Boards and Beyond: Dermatology A Companion Book to the Boards and Beyond Website Jason Ryan, MD, MPH Version Date: 1-17-2018 1 -17-2018
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Table of Contents Skin Epithelial Cells Skin Disorders I Skin Disorders II Pigment Disorders Vascular Tumors
1 5 8 13 16 18
Skin Infections Blistering Disorders Hypersensitivity Hypersensitivity Disorders Skin Cancer Neurocutaneous Disorders
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Skin Largest organ in the body Barrieragainstinfection Prevents water loss Three layers Epidermis: keratinocytes (squamous epithelial cells)
Skin
Dermis: connective tissue, vessels Subcutaneous fat (also called hypodermis or subcutis)
Jason Ryan, MD, MPH
Epidermal Layers
Epidermal Layers Stratum Lucidum Clear layer of dead skin cells
Stem cells
StratumCorneum Desmosomes form spines
Anucleated cells Filled with keratin filaments
Stratum Granulosum Keratohyalin Keratohyalin granules Form keratin filaments
Dermis
Dermatopathology Terms used to describemicroscopic describe microscopicfindings findings
Blood vessels
Used in analysis of skin biopsies Hyperkeratosis Parakeratosis Hypergranulosis Spongiosis Acantholysis Acanthosis
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Hyperkeratosis
Parakeratosis
Thickening of stratum corneum
Hyperkeratosis+ retained nuclei in stratum corneum
Excess quantity of keratin Seen in skin diseases (psoriasis) and malignancies
Hypergranulosis
Spongiosis
Increased thickness ofstratum of stratum granulosum
Fluid accumulation (edema) of epidermis
Classic finding in lichen planus
Seen in eczema, many other skin disorders
Acantholysis
Acanthosis
Loss of connectionsbetween connections betweenkeratinocyte
Diffuse epidermal hyperplasia
Often loss of desmosomes
Elongated rete ridges Spinous layer thickening
Detached, floating freely in epidermis Key feature ofpemphigus of pemphigus vulgaris
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Acanthosis Nigricans
Skin Lesions
Nigricans = darkened
Primary lesions
Hyperpigmented (dark) plaques on skin
Directly caused by disease process process
Intertriginoussites(folds) Classically neck and axillae
Macules, papules, vesicles, bulla
Described using standard terminology
Associated with insulin resistance
Modification of primary lesion lesion
Often seen obesity, diabetes
Or caused by trauma, external external factors
Rarelyassociatedwith malignancy malignancy
Scale, crust, erosion, fissure, fissure, ulcer
Gastric adenocarcinoma most common
Macules and Patches
Papules and Plaques
Flat lesions (not raised) raised)
Raisedlesions
Macule: <1cm Patch: >1cm
Papule:<1cm Plaque: >1cm
Maculopapular Rash
Vesicles and Bulla
Collection of small skin lesions
Fluid-filled lesions (blisters)
Some flat (macules)
Vesicle:<1cm
Some raised (papules) “Morbilliform”– “Morbilliform”– looks like measles Common in many disorders
Bulla (plural = bullae): >1cm
Drug rash Scarlet fever Syphilis Rubella
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Pustule
Wheal
Pus-filledvesicle
Smooth, elevated papule or plaque
White center
Surrounded by erythema (redness) Itchy Caused by dermal edema Component of urticaria (allergic reaction)
Scale
Crust
Peeling/flaking Peeling/flaking of stratum corneum
Dried exudate of skin lesion
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Epithelial Cells Form the epithelium Line cavities/surfaces of body Skin, lung, GI tract Secretesubstances(endocrine/exocrineglands) One of four types of animal tissue:
Epithelial Cells
Muscle Nerve Connective
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Basement Membrane
Basement Membrane
Fibrous, extracellular matrix of proteins Anchors epithelial cells to connective tissue
Twolayers Basal lamina Extracellular matrix secreted secreted by epithelial cells Contains laminin proteins Type IV collagen (Goodpasture’s/Alport syndrome)
Reticularlamina(reticularconnectivetissue) Reticular = like a net Anchors basal lamina to connective tissue
Basement Membrane
Connective Tissue
Cell Polarity
Cell Polarity
Sheets of epithelial cells bind together
Side facingcavity/lumen:apical cavity/lumen: apicalmembrane membrane Lumen of blood vessel
Different functions for each side of cell (“polarized”)
Lumen of GI tract Lumen of nephron Outside of body
Side away from cavity/lume cavity/lume n: basolateralmembrane basolateralmembrane
Basement Membrane
Basement Membrane
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Tubular Epithelial Cells Lumen (Urine)
Epithelial Cell Junctions
Interstitium/Blood
Join plasma membranes of adjacent cells
Na+
Fourtypes: Tight junctions
ATP
Adherens junctions Gap junctions
2Cl-
Desmosomes K
K
Cl-
Mg2+ Ca2+
Tight Junctions
Adherens Junctions
Occluding Junctions or Zonula Occludens
Belt Desmosomes or Zonula Adherens
Sealstwo Seals two cell membranes together
Found below tight junctions
Barrier to paracellular movement between cells Found near apical membrane
Anchors cells to one another Forms belt around cells Cadherin
Most apical adhesion adhesion between cells
Built from key proteins:
Cell membrane glycoprotein Attach to actin filaments in cells
Occludin Caludin TJ
TJ AJ
Basement Membrane
Desmosomes
Cadherin
Spot Desmosome or Macula Adherens
Macula = Latin for spot “Spots” of cell-cell attachment (not belts) Common in theskin the skin Attached to intermediate filaments
Calcium-dependent Calcium-dependentadhesion (CAD)proteins Glycoproteins Manysubtypes E-cadherin: lost in some forms of breast cancer
Made of keratin Found in cell cytoplasm cytoplasm
Linked by cadherins
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Keratins
Hemidesmosomes
Tough,fibrousstructuralproteins
Similar to desmosomes
Found in hair, skin
Contain intermediate filaments of keratin
Also horns, claws, hooves Keratinmonomersassemble intermediatefilaments
Linked byintegrins byintegrins Attach epithelial cells to basement membrane Laminin (basal lamina), collagen
Microfilaments 7-9nm Intermediate 10nm Microtubules 25nm
Gap Junctions
Epithelial Junctions
Channelconnections Form structure called connexon Allow small molecules to pass Too small for proteins, nucleic acids
Claudins/Occludens
TJ
Cadherin
AJ
Apical Side
Cadherin/ DM Keratin IF
Gap Integrin/ Keratin IF HemiDM
Skin Disorders Autoantibodies to desmosomes
Autoantibodies to hemidesmosomes
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Connexins
Acne Inflammation Inflammation of hair follicles and sebaceous glands Exocrine glands in skin in dermis Secrete oily substance substance called sebum
Skin Disorders I
Often contain hair follicles (“Pilosebaceous unit”)
Complex, multifactorial etiology
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Acne
Acne
Sebaceous glands enlarge at puberty ↑ androgens
Sebum: growth medium for bacteria
↑ sebum
Propionibacterium acnes
Adolescent acne: acne: men > women
Cutibacterium acnes
Men with androgen androgen insensitivity: no acne Women with excess androgens androgens (PCOS): acne
Normal skin flora
Increasedsebum Increased sebum and keratin Keratinocytes line hair shafts
keratin
Blocks ducts Bacterial growth behind blockage
Acne
Acne
Comedones allow bacterial growth
Affectsmost hormone-responsive hormone-responsiveglands
Comedo: debris blocking sebaceous duct duct (bumps on face)
upper back Face, Face, neck, chest, upper
Comedone: plural of comedo Microcomedo: microscopic comedo (not (not visible) Lipid-rich environment for bacterial growth Bacteria use triglycerides in sebum sebum as fuel
Inflammation Inflammation frombacterial proliferation proliferation
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Acne
Acne
Treatment
Multiple lesion types
Benzoylperoxide(topical)
Open comedos: blackheads
Breakdown keratin, unblocks pores (comedolytic)
Closed comedos (by skin): whiteheads
Bactericidal to P. acnes
Inflammatory lesions (papules/pustules) (papules/pustules)
Antibiotics
Scarring and hyperpigmentation may occur
Decrease P. acnes colonization of skin Clindamycin and erythromycin erythromycin
Retinoids(vitamin A derivatives)
Benzoyl Peroxide
Isotretinoin
Seborrheic dermatitis
Accutane
Red plaques with scale (flaky skin) Bind to nuclear receptors
Occurs on face and scalp
Retinoic acid receptors (RAR) (RAR)
Areas with lots of sebaceous glands
Retinoid X receptors (RXR)
Decreases keratin production in follicles Less follicular occlusion occlusion
No inflammation of sebaceous glands Associated with fungal infection by Malassezia
Treatment:topicalantifungalsand corticosteroids
Highlyteratogenic Highly teratogenic OCP and/or pregnancy test prior to Rx
Melanocytic Nevus
Melanocytic Nevus
Moles
Moles
Benign neoplasm of melanocytes
Congenital Present at birth
Tan/brown Tan/brown pigmented lesion s
Often have hairs growing from lesion
Uniformcolor Often round or oval shape
Acquired Appear in childhood childhood
Usually <6mm
Increase in number during adolescence adolescence Peak count in 30s Regress with age
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Melanocytic Nevus
Acquired Nevi
Moles Rarely develop dysplasia melanoma
Junctionalnevi
Atypical features may warrant biopsy/removal
Growth along dermal-epidermal dermal-epidermal junction
Not removed prophylactically prophylactically for prevention
Often found in children
Compoundnevi Growth extends into dermis dermis Loss of junctional lesion Found only in dermis Common in adults
Pseudofolliculitis barbae
Psoriasis
Razor bumps, shave bumps Inflammation from trapped hairs
Chronic inflammatory skin disorder
Associated with shaving Entrapment of recently cut, very short hairs Firm papules/pustules in area of beard growth
Pink or salmon colored colored
Common in black men (up to 80%)
Most commonly on extensor surfaces Knees
3% white men
Elbows
Psoriasis
Psoriasis Acanthosis(thickeningof epidermis)
Combination Combination of genetic and environmental factors Retained nuclei in stratum corneum
Believed to beautoimmune be autoimmune Strong association with HLA-C
Indicates hyperproliferation
Stratumspinosum Increased in size size Thinned or absent Neutrophils in stratum corneum corneum
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Psoriasis
Psoriasis
Most common type: plaque psoriasis
Commonlyinvolvesnails involves nails Nail pitting
Multiple other less common subtypes
Onycholysis (separation of nail from nailbed)
Guttate psoriasis
About 1/3 of patients developpsoriatic develop psoriatic arthritis
Pustular psoriasis Erythrodermic psoriasis
Seronegative spondyloarthritis
Inverse psoriasis
More common in patients patients with nail findings
Rosacea
Rosacea
Common skin disorder (3% population)
Inflammatoryskin Inflammatoryskincondition
Affects adults > 30 Celtics and Northern Europeans: greatest risk Affectslight-skinnedindividuals
Complex,poorlyunderstood pathology Chronic redness of nose and cheeks Papules and pustules May look similar to acne but no no comedones
Rosacea
Seborrheic keratosis
Other features
Facial flushing
Common benign tumors
Often triggered by environmental stimuli
Proliferationofimmature keratinocytes keratinocytes
Cold, heat, sun, hot drinks, spicy foods, alcohol
Occurs in older patients (>50) Arisespontaneously Commonly on trunk
Skin hypertrophy Thickened skin Most commonly on nose (rhinophyma)
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Seborrheic keratosis
Seborrheic keratosis
Flat
Dark cells similar to basal skin cells
Well-demarcated
(“horn cysts”) Keratin-filledcysts (“horncysts”)
Round or oval Dark, velvety surface surface
“Stuck on” on”
Leser-Trelat Leser-Trelat Sign
Verrucae
“Explosiveonset” “Explosive onset” of multiple itchy SK lesions Probably caused by cytokines Associatedwith malignancies malignancies
Warts Cellular proliferation caused by HPV Many types
Gastric adenocarcinoma most common
Verruca vulgaris (skin - most common) Verruca plana (skin - flat wart) Condyloma acuminatum (venereal warts)
Verruca Vulgaris Cutaneous Warts Most common manifestation of HPV infection Transmitted by contact with virus Common on hands Koilocytosis Cytoplasmic clearing (“halos”) around nucleus
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Erythema Nodosum Type IV hypersensitivity reaction Panniculitis Inflammation of subcutaneous fat fat
Skin Disorders II
Manytriggers: Infection (most commonly commonly Strep)
Crohn’s disease (may precede flare) Sarcoidosis
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Coccidiomycosis
Erythema Nodosum
Erythema Nodosum
Pathology Findings
Painful, Painful, red nodules Inflammation septa of fat between dermis and fascia
Most commonly on shins
Contrast with “lobular”: inflammation inflammation of fat lobules
Lichen Planus
Lichen Planus
Rare, chronic inflammatory skin disorder “Lichen” = tree moss “Planus” = flat Occurs in adults
6Ps “Pruritic, Purple, Polygonal, Planar, Papules and Plaques”
Itchy (often intense) Purple flat lesions Multiple,symmetricusuallyon arms/legs/wrists arms/legs/wrists Wrists, ankles are common sites
Resolves spontaneously over years Associated with hepatitis C
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Lichen Planus
Lichen Planus Lymphocytesat dermal-epidermal dermal-epidermaljunction
Mouth, tongue
Hyperkeratosis
Glans penis
Hypergranulosis
Wichhamstriae: striae: white dots/lines
“Sawtooth” pattern of rete ridges
Caused by hypergranulosis hypergranulosis (classic feature of L P) Best seen on oral lesions
Pityriasis Rosea
Pityriasis Rosea
Acute, self-limited skin rash
Begins with “heraldpatch” “herald patch” Single red/salmon-colored red/salmon-colored lesion
Eruption of skin lesions Self-limited Resolves 2-3 months
Round or oval Well demarcated Chest, neck, or back
Usually no treatment required
Days later: Multiple lesions on trunk
Cause unknown (possibly viral)
Multiple similar, smaller lesions lesions Groups of lesions Follow skin lines on back
“Christmas tree distribution”
Burns
Burns
1st degree/superficial: degree/superficial: epidermisonly
2nd degree/full thickness: epidermis, most dermis
Painful, red, blanch with pressure
Yellow or white
No blisters
Painful to pressure only
Heal within 7 days
Do not blanch Heal with scarring
2nd degree/partial thickness: epidermis, some dermis Blisters Painful, blanch with pressure Heal within 7 to 21 days
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Burns
Sunburn
3rd degree: entire epidermis and dermis
Delayed inflammatory response of skin
4th degree: skin and superficial fat
Caused by ultraviolet radiation (UVR) Two forms UV radiation UVB radiation: wavelength 280 to 320 nm UVA radiation: wavelength 320 to 400 nm
Both may cause sunburn UVB range most effective at causing sunburn
Sunburn Damage to epidermis and dermis UV radiation DNA damage apoptosis keratinocytesundergoingapoptosis “Sunburncells”: “Sunburncells”: keratinocytes Vasodilation Releaseinflammatory mediators Self-limited
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Melanin Gives color to skin and hair Protectsfromultraviolet radiation Formed from amino acid tyrosine
Pigment Disorders Jason Ryan, MD, MPH
Melanin
Freckles
Synthesizedinmelanocytes in melanocytes
Small brown/dark macules (flat)
Specialized secretory cells
Can darken on exposure to sun Increased amounts of melanin
Derived from neural crest
Found in basal layer of epidermis Synthesize melanin inmelanosomes in melanosomes Melanosomestransferredto keratinocytes keratinocytes
Albinism
Albinism
Oculocutaneous Albinism (OCA)
Oculocutaneous Albinism (OCA)
Family of genetic disorders
Hypopigmentation of hair, skin, eyes
Absent/reducedmelaninsynthesisin melanocytes
White hair, pink skin color, blue eyes ↑ risk of sunburns ↑ risk of skincancer
Normal number of melanocytes
Most common forms: ↓ activity tyrosinase
No UV light protection
Melanin
Basal cell carcinoma Squamous cell carcinoma carcinoma
Tyrosinase
Tyrosine
Melanoma DOPA quinone
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Tyrosine
Melasma
Melasma
Acquiredhyper Acquired hyper pigmentation pigmentation
Triggered by UV light in susceptible woman ↑ melanin synthesis Onset often with pregnancy or OCP
Irregular areas of tan/dark macules on face Often symmetrical Sun-exposed areas of face
↑ estrogen “Mask of pregnancy” of pregnancy”
Most common in women with dark complexions
May resolve after pregnancy
Cosmetic problem Treatment: Sun protection Skin lighteners: Hydroquinone Hydroquinone (inhibits tyrosinase)
Vitiligo
Vitiligo
Acquired,localizedpigmentdisorder
Darkskinned individuals Obvious areas of depigmentation
Autoimmune Autoimmune destruction destruction of melanocytes melanocytes
Light skinned individuals Failure to tan in localized region
No clinical signs of inflammation inflammation (warmth)
Cosmeticproblem
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Blood Blister Traumatic bleeding in dermis Intactepidermis Many vascular tumors look similar
Vascular Lesions
Diagnosis by patient characteristics Single vs. multiple
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Angiosarcoma
Angiosarcoma
Rare tumor of blood or lymph vessels
Occur in liver
Sarcoma = tumor of mesenchyme origin
Associated wi th vinyl chloride exposure exposure
Angio = blood vessel (endothelial (endothelial origin)
Occur in breast
Lymphangiosarcoma = derived from lymph endothelium endothelium
Often following radiation therapy
Hemangiosarcoma = derived from vascular endothelium
Often in setting of lymphedema after mastectomy
Hemangioma = benign version
Purple nodules or plaques Poor prognosis
Angiosarcoma
Bacillary Angiomatosis Angiomatosis
Occur beneath skin
Zoonotic infection by byBartonella Bartonella
Usually head and neck (sun exposed areas)
Bartonella quintana and Bartonella henselae
Often scalp or face
End-stage HIV and AIDS patients
Arise from dermis
Systemic infection blood vessels in skin Presents as numerous red/purple nodules
Older, Older, white males Median age: 65 to 70
Similar appearance to Kaposi sarcoma
Male to female ratio: 2:1
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Pyogenic Granuloma
Kaposi Sarcoma
Lobular capillary hemangioma
Common in HIV/AIDS
Benignvasculartumor
Angioproliferation
Blood vessel hyperplasia due to growthstimuli growth stimuli Most often on skin
HHV-8 (HumanHerpesvirus-8) Key differences from bacillary angiomatosis
Trunk, arms, legs, head, neck Can be mucosal: lips, gums
Kaposi Sarcoma: Lymphocytes
Classicstimuli: pregnancy and trauma
BA: Neutrophils/lymphocytes
Often bleed profusely
Cherry Hemangiom H emangioma a
Cystic Hygroma
Benigncapillary proliferations
Congenitalmalformation(newborns)
Common in middle-aged middle-aged or elderly Develop with aging Usuallymultiple
Large cyst containing lymph (benign) Caused by obstruction of lymph drainage
Classically develops on neck
Classically on the trunk May bleed from trauma
Cystic Hygroma
Glomus Tumor
Often identified onprenatal on prenatal ultrasound
Glomus body Structure in dermis of skin
Increased risk of fetal aneuploidy and malformations Trisomy 21 (Down) and Turner syndrome syndrome (XO)
Most numerous in fingers and toes
Cardiac and skeletal skeletal malformations
Contains modified smooth smooth muscle cells Regulates skin temperature
Increased risk of miscarriage or fetal death Often found together with nuchal translucency
Shunts blood away from surface in cold Preserves heat
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Glomus Tumor
Strawberry Hemangioma
Benign growth of modified smooth muscle cells
Benign hemangioma Excess proliferation of blood vessels
Occurs in fingers and toes
Appear in newborns
Usually at tips/ends
Common: Up to 10% Caucasian babies in some studies
“Subungual” = under nailbed
Usually a single lesion
Pink/purple papule or nodule Painful especially when exposed tocold to cold
Usually not present at birth Usually identified first few days/months after birth
“Paroxysms of pain” of pain”
Involute within few years
“Cold sensitivity”
Nevus Simplex
Nevus Flammeus
Stork bite/Salmon Patch
Port Wine Stain
Capillary malformation malformation (not a tumor)
Malformation Malformation of dermal capillaries and venules
Common on eyelids or back (nape) of neck
Slow/low blood flow Pink/redpatches
“Birthmark” Pink-redmacule Up to 60 percent of infants
Blanch when pressed
Fade first few years of life
Do not regress Grow as child grows
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Impetigo Superficialskin Superficialskininfection Neutrophils collect beneath stratum corneum Macules papules rupture erosions Dried sebum “Honey-colored” crust
Skin Infections
Highly contagious
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Impetigo
Impetigo
Impetigocontagiosa(non-bullous)
Bullousimpetigo
Traditional, most commonform
Seen in children
Face and extremities
Trunk commonly involved
Caused by S. aureus
S. aureus
Also “Beta-hemolytic step” – mostly S. Pyogenes (group A) Honey crusted lesions
S. Aureus Exfoliative Toxin
Scalded Skin Syndrome
Exfolatin
Newborndisease Colonization of skin with S. Aureus
Cleavesdesmoglein Cleaves desmoglein1complex 1 complex Desmosome protein Links keratinocytes together
Classically occurs 3 to 7 days of age Fever, diffuse erythema
Affectsstratum Affects stratum granulosum Leads to bullous impetigo
Sloughing of skin Damage intraepidermal Heals completely with no scar Nikolsky’s sign: skin slips off with gentle tug
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Erysipelas and Cellulitis
Erysipelas
Bacterial skin infections that often overlap Differ mainly by layer of skin involvement
Young children and older adults
Skin break/trauma bacterial entry
Usually Group A strep (S. Pyogenes) Acute onset: fevers, chills, rash Cleardemarcationrash/normalskin
Most common on legs (lower extremities) Erysipelas also on face
Cellulitis
Skin Abscess
Deep dermis
Collection of pus (neutrophils, bacteria) bacteria)
Middle-agedand elderly(rarely elderly (rarelychildren) Group A strep (S. Pyogenes) or S. Aureus
Walled-off in dermis or subcutaneous space Usually S. aureus Red, painful nodule
Slower onset
Tense, raised skin
Rash, focal pain, warmth over days
Maycomplicate cellulitis/erysipelas cellulitis/erysipelas
Ill-defined,spreadingborder
Usually requires incision and drainage
Necrotizing Fasciitis
Necrotizing Fasciitis
Infection offascia of fascia
Skincolor changes:red-purple-blue-gray-black red-purple-blue-gray-black
Involves muscle fascia and subcutaneous fat
Bullae
Destruction (necrosis) of tissue above fascia
Pain and tenderness May be “out of proportion to exam” Apparently minor rash with exquisite tenderness tenderness Patient may mistake infection for muscle injury Eventually pain stops (anesthesia) (anesthesia) from nerve destruction
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Necrotizing Fasciitis
Necrotizing Fasciitis
Crepitus
Often fulminant and deadly
Crackling sound when skin is pressed
Infection spreads along muscle fascia
From gas under skin
Poor blood supply
Methane and CO2 from bacteria
uncontrolled spread
Requiresurgentsurgical urgent surgical debridement
Necrotizing Fasciitis
Necrotizing Fasciitis
Type 1:
Classic case:
Polymicrobial
Minor skin trauma
Often anaerobes anaerobes (Bacteroides, Clostri dium, etc.)
Or diabetic/immunocompromise diabetic/immunocompromised d after surgery
Strep, staph, others others
Redness/warmth (can be confused with cellulitis)
Occurs in diabetics, diabetics, immunocompromised, vascular disease
Pain out of proportion to exam
Usually occurs following surgery
Fever, hypotension
Type 2: Group A strep (sometimes Staph) Occurs in otherwise healthy people after after skin injury
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Blisters Fluid-filled skin lesions Separation of skin layers Space filled with fluid
Blistering Disorders
Mayrupture Vesicle:<1cm Bulla (plural = bullae): >1cm Many causes Burns
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Friction
Pemphigus
Acantholysis
Pemphig: Pemphig: from Greek word for blister
Loss of connectionsbetween connections betweenkeratinocytes Often loss of desmosomes
Loss of connections between keratinocytes
Involve mucous membranes (mouth) and skin Subtypes:
Detached, floating freely in epidermis Key feature of pemphigus vulgaris
Pemphigus vulgaris (most common) Pemphigus foliaceus IgA pemphigus Paraneoplastic pemphigus
Pemphigus vulgaris
Pemphigus vulgaris Large, flaccid bullae that easily burst (not tense)
Component of desmosomes
Often few intact bullae, most rupture and scabbed
Type II hypersensitivity hypersensitivity reaction
Often presents first with oral bullae and ulcerations
Disrupts connections in stratum spinosum
Painful chewing/swelling
Fluid collects above basal layer
Occurs mostly in adults (30 to 60) Nikolsky’s sign Skin slips off with gentle tug Also seen in Staph Scalded Skin (child) Also seen in Stevens-Johnson Stevens-Johnson syndrome
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Pemphigus vulgaris
Bullous pemphigoid “Pemphigoid”: looks like pemphigus
Classic finding: (+) immunofluorescence for IgG “Reticular” pattern : like a net
Bullous pemphigoid antigens (proteins) BP180, BP230
Increased mortality: infection, side effects of Rx
Attach epithelial cells cells to the basement membrane
Bullous pemphigoid
Bullous pemphigoid
Bullae aresubepidermal, are subepidermal, nonacantholytic Less fragile (flaccid) than pemphigus vulgaris Numerous intact, tense bullae Less ruptured bullae with scabs
Biopsy:Eosinophils Biopsy: Eosinophils andlymphocytes Immunofluorescence:line Immunofluorescence: line at base of epidermis
Bullous pemphigoid
Dermatitis Herpetiformis Herpetiformis
Occurs in the elderly (median age 80 in one study)
Skin condition associated with celiacdisease
Rarelyinvolves mouth
Herpes-like lesions on skin Papules/vesicles in bilateral groups ("herpetiform")
Absent Nikolsky's sign sign
Pruritic (itchy) Classically on extensors: elbows, knees
Alsoincreased mortality Less than pemphigus Less bullae rupture
less chance chance of infection
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Dermatitis Herpetiformis Herpetiformis
Antibody Blistering Disorders
IgAdeposition in dermalpapillae Numerous, small lesions at tips of dermal papillae
Occurs in individuals with genetic gluten sensitivity Antibodies triggered by gluten cross-react at skin Biopsy: microabscesses (spaces) at tips of papillae Neutrophils
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Allergic Skin Reactions Urticaria = hives Urticaria = pruritic, raised wheals and angioedema Angioedema = deep mucocutaneous mucocutaneous swelling
Hypersensitivity Disorders Jason Ryan, MD, MPH
Urticaria
Urticaria
Allergic skin reaction reaction
Usually acute and self-limited
Usually caused by mast cell degranulation Type I hypersensitivity reaction
May be treated with antihistamines antihistamines and steroids May be a component of anaphylaxis
Antigen binding to IgE antibodies antibodies on mast cells Histamine release
Wheezing
No changes to epidermis epidermis Dermal edema
Mucosal swelling (lips/tongue) (lips/tongue)
Dilation of lymph vessels
Syncope
Hypotension
For fluid drainage
Atopic Dermatitis
Atopic Dermatitis
Eczema
Eczema
Chronicdisorderwith flares/remission flares/remission
Over 80% patients: ↑ serum IgE levels
Also a hypersensitivity disorder
70% of patients: family history of atopic diseases
Complex, incompletely understood pathogenesis
Commonlyco-occurswith allergicrhinitis/asthma
T-cells, cytokines
“Atopic march”
Usually “extrinsic”: reaction to environmental antigens Less common form: intrinsic
Usually occurs in children Red, pruritic (itchy) rash
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Atopic Dermatitis
Contact Dermatitis
Eczema Babies: face (cheeks) and scalp
Similar clinical features to eczema
Children/adults:
Localized to area of skin contact with allergen Type IV hypersensitivity disorder
Thickened (“lichenified”) plaques plaques Skin flexures Antecubital and popliteal fossae
Contact Dermatitis
Drug Rash “Non-immediate” reaction to drug Often seen with some penicillin antibiotics antibiotics Maculopapular Itchy or may be non-pruritic Absence of fever, wheezing, joint pain Days or weeks after starting drug
Classic causes (irritants) Poison ivy Nickel (jewelry) Laundry detergents
Treatment: Remove irritant Steroids
Romano A et al. Diagnosis of nonimmediate nonimmediate reactions to B-lactam antibiotics. antibiotics. Allergy 2004
Stevens-Johnson Stevens-Johnson Syndrome
Stevens-Johnson Syndrome
Severe skin reaction
Prodrome
Type IV hypersensitivity disorder
1-3 days before skin findings
May also involve mucous membranes Usually triggered by drugs Hallmark: necrosis of the epidermis
Fever Flu-like malaise
Lesions start on face/chest
Also seen in Staph Scalded Skin (child)
Spread symmetrically symmetrically Red, tender skin Progresses to v esicles/bullae esicles/bullae
Also seen in Pemphigus vulgaris
Sloughing of skin
Nikolsky sign Skin slips off with gentle tug
Mucosal lesions: 90% cases
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Stevens-Johnson Syndrome
Erythema multiforme multiforme
Toxic epidermal necrolysis
Skin disorder associated with infections (90% cases)
Severe form SJS (>30% skin)
Herpes simplex virus virus (most common) Mycoplasma pneumoniae (often in children)
High mortality
Also associated with some drugs
SJS 1-5%; TEN 25-35%
Sulfa drugs NSAIDs Phenytoin
Also some cancers and autoimmune diseases
Erythema multiforme multiforme
Erythema multiforme
Pathogenesis unclear
Multiple lesion types (multiforme) Macules, papules, vesicles
Most data from HSV-related cases Cell-media ted (type IV) autoimmune Triggered by viral antigens in keratinocytes keratinocytes
Lesions similar for one patient patient May differ between patients
Hallmark: “Target lesion” lesion” Dark/dusky central area area Surrounding red rings
Erythema multiforme multiforme
Erythema multiforme Typical case Oral or genital HSV eruption (or other tr igger)
Starts on “extensor surfaces of acral extremities” Backs of hands, feet
EM skin eruption occurs f ew days to 2 weeks later
Contrast with SJS: face
Lesions evolve over 3-5 days Resolve within 2 weeks (no tr eatment)
Spreads to center (“centripitalspread”) (“centripitalspread”) Mayinvolve mucous membranes
Rarely severe cases r equire steroids or other Rx
Mouth, eye, genitals Erythema Erosions (painful) Bullae
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Actinic Keratosis Solar keratosis Premalignantskinlesions Caused by sun exposure Growth of atypical epidermal keratinocytes Can lead to squamous cell carcinoma Increasing degrees of dysplasia
Skin Cancer
malignancy
Jason Ryan, MD, MPH
Actinic Keratosis
Squamous Cell Carcinoma
Solar keratosis Round, red/brown papules or plaques
2nd most common skin cancer
Sun exposed areas Biopsy:Hyperkeratosis,epidermalcell dysplasia corneum Perakaratosis: Perakaratosis : retained nuclei in stratum corneum
Arises from squamous cells in epidermis Occurs in sun-exposed areas Face, lip, ears, hands DNA damage by UV light
Occurs in older patients Rare <45 years old Common > 75 years years old
Less than 5% metastasize metastasize to regional nodes Rarelymetastasizebeyondnodes
Squamous Cell Carcinoma
Squamous Cell Carcinoma
Risk Factors
Red, scaling plaques with sharp borders
Sunexposure
Moreadvancedlesions: ulcerate,keratinproduction Organ transplant, HIV, long term glucoc glucocorticoids orticoids
May crust or bleed
Chronic skin inflammation Burns, chronic ulcers, draining sinus sinus tracts
Arsenic exposure Found in contaminated drinking water
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Squamous Cell Carcinoma
Keratoacanthoma
Pathology
Variant of SCC (“squamoproliferative (“squamoproliferativetumor”) tumor”)
Classic finding: keratin pearls
Usuallybenign,self-resolving hyperkeratosis “Dome -shaped” nodule with central hyperkeratosis Classic feature: rapid growth (weeks) regression Removed surgically or followed for regression
Bowen’s Disease
Basal Cell Carcinoma
Squamous cell carcinoma in situ
Most common skin cancer
Well-demarcated, Well-demarcated, scaly patch or plaque
Slow growing Most found early and excised Occur in sun-exposed areas Lowest potential for recurrence or metastases Basal < squamous < melanoma
Basal Cell Carcinoma
Basal Cell Carcinoma
“Pearly” papules or nodules
Nests of “basaloid” dark cells in dermis
May have telangiectasias on surface surface Dilated blood vessels
May ulcerate with crust in center Borders may be “rolled” (rounded, thickened)
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Basal Cell Carcinoma
Superficial BCC
“Palisading nuclei” Cells at periphery of nests line up in parallel
Special variant of BCC (~30% of BCCs) Light red to pink plaque Slight scale Most commonly occur on the trunk
Treatment SCC and BCC
Melanoma Highly malignant form of skin cancer
Cryotherapy Electrosurgery
ABCDE Asymmetrical Irregular border Color variation
Topicalchemotherap y
Diameter > 6mm 6mm
High risk lesions excised
Evolving over time
Larger lesions Recurrent lesions Lesions in specific locations Immunosuppressed patients (SCC)
Melanoma
Melanoma
Types
Types Lentigomaligna
Most common subtype subtype
Lentigo = small, flat, dark dark spot (large freckle)
75% of melanomas
Confined to epidermis epidermis Lentigo maligna = growing dark spot spot confined to epidermis
Nodular 15 to 30% of melanomas
Sometimes called “melanoma “melanoma in situ”
Aggressive subtype
Lentigo maligna melanoma = invasion of dermis
Grow vertically
Slow growing
50% melanoma deaths
Spreads, darkens, becomes lumpy
Occurs in elderly elderly
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years to develops
Melanoma
Melanoma
Types
Risk Factors Sunexposure
Least common type
Especially severe sunburns sunburns in childhood
Palms, bottom of foot, under nails
Nevi
Most common type dark-skinned patients
1/3 melanomas arise from dysplastic nevi High number of nevi associate associate with melanoma risk
Asians African-Americans
Light-sensitivity Light-sensitivity of skin type Light skin pigmentation Freckles Poor tanning ability
Melanoma
Melanoma
Diagnosis
Treatment and Prognosis
Biopsy
Tumor cells initially growradially grow radially Spread along epidermis and upper dermis
No single diagnostic feature
Eventually tumor shifts to vertical growth phase
Nests of melanocytes melanocytes Atypical cells, irregular nuclear shape
Tumor cells invade downward in dermis
↑ depth of tumor = ↑ risk of metastasis
Tumor markers:S100 markers: S100 Calcium binding protein in nucleus nucleus
Breslow thickness
Highly specific (low sensitivity)
Distance from granular epidermis to deepest tumor cells
Melanoma
Melanoma
Treatment and Prognosis
Genetics
Treatment: excision with wide margins
BRAF gene mutations Common (40 – 50%) in sporadic melanomas
Metastasis
BRAF = proto-oncogene
Hematogenous and lymphatic
Triggers cell proliferation on RAS activation
Lungs, liver, liver, brain (most common causes of death)
V600Emutation of BRAF gene 90% BRAF mutations = V600E mutation Treatable with BRAF inhibitors Vemurafenib and dabrafenib Increase survival in melanoma with V600E mutation
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Melanoma Genetics
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Neurocutaneous Disorders Phakomatoses Genetic disorders of skin, skin, nerves and eye Other structures sometimes involved (bones, kidneys)
Structures derived fromectoderm from ectoderm
Neurocutaneous Disorders
Neurofibromatosis
von Hippel-Lindau disease disease
Jason Ryan, MD, MPH
Neurofibromatosis Neurofibromatosis 1
Neurofibromatosis
NF1/von Recklinghausen disease
Familialcancersyndrome
Mutation of NF1 Tumor suppressor suppressor gene on chromosome 17
Geneticdisorder Autosomal dominant Mutations in NF1 or NF2 genes
Encodes for neurofibromin (tumor suppressor suppressor protein) Restricts RAS function Mutation RAS overactivity
NF1: Most common common type
uncontrolled growth
Autosomal dominant with 100% penetrance
Nerve tumors with skin and eye findings
All gene carriers have disease Children of affected affected individuals
50% chance of disease
Some patients: mild features Other patients: severe features
Neurofibromatosis Neurofibromatosis 1
Neurofibromatosis Neurofibromatosis 1
NF1/von Recklinghausen disease
NF1/von Recklinghausen disease
Neurofibromas
Lisch nodules
Benign tumors
Brown spots on iris
Develop on nerves Often cutaneous nerves
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Neurofibromatosis Neurofibromatosis 1
Neurofibromatosis Neurofibromatosis 1
NF1/von Recklinghausen disease
NF1/von Recklinghausen disease
Café-au-lait Café-au-lait spots “Coffee with milk”
Usually develop by 3 years of age
Light brown macules
Freckles
Curvature of long bones
Not random
Facial deformity of eye socket socket
Clusters in skin folds
Scoliosis
Axilla and groin
Neurofibromatosis Neurofibromatosis 1
Neurofibromatosis Neurofibromatosis 1
NF1/von Recklinghausen disease
NF1/von Recklinghausen disease Diagnosticcriteria
Hypertension Renal artery stenosis
Six or more café-au-lait spots
Rarely pheochromocytoma
Two or more neurofibromas
Some neurofibroma become malignant malignant
Optic glioma
Freckles in axilla or groin Usually not skin lesions
Two or more Lisch nodules
Peripheral nerve sheath tumors
Bone lesions
Occurs in adolescence or adulthood
1st degree relative with NF1
Presents as pain or sudden sudden growth of neurofibroma
Neurofibromatosis Neurofibromatosis 1
Neurofibromatosis Neurofibromatosis 2
NF1/von Recklinghausen disease Birth to 2 years years
Less common than NF1
Café-au-lait spots
Alsoautosomaldominant
Bone abnormalities
Mutation of NF2 gene Major features: CNS tumors
Optic gliomas
Age 2 to 6 Lisch nodules
“Acoustic neuromas”
Developmental delay
Occur in almost all patients
Meningiomas
Cutaneous neurofibromas
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Schwannoma
Tuberous Sclerosis
Schwann cells: Glial (non neurons) of PNS
Familialcancersyndrome
Classically located to CN VIII
Hallmark: hamartomas Benign malformation of cells/tissue
Hearing loss, tinnitus, ataxia
Resembles tissue of or igin (skin, lung, spleen)
Main clinical feature: seizures CNS hamartomas
Tuberous Sclerosis
Tuberous Sclerosis
Autosomaldominantwithvariableexpressivity
Widespreadtumor formation
De novo mutations: 80% cases (no family history)
Involves MULTIPLE organ systems Numerous hamartomas and other neoplasms Classicfeatures
Mutation in TSC1 or TSC2 gene TSC1: Hamartin TSC2: Tuberin
Seizures – most common presenting feature
Proteins inhibit mTOR
“Ash “Ash leaf spots”: Pale, hypopigmented skin lesions
Mechanistic target of rapamycin
Facial skin spots (angiofibromas)
Kinase
Intellectual impairment (mental retardation)
Mutation mTORoveractivity cell growth Especially cell size
Tuberous Sclerosis
CNS Tumors
Subependymal giant cell astrocytomas astrocytomas Low gradeastrocytoma grade astrocytoma
Corticaltubers Distorted cortex
Usually occur at interventricular foramen
Seizures
May obstruct ventricles hydrocephalus
Ependyma = lining of ventricles
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Tuberous Sclerosis
Tuberous Sclerosis
Angiofibromas
Ash Leaf Spots
Fibrous papules usually on face Usually oval or elliptical
Tuberous Sclerosis
Tuberous Sclerosis
Shagreen patches
Ungual fibromas
Connective tissue hamartoma
Fibromas beneath nailbeds
Usually found on lower back “Orangepeel” “Orange peel” or “leathery” texture
Tuberous Sclerosis
Tuberous Sclerosis
Rhabdomyomas
Renal Angiomyolipomas Angiomyolipomas
Tumors of muscle cells
Most frequent renal manifestation manifestation
Benign (do not metastasize)
Multiple/bilateral
Classic cardiac feature of TS ( 90% cases) Sometimesdetectedprenatal
Proliferation of epithelioid cells around vessels Growth and hemorrhage pain Maycause renin-dependenthypertension renin-dependenthypertension
Tumor embedded in ventricular wall Rare symptoms from obstruction, arrhythmia arrhythmia
Risk of chronic kidney disease Compression of normal renal tissue tissue
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Tuberous Sclerosis
Sturge-Weber Syndrome
Classic Case Child/infant
Congenital vascular disorder of capillaries Spontaneous gene mutation in early development
Seizures Ash-leaf spots Angiofibromas
Not inherited
Three classic features features Port-wine stain on face (bir thmark) Leptomeningeal angioma (brain tumor) Increased ocular pressure (glaucoma) (glaucoma)
Sturge-Weber Syndrome
Sturge-Weber Syndrome
Genetics
Port-Wine Stain/Nevus Flammeus
Spontaneousmutationin GNAQ gene
Malformation Malformation of dermal capillaries and venules
Occurs after fertilization (somatic (somatic mutation) mutation) Mosaicism (some cells normal, some mutated) Abnormalcapillary Abnormalcapillaryformation/growth formation/growth
Occurs on face in SWS Unilateral 1st /2ndtrigeminalarea Slow/low blood flow Pink/redpatches Apparent at birth Does not regress Grows as child grows
Sturge-Weber Syndrome
Sturge-Weber Syndrome
Leptomeningeal angioma
Glaucoma In infancy or e arly adulthood
Leptomeninges: pia mater and arachnoid
Exact mechanism unclear Abnormalities anterior chamber angle
Occurs on same side as port-wine stain May cause seizures (80% patients)
Elevated venous pressure pressure in episclera Choroidal hemangiomas
Often begin first 2 years of life
Causes vision impairment impairment
Maycause hemiparesis,headaches
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Sturge-Weber Syndrome
von Hippel-Lindau Hippel-Lindau Disease
Classic Case Newborn with port wine stain
Genetic cancer syndrome
Seizures Glaucoma
von Hippel-Lindau (VHL (VHL)) gene Chromosome 3 Codes for VHL VHL tumor suppressor protein Post-translational modification Addition of ubiquitin to proteins (small protein) Tagsproteins for destruction in proteasome
Cells behave as if hypoxic blood vessel growth
von Hippel-Lindau Hippel-Lindau Disease
von Hippel-Lindau Disease Renalcysts
Clumps of capillaries (“angiomatosis”)
Renal cell carcinomas (bilateral) Pheochromocytomas
Bright red on gross examination Well-circumscribed, benign No invasion or metastasis Symptoms: compression of other structures, structures, hemorrhage
Occur in CNS Rarely occur sporadically outside VHL Classic locations: cerebellum, spinal cord, retina
von Hippel-Lindau Hippel-Lindau Disease Requires“two hits” One abnormal gene inherited inherited (germline mutation) Second spontaneous mutation
disease
Similar to retinoblastoma, Li-Fraumeni, FAP
“Autosomal dominant”
Onset usually late childhood to young adulthood Takes years for second hit to occur occur
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