Neoplastic Dermatology


Figure 6-1 Porokeratosis. Several streaks of linear porokeratosis on the lower extremity. (From Bolognia JL, Jorizzo JL, Rapini RP. Dermatology, 3rd edn. Elsevier, 2012.)


Punctate porokeratosis: onset in adolescence; 1- to 2-mm “seed-like” papules on palms/soles


Porokeratosis palmaris, plantaris, et disseminata (PPPD): onset in childhood/adolescence; occurs on palms/soles initially


Porokeratotic eccrine ostial and dermal duct nevus: clinically resembles a nevus comedonicus of palm or sole (Fig. 6-2), but histology shows abundant cornoid lamellae arising from acrosyringium


image

Figure 6-2 Porokeratotic eccrine ostial and dermal duct nevus. Markedly hyperkeratotic spines arise from dilated eccrine ostia, corresponding to the histologic findings of coronoid lamellae. (From Bolognia JL, Jorizzo JL, Rapini RP. Dermatology, 3rd edn. Elsevier, 2012.)

Histology: cornoid lamella (angled column of parakeratosis w/ underlying hypogranulosis and dyskeratotic cells); centrally between two cornoid lamellae the epidermis may be atrophic, hyperplastic, normal, or BLK-like


SCC can develop in any subtype except punctate form (0% risk); second lowest risk in DSAP; highest risk in linear form





Epidermal nevus



Hamartoma of epidermis and papillary dermis; onset in first year of life


Papillomatous, pigmented, linear plaques along Blaschko’s lines


Variants:


Nevus unius lateris: extensive unilateral plaques on trunk


Ichthyosis hystrix: extensive bilateral lesions on trunk


Inflammatory linear verrucous epidermal nevus (ILVEN): along lines of Blaschko without associated neurologic defects


Epidermal nevus syndrome (Schimmelpenning syndrome): a/w developmental abnormalities (neurologic and musculoskeletal most commonly)


Histology: epidermal papillomatosis; orthohyperkeratosis


May see epidermolytic hyperkeratosis as a result of genetic mosaicism (defects in keratins 1 and 10) → ↑risk bullous congenital ichthyosiform erythroderma in offspring


Mutations in FGFR3 and PIK3CA have also been identified



Nevus comedonicus



Hamartoma; onset in childhood; worsens during puberty


Comedones in a linear array on face > trunk


FGFR2 mutations involved


FGFR2 also involved in Alagille syndrome, Apert syndrome, cardiocranial syndrome, and Crouzon syndrome


Histology: dilated epidermal invaginations filled w/ cornified debris



Flegel disease (hyperkeratosis lenticularis perstans)



Rare disorder with AD inheritance; adult-onset


Absent/altered lamellar granules (Odland bodies) on electron microscopy


Disc-shaped keratotic papules in symmetric distribution; distal extremities including palms/soles


Histology: discrete orthohyperkeratosis overlying atrophic epidermis; lichenoid dermal inflammation



Warty dyskeratoma



Onset in fifth to seventh decade; M > F


Solitary verrucous papulonodule w/ central keratotic plug usually on head/neck


Histology: cup-like epidermal invagination with acantholytic dyskeratosis and corp ronds/grains (Fig. 6-3)


“Cup-shape” and solitary nature distinguishes from Darier’s


image

Figure 6-3 Warty dyskeratoma. The outward growth is verrucoid. The inward-growing component shows suprabasilar acantholysis. (From Busam KJ. Dermatopathology: A Volume in the Series: Foundations in Diagnostic Pathology, 2nd edn. Elsevier, 2015.)



Premalignant/malignant


Actinic keratosis



Scaly, red plaques on sun-exposed areas; a/w chronic sun-exposure, male gender, older age, and fair skin phenotypes


UVB responsible for AK development → induces thymidine dimers (C→T or CC→TT)


p53 mutations within keratinocytes → impaired apoptosis


Histology: basal layer atypia (lower 1/3 epidermis) with budding/finger-like projections into dermis; “Flag sign”: overlying parakeratosis (pink) alternating with orthohyperkeratosis (blue); atypia and parakeratosis often spares follicles; solar elastosis in dermis


Treatment: destructive measures (cryotherapy, ED&C, CO2 ablation, topical 5-FU, imiquimod, PDT, ingenol mebutate, topical diclofenac, and TCA peel)


Rate of transformation to SCC = 0.075%–0.096% per year



Bowen’s disease (Squamous cell carcinoma in situ)



Can progress from actinic keratosis or occur de novo


Risk factors: elderly, chronic sun exposure, lightly pigmented skin, immunosuppression, arsenic exposure, ionizing radiation, HPV, and chronic irritation


Hyperkeratotic erythematous patch or plaque; may affect any site


Histology: acanthosis with full-thickness keratinocytic atypia, disorganized (“windblown”) architecture, ↑mitoses, dyskeratotic keratinocytes, and parakeratosis


Variants: pigmented, pagetoid, verrucous, Bowenoid papulosis (multiple hyperpigmented penile papules, rarely progresses to invasive SCC), and erythroplasia of Queyrat (juicy red, erosive plaques on glans penis; more often progresses to invasive SCC)


Treatment: excision, Mohs, and destructive therapies



Invasive squamous cell carcinoma



Erythematous scaly papulonodule/plaque; most commonly on head/neck and dorsal extremities


Risk factors: chronic sun-exposure, male gender, older age, fair skin phenotypes, genetic syndromes, immunosuppression, HPV, radiation, chronic nonhealing wound (Marjolin’s ulcer), hypertrophic LE/LP, arsenic exposure, and chronic LS&A (genital)


Histology: full-thickness keratinocytic atypia w/ dermal invasion; tumor often “paradoxically differentiated” (tumor cells are MORE eosinophilic/keratinizing than surrounding keratinocytes)


Variants: poorly differentiated, spindle cell, acantholytic, pseudoglandular, Bowenoid, and verrucous


Treatment: WLE, Mohs, ED&C, and radiation


↑Risk of metastasis: immunosuppressed state, location on lip/ear, diameter >2 cm, Breslow depth >2 mm, arising in burn/scar (Marjolin’s ulcer), poorly differentiated, and acantholytic (debatable)


Additional boards fodder


↑risk of SCC: patients w/ CLL, tobacco users, vemurafenib, long-term voriconazole prophylaxis, RA patients on MTX and etanercept, and organ transplant (65 times ↑risk)


Genetic syndromes associated with SCC:


Oculocutaneous albinism


Xeroderma pigmentosum


Dystrophic epidermolysis bullosa


Epidermodysplasia verruciformis


Dyskeratosis congenita


Porokeratosis, linear type


Keratitis, ichthyosis, deafness (KID) syndrome


Rothmund-Thompson syndrome


Werner’s syndrome


Chronic mucocutaneous candidiasis



Verrucous carcinoma



Low-grade, locally destructive SCC a/w HPV-6 and HPV-11


Large exo-endophytic nodule; three clinical variants:


Epithelioma cuniculatum: slow-growing mass plantar foot (Fig. 6-4)


image

Figure 6-4 Verrucous carcinoma of the foot (epithelioma cuniculatum). Verrucous carcinomas often reach large sizes before diagnosis because they are often treated as warts. (From Fitzpatrick JE, Morelli JG. Dermatology Secrets Plus 4th edn. Elsevier, 2011.)

Buschke-Lowenstein tumor (giant condyloma): large cauliflower-like growth in anogenital region


Oral florid papillomatosis: widespread oral lesions


Histology: very well-differentiated (minimal to no cytologic atypia); bulbous/pushing border, massive size and ↑depth of base = clues to malignancy



Keratoacanthoma



Variant of SCC with unique features: initial rapid growth over weeks→ self-resolves/involutes over months


Subungual KAs are the exception (do NOT involute)


Clinical variants: solitary, multiple, giant, intraoral, subungual, and keratoacanthoma centrifugum marginatum (can reach several centimeters)


KA syndromes:


Ferguson-Smith: AD inheritance, rapid onset of multiple KAs; onset third decade, sun-exposed areas, and resolves spontaneously


Grzybowski: sporadic; 1000s of milia-like KAs in later adulthood; can involve airway; a/w scarring, ectropion, and mask-like facies


Mnemonic: “Old (later onset) Grizzlies Growl (airway affected)”


Other associations: Muir-Torre syndrome (classic KAs, or KAs w/ sebaceous differentiation), immunosuppression, and HPV


Histology: crateriform, endophytic nodule w/ well-differentiated keratinocytes (lacks significant atypia), central keratin plug, and peripheral inflammation w/ eosinophils


Treatment: excision or Mohs; may observe if certain involuting



Basal cell carcinoma



Onset typically sixth to seventh decade, but can occur earlier; slow/indolent local growth; locally destructive (esp. morpheaform, infiltrative, and micronodular subtypes)


Due to UV exposure (intermittent and intense > chronic and cumulative)


PTCH (chromosome 9q) mutations (most common) > p53 point mutations (second most common)


Sun-exposed skin, rare on palms, soles, and mucous membranes


Numerous clinicopathologic variants (see Table 6-3)



Table 6-3


Basal Cell Carcinoma Variants



























Nodular Favors head/neck; histology: large nests (centrally +/ necrosis, cystic spaces); centrally, cells lack organization, prominent peripheral palisading, and may be ulcerated
Superficial Erythematous scaly patch, most common type in younger patients, trunk and extremities (>head/neck); histology: multiple buds from epidermis do not extend beyond papillary dermis
Morpheaform Scar-like pink to white plaque; histology: small angulated nests and cords within a sclerotic stroma; retraction not prominent; may be more deeply invasive
Micronodular Smaller nests than nodular type; micronodules are separated by normal intervening collagen, and does not form a circumscribed contour at the deep aspect
Fibroepithelioma of Pinkus Pedunculated, “soft/fleshy” lesion on lower back; histology: thin anastomosing strands form a network within pinker stroma; retraction and myxoid material are less prominent
Pigmented Nodular pattern BCC with aggregates of melanin in the nests and dermal melanophages
Infundibulocystic (keratotic, follicular) Well-circumscribed, comprised of basaloid and squamoid cells in anastomosing cords, w/ horn cysts → resembles benign follicular tumors (trichoepithelioma and basaloid follicular hamartoma)
Basosquamous Ambiguous term w/ variable meanings; may refer to: 1) BCCs with “squamoid appearance” (pinker cells, more cytoplasm, and keratinization), 2) carcinomas with features indeterminate between BCC and SCC, or 3) collision lesions of BCC + SCC

General histologic features: nests of basaloid, uniform cells w/ high N : C ratio, peripheral palisading, epidermal connection (at least focally), myxoid stroma, stromal–epithelial retraction, and mitotic/apoptotic activity


Treatment: WLE, Mohs, ED&C, radiation, imiquimod, topical 5-FU, and vismodegib (inoperable or metastatic BCC)


Essentially no metastatic potential (dependent on stroma for growth)


Basosquamous subtype may behave more like SCC → ↑metastatic potential


 



Box 6-1


Mnemonic


Genetic syndromes a/w multiple BCCs: “Green Berets Rarely Buy eXtra Shoes … but they get a lot of BCCs from being in the sun!”



Gorlin’s


Bazex-Dupré-Christol


Rombo


Brooke-Spiegler


Xeroderma pigmentosum


Schöpf-Schulz-Passarge




6.2 Cysts




Epidermoid cyst



Clinical features


Firm dermal nodule with central punctum; any site, but most commonly head/neck/upper trunk


Pathogenesis/histopathologic features


Derived from follicular infundibular epithelium; may arise primarily, or secondary to follicle disruption/traumatic implantation; lined by stratified squamous epithelium w/ intact granular layer and no adnexal structures in the wall (vs vellus hair cyst and dermoid cyst); laminated/flaky keratin centrally


Comments


Multiple epidermoid cysts may be a/w Gardner’s syndrome (often have pilomatricoma-like areas histologically)



Trichilemmal (pilar) cyst



Firm dermal nodule; 90% on the scalp; usually multiple (70%); subset AD inheritance


Pathogenesis/histopathologic features: Derived from isthmic follicular epithelium; stratified squamous epithelium lacking granular layer; dense pink homogenized keratin with frequent calcification centrally



Proliferating trichilemmal cyst/tumor



Clinical features


Slow-growing dermal nodule; scalp (90%); usually elderly women


Pathogenesis/histopathologic features


Resembles trichilemmal cyst but more proliferative centrally w/ areas of multicystic architecture; well-circumscribed at periphery; variable cytologic atypia and mitotic activity


Comments


Mostly benign, but small percentage behave aggressively → complete removal recommended



Dermoid cyst



Clinical features


Infants; occur along embryonic fusion lines (most commonly lateral eyebrow)


Pathogenesis/histopathologic features


Derived from entrapment of epidermis during embryogenesis; lined by stratified squamous epithelium with granular layer and adnexal structures (hair follicles and sebaceous glands) in cyst wall


Comments


Be careful if biopsy b/c may have intracranial connection



Vellus hair cyst



Clinical features


Multiple (“eruptive”) domed and flesh-colored or hyperpigmented papules; trunk; subset AD inheritance


Pathogenesis/histopathologic features


Same histology as epidermoid cyst, but has multiple vellus hairs in cyst cavity



Steatocystoma



Clinical features


Single or multiple (multiplex – AD inheritance) lesions; chest/axilla/groin; drain oily fluid if punctured


Pathogenesis/histopathologic features


Lined by thin stratified squamous epithelium with no granular layer and thin bright pink corrugated (“shark-tooth”) cuticle; sebaceous glands in wall


Comments


Multiplex form with KRT17 mutations; a/w pachyonychia congenita type 2



Hidrocystoma



Clinical features


Translucent bluish cysts; face


Pathogenesis/histopathologic features


Unilocular or multilocular cyst with low cuboidal lining +/− decapitation secretion (if apocrine); lumen appears empty


Comments


May be a/w Schöpf-Schulz-Passarge (multiple hidrocystomas, syringofibroadenomas, PPK, hypodontia, and hypotrichosis)



Bronchogenic cyst



Clinical features


Solitary; present at birth; suprasternal notch/anterior neck


Pathogenesis/histopathologic features


Sequestration of respiratory epithelium during embryogenesis; pseudostratified, ciliated columnar cells with goblet cells; +/− smooth muscle/mucous glands/cartilage in wall


Comments


Main clues for boards: cartilage, smooth muscle, and ↑↑goblet cells



Thyroglossal duct cyst



Clinical features


Children/young adults; midline anterior neck; moves w/ swallowing


Pathogenesis/histopathologic features


Columnar, cuboidal or stratified squamous lining with thyroid follicles in the wall (low cuboidal epithelium with bright pink contents)


Comments


Main clue for boards: pink thyroid follicles (pathognomonic)



Median raphe cyst



Clinical features


Men; ventral penis between urethral meatus and anus


Pathogenesis/histopathologic features


Variable lining of cyst; “dirty debris” within cyst; genital skin features (e.g., smooth muscle and small nerves)


Comments


Often presents w/ pain during intercourse



Branchial cleft cyst



Clinical features


Second or third decades; lateral neck (anterior SCM, preauricular, and mandibular)


Pathogenesis/histopathologic features


Pseudostratified columnar or stratified squamous epithelium with surrounding dense lymphoid tissue including lymphoid follicles w/ germinal centers


Comments


Main clue for boards: very prominent lymphoid aggregates/follicles



Pseudocyst of the auricle



Clinical features


Middle-aged men; scaphoid fossa


Pathogenesis/histopathologic features


Cystic space in cartilage with fluid, no epithelial lining and no inflammation in cartilage


Comments


a/w chronic trauma from cell phones or wrestling



Omphalomesenteric duct cyst



Clinical features


Umbilical polyp in children


Pathogenesis/histopathologic features


Occurs as a result of a failure to obliterate the connection between midgut and yolk sac during embryogenesis; ectopic columnar gastrointestinal mucosa



6.3 Melanocytic neoplasms




Ephelides (freckles)



1- to 3-mm areas of ↑pigmentation; darken w/ sun-exposure; sun-exposed areas of body, mainly face, dorsal upper extremities, and upper trunk


More common in blonde or red haired individuals; absent at birth, but appear in first 3 years of life


↑melanogenesis and ↑melanin transfer to keratinocytes


Histology: ↑basilar keratinocyte pigmentation +/− enlarged melanocytes without increased melanocyte density


No propensity for malignant transformation, however are a marker of UV damage



CALM (café-au lait macule)



Discrete uniform tan to brown macules or patches; may be seen in infants, children, and young adults; isolated finding in 10% to 20% of normal population


Multiple CALMs may be a/w numerous genodermatoses:


Neurofibromatosis type 1 > type 2


McCune-Albright syndrome


Russell-Silver


Noonan syndrome


Bloom syndrome


Tuberous sclerosis


MEN-I


Fanconi syndrome


Ataxia-telangiectasias


Histology: ↑melanin deposition in basilar keratinocytes



Solar lentigo



Multiple pigmented macules on sun-exposed areas; most common in Caucasians (essentially ubiquitous after 60 years of age) > light-skinned Asians


Histology: elongated bulbous rete ridges with hyperpigmentation (“dirty socks”); +/− mild increase in melanocyte density; solar elastosis in dermis



Lentigo simplex



Well-demarcated, evenly pigmented brown to black macule; any age and any anatomic site


Histology: basal layer hyperpigmentation; elongated rete ridges with mild ↑melanocyte density


Conditions a/w multiple lentigines:


LEOPARD


Carney complex (LAMB/NAME)


Peutz-Jeghers (especially oral/perioral)


Laugier-Hunziker


Cowden syndrome


Bannayan-Riley-Ruvalcaba (penile)


Xeroderma pigmentosum


Cronkhite-Canada



Mucosal melanotic macule



Compared with lentigo simplex can be more irregular and mottled


Oral lesions usually occur in adults > 40 years old on vermillion border > gingiva, buccal mucosa, or palate; genital lesions most common on labia minora


Histology: acanthosis; mild basilar hyperpigmentation +/− subtle increase in melanocyte density



Dermal melanocytosis



Congenital (Mongolian spot): present at birth in most Asians and blacks; lumbosacral region; presents with (p/w) gray-blue patch (as a result of the Tyndall effect where shorter light wavelengths are reflected by melanocytes); often resolves during childhood


Histology: sparsely distributed elongated dendritic melanocytes in lower 2/3 dermis, lying parallel to epidermis


Nevus of Ota: presents in first year of life or around puberty; ↑incidence in pigmented individuals (Asians and blacks); p/w coalescing gray/blue macules in V1/V2 distribution and frequent scleral involvement (60%); unilateral (90%) > bilateral; persists for life; may enlarge under hormonal influences; 10% develop glaucoma; rare malignant degeneration to uveal melanoma (perhaps higher risk in Nevus of Ota lesions with activating mutations in GNAQ)


Histology: elongated dendritic melanocytes more numerous than in congenital dermal melanocytosis; involves upper dermis


Other clinical variants:


Nevus of Ito: located on the shoulder, supraclavicular, and scapular regions; essentially no risk of progression to melanoma


Hori’s nevus: acquired nevus of Ota-like macules bilateral zygomatic region; East Asian females


Sun’s nevus: acquired, unilateral variant of Hori’s nevus


Mnemonic: There is only 1 Sun, but the (w)HOle face is affected in HOri’s”


Histologically, dermal melanocytoses are distinguished from blue nevi by their ↓cellularity, poor circumscription, and lack of dermal sclerosis



Blue nevus



Onset in childhood/adolescence, but can also occur in older patients, 25% of cellular blue nevi are congenital


Most common sites: scalp, sacral area, and distal extensor extremities


Derived from dermal melanocytes (persist during embryogenesis rather than populating epidermis)


Activating mutations in GNAQ and GNA11 seen in 83%; results in downstream MAPK pathway activation


Same mutations are the most common mutations in uveal melanoma (46%; concomitant BAP-1 loss in uveal melanoma leads to increased risk of metastasis and death)


Multiple blue nevi and epithelioid blue nevi (latter is much more specific) a/w Carney complex


Variants:


Common blue nevus:


Blue/gray macules or papules usually less than 1 cm


Elongated, dendritic melanocytes containing melanin pigment usually in the upper 2/3 dermis with associated sclerotic collagen; no junctional component


Cellular blue nevus:


Blue/gray/black plaques or nodules; often larger (1–3 cm); favor buttocks or scalp


Dense proliferation of plump/fusiform pale gray melanocytes containing little pigment + admixed dendritic melanocytes resembling common blue nevus cells; characteristically bulges into subcutis (“dumbbell configuration”)


Epithelioid blue nevus:


Heavily pigmented; usually seen and a/w Carney complex; histologically resembles “animal type melanoma,” but lacks mitoses and atypia


Malignant blue nevus (= melanoma): often arises within cellular blue nevus; scalp (#1); commonly see benign precursor within specimen; frequently have concomitant GNAQ/GNA11 mutations and BAP-1 loss (a/w more aggressive behavior, similar to uveal melanoma)



Recurrent melanocytic nevus



Repigmentation confined to the scar (vs pigment extending beyond biopsy site = melanoma); usually arises within 6 months of initial biopsy


Histology (three key features)


Dermal scar


Atypical junctional melanocytic proliferation (resembles MIS) confined to area above dermal scar


Bland dermal nevus remnants below/adjacent to scar



Balloon cell nevus



Clinically indistinguishable from ordinary nevi


Histology: >50% dermal melanocytes are “balloon cells” (large, pale, and polygonal melanocytes with foamy/vacuolated cytoplasm and variable pigmentation); balloon cell change is as a result of melanosome degeneration


Boards tip: can always identify conventional nevus somewhere within lesion



Halo nevus (Sutton nevus)



Pigmented nevus with surrounding hypopigmented zone; most commonly second decade; most commonly on the back; most commonly benign


May be a/w vitiligo or melanoma (rarely) at another site


Multiple lesions can occur idiopathically or w/ infliximab


Histology: bland nevus w/ lymphocytes intertwined (“mingling”) with melanocytes


In contrast, lymphocytes form a lichenoid band (“riot police barrier”) under and around melanoma



Spitz nevus



Acquired, usually solitary lesions in first two decades (use caution in diagnosing a patient in the fourth decade and older); most common on head/neck > extremities


Pathogenesis:


HRAS mutations/11p gains


No BRAF mutations


Recently described subset of atypical epithelioid Spitz nevi with loss of BAP-1 tumor suppressor gene (“BAPomas”; have unique histology, and unlike most Spitz nevi, have BRAF mutations)


Rapidly growing pink-red papulonodule; usually <1 cm


Histology (Fig. 6-5):


Symmetric and circumscribed; most often compound


Epidermal hyperplasia (vs consumption of epidermis in melanoma)


Large junctional nests with clefting around entire nest (vs discohesion of nests in melanoma, where the nest itself becomes fragmented)


Parallel “raining-down” orientation of nests and cells


Kamino bodies: pink clumps of BMZ material (collagen IV) within epidermis


Spitzoid” cytology: large epithelioid and spindled cells w/ abundant pink-purple (amphophilic) cytoplasm and prominent lilac-colored nucleoli (vs cherry red nucleoli in melanoma); usually not pigmented


Dermal component “matures” with depth (reduction in density and cell size)


Superficial mitoses allowable, especially in young patients → if numerous (>2–3); deep or atypical mitoses are present, raises concern for melanoma


image

Figure 6-5 Histology of Spitz nevus. Nests of cohesive spindled and epithelioid melanocytes with clefts between the nests and the hyperplastic epidermis. (Courtesy, Lorenzo Cerroni, MD) (From Bolognia JL, Jorizzo JL, Rapini RP. Dermatology, 3rd edn. Elsevier, 2012.)

Immunostains: S100A6+, S100+, Melan-A+, and p16+


p16 is frequently lost/diminished in atypical Spitz tumors and spitzoid melanoma


Treatment: controversial, but often complete excision is recommended


Boards fodder: FISH analysis very helpful in risk stratification of atypical Spitzoid lesions


Homozygous loss of 9p21 (most predictive gene locus; corresponds to p16/CDKN2a gene) → ↑risk of metastasis and death

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May 4, 2017 | Posted by in Dermatology | Comments Off on Neoplastic Dermatology

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