal. (146) and Fletcher CDM et al. {735} Type

Risk group

1

Myofibrob/astic sarcoma

Siles of involvement

Clinical course

> 70% elderly men; Slavic, Jewish, ltalian

Skin of lower extremities

lndolent

Flucke U. Franchi A.

Children and middle-aged men

Skin of extremities; visceral involvement common; lymphadenopathic type common in children

lndolent in adults; aggressive in children

Definition

latrogenic/ transplantassociated

Solid organ transplant recipients (0.5% of renal transplant patients}; patients receiving immunosuppressive therapy

Skin of extremities; may have visceral involvement

Variable; may resolve upon cessation of immunosuppressanls

AIDS-related

HIV-infected patients; more common in horno- and bisexual men at younger age than classic Kaposi sarcoma

Skin of head and neck, extremities, genitals, mucosa of upper aerodigestive tract; lymph nodes

Mycfibroblastic sarcoma is a low-grade malignant infiltrative tumour of the deep soft tissue, with a predilection for the head and neck. lt has a variety of appearances, from fasciitis-like or fibromatosis-like to fibrosarcoma-like.

Classic

Endemic (African) ~

1

1

Aggressive

ICD-0 code

8825/3

Synonym Localization The hard palate, followed by the gingiva and tongue, is the most common oral site. Up to 70% of patients with cutaneous Kaposi sarcoma also have oral lesions.

Clinical features Patients present with multiple red to violaceous macules or papules that progress to plaques or nodules. Bleeding, ulceration, and pain may be seen in advanced disease. Lymphoedema is uncommon !697,1812,1837).

mitoses {299,697,1811). Papillary tufting within large dilated anastomosing vesseis is seen in lymphang iomatous Kaposi sarcoma {1931}. The neoplastic cells are positive for HHV8, podoplanin (as recognized by 02-40), LYVE1, VEGFR3, PROX1, CD34, CD31, FLl1 , and ERG, with HHV8 positivity being most specific !1813).

Cell of origin Phenotypically, the cells of orig1n are lymphatic endothelial cells {322}.

Prognosis and predictiva factors Histopathology The histopathological appearance develops with disease progression. The patch stage shows irregularly shaped, slit-like vascular spaces dissecting collagen bundles, often parallel to the epithelium, with extravasated erythrocytes and lymphocytes: the plaque stage shows further spindle-cell proliferation associated with intraand extracellular hyaline globules; and the nodular stage shows widely infiltrating atypical spindled cells with increased

Oral Kaposi sarcoma has a higher fatality rate than does AIDS-related Kaposi sarcoma of the skin, due to associated poor prognostic factors such as immune status (e.g. CD4 count < 300 cells/ml), ulceration, and nodular type {4.58,1545). Kaposi sarcoma is often multifocal but rarely metastasizes.

Myofibrosarcoma

Epidemiology The tumours can occur in patients of any age, with a mean patient age of 40 years !724,1591).

Localization The oral cavity, including the tongue, is a preferred site. Rarely, these tumours arise in the nasal cavity and paranasal sinuses. Origin in bone, notably gnathic bone, can also occur. Low-grade myofibroblastic sarcoma can arise subcutaneously or in a submucosal localization but is in most cases deep-seated {312,724, 1268,1591).

Clinical features Myoíibroblastic sarcoma presents as a painless swelling or enlarging mass !1591 ).

Macroscopy The lesions are firm, with fibrous cut surfaces and typically poorly defined margins {1591).

Soft tissue and neural tumours

125

desmin , calponin, and CD34. In rare cases, h-caldesmon is detected , with only focal expression {724,1591). Expression of beta-catenin does not ru le out this tumour type (335). At the ultrastructural level, the neoplastic cells are spindle-shaped, with oval, often indented nuclei. The cytoplasm contains numerous rough endoplasmic reticulum cisternae (which often contain floccu lent material) and subplasmalemmal bundles of actin filaments, with or without focal densities, sometimes associated with subplasmalemmal attachment plaques Pinocytotic vesicles and fibronexus junctions are present in sorne cases {681,725).

Histopathology The p attern is that of a rather ce llular, fibromatosis-like or fibrosarcoma-like lesion composed of fascicles or broad sheets of cells, with or without focal herringbone or storiform arrangement. Checkerboard -like infiltration of the adjacent voluntary muscle is a key diagnostic feature. The tapered myofibroblastic

nuclei are atypical and show hyperchromasia. Mitotic figu res are variably present. There are scant or moderate amounts of cytoplas m. The background can be collagenous or myxoid. Transformation into high-grade sarcoma has been reported {312,724,1591 ). lmmunohistochemistry shows a myofibroblastic immunophenotype, with variable expression of SMA,

Oral mucosal melanoma

Complex genetic aberrations have been identified (734).

Prognosis and predictiva factors Local recu rrences are common, but metastatic spread (to lung, soft tissue, or bone) occurs rarely {1591}.

Williams M.O. Speight P. Wenig B.M.

Definition

Etiology

Oral mucosal melanoma is a malignant neoplasm of melanocytes.

Mucosal melanomas, which are biologically distinct from lesions of cutaneous origin, are caused by unknown factors .

ICD-0 code

Genetic profile

,

8720/3

Localization Epidemiology Oral mucosal melanoma is a rare entity, accounting fo r only about 0.5% of melanomas. There is a slight male predominance, and the median patient age at diagnosis is 55-66 years {385,1584, 2238).

Most cases arise on the palate or gingiva {546,1958,2243,2338}.

•

Clinical features The neoplasm, wh ich is often asymptomatic, presents as a 1.5 - 4 cm, blackishgrey, irregular, flat or nodular lesion , with

.. . .!--;. ·1"'"' ~· .. :• . .. ,..... .

..&-ll•..1•.....•:.....t.-..

Fig. 4.24 Oral mucosa! melanoma. Clinical presentation shows an irregular, variably pigmented lesion on the hard palate.

126

-' ~' ....., .... ... _,:

.J,!

--

Fig. 4.25 Oral mucosa! melanoma. A Large epithelioid cells with ample eosinophilic cytoplasm are scattered within the epithelial junction and submucosa. Pigmentation may not be identified. B S100 lmmunohistochemical staining highlights the melanocytic cells, showing both an in situ and an invasive pattern of growth.

Tumours of the oral cavity and mobile tang ue

ulceration present in one third of cases . Lymph node metastases at presentation are common, present in about 30% of cases /984).

invasive nests, and single cells infiltrate the submucosa. The cells are usually epithelioid, with prominent nucleoli, but spindled cells may be seen.

Cytology

Genetic profile

Aspirates of metastatic oral melanoma are identical to those of cutaneous melanoma. Preparations show malignan! epithelioid, spindled, or undifferentiated cells.

Associated mutations include alterations in KIT (occurring in 10- 30% of cases), RAS genes (in 10- 20%), and BRAF (in < 10%) {343,1475,1996}.

Histopathology


Atypical pigm ented melanocytes are present at the junction (in situ) and/or

lncidence varíes among different ethnicities (1475,2243,2338}.

Prognosis and predictive factors Cutaneous melanoma prognostic tactors (e.g . Clark leve! of invasion and Breslow tum our thickness) do not apply. The overall prognosis is poor, with a median survival of 2 years (11 31,1480,19 18,2238}.

Salivary type tumours Mucoepídermoíd carcinoma

Macroscopy Many ap pear as bluish , domed swellings.

lnagaki H. Bell D. Brandwein-Gensler M.

Histopathology and genetic profile

Clinical features

See the Mucoepidermoid carcinoma section (p. 163) in Chapter 7 (Tumours of salivary glands) .

The tumour presents as a slow-growing, painless, submucosal, fi xed (hard palate), or mobile (bucea! mucosa) mass. Palatal PAs are located laterally and rarely cross the midline. The tumour is typically detected early and rarely attains a size > 1-2 cm.

Definitlon Mucoepidermoid carcinoma is a d istinctive salivary gland malignancy com posed of mucinous, intermediate (clearcell), and squamoid tumour cells forming cystic and salid patterns. See also the Mucoepidermoid carcinoma section (p. 163) in Chapter 7 (Tumours of salivary glands).

ICD-0 code

8430/3

Prognosis and predictive factors This tumour has a favourable outcome. Most patients present with low-grade tumour and low-stage tumour (1700,1769}.

Macroscopy lntraoral PAs often lack encapsulation. Palatal examples frequently involve the periosteum or bone.

Pleomorphíc adenoma Bel! D. Brandwein-Gensler M. Chiosea S.

Histopathology

Synonym Mucoepidermoid tumour (not recommended)

Epidemiology lt is a rare tumour (213} that most commonly manifests as intraoral salivary gland carcinoma (in 37- 53% of cases), with a slight female predilection. A wide patient age has been reported, with the mean age in the sixth decade of lite [292,2402} .

Definition Pleomorphic adenoma (PA) is a benign tumour with variable cytomo rphological and architectural manifestations. The identification of epithelial and myoepithelial/stromal components is essential for the diagnosis of PA. See also the Pleomorphic adenoma section (p. 185) in Chapter 7 (Tumours of sa/ivary glands).

Localization The palate is the most common intraoral site, accounting for > 50% of intraoral cases {292,2402).

ICD-0 code

8940/0

PAs at these sites d isplay plasmacytoid myoepithelial cytological features and are often unencapsulated. Cutaneous adnexal d ifferentiation can be seen in palatal and lip PAs (i.e. tricholemmal, sebaceous, and infundibular cystic features with trichohyalin granules) (2098] . Ectomesenchymal chondromyxoid tumour is the main d ifferential diagnostic consid eration, especially in the tangue (52)

Genetic profile See the Pleomorphic adenoma section (p. 185) in Chapter 7 (Tumours of salivary glands).

Synonym


Benign mixed tumour

Prognosis of PA is generally good . PA does not recur alter adequate surgical excision. See also the P/eomorphic adenoma section (p. 185) in Chapter 7 (Tumours of salivary glands) .

Clinical features The tumou rs are often asymptomatic , but may cause symptoms, depend ing on the site and histological grade.

(678,1834,1900,2082}. PA with in the mobile tangue is uncommon {2355,2504).

Localization PAs ot the oral cavity most commonly arise in the palate, upper lip, and cheek

Salivary type tumours

127


Ferry J.A. Li X.-0.

Overview Definition Oral haematolymphoid tumours are neoplasms of lymphoid, plasma cell, histiocytic/dendritic, and myeloid origin arising in the oral cavity.

Epidemiology Lymphoma accounts for 3.5% of oral cavity malignancies (897). Approximately 2% of extranodal lymphomas arise in the oral cavity {761,2339). Among immunocompetent patients, lymphomas mainly affect older adults, and only rarely children. Th ere is a slight male preponderance {897,909,1211 ,2464}. Almost ali HIV-positive patients are young to middle-aged adult men {909}. The oral cavity is the most common head and neck site for involvement by myeloid sarcoma {2724). Oral p lasmacytoma is rare, accounting for 0-6% of head and neck extraosseous plasmacytomas (116,2078). Histiocytic/ dendritic cell neoplasms are rare (1810).

Etiology Most lymphomas arise sporadically. A minority of patients are HIV-positive (878, 909,1211) or iatrogenically immunocompromised (1387,1652).

Localization Lymphomas most often involve the palate or gingiva (and may involve subjacent bone), and less often involve the tangue, bucea! mucosa, floor of the mouth, or lips . One third to half of ali lymphomas arise from bone; the rest arise from the mucosa {1211,1952, 2464). Most patients have localized (stage 1/1 L) disease (897).

Clinical features Non-tender swelling - is most common (897,1211,1952,2464), followed by ulceration (12 11}, pain, paraesthesia, and numbness (1211,2464}. Systemic symptoms are uncommon {2464).

128

Macroscopy Oral haematolymp hoid tumours p resent as poorly defined or discrete masses, with or without ulceration.

Histopathology Lymphomas occurring in immunocompetent patients are heterogeneous. Ditfuse large B-cell lymphoma is most common (909,1211}, with germinal-centre and non-germinal-centre B-cell phenotypes reported {1790). Others include follicular lymphoma {909,1211); MALT lymphoma (909,1211); Burkitt lymphoma {1952}; mantle cell lymphoma {898, 2464}; rare B-lymphoblastic lymphoma (2464); and high-grade B-cell lymphoma, NOS {1790}. Burkitt lymphoma is among the most freq uent of the rare p aediatric lymphomas (1952). T-cell and NK-cell lymphomas are rare in western populations {1211 } but are not infrequent among Asians {1952). HIV-positive patients frequently develop diffuse high-grade Bcell lymphomas, including diffuse large B-cell lymphoma (909), plasmablastic


lymphoma (see Plasmablastic lymphoma, p. 129), and Burkitt lymphoma (878, 909). Most immunodeficiency-associated lymphomas are EBV-positive (560,909}. Lymphomas must be distinguished from indolent and self-limited disorders, such as primary mucosa! CD30-positive T-cell lymphoproliferative disorder (see below) {1000,2057) and EBV-positive mucocutaneous ulcer (595). The latter presents as a circumscribed ulcerative lesion in the tangue or bucea! mucosa of immunocompromised or elderly patients and is characterized by a polymorphous infiltrate with atyp ical large B cells often resembling Reed-Stern berg cells. EBVpositive mucocutaneous ulcer regresses spontaneously or has a relapsing-remitting course.

Prognosis and predictive factors Outcome depends on the type of lymphoma, disease stage, and patient characteristics, including HIV status (878,897, 909,2464).

CD30-positive T-ce/1 /ymphoproliferative disorder Feldman A. L. Soy S. Ferry J.A. Ko Y.-H. Li X.-0. Pileri S.A.

Definition CD30 -p ositive T-cell lymphoproliferative disorder (TLPD) is a neo plastic proliferation of large, CD30-positive T cells arising in the oral cavity or occasionally other mucosal siles in the head and neck. This entity constitutes a clinicopathological spectrum of lymphoproliferative lesions, analogous to the spectrum observed in primary cutaneous CD30-positive TLPD. This disorder must be distinguished from reactive inflammatory conditions of the oral cavity and from secondary involvement by systemic anaplastic large cell lymphoma.

ICD-0 code

Fig. 4.27 Primary CD30-positive T-cell lymphoproliferative disorder of the tongue. There is ulceration and infiltration of the skeletal muscle.

9718/3

Epidemiology There is a male predominance, with a male-to-female ratio of 2:1. The d isorder primarily affects adults, with a mean patient age in the sixth d ecade of lite {2108, 2542).

Localization The proliferation typically presents in the oral cavity or tongue, but similar lesions have been described in the nasopharynx, conjunctiva, and orbit {2013,2108, 2339,2542) .

Clinical features CD30-positive TLPD typically presents with a mass lesion, often with ulceration. Spontaneous regression may occur (716). Clinical history and staging are importan! for excluding secondary involvement by a systemic lymphoma.

Histopathology Primary mucosal CD30-positive TLPD demonstrates a morphological spectrum similar to that observed in primary cutaneous cases . The neoplastic cells are large atypical lymphoid cells with pleomorphic nuclei and abundan! cytoplasm. Cells resembling the hallmark cells of anaplastic large cell lymphoma often are seen. Most

cases show a diffuse or sheet-like g rowth p attern. A mixed inflammatory background may be present, including areas with prominent eosinophils or neutrophils {58,2108,2542]. So rne cases of !raumatic ulcerative granuloma with stromal eosinophilia may represen! the indolent end of the spectrum of CD30-positive TLPD {1 00 0). By definition, CD30 is positive, and staining is strong and uniform. The large lymp hoid cells typically show a T-cell phenotype, but often demonstrate loss of one or more pan-T-cell antigens. CD4 is expressed more frequently than CDS. Cytotoxic markers (i.e. TIA1, g ranzyme B. and perforin) are often expressed, and EMA may be positive. CD56, ALK, and EBV are negative {2542). The EBV-positive cases that have been reported in children most likely represen! ch ro nic active EBV infection instead {1019).

Genetic profile Clonal T-cell receptor gene rearrangements have been detected in most cases {2108,2542). Occasional cases carry rearrangements of the DUSP22- IRF4 locus on 6p25.3, similar to the rearrangements

observed in sorne primary cutaneous cases of CD30-positive TLPD and ALKnegative anaplastic large cell lymphomas {2108}.

Prognosis and predictive factors Most cases show complete resolution with local therapy (excision with or without radiotherapy), with or without the addition of systemic chemotherapy {23, 2108,2542). Occasional cases show spontaneous regression.

Plasmablastic lymphoma Boy S. Ferry J.A.

Definition Plasmablastic lymphoma (PBL) is a highgrade B-cell non-Hodgkin lymphoma with plasma cell immunophenotype and a predilection for extranodal sites. Diagnosis is challenging due to the overlap with plasma cell neoplasms and 8-cell lymphomas with plasmablastic differentiation. ALK-positive large 8 -cell lymphoma is excluded. Haematolymphoid tumours

129

Fig. 4.29 Plasmablastic lymphoma. Typical appearance in a 39-year-old HIV-positive man; the palate and bucea! vestibule are most commonly affected in oral mucosa! plasmablastic lymphoma.

ICD-0 code

PBL is strongly associated with HIVrelated immunosuppression , in the setting of which it is AIDS-defining . lt also occurs in HIV-negative older adults and iatrogenically immunocompromised patients. HIV-associated PBL affects males, usually with advanced-stage disease, al an average age of about 40 years. HIVnegative PBL more commonly affects females (aged > 60 years) with localized disease. Post-transplant PBL, which is rare, usually affects older patients with advanced-stage disease.

of reactive T cells, mature plasma cells, and pleomorphic giant cells. The neoplastic cells are negative far CD19, CD20, PAX5, ALK, and HHVB, although there is controversy regarding the allowance of sorne positivity for B-cell markers (246). Variable expression of CD4b, CD10, CD79a, CD56, EMA, CD38, VS38c, CD138, CD30, and cytoplasmic immunoglobulins has been described . MUM1/ IRF4, PRDM1/BL1 MP1, and XBP1 typically show strong, diffuse positivity, and the Ki-67 index is usually > 80%. EBV is positive in > 70% of HIV-associated and post-transplant cases and in 50% of HIVnegative cases.

Etiology

Genetic profile

PBL is associated with EBV infection, which is known to cause a surge in plasmablasts (720), and MYC deregulation, which enhances cellular proliferation {350,1235), but the exact molecular pathogenesis is unknown.

MYC aberrations (translocations or gains) occur in about half of ali cases (248,1652, 2455)

9735/3

Epidemiology

Localization Head and neck siles, especially the oral cavity (560}. oropharynx, nasopharynx, and sinonasal trae!, are affected. Lymph nodes are occasionally involved, typically in HIV-negative patients.

Langerhans ce/1 histiocytosis Pileri S.A. Feldman A. L. Cheu k W. Slater L.

Definition Langerhans ce ll histiocytosis is a neoplastic proliferation of Langerhans cells (1888).

ICD-0 code Synonyms

Histiocytosis X; eosinophilic granuloma; Hand- Schüller- Christian disease; Letterer- Siwe disease

Epidemiology This is a rare tumour, with an annual incidence of 5 cases p er 1 million population. The peak incidence is among patients aged 3- 5 years and there is a slight male predominance, with a maleto-female ratio of 1.5-2:1 {914,977,1 729, 2058).

Prognosis and predictiva factors PBL is highly aggressive, with poor survival (6- 12 months) (349,350,1467,1652) . Favourable prognostic factors include EBV and CD45 positivity {1445,1652}. low stage, HIV negativity, younger patient age, and absence of MYC-IGH gene fusion {350,351}.

Localization Head and neck involve ment occurs in

~-::~-i¡"'· _.ll. v -~ .o.· i,,u. _ · -l!x ,~r ~Vi ..1 .... - 1'i!~i....-.. i ,. ·• t1tG•,~~~. i~~¡ -~ -~ . , ,. ~ ~ G I\ _. ~~ .~

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Clinical features A mass in the mouth, nose, ar sinuses is the most common clinical presentation, with skin ar nada! involvement usually seen in post-transplant PBL (350,1445, 1467,1652).

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Histopathology

130

. g ::M!a '~

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PBL exhibits a mixture of immunoblast-like cells and plasmablasts (medium-sized to large cells with round nuclei, clumped chromatin, large nucleoli, and amphophilic cytoplasm) with varying numbers

9751 /3

~•'*-,._ :a~·h;::. !

Fig. 4.31 Langerhans cell histiocytosis. A Neoplastic cells show a large rim of acidophilic cytoplasm and grooved nuclei; in this case, mild atypia can be seen, as well as sorne eosinophils. B Neoplastic cells express CD207 (langerin), as shown by immunoperoxidase.


60-80% of cases (287,1410,1730). of which 25% are part of multisystemic disease {1730}. The most commonly involved sites are bone (skull vau lt, temporal bone, orbit, and jawbone). scalp and peri auricular skin, cervical lymph nodes, paranasal sinuses. and oral mucosa (977,1093}.

Clinical features Depending on the site of involvement, the clinical presentation may include pain and swelling, orbi tal mass. skin rash, cervical lymphadenopathy, aura! discharge, earache, vertigo, facial nerve palsy, and oral ulcer or mass.

Histopathology The neoplastic cells have grooved nuclei with minimal atypia {1888]. They are admixed with a variable number of inflammatory cells and express S100, CD1a, and CD207 (langerin). Ultrastructurally, they contain Birbeck granules {1344, 1888}.

not uncommon in head and neck tumou rs (287,1943}.

Extramedullary myeloid sarcoma

Clona! rearrangement of IGH and/or T-cell receptor genes occurs in 30% of cases (403}. sometimes signifying transdifferentiation of a lymphoid malignancy (699,2596}. BRAFV600E mutations (or less commonly, MAP2K1 or ARAF mutations) occur in about half of ali cases [118, 1719, 1720).

The clinical presentation is often nonspecific.

Histopathology

Li X.-0. Gaulard P.

Definition Extramedullary myeloid sarcoma is a tumour mass consisting of myeloid blasts with or without maturation. involving an extramedullary anatomical site. lt occurs de novo or can precede. coincide with. or follow the presentation of acule myeloid leukaemia, or can constitute blastic transformation of a myelodysplastic syndrome or myeloproliferative neoplasm {1887}.

ICD-0 code

9930/3

Synonyms Genetic profile

Clinical features

Granulocytic sarcoma; ch loroma

The tumour mass consists of diffuse sheets of myeloblasts characterized by round to folded nuclei, fine chromatin, small nucleoli, and scant to moderate amounts of eosinophilic cytoplasm, intermingled with a variable number of eosinophilic myelocytes. lmmunohistochemically, the tumour cells express various myeloid or myelomonocytic markers, such as myeloperoxidase, CD68 (as recognized by KP 1), lysozyme, CD33, C034 , KIT/C01 17, and CD163. CD43 is commonly positiva.

Genetic profile A variety of chromosomal aberrations, such as monosomy 7, trisomy 8, and inv(16), have been reportad [1887}. The t(8;21)(q22;q22) translocation is more common ly observad in paediatric series [1887,2 107}. About 16% of cases harbour NPM1 mutations {688}.

Epidemiology Extramedullary myeloid sarcoma has been reported to occur in 3-8% of patients with acute myeloid leukaemia [319} . The median age of patients with head and neck involvement is 61 years (range: 1-85 years), with a male-to-female ratio of 1.2-2.4:1 {2505,27241.

Prognosis and predictiva factors The prognosis varíes, but is often unfavourable. Patients without bone marrow involvement and those who undergo allogeneic or autologous stem cell transplantation seem to have a better outcome {1887.2505,27241.

Prognosis and predictiva factors Patients without high-risk organ involvement (e.g . of liver, spleen, bone marrow, or lung) have a favourable prognosis, with a mortality rate of < 10% {79 1,977]. However, permanent organ damage (e.g. permanent hearing loss. loss of dentition) and disease reactivation are

Localization

.

Any head and neck site can be involved, with the oral cavity being most frequently affected {2724}. Rarely, the nasopharynx is involved {61,1957,2505}.


131

CHAPTER 5 Tumours of the oropharynx (base of tongue, tonsils, adenoids)

Squamous cell carcinoma Salivary gland tumours Haematolymphoid tumours

WHO classification of tumours of the oropharynx {base of tongue, tonsils, adenoids) Squamous cell carcinoma Squamous cell carcinoma, HPV-positive Squamous cell carcinoma, HPV-negative

8085/3* 8086/3*

Salivary gland tumours Pleomorphic adenoma Adenoid cystic carcinoma Polymorphous adenocarcinoma

8940/0 8200/3 8525/3

Haematolymphoid tumours Hodgkin lymphoma, nodular lymphocyte predominan! 9659/3 Classical Hodgkin lymphoma Nodular sclerosis classical Hodgkin lymphoma9663/3 Mixed cellularity classical Hodgkin lymphoma 9652/3

Lymphocyte-rich classical Hodgkin lymphoma Lymphocyte-depleted classical Hodgkin lymphoma Burkitt lymphoma Foll icular lymphoma Mantle cell lymphoma T-lymphoblastic leukaemia/lymphoma Follicular dendritic cell sarcoma

9651 /3 9653/3 9687/3 9690/3 9673/3 9837/3 9758/3

The morphology codes are from the lnternational Classification of Diseases far Oncology (ICD-0) 1776A}. Behaviour is coded /0 far benign tumours; /1 far unspecified, barderline, ar uncertain behaviour: /2 far carcinoma in situ and grade 11 1 intraepithelial neoplasia; and /3 far malignan! tumours. The classification is modified from the previous WHO classification, taking into account changes in our understanding of these lesions. 'These new codes were approved by the IARC/WHO Committee for ICD-0.

TNM classification of carcinomas of the lip and oral cavity TNM classification of carcinomas of the lip and oral cavitya,b

N2b

T - Primary tumour

N2c

TX TO Tis T1 T2 T3 T4a (lip)

Primary tumour cannot be assessed No evidence of primary tumour Carcinoma in situ Tumour ~ 2 cm in greatest dimension Tumour > 2 cm but ~ 4 cm in greatest dimension Tumour > 4 cm in greatest dimension

N3

node, > 3 cm but::,; 6 cm in greatest dimension Metastasis in multiple ipsilateral lymph nodes, ali ~ 6 cm in greatest dimension Metastasis in bilateral or contralateral lymph nodes, all ::,; 6 cm in greatest dimension Metastasis in a lymph node > 6 cm in greatest dimension

Note: Midline nodes are considered ipsilateral nodes .

M - Distarit metastasis

Tumour invades through cortical bone, inferior alveolar nerve, floor of mouth, or skin (of chin or nose) T4a (oral cavity) Tumour invades through cortical bone, into deep/ extrinsic muscle of tongue (genioglossus, hyoglossus, palatoglossus, and styloglossus), maxillary sinus, or skin of face T4b (lip and oral cavity) Tumour invades masticator space, pterygoid plates, or skull base; or encases interna! carotid artery Note: Superficial erosion alone of bone / tooth socket by gingival primary is not sufficient to classify a tumour as T4.

MO M1

No distant metastasis Distant metastasis

Stage grouping Stage O Stage 1 Stage 11 Stage 111 Stage IVA Stage IVB Stage IVC

Tis T1 T2 T1-2 T3 T1 - 3 T4a Any T T4b Any T

NO NO NO N1 N0-1 N2 N0-2 N3 Any N Any N


N - Regional lymph nodes (i.e. the cervical nodes) NX NO N1 N2 N2a

134

Regional lymph nodes cannot be assessed No regional lymph node metastasis Metastasis in a single ipsilateral lymph node, ::,; 3 cm in greatest dimension Metastasis as specified in N2a, N2b, or N2c below Metastasis in a single ipsilateral lymph

•Adapted from Edge et al. {625A) - used with permission of the American Joint Committee on Cancer (AJCC), Chicago, lllinois; the original and primary source far this information is the AJCC Cancer Staging Manual , Seventh Edition (2010) publlshed by Sprlnger Science+Business Media - and Sobin et al. 12228A} . "A help desk for specific questions about TNM classification is available at http://www.uicc.org/resources/tnm/helpdesk.

Tumours of the oropharynx (base of tangue, tonsils, adenoids)

TNM classification of carcinomas of the oropharynx TNM classifícation of carcinomas of the oropharynx•,b

N2b

T - Primary tumour TX Primary tumour cannot be assessed TO No evidence of primary tumour Tis Carcinoma in situ T1 Tumour :::; 2 cm in greatest dimension T2 Tumour > 2 cm but:::; 4 cm in greatest dimension T3 Tumour > 4 cm in greatest dimension, or extension to lingual surface of epiglottis T4a Tumour invades any of the following: larynx, deep/extrinsic muscle of tongue (genioglossus, hyoglossus, palatoglossus, and styloglossus), medial pterygoid, hard palate, mandible; note that mucosal extension to lingual surface of epiglottis from primary tumours of the base of the tongue and vallecula does not constitute invasion of the larynx T4b Tumour invades any of the following: lateral pterygoid muscle, pterygoid plates, lateral nasopharynx, skull base; or encases the carotid artery

N2c

N - Regional lymph nodes (i.e. the cervical nades) NX Regional lymph nodes cannot be assessed NO No regional lymph node metastasis N1 Metastasis in a single ipsilateral lymph node, :::; 3 cm in greatest dimension N2 Metastasis as specified in N2a, N2b, or N2c below N2a Metastasis in a single ipsilateral lymph node, > 3 cm but :::; 6 cm in greatest dimension

N3

Metastasis in multiple ipsilateral lymph nodes, all:::; 6 cm in greatest dimension Metastasis ih bilateral or contralateral lymph nodes, ali :::; 6 cm in greatest dimension Metastasis in a lymph node > 6 cm in greatest dimension

Note: Midline nodes are considered ipsilateral nodes.

M - Distant metastasis MO No distant metastasis M1 Distant metastasis Stage grouping Stage O Tis Stage 1 T1 Stage 11 T2 Stage 111 T1-2 T3 T1-3 Stage IVA T4a Stage IVB T4b AnyT Stage IVC AnyT

NO NO NO N1 N0-1 N2 N0- 2 Any N N3 Any N


ªAdapted from Edge et al. {625AJ - used with permission of the American Joint Committee on Cancer (AJCC), Chicago, lllinois; the original and primary source for this information is the AJCC Cancer Staging Manual, Seventh Edition (201 O) published by Springer Science+Business Media - and Sobin et al. {2228AJ. bA help ctesk for specific questions about TNM c lassification is available at http://www.uicc.org/resources/tnm/helpdesk.

TNM classification of carcinomas of the oropharynx

135

Tumours of the oropharynx (base of tongue, tonsils, adenoids) 1ntrod uction

EI-Naggar A.f<. Takata T.

Like the nasopharynx, th e oropharynx is characterized by lymphoidbased mucosa and is the target of viral-associated carcinoma. The high incidence of HPV-associated oropharyngeal carcinoma has been firmly validated and this carc inoma is now considered a distinct entity. Accordingly, a separate chapter on tumours of the oropharynx has been established. Because of the geographical

and ethnic differences in the prevalence of HPV-associated squamous cell carcinoma, a separate entry for HPV-negative oropharyngeal squamous cell carcinoma has been included. To minimize redundancy and to maintain consistency, only selected salivary neoplasms commonly reported in the oropharynx are briefly discussed in this chapter. For more detailed information on these tumours, the readers are referred

to the paren! Chapter 7 (Tumours ot salivary glands, p. 159). Similarly, only haematolymphoid disorders commonly encountered at th is location are presented and discussed.

Squamous cell carcinoma Table 5.01 Comparison of HPV-positive and HPV-negative oropharyngeal squamous cell carcinoma (SCC)

Squamous ce// carcinoma, HPV-positive

Characteristics

50-56 years

Median age

Westra W.H. Boy S. EI-Mofty S.K. Gillison M. Schwartz M.R. Syrjanen S. Yarb rough W.G .

Risk factors

Sexual behaviour

Lymph nade metastasis

--

Postulated origin

--

Frequently cystic Reticulated epithelium of invaginated crypts

Dysplasia

Grading

Definition Oropharyngeal squamous cell carcinoma (OPSCC) associated with high-risk HPV (OPSCC-HPV) is an epidemiologically, pathologically, and clinically distinct form of head and neck squamous cell carcinoma. 8085/3

Synonym Non-keratinizing squamous cell carcinoma

Epidemiology The incidence of OPSCC-H PV has risen over the past three decades {391 , 392,1980). Patients w ith OPSCC-HPV are typ ically male, Wh ite, and of higher socioeconomic status {392,841}. The median patient age is 50-56 years (79, 841), with a male-to-female ratio of 4:1. 136

HPV-negative

60-70 years -

Smoking and alcohol use

-

1-

Morphology

ICD-0 code

HPV-positive

p16 immunostaining

-

--

Uncommonly cystic Surface epithelium

-

- ·,-

Rare

Often present

Commonly non-keratinizing SCC

Conventional SCC

Not applicable

Applicable

Positive

Negative

82%

57%

Overall survival rate (3 years)

-

Etiology

Clinical features

OPSCC-HPV is caused by high-risk HPV, with type 16 responsib le for > 90% of all cases {507,841,2105). Oral sex is an established risk factor for oral HPV infection. lndividuals with OPSCC-HPV are less likely than patients with HPV-negative OPSCC to be smokers; yet tobacco smoking is associated with significantly higher oral HPV prevalence and thus may play sorne role in the progression from oral HPV infection to OPSC(_-;-HPV (685).

Unlike HPV-negative OPSCC, OPSCCHPV typically presents at an advanced clinical stage, often as a small primary tumour with nodal involvement. Cervical lymphadenopathy, which may be cystic, is the most common clinical presentation .

Macroscopy Although primary tumours may be large, most are small and not apparent on gross inspection. Nodal metastases are often large and cystic {862}.

Local izati on OPSCC-HPV has a strong predilection for the base of tangue and the palatine tonsils {169).


Cytology Aspirates of metastatic lesions are cellular, with tumour cells forming cohesive

sheets and clusters and having hyperchromatic, pleomorphic, and overlapping nuclei {1115). The presence of squamous differentiation and keratinization is uncommon. Demonstration of p16 or HPV in tumour cells strongly suggests an oropharyngeal primary.

Histopathology OPSCC-HPV generally exhibits distinctive non-keratinizing morphology; grading is not currently advocated . Unlike in HPV-negative cases, dysplasia of the surface epithelium is rarely identified . OPSCC-HPV arises from crypt epithelium and grows b eneath the surface epithelial lining as nests and lobules, o/ten with central necrosis {2599}. Tumour nests are o/ten embedded in lymphoid stroma, and may be penetrated by lymphoid cells. Tumour cells display a high N:C ratio anda high mitotic and/or apoptotic rate, which often imparts a b asaloid appearance. Histological grading is not currently advocated. Keratinization is absent or inconsp icuous in most cases (414,8421, although a small subset of cases show keratin formation.

The morphological spectrum of OPSCCHPV includes variants with papillary (635, 1580), adenosquamous {1553), lymphoepithelioma-like (2187), sarcomatoid (201), and small-cell features {204) . Tumours resembling basaloid squamous cell carcinoma have also been described {171), as have tumours with populations of ciliated cells (206). The clinical behaviour of the morphological variants (oth er than the small -cell variant) is similar to that of OPSCC-HPV with typical morphology. HPV-related small ce!! neuroendocri ne carcinoma has an aggressive clinical behaviour and is morphologically characterized by small anaplastic cells with hyperchromatic moulded nuclei, numerous mitoses, and necrosis. Recognition of the small-cell variant is facilitated by an immunohistochemical profile that ineludes weak expression of squamous markers (e.g. p63, p40 , and CK5/6) and acquisition of neuroendocrine ,markers (e.g . synaptophysin, chromogranin, and CD56).

PCR-based assays) performed individually or in combination (2598}. Oiffuse immunoreactivity for p16 is a reliable surrogate marker for the presence of high-risk HPV in oropharyngeal carc inomas, and may be sufficient as a standalone test for HPV status in tumours with appropriate morphology arising at this site {1401}. The possibility of loss of p16 expression should also be considered (especially in patients with traditional risk factors), and additional testing for high-risk virus should be performed. Positive HPV testing may also point to the oropharynx as the most likely primary site for cervical lymph node metastasis of undetermined primary (170}. When p16 or HPV testing is not available, OPSCC can be diagnosed as "squamous cell carcinoma, HPV status unknown " or, if the tumour shows th e characteristic non-keratinizing morphology, as "squamous cell carc inoma, HPV not tested, morphology highly suggestive of HPV association".

HPV detection HPV can be detected by molecular assays (e.g. in situ hybrid ization and

Genetic profile HPV oncoproteins E6 and E7 inactivate p53 and RB by targeting them for Squamous cell carcinoma

137

protein degradation. Somatic mutations in TRAF3, an immune regulator, are unique to OPSCC- HPV. Oncogenic PIK3CA mutation or gene amplification is significantly more common in OPSCC-HPV than in HPV-negative cases {1817,2375).

-'!~

f

HPV lnfection

Viral/ lntegration

Viral Transcrlptlon

Prognosis and predictive factors OPSCC-HPV is associated with significantly better survival outcomes than is HPV-negative OPSCC (79, 686,191 1}, but this favourable prognosis may be tempered by th e adverse effects of cigarette smoking (79,843]. The risk of tumour recurrence and of the d evelopment of second primary malignancies is lower with HPV-positive OPSCCs than with HPV-negative cases, but longer follow-up data are needed {79}.

Squamous ce// carcinoma, HPV-negative

Fig. 5.02 Pathogenetic pathway of HPV in oropharyngeal squamous cell carcinoma. Viral DNA is integrated into host DNA. Transcription of HPV E6 and E7 mRNA leads to inactivation of p53 and RB proteins, and indirectly to accumulation of p16. Curren! methods can detect HPV at the level of DNA (in situ hybridization or PCR), mRNA (in situ hybridization or RT-PCR), and protein (p16 immunohistochemistry as a surrogate marker). Reprinted from Bishop JA et al. {200).

Syrjanen S. Assaad A. EI -Mofty S.K . Katabi N. Schwartz M.R.

Clinical features Patients typically present with sore throat and diflículty in swallowing or a neck mass {487).

Definition HPV-negative oropharyngeal squamous cell carcinoma (OPSCC) is a subset of OPSCC that lacks association with highrisk HPV.

ICD-0 code

8086/3

Synonym Keratin izing squamous cell carcinoma

Epidemiology Patients with HPV-negative OPSCC are older on average than patients with HPVrelated OPSCC (OPSCC -H PV; see Tab le 5.01, p. 136) (247 1\.

Macroscopy See the Squamous ce!/ carcinoma sec-

See the Squamous ce// carcinoma section (p . 109) in Chapter 4.

Localization Whereas most examples of OPSCCHPV target the base of tongue and the palataine tonsils, HPV-negative OPSCC more commonly involves the soft palatine.

138

Genetic profile See the Squamous ce!! carcinoma sec-

tion (p. 109) in Chapter 4.

tion (p. 109) in Chapter 4. The TP53gene is commonly mutated, in contras! to the wildtype TP53 found in OPSCC-HPV.

Cytology


Aspirates of metastatic lesions usually show featu res of keratinizing squamous cell carcinoma, with sheets and small clusters of malignan! squamous cells with intracellular and extracellular keratinization. Occasional cases have cytological features identical to those of HPVpositive tumours (i.e. non-keratinizing squamous cel l carc inoma) (241,637}.

See Table 5.01 (p. 136).

Histopathology Etiology

cel l carcino ma al other head and neck siles.

Unlike OPSCC-HPV, HPV-negative OPSCC typically exhibits differentiated squamous features (i.e. kerati nization, desmoplastic stromal reaction, and surface dysplasia) identical to !hose of squamous cell 9arcinomas at other head and neck mucosal sites {1 405). HPV status is negative (by p16 immunohistochemistry and/or molecular detection of HPV). The histological grading is similar to that used for squamous

Tumours of the oropharynx (base of tongue, tonsils, adenoids)


Pleomorphic adenoma

Adenoid cystic carcinoma

Localization Pleomorphic adenoma of the base of tangue, tonsils, and adenoids is rare (179, 1710,2687).

Bell D. Bullerdiek J . Katabi N.

Stenman G. Bel! D. Gnepp D.R .

Clinical features Presenting symptoms include a slowgrowing mass and mild dysphagia (1710}.

Definition Pleomorphic adenoma is a benign tumour with variable cytomorphological and architectural manifestations. The identification of epithelial and myoepithelial and stromal components is essential fa r the diagnosis. See also the Pleomorphic adenoma section (p. 185) in Chapter 7.

ICD-0 code

Histopathology Pleomorphic adenomas of the minar salivary glands, compared with those occurring in majar glands, are typically more cellular, with a less predominan! stromal componen! (930,2123}. Both epithelial and myoepithelial components are found, in varying compositions (2082}.

Definition Adenoid cystic carcinoma is a slowgrowing and relentless salivary gland malignancy composed of epithelial and myoepithelial neoplastic cells that form various patterns, including tubular, cribriform, and salid forms. See also the Adenoid cystic carcinoma section (p. 164) in Chapter 7.

ICD-0 code

8940/0

8200/3

Prognosis and predictive factors Synonym Benign mixed tumour

Complete excision is generally curative. Recurrence is not uncommon, due to microscopic satellite extension. The myxoid variant may have a higher recurrence rate (2082).

Epidemiology and clinical features See the Adenoid cystic carcinoma section (p. 164) in Chapter 7.

Histopathology The histology is identical to adenoid cystic carcinomas of majar and other minar salivary gland sites; see the Adenoid cystic carcinoma section (p. 164) in Chapter 7 (Tumours of sa/ivary glands).

Genetic profile See the Adenoid cystic carcinoma section (p. 164) in Chapter 7.

Prognosis and predictive factors The prognosis is similar to that of adenoid cystic carcinomas from the majar and other minar salivary gland siles (22, 1104); see the Adenoid cystic carcinoma section (p. 164) in Chapter 7.

._,.,.

'

,,

~

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:11:iia:.':i~,;t;

.

Fig. 5.03 A Unencapsulated submucosal pleomorphic adenoma of soft palate. B Pleomorphic adenoma. Myoepithelial cell nests in fibromyxoid and hyalinized stroma.


139

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Polymorphous adenocarcinoma Fonseca l. Bell D. Gnepp D.R. Seethala R. Weinreb l.

Localization

Cytology

Polymorphous adenocarcinoma occurs predominantly at th e junction of the hard and soft palate {239,461,1915,2198).

The cytological features are not specific far the diagnosis.

H istopathology Clinical features The tumours presentas pain less masses {352).

See the Polymorphous adenocarcinoma section (p. 167) in Chapter 7.

Genetic profile Definition

Macroscopy

Polymorphous adenocarcinoma is a malignant neoplasm characterized by cytological uniformity, morphological diversity, and an infiltrative growth pattern. See also the Polymorphous adenocarcinoma section (p. 167) in Chapter 7.

Polymorphous adenocarcinoma presents as a firm, circumscribed, unencapsulated, yellowish-tan tumour {1832).

ICD-0 code

Prognosis and predictive factors The overall survival rate is excellent (352, 671 ,1231,1832). but aggressive behaviour can occur. See the Polymorphous adenocarcinoma section (p. 167) in Chapter 7.

8525/3

Synonyms Polymorphous low-grade adenocarcinoma; terminal duct carcinoma; cribriform adenocarcinoma

Epidemiology The female-to-male ratio is 2:1, and > 70% of patients are aged 50- 70 years {239,1832,1915,2198).

140

The genetic profile {2569,2574) is discussed in the Polymorphous adenocarcinoma section (p. 167) in Chapter 7.

Fig. 5.05 Polymorphous adenocarcinoma. The cribriform variant is frequently characterized by the presence of optically clear nuclei.

Tumours of the oropharynx (base of tang ue, tonsils, adenoids)


/ntroduction Ferry J.A. Ko Y. -H.

Definition Oropharyngeal haematolymphoid tumours are neoplasms of lymphoid, plasma-cell, histiocytic/dendritic, or myeloid origin arising in the oropharynx. Epidemiology The Waldeyer ring (pharyngeal lymphoid ring) is the most common extranodal head and neck site for development of lymphoma {100}, affected in 36% {666,934} to 67% (37,682} of cases. Patients can be affected in childhood (905} through ad vanced age {1338,1372,1429,1790}, with mean and median palien! ages in the sixth (37,682,1372} and seventh (1790} decades of life. The male-to-female ratio is about 1-2:1 (905,1338 ,1 372,1790}, although MALT lymphomas show a slight female preponderance (1260}. Oropharyngeal p lasmacytoma accounts far 13-19% of all head and neck extraosseous p lasmacytomas {11 6,494,2078}. Myeloid sarcoma {2724} and histiocytic/ dendritic cell neoplasms {1810} are rare. Etiology A few patients are immunocompromised; their lymphomas may be EBV-positive (1790}.

Localization Within the Waldeyer ring, lymphoma most common ly involves tonsil, followed by nasopharynx, with the base of tangue leas! o/ten affected [37,682,1338,1 372} . Most lymphomas are localized (stage 1/11) {37,905,1338,1372}. Clinical features Dysphagia, odynophagia, and cervical lymphadenopathy are common (934, 1260,1338,2183}. Macroscopy Tonsillar ar base-of-tongue swelling, with or without ulceration, is apparent macroscopically (905,934}. Histopathology Diffuse large B-cell lymphoma is most common by far {37,682,1372), with germinal-centre and non- germinal-cen tre B-cell phenotypes reparted (1790,1968). Others include MALT lymphoma {333, 1260,1372,2239}; extranodal NK/T-cell lymphoma (1372); mantle cell lymphoma {1260,1372, 1790); fol licular lymphoma (1260,1372}; peripheral T-cell lymphoma, NOS (1372}; and rare classical · Hodgkin lymphoma (1939). Burkitt lymphoma is rare in adults (1372) but common among children (905}. lnfectious mononucleosis can mimic diffuse large B-cell lymphoma and classical Hodgkin lymphoma (1479}, and should be Q

•

·• .

excluded befare diagnosing lymphoma. EBV-positive mucocutaneous ulcer is also an importan! differential diagnosis far circumscribed ulcers {595}. MALT lymphoma should be distinguished from atypical marginal zone hyperplasia of mucosa-associated lymphoi d tissue - a rare monotypic, polyclonal lymphoproliferative disorder involving the tonsils of children (101}.

Prognosis and predictive factors The prognosis is relatively favourable. Outcome is worse with older patient age (682,1372}, T-cell phenotype {1372}, nontonsil primary, and high levels of lactate dehydrogenase (682}.

Hodgkin /ymphoma Jaffe E.S. Ott G.

Definition Hodgkin lymphoma is a B-cell-derived neoplasm in which relatively few neoplastic cells are seen, in a background rich in inflammatory cells. Th e two major forms are classical Hodgkin lymphoma and nodular lymphocyte-predominant Hodg kin lymphoma . The characteri stics of the neoplastic cells and the nature of the infl ammatory background differ in these two majar subtypes (1524) .

•

o

-. '·

A Haematolymphoid tumours

141

•

Fig. 5.07 Classical Hodgkin lymphoma of the tonsil. High-power view shows classic Reed-Sternberg cells and variants in a background of small lymphocytes.

ICD-0 codes Hodgkin lymphoma, nodular lymphocyte p redominan! 9659/3 Classical Hodgkin lymphoma Nodular sclerosis classical Hodgkin lymphoma 9663/3 Mixed cellularity classical Hodgkin lymphoma 9652/3 Lymphocyte-rich classical Hodgkin lymphoma 9651/3 Lymphocyte-depleted c lassical Hodgkin lymphoma 9653/3 Synonym Hodgkin disease Localization Both form s of Hodgkin lymphoma present most often in lymph nades. Primary presentations in oropharyngeal lymphoid tissue are rare {1103,1 175). Histopathology In classical Hodgkin lymphoma, the neoplastic cells (i.e. Reed-Sternberg cells and variants) frequently show downregulation of the B-cell programme. They are positive for PAX5 but most often negative for CD20 and CD79a. There is positivity for CD30 in virtually all cases and forCD15 in most. The inflammatory background is composed mainly of T cells, with variable numbers of plasma cells, histiocytes, and eosi nophils. EBV sequences are found in 15- 25% of cases overall, but the incidence of EBV positivity in classical Hodgkin lymphoma involving the Waldeyer ring (pharyngeal lymphoid ri ng) is higher: approximately 65% in one study {11 75). In nodular lymphocyte-predominant Hodgkin lymphoma, the neoplastic

142

cells have lobulated nuclear contours, basophilic nucleoli, anda thin rim of pale cytoplasm. The neop lastic cel ls (i .e . lymphocyte-predominant [LP] cells) retain expression of most B-cell antigens, including CD20, CD79a, PAX5, and OCT2, and are posit ive for BCL6. A nodular growth pattern is usually evident, with the B cells often distributed within the remnants of primary follicles. Normal small B cells are frequent, particularly early in the course of the disease. The LP cells are rosetted by T cel ls with the phenotype of T follicular helper (TFH) cells, expressing CD4 and PD1 (CD279), and T cel ls usually become more numerous over time. Overlap with T-ce ll lymphoma or histiocyte-rich large B-cell lymphoma may be seen {949} . Primary nodular lymphocyte-predominant Hodgkin lymphoma in the Waldeyer ring is rare.

Burkitt lymphoma Pileri S.A. Nakamura S.

Tumours of the oropharynx (base of tang ue, tonsils, adenoids)

Etiology In endemic BL, the neoplastic cells invariably contain EBV {1639). However, recent data suggest that the pathogenesis of this variant may be polymicrobial {3,2460). EBV infection is detected in about 30% ot sporadic cases and 25-40% of immunodeficiency-associated cases {1639). Localization lnvolvement of the head and neck (especial ly the jawbones) is frequent in endemic BL but rare in the other variants {1639).

Definition Burkitt lymphoma (BL) is a peripheral Bcell lymphoma that has an extremely high proliferation rate and often presents in extranodal sites. lt is composed of monomorphic medium-sized cells. Translocation involving MYC is highly characteristic but not specific. The diagnosis requires the combination of morphology, phenotype, and genetics. ICD-0 code

Epidemiology BL accounts for < 1% of ali peripheral Bce ll lymphoma cases {2377). Three variants are recognized: endemic (occurring in malaria-endemic reg ions of the world), sporadic (occurring where malaria is not endem ic) , an d im munodefic iency-associated (occurring in immunocompromised, typical ly HIV-positive, patients) [1639). Despite their common morphology and phenotype, these variants differ in terms of patient age and pathobiology. Endemic BL occurs in children and adolescents, whereas sporadic and immunodeficiency-associated Bls typically occur in adults {1639].

9687/3

Clinical features Patients often present with bulky disease and a high tumour burden, sometimes with leukaemic spread [2244). A pure leukaemic presentation, which is exceedingly rare, is usually associated with CNS involvement {2244). Histopathology The neoplastic cells tend to be cohesive and undergo apoptosis [1639,2434).

Follícular /ymphoma Ott G . Nakamura S.

Definition Follicular lymphoma is a malig nan! lymphoma composed of centroblasts and centrocytes, with at least a partially follicular pattern.

ICD-0 code

9690/3

Epidemiology Fig. 5.09 Burkitt lymphoma. MYC gene rearrangement, as shown by a dual-colour break-apart probe (in situ hybridization, DAPI nuclear staining).

They are intermingled with phagocytizing macrophages, which contribute to the characteristic starry-sky pattern (1639, 2434). The number of mitotic figures is exceed ingly high. Features of plasma-ce!! differentiation can be seen, especially in the immunodeficiency-associated varían! {2434). On immunophenotyping, the neoplastic cells are positive far CD20, CD1 0, and BCL6; negative far BCL2; and positive for MYC and Ki-67 (with a Ki-67 proliferation index of 100%) {2434}. In situ hybridization for EBV-encoded small RNA (EBER) reveals a variable prevalence of EBV infection, depending on the BL variant {1639,2434}.

Genetic profile The tumours cells carry clona! rearrangements of the IG gene family, with somatic hypermutation. FISH shows MYC translocation at band 8q24 to the IG H region at 14q32 or less frequently to IGL at 22q11 or IGK at 2p12 (178,1844). In about 10% of cases, FISH fails to demonstrate MYC translocation, but mostly due to technical limitations {1639}. The few BL cases that actually lack MYC translocation are characterized by deregulation of genes on 11q {2050}. Gene expression profiling studies have shown that the endemic and immunodeficiency-associated BL variants have almost identical signatures, whereas the endemic and sporadic vari ants have been found to diverge in their expression of 124 genes dependen! on RBL2 activity {531,1884). Next-generation sequenc ing has highlighted differences between endemic BL and sporadic BL (3}. The endemic variant shows cytomegalovirus and HHV8 (also called Kaposi sarcoma- associated herpesvirus)

infection within the non-neoplastic tissue in > 50% of cases; expression of EBV lytic genes, inversely associated with TCF3 activity; recurren! alterations in genes rarely mutated in the sporadic variant (AR/01A, CCNF, and RHOA) ; and fewer mutations in genes commonly altered in sporadic cases (MYC. /03, TCF3, and TP53) {3, 2099).

Prognosis and predictiva factors Both endemic BL and sporadic BL are highly aggressive but potentially curable. Staging is perfarmed according to the system developed by Murphy and Hustu {1677} and modified by Magrath (1511). lntensive chemotherapy regimens are associated with cure rates of 90% and 60- 80% far patients with low- and highstage disease. respectively {1639}. with particularly excellent results in childhood [1639}.

Cases involving the Waldeyer ring (pharyngeal lymphoid ring) typically constitute secondary tonsillar extension in individuals with widespread nada! disease (95}. lsolated manifestation in the oropharynx, wh ich is rare, is more often seen in children and young adults.

Histopathology The cytomorphology of fallicular lymphoma in the tonsil is the same as that of its counterpart in the lymph nade. Crowded atypical follicles that consist of centroblasts and centrocytes efface the normal architecture. The follicles are uniform in size and poorly demarcated; the starrysky pattern is usually absent. Large B-cell lymphoma with or without a follicular componen! in Waldeyer ring arising in children or young adults more often features large, expansile follicles composed of centroblasts or intermediate-sized blastoid cells exclusive ly, as well as attenuated mantle zones (1446,1 477,1785, 1942). Classic follicular lymphoma expresses CD20 and germinal centre markers (e.g.

,;j¡_,!"..4.};

Fig. 5.10 Follicular lymphoma of the tonsil. The tonsillar parenchyma shows infiltration by crowded atypical follicles that efface the normal architecture.


143

CD10, BCL6, and HGAL), and is BCL2positive in 85- 90% of cases. In contras!, large B-cell lymphoma with IRF4 rearrangement of the tonsil, which has a follicular growth pattern in many cases and arises in children and young adults, consistently and strongly expresses MUM1/ IRF4 in addition to germinal centre markers. lt variab ly expresses BCL2, and has a high proliferation index {1446,1942,2051).

Genetic profile Typical follicular lymphoma involving the tonsil in the setting of widespread disease usually harbours the t(14;18)(q32;q21) translocation. In contras!, MUM1/IRF4 positive large cell lymphomas occurring in chi ldren and young adults lack the 1(14;18) translocation, and a MUM1/IRF4 translocation can be demonstrated in about 50% of cases [1446,2051). In the 4th edition update of the WHO classification of tumours of haematopoietic and lymphoid tissues, MUM1/IRF4+ lymphoma in children and young adults is classified as "large B-cell lymphoma with IRF4 rearrangement" instead of a form of follicular lymphoma.

Prognosis and predictiva factors MUM1/ IRF4 expression and/or MUM1/ IRF4 translocation in follicular lymphoma of the tonsil is associated with favourable outcome.

Mantle ce// lymphoma Ko Y.-H .

Ferry J.A.

Detinition Mantle cell lymphoma (mantle cell neoplasia) is a mature B-cell neoplasm of small to medium-sized lymphoid cells, usually characterized by CCND1 trans location leading to cyclin D1 overexpression .

!CD-O code

9673/3

Epidemiology The overall incidence of MCL is approximately 0.5 cases per 100 000 person-years. The male-to -female ratio is 2.3- 2.5:1. The median patient age al diagnosis is 70 years {1393, 2216,2725).

Localization The head and neck region is the second 144

most common extranodal site, involved in 6.2% of MCLs [68). MCL accounts for 2.6% of al! Waldeyer ring (pharyngeal lymphoid ring) non-Hodgkin lymphoma cases, occurring most often in the tonsi l [1372,2217).

Clinical features Patients typically have a mass causing odynophagia and dysphagia. MCL of the head and neck presents with advanced disease at diagnosis less commonly (in 41% of cases) than does lymphoma of the lymph nades (in 87%) {68}.

Histopathology MCL shows a diffuse, vaguely nodular or mantle-zone pattern, with proliferation of small to medium-sized lymphoid cells with slight nuclear irregularity. Epithelioid histiocytes may be evenly scattered throughout the tumour. Sorne cases have blastoid or pleomorphic morphology [27,2674). In rare cases, cyc lin D1- positive lymphocytes are localized within mantles of hyperplastic lymphoid follicles (with in situ mantle ce!! neoplasia) {1264). The neoplastic cells are positive for slgM, lgD, CD20, and CD5 and negative for CD10, CD23, and BCL6. Cyclin 0 1 is expressed in virtually al! cases. SOX11 is useful for identifying rare cyclin 01- negative MCL {310,1693]. Aberran! immunophenotypes (e.g. with CD5 negativity, CD10 positivity, or CD23 positivity) may occur (34,2258,2479, 2723). .

Genetic profile Most cases have CCND1- /GH translocation. Cyclin 01-negative MCL may have CCND2 translocation {1597,2052,2164,

Tumours of the oropharynx (base of tongue, tonsils, adenoids)

2623). Mutations involving ATM and TP53 are common, occurring in 41% and 28% of cases, respectively (165,1116).

Prognosis and predictive factors MCL is an aggressive non-Hodgkin lymphoma, with a median overa!! survival of < 4 years (1393,2064}. The Mantle Ce!! Lymphoma lnternational Prognostic lndex correlates well with prognosis [2513}. Adverse prognostic factors include blastoid or pleomorphic morphology, diffuse p attern, high proliferation index, high expression of p53 protein , and MYC aberrations with overexpression (182,434, 2403}. Patients with primary extranodal disease (including in the head and neck) have better survival than do those with nodal disease [68).

T-lymphoblastic /eukaemia/lymphoma Ferry J.A. Gaulard P.

Definition T-lymphoblastic leukaemia/lymphoma (T-LBL/L) is a neoplasm of lymphoblasts committed to T-cell lineage.

!CD-O code

9837/3

Epidemiology lnvolvement of head and neck by T-LBL/L is rare. Among 109 reported cases of nasopharyngeal lymphoma, only one (0 .9%) was T-LBL/L (1054}. In a large series of chi ldhood non-Hodgkin lymphomas, 1% of al! lymphomas and

have clonal IGH . Cytogenetic and molecular genetic changes are heterogeneous. Many cases have an abnormal karyotype; translocations involving T-cell receptor genes are common {884,1889, 2329}. Activation of Notch signalling and loss of CDKN2A (also called P16/NK4a and P14ARF), which codes far the tumour suppressor proteins p16 (p161NK4a) and p14ARF, are also common (2476) .

Prognosis and predictive factors The outcome appears to be similar to that of T-LBL/L in other siles.

Follicular dendritic ce// sarcoma Cheuk W. Pileri S.A.

11:

'

f¡t. ~ Fig. 5.1 2 A,B lndolent T-lymphoblastic proliferation. A The interfollicular compartment is filled and expanded by a proliferation of TdT-positive T cells. B High-power view shows a population of relatively small, uniform cells, sorne with minimally enlarged nuclei and fine chromatin. C T-lymphoblastic lymphoma involving the tonsils. In contras! with indolent T-lymphoblastic proliferation, there is a monotonous infiltrate containing medium-sized bias! cells with convoluted nuclei and fine chromatin.

Definition Follicular dendritic cell (FDC) sarcoma is a tumour of nodal and extranodal sites that exhibits phenotypic featu res of FDCs.

ICD-0 code 5% of all T-LBUL cases were T-LBL/L of the head and neck (2642] . Patient age ranges from childhood to advanced age (771,2642}.

Localization T-LBL/L cases have been reported involving the oropharynx {2642). nasopharynx (1054,2642). salivary gland {2642). tangue (771}. and larynx (1541}. Staging may reveal widespread disease involving lymph nodes, mediastinum, and/or bone marrow (771,1541].

Clinical features The symptoms are related to the presence of a mass.

Histopathology Evaluation reveals a diffuse infi ltrate of small to medium-sized cells with oval or slightly to prominently irregular nuclei , dispersed to finely stippled chromatin, variably conspicuous nucleoli, and scant cytoplasm . Mitoses are frequent. T-LBL/L is typically positive for CD3, TdT, CD?, and CD1a; variably positive for CD10; and either double-positive or doublenegative for CD4 and CD8. The differential diagnosis inc ludes indolent T-lymphoblastic proliferation; a rare

disorder characterized by a proliferation of immature T cells in lymphoid tissue. Patients present with sore throat, hoarseness, or airway obstruction . Examination reveals prominent hypertrophy of oropharyngeal and nasopharyngeal lymphoid tissue, sometimes with cervical lymphadenopathy {2290,24'89}. Microscopic examination reveals sheets or c lusters of small to medium-sized ce lls with fine chromatin, inconspicuous nucleoli, and a high mitotic rate, but with no significan! cytological atypia and sparing fallicles. The cells are positive for CD3 and TdT, and have a high proliferation index. T-cell receptor genes are not clonally rearranged. The appearance resembles that of the normal thymic cortex, although without thymic epithelium. After therapy (surgical excision or chemotherapy) indolent T-lymphoblastic proliferation may rep eatedly recur, although without progression to bone marrow or peripheral blood involvement {1764,1765, 2290,2489}.

9758/3

Epidemiology FDC sarcoma accounts far < 1% of all head and neck tumours, although the head and neck region is the most common anatomical site of occurrence of this tumour. lt typically affects patients in midadulthood (mean patient age: 42 years). Although the patient age range is wide (9- 80 years), only 6% of al i cases occur in children (1187}. There is no sex predilection (1488,1810).

Etiology A minority (15%) of FDC sarcomas arise in the setting of hyaline-vascular Castleman disease, and a hyperplasia-dysplasia- neoplasia model of FDC proliferation has been proposed (373,379,412]. Sorne

Genetic profile Limited information is available about head and neck cases, but T-LBL/L in general has clonally rearranged T-cell receptor genes, and a minority of cases

~

Fig. 5.13 Follicular dendritic cell sarcoma of the tonsil. The surface epithelium is intact; this tumour shows partial involvement of !he tonsil (left field) and exhibits pushing borders.


145

studies have found clona! abnormalities in FDCs in hyaline-vascular Castleman disease, which may precede FDC sarcoma overgrowth (469, 1840). Overexpression of EGFR has been demonstrated in FDC sarcomas and dysplastic FDCs in hyalinevascular Castleman disease , providing a further link between the two conditions {2311). Ligand-dependent EGFR activation, which may be importan! for the survival and proliferation of neoplastic FDCs, could be a potential therapeutic target {2496).

Localization In the head and neck region, the most frequently affected siles are the cervical lymph nodes (involved in 40-50% of cases), followed by the Waldeyer ring (pharyngeal lymphoid ring; in 24-40%) and the soft tissue of the neck (in 10%) {11 87,1810). Other head and neck mucosa! sites can also be affected.

Clinical features Cases with lymph node involvement present with a neck mass. Tumours arising in the Waldeyer ring present with intraoral swelling or dysphagia. Systemic symptoms are rare. Most p atients (80- 90%) have localized disease at presentation.

146

Macroscopy The mean size of FDC sarcomas in the head and neck is 4.5 cm (1810). The tumours are solitary, round to ovoid circumscribed masses with a fleshy cut surface. Areas of haemorrhage and necrosis may be present.

The tumour cells are positive for FDC markers such as CD21, CD23, CD35, clusterin , CXCL13, and podoplanin (as recognized by 02-40). Cytokeratin is negative and EMA is often positive. Exceptionally, the cells can be positive for cytokeratin and TTF1 (11 05,2452).

Histopathology The morphological features are 'Similar to !hose of FDC sarcoma in other parts of the body. The tumours, which tend to have pushing invasive fronts, are composed of spindle to ovoid cells arranged in fascicular, whorled, or storiform patterns, accompanied by an admixture of small lymphocytes or lymphoid aggregates around blood vessels. The tumour cells have a moderate amount of pale eosinophilic cytoplasm and indistinct cell bord ers, imparting a syn cytial appearance. The nuclei are oval or elongated, with vesicular or granular fine ly dispersed chromatin, small distinct nucleoli, and a smooth nuclear membrane. Nuclear pseudoinclusions, binucleated tumour cells, and multinucleated tumour cells are often seen. The mitotic rate is usually 0- 1O mitoses per 10 high-power fields. High-grade nuclear pleomorphism, atypical mitoses, and coagulative necrosis are uncommon.


Prognosis and predictive factors FDC sarcoma is a low- to intermediategrade malignan! tumour with a recurrence rate of ;::: 40% and a distan! metastasis rate of;::: 25% {377,1810}. The overall and disease-specific survival rates, respectively, are 91% and 64% at 2 years and 81% and 34% at 5 years. Surgery is potentially curative for early-stage disease, but late recurrence and metastasis can occur many years after initial presentation {438). The most common metastatic sites are lung, liver, and lymph nodes. Large tumour size (> 4- 6 cm) has consistently been shown to co rrelate with poor prognosis {1810,2088}. Other proposed poor prognostic factors include disseminated disease, extensive necrosis, high mitotic rate (> 5 mitoses per 10 high-power fields), and significan! nuclear atypia (377, 521,1856).

CHAPTER 6 Tumours and tumour-like lesions of the neck and lymph nodes

Tumours of unknown origin Haematolymphoid tumours Cysts and cyst-like lesions

WHO classification of tumours and tumour-like lesions of the neck and lymph nodes /

Tumours of unknown origin Carcinoma of unknown primary Merkel cell carcinoma Heterotopia-associated carcinoma

8247/3 8010/3


The morphology codes are from the lnternational Classification of Diseases for Oncology (ICD-0) {776A}. Behaviour is coded /0 for benign tumours; /1 for unspecified, borderline, or uncertain behaviour; /2 for carcinoma in situ and grade 111 intraepithelial neoplasia; and /3 far malignan! tumours. The classification is modified from the previous WHO classification, taking into account changes in our understanding ot these lesions.

Cysts and cyst-like lesions Branchial cleft cyst Thyroglossal duct cyst Ranula Dermoid and teratoid cysts

lntroduction

The neck contains lymph nodes, soft tissue, fascia, skeletal muscle, nerves, blood vessels, lymphatic vessels, cartilage, bone, and paraganglia. Tumours and tumour-like lesions can arise in any of these components. An understanding of anatomy is critica! in the evaluation of lesions in the neck. Table Fig. 6.0 1 summarizes the levels used to classify the location of lymph nodes in the neck. The general diagnostic approach to lesions of the neck includes identification of where in the neck the lesion is, as well as clinical features such as patient age, sex, and cl inical presentation. Correlation with rad iographical fin dings, including determination of location, adjacent structures, size, solid versus cystic nature, and whether the lesion is circumscribed or infiltrative, is helpful. Given the close proximity of vital structures in the neck, core needle. biopsies are generally performed only by experienced c linicians. Fine-needle aspiration and excision are more frequently employed. Table 6.01 p resents a systematic approach to the evaluation of fine-needle aspirations from the neck. Given the complexity and the 148

Schwartz M.R . Vielh P.

small size of samples obtained, adjunc tive tests are useful in the evaluation of cytological and tissue specimens. These tests include immunohistochemistry, flow cytometry (for haematopoietic and

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la - Submental tJiangle lb - Submandibular triangle Ita • Anterior-inferior to spinal accessory llb • Posterior-superior to spinal accessory 111 - Middle 113 of interna! jugular vein IV- Lower 1/3 of Interna! jugular vein v - Postenor tnangle VI - Antenor cen~al cornpanment

d)

lymphoid lesions), gene rearrangements, in situ hybridization, cytogenetics. and PCR.

Lymph nodes The lymph nodes are the most frequent site of tumours in the neck. Lymph nodes can be involved by metastatic tumours, haematolymphoid tumours, and benign Table 6.01 Systematic approach to the evaluation of

fine-needle aspirations from the neck Is the aspírate satisfactory for evaluation? What is the cellularity? Is the lesion viable? Is the lesion salid or cystic? What type of general process is it - neoplastic, infectious, or other? Is it a haematopoietic, epithelial, mesenchymal, or neurogenic process? Is it a polymorphous or monomorphous population? Are the cells cohesiva (favours epithelial lesion) or dyshesive (favours haematopoietic, neuroendocrina)? What sized cell groups are present?

Fig. 6.01 Schematic anatomy of relevan! siles for the recording of tumours in neck lymph nades.

Tumours and tumour-líke lesions of the neck and lymph nodes

What is in the background (e.g. necrosis, mucín, clean background, lymphoglandular bodies)? Is the lesion benign, malignan!, or indetermínate?

Table 6.02 Lymph nodes most commonly involved by head and neck carcinoma Slte oral tongue Retromotar trigone

Most commonly involved nodes (in descendlng order of frequency) ] Subdigastric, submandibular, midjugular

IAngle of mandible, midjugular

floor of mouth

Jugulodigastric, submandibular

Tonsils

Angte of mandible, midjugular, lower jugular, ipsilateral and contralateral posterior cervical, parapharyngeal

Base of tangue

1 Midjugular, lower jugular; bilateral involvement common

Pharyngeal wall

Subdigastric, midjugular, posterior cervical, parapharyngeal, retropharyngeal

Supraglottic larynx

Subdigastric, midjugular

Glottis

Typically no nodal metastases

Hypopharynx

Upper, mid-, and lower jugular

Nasopharynx

Jugular, posterior cervical, supraclavicular; bilateral involvement common; wide distribution common

Paranasal sinuses

Subdigastric, submandibular

Ala nasi and nasal vestibule

Submandibular

Skin; upper/midface, temporal

Preauricular, intraparotid, periparotid

Skin; posterior scalp, neck

1 Postauricular, occipital, posterior triangle

processes. The most common malignancies in neck nodes are metastatic carcinoma from primaries in the head and neck (and less

commonly from primaries outside the head and neck) and metastatic melanoma. Metastatic squamous cell carcinoma from a head and neck primary is

the most common malignancy in neck nades. Table 6.02 summarizes the most common sites of metastases from key primary sites in the head and neck {47, 1436,1998}. The evaluation of cervical nodal metastases of unknown primary has changad dramatical ly over the past decade (1934, 2189,2292). This is due largely to the marked increase in incidence of HPV-related oropharyngeal squamous cell carcinomas. Many carcinomas previously diagnosed as cervical nodal metastases of unknown primary are now identified as being from occult oropharyngeal primaries (2491, 2672). These cases often present with small primaries and large bulky cervical nodal metastases (80,392,862}. Evaluation of nodal metastases far p16 expression (a surrogate marker for highrisk HPV intection) and/or for high-risk HPV by molecular tests helps in the identification of likely HPV-related primaries. Although rare, ectopic thymic tissue and thymic tumours may be encountered and should be considered in the differential diagnosis {200,637,1 277,20221.

lntroduction

149

Tumours of unknown origin

Carcinoma of unknown primary LewisJ.S. Richardson M. Syrjanen S. Westra W.H. Definition Metastatic carci,oma of unknown prima ry (CUP) is usually squamous or undif ferentiated and metastatic to neck lymph nades with no known primary tumour identified at initial presentation or after a thorough clinical work-up. ICD-0 codes Coding should be according to the morphology type. Synonym Cancer of unknown primary Epidemiology Although the reported figures have var ied over time and by study type, in gen eral, cervical metastatic carcinomas with no primary tumcur immediately apparent al initial presentation (i.e. CUP) constitute about 5% of all head and neck malig nancies (911,1842}. However, extensive clinical and radiographical work-up will identify primary tumour in most patients, and the remaining cases, so-called true

cervical nodal CUPs, constitute only 1-2% of head and neck malignancies (911,2293}. The literature contains only limited data addressing squamous cell carcinoma (SCC) versus undifferentiated carcinomas as cervical CUPs; most se ries group the two tumour types. SCCs constitute 75-80% of cases and undif ferentiated carcinomas 2-20% {883,911, 1129,2293,2412}, depending on geo graphical location. For example, in areas of endemic EBV infection such as south eastern Asia, the proportion of CUPs that are undifferentiated carcinomas may be higher {2412}. Localization CUPs occur most commonly in level 11 nades, followed by level 111 nodes, and < 10% of patients have bilateral neck involvement (883,2293). Approximately 50% of cases involve a single lymph nade. Most are of N stage N2a, b, or e (2412). In patients with CUP, the distribu tion of lymph node involvement may pro vide clues as to the site of tumour origin [1670l. EBV-related undifferentiated car cinomas of the nasopharynx initially me tastasize to retropharyngeal lymph·nodes and level 11 and V nades. HPV-related oropharyngeal carcinomas typically me tastasize to levels 11 and 111 f448,1670). Carcinomas of the facial skin and scalp frequently metastasize to intraparotid

Fig. 6.03 Lymph node with metastatic non-keratinizing squamous cell carcinoma of unknown primary mimicking branchial cleft cyst. A primary oropharyngeal carcinoma was subsequently identified.

Fig. 6.04 Metastatic non-keratinizing squamous cell carcinoma of unknown primary. lmmunostaining for p16 shows strong, diffuse nuclear and cytoplasmic positivity.

lymph nades. Supraclavicular metasta ses are more suggestive of a primary ori gin outside the head and neck.

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A

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~~_S!~:&r _ _ _ ,'!;_~ _ Fig. 6.02 Metastatic non-keratinizing squamous cell carcinoma of unknown primary with cystic change. A Low-power view displaying multiple cystic spaces with eosinophilie, proteinaceous contents and lined by a thin layer of tumour cells. B Tumour cells lining the cystic spaces show prominent mitotic activity and no obvious squamous maturalion; these are typical features oí (although not completely specific far) HPV-related carcinomas.

150

Tumours and tumour-like lesions of the neck and lymph nades

Clinical features CUP most commonly occurs in patients in their fifth or sixth decade of lite, and frequently occurs in current or former smokers. The male-to-female ratio is 2. 4:1 [1100,2540). The tumours present with symptoms of a neck mass and less often with pain, weight loss, and/or dysphagia {883). Cytology The cyto logy of aspirates of metastatic lesions may be helpful in determining possible primary sites. Far SCC, see Table 5.01 (p. 136), Chapter 5. Many CUPs are associated with HPV or EBV. Oetection of HPV ONA or p16 immunopositivity suggests the oropharynx as a likely primary site, whereas identification of EBV suggests a nasopharyngeal origin. Histopathology The morphology of CUPs mirrors that of tumours of known primary site. A large proportion of the tumours are nonkeratinizing , consisting of large, round ed nests or ribbons of cells with a high N:C ratio, hyperchromatic ovoid nuclei with inconspicuous nucleoli, brisk mitotic activity, frequent apoptosis, and numerous foci of necrosis {1405]. Cystic change is particularly common in non-keratinizing SCC metastases {862); these features are strongly associated with HPV-related oropharyngeal carcinoma. More rarely, cystic tumours have gland formation and even ciliated lining cells; these cases should not be misinterpreted as carcinoma arising in a branchial cleft cyst (206, 1946). Other tumours are conventional keratinizing SCC. Undifferentiated carcinomas can either consist of nondescript sheets of pleomorphic

cells or be lymphoepithe lial. In lymphoepithelial cases, the tumour cells have a syncytial appearance, with poorly defined cell borders, modest eosinophilic cytoplasm, and large round vesicular nuclei with prominent nucleoli. Most tumours, despite being histologically undifferentiated, show immunohistochemical evidence of squamous differentiation, being positive for p63, p40, and CK5/6 {1 202,2186}. Neuroendocrine carcinomas and adenocarcinomas arising in head and neck sites occasionally present with nodal disease, but the primary site is usually evident on microscopic examination and clinical evaluation.

Prognosis and predictive factors The survival rates vary with clinical stage and tumour type, and are better for CUP related to high-risk HPV {1128,2189,2421 , 2576].

Merkel cell carcinoma Perez-Ordonez B. Gnepp D.R. Thompson L.O.R. Williams M.O.

Definition Merkel cell carcinoma (MCC) is a primary neuroendocrine carcinoma of lymph nodes with microscopic, immunohistochemical, and genetic teatures similar to those of cutaneous MCC. ICD-0 code

8247/3

Synonyms Extracutaneous Merkel cell carcinoma; Merkel cell carci noma of lymph node; nodal Merkel cell carc inoma; unknown primary Merkel cell carcinoma; Merkel cell carcinoma of unknown primary

Tumours of unknown origin

151

-

-

Fig. 6.07 Merkel cell carcinoma of lymph node. A Tumour composed of small cells with inconspicuous cytoplasm and largely round to oval nuclei with dense chromatin; note the absence of nucleoli. B Perinuclear CK2D staining.

Epidemiology

Cytology

Nodal MCCs are extremely rare, accounting for only 0.05% of all MCCs {237l, They may represent metastasis from a regressed dermal primary.

Aspirates of metastatic lesions show cytological find ings identical to those of small cell neuroendocrine carcinomas from other sites {491).

Etiology

Histopathology

Origin vía malignant transformation of pre-existing intranodal epithelial rests or pluripotent stem cells has been postulated {670}. Merkel cell polyomavirus has been detected in 31% of nodal MCCs {543,1807). An association with other malignancies, particularly small lymphocytic lymphoma and chronic lymphocytic leukaemia, has been noted in as many as 36% of cases {1807,2358}.

The pathological and immunohistochemical features are similar to those of cutaneous MCCs. Tumours grow in sheets, with geographical necrosis, solid and organoid nests, trabecu lae. and cords, often separated by fibrovascular septa. Tumour cells are medium-sized and have scant cytoplasm, a high N:C ratio, and round to ovoid nuclei with finely dispersed salt-and-pepper chromatin with inconspicuous or small nucleoli. Rare cases have moderate amounts of cytoplasm with dense chromatin and visible nucleoli {670,18071. MCCs show diffuse expression of pancytokeratins. low-molecular-weight cytokeratins, and CK20, usually in perinuclear dots. Synaptophysin, chromogranin A, and CD56 are also positive. TdT and PAX5 are expressed in two th irds of cases. TTF1 and CK7 are usually negative {1807). Merkel cell polyomavirus large T antigen and DNA are detected by immunohistochemistry and PCR in 31% of cases {543,1807}. Ultrastructurally, tumour cells contain perinuclear globular aggregates of intermediate filaments and neurosecretory granules 1670).

Localization The head and neck lymph nodes are one of the most common sites of nodal MCC (affected in 21% of cases), second only to the ing uinal nodes (affected in 56%) {1807,2358). lt is unclear whether a subset of parotid gland small cell neuroendocrine carcinomas may be nodal MCCs.

Clinical features Nodal MCC presents as an enlarged lymph node. lt is most common in Caucasian males (male-to-female ratio: 4.5:1). The reported patient age range is 48- 92 years (mean: 65 years) {1807, 2358). Clinical history, physical examination, imaging, and follow-up are negative for cutaneous MCC.

Macroscopy Nodal MCCs replace most of the involved lymph nodes, display central necrosis, and range in size from 1.5 to 27 cm (mean: 6 cm) {1807,2358). 152

a 2-year disease-specific survival of 76.9% and can metastasize to brain. liver, bone, and non-regional lymph nodes {1807,2358). The only prognoslic factor is high-stage disease.

Heterotopía-assocíated carcinoma Ro J.Y. Brandwein-Gensler M. Schwartz M.R.

Definition Heterotopia-associated carcinoma is a carcinoma arising from heterotopic tissue elements (i.e. histologically normal tissue of a particular type that is present at an abnormal anatomical site). In the neck, most heterotopias consist of salivary or thyroid tissue, but heterotopic gastric and colonic tissues have also been (rarely) reported. Most carcinomas arising from heterotopic tissue are of salivary gland or thyroid origin.

ICD-0 code

8010/3

Synonyms Choristoma; ectopia; accessory tissueassociated carcinoma

Epidemiology Prognosis and predictive factor~ Nodal MCCs are classified as stage IIIB or IV disease and have a lower recurrence rate and better survival (median: 104 months) than do known cutaneous MCCs of similar stage (567, 2358). Stage III B nodal MCCs have

Tumours and turnour-like lesions of the neck and lymph nodes

Carcinomas arising from ectopic thyroid tissue or ectopic salivary tissue are rare, and < 1% of carcinomas arise in heterotopic thyroid or salivary tissue. Of the tew reported heterotopia-associated carcinoma cases, most thyroid and salivary cancers presented during the third and sixth

ctecades of lile, respectively {523,1555). They occur more commonly in women.

Localization Heterotopia-associated salivary carcinoma is usually seen in periparotid lymph nodes or along low anterior sternocleidornastoid muscle, with a right-side predilection {920). Heterotopia-associated thyroid carcinoma has been reported in lingual thyroid, thyroglossal duct cysts. ectopic intratracheal thyroid, midline ectopic thyroid , lateral neck, and branchial cleft cysts (706,1251).

Clinical features Heterotopia-associated carcinoma usually presents as a mass, but may be detected incidentally.

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,__._...._. _....._'"' ~ ~ ~~ Fig. 6.08 Heterotopia-associated carcinoma. A Primary mucoepidermoid carcinoma in periparotid lymph node. B Primary mucoepidermoid carcinoma in periparotid lymph node with mucinous carcinoma component. ---""--'---~--- ,

Macroscopy The lesions are usually 1.5-3.0 cm, but may reach > 4 cm.

Cytology Aspirates show cytological features identical to those of aspirates of the same lesions arising in their typical primary sites.

Histopathology Papillary thyroid carcinoma is by far the most common thyroid malignancy in heterotopic siles. followed by follicular carcinoma, squamous cell carcinoma, Hurthle cell carcinoma, anaplastic carc inoma, and medullary carcinoma (1251}. Tumours arising in heterotopic salivary gland tissue are rare, and about 80% are benign. Mucoepidermoid carcinoma is the most common carcinoma in this setting, followed by acinic cell carcinoma; adenocarcinoma, NOS; and cystadenocarcinoma. Other types of carcinoma have also been reported, but unlike among eutopic salivary gland carcinomas, adenoid cystic carcinoma is particularly rare {1725).

-:.-....; Fig. 6.09 Papillary thyroid carcinoma arising in association with thyroglossal duct cyst. Papillary structures and occasional psammoma bodies are seen; at the right, a respiratory epithelium-lined cyst and skeletal muscle fibres are seen; also seen are scattered benign thyroicl follicles.

The major differential diagnosis is metastasis to lymph node. Most cases of carcinoma in lateral neck ectopic thyroid are thought to constitute nodal metastasis trom an undetected primary in the thyroid gland. Most alleged carcinomas arising in branchial cleft cysts are thought to be metastatic squamous cell carcinoma from an undetected oropharyngeal carcinoma.

Prognosis and predictive factors The most importan! prognostic factors are tumour size, stage, and grade. With reported follow-up ranging from 1 month to 17 years , most patients are alive and disease-free {523 ,1251}.

Tumours of unl
153


Wakely P.E. Li X.-0. Schwartz M.R.

Definition

{2522}. Accurate distinction of lymphoma from other non-lymphoid neoplasms and from reactive conditions is possible when cytology is coupled with appropriate ancillary tests such as flow cytometry, immunohistochemistry, in situ hybridization FISH, cytogenetics , and/or assessment of gene rearrangements. A variety of NHLs can be subclassif ied in this manner. Fine-needle aspiration is particularly applicable in cases where recurrent lymphoma is suspected.

Lymphomas are neoplastic clonal proliferations of lymphoid cells. This category is subdivided into Hodgkin lymphoma (HL) and non-Hodgkin lymphoma (NHL).

Epidemiology Both HL and NHL are more common in developed countries. There is a slight male predominance. Caucasians have the highest incidence of NHL, whereas the indigenous peoples of North America are leas! affected. After the age of 10 years, the incidence of NHL increases with each passing decade. The incidence of HL spikes in the second to fourth decades of lite. NHLs are subdivided into B-cell, T-cell, and NK-cell types, with 80- 85% of being B-cell neoplasms. Follicular lymphoma and diffuse large B-cell lymphoma are the most common NHLs encountered in neck nades. HL has two major subtypes: classical and nodular lymphocyte-predominant, with the classical variant constituting 95% of ali cases.

various extranodal siles in the head and neck [2373}.

Clinical features Lymphomas commonly present as a painless nodal swelling in the neck. In sorne lymphomas, a concomitant anterior mediastinal mass is present. Non-specific constitutional symptoms include weakness and fatigue. Lymphomas may be associated with so-called B symptoms: fever, weight loss, and night sweats.

Macroscopy

Histopathology

Enlarged neck nodes may be single or matted together as a group. The cut surface shows a homogeneous pale-tan to off-white, soft or firm, bulging mass. Yel lowish necrotic foci may exist in sorne high-grade lymphomas. Sorne HL subtypes display a nodular cut surface showing a variable amount of fibrosis that manifests as strands of connective tissue arborizing throughout the node.

The characteristic low-power appearance of ali nodal-based NHLs is partial or complete alteration of the normal architecture of the lymph node by a proliferation of abnormal lymphoid cells. This proliferation may show a follicular, sinusoidal, mantlezone, or diffuse confluent pattern of effacement. Higher-grade lymphomas are associated with increased mitotic figures, tingible body macrophages, and necrosis (manifesting as individual cell apoptosis or geographical zones of necrosis). The cells of large cell lymphoma have a diameter 2- 4 times that of small resting lymphocytes, rou nd to ovoid nuclei with a vesicular appearance, coarsely granular chromatin, and discrete nucleoli. The cytoplasm is modest in amount and basophilic. More anaplastic forms of large cell lymphoma display multinucleation, irregular

Cytology Localization Lymphomas typically arise from lymph nodes in the anterior or posterior cervical, postauricular, occipital, or supraclavicular reg ions. HL may arise in a single node or a chain of nodes, but only rarely in extranodal siles. Although typically nodal, NHL may develop in

The use of cytopathology in the diagnosis of haematolymphoid neoplasms has evolved over the past three decad'es . Although the diagnostic standard for newly diagnosed patients remains histopathology in many centres, fine-needle aspiration cytopathology has proven useful in centres that use ancillary techniques

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Fig. 6.10 A Mantle cell lymphoma. An isomorphic population of small lymphocytes displays irregular nuclear contours, evenly dispersed chromatin, absent nucleoli, and minimal cytoplasm (Romanowsky stain). B Hodgkin lymphoma. A classic Reed- Sternberg cell dwarfs surrounding lymphocytes and neutrophi/s; huge nuclei mirroring one another contain enlarged misshapen nucleoli (Papanicolaou stain).

154

Tumours and tumour-like lesions of the neck and lymph nodes

nuclear contours, and large acidophilic nucleoli. Small cell subtypes of NHL have a monotonous population of lymphocytes that are slightly larger than mature resting lymphocytes. Depending on the subtype, nuclei are rounded or angulated with finely granular or clumped chromatin. Nucleoli, if visible, are small. Reed- Sternberg cells and variants are a minor componen! of the polymorphous population of lymphocytes, eosinophils, plasma cells, and neutrophils in classical HL. The common nodular sclerosis variant of classical HL typically contains so-called

lacunar-type Reed-Sternberg cells, which have polylobated nuclei and a retracted cytoplasm in formalin-fixed tissue. Positive CD30, CD15, and PAX5 staining is helpful for recognizing these cells.

Genetic profil e Most NHLs show clonal rearrangements of either IG genes (in 8-cell lymphomas) or T-cell receptor genes (in T-cell lymphomas). Severa! B-cell lymphomas have characteristic genetic abnormalities that can be used in differential diagnosis.

Prognosis and predictiva factors The prognosis of NHL is highly variable, depending on histological type and the lnternational Prognostic lndex, which consists of cl inical stage, serum lactate dehydrogenase, patient age, performance status, and involvement of extranodal sites {2732). HL is curable by rad iation and chemotherapy in about 85% of cases. Clinical stage is the principal prognostic factor in determining survival.

Cysts and cyst-like lesions Branchial cleft cyst

for 20% of cases) and 20- 40 years (accounting for 75%). Males and females are equally affected {599,906}.

Ro J.Y. Bell D. Gnepp D.R. Wenig B.M .

Etiology

Clinical features Patients present with painless cervical swelling. Bilateral lesions suggest syndromic or famil ia! association. Dysphagia, dysphonia, dyspnoea, and stridor may occur. Spontaneous rupture of an infected cyst may occur, resulting in a purulent draining sinus to the skin or pharynx.

Branchial cleft cysts were previously described as congenital malformations re sulting from imperfect obliteration of the branchial clefts, arches, and pouches. Other theories of their etiology include cervical lymph node cystic transformation and incomplete obliteration of cervical sinus or thymopharyngeal ducts {251, 594,866,2173).

The cysts are unilocular and contain clear to grumous material. They have a wide size range, and can reach 10 cm .

Synonyms

Localization

Cytology

Lateral neck cyst; cervical lymphoepithelial cyst

The typical localization is the lateral neck near the mandibular ang le, along the anterior border of sternocleidomastoid muscle, but these cysts can occur anywhere from the hyoid bone to the suprasternal notch. They are equally distributed on the left and right sides of the neck, with rare bilateral occurrence {599,906}.

Preparations show neutrophils, lymphocytes, and debris admixed with mature squamous cells, including degenerate forms {906,2378).

Definition A branchial cleft cyst is a lateral neck cyst, derived most often (approximately 90% of ali cases) from remnants of the second branchial apparatus. First, third, and fourth branchial cleft anomalies are rare.

Epidemiology Branchial cleft cyst accounts for about 20% of cervical cysts and 90% of lateral cervical cysts (879). lt has bimodal patient age peaks at < 5 years (accounting

Macroscopy

Histopathology Branchial cleft cysts are usually unilocular. They are lined by stratified squamous

• 8 Fig. 6.11 Branchial cleft cyst. A Scattered mature squamous epithelial cells are seen admixed with neutrophils, lymphocytes, histiocytes, and necrotic debris (Diff-Quik stain). B A unilocular cyst, lined by stratified squamous epithelium. Under the epithelial lining, lymphoid tissue with germinal centres is present. CThe cyst is lined by respiratory epithelium, with scattered goblet cells; beneath the cyst, only a few lymphocytes and eosinophils are present.

Cysts and cyst-like lesions

155

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Fig. 6.12 Thyroglossal duct cyst. A The cyst is lined by benign epithelium that is variable, even within the same cyst, and consists of columnar, cuboidal, and flat cells; the cyst contents are thin and mucinous, unless infected; thyroid follicles {al lower left) are seen in 31-62% of cases (1454,2560}. B The cyst is lined by ciliated pseudostratified respiratory and squamous epithelium and cuboidal cells; a subepithelial lymphoid infiltrate is present.

epithelium in 90% of cases and less com· monly by respiratory epithelium, with occasional goblet cells and transitional areas in both epithelial types. The lumen is fi lled with keratin debris. Lymphoid tissue with germinal centres is present in the wall. Carcinoma either does not occur in branchial cleft cysts or is vanishingly rare (251) . Presumed branchial clefl cysts with cytological atypia in patients aged > 40 years should raise the possibility of metastatic carcinoma from the oropharynx. In this set· ting, the value of p16 immunostaining for differential diagnosis is limited, because p1 6 is overexpressed in almost 50% of branchial cleft cysts (326,2663}.

Prognosis and predictive factors Branchial cleft cysts are benign. After complete surgical excision, there is only a low risk of recurrence (< 3%) without infection befare surgery, but the risk increases to nearly 20% if the cyst is infected or previously incised, drained, or incompletely removed .

Thyroglossal duct cyst Prasad M.L. Bell D. Gnepp D.R. Richardson M.

Definition A thyrog lossal duct (TGD) cyst is a cystic dilatation of a persisten! TGD.

Epidemiology TGD cyst is the most common congenital mass in the neck, presenting in patients of any age, with no sex predilection (277, 547,1334,1434). Thyroglossal tract remnants are found in 7% of autopsies (651, 1310}.

Etiology

Histopathology TGD cyst is lined by benign epithe lium, usually respiratory or squamous in type, and may show thyroid follicles and mucous glands in the wall. Severe inflammation, abscess , and granulomatous reaction with choleste rol granulomas may obliterate the cyst lining . Malignancy (most often papillary thyroid carcinoma) can infreq uently supervene.

The TGD arises from the endoderm at the base of tangue and descends in the midline of neck to form the thyroid gland. Persistence of TGD with accumulation of secretions from its epithelium may lead to cyst formation (51).


Localization

TGD cyst may rare ly be inherited in an autosomal dominan! manner (2089}.

The typical localization is th e midline of the neck or within 2 cm of it, at the l'evel of the hyoid, infrahyoid, or suprahyoid (submental). Uncommon locations include intralingual, intrahyoid, an d intrathyroidal {1334,2240).

Prognosis and predictive factors Recu rrences may occu r after inadequate excision (547). The p rog nosis of papillary thyroid carcinoma complicating a TGD cyst is excellent [439,948 ,1827).

Clinical features TGD cysts may present as an asymptomatic mass, draining sinus, fistula, or recurren! swelling that moves with swallowing. Ultraso nography confirms the presence of thyroid gland and detects any associated malignancy [439).

Ranula Katabi N. Gnepp D.R. Wen ig B.M.

Macroscopy

Definition

The cysts are generally < 2 cm in size (range: 0.5-10 cm) (51,790). The cyst contents are thin and mucoid, unless infected. Solid areas should raise ·suspic ion for malignancy {439).

Extravasation of mucus with in an intraoral cystic cavity, usually associated with the sublingual gland {647).

Synonyms

Cytology

Thyroglossal duct remnant; thyroglossal cyst (1640)

Asp irates show inflammatory cells and debri s admixed with mature squamous

156

cells or ci liated columnar cells . Thyroid follicular epithelium is sometimes seen.

Tumours and tumour-like lesions of the neck and lymph nodes

Synonyms Mucocoe le; retention cyst; mucus extravasation

by epithelium, which can be squamous, cuboidal, or columnar. A plunging ranula is a pool of mucin surrounded by fibrous tissue and inflammatory cells (frequently histiocytes), without an epithelial lining. Mucicarmine staining or periodic acidSchiff (PAS) with diastase may be helpfu l in identifying extravasated mucin.

Prognosis and predictive factors Complete excision, including removal of the traumatized salivary duct, is the treatment of choice {2720}. lnadequate excision can result in recurrence.

Fig. 6.14 Dermoid cyst. Cut surface of a midline neck dermoid cyst; the cyst is unilocular and filled with keratin.

Dermoid and teratoid cysts Epidemiology These are rare lesions. There is no sex predilection, and they can affect patients of any age (2592) .

Chiosea S. Gnepp D.R . Wenig B.M.

Etiology Trauma to an excretory duct is the most common etiology.

Definition A dermoid cyst is a cyst containing ectoderm- and mesoderm-derived tissues. The additional presence of endodermal derivatives defines a teratoid cyst.

Localization Simple ranulas occur in the (lateral) !loor of the mouth in association with the excretory duct of the sublingual gland {2592). In plunging ranula, extravasated mucin dissects through the muscle of the floor of the mouth into the neck {2720). Clinical features There are two types of ranulas: simple and plunging (deep) {2592,2720}. Simple ranulas presentas a painless mass in the oral cavity floor. Plunging ranulas present as a painless neck mass. Ranulas are usually unilateral and unifocal, but may be bilateral or multiple {2592).

Synonyms Nasal dermoid sinus cyst; cystic dermoid; cystic teratoma Epidemiology Dermoid cysts of the head and neck account for as many as 7% of ali dermoid cysts {1929}. There is no cleaf sex predilection [1815}. About two thirds of dermoid cysts are recognized in patients aged < 5 years.

Macroscopy Ranulas usually present as blue, fluctuant, painless masses, and can reach severa! centimetres in size {142}.

Localization The cysts are predominantly subcutaneous. The most common sites are the midline neck or nose, nasolabial fold, and lateral third of the eyebrow (i.e . embryological fusion lines) (1780}. Lateral dermoid cysts are rare {2372).

Histopathology A simple ranula is a pseudocyst that contains mucin and may be focally lined

Clinical features Dermoid cysts present as a non-pulsatile painless mass, pit (with protruding hair),

or fistula. Midline nasal dermoid cysts must be assessed (by imaging studies) for intracran ial or deeper soft tissue and/ or bony extension.

Macroscopy The cysts can reach 12 cm in size and have keratinous (yellowish-white) contents. H istopathology Dermoid cysts are lined by squamous epithelium with mature cutaneous adnexal structures (e.g. sebaceous glands and hair follicles). The absence of cutaneous adnexal structures is indicative of epidermoid cyst. ldentification of endodermal derivatives (e.g. gastrointestinal or respiratory mucosa or smooth muscle) is diagnostic of a teratoid cyst. Prognosis and predictive factors Complete surgical excision is the primary treatment {1780). Recurrence is rare.

Cysts and cyst-like lesions

157

CHAPTER 7 Tumours of salivary glands

Malignant tumours Benign tumours Non-neoplastic epithelial lesions Benign soft tissue lesions Haematolymphoid turnours

WHO classification of tumours of salivary glands

Malignant tumours Mucoepidermoid carcinoma Adenoid cystic carcinoma Acinic cell carcinoma Polymorphous adenocarcinoma Clear cell carcinoma Basal cell adenocarcinoma lntraductal carcinoma Adenocarcinoma, NOS Salivary duct carcinoma Myoepithelial carcinoma Epithelial- myoepithelial carcinoma Carcinoma ex pleomorphic adenoma Secretory carcinoma Sebaceous adenocarcinoma Carcinosarcoma Poorly differentiated carcinoma Undifferentiated carcinoma Large ce ll neuroendocrine carcinoma Small cell neuroendocrine carcinoma Lymphoepithelial carcinoma Squamous cell carcinoma Oncocytic carcinoma

8020/3 80 13/3 8041/3 8082/3 8070/3 8290/3

Uncertain malignant potential Sialoblastoma

8974/1

Benign tumours Pleomorphic adenoma Myoepithelioma Basal cell adenoma Warthin tumour Oncocytoma

8940/0 8982/0 8147/0 8561/0 8290/0

160

Tumours of salivary glands

8430/3 8200/3 8550/3 8525/3 8310/3 81 47/3 8500/2 8140/3 8500/3 8982/3 8562/3 8941/3 8502/3* 8410/3 8980/3

Lymphadenoma Cystadenoma Sialadenoma papilliferum Ouctal papillomas Sebaceous adenoma Canalicular adenoma and other ductal adenomas

8563/0* 8440/0 8406/0 8503/0 8410/0 8149/0

Non-neoplastic epithelial lesions Sclerosing polycystic adenosis Nodular oncocytic hyperplasia Lymphoepithelial sialadenitis lntercalated duct hyperplasia Benign soft tissue lesions Haemangioma Lipoma/sialolipoma Nodular fasciitis

9 120/0 8850/0 8828/0

Haematolymphoid tumours Extranodal marginal zone lymphoma of mucosa-associated lymphoid tissue (MALT lymphoma)

9699/3

The morphology codes are from the lnternational Classification of Diseases for Oncology (ICD-0) !776AJ. Behaviour is coded /O for benign tumours; /1 for unspecified, borderline, or uncertain behaviour; /2 for carcinoma In situ and grade 111 intraepithelial neoplasia; and /3 for malignant tumours. The c lassification is modified from the previous WHO classification, taking into account changes in our understanding of these lesions. *These new codes were approved by the IARC/WHO Committee for ICD-0.

TNM classification of carcinomas of the major salivary glands

TNM classificationª·b,c T - Primary tumour TX Primary tumour cannot be assessed TO No evidence of primary tumour T1 Tumour 5 2 cm in greatest dimension, without extraparenchymal extension Tumour > 2 cm but 5 4 cm in greatest dimension, T2 without extraparenchymal extension T3 Tumour > 4 cm and/or with extraparenchymal extension T4a Tumour invades skin, mandible, ear canal, or facial nerve T4b Tumour invades base of skull or pterygoid plates, or encases carotid artery Note: Extraparenchymal extension is clinical or macroscopic evidence of invasion of soft tissues or nerve, except !hose tissues/ nerves listed under T4a and 4b. Microscopic evidence alone does not constitute extraparenchymal extension for classification purposes.

N - Regional lymph nades (i.e. the cervical nades) NX Regional lymph nades cannot be assessed NO No regional lymph node metastasis N1 Metastasis in a single ipsilateral lymph node, 5 3 cm in greatest dimension N2 Metastasis as specified in N2a, N2b, or N2c below N2a Metastasis in a single ipsilateral lymph nade, > 3 cm but 5 6 cm in greatest dimension N2b Metastasis in multiple ipsilateral lymph nades, all 5 6 cm in greatest dimension N2c Metastasis in bilateral or contralateral lymph nades, ali 5 6 cm in greatest dimension N3 Metastasis in a lymph node > 6 cm in greatest dimension

M - Distant metastasis MO No distan! metastasis M1 Distan! metastasis Stage grouping Stage 1 T1 Stage 11 T2 Stage 111 T3 T1- 3 Stage IVA T1 - 3 T4a Stage IV B T4b Any T Stage IVC Any T

NO NO NO N1 N2 N0- 2 Any N N3 Any N

MO MO MO MO MO MO MO MO M1

ªThis classification applies to carcinomas of the majar salivary glands: parotid, submandibular (submaxillary), and sublingual; carcinomas arising in minar salivary glands (i.e. the mucus-secreting glands in the lining membrane of the upper aerodigestive tract) are not included in this classification, but instead at their anatomical site of origin (e.g. the lip). bAdapted from Edge e t al. {625AJ - used with permission o f the American Joint Committee on Cancer (AJCC), Chicago, lllinois; the original and primary source far this information is the AJCC Cancer Staging Manual, Seventh Edition (2010) published by Springer Science+Business Media - and Sobin et al. {2228A). ºA help desk far specific questions about TNM classification is available at http://www.uicc.org/resources/tnm/helpdesk.

Note: Midline nades are considered ipsilateral nades.

TNM c lassification of carcinomas of the majar salivary glands

161

lntroduction

In this volume, Chapter 7 is the main reference on ali salivary gland tumours occurríng throughout the head and neck. In recognition of cytology as an initial tool in assessing salivary gland masses, it has been included, when appropriate, in most malignan! and selected benign entities. To allow flexíbility in grading and the enrolment of patients ín clínica! Iríais the term "low-grade" has been omitted across entities. Another notable modification in this editíon is the grouping of rare epithelial carcinoma subtypes that share similar patholog ical and clinical characteristics under "adenocarcinoma, NOS", includíng cystadenocarcinoma, mucinous adenocarcinoma, and intestinal adenocarcínoma. Similarly, ductal papilloma subtypes (intraductal and inverted) are discussed together in a single section. Given the

162


EI- Naggar A.K .

multítude of existing entitíes and the remarkable overlap of cellular and phenotypic features wíthin and between salivary gland carcinomas, only thoroughly documented new phenotypes were considered . This approach led to the inclusion of secretory carcinoma as the only new entity in this edítion. Reported entíties and subentities lacking consensus support and/or validatíon by independent investigators have not been included in thís editíon. In this chapter, efforts were made to limít the hístomorphological, lineage, and bíolog ícal features discussed to those considered to be validated and re levan! to curren! diagnostíc and clinical practice. Similarly, only molecular and cytogenetic fíndings that have been ídentified by índependent authors and in large series are díscussed. Although the future íntegration of molecular genetíc findings into

the biological and therapeutíc stratification of certain salivary carcinomas is inevitable, none of the reported markers are yet clínically applicable. As in other chapters of this 4th edítion volume, poorly dífferentiated carcinomas (small cell and large cell) have been renamed poorly differentiated neuroendocríne and non-neuroendocrine carcinomas far consistency. Lastly, sialoblastoma and paraganglíoma have been reclassif ied from indeterminate to malignan! and coded accordingly.

Malig nant tumours

Mucoepidermoid carcinoma Brandwein-Gensler M. Bell D. lnagaki H. Katabi N. Leivo l. Seethala R. Triantafyllou A.

Definition Mucoepidermoid carcinoma (MEC) is a distinctive salivary gland malignancy composed of mucinous, intermediate (clear-cell), and squamoid tumour cells formi ng cystic and salid patterns . ICD-0 code

8430/3

Synonym Mucoepidermoid tumour Epidemiology MEC occurs overa wide age distribution, and is the most common salivary gland malignancy in children and young adults, with a peak incidence in the second decade of life {1995). Etiology MEC may develop secondary to radiation or chemotherapy during childhood, with a median latency period of 8 years {2495). Localization The parotid is the most common site far MEC, followed by the palate, submandi-

,

bular gland, and other intraoral minar salivary gland sites (309,1899). Primary intraosseous (central) MECs are rare (275, 1425)

Clinical features The clinical presentation varíes depending on tumour site, size, and grade. Cystic intraoral MEC can mimic a mucocoele. Mucinous MEC may fluctuate in size due to cyst rupture and may present as a mucin-draining cutaneous fistula. Macroscopy MECs typically present as a soft or firm circumscribed or infiltrative mass, commonly with a cystic component. Cytology Aspirates of low-grade, mostly cystic lesions show predominately mucus and macrophages. Occasional bland epithelial cells may be seen. Aspirates of higher-grade lesions are more cellular, showing an admixture of epithelial cell types typical of the lesions. Cytological pleomorphism, mitotic activity, and nec rosis may be seen {1248). Histopathology MEC is characterized by variable components of squamoid, mucin-producing, and intermediate-type cells, with a cystic and salid growth pattern. Overt keratinization is rare. Oncocytic, clear-cell, and sclerosing variants have been described . Mucicarmine staining and periodic acid-Schiff (PAS) stain with diastase

~

demonstrate intracytoplasmic staining in mucinous cells. The rare oncocytic variant is composed mainly of polygonal/columnar oncocytic cells with scattered mucocytes, and few if any squamoid cells [782). The sclerosing variant is characterized by dense hyalinizing fibrosis {1585,2360). Salid MECs tend to demonstrate predominan! squamoid and intermediate cells, with a subtle transition between these two components. Low-grade MEC is cystic, mucous cellrich, and well circumscribed . lntermediate gmdc MECs are generally more salid and less circumscribed and show a diversity of appearances, including mucin extravasation. High-grade MEC displays one or more of the following features: nuclear anaplasia; necrosis; increased mitotic rate; and perineural, lymphovascular, or bony invasion {105,124,255,876}. The diagnosis of high-grade MEC requires al least focal intracellular mucin positivity; the tumours typically contain foci of low or intermediate MEC. The diagnosis should be reconsidered in the presence of keratin pearls, extreme nuclear pleomorphism, or a history of skin cancer. Necrotizing sialometaplasia, pleomorphic adenoma with squamous metaplasia, and sclerosing polycystic adenosis can be misclassified as MEC. Cystic oncocytic MEC with lymphoid componen! can mimic Warthin tumour (MEC may develop in Warthin tumour) . The sclerosing variant can be mistaken far sclerosing sialadenitis.

-

Fig. 7.01 Mucoepidermoid carcinoma. A Circumscribed tumour with dominan! clear-cell composition. B Oncocytic variant. The finding of larger intermediate cells with clear cytoplasm guides this diagnosis to mucoepidermoid carcinoma; intracytoplasmic mucin is also present. C lntracytoplasmic mucin is a requisite finding.

Malignan! tumours

163

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Genetic profile

Epidemiology

Most MECs are characterized by a t(11;19)(q21;p13) translocation and CRTC1-MAML2 gene fusion (1 122,2116), whereas a small subset show a 1(11;15) (q21 ;q26) translocation and CRTC3MAML2gene fusion (1700\. Tumours with translocation and gene fusion tend to be of low to intermediate grade (1122,2116) and reported in younger patients {1700), but high-grade MEC can also be fusionpositive. Rare cases with t(6;22)(p21 ;q12) translocation and EWSR1-POU5F1 gene fusion have been reported (1638). Although these fusion find ings have been validated, their diagnostic and c linical implications in the pathological evaluation of these tumours remain uncertain.

The annual incidence of ACC is about 2 cases per 100 000 population in the USA {646}, and the median patient age at diagnosis is 57 years. There is no ethnic predilection, and the female-to-male ratio is about 1.5:1 {244,646}. ACC accounts for < 1% of ali head and neck cancers and < 10% of ali salivary gland neoplasms.


Patients usually present with swelling or masses, and may have numbness, paraesthesia, or pain. lnvolvement of motor nerves can cause facial or tongue weakness (517,2253).

Localization ACC occurs most frequently in the major salivary glands, but more than one third of cases occur in minor glands in the oral cavity, sinonasal trae!, or (rarely) other siles {244,646}.

Clinical features Low- and intermediate-grade MECs are less aggressive and are generally cured by complete surgical excision {1 195, 1569}. The 10-year overa!! survival rates for low-, intermediate-, and high-grade MECs are approximately 90%, 70%, and 25% , respectively (1899).

Macroscopy ACC typically presents as a firm, greyish-white, unencapsulated and infiltrative mass of variable size (2251). The rare

finding of necrosis and/or haemorrhage may indicate the presence of high-grade tumour {2117).

Cytology Aspirates are composed of groups of compact uniform basaloid cells, usually associated with metachromatic spheres or cylinders of acellular hyaline stroma {1247,1671,1690\. Neither the cytological features of a high-grade malignancy nor keratinization is seen.

Histopathology ACCs can manifest a variety of tubular and cribriform structures with variably solid components. The most recognizable architectural form is the cribriform pattern, characterized by nests of tumour cells interrupted by sharply punched-out spaces fi lled with basophilic matrix. The tubular pattern is composed of bilayered tubu les with true lumina. The tumour cells show scant cytoplasm and typically have small angulated and hyperchromatic nuclei. The solid growth pattern is characterized by sheets of tumour cells without lumen formation and may consist of epithelial or myoepithelial elements.

Adenoid cystic carcinoma Stenman G. Licitra L. Said-AI -Naief N. van Zante A. Yarbrough W.G .

Definition Adenoid cysti c carcinoma (ACC) is a slow-growing and relentless salivary gland malignancy composed of epithelial and myoepithelial neoplastic cells that form various patterns, including tubular, cribriform, and solid forms.

ICD-0 code 164

8200/3


Fig. 7.03 Adenoid cystic carcinoma. Spectral karyotype of a MYB-NFIB fusion-positive tumour with a t(6;9)(q22· 23;p23-24) chromosomal translocation as the sole cytogenetic anomaly.

Perineural invasion is virtually ubiquitous. Rarely, ACC can undergo high-grade transformation or dedifferentiation; this diagnosis should not be made in the absence of conventional ACC (1681 ,2117). lmmunohistochemical stain ing for KIT (CD117) is typical ly restricted to inner epithelial cells and p63 and SMA to peripheral myoep ithelial ce lls {78}. MYB and MYB-NFIB antibodies are currently being evaluated {270,2597). The majar entities to be distinguished from ACC are pleomorphic adenoma, polymorphous adenocarcinoma, epithelial-myoepithelial carcinoma, and basal cell adenocarcinoma.

prognosis, whereas losses of 14q are exclusively seen in mainly tubular and cribriform pattern tumours (1862,1955}. Whole-exome sequencing of ACCs has revealed a wide mutational diversity and a low exonic somatic mutation rate, with mutations in genes involving a wide variety of pathways, including f ibroblast growth factor, insulin-like growth factor, Pl3K and NOTCH signalling (PIK3CA, FOX03, INSRR, NOTCH1, and NOTCH2) (1002,2277}. KIT and EGFR, which are frequently overexpressed in ACC, are only rarely mutated or amplified (516, 1002,1625,2277}.

Genetic susceptibility Genetic profile The key genomic alterations are a t(6;9) chromosomal t rans location or more rarely a t(8;9) translocation, resulting in fusions involving the MYB or MYBL1 oncogenes and the transcription factor gene NFIB (266,1629,1745,1861 }. MYB/MYBL 1 activations due to gene fusion or other mechanisms are foun d in > 80% of ACCs and may be useful potential therapeutic targets {270,1630, 2271 }. Losses of 1p and 6q are associated with salid form tumours with poor

Germline BRCA mutations and genetic variants in DNA double-strand break repair genes have been associated with an increased risk of salivary gland cancers, including ACC (2157,2658}.

common ly to the lungs , tollowed by bone, liver, and brain (2185}. Factors that influence survival include tumour stage, node status, patient age, tumour site, large nerve perineural invasion, and surgical margins (71,449,1981). Generally, tumours with tubular and cribriform growth patterns have a less aggressive clinical course than do tumours with a salid componen! constituting more than one third of the tu mour {509,2328]. Radical surgical excision, with or without postoperative radiation, is the treatment of choice; overall survival is poorer with a single-modality approach {1981}. lntensity-modulated rad iotherapy plus carbon ion boost has recently been shown to improve locoregional control and progression -free and overall survival {1 126,1 127, 1348).

Prognosis and predictive factors The 10-year survival rate is 50- 70% (459, 1535,1981 }, and the local recu rrence rate is highly variable. Lymph node involvement is uncommon, but is more frequent in solid variants (2477}. Distan! metastasis is reported in > 50% of cases, most

Malignant tumours

165

Acinic ce// carcinoma Simpson R.H.W. Chiosea S. Katabi N. Leivo l. Vielh P. Williams M.O.

Definition Acinic cell carcinoma is a malignant salivary gland neoplasm composed of cancer cells with acinar features. A subset of this entity has been reclassified as secretory carcinoma (208}. ICD-0 code

8550/3

Synonyms Acinic cell adenocarcinoma; acinar cell carcinoma Epidemiology The mean patient age at presentation is approximately 50 years, with a female-tomale ratio of 1.5:1 {430,1826}. About 35% of patients are aged > 60 years, and 4% are aged < 20 years. Acinic cell carcinoma is the second most common salivary gland malignancy in ch ildren. Localization More than 90-95% of acinic cell carcinomas occur in the parotid glands. Clinical features The tumours typically present as slowgrowing, solitary, unfixed masses, but sorne are multinodular and/or fixed to skin. One third of patients experience pain and 5-10% develop facial paralysis.

166


Macroscopy Most tumours are circumscribed (occasionally cystic) solitary nodules of varying size, but sorne are poorly defined. Cytology Aspirates are usually cellular, and composed of sheets, microcystic structures, or follicles of serous acinar cells. The cells typically display granular cytoplasm encasing hyperchromatic, round, relatively monomorp hic nuclei. Admixed capillaries are often seen {48,1245!. Histopathology Acinar and ductal cells with variable vacuolated, clear, oncocytic, and hobnail features forming salid, microcystic, and follicular patterns are present. The papillary cystic component, if present, has macrocystic spaces with papillary proliferations. A prominent lymphoid infiltrate can be seen \103,1604). The acinar cells are large and polygonal, with basophilic granular cytoplasm and round, eccentric nuclei. The granules give a diastase-resistant positive periodic acid-Schiff (PAS) reaction, which may be focal, but the test is not necessary far diagnosis. Acinic cell carcinomas rarely show mitoses, .!1ecrosis, or significant pleomorphism, and can be considered low-/intermediate-grade malignancies. The presence of neural invasion and stromal hyalinization is associated with aggressive behaviour (152,641, 649,2255).

1

.;.

'

•

Fig. 7.08 Acinic cell carcinoma. D0G1 stains most acinic cell carcinomas.

A subset of tumours may display an undifferentiated componen!, predominantly salid or cribriform with glandular patterns and areas of necrosis (poorly differentiated transformation ar dedifferentiation) \430,2199,2384}. Although non-specific, DOG1 and SOX1 O are immunopositive in acinar and intercalated duct cells {408,1767). Acinic cell carcinoma is usually immunonegative for mammaglobin, which is useful in its distinction from secretory carcinoma. Genetic profile Pl3K pathway alterations have been reported (581}, but the biological and therapeutic significance of these findi ngs remains unknown (669}. Prognosis and predictive factors Although acinic cell carcinoma is general· ly not aggressive, a proportion can metas· tasize to cervical lymph nades and lung.

A recurrence rate as high as 35% has been reported {649,928,973,1013,1400, 1703,2405}. The 20-year survival rate is approximately 90%, with a slightly better rate for females {1826}. Poor prognostic factors include large tu rnour size, involvement of the deep lobe of the parotid gland , and incomplete resection. Multiple recurrences and cervical lymph node and distan! metastases predict poor prognosis. Compared with conventional acinic cell carcinomas, cases with high-grade transformation have been reported to be associated with a shorter mean overall survival (40 months versus 125 months) {430}.

Polymorphous adenocarcinoma Fonseca l. Assaad A. Katabi N. Seethala R. Weinreb l. Wen ig B.M .

Macroscopy PACs typically present as firm , c ircumscrib ed, unencapsulated, yellowish-tan lobulated nodules of variable size (average: 2.1 c m) {1832}.

Cytology

Fig. 7.10 Polymorphous adenocarcinoma. Note the multinodular surface and the haemorrhage.

Epidemiology PAC is the second most common intraoral malignan! salivary gland tumour, accounting for 26% of ali carcinomas al this site (2524). The female-to-male ratio is about 2:1. The patient age ranges from 16 to 94 years, with a mean of 59 years {1832). More than 70% of patients are aged 50- 70 years {1832). Few examples of PAC have been reported in chi ldren {1 231,1832,2430).

Local ization

Polymorphous adenocarcinoma (PAC) is a malignan! epithelial tumo ur characterized by cytological uniformity, morphological diversity, and an infiltrative growth pattern.

App roximately 60% of PAC cases involve the palate. Other intraoral locations are the bucea! mucosa, retromolar region, upper lip, and base of tangue {1231, 1832). Uncommon locations include the majar salivary and lacrimal glands, nasopharynx, and nasal cavity (1231,1832, 2587}.

ICD-0 code

Clinical features

Definition

8525/3

Synonyms Polymorp hous low-grade adenocarcinoma; terminal duct carcinoma ; lobular carcinoma; cribriform adenocarcinoma of tongue/minor salivary glands

-A , ·.

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PACs typically present as a · painless mass ot variable duration (from a few weeks to 40 years) {352) . Bleeding, telang iectasia, and ulceration of the overlying mucosa may occasionally be found.

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Due to their locations, PACs are rarely sampled by aspiration. lf accessible, smears show sheets and clusters of epithelial cells, with papillary formations. The cytological features ot high-grade malignancy and squamous d itterentiation are not seen unless dedifferentiation is present {1250).

Histopathology PAC is typically submucosal in location and unencapsulated. The tumour histopathology is characterized by cytolog ical unitormity, histological d iversity, and an infiltrative growth pattern. Due to the aggressive clinical behaviour of sorne ot these tumours, the term "low-grade" is omitted but can be used on a case-bycase basis. Neoplastic cells are small to medium-sized and uniform in shape, with bl and, minimally hyperchromatic, oval nuclei and only occasional nucleoli. Mitoses are uncornmon and necrosis is seen in high-grade transfo rmation. A salient and prominent teature is the wide variation of morphological configurations within and between tumours. The main microscopic architectural patterns are lobular, trabecular, microcystic or cribriform (as in adenoid cystic carcinoma), salid, and papillary-cystic. An eddy-like pattern can be observed al the peripheral boundaries of tumour. Foci ot oncocytic, clear, squamous, or mucous cells can be observed . Tumour stroma can be mucinous or hyalinized. Perineural involvement is common.

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.. .1. ... ·.:.!.;.,,. \, ~-11..J..W:.u.i<- r l ~ -._... ' Fig. 7.09 Polymorphous adenocarcinoma. A Tumour of minor salivary gland presenting as submucosal, well-circumscribed nodule. B A storiform pattern may be present in the periphery; neurotropism is common.

Malignan! tumours

167

lnvasion into adjacent bone may be seen in tumours of the palate or mandible. A cribriform variant {1604A), initially reported at the base of tangue and later in other minor salivary gland siles, is considered by sorne authors to constitute a separate entity {1604A,2198}; however, this phenotype is considered a feature within the PAC morphological spectrum by others. According ly, this variant is considered an emerging entity pending further evidence to justify a separate classification {2655A}. The tumour cells are immunoreactive for cytokeratins (e.g. CK7, in 100% of cases) 11577), S100 protein (in 97%), CEA (54%), GFAP (15%), MSA (13%), and EMA (12%) {1855,1916,2587). Expression of galectin 3 has been reported to be significan! in PACs {1850}. BCL2 is overexpressed in most cases {185 5), and mammaglobin is positive in 67- 100% of tumours 1207,1927). Staining for p63 is reported in 100% of cases, whereas p40 is consistently negative; this pattern is helpful (although not infallible) in the differential diagnosis {2011}. KI T (CD117) positivity has been described in about 60% of tumours {1 850).

Prognosis and predictive factors The overall survival of patients with PAC is generally good {352,671,1231 ,1832, 2118). A review of larg e series with longterm follow-up found local recurrence rates of 10- 33% (average: 19%) {1231 , 1832). Of these, 50% occurred 5 years after initial diagnosis {1231,1832). The range of reported regional metastasis rates is 9-1 5% {352,1231 ,1832). Distant metastases have seldom been reported {352,1231 ,1832,2118}. Deaths have occurred after prolonged periods {352,1231, 1832). High-grade transformation of PAC has been reported and is associated with an unfavourable prognosis {1681,2180}.

A variety of molecular and genetic findings have been reported in PAC, among these are HRAS mutations {2569]. inc luding alterations of th e PRKD gene family {2574): rearrangements of PRKD1, PRKD2, and PRKD3 {2574} and activating mutation of PRKD1 (p.Glu710Asp, exon 15). This activating mutation has also been rarely detected in other salivary gland tumours {2569). PRKD1 and PRKD3 rearrangements have also been found in clinically aggressive tumours. The diagnostic and biological significance of these findings is unknown. 168


Localization CCCs most frequently occur in intraoral salivary gland sites (p alate and base of tangue) {1 614,2 137,2182,2530) but may also occur in other siles {361,659,783, 784,951,988 ,1694,1755,1993,2053,2231, 2308,2719}.

Clinical features CCC most commonly presents as swelling and may be ulcerated or associated with p ain, bone invasion , and soft tissue fixation .

Macroscopy

Clear ce// carcinoma

Tumours present as a poorly circumscribed, solid, greyish-white mass. Prominent hyalinization may be grossly apparent.

Wenig B.M . Bell D. Chiosea S. lnagaki H. Seethala R.

Cytology

Definition Genetic profile

in the fifth to eighth decades of life. CCC is rare in chi ldren.

Clear cell carcinoma (CCC) is a low-grade salivary gland carcinoma composed of malignan! cells with clear cytoplasm, with or without hyalinization. lt has a squamoid phenotype and lacks features of other clear cell-rich salivary gland carcinomas.

ICD-0 code

8310/3

Synonym Hyalinizing clear cell carcinoma

Epidemiology CCC is more common in women {1614, 1755,2137,2231} and typically presents

As pirates comprise groups (often sheets) of cohesive small and large epithelial cells with prominent cell borders and uniform, round to ovoid nuclei with granularlooking chromatin, small nucleoli, and abundan! clear cytoplasm.

Histopathology CCCs are unencapsulated and infiltrative with salid sheets, nests, cords, trabeculae, and single-cell growth patterns. Perineural and bone invasion are common. Ducts and gland-like spaces can be seen. Most cases are characterized by sclerotic or hyalinized strorna surrounding tumour nests juxtaposed to variable fibrocellular myxoid stroma {1614}. The tumo ur cells are polygonal, with distinct cell borders and lightly eosinophilic to

clear cytoplasm /1614). CCC may also show overt squamous and even mucinous differentiation. lntracytoplasmic glycogen that gives a diastase-sensitive positive period ic acid- Schiff (PAS) reaction is present in CCC. The tumour may also show pune tate or even overt intracytoplasmic mucicarm ine staining. CCCs are positive for cytokeratins and p63, and negative for other myoepithelial markers /361,1326, 1614, 2137,2182,2530).

Genetic profile CCC shows consistent EWSR1-ATF1 gene fusion (84,2137,2354,2566}.

Basal ce// adenocarcinoma

Most BACs occur in the parotid gland /502,650,745,1816}.

Fonseca l. Gnepp D.R. Seethala R. Simpson R.H .W. Vielh P. Williams M.O.

Clinical features BAC usually presents as a slow-growing nodule. A subset of basal cell adenocarcinomas may be associated with multiple skin adnexal tumours (650,1069,2111, 2691).

Definition Basal cell adenocarc inoma (BAC) is a salivary gland malignancy with variable basal and myoepithelial neoplastic cells forming nests and glandular structures.

Macroscopy BAC presents as an unencapsulated, firm, light-tan mass .

Cytology ICD-0 code

8147/3

Prognosis and predictiva factors CCCs are low-grade malignancies associated with a good prognosis after complete surgical excision. Local recurrence and nodal metastases may occur {2231}. Distant metastasis and death due to disease occur rarely {1754). lnstances of high-grade transformation of CCC with EWSR1 rearrangement have been reported {1135).

Localization

Synonyms Basal ce ll adenocarcinoma ex monomorphic adenoma; malignant dermal analogue tumour

Epidemiology

.

BAC is rare {502,745,1816,2709}. Most patients are in th eir sixth or seventh decade of lile {502,745,1816,2709}. There is no sex predilection {650,2709).

Aspirate smears are cellular and show basaloid clusters of monomorphic small cells, with sean! cytoplasm and frequent naked nuclei (1241,24321. Stroma is sean! to absent; in the membranous type, it consists mainly of hyaline matrix that ranges from interdigitating strands to small cylindroma-like droplets . Squamoid and sebaceous features may be noted /2262).

Histopathology Tumours may exhibit solid, tubular, trabecular, and membranous patterns with infiltrative borders . Tumour cells typically Malignan! tumours

169

display peripheral palisading of basal cells with occasional inner lighter epithelial cells with variable deposition of basement membrane-like material. Perineural and vascular invasion is found in about one quarter of cases. Compared with adenoid cystic carci noma, BAC shows more vesicular nuclei, peripheral palisading, and squamous and sebaceous elements. BACs are distinguished from adenomas by their infiltrative features and perineural and angiolymphatic invasion, and may show increased mitotic activity and necrosis. They consist of small nests, cords, and ducts with peripheral basal and inner cuboidal epithelial cells. Staining for cytokeratins and myoepithelial markers highlights the dual-cell composition of BAC.

Genetic profile A subset of these tumours, mainly of the membranous type, contain CYLD alterations {435). Genetic susceptibility Rare examples of BACs occur in the setting of familial/multiple cylindromatosis syndromes, such as Brooke-Spiegler syndrome (multiple familia! trichoepithelioma), presumably in association with germline CYLD mutations {435). Prognosis and predictiva factors Local recurrence occurs in approximately one third of BACs {1674), but complete surgical excision with clear margins is curative in most cases. Regional lymph node metastasis, distant metastasis, and disease-related death are rare.

lntraductal carcinoma Loening T. Leivo l. Simpson R.H .W. Weinreb l.

Definition 1ntraductal carcinoma is characterized by intracystic/intraductal proliferations of neoplastic epithelial cells {225). ICD-0 code

8500/2

Synonyms Cribriform cystadenocarcinoma, l0wgrade; intraductal carcinoma, low-grade; salivary duct carcinoma Epidemiology These are rare tumours, with insufficient epidemiological data {561,1077,1303, 1322}.

Localization The parotid gland is the most common site {256 ,561,1303).

170


(with or without necrosis) and numerous mitotic figures characterize intermediate- and high-grade forms of intraductal carci noma {256,561,2361,2573). These lesions must be distinguished from variants of adenocarcinoma, NOS, including cystadenoca re in orna.

Prognosis and predictiva factors The prognosis is excellent alter complete excision. Nodal and distan! metastases have not been reported to date. The significance of focal invasion by these lesions is uncertain {256,561 ,1303,1313,1697,2178}.

Adenocarcinoma, NOS Leivo l. Brandwein-Gensler M. Fonseca l. Katabi N. Loening T. Simpson R. H.W.

Definition Salivary gland adenocarcinoma, NOS, represents a spectrum of epithelial carcinomas forming ductal and/or glandular structures (with or without cystic formation) exclusive of known epithelial salivary gland carcinomas .

ICD-0 code

8140/3

Synonyms

.

- ·~ "-.a

Fig. 7.15 lntraductal carcinoma. A Low-power view of lobular and cystic areas. This cyst is lined by epithelium with partly rigid (cribriform) structures; the arrow indicates a neighbouring invasive carcinoma. B Mixture of cysts and smaller ducts, as well as of florid and atypical ductal hyperplasia (equivalen! to low-grade intraductal carcinoma). C lntraductal carcinoma (intermediate to high grade). Large ducts lined by neoplastic cells with micropapillary features.

Clinical features Patients may present with a swelling, which is commonly asymptomatic {1303,2573).

Macroscopy The repo rted tumours have been described as typical ly small, unencapsulated, and cystic {256,561}.

Histopathology These lesions display a range of cytological features and can be graded as low-grade,

intermediate-grade, or high-grade intraductal carcinoma on the basis of the degree of the cytological abnormalities. Low-grade tumours are mostly cystic with cribriform and papillary patterns, similar to breas! lesions, ranging fr9 m florid ductal hyperplasia to ductal carcinoma in situ {256,561}. The tumour cells are monotonous and may display cuboidal, mucinous, and apocrine features, with occasional intracytoplasmic iron p ig ment. Moderate to marked cellular atyp ia

Unclassified adenocarcinoma; d uctal carcinoma/adenocarcinoma; cystadenocarcinoma; mucinous cystadenocarcinoma; papillary cystadenocarcinoma; intestinal-type adenocarcinoma [53,1621, 2256,2524,2603)

Epidemiology Adenocarcinoma, NOS, accounts for approximately 10-15% all salivary gland carcinomas (213,2256,2524}. The average patient age is about 58 years, but a wide age range has been reported {213, 2520) . These tumours are extremely rare in children {1521).

Localization More than 50% of these tumours arise in the parotid gland {213,750,2256); 40% arise in minar glands, most often in the hard palate, buccal mucosa, and lips [750,2524, 2536).

Malignan! tumours

171

including small confluent nests or cords, large islands with intervening connective tissue, and solid densely cellular strorna. Tumours can be graded (on the basis ot the degree of cellular atypia) as low-, intermediate-, or high-grade. Ductal and glandular structures are common in lowand intermediate-grade tumours but less frequent in high-grade tumours. For the diagnosis of adenocarcinorna, NOS, to be rendered, the most common primary subtypes must first be excluded, including salivary duct carcinoma, high-grade mucoepidermoi d carcinoma, polymorphous adenocarcinoma and metastatic adenocarcinoma [1737). lrnmunohistochemistry can be helpful in distinguishing adenocarcinoma, NOS, from acinic cell carcinoma (CK18, DOG1) (1081}, and from tumours with myoepithelial/basal-cell composition (calponin, SMA, CK5/6, p63). The uncommon subtypes of these tumours include mucinous adenocarcinoma with variable cystic formation (formerly called cystadenocarcinoma) [53,750, 1621,2603,2659A}, and intestinal-type adenocarcinoma [173,838,2215}. lntestinal-type adenocarcinomas can be positive for CK20 and CDX2. These tumours have an aggressive clinical course. Whether they constitute a separate entity is unclear.


Clinical features Most tumours of major glands present as asymptomatic solitary firm or cystic masses. Occasionally, they may be painful. Tumours in the palate are often ulcerated and may erode bony structures. The duration of these tumours varíes consid erably, from 1 to 10 years [2256).

Macroscopy The tumours may be partly circumscribed, but may have an irregular and infiltrative appearance. The cut surface is commonly tan or yellow, with or without

172


areas of necrosis and haemorrhage.

Cytology The cytological features are non-specific and depend on the neoplasm's grade and other histological féatures [2256).

Histopathology Tumours display ductal or glandular proliferations with or without cystic formation . The tumour cells can be cuboidal, columnar, polygonal, clear, mucinous, oncQcytoid, and/or plasmacytoid in morphology and arranged in a variety of growth patterns,

Prognosis is influenced by tumour location, tumour grade, and clinical stage [214,2256,2520,2524}. High-grade adenocarcinoma, NOS, is an aggressive malignancy {2520}. A study of adenocarcinoma, NOS (excluding the cystadenocarcinoma and intestinal subtypes) reported 15-year survival rates for low-, intermediate-, and high-grade tumours of 54%, 31%, and 3%, respectively {22561. Generally, survival of adenocarcinoma with significan! cystic formation is excellent after adequate surgical resection, with few reported recurrences {750}. The reports of intestinal-type adenocarcinoma suggest an aggressive behaviour {173,838}, but further validation of these findi ngs is needed.

Salivary duct carcinoma Nagao T. Licitra L. Loening T. Vielh P. Williams M.O.

Definition Salivary duct carcinoma (SDC) is an aggressive epithelial malignancy resembling high-grade mammary ductal carcinoma. lt can occur de novo or as the outcome of a malignan! component of carcinoma ex pleomorphic adenoma.

8500/3

ICD-0 code Synonym High-grade ductal carcinoma

Epidemiology SDC accounts foras many as 10% of ali salivary gland malignancies {850). lt has a distinct male predilection and generally affects elderly individuals, with peak incidence in the sixth and seventh decades of lite {143,1106,111 9). Localization Most tumours arise from the parotid gland {1106,1 119,2470}.

Fig. 7.20 Salivary duct carcinoma A Sarcomatoid variant. Biphasic neoplasm with both conventional salivary duct carcinoma (left) and sarcomatoid elements with a fascicular pattern of atypical spindle cells (right). B Mucin-rich variant. Mucin lakes containing islands of carcinoma cells (right) in addition to the conventional salivary duct carcinoma component (left).

C linical features SDC presents as a rapidly growing tumour, commonly associated with facial nerve palsy, pain , and cervical lymphadenopathy. In cases ari sing as carcinoma ex pleomorphic adenoma, a rapid increase in size of a longstanding pre-existing mass is commonly reported. Mac roscopy The tumours vary in size and are infiltrative. On cut surface, they are grey to white, with occasional small cysts and foci of necrosis. Cytology Aspirates are cellular and typically contain 30 clusters, sometimes with papillary

configurations and flat sheets of epithelial tumour cells with necrotic backgrounds {1205,1249}. The tumour cells are large and polygonal, with abundan! cytoplasm. The nuclei are pleomorphic and have prominent nucleoli. Histopathology The tumour has a striking resemblance to high-grade ductal carcinoma of the breast, including large ducts with comedonecrosis and cribriform and Romanbridge-like features. Both lymphovascular and perineural invasion is common. A hyalinized nodule suggestive of a pre-existing pleomorphic adenoma may be identified . SDC cells are typically apocrine, oncocytoid, and characterized by abundan!

-

Fig. 7.19 Salivary duct carcinoma. A lnvasive micropapillary variant. Morula-like small cell clusters without fibrovascular cores, surrounded by a clear space. BCarcinoma cells show a diffuse nuclear immunopositivity far androgen receptor. C Diffuse and strong membranous immunostaining far ERBB2/HER2.

Malignan! tumours

173

Epidemiology Myoepithelial carcinomas are uncommon and can present in patients of any age, with no sex predilection.

Localization Most cases occur in the parotid gland. The palate and submandibular gland are the next most common sites.

Clinical features Patients present with a painless mass, occasional ly with a recent rap id increase in size. Facial weakness/paresis may occur if there is facial nerve involvement. Fig. 7.21 Salívary duct carcinoma. FISH analysis is positive for ERBB2 (also called HER2) gene amplification, showing numerous red signals (ERBB2) versus a normal number of green signals (centromere 17).

cytoplasm and large pleomorphic nuclei with coarse chromatin and prominent nucleoli. Mitotic figures are easily identifiable. Rhabdoid features {1315), squamous features, and osteoclast-like giant cells are rare {2433). Several histological manifestations of SDC have been described {2610), including sarcomatoid {975,1682), mucin-rich {2181), invasive micropapillary {1683), and oncocytic carcinomas {2178). Approximately 70% ot SDCs in both men and women show diffuse nuclear staining for androgen receptor {578,1171,1558, 2610). Estrogen receptor and progesterone receptor are negative {578,1171,1396, 2606). High ERBB2 (also called HER2) expression is found in approximately 2530% of cases {578,1465,1558,2611).

Prognosis and predictive factors SDC is one of the most aggressive malignant salivary gland tumours, with frequent local recurrence and reg ional lymph node and distant metastasis {143, 11 06,1119). Of the reported patients with SDC, 55- 65% have died of disease, usually within 5 years {1106,1119,1146).

Myoepithelial carcinoma

174


Definition Myoepithelial carcinoma is a malignancy entirely composed of neoplastic myoepithelial cells with an infiltrative growth .

ICD-0 code Synonym Malignant myoepithelioma

Myoepithelial carcinomas typically present as unencapsulated soft to firm masses. The cut surface is grey to tanwhite and occasionally haemorrhagic, with cystic degeneration and necrosis.

Cytology Aspirate smears show a mixture of spindled, epithelioid, and/or plasmacytoid cells in small groups or large fragments. Nuclei can be round or oval, with variable cytoplasmic features (421).

Histopathology

Bell D. Di Palmas. Katabi N. Schwartz M.R. Seethala R. Skálová A.

Genetic profile AR copy-number gain and splice variants (as seen in prostate) have been identified in both sexes {1464). ERBB2 (also called HER2) gene amplification is seen in as many as 25% of cases 1431, 1558,1705,2611). PLAG1 and/or HMGA2 rearrangements are identified in most cases of SDC ex pleomorphic adenoma (123,1196).

Macroscopy

8982/3

Myoepithelial carcinomas are composed of disorganized nodules of malignant myoepithelial cells, with pushing to infiltrative borders. The tumour cells can form solid, trabecular, and reticular patterns. The stroma can be myxoid and/or hyalinized. The tumour may display central necrosis and pseudocyst formation. Tumour cells display a mixture of spindle, plasmacytoid, epithelioid, and clearcell morphological features. Vacuolated/ signet ring- like morphologies have also been described {148,852}. The tumours typically express myoepithelial markers such as SMA and p63, as well as S100 and cytokeratins.

Genetic profile An EWSR1 gene rearrangement has been described in a subset of myoepithelial carcinomas that have aggressive features and are composed predominantly of clear cells, with frequent necrosis !2204).

Prognosis and predictive factors Myoepithelial carcinomas are associated with diverse clinical outcomes and have a propensity for distan! (usually lung) metastasis rather !han regional lymph node metastasis !577,1 271,2083,2297). About one third of patients are cured with resection and one third experience metastatic and progressive disease (1271).

Epithelia/-myoepithelial carcinoma Seethala R. Bell D. Fonseca l. Katabi N.

Localization Definition Epithelial-myoepithelial carcinoma (EMC) is a malignan! salivary gland tumour composed of a biphasic arrangement of inner luminal ductal cells and outer myoepithelial ce lls.

ICD-0 code

8562/3

Most cases arise in the parotid gland and submandibular gland {2115,2486). Less common siles include the sinonasal cavity and palate {2115).

Clinical features EMC typically presents as a slow-growing painless mass. Facial nerve symptoms and lymphadenopathy are·rare.

Synonym Adenomyoepithelioma

Epidemiology EMC is an uncommon salivary gland neoplasm, accounting for < 5% of all salivary gland malignancies !2486). lt predominates in the sixth and seventh decades of lite and has a slight female predilection.

Macroscopy EMC is characteristically a multinodular, fi rm to rubbery mass with a pushing border. Partial encapsulation and cystic change are noted in 30% of cases (2115}. EMCs of the minor salivary and sinonasal seromucinous glands are submucosal and less delineated, and 40% of cases show overlying mucosal ulceration.

ductal cells with dense eosinophilic cytoplasm and outer abluminal polygonal myoepithelial cells with classically clear cytoplasm (744,2114,2115). Solid overgrowth and necrosis may be present. Perineural invasion is common and vascular invasion less so {744,2115). A spectru m of phenotypes (i.e. oncocytic, spindled, clear, sebaceous) may be seen in both ce ll components in a small subset of tumours. Myoepithelial anaplasia and high-grade transformation have also been described {211 4,21 15,2 119). Low-molecular-weight cytokeratins are strongly positive in the ductal componen! and are less intense in the myoepithelial componen!. Myoepithelial markers (e. g. SMA, HH F35, p63, and calponin) highlight the abluminal compartment (21 15). S100 stains both the myoepithelial and the ductal components to variable degrees.

Cytology The tumour cells present as 30 clusters with a dual-cell population of larger pale myoepithelial cells and smaller eosinophilic ductal cells. Naked nuclei are common and stroma is sean!, with sorne · hyaline globules (1616). Fig. 7.23 Epithelial-myoepithelial carcinoma. This parotid tumour shows a multinodular pattern of invasion, abutting dermis; tumour nodules are firm and white, with central haemorrhage and cystic degeneration.

Genetic profile No characteristic genetic have been identified.

landmarks

Histopathology EMC displays a multinodular pattern and is characterized by a biphasic or bilayered arrangement of small inner luminal Malignan! tumours

175

Prognosis and predictive factors EMC is usually indolent, but local recurrence is not uncommon {2115}. Lymph node and d istan! metastasis is rare. In the SEER database, the d isease-specific survival rate is 80% at 180 months \2486). Significan! prognostic factors include tumour size, margin status, high-grade transformation , myoepithelial anaplasia, necrosis, and angiolymphatic invasion \744,2021,2115}.

Carcinoma ex p/eomorphic adenoma

A

_ -.,1..___ _ _ _

PA componen! is grossly visible in most cases, usually as a sclerotic, calcified no dule.

Wi lliams M.O. lhrler S. Seethala R.

Cytology Definition Carcino ma ex pleomorphic adenoma (PA) is an ep ithelial and/or myoepithelial malignancy developing from primary or recurren! PA. The carcinoma componen! can be e ither purely epithelial or myoepithel ial in presentation, with infiltration into the surrounding g landular and extraglandular tissue.

ICD-O code

8941/3

Epidemiology Carcinoma ex PA accounts for 3 .6% of all salivary gland tumours (range: 0 .9- 14%) and 12% of all salivary g land malignancies (range: 2 .8- 42.4%). On average, 12% of cases (range: 7- 27%) develop in the setting of recurren! PA (63,104,1399,1453) . This malignancy occurs slightly more often in women than in men, with peak incidence in the sixth and seventh decades of life (one decade later than the peak incidence of PA) {892,1196,2564).

Smears typically show teatures of PA or high-grade adenocarcinoma. Rarely, both components are identified \1240,1242).

Histopathology Carcinoma ex PA should not be considered a standalone d iagnosis, because the type and extent of the carcinoma component impact the management of patients. The histological type of the malignan! com ponen! must be recorded. Most tumours are high-g rade adenocarcinoma, typically of salivary duct carcinoma phenotype \1 197,1399) . Other common carcinomas include myoepithelial carcinoma Pleomorphic adenoma(PA)

lntracapsular • carcinoma

Precursor leslo n: Mixed luminal cells( q formlng ducts ( ( ) ) and a blumlnal ( supportlng cells

Abnormal proliferatlon within/betwee n existing ducts in a PA

Genetic profile Carcinoma ex PA shares fusion genes identified in PA (i.e. the transcription factor genes PLAG1 and HMGA2) [1860, 2009,2510). The alterations frequently reported in the salivary duct carcinoma subtype are mutations in TP53 (present Minimally invasive

Widely invasive

Breach of the PA capsul e by carcinoma cells, measured in mm

Extending lnto the gland and often soft tlssue. The PA compone n! may be hyalinized

Abnormal Lumina1(~ loroliteration • Nuclear enlargement

•

Most cases of carcinoma ex PA arise in the parotid gland (1 197,1 228,2415,2564).

Carcinoma ex PA often presents as a rapidly growing mass (which may be painful) within a pre-existing, longstanding mass (PA).

(often low-grade), w hich accounts for 35% of cases \1197,1399,2203,2204). lntracap sular carcinomas constitute carcinomas confined within the PA. They are typically ductal and high-grade \63, 576,892,1399). Minimally invasive carcinoma ex PA may constitute early disease [2415,2564). Assessing this feature is not always feasible in tumours w ith positive margins o r in those orig inating in minor salivary gland siles or within multinodular/recurrent PA \892).

• Promlnent nucleoll

Localization

Clinical features

!/

Fig. 7.25 Carcinoma ex pleomorphic adenoma of the parotid gland. A Well-circumscribed heterogeneous mass with peripheral hyalinized pleomorphic adenoma. B Minimally invasive carcinoma ex pleomorphic adenoma shows a hyalinized pre-existing pleomorphic adenoma with a 3 mm focus of carcinoma extending beyond the pleomorphic adenoma capsule (arrows).

r

lumlna~ ducta l) . . Express CK7, CK18

Ab luminal (myoepithellal) Express CK14, p63, SMA

@''' ,

"' \ •

• Interna! proliíeratlon of abluminal cells may be difficult

Macroscopy The gross appearance of carcinoma ex PA varíes, and as many as 64% of cases are infiltrative \1399,1453) . A residual 176


to call carcinoma ex~PA until

lnvaslve (next lnset)

Fig. 7.26 Schematic illustration of the development of carcinoma ex pleomorphic adenoma as a multistep progression from pleomorphic adenoma.

in 50-75% of cases), amplification in MDM2 and HMGA2 (12q13-1 5; in 50%), and amplification in ERBB2 (also called HER2; in 31 - 38%) {431,1860,1988,2009}. Recen! genomic studies have shown that most tumours have a high degree of genetic instability and many copy-number alterations /954,2510,2661}.

Prognosis and predictive factors Carcinoma ex PA is an aggressive malig nancy, with local or distan! metastasis oc curring in as many as 70% of cases and a 5-year overall survival rate of 25-65%. More-favourable outcomes are seen with intracapsular and minimally invasive tumours, together accounting for 21-58% of cases /892,1 197,1399,2564). lntracapsular carcinoma ex PA has a very low reported rate of recurrence or regional metastasis {576,580,1082,1453}. Morerecent studies have found minimally invasive tumours (defined as < 4-6 mm extension beyond the pleomorphic adenoma border) to be prognostically favourab le {892,11 97,1399,2564}, with this criterion showing superior prognostic significance over pT classification alone /241 5,2564). The risks of local recurrence, metastasis, and fatal outcome are greatly increased with invasive tumours. Further validation of this preliminary threshold for defining extent of invasion is required.

Epidemiology A 2008 study of mammary acinic cell carcinomas found secretory carcinoma to be distinct from acinic cell carc inoma {1975). Secretory carcinoma was fi rst documented in salivary glands in a 2010 study {2202}, and 232 cases have been reported since. Secretory carcinoma usually presents in adults, with a mean patient age of 46. 5 years (range: 10- 86 years) and an equal sex distribution /196,208,429,1514,2132,2138,2191, 2202}.

Localization The most common site of occurrence is the parotid gland, followed by the oral cavity an d submandibular gland (196, 208,429,2132,2138,2191 ,2202}.

presents as a painless, slow-growing mass.

Macroscopy Grossly, tumours are poorly defined and rubbery, with a light-tan cut surface . Occasionally, cyst formation with yellowishwhite ·fluid is encountered.

Cytology Aspirate material consists of cohesive epithelial ce lls and/or papillary fragments or dispersed cells, sometimes with cystic debris. The neoplastic cells are p henotypically epithelial, with abundan! and variable, granular to vacuolated , eosinophilic to clear cytoplasm and single nucleoli {210,891 ,11 56,1935,2062}.

Histopathology Clinical features Secretory carcinoma

most commonly

Secretory carcinoma can be circumscribed or (often) infiltrative, with occa-

Secretory carcinoma Skálová A. Bell D. Bishop J.A. lnagaki H. Seethala R. Vielh P.

Definition Secretory carcinoma is a generally lowgrade salivary gland carcinoma characlerized by morphological resemb lance to mammary secretory carcinoma and ETV6-NTRK3 gene fus ion.

ICD-0 code

8502/3

Synonym Mammary analogue secretory carcinoma

Malignan! tumours

177

sional perineural invasion. The tumours exhibit a lobulated growth pattern with fibrous sepia and are composed of microcystic/solid, tubular, follicu lar, and papillary-cystic structures with distinctive luminal secretion. The tumour cells have eosinophilic granular or vacuolated cytoplasm with small, uniform nuclei. Unlike acinic cell carcinomas, secretory carcinomas show no secretory zymogen cytoplasmic granules that give a true positive periodic acid-Schiff (PAS) reaction . Secretory carcinoma with high-grade transformation has been reported {2201}. Secretory carcinomas are characteristical ly positive for S100 protein and mammaglobin. Most cases are DOG1-negative {408}.

Genetic profile Secretory carcinoma harbours a recurrent translocation t(12;15)(p13;q25), which results in fusion of the ETV6 gene on chromosome 12 and the NTRK3 gene on chromosome 15. The presence of ETV6-NTRK3 fusion has not yet been demonstrated in any other salivary gland tumours. Rarely, ETV6 can be fused with non-NTRK3 partners {1102A}. However, the fusion has been considered to be a multilineage alteration in several non-salivary gland tumours (76,1275,1325,1374). Prognosis and predictiva factors Secretory carcinoma is usually an indolent salivary gland malignancy. Lymph nade metastases are reported in as many as 25% of cases, but distant metastases are rare {430,1514,2130,2132, 2138,2201,2447}. High clinical stage and high-grade transformation are the main adverse prognostic factors.

178


Sebaceous adenocarcinoma Gnepp D.R. Assaad A. Ro J.Y.

Definition Sebaceous adenocarcinoma is a malignant tumour composed mainly of neoplastic sebaceous cells of variable maturity arranged in sheets and/or nests, that display variable degrees of pleomorphism, nuclear atypia, and invasiveness. ICD-0 code

8410/3

Epidemiology Sebaceous adenocarcinomas are rare tumours with a biphasic age distribution. The peak incidences are in the third and seventh to eighth decades of life, with a wide patient age range (6-93 years) {64, 851}. The male-to-female ratio is approximately 1:1 {64,2337). Localization To date, about 50 cases of salivary gland sebaceous adenocarcinoma in head and neck siles have been reported {64,851, 1530,2337,2537}. In the parotid gland, 35 cases arase de novo and 2 tumours occurred as the carcinoma component of carcinoma ex pleomorphic adenoma {466]. Only 3 tumours have been reported in the submandibular gland, and the rest occurred in various minor glands. Clinical features Patients typically present with a painful mass and varying degrees of facial

nerve paralysis, and occasionally with fixation to the skin. In rare cases, patients develop a non-tender mass.

Macroscopy Tumours range from 0.6 to 9.5 cm in greatest dimension and are frequently well circumscribed or partially encapsulated, with pushing or locally infiltrati ng margins. Their cut surfaces can be yellow, tan -white, greyish-white, white, or pale pink {851 ). Cytology Smears are cellular, showing neoplastic cells arranged in groups and scattered single pleomorphic tumour cells with vacuolated cytoplasm. Histopathology The adenocarcinomas are arranged in multiple, variably sized nests and/or sheets composed of tumour cells with hyperchromatic nuclei, abundant clear vacuolated to eosinophilic cytoplasm, and mild to marked cellular pleomorphism. Cellular pleomorphism and cytological atypia are much more prevalen! than in sebaceous adenomas. Tumour necrosis is frequent. Perineural invasion is noted in approximately 20% of cases, whereas vascular invasion is rare. Rare oncocytes and foreign-body giant cells with histiocytes may be observed. Sebaceous adenocarc inoma is typically positive for EMA, CA15-3, and androgen receptor; negative with BerEP4; and positive with antiadipophilin {83).

Prognosis and predictiva factors The tumours may recur and can rarely metastasize. The 5-year overall survival rate is 62% , which is slightly lower than in sebaceous adenocarcinoma in the skin or orbit (84.5%) {851). Oral tumours may have a better prognosis: none of 6 tumours included in a recent review had recurred or metastasized; however, fol lowup was < 5 years for 4 of the cases (42).

ICD-0 code

8980/3

Epidemiology Carcinosarcoma is a rare entity, with < 100 reported cases. The mean patient age at diagnosis is in the sixth to seventh decade of lite, with a wide age range potentially affected {849,2275,2480}. There is amale predominance.

Etiology

Carcinosarcoma Williams M.O. Di Palma S. Gillison M. Nagao T. Simpson R.H.W.

Carcinosarcomas have been described arising both de novo and from longstanding or recurrent pleomorphic adenomas (carcinosarcoma ex pleomorphic adenoma) {938,1317,2346).

Localization Most carcinosarcomas arise in the majar sali vary glands, with two thirds of cases arising within the parotid (2275(

Definition Carcinosarcoma is a biphasic salivary gland malignancy composed of distinct carcinoma and heterologous sarcomatous components.

Clinical features Patients often present with a rapidly growing mass.

Macroscopy Carc inosarcoma usually presents as a large mass of variegated fleshy tumour with necrotic and haemorrhagic features.

Cytology Asp iration preparations typically show highly pleomorphic malignan! cells with epithelial and mesenchymal characteristics {1099,1343).

Histopathology Carcinosarcoma is composed of a malignan! epithelial componen! - typically poorly differentiated (adeno)carcínoma, NOS and a high-grade sarcoma componen!, which can be chondrosarcoma, osteosarcoma, or pleomorphic rhabdomyosarcoma. Staining for cytokeratins predominantly highlights the carcinoma componen!, and there is gain of mesenchymal markers in the sarcoma componen!. Carcinosarcoma should not be confused with sarcomatoid carcinoma or with de-

Malignan! tumours

179

differentiation within distinct salivary gland carcinomas, including salivary duct carcinoma, for management purposes {1096,1482,1533}.

Prognosis and predictive factors Th is is an aggressive malignancy, with morbidity due to both local recurrence and metastatic spread (to lung, bone, and CNS). Surgery combined with radiation therapy may aid local control. Mean survival is< 2.5 years {2275,2480).

Poor/y differentiated carcinoma Chiosea S. Gnepp D.R. Perez-Ordonez B. Weinreb l.

Definition Poorly differentiated carcinomas of salivary glands are primary carcinomas showing large and small cell types with or without neuroendocrine differentiation. These diagnoses can only be made alter excluding metastasis and other primary salivary gland tumours.

ICD-0 codes Undifferentiated carcinoma 8020/3 Large cell neuroendocrine carcinoma 8013/3 Small cell neuroendocrine carcinoma 8041/3

Synonyms Large cell carcinoma; neuroendocrine carcinoma; anaplastic/undifferentiated carcinoma; small cel l carcinoma (SmCC)

Epidemiology Among the reported cases of these tumours {213 1). the median patient age at presentation is 64 years (range: 5- 91 years), and the male-to-female ratio is about 2.4:1 {413,859,1206,2660}.

Localization Most large cel l neuroendocrine carcinomas (LCNECs), small cell neuroendocrine carcinomas (SmCCs), and nonneuroendocrine carcinomas of salivary glands occur in the parotid gland {2660}.

Clinical features Most patients with high-grade neuro180


Fig. 7.31 Small cell neuroendocrine carcinoma. A Small cell carcinoma invading adjacent salivary tissue. BCoagulative necrosis, tumour cells with nuclear moulding and scant cytoplasm. C Positive synaptophysin immunohistochemistry.

endocrine carcinoma and nonneuroendocrine carcinoma present with a painless mass. Sorne present with facial nerve paralysis. More than 50% of patients with SmCC present with regional lymph nade metastases {346,1170,1689, 2131).

Macroscopy High-grade neuroendocrine carcinoma usually presents as a poorly defined firm white mass measuring 2- 5 cm.

Cytology The cytological features seen in aspirates are identical to those seen in aspirates of SmCCs or LCNECs from other sites {1243}.

Histopathology Both SmCCs and LCNECs are highgrade carcinomas characterized by organoid cellular growth with minimal differentiation, high mitotic rates, and the frequent prese nce of coagulative necrosis. SmCCs are distinguishea from LCNEC by their scant cytoplasm, smaller ce ll size (< 2-3 times the diameter of a normal lymphocyte), angulated moulded nuclei with inconspicuous nucleoli, and smudgy basophilic material surrounding

intratumoural blood vesse ls. LCNEC cells have relatively abundant cytoplasm and prom inent nucleoli {2044,2655). A case of SmCC arising in pleomorphic adenoma has been reported {452). The tumour cells may express synaptophysin and/or chromogran in by immunohistochemistry {413). SmCC can show perinuclear dot-like positivity for pancytokeratins and CK20, similar to the expression pattern seen in cutaneous Merkel cell carcinoma {413,2525). Whether these tumours constitute primary Merkel cell carcinoma is still uncertain. One case each of parotid and submandibular gland Merkel cel l carcinoma- like carcinoma with polyomavirus has been reported {543, 1469). The small-cell variant should be distinguished from small round blue cell tumours (e.g. desmoplastic small round cell tumour and other Ewing family tumours), salid adenoid cystic carcinoma (197,1411 ,1809). metastatic neuroblastoma, lymphomas, and melanoma.

Genetic profile Sufficient data are not yet available. RB1 inactivation in virus-negative Merkel cell carcinoma has been reported in 4 cases of salivary gland neuroendocrine carcinoma, but the significance of this finding

is unknown. Mutations and copy-number variation have also been re ported in TP53, NOTCH1, PTEN, and CDKN2A (also called P16) {881,1689).

Prognosis and predictive factors The 2-year overall survival rate for patients with SmCC is 56% {2131). In one study, 3 of 7 patients with well-characterized cases of LCNEC died of disease despite receiving chemoradiotherapy (2660).

Lymphoepithelial carcinoma Lewis J.S. EI-Mofty S.K. Nicolai P.

Definition Lymphoepithelial carcinoma (LEC) is an undifferentiated carcinoma characterized by a syncytial growth pattern and a dense, non-neoplastic lymphoid infiltrate. ICD-0 code

8082/3

Synonyms Malignan! lymphoepithelial lesion; undifferentiated carcinoma with lymphoid stroma; lymphoepithelioma-like carcinoma. Epidemiology LEC is an uncommon salivary gland malignancy, with an incidence of < 1%. LEC is rare in western countries but is more common in certain populations, including North American Eskimo peoples (the lnuit in particu lar), the indigenous peoples of Greenland {43). South-Eastern Asians {2154,2426). Japanese {16841, and Northern Africans {926,1391). The average patient age is in the sixth decade of lite, and there is no clear sex predilection. Etiology Overall, most LECs are associated with EBV infection (1301). but in western populations, only a minority of cases are related to EBV (69]. Localization Most LECs arise in the parotid gland. Clinical features Patients typically present with a painless mass {1301). Very few have pain or facial

-

L

Fig. 7.33 Lymphoepithelial carcinoma of the parotid gland. High-power view showing haphazardly arranged tumour cells with poorly defined borders (syncytial appearance), vesicular chromatin with prominent nucleoli, dense lymphoplasmacytic inflammatory infiltrate, 'and apoptotic bodies .

nerve paralysis (2 154,2533].

Macroscopy Grossly, the tumours are well circumscribed and lobulated, with a fi rm, tan wh ite cut surface (2584). Cytology Aspirate smears show single to clustered, medium-sized to large, polygonal and spind led cells with prominent nucleoli. Most LECs have an admixed , heterogeneous population of lymph oid cells (910,2041). The cytological find ings are identical to !hose seen in aspirates of metastatic undifferentiated non-keratinizing nasopharyngeal carcinomas. Histopathology The tumours consist of sheets, nests, and cords of cells with modest eosinophilic cytoplasm and large, vesicular,

Fig. 7.34 Lymphoepithelial carcinoma of the parotid gland. In situ hybridization far EBV-encoded small RNA (EBER) shows extensive, strong nuclear positivity.

generally round nuclei with prominent nuc leoli and indistinct cel l borders. There is typically abundan! Malignan! tumours

181

lymphoplasmacytic cell infiltrate in and around the tumour nodules {2084,2154, 2533). Squamous differentiation, spindle-cel l features, and basaloid features are occasionally present. Mitotic activity is brisk, and areas of necrosis may be present (769,2584). The tumours are positive for cytokeratins and are typically diffusely positive far EBVencoded small RNA (EBER) by in situ hybridization (2584). The differential diagnosis far primary LEC ineludes primary undifferentiated carcinoma and metastatic undifferentiated nasopharyngeal carcinoma (2533}.

Prognosis and predictiva factors Nodal metastases occur in as many as 40% of patients {1413,2533). Distant metastases occur in 10-20% of patients. Overall and progression-free survival rates at 3 years of more than 90% have been reported (1413), and the 5-year overall survival rate averages 70- 80% across studies {1038,1413, 2154,2533}.

struction and lithiasis as a result of ductal squamous metaplasia and dysplasia.

Clinical features Patients usually present at advanced disease stage, with a painful mass and facial nerve palsy.

Histopathology

Chiosea S. Hunt J.L. Nagao T. Westra W.H.

Definition Primary salivary gland squamous cell carcinoma (SCC) is rare and the diagnosis can only be made after the exclusion of prior cutaneous SCC.

ICD-0 code

8070/3

Epidemiology Primary salivary gland SCC is very rare {407.746,2254). The majority of published cases most likely constitute squamous differentiation of other salivary gland carcinomas or metastatic SCC from dermal primary {401,741,817,1543}.

The tumours are typically moderately to well-differentiated SCCs with infi ltrative growth, desmoplasia, and infiltration of periglandular soft tissue arising from or near a majar salivary duct. The findings of squamous dysplasia and transition from dilated salivary duct support a primary salivary gland origin. Oral mucosa! dysplasia extending into the submandibular salivary duct should be ruled out {519} . Most parotid SCCs derive from primary cutaneous SCC, most commonly through metastasis. The differential diagnosis includes cystic metastatic SCC {1686, 2543). Squamous differentiation may be seen in salivary gland carcinomas undergoing high-grade transformation {2 117}. The absence of mucous and intermediate cells and keratinization excludes high-grade mucoepidermoid carcinoma {407).

Localization

Oncocytic carcinoma is a malignant epithelial neoplasm composed exclusively of neoplasti c oxyphilic cells and does not display any histopathological features of other specific salivary gland tumour types.

ICD-0 code

8290/3

Synonyms Malignant oncocytoma; adenocarcinoma

oncocytic

Epidemiology Oncocytic carcinoma is an extremely rare salivary gland malignancy.

Localization Most reported cases have been located in the parotid gland. The submandibular gland is the second most common site.

Clinical features Patients usually present with painless, slow-growing swellings.

Macroscopy Prognosis and predictiva factors

The reported cases have been limited to the parotid.

Nagao T. Fonseca l. Seethala R.

Definition Macroscopy Most tumours are firm and infiltrative.

Squamous ce/1 carcinoma

Oncocytic carcinoma

The prognosis and predictive factors are unknown due to the entity's rarity. ·

The tumour is generally described as a greyish-yellow, irregular but well-defined mass.

Histopathology Etiology Primary salivary gland SCC may arise in patients with longstanding ductal ob182


Oncocytic carcinoma is characterized by large polyhedral cells (with abundant granular eosinophilic cytoplasm

and round to oval vesicu lar nuclei) forming organoid nests and trabeculae with infiltrative features. Tubular stru ctures, nuclear pleomorphism and vascular invasion may be seen {1570,2302). The differential diagnosis includes the oncocytic variant of mucoepidermoid carcinoma as well as salivary duct carcinoma. Oncocytic mucoepidermoid carcinoma disp lays the features typical of mucous ce lls {808,2571). Salivary duct carcinoma can mimic oncocyti c carcinoma but exhibits other patterns, especially comedonecrosis. Cases previously diagnosed as highgrade oncocytic carc inoma may in fact constitute a subtype of salivary duct carcinoma {713).

Prognosis and predictive factors The rarity of this entity precludes a re liable assessment of its biological behaviour. Complete excision is generally curative {1570).

Sialoblastoma

Epidemiology Most tumours are identified at birth or shortly afterwards, with no sex predilection . Occasional sialoblastomas may present in the second decade of lite (1835,2073).

Brandwein-Gensler M. Li J. RoJ.Y. Simpson R.H.W. Skálová A.

Localization Most sialoblastomas arise in the parotid {495,1662,2497).

Definition Sialoblastoma is a rare primitive basaloid salivary g land tumour of infancy with marked resemblance to salivary g land anlage structures and uncertain malignan! p otential.

ICD-0 cede

8974/1

Clinical features Most affected infants present with facial swelling and occasional skin ulceration. There have been case reports o/ concu rrent sialoblastoma and hepatoblastoma [2286), sebaceous naevi {887,2236). and congeni ta l naevus {21 12}

Synonyms

Macroscopy

Congenital basal cell adenoma; congenital hybrid basal cel l adenoma~adenoid cystic carcinoma; embryoma

Th e gross appearance is that of an expansile lobulated mass that either is circumscribed or extends into surrounding ti ssues.

Malignan! tumours

183

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-

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Fig. 7.38 Sialoblastoma. A Adenoid cystic-like pattern.

Histopathology Two distinct patterns are observed; one consists of differentiated budding ducts and the other is solid, organoid, and lobular. The budding ducts have columnar cells or primitive basaloid-appearing reserve cells. The solid form is composed of cuboidal epithelial cells with round to oval nuclei, single or few nucleoli , fine chromatin, and pink cytoplasm. Subtle peripheral palisading and cribriform pseudoglands may be seen.

184


Sorne tumours display malignan! cytological features (e.g. brisk mitotic rate, necrosis, pleomorphism, and perineural invasion), especially with disease progression (1781). Prognosis and predictive factors Primary resection is curative for two thirds of patients {320,524,2019,2483). lncreased mitotic rate, high Ki-67 proliferative index, and tumour necrosis are associated with poor prognosis. Local

recurrence (single or multiple) or disease persistence is reported in approximately one quarter of patients {1041 ,2366,2483, 2612). lsolated metastasis (to cervical lymph node or lung) is uncommon (reported in 3 of 38 cases).

Benign tumours /

Pleomorphic adenoma

Localization

Bell D. Bullerdiek J. Gnepp D.R. Schwartz M.R . Stenman G. Triantafyliou A.

Most examples occur in the parotid, with the remainde r occurring in other sites (typicaliy the palate and submand ibular gland) {677,2251}. PA is usually solitary, but metachronous and synchronous tumours do occur {482,857,1048,1615, 2079}.

Clinical features Definition Pleomorphic adenoma (PA) is a benign tumour with variable cytomorphological and architectural manifestations. The identification of epithelial and myoepithelial/stromal components is essential for the diagnosis of PA.

ICD-0 code

8940/0

PA is a slow-growing, painless mass, wh ich may be present for many years. The symptoms and signs depend on the location (2251). Facial nerve weakness and rapid enlargement are more likely to be associated with tumours of large size and with malignan! transformation {217). PA in the deep lobe of the parotid may present as an oral retrotons illar mass or a parapharyngeal space tumour.

Synonym Benign mixed tumour

Epidemiology PA is the most common salivary gland tumour in both c hildren and adults, accounting for the majority of ali salivary gland neoplasms. The annual incidence is approximately 2~3.5 cases per 100 000 population {1895}. PA occurs in individuals of ali ages, but is most common in the third to sixth decades of life; the average patient age at presentation is approximately 45 years /1895,2251). The female-to-male ratio is 2: 1.

Etiology The incidence o/ PA has been reported to increase 15- 20 years alter exposure to radiation.

Macroscopy PAs typicaliy present as a single, firm, mobile, well-circumscribed mass. On cut surface, they vary from light tan to grey, with or without cartilaginous features {1863}. Degenerative and cystic changes can be seen. Haemorrhage and infarction may occur secondary to prior fineneedle aspiration. Recurren! tumours characteristically present as multiple nodules of variable size.

Cytology Aspiration preparations contain variable combinations of bland ductal epithelial celis, myoepithelial cells, and chon dromyxoid stroma. ldentification of the typical fibrillary stroma is essential, and

it characteristicaliy appears magenta on air-dried Romanowsky preparations /1244,2503}.

Histopathology The tumours are composed of variable epithelial and myoepithelial/stromal components in a mixture of patterns . Spindled myoepithelial cells stream from the ductal elements into the chondromyxoid stroma. Celis may show a spectrum of phenotypes , including oval, spindled, epithelioid, clear, and plasmacytoid (hyaline). Verocay-like arrangements can be seen. Squamous metaplasia and keratin pearls are not unusual. Mucous cells, sebocytes, and oncocytic phenotypes are less com mon (2420). The stromal elements can be myxoid, lipomatous, chondromatous, and/or osseous. Tyrosine-rich crystalloids, collagenous stellate fibriliar structures, and microliths can be present (2420}. Ductal atypia, diffuse fibrosis, and necrosis should prompt more extensive sampling to exclude malignancy. lntravascular tumour cells may be an artefactual finding caused by either f ine-needle aspiration or intraoperative trauma {2192}.

Genetic profile Approximately 70% of PAs show translocations (with breakpoints in 8q12 and 12q14-15) or intrachromosomal rearrangements with sporadic non-clon a! changes (2269,2270). The translocations and rearrangements resu lt in gene fus ions involving the transcription factor genes PLAG1 on 8q12 {1190) and )~

.

\

A

B

Fig, 7.39 Pleomorphic adenoma. A Grossly, pleomorphic adenoma is typically a single, firm, mobile, well-circumscribed mass. B Recurren! tumours characteristically presentas multiple nodules of variable size.

Fig. 7.40 Pleomorphic adenoma, well delineated from the salivary gland by a fibrous capsule.

Benign tumours

185

HMGA2 on 12q14-1 5 {828,829,2269, 2270). PLAG1 encodes a cell cycle progression- related zinc finger prote in that is activated due to promoter swapping with various fusion partner genes (i.e. CTNNB1, FGFR1, LIFR, CHCHD7, or TCEA 1). Overexpression leads to deregulation of PLAG1 target genes, most importantly /GF2 (2270,2515) . HMGA2 encades a high-mobility group protein that functions as an architectural transcription factor. The gene is activated by gene fusions in wh ich the 3' end of HMGA2 is replaced by the 3' ends of the fusion partner genes NF/8, WIF1, or FHIT In a subset of tumours, the HMGA2- WIF1 fusions are coamplified with the MDM2 gene on 12q15 {1860}. HMGA2 fusions actívate expression of the cell cycle regulators cyclin A1 and cyclin B2 (2270). PLAG1 and HMGA2 fusions have not been encountered in any subtype of salivary gland tumour except carcinoma ex PA, and may therefore be used as biomarkers to distinguish PA from its morphological mimics {1196,2269, 2270f. Downregulation of WIF1 (WNT inhibitory factor 1) was recently described in a subset of PAs, associated with an increased risk of malignan! transformation {1951}. Mutation and overexpression of HRAS has also been found in a subset of

186

Tumours ot salivary glands

PAs (1613,22721. A recent study demonstrated that myoepithelial cells n PA express th e stem ce ll marker CD44 (1070).

followed by head and neck and lung {1532). The prognosis of most histologically benign lesions is generally good.

Prognosis and predictive factors Recurrence rates are low. Complete resection ensures the lowest rates (470}. Tumour disruption and spillage have also been reported as variables with an independ ent effect on recurrence; 26.9% of punctured tumours and 80% of cases with spillage recurred {1982). Female sex, young age at initial treatment, and enucleation rather !han parotidectomy may be risk factors far recurrence (2622). Malignan! transformation occurs in approximately 6.2% of PAs (849). Multiple recurrences, deep parotid lobe location , male sex, and older patient age are associated with increased malignancy.

Myoepithelioma Fonseca l. Bell D. Bishop J.A. Gnepp D.R.

Definition Myoepithelioma is a benign salivarygland tumou r composed almos! exclusively of cells with myoepithelial differentiation. /:i .

1-.,,:-:·.,

fAJ,,. ',;''/ ft_

Metastasizing pleomorphic adenoma Metastasizing PA is histologically indistinguishable from PA, but produces sec ondary tumours in distant sites. To d ate, 81 cases have been d escribed {1252). Metastasizing PA often occurs after multipl e local recurrences, with a reported interval between diagnosis of primary PA and distant metastases of 3- 52 years. The most common distan! site is bone,

f

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Fig. 7.43 Myoepithelioma. Gross view showi.ng a WS: circumscribed tumour with a tan-fleshy, part1ally cys cut surface.

Fíg. 7.44 Myoepithelioma. A Epithelioid cell type. B Plasmacytoíd cell type. C Organoid arrangement of epithelioid myoepithelial cells.

ICD-0 code

8982/0

Synonyms Myoepithelial celi tumour; myoepithelial adenoma; monomorphic adenoma

Epidemiology Myoepitheliomas account for 1.5% of ali tumours in the majar and minar salivary glands and constitute 2.2% and 5.7%, respectively, of ali benign majar and minar salivary gland tu mours. Males and females are affected with equal frequency (59,144,526,2110,2179,2437). Most tumours occur in adults, but rare examples in children have been reported {1328,2662). The patient age range is 9-85 years (mean: 44 years), with an incidence peak in the third decade of life.

Localization Myoepitheliomas develop most commonly in the parotid gland, foliowed by the hard and soft palate (accounting for 40% of cases) {647}.

Clinical features Myoepitheliomas are well -circumscribed salid tumours. They typically present as painless slow-growing masses {59,2179, 2437}.

Histopathology Myoepithelioma can display spindle, plasmacytoid, hyaline, epithelioid, and clearcell features. The tu mours typically show nests or cards of round to polygonal cells, with centrally located nuclei and a variable amount of eosinophilic cytoplasm. Occasional ducts and intercellular microcystic spaces may be present. The reticu lar variant of myoepithelioma is characterized by net-like arrangements of interconnected cel l cords (526). lntracellular mucin and signet ring-shaped celis have also been recently described (852,853f. Myoepitheliomas are positive for cytokeratins (CK7 and CK14). The tu mour cells variably display immunoreactivity to anti-alpha-SMA, MSA, calponin, S100, and GFAP. Occasional myoepitheliomas (especially cases of the p lasmacytoid variant) may not stain with any of the myoepithelial markers.

Prognosis and predictiva factors Myoepitheliomas are benign neoplasms. Recu rrences are infrequent and are more commonly associated with incomplete excision {1378,2110}. Myoepitheliomas may rarely undergo malignan! transfarmation to malignan! myoepithelial carcinoma, especially in longstanding tumours and in cases with multiple recurrences (59).

Basal ce// adenoma Li J. Fonseca l.

Definition Basal cell adenoma (BCA) is a benign salivary gland neoplasm composed of small basaloid cells, with occasional inner ductal epithelial cells forming nests and cords .

ICD-0 code

8147/0

Synonyms Monomarphic adenoma; basaloid salivary gland adenoma; membranous adenoma

Epidemiology BCAs account for 1- 3.7% of ali salivary gland tumou rs {668,2402). They are most frequent in elderly adults; the average patient age al presentation ranges from 57 years to > 70 years, with a slight female predilection.

Localization Most BCAs arise in the majar salivary glands. The parotid gland is the most common site (accounting for > 80% of

Macroscopy Myoepitheliomas have a salid, tan to yel low appearance, with glistening cut surface.

Cytology Smears show single cells and celi clusters with a variable stroma component. The neoplastic celis are typically b land and can appear spindled, epithelioid, or plasmacytoid. Cytoplasmic features vary between tumours.

Fíg. 7.45 Basal cell adenoma. A Solid pattern: various shapes and sizes of islands of basaloid cells, with peripheral palisading. B Tubular pattern: numerous small lumina lined by duela! cells. One to severa! layers of basaloid cells surround ductal cells.

Benign tumours

187

Prognosis and predictive factors The prognosis is generally very gooct, with a very low recurrence rate; except far the membranous type, which has a recurrence rate of approximately 25%. Basal celi carcinoma transformation of BCA occurs rarely, with a higher frequency in the membranous type (153).

Warthin tumour Nagao T. Gnepp D.R. Simpson R.H.W. Vielh P.

Definition

Fig. 7.46 Basal cell adenoma. A Focally, cystic degeneration is common. B Trabecular pattem of basal cell adenoma. e CK7 immunopositivity is confined to the ductal cells. D SMA immunoexpression is typically localized in peripheral tumour cells, indicating myoepithelial differentiation.

Warthin tumour is a benign salivary gland tumour composed of oncocytic epithelial celis lining ductal, papillary, and cystic structures in a lymphoid stroma.

ICD-0 code cases), foliowed by the submandibu lar gland. BCA is extremely rare in th e minor glands (2402,2615}.

Clinical features The tumours are typically wel l-defined and movable solitary masses. The membranous type may present as multiple nodules and may coexist with dermal cylindromas or trichoepitheliomas (1069, 2111,2691).

Macroscopy BCAs present as well-circumscribed, usually encapsulated nodules measuring 0.2- 5.5 cm {2615}, except for the membranous type, which may be multinodular. On cut section, they are solid and homogeneous or partially cystic, with a greyish-white to pinkish-red colour {2401). Histologicaliy this entity can only be distinguished from its malignant counterpart by the lack of invasiveness into surrounding tissues.

8561/0

Histopathology The tumours show a mixture of solid, trabecular, tubular, and membranous patterns. They are composed of basaloid cells with scant cytoplasm, indistinct cell borders, and round to oval nuclei, and may show peripheral palisading. Large cells with paler-staining nuclei may be present in the centre of the basaloid nests . The membranous pattern features prominent hyaline material, with intercel lular coalescing droplets within tumour nests {1208,1412,1485,2401,2615}. Pancytokeratin staining is positive in ali tumour cells but most intense in ductal cells. The palisading cells stain for myoepithelial markers, indicating basal/ myoepithelial differentiation {1642,1685}.

Genetic profile A few studies have reported frequent al terations at chromosomes 8p22, 19q13.4, and 16q12-13 {435,6421, anda case report of t(7;13) and inv(13) has been pub lished {2190).

Synonyms Adenolymphoma; papiliary cystadenoma lymphomatosum; cystadenolymphoma

Epidemiology Warthin tumour is the second most common salivary gland tumour, accounting for approximately 5- 15% of ali salivary gland tumours. These tumours commonly affect individuals in their sixth to seventh decade of lite. A slight male predominance has been reported (679}. Warthin tumours have been linked to cigarette smoking {1895A,2038A}.

Etiology Radiation exposure has been suggested to be associated with tumorigenesis {2048}. A relationship between Warthin tumours and autoimmune diseases (804, 1778} and EBV infection has also been

Cytology Aspirate smears typicaliy show numerous uniform basaloid celis with round or oval nuclei and scant cytoplasm. The celis form irregular nests and trabeculae, and occasionally tubu lar or peripheral palisading structures. Background stroma both separate from and intermixed with the epithelial cells may be seen (1159,1241,2499}. 188


Genetic susceptibility Sorne BCAs occur in the setting of Brooke-Spiegler syndrome (multiple familia! trichoepithelioma), a rare autosomal dominant hereditary disorder caused by mutations of the CYLD gene on chromosome 16 {1208,2111}. Fig. 7.47 Warthin tumour presenting as a well-circum· scribed, mottled light-tan mass.

reported [2071}, but has not been substantiated !2469).

Localization The tumours are almost exclusively restricted to the parotid gland but sornetimes occur in the periparotid lymph nodes (645,2465). Most tumours are located in the inferior pole of the parotid gland. The tumours occasionally occur multifocally, either synchronously or metachronously, in the same or bilateral glands (1329,1513). They may be associated with other types of salivary gland tumours (857). Clinical features Patients present with painless, slowgrowing, and fluctuant swellings. Pain or facial nerve palsy is uncommon {679l but may occur in the metapl astic (or infarcted) variant (680). On technetium-99m pertechnetate imaging, Warthin tumours present as hot lesions.

Macroscopy Most Warthin tumours are well-circumscribed spheric al to oval masses. Solid areas and multiple cysts with papillary projections are apparent on the cut surface. The cystic spaces often contain mucoid, creamy white, or brown fluid.

Histopathology The tumours are composed of varying proportions of papillary-cystic structures lined by oncocytic epithelial cells and a lymphoid stroma with germinal centres !2121 }. The epithelial componen! is formed of inner columnar and outer cuboidal cells. Limited foci of squamous, mucous, ciliated, and sebaceous cells can be present. A granulomatous reaction with Langhanstype giant cells may be seen {2033}. lnfarcted or metaplastic tumours may have marked mucinous or squamous metaplasia and stromal reaction, which may present diagnostic challenges (579,680, 1095,211 6,2121,2203}.

with eosinophilic granular cytoplasm resulting from an accumulation of mitochondria.

ICD-0 code

8290/0

Synonyms Oncocytic adenoma; oxyphilic adenoma

Epidemiology Oncocytoma is uncommon, accounting for about 2% of all salivary gland neoplasms. lt occurs most commonly in the sixth to eighth decades of life, with a mean patient age of 64 years and no sex predilection overall. However, a marked

.

Prognosis and predictiva factors Complete surgical excision with an adequate margin is usually curative (664). The local recurrence rate is low; when recurrence does occur, it is probably due to multifocal tumours or inadequate excision {667}. Malignan! transformation in Warthin tumour is extremely rare; however, there are a few reported examples in both the epithelial !748,749,1225,1688, 2195,2614) and the lymphoid component {131,298,1583,1868).

Fig. 7.49 Oncocytoma of the parotid gland with central fibrosis.

Oncocytoma Cytology Smears typically show bland, oncocytic epithelial cells with polymorphous lymphocytes and cellular debris {128,736, 1246). Squamous cells and mucinous differentiation with mixed inflammation and cytological atypia can be uncommonly seen !736,2487, 2502).

Katabi N. Assaad A.

Definition Oncocytoma is a benign salivary gland tumour composed predominantly of oncocytes, which are large epithelial cells Benign tumours

189

female predilection has been reported among patients with clear cell oncocytoma (143].

Etiology There is a link between radiation and oncocytoma {1181]. Localization Most cases occur in the parotid. Oncocytoma may also occur in the submandibular gland and minar salivary glands (2393}. Clinical features Symptoms vary according to site of occurrence. Oncocytoma usually presents as a unilateral painless swelling. Rare bilateral cases have been reported !571}. Macroscopy Oncocytomas are well -circumscribed, lobulated , reddish-brown nodules. Cytology Smears show oncocytic cells with granular eosinophilic cytoplasm arranged in sheets, papillary structures, and si ngle cells . Cytological atypia is minimal al most (1417] . Histopathology The oncocytes are characterized by abundan! eosinophilic granular cytoplasm and centrally located vesicular nuclei, typically with a single prominent nucleolus. The oncocytes are arranged in sheets, nests, trabeculae, and duct-like pattern s, separated by thin fibrovascular stroma. Microcysts and macrocysts may be observed . Occasionally, the entire tu mour may consist of clear cells , referred

190


to as clear cell oncocytoma {1570}. The tumour cells stain with phosphotungstic acid haematoxylin . Although oncocytoma is traditionally thought of as a neoplasm vyith a single cell type, a basal cell popÚlation (positive for p63 and CK5/6) is present in ali oncocytomas {2563). The find ing of multiple unencapsulated nodules and residual non-oncocytic salivary gland parenchyma within the nodules favours nodular oncocytosis rather than oncocytoma {831,2242). The absence of lymphoid stroma and papillary cystic architecture distinguishes oncocytoma from Warthin tumour {216,2563}.

Prognosis and predictive factors Surgical excision is the treatment of choice. True recurrences are rare, but additional oncocytomas may arise in residual parotid . An association between marked clear-ce ll change and recurren! and bilateral disease has been reported (532).

Lymphadenoma Prasad M.L. Chiosea S. lhrler S. Skálová A.

Definition Lymphadenoma is a rare benign salivary gland tumour that consists of a well-circumscribed biphasic proliferation of epithelial cells and reactive lymphoid tissue. Sebaceous and non-sebaceous forms can be distinguished.

ICD-0 code

8563/0

Epidemiology These are rare tumou rs with no sex predilection. The palien! age range is 1078 years (median: 65 years) {2120). Nonsebaceous cases account for one third of lymphadenomas, and tend to affect younger individuals (median patient age: 50 years), including children (527,1500, 1647,2562}. Localization The parotid gland is the most common site (affected in > 80% of cases). Tumours in the minar salivary glands of the oral cavity and in the submandibular gland have,also been reported, as have multiple synchronous tumours {4,2120} Non-sebaceous 11ymphadenomas appear to occur excl4sively in the parotid gland or periparotfd area {1 442,1500, 1647,2562}. Clinical features Lymphadenoma presents as a painless, slow-growing, and mobile mass of a few months' to severa! years' duration {1442}. Macroscopy The tumours measure 0.6- 6 cm (median: 2 cm). They are usually encapsulated and have a solid or multicystic, grey to yellow cut surface. The cyst contents are frequently gelatinous and sebaceous {2120) . Cytology Preparations are hypercellular, with fragments of tightly cohesive, bland epithelial cells. Most cells appear basaloid; however, cytoplasmic characteristics vary,

with sorne cells having abundan! foamy cytoplasm. Background polymorphous 1ymphocytes are present {3481.

Cystadenoma

presents as a slow-growing painless mass. Minor gland tumours present as smooth-surfaced nodules, frequently with a cyst-like appearance. The clinical differential diagnosis often includes mucocoele.

Budnick S. Simpson R.H.W.

Histopathology The epithelial component, which constitutes 20- 70% of the tumour, shows anastomosing cords and nests of basaloid cells, as well as tubuloglandular structures. Small to medium-sized cysts and intraepithelial lymphocytes are frequently seen and can be associated with eosinophilic, hyaline, basement membrane-like material. Sebaceous differentiation is typically seen in sebaceous lymphadenoma. Rupture and leakage of sebum may elicit an epithelioid granulomatous response with foreign-body giant cells {1442,1500,2120,2562} . Squamous differentiation with keratinization may be seen, especially alter fine-needle aspiration biopsy. The lymphoid component consists of reactive lymphoid follicles with germinal centres. lmmunohistochemistry is generally not helpful. Lymphadenoma can readily be distinguished from lymphoepithelial carcinoma and metastatic carcinoma {1442,1500,2120,2562}.

Definition Cystadenoma is a rare benign salivary gland neoplasm characterized by a predominantly multicystic growth pattern , with the cysts lined by proliferative, frequently papillary epithelium that often shows oncocytic differentiation.

Macroscopy

ICD-0 code

Histopathology

8440/0

Synonyms Cystic duct adenoma; intraductal papillary hyperplasia (non-neoplastic); Warthin tumour without lymphoid component

Epidemiology Cystadenoma accounts foras many as 4% of all salivary gland neoplasms {24091. The tumour is more common in women than in men {2591}. The average patient age is in the fifth to seventh decade of lite {27141.

Localization Prognosis and predictiva factors Lymphadenomas are benign tumours cured by complete excision. Rarely, malignan! transformation may occur in sebaceous cells (sebaceous lymphadenocarcinoma) or basal cells (basal cell adenocarcinoma). Lymphadenocarcinoma typically shows residual benign lymphadenoma {497,854,21 20).

The localization of the tumour varíes by study, but there appears to be a relatively equal distribution between the minor and major salivary glands. The parotid is involved in about 45-50% of cases, with the minor glands of the lip and buccal mucosa being the next most .common siles (2409).

Clínica! features In the major salivary glands, the tumour

Most tumours are multicystic; the gross appearance shows multiple small cysts, often including normal minor salivary gland at the periphery. lntraluminal proliferation may be evident.

The tumours are well circumscribed and freq uently present as multicystic lesions, although 20% are unilocular {2714}. The cysts are separated by generally thin fibrous connective tissue. The lumen usually shows papillary projections lined by columnar and/or cuboidal epithelium , frequently with sorne degree of oncocytic differentiation. The oncocytic pattern may predominate. Mucous cells may be seen, and apocrine differentiation has been reported ; squamous epithelium may be present focally but rarely predominates. The lumen may contain eosinophilic material with scattered epithelial, inflammatory, or foamy cells. The surrounding fibrous stroma often contains seromucous glands. The tumours do not show cytological atypia, mitoses, or an invasive growth pattern.

Prognosis and predictive factors The tumours are benign, and conservative local excision is appropriate. Recurrence is rare.

Benign tumours

191

Sía/adenoma papilliferum

Macroscopy

Foschini M.P. Bell D. Katabi N.

Sialadenoma papilliferum is usually polypoid and pedunculated , with a verrucoid surface and well-circumscribed margins. On cut section, cystic spaces are occasionally visible.

Definition

Histopathology

Sialadenoma papilliferum is an exophytic lesion with an inward papillary proliferation of mucosa! and salivary duct epithelium.

The etiological factors are unknown. lnflammation and sialolithiasis have been suggested as possible causes.

At low power, b oth surface and submucosal components can be observed. The surface component displays papillary projections that are lined by squamous epithelium and extend to submucosa to form cystic-like spaces. At higher power, acanthosis and parakeratosis of the squamous epithelium can be seen. The ductal structures are lined by luminar cuboidal cells (luminal cells) and flattened myoepithelial cells (abluminal cells). Rare mucocytes can be present among the luminal cells. lnflarrimatory infiltration may be present. On immunohistochemistry, myoepithelial cells (positive for SMA, S100, and GFAP) and cel ls positive only for the high-molecular-weight cytokeratins CK13 and CK14 can be seen (1512).

Localization


The intraoral minor salivary glands are frequently affected, with the hard pal ate and bucea! mucosa being the most common si tes of origin (693,1288,2441). Rare cases have been described in the parotid {1466}.

Surgical excision is curative. Recurrences are exceed ingly rare {261,1891}.

ICD-0 code

8406/0

Epidemiology Sialadenoma papilliferum is rare and mainly affects adults, with the peak incidence in the eighth decade of lite. Occasional cases have been reported in adolescents and children. Females and males are equally affected.

Etiology

Cases with malignan! transformation have been reported (1448,1910,2165).

Ductal papillomas Richardson M. Bell D. Foschini M.P. Gnepp D.R. Katabi N.

Definition Ductal papillomas are luminar ductal epithelial proliferations that occur at various siles within the salivary duct system. Based on their growth pattern , they can be subc lassified as either intraductal papilloma or inverted ductal papilloma.

ICD-0 code

8503/0

Synonym Epidermoid papillary adenoma

Epidemiology The precise incidence of du ctal papilloma is unknown, but both intraductal papilloma and inverted papilloma are

Clinical features Sialadenoma papilliferum presents as a longstanding exophytic papillary mucosa! lesion, most often clinically diagnosed as squamous cell papilloma. Parotid lesions can present as ulcerated cutaneous lesions, simulating a malignant tumour.

192


\ A\;,,,,

~

-

..__,__.... _

--

Fig. 7.54 lntraductal papilloma. A lnterlobular duct containing a delicate papillary network of cuboidal and columnar cell-lined vascular fronds. B The surrounding ductal lining and the columnar ductal lining cells are similar.

considered to be rare (261,2049). The lesions arise in adults (patient age range: 22-77 years), with no sex predilection (261). Rare occurrence in children has also been reported (1747).

Etiology The etiology of ductal papilloma remains unknown. Masticatory trauma and an association with HPV have been reported (20491.

with occasional surface access. The proliferative components display broad sheets of monotonous epithelial cells with central thin fibrovascular cores. Occasional microcysts within the epithelium are noted. The differential diagnosis for intraductal papillomas includes mucoepidermoid carcinoma {1287); however, intraductal papilloma lacks the multicystic, multinodular, and infiltrative growth pattern of mucoepidermoid carcinoma.

Localization


The oral minor salivary glands are the most common siles of occurrence. The tumours occur most frequently in the lower lip, followed by the cheek mucosa, floor of the mouth, palate, and tangue. There have been reported cases in ali majar salivary glands, most commonly in the parotid (261,1164,1747) .

Complete excision is curative. No cases of malignan! transformation have been reported {32,261).

Clinical features Both inverted and intraductal papillomas present as painless submucosal nodules of duration that varíes from a few weeks to severa! years.

Macroscopy The reported size range is 0.5- 2 .0 cm. The tumours often present as nodular (intraductal papillary) growths {1164).

59 years (range: 22-90 years). There is a

slight male predominance, with a maleto-female ratio of 4:3. Unlike with cutaneous sebaceous neoplasms, there is no increased risk of developing a visceral carcinoma.

Localization About 61% of cases occur in the major salivary glands: 48% in the parotid gland and 13% in the submandibular gland. The other 39% occur in the minar salivary glands, most commonly in the bucea! mucosa and lower molar/retromolar reg ions.

Clinical features Patients present with a painless mass.

Sebaceousadenoma

Macroscopy Gnepp D.R. Bel! D. Hunt J.L. Seethala R.

Sebaceous adenomas range in size from 0.4 to 6 cm. They are typically well circumscribed to encapsulated, and are greyish-white to yellowish-grey on cut surface.

Definition

Cytology

Sebaceous adenoma is a rare, usually well-circumscribed tumour composed of irregularly sized and shaped nests of sebaceous cells without cytological atypia, often with areas of squamous differentiation and cystic change.

Smears are cellular and show aggregates of bland basaloid cells with various numbers of cytoplasmic vacuoles {88).

Histopathology lntraductal papilloma arises in the terminal portian of the salivary gland excretory duct, at the junction with the mucosa! surface. The lesion is typically well circumscribed, with broad luminal papillary projections composed of cylindrical or epidermoid cells lined by columnar goblet cells (11 64). lnverted ductal papilloma typically manifests asan unencapsulated endophytic squamoid cell proliferation

ICD-0 code

8410/0

Epidemiology Sebaceous adenomas are rare, accounting for approximately 0.1% of salivary gland neoplasms and slightly less than 0.5% of ali salivary gland adenomas {851). Slightly more than 30 cases have been reported to date {88,851,2705). The mean patient age at presentation is

Fig. 7.56 Sebaceous adenoma. Squarnoid cell nests with sebaceous differentiation in a lymphoid si roma .

Benign tumours

193

Histopathology Sebaceous adenomas are well circumscribed and do not show any invasion. They are composed of variously sized sebaceous cell nests, which vary in tortuosity and frequently are embedded in a fibrous stroma. The tumours can be microcystic or may contain dilated salivary ducts with foci of sebaceous differentiation. Pleomorphism and cytological atypia are minimal; necrosis and mitoses are not usually found. Sebaceous adenomas often contain areas of squamous differentiation and occasionally show marked oncocytic metaplasia. Histiocytes, foreign-body giant cells, or both may be seen focally. The sebocytes in salivary gland sebaceous adenomas have an immunohistochemical staining profile similar to that seen in sebaceous adenomas elsewhere, staining positive for p63, EMA, adipophilin, and perilipin. lf there is a lymphoid background, the diagnosis of sebaceous lymphadenoma is more appropriate . Prognosis and predictive factors These are benign tumours. lf completely excised, they do not recur.

Canalicular adenoma and other ductal adenomas Bloemena E. Katabi N.

Definition Canalicular adenoma is a benign salivary gland tumour composed of monomorphous epithelial ductal cells arranged in anastomosing cords within cell-poor vascular stroma. ICD-0 code

~


.

-\

.. t

, ,., .

'

Fig. 7.57 Canalicular adenoma. A Multiple canalicular adenomas and adenomatous changes in a minor salivaiy gland. B Thin anastomosing cords and paucicellular stroma.

Epidemiology Canalicular adenomas occur in the fourth to seventh decades of lite and rarely befo re the age of 50 years. Men are more often affected than women (292,2385}. In western countries, canalicular adenoma accounts for 0.5- 12% of ali minor sali vary gland tumours (292,1900,2524,2676}. In series from China, no canalicular adenomas were repo rted in minar salivary glands (2536,2546). Localization Canalicular adenoma is a tumour of the minor salivary glands. Most cases (80%) occur in the upper lip. The bucea! mucosa, and rarely the palate and other sites, may also be involved (2385). Clinical features Patients present with an asymptomatic, painless swelling, or the tumour is discovered incidentally during dental examination. In about 13% of cases, the rumours present multifocally (including bilaterally), typically in the upper lip and bucea! reg ion (518,1529,2020,2059,2385}. Macroscopy Canalicular adenomas are well-circumscribed brown to yellowish tumours (1055, 2059,2385} .

8149/0

Synonyms Ductal adenoma; striated duct adenoma

194

1.._~t l

111w.1. .

Histopathology The tumours are well delineated and lobulated . Multiple small nodules can be

found within the affected salivary gland. Cyst formation can be present and may be accompanied by haemorrhage and haemosiderin-laden macrophages. The tumour cells are uniform columnar to cuboidal epithelial cells arranged in anastomosing, branching, or budding parallel co rds, which are sometimes widely separated or sometimes join and form beaded edges. The tumour cell nuclei are monomorphous, with finely dispersed chromatin and inconspicuous nucleoli. Mitoses are rare. The cells are positive for cytokeratins. S100 shows strong and consisten\ nuclear and cytoplasmic staining. p63 is negative and KIT (CD117) is positive {627,628, 786,919,2385,2676,2704}. The difference between canalicular adenoma and reported cases of striated adenoma (2572) is arbitrary, and the clinical relevance of these variants is unknown. The exclusive luminal differentiation of canalicular adenoma is a distinguishing feature from basal cell adenoma and adenoid cystic carcinoma.

Prognosis and predictive factors The prognosis is excellent, and local excision is curative. Due to the multifocal growth of these tumours, it is difficult to ascertain whether a recurrence of canalicular adenoma is a true recurrence ora result of multinodularity.

Non-neoplastic epithelial lesions

Sclerosing polycystic adenosis Seethala R. Gnepp D.R. Skálová A. Slater L. Wílliams M.O.

Clinical features Sclerosing polycystic adenosis is a painless slow-growing mass, usually of < 1 year in duration. Pain and ting ling are rare.

Macroscopy

Slater L. Bell D. Gnepp D.R.

The tumours are firm and well delineated, with a mean size of 3.0 cm. The cut surtace is pale, glistening, and multicystic .

Defin ition

Definition

Histopathology

Sclerosing polycystic adenosis is a benign salivary gland lesion with close morphological resemblance to fibrocystic changes and sclerosing adenosis of the breast (2219}.

Sclerosing polycystic adenosis is a wellcircumscribed lobular proliferation of ducts with granular, vacuolated, or apocrine cellular features and with acini containing coarse red zymogen granules embedded in a f ibrosclerotic stroma. Ductal elements may be proliferative, creating a resemblance to low-grade ductal carci noma in situ (858,1869,2196}.

Synonyms Sclerosing adenosis; sclerosing polycystic sialadenopathy; polycystic adenosis; sclerosing polycystic adenoma

Nodular oncocytic hyperplasia

Nodular oncocytic hyperplasia (NOH) is a rare lesion characterized by multiple non-neoplastic nodular proliferations composed of cells with abundan! granular eosinophilic cytoplasm (oncocytes) and/or clear cytoplasm (clear cells) in one or both parotid glands .

Synonyms Multifocal nodular oncocytic hyperplasia (MNOH); nodular oncocytosis; clear cell oncocytosis

Genetic profile Epidemiology This is a rare lesion, with about 60 reported cases. The mean patient age is about 40 years (range: 7-84 years), with a female-to-male ratio of 1.3:1.

The occurrence of X-chromosome inactivation, wh ich has been detected in certain cases by the human androgen receptor (HUMARA) assay, suggests that sclerosing polycystic adenosis may be monoclonal in nature (2194).

Localization Most cases (> 70%) involve the parotid, but sclerosing polycystic adenosis can also occur in the submandibular gland, oral cavity, and (rarely) nasal cavity (2295)

Epidemiology NOH accounts for < 1% of salivary gland tumours. The average patient age at presentation is approximately 57 years (range: 39- 80 years), and 85% of cases occur in women.


Etiology

Sclerosing polycystic adenosis recurs in 11% of cases that are multifocal or incompletely excised {858). One case showed malignan! transformation alter 3 recurrences overa span of 32 years (321).

The cause of NOH remains largely unknown . Recent evidence suggests that HPV infection (HPV 53) and mutations in mitochondrial DNA (m.4561TA) could play a role in inducing the lesions (1306).

Non -neoplastic epithelial lesions

195

Localization NOH occurs exclusively in the parotid gland. lt presents as bilateral parotid tumours in approximately 40% of cases. Macroscopy Affected parotid glands show scattered, we ll-circumscribed, brown or mahogany to whitish-tan nodules ranging in size from 0.2 to 2.5 cm (2435). A large dominant mass may constitute an oncocytoma arising within NOH, especially if the mass is well circumscribed and partially encapsulated {1068,2155).

acinic cell carcinoma or metastatic renal cell carcinoma. The nodules are composed of uniform polygonal cells with granular eosinophilic and/or clear cytoplasm and centrally located uniform oval pyknotic (dark) and/or pale nuclei with small nucleoli.

Prognosis and predictive factors NOH is a benign, non-neoplastic condition; malignan! transformation has not been reported.

Lymphoepithelial sía/adenitis Histopathology There are irregularly shaped, unencapsulated oncocytic nodules scattered within normal parotid architecture {1806). The nodules are composed of densely packed, back-to-back acinar or tubuloacinar structures {882,2081). As the lesiona! nodules expand and coalesce, adjacent normal parotid serous acini, ducts, and adipocytes focally become entrapped within nodules. This finding may be helpful in distinguishing NOH with clear-cell features from clear cell

Bloemena E. Bell D. Chiosea S.

Definition Lymphoepithelial sialadenitis is a benign lesion characterized by acinar atrophy, ductal hyperplasia, and epimyoepithelial islands in lymphoid stroma . Synonyms Benign lymphoepithelial lesion; myoepithelial sialadenitis Epidemiology The patients affected are predominantly females (with a female-to-male ratio of 3:1) in their fourth to seventh decade of life {648) .

Fig. 7.60 Nodular oncocytic hyperplasia. Variable nodules scattered within the parotid gland.

196


Etiology Lymphoepithelial sialadenitis is considered an autoimmune lesion and is one of the cardinal components of Sjógren syndrome. However, lymphoepithelial sialadenitis can also occur as an isolated salivary gland lesion {1501 ).

Localization The typical localization is the parotid gland and less frequently the submandibular glands {648}. Clinical features The lesions present as painless swelling of the affected gland, either unilaterally or bilaterally {1501). Cytology Smears show polymorphous lymphocytes with variable amounts of benign salivary gland epithelium and reactive stromal tissue. Histopathology Lymphoepithelial sialadenitis is characterized by parenchymal atrophy and islands of epimyoepithelial cell proliferation in lymphoid infiltrate. The lobular architecture of the gland with interlobular fibrous sepi a is usually preserved {1083J. Unlike in chronic sclerosing sialadenitis, fibrosis and obliterative phlebitis are not observed in lymphoepithelial sialadenitis {830).

i!'J,-.

~ ~~~·

.,·.: ,~

,

:\~.. ~f '

-~

'

.

Fig. 7.61 Lymphoepithelial sialadenitis in which ~e epimyoepithelial islands are highlighted by cytokeratin (MNF116) staining; normal salivary gland parenchymals seen at the left.


Synonyms

Clinical features

Patients with lymphoepithelial sialadenitis are at risk of developing MALT lymphoma (648). The period from the diagnosis of lymphoepithelial sialadenitis to the development of malignant lymphoma is highly variable in duration: from 6 months to 29 years (620,648,689}.

lntercalated duct adenoma; adenomatous ductal proliferation

Most cases are incidental, detected with other salivary gland lesions (e.g. basal cell adenoma or epithelial-myoepithelial carcinoma) {418,1642,2570).

Epidemiology Fewer than 80 cases have been reported (190,408,418,575,1494,1642, 1713,2570, 26901, with a male-to-female ratio of 3:2. The mean patient age at presentation is about 52 years.

lntercalated duct hyperplasia lntercalated duct hyperplasia is considered a reactive or hyperplastic process (1642,2570,2690}. A precursor role far sorne salivary gland tumours h·as been suggested (418,575,2570).

Definition lntercalated duct hyperplasia/lesion is a salivary ductal proliferation resembling intercalated ducts.

Grossly visible lesions are well circumscrib ed and tan (1713}.

Histopathology Etiology

Chiosea S. Seethala R. Williams M.O.

Macroscopy

lntercalated duct hyperplasia manifests as a nodular formation composed of small ductules of attenuated myoepithelial and cuboidal ductal cells. lt is considered hyperp lastic {2570}. lf well circumscribed, it must be distinguished from the striated form of ductal adenoma.

Localization The majority (85%) of cases arise in the parotid, 11% in the submandibular gland, and 4% in the oral cavity {190,408,418, 575,1494,1642,1713,2570,2690}.

Prognosis and predictiva factors lntercalated duct hyperplasia is a benign hyperplastic lesion .

Non-neoplastic epithelial lesions

197

Benign soft tissue lesions

Haemangioma Flucke U. Bullerdiek J. lhrler S.

Macroscopy


The neoplasm presents as a nodular, greyish-red mass, with a usually salid cut surface (280,1680}.

lnfantile lesions grow rap idly initially, and most involute subsequently. Successful treatment options include propranolol, steroid injection, endovascular sclerotherapy, and surgery (2577 }.

Histopathology Definition Haemangioma is a benign vascular lesion characterized by a proliferation of endothelial cells and pericytes.

ICD-0 code

9120/0

Synonym Benign haemangioendothelioma

Epidemiology Haemangiomas are the most common benign salivary gland tumours in infants, and account for about 50% of parotid tumours. The female-to-male ratio is 2:1

The lesions are lobulated and composed of thin-walled vessels of various sizes and shapes. Lumina may be subtle, with densely packed endothelial cells, especially in the early stage. Larger, more obvious lumina are a sign of maturation. There is no nuclear atypia. Mitotic figures may be present. The lesions surround and replace pre-existen! salivary gland tissue (280,1531,1680}. On immunohistochemistry, CD34 staining highlights the endothelial ce lls and SMA staining highlights the pericytic componen! (280}.

lipoma/ sialolipoma lhrler S. Bullerdiek J. Flucke U. Wenig B.M.

Definition Salivary gland lipoma and sialolipoma are neoplastic lip omatous growths within major salivary glands. Sialolipoma also contains epithelial components, whereas ordinary lipoma does not.

(177,1281,1385, 25 77).

ICD-0 code

8850/0

Localization Synonyms

Haemangiomas occur almost exclusively in the parotid gland (1281,2577).

Salivary lipoma; adenolipoma; oncocytic si alolipoma; oncocytic lipoadenoma

Clinical features Patients present with a mass {177}. Most tumours are limited to th e parotid gland, but extensive lesions also involve the surrounding tissue . They can cause disfigurement and distortion of anatomical structures. Shunting has been reported as a rare complication (2577).

Epidemiology

Fig. 7.65 Sialolipoma presenting as well-circumscribed, homogeneous yellow mass.

Lipoma and sialolipoma constitute :::; 0.5% of salivary gland tumours. Ordinary lipomas are about twice as common as sialolipomas . Both forms manifest in patients of middle to older age, and ordinary lipoma shows amale predominance {18,2264}.

Localization Most lipomas and sialolipomas (~ 90%) develop in the parotid glands. They de· velop rarely in the submandibu lar glands and only exceptionally in the minor salivary glands (16,1687,2264}.

Clinical features Lipomas and sialolipomas are usually slow-growing and clinically asymptomatic (16,18,1687,2264}.

198


Local ization Nodular fasciitis usually develops in the parotid gland (400,1849/, with one re ported case in the submandibular gland (1111 l.

Clinical features Nodular fasciitis typically grows rapidly, usually without clinical symptoms or pain.

Macroscopy Grossly, nodular fasciitis may appear circumscribed or infiltrative, but is not encapsulated. lt is typically about 2- 4 cm

Macroscopy Lipomas/sialolipomas are well -circumscribed yellowish tumours.

Histopathology Salivary gland lipomas are similar to other lipomas and may have an incomplete rim of atrophic salivary gland parenchyma. Variants of ordinary lipoma (e.g. spindle cell lipoma, angiolipoma, and pleomorphic lipoma) are extremely rare {16,18,

[341,400,986,11 11,2035).

Nodular fasciítis

Histopathology lhrler S. Bullerdiek J. Flucke U.

Definition Nodular fasc iitis is a self-limiting fibrous neoplasm composed of fibroblastic/myofibroblastic cells.

2264/.

Sialolipomas can demonstrate a range of non-oncocytic to oncocytic features [16,18, 1239). They contain lobules of parotid parenchyma with evenly interspersed adipose tissue and occasionally focal sebaceous differentiation (18,1112,1687). The differential diagnoses include other salivary gland tumours with lipomatous metaplasia (e.g. pleomorphic adenoma and myoepithelioma (2200)) and atrophic salivary gland parenchyma (16,18,1112,1687).

ICD-0 code

8828/0

Synonym

Genetic profile

Pseudosarcomatous fasciitis

Rearrangement of the USP6 gene is found a large proportion of cases (661 ,1771}.

Epidemiology Only about 30 cases have been reported, accounting for about 1% of ali cases of nodular fasciitis. The lesion ari~es most frequently in the third and fourth decades of lite and rarely in children, with no sex predilection (400,1849).

Prognosis and predictive factors Ali cases are cured by excision, with no reported recurrences.

The neoplasm typically presents as a fibroblastic/myofibroblastic proliferation with a tissue culture- like growth pattern and no cellu lar atypia. Lesions in the salivary glands are histologically and immunohistochemically identical to conventional subcutaneous cases . lncreased mitotic activity and/or focal infiltration can lead to misdiagnosis as sarcoma. Misdiagnosis is also possible on cytological specimens (400,1849 ,2035}.

Prognosis and predictive factors Conservative surgery is sufficient. Recurrence is very rare, even with incomplete excision. Spontaneous regression has been described in cases diagnosed by cytology using fine-needle aspiration (341, 986,1849}.

Etiology The etiology is unknown. Post-traumatic development has been reported in a minority of cases (20 14).

Benign soft tissue lesions

199


lntroduction Cheuk W. Ferry J.A.

Overview Salivary gland lymphomas are uncommon. They constitute 1.7-6% of ali salivary gland neoplasms (847,2103) and 6-26% of ali extranodal lymphomas in the head and neck region (423,666,934, 947,1711). Primary salivary gland lymphoma that manifests initially in the salivary gland is more common than secondary lymphoma as part of disseminated disease (1804}. The parotid gland is the most common site (affected in approximately 70% of cases), followed by the submandibular gland (approximately 20%) and the minor salivary gland (< 10%) (944, 1107,1262,2625). The parotid gland contains intraglandular lymph nodes, and lymphoma may arise in glandular parenchyma (extranodal lymphoma) or within the intraparotid lymph nodes (nodal lymphoma) (209?¡. lt is often difficult to distinguish between the two, because intraparotid lymph nodes in turn may harbour salivary gland inclusions that can undergo proliferation when involved by lymphoma (21). MALT lymphoma, foll icular lymphoma, and diffuse large B-cell lymphoma (DLBCL) together account fo r most cases of lymphoma in the gland parenchyma, whereas lymphoma arising from intraglandular lymph nodes shows a much wider spectrum, consisten! with its nodal counterparts elsewhere in the body (1107}. Clinical features Salivary gland lymphoma usual ly affects patients in late adulthood, with a median patient age of 57-63 years (1262,1804, 2407). There is a slight female preponderance, probably dueto cases of MALT lymphoma arising in association with Sjogren syndrome, which is much more common in females. Bilateral disease is seen in 2.3-10% of cases {698,2008). Most patients present with painless 200


enlarging masses, but sorne have pain, facial nerve paralysis, or cervical lymph node enlargement. Sorne cases present with features of obstructive sialadenitis {1350). B symptoms are very rare. More than 80% of cases present with localized disease (stage I or 11).

Lymphoma subtypes MALT lymphoma is the most common primary salivary gland lymphoma. The frequency of fol licular lymphoma of the salivary gland varies significantly across studies, from 0- 8% in sorne series {619,1107,2008} to 22-30% in others {126 1,1262,1692}, despite thf¡) fact that strict criteria have been applied to exclude nodal disease arising in intraglandular lymph nades. Patients with follicular lymphoma are on average about 10- 15 years younger than those with MALT lymphoma of the salivary gland,

and there is no association between follicular lymphoma and autoimmune disease {1262,1692}. Morphologically, salivary gland follicular lymphoma is similar to follícular lymphoma occurring in other parts of the body. DLBCLs account for 7- 27% of salivary gland lymphomas {619,1262,1692,2008), and a substantial proportion of cases have a MALT lymphoma componen! constituting transformation {1262}. DLBCL has a more aggressive clinical behaviour than do MALT lymphoma and follicular lymphoma o! the salivary gland. According to the lnternational Extranodal Lymphoma Study Group series, salivary gland DLBCLs, like other extranodal DLBCLs of the head and neck region, are associated with worse survival than are their nodal counterparts of similar stage (1596} Rare cases of mantle cell lymphoma, chronic lymphocytic lymphoma, Burkitt

lymphoma, peripheral T-cell lymphoma, extranodal NK/T-cell lymphoma, anaplastic large cell lymphoma, adult T-cell lymphoma/leukaemia, classical Hodgkin 1ymphoma, and n~dular lymphocytepredominant Hodgk1n lym phoma have been reported in the salivary glands, with most cases probably constituting nodal disease within the salivary gland 121, 1267,2407,2666). The prognosis of these 1ymphomas does not seem to differ from that of lymphomas of the same type arising in other parts of the body. Rare cases of lymphoma have been reported in the lymphoid stroma of Warthin tumour; most commonly follicular lymphoma, followed by DLBCL and others 1833,1793,2086). Most patients have disseminated lymphoma at diagnosis or subsequently, suggesting that this composite tumour may constitute a nodal extension of systemic lymphoma, which is consisten! with the hypothesis that Warthin tu mour derives from neoplastic proliferation of salivary gland remnants entrapped in an intraglandular lymph node. Other haematolymphoid tumours (e.g. myeloid sarcoma 1313), histiocytic neoplasms {2101), and plasmacytoma {40,1588)) are very rare in the salivary glands.

Extranodal marginal zone /ymphoma of mucosaassociated lymphoid tissue (MALT lymphoma) Cheuk W. OttG.

gland MALT lymphoma is 0.086 cases per 100 000 pop ulation, with no sig nifican! change over the past two decades {2485). The median patie~t age is 58 years. There is a significan! female predominance (female-to-male ratio: 1.5-3:1) dueto a strong association with Sjogren syndrome {74,1033,2485).

Etiology Definition Extranodal marginal zone lymphoma of mucosa-associated lymphoid tissue (MALT lymphoma) is an indolent mature 8-cell neoplasm showing architectural and cytological similarities with reactive mucosa-associated lymphoid tissues occurring in various extranodal sites {1094).

ICD-0 coda

9699/3

Epidemiology The head and neck region is the second most frequent site of MALT lymphoma, following the gastrointestinal tract. MALT lyrnphoma is the most common type of lyrnphoma in the salivary glands. In the USA, the annual incidence of salivary

A well -established etiological factor of MALT lymphoma is chronic inflammation related to infectious disease or autoimmune disorder, which leads to the de novo formation of lymphoid tissue in organs otherwise devoid of mucosa-associated lymphoid tissue. Lymphoepithelial sialadenitis is the precursor lesion for salivary gland MALT lymphoma. Among patients with Sjogren syndrome, the risk of developing lymphoma is 5- 20 times as high as the risk in the general population {1743, 2514). Monoclonal B cells are detected frequently (in > 50% of cases) in tissues from patients with Sjogren syndrome, and selective expansion of these monoclonal B cells, with the acquisition of further mutations such as in the TNFAIP3 gene

(also called A20), has been associated with lymphoma development (915,1743). Hepatitis C infection may be another predisposing factor in 25% of salivary gland MALT lymp homas 191). lgG4-related disease is an idiopathic, mass-forming chronic inflammatary lesion that frequently involves the salivary gland and ocular adnexa, and there is anecdotal evidence of the development of MALT lymphoma in this setting {419,1757).

Localization MALT lymphoma arising in the head and neck region most frequently affects ocular adnexa (accounting for 60% of cases), followed by the majar and minar salivary glands (30- 40% of cases) and less commonly the Waldeyer ring (pharyngeal lymphoid ring) {2303,2594). lnvolvement of the larynx, oral cavity, or sinonasal tract is rare {1541 ,1873,2363).

Clinical features Most patients present with painless enlarging masses. Sorne may have pain, facial nerve paralysis, or cervical lymph node enlargement. Laryngeal tumours Haematolymphoid tumours

201

may present with hoarseness and stridor. B symptoms are rare.

Macroscopy The tumours are non-circumscribed, firm, and tan-coloured. lnterspersed cysts formed by dilated ducts are a common fi nding in salivary gland MALT lymphoma. Histopathology The histological features of MALT lymphoma in the head and neck region are similar to !hose of MALT lymphoma occurring elsewhere, with confluent sheets of lymphoid cells effacing the architecture. In salivary glands, early lesions consist of lymphoid cells that form socalled collars around frequently obliterated ducts, and often have a monocytoid appearance. These collars are not seen in lymphoepithelial sialadenitis of Sjógren syndrome unassociated with lymphoma, where the epimyoepithelial islands are predominantly composed of proliferating epithelial cells insinuated by

small lymphocytes and accompanied by basement membrane-like material. In later stages, the infiltrate can be nodular, perifollicular, and diffuse, often featuring a mixture of cell types including small lymphocytes, centrocyte-like cells, and monocytoid cells. lntermediate-sized to large blastic cells are often inters persed in small numbers. Plasma-cell differentiation occurs in one third of cases. In the Waldeyer ring, the diagnosis of MALT lymphoma is more difficult to make, because the epithelium is normall y heavily infiltrated by lymphoid cells. The diagnosis rests on the presence of dense lymphoid infiltrates effacing the normal architecture. The lymphoma cells express B-lineage markers such as CD20, CD22, and PAX5. They usually express lgM and sometimes express lgG or lgA, • but do not express lgD. They are typically negative for CD5, CD10, BCL6, CD23, and cyclin 01. IRTA1, a marker of marginalzone- cell differentiation, is positive in the majority of cases {687). Coexpression of

CD43 or T-bet can aid in the diagnosis of lymphoma, as can the demonstration of immunoglobulin light chain restriction in lymphoid cells (optimally by flow cytometry) and/or in plasma cells on paraffin sections (if there is plasmacytic differentiation). A small subset of MALT lymphomas (< 4% of cases) that express CDS may be associated with a more aggressive behaviour (714,2593).

Genetic profile lmmunoglobulin heavy chain (IGH) and light chain (IGL) genes are clonally rearranged , and show variable mutated regions. Trisomy 3 and 18 are common in head and neck MALT lymphomas (2356). Among the recurrently observed translocations in MALT lymphoma, the !(14;18) (q32;q21) (/GH-MALT1) translocation is seen in only a small proportion of cases, and t(1 1;18)(q2 1;q21) (BIRC3/ AP/2-MALT1) is even rarer {2291). lnactivating mutations, deletions, and promoter hypermethylation of the TNFAIP3 gene (also called A20) have been described mainly in translocation-negative salivary gland MALT lymphomas {387). Prognosis and predictiva factors Most patients with head and neck MALT lymphoma have localized disease at presentation {939), and the 5-year disease-free survival and overall survival rates, respectively, are 54% and 82-95% in salivary gland MALT lymphoma [74, 2485). Large-cell transformation is associated with a more aggressive clinical course {945}.

Fig. 7.71 Tonsil MALT lymphoma. The normal lobular architecture of the tonsil has been effaced by dense and expansile sheets of lymphoma cells.

202


CHAPTER 8 Odontogenic and maxillofacial bone tumours

Odontogenic carcinomas Odontogenic carcinosarcoma Odontogenic sarcomas Benign epithelial odontogenic tumours Benign mixed epithelial and mesenchymal odontogenic tumours Benign mesenchymal odontogenic tumours Odontogenic cysts of inflammatory origin Odontogenic and non-odontogenic developmental cysts Malignant maxillofacial bone and cartilage tumours Benign maxillofacial bone and cartilage tumours Fibro-osseous and osteochondromatous lesions Giant cell lesions and bone cysts Haematolymphoid tumours

WHO classification of odontogenic and maxillofacial bone tumours

Odontogenic carcinomas Ameloblastic carcinoma Primary intraosseous carcinoma, NOS Sclerosing odontogenic carcinoma Clear cell odontogenic carcinoma Ghost cell odontogenic carcinoma

9270/3 9270/3 9270/3 9341/3* 9302/3*

Odontogenic carcinosarcoma

8980/3

Odontogenic sarcomas

9330/3

Malignant maxillofacial bone and cartilage tumours Chondrosarcoma 9220/3 Chondrosarcoma, grade 1 9222/1 Chondrosarcoma, grade 2/3 9220/3 Mesenchymal chondrosarcoma 9240/3 Osteosarcoma, NOS 9180/3 Low-grade central osteosarcoma 9187/3 Chondroblastic osteosarcoma 9181/3 Parosteal osteosarcoma 9192/3 Periosteal osteosarcoma 9193/3

Benign epithelial odontogenic tumours 9310/0 Ameloblastoma Ameloblastoma, unicystic type 9310/0 Ameloblastoma, extraosseous/peripheral type 9310/0 9310/3 Metastasizing ameloblastoma Squamous odontogenic tumour 9312/0 Calcifying epithelial odontogenic tumour 9340/0 9300/0 Adenomatoid odontogenic tumour

Benign maxillofacial bone and cartilage tumours Chondroma 9220/0 Osteoma 9 180/0 Melanotic neuroectodermal tumour of infancy 9363/0 Chondroblastoma 9230/1 Chondromyxoid fibroma 9241/0 Osteoid osteoma 9191 /0 Osteoblastoma 9200/0 Desmoplastic fibroma 8823/1

Benign mixed epithelial and mesenchymal odontogenic tumours Ameloblastic fibroma Primordial odontogenic tumour Odontoma Odontoma, compound type Odontoma, complex type Dentinogenic ghost cell tumour

Fibro-osseous and osteochondromatous lesions Ossifying fibroma 9262/0 Familia! gigantiform cementoma Fibrous dysplasia Cemento-osseous dysplasia Osteochondroma 9210/0

Benign mesenchymal odontogenic tumours Odontogenic fibroma Odontogenic myxoma/myxofibroma Cementoblastoma Cemento-ossifying fibroma

9330/0 9280/0 9281/0 9282/0 9302/0

9321/0 9320/0 9273/0 9274/0

Giant cell lesions and bone cysts Central giant cell granuloma Peripheral giant cell gran uloma Cherubism Aneurysmal bone cyst Simple bone cyst

9260/0

Odontogenic cysts of inflammatory origin Radicular cyst lnflammatory collateral cysts

Haematolymphoid tumours Solitary plasmacytoma of bone

Odontogenic and non-odontogenic developmental cysts Dentigerous cyst Odontogenic keratocyst Lateral periodontal cyst and botryoid odontogenic cyst Gingival cyst Glandular odontogenic cyst Calcifying odontogenic cyst 9301/0 Orthokeratinized odontogenic cyst Nasopalatine duct cyst

The morphology codes are from the lnternational Classification of Diseases for Oncology (ICD-0) (776AJ . Behaviour is coded /O for benign tumours; /1 for unspecified. borderline, or uncertain behaviour; /2 for carcinoma in situ and grade 11 1intraepithelial neoplasia; and /3 for malignant tumours. The classification is modified from the previous WHO classification, taking into account changes in our understanding of these lesions . "These new codes were approved by the IARC/WHO Committee for ICD-0.

204

Odontogenic and maxillofacial bone tumours

9731/3

lntroduction

In comparison with the previous edition, the numl.Jer of entiti es discussed in this chapter has increased by almos! 50% . Reasons for this are the addition of the odontogenic cysts, a group of diseases left out befare but now included given that sorne of them may recur, and the addition of selected bone tumours and haematolymphoid disorders that either have the jaws and other maxillofacial bones as a predilection site orare importan! in view of their differential diagnosis. The emphasis in this chapter lies on the odontogenic tumours (OGTs). OGTs are rare, constituting < 1% of ali oral tumours. Most OGTs are benign, but sorne show locally aggressive growth and a high rate of recurrence. OGTs are derived from cells of odontogenic apparatus and th eir remnants. Both benign and malignan! OGTs are subclassified into epithelial tumours, mixed epithelial and mesenchymal tumours , and mesenchymal tumours. Classification of odontogenic tumours is in general a hotly debated subject, and attempts have been made to simplify the classification as much as possible, leaving out any unproven references to histogenesis or precursor lesions. As a consequence, only one type of ameloblastic carc inoma and one type of primary intraosseous carcinoma have

Takata T. Slootweg P.J.

been retained, leaving out adjectives or prefixes such as primary, dedifferentiated, etc. The same considerations have led to the recognition of only one type of odontogenic sarcoma; adjectives such as ameloblastic and prefixes like fibro-odonto- and fibrodentino- have no diagnostic or clinical relevance. Am eloblastic fibro-dentinoma and ameloblastic fibrodentinoma have been dropped as well-defined entities deserving their own place, because there was a general feeling th at they in most cases represen! developmental stages of either complex or compound odontoma and that retaining them as separate entities would therefore be illogical. Odonto-ameloblastoma has also been dropped as available data on this condition were considered to be insufficient to justify its recognition as a genuine entity, lesions reporte d under this label probably being a coincidental mixture of an ameloblastoma or other epithelial odontogenic tumour with an odontoma or a developing tooth. Much discussion has been devoted to the distinction between non-n eoplastic and neoplastic cystic lesions, which especially concerned the odontogenic keratocyst (OKC) / keratocystic odontogenic tumour (KCOT) and the calcifying cystic odontogenic tumour (CCOT) / calcifying odonto-

genic cyst (COC). lt was concluded that most cases of KCOT and CCOT behave c linically as non-neoplastic lesions and are treated as cysts. Therefore, there was consensus that they should be reclassified as OKC and COC, respectively, until there is more definite evidence for classifying them as KCOT and CCOT, thus reintroducing the time-honoured names in use befare their labelling as tumours in the previous WHO classification.New entities that have been identif ied since the previous WHO classification have been added: sclerosing odontogenic carcinoma, odontogenic carcinosarcoma, and primordial odontogenic tumour. Regarding the bone lesions, within the group of ossifying fibromas , the prefix cementohas been added to the variant that is confined to the jaws and that, although strictly speaking, should be listed among the mesenchymal odontogenic tumours, nevertheless has been included among the fibro-osseous lesions in view of differential diagnostic consi derations. Finally, fami lia! gigantiform cementoma remains an enigmatic cond ition evad ing precise characterization but has nevertheless been mentioned in the hope of more clarity in the near future.

lntroduction

205

Odontogenic carcinomas

Ameloblastic carcinoma Odell E.W. Muller S. Richardson M.

Definition Ameloblastic carcinoma (AC) is a rare primary epithelial odontogenic malignant neoplasm. lt is the malignant counterpart of ameloblastoma. ICD-0 code

9270/3

Synonyms AC, secondary or dedifferentiated types; intraoral basal cell carcinoma of the gingiva (obsolete) Epidemiology In the USA. the overall annual incidence of malignan! ameloblastomas (i.e. both AC and the rarer metastasizing ameloblastoma) is 1.79 cases per 10 million population, increasing with patient age (1997}. but only about 100 cases have been reported (1182). Males are at slightly greater risk than females, and most cases arise in patients aged > 45 years, with a small incidence peak in childhood . In China, malignan! ameloblastomas account for approximately 2% of ali ameloblastomas, and the mean palien! age is younger (1414).

Fig. 8.02 Ameloblastic carcinoma arising in the right maxllla, on CT (left) and MRI (right), showing a large, expanding mass with cortical destruction and internal signal intensity variation.

thirds of ali lesions occurring in the mandible {1182}. Most cases arise de novo, but sorne arise in pre-existing ameloblastomas. ACs are more frequent in the mandible than in the maxilla {1182,1714). A very small number of cases have been described arising in peripheral ameloblastoma (1877}. The primary and secondary types have similar histological features and behaviour.

Localization The posterior segments of the jaws are the most common site, with half to two

Clinical features Large and longstanding lesions show poorly defined or irregularly marginated radiolucencies consisten! with malignancy, often with cortical expansion, perforation, and infiltration into adjacent structures. However, sorne cases have appeared as benign radiolucencies. A single case with hypercalcaemia has been reported (490).

Fig. 8.01 Ameloblastic carcinoma.A very large ulcerated tumour arising in the mandible.

H istopathology AC is defined by the combination of cytological features of malignancy and the histological pattern of an ameloblastoma, in either the primary or a metastatic lesion . AC can have the follicular or plexiform patterns of ameloblastoma or ·can be formed of sheets, nests, or broad trabeculae of epithelium. The peripheral cell layer shows peripheral palisading, and reverse nuclear polarity is usually present at leas! focally. There is loss of

206


the organized stratification of basal cells, stratum intermedium, and stellate reticulum that is typical of ameloblastoma, which is more marked in higher-grade lesions. The centre of epithelial sheets or islands may be replaced by salid basaloid epithelium, acanthomatous epithelium, or spindle cells, or may show cystic degeneration. Defining the borderline between ameloblastoma and AC is difficult, and overdiagnosis is to be avoided {863}. Malignan\ features such as pleomorphism, increased N:C ratio, nuclear hyperchromatism, mitotic activity, abnormal mitoses, and vascular or perineural invasion may ali be present. Necrosis is useful and ranges from subtle clusters of apoptotic cells within islands to overt comedonecrosis or more extensive necrosis. Mitotic activity alone cannot be interpreted as a feature of malignancy. Mitotic figures are more frequent alter incisional biopsy. Cellularity and mitotic activity are also more marked in maxillary than in mandibular ameloblastomas and do not by themselves indicate malignancy. lnfiltration must also be evaluated cautiously because benign ameloblastoma infiltrates the medullary cavity of bone . ACs express SOX2 (1375} and have a higher Ki -67 proliferation index than do benign ameloblastomas {233}. but these features provide no proven additional

Fig. 8.03 Ameloblastic carcinoma. A Architectural features of ameloblastoma, a peripheral basaloid !ayer and stellate reticulum-like central epithelium, but with frequent mitotic figures and atypia. B Marked atypia and a peripheral basal !ayer of palisading cells with reversed nuclear polarity. C Loss of ameloblastoma architecture and progression to highergrade spindle morphology. D Focus of incipient necrosis consisting of numerous clustered apoptotic cells.

diagnostic value over routine histological features. Occasional lesions have a partial or completely spindle-celi morphology and may be difficult to distinguish from odontogenic carcinosarcoma or sarcoma, because not ali reported examples have retained keratin immunopositivity {1165, 2703). Sorne of these spindle-cell lesions have foliowed an aggressive course. lf the features of ameloblastoma are not evident in a cytologically malignant odontogenic neoplasm, an alternative diagnosis of primary intraosseous carcinoma or clear cell odontogenic carcinoma should be considered. The distinction between these entities is not well defined, and AC may show both keratinization and clearcell change.

Genetic profile BRAF mutations identical to those seen in ameloblastoma have been described in AC {283 l. Prognosis and predictive factors Approximately one third of patients develop pulmonary metastases, whereas

cervical lymph node metastases are unusual {1284l. The median overall survival is 17.6 years, with maxillary lesions twice as likely as mandibular lesions to cause death {1997), but many series report shorter median survivals (-5 years) {1284). Radical surgical excision is the primary treatment, with a local recurrence rate of 28% {2681). Radiotherapy seems to provide little additional benefit but tends to be used in the salvage setting . Aggressive multimodality treatment from the outset has been recommended !1 4 14).

Primary intraosseous carcinoma, NOS Odeli E.W. Alien C.M. Richardson M.

Definition Primary intraosseous carcinoma, NOS (PIOC) is a central jaw carcinoma that cannot b e categorized as any other type

of carcinoma. lt is assumed to arise from odontogenic epithelium. Sorne cases arise in odontogenic cysts or other benign precursors.

ICD-0 code

9270/3

Synonyms Primary intraosseous squamous celi carcinoma: primary intra-alveolar epidermoid carcinoma: primary odontogenic carcinoma Epidemiology PIOC is rare. As of 2011, only 116 cases arising in cysts had been reported !224) . As of 2001, 35 cases with no precursor lesion had been reported {2379}. The stringent diagnostic criteria for confident diagnosis of odontogenic origin are difficult to assess with certainty, and a precursor benign lesion can be confidently excluded or confirmed in only a minority of cases {654}. Ali types of PIOC (whether developing in cysts or not) show a male predilection, with a male-to-female ratio of almost 2:1 (reflecting the prevalence of cysts) and a mean patient age Odontogenic carcinomas

207

cortication or tooth resorption. Advancect lesions develop fully malignan\ appearances. The only evidence of the benign precursor cyst may be in previous radiographs.

Fig. 8.04 Primary intraosseous carcinoma. Subtle early signs of intraosseous carcinoma in the dental follicle of the unerupted lower premolar, with slight expansion and loss of cortication (left); 2 years later, there is extensive destruction and pathological fracture (right).

at diagnosis of 55-60 years {224,1049). although the age range is broad, and cases have been reported in children. Localization PIOC is more frequent in the posterior body and ramus of the mandible than in the maxilla. Maxillary lesions are usually in the anterior segment {224,2379, 2736). Determining origin is important for diagnosis. Carcinoma arising in the oral mucosa and infiltrating the mandible, an antral primary, and metastatic carcinoma must be excluded, and ulceration to the oral cavity is normal ly considered to preelude definitive diagnosis. PIOC in the mandible usually arises above the inferior dental canal, whereas metastases usually have their epicentre below it. Cases arising in cysts are more common in the mandible {224). Clinical features Most lesions are asymptomatic incidental

208

radiographical findings. More-advanced lesions cause non-specific signs and symptoms suggesting malignancy: slow-growing swelling of the jaw, pain, ulceration, loosening ofteeth, non -healing extraction sockets, pathological fracture, and nerve signs. Radiographically, the tumours produce a poorly defined, noncorticated radiolucency, often with root resorption and cortical perforation (2736}. Cases arising in cysts may produce an apparently multilocular or scalloped radiolucency. Approximately 40% of pati ents have metastasis at presentation {2736}. Radicular/residual cysts are the most common precursors , followed by dentigerous cysts and odontogenic keratocysts, reflecting their relative prevalence. When the tumour is detected early, the rad iological features appear benign and the carcinoma is an incidental histological find ing on enucleation {1217,1516). More frequently, there is subtle loss of


Histopathology Almost ali lesions are squamous in type and composed of islands or small nests of neoplastic squamous epithelium, with prickle-cell differentiation and without prominent keratinization (654,672}. Many appear cytologically bland, and most are considered moderately differentiated. Necrosis is unusual. Sorne show limited peripheral palisading or a plexiform pattern that suggests their odontogenic origin (654}. PIOC is a diagnosis of exclusion. This requires histological, rad iographical, and clinical information to exclude metastases (which are much more common), mal ignan\ odontogenic tumours of specific types, carcinomas of the maxillary antrum and nasal mucosa, and intraosseous salivary gland neoplasms. These distinctions are often impossible on histological grounds alone. Negative CK19 staining indicates that an odontogenic epithelial origin is unlikely. Particularly close mimics are squamous odontogenic tumour and salid odontogenic keratocyst, whereas keratinizing ameloblastom a and central high-grade mucoepidermoid carcinoma are more readily distinguished . When cases arise in odontogenic cysts, there may be a histological transition between the carcinoma and the benign precursor, but the carcinoma eventually effaces the res idual benign lesion. Hall are well differentiated and half moderately differentiate d. Occasionally, dysplasia

may be encountered in the cyst epithelium , or there may be a verrucous cyst lining similar in appearance to a verrucous dysplastic lesion of oral mucosa 193, 2442). These cases behave as dysplastic 1esion or carcinoma in situ when they are limited to the cyst. Squamous cell carcinoma has also been reported to arise in ameloblastoma and other benign odontogenic tumours. When a carcinoma is squamous and the histological features of specific malignan! odontogenic carcinomas are absent, the carcinoma is best classified as PIOC.

Prognosis and predictive factors An insufficient number of cases has been reported to determine outcome, but prognosis is generally poor and is best predicted by histological grade 11049). Radical resection has been the primary treatment modality 1654,2736}. with neck dissection for metastasis or reconstruction. Multimodality treatment provides added benefit and has been reported to provide a 3-year survival rate of 40%. As many as 60% of lesions recu r locally 11049) ; in one series, patients with local recurrence all died of the disease 12736). Distan! metastasis is infrequent and is usually to lung (2444). As of 2001, the 5-year survival rate of reported cases was 52% 12379). Cases arising in cysts often appear to be better differentiated and have a more prolonged course, but the 5-year survival rate of reported cases is slightly lower, at 40% [224}. When cysts are found to harbour incidental dysplasia or carcinoma in situ alter enucleation, conservative clase follow-up is appropriate 1224).

Epidemiology Fewer than 10 cases have been reported {1061,1075,1092), with 3 cases discussed in the first report 11273), but the entity may be underrecognized or described under another name (1075,2087). Males and females are equally affected.

Localization The mandible is more frequently affected, in the premolar and molar reg ions. The reported cases in the maxilla occurred in the anterior and molar regions . Clinical features SOC presents as swelling, sometimes with nerve signs. Radiographically there

is poorly defi ned radiolucency with frequent cortical bone destruction, tooth root resorption, and extension beyond radiographical margins. Sinus involvement has been reported.

Histopathology SOC is characterized by single-file thin cords, nests, and strands of epithelium in a densely sclerotic stroma. Epithelium or stroma may domínate in different areas. The epithelium may be compressed and only visible on immunohistochemistry. Cytologically, individual epithelial cells are bland, with infrequent mitoses. Their cytoplasm may show vacuolation or partial clearing. There is no squamous

Fig. 8.06 Sclerosing odontogenic carcinoma. A Fine epithelial strands infiltrating around a muscle fibre. B CK19 immunopositivity reveals unsuspected fine strands of dispersed carcinoma cells, consistent with an odontogenic origin.

Sclerosing odontogenic carcinoma Odell E.W. Koutlas l.

Definition Sclerosing odontogenic carcinoma (SOC) is a primary intraosseous carcinoma of the jaws, with bland cytology, rnarkedly sclerotic stroma, and aggressive infiltrat ion.

ICD-0 c ede

9270/3

-

.

"

Fig. 8.07 Sclerosing odontogenic carcinoma. High-power view shows cytologically bland epithelium in a dense collagenous stroma.


209

differentiation. Despite the benign appearance, there is invasion of skeletal muscle. and perineural infiltration is characteristic. Necrosis is not reported {1273,1986}. The epithelial cells are immunopositive for CK19, CKS/6, and p63 but are only focally and subtly positive for CK7 {1092,1273, 2348) and negative for CAM5.2 {1 061, 1273]. Membrane staining for E-cadherin is variable. Diagnosis mus! exclude metastasis, epithelium-rich central odontogenic fibroma, calcifying epithelial odontogenic tumour, clear cell odontogenic carcinoma (1061, 1273,2348). and desmoplastic amelob lastoma. This may be difficult in small biopsies. Despite its resemblance to epithelium-rich central odontogenic fibroma {2348} and its benign-looking epithelial islands, SOC shows aggressive infiltration. lt is unclear whether SOC is a distinct entity ora histopathological pattern {1074, 2641], but it merits recognition so that its characteristics may be defined more fully.

by sheets and islands of vacuolated and clear cells.

ICD-0 code

9341/3

Synonyms Clear cell odontogenic tumour; clear cell ameloblastoma (both obsolete)

Epidemiology Nearly 100 well-characterized cases have been reported. The incidence is unknown. The carcinoma is more common in women than in men (with a maleto-female ratio of 1:1 .6), and the mean patient age at diagnosis is 53 years. Most cases arise in patients aged 40- 70 years (1484).

Localization The mandible is the site of origin three times as freq uently as the maxilla, with 43% of ali lesions arising in the posterior body and lower ramus {1484).


Clinical features

SOC is a low-grade carcinoma. Resection has been the main treatment, and only one recurrence has been reported, fol lowing initial curettage (1092). No role for radiotherapy is defi ned . Metastasis is not described.

Clear cell odontogenic carcinoma may cause non-specific signs and symptoms, such as slow-growing swelling of the jaw, pain, ulceration, loosening of teeth, nerve signs, and a poorly defined rad iolucency, often with root resorption and sometimes soft tissue invasion (624,1484). Many cases are asymptomatic. and small lesions may appear deceptively localized rad iographically.

C/ear ce// odontogeníc carcinoma Odell E.W. Bilodeau E.A. Maiorano E. Neville B.W.

Definition Clear cell odontogenic carcinoma is an odontogenic carcinoma characterized

210

Histopathology The tumour is composed predominantly of epithelial cells that have clear to faintly eosinophilic cytoplasm, well -demarcated cell membranes, and irregular small dark-staining nuclei {129,935}. The clear cells are organized in lobular sheets, islands, trabeculae, or strands. and at their periphery there is almost always a

Odon togenic and maxillofacial bone tumours

Fig. 8.09 Clear cell odontogenic carcinoma. Resection specimen showing a poorly defined destructive radiolucency in the posterior body and ramus of mandible.

basaloid cell population of small dark unvacuo lated cells (biphasic pattern). Much less frequently, the pattern may be focally reminiscent of ameloblastoma, with an outer !ayer of columnar clear cells showing reversed nuclear polarity. Completely clear-cell examples (monophasic pattern) are rare. The histological appearance can be bland , with only mild atypia and few mitoses. Necrosis, overt cytological malignancy, and perineural spread are seen in higher-grade examples. The clear cells are negative for mucin but are glycogen-rich, as evidenced by diastase-labile periodic acid- Schiff (PAS) positivity, although glycogen may be lost during fixation or decalcification. The clear cells are immunopositive for various cytokeratins, but CK14, CK19, and pancytokeratin AE1/AE3 are the most useful and re liable diagnostic markers. The cells are negative for vimentin, S100 protein, desmin, SMA, HMB45, alpha1-antic hymotrypsin, CD10, CD31, CD45. and GFAP {129,1423,1484,2711 ). The Ki67 proliferative index is highly variable. Dentinoid has been reported in 7% of cases [1484] but is generally a minar inductive c hange. However, occasional lesions have shown extensive dentinoid and may be a separate entity [1658). The appearances are distinctive bu!

not pathognomonic, and diagnosis requires exclusion of other clear cell-rich neoplasms, including salivary gland neoplasms, melanoma, metastatic renal ce/1 carcinoma, and the clear-ce/1 variant of calcifying epithelial odontogenic tumour [513). Ameloblastoma with clearce/1 differentiation and clear ce/1 calcifying epithelial odontogenic tumour can be problernatic differential diagnoses, but clear-ce/1 change in these lesions is usually focal.

Ghost ce// odontogenic carcinoma

Localization

Ode/1 E.W. Ledesma-.Montes C.

Definition Ghost ce/1 odontogenic carcinoma (GCOC) is an odontogenic carcinoma characterized by ghost-cel/ aberran! keratin ization and dentinoid deposition in variable quantities.

Genetic profile More than 80% of cases show rearrangernents of EWSR1 {191); on the basis of fewer cases, ATF1 was confirmed as the translocation partner (191 ,2667). This is the same translocation found in clear ce/1 salivary gland carcinoma, and given their rnorphological similarity, it has been theorized that these are related tumours [84). A single case has been reported to harbour a BRAF V600E mutation, but this rnay suggest clear cell ameloblastic carcinoma {589). The exorne sequence of a different single case has been published [332] .

Prognosis and predictive factors Clear ce/1 odontogenic carcinomas vary in behaviour from indolent tumours to cases that frequently recur. The tumours have metastasized in approximately 12% of reparted cases, usua/ly to cervical lymph nodes and lungs, and less frequently to bone. Metastases at presentation are rare. The outcome has been death in 15% of cases, with a median survival of 14 years. Recurrence and metastasis may develop after many years (624,1 484). Complete surgical resection is the primary treatment. Adjuvant radiotherapy does not have a defined role, but may be approp riate far cases showing soft tissue extension, aggressive growth, or incomplete surgical margins {624).

ICD-0 code

9302/3

Synonyms Calcifying ghost ce// odontogenic carcinoma; malignan! epithelial odontogenic ghost ce// tumour; carcinoma arising in a calcifying odontogenic cyst; aggressive epithelial ghost ce// odontogenic tumour; malignan! calcifying odontogenic cyst; malignant calcifying ghost cel/ odontogenic tumour

GCOC is twice as common in the maxilla as in the mandible. Mandibular lesions are usual/y in the molar area. Ali reported cases have been intraosseous. App roximately 40% of cases have been confirmed to arise in a benign precursor, a calcifying odontogenic cyst, or a dentinogenic ghost cel/ tumour (DGCT) {556); the rest arise de novo {1357).

Clínica/ features GCOC causes non-specific signs and symptoms suggesting malignancy: slowgrowing swelling of the jaw, p ain, ulceration , loosening of teeth, nerve signs, root reso rption, and sometimes soft tissue invasion. lmaging shows a poorly demarcated, osteolytic radiolucency, with half of al/ cases showing variable radiopaque material (556), reflecting mineralization in ghost cel/s, dentinoid formation, ar residual benign precursor. Displacement and resorption of tooth roots are common.

Macroscopy Epidemiology GCOC is about the rarest of the ghost ce// lesions, accounting for < 3% of al/ cases {1357). Approximately 40 cases have been reported , with more than half occurring in Asian patients {556}. The carcinoma is tour times as com mon in men as in women, with p eak incidence in patients aged 40- 60 years {556) . The patient age range is 11-79 year~ (mean: 39.7 years) {30,556}.

Appearances range from salid to multicystic, usual/y with a gritty consistency on section .

Histopathology GCOC, DGCT, and calcifying odontogenic cyst form a spectrum of histological appearances and behaviour {1357,1373]. The diagnosis of GCOC requires cytological evidence of malignancy, including mitotic activity; pleomarphism and hyper-


211

chromatism; necrosis; and an infiltrative growth pattern associated with ghost ce ll keratinization, dentinoid formation, or evidence of a DGCT or calcifying odontogenic cyst precursor. The malignan! epithelial cells form sheets, strands, and islands in a fibrous or hyalinized stroma. The cells are unifo rm, small basaloid cells with round dark nuclei in most cases, but can be larger with pleomorphic vesicu lar nuclei. Mitoses are frequent. Ghost ce lls (i.e. keratinizing cells with aberran! terminal differentiation) are large, rounded pale-staining cells with empty central nuclear spaces, found in varying numbers. They may be dispersed, isolated, or in clusters (1357,1373,1486,1 986l. Dentinoid may be present and the amount of ghost cell keratinization and dentinoid are highly variable; both can be formed by the malignan! epithelium and in one pattern are widely and evenly dispersed. In the other pattern, ghost cell keratinization and dentinoid are more localized, possibly associated with an overgrown or residual benign precursor. Small foci of ghost cells

212

occur in many odontogenic tumours and do not alone indicate malignancy or the diagnosis. Two thirds of cases are immunopositive far p53 protein (556,1486, 1664). Not all carcinomas arising in calcifying odontogenic cyst and DGCT are necessarily GCOCs; they should be diagnosed according to their predominan! differentiation pattern. The diagnosis of GCOC (versus DGCT) is favoured by p53 positivity and a high proliferative fraction. Although cut-off values have not yet been defined (556, 868,874,1486}. expression of these markers increases upan transformation (1664, 2726l . Overlap lesions between GCOC and calcifying odontogenic cyst have been reported {94).

Genetic profile A single case has genomic and exorne sequencing data showing a distinctive molecular profile, including (among many changes) multiple changes in the SHH signalling pathway, a deleted exon in UBR5, and a novel APC mutation


(242). This APC mutation is possibly a link between one case of GCOC and Gardner synd rome (familia! colorectal polyposis) (727).

Prognosis and predictive factors The prog nosis is unpredictable due to the wide variety of growth patterns reported with the tumours ranging from slow-grow'. ing, locally invasive carcinomas to highly aggressive and rapidly growin g tumours with local recurrence and metastasis (90). Most are relatively low-grade. Wide surgical resection is the primary treatment and is successful in two thirds of reported cases. Only a minority of cases have been treated with adjuvant radiotherapy, and its role remains undefined {30). Aggressive multimodality therapy with immunotherapy has proven successful in a case with regional lymph node metastasis {30}. Death followed local recurrence in 3 cases and distan! metastasis in 2 cases among 25 reported cases (90). The overall 5-year survival rate in th e first 16 reported cases was 73% (1486).


EI-Mofty S.K.

Definition Odontogenic carcinosarcoma is extremely rare. lt is a true malignant mixed odontogenic neoplasm similar in pattern to ameloblastic fibrosarcoma, but in which both the epithelial and the mesenchymal components are cytologically malignan! {1276).

occasional multinucleation and mitosis. The epithelial componen! is frankly malignan!, with large hyperchromatic nuclei and an increased N:C ratio. The typical ameloblastic features such as peripheral nuclear palisading and inner stellate reticulum may be lost focally. Ameloblastic carcinoma associated with malignan! spindle-cell proliferation {427,2167,2350, 2686) is best classified as sarcomatoid ameloblastic carcinoma rather than true odontogenic carcinosarcoma. In one case. p53 and Ki-67 immunostaining showed p53 positivity in 90% of the cells and a Ki-67 proliferation index of 45% in high-staining areas. in both the carcinoma and the sarcoma components {558f.

ICD-0 code

8980/3

Synonyms Ameloblastic carcinosarcoma; malignant odontogenic mixed tumour Epidemiology Odontogenic carcinosarcoma is very rare, with only a few single-case reports published [558,1294,2205}. The tumours may be preceded by ameloblastic fi broma or ameloblastic fibrosarcoma. Localization The mandible is the only reported site of occurrence. Clinical features Cases have been reported in two men (aged 52 and 55 years) [1294,2205} and in a 19-year-old woman [558). The size of the lesions was 6.0- 8.0 cm. The tumour presents as expansion of the body of the mandible and ramus, of severa! months' duration. lt may be painless or associated with numbness of the lip.

Fig. 8.11 Odontogenic carcinosarcoma. CT shows a large, expansive, radiolucent lesion in the left mandible. Reprinted from Delair D et al. {558}.

Radiographically, the lesions are large, expansile radiolucencies with poorly defi ned borders. Cortical perforation and root resorption have been reported.

Macroscopy The tumours are multinodular and tan, with a fleshy appearance [558). Histopathology . The overall architecture resembles that of ameloblastic fibroma, with budding and branching epithelial cords widely separated by hypercellular fi broblastic stroma. The cells in the sarcomatous componen! are markedly pleomorphic, with enlarged and bizarre nuclei and

Prognosis and predictiva factors Due to the very limited number of reported cases and to insufficient followup, prognostic information is lacking. In one reported case {1294). a 51-year-old man had multiple recurrences during a 5-year period following segmenta! resection; distant metastasis to lung and bone occurred 1 year after re-resection of the recurren! tumour. In another case, in a 19-year-old woman [558). there was no evidence of recurrence 2 years alter hemimandibulectomy.


213

Odontogenic sarcomas

Wright J.M.

admixed with the AFS, further suggesting an origin from AF.

Localization The ratio of mandibular to maxillary incidence is approximately 4:1, and there is a predilection for the posterior jaws (267f.

Clinical features

Fig. 8.1 3 Odontogenic sarcoma. Asymmetrical, poorly marginated radiolucency of the right posterior mandible.

Definition Odontogenic sarcomas are a group of mixed odontogenic tumours in which the epithelial component is cytologically benign and the mesenchymal component shows cytological features of malignancy. Ameloblastic fibrosarcoma (AFS) is by far the most common type, and is generally considered to be the malignan! counterpart of ameloblasti c fibroma (AF). Sorne odontogenic sarcomas (ameloblastic fibrodentinosarcomas) produce dentin/dentinoid. Others (ameloblastic fibro-odontosarcomas) produce enamel/ enameloid and dentin.

ICD-0 code

9330/3

Epidemiology AFSs can occur in patients of any age (reported range: 3-89 years), with an

214

overall mean patient age of 27.3 years, which is considerably older than the mean age for AF {836}. Cases in which previous AF can be demonstrated occur ata mean patient age of 33 years [1675). and cases in which the benign AF cannot be demonstrated occur 10 years earlier {267). Males are affected about 1.5 times as frequently as females.

Etiology The etiology is unknown, but AFS is generally thought to arise in a pre-existing benign AF, although this benign precursor lesion is only demonstrated in about hall of all cases {1327). This fi nding has led sorne authors to speculate that sorne AFSs arise de novo, but the lack of documentation of a pre-existing AF does not prove a de novo origin. Additionally, sorne cases have clearly benign AF


Th e clinical features are those of any lowgrade malignancy an expansile mass with nerve deficit. Most odontogenic sarcomas are poorly marginated lesions. AFS. is always radiolucent, but lesions producing dentin (with or without enamel) . can contain opacities.

Histopathology Odontogenic sarcomas are mixed odontogenic tumours in which the epithelial componen! is bland and cytologically benign and the mesenchymal componen\ is malignant. The epithelial component ranges from lamina-like strands to larger islands of epithelium with peripheral palisading. The amount of epithelium varies, most likely in relation to the age of the neoplasm as the malignant mesenchymal component overgrows the benign epithelial component. The stromal component displays nuclear crowding, with hypercellularity and variable degrees of cytological atypia, including increased mitoses.

Prognosis and predictive factors Odontogenic sarcomas are considered low- to intermediate-grade sarcomas, although anaplastic variants have been reported. About one third of patients experience recurrence, but distan\ metastasis is seen in < 5% of patients, and the overall mortality rate is about 25% [836).

Benign epithelial odontogenic tumours

Ameloblastoma Vered M. Muller S. Heikinheimo K.

Definition Ameloblastoma is a benign intraosseous progressively growing epithelial odontogenic neoplasm characterized by expansion and a tendency for local recurrence if not adequately removed. ICD-0 code

9310/0

Synonyms Conventional ameloblastoma; classic intraosseous ameloblastoma; solid/multicystic ameloblastoma Epidemiology Although rare (with an estimated annual incidence of only about 0.5 cases per million population), ameloblastoma is the most common odontogenic tumour, excluding odontomas {291,981). The peak incidence of diagnosis is in the fourth and fifth decades of lile, with a patient age range of 8- 92 years and no sex predilection {291,785,980). For BRAFV600Emutant cases, the reported mean patient age at diagnosis is about 34 years, compared with about 54 years for BRAFwildtype cases {279). Localization Approximately 80% of ali ameloblastomas are fo und in the mandible; they

Fig. 8.15 Ameloblastoma. Gross specimen showing a

tumour that is partly salid and partly cystic.

Fig. 8.16 Ameloblastoma. A The radiographical presentation is that of an extensive multilocular (so-called soapbubble) radiolucency involving the posterior mandible, ascending ramus, and coronoid process; root resorption and tooth displacement are observed. B This tumour is located in the area of a missing lateral maxillary incisor and presents as a mixed radiolucent and radiopaque lesion; histopathologically, it was diagnosed as a desmoplastic ameloblastoma.

occur most often in the posterior region, fol lowed by the anterior mandible, posterior maxilla, and anterior maxilla {291,785,980,1646,2171). Desmoplastic ameloblastoma has a predilection for the anterior region of the jaws, especially the maxilla {1881). Ameloblastomas· of the sinonasal trae! are rare {2090}.

Clinical features The early manifestation is of a slow, painless expansion, which can later exhibit accelerated growth {369). With increasing size, complications include loosen ing of teeth, malocclusion, paraesthesia, pain, soft tissue invasion, facial deformity, limited mouth opening, difficulty with mastication, and airway obstruction. Uncontrolled tumour growth can be fatal. Radiographically, a corticated multilocular so-called soap-bubble or honeycomb radiolucency is common (although not pathognomonic). A unilocular appearance is less common. Buccal anc;J lingual expansion is often observed. Resorption of involved roots and association with an unerupted tooth may occur. Desmoplastic ameloblastoma may show a mixed rad iolucent and radiopaque appearance mimicking th at of a fibro-osseous lesion

{1881, 2313). Rarely, incipient, root-related ameloblastomas can be incidentally discovered {1078).

Macroscopy Ameloblastomas range from salid to variably cystic.

entirely

Histopathology The most common type is the fo llicular type, which resembles the epithelial componen! of the enamel organ within a fibrous stroma; the peripheral cells are columnar to cuboidal (ameloblast-like), with hyperchromatic nuclei arranged in a p alisading pattern with reverse polarity {2500). The central core is reminiscent of stellate reti culum, with Joosely arranged angular cells that often undergo cystic change. The second most common type is the plexiform type, composed of anastomosing strands of ameloblastomatous epithelium with an inconspicuous stellate reticulum and cyst-like stromal degeneration . Other histopathological types include acanthomatous, granular, and basaloid {980}. The desmoplastic ameloblastoma consists of cuboidal to flat peripheral ce lls with central spindleshaped cells and densely collagenous


215

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stroma with possible metaplastic bone. Admixed histopathological types can be found in each ameloblastoma. Rarely, ameloblastoma can arise in association with odontoma, and this has historically been referred to as odontoameloblastoma (1 655) .

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Ameloblastoma originates from dental lamina, as indicated by the expression of early dental epithelial markers such as PITX2, MSX2, DLX2, RUNX1, and !SL1 {968,11 61).

Genetic profile

A

e

Fig. 8.18 Ameloblastoma. A Mutated pathways in ameloblastoma, with proteins encoded by the mutated genes indicated in purple. B Positive immunohistochemical staining far V600E-mutant BRAF in lhe tumour epithelium; staining is cytoplasmic. e Sanger sequencing electropherogram of a BRAF V600E-mutant ameloblastoma. The point mutation (C 1799 T->A) responsible far lhe V600E substitution is indicated by the arrow.

216


Mutations in genes that belong to the MAPK pathway are present in almost 90% of ali ameloblastomas (279}, with BRAFV600E being the most common mutation [279,589,1309,2321). Additional MAPK pathway mutations inciude KRAS, NRAS, HRAS, and FGFR2 mutations [279,232 1). The high frequency and the pattern of mutual exclusivity of these mutations emphasize the importance of

T ble a01 Prevalence of mutations in maxillary and mandibular ameloblastomas {279,1309, 2321} a Prevalence of mutations Locatlon of ameioblastoma BRAF RASfamlly FGFR2 Maxilla Mandible

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72%

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the MAPK pathway in the pathogenesis of ameloblastoma (279,1309,2321 ). NonMAPK pathway mutations include SMO, SMARCB1, CTNNB1, and PIK3CA mutations, among which SMO mutations are very common, suggesting a functional role (279,2321). These non-M APK pathway mutations tend to co-occur with the MAPK pathway mutations.

Prognosis and predictive factors Curren! treatm ent is wide surgical excision, including an area of bone beyond radiographical margins. Conservative surgery yields a high recurrence rate (60- 80%) {1907) . Histological type does not determine prognosis {1907). More than 50% of recurrences occur withi n 5 years alter initial treatment. Follow-up should be at leas! 25 years, but lifelong follow-up should be considered {981). BRAF-targ eted therapy offers a novel option to com plement surgery in selected cases of aggressive and/or recurren! ameloblastoma {279,2321).

r

rad iolucency, often associated with an unerupted tooth, most often the mandibular third molar. Cases unrelated to tooth impaction may have a scalloped outline {675,1874). Root resorption is common, and cortical perforation is present in approximately one third of cases {2015).

SMO 55%

1

5%

preponderance overall, but UAM notassociated with an impacted tooth shows a minor female predilection (12,1345,1376, 1420,1874).

Macroscopy UAM presents as a monocystic lesion, occasionally with thickenings that can fill the entire lumen.

Localization UAMs are most often located in the mandibular third molar area and ascending ramus, followed by the body and symphysis {12,1368,1420,1874). Most maxillary cases occur in the posterior areas . UAMs can also be found in inter-rad icular or periapical locations and edentulous areas {1376).

Clinical features UAM usually occu rs asan asymptomatic, painless jaw expansion. Radiographically, it presents as a well-defined unilocular

H istopathology The luminal type shows a simple cyst lined by ch aracteristic ameloblastomatous epithelium (with peripheral palisading and nuclear polarization and overlying loosely arranged cells that may resemble stellate retic ulum). Usually, this pattern is only focal, and in other areas ameloblastomatous features are less pronounced. The intraluminal type is characterized by intraluminal extensions of the lining epithelium, usually in a plexiform pattern . A definitive diagnosis of UAM

Ameloblastoma, unicystic type Vered M. Muller S. Heikinheimo K.

Definition Unicystic ameloblastoma (UAM) is a variant of intraosseous ameloblastoma that occurs as a single cystic cavity, with or without luminal proliferation.

ICD-0 code

Fig. 8.19 Unicystic ameloblastoma. The radiographical presentation is that of an extensive, well-defined unilocular radiolucency in association with an impacted and displaced mandibular third molar.

can be made only after careful examination of the entire lesion. About half to two thirds of Jesions previously diagnosed as UAM may have a mu ral componen! (1874); and there is sorne evidence that these behave more aggressively, like conventional ameloblastoma {1420).

9310/0

Genetic profile Epidemiology UAM accounts for 5- 22% of ali ameloblastomas {1874). Approximate ly 50% of cases are diagnosed in the second decade of lite, with a patient age range of 1-79 years {12,999,1420). The mean patient age is 16 years for cases associated with an impacted tooth and 35 years in the absence of impaction {1345, 1376,1420,1874). There is a slight male

In the few studies carri ed out to date, BRAFV60 0E has been the most common mutation {279,589}.


Fig. 8.20 Unicystic ameloblastoma. Gross specimen showing the characteristic single cystic cavity. lntraluminal proliferations occupy a large part of the lumen.

Because UAM radiographically mimics a cyst, initial treatment often consists of enucleation. Further treatment is determined by the pattern and extent of the ameloblastomatous proliferation in


217

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less, sessile, exophytic lesion with a smooth or papillary/granular surface; the oral mucosa can be of normal colour or red to dark red. The mean diameter is about 1.3 cm. Adjacent teeth may be tilted. Duration can be as long as 20 years (1877). The clinical impression is often of a reactive lesion. Radiographically, a superficial erosion or bony depression (cupping, saucerization) may be seen.

Fig. 8.22 Unicystic ameloblastoma. lmmunohistochemistry for V600E-mutant BRAF shows positive cytoplasmic staining of the neoplastic epithelium.

relation to the cyst lumen upon removal of the entire lesion and processing of multiple blocks. When mural involvement is identified. the tumour may behave biologically as AM and requires either additional surgery or more careful follow-up. Any recurrence should be managed as AM. Whether lesions with mural involvement should remain a more aggressive subtype of UAM or be reclassified as conventional AM requi res further study. In general, UAMs require long-term fol low-up, because recurrence may occur 1O years ar longer after initial treatment.

Ameloblastoma, extraosseous/peripheraltype Vered M. Muller S. Heikinheimo K.

Definition Extraosseous ameloblastoma is a benign tumour that occurs in the soft tissues of the gingiva or edentulous alveolar

areas, showing microscopic features of ameloblastoma.

ICD-0 code

9310/0

Synonyms Soft tissue ameloblastoma; ameloblastoma of mucosal origin; ameloblastoma of the gingiva Epidemiology The extraosseous type accounts· for 1-10% of all ameloblastomas (1877,2478). The mean palien! age is 50- 54 years, with a range of 9-92 years . Approximately two thirds of ali cases occur in the f ifth to seventh decades of life {1877). The male-tofemale ratio is 1.4:1. Localization The most common location is th e soft tissues in the mandibular retromolar area, followed by the maxillary tuberosity. Most tumours are found on the lingual aspee! of the mandible. Clinical features Extraosseous ameloblastoma is a pain-

Macroscopy The tumour presents as a firm mass with occasional tiny cystic spaces. Histopathology Ali histopathological features of intraosseous ameloblastoma can be encountered {2225). The malignant variant of extraosseous ameloblastoma is extremely rare (1877,2335}. Differential diagnosis may include basal cell carcinoma of oral mucosal origin, extensions from skin tumours (2633}, or salivary gland tumours with a peripheral palisading pattern {1877}.

Prognosis and predictive factors Conservative removal with free marg ins is expected to be curative. Recurrence is rare, but long-term follow-up is warranted.

Merasras~mgamembrastoma Odell E.W. Tilakaratne W.M.

Definition Metastasizing ameloblastoma is an ameloblastoma that metastasizes despite its benign histolog ical appearance. ICD-0 code

9310/3

Epidemiology In the USA, the overall annual incidence of malignan! ameloblastoma (i.e. both ameloblastic carcinoma and the rarer metastasizing ameloblastoma) is 1.79 cases per 10 million population, increasing with p atient age (1 997). Localization The primary site is more frequently the mandible than the maxilla, and the primary lesion is usually a solid ar multicystic type of ameloblastoma (590}. Metastatic deposits are most frequent 2 18


in 1ung (occurring in 70% of cases), followed by lymph nodes (28%), and bone (12%) (590,1296,1346,2212l.

Clinical features Metastasizing ameloblastoma is defined by its clinical behaviour rather !han its histology; the diagnosis can be made only in retrospect, after the occurrence of metastatic deposits. The term "atypical ameloblastoma" has been used to denote lesions with fatal outcome for various reasons (i.e. metastasis, histological atypia, or relentless local spread) (70 }. but should be avoided. There is usually a long laten! period before metastasis, and sorne cases occur after repeated surgical intervention f590l .

Histopathology For this diagnosis to be made, both primary and metastatic lesions must have histological features of benign ameloblastoma. There are no specific features predictin g metastasis. Metastatic ameloblastomas with significan! atypia are ameloblastic carcinomas {1726}.

Prognosis and predictiva factors The overall 5-year survival rate is 70%, but survival depends on the site of metastasis and surgical accessibility. Radiotherapy and chemotherapy have no proven benefit f 590}.

Squamous odontogenic tumour Wright J.M. Devilliers P. Hille J.

Fig. 8.24 Squamous odontogenic tumour. Characteristic radiolucency contacting tooth roots.

Definition Squamous odontogenic tumour (SOT) is a benign epithel ial odontogenic tumour in which the tumour cells show terminal squamous differentiation.

ICD-0 code

9312/0

Epidemiology S0Ts are rare neoplasms, with < 50 cases pl..Jblished. Th ey show a wi de patient age distribution, with a mean age of about 38 years. The male-to-female ratio is 1.8:1 {119).

Localization Most SOTs presentas single intraosseous tumou rs. The maxilla and mandible are affected equally, and there is a predilection for the anterior maxil la and posterior mandible. Rarely, multifocal and ·extraosseous tumours have been reported (1024, 1624}.

Clinical features Most patients are young and asymptomatic. The tumours grow slowly, and the

presence of bony expansion is a function of the duration of the tumo ur. Affected teeth may become mobile. Radiographically, most lesions present as unilocular rad iolucencies, although m ultilocularity has been reported. Most lesions show continuity with one or more tooth roots. One of the more characteristic radiographical presentations is a triangular radiolucency between teeth showing root divergence, with the base of the triangle towards the root apices (1151}. Lesions may or may not show cortication in their margins. Root resorption is rare. A single case of squamous cell carcinoma in association with SOT has been reported (1079}.

Macroscopy Most lesions are curetted and show nondescript frag ments of soft ti ssue.

Histopathology The tumour consists of islands of b land terminally differentiated squam ous epithelium of va ryi ng shape and size. The islands are occasionally tightly packed together in a jigsaw-puzzle architecture.


219

The peripheral layer of cells is characteristical ly flattened. Centrally, there is a tendency for microcystic degeneration, individual cell keratinization, and calcification. Mitoses are rarely encountered. The tumou r can be misdiagnosed as ameloblastoma, acanthomatous or desmoplastic variants, or squamous cell carcinoma, but it does not have peripheral palisading with reverse nuclear polarity, and the cytological features are bland. Proliferations with microscopic featu res similar to those of SOT have been reported in the walls of od ontogenic cysts, but these proliferations do not develop into SOTs, and have been called SOT-like proliferations (2643).

tumour that secretes an amyloid protein that tends to calcify.

ICD-0 code

9340/0

Synonym Pindborg tu mour

Epidemiology CEOT is relatively rare, accounting for :<::: 1% of specimens submitted to oral pathology laboratories. lt can occur in patients of any age, with a predilection for individuals in their third to sixth decade of lite. The mean patient age at diagnosis is about 40 years. Th e sexes are equally affected, but the peak incidence is about a decade earlier in males than in females .

Clinical features Patients tend to be asymptomatic and the neoplasm grows slowly, ultimately producing bony expansion . Radiographically, about two thirds of lesions are mixed radiolucent and radiopaque and about one third are radiolucent, but predominantly radiopaq ue tumours have also been seen. The degree of calcification correlates with the age of the lesion. The classic so-called driven-snow appearance is not common. Lesions are most frequently unilocular, but about one quarter are multilocular. Borders tend to be well defined, if not corti cated , but about one fifth of lesions are diffuse {1178). About 50-60% of lesions are associated with unerupted teeth (1178,"1876 }.

Genetic profile NOTCH receptors and their ligands may play a role in the cytodifferentiation of SOT [2172).


Localization

Macroscopy

The mandible is affected twice as often as the maxilla, and there is a predilection for the body. Approximately 6% of cases are extraosseous (1876).

There are no characteristic gross pathological features. The tumours are solid, with variable amounts of calcification. Rarely, cystic variants have been reported (877).

Genetic susceptibility is minimal. An isolated familia! case, affecting three family members, has been re ported (1377}.

Histopathology

Prognosis and predictive factors Most SOTs have been removed conservatively by surgery. Recurrence is rare.

Calcifying epithelial odontogenic tumour Wright J.M. Devilliers P.

Definition Calcifying epithelial odontogenic tumour (CEOT} is a benign epithelial odontogenic

220

Fig. 8.27 Calcifying epithelial odontógenic tumour. Characterislic radiographical features of an expansile, mixed radiolucenVopaque lesion.


CEOTs display a variety of architectural patterns, ranging from small or almost inconspicuous islands, cords, or trabeculae to large sheets of neoplastic epithelial cells. The cells tend to be polyhedral, with abundant well-defined cytoplasm; intercellular bridges can be seen in sorne tumours. The tumour nuclei are characteristically pleomorphic, and giant nuclei are often seen. Despite this pleomorphism, which might raise the possibility of malignancy, the mitotic rate is very low. The neoplastic cells secrete a unique odontogenic amyloid protein provisionally called AODAM, which is encoded by exons 5-10 of the odontogenic ameloblast-associated protein (OOAM) locus (1676,2233). As AODAM is secreted

extracellularly, it forms small rounded to irregular homogeneous masses of lightly eosinophilic hyaline material that stain positively for amyloid. As more protein is secretad, the masses tend to coalesce and ultimately calcify, often in concentric rings (so-called Liesegang rings). The neoplasm will infiltrate adjacent bone. variations include clear-cell change indicating glycogen accumulation, which can be focal or diffuse; a clear-cell varían! of CEOT is well documentad (985}. Variable numbers of Langerhans cells have been reportad in CEOT {2344). The tumours are well documentad as hybrid lesions with other odontogenic neoplasms, particularly with adenomatoid odontogenic tumour (1875}, but the CEOT-like areas tend to be focal, and the hybrid tumours behave biologically like adenomatoid odontogenic tumours. CEOTs must be distinguished from CEOT-like areas found in the follicles of unerupted teeth (110). CEOT must be distinguished from ameloblastoma, but CEOT lacks peripheral palisading and secretes an amyloid protein that calcifies. The cytological atypia that characterizes CEOT raises the possibility of malignancy, but the lack of mitoses, the low Ki-67 proliferation index, and the presence of stromal amyloid protein with calcification should allow for the distinction. However, malignan! variants of CEOT have been documentad {562}. Clear-cell change raises the possibility of clear cell odontogenic carcinoma or metastatic clear cell carcinoma. However, clear cell CEOT is distinct from clear cell odontogenic carcinoma in that it secretes an amyloid protein that calcifies, and it lacks the EWSR1 and ATF1 gene rearrangement of clear cell odontogenic carcinoma. Metastatic clear cell carcinomas do not secret a calcifiable matrix

and they have a different immunohistochemical phenotype.

Genetic profile PTCH mutations have been reported in CEOT, but the tumour is nota componen! of naevoid basal cell carcinoma syndrome {1843) . Prognosis and predictiva factors Although the tumours infiltrate medullary bone, they are not as biologically aggressive as ameloblastoma. Most cases are treated with local surgical removal, and the overall recurrence rate is about 15% (759}.

Adenomatoid odontogenic tumour Wright J.M. Kusama K.

Definition Adenomatoid odontogenic tumour (AOT) is a benign epithelial tumour that shows duct-like structures. ICD-0 code

9300/0

Epidemiology AOTs account for < 5% of odontogenic tumours {520,1875) and occur twice as frequently in females as in males. They have a strong predilection for i[ldividuals in their first three decades of lite, with about two thirds of all cases occurring in teenagers and 87% of all cases occurring in the second or third decade of lite {1880,1987}. Tumours occurring in patients older than th ei r mid-30s are distinctly uncommon {1882}.

Fig. 8.29 Follicular adenomatoid odontogenic tumour (asterisk) in the anterior maxilla of a 16-year-old girl.

Localization More than 95% of AOTs are intraosseous, but extraosseous variants have been documentad. The tumours are twice as common in the maxilla as in the mandíble and have a very strong predilection for the anterior jaws. About three quarters of cases occur in association with unerupted teeth in a pericoronal relationship, which has led sorne authorities to subclassify the tumours as follicular or extrafollicular. Unerupted caninas are affected in about 60% of cases {1875,1880, 1882,1987). Clinical features AOTs have limitad growth potential and are considerad by many to be hamartomas. Patients are invariably asymptomatic, and bony expansion may or may not be present. On imaging, the tumours tend to be well defined and symmetrical. The lesions progress to produce cortical expansion slowly, but in about two thirds of cases, small foci of radiopacity can be detectad. AOTs can be radiographically indistinguishable from dentigerous cysts, unless they extend apically beyond the cementoenamel junction of the affected tooth. Teeth are frequently displaced but root resorption is rare. The lesions slowly


221

progress to produce cortical expansion, but cortical perforation is unusual. Extraosseous variants produce gingival swellings without characteristic features.

Macroscopy Most AOTs enucleate and are smooth, rounded , symmetrical masses. On cut surface, the lesions range from solid to cystic, and follicular lesions often contain the affected tooth.

Histopathology The tumours tend to be encapsulated but produce a variety of architectural patterns, rnost notably multiple, variably sized nodules of nondescript to sp indled epithelial cells with minimal stroma. Within these nodules are variably sized rosette- or duct-like spaces, from wh ich the tumour gets its name. These are lined by a columnar or cuboidal epithelium, with the nuclei tending to be disp laced away from the lumen. In sorne turnours, the duct-like spaces can be

inconspicuous . There is frequently eosinophilic material within the tumour, rnost likely constituting a secretory product of the turnour. There are often patterns of anastornosing larnina-like cords of tumour cel ls in a plexiform pattern, which is more prominent at the periphery. Small foci of calcification are frequently seen, and this phenomenon has been likened to an abortive attempt at enamel matrix secretion. Sorne tumours contain larger areas of calcified rnatrix, sorne of which has been reported to be dentinoid or cementoid. Many tumours contain macrocystic or variably sized microcystic areas. AOT and AOT-like areas have been recognized with other odontogenic tumours, such as odontomas, adenomatoid dentinoma, and calcifying epithelial odontogenic tumour (CEOT). More than 25 cases of AOT/CEOT have been reported, and sorne authors recommend the designation "combined epithelial odontogenic tumour" {1882). but the

current consensus is that the CEOT-like areas are simply part of the histological spectrum of AOT {1654,1875). lmmunophenotype The Ki-67 index and BCL2 index are lower in AOT than in solid ameloblastoma {1 964). The expression of amelogenesis-related proteins such as odontogenic ameloblast-associated protein, amelotin, ameloblastin, and amelogenin {496}, as well as TGF-beta 1 / SMAOs {1185}. has been shown to be more intense in AOT than in ameloblastoma. Strong cytoplasmic expression of beta-catenin has been demonstrated, although no molecular anomaly within the beta-catenin gene (CTNNB1) is evident {941). These findings may reflect the hamartomatous behaviour of AOT.

Prognosis and predictiva factors AOTs are encapsulated and they invariably enucleate. Recurrence rates are exceeding ly low.

Benign mixed epithelial and mesenchymal odontogenic tumours . Ameloblsstic ñbroms Muller S. Vered M.

Definition Ameloblastic fibroma (AF) is a rare, benign, true mixed tumour composed of odontogenic mesenchyme resembling dental papilla and epithelial tissue resembling odontogenic epithelium, in which no dental hard tissues are present.

ICD-0 code

9330/0

Epidemiology AF constitutes 1.5- 6.5% of ali odontogenic tumours {293,1879). The mean patient age is 14.9 years (range: 7 weeks to 57 years) {293,1653). Most 222

Fig. 8.30 Ameloblastic fibroma of the right mandible in a 12-year-old patient. presenting as a multilocular radiolucency with sclerotic border. The first molar is impacted and displaced, the tooth bud of the second premolar is displaced, and the roots of the primary second molar are resorbed.


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tumours (80%) occur in patients younger than 22 years (i.e. befare the end of odontogenesis). The male-to-female ratio is 1.4:1 .

Localization The ratio of mandibular to maxillary locali zation is 3.3:1. The posterior area of the jaws is the most common location (affected in 82% of cases), particularly the mandible (74%); a minority of cases occur in either the anterior region or both the posterior and anterior regions (-10% each) (293).

Clinical features AFs are usually slow-growing, painless tumours. They can cause jaw expansion and (rarely) reach remarkable size, with facial deformity. Radiographically, AF is an incidental finding in 12% of cases, but the majority (56%) present as well-defined, usually small, unilocular rad iolucencies (293). Multilocular tumours are frequently associated with larger lesions. Association with an impacted tooth (usually a first or second permanent molar) is seen in 80% of cases. Root resorption and cortical perforation are uncommon.

Macroscopy The tumour is a solid, possibly encapsulated mass with a smooth outer surface.

Histopathology The mesenchymal componen! is myxoid and cel l-rich and resembles the dental papilla of the tooth bud. The epithelial componen! can demonstrate a pattern of narrow, elongated strands of two tight and parallel-running layers of cuboidal to columnar cel ls. Towards the edges, there

are occasional thickenings, with a stellate reticulum-like area notable between the peripheral cuboidal cells. The epithelial componen! can also show a pattern resembling the follicu lar stage of the enamel organ . A collagenous capsule may be observed. On the basis of histopathological features, it is not possible to distinguish between AFs (true neoplasms) and early-stage odontomas befare they differentiate and mature (290,293l. However, rare AFs show formation of dental hard tissues and reach an exceptional size. These lesions have been referred to as ameloblastic fibrodentinomas or ameloblastic fibro-odontomas (293). but are most likely developing odontomas.

Genetic profile lnitial investigations found BRAFV600E mutation (in 2 cases {279l) and a low freque ncy of fractional allelic loss of tumour suppressor gene loci (805).

Prognosis and predictiva factors Small, asymptomatic tumours, especially in young children, are removed conservatively; however, ultraconservative treatment might result in recurrence, which occurs in about 16% of cases. Extensive, destructive tumours should be treated radically. Sarcomatous transformation is rare, although about 50% of such cases are reported to have developep in the setting of a recurren! AF (38,1327).

Primordial odontogenic tumour Mosqueda-Taylor A. Neville BW

Definition Primordial odontogenic tumour is a tumour composed of variably cellu lar loase fibrous tissue with areas similar to the dental papilla, entirely surrounded by cuboidal to columnar epithelium resembling the interna! epithelium of the enamel organ.

Epidemiology This is a recently described tumour, with only 7 cases reported to date. The reported patient age range is 3- 19 years, with a mean pal ien! age of 12.5 years and no sex predilection (1659,2206).

Localization Primordial odontogenic tumour occurs intraosseously, with a marked preference for the mandible; the ratio of mandibular to maxillary incidence is 6:1.

Clin ical features AII cases have been found as well-defined radiolucencies associated with an unerupted tooth (most commonly the lower third molar), producing an apparent pericoronal relationship on radiographical image. Most primordial odontogenic tumours are asymptomatic , but they may cause cortical expansion with displacement and root resorpti on of neighbouring teeth.

Benign mixed epithelial and mesenchymal odontogenic tumours

223

e Fig. 8.32 Primordial odontogenic tumour. A,B Well-defined radiolucencies surrounding and displacing an embedded tooth; note in both cases the resorption of the roots of adjacent molar teeth. Reprinted from Mosqueda-Taylor A et al. (1659). C Macroscopic aspect of the tumour shown in panel B, with adjacent removed teeth; salidwhite mass with no evidence of cystic changes. Note the tooth displaced towards the periphery of the tumour (top).

Macroscopy The crown of the adjacent tooth was embedded in the tumour in 3 of the repo rted cases; in the other 4 cases, the associated teeth were easily detached from the tumours. Al i lesions were well circ umscribed and salid, forming multilobulated whitish masses, with no cystic spaces on sectioning.

H istopathology The tumour is composed of loose fibrous tissue containing variable numbers of fusiform and stellate fibroblasts , with minimal collagen production. Sorne areas have the appearance of cell-rich mesenchymal tissue. A characteristic finding is that the entire periphery of the tumour is covered by columnar or cuboidal epithelium, which in sorne areas shows scant, superficial layers of fusiform cells surrounded by a thin fibrous capsu le. Occasionally, epithelial islands or cords are seen within the lesion as a result of tangential sectioning, due to the infolding of the surface. No evidence of odontoblastic differentiation or dentine has been found to date. The tu mour mesenchymal cells are positive for vimenti n and negative for alpha-SMA , desmin, S100, and CD34. The Ki-67 index is very 224

low (< 2%). Th e epithelial componen! is strongly positive for pancytokeratins (AE1/AE3), CK5, and CK14, whereas CK19 is variably expressed by columnar cells. Given the relatively young palien! age at presentation of ali cases and the apparent relationship of the lesion with uneru pted teeth, the tumoural ti ssue may constitute a mesenchymal proliferation very similar to the dental papilla of a developing tooth.

Prognosis and predictiva factors The tumours are cured by local excision, with no recurrences repo rted after followup of 6 months to 20 years.

Odontoma Vered M. Fowler C.B. Neville B.W. Soluk Tekke~in M.

Definition Odontomas are mixed epithelial and mesenchymal tumour-like malformations (hamartomas) composed of dental hard and soft tissues. They are subdivided


into compound odontoma and complex odontoma.

ICD-0 codes Odontoma Odontoma, compound type Odontoma, complex type

9280/0 9281/0 9282/0

Epidemiology Odontomas are the most common odontogenic tumours. They are typically diagnosed during the first two d ecades of lile and have no sex predilection (2235).

Etiology The etiology is unknown, but genetic mutation in a tooth germ is a possible factor (956, 1898,2731). Lesions formerly designated as ameloblastic fibro-odontoma probably represent immature stages of complex odontoma in most instances.

Localization Although odontomas can occur in any tooth-bearing area, compound odontornas are mainly located in the anterior maxilla, whereas complex odontomas are found most often in the posterior mandible, followed closely by the anterior maxilla (2235).

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B Fig. 8.34 Compound odontoma. A Compound odontoma located between the roots of the canine and second premolar; the first premolar is impacted and displaced; the radiopaque product appears as tooth-like structures. B Macroscopic view shows numerous rudimentary teeth of various shapes and sizes.

Fig. 8.37 Compound odontoma. Microscopic section shows structures reminiscent of single-rooted, small teeth.

The radiological features of co mpound odontomas are frequently diagnostic, although complex odontomas may be confused with other highly calcified bone lesions (2309l.

Fig. 8.35 Complex odontoma. A Complex odontoma associated with an impacted maxillary third molar; !he radiopaque product consists of a mostly homogeneous mass of calcified tissue. B Macroscopic view shows an irregular hard mass attached to a molar tooth.

Macroscopy Compound odontomas usually appear as a cluster of white, tooth-like structures or denticles of varying size and shape. Complex odontomas appear asan amorphous, white, bony, hard mass. Both may be surrounded by varying amounts of capsu le-like, tan-coloured soft tissue.

Radiographically, odontoma is typically located between roots or over the crown of an impacted tooth and presents as a well-demarcated radiopacity surround ed by a thin soft tissue capsule and an adjacent corticated layer of bone. The radiopaque product in compound odontomas consists of numerous footh-like structures, whereas in complex odontomas it consists of a disorganised mass of calcified tissue. An early-stage (developing) odontoma may appear as a radiolucency with focal areas of calcif ication .

Histopathology Compound odontoma consists of multiple rudimentary teeth exhibiting dentin, cementu m, enamel matrix, and pulp . Adjacent fibrous connective tissue consisten! with dental follicle is often present. Early-stage odontomas show tissue that resembles a developing tooth germ , with little mineralized product. Mature comp lex odontomas consist primarily of tubular dentin that encloses zones of enamel matrix; reduced enamel epithelium with occasional scattered ghost cells may

B

Clinical features Odontomas are frequently associated with an unerupted tooth and are usually detected on routine radiog raphs. Although asymptomatic, they may become secondarily inflamed due to trauma or eruption, and they can cause impaction, malposition, diastema, aplasia, malformation , and devitalization of adjacent teeth. The diameter ranges from < 1 cm to 6 cm, with larger odontomas producing expansion of the jaws. Multifocal odontomas have been reported (2309).

. ~~w.(~~-,.,_ Fig. 8.36 Complex odontoma. A Section alter decalcification shows a conglomerate of dentin admixed with small areas of enamel matrix (arrows); clefts or hollow circular structures (asterisks) represen! !he mature enamel that was removed during demineralization. B Enamel matrix (asterisk) and partially decalcified enamel (upper-right) surrounded by reduced enamel epithelium (arrow).

Benign mixed epithelial and mesenchymal odontogenic tumou rs

225

surround clefts or hollow circular structures, which represen! mature enamel that was removed during demineralization. A !hin layer of cementum is often present at the periphery of the mass. The soft tissue capsule, if present, often includes immature connective tissue with cords or islands of ameloblastic epithelium - a pattern similar to that seen in ameloblastic fibroma (2235). Rarely, an ameloblastoma may arise in association with an odontoma; such cases have historical ly been called odontoameloblastoma, an entity dropped now (1655).

Genetic susceptibility Multifocal odontomas or supernumerary teeth may occur in patients with Gardner syndrome (familia! colorectal polyposis).

Prognosis and predictive factors Odontomas are removed by conservative surgery, due to their low growth potential. Recurrence after complete removal is unusual. The prognosis is excellent (2235}.

Dentínogeníc ghost ce// tumour Carlos R. Ledesma-Montes C.

Definition Dentinogenic ghost cell tumour (DGCT) is a benign but local ly infiltrating neoplasm of odontogenic epithelium. lt has biphasic morphology, consisting of a predominan! ameloblastomatous proliferation and a less prominent component

226

Fig. 8.38 Dentinogenic ghost cell tumour. Unilocular radiolucent- radiopaque lesion with well-defined borders in a 60-year-old woman.

of basaloid to stellate reticulum cells. Th e tumour characteristically contains aberrant keratinization, with a vari able number of ghost cells and material morphologically resembling dentinoid or osteodentin (289,1648,2307}.

ICD-0 code

9302/0

Local ization The most frequently affected intraosseous siles are the posterior maxilla and mandible, and there is a slig ht predilection for the mandible (affected in 53% of cases) (289 ). Sporad ic peripheral cases have been reported in the gingiva and alveolar mucosa (323}.

Synonym

Clinical features

Calcifying ghost cell odontogenic tumour

Most patients w ith DGCT present with progressive swelling caused by cortical bone expansion. Rad iographically, 78% of lesions are unilocular and 22% are multi locular. Most lesions are mixed radiolucent and radiopaque (78%) or completely radiolucent, and most (6 8%) have well-defined bord ers. Poorly d efined bord ers are seen in 32% of the reported cases with available rad iological information. Pain occurred in 52% of the cases, whereas the other 48% we re completely asymptomatic. Root resorption is thought to be present in approximately 18% of cases; however, this fig ure may in fact be

Epidemiology DGCT is the rarest of the ghost cell lesions , accounting for < 3% of ali cases {1357). Approximately 45 cases have been reported, with more than half occurring in Asian patients (556). The tumour is twice as common in men as in women, with peak incidence in patients agea 4060 years (556}. The reported patient age range is 11- 79 years (mean: 39.7 years) (30,556).


higher, as most reports do not mentían th is finding. DGCT can occas1onally be associated with an odontoma (289,1076, 1154,1357).

Macroscopy The tumours are salid, with macroscopic areas of calcification. Microcystic areas rnay be present, but they do not constitute a significant area of the tumour, generally accounting for < 5% of th e resected specimen.

Histopathology The main histological componen! is odontogenic epithelium, with areas closely resembling ameloblastoma. Microcystic spaces can be present within the epithelium . Sorne tumours have a significan! componen! of basaloid hyperchromatic and isomorphic cel ls, displayed in sheets. Mitotic f igures are rare . A striking feature is the presence of aberrant keratinization with occasional calcification - the socalled ghost cells, wh ich are present in variable numbers. When the keratinized cells com e in contact with the connective tissue, an inflammatory foreign body reaction with multinucleated giant cel ls can be elicited . Dentinoid or osteodentin-like material is formed directly adjacent to the epithelial cel ls, which are often trapped in small groups within this otherwise acellular material. These trapped cells may have c lear cytoplasm. Mature connective tissue may be admixed with th e main odontogenic epithelial componen! of the tumour. Special care must be taken to distinguish DGCT from ameloblastoma with ghost cells, a phenomenon well descri bed in ameloblastomas and other odontogenic lesions {289,323,1648,2307). The proportion of ghost cells (> 1- 2%) and the presence of dentinoid are importan! features in establishing the diagnosis of DGCT. True dentinoid is difficult to prove as part of this tumour, and in sorne instances it

may represen! hyalinization or induction of the adjacent connective tissues as a result of signalling from the odontogenic epithelium. The epithelial cells can express CK5, CK7, CK14, and CK19. The Ki-67 proliferation index is < 5% . CD138 (also called syndecan-1) and MMP9 protein expression have been assessed in tumour and stromal cells, bu t the number of cases is limited and expression is varied; more studies are necessary to establish the roles of CD138 and MMP9 in the locally invasive nature and biological behaviour of this tumour {868,874].

Prognosis and predictive factors Oue to the small number of reported cases, conclusions cannot be drawn regarding the optimal treatment option for DGCT. However, treatm ent is known for 40 of th e 45 reported cases .

In 21 cases, conservative surgery (i.e. enucleation, curettage, or simple excision) was perform ed, with a recurrence rate of 73% after a follow-up period of 1- 20 years. In the 19 reported cases treated with more radical surgery (i.e. marginal or segmental resection), the recurrence rate was 33% after a followup period of :::: 1 year. There is a single case report of malignan! transformation occurring after five recu rrences. On the basis of the limited number of cases, the recomm ended surgical treatment is segmental resection (i.e. wide local re section), performed in a manner similar to that recommended for ameloblastomas. Long -term postsurgical follow-up is necessary. Peripheral (extraosseous) tumours are managed by simple excision, and recurrences are rare {289,323, 1357,2307).

Benign mixed epithelial and mesenchymal odontogenic tumours

227

Benign mesenchymal odontogenic tumours /

Odontogenic fibroma van Heerden W.F.P. Kusama K. Neville B.W.

Definition Odontogenic fibroma is a rare neoplasm of mature fib rous connective tissue, with variable amounts of inactive-looking odontogenic epithelium, with or without evidence of calc ification. There are two clinical variants: intraosseous or central odontogenic fibroma and extraosseous or peripheral odontogenic fibroma.

ICD-0 code

9321/0

Epidemiology Central odontogenic fibroma has a wi de patient age range and a slight female predilection. Peripheral odontogenic fibroma is more common than central odontogenic fibroma, occurs twice as frequently in females as in males , and has an age peak in the second to fourth decades of life [673 ,1657).

Localization Odontogenic fibroma occurs with relatively equal frequency in the maxilla and mandible. Most maxi llary central odontogenic fi bromas occur anterior to the fi rst molar, whereas about hall of ali mandibular central odontogenic fibromas are found posterior to the first molar [673, 1657). Peripheral odontogenic fibromas tend to be more com mon in the anterior gingival regions (673). Small radiolucencies with central odontogenic fibromalike /satures sometimes occur aroun d crowns of impacted teeth, but these should be cons idered hyperplastic dental follicles rather than true neoplasms.

Fig. 8.41 Central odontogenic fibroma. Radiograph of left mandible showing well-defined radiolucency with radiopacities.

present as well -defined unilocular radiolucencies, but larger tumours may become multilocular. Corticated margins are often present. Oivergence or resorption of the roots of adjacent teeth may be noted. Peripheral odontogenic fi broma usually develops as a slow-growing, sessile gingival mass with an intact mucosa! surface.

Histopathology


Central odontogenic fibroma is composed of moderately cellular or collagenous connective tissue with varying amounts of inactive-looking odontogenic epithelial island s or strands. The epithelium may vary from being totally absent to being a conspicuous feature. Hard tissue formation may be present, with /satures of mineralized dentinoid or cementum-like

Central odontogenic fi broma is usually treated by enucleation and curettage, which sometimes req uires removal of adjacent involvcd tccth. Rccurrence is uncommon. Peripheral odontogenic fibroma is treated by surgical excision, which should proba bly extend down to the periosteum, because a recurrence rate of 50% has been reported (1994).

Clinical features Small central odontogenic fibromas are often asymptomatic , although larger tumours may present with pain , bony expansion, and loosening of teeth . Small central odontogenic fibromas usually 228

calcifications associated with the odontogenic epithelium. A wel l-defined capsule is rare. Similar features are seen in peri pheral odontogen ic fibroma. Central odontogenic fibroma with amyloidlike protein deposition and central odontogenic fibroma associated with a central giant cell granuloma have been described as ra re variants {673,2689}. An unusual tumour, called granular cell odontogenic tumour, has been repo rted and is considered to be a variant of central odontogenic fibroma. lt is composed of stromal granular cells, with variable amounts of odontogenic epithelium (2077). Sclerosing odontogenic carcinoma may share sorne histological features with central odontogenic fibroma and should be considered in the differential diagnosis. However, sclerosing odontogenic carcinoma is characterized by an infiltrative pattern and prominent perineural infiltration.


Clinical teatures

odontogenic myxoma/ myxofibroma

Odontogenic myxoma consists of ran domly oriented ste llate, spindle-shaped, and round cells with long, fine, anastomosing, pale or slightly eosinophilic cytoplasmic processes. The cel ls are evenly dispersed in an abundan! alcianophilic myxoid ground substance that characteristically contains minimal fine collagen libres . Binucleated cells, mild pleomorphism, and mitotic figures may occur and can mimic atyp ia (136}. Sorne

odontogenic myxomas (designated myxofibromas) produce collagen fibres, but these lesions always retain sorne degree of prominent ground substance on Alcian blue staining. There is no evidence that the myxofibromatous variant behaves differently. Histochemistry and immunochemistry reveal the ground substance to be rich in acid mucopolysaccharide, primarily hyaluronic acid, and to a lesser deg ree chondroitin sulfate. Orosomucoid 1 protein is consistently overexpressed [812}. Dispersed microscopic rests of odontogenic epith elium are present in about 5% of lesions {1549} and are not requ ired for histological diagnosis. Histologically, odontogenic myxoma is almost identical to the dental papilla of a developing tooth, normal dental follicle, and myxoid enlarged or so-called hyperplastic dental follicle. Misdiagnosis of these entities should be avoided by correlation with the clinical and radiographical features [1227). For maxillary cases, confusion with nasal polyps is a risk. Because any odontogenic tumour forming dental hard tissues can contain areas of fo llicle and dental papilla-like tissue, areas similar to myxoma can be found as a componen! of many odonto genic tumours, particularly primordial odontogenic tumour {1659). Odontogenic myxoma permeates the surrounding medullary spaces of bone, driven by matrix secretion rather than cellular infiltration. This produces a pseudomalignant growth pattern , so the diffe rential diagnosis may include myxoid nerve sheath tumours, chondromyxoid fibroma, low-grade myxofibrosarcoma, and other myxoid sarcomas. However, the histological appearance of odontogenic myxomas is generally distinctive.

Fig. 8.43 Odontogenic myxoma in the body of the mandible, showing thin expanded cortex and bony septa in bone window (left) and low soft-tissue density (centre). The high proton density resulting from the high water content in the myxoid tissue gives a hyperintense signa! on T2-weighted MRI (right).

Fig. 8.44 Odontogenic myxoma. Radiograph showing a myxoma in the posterior mandible, with characteristic straight and criss-crossing septa.

Qdell E.W. Adebiyi K.

Definition odontogenic myxoma is a benign odontogenic neoplasm characterized by stellate and spindle-shaped cells dispersed in an abundan! myxoid extracel lular matrix. When a greater amount of collagen is evident, the term "odontogenic myxofibroma" may be used.

ICD-0 code

9320/0

Epidemiology In most studies, odontogenic myxoma is the third most frequent odontogenic tumour (after odontoma and ameloblastoma) {291,1763,2332). lt has been estimated to account for 2- 5% of cases in A/rica {1763). China (1137). and the USA (291). The patient age range of reported cases is 1- 73 years, with most cases diagnosed in the second to fourth decades of life {1549) . In most series, odontogenic myxoma is up to twice as common in females as in males {1549,1744). but not in all African populations {1763).

Odontogenic myxomas are asymptomatic radiolucencies when small and cause painless expansion with continued growth. Cortical perforation may develop when they are large. Unilateral sinonasal obliteration may mimic nasal polyposis. Radiographically, odontogenic myxomas appear as unilocular or multilocular radiolucencies, sometimes showing a fine soap-bubble or honeycomb appearance, occasionally with fine straight tennisracket trabeculations {1 744). The margins of the tumour appear wel l defined and corticated on routine radiographs , but these provide inaccurate representations of the actual anatomical limits, wh ich are relatively diffuse and better defined by CT or MRI {1219). Root displacement occurs , as does roo! resorption. Larger odontogenic myxomas may present with a periosteal reactive bone layer.

Macroscopy Gross examination reveals a greyishwh ite mass with a typical translucen! mucinous appearance. The cons isten cy varíes from gelatinous to firm, depend ing on the amount of collagen present, and fine white bands of col lagen may be visible on the cut surface.

Histopathology Localization Two th irds of odontogenic myxomas are located in the mandible, and one th ird in the maxilla {15 49). Odontogenic myxomas are most common in the molar regions . Maxillary lesions tend to obliterate the maxillary sinuses as an early feature, and expansion is an early and consisten! feature in all. Very occasional cases have been reported to occur extraosseously in the ging iva {1960).

Benrgn mesenchymal odontogenic tumours

229

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·lJ i, ~ Fig. 8.46 Odontogenic myxoma. A Normal dental follicle resembling myxoma. The smooth periphery and a few residual cells of the reduced enamel epithelium indicate the correct diagnosis. B Cytological atypia, hyperchromatism, and anisonucleosis are seen in a minority of lesions. •

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Genetic profile Odontogenic myxoma has been associated with tuberous sclerosis (946) and naevoid basal cell carc inoma syndrome {2146) in isolated cases but is not genetically related to Carney complex or other soft tissue myxomas or their associated syndromes (870). Prognosis and predictiva factors The permeative margin makes effective curettage difficult. Small lesions are usually treated conservatively by curettage, with the expectation of Jow risk of recurrence, but larger lesions require complete excision with free margins (228). Recurrence rates in various studies average about 25%, but the prognosis is good. Recurrence usually follows incomplete removal within 2 years, but may occur much later. A single case of possible malignan! behaviour has been reported (1800), but there are no accepted criteria to define malignancy, and Jarge benign lesions may prove difficult to eradicate without radical surgery. 230

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Cementoblastoma EI-Mofty S.K.

Definition Cementoblastoma is a distinctive benign odontogenic tumou r that is intimately associated with the roots of teeth . lt is characterized by the formation of calc ified cementum-like tissue, which is deposited directly on a tooth root. ICD-0 code

-

-

mean of 20.7 years . Three quarters of patients are aged < 30 years {260,633). The sex distribution varies among different series, from male p redominance to equal d istribution to female predominance {633).

Localization The mandibular molars and premolars are the most common siles of cementob lastoma, with > 75% of the cases occurring in th is location. The maxillary moJars and premolars are the second most

9273/0

Synonyms Benign cementoblastoma; true cementoma Epidemiology Cementoblastoma is a relatively rare tumour, accounting far 1- 6% of ali odontogenic tumours (1487,1656}. Only about 100 cases have been reported in the literature to date (260}. The reported patient age range is 8-4 4 years . with a


Fig. 8.47 Cementoblastoma. Radiograph showing a cementoblastoma associated with the roots of the mandibular second molar and obliterating sorne radiographical details of the roots.

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Fig. 8.48 Cementoblastoma. A Thick trabeculae of cementum attached to a tooth root. B Radiating columns of calcified matrix rimmed with plump cementoblasts at the periphery of the lesion.

common site. Association with primary teeth is very rare 1260,633}. Clinical features Cementoblastoma is associated with buccal and lingual/palatal expansion of the affected bony cortical plates. A characteristic feature is pain, commonly described as sharp and similar to toothache. The tumour is slow-growing but can attain a large size if left untreated (633,1123). The radiographical appearance is characteristic and almos! pathognomonic. The tumour presents as a well-defined radiopaque mass that obliterates the radiographical details of the root of the affected tooth. A thin radiolucent zone surrounds the central opacity. Cortical plate expansion and deviation of the surround ing teeth roots occur as the tumour grows {260,633}. Macroscopy Grossly, cementob lastoma presents as a calcified mass that is adherent to the root or roots of a tooth and surrounded

by a grey to tan layer of irregular soft tissue. The tumours are usually excised intact with the tooth, with an average size of 2.0 cm. Histopathology Calcified cementum-like tissue is deposited in thick trabeculae on an intact or partially resorbed root. The formed cementum is strongly basophilic and shows numerous irregular reversa! lines resembling Pagel disease of bone (osteitis deformans). Plump, active-looking cementoblasts rim the trabeculae, which are present in fibrovascular stroma with numerous dilated vessels and occasional clusters of multinucleated osteoclastlike cells. Characteristically, rad iating columns of uncalcified matrix surfaced with plump cementoblasts a'nd interspersed with fibrovascular tissue are present at the periphery of the densely calcified mass . These peripheral microscopic fields of cementoblastoma bear significan! resemblance to osteoblastoma. Although osteoblastomas of the jaws may grow to envelop the roots of teeth,

they do not originate from the surface of the roots and do not adhere to it. Prognosis and predictiva factors lncomplete removal commonly leads to recurrence {11 23).

Cemento-ossifying fibroma Odell E.W.

Cemento-ossifying f ibroma (COF) is a distinct type of ossify ing fibroma that occurs in the tooth-bearing areas of the jaws and is believed to be of odontogenic origin. lt is a benign fibro-osseous lesion and is discussed in more detail in the Ossifying fibroma section on pages 251-252. ICD-0 code

Benign mesenchymal odontogenic tumours

9274/0

231

Odontogenic cysts of inflammatory origin

Speight P. Soluk Tekke~in M.

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Radicular cyst Definition Radicular cyst is an odontogenic cyst of inflammatory origin associated with nonvital teeth. A residual cyst is a radicular cyst that remains in the jaws after extraction of the affected tooth.

Fig. 8.51 Radicular cyst. A An inflamad fibrous wall lined by hyperplastic arcading epithelium; foamy histiocytes (arrows) are seen in the infiltrate. B A nodule of cholesterol clefts.

Fig. 8.49 Radicular cyst. Typical radiographical appearance of a well-demarcated radiolucency at the apex of a non-vital tooth that has been root treated. Fig. 8.52 Radicular cyst. Focal accumulation oi hyaline bodies in the epithelial lining.

range, with peak incidence in the fo urth and fifth decades of life. A slight male predilection has been reported (1149 }.

Etiology

Fig. 8.50 Radicular cyst. A residual cyst appears as corticated radiolucency at the site of previous tooth extraction.

Synonyms lnflammatory dental cyst; dental cyst; periapical cyst; apical periodontal cyst

Epidemiology Radicular cysts are th e most common cyst of the jaws and account for about 55% of ali odontogenic cysts {1 145,1149). They occur over a wide patient age

232

The epithelial lining derives from proliferation of the remnants of the Hertwig epithelial root sheath (epithelial cell rests of Malassez) in the periodontal ligamen! as a result of inflammation following pulpal necrosis, usually due to dental caries. A cyst cavity is formed, which enlarges as a result of hydrostatic pressure accompanied by bone resorption.

Localization The maxilla is the most commcin site, with 50% of cases arising in the anterior region (1149}. Radicular cyst is almos! always located at the tooth apex, but a lateral radicular cyst may be associated with a lateral root canal.


Clinical features Many rad icular cysts are symptomless and discovered inc identally on radiological examination of a carious or non-vital tooth. Overall, radicular cyst is probably the single most common cause of expansion of th e jaws . Radiographs show a round or oval, unilocular, well-d emarcated radiolucency at the apex of a tooth, usually about 1-2 cm in diameter. Large lesions can also occur. Residual cysts are found as well-defined rad iolucencies at a site of previous tooth extraction. Radicular cyst is always associated with a non-vital tooth, and this is an important criterion for diagnosis.

Histopathology Radicular cysts have a wall composed of inflamed fibrous or granulation ti ssue lined by non-kerati nized stratified squamous epithelium. The epithelium is

proliferative, with elongat~d. rete pegs, often forming a charactenst1c arcad1ng pattern . Mature cysts and residual cysts are less inflamed and may show a more regular thin epithelium. The inflammatory infiltrate is mixed, and may contain prominent foamy histiocytes or deposits of cholesterol crystals with foreign-body giant cells, which may form luminal nodules. Hyaline or Rushton bodies are often seen and are characte ristic (although not specific) of radicular cyst {113}. Other changes include mucous metap lasia with goblet cells, cilia, or small areas of keratinization .

Prognosis and predictive factors Depending on their specific clinical and radiological features, periapical lesions are often treated by extraction of the tooth or apicoectomy with enucleation of the cystic cavity, or by non-surgical root canal treatment. Although lesions may persist as residual cysts, recurre nce is rare (1727).

Fig. 8.53 lnfiammatory collateral cyst. The paradental cyst appears as well-demarcated, corticated radiolucency at the distobuccal aspee! of a partially erupted lower third molar. The periodontal ligamen! and lamina dura are intact (arrows).

Definition

Synonyms lnflammatory paradental cyst Mandibular buccal bifurcation cyst: mandibular infected buccal cyst; juvenile paradental cyst

Epidemiology ICCs account for as many as 5% of all odontogenic cysts (492,1149}. The peak incidence of PCs is among patients aged 20-40 years . The male-to-female ratio is 2:1 (492,1878}.

Etiology The etiopathogenesis is uncertain. ICCs are of inflammatory origin, associated with pericoronitis. Cyst formation may be exacerbated by a down-growth of enamel on the buccal aspect of the involved tooth (492,751} or by food impaction

from the follicular space surrounding a partially erupted tooth [471 }. PCs tend to be mesially located on mesioangular impactions, distal on distoangular impactions, and buccal on vertical impactions {471).

/nf/smmatory collateral cysts lnflammatory col lateral cysts (ICCs) arise on the buccal aspect of the roots of partially or recently erupted teeth as a result of inflammation in the pericoronal tissues . There are two main types: paradental cysts (PCs) arise on the lower third molars and mandibular buccal bifurcation cysts (MBBCs) arise on the lower first or second molars.

Fig. 8.55 Paradental cyst appearing as an open pocket, composed of an inflamed fibrous wall lined by hyperplastic cpithclium.

Fig. 8.54 lnflammatory collateral cyst. The mandibular buccal bifurcation cyst is corticated and overlies the roots of a lower second molar tooth.

MB BCs often present with painless swelling, but infection with pain and suppuration may be seen. The tooth is usually ti lted buccally, with deep periodontal pockets. Radiology shows a we ll-demarcated buccal radiolucency, which may extend to the lower border of the mandible {1878). A periosteal reaction with laminated new bone formation may b e visible {2 151).

Histopathology (471 ]. ICC may arise from proliferation of

the reduced enamel epithelium, but recent studies suggest an origin from sulcular or junctional epithelium {1552).

Localization More than 60% of ICCs are PCs on mandibular third molars. Most of the remain der are MBBCs. Bilateral cases are not uncommon {1878,2151]. Lesions in the maxilla are very rare and may arise in association with an erupting canine.

Clinical features PCs are usually associated with a history of longstanding pericoron itis, with associated symptoms of pain, swelling, and trismus. The associated teeth are vital. PCs are well demarcated, often corticated, and superimposed over the buecal aspee! of the roots of the teeth. The periodontal ligamen! and lamina dura are normal (492}. and the lesion is distinct

The histology is not specific, and is indistingu ishable from that of a radicular cyst. Cholesterol clefts, foamy macrophages, and haemosiderin deposits may be seen. The lining may be attached at the cementoenamel junction or be continuous with the epithelium of the pericoronal tissues, forming an invagination or pocket protrudi ng down the root of the tooth {492, 539,1552}.

Prognosis and predictive factors ICCs are treated by simple enucleation. lnvolved third molars are usually extracted, but molars involved by MBBC may be conserve d.

Odontogenic cysts of inflammatory origin

233

Odontogenic and non-odontogenic developmental cysts

Dentigerous cyst

of about 3:2 (1149,2713). Eruption cysts account for < 2% of cases and occur in children {1149).

Speight P. Fantasía J.E. Neville B.W.

and small lesions are often discovered on radiological investigation for a missing tooth. However, the cyst may reach a large size and present as a slowly enlarging expansion of the jaw. lf the cyst is infected, there may be pain and swelling. Radiographs show a unilocular, welldemarcated radiolucency, often with a corticated margin, that surrounds the crown of the unerupted tooth, which may be displaced. Eruption cyst presents as a smooth, soft swelling overlying an erupting tooth. lt is often translucen!, but trauma may resu lt in haemorrhage, imparting the appearance of a haematoma.

Etiology Dentigerous cyst is a developmental cyst, but the pathogenesis is uncertain. The cyst arises due to an accumulation of fl uid between the reduced enamel epithelium of the dental follicle and the crown of the unerupted tooth.

Definition Dentigerous cyst is an odontogenic cyst that is attached to the cervical region of an unerupted tooth and envelops the crown. Eruption cyst is a variant of dentigerous cyst found in th e soft tissues overlying an erupting tooth .

Localization About 75% of dentigerous cysts are associated with unerupted mandibular third molars (1149,2713). Other common siles, in descending order of frequ ency, are the maxillary canines, maxillary third molars, and mandibular second premolars {1149, 2713}. Eruption cysts most com monly occur overlying mandibular dec iduous incisors or maxillary f irst permanent molars

Synonym Follicular cyst

Epidemiology Dentigerous cysts account for about 20% of ali odontogenic cysts (1145,1149) and are the second most common cyst of the jaws . They occur overa wide patient age range, with peak incidence in the second to fourth decades of lile. There is a male predilection, with a male-to-female ratio

Macroscopy The cyst is attached to the cervical region of the tooth at the cementoenamel junction and is lined in part by the crown of the involved tooth.

H istopathology

[28,222}.

Typical histology shows an uninflamed wall of loose fi brous tissue, often with a slightly myxoid appearance, lined by thin, regular epithelium 2-4 cell layers thick. The wall may contain small quiescent rests of odontogenic epithelium. Metaplastic changes may include mucous cells and ci lia (1432,2345). Hyaline or Rushton bodies are also occasionally seen (1432). Dentigerous cyst is often inflamed and may exhibit epithelial hyperplasia, with adjacent cholesterol crystals.

Clinical features Dentigerous cyst is usually symptomless,

B

Prognosis and predictiva factors Dentigerous cysts are treated by enucleation, with removal of the impacted tooth.

Fig. 8.56 Dentigerous cyst. A Radiology shows a well-demarcated radiolucency enveloping the crown of a lower third molar tooth. B lntact specimen associated with a canine tooth; the cyst wall surrounds the crown of the tooth. .

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234


Eruption cyst can be marsup ialized to allow the affected tooth to erupt normally. They do not recur.

Odontogenic keratocyst Speight P. Devilliers P.

Li T.-J. Odell E.W. Wright J .M.

Definition Odontogenic keratocyst (OKC) is an odontogenic cyst characterized by a thin, regular lining of parakeratinized stratified squamous epithelium with palisading hyperchromatic b asal cells.

Fig. 8.58 Odontogenic keratocyst. A patient with naevoid basal cell carcinoma syndrome with multiple odontogenic keratocysts in the mandible and maxilla.

Synonym Keratocystic odontogenic tumo ur

Epidemiology OKCs account for 10-20% of odontogenic cysts and are the third most co mmon cyst of the jaw s (1145,1149). They occur over a wide patient age range, with a p eak incidence in the second to third d ecades of life and a second, smaller peak among p atie nts aged 50- 70 years {1149). Most studies find a slight male predilection [2153}. As many as 5% of ali OKCs occur as part of naevoid basal ce!! carcinoma syndrome (Gorlin synd rome) (1419}; these cases tend to be multip le and to occur in younger patients (2638).

Fig. 8.59 Odontogenic keratocyst. A A unilocular radiolucency at the angle of the mandible extending to the posterior aspee! of the ramus (arrows). B An extensiva multilocular lesion from the midline, filling the body of the mandible and extending into the ramus; the lesions are well demarcated and mostly corticated.

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Etiology OKC is a developmental cyst that arises from remnants of the dental lamina. There is an association with mutation or inactivation of the PTCH1 gene, which activates the SHH signalling pathway and results in aberrant cell proliferation of the OKC epithelium (1419,2153).

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Localization OKCs are most frequently (in 80% of cases) found in the mandible, with as many as hall of ali lesions located in the posterior body and ramus {1 149,2153). Cysts found in the posterior maxilla are more often associated with naevoid basal ce!! carcinoma synd rome (2639).

Clinical features OKCs are frequently large at first p resenOdontogenic and non-odontogenic developmental cysts

235

support a neoplastic origin of OKC. lt is felt therefore that OKC remains the rnost appropriate name for this lesion.


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Fig. 8.61 Odontogenic keratocyst. Enucleated specimens are often fragmented, but show a typical uninflamed fibrous wall with thin, regular, folded epithelial lining.

tation . Most lesions present as painless radiolucencies and are found incidentally during radiographical examination for other reasons. Large lesions may cause displacement of teeth. Maxillary lesions may displace the orbit and are more often infected. Radiology shows a well-demarcated radiolucent lesion, often with a corticated margin. The lesions may be unilocular (with or without a scalloped margin) or may be multilocular. The posterior body and lower ramus of the mandible is the most common site, and lesions often surround the crown of the third molar, resulting in an appearance similar to that of dentigerous cyst. Lesions tend to grow in a posteroante· rior direction, resulti ng in large lesions with relatively little swelling or cortical expansion. About 10% of patients have multiple OKCs (either metachronous or synchronous), and half of these patients have naevoid basal cell carcinoma syndrome (2153,2639). In addition to multiple OKCs, patients with naevoid basal cell carcinoma syndrome have multiple basal cell carcinomas and other developmental anomalies.

Histopathology Typical histology shows an uninflamed f ibrous wall lined by a folded, thin, regular parakeratinized epithelium 5-8 cell layers thick, without rete ridges. The parakeratin surface is typically corrugated, and the basal layer is we ll defined and often palisaded, with hyperchromatic nuclei and focal areas showing reversed nuclear polarity. These features are diagnostic and · distinguish OKC from other jaw cysts that can show keratinization. 236

Mitotic figures are often seen, but these are normal. 1nflamed lesions lose these typical features and are lined by nonspecific stratified squamous epithelium with sorne degree of hyperplasia. OKCs may show small satellite cysts or solid islands in the wal l, or may have budding of the basal layer. These features are more common ly seen in cysts associated with naevoid basal cell carcinoma syndrome (2637]. Occasionally, OKCs are of the so -called solid variant: composed of multiple small cysts and epithelial islands in a dense collagenous stroma [2493). Careful examination is essential to differentiate this lesion from squamous cell carc inoma ar acanthomatous ameloblastoma. The true nature of this variant and its relationship to ccinventional OKC is uncertain, and further research is needed.

Genetic profile A variety of molecular and genetic alterations have been identifi ed in OKC {871, 1419}. the most notable of whic h are alterations in the PTCH1 gene. Naevoid basal cell carcinoma syndrome and basal carcinomas are associated with mutations and inactivation of the PTCH1 gene, and similar changes are found in as many as 80% of both syndromic and sporadic OKCs {1 419,1938). Loss of heterozygosity (LOH) on the 9q22.3 region (where the PTCH1 gene has been mapped) has been found in other developmental.cysts, including dentigerous cyst [1394, 1841), but this work needs confi rmation, and sequencing data on these lesions has not yet been presented. Further research is needed, but at the present time there appears to be insufficient evidence to


Treatment is most often by enucleation, or by surgical resection for large lesions. Recurrences were more frequent in the past but are dramatically reduced with meticulous treatment. A systematic review found an overall recurrence rate of about 25% but the recu rrence rate after enucleatio~ with Carnoy's solution was 8% (1144). Recurrence after resection was rare (occurring in < 2% of cases). Recurrences rnay be due to incomplete removal or the presence of persisten\ daughter cysts. Large lesions can be marsupialized fol lowed by enucleation (1906), and meta-analysis suggests that this approach is associated with lower recurrence rates than surgery (2649). There is no evidence of any ditference in behaviour between syndrornic and sporadic OKCs and the management is the same (718].

Lateral periodontal cyst and botryoid odontogenic cyst Speight P. Fantasía J .E. Neville B.W.

Definition Lateral periodontal cyst (LPC) is a developmental odontogenic cyst lined by non-ke ratinized epithelium, occurring on the lateral aspee! or between the roots of erupted teeth. Botryoid odontogenic cyst (BOC) is the multicystic variant of LPC {2556].

Epidemiology LPCs/BOCs account for < 1% ot odontogenic cysts [1149,2150]. They occur over a wide p atient age range, with peak incidence in the sixth and seventh decades of life {1953). A slight male pred ilection has been noted in most series (2150).

Etiology LPC/BOC arises from odontogenic epithelial remnants, but the source is controversia!. Origin from dental lamina, reduced enamel epithelium, or rests of Malassez has been proposed.

Localization LPCs/BOCs most frequently occur in the

mandible, with < 20% arising in the maxilla. Almos! all lesions have been reported to arise anterior to the molars, in particular in the premolar region {2150}. Multifocal occurrence has been reported {2188}.

Macroscopy

Clinical features

Histopathology

LPCs/BOCs are usually asymptomatic, and most are identified incidentally on radiographs. lnfrequently, there is expansion of bone, usually on the buccal aspee!. On rad iographs, LPC is a we lldemarcated, often corticated unilocular radiolucency juxtaposed to th e lateral surface of the tooth root. Most lesions are :::; 1 cm in size. BOC often has a multilocular radiograph ical appearance {2068}.

LPC has a characteristic histopathology that is similar to that of gingival cyst of the adult. lt exhibits a thin lining of non-keratinized epithelium, typically consisting of a single or double !ayer of cells, with focal plaque-like epithelial thickenings {1953). These often have a whorled appearance, and the cells may have clear cytoplasm due to accumulation of glycogen. Separation of

LPC is unicystic and may contain clear fluid. BOC may show a bosselated surface due to the presence of multiple cystic compartments.

the epithelial lining from the connective tissue wall is a common finding . The fibrous wall is uninflamed, but nay show a hyalinized band immediately beneath the cyst lining . The microscopic appearance of BOC is similar to that of LPC, except there are multiple cystic spaces .

Prognosis and predictive factors LPC can be treated by enucleation, without the removal of the adjacent tooth or teeth. Recurrence of simple unilocular cysts is rare , but recurrence is documented in as many as 20% of BOCs, probably due to the multicystic nature of the lesion {1953,2068}.

Fig: 8.63 Lateral periodontal cyst. Radiography shows a corticated radiolucency between the roots of the mandibular left second incisor and canine.


237

Fig. 8.65 Gingival cyst of the adult presenting as a blister-like lesion (arrow).

Fig. 8.66 Gingival cyst of the adult. A Plaque-like thickenings have a whorled appearance; note the basilar clear cells in the adjacent thin epithelial lining. B There is a !hin epithelial lining with focal thickenings.

Gingival cyst

premolar/canine region {2150,2519). In th e maxillary gingiva, ging ival cysts may be seen in the incisor and premolar/canine areas . They are found on the buecal surface of the alveolus in almost ali cases. In infants, the cysts occur on the edentulous alveolar ridg e ot the mandible or maxilla.

Speight P. Kessler H.

Definition Gingival cysts are odontogenic cysts found in the alveolar mucosa. They can arise in adults and in infants.

Synonyms Alveol ar cyst; Bohn nodules (in infants)

Epidemiology Gingival cyst of the adult is rare, accounting for < 0.5% of odontogenic cysts {1149). lt occurs in adults aged 40-60 years, with a slight female predi lection {1149,2519). Gingival cyst of the infan'. is common . lt is found in as many as 90% of neonates, but is rare in infants aged > 3 months.

Etiology The etiology is unknown. Gingival cysts are thought to be developmental cysts that arise from remnants of the dental lamina in the ging ival or alveolar soft tissues (rests of Serres).

Localization In adults, most gingival cysts (as many as 75%) occur in the mandible in the

238

Clinical features Gingival cysts of the infant present as small (< 2 mm) white nodules on the alveolar mucosa, and are often multiple. Gingival cysts of the adult typically present as a painless, small , dome-shaped elevation of the attached gingiva, resembli ng a blister. Occasional lesions are found in the moveable mucosa, at its junction with the attached gingiva. Lesions often have a light-blue to bluish-grey, translucent appearance, but may appear clear. Radiographs fail to reveal the lesion in most cases, although superficial erosion of the underlying bone cortex may occasionally be seen radiograph ically.

into the lumen or into the connective tissue wall. Clear cells are often present. Occasionally, the cyst lining is thicker and appears stratified squamous in character. The connective tissue wall may contain islands of epithelium resembli ng epithelial plaques. Gingival cysts of the infant are rarely seen histologically, but most appear to be lined by thin keratinized epithelium (2 149).

Prognosis and pred ictiva factors In ;:irl 11lts , simple excision is the treatmP.nt of choice and is typically curative. Recurrence has not been reported. Gingival cysts of the infant undergo involution or resolve spontaneously and do not need to be treated.

Glandular odontogenic cyst Speight P Fowler C.B. Kessler H.

Histopathology The cyst lies just below the normal oral epithelium and is typically uninflamed and lined by thin epithelium com posed of a single or double layer of cuboidal to squamous cells without rete ridges . Focal, abrupt thickening is often present, producing plaques that protrude


Definition Glandular odontogenic cyst (GOC) is a developmental cyst with epithelial features that simulate salivary gland or glandular differentiation.

Calcifying odontogenic cyst Speight P. Ledesma-Montes C. Wright J.M.

Definition Calcifying odontogenic cyst (COC) is a simple cyst lined by ameloblastoma-like epithelium, which contains focal accumulations of ghost cells.

ICD-0 code Fig. 8.68 Glandular odontogenic cyst. Radiography shows an extensive multilocular lesion crossing the midline and filling the body of the mandible.

Synonym Sialo-odontogenic cyst

Epidemiology GOC is rare, accounting far < 0.5% of all odontogenic cysts (1149). lt occurs over a wide patient age range, with an incidence peak in patients aged 40-70 years. There is no sex predi lection .

Etiology The etiology is unknown. GOC is thought to be a developmental cyst that arises from remnants of the dental lamina.

Localization GOC occurs exclusively in the jaws, with the mandible involved in about 75% of cases. Lesions in the maxilla tend to occur anteriorly (752).

Clinical features The most common presentation is painless swelling. Radiographs reveal a well-de fined unilocular or multilocular radiolucent lesion, which may have a scalloped border. GOC is typically associated with the roots of multiple teeth, and tooth displacement or root resorption is common (813). Association with an impacted tooth is extremely rare, and extreme caution should be exercised in diagnosing GOC when the lesion is in a dentigerous relationship. Mandibular lesions may reach a large size and can cross the midline (813,1176).

Histopathology Statistical analysis has shown that a confident diagnosis of GOC can be made when at least 7 of 10 specific criteria are present (752,1177). Sorne criteria are present in all cases: (1) variab le lhickness of the epithelium lining the

cyst, from 2-3 cell layers of flattened squamous or cuboidal cells to thicker, stratified squamous epithelium, and (2) a luminal layer of cuboidal to low columnar cells, sometimes referred to as hobnail cells, present al least focally. Other criteria are present in most cases: (3) intraepithelial microcysts, (4) apocrine metaplasia of the luminal cells, (5) clear cells in the basal and parabasal layers, (6) papillary projections (tufting) into th e lumen, and (7) mucous cells. The other three microscopic criteria for diagnosis are (8) epithelial spheres similar to !hose seen in lateral periodontal cyst, which are frequently identified; (9) cilia, which are occasionally seen ; and (10) multiple cystic compartments, which are sornetimes present. GOC may share sorne features with central mucoepitiermoid carcinoma, and great care must be taken in the interpretation of incisional biopsies. However, GOCs have been found to be consistently negative far MAML2 gene rearrangements {209). This suggests that the two are separate entities, but the number of cases tested is small, and this finding does not preclude the possibility that central mucoepidermoid carcinoma could develop from a pre-existing GOC.

9301/0

Synonyms Calcifying cystic odontogenic tumour; calcifying ghost cell odontogenic cyst; Gorlin cyst

Epidemiology COC is rare, accounting far < 1% of all odontogenic cysts (1149). lt occurs over a wide patient age range, with a mean pal ien! age of about 30 years [288,1357).

Prognosis and predictive factors Enucleation is the most common treatment far GOC, but is associated with a high recurrence rate (30-50%) (1179). Recurrence can be late, with one study reporting a mean time to fi rst recu rrence of 8 years (752). Far this reason·, resection has been advocated, particularly for large or multilocular lesions (11 79).

Fig, 8.69 Calcifying odontogenic cyst. Typical radiology shows a well-demarcated unilocular radiolucency. A Tooth resorption may be seen. B Many cases show foci of calcified tissue.


239

genic ghost cell tumour and ghost cen odontogenic carcinoma (1357} . There has been considerable debate as to whether it is a neoplasm or a developmental cyst {1021,1357,2410). On the basis of its behaviour and clinicopathological features COC is now thought to be a developmen'. tal cyst that arises from the dental lamina {1021,1422,1 973,2148,2410 ).

Localizati on COC can arise in either jaw, usua\ly in the anterior regions (288,1357}. Lesions associated with odontomas have a predilection far the anterior maxilla {1357). Occasional lesions (as many as 10%) are extraosseous and are found in the anterior reg ions of either jaw (102 1). Clinical features The most ·common presentation is a painless swe\ling of th e jaws. Radiographs revea\ a wel\-defined radiolucent lesion, which is usually uni\ocular and may have a scalloped border. Tooth displacement and root resorption are common (288,2357}. About half of all cases have amounts of calcified tissue (288} oran associated odontoma {1001, 1357). Extraosseous lesions present as gingival swellings, sometimes with pain or tenderness.

COC associated with odontoma has a peak incidence in the second decade of lite (288,1021}. There is no sex predilection.

240

Etiology COC is one of a group of ghost cell lesions of the jaws, along with dentino-


Histopathology COC is unicystic and is lined by epithelium of variable thickness. Sorne areas may be only a few cells thick or may show squamous change. However, the key diagnostic feature is the presence of a we\1-defined basal layer of palisading columnar cells and a thick overlying \ayer resemb ling the stellate reticulum of the enamel organ, with focal accumulations of ghost cells, which may calcify. Many lesions show luminal projections of ghost cells or of ameloblastoma-like epithelial proliferations. Small satellite cysts, islands of epithelium , or ghost cells may be seen in the fibrous capsu le. A variable amount of dentinoid is sometimes laid down adjacent to the epithelial lining {288,102 1}. In about 20% of cases, dental hard tissues resembling an odontoma are found (1 0 01,1021,1357}. Occasionally, areas resembling ameloblastic fibroma , ameloblastic fibro-odontoma, or adenomatoid odontogenic tumour can be detected (1357}.

prognosis and predictive factors Enucleation is the treatment of choice. Recurrence is rare and has been reported to occur in < 5% of cases (288 1.

Orthokeratinized odontogenic cyst Speight P. Fantasía J. E. Neville B.W.

Definition Orthokeratinized odontogenic cyst (OOC) is an odontogenic cyst that is entirely or predominantly lined by orthokeratinized stratified squamous epithelium.

Synonym OOC was originally retened to as an orthokeratinized variant of odontogenic keratocyst {2 153,2644). However, this terminology should be avoided, because OOC is a distinct entity.

. ._. •

·~ .,\ ~~

Etiology OOC is a developmental odontogenic cyst, but its pathogenesis is uncertain . An origin from remnants of the dental lamina is most likely {14211.

Localization OOCs are most frequently found in the mandib le (accounting for 90% of cases), with about 75% of ali lesions found in the posterior regio ns {499,598,1421 J. Multiple and bilateral cases have been reported {410,1892}.

.. - ~

..-:.' ( '

...

;:v..-:

-

.•.,y¡-

.

Fig. 8.71 B Orthokeratinized odontogenic cyst. A thin, regular, epithelial lining with a thick keratin !ayer that is lamellated and extends into the lumen.

shows a well-demarcated unilocular radiolucent lesion, often with a corticated margin. Occasional cases are multilocu lar {597,598}. The posterior body of the mandible is the most common site, and about half of ali lesions are associated with an impacted tooth, often resulting in an appearance similar lo lt 1al oí dentigerous cyst {499,598}. Rare cases of multiple cysts have been reported, but there is no evidence of any association with naevoid basal ce ll carcinoma syndrome (Gorlin syndrome) {410}.

Synonym

Histopathology Histology shows an un inflamed fibrous wall lined by thin, regular epithelium 5- 8 cell layers thick, but w ithout rete ridges. The surface exhibits orthokeratinization, with a prominent g ranular cell layer. Unlike in odontogenic keratocyst, the keratin surface is not corrugated, but is thick and lamellated. The basal cells a:re flat or cuboidal, but do not show palisading or hyperchromatic nuclei {2644}. Focal areas may be non-keratinized or parakeratinized, but these areas constitute a minar componen! of the lining and are often as sociated w ith inflammation {2644}.

lncisive canal cyst

Epidemiology NDC accounts for about 5% of ali cysts of the jaws, and for as many as 80% of ali non-od ontogenic cystic lesions {520,1150}. lt occurs most frequently in patients aged 30-60 years , w ith a maleto -female ratio of about 3:1 {2152}.

Etiology NDC is a developmental cyst, thought to arise from epithelial remnants of the nasopalatine duct within the incisive canal.

Localization NDCs are found exclusively in the midline of the anterior hard p alate.

Clinical features Most lesions present towards th e oral cavity and present as a sessile swelling just posterior to the incisors. Occasionally, a lesion may arise deeper w ithin the

Prognosis and predictive factors Treatment is by enucleation. Recurrence is rare and has been reported in < 2% of cases {499,597,598}.

Nasopalatine duct cyst Speight P. Wright J.M .

Clinical features OOC usually presents as a painless swelling {499,598}. but many are found incidentally durin g radiog raphical examination for other reasons. Radiology

~

Fig. 8.71A Orthokeratinized odontogenic cyst. Radiology shows a well-demarcated unilocular radiolucency associated with an unerupted third molar.

Epidemiology Due to changes in terminology, the true prevalence of OOC is uncertain, although it is known to be rare. In most series of keratinizing odontogenic cysts, OOCs account for about 10% of cases (499,2644}. Therefore, OOCs probably account for about 1% of ali odontogenic cysts overall. They occur over a wide patient age range, w ith peak incidence in the third and fourth decades of life (2644). Most studies show a male predilection {598,2644}.

.\

Definition Nasopalatine duct cyst (NDC) is a non-odontogenic cyst of developmental origin that arises in the midline of the anterior maxilla.

Fig. 8.72 Nasopalatine duct cyst. An anterior occlusal radiograph shows a typical nasopalatine duct cyst; the lesion is in the midline of the anterior hard palate and has a well-demarcated, corticated margin. The anterior incisor teeth appear normal and the lamina dura and periodontal ligament are intact (arrow).


241

On rad iology, the normal incisive canal can be as large as 6 mm; therefore small rad iolucencies of ~ 6 mm that ar~ asymptomatic and with vital teeth can be considered to be within normal anatomical limits and only need to be followed radiographically (2152,2320}.

-

Fig. 8.73 Nasopalatine duct cyst. Histology shows the varied epithelial lining; it is mostly simple non-keratinized squamous epithelium, but areas with goblet cells (arrow) and well-formed respiratory epithelium (arrowhead) may also be seen.

incisive canal and present as a swelling on the labial alveolus oras bulging of the floor of the nose (362,2152). NDCs are often traumatized and may become infected. Radiology is almost always diagnostic and shows a well-demarcated, often corticated rad iolucency

242

in the midline of the hard palate, between the roots of the incisors, which may be displaced but are vital. The lamina dura of the teeth is intact. The average cyst diameter is about 18 mm (2320), and lesions may have a characteristic heart shape .


H istopathology In > 90% of cases, NDCs are lined by stratified squamous epithelium, with focal areas of cuboidal, columnar, or ciliated change. About half of all cases contain areas of respiratory epithelium, but < 10% of cases are lined entirely by respiratory epithelium {2152,2320}. The cyst walls contain prominent neurovascular bundles and occasionally contain small mucous glands or cartilage. Traumatized cysts are inflamed. Prognosis and predictive factors NDCs can be enucleated and do not normally recur.

Malignant maxillofacial bone and cartilage tumours

Chondrosarcoma Baumhoer D. Casiraghi O. Coleman H. Hunt J.L. Triantafyllou A.

Definition Chondrosarcoma, NOS, is a malignant bone tumour that produces cartilaginous matrix.

Fig. 8.74 Chondrosarcoma (T) involving the lower part of the nasal septum and nasal fossa, showing a ver¡ high signal on axial T2-weighted MRI.

ICD-0 codes Chondrosarcoma 9222/1 Chondrosarcoma, grade 1 Chondrosarcoma, grade 2/3 9220/3

Macroscopy Chondrosarcomas often exhibit a lobular architecture, with a glistening bluish-grey or white salid cut surface.

Synonyms Chondrosarcoma, grade I; atypical cartilaginous tumour

Histopathology Chondrosarcoma generally shows osteodestructive growth, with entrapment of pre-existing trabecular bone and/or cortical permeation. Because chondromas in the maxillofacial bones are exceptionally rare, tumours with pure cartilaginous differentiation should always be assumed to be chondrosarcoma until proven otherwise. Chondroblastic osteo~arcoma is far more common than chondrosarcoma, especially in the jawbones, requiring a thorough histological search to exclude neoplastic osteoid deposits. In the temporomandibular joint, synovial

Epidemiology These tumours are rare in the jaw and facial bones, and account far approximately 3-4% of ali chondrosarcomas {2045,2446). Patients of any age can be affected, but there is a slight predilection far middle-aged men {1254). Etiology Chondrosarcomas in the maxillofacial skeleton generally develop sporadically; manifestations of Ollier disease and Maffucci syndrome with malignant transformation are exceedingly rare {1067).

chondromatosis should be ruled out, especially if the tumour shows a lobular architecture and no unequivocal signs of infiltrative growth. Well-differentiated tumours resemble hyaline cartilage and show oval to polygonal cells within !acunar spaces surrounded by a cartilaginous matrix. The nuclei are small and uniform, with round to oval outlines and evenly distributed dense chromatin. Biand multinucleation frequently occurs. With increasing grade, the nucleoli become discernible due to open chromatin. Nuclear atypia, increased cellularity, decreased volume of cytoplasm, myxoid background, and mitoses are also associated with higher tumour grade. Highgrade lesions usually show ¿: 2 mitoses per JO high-power fields and marked cellular pleomorphism. lmmunohistochemistry is of limited diagnostic value; however, the tumour cells usually stain with antibodies against 8100, S0X9, and podoplanin {1756).

Genetic profile Chondrosarcomas harbour IDH1/2 mutations in 49-61% of cases {65,66,1216). Genetic testing might be useful to exelude chondroblastic osteosarcoma, particularly on smal l needle-core biopsias.

Localization The maxilla and the nasal septum seem to be more frequently involved than the mandible; however, chondrosarcoma can occur in any maxillofacial bone {1254,2045). Clinical features The symptoms are non-specific and depend on the site of origin. lnvolvement of the nose can resu lt in nasal obstruction; in ali other sites, asymptomatic or painful swellings are the most common finding. Fig. 8.75 Chondrosarcoma. Cartilaginous tumour cells and matrix encasing !amellar bone as a sign of osteodestructive growth.

Malignan! maxillofacial bone and cartilage tumours

243

Prognosis and predictive factors Histological grade and complete resection with clear surgical margins are the most importan! prognostic factors.

Mesenchymsl chondrossrcoma Baumhoer D. Casiraghi O. Hunt J.L. Triantafyllou A.

Definition Mesenchymal chondrosarcoma is a biphasic malignant tumour composed of small round blue cells and islands of differentiated hyaline cartilage. ICD-0 code

9240/3

Epidemiology Mesenchymal chond rosarcomas are ve ry rare. They generally develop in the second to fourth decade of lite. There is no sex predilection (768,"1696,1845]. Localization The tumours can develop in bones (accounting for 65-79% of cases) and adjacent soft tissues. The cran iofacial bones (especially the jaws) are most commonly affected {1696,2280 ,2341 ,2490] . Clinical features Th e symptoms are non-specific and depend on the site of orig in .

Macroscopy The tumours are often well defined and have a grey to pink cut surface. Foci of calcifications and/or necrosis can be prominent.

osteosarcoma is an aggressive highg rade tu mour, p eriosteal osteosarcoma is of intermediate grade, and low-grade central and parosteal osteosarcomas are low-grade subtypes.

Histopathology Although the proportions vary, mesenchymal chondrosarcomas always show small round blue cells with intermingled islands of highly differentiated cartilage. The small round blue tumour cells have ovoid and hyperchromatic nuclei and scant cytoplasm. Mitoses, including atyp ical forms, are com mon. Occasionally, the round cells develop a more spindle-shaped morphology, and there is generally a prominent, haemangiopericytoma-l ike vascular pattern. lmmunohistochemically, the tumour cells express S0X9 {690,2558}.

ICD-0 codes Osteosarcoma, NOS Low-grade central osteosarcoma Chondroblastic osteosarcoma Parosteal osteosarcoma Periosteal osteosarcoma

Genetic profile Mesenchymal chondrosarcomas • typically show HEY1-NCOA2 fusions {1699, 1751,2539). IDH1 and IDH2 mutations are absent {522}.

9180/3 9187/3 9181/3 9192/3 9193/3

Synonyms Osteogenic sarcoma; intraosseous welldifferentiated osteosarcoma (9187/3) Epidemiology Osteosarcoma is rare, with an overall annual incidence of approximately 4 cases per 100 000 population. Most cases are high-grade tumours that affect the metaphysis of long bones in children andadolescents, with a particular predilection for the femur, tibia, and humerus. The fourth most com mon site of origin is the jawbo nes, accounting for about 6% of cases. Osteosarcomas in th is location tend

Prognosis and predictive factors Because d istant metastases can occur alter years to decades, long-term fo llowup is necessary. However, tumours of the jaws seem to have a favourable outcome {2490},

Osteosarcoma Baumhoer D. Lopes M. Raubenheimer E.

Fig. 8.76 Sinonasal mesenchymal chondrosarcoma. The tumour involves the maxillary sinus, nasal cavity, and ethmoidal sinus, and shows central calcifications, as shown on axial bone-window CT.

244

Definition Osteosarcoma constitutes a group of malignan! bone tumours whose neoplastic cells produce bone. Conventional


Fig. 8.78 High-grade osteosarcoma of the mandible. CT shows a heavily mineralized tumourwith osteodestruclive growth and an aggressive-appearing periosteal reaction.

Pagel disease of bone (osteítis deformans) increases the risk for developing secondary osteosarcoma {411 ,2145).

Localization There is a predilection for the jawbones (particularly the mandible), but any craniofacial bone can be involved {160,2461).

Fig. 8.79 High-grade osteosarcoma of the maxilla. Lowmagnification view showing a polypoid osteosarcoma attached to the alveolar bone and in clase contact with the gingival surface and the palatal mucosa.

to develop 10- 20 years later than do their peripheral counterparts, and affect men and women equally (160,1369). Similar to the proportion seen in the peripheral skeleton, 2-8% of ali maxillofacial osteosarcomas are low- or intermediate-grade tumours, with a predominance of the lowgrade central subtype {160,1369).

Etiology Most cases develop spontaneously; however, prior radiotherapy or underlying

...

Clinical features The symptoms, which are non-specific, include pain, swelling, and loosening of teeth. Radiographicall y, osteosarcomas presentas mixed rad iolucencies correlating with the amount and kind of neoplastic matrix. Aggressive features, including cortical permeation and periosteal re action, generally reflect the histological grade. With gnathic tumours, widening of the periodontal ligamen! space of the involved teeth may be observed. Macroscopy Depending on the type, amount, and mineralization of the lesiona! matrix, osteosarcoma can present with tan-white and salid or more grey, glistening, and soft cut surfaces. Areas of haemorrhage, necrosis, and cystic change are frequently observe d.

..

.,..·.~• ..· .. Fig. 8.80 High-grade chondroblastic osteosarcoma. A Highly pleomorphic tumour cells producing neoplastic lace-like osteoid. B Highly pleomorphic tumour cells producing neoplastic cartilage. C Spindle-cell proliferation showing only minar atypia and immature deposits of bone.

Histopathology Conventional osteosarcoma is defined by highly atypical cells producing neoplastic osteoid . High-grade osteosarcomas consist of anaplastic and highly pleomorphic cells with a broad spectrum of morphologies. Osteoblastic differentiation is evidenced by polygonal ar epithelioid cells, whereas the cells in chondroblastic and fibroblastic variants resemble highly atypical chondrocytes and f ibroblasts, respectively. Low- and intermediate-grade subtypes generally demonstrate more subtle atypia; mitotic activity can be scarce. The extent of matrix can vary significantly, rang ing fro m focal , immature, and lace-like osteoid to heavily mineralized sclerotic bone. The tumours generally show an aggressive and osteodestructive growth replacing the marrow spaces. As a result, preexisting trabeculae become surrounded and eroded by tumou r infiltrates and encased by neoplastic bone . Frequently, fibroblastic components and/or neoplastic cartilage can also be found , and the predominan! matrix defines the tumours as osteoblastic, chondroblastic, and fibroblastic subtypes. Chondroblastic osteosarcoma is proportionally more comm on in the jawbones and can histologically mimic chondrosarcoma, which is far less frequent in the maxillofacial bones {455). Small-cell and telangiectatic variants have been reported but are exceptionally rare. Low-grade central and parosteal osteosarcomas consist of irregular woven bone trabeculae embedded in a fibroblastic stroma with only minimal atypia. The stromal componen! can predominate and is of low to moderate cellularity. Rarely, scattered foci of atypical cartilage can be present. Positive staining with antibodies against MDM2 and CDK4 might aid in distinguishing low-grade osteosarcoma from benign fibro-osseous mimics (615,2684). Periosteal subtypes generally demonstrate a predominan! chondroblastic differentiation, with intermediate-grade atypia. Genetic profile Peripheral osteosarcomas have highly complex karyotypes, with abundan! structural and numerical aberrations frequently caused or influenced by chromothripsis (1167). Whether the favourable outcome of gnathic osteosarcomas is associated with differences in their genomic landscapes is yet to be determined. Low-grade central

Malignan! maxillofacial bone and cartilage tumours

245

and parosteal osteosarcomas show amplifications of the MDM2 gene in as many as 29% and 79% of cases, respectively (1820,2056), whereas MDM2 amplification is found in only 12% of conventional osteosarcomas (1582}.

Genetic susceptibility The risk of osteosarcoma is increased in several rare tumour syndromes, including Li- Fraumeni syndrome, retinoblastoma, Werner syndrome (adult progeria), and Rothmund-Thomson syndrome (poikiloderma atrophicans with cataract).

Prognosis and predictiva factors Osteosarcomas of the jaws metastasize far less frequently (in 6-21% of cases), and later on in the course of disease, than do their peripheral counterparts, which is why resection with clear margins is the most important prognostic factor - resulting in 10-year survival rates of > 80% {160,455,895}. The role of (neo)adjuvant treatment for osteosarcomas of the jawbones is controversia!, especially for cases in which a complete resection is surgically feasible {160,111 8,1828,2220, 2374). Low-grade osteosarcomas can

typically be cured by complete resection without additional treatment modalities {160). These prognostically favourable characteristics are restricted to tumours of the jaws only. Extragnathic osteosarcomas of the skull or fac ial bones behave as aggressively as tumours of the peripheral skeleton and are general/y treated accordingly (by chemotherapy and surgery) (1 118).

Benign maxillofacial bone and cartilage tumours

Chondroma

Osteoma

Toner M. van Heerden W. F.P.

Toner M. Al len C.M. Castle J.

asymptomatic {1691}. Rad iographically, osteoma presents as a well-demarcated radiopaque mass, usual/y < 2 cm in size. Sino-orbital osteomas may present with pain, headache, or visual changes.

Histopathology

Definition Chondroma is a benign neoplasm of hyaline cartilage that arises within the medullary cavity of bone.

ICD-0 code

Definition Osteoma is a benign neoplasm composed of mature bone, limited almost exclusively to the craniofacial bones·.

9220/0

ICD-0 code

9180/0

Synonym Enchondroma

Epidemiology

Localization

Most osteomas occur in the third to fifth decades of lite, with a male predominance {1336).

Chondromas are very rare in the head and neck reg ion, with only isolated cases described {1088).

Clinical features This is a slow-growing painless tumour. lt is usually radiolucent, with central areas of rad iopacity.

H istopathology The tumour consists of mature bland cartilage with a circumscribed edge, without atypia or cellularity. Because benign chondromas are so rare in the craniofacial region, malignancy must be considered in a/1 cartilaginous lesions in this area. 246

Osteomas are composed of !amellar bone (compact, trabecular, or a combination of both) that merges with and may protrude from the surface of the bone (11 80}. Sorne examples have more abundan! fibrous stroma and sorne contain osteoblastoma-like areas, which are thought to represen! remodelling within the lesion rather than constituting a tumour subtype. This is more common in sino-orbital osteomas but is not associated with a more aggressive clinical course

Localization

{1571).

Both surface and central osteomas are more common in the mandible than in the maxilla, with the mandibular condyle being a common site (1180}. Central osteomas are usually mandibular or sinoorbital in location. Sino-orbital cases occur in the nasal cavity, orbit, and paranasal sinuses (most commonly the frontal sinus) {1571) . •

Multiple osteomas may be a manifestation of fam ilia! adenomatous polyposis (Gardner syndrome), an autosomal dominan! disorder characterized by mutation of the APC gene {1359). In this setting, the osteomas may increase in size over time.

Clinical features


Surface osteomas can present as a painless swelling on the surface of the bone, whereas central lesions are often

Recurrence is rare alter surgical excision.



Melanotíc neuroectodermal tumour of infancy Prasad M.L. Nelson B. Tilakaratne W.M.

Detinition Melanotic neuroectodermal tumour of infancy (MNTI) is a locally aggressive, rapidly growing tumour consisting of a biphasic population of small neuroblast-like and larger melanin-producing epithelioid cells.

ICD-0 code

Fig. 8.81 Melanotic neuroectodermal tumour of infancy. A 6-month-old infant presented with a rapidly growing mass in the maxillary alveolar ridge. The mass is well defined, with focal dark-brown discolouration and a tooth bud protruding from its surface.

9363/0

Synonyms

Clinical features

Melanotic progonoma; retina! anlage tumour (both synonyms are obsolete and not recommended)

The tumour presents as a sessile, painless, rapidly enlarging mass in the up per alveolus, causing facial deformity and feed ing disruption. lt may be bluishblack in colour, due to its melanin con tent. lmaging shows a mass that destroys the maxillary bone; may extend into the sinus, nasal cavity, or orbit; and may en trap developing tooth buds . A subset of tumours produce vanillylmandelic acid {394,1944).

Epidemiology MNTI is rare. More than 90% of patients are infants, with a median age of 5 months, although exceptional cases at birth or in adults have also been reported . There is a slight male predilection [394,1 173,1285,1944}.

Localization

Macroscopy

More than 90% of cases occur in the craniofacial regions, most commonly in the maxilla (accounting for > 60% of cas es), followed by the skull , mandible (6% of cases), and brain {1285,1944,2031). Outside the head and neck, the most common siles are the testis and epididymis. Rare cases occur in the ovary, uterus, mediastinum, scapula, and bones and soft tissues of the extremities {130,2445).

The median tumour size is 3.5 cm (range: 1- 20 cm) {1173,1944). Th e tumours are smooth, firn, unencapsulated, general ly non-ulcerated, and pigmented.

H istopathology The tumour consists of a biphasic population of small neuroblast-like cells and larger melanin-producing epithelioid cells arranged in an alveolar architecture,

with cords and trabeculae intersected by dense fibroblastic stroma . The melanotic epithelioid cells generally surround nests of small cells, but may form solid and l tihulogl;mrltil;ir structures. The intracytop lasmic melanin corresponds to melanosomes ultrastructurally {553,1872). lnfiltration of bone and entrapped odontogenic tissue is frequently present. Mitoses and necrosis are generally absent but may be seen {1 47). The presence of characteristic clinical and histological features may obviate the need for immunohistochemistry. Both small and large tumour cells express vimentin, synaptophysin, and neuron-specific enolase. The epithe lioid cells are also positive for pancytokeratin markers and HMB45 , but negative for other melanoma markers. The tumour cells are typ ically negative for chromogranin, neu rofilaments, S100 protein, and desmin, although focal rhabdomyo blastic and glial differentiation has been rarely reported {652,1872). MNTI must be distinguished from other malignan! small round blue cell tumours, which have worse prognoses (e.g. Ewing sarcoma / primitive neuroectodermal tumour, rhabdomyosarcoma, and lymphoma). These tumours do not have the characteristic biphasic morphology of MNTI, and have distinctive immunohistochemical profiles. In MNTI, abundan! melanin pigment is usually apparent at low magnification, or can b e demonstrated by Fontana- Masson staining if necessary. CD99 may show membranous expression in the small and large tumour cells of sorne MNTls {1 47] .

Benign maxillofacial bone and carti lage tumours

247

-

·~

B Chondroblasts stain positive with cytokeratins.

Genetic profile Most MNTls are diploid but sorne are aneuploid {1173,1872}. BRAFV600E mutation has been reported in one case {869).

Chondroblastoma

Histopathology


Definition

Despite rapid growth and local destruction, most MNTls are cured by complete excision. Recurrence occurs in approximately 20% of cases, usually within 6 months of treatment (1285,2031). The risk of recurrence appears to correlate with patient age at diagnosis; it is highest in patients diagnosed within 2 months of birth, lowest in those diagnosed alter 4.5 months of age, and intermediate in those diagnosed at 2-4.5 months of age {1944}. The tu mours rarely (in -3% of cases) behave in a malignan\ fashion, with distan\ metastases consisting of small neuroblast-like cells {553,1285,1872,2031). No histological features or biological markers are known to predict behaviour.

Chondroblastoma is a benign chondroid-producing neoplasm composed of chondroblasts.

The tumour cells are polygonal, with welldefined borders and nuclear grooves. lntermingled multi nucleated giant cells, chondro-osteoid matrix, and co-called chicken-wire calcifications can be found in varying amounts. The tumour cells at least focally express S100, S0X9, cytokeratins (CK8, CK18, and CK19), and p63 {1008 ,2126}.

ICD-0 code

Genetic profile

Baumhoer D. · van Heerden W.F.P.

9230/1

Epidemiology Chondroblastoma of the maxillofacial bones is exceptionally rare, with < 100 cases reported in the literature {957, 2263).

H3F3B point mutations are highly specific for chondroblastoma (172}.

Prognosis and predictive factors As many as 50% of cases recur, and metastasis has rarely been reported (180}.

Localization The tumours develop almost exclusively around the temporomandibu lar joint, particularly in the squamous part of the temporal bone {185,957,1269,2263}.

,4 B Higher magnification sha::S stellate and

248


Chondromyxoid fibroma Baumhoer D. van Heerden W.F.P.

Definition Chondromyxoid fibroma is a benign cartilaginous bone tumour with a characteristic lobular architecture and a chondrornyxoid background.

ICD-0 code

•·

9241/0

Epidemiology Chondromyxoid fibroma is rare, and tumours of the maxillofacial bones account fa r only 5% of all cases {2646).

Localization There is a slight predilection far the jawbones, but all bones can be affected

Radiographically, cortical sclerosis surrounds a radiolucent nidus. In gnathic lesions , the nidus may be more radiopaque {2280). Most osteoid osteomas do not grow beyond 20 mm in diameter {73 ).

Histopathology

/1 11,715,927,1504 ,1566}.

Histopathology The spindle-shaped to stellate tumour cells generally show abundan! eosinophilic cytoplasm, grow in lobules with hypocellular centres and more hypercellular peripheries, and are surrounded by a chondromyxoid matrix. Hyperchromatic nuclei, multinucleated giant cells, calcifications, and/or hyaline cartilage can commonly be observed 12646).

Histologically, osteoid osteoma is essentially identical to osteoblastoma. Osteoid osteoma is distinguished from osteoblastoma only on the basis of tumour size (;::; 20 mm) and the presence of a surround ing zone of sclerotic bone {1733}.

Prognosis and predictiva factors Recurrence al ter treatment is very rare .

Osteoblastoma Osteoid osteoma

Toner M. Allen C.M. Castle J.

Toner M. Allen C.M. Castle J .

Definition Definition Osteoid osteoma is a benign boneforming tumour characterized by limited growth potential .

ICD-0 code

9191/0

Epidemiology Osteoid osteoma is very rare in the maxillofacial bones.

Osteoblastoma is a benign bone-forming tumour with prom inent osteoblastic rimming, form ing a mass > 20 mm in size.

ICD-0 code

9200/0

Epidemiology This is a rare tumour occurring mostly in the second to third decades of lite, with a slight male predominance {1147).

Localization Clinical features Osteoid osteoma typically presents with pain disproportionate to the tumour size. The pain is often nocturnal and relieved by aspirin, although relief with aspirin is less common far jaw tumours {1147).

About 10% of osteoblastomas are found in the craniofacial bones, most commonly the posterior mandible (328).

but more commonly present with localized swelling and pain that may mimic toothache, not relieved by aspirin. Plain radiography shows a circumscribed round to oval lesion varying from rad iolucent to radiopaque, without a sclerotic border or periosteal reaction. Root resorption is rare {328), but the tumour may mimic malignancy rad iologically.

Histopathology The tumour is composed of haphazard mineralized trabecu lae of bone and osteoid rimmed by osteoblasts and with a cellular vascular fibrous stroma and occasional osteoclasts. Sorne of the bone may be strongly haematoxophilic, resulting in the characteristic so -called blue-bone appearance. Mitoses are rare . In sorne cases, the osteoblasts appear epithelioid, with admixed immature bone, which raises concern of malignancy. These tumours have been called aggressive or epithelioid osteoblastoma. Although this morphology can be associated with a clinically aggressive course, this is not always the case. Tumour size > 4 0 mm and an anatomical site that makes removal difficult are better predictors of behaviour for such lesions [942,2280). The absence of nuclear atypia, permeative growth into surrounding bone, and atypical mitoses distinguish osteoblastoma from osteosarcoma {1489). Cementoblastoma is a tumour that arises from and is fused to dental roots . The histology of osteoblastoma and cementoblastoma are identical except that the blue-bone appearance is uncommon in cementoblastoma (see Cementoblastoma, p. 230) 11963).

Prognosis and predictive factors Clinical features Osteoblastomas can be asymptomati c

Recurrence may occur alter incomplete removal.

Benign rnaxillofacial bone and cartilage tumours

249

Desmoplastic fibroma Flucke U. Coleman H.

Definition Desmoplastic fibroma is a locally aggressive (myo)fibroblastic lesion of bone.

ICD-0 code

8823/1

Synonym Desmoid tumour of bone

Epidemiology Most patients are aged (mean: 16 years) (2634).

< 30 years

Local ization Approximately 86% of gnathic cases occur in the mandible, with a predilection for the ramus and angle region f2352, 2634).

Clinical features The lesions are slow-growing and commonly painless {2634). They are radiographically well defi ned, without mineralization (1089).

Macroscopy Fig. 8.86 Osteoblastoma. A Characteristic, so-called blue-bone appearance in a mandibular osteoblastoma. B Epithelioid osteoblasts in a mandibular osteoblastoma.

The lesions are firm and white, with a coarse cut surface and focal myxoid areas. Cortical perforation with extension into soft ti ssue may occur (738}.

Histopathology Histology shows an infiltrative/permeative lesion composed of fascicles of uniform (myo)fibrob lasts with slender tapering nuclei. Mitoses are occasionally present, but are never atypical. The background stroma is collagenous, but may have myxoid areas . Coarse keloid-like col lagen bundles are occasionally observed. There are small capillaries with para\lel a\ignment to the fascicles. Perivascular oedema is typical (738,2043). The tumour cells are variably SMA-positive, and nuclear beta-catenin expression has been reported in rare cases {738,959).

Genetic profile Activating CTNNB1 hotspot mutations or APC mutations are driving events [738, 1029).

Prognosis and predictive factors Recurrence may occur {2634). 250


Fibro-osseous and osteochondromatous lesions

ossifying fibroma EI-Mofty S.K. Nelson B. Toyosawa S.

Definition Ossifying fibromas are benign fibroosseous neoplasms affecting the jaws and the craniofacial skeleton. The three clinicopathological variants that have been identified are ossifying fibroma of odontogenic origin - also cal led cemento-ossifying fib roma (COF) - and two d istinct juvenile ossifying fi bromas: juvenile trabecular ossifying fibroma (JTOF) and juvenile psammomatoid ossifying fibroma (JPOF) {632,2208).

ICD-0 code Ossifying fibroma

9262/0

Synonyms Cemento-ossifying fibroma: central ossifying fibroma; cementifying fibroma; periodontoma Juvenile ossifyi ng fibroma: juveni le active ossifying fi broma; juvenile aggressive ossi fying fibroma

Fig. 8.89 Juvenile trabecular ossifying fibroma. CT showing a circumscribed, expansive lesion of the maxilla; cortical thinning is observed.

Fig. 8.91 Juvenile psammomatoid ossifying fibroma. CT shows an expansile, well-defined, but incompletely corticaled /esion with ground-glass appearance at the ethmoid area.

minantly affects children and adolescents , with a mean pati ent age of 8.512 years {632). The sexes are equally affected. JPOF is a rare tumour. The reported mean patient age ranges from 16 to 33 years. However, the overall patient age range is wide; cases have been reported in patients as young as 3 months and as o ld as 72 years {632,638,221 4). There is no sex predilection.

JTOF occurs in the maxilla and mandible, with the maxilla being a more common site. Extragnathic occurrence is extremely ra re. JPOF may occur in the jaws but it predominantly affects the extragnathic craniofacial bones, particularly the periorbital frontal and ethmoid bones {632).

Epidemiology

Localization

COF is rare. The peak incidence is in the third and fourth decades of lile. There is a definite female predilection, with a female-to-male ratio as high as 5: 1 {638, 674). JTOF is a rare bone tumour. lt precio-

COF occurs exclusively in the toothbearing areas of the mandible and maxilla. The mandible is far more commonly involved than the maxilla. The mandibular premolar and molar area is the most common site.

Clinical features COFs present as a painless expansion of the bucea! and lingual plates of the affected bone. Large lesions can expand the inferior border of the mandible or the floor of the maxillary sinus. Radiographically, early lesions are typically rad io lucent. Over time, the tumour becomes p rogressively more radiopaque {638, 676,2208). JTOFs are characterized by

Fig. 8.88 Cemento-ossifying fibroma. Radiography showing a well-defined, expansive radiolucent lesion with radiodense areas present in the mandibular molar area.


251

progressive and sometimes rapid expan sion of the affected bone. In the maxilla , obstruction of the nasal passages and epistaxis can occur. Radiographically, the tumour is expansile and fairly well demarcated. lt may be radiolucent or may show various deg rees of opacification. Cortical thinning and perforation can occur [632,2213). JPOFs present as bony expansions that may involve the orbit or nasal bones and sinuses. Tumour expansion can resu lt in proptosis, visual symptoms, and nasal obstruction. The rapid tu mour growth that has been observed in sorne cases is most likely caused by secondary aneurysmal bone -cyst formation (632,638 }.

Macroscopy An important feature of COF is that it is wel l defined and can be shelled out relatively easily from the surrounding tissue. Grossly, the tumour is submitted in one piece or in large fragments that are yellowish-tan and may be haemorrhag ic and feel gritty when cut with a scalpel {638,676}. On cut surface, JTOF shows curvilinear haemorrhagic strands not seen in other types of ossifying fibroma [2210).

Histopathology COF is wel l defined and may be en-

Fig. 8.93 Cut surface of specimen of juvenile trabecular ossifying fibroma. Curvilinear haemorrhagic strands create a distinct pattern typical for this lesion.

252

capsu lated. lt is composed of hypercellular fib roblastic stroma containing variable amounts of calcified structures. The stromal cells have hyperchromatic nuclei but no marked atypia. Mitosis is not easily found. The calc ified structures are composed of variable amounts of os teoid or bone and lobulated basophilic masses of cementum -like tissue. These structures may coalesce and form curvilinear trabeculae, wh ich may be acellular. The ratio of bone to cementum- like tissue varies from lesion to lesion; in sorne tumours, one type of calc ified tissue may domínate. Osteoblastic rimm ing of the bone trabecu lae is evident. Polarized light microscopy shows both woven and !amellar bone. The cementum-like tissue is o/ten woven, and may show a characteristic quilted pattern. JTOF is unencapsulated but nevertheless maintains a well-delineated border. lt has a characteristic loose archif'ecture, with hypercellular stroma composed of spindle cells with little collagen production. Osteoid develops directly from the fibrous stroma and forms long slender strands that have been likened to paint brush strokes. Irregular mineralization takes place at the centre of the strands, resulting in the production of immature bone trabeculae that are devoid of osteoblastic rimming and show no evidence of maturation. Aggregates of osteoclastic giant cells are typically found in the stroma. Occasional mitoses may be observed in the stromal cells . Aneurysmal bone-cyst formation has been reported in sorne cases [632,2208,2213). JPOF is unencapsulated and is characterized by multip le small uniform ossicles (psammomatoid bodies) embedded in cel lular stroma composed of spindled and stellate cells {632,638 ,2214). The psammomatoid bodies are basophilic and bear sorne resemblance to


dental cementum . At the periphery of the lesion, these structures may coalesce and form bone trabeculae. Cystic degeneration and aneurysmal bone-cyst formation may occur.

Genetic profile Mutati ons in COC73 (also called HRPT2) have been reported in sporadic cases (537,1890). COF lacks the GNAS gene mutation that is characteristic of fibrous dysplasia.

Genetic susceptibility Multiple ossifying fibromas may be associated with hyperparathyroidism-jaw tumou r syndrome, which is caused by COC73 (also called HRPT2) mutations {340). Lesions with similar histological features have been reported in a familia! setting as g igantiform cementoma (see next section) {634f.

Prognosis and predictive factors COF is a slow-growing benign neoplasm. lt can be surgically excised conservatively, with no recurrence in most cases. Untreated tumours can attain a massive size and may require en bloc resection. Sarcomatous transformation has not been documented {633,638,674}. Multiple recurrences have been reported following conservative excision of both JTOF and JPOF. Malignant transformation has not been reported {632].

Familia/ gigantiform cementoma EI-Mofty S.K.

Definition Familia! gigantiform cementoma (FGC) is a rare form of fibro-osseous lesion of the jaws characterized by early onset of multifocal/multiquadrant progressively expansive lesions that may be massive and cause remarkable facial deformity. No other bones are affected .. Autosomal dominant inheritance is seen among sorne cases whereas others are familia!. Sporadic cases without known heritable features have also been described.

and extensive involvement of the jaws. Simple cosmetic recontouring procedures result in recurrences, which may be multiple and occasionally at a more accelerated rate {3A,634,676,2138A}.

Fibrous dysp/asia EI-Mofty S.K. Nelson B. Toyosawa S.

Oefinition Fibrous dysplasia (FO) is a skeletal anomaly in which normal bone is replaced and distorted by poorly organized and inadequately mineralized immature bone and fibrous tissue. lt may involve a single bone (monostotic FO) or multiple bones (polyostotic FO). A variety of endocrinopathies accompany polyostotic FO in McCune-Albright syndrome. Although FO occurring in multiple adjacent craniofacial bones is considered to be monostotic, the term "craniofacial fibrous dysplasia" is preferred far such cases {2523}.

Fig. 8.95 Familia! gigantiform cementoma in a 3-yearold female palien!. CT sean showing bilateral, massive expansive masses of the maxilla and mandible with wellcircumscribed borders presenting as radiolucent areas containing radiopaque calcifications.

Histopathology The microscopic features of FGC are analogous to those of cemento-ossifying fibroma characterized by hypercellular fibroblastic stroma with monomorphic appearing spindle shaped fibroblasts and collagen fibres. Oispersed throughout the stroma are mineralized structures of immature bone trabeculae and cemen tum-like tissue. The latter is formed of hypocellular basophilic and curvilinear structures resembling cementicles that are normally seen in the periodontal ligament. Under polarized light, Sharpey's fibres are seen to project radially from these spheroidal deposits.

Fig. 8.97 Fibrous dysplasia. A Waters' (occipitomental) view of craniofacial fibrous dysplasia involving the right maxilla, showing ground-glass appearance, with indistinct borders. B Polyostotic fibrous dysplasia involving the maxilla and base of the skull, with obliteration of the maxillary sinus. Frontal (coronal) bone-window CT.

Prognosis and predictiva factors Surgical management of FGC is a challenge due to rapid regrowth of the lesions Fibro-osseous and osteochondromatous lesions

253

Synonym Craniofacial fibrous dysplasia

Epidemiology FO accounts far approximately 7% of ali benign bone tumours {618). lt appears to be a disorder of growing bones; most cases are initi ally identified in children and adolescents. Monostotic FO is 6- 10 times as common as polyostotic FO (735).

ground-glass appearance, with indistinct borders that blend imperceptibly with the surrounding uninvolved bone (596). In affected jaws, narrowing of th e periodontal ligament spaces and effacement of the lamina dura surrounding the teeth are suggestive of FO.

should be delayed foras long as possible {2523). Simple contouring of the affected facial or skull bones to normal dimension has proven to be adequate. Very rareJy, spontaneous malignant transformation occurs (2027).

Macroscopy

Cemento-osseous dysplasia

The affected bone is ru bbery, compressible, and greyish-white, with a gritty texture when cut with a scalpel.

Etiology FO is caused by postzygotic activating missense mutations in the GNAS gene, which encades the alpha subunit of the stimulatory G protein (G 5 -alpha) {186, 2158,2575). Constitutively active G5 alpha stimulates adenylyl cyclase activity, resulting in overexpression of cAMP and subsequent changes in the properties of bone osteoprogenitor cells, leading to abnormal bone formation (1989, 1990,1991}.

Local ization The milder forms of FO affect only a few bones (usually asymmetrically), localized to one region of the body. The craniofacial bones and the femur are the two most common sites of both monostotic and polyostotic FOs, but any bone can be affected (735). In the gnathic bones, FO occurs more often in the maxilla than in the mandible, and may extend to involve adjacent bones such as the zygomatic and sphenoid bones {2523}.

Clinical features The initial presentation usually consists of painless swelling of the jawbones, often leading to facial asymmetry. The disease is typically diagnosed within the first two decades of life (2523). Jaw involvement may lead to displacement of teeth and malocclusion, although the dental arch is generally maintained {35). Cases affecting the paranasal sinus, orbits, and foramina of the base of the skull can produce a variety of symptoms, includ ing nasal obstructi on, visual loss, headache, and hearing loss (634). In McCuneAlbright syndrome, café-au-lait skin pigmentation and endocrine abnormalities are present {618). The radiographical appearance of FO depends on the stage of development. Early lesions may appear radiolucent, whereas later lesions may appear sclerotic. Classic lesions typically have a 254

Histopathology The lesions consist of fibrous and osseous tissue in varying proportions depending on the disease stage. The fibrous tissue consists of bland fibroblastic cells. Mitotic figures are uncommon. The osseous tissue is composed of irregularly shaped trabeculae of immature woven bone without osteoblastic rimming {41). These trabeculae often assume curvilinear forms, which have been likened to Chinese characters in appearance. The lesiona! bone fuses with the adjacent normal bone (41,2209). Unlike FO in long bones, craniofacial lesions may undergo progressive maturation to !amellar bone (2209,2523). A small proportion of cases contain nodules of hyaline cartilage. Cases with abundant cartilage have been termed fibrocartilaginous dysplasia (1098).

EI-Mofty S.K. Nelson B. Toyosawa S. Wright J.M.

Definition Cemento-osseous dysplasia (COO) is a non-neoplastic fibro-osseous lesion of the tooth-bearing regions of the gnathic bones.

Synonyms Osseous dysplasia; cementa! dysplasia; cementoma

Epidemiology COO is the most common benign fibroosseous lesion of the jaws. There is a strong predilection far middle-aged Black women; an age-adjusted prevalence rate of 5.5% among Black females has been reported {62,529,2127).

Genetic profile

Localization

Activatin g missense mutations in the GNAS gene have been detecteá in monostotic and polyostotic FOs, as well as in McCune-Albright syndrome.

COO occurs exclusively in th e toothbearing regions of the jaws.

Prognosis and predictive factors In most cases, the lesions seem to stabilize with skeletal maturation; therefore, surgical intervention in younger patients

Clinical features COO has traditionally been divided into three variants (largely on the basis of anatomical location): periapical COO is associated with the apical areas of mandibular anterior teeth; focal CO O is associated

Fig. 8.99 Cemento-osseous dysplasia. Radiography shows lesions of mixed radiolucent and radiopaque florid cemento-osseous dysplasia in both quadrants of the mandible.


Localization The reported siles are the skul l base, maxillary sinus, zygoma, and mandible (condyle and coronoid processes).

Clinical features

with a single tooth; and florid COD has multifocal (multiquadrant) involvement. The lesions are usually asymptomati c and may only be discovered on routine dental radiographs {1791}. COD is associated with vital teeth; however, it may also be found in edentulous areas. The lesions are generally non-expansive, but florid cases are the exception; they may be expansile and present with pain and discharge secondary to infection {529, 1316}. Radiographical evaluation of COD is essential. ldeally, these lesions should be identified clinically and radiographically, without the need for biopsy. The lesions may be radiolucent, radiodense, or mixed . Serial radiographs may show increased density and calcification as a lesion matures . A focus of COD is generally well defined and demonstrates a thin radiolucent rim. The periodontal ligamen! should appear intact, and the lesion should not be fused to the roots (529,634,1 316}.

Prognosis and predictive factors Once a diagnosis of periapical and focal COD has been established, patients require no treatment and can be monitored during routine dental appointments. lndividuals with florid COD may require clase clinical follow-up for complications of osteomyelitis {529,1316} .

The symptoms are related to tumour location . Asym metry, malocclusion, pain, and limited mouth opening are the most common features of cases in the mandible {2023). lmaging reveals a lobulated bony outgrowth in continuity with the cortex and medulla of the bone of origin, with a !hin cartilaginous cap (although the cap is not always visible).

Macroscopy Osteochondromas can be sessile or pedunculated.

Histopathology

Osteochondroma Toner M. van Heerden W.F.P.

Definition Osteochondroma is a cartilage-capped bony projection arising on the externa! surface of bone, continuous with underlying bone. Categorization as a benign neoplasm rather than a reactive lesion is favoured {2023).

The tumour consists of perichondrium covering a hyaline cartilaginous cap and bony stalk {2010}. The cartilaginous cap is typically < 2 cm in thickness. The osteochondral junction resembles the growth plate, and the zone of endochondral ossification matures into cancellous bone. There is minimal atypia, and binucleated forms are rare. The cortex and medulla are continuous with the underlying bone. Absence of BCL2 expression may be helpful in distinguishing osteochondroma from chondrosarcoma {925).

Genetic profile ICD-0 code

9210/0

Macroscopy The lesions are grossly fragmented, gritty, and tan and brown .

Osteochondromatous exostosis

Histopathology

Epidemiology

AII the variants of COD have analogous microscopic features, characterized by a variably cellular fibrous stroma with areas of swirling and/or loose collagen . Within the stroma are mineralizing tissues consisti ng of osteoid, bone, and cementumlike material. As the lesions mature, they become increasingly calcified {1316). Dense hypocellular sclerotic masses may form, especially in florid COD. Osteoblastic rimming is generally rare. The vascularity is pronounced and results in free blood within biopsied specimens. No capsule is identified. lnflammation may be seen in cases of florid COD that become infected {634). Cystic changes resembling simple bone cyst may occur in flori d cases .

Osteochondroma is one of the most common lesions of the axial skeleton but is much rarer in the maxillofacial bones, because it occurs at sites of endochondral ossification, which are limited in this region. Less than 1% of all osteochondromas occur in the head and neck. Osteochondromas in the maxillofacial bones occur in the fourth to fifth decades of lile, which is later than elsewhere in the body.

Synonym

Homozygous deletion of the EXT1 gene, located at 8q22-24.1, occurs in chondrocytes in sporadic osteochondromas. Abnormal ities of both EXT1 and EXT2 are associated with hereditary multiple osteochondromas (201O).

Genetic susceptibility About 15% of patients with osteochondromas have hereditary multiple osteochondromas/exostoses, but this condition rarely involves the maxillofacial bones {2010}.

Prognosis and predictive factors Excision is curative, although recurrence is possible following incomplete removal. Malignan! transformation is very rare.

Etiology Trauma may be an etiological factor {2023}. An association with externa! radiation therapy in childhood has been suggested.


255

Giant cell lesions and bone cysts

Central giant ce// granuloma Raubenheimer E. Jordan R.C.

Definition Central giant cell granuloma (CGCG) is a localized, benign but sometimes aggressive osteolytic lesion of the jaws characterized by osteoclast-type giant cells in a vascu lar stroma.

Synonyms Central giant cell lesion ; reparative giant cell granuloma (obsolete)

Epidemiology CGCGs account far 10% ot benign gnathic tumours. Most cases occur in females and in patients aged < 20 years (729).

Localization The lesions are more frequent in the anteri or jaws, in particular the mandible. Multiple lesions should raise suspicion for Noonan syndrome, LEOPARD syndrome, or neurofibromatosis type 1 [2492).

Fig. 8.102 Central giant cell granuloma. Occlusal radiograph showing mandibular expansion and tooth displacement in a multilocular central giant cell granuloma.

osteoclast-type multinucleated giant cells in a vascu lar background , with haemorrhage and haemosiderin pigment. The lesion may have a lobular architecture separated by fibrous sepia with osteoid and woven bone. Other giant cell lesions with similar teatures (such as cherubisrn, hyperparathyroidism, and aneurysrnal bone cyst) must be excluded. The giant cells in CGCGs show reactivity tor osteoclast and macrophage markers {729,2413,2492). The mononuclear stromal cell is the proliferative componen!.

Genetic profile resorption . More advanced lesions may be multilocular. About 30% of cases follow an aggressive clinical course characterized by pain, tooth resorption and displacement, cortical perforation, and invasion of perignathic tissues (2492). MR I and PET-CT are helpful in delineating soft tissue involvement and multicentricity, respectively {1572).

Macroscopy The lesion has a fleshy, reddish-brown, haemorrhagic appearance.

CGCG does not have a defined genetic protile, and lacks the point mutations in the histone H3F3A gene that characterize giant cell tumour of b one (1922}.

Genetic susceptibility Most CGCGs have no genetic association , but a minority of cases (most cornmonly cases associated with neurofibromatosis type 1, Noonan. syndrome, ar LEOPARD syndrome) arise in patients with germline mutations in the genes encoding specific proteins of the RAS/MAPK pathway {729,1723}.

Clinical features

Histopathology

CGCGs generally present as slowgrowing, asymptomatic, expansile, well defined radiolucencies, without tooth

CGCG is characterized by an unencapsulated proliferation of mononuclear spindle-shaped and polygonal ce lls with

Fig. 8.101 Central giant cell granuloma presenting as a well-circumscribed radiolucency in the anterior mandible.

Fig. 8.103 C~ntr; I giant cell granuloma. Osteoclast-like giant c;lls and mononuclear cells in a vascular stroma with reactive osteoid formation.

256


Prognosis and predictiva factors Most CGCGs respond favourab ly to local c urettage. A higher recurrence rate

is associated with an aggressive clinical course [2492) and association with Noonan syndrome or neurofibromatosis type 1 [729). To limit the extent of resection of large lesions, intralesional or systemic pharmacological agents such as steroids, calcitonin , interferon, and the RANK ligand inhibitor denosumab may be considered [54,2492).

Peripheral giant ce// granuloma

Fig. 8.104 Peripheral giant cell granuloma. A Manifesting as a broad-based, non-ulcerated polyp on the alveolar mucosa of the right mandible. B Cut surface of an excision specimen, showing a fleshy reddish-brown appearance.

Raubenheimer E. Jarcian R.C.

Definition Peripheral giant cell granuloma is a reactive localized proliferation of mononuclear cells and osteoclast-type giant cells in a vascular stroma outside bone. lt occurs in the gingiva or alveolar mucosa.

Synonym Giant cell epulis

Epidemiology Peripheral giant cell granuloma is the most common giant cell lesion affecting the oral tissues {2136).

Etiology The lesion occurs as a result of local irritation of the mucoperiosteum or the coronal part of the periodontal ligamen! by dental calculus deposits or other types of chronic irritation {388).

proliferation of mononuclear spindleshaped and polygonal cells with giant cells in a vascularized background. Foci of haemorrhage, haemosiderin pigment, and scattered deposits of immature bone are frequent. •

Prognosis and predictive factors Localization Peripheral giant cell granuloma is more common in the gingiva and edentulous alveolar ridge of th e mandible, but can also affect the maxilla {2136).

Surgical removal is advised, and the recurrence rate is low. The lesions may even regress after removal of the irritan!.

Clinical features

Macroscopy Due to vascularity, the cut surface of the specimens often has a fleshy redd ishbrown appearance.

Jordan R.C. Raubenheimer E.

Definition Cherub ism is an autosomal dominan! inherited condition characterized by symmetrical expansion of the ma>.
Synonyms Histopathology Histology shows

an

unencapsulated

The incidence of cherubism is unknown, but the condition is rare (367). Cherubism presents in childhood ar preadolescence and is most often followed by partial or complete regression in adulthood. Most cases are familial, with variable penetrance and expressivity. De novo cases from sporadic mutati ons can also occur.

Etiology

Cherubism The proliferation presents as a sessile or pedunculated soft-pink to purplish-blue lump with a smooth, ulcerated , or papillomatous surface {2136}. A shallow indentation of the adjacent alveolar bone may be present {388).

Epidemiology

Familia! fibrous dysplasia; juvenile fibrous dysplasia (both terms are obsolete)

Mutations of the SH3BP2 gene, located on chromosome 4p16.3, have been identified in about 80% of cases of cherubism (1523). The majority of mutations occur in exon 9, within a proline-rich sequence 6 amino acids long , resu lting in a constitutively active form that increases the activity of osteoclasts {2443).

Localization Both jaws are affected bilaterally, with the mandible affected more extensively than the maxilla. The condition appears to start around the first molars, but typically spares the condyles. In the maxilla, cherubism begins in the tuberosity and subsequently affects other areas. Giant cell lesions and bone cysts

257

Fig. 8.106 Cherubism. A A child showing bilateral maxillary and mandibular bone expansion, with malpositioned and displaced teeth. B Panoramic radiograph showing multifocal radiolucent lesions of the maxi\la and mandible, with missing and displaced teeth.

Fig. 8.108 Aneurysmal bon e cyst. Panoramic radiograph showing the features of an aneurysmal bone cyst involving the right mandible of an 8-year-old boy.

Noonan syndrome {1723), and the bone lesions of hyperparathyroidism. Variably cellular mesenchymal tissues contain fo cally aggregated clusters of multinucleated giant cells. Eosinophilic cuff- like perivascular deposits can be seen, but are nota consisten! finding .

separated by fibrous septa containing osteoclast-type giant cells.

Clinical features Slow, symmetrical expansion of the jaws occurs befare the age of 6 years. Expansion of the maxilla may cause retraction of the facial skin, including the eyelids, leading to scleral exposure and the characteristic so-called heavenly gaze, which is similar to the facial appearance of putti (angelic children) in Renaissance paintings (incorrectly referred to as cherubs in the Baroque period of art). Females are typically more severely affected than males (1921]. Bone expansion leads to tooth displacement, altered tooth eruption, loosening of teeth, speech alteration, and visual impairment {1921}. Radiographically, the affected bones have a multiloculated, so-called soap-bubble radiolucent quality {1967}. The cortices may be thinned, and with time the fibrous tissue is replaced by new bone, leading to sclerosis.

Genetic susceptibility The condition occurs in famil ies and is inherited in an autosomal dominant manner (729]. Prognosis and predictive factors Most cases regress alter puberty {1921), but sorne cases show continued growth with little regression {345}. Befare puberty, surgery should be performed only in severe cases, where it wi ll provide a functional benefit.

Aneurysmal bone cyst

Macroscopy Similar to the appearance of other giant cell lesions, the tissue may be red and haemorrhagic with areas of cystic change .

Jordan R.C. Koutlas l. Raubenheimer E.

Histopathology The histology is not specific, and may resemble that of other giant cell lesions of the jaws, such as giant cell granu loma,

Definition Aneurysmal bone cyst (ABC) is a cystic or multicystic expansile osteolytic neoplasm composed of blood-filled spaces

258


ICD-0 code

9260/0

Epidemiology ABC is rare, with an estimated annual incidence of approximately 0.15 cases per 1 million population (1381]. About 1.5% of ali cases occur in the jaws. Ali age groups are affected, but > 80% of cases occur in younger patients, usually within the first two decades of lite. The sexes are equally affected overall, but a male predilection has been reported for cases of the jaws [1663]. Localization More than 60% of cases occur in the mandible; more frequently in the posterior reg ions {1663}. Maxillary lesions have a more uniform anatomical distribution. Other sil es in the craniofacial complex can also be affected . Clinical features There is enlargement, which is frequently painful {1663}. The teeth remain vital, but tooth mobility and displacement are common. Maxillary tumours c an extend to the sinuses, nose, and orbits and can result in exophthalmos. Radiographically, there is expansion with well -delineated

unilocular or multilocular radiolucencies. Perforation of the cortex can occur with extension to the adjacent soft tissues. Root resorption is seen . CT may revea! bone septa compartmentalizing the lesion. CT and MRI demonstrate flu id-fluid levels that are characteristic of (but not specific for) ABC (2427).

Macroscopy The cysts are haemorrhagic and multicameral, featuring fibrous septa of variable thickness. Solid areas may be identified; these constitute either the solid portion of the primary tumour or a portian of tumour that has undergone secondary ABC- like changes. 'Rarely, the entire Jesion is salid. Histopathology ABC is composed of blood-filled or empty sinusoidal spaces that are lined by macrophages and fibroblasts and are separated by fibrous septa containing scattered multinucleated osteoclastlike giant cells. Woven bone can appear prominently basophilic (the so-cal led blue-bone appearance), but this is not diagnostic. The solid variant can featu re cellu lar areas (which may be mitotically active) and few inconspicuous cystic spaces. ABC-like areas (secondary ABC) can occur in a variety of other disorders of bone, including osteoblastoma, fibrous dysplasia, and ossifying fibromas. Genetic profile Rearrangements of CDH11 and/or USP6 are seen in 69% of primary ABCs (1772} but not in secondary ABCs. Other fusion partners for CDH11 include COL1A1, OMD, THRAP3 (also called TRAP150), and CNBP (also cal led ZNF9) . Fusion results in the upregulation of USP6. Although the mechanism is not wel l understood, USP6 upregulation may affect actin remodelling and vesicular trafficking, which regulate cell moti lity and invasiveness (1550}. Familia! cases have been described (1 380}, but not in the jaws or skull.

Simple bone cyst Raubenheimer E. van Heerden W.F.P. Wright J.M.

Definition Simple bone cyst (SBC) is an intraosseous cavity that is devoid of an epithelial lining and is either empty or filled with serous or sanguineous flu id. Synonyms Traumatic bone cyst; haemorrhagic bone cyst; unicameral bone cyst; solitary bone cyst Epidemíology SBCs have an equal sex distribution and occur in young patients (in the second or third decades of life) (1025}. One third are associated with florid osseous dysplasia in populations where florid osseous dysplasia is common (368]. An older average patient age and a female

predom inance have been reported for SBCs associated with florid osseous dysplasia (368}.

Etiology The etiology is unknown. Trauma does not seem to play a role; the incidence in patients with a history of trauma is the same as that in the general populati on {2301}. Localization SBCs are usually solitary and typically affect the metaphysis of long bones. In th e head and neck region, they occur mostly in the mandible, with a predilection for the body of the mandible (1025). Multiple SBCs account for 13% of cases {2301) Clinícal features Although a small number of cases manifest with a pathological fracture, SBCs are generally asymptomatic, and are usually found incidentally during routine examination. Radiologically, they

Fig. 8.109 Simple bone cyst cavity in the left mandible. A Note the scalloping between the roots of the associated teeth. B Florid osseous dysplasia with a multilocular simple bone cyst cavity in the right mandible.

Prognosis and predictiva factors ABC can be treated with curettage, but en bloc resection may be necessary for large , destructive tumours. The recurrence rate is approximately 10%, with soft tissue extension. Fig. 8.110 Simple bone cyst. Curettings of the wall of a simple bone cyst cavity showing connective tissue, lace-like osteoid, and !amellar bone.

Giant cell lesions and bone cysts

259

are well-defined radiolucencies that frequently extend between the roots of associated teeth, without resorption or displacement {1025). Larger examples may be multilocular. A minority of cases (17.6%, 2.9% , and 11 .8%, respectively) show bone expansion, loss of the periodontal ligament space, and effacement of the lamina dura. Expansion of the cortical plates and loss of the lamina dura are more frequent in cases associated with osseous dysplasia (368}.

Macroscopy Upon surgical exp loration, the cavity is either empty or filled with serous or

sanguineous fluid. The inferior alveolar nerve is often visible inside the cavity {2038}.

Histopatholqgy The term "simple bone cyst" is in fact somewhat of a misnomer, because the specimens never have an epithelial lining . Compressed connective tissue is often seen lining the cavity, sometimes with myxomatous change and often with immature lace-like osteoid or spiky collagen deposits (161 }. Prognosis and predictive factors Surgical exploration and curettage are


Solitary plasmacytoma of bone Definition Solitary plasmacytoma of bone (SPB) is a localized proliferation of monoclonal plasma cells involving bone. No other bony lesions are present on imaging studies, and there are no diagnostic clinical features of plasma cell myeloma. Minimal bone marrow involvement (< 10% plasma cells) may be seen in a subset of patients. ICD-0 code

9731/3

Synonyms Plasmacytoma of bone; osseous plasmacytoma Epidemiology SPB is rare, accounting far 3-5% of ali plasma ce ll neoplasms. There is a male predominance, with a male-to-female ratio of 2:1, and the median patient age is 55 years {1087}. Localization SPB presents as a solitary bone lesion, with the axial skeleton (in particular the vertebrae) involved more frequently than the appendicular skeleton [1087] . In the head and neck region, thi s lesion occurs much more frequently in th e mandible

260

often sufficient to stimulate bleeding and facilitate osteogenesis. Spontaneous healing has been reported. One quarter of solitary SBCs recur. Cases of multiple lesions have a higher recurrence rate {1025). Lack of bone formation can usually be demonstrated within the first year after treatment, and regular follow-up is recommended {2038}. Curettage is not recommended for cases associated with uncomplicated mature florid osseous dysplas·a, due to the likelihood of inducing sequestration of the hypovascular mineralized masses.

Feldman A.L. Ott G.

plasmacytoma with :?: 10% clonal plasma cells in the bone marrow qualifies instead as plasma cell myeloma.

Fig. 8.111 Solitary plasmacytoma involving the mandible of a 73-year-old man. The tumour is composed of sheets of plasma ce lis.

th an in the maxilla, most commonly in the bone marrow-rich areas of the body, angle, and ramus {24).

Clinical features The most common symptoms of head and neck SPB are pain in the jaws and teeth, migration of teeth, haemorrhage, and swelling {1901). A monoclonal serum or urine paraprotein (M protein) may be present, but hypercalcaemia, renal insufficiency, and anaemia are absent (1087, 1950). On imaging studies, multifocal bone involvement is absent {582.,1667) . Two types of SPB have been defined: one with no bone marrow involvement and the other with minimal involvement (< 10% clonal plasma cells in the bone marrow) (992,1803,1950} . A solitary


Histopathology The histopathological features are similar to those of plasma cell myeloma. Typically, the plasma-cell nature of the tumour is readily apparent, although br sorne poorly differentiated (e.g. anaf:lastic) cases, immunohistochemistry or additional studies may be required to confirm lincngc. The immunophenotype of SPB is also similar to that of plasma cell myeloma. lmmunohistochemistry for the kappa and lam bda immunoglobulin light chains can be helpfu l to supp ort plasma cell clonality. Prognosis and predictive factors Most patients achieve local control with radiotherapy. Median overall survival is about 10 years {1087}. About 10% of cases with no bone marrow involvement and 60% of cases with minimal involvement progress to plasma cell myeloma within 3 years (1950}. Adverse prognostic factors include older age, lesion size > 5 cm, monoclonal free light chains in urine, an abnormal serum free lightchain ratio, and persistence of M protein 1-2 years after diagnosis {585,588,1087, 1426,2429,2608}.

CHAPTER 9 Tumours of the ear

Tumours of the externa! auditory canal Tumours of the middle and inner ear

WHO classification of tumours of the ear

Tumours of the externa! auditory canal Squamous cell carcinoma Adenocarcinoma Ceruminous adenocarcinoma Adenoid cystic carcinoma Mucoepidermoid carcinoma Ceruminous aoenoma

8070/3 8420/3 8420/3 8200/3 8430/3 8420/0

Tumours of the middle and inner ear Squamous cell carcinoma Aggressive papillary tumour Endolymphatic sac tumour Otosclerosis Cholesteatoma

262

Tumours of the ear

8070/3 8260/1 81 40/3

Vestibular schwannoma Meningioma Middle ear adenoma

9560/0 9530/0 8140/0

The morphology codes are from the lnternational Classification of Diseases far Oncology {ICD-0) {776A}. Behaviour is coded /O far benign tumours; /1 far unspecified, borderline, or uncertain behaviour; /2 far carcinoma in situ and grade 111 intraepithelial neoplasia; and /3 far malignan! tumours. The classification is modified from the previous WHO classification, taking into account changes in our understanding of these lesions.

Tumours of the ear

Jntroduction Slootweg P.J. Takata T.

Tumours of the ear can be subdivided into those of the externa! auditory canal, the middle ear, and the inner ear. In this edition, the number of entities included has been reduced, by omitting tumours that can occur at these siles but have

been extensively discussed elsewhere and have no specific site-related features requi ring further consideration. For tumours of the externa! auditory canal, site-specific features of squamous cell carcinoma are briefly mentioned, the main discussion being devoted to lesions from the ceruminous glands, which are specific to this site. For practica! reasons , tumours of the middle and inner ear are listed together, because their site of origin cannot always be determined beyond

doubt in a given patient. Otosclerosis has been added as a new entity, because there are sorne indications of a potentially neoplastic behaviour of this lesion. Several refinements have been made in th e c lassification and nomenclature of adenoma and adenocarcinoma. Middle ear paraganglioma, also known as glomus jugulare tumour, is discussed in Chapt er 10.

Tumours of the external auditory canal Squamous ce// carcinoma Sandison A . Thompson L.D.R.

Definition Squamous cell carcinoma (SCC) of the externa! auditory canal is a malignan! neoplasm of squamous epithelium arising within the externa! auditory canal. ICD-0 code

8070/3

Synonyms Epide rm oid carcinoma, squamous carcinoma

Fig. 9.01 Squamous cell carcinoma of the externa! auditory canal. Subtotal pinnectomy specimen showing an ulcerated tumour occluding the ear canal; this tumour extended into the adjacenl parotid gland.

Epidemiology The annual incidence of SCC of the externa! auditory canal is about 1 case per 1 million population [1787). Patients are usually aged 55-65 years, and· there is a female predominance, in contrast to the male predominance seen with pinna tumours {1142).

Etiology Whereas actinic overexposure and frostbite are suggested etiolog ies for pinna carcinomas, chronic inflammati on and radiation are suggested etiologies for carcinomas of the externa! auditory canal and middle ear {730,1 4 61,1787,2169}. Rarely, papilloma may transform into

scc {1595).

Localization Tumours usually arise on the pinna; few cases affect the externa! auditory canal {2162,2595,2624).

Tumours of the externa! auditory canal

263

Clinical features An excoriated or ulcerated mass affecting the pinna. Otitis media, otitis externa, pain, hearing changes, cholesteatoma, and stenosis are common presenting symptoms (456,1031,2595}. with nerve symptoms noticed later (1979,2715}.

ceruminous glands of the externa! auditory canal.

Macroscopy The gross appearance is that of a warty, exophytic mass, possibly occluding the externa! auditory canal and invading the tympanum.

Synonyms Ceruminal adenocarcinoma; cylindroma (to be discouraged)

Histopathology The histology is similar to that of SCC occurring elsewhere. Spindle-cell and acantholytic morphologies may be seen, as well as (rarely) verrucous SCC. Desmoplastic stroma and inflammation are often present (456,1031,1563,1787,2260). Prognosis and predictiva factors Externa! auditory canal SCC is aggressive, afien with local recurrence and lymph nade metastases, and frequently involving vital structures. Poor prognostic factors include high clinical stage, tumour depth > 8 mm, and lymphovascular invasion (456,730,1563,1752,1787,2595}.

ICD-0 codes Adenocarcinoma Adenoid cystic carcinoma Mucoepidermoid carcinoma

8420/3 8200/3 8430/3

Epidemiology Ceruminous adenocarcinoma is rare, accounting for < 2.5% of ali externa! auditory canal neoplasms [493,1865 ,2390). Localization The tumours occur in the outer half of the externa! auditory canal, excluding direct extension from parotid gland (493,1110, 1865}. Clinical features Women are more often affected , with a female-to-male ratio of 1.5:1. The average patient age is 50 years (range: 21- 92 years). Patients present with pain, hearing loss, and tinnitus (493,552,1498, 1605). lmaging defines tumour extent and excludes direct extension from the parotid gland or nasopharynx.

Ceruminous adenocarcinoma Sandison A. Stenman G. Thompson L.D.R.

Definition Ceruminous adenocarcinoma is a malignan! neoplasm derived from the

264

Tumours of the ear

Macroscopy The tumours can be as large as 3 cm, with a mean size of 1.4 cm. Histopathology The unencapsulated cellular tumour infiltrates soft tissue and bone, showing variable salid, cystic, cribriform, glandular. and single-cell patterns. Perineural

invasion and comedonecrosis are often present. Cytoplasmic apocrine features are common. There is nuclear pleomorphism, with prominent nucleoli easily identified along with increased mitoses. Ceroid pigment is absent. Adenocarcinomas are subclassified as adenocarcinoma, adenoid cystic carcinoma, and mucoepidermoi d carcinoma. Adenoid cystic carcinoma and mucoepidermoid carcinoma are histologically identical to their salivary gland counterparts . There is a biphasic immunohistochemistry: luminal cells are positive for CK7 and KIT (CD117); basal cells are positive for p63, S100 protein, and CK5/6 (493 ,1102,1478}. Genetic profile Adeno id cystic carc inomas are characterized by a t(6;9) chromosomal translocation resulting in a MYB-NF/8 gene fusion, similar to that seen in adenoid cystic carcinomas of the salivary glands (1861, 1862}. No genetic data are available on cerum inous adenocarcinoma or mucoepidermoid carcinoma. Prognosis and predictiva factors Recurrences are common. associated with positive margins or high-grade histology. Death results from the destruction of local vital structures or distan! bloodborne metastases (to the lungs) (493, 1110,1528,1865}.

Ceruminous adenoma Sandison A. Thompson L.D.R.

Definition Ceruminous adenoma is a benign tumour of the wax-producing glands of the externa! auditory canal.

- -

Fig. 9.05 Ceruminous adenoma. lmmunostaining for

ICD-0 code

8420/0

CK5/6 highlights the basal cells.

pleomorphic adenoma, and ceruminous syringocystadenoma papilliferum. The histological features of these subtypes are similar to those of the named variant (i.e. pleomorphic adenoma), but there are concu rrent histological features of ceruminous differentiation. lnner cuboidal cells are positive for CK7, pancytokeratin, and CD117 and may show decapitation secretion and acid-fast fluorescent yellow ceroid pigment {324, 2390,2600). Neuroendocrine markers are negative (1340,2390). Differential diagnoses include middle ear adenoma and cerum inous adenocarcinoma.

Synonyms

Clinical features

Ceruminoma; ceruminal adenoma; ceruminous pleomorphic adenoma; ceruminous syringocystadenoma papilliferum

Symptoms include hearing loss and otorrhoea; pain is rare, unless associated with inflammation [1090}.


Macroscopy

Recurrence is unlikely after complete excision {1340}.

Epidemiology There is a wide patient age range (12- 85 years), with a mean patient age in the fifth decade of lite. There is an equal sex distribution {23901, and children are rarely affected (1510).

Localization These tumours are confined to the skin over the cartilaginous externa! auditory canal (the outer half).

The tumour presents as a superficial, skin-covered, non-ulcerated mass as large as 4 cm in size.

Histopathology Histology shows unencapsulated, circumscribed, regular bilayered glands in fibrous stroma. The growth pattern is variable, and the tumour may be pseudo-infiltrative. Three histological types are recog nized: ceruminous adenoma, ceruminous

Tumours of the externa! auditory canal

265

Tumours of the middle and inner ear /

Squamous ce// carcinoma

extension. Nodal metastases, wh ich are unusual, affect neck levels 11 and 111 {834). Distant metastases are rare. SCC may be mistaken for chron ic otitis media.

Sandison A. Thompson L.D.R. Wenig B.M.

Aggressive papillary tumour Definition Squamous cell carcinoma (SCC) of the middle ear is a malignant neoplasm of squamous epithelium arising within the middle ear.

ICD-0 code

8070/3

Epidemiology SCC is rare in the middle ear. The mean p atient age at presentation is 60 years (range: 21-89 years). There is a reporte d predilection fo r the left ear of elderly men {834).

Etiology The etiology is unknown, but chronic otitis media is a predisposing factor in 75-85% of cases (1043).

Localization SCC of the middle ear can originate in the middle ear or can extend from an externa! auditory canal SCC. lt does not arise from the epidermoid formation (an

Sandison A . Fig. 9.07 Squamous cell carcinoma of the middle ear. Al surgery, the well-differentiated tumour (indicated by the arrow in Fig. 9.06) was found to be extensively infiltrating the middle ear and surrounding structures.

embryonic epithelial rest associated with congenital cholesteatoma). lntracranial spread occurs with erosion through the thin bony plate overlying the carotid canal in the medial wall of the middle ear at the junction with the Eustachian tube. Direct spread into the inner ear (via perineural invasion along the eighth cranial nerve) is uncommon {1603).

Clinical features Patients report aural discharge and conductive hearing loss. Otalgia, bleeding, and fac ial palsy are common {701,834, 1389).

Histopathology The histology is similar to that described at other sites. There may be associated carcinoma in situ of cuboidal middle ear epithelium .


266

Tumours of the ear

ICD-0 code

8260/1

Synonym Papillary adenocarcinoma of the middle ear

Epidemiology The mean patient age at presentation is 34 years (range: 16- 55 years), with patients often symptomatic for severa! years befare diagnosis. The tumour is rare, with relatively few cases reported in the literature, but there appears to be a female predominance.

Localization Macroscopy A plaque-like or polypoid mass may be seen or palpated in the ear canal. Tumour may fill the middle ear and extend into the mastoid air space.

Fig. 9.06 Squamous cell carcinoma of the middle ear. Axial slice from a CT of left temporal bone showing the tumour (arrow) causing cortical bone breach posteriorly with extension into a few mastoid air cells.

Definition Aggressive papillary tumour is a locally invasive, papillary epithelial neoplasm .

The prognosis is generally poor, due to advanced disease at presentation and delayed diagnosis. Outcome is related to stage at presentation {1 15), with a wide range of reported 5 -year survival rates (25-83%) following surgery and radiotherapy {701,1341 ,1389,1557). Death usually results from direct intracranial

The tumour can be found in any area of the middle ear, including the mastoid process and air cells, and may fill the tympanic cavity. In ali but 3 of the described cases (510,1084,2268), there was extensive invasion outside the middle ear, involving the apical portion of the petrous bone in most cases. In a few cases, the tumour reached the cerebellopontine angle and the cerebellum. In cases with widespread involvement of the temporal bone, origin from the endolymphatic sac has been suggested {964).

Clinical features Patients present with cli nical and audiological features that suggest a tumour in the middle ear. In almost ali reported cases, there has been extensive invasion outside the middle ear [614,793,794, 1908,2285).

A

.;,;,"0.:1.;~ ·~,

..

...

·,,. · ._,· - B

·~~~

Fig. 9.08 Aggressive papillary tumour of the middle ear. A The tumour shows a papillary glandular patlern, with complex papillae lying loase ar infiltrating loase fibrous connective tissue. B The papillae are lined by peripheral basal and inner cuboidal to columnar epithelial cells with uniform nuclei and eosinophilic cytoplasm.

Macroscopy The middle ear cleft (including the mastoid air cells) is usually filled with a papillary tumour. Bone invasion is often seen.

surgery and postoperative radiotherapy {614).

Endo/ymphatic sac tumour Histopathology A papillary glandular pattern is present, with complex interdigitati ng papillae lying loosely or infiltrating fibrous connective tissue. The papillae are lined by basal and low cuboidal to columnar epithelial cells with uniform nuclei, eosinophilic cytoplasm, and indistinct cell borders. Thyroid follicle- like areas may be present, resemb ling endolymphatic sac tumour. The tumours express cytokeratin, EMA, and S100. Metastatic papillary carcinoma of the thyroid can be excluded by immunostaining for thyroglobulin.

Sandison A.

Definition Endolymphatic sac tumour (ELST) is a low-grade malignant epithelial tumour arising from the endolymphatic sac in the temporal bone.

ICD-0 code

8140/3

Synonyms

Clinical features

Low-grade papillary adenocarcinoma of endolymphatic sac origin; Heffner tumour

Non-specific presenting symptoms inelude hearing loss, tinnitus, aura! fullness, and vertigo {1470,1527). As the tumour spreads, patients may develop facial nerve paralysis and/or cerebellar disorders.

Cell of origin

Epidemiology

Both the endolymphatic sac and the middle ear epithelium have been con sidered as possible sites of origin (1673,2174).

ELST is rare. lt occurs mostly in adults, over a wide age range; it has been described in a 4-year-old child {1305). There may be a slight female predominance. About one third of cases are associated with von Hippel- Lindau disease (VHL), an autosomal dominan! familial cancer syndrome {1527).

Genetic susceptibility Sorne cases of aggressive papillary tumour of the middle ear have been associated with von Hippel-Lindau disease.

Etiology Prognosis and predictive factors Complete surgical excision is the treatment of choice. However, surgery carries the risk of high morbidity, because resection may necessitate the sacrifice of cranial nerves. Various treatment modalities may be employed {depending on the stage at presentation), including radiotherapy alone and the combination of

{955,1600). As tumours grow, they may destroy petrous temporal bone and extend into the middle ear and the middle and posterior cranial fossae and into the cerebellopontine angle (150,964). Correlation with imaging helps distinguish ELST from middle ear adenoma, meningioma, and choroid plexus papilloma. Jugular glomus tumours and middle ear paraganglioma involve the jugular foramen and the middle ear rather than extending into the retrolabyrinthine temporal bone. Schwannoma is usually well circumscribed and c entred on the jugular foramen, and does not involve the retrolabyrinth ine temporal bone.

About 10% of patients with VHL develop ELST, of which about 30% of cases are bilateral (1527,1578). The prevalflnce of VHL is approximately 1 case per 39 000 population {1470).

Localization Early-stage tumours are confined to the endolymphatic sac in the inner ear

Histopathology The architecture is variable; the tumour can be both papillary and cystic. There is usually a single !ayer of tumour cells, but the tumour may appear bilayered. The tumour cells may be flattened, attenuated, and cuboidal or columnar, with bland, eccentrically located nuclei and pale eosinophilic or clear cytoplasm . Small glands and follicular structures may be present, containing deeply eosinophilic colloidlike secretions that give a strongly positive periodic acid- Schiff (PAS) reaction and resembling thyroid tissue. PAS may demonstrate intracytoplasmic inc lusions in tumour cells. Mucin stains are negative. Mitoses and necrosis are not seen .

Tumours of the middle and inner ear

267

Fig. 9.09 Endolymphatic sac tumour. On axial postcontrast MRI, the tumour presents as a large heterogeneous mass centred on !he left cerebellopontine angle cistern; fluid levels are seen in cystic components. There is distortion and mass effect on !he left cerebellar hemisphere.

The tumour is poorly defined, and diagnosis may be obscured by adjacent vascular granulation tissue in subsurface tissue, associated with haemosiderin deposition, chronic inflammation, cholesterol clefts, and dystrophic calcification. ELST may be misdiagnosed as a reactive or inflammatory process, especially if biopsies are small and not representative. The differential diagnosis includes metastases. lmmunostaining for CD10, CAIX, and PAX8 is positive in renal cell carcinoma, but negative in ELST. Metastatic thyroid carcinoma can be excluded with TTF1 and thyroglobulin immunostains. Metastatic prostate carcinoma expresses prostate-specific antigen and P504S.

Cell of origin The tumour is thought to arise from papillary epithelium of the endolymphatic sac.

Genetic profile The VHL gene, mapped to chromosome 3 (3p25-26) {2124), is a tumour suppressor gene \1342). lts product forms a multiprotein complex with a role in oxygen sensing. The VHL gene regulates VEGF. lnactivation results in upregulation of VEGF and ang iogenesis. A loss-of-function mutation results in overexpression of HIF1 , promoting angiogenesis and tumorigenesis. Genetic analysis of the hereditary fo rm of ELST has shown inherited (germline) mutations together with deletion of the wildtype VHL allele, supporting Knudson's hypothesis of the sequence of events required for tumorigenesis {1253, 2197} and supporting the clinical {1527) and genetic {2512) association of the tumour with VH L.

Otosclerosis Sandison A.

Definition Otosclerosis is a bone lesion that develops in the otic capsule and may affect hearing and balance. Synonym Otospongiosis

Genetic susceptibility Screening far ELST by audiological testing and MRI with gadolinium is recommended for individuals who have been d iag nosed with or who have a family history of VHL {1578}. Patients with sporadic ELST should be screened for VHL.

Epidemiology Otosclerosis affects about 3 in 1 000 White adults (2025); it is rare in Asians and Africans. The reported incidence is higher in patients with hearing loss (5-9%) and higher still in patients with conductive hearing loss in particular (18- 22%) (550,1188}. Hearing loss usually develops in the third to fifth decade of lite, and there is a female-to-male ratio of 2-3:1 . Althoug h < 0.5% of affected people develop symptoms, an autopsy study has shown that silent, so-called histological otosclerosis may have a much higher incidence {549}.

Prognosis and predictiva factors Complete surgical excision may be curative {1470). However, surgery carries the risk of high morbidity, because it may require resection of petrous temporal bone and mastoid, necessitating sacrifice of cranial nerves. Advanced tumours may be treated by radibtherapy alone or by a combination of surgery and postoperative radiotherapy. The prognosis depends on the tumour size at presentation and the adequacy of surg ical excision. Rarely, distant metastases have been described (2365).

Etiology The etiology is not understood. Otosclerosis has been considered to be a disorder of bone remodelling of the otic capsule possibly associated with abnormal collagen synthesis, aberrant expression of inflammatory mediators, or viral infection \1188,2025). However, the argument has recently been made that otosclerotic plaques behave like low-grade neoplasms, in that pre-existing normal structures in the cochlear and vestibular otic capsules are invaded and replaced {1602}. Autopsy studies have also shown

;·.,

.. 268

Tumours of the ear

as 50% of recorded cases are sporad ic {2025). Multiple gene loci have been identified that may be associated with otosclerosis, but the mechanism is unknown [1188). A recent systematic literature review determined that the available data are insufficiently robust to guide genetic counsell ing {212).

Otic capsule

Prognosis and predictive factors The prognosis is good. Untreated, otosclerosis leads to very significan! hearing loss, but total deafness is rare . Medical treatment options are available, but the best treatm ent is surgery, and the aim is to improve the conductive hearing loss {2025). Complications include a low risk of sensorineural hearing loss, which cannot be improved, and facial nerve injury. Tinnitus may become worse.

Cholesteatoma Sandison A.

Definition Fig. 9.11 Otosclerosis. Otosclerotic plaque in the cochlear part of the otic capsule. The lesion appears to arise from periosteum and infiltrates into cochlea, vestibular region, and stapes joint. The basophilic front contains primitive osteoblasts and Volkmann canals (perforating holes), whereas there is more mature, spongiform bone behind this, closer to the origin. Adapted from Michaels L and Soucek S {1602).

that, like neoplasms, the lesions continue to grow and expand throughout life {1602).

conductive hearing loss, which is bilateral in 80% of cases {2025) .

Localization

Macroscopy

Disease is usually bilateral and symmetrical. A bony plaque develops in the otic capsule (predominantly in the region posterior to the coc hlea), which the n involves the stapes footplate, resulting in conductive hearing loss {1601,2025). The lesion broadly expands in all directions into the otic capsule. lt passes through the stapedovestibular joint and along the stapes footplate. lnferiorly and laterally, it may involve branches of the vestibulocochlear nerve (eighth cranial nerve) to the saccule. Anterior cochlear plaques of otosclerosis may also be present. These have a wide area of contact w ith the periosteum bordering the canal for the interna! carotid artery. Occasional plaques have been described in other locations within the otic capsule.

Biopsy is seldom performed. Morphology is based on analysis of temporal bones examined at autopsy. Stapedectomy specimens may contain otosclerotic plaque tissue, w hich is usually associated with the anterior par! ot the foot plate.

Histopathology Otosclerosis presents as well-demarcated tumour-like masses ot predominantly immature trabecular bone and vascu lar stroma forming in the otic capsule. Le siona! cellularity varies, and active bone remodelling may be identified, with cytological atypia of osteocytes {1601,2025). One study reported histological changes in patients' stapes bone suprastructu re {344).

Genetic profile Clinical features Patients usually present with progressive

There is a strong familia ! link (-60%) in clinical otosclerosis cases, but as many

Cholesteatoma is a cystic or open mass of keratinizing squamous epithelium in air-filled spaces of temporal bone. Although not neoplastic, it has a propensity to erode local structures and to recur after excision .

Epidemiology The reported annual incidence of c ho lesteatoma is 3-15 cases per 100 000 ch ildren and 9 - 13 cases per 100 000 adults. A male predominance has been reported. Congenital cholesteatoma affects infants and young ch ildren. In one large series, 72% of cases occurred in males (1912). Acquired cholesteatoma affects older children and young adults. Cholesteatoma is more prevalen! in developing countries, but there does not appear to be an association with socioeconomic status {1212,1481,1779). There is an ethnic predilection, with the d isease seen most commonly in White people, followed by Africans; it is rarely seen in non- lndian Asians {1299,1724).

Etiology Congenital cholesteatoma develops behind the intact eardrum and is believed to originate from an embryonic rest (the epidermoid formation) (1598). Acquired


269

Genetic profile Clinically, cholesteatoma behaves as a low-grade neoplasm, and recen! studies have shown altered exp ression in cholesteatoma of several genes associated with intercellular signalling and cellgrowth control. These alterations include upregulation of EGFR, TGF-alpha, and metalloproteinases, as well as downregulation of tumour suppressor genes and altered expression of proto-oncogenes {1298,1299}. The mechanisms involved in the development of cholesteatoma are unclear. Fig. 9.12 Cholesteatoma. Non-echoplanar imaging diffusion study showing high signal in the left petrous apex, characteristic of cholesteatoma.

Fig. 9.14 Cholesteatoma. Strips of keratinizing squamous epithelium with abundan! keratin ílakes are usually seen; there may be associated chronic inílammation and foreign body-type reaction in underlying stroma, as shown.

Clinical features

Fig. 9.13 Cholesteatoma of the externa! ear canal. Otoscopy shows drum retraction, ulceration, and haemorrhage.

Patients typically report hearing loss associated with foul-smelling aural discharge. The mass can remain undetected an d grow large, with a ris k of intratemporal or intracranial complications. Destruction of the bone overlying the semicircular canals can resu lt in dizziness and b alance disorders, and facial paralysis may resu lt if the fac ial nerve canal is affected {1299).

Macroscopy cholesteatoma is associated with a perforated eardrum. Most cases are associated with recurrent infection resulting in squamous epithelium growing down into the middle ear from the tympan ic mem brane {2583). Acqui red cho lesteatoma is also known to occur following tympanic membrane retraction, due to deep ingrowth of squamous epithelium from the fundus of th e retraction pocket into the middle ear. Cholesteatoma may also develop following a blast injury that causes perforation of the tympanic membrane (1282}. Cytokines and inflammatory mediators have been implicated in the development of cholesteatoma {424,1298).

Localization Congenital cholesteatoma arises in the anterior superior quadrant of the mesotympanum. Acquired cholesteatoma most commonly arises in the superior posterior middle ear (1599). Rarely, cholesteatoma is diagnosed in the externa! ear canal, where it must be distinguished from infection and other inflammatory conditions {969,182 1}. 270

Tumours of the ear

Cholesteatoma presents as a pearlywhite mass in the middle ear cavity. Cholesteatoma of the ear canal may be difficult to distinguish from other • inflammatory/infective disorders or squamous neoplasia {969,1821}.

Histopathology Biopsied cholesteatoma material typical ly consists of abundant anucleate keratin squames that make up the corneal layer of the squamous epithelium, together with otherwise normal ke ratinizing squamous epithelium. There may be evidence of increased proliferation of the deeper epithelial layers of the cholesteatoma matrix, with down-growths into the underlying stroma. The granular layer is usually prominent and a helpful diagnostic finding . The epithelium lacks atypia and often lacks rete pegs, yielding an atrophic appearance. There is usually an inflamed fibrous connective tissue stroma, a helpful fi nding for the diagnosis. Concurren! disorders (otic polyp, cho lesterol granuloma, encephalocoele) may be present.

Prognosis and predictive factors Treatment is surgery. The risk of recurrence is high, and follow-up is by surgery and direct observation . Follow-up scans with diffusion-weighted MRI may be effective for detecting disease recurrence {1136}. Long -term follow-up is required , because late recurrence can occur. Rare com plications of surgery include complete neurosensory hearing loss in the affected ear and damage to the facial nerve (the risk is usually < 1%).

Vesübularschwannoma Sandison A. Thompson L.D.R. Wenig B.M.

Definition Vestibular schwannoma is a benign peripheral nerve sheath tumour arising within the interna! auditory canal or within the labyrinth.

ICD-0 code

9560/0

Synonyms Acoustic neuroma; vestibular neuroma; neurilemmoma

Epidemiology Vestibular schwannoma is the most common tumour of temporal bone, accounting for 5- 10% of all intracranial tumours and 80- 90% of all cerebellopontine angle tumours; however, it is found incidentally in < 1% of adult autopsies performed for otherreasons {250,1386!. Overall, patients typically present in their fifth to sixth decade of life, but patients with neurofibromatosis type 2 (N F2) present significantlY younger (1 701}.

unsteady gait, and balance alterations may also occur. Facial pain, weakness, and loss of taste are more common with brain stem compression by the tumour (250). A fu nnelshaped widening of the interna! auditory canal or a mushroom-shaped mass (with the stalk in the canal and the flange within the cerebellopontine angle) can be seen as a hyperintense area on T2weighted MRI (1525). The tumours are radiographically staged on the basis of location, size, and extent (2125). Fig. 9.15 Vestibular schwannoma. On coronal slice from postcontrast MRI, the well-circumscribed lesion in the right cerebellar pontine angle can be clearly seen; the tumour is bright in comparison with the adjacent brain tissue and contains cystic hypointense areas.

greater risk of recurrence or malignan! transformation (167,2559). However, a watchful waiti ng approach (vs surgery) may be employed, because the tumou rs grow 1-4 mm per year {1449,1738}.

Meningioma Sandison A. Thompson L.D.R.

Definition Macroscopy A smooth, lobulated tumour mass creates a globular, eccentric mass, frequently attached to the eighth cranial nerve, which may be stretched or comp ressed. The tumou rs are usually < 2 cm (due to anatomical confines), with a firm, yellowish-tan, solid to cystic appearance.

Meningioma is a benign neoplasm of meningothelial (arachnoid) cells.

ICD-0 code

9530/0

Epidemiology Meningiomas constitute about 20-36 % of intracranial neoplasms. Primary

H istopathology

High-power view

Etiology For most cases the etiology is unknown, but trauma dueto extended occupational exposure to excessively loud noise may be a potential risk factor, whereas mobile phone use is nota demonstrated risk factor (1651). lnherited cases (associated with NF2) are uncommon (1 701).

Localization Most cases are unilateral and sporad ic cerebellopontine angle tumours arising within the vestibular division of the eighth cranial nerve, rarely affecting the cochlear d ivision (1717,2012}. When the tumours are bilateral or multicentric, there may be association with NF2 (1701). Rarely, the interna! auditory meatus may b e involved (250,2651).

The histological features are characteristic of a schwannoma, with cel lular (Antoni A) areas of closely packed spindle cells with nuclear palisading, adjacent to microcystic or loosely reticular (Antoni B) areas. The cells are fusiform, with fibril lary cytoplasm and buckled nuclei. They lack significan! pleomorphism, with limited mitoses and no necrosis. Perivascular hyalinization of medium-sized vesse ls is characteristic. Ancient change (nuclear degeneration) is usually only focal, whereas significan! pleomorphism, necrosis, and iñcreased mitoses suggest malignant peripheral nerve sheath tumour (135). The tumour cells are strongly positive for S100 protein and S0X10; GFAP staining is weak to absent; and CD34, NFP, BCL2, and EMA are negative (1608,2416). The Ki-67 proliferation index is higher in NF2associated tumo urs than in sporadic lesions {25}. The tumours should be distinguished from meningioma , neurofibroma, solitary fibrous tumour, p aragang lioma, and malignan! peripheral nerve sheath tumou r.

Genetic profile Clinical features The most common clinical manifestatio ns, usually present for many years, are unilateral progressive sensorineural hearing loss (occurring in > 90% of cases) and tinnitus (in 70% of cases) {2237,2261,2456). Headache, vertigo,

NF2 gene mutations (usually resulting in loss of merlin) are identified in .< 5% of tumours , most commonly in patients < 21 years of age {913}.

Prognosis and predictive factors Larger tumour size (> 18 mm) and NF2 association are features associated with

-

-

Fig. 9.1 7 Meningioma of themiddle ear. AThe characteristic whorled architecture of meningothelial meningioma is noted beneath an intact squamous epithelium. B Lobules and nests of bland epithelioid tumour cells are seen in syncytial architecture. C There is strong CAM5.2 reaclivity in a prepsammomatous pattern, quite characteristic of meningioma .


271

extracranial (i.e. ectopic or extracalvarial) meningiomas of the ear and temporal bone are rare, accounting for only about 2% of ali meningiomas and about 10% of ear and temporal bone tumours {2029,2386}. Meningioma affects women more often than men, with a femaleto-male ratio of 2:1. The mean patient age at presentation is 50 years (range: 10-90 years). The average patient age is older among women than among men (1920,2279,2386}.

Etiology The roles of radiation exposure and sex hormones in the genesis of ear and temporal bone meningiomas are unproven. Composite tumours as a result of a schwannoma merging with a meningioma may be seen in the setting of neurofibromatosis type 2 {1701).

Localization The tumours involve subsites in the temporal bone, in arder of frequency: the middle ear, interna! auditory meatus, jugular foramen, and roo/ of the Eustachian tube (1920,2029,2386}.

Clinical features Patients present clinically with hearing loss, tinnitus, otitis media, pain, headaches, dizziness, and/or vertigo, with symptoms usually having been present for years {2029,2279). Direct extension from the CNS must be radiographically or clinically excluded {2029,2386}. En plaque tumours must be excluded. lmaging usually shows bone erosion, sclerosis, and hyperostosis with temporal air ce!! opacification (2163,2279,2647).

are meningothelial, psammomatous, and fibroblastic. Lesiona! cells express EMA, CAM5 .2, and pancytokeratin as well as CK7 {pre- psammoma- body pattern), but Si00 prote in (weakly), claud in 1, progesterón e receptor, and vimentin are also positive. lmmunostaining for GFAP, SMA. synaptophysin, and chromogranin is negative.

Genetic susceptibility Meningiomas are well described in neurofibromatosis type 2, with chromosome 22 deletions being the most consisten! cytogenetic findi ng.

Prognosis and predictiva factors The prognosis is good, with a 5-year survival rate of about 85%, although recurrent or persisten! tumour is common (seen in 20% of cases). Mastoiditis and meningitis are the most common complications of surgery (2029,2279,2386, 2647).

Sandison A. Bell D. Thompson L.D.R.

Histopathology Definition Middle ear adenoma is a benign neoplasm of the middle ear showing cytomorphological and immunohisfochemical evidence of dual neuroendocrine and mucin-secreting differentiation.

ICD-0 code

8140/0

Synonyms Neuroendocrine adenoma of the middle ear; middle ear adenomatous tumour; carci noid of the middle ear; middle ear adenoma with neuroendocrine d ifferentiation; amphicrine adenoma

Histopathology

Tumours of the ear

The most common presenting symptorn is unilateral hearing loss (of the conductive type if the ossicular chain is involved) (19,614,2055,2414). Pressure, fullness, tinnitus, discharge, bleed ing, and otitis media are uncommonly seen. Otoscopic examination shows a soft tissue mass behind a usually intact tympanic mernbrane. Nerve compression is uncommon {1371} and serological evidence of neuroendocrine function is rare. CT (without contras!) or MR I visualizes tumour extent and exact location. There is usually no temporal bone destruction, although ossicular encasement is common (593, 1846,2414).

The tumour is white, grey, or reddish brown. lt is unencapsulated, frequently entrapping and destroying the ossicles. Most tumours are < 1 cm in size {19, 2055,2414).

Middle ear adenoma

Macroscopically, there is a gritty, granular mass infiltrating bone. The mass is usually < 1.5 cm in size, due to the anatomical confines of the region.

272

Clinical features

Macroscopy

Macroscopy

Microscopical ly, the tumour infiltrates bone and soft tissues of the reg ion, showing a well-developed meningothelial and whorled architecture. Lobules and nests of bland epithelioid tumour cells are seen in a syncytial architecture. Nuclei are round to oval, with delicate nuclear chromatin distribution and frequent intranuclear cytoplasmic inclusions. Psammoma bodies or pre-psammoma bodies may be seen. The most common types

the middle ear cavity, including in the tympanic membrane, and occasionally extend into the mastoid, Eustachian tube or externa! auditory canal {19,99,2055, 2414). '

Epidemiology This is a rare tumour of the middle ear, accounting for < 2% of ear tumours. lt has an equal sex distribution and has been reported over a wide patient age range (13- 80 years), with a mean patient age at presentation of 45 years {19,593, 1846,2414) .

Localization These tumours can arise anywhere in

The tumours lack a surface origin, showing an infiltrative, unencapsulated, moderately cellular growth of a variety of patterns, including glandular, trabecular, salid, acinar, cribriform , pseudoalveolar, organoid, nested, diffuse , and singlecell. The duct-like structu res show a loosely cohesive back-to-back appearance, and are often separated by a fibrotic to desmoplastic stroma. The neoplastic cells show a dual cell population of inner, luminal, slightly flattened eosinophilic cells frequently associated with a secretion, subtended by a basal, cuboidal to columnar cell population (19,1478, 2414} . The cells may have an eccentric (plasmacytoid) placement of a round to oval nucleus, showing delicate, fine, salt-and-pepper nuclear chromatin distribution. The nucleoli are small {99,1984, 2554). Mitoses are sparse, and there is no necrosis, perineural invasion, or lymphovascular invasion. lsolated pleomorphism may be seen, but is not profound. Concurren! cholesteatoma or cholesterol granuloma may be seen . There is variable but consistently present reaction with pancytokeratin, CAM5.2,

CK7 (luminal cells), CK5/6 and p63 (abluminal cells), synaptophysin, chromogranin, and CD56, along with various polypeptides (e.g . human pancreatic polypeptide) and transcription factors (e.g. ISL1 ). S100 protein, SMA, TTF1, CDX2, and PAX8 are negative {19,1478, 2414). Sorne cases may not show immunohistochemical neuroendocrine markers, but these do not require a separate designation. Ultrastructural examination shows two distinct cell types: type A api cal cells with microvilli and secretory mucus granules and type B cells with solid,

dense-core neurosecretory granules. There are also transitional forms of both types, confirming the dual differentiation {2554}. Mucoprotein luminal and cytoplasmic secretions are highlighted with periodic acid-Schiff (PAS) and Alcian b lue staining, and neurosecretory granules are highlighted by Grimelius stain {2414,2554}. Although it is not wrong to consider these tumours carcinoids {572, 1643,1954,2055}. it is appropriate to refer to these tumours as adenoma with neuroendocrine features, in line with curren! tumour taxonomy.

Prognosis and predictive factors Th e tum our usually peels away easily, but if middle ear bones are not included in the resection, recurrence or p ersistence is seen in about 15% of cases {614,1846, 2414). Parotid gland involvement via direct extension from a widely infiltrative tumour does not constitute metastatic disease (1371,1643,1954l A metastatic potential may exist; there is no indisputable evidence and further investigation is required.


273

CHAPTER10 Paraganglion tumours

Carotid body paraganglioma Laryngeal paraganglioma Middle ear paraganglioma Vagal paraganglioma

WHO classification of paraganglion tumours

8692/3* 8693/3* 8690/3* 8693/3*

Carotid body paraganglioma Laryngeal paraganglioma Middle ear paraganglioma Vagal paraganglioma

The morphology codes are from the lnternational Classification of Diseases far Oncology (ICD-0) {776AI. Behaviour is coded /0 for benign tumours; / 1 for unspecified, barderline, or uncertain behaviour; /2 for carcinoma in situ and grade 11 1 intraepithelial neoplasia; and /3 far malignant tumours. The classification is modified from the previous WHO c lassification, taking into account changes in our understanding of these lesions. 'These new codes were approved by the IARC/WHO Committee for ICD-0.

Paraganglion tumours

lntroduction Chan J.K.C .

There have been remarkable advances in our knowledge of the molecular genetics of paragangliomas since publication of the 3rd edition of the WHO classification {304,722}. Paraganglioma has been shown to have the highest degree of heritability among human neoplasms,

276


with as many as 40% of ali cases being associated with germline mutation in a known susceptibility gene {512, 722}. As a result, the Endocrine Society guidelines recommend referring ali patients with paraganglioma (including patients with an apparently sporadic tumour) for c linical genetic testing {1383}. In this 4th edition of the WHO c lassification, head and neck paragangliomas are classified as in the previous edition, with one change in terminology, from

"jugulotympanic paraganglioma" to "middle ear paraganglioma". The term "malignan! paraganglioma", traditionally used to refer to tumour complicated by metastasis, is no longer used in this classification because it is now recogn ized that all paragangliomas have sorne potential for metastasis (albeit variable). Tumours previously referred to as "malignant paraganglioma" can be described as "metastasizing paraganglioma" or "paraganglioma with metastasis" .

Carotid body paraganglioma

Kimura N. Capella C. GillA. Komminoth P.

Lam A.K.Y. Tischler A.S. Williams M.O.

/

Definition Carotid body paraganglioma is a neuroendocrine neoplasm ans,ng from the carotid body paraganglia near the carotid bifurcation.

ICD-0 code

8692/3

produce catecholamines are rare (accounting for < 5% of cases) {67,1332, 1753,1937,2047}. but are more common in metastatic tumours {1576}. lmaging with contrast confirms a hypervascular, well-defined mass at the carotid bifurcation.

Synonyms

Macroscopy

Carotid body tumour; chemodectoma; non-chromaffin paraganglioma

Paragangliomas are firm, rubbery, and often well circumscribed . The tumour size range is 2-6 cm, which may include a portian of the arterial wall with lumen.

Epidemiology Carotid body paragangliomas account for the majority (60%) of head and neck paragangliomas. They present in adults in their fifth or sixth decade of life (or about a decade younger in metastatic cases) {389,1576). There is a female-tomale ratio of 2 :1, and this female predilection is even more pronounced in popu lations living at high altitudes, where the female-to-male ratio is 8:1 {1365, 2006). Bilateral paragangliomas occur in as many as 10-25% of cases, with 4- 6% of cases being metastatic {67,1332,1753, 1937,2047}.

Cytology Aspirates are usually bloody, with low to moderate cellularity, showing single or clusters of cells with poorly defined borders and basophilic cytoplasm. Nuclei are round to elongated, with mild to moderate pleomorphism and prominent nucleoli. Reddish cytoplasmic granules may be identified on Giemsa-stained preparations {931).

Histopathology The organoid (Zellballen) pattern of the normal paraganglion is typically seen. However, a wide range of variant morphology may be observed, including trabecular, spindled, and angioma-like patterns, as well as a sclerosing pattern characterized by extensive collagen deposition with features mimicking those of an invasive malignan! neoplasm {1321). The tumours are composed of two cell types: chief cells, which have abundan! pale eosinophilic cytoplasm with slightly to moderately atypical nuclei, and sustentacular cells, which are slender, spindled, and located peripherally in the nests. A prominent vascular network separates the tumour nests . Mitotic f igures are usually rare. There is no cellular polarity within the nests, which helps to distinguish these tumours from other neuroendocrine tumours, such as carcinoid. The chie! cells express synaptophysin, chromogranin A, CD56, and somatostatin

Etiology Carotid body paragangliomas are predominately parasympathetic, with genetic factors identified in one third of cases. Chronic hypoxia, including that due to living at high altitudes, is a risk facto r (2006).

Localization Caroti d body paragangliomas arise at the bifu rcation of the common carotid artery. They may be associated with the externa! or interna! carotid branch and may grow circumferenti ally around the vessel (Shamblin class 111 ) {2141).

Clinical features The usual presentation is an asymptomatic or pulsatile high neck mass near the anterior border of th e sternocleidomastoid muscle near the mandible. Pain, syncope, and Horner syndrome (oculosympathetic palsy) are rare manifestations. Clinically functional tumours that

Fig. 10.01 Carotid body paraganglioma. A Circumscribed bilateral carotid body paragangliomas (arrows) on coronal contrasted CT. B Angiography of the larger, right paraganglioma shows the highly complex vascular network of vessels (arrow) that often necessitates embolization prior to resection. e On cut surface, the tumour has a homogeneously tan-pink, elastic, firm appearance, with areas of fibrosis.


277

receptor 2A (653,1232}, and are typi cally negative far cytokeratin, carcinoembryonic antigen, and calcitonin. Approximately 30% express tyrosine hydroxylase, which is requi red far catecholamine synthesis {1786), but staining is often only focal {2408), consistent with the typical lack of clinical function. The sustentacular cells express S100 protein and GFAP, but are negative far epithelial and neuroendocrine markers. The Ki-67 (M IB1) proliferation index is generally < 1%, consistent with the slow growth of carotid body paragangliomas (555). The loss of immunohistochemical staining of neoplastic chief cells far the SDHB protein has recently been found to be significantly correlated with germline mutation of any of the SDH complex genes, but is not seen in sporadic ar non- SDH-mutant cases (2472). This immunohistochemical test can therefore be used as a screening method to guide genetic testing. Tumours that should be distinguished from paragangliomas include carcinoid and well-differentiated neuroendocrine tumour, medullary thyroid carcinoma, hyalinizing trabecular tumour of the thyroid gland, and (rarely) haemangiopericytoma 278


and glomus tumour. The combination of positive immunostaining far chromogranin A, synaptophysin, GFAP, S100 protein, and tyrosine hydroxylase and the absence of cytokeratin is helpful far distinguishing paragangliomas from · these tumours.

Genetic susceptibility Collectively, phaeochromocytomas, sympathetic paragangliomas, and head and neck (parasympathetic) paragangliomas are the most hereditarily driven of all human tumours, with at least 19 susceptibility genes identified to date (1 798} (see Table 10.01). Tumour location, multiplicity, biochemical function, metastatic risk, and syndromic associations depend on the specific gene involved . A predisposing germline mutation is present in :;,: 30% of all patients and in 7- 13% of those presenting with an apparently sporad ic tumour {272). Most mutated genes causing hereditary paragangliomas have an autosomal dominant mode of inheritance, with loss or inactivation of the wildtype allele in a tumour. Exceptions are th e RET proto-oncogene and EPAS1 (also called HIF2A), which exhibits

gain-of-function mutations not requiring a second hit, although allelic imbalance can occur (1256). lnheritance of three genes (SOHO, SDHAF2, and MAX) involves a parent- of-origin effect, such that transmission can occur from either parent, but an affected child usually develops paraganglioma only if the mutated gene was received from the father (164). This may lead to generation skipping of tumour susceptibility in affected families, which mus! be considered when family history is examined. To date, genomic imprinting at the disease gene locus has not been unequivocally identified as the mechanism of this parent-of-origin effect, and severa! other mechanisms have also been proposed {164). Th e highest rates of head and neck paraganglioma are associated with germline mutations in SDHD or SDHC, followed by S0HAF2 and SOHB (Table 10.01) (176, 1060). These genes, along with SOHA. are collectively known as the SDH genes. Most head and neck paragangliomas in SOHD-mutation carriers are multiple, and approximately 85% are carotid body paragangliomas {307,1824). In contrast. SOHC mutation is usually associated with

single head and neck paragangliomas. SDHB mutation is associated mainly with extra-adrenal abdominal and pelvic paragangliomas (227}, although tumours can also be found in the head and neck {844). Most hereditary paragangliomas have syndromic associations with other endocrine and/or non-endocrine tumours that have only recently been recognized {512,1798}. These tumours can present before, after, or simultaneously with paraganglioma, making it difficult to recognize index patients. The identification of an association of germline SDH gene defects with

and paraganglioma syndromes overlap or are part of the same disease. Another condition in which paraganglioma can be found is Carney triad {338). Affected individuals (mostly females) present with paraganglioma, gastrointestinal stromal tum our, and pulmonary chondroma. To date, no inherited trait has been established, although Carney triad can rarely be allelic to Carney~Stratakis syndrome (231}. Deletions within the 1pcen13-q21 region (which harbours the SDHC gene) and aberrant DNA hypermethylation of SDHC have been proposed as possible mechanisms of tumour development in Carney triad (924,1560}. Somatic mutations of hereditary susceptibility genes are found in as many as 20% of truly sporadic phaeochromocytoma/ paraganglioma cases without indication of heritable disease {512). SDH genes are seldom or never mutated in the nonfami lial, sporadic tumours, whereas somatic NF1 mutations are common {512) (see Table 10.01). However, these driver gene mutations alone are not sufficient for tumorigenesis in either hereditary or sporadic tumours, and the complete set of requirements remains unknown.

the development of pituitary adenoma, paraganglioma, and phaeochromocytoma, called the 3P association, has expanded the spectrum of tumours considered to be SDH-associated (2650). The fami lia! occurrence of combined gastrointestinal stromal tumour and paraganglioma has been termed Carney-Stratakis syndrome (or paraganglioma and gastric stromal sarcoma) (339}. Since the initial description of this association in 2002, it has been demonstrated that most of these patients harbour mutations in one of the SDH genes (1823,2289}, indicating that Carney~Stratakis syndrome

Table 10.01 Major mutated genes causing hereditary head and neck paraganglioma (HNPGL) 1

Syndrome

Chromosome

lnheritance

Frequency of HNPGLin gene carriers

SDHD

PGL1/CSS

11q23

AD-PT

79-89%

Multiple

4%

14- 53%

12- 39%

RCC, GIST, PA

{1762, 1798, 1824)

SDHAF2

PGL2/CSS

11q12.2

AD-PT

73-86%

Multiple

Low

-

-

None reported

(1762,1798}

SDHC

PGL3/CSS

1q23.3

AD

88%

Single

3%

< 3%

Very rare

RCC, (GIST)

(1798,1 824}

SDHB

PGL4/CSS

1p36.3

AD

27- 62%

Multiple

23%

18-28%

5p15.33

AD

?

Single

Low

1

Gene

...

-

Number of tumours

Rlskof metastasis

PCC

Thoracoabdomlnal PGL

Other syndromic leslons

References

! r--

SDHA

-

1

-

52- 84% 1 RCC, GIST, PA

....

-

PGL5/CSS

Rare

+

(RCC), GIST, PA

(303,1 798}

-

f-

(227,1762, 1798,1824)

VHL

VHL

3p25-26

AD

0.5%

Single

4%

10-34%

Rare

RCC, HB

{1762,2527}

RET

MEN2

10q11.2

AD

Very rare

Single

<5%

50%

Rare

MTC, HPT, (GNM)

{488,2526}

1- 5%

Rare

Café-au-lait spots, NF, PNST, SOM, Lisch nodules, GIST

(488,1739)

+

+

None reported

{1762)

~

NF1

NF1

'

1

17q11.2

AD

Very rare

Non-syndromic

12% 1

1

1

TMEM127

Single

2q11 .2

AD

1- 2%

Multiple

Low

Parentheses within the column "Other syndromic lesions" lndicate that the lesion is not obligatory and/or is a rare componen! of the syndrome. AD, autosomal dominan!; ADPT, autosomal dominan! with paternal transmission (disease is inherited only from paternal carrier); CSS, Carney- Stratakis syndrome (paraganglioma and gastric stromal sarcoma); GIST, gastrointestinal stromal tumour; GNM, ganglioneuromatosis; HB, haemangioblastoma; HPT, hyperparathyroidism; MEN2, multiple endocrine neoplasia type 2; MTC, medullary thyroid carcinoma; NF, neurofibroma; NF1, neurofibromatosis type 1; PA, pituitary adenoma; PCC, phaeochromocytoma; PGL, paraganglioma; PGL1 - 5, paraganglioma syndrome types 1- 5; PNST, peripheral nerve sheath tumour; RCC, renal cell carcinoma; SOM, duodenal somatostatinoma; VHL, von Hippel-Lindau disease.


279

A variety of other changes, including mutations of additional genes, copy-number chan ges reflected in chromosomal gains or losses, and epigenetic modifications, have been identified. SDH-mutant tumours show frequent combinations of -1p and +1q, whereas VHL-mutant tumours have combined deletions at 3pq and 11p. Gains of genomic material occur less frequently, and amplifications have not been reported . SDH genes (in particular SDHB) in SDH-mutant paragangliomas are hypermethylated, leading to silencing of genes involved in neuroendocrine differentiation ¡353,1390). In contrast, sporadic tumours and tumours with mutant RET, NF1, MAX, TMEM127, or HRAS are associated with widespread hypomethylation outside of CpG islands {1390). lt has been suggested that DNA methylation profiling might be useful to predict tumour aggressiveness {536). The expression profiles of microRNAs are reported to be differentially expressed in genetic subtypes of paraganglioma and to correlate with transcriptome-based classifications {355,1080). More recently, a refined classification based on integrated genomic analyses, including chromosomal changes, microRNA profiles, and epigenetic alterations {354,355,740}, has been proposed .

Prognosis and predictiva factors Carotid body paragangliomas are slowgrowing tumours. The most common treatment is surgery with or without adjuvant radiation, although more conservative approaches have been suggested {2133,651A). Overall, recurrence alter

280


Table 10.02 PhaeochromocytomaI paraganglioma susceptibility genes

Types of mutalions

Genes

Germline only

SDHA, S0HAF2, SDHC, KIF18, TMEM127, FH

Germline and somatic

NF1, RET, VHL, SDHD, SOHB, MAX

Somaticonly

HRAS,ATRX

Somatic and somatic mosaicism

EPAS1 (also called HIF2A)

Single patients or families

MEN1, EGLN1 (also called PDH2), EGLN2 (also called PDH1), MDH2, IDH1

Table 10.03 The most importan! somatic mutations in sporadic phaeochromocvtoma/oaraaanalioma

Gene

Frequency of mutation

References

NF1

21-41%

{305,2581}

ATRX

12.6%

{723)

HRAS

5-10%

(498,1491,1788}

VHL

9.2%

{308}

5-7.4%

(475,2580}

CDKN2A

7%

(355}

RET

5%

(308}

TP53

2.35-10%

{355,1491}

MET

2.5%

(355}

BRAF

1.2%

(1491}

MAX

1.65-2.5%

{306,308}

EPAS1 (also called HIF2A)

IDH1

Very rare

(788}

KIF18

Very rare

(2096}

SDH family

Very rare

{162,501,1824,2473}

resection occurs in < 10% of cases, but the rate may exceed 50% among patients with SDHB mutations, suggesting that treatment strategies can be tailored according to genotype {651A). There are no validated histological criteria to predict metastasis at present. The overall 5-year survival rate for metastasizing paraganglioma (including

-

cervical nodal metastasis and distan! metastasis) is 88% . Patients with distan! metastases and patients with SDHB-mutant paragangliomas have the lowest 5-year survival rates: 11% and 36.5%, respectively (302,1365,2133).

Laryngeal paraganglioma

Kimura N. Capella C. GillA.

Definition

should be taken to avoid misdiagnosis of laryngeal carcinoid tumours or neuroendocrine carcinomas as paragangliomas [140,1678).

Laryngeal paraganglioma is a neuroendocrine neoplasm derived from either the superior or the inferior paraganglia of the larynx.

ICD-0 code

8693/3

aryepiglottic fold 1140). Subglottic paragangliomas (15% of cases) arise from the inferior pair of laryngeal paraganglia, and may extend laterally to present as thyroid masses (1678). Right-side laryngeal paragangliomas are more common; the ratio of right-side to left-side incidence is 2 .3:1 (140).

Synonyms Chemodectoma; non-chromaffin paraganglioma

Epidemiology True laryngeal paragangliomas are very rare. Sorne cases previously reported as laryngeal paraganglioma may in fact be misidentified carcinoid tumours, and only 76 definite cases of laryngeal paraganglioma had been reported by 2004 (1678). Unlike other neuroendocrine tumours of the larynx, paraganglioma is more common in females, with a female-to-male ratio of 3:1 {1678,1893}. Most tumours present in the fourth to sixth decades of life, but a wide patient age range has been reported (5- 83 years) (1678).

Clinical features Paragangliomas may present with dysphagia, dyspnoea, or stridor, but th e symptoms largely depend on location; supraglottic tumours more com monly present with hoarseness, whereas subglottic tumours more commonly present as a mass (often in the thyroid) (1678, 2223). Symptoms due to catecholamine production occur rarely, if ever {140, 1678). and most tumours reported as functional laryngeal paraganglioma are probably misidentified atypical carcinoids (1097,1160,2498}.

Macroscopy

Localization

Laryngeal paragangliomas are usually well-circumscribed submucosal masses (140).

The larynx contains two pairs of paraganglia: superior and inferior (140). Supraglottic paragangliomas (82% of cases) appear to arise from the superior pair of laryngeal paraganglia, and present as a submucosal mass in the reg ion of the

The morphology and immunohistochemical profile are similar to !hose of paragangliomas at other siles (see Carotid body paragang/ioma, p. 277). Particular care

Komminoth P. Lam A .K.Y. Tischler A.S. Williams M.O.

Genetic susceptibility In head and neck paragangliomas, germline mutations of the succinate dehydrogenase genes (SDHA , SOHB, SDHC, and SOHO) are particularly common [163,814,837,2024]. and these mutations have been reported or presumed in laryngeal paragangliomas {814,2024l.

Prognosis and predictive factors Surg ical excision is the treatment of choice j705}. Recurrence after surgery has been reported in as many as 17% of patients, 1-1 6 years after excision (140). However, given the frequent association with germline mutation, many such cases may in fact constitute second primary tumours rather than true recurrence. Metastasis is exceptional; the few cases previously reported as "malignan!" laryngeal paraganglioma were in fact misidentified atypical carcinoids {140). The best estímate of the rate of metastasis is 2% (533,705,2026).

Histopathology

Fig. 10.04 Laryngeal paraganglioma. A Contrast-enhanced sagittal CT shows an enhancing heterogeneous mass (arrow) filling the left supraglottic region. B Nests of paraganglion cells (arrow), called Zellballen, are noted beneath the squamous mucosa, accompanied by prominent vasculature.

Laryngeal paraganglioma

281

Middle ear paraganglioma

Kimura N. Capella C. Gill A. Komminoth P.

Lam A.K.Y. Tischler A.S. Williams M.O.

/

Definition Middle ear paraganglioma is a neuroendocrine neoplasm arising from the paraganglia in the adventitia of the jugular bulb or on the medial promontory wall of the middle ear. ICD-0 code

8690/3

Synonyms Jugulotympanic chemodectoma; glomus jugulare tumour; glomus tympanicum tumour Epidemiology Middle ear paragangliomas account far about 29% of all head and neck paragangliomas {660,2721). About 66-90% of middle ear paragangliomas occur in women. The patient age range is 26-79 years (mean: 55 years), and bimodal incidence peaks are seen in the fourth and seventh decades of life {336). In men, the tumour presents ata younger age and the fami lia! type occurs more frequently. Localization Most middle ear paragangliomas are jugular neoplasms, originating from a paraganglion in the adventitia of the jugular bulb. Less commonly, they are tympanic neoplasms, arising from a paraganglion associated with the tympanic nerve (nerve of Jacobson). Jugular neoplasms invade petrous bone, whereas tympanic neoplasms occupy the middle ear cavity. Middle ear paragangliomas can be bilateral and associated with paragangliomas of other sil es (e .g. carotid body and vagal paragangliomas) (336). They can also coexist with phaeochromocytoma. Clinical features Patients commonly present with pulsatile tinnitus, subjective hearing loss, and aural fullness. Otalgia and symptoms suggestive of lower cranial neuropathy

282


B Fig. 10.05 Middle ear paraganglioma. A Typical appearance on axial contrast-enhanced T1-weighted MRI. The contrast-enhanced jugular foramen neoplasm (arrows) has the typical salt-and-pepper appearance, due to the combination of foci of haemorrhage (the sal!) and flow voids (the pepper). B On otoscopy, the tumour is recognizable as a vascular mass appearing behind the intact tympanic membrane.

Histopathology The histology and immunoprofile are similar to those of carotid body paraganglioma (see Carotid body paraganglioma, p. 277). Lack of immunoreactivity for cytokeratins and p63 is useful in the differential diagnosis from middle ear adenoma {1478).

·-. '

Fig. 10.06 Middle ear paraganglioma showing nests of tumour cells with rich vascular network.

(e.g. dysphonia and dysphagia) may be noted. On otoscopic examination, the tumour is recogn izable as a red, vascular mass either appearing behind the intact tympanic membrane or protruding through the tympanic membrane into the externa! canal. Neurosecretory function is rare. Macroscopy The neoplasm presents as an irregular, red, fleshy mass. The jugular variety invades the petrous portian of the temporal bone as well as the middle ear cavity. Massive middle ear paragangliomas with extensive erosion of the petrous bone and intracranial impingement are rare. In exceptional cases, the tumour extends intravenously. The tumou r appearance can be modified by preoperative ·1umour embolization and/or radiotherapy.

Genetic susceptibility Hereditary syndromes such as neurofibromatosis and phaeochromocytomaparaganglioma syndrome have been reported in patients with middle ear paraganglioma (226,548,2091) . Middle ear paraganglioma can occur in familia! settings, typically with multiple tumours and together with carotid body paraganglioma. Prognosis and pred ictiva factors Metastasis has been reported in as many as 5% of cases (1526). In older patients, the tumour often remains stable far many years and may have slow growth with progressive cranial neuropathy; therefore, observation can be a reasonable management strategy (337). Lack of immunostaining far SDHB is associated with an increased risk of metastasis.

Vagal paraganglioma

Kimura N. Capella C . Gill A.

Definition

Macroscopy

Vagal paraganglioma is a neuroendocrine neoplasm arising from paraganglia in the vaga l trunk near its exit from the brain stem. Paragangliomas associated with peripheral vagus nerve branches are usually defined by their anatomical site (e.g. laryngeal paragangliomas).

Most vagal paragangliomas are globoid or elongated tumours, partially or completely surrounded by a fib rous capsule. The most rostral examples can be coneshaped because of adhesion to the skull base, or dumbbell-shaped because of intracran ial extensio n through the jugular foramen {970}. The cut surface is variably pinkish-grey, p inkish-tan, o r yellowish-tan, w ith areas of fibrosis and haemorrhage.

ICD-0 code

8693/3

Synonyms Glomus vagale tumour; chemodectoma; non-chromaffin paraganglioma

Epidemiology Vagal paragangliomas account for approximately 13% of a ll head and neck paragangliomas. They are the third most common paragangliomas in this body site, alter carotid body and middle ear tumours {660,2721). They usually present in middle-aged patients (mean patient age: 41-47 years (660}) but have also been reported in chi ldren and in elderly patients. Most series show a female predominance (with 50- 85% of cases occurring in females) (188, 1618,1722, 2226}. Multicentric tumours are seen in 17- 37% of cases overall and in as many as 80% of cases in patients with a positive family history (327). Vaga! paragangliomas can occur bilaterally and in combination with other paragangliomas [2721}.

Localization Vaga! paragangl iomas arise from microscopic variably distributed paraganglia within or adjacent to the vagal nerve and its ganglia. Most tumours occur within the first 2 cm of the nerve, at th e level of the inferior (nodose) ganglion, but sorne are more rostral o r more caudal. Anatomical imaging typically shows tumours superior to the carotid bifurcation, displacing the bifurcation anterio rly and medially but not enlarging it. These findings distinguish vagal paragangliomas from their carotid body counterparts.

Komminoth P. Lam A. K.Y. Tisch ler A.S.

Histopathology Fig. 10.07 Vagal paraganglioma. MR angiogram showing a vagal paraganglioma on the left (red arrow) and a carotid paraganglioma on the right (white arrow). The vagal tumour is located well above the carotid bifurcation, displacing it anteriorly and medially.

Vagal paragangliomas are morpholog ica lly and immunohistochemically similar to other paragangliomas in the head and neck (see Carotid body paraganglioma, p. 277).

Clinical features


The signs and symptoms depend on the tumour location in relation to the vagus nerve, the consequent location w ithin the parapharyngeal space {970}. tumour size, and the presence or absence of infiltration. Cranial nerve palsies can be caused by direct involvement of the vagus nerve or compression of nerves IX, XI, and XII. Other reported manifestations include Horner syndrome (oculosympathetic palsy) caused by damage to the cervical sympathetic chain and slowgrowing masses that displace or infiltrate adjacent t issues (970). Historically, many patients presented with palpable masses in the neck or pharynx and intracranial extension with damage to multiple eranial nerves (970,2448). In recent stu dies. vaga! paragangliomas are sometimes first detected by imaging of patients with a personal or family history of paragangliomas or as incidentalomas, and as many as 70% of these patients are asymptomatic {1 332). Less than 4% of vagal paraga[)gliomas are clinically functional, producing norepinephrine or dopamine {660,893}. In suspected functional cases, care must be taken to rule out the possibility that the hormone is being produced by a second primary tumour.

The p redisposing mutations usually involve one of the genes encoding succinate dehydrogenase subunits. Rare cases involve mutations of S0HAF2, the gene encoding the flavination factor for SDHA {1295). In a series of 37 vagal paragangliomas w ith an inherited basis, 33 cases (89%) harboured mutations in SDHD, 3 cases (8%) in SDHB, and 1 case (3%) in SDHC {2334).

Prognosis and predictive factors The prognosis depends on tumour location, size, and genotype, as well as comorbid ities. including other paragang liomas. Currently, the majar treatment options are external-beam radiotherapy and stereotactic radiosurgery, which are sometimes used in combinations that may include chemotherapy {327f. Although the surgical cure rate is > 90%, almost all surgically treated patients have severe vagal nerve deficits, and as many as 61% have postoperative neurological compl ications caused by damage to other cranial nerves {327}. In contras!, two series that monitored vagal and other head and neck paragangliomas for periods of 1- 17 years showed that untreated tumours usually grow very slowly or remain stable for long periods (111 4,1332}. Vagal paraganglioma

283

indicating that clase abservation without treatment can be an optian {252}. In sorne series, vagal paragangliamas have been reparted to have a higher frequency of metastasis than ather head and neck paragangliamas, with metastasis accurring in as many as 16% of vagal

284

Paraganglion tumaurs

tumaurs versus in 2- 6% af caratid bady and middle ear tumaurs (327) . However, in sorne cases, the passibility of a secand primary rather than metastasis may nat have been ruled out. The most cammon site af metastasis is the cervical lymph nades (accounting far as many as

73% of cases), followed by bane, lung, and liver {970}. Because metastases may accur after years ar decades, lang-terrn follaw-up is required. Overall survival with distan! metastases varies, but can exceed 1O years even without treatment.

Contributors

Dr Kehinde ADEBIYI Oepartment of Oral Pathology and Oral Medicine Lagos State University College of Medicine Lagos NIGERIA Tel. +234 8033 447 558 [email protected]

Dr Elizabeth A. BILODEAU Oepartment of Diagnostic Sciences University of Pittsburgh School of Dental Medicine 3501 Terrace Street, Gi35 Salk Annex Pittsburgh PA 15261 USA Tel. +14123837949 [email protected]

Dr Steve BUDNICK Atlanta Oral Pathology 1209 Springdale Road Decatur GA 30033 USA Tel. + 1 678 592 3386 [email protected]

Dr Carl M. ALLEN Division of Oral & Maxillofacial Pathology & Radiology College of Dentistry, The Ohio State University Central Ohio Skin & Cancer, lnc 300 Polaris Parkway, Suite 3300 Westerville OH 43082 USA Tel.+ 1 614 823 5597 Fax+ 1 614 823 5468 [email protected]

Dr Justin A. BISHOP Department of Pathology Johns Hopkins University School of Medicine 401 North Broadway, Weinberg 2249 Baltimore MD 21231 USA Tel. +1410 955 8116 Fax +1410 955 0115 [email protected]

Dr Jórn BULLERDIEK University of Bremen Leobenerstrasse, ZHG 28359 Bremen GERMANY Tel. +49 42121861501 Fax +49 421 218 61505 bullerd@uni-bremen,de

Dr Adel ASSAAD Virginia Masan Medical Center 1100 9th Avenue Seattle WA 98101 USA Tel. +12066241144 [email protected]

Dr Elisabeth BLOEMENA Department of Oral and Maxillofacial Surgery, Department of Pathology VU University Medical Center, Academic Centre for Dentistry De Boelelaan 11 í 7 1081 HV Amsterdam THE NETHERLANDS Tel. +31 20 444 40 14 [email protected]

Dr Cario CAPELLA Department of Surgical and Morphological Sciences University of lnsubria - Varese Via O. Rossi 9 21100 Varese ITALY Tel. +39 332 270 601 Fax +39 332 270 600 [email protected]

Dr Daniel BAUMHOER'

DrSonja BOY

Department of Pathology University Hospital Base! Schoenbeinstrasse 40 4031 Basel SWITZERLAND Tel.+41613286892 Fax +41 61 265 35 13 daniel,[email protected]

Unit of Oral Pathology School of Oral Health Sciences Sefako Makgatho Health Sciences University Molotlegi Street 1 Ga-Rankuwa, Pretoria SOUTH AFRICA Tel. +27 82 654 3256 Fax +27 12 521 427 4 [email protected]

Dr Antonio CARDESA Department of Anatomic Pathology Faculty of Medicine, University of Barcelona August Pi i Sunyer Biomedical Res. lnstitute Villarroel, 170 08036 Barcelona SPAIN Tel. +34 93 227 5450 Fax +34 93 227 5717 [email protected]

Dr Diana BELL*

Dr Margare! BRANDWEIN-GENSLER' Department of Pathology & Anatomical Sciences State University of New York at Buffalo Erie County Medica! Center 462 Grider Street Buffalo NY 14215 USA Tel. +1716898 3114 Fax + 1 716 898 3090 [email protected]

Dr Roman CARLOS Oral Pathology, Clínico de Cabeza y Cuello Hospital Herrera-Llerandi 6a. Avenida 7-39 Zona iO Edificio 1-as Brisas of. 501 0101 O Guatemala City GUATEMALA Tel. +502 2362 6001 ext Fax +502 2362 6003 [email protected]

Oepartment of Pathology University of Texas MD Anderson Cancer Center í 515 Holcombe Boulevard, Unit 0085 Houston TX 77030 USA Tel. +1713792 2041 Fax+17137458610 [email protected]

*lndicates participation in the Working Group Meeting on the WHO Classification of Head and Neck Tumours that was held in Lyon, France, 14-16 January 2016. # lndicates disclosure of interests.

Contributors

285

Dr Odile CASIRAGHI Gustave Roussy, Université Paris-Saclay Département de Biologie et Pathologie Médicales 114 Rue Édouard-Vaillant 94805 Villejuif FRANGE [email protected]

Dr Hedley COLEMAN Tissue Pathology & Diagnostic Oncology lnstitute for Clinical Pathology and Medica! Research Sydney Westmead, Locked Bag 9001 NSW, 2145 Sydney AUSTRALIA Tel. +61 2 9845 7772 Fax +61 2 9687 2330 [email protected]

Dr Hanadi A. FATANI Pathology and Clinical Laboratory Medicine Administration King Fahad Medica! City Riyadh SAUDI ARABIA Tel. +966 112889000 ext. 11540 [email protected]

Dr James CASTLE Department of Oral & Maxillofacial Pathology Naval Postgraduate Dental School, NMPDC Walter Reed National Military Medical Center 8955 Wood Road Bethesda MD 20889-5628 USA Tel.+ 1 301 295 5373 Fax +1 301 2951216 james.t.castle4.mil@maiLmil

Dr Patricia DEVILLIERS Department of Anatomic Pathology Dynamic Pathology 14730 Second Avenue Circle Northeast Bradenton FL 34212 USA Tel. + 1 205 790 5866 [email protected]

Dr Andrew L. FELDMAN# Department of Laboratory Medicine and Pathology Mayo Clinic 200 First Street Southwest Rochester MN 55905 USA Tel. + 1 507 284 4939 Fax+ 1 507 284 5115 [email protected]

Dr John K.C. CHAN" Department of Pathology Queen Elizabeth Hospital Gascoigne Road, Kowloon Hong Kong SAR CHINA Tel. +852 3506 6830 Fax +832 2385 2455 [email protected]

Dr Silvana DI PALMA Department of Histopathology Royal Surrey County Hospital Egerton Road Guildford, Surrey GU2 ?XX UNITED KINGDOM Tel. +441483 571 122 ext. 2371 Fax +441483 452 718 [email protected]

Dr Judith A. FERRY' Department of Pathology Massachusetts General Hospital 55 Fruit Street Bastan MA 02114 USA Tel. +1617726 4826 Fax+16177269312 [email protected]

DrWah CHEUK Department of Pathology Queen Elizabeth Hospital Gascoigne Road, Kowloon Hong Kong SAR CHINA Tel. +852 3506 5739 Fax +852 2385 2455 [email protected]

Dr Samir K. EL-MOFTY'

Dr Uta FLUCKE

Department of Pathology and lmmunology Washington University School of Medicine Campus Box 8118, 660 South Euclid Avenue Saint Louis MO 631 iO USA Tel. + 1 314 362 2681 Fax +1 314 747 4392 [email protected]

Department of Pathology Radboud University Nijmegen Medica! Center PO Box 9101 6500 HB Nijmegen THE NETHERLANDS [email protected]

Dr Simon CHIOSEA Department of Pathology UPMC Presbyterian Hospital 200 Lothrop Street, PUH A610.3 Pittsburgh PA 15213 USA Tel. +1412647 5565 Fax +1412647 7799 [email protected]

Dr Adel K. EL-NAGGAR' University of Texas MD Anderson Cancer Center 1515 Holcombe Boulevard, Unit 0085 Houston TX 77030 USA Tel. +1713792 3109 Fax +17137451105 [email protected]

Dr Shih-Sung CHUANG# Department of Pathology Chi Mei Medica! Center 901, Chung Hwa Road 7i004 Tainan Taiwan CHINA Tel. +886 6 281 2811 ext. 53686 Fax +886 6 251 1235 cmh5301 @mail. chimei .org. tw

Dr John Edward FANTASIA Department of Dental Medicine Long lsland Jewish Medica! Center Hofstra Northwell School of Medicine 270-05 76th Avenue New Hyde Park NY 11040 USA Tel. +1718470 7116 Fax +1516470 5644 [email protected]

286

Contributors

Dr Isabel FONSECA Faculdade de Medicina, Universidade de Lisboa & Instituto Portugués de Oncología Francisco Gentil - Lisboa Avenida Professor Egas Moniz 1649-028 Lisbon PORTUGAL Tel. +351 217229825 Fax +351 217200475 [email protected]

Dr Maria Pia FOSCHINI Dipartimento di Scienze Biomediche e Neuromotorie University of Bologna Via Altura 3 40123 Bologna ITALY Tel. +39 051 6225523 Fax +39 051 6225759 [email protected]

Dr Craig B. FOWLER Oepartment of Oral and Maxillofacial Pathology University of Kentucky College of Dentistry 800 Rose Street. MN528 Lexington KY 40536-0297 USA Tel. + 1 859 323 5515 Fax + 1 859 323 2525 [email protected]

Dr Maura GILLISON Division of Medica! Oncology The Ohio State University 420 West 12th Avenue, Room 690 Columbus OH 4321 O USA Tel. +1614247 4589 Fax+ 1614688 4245 [email protected]; [email protected]

Dr Alessandro FRANCHI

Dr Douglas R. GNEPP•

Oipartimento di Chirurgia e Medicina Traslazionale (OCMT) UniversitB degli Studi di Firenze e/o Anatomia Patologica - Largo Brambilla 350134 Firenze ITALY Tel. +39 55 447 8102 Fax +39 55 275 1731 al e ssand ro. franc hi@u nif i. it

Department of Head and Neck Pathology University Pathologists Diagnostics 1030 President Avenue, Suite 213 Fall River MA 02720 USA Tel. + 1 401 996 3981 Fax + 1 508 235 6310 [email protected]

Dr Christopher A. FRENCH#

Dr Jennifer R. GRANDIS•

Department of Pathology Brigham and Women's Hospital Harvard Medical School 77 Avenue Louis Pasteur, Room 630G Bastan MA 02115 USA Tel.+16175254415 Fax+ 1 617 525 4422 [email protected]

Department of Otolaryngology Head and Neck Surgery University of California, San Francisco 550 16th Street, Box 0558 San Francisco CA 94143 USA Tel.+14155148899 jennifer [email protected]

Dr Stephan IHRLER Labor für Dermatohistologie und Oralpathologie Bayerstrasse 69 80335 Munich GERMANY Tel. +49 89 9788 0450 Fax +49 89 3402 327 4 [email protected]

Dr Nina GALE*

Dr Kristiina HEIKINHEIMO

Dr Hiroshi INAGAKI#

lnstitute of Pathology Faculty of Medicine, University of Ljubljana Korytkova 2 1000 Ljubljana SLOVENIA Tel. +386 1 543 7151 Fax +386 1 543 7104 [email protected]

Department of Oral Diagnostic Sciences lnstitute of Dentistry University of Eastern Finland Yliopistonranta 1, Box 1627 70211 Kuopio FINLAND Tel. +358 50 564 2669 [email protected]

Department of Pathology and Molecular Diagnostics Nagoya City University i Kawasumi Mizuho-ku Aichi Prefecture 467-8601 Nagoya JAPAN Tel. +81 52 853 8005 [email protected]

Dr Philippe GAULARD

Dr Tim HELLIWELL

Department of Pathology Henri Mondar Hospital, INSERM U841 51 Avenue du Maréchal de Lattre de Tassigny 9401 O Créteil FRANGE Tel. +33149812743 Fax +33 1 49 81 27 33 [email protected]

Molecular and Clinical Cancer Medicine University of Liverpool Duncan Building, Daulby Street Liverpool L69 3GA UNITED KINGDOM Tel. +441517064492 Fax +44 151 706 5859 [email protected]

Dr Elaine S. JAFFE# Laboratory of Pathology, Center for Cancer Research, National Cancer lnstitute Building 10, Room 3S 235, 10 Center Orive MSC-1500 Bethesda MD 20892-1500 USA Tel. + 1 301 480 8040 Fax + 1 301 480 8089 [email protected]

Dr Anthony GILL

DrJos HILLE Department of Oral & Maxillofacial Pathology University of the Western Cape & National Health Laboratory Service Tygerberg, Cape T own SOUTH AFRICA Tel. +27 21 938 4041 Fax +27 21 938 6559 [email protected]

Department of Anatomical Pathology Royal North Shore Hospital Reserve Road NSW 2065 St Leonards AUSTRALIA Tel. +61 2 9926 4399 Fax +61 2 9926 4084 [email protected]

Dr Jennifer L. HUNT Department of Pathology University of Arkansas far Medical Sciences 4301 West Markham Street, Mail Slot #517 Little Rock AR 72205 USA Tel. +15016865170 Fax +1 5012961184 [email protected]

Dr Keith HUNTER Oepartment of Oral & Maxillofacial Pathology University of Sheffield 19 Claremont Crescent Sheffield S10 2TA UNITED KINGDOM Tel. +4411042717956 Fax +44 1104 271 7863 [email protected]. uk

Dr Robert JAKOB• Data Standards and lnformatics lnformation, Evidence and Research World Health Organization (WHO) 20 Avenue Appia i2i 1 Geneva 27 SWITZLERAND Tel. +4122791 58 77 Fax +41227914894 [email protected]

Contributors

287

Dr loannis KOUTLAS

Dr limo LEIVO Department of Pathology University of Turku Kiinamyllynkatu 1O 20520 Turku FINLAND [email protected]

Dr Richard C. JORDAN Department of Oral Pathology Pathology & Radiation Oncology University of California, San Francisco i 701 Divisadero Street, Room 280 San Francisco CA 94115 USA Tel. +1415608 9378 Fax +1415353 7553 richard [email protected]

Division of Oral and Maxillofacial Pathology University of Minnesota School of Dentistry i6-i 16B Moas Tower 515 Delaware Street Southeast Minneapolis MN 55455 USA Tel. +1612624 8607 Fax + 1 612 626 3076 [email protected]

Dr Nora KATABI

Dr Kaoru KUSAMA

Dr James S. LEWIS#

Department of Pathology Memorial Sloan Kettering Cancer Center 1275 York Avenue New York NY 10065 USA Tel. +12126393349 [email protected]

Division of Pathology, Department of Diagnostic and Therapeutic Sciences Meikai University School of Dentistry 1-1 Keyakidai, Sakado 350-0283 Saitama JAPAN Tel. +81 49 279 2773 Fax +8149286 6101 [email protected]

Department of Pathology, Microbiology, and lmmunology Vanderbilt University Medical Center 12'11 Medical Center Orive, Room 30200 Nashville TN 37232 USA Tel. + 1 615 343 0233 Fax+16153221303 [email protected]

Dr Harvey KESSLER# Oepartment of Diagnostic Sciences Texas A&M University Baylor College of Dentistry 3302 Gastan Avenue Dallas TX 75246 USA Tel. +1214828 8116 Fax+12148288306 [email protected]

Dr Hans Michael KVASNICKA Senckenberg lnstitute of Pathology University of Frankfurt Theodor-Stern-Kai 7 60590 Frankfurt am Main GERMANY Tel. +49 69 6301 4900 Tel. +49 69 6301 3903 [email protected]

Dr Jean E. LEWIS

Dr Noriko KIMURA'

Dr Sunil R. LAKHANJ•

Dr Jiang LI

Clinical Research, Pathology Division National Hospital Organization Hakodate Hospital 18-16 Kawahara 041-8512 Hakodate JAPAN Tel. +81 138 51 6281 Fax +81 138 30 1020 [email protected]

Department of Molecular & Cellular Pathology University of Queensland The Royal Brisbane & Women's Hospital Level 6, Building 71/918 QLD 4069 Brisbane Herston AUSTRALIA Tel. +61 7 3346 6052 Fax +61 7 3346 5596 [email protected]

Department of Oral Pathology 9th People's Hospital, Shanghai Jiao Tong University, School of Medicine 639 Zhi-Zao-Ju Road 200011 Shanghai CHINA Tel. +86 136 11791235 Fax +86 21 5331 5687 lijiang [email protected]

Dr Young-Hyeh KO

Dr Alfred King Yin LAM

Dr Tie-Jun LI

Department of Pathology Samsung Medica! Center, Sungkyunkwan University 50 lrwondong Gangnamgu 135-710 Seoul REPUBLIC OF KOREA Tel. +82 2 3410 2762 Fax +82 3 341 O 0025 yhko3i [email protected]

School of Medicine Griffith University Gold Coast Campus OLD 4222 Gold Coast AUSTRALIA Tel. +61 7 5687 6543 Fax +61 7 5687 6797 [email protected]

Department of Oral Pathology Peking University School of Stomatology 22 South Avenue Zhonguancun Haidian District 100081 Beijing CHINA Tel. +86 106 217 9977 ext. 2203 Fax +86 106 217 3402 [email protected]

Dr Paul KOMMINOTH lnstitute of Pathology Stadtspital Triemli Birmensdorferstrasse 497 8063 Zurich SWITZERLAND Tel. +4144466 21 22 Fax +41 44 466 21 38 [email protected]

Dr Constantino LEDESMA-MONTES

Dr Xiao-Qiu LI

Laboratorio de Patología Clínica Facultad de Odontología National Autonomous University of Mexico Circuito Institutos S/N Ciudad Universitaria Col Copilco CU MEXICO Tel. +52 55 5622 5562 Fax +52 55 5550 3497 [email protected]

Department ot Pathology Fudan University Shanghai Cancer Center 270 Dong-An Road 200032 Shanghai CHINA Tel. +86 21 3477 8242 Fax +86 21 6417 0067 [email protected]

288

Contributors

Department of Pathology Mayo Clinic 200 First Street Southwest Rochester MN 55905 USA Tel. + 1 507 288 6878 Fax + 1 507 284 1599 [email protected]

Dr Lisa LICITRA# Department of Head and Neck Cancer Medical Oncology, Fondazione IRCCS lstituto Nazionale dei Tumori Via G. Venezian 1 20133 Milan

ITALY Tel. +39 2 2390 2150 Fax +39 2 2390 3769 [email protected]

Dr Adalberto MOSQUEDA-TAYLOR Departamento de Atención a la Salud Universidad Autónoma Metropolitana Xochimilco Calzada del Hueso í "100, Col. Villa Quietud 04960 DF Mexico City MEXICO [email protected]

Dr Brad W. NEVILLE# Oral Pathology, Department of Stomatology Medical University of South Carolina College ot Dental Medicine í 73 Ashley Avenue, Room 539 Charleston 29403 USA Tel. + 1 843 792 4495 Fax + 1 843 792 3697 neví[email protected]

se

Dr Mark UNGEN Oepartment of Pathology University of Chicago School of Medicine 584 í South Maryland Avenue, MC6101 Chicago IL 60637 USA Tel.+ 1 773 702 5548 Fax + 1 773 834 7644 [email protected]

Dr Susan MULLER Department of Otolaryngology Head and Neck Surgery Emory University í 209 Springdale Road Atlanta GA 30306 USA Tel.+ 1404501 7445 Fax + 1 404 501 7460 [email protected]

Dr Scott LIPPMAN Moores Cancer Center University of California, San Diego 3855 Health Sciences Orive, MC 0658 La Jolla CA 92093 USA Tel.+ 1 858 822 1222 Fax + 1 858 822 0207 [email protected]

Dr Alfons NADAL Department of Anatomic Pathology Medica! Faculty, University of Barcelona August Pi i Sunyer Biomedical Res lnstitute Casanova, í 43 08036 Barcelona SPAIN Tel. +34 93 227 5450 Fax +34 93 227 5450 [email protected]

Dr Karin NYLANDER Department ot Medical Biosciences Umeá University 2 Sjukhusomrádet 901 85 Umei\ SE SWEDEN Tel. +46 90 785 15 91; +46 70 558 05 23 [email protected]

Dr Thomas LOENING Gerhard Seifert Reference Centre Hansepathnet Papenreye 23 22453 Hamburg GERMANY Tel. +49 40 554 952 83 Fax +49 40 554 952 60 [email protected]

Dr Toshitaka NAGAO' Department of Anatomic Pathology Tokyo Medical University 6-7-í Nishishinjuku, Shinjuku-ku 160-0023 Tokyo JAPAN Tel. +81 3 3342 6111 Fax +81 3 3342 2062 [email protected]

Dr Edward W. ODELL' Department of Head and Neck/Oral Pathology King's College London, Guy's and St Thomas' NHS Foundation Trust Floor 4 Tower Wing, Guy's Hospital London SE1 9RT UNITED KINGDOM Tel. +44 207 188 4378 [email protected]

Dr Marcio LOPES Oral Diagnosis, Piracicaba Dental School, State University of Campinas (UNICAMP) Cidade Universitária 'Zeferino Vaz', Sarao Geraldo - Campinas 13083-970 Piracicaba, Sao Paulo BRAZIL Tel. +5519 3412 5319 Fax +55 19 3412 5218 [email protected]

Dr Shigeo NAKAMURA Department ot Pathology and Laboratory Medicine Nagoya University Hospital 65, Tsurumai-cho, Showa-ku 466-8560 Nagoya JAPAN Tel. +8152744 2896 Fax +81 52 744 2897 [email protected]

Dr Eugenio MAIORANO Department of Emergency and Organ Transplantation, Pathological Anatomy University of Bari Aldo Moro Policlinico, Piazza G. Cesare, í 1 70124 Bari

Dr Brenda NELSON

Dr Andre M. OLIVEIRA

Department of Anatomic Pathology Naval Medical Center San Diego 34800 Bob Wilson Orive San Diego CA 92134-5000 USA brenda. l. nelson24. [email protected]

Departments ot Laboratory Medicine and Pathology and Anatomic Pathology Mayo Clinic 200 Second Street Southwest Rochester MN 55905 USA Tel. +15072842511 Fax+ 1 507 285 1599 [email protected]

ITALY Tel. +39 080 547 8292 Fax +39 080 547 8263 [email protected]

Dr Piero NICOLAI Department ot Otorhinolaryngology Head and Neck Surgery University ot Brescia - Spedali Civili Brescia Piazzale Spedali Civili 1 25123 Brescia

ITALY Tel. +39 303 995 319 Fax +39 303 995 212 pieronicolaí@virgilio.it

Dr Hiroko OHGAKI' Section of Molecular Pathology lnternational Agency far Research on Cancer í 50 Cours Albert Thornas 69372 Lyon Cedex 08 FRANGE Tel. +33 4 72 73 85 34 Fax +33 4 72 73 86 98 [email protected]

Contributors

289

on

DrGerman Department of Clinical Pathology Robert Bosch Hospital Auerbachstrassse i iO 70376 Stuttgart GERMANY Tel +49 711 8101 3394 Fax +49 711 8101 3619 [email protected]

Dr Jesper REIBEL Department of Odontology University of Copenhagen 20 Noerre Alié 2200 Copenhagen N DENMARK Tel +45 353 26720 [email protected]

Dr Ann SANDISON' Department of Histopathology Charing Cross Hospital Fulham Palace Road London W6 BRF UNITED KINGDOM Tel +44 20 3311 7139 Fax +44 20 33111364 [email protected]

Dr Bayardo PEREZ-ORDONEz• Department of Laboratory Medicine and Pathobiology, University of Toronto Toronto General Hospital 200 Elizabeth Street, Room i i E-444 Toronto ON MSG 2C4 CANADA Tel + 1416340 3852 Fax+14163405517 [email protected]

Dr Mary RICHARDSON Department of Pathology and Laboratory Medicine Medicar University of South Carolina Children's Hospital 165 Ashley Avenue, Room EH303D4 Charleston se 29425 USA Tel. +18437921994 [email protected]

Dr Sulen SARIOGLU Department of Pathology Dokuz Eylül University Faculty of Medicine Mithatpasa Cad. No:1606 Saglik Yerleskesi 35340 lnciralti-Balcova TURKEY Tel. +90 232 412 3408 ext. 3408 Fax +90 232 277 7274 [email protected]

Dr Bengt Fredrik PETERSSON Department of Pathology National University of Singapore Yang Loo Lin School of Medicine NUHS Tower Block Kent Ridge Road, (S), 119228 1i 9077 Singapore SINGAPORE Tel +65 6772 4304 [email protected]

DrJae Y. RO Department of Pathology & Genomic Medicine, Houston Methodist Hospital Weill Medical College of Cornell University 6565 Fannin Street Houston TX 77030 USA Tel. +1713441 2263 Fax +17137931603 [email protected]

Dr Mary R. SCHWARTZ Department of Pathology and Genomic Medicine Houston Methodist Hospital 6565 Fannin Street, M227 Houston TX 77030 USA Tel. +17134416482 [email protected]

Dr Stefano A. PILERI# Haematopathology Unit European lnstitute of Oncology 40121 Milano, ITALY Tel. +39 02 57 489521; [email protected]

Dr Brian ROUS* National Cancer Registration Service, Eastern Office Victoria House, Capital Park Fulbourn, Cambridge CB21 5XB UNITED KINGDOM Tel +44122 321 3625 Fax +44122 321 3571 [email protected]

Dr Raja SEETHALA• Department of Anatomic Pathology UPMC Presbyterian Hospital 200 Lothrop Street, Room A614 Pittsburgh PA 15213 USA Tel + 1412647 9051 Fax+ 14126477799 [email protected]

Dr Manju Lata PRASAD Department of Pathology Yale University School of Medicine 31 O Cedar Street, PO Box 208023 New Haven CT 06520-8023 USA Tel + 1 203 785 4479 Fax + 1 203 737 2922 [email protected]

Dr Nasser SAID-AL-NAIEF OMFP Laboratory OHSU School of Dentistry 2730 Southwest Moody Avenue, CLSB 5N008 Portland OR 97201 USA Tel +1503494 0041 [email protected]

Dr Roderick H.W. SIMPSON' Department of Anatomical Pathology University of Calgary 1403 29th Street Northwest, Foothills Medical Centre, 11 th Floor Calgary AB T2N 2T9 CANADA Tel. + 1 403 944 8506 Fax +1403944 4748 roderi ck. si m pson@docto rs. org .uk

Dr Erich RAUBENHEIMER Oral Pathology Sefako Makgatho Health Sciences University Molotlegi Street Ga-Rankuwa 0208 SOUTH AFRICA Tel +27 12 521 4839 [email protected]

Dr Tuula SALO Department of Oral and Maxillofacial Diseases University of Helsinki Box 41 (Mannerheimintie 172) 00014 Helsinki FINLAND Tel +358 40 544 1560 [email protected]

Dr Alena SKÁLOVÁ' Department of Pathology Charles University in Prague Faculty of Medicine in Plzen Faculty Hospital, Ed. Benese i3 305 99 Pilsen CZECH REPUBLIC Tel +420 377 402 545 Fax +420 377 402 634 [email protected]

University of Bologna School of Medicine 40138 Bologna, ITALY Tel. +39 05i 636 3044: [email protected]

290

Contributors

Dr Leland SLATER Scripps Oral Pathology Service 5190 Governor Orive, Suite 106 San Diego CA 92122 USA Tel. + 1 858 784 0600 Fax + 1 858 784 0604 [email protected]

Dr Edward B. STELOW• Department of Pathology, Division of Surgical Pathology and Cytopathology University of Virginia School of Medicine PO Box 800214 Charlottesville VA 22908-0214 USA Tel. +14349824185 Fax + 1 434 982 6130 [email protected]

Dr Arthur S. TISCHLER Department of Pathology Tufts Medica! Center 800 Washington Street, Box 802 Bastan MA 021 1 1 USA Tel. +16176361038 Fax +1617636 8302 atisch Ie r@tufts med icalce nte r. org

Dr Mary TONER Department of Histopathology, CPL Trinity College St. James's Hospital Dublin 8 IRELAND [email protected]

Dr Philip SLOAN#

Dr Góran STENMAN'

Department of Cellular Pathology Newcastle University New Victoria Wing, RVI Newcastle upan Tyne NE1 4LP UNITED KINGDOM Tel. +441912821517 Fax +441912825892 philip [email protected]. uk

Department of Pathology and Genetics Sahlgrenska Cancer Center University of Gothenburg SE-405 30 Gothenburg SWEDEN Tel. +46 31 786 6733 [email protected]

Dr Pieter J. SLOOTWEG•

Dr Stina SYRJÁNEN#

Dr Satoru TOYOSAWA

Department of Pathology Radboud University Nijmegen Medica! Center Geert Grooteplein Zuid 10, Route 812 PO Box 9101 6500 HB Nijmegen THE NETHERLANDS Tel. +31248186232; +31657595780 [email protected]

Department of Oral Pathology, lnstitute of Dentistry, Faculty of Medicine, University of Turku and University Hospital Turku Lemmink8.isenkatu 20520 Turku FINLAND Tel. +358 2 333 8349 Fax +358 2 333 8399 [email protected]

Department of Oral Pathology Osaka University Graduate School of Dentistry 1-8 Yamada-Oka, Suita 565-0871 Osaka JAPAN Tel. +81 6 6879 2891 Fax +81 6 6879 2895 [email protected]

Dr Merva SOLUK TEKKE$1N Department of Tumour Pathology lnstitute of Oncology, lstanbul University Capa/Fatih 34093 lstanbul TURKEY Tel. +90 212 414 2434 Fax +90 212 534 8078 [email protected]

Dr Takashi TAKATA' Department of Oral & Maxillofacial Pathobiology lnstitute of Biomedical & Health Sciences Hiroshima University i-2-3 Kasumi, Minami-ku 734-8553 Hiroshima JAPAN Tel. +8182257 5631 Fax +8182257 5619 [email protected]

Dr Asterios TRIANTAFYLLOU Department of Oral and Maxillofacial Pathology School of Dentistry, University of Liverpool Pembroke Place Liverpool, Merseyside L3 5PS UNITED KINGDOM Tel. +441517065243 [email protected]

Dr Paul SPEIGHT'# Unit of Oral & Maxillofacial Pathology School of Clinical Dentistry University of Sheffield 19 Claremont Crescent Sheffield S10 2TA UNITED KINGDOM Tel. +44 7774 704 869 [email protected]

Dr Lester D.R. THOMPSON' Department of Pathology, Southern California Permanente Medical Group Woodland Hills Medica! Center 5601 De Soto Avenue Woodland Hills CA 91365 USA Tel.+ 1 818 719 2613 Fax+18187192309 [email protected]

Dr Willie F.P. VAN HEERDEN Department of Oral Pathology & Oral Biology School of Dentistry, University of Pretoria PO Box 1266 0001 Pretoria SOUTH AFRICA Tel. +2712 319 2320 Fax +27 12 321 2225 [email protected]

Dr Stefan STEENS

Dr Wanninayake M. TILAKARATNE Department of Oral Pathology, Faculty of Dental Sciences University of Peradeniya Peradeniya SRI LANKA Tel. +94 81 239 7435 Fax +94 81 238 8948 [email protected]

Dr Annemieke VAN ZANTE Department of Pathology University of California, San Francisco, School of Medicine 1600 Divisadero Street, MZ Building B San Francisco CA 94143 USA Tel. +1415885 7256 [email protected]

Department of Radiology and Nuclear Medicine Radboud University Nijmegen Medical Center Geert Grooteplein Zuid iO, Route 766, Room 17 6525 GA Ni¡megen THE NETHERLANDS Tel. +31 24 361 44 99 [email protected]

Contributors

291

Dr Marilena VERED Department of Oral Pathology & Oral Medicine School of Dental Medicine, Tel Aviv University Room 246 IL-69978 Tel Aviv-Yafo ISRAEL Tel. +972 3 640 9305 Fax +972 3 640 9250 [email protected]

Dr llan WEINREB Department of Laboratory Medicine and Pathobiology, University of Toronto Toronto General Hospital 200 Elizabeth Street, Room i I E-444 Toronto ON M5G 2C4 CANADA Tel. +1416340 5146 Fax+14163405517 [email protected]

Dr John M. WRIGHT' Department of Diagnostic Sciences Texas A&M University Baylor College of Dentistry 3302 Gastan Avenue Dallas TX 75246 USA Tel. +12148288118 Fax+ í 214 828 8306 [email protected]

Dr Philippe VIELH' Département de Pathologie Laboratoíre National de Santé 1 Rue Louis Rech L-3555 Dudelange LUXEMBOURG [email protected]

Dr Bruce M. WENIG' Moffitt Cancer Center Section Head, Head and Neck, and Endocrine Pathology Senior Member Anatomic Pathology Department of Pathology 12901 Magnolia Orive Tampa, FL 33612 USA Fax+ 813-632-1708 [email protected]

Dr Wendell G. YARBROUGH Department of Surgery Yale University Medical Center Yale Otolaryngology, PO Box 208041 New Haven CT 06520-8041 USA Tel. + 1 203 785 4862 Fax + 1 203 200 2028 [email protected]

Dr Nadarajah VIGNESWARAN Department of Oral & Maxillofacial Pathology University of Texas Health Science Center at Houston School of Dentistry 7500 Cambridge Street, Suite 1210 Houston TX 77054 USA Tel. + 1 713 486 4410 nadaraí[email protected]

Dr William H. WESTRA' Department of Pathology Johns Hopkins School of Medicine 401 North Broadway Baltimore MD 21287 USA Tel. +1410614 3964 Fax+14109550115 [email protected]

Dr Rosnah Binti ZAIN* Department of Oral Cancer Research & Coordinating Centre Faculty of Dentistry, University of Malaya 50603 Kuala Lumpur MALAYSIA Tel. +601 2609 5428 Fax +603 7954 7301 [email protected]

Dr Paul E. WAKELY, Jr Department of Pathology The Ohio State University Wexner Medical Center 405 Doan Hall, 410 West 10th Avenue Columbus OH 43210 USA Tel. +1614293 9235 Fax + 1 614 293 7626 [email protected]

Dr Michelle D. WILLIAMS Department of Pathology University of Texas MD Anderson Cancer Center 1515 Holcombe Boulevard Unit 0085 Houston TX 77030 USA Tel. + 1 713 794 1765 Fax +17135631848 [email protected]

Dr Nina ZIDAR lnstitute of Pathology Faculty of Medicine University of Ljubljana Korytkova 2 iOOO Ljubljana SLOVENIA Tel. +3861 543 7149 [email protected]

Declaration of interests Dr Chuang reports having received travel support from Millennium: The Takeda Oncology Company.

Dr Kessler reports receiving personal consultancy fees far medicolegal work from two law firms representing defendants in tobacco litigation.

Dr Feldman reports holding intellectual property rights far a patent held by the Mayo Clinic on the activity of interferon regulatory factor 4 (IRF4) in T-cell lymphomas. Dr Feldman reports being part of a pending patent application, with the Mayo Clinic, far detecting translocations of TBL 1XR1 and TP63 nucleic acid.

Dr French reports receiving personal consultancy fees from GlaxoSmithKline Dr lnagaki reports having received personal consultancy fees from Kyowa Hakko Kirin. Dr lnagaki reports having received personal speaker's fees from Kyowa Hakko Kirin and Zenyaku Kogyo. Dr Jaffe reports receiving royalties from Elsevier.

292

Contributors

Dr J.S. Lewis reports having received personal research support, through Washington University in St. Louis, from Advanced Cell Diagnostics. Dr Licitra reports receiving personal consultancy fees from Eisai, Bristol-Myers Squibb, MSD, Merck Serano, Boehringer lngelheim, Debiopharm, Sobi, Novartis, AstraZeneca, Bayer, and Roche. Dr Licitra reports that the Fondazione IRCCS lstituto Nazioñale dei Tumori receives research support from Eisai, MSD, Merck Serono, Boehringer lngelheim, Novartis, AstraZeneca, and Roche. Dr Ucitra reports receiving travel support from Merck Serano, Debiopharm, Sobi, and Bayer.

Dr Neville reports receiving royalties from Elsevier. Dr Pileri reports receiving personal consultancy fees from Takeda. Dr Sloan reports having received persona! consultancy fees from Navidea Biopharma~ ceuticals. Dr Sloan reports having provided expert testimony to the European Medicínes Agency for Navidea Biopharmaceuticals.

Dr Speight reports receiving royalties from Blackwell Munksgaard.

Dr Syrja.nen reports receiving personal consultancy fees from Bionit. Dr Syrjanen reports receiving travel support from EHNS/AXON.

IARC/WHO Committee for the lnternational Classification of Diseases for Oncology (ICD-0)

Dr Freddie BRAY Section of Cancer Surveillance lnternational Agency for Research on Cancer 150 Cours Albert Thomas 69372 Lyon Cedex 08

FRANGE Tel. +33 4 72 73 84 53 Fax +33 4 72 73 86 96 [email protected]

Dr Adel K. EL-NAGGAR University of Texas MD Anderson Cancer Center 1515 Holcombe Boulevard, Unit 0085 Houston TX 77030 USA Tel. +1713792 3109 Fax +17137451105 [email protected]

Dr Hiroko OHGAKI Section of Molecular Pathology lnternational Agency for Research on Cancer i50 Cours Albert Thomas 69372 Lyon Cedex 08 FRANGE Tel. +33 4 72 73 85 34 Fax +33 4 72 73 86 98 [email protected]

Dr Marion Pli'lEROS Section of Cancer Surveillance lnternational Agency for Research on Cancer 150 Cours Albert Thomas 69372 Lyon Cedex 08

FRANGE Tel. +33 4 72 73 8418 Fax +33 4 72 73 80 22 [email protected]

Mrs April FRITZ A Fritz and Associates, LLC 21361 Crestview Road Reno NV 89521 USA Tel. + 1 775 636 7243 Fax+18888913012 [email protected]

Dr Brian ROUS National Cancer Registration Service, Eastern Office Victoria House, Capital Park Fulbourn, Cambridge CB21 5XB UNITED KINGDOM Tel. +44122 321 3625 Fax +44 122 321 3571 [email protected]

Dr Robert JAKOB Data Standards and lnformatics lnformation, Evidence and Research World Health Organization (WHO) 20 Avenue Appia 1211 Geneva 27 SWITZERLAND Tel. +41 22 791 58 77

Dr Pieter J. SLOOTWEG

Fax+41227914894

Department of Pathology Radboud University Nijmegen Medical Center Geert Grooteplein Zuid 10, Route 812, PO Box 9101 6500 HB Nijmegen THE NETHERLANDS Tel. +31 24 8186232; +31 6 57595780 [email protected]

[email protected]

Dr Paul KLEIHUES Faculty of Medicine University of Zurich Pestalozzistrasse 5 8032 Zurich SWITZERLAND Tel. +41443622110 [email protected]

Dr Leslie H. SOBIN Frederick National Laboratory for Cancer Research, Cancer Human Biobank National Cancer lnstitute 6110 Executive Boulevard, Suite 250 Rockville MD 20852 USA Tel. + 1 301 443 7947 Fax+ 1 301 402 9325 [email protected]

ICD-0 Committee

293

Sources of figures and tables

Sources of figures 1.01 1.02A-C 1.03A-C 1.04A,B 1.05 1.06A,B 1.07A-C 1.0BA,B 1.09A-D 1.10 1.11A-D 1.12A-D 1.13A,B 1.14 1.15A,B 1.16A,B 1.17A 1.17B 1.17C,D 1.18A,B 1.19A,B 1.20 1.21A-C 1.22A 1.22B 1.23A,B 1.24 1.25 1.26 1.27A 1.27B-D 1.28 1.29 1.30 1.31 1.32A,B 1.33A-D 1.34A-D

1.35 1.36A,8 1.37A 1.378 1.38A,B 1.39 1.40A 1.408 1.41A 1.41B

294

Bishop JA Bishop JA Bishop JA Bishop JA Lewis JS Bishop JA Thompson LDR Bishop JA French CA French CA Thompson LDR Stelow EB Nicolai P Stelow EB Stelow EB Stelow EB Franchi A Wenig BM Thompson LDR Hunt JL Hunt JL Hunt JL Wenig BM Perez-Ordonez B Eusebi V University of Bologna, ltaly Bell D Franchi A Franchi A Flucke U Franchi A Thompson LDR Thompson LDR Thompson LDR Thompson LDR Thompson LDR Lewis JE Lewis JE Reprinted from Wang X, Bledsoe KL, Graham RP, et al. (2014). Recurren! PAX3-MAML3 fusion in biphenotypic sinonasal sarcoma. Nat Genet. 46:666-8. With permission from Macmillan Publishers Ud. 8ell D 8ell D Flucke U Wenig BM Thompson LDR Thompson LDR Thompson LDR Wenig BM Flucke U Reprinted from Flucke U, Vogels RJ, de Saint Aubain Somerhausen N, et al. (2014). Epithelioid hemangioendothelioma: clinicopathologic, immunhistochemical, and

Sources of figures

1.42A,B 1.43A,B 1.44A,B 1.45A,B 1.46A,B 1.47 148

149A,B 1.SOA,B 1.51A-C 1.52A,B,D 1.52C 1.53 1.54 1.55A,B 1.56A 1.568 1.57 1.58

1.59 1.60A,8 1.61 1.62 1.63A-D 1.64A,B 2.01

2.02

2.03A,B 2.04A-C 2.05A-C 2.06A-C 2.07 2.08A,B 2.09 2.10A 2.10B 2.11 2.12A-D 2.13

2.14A-D 2.15A,B

molecular genetic analysis of 39 cases. Diagn Pathol. 9:í31. Thompson LDR Thompson LDR Thompson LDR Thompson LDR Thompson LDR Wenig BM McDermott M Paediatric Laboratory Medicine Our Lady's Children's Hospital, Crumlin, Dublin, lreland Chuang S-S Chan JKC Chuang S-S Chan JKC Chuang S-S Chan JKC Chan JKC Feldman AL

3.01A-C 3.02A-D 3.03 3.04 3.05A-C 3.06A-C 3.07A 3.07B 3.08 3.09A-C 3.10 3.11 3.12 3.13 3.14 3.15A,B 3.16 3.17A 3.17B

Slootweg PJ Wenig BM Bell D Ginsberg LE Division of Diagnostic lmaging MD Anderson Cancer Center Houston (TX), USA Bell D Thompson LDR Williams MD Williams MD Williams MD Williams MD Reproduced with permission from the Census and Statistics Department, Departmerit of Health, Hong Kong Cancer Registry, Hospital Authority, http://www.chp.gov .hk/en/ content/9/25/54.html. LeeAWM Department of Clinical Oncology, University of Hong Kong, Hong Kong SAR, China Chan JKC Chan JKC Chan JKC Chan JKC Chan JKC Chan JKC Stelow EB Chiosea S SkálováA Thompson LDR Thompson LDR Mahajan A Diagnostic Radiology Yale University School of Medicine New Haven (CT), USA Prasad ML Baumhoer D

3.18 3.19A,8 3.19C 3.20A,8 3.21 3.22A,8 3.23 3.24 3.25A,8,D 3.25C 3.26 3.27 3.28 3.29 3.30A-C 3.31 3.32 3.33A,B 3.34 3.35 4.01A,8

4.02 4.03 4.04A,B 4.05A-C 4.06A,B 4.07A 4.078 4.08A,B 4.09 4.10A,B

Zidar N Zidar N Zidar N Zidar N Zidar N Lewis JS El-Mofty SK Thompson LDR Thompson LDR Bishop JA Bishop JA Thompson LDR Bishop JA Gale N Gale N Gale N Gale N Gale N Attwood R Division of Otorhinolaryngology, Head & Neck Surgery Stellenbosch University and Tygerberg Academic Hospital Cape Town, South Africa Richardson M Richardson M Gale N Slootweg PJ Perez-Ordonez B Thompson LDR Thompson LDR Perez-Ordonez B Bishop JA Thompson LDR Perez-Ordonez B Bloemena E Flucke U Wenig BM Wenig BM Gale N Gale N Gale N Chan JKC Ferry JA Reprinted from Ferlay J, Soerjomataram 1, Ervik M, et al. (2013). GLOBOCAN 2012 v1.0, Cancer lncidence and Mortality Worldwide: IARC CancerBase No. i i [Internet]. Lyon, France: IARC; Available from: http://globocan.iarc.fr, accessed on 3 March 20i 6. Sloan P Sloan P Vigneswaran N Reibel J Reibel J Odell EW MullerS MullerS Vigneswaran N MullerS

4.11 4.12 4.13 4.14

Takata T Odell EW Allen CM

van der Waal

Korea University Anam Hospital Seoul, Republic of Korea 6.09

Department of Pathology

VU University Medical Center 4.15 4.16A·D 4.17 4.18A·D 4.19A,B 4.20 4.21A,B 4.22A,B 4.23 4.24 425A,B 4.26 4.27 4 28A,B 4.29 4.30A,B 4.31A,B 4.32A,B 5.01A·D 5.02

Amsterdam, The Netherlands Allen CM

Bishop JA Allen CM Allen CM Thompson LDR Flucke U

Wenig BM Thompson LDR Flucke U Williams MD Williams MD Ferry JA

Feldman AL Feldman AL BoyS Chan JKC

Pileri SA Li X-O Westra WH

Reprinted from Bishop JA, Ma XJ, Wang H, et al. (2012)

Detection of transcriptionally active high-risk HPV in patients

with head and neck squamous cell carcinoma as visualized

by a novel E6/E7 mRNA in situ

5.03A,B 5.04A

5,048 5.05 5.06A,B 5.07 5.0SA,B 5.09

5.10 5.11 5.12A,B

5.12C 5.13 5.14A-C 5.15A-C 6.01

hybridization method. Am J Surg Pathol. 36: 187 4-82. With permission from Wolters Kluwer Health. Bell D

Reprinted from Li J, Perlaky L, Rao P, et al. (2014). Development and characterization of salivary adenoid cystic carcinoma cell line. Oral Oncol. 50:991-9, with permission from Elsevier. Bell D

Skálová A Jaffe ES Jaffe ES

Pileri SA Pileri SA OttG Ko Y-H

Ohgami RS Department of Pathology Stanford University Stanford (CA), USA Chan JKC Chan JKC Chan JKC Chan JKC

MD Anderson Cancer Center ©'89 MDACC

6.02A,B 6.03 6.04 6.05A,B 6.06 6.07A,B 6.08

Lewis JS Chan JKC

Lewis JS Lewis JS Perez-Ordonez B Perez-Ordonez B KimCH Department of Pathology

Cho KJ

Asan Medical Center University of Ulsan College of Medicine Seoul, Republic of Korea

1

6.10A,B 6.11A,C 6.118 6.12A,B 6.13 6.14 6.15 7.01A,B,C 7.02A,C 7.02B 7.03 7.04A,B 7.05A,B 7.05C 7.06 7.07A-D 7.08 7.09A,B 7.10 7.11A,B 7.12A,B 7.13A,B 7.13C 7.14A,B 7.14C 7.140 7.15A 7.15B 7.15C 7.16A 7.16B-D 7.17 7.18A-C 7.19A-C 7.20A,B 7.21 7.22A 7.22B,C 7.23 7.24A,B 7.24C,D 7.25A 7.25B 7.26 7.27A-F 7.28A,B 7.29A 7.29B 7.30A,B 7.31A-C 7.32 7.33 7.34 7.35 7.36A,B 7.37A,B 7.3SA,B 7.39A,B 7.40 7.41A,B 7.42A·C 7.43 7.44A 7.44B 7.44C

7.45A,B 7.46A-D 7.47 7.48A,B 7.49 7.50 7.51A

Wakely PE Ro JY See above (6.09)

Chiosea S

Bell D EI-Naggar AK Stenman G Stenman G van Zante A Stenman G EI-Naggar AK Simpson RHW Simpson RHW Fonseca 1 Fonseca 1 Skálová A

Wenig BM Wenig BM Seethala R Fonseca 1 Williams MD Seethala R Weinreb 1

Loening T Leivo 1 Leivo 1 Loening T Leivo 1

Nagao T Nagao T Nagao T Nagao T Skálová A Bell D

Seethala R Seethala R Fonseca 1 WilliamsMD lhrler S Williams MD Skálová A

Nagao T Nagao T EI-Naggar AK EI-Naggar AK

Reprinted from Weiler C, Agaimy A, Zengel P, et

Prasad ML Katabi N Chiosea S

Brandwein-Gensler M

Li j Li j

7.518 7.52A,B 7.53A,B 7.54A,B 7.55A,B 7.56 7.57A 7.57B 7.58A,B 7.59A,B 7.60 7.61 7.62 7.63A,B 7.64 7.65 7.66 7.67 7.68A-C 7.69A-C 7.70A,B 7.71 8.01 8.02 8.03A-D 8.04 8.05A,B 8.06A,B 8.07 8.08A,B 8.08C

8.09 8.10 8.11

al. (20i2). Nonsebaceous lymphadenoma of salivary glands: proposed development from intraparotid lymph nades and risk of misdiagnosis. Virchows Arch. 460:467-72. Prasad ML Budnick S Bell D

Richardson M Richardson M Nagao T Bloemena E EI-Naggar AK Seethala R Slater L Bell D

Bloemena E Bell D Seethala R Bullerdiek J EI-Naggar AK Bullerdiek J Flucke U Cheuk W Cheuk W Cheuk W Cheuk W Muller S Odell EW Odell EW Odell EW Odell EW

Koutlas 1 Odell EW Odell EW

Bang G e/o Bang AK Dept. of Archaeology, History, Cultural Studies and Religion University of Bergen Bergen, Norway Odell EW

Williams MD Nagao T Williams MD Chiosea S Lewis JS Lewis JS Lewis JS

Takata T Reprinted from Oral Surg Oral Med Oral Pathol Oral Radial Endod. 103. Delair D, Bejarano PA, Peleg M, et al. Ameloblastic carcinosarcoma of the mandible arising in ameloblastic fibroma: a case report and review of literature.

Bell D

Pages 516-20 (2007). With

RoJY

Nagao T Brandwein-Gensler M Brandwein-Gensler M Bell Bell Bell Bell Bell

D D D D D

Fonseca 1 Bishop JA Bell D

permission from Elsevier. 8.12A,B 8.13 8.14A 8.14B 8.15 8.16A 8.16B 8.17A-D 8.18A-C 8.19

See above (8.11) WrightJM WrightJM Odell EW

Slootweg PJ Vered M Muller S Vered M Heikinheimo K Vered M

Sources of fígures

295

8.20 8.21 8.22 8.23

8.24 8.25A,B 8.26A,B 8.27 8.28A,8 8.29

8.30 8.31A,B 8.32A,B

8.32C

8.33A,C 8.33B 8.34A 8.34B 8.35A 8.35B 8.36A 8.36B 8.37 8.38 8.39A,8 8.40 8.41 8.42 8.43 8.44 8.45A,B 8.46A,B 8.47 8.48A,8 8.49 8.50 8.51A,8 8.52 8.53 8.54 8.55 8.56A,B 8.57A-C 8.58 8.59A,B 8.60A,B,D 8.60C 8.61

296

Muller S Wright JM Heikinheimo K Reprinted from Dissanayake RK, Jayasooriya PR, Siriwardena DJ, et al. (2011). Review of metastasizing (malignant) ameloblastoma (METAM): pattern of metastasis and treatment. Oral Surg Oral Med Oral Pathol Oral Radial Endod.111:734--41. With permission from Elsevier. WrightJM WrightJM WrightJM WrightJM WrightJM Kusama K, lde F Division of Pathology Department of Diagnostic & Therapeutic Sciences Meikai University School of Dentistry, Saitama, Japan Muller S Vered M Reprinted with permission from Mosqueda-Taylor A, Pires FR, Aguirre-Urízar JM, et al. (2014). Primordial odontogenic tumour: clinicopathological analysis of six cases of a previously undescribed entity. Histopathology. 65:606-12. Pires FR Department of Oral Pathology Rio de Janeiro State University Rio de Janeiro - RJ, Brazil See above (8.32C) See above (8.32A,B) Fowler CB Neville BW Fowler CB Soluk Tekke~in M Neville BW Vered M Vered M Carlos R Carlos R Carlos R van Heerden WFP van Heerden WFP Odell EW, Nortje CJ, van Rensburg LJ e/o Odell EW Thompson LDR Odell EW Odell EW EI-Mofty SK EI-Mofty SK Soluk Tekke~in M Soluk Tekke~in M Speight P Speight P Speight P Speight P Speight P Neville BW Speight P Li T-J Li T-J Speight P Li T-J Speight P

Sources of figures

8.88 8.89 8.90A,B 8.91 8.92A,B 8.93 8.94 8.95 8.96A,8 8.97A,8 8.98A,8 8.99 8.100A,B 8.101 8.102 8.103 8.104A,B 8.105 8.106A,B 8.107A-C 8.108 8.109A 8.109B 8.110 8.111

Neville BW Speight P Neville BW Neville BW Kessler H Speight P Kessler H Speight P Speight P Speight P WrightJM Speight P WrightJM Neville BW Speight P Speight P Casiraghi O Baumhoer D Casiraghi O Slootweg PJ Baumhoer D Lopes M Slootweg PJ Baumhoer D Lopes M Manojlovié S Department of Pathology University of Zagreb School of Medicine Zagreb, Croatia Prasad ML Baumhoer D Baumhoer D Baumhoer D Toner M Baumhoer D Reprinted with permission from Flucke U, Tops BB, van Diest PJ, et al. (2014). Desmoid-type fibromatosis of the head and neck region in the paediatric population: a clinicopathological and genetic study of seven cases. Histopathology. 64:769-16. Toyosawa S EI-Mofty SK EI-Mofty SK EI-Mofty SK EI-Mofty SK Slootweg PJ EI-Mofty SK EI-Mofty SK EI-Mofty SK Toyosawa S Toyosawa S Nelson B Nelson B Raubenheimer E Jordan RC Baumhoer D Raubenheimer E Raubenheimer E Jordan RC Koutlas 1 Koutlas 1 WrightJM van Heerden WFP Raubenheimer E Feldman AL

9.01 9.02

Sandison A Sandison A

8.62A 8.62B 8.63 8.64 8.65 8.66A 8.668 8.67A-C 8.68 8.69A 8.69B 8.70A,B 8.70C 8.71A-8 8.72 8.73 8.74 8.75 8.76 8.77A 8.778 8.78 8.79 8.80A,C 8.80B 8.81

8.82A,8 8.83A,8 8.84A,8 8.85 8.86A 8.868 8.87

9.03A,B 9.04A,B 9.05 9.06 9.07 9.08A,B 9.09 9.10A,8 9.11

Thompson LOR Thompson LDR Thompson LDR Sandison A Sandison A Sandison A Sandison A Sandison A Adapted with permission from Michaels L, Soucek S. Atypical mature bone in the

otosclerotic otic capsule

9.13 9.14 9.15 9.16 9.17A-C 9.18A-D

as the differentiated zone of an invasive osseous neoplasm. Acta Otolaryngol. 2014:134: 118-23. Madani G lmaging Charing Cross Hospital Imperial College Healthcare London, United Kingdom Sandison A Sandison A Sandison A Thompson LDR Thompson LDR Thompson LDR

10.01A,8 10.01C 10.02A-D 10.03A,B 10.04A,B 10.05A,B 10.06 10.07

Williams MD Kimura N Kimura N Kimura N Williams MD Capella C Lam AKY Tischler AS

9.12

Sources of figures on front cover Top left Top centre Top right Middle left Middle centre Middle right Bottom left Bottom centre Bottom right

Jordan RC (see Fig. 8.106A) Maha¡an A (see Fig. 2.13) Gale N (see Fig. 3 31) Stenman G (see Fig. 7.04B) Leivo 1(see Fig. 7.17) Kimura N (see Fig. 10.02C) Pileri SA (see Fig. 5.09) Ferlay Jet al. (see Fig. 4.01) Stenman G (see Fig. 7.03)

Sources of tables í .01 í .02

1.03 í .04

Lewis JS Reprinted from Neurosurgery Clinics of North America, Volume 24, lssue 1, January 2013, Ow TJ, Bell D, Kupferman ME, et al., pages 51-65, copyright (2013), with permission from Elsevier. Bell D Williams MD

2.01 2.02

Chan JKC Chan JKC

3.01 3.02 3.03

Cardesa A Prasad ML Gale N Gale N

4.0i 4.02 4.03 4.04 4.05

Sloan P Consensus group Consensus group Consensus group Adapted with permission from Warnakulasuriya S, Ariyawardana A (2016). Malignant transformation of oral leukoplakia: a systematic review of observational studies. J Oral Pathol Med. 45155-66. Adapted from Barnes L, Eveson JW, Reichart P, et al., eds (2005). WHO Classification of Tumours. Pathology and Genetics of Head and Neck Tumours. Lyon: IARC Press; and Fletcher DCM, Bridge JA, Hogendoorn PCW, Mertens F (2013). WHO Classification of Tumours of Soft Tissue and Bone. Lyon: IARC Press

4.06

6.01 6.02

Schwartz MR Schwartz MR

8.01

Heikinheimo K

"10.01 10.02 "10.03

Komm noth P Komm noth P Komm noth P

Sources of tables

297

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References

339

Subject index

Ameloblastoma of mucosa! origin 218

A

BOC See Botryoid odontogenic cyst

Ameloblastoma of the gingiva 218

Bohn nodule 238

ABC See Aneurysmal bone cyst

Ameloblastoma, unicystic type 217, 2"18

Botryoid odontogenic cyst 236, 237

Abrikossoff tumour 100, 121

Amphicrine adenoma 272

Botryoid rhabdomyosarcoma 36

AC See Ameloblastic carcinoma

Anaplastic large cell lymphoma 75

Branchial cleft cyst 148, 155

ACC See Adenoid cystic carcinoma

Anaplastic/undifferentiated carcinoma 180

BRCA 165

Accessory tissue-associated carcinoma i 52

Androgen receptor 74, 75, 173, 174, 178,

BRD4 21

Acinic cell carcinoma 160. 166 Ackerman tumour 84 Acoustic neuroma 270 ACTB-GLI i fusion 45 Adenocarcinoma 12, 160, 171, 172, 264 Adenoid cystic carcinoma 71, 99, 139, 164 Adenolipoma 198

195 Aneurysmal bone cyst 204, 258

Brooke-Spiegler syndrome 170, i 88 BSCC See Basaloid squamous cell carcinoma

Angiocentric lymphoma 52 Angiofibroma 74

BSNS See Biphenotypic sinonasal sarcoma

Angiosarcoma 12, 38

Burkitt lymphoma 52, 75,128,134,141,142, 143

Anti-adipophilin 178 Antoni A/ Antoni B 124 AODAM 220

e

AOT See Adenomatoid odontogenic tumour

CA See Condyloma acuminatum

Adenomatous ductal proliferation 197

APC 43,212,246,250

CA15-3 178

Adenomyoepithelioma 175

Apical periodontal cyst 232

CAIX 26, 268

Adenosquamous carcinoma 78, 89, 1í O

ARAF 131

Calcifying cystic odontogenic tumour 239

ARID1A 143

Calcifying epithelial odontogenic tumour 204,

Adenolymphoma 188 Adenoma in laryngocoele 99 Adenomatoid odontogenic tumour 204, 221

Adult neuroblastoma 56

AdulHype fibrosarcoma 34

ASC See Adenosquamous carcinoma

AE1 19, 22, 32, 49, 88,110,210, 224

ATF1 169,211,221

AE1/AE3 19,224

ATG5 53

AE3 19, 22, 32, 49, 88, 110, 210, 224

ATIC 102

Calcifying ghost cell odontogenic cyst 239

Aesthesioneuroblastoma 57

ATM 36, 144

Calcifying ghost cell odontogenic tumour 226

Aesthesioneurocytoma 57

Atypical carcinoid 96

Calcifying odontogenic cyst 204, 239, 240

Aesthesioneuroepithelioma 57

Atypical cartilaginous tumour 243

Calponin 17, 32, 126, 172, 175, 187

AF See Ameloblastic fibroma

AURKA 42

CAM5.2 22, 32, 59, 86, 89,210, 272, 273

B

CAMTA1 46

BAC See Basal cell adenocarcinoma

Cancer of unknown primary í 50

AFS See Ameloblastic fibrosarcoma Aggressive epithelial ghost cell odontogenic tumour 211 Aggressive fibromatosis 43 Aggressive papillary tumour 262, 266, 267 AIM1 53 AKT1 123 Alcohol consumption 28, 65, 81, 86-90, 93, 109, 112, 114 ALK-positive large B-cell lymphoma 129 Alpha-fetoprotein 27

Basal cell adenocarcinoma 160,169,170

Capillary haemangioma 47, 48

Basal cell adenoma 160, 187, i88

Carcinoid 95

Basaloid salivary gland adenoma 187

Carcinoid of the middle ear 272

Basaloid squamous cell carcinoma 18, 64,

Carcinoma arising in a calcifying odontogenic

65,68,69, 78,85,86 BCA See Basal cell adenoma BCL2 42, 44, 50, 59, 143, 144, 168, 222,

255,271 Beckwith-Wiedemann syndrome 37

Ameloblastic carcinoma 204,206,207,213

Benign cementoblastoma 230

Ameloblastic carcinosarcoma 213

Benign haemangioendothelioma 198

Ameloblastic fibroma 204,213,214,222,

Benign lymphoepithelial lesion 196

Ameloblastic fibrosarcoma 214 Ameloblastoma 204,211, 215-218

211

Canalicular adenoma i 60, 194

Alveolar cyst 238 Alveolar rhabdomyosarcoma 12, 18, 36

223,226,240

220-222 Calcifying ghost cell odontogenic carcinoma

Benign mixed tumour 33, 99, 127, 139, i85 Benign peripheral nerve sheath tumour 48, 49, 123, 270

cyst 21 i Carcinoma ex pleomorphic adenoma 160, 176 Carcinoma of unknown primary i 48, 150, 151 Carcinosarcoma 26, 88,160,179,204,205, 207,213 Carotid body paraganglioma 277-279, 281-283 Carotid body tumour 277 Cartilage tumours 78, í 02

Ameloblastoma, extraosseous 218

Benign soft tissue tumours 12, 47

Cavernous haemangioma 47

Ameloblastoma, peripheral type 218

Biphenotypic sinonasal sarcoma 12, 40, 41

CCC See Clear cell carcinoma

340

Subject index

CCND1 144 CCNF 143 CD1a 131,145

Chloroma 131

CUP See Carcinoma of unknown primary

Cholesteatoma 262, 269, 270

CD4 53, 125, 129, 142, 145 CD5 53, 144, 202 CDS 53, 129, 145 CD10 26,130, 143-145, 200,202,210,268 CD20 37, 55,130, 142-144, 202

Chondroblastoma 204, 248 Chondroma 78, 102,103,204,246 Chondromesenchymal hamartoma 12, 51, 52 Chondromyxoid fibroma 204, 248, 249

CXCL 13 146 CYLD 170, 188 Cylindrical cell carcinoma 16

CD21 146 CD23 144,146,202 CD30 27, 53,106, 128-130, 142,155 CD30-positive T-cell lymphoproliferative

Chondroblastic osteosarcoma 204, 244

Cylindrical cell papilloma 29 Cylindroma 169, 264 CYP2E1 69

Chondrosarcoma 78, 102, í03, 204, 243

Cystadenocarcinoma 153, 162, 170- 172

Chordoma 76

Cystadenolymphoma 188

Choristoma 152

Cystadenoma 160, 191

CIC-DUX4 fusion 57

Cystic dermoid 157 Cystic duct adenoma 191

CD31 38, 44, 46, 48, 75, 123,125,210 CD33 131 CD35 146

CK1/2/10/11 29 CK8 19, 82, 248 CK10 29 CK10/13 29 CK14 187,192,210,224,227

CD43 CD44 CD45 CD57 CD68

CK17 32 CK18 19, 51, 59, 82,172,248 CK19 32, 70, 76, 208-210, 224,227, 248 CK20 22, 24, 26, 32, 69, 89,152,172,180 Classical Hodgkin lymphoma 134, 141, 142

disorder 129

131, 202 186 19, 83, 130, 21 O 53, 100, 120, 121 100,121,131

CD79a 55, 130, 142 CD99 37,42,56,57, 59,247 CD138 55,130,227 CD163 131 CD207 130, 131 CDC73 252 CDH11 259 CDK2NA 36 CDK4 101, 245 CDKN2A 24, 83, 92,111,115,145,181,280 CDX2 24,26,32, 172,273 Cementa! dysplasia 254 Cementifying fibroma 251 Cementoblastoma 204, 230, 231, 249 Cementoma 204, 205, 230, 252-254

Classic intraosseous ameloblastoma 215 Claudin 5 38 Clear cell ameloblastoma 210 Clear cell carcinoma 160, 168, 169 Clear cell odontogenic carcinoma 204, 21 O Clear cell odontogenic tumour 210 Clear cell oncocytosis 195

CLTC 102 Clusterin 146

CNBP 259 COC See Calcifying odontogenic cyst COD See Cemento-osseous dysplasia COF See Cemento-ossifying fibroma COL1A1 259 Colloid-type adenocarcinoma 23

Cemento-osseous dysplasia 204, 254, 255

Colonic-type adenocarcinoma 23

Cemento-ossifying fibroma 204, 231, 25 i,

Columnar cell papilloma 29

253 Central giant cell granuloma 204, 256 Central giant cell lesion 256 Central odontogenic fibroma 228 Central ossifying fibroma 251

Condyloma acuminatum 106, 116

CEOT See Calcifying epithelial odontogenic tumour

Congenital basal cell adenoma 183 Congenital epulis 119 Congenital gingival granular cell tumour 119 Congenital granular cell epulis 106, 119 Congenital hybrid basal cell adenoma adenoid cystic carcinoma 183

Cystic teratoma 157

D 02-40 38, 104, 123, 125, 146 Dandy.-Walker syndrome 72

DDX3X 53 Dental cyst 232 Dentigerous cyst 204, 234 Dentinogenic ghost cell tumour 204, 211,

212,226,227 Dermoid cyst 157 Dermoid polyp 72 Desmoid tumour 43, 250 Desmoid tumour of bone 250 Desmoid-type fibromatosis 12, 43 Desmoplastic fibroma 204, 250 DGCT See Dentinogenic ghost cell tumour

DICER1 52 Diffuse large B-cell lymphoma 52, 61, 64, 75, 104,128,141,154,200 DLBCL See Diffuse large 8-cell lymphoma DLX2 216 DOG1 26,166,172,178 Ductal adenoma 194 Ductal carcinoma/adenocarcinoma 171 Ductal papilloma 192 DUSP22-IRF4 rearrangement 129 Oysplasia 91

E E6 28, 29, 137, 138 E7 28, 29, 137, 138 EBV-encoded small RNA íB, 22, 53, 54, 68,

Ceruminal adenocarcinoma 264

Congenital pleomorphic adenoma 71

Ceruminal adenoma 265

Conventional ameloblastoma 215

Ceruminoma 265

Conventional squamous cell carcinoma 81

Ceruminous adenocarcinoma 262, 264

Costello syndrome 37

Ceruminous adenoma 262, 265

Craniofacial fibrous dysplasia 254

Ectopic pituitary adenoma 64, 72, 73

128,130,142,143,181,182 Ectomesenchymal chondromyxoid tumour

106,119,120,127

Ceruminous pleomorphic adenoma 265

Craniopharyngioma 64, 73

ELST See Endolymphatic sac tumour

Ceruminous syringocystadenoma papilliferum

Cribriform adenocarcinoma 140, 167

Embryoma 183

265 Cervical lymphoepithelial cyst 155

Cribriform cystadenocarcinoma, low-grade

Embryonal rhabdomyosarcoma i 2, 36

CGCG See Central giant cell granuloma Chemodectoma 277, 281-283 Cherubism 204, 257, 258

170 CRTC1-MAML2 gene fusion í64 CRTC3-MAML2 gene fusion 164 CTNNB1 43,44, 73, 75,186,217,222,250

EMC See Epithelial-myoepithelial carcinoma EMCMT See Ectomesenchymal chondromyxoid tumour Enchondroma 246

Subject index

341

Endolymphatic sac tumour 262, 267, 268

FDC See Follicular dendritic cell sarcoma

HER2 173,174,177

ENKTL See Extranodal NK{T-cell lymphoma

FDG-PET 103 FGC See Familia! gigantiform cementoma

Hereditary multiple osteochondromas 255

FGFR2 216, 217 Fibroblastic osteosarcoma 34

HEYI-NCOA2 gene fusion 244

Enteric-type adenocarcinoma 23 Eosinophilic granuloma 130 EPAS1 278, 280 Epidermoid carcinoma 14, 81,263 Epidermoid papillary adenoma 192 Epiphora 38 Epithelial hamartoma 32

Fibroneuroma 49 Fibrosarcoma 12, 34 Fibrous dysplasia 204, 253 FLl1 38, 46, 48, 56, 57, 59, 125

Heterotopia-associated carcinoma 152, 153 High-grade non-lTAC See High-grade non-intestinal-type adenocarcinoma HHF35 175

HHV8 124, 125, 130, 143 HIF2A 278, 280

FNCLCC 36 Focal epithelial hyperplasia 117 Follicular cyst 234 Follicular dendritic cell sarcoma 145 Follicular lymphoma 134, 143,154,200 FOX01 37, 41 FOX03 53, 165 Fungitorm papilloma 30

High-grade ductal carcinoma 173

ETV6-NTRK3 gene fusion 177, 178

G

HMGA2 174,176,177,186

Everted papilloma 30 Ewing sarcoma/primitive neuroectodermal

Gardner syndrome 43, 212, 226, 246

Epithelial-myoepithelial carcinoma 160, 175 Epithelioid haemangioendothelioma 12, 38, 45, 46 ER-alpha 72 ERBB2/HER2 173, 174, 177 ERG 38, 46, 123, 125 ESR1 69 ETV6 177, 178

tumour 56, 61 EWSRI-ATF1 gene fusion 169 EWSRI-FLl1 gene fusion 57 EWSR1 gene rearrangement 175 EWSRi-POU5F1 gene fusion í64 Exophytic papilloma 30, 31 EXT1 255 EXT2 255 Extracranial pituitary adenoma 72 Extracutaneous Merkel cell carcinoma 151 Extramedullary myeloid sarcoma 52, 64, 75, 104,106,131 Extramedullary plasmacytoma 54, 55 Extranodal marginal zone lymphoma of mucosa-associated lymphoid tissue See MALT lymphoma Extranodal NK{T-cell lymphoma 12, 52-54, 75, 141 Extranodal NK{T-cell lymphoma, nasal-type 52 Extraosseous ameloblastoma 218 Extraosseous plasmacytoma 12, 52, 54, 55, 64, 75,104 Extrasellar pituitary adenoma 72

F Familia! adenomatous polyposis 43, 246 Familia! fibrous dysplasia 257

High-grade non-intestinal-type adenocarcinoma 24-26 Histiocytosis X 130 HIV 52, 115, 117, 124, 125, 128, 130, 142 HL See Hodgkin lymphoma HMB45 34, 47, 61, 82,210,247 Hodgkin lymphoma 68, 75,129,134,141, 142, 144, 154, 201

GATA2 72 GCOC See Ghost cell odontogenic

Horner syndrome (oculosympathetic palsy)

carcinoma Ghost cell odontogenic carcinoma 204, 211,

HPV 6 28, 29, 93-95

212 Giant cell angiotibroma 45 Giant cell epulis 257 Gígantiform cementoma 204, 205, 252, 253 Gingival cyst 204, 238 Glandular hamartoma 31, 32 Glandular odontogenic cyst 204, 238, 239 Glomus jugulare tumour 282 Glomus tympanicum tumour 282 Glomus vagale tumour 283 GLUT1 123 GNAS 252, 254 GOC See Glandular odontogenic cyst Gorlin cyst 239 Granular cell myoblastoma 100, 121 Granular cell neurofibroma "100, 121 Granular cell schwannoma 100, 121 Granular cell tumour 78, 100, í06, 121 Granulocytic sarcoma 13 í GSTM1 69

48,277,283 HPV 11

94

HPV 16/18 28, 29 HPV32 117 HPV-negative sinonasal squamous cell carcinoma 17 HPV-positive sinonasal squamous cell carcinoma i 7 HPV 16, 17, 21, 25, 28, 29, 69, 86, 136-138, 149, 151 HRAS 37,111,168,186,216,280 Human papilloma virus 16 Hyperparathyroidism jaw tumour syndrome 252

ICC See lnflammatory col lateral cyst ID3 143 1DH1/2 mutation 243, 244, 280 lgA 54, 55, 67, 202 IGF2 186

H H3F3A/ H3F3B point mutation 248, 256

Faciocutaneoskeletal syndrome 37

High-grade myxotibrosarcoma 35

HACE1 53 Haemangioblastoma 38, 279 Haemangioma 12, 47, 106, 123, 160, 198 Haemangiopericytoma 45

lgG 55, 67, 202 lncisive canal cyst 241 lnfantile fibromatosis (desmoid variant) 43 lnfectious mononucleosis 141 lnflammatory collateral cyst 204,233 lnflammatory dental cyst 232

Haemangiosarcoma 38 Haemorrhagic bone cyst 259

lntlammatory myofibroblastic tumour 78, 101,

Fanconi anaemia 111, 112

Hairy polyp 64, 72 Hand-"Schüller-Christian disease 130 Heck disease 117

lnflammatory paradental cyst 233 INSRR 165

FO See Fibrous dysplasia

Heffner tumour 267

lntercalated duct adenoma 197

Familial gigantiform cementoma 253 Familial/multiple cylindromatosis syndrome 170 FANCA 36

342

Subject index

102 lnflammatory pseudotumour 101

lntercalated duct hyperplasia "160, 197 lntestinal-type adenocarcinoma i2, 14, 15, 23-26, 171,172

Laryngeal paraganglioma 275, 276, 281 Lateral neck cyst i 55

lntraductal carcinoma 160, 170, i7í

Lateral periodontal cyst 204, 236, 237 LCNEC See Large cell neuroendocrine

lntraductal papillary hyperplasia (non-neoplastic) 191 lntraoral basal cell carcinoma of the gingiva

LEC See Lymphoepithelial carcinoma Leiomyoma 12, 47

206 lntraosseous well-differentiated osteosarcoma 244 lnverted Schneiderian papilloma 28 lnverting papilloma 28 ISL 1 216,273 ITAC See lntestinal-type adenocarcinoma

carcinoma

Leiomyosarcoma 12, 34, 35, 47 LEOPARD syndrome 256 Lethal midline granuloma 52 Letterer-Siwe disease 130 LG non-lTAC See Low-grade non-intestinal-type adenocarcinoma Li-Fraumeni syndrome 37, 1i 1, 246 Lipoma 101,198,199

J

Liposarcoma 78, 100

JAK3 53

LMP1 53, 69

JAK/STAT 53 JPOF See juvenile psammomatoid ossifying

Lobular capillary haemangioma 47, 48 LOH 29, 83, 92, 113, 236

fibroma JTOF See Juvenile trabecular ossifying fibroma

Low-grade adenocarcinoma 24, 30, 70, i 40 Low-grade central osteosarcoma 204, 244

Jugulotympanic chemodectoma 282 Juvenile active ossifying fibroma 25 í Juvenile aggressive ossifying fibroma 251 Juvenile angiofibroma 74 Juvenile fibrous dysplasia 257 Juvenite nasopharyngeal angiofibroma 74

Low-grade non-intestinal-type adenocarcinoma 24-26 Low-grade papillary adenocarcinoma of endolymphatic sac origin 267 Low-grade papillary tumour 24 Low-grade salivary duct carcinoma 170 Low-grade sinonasal sarcoma 40 Low-risk HPV 28

Juvenile ossifying fibroma 25 í Juvenile paradental cyst 233 Juvenile psammomatoid ossifying fibroma

LPC See Lateral periodontal cyst

251, 252 Juvenile trabecular ossifying fibroma

Lymphadenoma 160, 190, 191 Lymphangioepithelioma i 22

251, 252

LTA See Lymphotoxin alpha gene

Lymphangioma í06, 122, 123

K

Lymphangiomatous polyp í 22 Lymphocyte-depleted classical Hodgkin

Kaposi sarcoma i06, 124, 125, 143

lymphoma 142 Lymphocyte-rich classical Hodgkin

Kaposi sarcoma-associated herpesvirus 124 Keratinizing squamous cell carcinoma 12, 14,29, 64,65,68, 138 Keratocystic odontogenic tumour 235 KIF18A 42 KIT See CD117

lymphoma i42 Lymphoepithelial carcinoma 12, 18, 65, 78, 90,110,160,181,182 Lymphoepithelial sialadenitis 160, 196, 197,

K-NPC See Keratinizing nasopharyngeal

201 Lymphoepithelioma-like carcinoma 18, 90,

carcinoma KRAS 24,216 KSCC See Keratinizing squamous cell

Lymphotoxin alpha gene 54 Lysozyme 32, 131

carcinoma KSHV See Kaposi sarcoma-associated herpesvirus

137, 181

LYVE1 123,125

M

L

Malignant angioendothelioma 38

Langerhans cell histiocytosis 106, 130 Large cell neuroendocrine carcinoma í 2, 2i,

tumour 211 Malignant calcifying odontogenic cyst 211

Malignant calcifying ghost cell odontogenic

22, 78, 97, 98, 160, 180, 181 Laryngeal granular cell tumour 100

Malignant epithelial odontogenic ghost cell tumour 211

Malignant tibrous histiocytoma 35 Malignant Malignant Malignant Malignant

haemangioendothelioma 38 lymphoepithelial lesion 181 midline reticulosis 52 myoepithelioma 17 4

Malignant neurilemmoma 39 Malignant oncocytoma i 82 Malignant peripheral nerve sheath tumour 39,40 Malignant rhabdomyoma 36 Malignant schwannoma 39 Malignant surface epithelial tumours 77, 78, 81, 105, 109 Malignant teratoma 26 MALT lymphoma 52, 54, 55, 75, 104, 128, 141,160,197,200,201,202 MAML2 89, 164, 239 MAML3 40, 41 Mammary analogue secretory carcinoma 177 Mandibular buccal bifurcation cyst 233 Mandibular infected buccal cyst 233 Mantle cell lymphoma 75,128, i34, 14i, 144, 154, 200 MAP2K1 131 MAPK 216,217, 256 MCC See Merkel cell carcinoma McCune-Albright syndrome 253, 254 MDM2 101,177,186,245,246 MEC See Mucoepidermoid carcinoma MED12 36 Melanoma 12, 18, 34, 35, 60, 61, 82,105, 106,126,127,149,180,211,247 Melanotic neuroectodermal tumour of infancy 204,247 Melanotic progonoma 247 Membranous adenoma 187 Meningioma 12, 50, 262, 271, 272 Merkel cell carcinoma 148,151,152,180 Mesenchymal chondrosarcoma 204, 244 Mesenchymoma 51 Metastasizing ameloblastoma 204,218,219 MFEH See Multifocal epithelial hyperplasia MIB1 278 Microglandular adenosis of nose 32 Middle ear adenoma 262, 272, 273 Middle ear adenomatous tumour 272 Middle ear adenoma with neuroendocrine differentiation 272 Middle ear paraganglioma 263, 276, 282 Midline carcinoma of children and young adults with NUT rearrangement 20 MIR143-NOTCH fusion 44 Mixed cellularity classical Hodgkin lymphoma 142 MMP9 227 MNOH See Multifocal nodular oncocytic hyperplasia Subject index

343

MNTI See Melanotic neuroectodermal

Neuroectodermal/melanocytic tumours

tumour ot infancy Moderately differentiated neuroendocrine

12, 56 Neuroendocrine adenoma of the middle ear

carcinoma 96 Monomorphic adenoma 187 Monostotic fibrous dysplasia 253

272 Neuroendocrine carcinoma 12, 21, 83, 95-97

MPNST See Malignant peripheral nerve sheath tumour MSA 36, 37, 41, 44, 47,168,187 MSX2 216 MUC2 24, 26 Mucinous cystadenocarcinoma 171 Mucocoele 156 Mucoepidermoid carcinoma 127, 163 Mucoepidermoid tumour 127, 163 Mucosal melanoma 12, 60 Multifocal adenomatous oncocytic hyperplasia 195 Multifocal epithelial hyperplasia í06, 117, 118 Multifocal nodular oncocytic hyperplasia 195 Multiple familia! trichoepithelioma 170, í88 MUM1/IRF4 55, 130, 144 MYB 17, 71,164,165,264 MYBL1 165 MYB-NFIB genefusion 71,164,165,264 MYC 130, 142-144 MYC-IGH fusion í30 MYCL 69 MYF4 37 MYOCD 36 MYOD1 37, 41,122

Neuroendocrine tumours 78, 95 Neurotibroma 12, 49, 50,106, 123, 124 Neurofibromatosis type 1 37, 39, 40, 49, 50, 124,256,257,279,280 Neurotibromatosis type 2 51, 124, 270-272 Neurofibrosarcoma 39 NFI See neurofibromatosis type 1 NF2 See neurofibromatosis type 2 NFP 49,50, 56,271 NK-cell lymphomas 128 NKSCC See Non-keratinizing squamous cell

Oncocytic papilloma 29, 30 Oncocytic Schneiderian papilloma 29 Oncocytic sialolipoma í98 Oncocytoma 99, 160, 182, 189, 190, 196 OOC See Orthokeratinized odontogenic cyst

Nodular oncocytosis 190, 195 Nodular sclerosis classical Hodgkin lymphoma i 42 NOH See Nodular oncocytic hyperplasia Non-chromaftin paraganglioma 277, 281, 283 Non-intestinal type adenocarcinoma 14, 24 Non-lTAC See non-intestinal type adenocarcinoma Non-keratinizing carcinoma 65 Non-keratinizing squamous cell carcinoma

NOTCH1/NOTCH2 165,181 NPC See Nasopharyngeal carcinoma

Nasal chondromesenchymal hamartoma 51 Nasal dermoid sinus cyst 157 Nasopalatine duct cyst 204, 241, 242 Nasopharyngeal angiofibroma 74 Nasopharyngeal carcinoma 18, 64, 65, 67, 69,90 Nasopharyngeal papillary adenocarcinoma 64, 70 NCOA2 37, 244 NDC See Nasopalatine duct cyst

NPM1 131 NRAS 61,216 NTRK3 177, 178 NUT carcinoma i2, 14, 17, 18, 20-22, 61 NUTM1 20, 21 NUT midline carcinoma 20

o Oat cell carcinoma 97 ODAM See Odontogenic ameloblast-associated protein Odontogenic ameloblast-associated protein 220 Odontogenic carcinosarcoma 204, 21'3 Odontogenic cyst 204,208,211,212,232, 234-241

Neumann tumour 119 Neurilemmoma 39, 48,123,270

Odontogenic fibroma 204, 228

Neurinoma 123

Odontogenic myxofif)roma 229

344

Subject index

Oncocytic adenoma 189 Oncocytic adenomatous hyperplasia 99 Oncocytic carcinoma 160, 182, 183

Nodular oncocytic hyperplasia 160, 195, 196

Notch 41, 145, 220

NAB2-STAT6 gene fusion 44, 45

OMP 59 ONB See Olfactory neuroblastoma Oncocytic adenocarcinoma 182

100 Oncocytic papillary cystadenomatosis 99

Myoepithelioma I i9, 160, 186, 187

N

Olfactory placode tumour 57 OMD 259

Nodal Merkel cell carcinoma 151 Nodular fasciitis 160, 199

Myofibroblastic sarcoma 106, 125, 126

Myosin 37, 122

OGG1 69 OKC See Odontogenic keratocyst Olfactory neuroblastoma 12, 18, 57-59

carcinoma NK/T-cell lymphorna 75

12, 15, 18, 64-69, 136 Noonan syndrome 256-258

Myosarcoma 36

Odontoma 204, 224 OED See Oral epithelial dysplasia

Oncocytic cyst 99 Oncocytic lipoadenoma 198 Oncocytic papillary cystadenoma 78, 99,

Myoepithelial carcinoma 160, 174 Myoepithelial sialadenitis 196

Myofibrosarcoma 125 Myoglobin 37, 122

Odontogenic myxoma 204, 229, 230 Odontogenic sarcoma 203, 204, 214

Odontogenic keratocyst 204, 235, 236

OPMDs See Oral potentially malignant disorders OPSCC See Oropharyngeal squamous cell carcinoma Oral condyloma acuminatum 116 Oral epithelial dysplasia 106, 112-114 Oral mucosal melanoma i06, 126 Oral potentially malignant disorders 108,112 Oral potentially malignant disorders and oral epithelial dysplasia 112 Oral squamous cell carcinoma 109-11 i Oropharyngeal squamous cell carcinoma 136-138 Orthokeratinized odontogenic cyst 204,241 osee See Oral squamous cell carcinoma Osseous dysplasia 254 Osseous plasmacytoma 260 Ossifying fibroma 204,231,251 Osteoblastoma 204, 249, 250 Osteochondroma 204, 255 Osteochondromatous exostosis 255 Osteogenic sarcoma 244 Osteoid osteoma 204, 249 Osteoma 204, 246 Osteosarcoma 204, 244 Otosclerosis 262, 263, 268, 269 Otospongiosis 268 Oxyphilic adenoma 99, i 89

p

Polymorphous low-grade adenocarcinoma 140, 167

ROR2 36 Rothmund-Thomson syndrome 246

p14ARF/p161NK4a 115,145 PA See Pleomorphic adenoma PAC See Polymorphous adenocarcinoma Papillary adenocarcinoma of the middle ear

Polyostotic fibrous dysplasia 253, 254

RRP See Recurrent respiratory

Polytetrafluoroethylene (Teflon) injection 103 Poorly differentiated carcinoma 160, i 65,

papillomatosis RUNX1 216

266 Papillary cystadenocarcinoma í 71 Papillary cystadenoma lymphomatosum í 88

Poorly differentiated neuroendocrine carcinoma 21, 22, 78, 97 PRDM1 53, 130

S45F/S45P 43

Papillary squamous cell carcinoma 78, 87 Papilloma i06, 1í 5

Primary intra-alveolar epidermoid carcinoma

Salivary gland adenocarcinoma 171 Salivary gland anlage tumour 64, 71

Paraganglioma 162, 263, 267, 271, 276-280,

180

207 Primary intraosseous carcinoma 204,

281-283 Paranasal sinus tumours 38, 58 Paranasal tumours 52 Paraneoplastic syndromes 58 Parosteal osteosarcoma 204, 244 PAX3 37, 40, 41 PAX7 37 PAXB 26,268,273 PBL See Plasmablastic lymphoma Periapical cyst 232 Periodontoma 251 Periosteal osteosarcoma 204, 244 Peripheral giant cell granuloma 204, 257 Peripheral neuroblastoma 56 Peripheral neuroectodermal tumour 56 Peripheral neuroepithelioma 56 Peripheral T-cell lymphoma 52, 53, 75, 141, 201 Phaeochromocytoma-paraganglioma syndrome 282 PIK3CA 69, 83,111,138,165,217 Pindborg tumour 220 PIOC See Primary intraosseous carcinoma PIT1 72 Pituitary adamantinoma 73

PITX2 216 PLAG1 174,176,185,186 PLAP 27 Plasmablastic lymphoma 106, 129, i30 Plasma cell gran uloma 101 Plasmacytoma 12, 52, 54, 55, 64, 75, i04, 128,141,201,204,260 Pleomorphic adenoma i2, 33, 78, 99, i06, 127, 134, 139, 160, 185, 186

207-209 Primary intraosseous squamous cell carcinoma 207 Primary odontogenic carcinoma 207 Primordial odontogenic tumour 204, 223, 224 PRKD1, PRKD2, PRKD3 168 Proliferative verrucous leukoplakia 47, 106, 113-115, 123 PROX1 123, 125 PSCC See Papillary squamous cell carcinoma Pseudosarcomatous fasciitis 199 PTCH 221 PTCH1 59,122,235,236 PTEN 36,111,181

s Salivary duct carcinoma 160, 173, 174

Salivary type tumours 127 Sarcomatoid carcinoma 17, 34, 88,179 sse See Simple bone cyst

see

See Squamous cell carcinoma

Schneiderian carcinoma i 6 Schneiderian papilloma 28-30, 40 Schneiderian papilloma, inverted type 28 Schwannoma 12, 48, 106, 123, 124, 267 Sclerosing adenosis 195 Sclerosing odontogenic carcinoma 204, 209, 228 Sclerosing polycystic adenoma 195 Sclerosing polycystic adenosis 160, 195 Sclerosing polycystic sialadenopathy 195 sesee See Spindle cell squamous cell carcinoma

PTGS2 83

soe See Salivary duct carcinoma

PTPRK 53 PVL See Proliferative verrucous leukoplakia

SDH 278-280 SDHA 278-281, 283

Pyogenic granuloma 47, 123

SDHAF2 278-280, 283

R

SDHB 278-283

Radicular cyst 204, 232

SDHC 278-281, 283 SDHD 278-281, 283

RANBP2 102

Sebaceous adenocarcinoma 160, 178

Ranula 148, 156, 157 RAS 26,127,217,256

Sebaceous adenoma i 60, 193 Secretory carcinoma 160,177, i78

RB1 36, 180 RBL2 143

Septal papilloma 30

REAH See Sinonasal respiratory epithelial

Seromucinous hamartoma 12, 32 SF1 72

adenomatoid hamartoma Recurrent respiratory papillomatosis 93-95 Renal cell-like carcinoma 24, 26 Reparative giant cell granuloma 256 Respiratory epithelial adenomatoid hamartoma 31 RET 278-280

Seromucinous adenocarcinoma 24

SH3BP2 257 SHH signalling pathway 59,212,235 Sialadenoma papilliferum 160, 192 Sialoblastoma i 60, 183, 184 Sialolipoma 160, 198

Pleomorphic liposarcoma 35 Pleomorphic rhabdomyosarcoma 12, 36 Pleomorphic rhabdomyosarcoma, adult type

Retention cyst 156

Simple bone cyst 204, 259

36 Podoplanin 123, 125,146,243

Retina! anlage tumour 247 Retinoblastoma 57, 246

Sinonasal ameloblastoma 12, 51 Sinonasal angiosarcoma 38

Poikiloderma atrophicans with cataract See Rothmund-Thomson syndrome

Rhabdomyoma 106, 122

Sinonasal Burkitt lymphoma 52 Sinonasal cavity tumours 38

Polycystic adenosis 160, 163, 195 Polymorphic reticulosis 52 Polymorphous adenocarcinoma i34, 140, 160, 167, 168

Rhabdomyosarcoma 12, 36, 37, 57 Rhabdosarcoma 36 RHOA 143 RIC8B 59 Ringertz tumour 30

Sialo-odontogenic cyst 239

Sinonasal exophytic papilloma 30 Sinonasal fibrosarcoma 34 Sinonasal glomangiopericytoma i2, 44 Sinonasal haemangiopericytoma-like tumour 44

Sub¡ect índex

345

Sinonasal keratinizing squamous cell carcinoma 14 Sinonasal mucosal melanoma 60, 61 Sinonasal neuroendocrine carcinoma 21, 22 Sinonasal neurofibroma 49 Sinonasal non-intestinal-type adenocarcinoma 24 Sinonasal papilloma 12, 28 Sinonasal oncocytic papilloma 29 Sinonasal papilloma, exophytic type 30 Sinonasal papilloma, inverted type 28 Sinonasal papilloma, oncocytic type 29 Sinonasal respiratory epithelial adenomatoid hamartoma 31, 32 Sinonasal rhabdomyosarcoma 36 Sinonasal schwannoma 48 Sinonasal teratocarcinosarcoma 26 Sinonasal tract meningioma 50 Sinonasal tract tumours 56 Sinonasal undifferentiated carcinoma 12, 14, 16, 18, 19,26,30 Small cell neuroendocrine carcinoma 12, 21, 22, 78, 97, 98, 160, 180, 181 SMARCB1 16, 17, 19-21, 39, 61,217 SmCC See Small cell neuroendocrine carcinoma SMO 217 SNUC See Sinonasal undifferentiated carcinoma SOC See Sclerosing odontogenic carcinoma Soft tissue ameloblastoma 218 Solid/multicystic ameloblastoma 215 Solitary bone cyst 259 Solitary fibrous tumour 12, 45 Solitary plasmacytoma of bone 204, 260 SOT See Squamous odontogenic tumour SOX2 20,206 SOX11 144 SPB See Solitary plasmacytoma of bone Spindle cell melanoma 34 Spindle cell rhabdomyosarcoma 12, 34, 36, 37 Spindle cell squamous cell carcinoma 12, 17, 78,87,88, 102 Sé¡uamous cell carcinoma 109, 182,263,

266 Squamous cell carcinoma, HPV-negative 138 Squamous cell carcinoma, HPV-positive 136 Squamous cell papilloma 78, 85, 93, 106, 115,116 Squamous cell papillomatosis 78, 93 Squamous intraepithelial lesion 91,112,316 Squamous intraepithelial neoplasia 91, 92 Squamous odontogenic tumour 204,219 SS18 41, 42 SS18-SSX fusion 41

346

Subject index

ssx

41, 42 STAT3 53 STAT6 44, 45, 51 Striated duct adenoma 194 Sturge--Weber syndrome 48 Swedish snuff 109 Synovial sarcoma 12, 34, 41, 42 Synovioma 41

T t(6;22)(p21;q12) translocation 164 t(11; 18)(q21 ;q21) (B1RC3/APl2-MALT1) translocation 202 t(11; 19)(q21;p13) translocation 164 t( 12;15)(p13;q25) translocation 178 t(14;18)(q32;q21) (IGH-MALT1) translocation 202 t(15;i9) carcinoma 20 t(X;1S)(p11;q11) translocation 41, 42 T41A 43 T-cell lymphoproliferative disorder 128, 129 TCF3 143 Teratocarcinosarcoma 26, 27 Teratoid cyst 157 Teratoid potyp 72 TERC 69 Terminal duct carcinoma 140, 167 Terminal tubulus adenocarcinoma 24 TFE3 46 TGD cyst See Thyroglossal duct cyst TGF-alpha 270 TGF-beta 1 /SMAD 222 THRAP3 259 Thyroglossal duct cyst 156 Thyroglossal duct remnant í 56 Thyroid-like low-grade nasopharyngeal papillary adenocarcinoma 70 T-LBL/L See T-lymphoblastic leukaemia/ lymphoma TLE1 41,42 TLPD See T-cell lymphoproliferative disorder T-lymphoblastic leukaemia/lymphoma 134, 144 TMEM127 279,280 TNFAIP3 201, 202 Tobacco 14,65,81,84,86,87,91, 93,95, 96,109,110,112,114,136 TPIT 72 TPM3 102 TPM4 102 TRAF3 138 Transitional cell carcinoma 16 Transitional cell papilloma 30 Traumatic bone cyst 259 True cementoma 230 TIF1 21, 70, 96-98, 146,152,268,273 Tubulopapillary low-grade adenocarcinoma 24

u UAM See Unicystic ameloblastoma UBR5 212 Unclassified adenocarcinoma 171 Undifferentiated carcinoma 65, 160, 180,181 Undifferentiated pleomorphic sarcoma 12,34,35 Unicameral bone cyst 259 Unicystic ameloblastoma 217, 2"18 Unknown primary Merkel cell carcinoma 151 USP6 199, 259

V Vaga! paraganglioma 276, 283 VC See Verrucous squamous cell carcinoma VEGF 83,268 VEGFA 83 VEGFR3 123, 125 Venereal condyloma 116 Verruca vulgaris 106, 117 Verrucous squamous cell carcinoma 29, 78, 84, 85, 116 Vestibular neuroma 270 Vestibular schwannoma 262, 270, 271 VHL See Von Hippel-Lindau disease Van Hippel-Lindau disease 48, 267, 268, 279,280 VV See Verruca vulgaris

w Warthin tumour 160,163, 188-191, 201 Well-differentiated liposarcoma 101 Well-differentiated neuroendocrine carcinoma 78,95,96 Werner syndrome 246 WHSC1L1 21 WWTR1-CAMTA1 fusion 46

X XBP1 130 XRCC1 69

y YAP1-TFE3 fusion 46


3D AJCC BCL2 BCL6 cAMP CDK4 CNS CT DNA EBER EBV EGFR EMA FDG-PET FISH FLAIR GFAP H&E HHV8 HIV HPV ICD-0 lg LOH MAPK MDM2 MRI mRNA N:C ratio NKcell PAS PCR PET PET-CT RB RNA RT-PCR SDHA SDHB SEER SMA SMARCB1 STAT6 TdT TNM

Three-dimensional American Joint Committee on Cancer B-cell lymphoma 2 protein B-cell lymphoma 6 protein Cyclic adenosine monophosphate Cyclin-dependent kinase 4 Central nervous system Computed tomography Deoxyribonucleic acid Epstein-Barr virus-encoded small ribonucleic acid Epstein-Barr virus Epidermal growth factor receptor Epithelial membrane antigen

í 8F-Fluorodeoxyglucose positron emission tomography Fluorescence in situ hybridization Fluid-attenuated inversion recovery Glial fibrillary acidic protein Haematoxylin and eosin Human herpesvirus 8 Human immunodeficiency virus Human papillomavirus lnternational Classification of Diseases for Oncology lmmunoglobulin Loss of heterozygosity Mitogen-activated protein kinase Mouse double minute 2 homologue Magnetic resonance imaging Messenger ribonucleic acid Nuclear-to-cytoplasmic ratio Natural killer cell Periodic acid-Schiff Polymerase chain reaction Positron emission tomography Positron emission tomography-computed tomography Retinoblastoma protein Ribonucleic acid Reverse transcriptase polymerase chain reaction Succinate dehydrogenase [ubiquinone] flavoprotein subunit, mitochondrial Succinate dehydrogenase [ubiquinone] iron-sulfur subunit, mitochondrial Surveillance, Epidemiology, and End Results Smooth muscle actin SWI/SNF-related matrix-associated actin-dependent regulator of chromatin subfamily B member 1 Signal transducer and activator of transcription 6 Terminal deoxynucleotidyl transferase Tumour, nade, metastasis


347

Who Classification of Head & Neck Tumors - 2017

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