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Skin-Nonmelanocytic tumors

Last revised 10 January 2011

Last major update November 2008

Copyright (c) 2005-2010, PathologyOutlines.com, Inc.

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Table of Contents Skin - Nonmelanocytic tumors

Primary references

Benign (nonmelanotic) epidermal tumors or tumor-like lesions: acquired digital fibrokeratoma, clear cell papulosis, cutaneous horn, fibroepithelial polyp, hair follicle nevus, large cell acanthoma, melanoacanthoma, pseudoepitheliomatous hyperplasia, seborrheic keratosis, verrucous hyperplasia

Cysts: apocrine cystadenoma, bronchogenic cyst, cystadenoma, dermoid cyst, hidrocystoma, keratinous cyst, pigmented follicular cyst, steatocystoma, vellous hair cyst

 

Adnexal tumors: general

Apocrine glands: general, apocrine tubular adenoma, hidradenoma papilliferum

Eccrine sweat glands: acrosyringeal adenomatosis, aggressive digital papillary adenoma, chondroid syringoma, clear cell acanthoma, cutaneous lymphadenoma, eccrine acrospiroma, eccrine cylindroma, eccrine poroma, eccrine spiradenoma, intraepidermal epithelioma, mucinous carcinoma, myoepithelioma, papillary eccrine adenoma, papillary syringadenoma, sclerosing sweat duct carcinoma, sweat gland carcinoma, syringoma

Hair follicles: folliculofibroma, inverted follicular keratosis, keratinous cyst, keratoacanthoma, pilar tumor, pilomatrixoma, trichilemmoma, trichoepithelioma, trichofolliculoma, warty dyskeratoma

Sebaceous glands: nevus sebaceous of Jadassohn, sebaceous adenoma, sebaceous carcinoma, senile sebaceous hyperplasia

 

Premalignant/in situ: carcinoma in situ-general, actinic keratosis, bowenoid papulosis, Bowen’s disease, Paget’s disease

 

Carcinoma (non adnexal): adenoid cystic carcinoma, adenoid squamous cell, adenosquamous, basal cell, lymphoepithelioma-like, Merkel cell, Merkel-staging, metastatic, mucoepidermoid, small cell, spindle squamous cell, squamous cell, verrucous carcinoma, staging

 

Lymphoma and related disorders: general, acute lymphoblastic, anaplastic large cell, angiocentric, blastic NK leukemia / lymphoma, diffuse large B cell, follicular, Hodgkin’s, HTLV-1, intravascular, Jessner’s lymphocytic infiltration of skin, leukemia, lymphoid hyperplasia, lymphomatoid papulosis, mantle zone, mast cell disorders, mycosis fungoides, NK/T cell, peripheral T cell, primary cutaneous (general), Woringer-Kolopp disease

 

Vascular tumors: acquired angioma, angiokeratoma, angiosarcoma, bacillary angiomatosis, benign hemangioendothelioma, benign lymphangioendothelioma, glomus, hemangioma, hemangioendothelioma and subtypes, intravascular papillary endothelial hyperplasia, Kaposi’s sarcoma, Kimura’s disease, lymphangioma, pyogenic granuloma, reactive angioendotheliomatosis, vascular leiomyoma, verruga peruana

 

Other tumors of skin: angiofibroma, atypical fibrous histiocytoma, atypical fibroxanthoma, benign cystic teratoma, benign fibrous histiocytoma (superficial), collagenous fibroma, connective tissue nevus, deep benign fibrous histiocytoma, dermatofibrosarcoma protuberans, dermatomyofibroma, endometriosis, epithelial sheath neuroma, granular cell tumor, hamartoma of scalp, histiocytoma, inclusion body fibromatosis, inflammatory pseudotumor, keloid, Langerhans cell histiocytosis, leiomyoma, leiomyosarcoma, malignant fibrous histiocytoma, malignant peripheral nerve sheath tumor, meningioma, meningioma-like tumor of skin, multicentric reticulohistiocytosis, neurofibroma, neurothekeoma, palisaded encapsulated neuroma, perineurioma, pleomorphic fibroma, schwannoma, sclerosing fibroma, sinus histiocytosis with massive lymphadenopathy, striated muscle hamartoma, supernumerary digit, xanthoma, xanthogranuloma

 

Go to Skin - Nontumor chapter

Go to Skin - Melanocytic tumors chapter

 

Primary references

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AJCC Cancer Staging Manual (7th ed)       

American Journal of Surgical Pathology (AJSP), January 2003 to February 2005

Archives of Pathology and Laboratory Medicine (Archives), Jan 2005 to February 2005 (must do cutaneous)

Human Pathology (Hum Path), Feb 2004 to December 2004 (must do cutaneous)

Modern Pathology (Mod Path), Jan 2003 to January 2005 (must do cutaneous)

Rosai, J: Ackerman’s Surgical Pathology (9th Ed); 2004

Sternberg, S: Diagnostic Surgical Pathology (4th Ed); Lippincott Williams & Wilkins, 2004

Journal search terms: skin, epidermis, dermis, cutaneous

 

 

Benign nonmelanotic epidermal tumors / tumor-like lesions

Acquired digital fibrokeratoma

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Definition: collagenous protrusions covered by hyperkeratotic epithelium, often at interphalangeal joints; dermis lacks adnexae

Micro images: contributed by Angel Fernandez-Flores, MD, PhD, Hospital El Bierzo and Clinica Ponferrada, Spain - acquired digital fibrokeratoma #1#2#3#4

 

Clear cell papulosis

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Children 0-3 years

Gross: small white maculopapular lesions

Micro: large pale cells (Toker’s cells), single or in clusters

Positive stains: CEA, EMA, low molecular weight keratin

DD: Paget’s disease

 

Cutaneous horn

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Also called cornu cutaneum

Usually caused by actinic keratosis, also verruca, seborrheic keratosis, inverted follicular keratosis, squamous cell carcinoma

Gross: protruding skin lesion composed or keratin and resembling a horn

Micro: usually epidermal type keratin (with granular layer); occasionally has trichilemmoma-like features (no granular layer but deep red granules)

 

Fibroepithelial polyp

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Also called acrochordon, squamous papilloma, skin tag, soft fibroma

Common, non-neoplastic, no clinical significance

Ages 40+ years; usually face, neck, trunk, intertriginous areas

Associated with diabetes, intestinal polyposis; increase during pregnancy

May be a common endpoint of various processes, including seborrheic keratosis or warts

Gross: soft, flesh-colored, baglike tumor, attached to skin by slender stalk

Micro: papillary, fibrovascular cores covered by squamous epithelium; may have ischemic necrosis due to torsion

 

Hair follicle nevus - Skin-Nonmelanocytic tumor chapter

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Rare

Case reports: 2 year old boy with nose nodule (Pediatr Dermatol 2008;25:60), 26 year old man with small soft nodules on his nose since childhood (Eur J Dermatol 2008;18:185), in a distribution following Blaskho's lines (J Am Acad Dermatol 2002;46:S125)

Dermoscopy: many uniform hair follicles and an interfollicular pseudo-pigment network in the nodules

Micro: well-differentiated hair follicles and sebaceous glands; no cartilage (seen in accessory tragus), central cysts or a central canal (seen in trichofolliculoma)

EM: follicular germ cells present; active fibroblasts around the follicles merge with colloid substance (J Dermatol 2001;28:324)

 

Large cell acanthoma

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Sun exposed skin, usually cheek or forehead

Benign, although may be related to actinic keratosis

Gross: light-tan to dark brown macule

Micro: atrophic, acanthotic or verrucous epidermis; hyperpigmented basal layer with rounded contour of rete ridges; larger than usual keratinocytes (large nuclei and cytoplasm) compared to adjacent normal epidermis; no atypia

 

Melanoacanthoma

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May be a pigmented variant of seborrheic keratosis

Benign

Micro: resembles seborrheic keratosis but with prominent, dendritic melanocytes with abundant melanin granules; melanocytes are scattered throughout the lesion; no atypia

 

Pseudoepitheliomatous hyperplasia

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Due to reparative changes associated with ulcer, trauma, chronic irritation, North American blastomycosis, tuberculosis, syphilis, granular cell tumor, Spitz nevi, melanoma

Micro: deep tongues of epithelial cells that may appear invasive but are thin, elongated, anastomosing and surrounded by inflammatory cells (acute/subacute); also dermal fibrosis and vascular proliferation; no/rare atypia

DD: squamous cell carcinoma (thicker strands, atypia, usually no prominent inflammatory infiltrate)

 

Seborrheic keratosis

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Common; usually age 40+ years

Benign, although may coexist with malignancy

Usually affects trunk, head and neck, extremities; only hair bearing skin

Not HPV related, although HPV present in morphologically similar cases of epidermodysplasia verruciformis and bowenoid changes

Dermatosis papulosa nigra: in blacks

Leser-Trelat sign: sudden appearance or increase in number and size of seborrheic keratoses, associated with internal malignancy

Treatment: superficial curettage, freezing

Gross: exophytic, sharply demarcated, pigmented lesions that protrude above surface of skin, appear to be stuck to skin, single or multiple, soft, tan-black

Micro: basal keratinocyte proliferations

Patterns: acanthotic – most common, rounded verrucous surface; thick layer of basal cells mixed with horn cysts (contain keratin) and pseudohorn cysts (downgrowth of keratin into tumor mass); no prominent granular layer; some cells contain melanin due to transfer from neighboring melanocytes

irritated – pronounced squamous metaplasia with abundant eosinophilic cytoplasm and whorled squamous eddies; often atypia and mitotic figures; resembles carcinoma

inverted follicular keratosis – irritated seborrheic keratosis that grows downward and involves hair follicles

Also hyperkeratotic, adenoid, acantholytic and desmoplastic patterns

Positive stains: low molecular weight keratin

Negative stains: high molecular weight keratin (usually), HPV

DD: squamous cell carcinoma (particularly desmoplastic pattern)

 

Verrucous hyperplasia

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Papillomatosis associated with hyperkeratosis

Benign

Nonspecific change, associated with various entities

Epidermal nevus: if present since birth or early childhood; higher risk for basal cell carcinoma or adnexal tumors

Nevus sebaceous of Jadassohn: associated with malformed adnexal structures (see below)

Verruca vulgaris: exophytic growth with marked hyperkeratosis, focal parakeratosis, papillomatosis resembling church spires, prominent granular layer, koilocytosis, dilated vessels within papillary dermis

 

 

Cysts

Apocrine cystadenoma

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Usually face, solitary or multiple

Lined by sweat duct-like epithelium which may have apocrine features

 

Bronchogenic cyst

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Lesion of suprasternal notch, discovered shortly after birth

Probably derived from branchial clefts, not bronchi

Micro: lined by bronchial (pseudostratified, ciliated columnar) epithelium

 

Cystadenoma

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Also called cutaneous ciliated cyst

Usually extremities of teenage girls

May have mullerian derivation, although rarely described in males

Micro: cylindrical cells with cilia

 

Dermoid cyst

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Resemble keratinous cysts of epidermal type, but also have hair adnexae

Usually face of children along embryonic closure lines

 

Hidrocystoma

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Usually face, solitary or multiple

Lined by two rows of sweat duct-like epithelium which may have apocrine features

Micro images: contributed by Angel Fernandez-Flores, MD, PhD, Hospital El Bierzo and Clinica Ponferrada, Spain - #1#2#3

 

Keratinous cyst

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See below

 

Pigmented follicular cyst

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Hyperpigmented lesion with epidermal-type keratinization, contains laminated keratin, pigmented hair shafts, some growing hair follicles

 

Steatocystoma

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Solitary (simplex, often scrotal) or disseminated (steatocytoma multiplex, autosomal dominant, dermal nodules 1-3 mm of upper arms, axilla, scrotum and presternal skin)

Gross: cysts contain clear fluid

Micro: cyst with elaborate inner folding of cyst wall with undulations of thin layer of stratified squamous epithelium resembling ductal portion of sebaceous gland; also lobules of sebaceous glands and small hair follicles

 

Vellous hair cyst

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Children and young adults

Small, multiple cysts over chest wall and extremities

Micro: cyst lined by flattened, follicular sheath epithelium; contains numerous vellous hairs and soft keratinous material in lumen

 

 

Adnexal tumors

Adnexal tumors-general

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Usually differentiate only along one adnexal line, but there may be divergent differentiation within 1 or more tumors within the same patient

Algorithms (from Sternberg)

Cystic lesions:

(a) glandular lesions are hidrocystoma (two rows of cells) or cutaneous ciliated cyst (cylindrical cells with cilia)

(b) lesions with squamous keratinization are trichilemmal cysts, pilomatricoma, steatocytoma (sebaceous lobules in wall), vellous hair cyst (hair shafts in lumen), epidermoid cyst (contains lamellated keratin), dermoid cyst (adnexal structures in wall), trichofolliculoma (radiating immature hairs) or warty dyskeratoma (acantholytic dyskeratosis)

Basaloid tumors:

Trichoepithelioma / trichoblastoma (ribbons of basaloid cells, cysts and fibroblastic stroma), trichofolliculoma (mature and immature hair follicles), cylindroma (jigsaw-puzzle appearance with thickened basement membrane), spiradenoma (basaloid cells with 2 cell types), sebaceous adenoma or carcinoma, eccrine poroma (large nodules connected to epidermis), eccrine acrospiroma (large dermal nodules), pilomatricoma (ghost cells)

Squamoid tumors:

(a) solid lobules of eosinophilic cells are pilar sheath acanthoma (connected to crater-like cavity) or acrospiroma (not connected to crater-like cavity)

(b) lobules with clear cells are acrospiroma (luminal differentiation), trichilemmoma (epidermal connection, peripheral palisading, thick basement membrane) or sebaceous tumors

(c) lobules of squamous cells with central keratinization are proliferative trichilemmal tumor

Glandular tumors:

(a) apocrine differentiation: papillary hydradenoma (papillary fronds, vulvar/perianal) or tubular apocrine adenoma (epidermal connection)

(b) syringoma: small ducts with 2 rows of cells

(c) papillary eccrine adenoma: cystic ducts and papillary fronds

(d) papillated ducts open to epidermis: papillary syringadenoma (scalp) or nipple adenomatosis (nipple)

(e) mixed tumor (chondroid syringoma): chondromyxoid stroma and tubular or anastomosing glands

(f) sebaceous hyperplasia (lobular arrangement around a central duct), adenoma or carcinoma

 

 

Adnexal tumors-apocrine glands

Adnexal tumors of apocrine glands - general

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Eccrine sweat gland tumors may exhibit apocrine differentiation

Pure apocrine tumors are rare

 

Apocrine tubular adenoma

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Micro: lobular pattern of dermal and subcutaneous tubular apocrine structures with epidermal connection; resembles papillary syringadenoma

 

Hidradenoma papilliferum

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Also called papillary hydradenoma

Perianal or vulvar

Micro: papillary fronds, ducts lined by apocrine type cells which show decapitation secretion and fibrous stroma

 

 

Adnexal tumors-eccrine sweat glands

Acrosyringeal adenomatosis

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Also called eccrine syringofibroadenoma

Gradual and symmetric spread of papular lesions over large areas of body

Micro: diffuse proliferation of acrosyringium-related cells in epidermis and dermis

 

Aggressive digital papillary adenoma

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Usually digits

Recurs locally

Malignant counterpart has poor glandular differentiation, necrosis, atypia, invasion; metastasizes to lung in many cases

Micro: tubuloalveolar and ductal structures, also areas of papillary projections protruding into lumina (may resemble breast carcinoma)

 

Chondroid syringoma

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Also known as mixed tumor of skin

Usually benign

Face, head, neck, extremities, trunk or back

May have areas of apocrine, follicular and sebaceous differentiation

Gross: nodular, circumscribed, nonulcerated

Micro: myoepithelial and epithelial type cells, some with abundant hyaline cytoplasm, in chrondomyxoid stroma; may have eosinophilic globules with radiating fibrillary structures around their lumina, similar to mammary collagenous spherulosis

Micro images: contributed by Angel Fernandez-Flores, MD, PhD, Hospital El Bierzo and Clinica Ponferrada, Spain - #1#2#3#4 

Positive stains: inner epithelial layer - keratin, EMA, CEA; outer myoepithelial layer – vimentin, S100, NSE; variable smooth muscle actin, GFAP

 

Apocrine mixed tumors

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Epithelial component is branching tubular structures with two cell layers; inner layer is columnar with eosinophilic cytoplasm, “decapitation” type secretion, often squamous metaplasia and basal nuclei

 

Clear cell acanthoma

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Legs of females, may be multiple

Acanthoma: benign tumor of epidermal keratinocytes

Gross: moist flat plaque

Micro: intraepithelial tumor of clear keratinocytes with dermal inflammation and abrupt transition to normal epidermis; may have melanocytic proliferation, psoriasiform acanthosis, parakeratosis

Positive stains: glycogen

DD: seborrheic keratosis

 

Cutaneous lymphadenoma

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May be related to eccrine spiradenoma

Micro: multiple rounded lobules of basaloid cells with some peripheral palisading, focal keratinization, occasional duct formation, mixed with small lymphocytes

 

Eccrine acrospiroma

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Also called solid-cystic or nodular hidradenoma

Arises from sweat gland distal excretory duct

Gross: nodules with cystic foci high in dermis

Micro: nests/lobules of cells resembling eccrine poroma with either clear cytoplasm or prominent squamous metaplasia; may have marked vascularity; small and large lumina are lined by cuboidal ductal cells or columnar secretory cells; cystic spaces may be due to degeneration of tumor cells

Micro images: contributed by Angel Fernandez-Flores, MD, PhD, Hospital El Bierzo and Clinica Ponferrada, Spain - #1#2#3#4#5

Positive stains: keratin, EMA, CEA, S100, vimentin

DD: glomus tumor (different staining pattern)

 

Eccrine cylindroma

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Also called turban tumor, particularly when a large, multicentric scalp tumor

Somewhat common; solitary, small, slow growing adenoma, 90% in head and neck

Usually ages 40+ years, 90% women

Rarely associated with similar tumors in major salivary glands

Familial form (turban tumor syndrome, Brooke-Spiegler syndrome): autosomal dominant, multiple tumors of children / teenagers that may also involve trunk and extremities, or in association with spiradenoma, trichoepithelioma, milia or membranous variant of basal cell adenoma of salivary glands; due to mutations in CYLD gene at #16q12-13

Rarely undergoes malignant transformation

Spiradenocylindromas: features of cylindroma and eccrine spiradenoma; usually painful

Gross: pink-red dome-shaped nodule with smooth surface

Micro: compact nests of basaloid cells that fit together like a jigsaw puzzle, surrounded by thick basement membrane

Micro images: #1; #2; #3; #4

Molecular: mutation in CYLD gene in #16 associated with multiple cylindromas

EM: differentiation towards intradermal coiled duct region of eccrine sweat glands

 

Eccrine poroma

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Palms and soles, also other sites

Benign, although eccrine porocarcinomas also exist

May be a subtype of eccrine acrospiroma

Gross: “moat and hillock” pattern

Micro: cords and nests of small keratinocytes attached to the epidermis; nests are sharply delimited from adjacent epidermis; also ducts and sharply delimited islands of squamous epithelium; either intraepidermal (“hydroacanthoma simplex”), intradermal (“dermal duct tumor”) or mixed (most common); dermis has reactive vessels and inflammatory infiltrate; also heavily pigmented variants

Micro images: #1; #2; #3; #4

Positive stains: EMA

EM: features of eccrine gland acrosyringium

DD: basal cell carcinoma, seborrheic keratosis, acrosyringeal adenomatosis

 

Malignant eccrine poroma

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Also called porocarcinoma

Most common sweat gland carcinoma

Usually lower extremities, may be pedunculated

Recurs locally, also metastasizes to regional lymph nodes

Micro: malignant eosinophilic and clear cells in lobular masses or islands with cystic cavities due to extensive necrosis; eosinophilic cells are polyhedral or fusiform with variable cytoplasm, hyperchromatic nuclei, distinct nucleoli, indistinct cell boundaries; clear cells are large and polyhedral with abundant clear cytoplasm and distinct cell borders; resembles eccrine poroma, but with obvious atypia and frequent mitotic figures; also epidermotropism resembling Paget’s disease; variable squamous differentiation, clear cell change and pigmentation

Either horizontal pattern (intraepidermal, like superficial spreading melanoma) or nodular (into dermis, like nodular melanoma)

DD for horizontal pattern: intraepidermal poroma (no atypia), seborrheic keratosis (no atypia), Bowen’s disease (more atypical keratinocytes, more severe architectural abnormalities), Paget’s disease (large cells, clear cytoplasm, mucin+)

DD for nodular pattern: squamous cell carcinoma (prominent keratinization, keratin pearls, no cystic cavities), sebaceous carcinoma (clear cells with bubbly cytoplasm), proliferating trichilemmal tumors (solid and cystic, well demarcated with palisading of peripheral layer), metastatic renal cell or other clear cell tumors, balloon cell melanoma

 

Eccrine spiradenoma

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Extremely painful lesions, anywhere in body

Rarely transforms to high grade malignancy

Micro: sharply circumscribed, lobular adenomas; very cellular; cells have scant cytoplasm; high vascularity; variable T cells

Micro images:  #1#2#3#4#5

contributed by Dr. Amy Lynn, Toledo, Ohio - image

EM: epithelial and myoepithelial cells

DD: synovial sarcoma, metastatic carcinoma, thymoma, cutaneous lymphadenoma

 

Intraepidermal epithelioma of Borst-Jadassohn

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Heterogeneous group of disorders, including irritated seborrheic keratosis, eccrine poroma and other intraepidermal sweat gland tumors

 

Mucinous carcinoma

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Also called adenocystic carcinoma

Scalp of elderly patients

Micro: resembles mammary colloid carcinoma with lakes of mucin containing small tumor cell clusters; may also have an infiltrating ductal pattern

DD: metastatic carcinoma

 

Myoepithelioma

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Tumors with myoepithelial cells but no epithelial cells

Usually benign lesions of extremities, but should be completely excised

May recur locally, rarely metastasize

Usually male, mean age 22 years (range 10-63 years)

Part of a continuum with mixed tumors (ductal structures but few myoepithelial cells)

Mitotic activity may predict more aggressive tumor

Gross: mean 1 cm, range 0.5 to 2.5 cm

Micro: well circumscribed dermal lesions, not connected to epidermis, may extend into superficial subcutis; either composed of (a) solid proliferation of ovid, spindled, histiocytoid or epithelioid cells with abundant eosinophilic syncytial cytoplasm and little stroma; or (b) reticular architecture with epithelioid, plasmacytoid or spindle cells in myxoid or hyalinized stroma; cells have ovoid/spindled nuclei, mild pleomorphism, small necrotic areas, fatty metaplasia, minimal mitotic figures (0-6/10 HPF), no ductal differentiation

Positive stains: required for diagnosis by Fletcher - (a) EMA+ or keratin+ and (b) S100 and (c) GFAP (50%) or muscle markers calponin, smooth muscle actin (57%) or muscle specific actin (HHF)

DD: benign mixed tumor, epithelioid benign fibrous histiocytoma (lower limbs, circumscribed, polypoid, plump and often binucleate epithelioid cells, may entrap dermal collagen, keratin-, myogenic markers-, S100-), Spitz nevus (large epithelioid melanocytes with prominent nucleoli, junctional component, downward maturation, HMB45+, S100+, EMA-, keratin-, myogenic markers-), epithelioid sarcoma (distal extremities of young adults, infiltrates along fibrous septa and fascial planes, discontinuous growth, S100-, GFAP-), cellular neurothekeoma (nested architecture, sclerotic dermal collagen, NKI-C3+, S100-, EMA-, keratin-), leiomyoma

References: Hum Path 2004;35:14

 

Myoepithelial carcinoma

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Severe cytologic atypia and high mitotic rate

 

Papillary eccrine adenoma

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Usually distal extremities of blacks

Recur locally, don’t metastasize

Micro: eccrine duct-like structures, often dilated and with intraluminal papillomatosis

EM: differentiation towards secretory epithelium of sweat glands

DD: low grade eccrine carcinoma

 

Papillary syringadenoma

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Warty tumor of scalp, neck and face

Any age

Slow growing or a recent change in an apparent birthmark

1/3 have adjacent nevus sebaceous, 10% have adjacent basal cell carcinoma

Eccrine syringofibroadenoma: with prominent fibrous stroma

Syringocystadenocarcinoma papilliferum: malignant counterpart

Micro: glandular papillary proliferation connected to skin surface, dense plasma cell infiltrate

Positive stains: plasma cells are IgA+, IgG+

 

Sclerosing sweat duct carcinoma

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Also called microcystic adnexal carcinoma

Slow growing nodule or plaque, usually on upper lip or face

Commonly recurs, metastases very rare

Micro: cords and nests of bland keratinocytes, keratin cysts and ductal differentiation; dense collagenous stroma; is invasive, may extend into subcutis or perineurial spaces; resembles syringoma; rarely is sebaceous differentiation

 

Sweat gland carcinoma

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Uncommon

Usually adults

Difficult to diagnose; may be life threatening

Low grade: microcystic carcinoma, adenoid cystic carcinoma, mucinous carcinoma, extramammary Paget’s disease, mucoepidermoid carcinoma

Intermediate grade: ductal adenocarcinoma, aggressive digital papillary adenocarcinoma, acrospirocarcinoma

High grade: porocarcinoma, clear cell acrospirocarcinoma

Unknown grade: signet ring cell carcinoma, papillary syringadenocarcinoma

Includes malignant eccrine poroma (most common), mucinous carcinoma, sclerosing sweat duct carcinoma; also malignant chondroid syringoma (malignant mixed tumor), malignant myoepithelioma, malignant dermal cylindroma, malignant syringoma (syringoid eccrine carcinoma), malignant acrospiroma, aggressive digital papillary adenocarcinoma, apocrine carcinoma, adenoid cystic carcinoma, mucinous syringometaplasia

Benign sweat gland tumors can also undergo malignant transformation to high grade carcinoma

Micro: may resemble breast carcinoma, renal cell carcinoma, basal cell carcinoma

Positive stains: GCDFP-15, estrogen receptor, keratin, EMA, CEA

Negative stains : actin

DD: metastatic breast carcinoma, renal cell carcinoma

 

Syringoma

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Multiple, yellow, papulonodular lesions on lower eyelids of women

Also face and neck, vulva, dorsal proximal and middle phalanges of hand or eruptive forms (below)

Appears to derive from sweat duct ridge

Micro: upper dermal clusters of small ducts lined by two layer thick epithelium, occasionally with comma shaped extensions; may have clear cells (due to glycogen); not infiltrative, no atypia, no mitotic figures, no local destruction

Micro images: contributed by Angel Fernandez-Flores, MD, PhD, Hospital El Bierzo and Clinica Ponferrada, Spain - #1#2

EM: eccrine origin

DD: basal cell carcinoma

 

Eruptive syringoma

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Neck, anterior trunk, axilla, shoulder, anterior surfaces of arms, abdomen or pubic areas of young men or women

May be reactive, not neoplastic

 

Syringomatous carcinoma

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Infiltrative epithelial tumors resembling syringomas

Micro: tubules, keratinizing cystic structures, islands and cords within desmoplastic stroma; involve epidermis and diffusely infiltrates dermis

DD: syringoma (usually multiple, limited to upper dermis, not infiltrative, no atypia, no mitoses, no local destruction), syringomatous carcinoma of salivary glands (in oral mucosa not skin)

 

 

Adnexal tumors-hair follicles

See also cysts (above)

 

Folliculofibroma

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Associated with Birt-Hogg-Dube’ (BHD) syndrome (autosomal dominant, multiple folliculomas on head and neck, acrocordons and trichodiscomas; also renal cell carcinoma [various types], renal oncocytoma and oncocytic hybrid tumors, lung cysts and spontaneous pneumothorax)

Human gene at 17p11.2 encodes folliculin, normally expressed in skin and adnexae; frameshift mutations occur in BHD causing premature protein termination

Tumor considered a hamartoma of hair follicle

Gross: skin papules

Micro: thin epidermal strands originating from a central hair follicle with prominent connective tissue

References: Mod Path 2004;17:998 (mRNA expression of Birt-Hogg-Dube’ mRNA)

 

Inverted follicular keratosis

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Eyelid or face of elderly

May be irritated seborrheic keratosis, irritated verruca vulgaris or keratotic lesion of infundibular region of hair follicle

Gross: single nodule or papule projecting above skin surface

Micro: well circumscribed with squamous eddies containing an inverted papillomatous and acanthotic component; no inflammation

 

Keratinous cyst

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Most probably arise from infundibular portion of hair follicles

Clinically called (incorrectly) sebaceous cyst

Lesions of palm, sole or other sites may contain HPV 57 or 60

Cysts contain keratin and lipid debris from sebaceous secretions

Cysts may be painful if ruptured

Epidermal (epidermoid) type: also called infundibular cyst; lined by keratinized epithelium with distinct granular layer, contain lamellated keratin but no calcification; may have seborrheic keratosis-like changes in cyst wall

Trichilemmal (pilar) type: also called isthmus-catagen cyst; often on scalp, has trichilemmal-type keratinization (sudden keratinization without a granular layer), uneven boundary between keratinized and non-keratinized cells; non-lamellated keratin within the cyst, often with nucleated cells, often calcified

Micro images: Trichilemmal type #1#2#3

 

Keratoacanthoma

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May represent proliferation of infundibular portion of hair follicle (since keratinization occurs without a granular cell layer), or a subtype of well differentiated squamous cell carcinoma

80% males, usually sun exposed skin of face; younger age group than squamous cell carcinoma of skin

Familial cases may be multiple

Appears to be different from squamous cell carcinoma based on different telomerase, p53 and COX2 activity (Mod Path 2004;17:468)

Usually arises from normal skin, grows rapidly for 4-8 weeks, then regresses over 6 months to leave a depressed, annular scar

Rarely metastasizes, usually in immunosuppressed patients

Also associated with inflammatory dermatoses, congenital lesions, genetic diseases, scars

Gryzbowski type: numerous eruptive lesions

Ferguson-Smith type: multiple ulcerating tumors with atypical distribution

Gross: flesh colored, dome shaped lesion with central, keratin-filled crater

Micro: early (evolving) phase  is composed of well circumscribed solid lobules of large, pale squamous cells with little keratinization, distorted follicular infundibulum, mild atypia; stable phase has central crater filled with keratin but no granular layer, larger more irregular infiltrating squamous nests and islands, accompanied by marked inflammatory infiltrate with lichenoid features and eosinophils but no plasma cells; may be deeply infiltrative, with microabscesses of neutrophils and eosinophils approaching surface; often marked atypia, mitotic figures, atypical mitotic figures at periphery, perineural invasion, rarely vascular invasion; regressing (resolving) phase has keratin filled crater, mature epithelium without atypia, flattening of cup-shape, horizontal fibrosis in dermis, reduction of inflammation, transdermal elimination of elastic fibers

Note: overhanging edges, keratin-filled crater and hemispheric shape are most important features in differentiating from squamous cell carcinoma

Variants: actinic-arises from actinic keratosis and has marked atypia; follicular-plaque with numerous vertical strands of squamous epithelium resembling keratoacanthoma; giant-10-15 cm, may cover most of a member

Micro images: (1) a: early lesion with central keratin-filled crater and overhanging lips; b: telomerase negative; c: p53 (basal staining); d: COX2 negative; (2) stable phase with large irregular infiltrating squamous cell nests and islands; (3) regressing phase with scalloped epithelial remnants and perforating strands of elastin fibers

Negative stains: p53 (usually)

DD: well differentiated squamous cell carcinoma

 

Subungual keratoacanthoma

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May arise from nail matrix

Rapidly growing mass in tip of finger or toe

Associated with lytic, cup shaped defect of distal digit

 

Pilar tumor

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Also called proliferating trichilemmal cyst

Neoplastic version of trichilemmal cyst

Women, base of neck and scalp

Usually benign, may recur locally, metastases are very rare and seen only with obvious malignant cytologic features resembling a focal trichilemmal carcinoma or a sarcomatoid carcinoma

Gross: pure tumors are multinodular, may be huge; may coexist with trichilemmal cyst

Micro: solid with pushing borders and lobulated contour, usually involves epidermis but may open into skin surface; bands of squamous epithelium with trichilemmal-type keratinization; may have prominent atypia, focal stromal invasion

Molecular: nondiploid DNA

 

Pilomatrixoma

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Also called pilomatricoma, calcified epithelioma of Malherbe

Benign tumor arising from hair matrix

Usually children and young adults in head, neck or upper extremities

Gross: nodular, subepidermal

Micro: solid nests of basaloid cells undergoing abrupt trichilemmal-type keratinization; ghost cells, often foreign body reaction, calcification or ossification with extramedullary hematopoiesis; occasional transepidermal perforation

Micro images: contributed by Dr. Amy Lynn, Toledo, Ohio - image

contributed by Dr. Asmaa Gaber Abdou and Dr. Mona Kandil, Menofiya University, Egypt - #1#2#3#4#5#6#7#8#9

DD: basal cell carcinoma

 

Aggressive pilomatrixoma: atypical histology, locally invasive with local recurrence

Malignant pilomatrixoma: cytologic atypia, infiltrative border, transitions to squamous cells; clear cells, necrosis, mitotic figures, variable sarcomatoid features; commonly recur locally, may metastasize

 

Trichilemmoma

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Also called tricholemmoma

Benign

Cowden’s syndrome: multiple trichilemmomas, multiple hamartomas in skin, oral mucosa, breast, thyroid and intestines, as well as malignancies at these sites

Micro: lobular or plate-like growth of pale pink, glassy cells that resemble infundibulum (upper portion of hair follicle); often palisading at periphery, thickened basement membrane, occasional central keratinization; desmoplastic variant simulates malignancy

Micro images: #1; #2; #3; #4; #5

 

Trichilemmal (tricholemmal) carcinoma

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Indolent, with only rare metastases

Micro: lobular growth of clear tumor cells with trichilemmal-type keratinization, numerous mitotic figures, invasion of reticular dermis, ulceration

 

Trichoepithelioma

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Chronic hair follicle tumors

Often in children, may be familial

Autosomal dominant related tumors are multiple, semitransparent, dome-shaped papules on face, scalp, neck, upper trunk

Gross: often multiple, may be huge, no ulceration

Micro: basaloid cells (like cylindroma) that form primitive hair follicle-germ structures with fibromyxoid stroma; cells are often in fronds, may have 2 or more layers of basaloid cells, may have papillary mesenchymal bodies

Micro images: contributed by Angel Fernandez-Flores, MD, PhD, Hospital El Bierzo and Clinica Ponferrada, Spain - #1#2#3#4

DD: basal cell carcinoma

 

Desmoplastic trichoepithelioma

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Benign, resembles basal cell carcinoma-morphea type

Usually solitary tumor

Micro: extensive fibrous stroma surrounds epithelial islands

Negative stains: stromalysin-3 (positive in most basal cell carcinomas)

 

Trichofolliculoma

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Gross: solitary and nodular

Micro: highly organoid hamartomatous lesions that recapitulate various phases of normal hair follicle; have central dilated follicle surrounded by proliferating epithelium with various phases of follicle formation; often Merkel cells present

DD: trichoepithelioma, basal cell carcinoma

 

Warty dyskeratoma

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Also called isolated follicular keratosis

Small maculopapular lesion of sun-exposed skin

Either follicular counterpart of actinic keratosis or a follicular neoplasm

Not related to Darier’s disease

Micro: follicular acantholysis and dyskeratosis

Micro images: #1;  #2;  #3;  #4;  #5;  #6;  #7

 

 

Adnexal tumors-sebaceous glands

Nevus sebaceous of Jadassohn

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Type of epithelial nevus on scalp and face

Congenital, enlarges over time

May transform to basal cell carcinoma, trichoblastoma or rarely squamous cell carcinoma

Micro: hamartoma composed of large sebaceous glands, heterotopic apocrine glands, defective hair follicles, acanthosis and epithelial papillomatosis

 

Sebaceous adenoma

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Micro: nodular lobulated growth with dark and light areas corresponding to generative cells (dark) and sebaceous cells (light) with cytoplasmic lipid vacuoles; not as organoid as sebaceous hyperplasia

DD: angiofibroma with sebaceous hyperplasia of tuberous sclerosis

 

Sebaceous carcinoma

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Rare

Tumors of eyelids, caruncles and orbit are more aggressive than skin tumors

May follow radiation therapy

Also associated with Muir-Torre syndrome (multiple cutaneous tumors with sebaceous and hair follicle differentiation and multiple internal malignancies; tumors have cystic growth pattern)

Poor prognostic factors: necrosis

Micro: sebaceous differentiation, but also marked atypia, mitotic figures, invasion

Micro images: #1#2#3#4#5#6#7

Positive stains: keratin, EMA, LeuM1, variable androgen receptors

Negative stains: CEA, S100

DD: basal cell carcinoma with sebaceous differentiation, squamous cell carcinoma with hydropic change

 

Senile sebaceous hyperplasia

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Most common sebaceous gland lesion

Usually elderly patients on nose or cheeks

Micro images: #1; #2

 

 

Premalignant or noninvasive

Carcinoma in situ-general

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Controversial

Typical progression in cervix from mild to moderate to severe dysplasia to invasion may not apply to skin

Actinic keratosis with only a single layer of atypical keratinocytes may be invasive, but Bowen’s disease seldom does

Mucosal variants in glans penis and vulva are associated with more aggressive behavior

Micro: by definition requires full thickness keratinocyte atypia, although may be surrounded by normal keratinocytes; marked nuclear and architectural atypia, numerous mitotic figures, atypical mitotic figures, apoptotic cells; variable melanin, variable lymphocytic infiltrate; may have hemangiomatous vascular proliferation, amyloid globules, adnexal differentiation

 

Actinic keratosis

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Also called solar keratosis, senile keratosis

Buildup of excessive keratin due to chronic exposure to sunlight

On sun-exposed sites (face, arms, dorsum of hands)

Called actinic cheilitis in lips

May become invasive with only a single layer of atypical keratinocytes

Risk factors: fair skin, ionizing radiation, hydrocarbon or arsenic exposure, renal transplant

Treatment: curettage, cryotherapy, topical chemotherapeutic agents

Gross: tan-brown, red or skin colored, circumscribed lesions, sandpaper texture, may have cutaneous horn (due to excessive production of parakeratotic scale)

Micro: basal cell and squamous layer atypia and disorderly maturation, hyperkeratosis, parakeratosis; may have atrophy of epidermal surface; usually no granular layer except at follicular orifices; elastosis and often chronic inflammation of dermis; follicular apparatus and intraepidermal sweat duct are spared; may have coexisting melanocytic atypia

Variants: acantholytic (lack of intercellular adhesion with clefts containing rounded, acantholytic cells), atrophic (epidermis has only 3-4 layers of keratinocytes), basaloid, bowenoid (full thickness atypia), epidermolytic (vacuolar changes of keratinocytes at upper spinous and granular layers with coarse keratohyalin granules), hyperkeratotic (with cutaneous horn), pagetoid, pigmented (resembles solar lentigo, which lacks atypia and has downward projections)

Positive stains: p53 (75%)

 

Bowenoid papulosis

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Multiple pigmented papular lesions of anogenital area, resembling condyloma acuminatum

Young adults

May regress spontaneously

Almost never invasive

Micro: resembles carcinoma in situ, but with localized acanthosis similar to condylomas; low power view is “salt and pepper” due to dark nuclei and clear vacuolar cytoplasm; usually no adnexal involvement

Positive stains: HPV

Molecular: HPV type 16 is most common

 

Bowen’s disease

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Usually on skin NOT exposed to sunlight, such as trunk

Called erythroplasia if at glans penis, vulva, oral cavity

Often considered as carcinoma in situ or squamous intraepidermal neoplasia

Gross: slightly raised, large scaly erythematous plaque with irregular border; usually single patch or verrucous growth

Micro: atypia is prominent and throughout epidermis; includes nuclear hyperchromasia and multinucleation, individual cell dyskeratosis, increased mitotic figures, atypical mitotic figures; also cytoplasmic vacuoles, markedly altered maturation, but usually still some surface keratinization; may extend into eccrine sweat glands (not considered invasive disease); intercellular bridges present; rarely pagetoid cells or ground glass cytoplasm

Micro images: contributed by Dr. Amy Lynn, Toledo, Ohio - image #1#2

Positive stains: p53, HPV, high molecular weight cytokeratin

Molecular: aneuploid

DD: bowenoid actinic keratosis (circumscribed, in sun-exposed areas with clinical appearance of actinic keratosis), chronic arsenic ingestion

 

Paget’s disease (extramammary)

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May originate from intraepidermal portion of sweat glands or primitive basal cells with ability to differentiation towards glandular elements

Labia majora, scrotum and perineum are most common sites

Due to underlying carcinoma in 10-20% of cases of vulvar disease

Treatment: complete surgical excision

Gross: erythematous, eczematous or ring-shaped; often multicentric, extensive, pigmented

Micro: malignant cells in epidermis with differentiation towards local glandular structures; almost always simultaneous involvement of eccrine glands or hair follicles; dermal invasion is less common (rare in vulva, more common in perianal region); cells are large, pale, vacuolated and usually just above basal layer of epidermis; single, clusters or glandular formations; may have cleft-like spaces between Paget’s cells and neighboring keratinocytes; no intercellular bridges, no dyskeratosis

Positive stains: mucin, EMA, CEA, PAS, low molecular weight cytokeratin (CAM 5.2, CK7); vulva - GCDFP-15 and androgen receptors; perianal - CK20

EM: cells with glandular differentiation, not melanocytes or keratinocytes

DD: pagetoid Bowen’s disease, pagetoid actinic keratosis, melanocytic lesions, metastatic epidermotropic carcinomas, clear cell papulosis

 

 

Carcinoma (non-adnexal)

Adenoid cystic carcinoma

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Micro: cribriform and tubular structures in dermis

DD: metastases from salivary gland tumors, basal cell carcinoma

 

Adenoid squamous cell carcinoma

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Also called pseudoglandular or acantholytic squamous cell carcinoma

Due to a desmosomal defect that causes lack of cell adhesion (acantholysis)

May resemble angiosarcoma

Usually sun-exposed skin, often associated with actinic keratosis with acantholysis

DD: adenocarcinoma (primary or metastatic), adenosquamous carcinoma

 

Adenosquamous carcinoma

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Rare, aggressive

Micro: squamous differentiation and mucin production

 

Basal cell carcinoma

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Most frequent form of skin cancer

Usually sun exposed skin (not mucosal surfaces), in proportion to number of pilosebaceous units present

Rosai claims these tumors attempt to differentiate toward pilosebaceous units, but often this is not readily apparent

Often multiple tumors

Usually older adults

Slow and indolent, untreated cases may invade subcutis, skeletal muscle and bone; facial tumors may invade skull, nares, orbit or temporal bone; only 100 metastatic cases described, often associated with basal cell nevus syndrome or basosquamous histology, on sunlight-protected skin

Metastases are rare; 60% to regional lymph nodes, also lung, liver, bone

Risk factors: fair skin, blue eyes, immunosuppression (higher incidence, more aggressive tumors), xeroderma pigmentosum

Also associated with nevus sebaceus of Jadassohn, chronic venous stasis of lower leg, arsenic, Xrays, skin injury, chickenpox scars, tattoos, hair transplant scars, immunosuppression

Less common in children or young adults, sunlight-protected skin; rarely coexists with benign nevus

 

Basal cell carcinoma (continued)

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Basal cell nevus syndrome: also called Gorlin’s syndrome; autosomal dominant, young patients with multiple basal cell carcinomas (with more varied histologic types than normal, often superficial and multicentric, often with osteoid), palmar pits (in situ basal cell carcinomas), dural calcification, keratinous cysts of jaws, skeletal abnormalities, occasional abnormalities of CNS, mesentery and endocrine organs; due to mutations in PTC (patched) gene on 9q22.3

Poor prognostic factors: dense fibrous stroma and loss of peripheral palisading; reduced expression of syndecan-1 and bcl2, greater expression of p53 and aneuploidy, basosquamous histology, perineurial invasion, positive margins

Case report: malignant basomelanocytic tumor with subsequent metastatic melanoma (AJSP 2004;28:1393)

Treatment: excision with frozen section evaluation of margins, curettage, desiccation, radiation therapy; 1/3 with positive margins will recur

Gross: nodular, ulcerative, superficial, erythematous or sclerosing (morphea-like); often with telangiectasia (prominent, subepidermal vessels)

Micro: almost always epidermal attachment; nests or lobules of hyperchromatic but uniform basaloid cells with peripheral palisading, surrounded by loose stroma, often with myofibroblasts and mucinous changes; also cleft-like retraction spaces (due to stromal mucin); may appear pigmented due to dermal melanophages; variable Langerhans cells; occasional amyloid; rare spindled tumor cells, mitotic activity, atypical mitotic figures, bizarre tumor giant cells, atypical stromal cells, osseous metaplasia, collagen crystal-like structures, eccrine differentiation, thickened basement membrane or perineurial invasion

Patterns are solid, cystic, adenoid, keratotic (resembles squamous cell carcinoma, but has apopototic keratinocytes, no atypia, abundant stroma), pigmented, infiltrating, sclerosing (morphea-like, with slender, deeply infiltrating nests and abundant reactive stroma)

 

Basal cell carcinoma (continued)

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Micro images: contributed by Dr. Amy Lynn, Toledo, Ohio - superficial tumor

Positive stains: keratin, BerEP4, p53, bcl2

Negative stains: EMA, CEA, involucrin

Cytogenetics: +18, +9, +20, +7, +5; also loss of heterozygosity at 9q22.3 and trisomy 6

DD: basaloid proliferations associated with dermatofibromas, actinic keratosis or Bowen’s disease, trichoepithelioma (also basaloid but with follicle-like structures and no clefts)

References: Hum Path 2004;35:1549 (renal transplant patients)

 

Basosquamous (metatypical) carcinoma: basal cell carcinoma plus atypical squamous cells; more aggressive than classic basal cell carcinoma; may metastasize

 

Clear cell basal cell carcinoma: tumor cells with prominent cytoplasmic vacuoles or signet ring morphology

 

Fibroepithelial tumor: also called Pinkus’ tumor, fibroepithelioma; polypoid variant, often on back, with abundant stroma

 

Granular basal cell carcinoma: contains tumor cells resembling those in granular cell tumor; no clinical significance

 

Infundibulocystic basal cell carcinoma: has hair follicle differentiation

 

Superficial (multicentric) basal cell carcinoma: arises in skin of trunk and other sites with sparse fine hairs and thin epidermis; primarily grows laterally, has high recurrence rate, tumors may also regress; has multiple small tumor nests attached to undersurface of epidermis with associated stromal proliferation

 

Lymphoepithelioma-like carcinoma

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May represent a primitive adnexal tumor

Micro: resembles upper respiratory tract tumor, with nests of high grade tumor cells in a syncytium, with a marked lymphocytic infiltrate; but also has features of sweat gland, follicular or apocrine differentiation

Negative stains: EBV

 

Merkel cell carcinoma

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Also called neuroendocrine carcinoma of skin; originally called trabecular carcinoma

Usually adults or elderly; 60% women

Face and extremities

May be associated with squamous cell carcinoma (in situ or invasive), basal cell carcinoma, eccrine duct-like structures

Aggressive; regional nodal metastases are common; distant metastases to liver, lung, bones; also testis or other unusual sites

Rarely appears to arise initially in lymph node, probably due to regression of primary skin tumor

May derive from Merkel cell in epidermis, derived from neural crest, important for tactile sensation in lower animals

Treatment: wide local resection, regional lymph node resection; radiation therapy and chemotherapy as needed

Gross: nodular or ulcerated red-violet lesion

Gross images by anonymous contributor: hip lesion #1#2#3

Micro: dermal or subcutaneous centered tumor with monotonous round tumor cells and diffuse infiltration of subcutis; may have focal trabecular pattern; cells have scant eosinophilic cytoplasmic rim, round and vesicular nuclei with finely granular and dusty chromatin and multiple nucleoli; also apoptotic nuclei and frequent mitotic figures; may have vascular stroma with plump endothelial cells; epidermis is usually spared; rarely has leiomyosarcoma or atypical fibroxanthoma-like areas

Micro images:  #1#2#3#4#5#6#7#8

FNA image by anonymous contributor: small blue cell tumor (was CK20+ with perinuclear dot like staining, CD45-, TTF-; flow was CD56+, CD45-)

Positive stains: low molecular weight keratin, CK20 (perinuclear dot like staining), EMA, neurofilament, neuron-specific enolase, CD56 (J Cutan Pathol 2005;32:541); variable chromogranin, synaptophysin and CD117

Negative stains: TTF1, CD45/LCA

EM: dense core neurosecretory granules and tightly packed intermediate filaments; well developed desmosomes

Molecular: abnormalities in #1, #11, #12; 1p35-36 deletion

DD: lymphoma, metastatic small cell carcinoma of lung, basal cell carcinoma

 

Merkel cell carcinoma - staging

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Click here for staging Merkel cell carcinoma of eyelid

 

Primary tumor (T)

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TX: Primary tumor cannot be assessed

T0: No evidence of primary tumor (e.g. nodal/metastatic presentation without associated primary)

Tis: In situ primary tumor

T1: Less than or equal to 2 cm maximum tumor dimension

T2: Greater than 2 cm but not more than 5 cm maximum tumor dimension

T3: Over 5 cm maximum tumor dimension

T4: Primary tumor invades bone, muscule, fascia or cartilage

 

Regional lymph nodes (N)

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NX: Regional lymph nodes cannot be assessed

N0: No regional lymph node metastasis

cN0: Nodes negative by clinical exam (inspection, palpation or imaging), no pathologic node exam performed

pN0: Nodes negative by pathologic exam

N1: Metastasis in regional lymph node(s)

N1a: Micrometastasis (diagnosed after sentinel or elective lymphadenectomy)

N1b: Macrometastasis (defined as clinically detectable nodal metastases confirmed by therapeutic lymphadenectomy or needle biopsy)

N2: In transit metastasis (a tumor distinct from the primary lesion and located either between the primary lesion and the draining regional lymph nodes, or distal to the primary lesion

 

Distant metastasis (M)

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M0: No distant metastasis

M1: Metastasis beyond regional lymph nodes

M1a: Metastasis to skin, subcutaneous tissues or distant lymph nodes

M1b: Metastasis to lung

M1c: Metastasis to all other visceral sites

 

Stage grouping

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Stage 0:  Tis N0 M0

Stage IA: T1 pN0 M0

Stage IB:  T1 cN0 M0

Stage IIA:  T2-3 pN0 M0

Stage IIB:  T2-3 cN0 M0

Stage IIC:  T4 N0 M0

Stage IIIA:  Any T N1a M0

Stage IIIB:  Any T N1b/N2 M0

Stage IV:  M1 (Any T, Any N)

 

Metastatic carcinoma to skin

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Men: usually from lung (25%), colon, melanoma, kidney, upper aerodigestive tract

Women: usually from breast (69%), lung, melanoma, kidney, ovary

Most common sites of metastases to skin are chest, abdomen, head and neck; metastasis is often close to site of primary

Gross: multiple firm, nonulcerated nodules; may be solitary

Micro images: metastatic breast cancer is p63 negative (basal epidermis is p63+)

Negative stains: p63 is negative in metastatic adenocarcinoma vs. positive in cutaneous adnexal tumors (Mod Path 2005;18:137)

DD: sweat gland tumor (resembles renal cell carcinoma), dermatofibrosarcoma protuberans (resembles signet ring carcinoma), Merkel cell carcinoma (resembles neuroendocrine metastases)

 

Mucoepidermoid carcinoma

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Very rare in skin (~ 30 cases reported)

Probable sweat gland origin

Resembles similar tumor of salivary gland

Usually low to intermediate grade

Case reports: 79 year old white woman with axillary mass (AJSP 2005;29:131)

Micro: circumscribed, not attached to surface; dermal lobules or cystic growth of low grade epidermoid, intermediate, mucinous cells and clear cells; peritumoral fibrosis is common

Positive stains: mucin, keratin, CK7, pCEA, EMA

Negative stains: CK20, GCDFP-15

DD: adenosquamous carcinoma (high grade tumor, often involves epidermis, adenocarcinoma component is well-differentiated), metastatic salivary gland tumor (usually high grade), mucinous metaplasia

 

Small cell neuroendocrine carcinoma

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May be a variant of Merkel cell carcinoma or a metastases

 

Spindle squamous cell carcinoma

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Also called metaplastic carcinoma

Sun exposed areas, particularly the lip

Carcinosarcoma: sharp segregation exists between epithelial and sarcoma-like areas

Sarcoma-like tumor of skin: cannot rule out a mesenchymal tumor

Micro: tumor is contiguous with basal layer of epidermis; usually at least focal squamous cell carcinoma

Positive stains: keratin, vimentin, p63 (J Cutan Pathol 2006;33:413)

DD: melanoma, atypical fibroxanthoma

 

Squamous cell carcinoma

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Common, derived from keratinocytes in epidermal layer

Usually men, associated with sun exposure (UV light may induce p53 mutations and diminish surveillance function of Langerhans cells in epidermis), PUVA treatment for psoriasis, arsenic, tars/oils, chronic ulcers, draining osteomyelitis, old burn scars, necrobiosis lipoidica, hidradenitis suppurativa, ionizing radiation

Risk factors: immunosuppression (post-transplant or HIV), xeroderma pigmentosa (disorder with diminished capacity for DNA repair after UV light exposure, due to gene at 9q22.3; associated with squamous cell, basal cell carcinoma and melanoma), lack of pigmentation in skin, actinic keratosis (precursor lesion), epidermodysplasia verruciformis; very rare in blacks

5% are node positive at diagnosis; metastatic rate is 5-10% in transplant patients, who do poorly with metastatic disease

Slow growing, locally invasive but rarely metastasizes outside nodes (but see above); most common site is lung

Metastases more likely in tumors that originate in scars or ulcers

Prognosis: excellent; metastases uncommon if tumor < 1.5 cm deep; 5% metastasize if 2 cm or more and definite dermal invasion

Good prognostic factors: low stage, no/superficial dermal invasion, small vertical tumor thickness (< 4 mm), well differentiated, short duration, location other than scalp, ears, lips, nose, eyelids or soft tissue (which readily invade subcutaneous tissue)

Treatment: surgical excision with adequate margins; also currettage, electrodesiccation, cryotherapy, radiation therapy

Gross: often white plaque (leukoplakia); may have induration, ulceration, hemorrhage

Micro: atypia at all levels of epidermis; 80% are well differentiated with keratin pearls, intercellular bridges and no/rare keratohyaline granules; invade dermis by definition; may contain non-neoplastic melanocytes that transfer melanin to tumor cells; occasionally clear cells, rarely signet ring cells

Spindle, adenoid and verrucous variants are described separately

Other variants are acantholytic (pseudoglandular, tumor clefts produed by acantholysis of tumor cells) and pseudoangiosarcomatous (clefts separate neoplastic lobules)

Low grade (well differentiated): cell differentiation, uniform cell size, intact intercellular bridges, no/rare mitotic figures, no/mild pleomorphism

High grade (poorly differentiated): little cell differentiation, pleomorphism with spindle cells, necrosis, marked mitotic activity, deep invasion

Micro images: (1) a: moderately differentiated (H&E); b: telomerase+; c: COX2+; d: p53+

Positive stains: high molecular weight keratin, EMA, involucrin, p53 (50%), variable CEA

Negative stains: Ber-EP4, usually CK7 and CK20 (head and neck tumors, Mod Path 2004;17:407)

DD: keratoacanthoma (for well differentiated tumors)

 

Verrucous carcinoma

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Also known as epithelioma cuniculatum

Usually mucosal sites such as oral cavity, glans penis, vulva, cervix

Rarely on skin; usually sole of foot with frequent extention to bone; nodal metastases are rare

Gross: ulcerating, fungating or polypoid mass with sinus tracts opening onto skin surface

Micro: very well differentiated, ulcerating, fungating mass with deep sinus tracts; composed of lobules of mature squamous epithelium with minimal atypia; tumor lobules may invade and destroy bone; few mitotic figures, variable stromal response

Positive stains: HPV (frequently, usually 16, 6, 11)

DD: cysts, benign keratoses

 

Staging of skin carcinomas

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Staging of melanomas is described in Skin-Melanocytic tumors chapter

Staging of eyelid tumors is described in the Eye chapter

Includes spindle cell variant of squamous cell carcinoma and adnexal carcinomas

Applies to clinical and pathologic staging

 

Primary tumor (T)

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TX: Primary tumor cannot be assessed

T0: No evidence of primary tumor

Tis: Carcinoma in situ

T1: Tumor 2 cm or less in greatest dimension with less than 2 high risk features

T2: Tumor more than 2 cm, but not more than 5 cm in greatest dimension

T3: Tumor more than 5 cm in greatest dimension

T4: Tumor invades deep extradermal structures (i.e. cartilage, skeletal muscle or bone)

 

Note:

● High risk features include:

. Depth/invasion: > 2 mm thickness, Clark level of IV or higher or perineural invasion

. Anatomic location: primary sites of ear or non-hair bearing lip

. Differentiation: poorly differentiated or undifferentiated

● For multiple simultaneous tumors, the tumor with the highest T category will be classified and the number of separate tumors will be indicated in parentheses, e.g. T2 (5)

 

Regional lymph nodes (N)

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NX: Regional lymph nodes cannot be assessed

N0: No regional lymph node metastases

N1: Metastasis in a single ipsilateral lymph node, 3 cm or less in greatest dimension

N2: Metastasis in a single ipsilateral lymph node, more than 3 cm but not more than 6 cm in greatest dimension; or in multiple ipsilateral lymph nodes, none more than 6 cm in greatest dimension; or in bilateral or contralateral lymph nodes, none more than 6 cm in greatest dimension

N2a: Metastasis in a single ipsilateral lymph node, more than 3 cm but not more than 6 cm in greatest dimension

N2b: Metastasis in multiple ipsilateral lymph nodes, none more than 6 cm in greatest dimension

N2c: Metastasis in bilateral or contralateral lymph nodes, none more than 6 cm in greatest dimension

N3: Metastasis in a lymph node, more than 6 cm in greatest dimension

 

Distant metastasis (M)

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M0: No distant metastasis

M1: Distant metastasis

 

Stage grouping

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Stage 0:    Tis N0 M0

Stage I:     T1 N0 M0

Stage II:    T2 N0 M0

Stage III:   T3 N0 M0 or T1-3 N1 M0

Stage IV:   T1-3 N2 M0 or any T N3 M0 or T4 any N M0 or any T any N M1

 

Notes:

● Patients with primary clinical squamous cell carcinoma or other cuatneous carcinomas with no evidence (clinical, radiologic or pathologic) of regional or distant metastases are divided into two stages: Stage I for tumors measuring 2 cm or less in size and Stage II for those that are greater than 2 cm in size.  If there is clinical concern for extension of tumor into bone and radiologic evaluation is negative, these data may be included to support the Stage I vs. II designation.  Tumors that are 2 cm or less in size can be upstaged to Stage II if they contain two or more high-risk features.

● Stage III patients are those with (1) clinical, histologic or radiologic evidence of one solitary node measuring 3 cm or less in size or (2) Tumor extension into bone: maxilla, mandible, orbit or temporal bone.

● Stage IV patients are those with (1) tumor with direct or perineural invasion of skull base or axial skeleton, (2) 2 or more lymph nodes or (3) single or multiple lymph nodes measuring > 3 cm in size or (4) distant metastasis.

 

Lymphoma and related disorders

General

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See also Lymphoma chapters

Equal incidence of B and T cell disorders (noncutaneous lymphomas have B cell predominance)

May be primary to skin or part of systemic disease

Common primary cutaneous lymphomas are: T cell - mycosis fungoides; B cell - diffuse large B cell lymphoma, extranodal marginal zone lymphoma, follicular lymphoma

Note: lymphocytes in skin are significant, since not usually present, although may be due to dermatoses

B cell lymphomas: triangular architecture with base in subcutis, compact and nodular infiltrates with perivascular cuffing; epidermis not involved

T cell lymphomas: heterogenous; may have epidermal involvement; may have large reactive component mixed with tumor cells

Epidermotropic: mycosis fungoides, pagetoid reticulosis, mycosis fungoides associated follicular mucinosis, adult T cell leukemia / lymphoma

Superficial dermal: Sezary syndrome

Dermal involvement: lymphoid hyperplasia, inflammatory pseudotumor, follicular center cell lymphoma, marginal zone lymphoma, diffuse large B cell lymphoma, plasmacytoma, lymphomatoid papulosis, granulomatous slack skin disease, CD30+/- large T cell lymphoma, pleomorphic small/medium-sized T cell lymphoma, blastic NK cell lymphoma

Subcutaneous: subcutaneous panniculitis-like T cell lymphoma

Angiocentric: lymphomatoid granulomatosis, nasal type NK/T cell lymphoma

Intravascular: intravascular large B cell lymphoma

 

Acute lymphoblastic lymphoma

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Most common type of cutaneous lymphoma in children; rare in adults

Aggressive behavior; T cell subtypes have best prognosis; stem cell transplantation may improve survival

Either B cell (CD19+, CD20+, CD79a+), T cell (surface CD3+) or nonB nonT (negative for B cell markers and CD3)

NonB nonT include (a) CD7+ stem cell lymphoma (CD7+, CD4-, CD56-, CD33 variable), (b) blastic NK lymphoma (CD56+, CD4-, CD33-, CD123-, CD7 variable), (c) myeloid/NK precursor cell leukemia (CD56+, CD4-, CD7+, CD33+), (d) CD4+ CD56+ hematodermic malignancy (CD4+, CD56+, CD123+, CD7 variable, CD33-)

CD4+ CD56+ hematodermic malignancy frequently has skin lesions, an aggressive clinical course and poor prognosis

References: AJSP 2003;27:1366

 

Anaplastic large cell lymphoma

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Usually elderly men

Either primary cutaneous, systemic ALK+ or systemic ALK negative

Primary cutaneous tumor has good prognosis

May have regressive phase

Gross: solitary or multiple lesions

Micro: large anaplastic tumor cells infiltrate dermis and subcutis, may resemble lymphomatoid papulosis, often pseudoepitheliomatous hyperplasia

Variants: lymphohistiocytic, sarcomatoid, Hodgkin’s-like, small cell, monomorphic, myxoid, neutrophil-rich (associated with HIV+)

Positive stains: CD30 (diffuse membrane and paranuclear dot-like staining); usually T cell markers, NPM-ALK transcript

Molecular: t(2;5) generates NPM-ALK fusion transcript

DD: CD30+ non-neoplastic cutaneous infiltrates

 

Angiocentric lymphoma

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Affects lungs, skin, CNS

Gross: multiple plaques, nodules or ulcerated nodules

Micro: perivascular to diffuse dermal infiltrate with vascular invasion in 50%, also perineural invasion, adnexal destruction, extensive necrosis; epidermis is uninvolved; infiltrate composed of atypical and normal appearing lymphocytes, plasma cells, hstiocytes; atypical lymphocytes are high grade malignant cells

Positive stains: usually T cell

 

Blastic natural killer cell leukemia/lymphoma

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Systemic disease, highly aggressive

Estimated 5 year survival is 0%; eventually becomes leukemia

Recommended to separate off CD4+ CD56+ CD123+ cases as “CD4+ CD56+ hematodermic malignancy”, which frequently has skin lesions and also has poor prognosis (AJSP 2003;27:1366)

Gross: usually multiple bruise-like deep red plaques/tumors

Micro: involves dermis and surrounding adnexa, subcutis but no epidermal involvement; grenz zone present; composed of monomorphous medium sized cells with fine chromatin resembling blasts of acute myelogenous leukemia (although AML is CD56-); may actually derive from common myeloid and NK precursor called plasmacytoid type 2 dendritic cell

Positive stains: usually CD4 and CD56, variable TdT and CD3

Negative stains: CD8, TIA1, EBV

 

Diffuse large B-cell lymphoma

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Primary cutaneous cases, by definition, arise in skin with no known extracutaneous disease within 6 months of initial diagnosis

Represents 20% of primary cutaneous lymphomas; others are extranodal marginal zone lymphoma, follicular lymphoma, T cell lymphomas

Usually men (85%), mean age 64 years

Better outcome than other large B cell lymphomas, although similar to primary cutaneous follicular lymphoma - relapse common but estimated 5 year survival is 97%

CD10+ tumors in head and neck have increased risk of relapse

Can divide into follicular center type (CD10+, bcl6+, CD138- but without bcl2 translocations) and those with post-follicular center or activated B cell phenotype (CD10-, bcl2 usually negative); secondary cases are more like classic follicular lymphoma (AJSP 2003;27:356)

Treatment: surgery, localized radiotherapy; systemic chemotherapy only for generalized skin lesions or disseminated lesions

Case reports: t(14;18)(q32;q21) involving IgH and MALT1 (not bcl2, distinguish MALT1 from bcl2 by FISH (Hum Path 2003; 34:1212); two patients with T cell rich B cell lymphoma (Mod Path 2001;14:10)

Gross: solitary or grouped papules, plaques or tumors, usually in head, neck and trunk of older patients

Micro: either (a) mixed large and small B cells, (b) grade 3 follicular lymphomas (usually in head/neck and CD10+) or (c) monomorphous large cell (AJSP 2001;25:307)

Micro images: A: Grenz zone; B: occasional large cells; C: CD3+ reactive lymphocytes; D: CD20+ tumor cells

Positive stains: tumor cells - CD20; variable bcl2 and bcl6; reactive T cells - CD3, CD45RO (UCHL-1)

Negative stains: tumor cells - CD3 (positive in background cells), CD10 (usually)

Flow cytometry: reactive T cells are 65-90% of cells (Archives 1999;123:1236)

References: AJCP 2002;117:574 (study of 15 cases)

 

Leg

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5-10% of primary cutaneous diffuse large B cell lymphomas cases

Usually elderly patients

May have poorer prognosis (AJSP 2003;27:1538), although somewhat controversial (Hum Path 2002;33:937)

Gross: solitary or grouped red/blue nodules

Micro: dense, diffuse large cells infiltrating entire dermis, usually thin grenz zone, cells resemble immunoblasts (large oval vesicular nuclei with prominent nucleoli) or centroblasts (large noncleaved nuclei, prominent nucleoli)

 

Hodgkin’s lymphoma of skin

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Usually indicates stage IV disease

Rarely is primary in skin

Gross: nodules or papules distal to involved lymph nodes

 

Human T cell lymphoma 1 related lymphoma (HTLV-1)

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Rapid clinical course

Micro: high grade, spares epidermis, may be angiocentric

 

Intravascular lymphoma

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Also called angiotropic lymphoma, malignant angioendotheliomatosis

Usually diffuse large B cell (occasionally T cell) lymphoma

May present initially in cervix, prostate, other sites

Micro: large atypical tumor cells in lumen or wall of vessels

 

Jessner’s lymphocytic infiltration of skin

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May be a variant of lymphoid hyperplasia

Related to discoid lupus erythematosus

Violaceous nodules of head and neck or trunk

Micro: lymphocytes and plasmacytoid monocytes, no distinct epidermal changes

 

Leukemia

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Skin involvement (“leukemia cutis”) occurs in 5% with CML, 8% with CLL, 10% with monocytic leukemia

Usually is abnormal peripheral blood count at diagnosis

Skin involvement is rarely initial manifestation of recurrence (Am J Clin Pathol 2008;129:130)

Myeloid leukemia with monocytic differentiation more commonly involves the skin than other types of myeloid leukemia; may also have accompanying vasculitis (Am J Clin Pathol 1997;107:637)  Aggressive behavior and short survival (J Am Acad Dermatol 1999;40:966)

Case reports: 68 year old woman with history of AML (Case of Week #140)

Treatment: systemic chemotherapy directed at eradicating the leukemic clone

Gross: multiple nodules/papules

Micro: in CLL, may be perivascular, periadnexal, nodular or bandlike dermal infiltrate; infiltrate in leukemic patients is often NOT neoplastic, but reactive

AML - dermis and superficial subcutaneous fat are diffusely infiltrated by a monotonous population of large cells with a high nuclear to cytoplasmic ratio, round to slightly irregular nuclear contours, finely dispersed chromatin and prominent nucleoli

Micro images: AML - #1#2#3#4CD45CD43CD117CD68

Positive stains: myeloblasts - chloroacetate esterase (Leder stain), myeloperoxidase

References: eMedicine

 

Lymphoid hyperplasia

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Usually on face of women

May be due to trauma or insect bites

Gross: solitary nodules or plaques

Micro: lymphocytic and histiocytic infiltrate with tingible body macrophages, plasma cells, eosinophils; often germinal cells or lymphoid follicles, hyperplastic vessels or epidermal hyperplasia; usually spares epidermis

Positive stains: both kappa and lambda light chain expression, both B and T cells

DD: MALT lymphoma (marginal zone cells, Dutcher bodies, sheets of plasma cells)

 

Lymphomatoid papulosis

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Rare, self-healing, recurrent papular eruption

Indolent clinical course, although 10% are associated with or evolve to anaplastic large cell lymphoma

May be self healing “benign” phase of anaplastic large cell lymphoma (per Rosai)

May resemble pityriasis lichenoides et varioliformis acuta, or have large ulcerated plaques and nodules

Treatment: regular follow-up

Micro: wedge shaped on low power with base of lymphocytes at epidermis and tip deep within reticular dermis; polymorphic superficial dermal infiltrate, usually perivascular, with thin epidermis; occasional atypical lymphoid cells resembling Reed-Sternberg cells or “lumps of coal”; often obscures dermoepidermal junction with variable epidermotropism

type A: pleomorphic CD30+ lymphocytes with hyperchromatic nuclei that may mimic Reed-Sternberg cells; also mixed inflammatory infiltrate; CD3+, CD4+, CD8-, CD20-, CD30+, CD56-  

type B: relatively small hyperchromatic lymphocytes with complex nuclear membranes; CD3+, CD4+, CD8-, CD20-, CD30-, CD56-

Micro images: contributed by Angel Fernandez-Flores, MD, PhD, Hospital El Bierzo and Clinica Ponferrada, Spain - type A - #1#2#3CD30 

Molecular: T cells are clonal, but this doesn’t predict transformation to lymphoma

DD: arthropod bite

 

Mantle zone lymphoma

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Chronic and protracted clinical course

Micro: extensive nodules in reticular dermis and subcutis of small lymphocytes with irregular nuclear membranes and clumped chromatin; forms wide mantle zones around germinal centers

Positive stains: B cell markers, bcl1

 

Mast cell disorders

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Most cutaneous mast cell disorders have a good prognosis

Mastocytosis: monomorphic population of mast cells with rare eosinophils

Urticaria pigmentosa: common form of mastocytosis, numerous small yellow-brown papules, become hives when rubbed

Micro: variable dermal mast cell infiltration; variable eosinophils

Positive stains: toluidine blue and Giemsa demonstrate metachromasia (granules are purple-red), Leder chloroacetate esterase, CD117/c-kit

DD: normal skin or dermatoses (must search to find mast cells even with special stains)

 

Mycosis fungoides

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Most common primary cutaneous T cell lymphoma

Usually elderly or other adults

May arise from progression of large plaque psoriasis

Usually protracted clinical course over years

By definition, are negative for HIV1, HIV2, HTLV

Sezary syndrome: peripheral blood involvement by cerebroid cells with PAS+ granules, lymphadenopathy, diffuse erythema and scaling of entire body surface; usually less epidermotropism; lymph nodes may have tumor cells or dermatopathic lymphadenitis (no atypical T cells, normal architecture, no clonality)

Poor prognostic factors: generalized plaques/tumors, diffuse erythema, lymphadenopathy

50% have nodal or visceral involvement that may resemble large cell lymphoma

Sepsis is a common terminal complication

Treatment for skin limited disease: total skin electron beam irradiation, topical chemotherapy, PUVA

Molecular: clonal proliferation of mature CD4+ epidermotrophic lymphocytes; low CD8/CD3 ratio in epidermal tumor cells (Mod Path 2003;16:857)

DD: drug reaction, inflammatory dermatoses (resemble early mycosis fungoides)

 

Premycotic (patch) stage

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Usually indolent course

Gross: erythematous, scaly and pruritic skin

Micro: chronic non-specific dermatitis with psoriasiform changes in epidermis; often associated changes of lichen simplex chronicus due to repeated rubbing

 

Mycotic stage

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Gross: infiltrative plaques

Micro: dermal polymorphous infiltrate of atypical lymphocytes with cerebriform nuclei alone or clustered in epidermis and in small sheets in dermis; also Pautrier’s microabscesses, palisading along epidermal basal layer, tumor infiltrates around hair follicles, variable follicular mucinosis

Micro images: low CD8 expression (B) compared to inflammatory dermatoses (D)

 

Tumorous stage

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Treatment: systemic chemotherapy

Micro: dense dermal infiltrates of atypical T cells with cerebroid nuclei (with thin sections); may have reactive B cell component also

Positive stains: CD4 (usually)

Negative stains: CD2, CD3, CD5, CD7

Molecular: T cell receptor gene clonality

DD: acute or chronic dermatitis with cerebroid cells

 

NK/T cell lymphoma, extranodal, nasal type

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Aggressive tumors, usually in GI tract, less commonly in skin

More common in Asia and South American than Western countries

Estimated 5 year survival: 0%

Micro: may involve epidermis, dermis or subcutis; polymorphous lymphoid infiltrate with eosinophils, plasma cells, histiocytes; lymphocytes are usually large pleomorphic cells with vesicular nuclei and prominent nucleoli; also medium or small with irregular nuclei; usually angiocentric (52%) with necrosis (62%); apoptosis common; occasionally clear cytoplasm

Micro images: tumor from various sites, including skin - a: vascular infiltration/destruction; b: small cells with slightly irregular nuclei and inflammatory infiltrate; c: small and medium sized cells; d: large lymphoid cells with vesicular nuclei and distinct nucleoli; e: EBER+ by ISH

Positive stains: CD2, CD3epsilon, CD56, TIA, granzyme B, EBER by ISH

Negative stains: CD20

References: Mod Path 2004;17:1097 (skin and other sites)

 

Peripheral T cell lymphoma

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50% of T cell lymphomas in Western countries; a large and heterogenous group of lymphomas

Median age 62 years

Usually present with advanced stage disease with nodal involvement and variable marrow or extranodal involvement

May have primarily skin involvement

Aggressive; recurrences, progressive disease and death due to disease are common

May resemble classic Hodgkin’s lymphoma due to Reed-Sternberg like cells, and occasional cases are CD15+ and CD30+ (AJSP 2003;27:1513)

Positive stains: CD45 (usually), T cell markers on all cells; occasionally CD15+ and CD30+ in both Reed-Sternberg like cells and background cells

Negative stains: aberrant T cell expression (i.e. loss of some T cell markers)

Molecular: clonal rearrangement

DD: Hodgkin’s lymphoma (background cells have normal morphology and normal T cell antigen expression; Reed-Sternberg like cells are negative for T cell antigens)

 

Primary cutaneous lymphoma

Primary cutaneous B cell lymphoma

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< 20% of primary cutaneous lymphomas

Consists of follicular lymphoma, marginal zone lymphoma and diffuse large B cell lymphoma

Marginal zone lymphomas often associated with Borrelia burgdorferi infection

By definition, no evidence of extracutaneous disease is identified for 6 months after initial diagnosis

Similar morphology to nodal disease, but more indolent

Molecular: t(14;18) is rare in cutaneous follicular lymphoma, but is characteristic of nodal follicular lymphoma

References: Mod Path 2004;17:623 (mutational analysis)

 

Subcutaneous, blastic NK, NK/T cell or other cytotoxic T cell lymphoma (excluding mycosis fungoides)

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These cases include patients with skin and non-skin disease at diagnosis, as well as skin only

All CD30 negative with medium/large cells or subcutaneous panniculitis-like

(a) subcutaneous panniculitis-like T cell lymphoma: indurated, erythematous and discolored plaques on extremities; alpha/beta CD8+ cytotoxic T cells, with almost exclusive involvement of subcutaneous tissue resembling lobular panniculitis; recommend to exclude cases with epidermal involvement from this category; tumor cells have pleomorphic nuclei and adipocyte rimming (not specific for this diagnosis); CD3+, CD8+, TIA1+, EBV-, estimated 5 year survival is 80% with systemic steroid therapy

(b) blastic NK cell lymphoma: usually multiple bruise-like deep-red plaques/tumors; involves dermis and surrounding adnexa, grenz zone present, subcutis but no epidermal involvement; monomorphous medium sized cells with fine chromatin resembling blasts of acute myelogenous leukemia (although AML is CD56-); may actually derive from common myeloid and NK precursor called plasmacytoid type 2 dendritic cell; CD3-, CD4+, CD8-, CD56+, TIA1-, TdT variable, EBV-; estimated 5 year survival is 0%; eventually become leukemia

(c) NK/T cell lymphoma, nasal type: multiple patches, plaques or nodules; may involve epidermis, dermis or subcutis; medium-large pleomorphic or blastic nuclei; CD3epsilon+, TIA1+, EBV+; estimated 5 year survival is 0%

(d) epidermotrophic CD8+ T cell lymphoma: multiple plaques and tumors, similar to disseminated pagetoid reticulosis; ulceration common; alpha/beta negative, CD8+ cytotoxic T cells, with predominant involvement of epidermis, also dermis, adnexae and subcutis; CD3+, CD8+; TIA1+, betaF1+; EBV-; estimated 5 year survival is 0%; must rule out mycosis fungoides

(e) cutaneous gamma/delta T cell lymphoma: multiple plaques and tumors, similar to disseminated pagetoid reticulosis; epidermal involvement with necrosis, interface dermatitis, adnexal involvement, gamma/delta T cells; CD4-, CD8-, CD56+, TIA1+, EBV-, estimated 5 year survival is 0%

(f) cutaneous alpha/beta pleomorphic T cell lymphoma: solitary or multiple plaques and tumors; often epidermal necrosis and adnexal involvement; alpha/beta T helper cells (CD8-) with expression of cytotoxic markers betaF1 and TIA1, different from subcutaneous panniculitis-like T cell lymphoma and epidermotrophic CD8+ T cell lymphoma; estimated 5 year survival is 0%

(g) cutaneous medium/large pleomorphic T cell lymphoma, not otherwise specified: multiple plaques and tumors, don’t fit other categories

References: AJSP 2004;28:719

 

Woringer-Kolopp disease

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Also called pagetoid reticulosis

Indolent, T cell cutaneous proliferative disorder

Related to mycosis fungoides

Disseminated lesions are called Ketron-Goodman type of pagetoid reticulosis

Gross: solitary erythematosquamous patch

Micro: monomorphic intraepidermal infiltrate of mycosis fungoides-like cells, in Paget’s disease type pattern

 

 

Vascular tumors

Acquired (tufted) angioma

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Also called Nakagawa’s angioblastoma; benign, juvenile or infantile hemangioendothelioma

May be the same entity as kaposiform hemangioendothelioma

Slowly enlarging multiple red plaques on shoulders and upper back of children or teenagers

Micro: multiple vascular lobules similar to pyogenic granuloma but more cellular, resembling cannonballs, and with semilunar vessel at periphery of lobule (versus central and open vessel in pyogenic granuloma); variable mitotic figures, no atypia

Positive stains: Ulex europaeus and factor VIII related antigen only in endothelium of larger vascular channels

 

Angiokeratoma

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Micro images: contributed by Angel Fernandez-Flores, MD, PhD, Hospital El Bierzo and Clinica Ponferrada, Spain - #1#2#3

 

Angiosarcoma

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Also called malignant hemangioendothelioma

Skin cases are in head and neck of elderly, not young patients, unless also associated with chronic lymphedema or radiotherapy (these lesions are often called lymphangiosarcomas)

Slow growing but highly aggressive with frequent recurrences that involve extensive areas of face and scalp; metastasize to regional lymph nodes, lungs, other organs

Gross: violet elevated nodules on flat lesion with ill defined margins; may be verrucoid

Micro: infiltrating, freely anastomosing channels lined by spindled to epithelioid endothelial cells with marked atypia, surrounding adnexae and dissecting dermal collagen; intracytoplasmic vacuoles represent lumina; also areas resembling Kaposi’s sarcoma and undifferentiated foci resembling melanoma or carcinoma; may have focal granular cell features; may extend into scalp aponeurosis

EM: features of endothelial cells

Molecular: not diploid by flow cytometry

DD: epithelioid variants resemble epithelioid hemangioendothelioma or epithelioid hemangioma; squamous cell carcinoma, epithelioid sarcoma, hamartoma of scalp with ectopic meningothelial elements

 

Bacillary angiomatosis

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Due to infection by Bartonella henselae

May involve soft tissue, lymph nodes, internal organs

May coexist with Kaposi’s sarcoma

Reactive but mimics a neoplasm, and commonly presents as multiple cutaneous neoplasms in HIV patients

Treatment: antibiotics

Gross: red papules/nodules

Micro: lobules of capillaries with epithelioid endothelial cells; also fragmented neutrophils, granular purple extracellular bacteria

Positive stains: silver stains (bacteria)

EM: bacteria present

DD: verruga peruana, Kaposi’s sarcoma

 

Benign (infantile) hemangioendothelioma

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Micro: lobular with marked hypercellularity; vascular lobules (of pyogenic granuloma) also present

 

Benign lymphangioendothelioma

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Also called acquired progressive lymphangioma

Gross: bruise-like lesion

Micro: anastomosing vascular channels, but no atypia

DD: angiosarcoma, Kaposi’s sarcoma

 

Glomus tumor

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Usually painful subungual tumors

Micro: dermal or subcutaneous tumors, either solid or vascular, composed of glomus cells, a modified smooth muscle cell with abundant cytoplasm and oval nucleus; either (a) solid variant - proliferation of glomus cells with no/rare vascular lumina or (b) vascular variant - abundant vascular lumina that may resemble cavernous hemangioma

Micro images: contributed by Angel Fernandez-Flores, MD, PhD, Hospital El Bierzo and Clinica Ponferrada, Spain - #1#2#3#4 

DD: cavernous hemangioma, blue rubber bleb nevus syndrome (multiple tumors), acrospiroma

 

Hemangioma

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Childhood tumors are often malformations, not neoplasms

 

Capillary hemangioma

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Also called strawberry hemangioma

Children: usually regress by fibrosis

Adults: may slowly enlarge or thrombose

Micro: well formed vascular channels in dermis with endothelial lining and containing red blood cells; no atypia

DD: dermal vascular hyperplasia (with venous stasis), pyogenic granuloma, Kaposi’s sarcoma, angiosarcoma, hemangioendothelioma

 

Cavernous hemangioma

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Markedly dilated dermal vessels, may elevate overlying epidermis, which may be atrophic

Associated with Maffucci’s syndrome, blue rubber bleb nevus syndrome, Kasabach-Merritt syndrome

 

Epithelioid hemangioma

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Also called histiocytoid hemangioma, angiolymphoid hyperplasia with eosinophilia

All racial groups

Head and neck nodules, often periauricular

Benign in skin; may be reactive

Occasionally overlies soft tissue epithelioid hemangioendothelioma or occurs in bone

No/rare regional lymphadenopathy

Normal serum eosinophils, IgE

Gross: small, superficial, dermal papulonodules, frequently erythematous, with bleeding

Micro: proliferation of blood vessels with epithelioid endothelial cells exhibiting abundant eosinophilic cytoplasm with variable cytoplasmic vacuoles resembling intracytoplasmic lumina and large vesicular nuclei with variable atypia; usually heavy infiltrate of eosinophils and lymphocytes with germinal centers; may have lobular solid pattern

DD: epithelioid hemangioendothelioma (usually not cutaneous), epithelioid angiosarcoma (marked atypia), lobular pyogenic granuloma (no epithelioid endothelial cells), Kimura’s disease (usually Asians with elevated serum eosinophils and IgE, usually regional lymphadenopathy)

 

Glomeruloid hemangioma

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Associated with Castleman’s disease and POEMS syndrome (Polyneuropathy, Organomegaly, Endocrinopathy, M-protein and Skin changes)

Micro: dermal vascular spaces contain glomeruloid structures formed by capillaries; occasional cells have PAS+ eosinophilic globules

Micro images: contributed by Angel Fernandez-Flores, MD, PhD, Hospital El Bierzo and Clinica Ponferrada, Spain - #1#2

 

Hobnail hemangioma

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Endothelial cells protrude into vessel lumina

contributed by Drs. Asmaa Gaber Abdou and Nancy Asaad, Menofiya University, Egypt - lower lip of female - #1#2#3#4

 

Juvenile hemangioma

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Spontaneously involutes, not associated with Kasabach-Merritt phenomenon

Positive stains: GLUT1+, LewisY+

DD: kaposiform hemangioendothelioma (doesn’t involute, GLUT1-, LewisY-, often associated with Kasabach-Merritt phenomenon)

 

Microvenular hemangioma

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Young to middle-aged adults; also pregnant women or women on oral contraceptives

Small, enlarging, purple-red nodules or plaques of extremities

Duration up to 4 years

Micro: transdermal proliferation of irregular branching venules with indistinct lumina, no atypia, no fat invasion (although may grow along collagenous septa of subcutis); variable dermal fibrosis and lymphocytes; resembles acquired (tufted) angioma, stasis change, sclerosing hemangioma

Positive stains: endothelial cells are strongly Ulex europaeus lectin 1+, weakly positive for factor VIII related antigen

DD: dermatofibroma, Kaposi’s sarcoma (irregularly anastomosing vascular spaces, plasma cells, hyaline globules, fascicles of spindle cells)

 

Spindle cell hemangioma

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Bland spindle cell proliferations between vascular lumina with extravasated erythrocytes (similar to Kaposi’s sarcoma), but also with vacuolated cells and epithelioid endothelial cells (unlike Kaposi’s sarcoma)

 

Hemangioendothelioma and subtypes

Epithelioid hemangioendothelioma

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Superficial and soft tissues in adults

Micro: nests and cords of cells with abundant eosinophilic cytoplasm and prominent intracytoplasmic lumina

DD: carcinoma

 

Kaposiform hemangioendothelioma

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Rare tumor of childhood (mean age 4 years, range 2 weeks to 20 years)

Some cases may have been called acquired tufted angioma

Intermediate malignancy; does not regress

50% are associated with Kasabach-Merritt phenomenon (profound thrombocytopenia and life-threatening hemorrhage); occasionally associated with lymphangiomatosis

Usually on extremities or head and neck

May affect skin or deep soft tissue

Metastases limited to regional perinodal soft tissue; mortality due to underlying Kasabach-Merritt phenomenon

Gross: skin lesions are slightly raised, blue-red

Micro: biphasic with vascular and lymphatic component; irregular, infiltrating nodules of compressed vessels, evoking a dense hyaline stromal response; vessels are tightly coiled and highly convoluted, and budded off larger vessels, resembling either capillary hemangioma or Kaposi’s sarcoma; scattered epithelioid or glomeruloid islands are associated with pericytes, hemosiderin and fibrin thrombi; also has lymphatic component with thin-walled vessels

Positive stains: CD31, CD34, FLI1+

Negative stains: GLUT1 (glucose transporter protein isoform 1), Lewis Y antigen, HHV8

DD: juvenile hemangioma (spontaneously involutes, not associated with Kasabach-Merritt phenomenon, GLUT1+, LewisY+)

References: AJSP 2004;28:559

 

Retiform hemangioendothelioma

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Low grade variant of angiosarcoma

Usually distal extremities of young individuals

Weiss and Goldblum use term “hobnail hemangioendothelioma” for retiform and Dabska-type tumors, which they believe to be closely related

Rarely multiple (Am J Dermatopathol 1996;18:606)

2/3 recur, particularly without wide local excision; low rate of metastases, no tumor related deaths

Case reports: Case of the Week #107

Treatment: wide local excision;  

Gross: lesion of reticular dermis and subcutaneous tissue

Micro: retiform (net-like, similar to rete testis) pattern of blood vessels that disperse through reticular dermis and subcutis; vessels lined by monomorphic hobnail endothelial cells with scant cytoplasm and rounded, naked-type nuclei; often prominent lymphocytic infiltrate; no epithelioid areas or cytoplasmic vacuoles (AJSP 1994;18:115)

Micro images: #1;  #2;  #3#4#5CD31 #1#2   

Positive stains: endothelial cells - CD34 (strong), CD31, vWF

Negative stains: endothelial cells - keratin.

DD: angiosarcoma (may focally have low grade features, but also exhibits areas of marked atypia and pleomorphism; also dissects between individual collagen bundles and has mitotic activity), hobnail hemangioma (smaller, more superficial and more localized, with papillary dermal vessels that disappear into reticular dermis)

 

Spindle cell hemangioendothelioma

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Dermis and subcutis

Frequent local recurrences, only rare metastases

Micro: thin-walled, large cavernous blood vessels and spindle cells

 

Intravascular papillary endothelial hyperplasia

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Also called Masson’s hemangioma

Often fingers and hemorrhoids

In skin, associated with preexisting pyogenic granuloma or hemangioma, vascular malformations or hemangiomas of blue rubber bleb nevus syndrome

Due to exuberant recanalization of a thrombus

May be secondary to trauma or superimposed on pyogenic granuloma or cavernous hemangioma

Slow growing, tender, blue-red, deep dermal to subcutaneous mass

Rarely recurs after excision

Micro: dilated vessel contains papillary proliferation of plump endothelial cells without atypia overlying fibrous tissue; fibrin deposition and thrombi present; variable pleomorphism and stratification, no/rare mitotic figures, no necrosis, no solid cellular areas

DD: angiosarcoma

 

Kaposi’s sarcoma

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Derived from vasoformative mesenchymal multipotential cells

Low grade vascular neoplasm

Described by Kaposi in 1872

Note: HHV8 also present in primary effusion lymphoma, some cases of multicentric Castleman’s disease, reactive angioendotheliomatosis, plasmacytic lymphoma

 

Classic Kaposi’s sarcoma

Non-HIV associated

10% of all malignant tumors in equatorial (central) Africa, usually young adults and children

Also common in some Mediterranean regions among males; rare in US

Usually prolonged course; elderly patients may die of recurrent disease

Poor prognosis if over 50 years old and immunosuppression or in African cases

 

HIV associated Kaposi’s sarcoma

More common than classic form in US and Western world due to HIV (usually male homosexuals)

Similar to cases associated with organ transplant recipients, systemic Castleman’s disease, angioimmunoblastic lymphadenopathy, lymphoma, other malignancies

More rapid clinical course than classic disease

Frequent involvement of lymph nodes, lungs, GI tract

 

Treatment: radiotherapy, chemotherapy, excision

Gross: multiple blue/violet dermal nodules/plaques on feet and legs, progressing proximally; may be polypoid and resemble pyogenic granuloma; nodules may also be in subcutis, but these are clinically indolent

Macular stage: red-blue cutaneous discoloration, often lower extremity

Micro: spindle cells forming slits with extravasated red blood cells, hemosiderin laden macrophages, lymphocytes and fibrosis; minimal atypia; may have numerous eosinophilic, PAS+ hyaline bodies (may be ingested erythrocytes); moderate mitotic activity

Early changes may be limited to spindle cells in papillary dermis and vasculature around sweat glands, and not be diagnostic

Note: AIDS patients also have vascular lesions resembling angiosarcoma, epithelioid hemangioma, lymphangioma

Macular stage: thin-walled, angulated vessels throughout dermis, with hemosiderin and plasma cell infiltrate

Patch stage: angulated lumina that dissect dermal collagen; vessels may proliferate around well-developed round venules (premonitory sign); angiomatoid vascular spaces with red blood cells are surrounded by spindle cells in short fascicles

Tumor stage: solid nodules with extensive spindle cells and red blood cells in slit-like lumina; no/rare mitotic activity or atypia

Lymphangioma-like variant: thin, angulated vessels with no red blood cells

Positive stains: Factor VIII related antigen, CD31, CD34, thrombomodulin, latent nuclear antigen-1 of HHV-8 (Kaposi sarcoma-associated herpes virus)

Molecular: diploid and clonal; HHV8 present in almost 100% of lesions (classic, HIV, or other types)

DD: arteriovenous malformation, acroangiodermatitis, cutaneous angiosarcoma, pyogenic granuloma, tufted angioma, bacillary angiomatosis, pigmented purpuric dermatosis, benign fibrous histiocytoma, spindle cell hemangioendothelioma (usually dermis and subcutis)

References: Mod Path 2004;17:456 (immunostain for HHV8 latent nuclear antigen-1)

 

Kimura’s disease

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Rare chronic inflammatory disorder of deep subcutaneous tissue, etiology unknown

Usually head and neck, often associated with regional lymphadenopathy or salivary gland involvement

Usually affects Asian males, but similar presentation in US (AJSP 2004;28:505)

Almost always affects nodal sites; often associated dermal involvement

Usually peripheral blood eosinophilia and elevated serum IgE

Benign and reactive

May recur, no/rare death from disease

Gross: large tumor-like lesions

Micro: lymph nodes have preserved architecture, but also follicular hyperplasia, prominent eosinophilic infiltrates, proliferation of postcapillary venules; marked fibrosis in advanced stage disease

DD: angiolymphoid hyperplasia with eosinophilia, hypersensitivity or drug reactions, infections

 

Lymphangioma

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Usually infants or children age 5 years or less

Neck, axilla, breast, chest, buttock, thigh

Either superficial (lymphangioma circumscriptum, associated with surgery or radiotherapy for breast carcinoma), cystic (cystic hygroma) or deep (lymphangioma cavernosum)

Treatment: excision, but 25% recur

Micro: grouped translucent papules with thin vascular lumina that impinge on epidermis; often deep remnants in subcutaneous tissue

 

Pyogenic granuloma

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Also called granuloma pyogenicum, lobular capillary hemangioma

Very common

Rapidly growing polypoid red mass surrounded by thickened epidermis, often in finger or lips

May be associated with keratinous cyst

Benign, often regresses spontaneously

May be disseminated, occur within port-wine stains, be in deep dermis / subcutis or be intravenous

Treatment: none, excision (may recur as multiple satellites)

Gross: fleshy cutaneous tumor

Micro: lobular pattern of vascular proliferation with inflammation and edema resembling granulation tissue; thin epidermis at top with variable ulceration; acanthosis and hyperkeratosis at sides; central branching vessel is called capillary or vascular lobule, with no/rare red blood cells, surrounded by endothelial cells; variable mitotic activity; deep lesions often lack edema and inflammation

Variants: classic polypoid, dermal, subcutaneous, intravenous, eruptive, with multiple satellites

DD: benign (infantile) hemangioendothelioma, venous stasis, acrodermatitis, reactive angioendotheliomatosis, verruga peruana, bacillary angiomatosis

 

Reactive angioendotheliomatosis

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Usually occurs in skin, associated with systemic disease

Micro: multiple clusters of closely packed capillaries lined by endothelial cells without atypia; also striking proliferation of endothelial cells forming capillaries within preexisting dilated blood vessels; may have fibrin microthrombi, epithelioid endothelium

Positive stains: CD31, CD34, factor VIII related antigen

 

Vascular leiomyoma

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Also called angioleiomyoma

Single, painful, deep-seated nodule

Micro: sharply circumscribed nodule of dermis or subcutis; solid or vascular; related to glomus tumors, but tumor cells are spindled and smooth muscle bundles are ill-defined; rarely arises in vessels

 

Verruga peruana

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Endemic in Peru

Due to infection by Bartonella bacilliformis, a gram negative, flagellated, motile bacteria

Micro: vascular proliferative process with Rocha-Lima inclusions (large cytoplasmic inclusions of endothelial cells)

References: J Infect Dis 1992;165:1138

 

 

Other tumors of skin

Angiofibroma

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See also Soft Tissue Part 1 - cellular angiofibroma

Also called fibrous papule of face

Usually on nose of middle-aged; also corona of penis and oral cavity

Associated with tuberous sclerosis

May be derived from dermal dendrocytes

Gross: solitary, dome-shaped, firm lesion

Micro: increased blood vessels with dilated lumina, fibroblastic stroma containing stellate or multinucleated cells similar to pleomorphic fibroma; numerous hair follicles surrounded by collagen fibers; normal or slightly acanthotic epidermis with vacuolated clear cells

contributed by Drs. Asmaa Gaber Abdou and Nancy Asaad, Menofiya University, Egypt - 30 year old man with nose lesion - #1#2#3#4

DD: involuting nevus, telangiectasia, angioma (none have stellate cells or cellular stroma)

 

Atypical fibrous histiocytoma - skin-tumor chapter

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Definition: cellular, circumscribed dermal lesion of spindled fibroblasts, myofibroblasts, histiocyte-like cells and often giant cells with marked nuclear pleomorphism and mitotic figures (often atypical), but no tumor cell necrosis and no vascular invasion

Rare variant of cutaneous fibrous histiocytoma, also called pseudosarcomatous fibrous histiocytoma, dermatofibroma with monster cells

First described in 1983 (J Cutan Pathol 1983;10:327)

May be misdiagnosed as sarcoma (Histopathology 1990;17:167)

Median age 38 years (range 5-79 years), no gender preference

Solitary lesions usually arise on extremities or trunk (Am J Dermatopathol 1986;8:467); also head and neck, vulva

Occasional local recurrence (14%) or distant metastasis (AJSP 2002;26:35)

Case reports: 25 year old woman with recurrent leg lesion (Eur J Dermatol 1998;8:122), 62 year old woman with leg lesion (Tokai J Exp Clin Med 2004;29:49), 64 year old woman with 3 cm back lesion (Am J Dermatopathol 2002;24:36), 79 year old woman with leg lesion (Am J Dermatopathol 1997;19:312), 90 year old man with scrotal lesion (Ann Diagn Pathol 2003;7:370)

Treatment: complete excision with negative margins

Gross: median 1.5 cm (0.4 to 8 cm), nodular or polypoid

Micro: involvement of dermis and superficial subcutaneous tissue by pleomorphic, plump, spindle or polyhedral cells with large hyperchromatic, irregular or bizarre nuclei; background of classic fibrous histiocytoma including spindle cells with storiform pattern and entrapped thick collagen bundles, especially at the periphery; variable multinucleated giant cells, often with bizarre nuclei and foamy or hemosiderin-rich cytoplasm; 0-15 mitotic figures/10 HPF, frequently atypical; necrosis occasionally present

Micro images: enlarged cells with hyperchromatic nuclei, but no/rare mitotic figures #1#2#3

Positive stains: vimentin, CD34 (occasionally)

Negative stains: CD68, S100, keratin (MNF116), EMA; <1% positive for MIB1 (Am J Dermatopathol 2004;26:367)

DD: pleomorphic sarcoma, pleomorphic fibroma, atypical fibroxanthoma (sun damaged areas of head and neck in elderly, presents as dome shaped or ulcerated nodule, tumor cells abut epidermis without a grenz zone [relatively normal collagen forming a boundary between normal epidermis and a dermal lesion], also marked actinic elastosis, no classic features of fibrous histiocytoma)

References: Am J Dermatopathol 1987;9:380

 

Atypical fibroxanthoma [AFX] - skin-tumor chapter

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Definition: dermal variant of MFH-pleomorphic with low grade behavior

Also called intermediate fibrous histiocytoma

See also Ear chapter

Rapidly growing dome-shaped or polypoid nodule on sun-damaged areas of head and neck of elderly

Rarely presents as large mass in limb or trunk of younger individuals, or post radiation therapy

May clinically resemble carcinoma

Must exclude tumors with AFX like patterns, other lines of differentiation, significant involvement of subcutis, necrosis, vascular invasion or infiltrative margins

Poor prognostic indicators: history of immunosuppression, recurrence

Case reports: 81 year old woman with lower leg lesion (Dermatology Online Journal 14(1)), 63 year old man with metastatic tumor from eyebrow area to face (Archives 2006;130:735), 81 year old man with widespread peritoneal metastases (AJSP 2006;30:1041)

Treatment: local excision; rarely recurs or metastasizes

Gross: polypoid, ulcerated, usually small

Gross images: irregular polypoid tumor

Micro: bizarre tumor cells in hypercellular, spindly stroma with frequent mitotic figures, many atypical; also smaller fibroblastic, myofibroblastic and histiocyte-like cells with pleomorphism and angulated nuclei; histologically identical to MFH-pleomorphic but centered in dermis; background stroma appears inflammatory or reactive; pushes aside surrounding pilosebaceous units and eccrine glands; typically does not involve epidermis or subcutaneous tissue; no grenz zone; lacks classic features of fibrous histiocytoma (entrapped hyalinized collagen bundles and epidermal hyperplasia); no necrosis, no vascular invasion, no infiltrative margins

variants: clear cell (J Cutan Pathol 2006;33:343), granular cell (Am J Dermatopathol 2007;29:84)

 

Atypical fibroxanthoma (AFX) - Skin-tumor chapter (continued)

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Micro images: exophytic cellular nodule with ulcerationfascicles of atypical spindle cellstumor is limited to dermis but otherwise resembles MFH-pleomorphic with marked cellularity, prominent pleomorphism, mitotic figures and clumped chromatinmarked cellularity and pleomorphismcharacteristic bizarre cellsspindle variant has less pleomorphismspindle and epithelioid cells with atypiaulcerated tumor #1#2#3#4#5nodular spindle cell tumor #1;  #281 year old woman with lower leg lesionfig A: edge of lesion shows hyperchromatic cells next to elastotic dermis (arrow), fig B/C: atypical spindle cells and histiocytes, atypical mitotic figure (arrow), fig D: alpha-1-antichymotrypsin positivefigure 1: eyebrow primary, figures 2-4: facial metastasis (fig 4 is CD68)Factor XIIIap53

contributed by Dr. Angel Fernandez-Florez, Hospital El Bierzo, Spain - #1#2#3CD68CD117CD10AE1-AE3

Positive stains: vimentin, CD68, alpha-1-antitrypsin, alpha-1-antichymotrypsin, Factor XIIIa (focal), CD117 (Am J Dermatopathol 2008;30:34), CD99 (73%, AJCP 2002;117:126), CD10 (Australas J Dermatol 2005;46:235), calponin (30%, Virchows Arch 2002;440:404), desmin (30%), smooth muscle actin (30%)

Negative stains: keratin, EMA, S100 (although S100+ Langerhans cells may be present), HMB45 (rarely positive, J Cutan Pathol 2004;31:284), caldesmon

EM: myofibroblasts, fibroblasts and primitive mesenchymal cells

Molecular: diploid

DD: squamous cell carcinoma-spindle cell type; desmoplastic melanoma (may have focal AFX-type features and stain negative for melanocytic markers, Am J Dermatopathol 2007;29:551), atypical fibrous histiocytoma

References: eMedicine

 

Benign cystic teratoma

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Rarely presents as skin nodule

Less common than dermoid cyst

Micro: tissue components from all 3 germinal layers

 

Benign fibrous histiocytoma (superficial) - skin-tumor chapter

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Definition: storiform pattern of bland spindle cells and foamy histiocytes centered in dermis with possible extension to subcutis, with variable hemosiderin, multinucleated giant cells, chronic inflammatory cells and pseudoepitheliomatous hyperplasia

Also called dermatofibroma (particularly if sclerotic and hypocellular), dermal fibrous histiocytoma

See also Bone, Eye-Conjunctiva, Eye-Orbit and Heart chapters

Very common benign, indolent tumor of adults, common site is legs of women 20-50 years old

May be associated with trauma

Line of differentiation is uncertain

Case reports: balloon cell fibrous histiocytoma (Am J Dermatopathol 2007;29:197)

Treatment: excision; local recurrence rare even with involved margins; rarely is locally aggressive or metastatic (more common for facial lesions, extension into subcutis or cellular and mitotically active)

Gross: tan-brown, firm, mobile, painless papule < 2 cm in dermis; size varies slightly with time, may dimple upon lateral compression Gross images: inward dimpling is due to tumor binding to subcutis (arrow)

Micro: well defined but non-encapsulated; storiform pattern of spindled and bland fibroblasts and histiocyte-like cells in mid-dermis and subcutaneous tissue with infiltrative margins but sparing epidermis; spindle cells have scant cytoplasm, thin elongated nuclei with pointed ends; nuclei almost touch each other unlike smooth muscle lesions; also foamy histiocytes with variable hemosiderin, some multinucleated giant cells, branching vessels, chronic inflammatory cells, pseudoepitheliomatous hyperplasia and epidermal hyperpigmentation; may be cellular but scant mitotic figures

Micro images: tumor is often more basophilic than surrounding dermisbasophilia is due to increased cellularitysharp border between tumor and subcutissome fat may be entrapped at edge of lesion (must differentiate from infiltration of DFSP)tumor cells are mostly fibrous in this focustumor cells in this focus are composed of histiocyte-like cells and foam cellsrandomly arranged foam cells, fibroblasts and histiocyte-like cells, note that foam cells are somewhat specific for this lesionfoam cells with vacuolated cytoplasmfoam cells vary from none (top), mixed (middle) to predominating (bottom)fibroblastic cells with vacuolated cytoplasm in collagenous stromatumor with hyperplastic epithelium #1#2less common finding of predominantly foam cells and cholesterol cleftshyperplastic epidermis and sclerotic stroma #1#2#3epithelial hyperplasia-left side shows squamous/basaloid differentiation, right side shows follicular differentiationspindle cell nodulepaucicellular dermal tumorspindle cells in dense collagenous stromacellularity changes over time from subtle increase in fibroblasts (fig A) to cellular tumor (fig B/C) to sclerotic lesion (fig D-right side)vulvar tumor has uniform spindle cells confined to dermislow Ki-67 compared to DFSP and AFX

 

Benign fibrous histiocytoma (superficial) - skin-tumor chapter

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Positive stains: vimentin, Factor XIIIa; also tenascin at dermoepidermal junction (Hum Path 2001;32:50), calponin (65%); variable actin, desmin and myosin

Negative stains: CD68, CD34, bcl2; Ki-67 < 10% (Archives 2006;130:831)

Molecular/cytogenetics: often clonal

DD: Kaposi’s sarcoma, dermatofibrosarcoma protuberans, leiomyoma or leiomyosarcoma (confusion based primarily on immunostaining of fibrous histiocytomas), malignant fibrous histiocytoma, atypical fibroxanthoma, Rosai-Dorman disease

References: AJSP 2002;26:35

 

Variants of benign fibrous histiocytoma (superficial)

Aneurysmal variant of benign fibrous histiocytoma - skin-tumor chapter

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Definition: rare variant with dermal spindle cells and lakes of blood, but no endothelium

First described in 1981 (Cancer 1981;47:2053)

Early lesion also called hemosiderin variant

Similar to sclerosing hemangioma variant (which has more prominent capillaries), but differs from lung lesion called sclerosing hemangioma

Usually extremities or trunk; often rapid growth and pain (J Clin Pathol 1996;49:313)

Tends to recur after excision; rarely metastasizes

Case reports: 48 year old woman with recurrent tumor (J Clin Pathol 2004;57:312), abdominal lesion (Dermatology 2007;214:82)

Gross: blue, black or dark red; cystic

Gross images: nodule resembles melanoma

Micro: storiform pattern of fibrohistiocytic cells (as in classic fibrous histiocytoma), also large cystic spaces filled with blood, but without an endothelial lining, often bizarre cells present; may have hemangiopericytoma-like vascular pattern; may have up to 10 MF/10 HPF

Micro images: non-endothelial lined clefts or lakes containing blood #1#2fibrohistiocytic cellular proliferation with numerous blood filled cysts #1#2cysts lack an endothelial liningcysts have a squamous lining #1 (unusual finding)#2hemangiopericytoma-like pattern #1#2large amounts of hemosiderinhemosiderin plus marked sclerosis

Positive stains: vimentin, Factor XIIIa (in non cystic areas, J Dermatol 2002;29:744), NKI-C3 (60%), smooth muscle actin (45%)

Negative stains: CD31, CD34

EM: hemosiderin containing histiocyte-like cells, fibroblast-like cells and intermediate cells; no prominent proliferation of endothelial cells (Am J Dermatopathol 1995;17:179)

Cytogenetics: single case report of recurrent tumor with t(12;19) (Cancer Genet Cytogenet 2006;164:155)

DD: Kaposi’s sarcoma, angiosarcoma (APMIS 2006;114:744), melanoma

References: Histopathology 1995;26:323

 

Angiomatoid fibrous histiocytoma - skin-tumor chapter

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Definition: uncommon variant with thick pseudocapsule, marked chronic inflammatory infiltrate and cystic areas of hemorrhage

First described in 1979 (Cancer 1979;44:2147)

Not a WHO diagnosis

Formerly called angiomatoid malignant fibrous histiocytoma

Teens/young adults, often on extremities in areas of lymphoid tissue (popliteal fossa, decubital fossa) or neck

Often fever, malaise, anorexia or paraproteinemia

Considered to have low to intermediate malignant potential; may recur locally (10%), distant metastases are rare (1%)

May not actually be fibrohistiocytic - Rosai believes origin is vessel related myoid cells with inflammatory features

Case reports: mediastinal tumor (Ann Thorac Surg 2001;72:283), pleomorphic tumor with minimal angiomatoid or lymphoid features (J Cutan Pathol 2008 Apr 16 [Epub ahead of print]), cystic structures of sweat duct origin (Pathol Int 2007;57:513), 25 year old man with t(12;22) and intracerebral primary (AJSP 2008;32:478)

Gross: circumscribed, multinodular or multicystic hemorrhagic mass; median 2 cm, usually subcutaneous

Micro: thick fibrous pseudocapsule surrounds nodules of monomorphic bland spindle to ovoid eosinophilic cells, often highly cellular with hemorrhagic cyst like spaces, large aggregates of chronic inflammatory cells at edge of tumor in lymphoid follicles; may have moderate pleomorphism and mitotic activity

Cytology: histiocyte-like cells in clusters or dispersed, also eosinophilic mesenchymal fragments in bloody background with lymphocytes; tumor cells have moderate pleomorphism with abundant fragile cytoplasm and prominent nucleoli (Diagn Cytopathol 2005;33:116)

Micro images: tumor with heavy chronic inflammatory infiltrate resembles a lymph node - consider angiomatoid fibrous histiocytoma in an apparent lymph node that is out of place in soft tissuechronic inflammatory cells are accompanied by nodules of cells with round/oval nuclei that surround hemorrhagic cystic spaces #1#2cells surrounding cystic spaces are uniform with round/oval nucleisome tumors have moderate pleomorphismmediastinal tumorvarious images #1#2#3

Virtual slides: angiomatoid fibrous histiocytoma

Positive stains: CD68, desmin (40-50%), EMA (40%), CD99 (45%), actin (14%)

Negative stains: Factor VIII, CD34, keratin

Cytogenetics/molecular: usually t(12:16)(q13:p11) [ATF1-FUS] or t(12:22)(q13:q12) [ATF1-EWSR1], which is also present in GI clear cell sarcoma; also EWSR1-CREB1 (Genes Chromosomes Cancer 2007;46:1051, Clin Cancer Res 2007;13:7322

Cytogenetics/molecular images: t(12;16) karyotypediagram

DD: aneursymal variant of benign fibrous histiocytoma (no thick pseudocapsule, no inflammatory cells, no significant pleomorphism)

References: Archives 2008;132:273, Hum Path 1999;30:1336, Atlas of Genetics and Cytogenetics

 

Atypical fibrous histiocytoma - skin-tumor chapter

See above

 

Cellular variant of benign fibrous histiocytoma - skin-tumor chapter

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Definition: more cellular than usual fibrous histiocytoma, elongated cells are arranged in storiform pattern or fascicles

5% of dermal fibrous histiocytomas

Young or middle-aged adults, 60% men

Extremities or head and neck are most common

20% recur; rare metastases (AJSP 1996;20:1361)

Gross: up to 2.5 cm

Micro: fascicular or storiform but no “tight” storiform pattern, cells plumper than DFSP with eosinophilic cytoplasm and tapering nuclei; mean 3 mitotic figures/10 HPF but may be >10 MF/10 HPF, extension into subcutaneous fat in 1/3 cases; at least focal inflammatory cells, foam cells or giant cells; epidermal changes in 58%, focal central necrosis in 12%

Micro images: elongated cells are arranged in fascicles or storiform patternstoriform growthspindled tumor resembles a leiomyomadeep tumor extensionmore cellular than classic tumortumor cells are more histiocyte-like and foam cells are presenthyperplastic and acanthotic epitheliumDFSP (fig A-C) versus cellular fibrous histiocytoma (fig D-F) with H&E, CD34 and APOD (new marker)

Positive stains: vimentin, CD163, CD68 (83%, J Cutan Pathol 2006;33:353), CD63/NKI-C3 (50%), Factor XIIIa (48%), focal smooth muscle actin

Negative staining: CD34, CD117 (J Cutan Pathol 2007;34:857), desmin, S100, keratin

DD: dermatofibrosarcoma protuberans (tight storiform pattern, cells more spindly than cellular fibrous histiocytoma, CD34+ [strong], Factor XIIIa negative), leiomyosarcoma

References: AJSP 1994;18:668

 

Epithelioid variant of benign fibrous histiocytoma - skin-tumor chapter

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Definition: variant with 50% or more of tumor cells having epithelioid morphology

Uncommon, usually presents as small (1 cm or less), solitary, elevated nodule in extremities

Mean/median age 40-42 years (Br J Dermatol 1989;120:185), no gender preference

May arise from dermal microvascular unit (J Cutan Pathol 2003;30:415)

Case reports: Case of the Week #116, underlying a damaged artery (J Dermatol 2005;32:721)

Treatment: excision, only rarely recurs (Histopathology 1994;24:123)

Micro: circumscribed with uniform, medium to large angulated epithelioid cells (50%+ of tumor cells) that are often perivascular; overlying epidermal effacement, minimal inflammation, no prominent giant cells

Micro images: histiocyte-like cells with abundant cytoplasm, no/rare spindle cells #1#2#3epithelioid cells in hyalinized stromalow power - #1#2high power - #3#4vimentinFactor XIIIa+CD68 negativekeratin negativeMelanA negative

Positive stains: Factor XIIIa, vimentin

Negative stains: keratin, S100, myogenic markers, CD68, CD163

DD: solitary epithelioid histiocytoma (dense eosinophilic and glassy cytoplasm, often with spiked cytoplasmic extensions, variable nuclear grooves and multinucleated cells, frequent lymphocytes and neutrophils, CD68+, CD163+ AJSP 2006;30:521), Rosai-Dorfman disease (multiple skin lesions and adenopathy, histiocytes are S100+ and pleomorphic with emperipolesis, also prominent B cells and plasma cells), granulomas (epithelioid histiocytes in well formed clusters, surrounded by lymphocytes), melanoma (tight clustering of atypical cells, S100+, HMB45+), epithelioid sarcoma (deep seated, granuloma-type clusters with necrosis, more atypia, keratin+, CD163-), histiocytic sarcoma (marked atypia and mitotic activity)

References: AJSP 1994;18:583 

 

Juvenile xanthogranuloma - skin-tumor chapter

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Definition: benign, usually self-limited, non-Langerhans cell histiocytic disorder of skin

Also called nevoxanthoendothelioma

See also Breast-nonmalignant, Eye-uvea and Liver-tumor chapters

Proliferative disorder of dendrocytes

Uncommon (< 0.5% of pediatric tumors in one study)

Usually infants (median age 5 months) with a congenital mark, although 10-30% occur in adults; male/female = 1.4:1

Skin of face or trunk, less commonly in subcutis, skeletal muscle, eye, peripheral nerve or testis

20% of patients have multiple lesions, usually males

May spontaneously regress leaving depressed area of skin with variable hyperpigmentation

In neonates, rarely associated with giant cell hepatitis and tumor in liver and viscera, requiring chemotherapy

Case reports: Case of Week #5

Treatment: conservative excision; multisystemic disease requires Langerhans cell histiocytosis-type chemotherapy (Pediatr Blood Cancer 2008;51:130)

Gross: up to 2 cm, yellow-red, papulonodular

Gross images: 10 year old girl with 6 cm arm lesion

Micro: dense dermal infiltrate of lymphocytes, histiocytes, Touton giant cells (usually), eosinophils and neutrophils, which may extend into subcutis; late - epidermis thins out, rete ridges become elongated; deep lesions - more cellular and monotonous with fewer Touton cells

Cytology: deep seated mass - vague, granulomatous aggregates with monotonous, CD68+ histiocytic cells (Acta Cytol 2007;51:473)

Micro images:  foam cells, Touton giant cells and scattered lymphocytes #1#2adult patientlow powermedium power #1#2high power #1#2 

comparison of histiocytic giant cell types - Touton type-ring (wreath) of nuclei surrounding foamy cytoplasm with cytoplasm usually also visible around the nuclei; Langhans type-nuclei form a horseshoe arrangement, not necessary a distinct category from Touton type, foreign-body type-haphazard nuclear arrangement

 

Juvenile xanthogranuloma - skin-tumor chapter (continued)

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Positive stains: CD68, HAM56, Factor XIIIa; also NKI-C3/CD63 (60%)

Negative stains: S100, CD1a

EM: no Birbeck granules, may have cytoplasmic lipid

DD: Langerhans cell histiocytosis (more common, tumor cells have coffee bean nuclei/nuclear grooves, no Touton giant cells, are S100+ and CD1a+ and negative for CD68, HAM56 and Factor XIIIa, have Birbeck granules by EM), xanthomas (associated with hyperlipidemia, uniform collection of foam cells and variable Touton giant cells, but no other inflammatory cells)

References: AJSP 2003;27:579, AJSP 2005;29:21, eMedicine #1#2

 

Collagenous fibroma

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Also called desmoblastic fibroblastoma

Subcutaneous lesion, often with fascial involvement

Micro: bland stellate and spindled fibroblasts with collagenous or myxoid matrix

 

Connective tissue nevus - Skin-Nonmelanocytic tumors chapter

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Rare connective tissue hamartomas derived from cells of mesodermal origin

Case reports: 8 year old girl with connective tissue nevus with zosteriform distribution (Pediatr Dermatol 2007;24:557), 8 year old boy with linear connective tissue nevus (Pediatr Dermatol 2007;24:439), 25 year old man with 40 nodules/papules distributed in zosteriform pattern (Am J Dermatopathol 2007;29:303)

 

Deep benign fibrous histiocytoma- skin-tumor chapter

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Definition: benign fibrous histiocytoma of subcutaneous tissue, deep soft tissue or parenchymal organs, with no dermal involvement

Rare, <1% of fibrohistiocytic tumors

Usually adult males > 25 years

Head and neck and lower limb

Treatment: excision; may recur if incompletely excised, rare metastases

Gross: well circumscribed with pseudo-capsule, typically 4 cm, variable hemorrhage

Micro: prominent storiform pattern of uniform spindle cells with ill defined eosinophilic cytoplasm and bland, elongated or plump vesicular nuclei with no atypia; often hemangiopericytoma-like vasculature; scattered lymphocytes, either multinucleated giant cells, osteoclastic giant cells or foam cells in 59%; usually less than 5 mitotic figures/10 HPF; stroma is myxoid or hyaline; borders are non-infiltrative, with no trapping of fat cells; necrosis or angiolymphatic invasion are rare

Micro images: circumscribed tumor with no trapped fatcellular tumortumor with more fibrous stromafoam cells help distinguish from DFSPfocal storiform pattern and cellular uniformityhemangiopericytoma-like vascular pattern #1#2 

Positive stains: CD34 (40%), smooth muscle actin (38%)

Negative stains: keratin, EMA, desmin, S100

DD: solitary fibrous tumor, dermatofibrosarcoma protuberans (DFSP) (not circumscribed, usually infiltrative borders, little cellular heterogeneity, usually no foam cells, CD34+, Factor XIIIa negative, Semin Cutan Med Surg 1999;18:91)

References: AJSP 2008;32:354, AJSP 1994;18:677, AJSP 1990;14:801

 

Dermatofibrosarcoma protuberans (DFSP) - skin-tumor chapter]

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Part of WHO classification for skin tumors, not soft tissue tumors

Definition: low to intermediate grade malignancy, usually of dermis, with prominent storiform pattern of monomorphic fibroblast-like cells that invade into subcutis

Also called intermediate (borderline) fibrous histiocytoma

Slow growing, low-grade malignant neoplasm of trunk and various sites but not hands and feet

Rare, usually adults 20-40 years, more common in blacks in US (J Am Acad Dermatol 2007;56:968)

Can occur in infants (Arch Dermatol 2007;143:203) and children (J Plast Reconstr Aesthet Surg 2007 Dec 18 [Epub ahead of print])

May be a peculiar type of nerve sheath tumor since CD34 positive, or may derive from a subset of CD34 positive dermal dendritic cells                                                                                   

Locally aggressive, low rate of metastasis (only after repeated failures at local control); may progress to fibrosarcoma or MFH

Giant cell fibroblastoma is considered the juvenile variant of DFSP as it has the same translocation (AJSP 2003;27:27)

Bednar’s tumor: 5-10% of cases; pigmented variant due to dendritic cells with melanin, S100+ only in pigmented cells, HMB45 negative; associated with black patients

Case reports: atrophic variant (J Dermatol 2006;33:486), granular cell variant (AJSP 2002;26:932), myoid differentiation in fibrosarcomatous DFSP (Acta Dermatovenerol Alp Panonica Adriat 2006;15:39), sclerosing variant (Int J Dermatol 2006;45:59)

 

Dermatofibrosarcoma protuberans (DFSP) - skin-tumor chapter]

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Treatment: must excise subcutaneous fat (wide local excision with 2-3 cm margins) to prevent recurrence (Plast Reconstr Surg 2007;119:1779), three dimensional histologic evaluation of margins recommended (Ann Surg Oncol 2004;11:438), imatinib may be effective although tumor is CD117 negative (J Clin Oncol 2005;23:866)

Clinical images: papulonodular thigh lesions

Gross: nodular, polypoid or plaque-like, centered in dermis, can occur in deep soft tissue; mean 5 cm, gray-white (brown/black if melanocytes present), may appear circumscribed; hemorrhage and necrosis are rare

Micro: non circumscribed, highly cellular, “tight” storiform pattern (cells radiating in spokes at right angles around a central point that often contains a vessel) that infiltrates deeply into subcutaneous tissue and entraps fat cells to form characteristic honeycomb pattern; some tumors show areas of fascicular growth; storiform pattern may be absent in early plaque stage; cells are monomorphic, thin and spindly with scant eosinophilic cytoplasm and hyperchromatic nuclei resembling neurofibroma; may have numerous mitotic figures, but not atypical ones; collagen usually non-polarizable and thin; only mild pleomorphism and focal atypia; may coexist with giant cell fibroblastoma; usually no significant pleomorphism, no/rare histiocytes, no histiocyte-like cells, no foam cells, no giant cells or other inflammatory cells

Variants: atrophic (depressed lesion), collagenous (with central thick collagen bundles), granular cell (S100 negative), myxoid (see below), palisading, pigmented, sclerosing

Cytology: homogeneous with isolated spindle cells, often tissue fragments with storiform pattern, fibrillary stromal fragments, naked nuclei; occasional slight to moderate atypia (Diagn Cytopathol 2004;30:261)

 

Dermatofibrosarcoma protuberans (DFSP) - skin-tumor chapter]

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Micro images: small uniform cells radiating like pinwheels from central area that often has a blood vessel is characteristicuniform cells with no significant pleomorphism, minimal intercellular collagen, no/rare foam cells or giant cells, which are characteristic of benign fibrous histiocytomafine strands of collagen are presentinfiltration of fat causes tumor cells to surround fat cells #1#2#3#4-residual fat cells are in linear arrangement resembling a string of pearls, which is characteristic of DFSP but not benign fibrous histiocytomaDFSP with diminished storiform pattern but CD34+ (not shown)pigmented cells are not commonvariants-with fibrosarcoma, myxoid, pigmented

frozen sections: intradermal and extension into adipose tissue

Positive stains: CD34 (strong in 95%), vimentin; also actin (focal), ApoD (AJSP 2004;28:1063), bcl2, NKI-C3 (AJCP 1992;97:478), CD99 (J Cutan Pathol 2008 Jan 14 [Epub ahead of print])

Negative stains: Factor XIIIa (usually), keratin, EMA, S100, HMB45, desmin, CD117 (J Cutan Pathol 2007;34:857)

EM: stellate or spindle cells with long, slender, ramified cell processes joined by primitive junctions, often with subplasmalemmal densities; commonly multivesicular buds (Ultrastruct Pathol 2006;30:283)

Molecular/cytogenetics: t(17,22)(q21;q13) [collagen type 1 alpha 1 gene and platelet derived growth factor beta chain gene, OMIM #607907] found in almost all cases using multiplex RT-PCR (Hum Path 2008;39:184); also supernumerary ring chromosomes derived from t(17;22) (Oncogene 2001;20:2965), rarely other translocations (Virchows Arch 2008 Feb 6 [Epub ahead of print])

DD: benign fibrous histiocytoma (also storiform but non-infiltrative, less cellular than DFSP, Factor XIIIa positive, CD34 negative), thymoma (storiform but different location, CD34 negative), MFH-pleomorphic or atypical fibroxanthoma (storiform pattern but also moderate/marked pleomorphism and nuclear atypia)

References: eMedicine

 

Indeterminate lesions between DFSP and dermatofibroma - skin-tumor chapter

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Report of 10 tumors with features of both tumors, all Factor XIIIa+, CD34+, although in different cells (AJSP 2000;24:996)

Clinically, one recurrence at mean 22 months follow-up

Recommend complete excision

 

Myxoid variant of DFSP - skin-tumor chapter

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Definition: DFSP with 50%+ myxoid stroma

Uncommon; median age 40 years, male and female

Extremities, head and neck, trunk, anogenital region

Associated with recurrent tumor

Similar prognosis as classic DFSP (AJSP 2007;31:1371)

Case reports: Case of the Week #132

Treatment: complete excision; occasional recurrences (Am J Dermatopathol 2007;29:443)

Gross: median 3 cm, white-tan-gray-yellow, firm to gelatinous

Micro: infiltrative, often hypocellular, sheet-like, bland spindle cells with pale eosinophilic cytoplasm, spindled nuclei, no pleomorphism; stroma is myxoid with prominent thin walled vessels; diffuse infiltration of fat; also cellular areas typical of DFSP

Micro images: various images; case of the week - #1#2#3#4#5

Virtual slides: myxoid DFSP

Positive stains: CD34

Negative stains: S100, muscle markers, CD99

DD: myxoid neurofibroma (wavy nuclei, often intratumoral axons, strong S100+), superficial angiomyxoma (myxoid stroma with numerous small vessels, may be CD34+, but does not infiltrate fat, tends to be less cellular), myxoid liposarcoma (vessels are more abundant, delicate and branching, lipoblasts are prominent)

 

Sarcomas arising in DFSP - skin-tumor chapter

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Usually resembles fibrosarcoma; rarely MFH-pleomorphic

In cases with wide local excision and negative margins, 20% recur, metastatic rate varies from 0% (AJSP 2000;24:1125), to 10% (AJSP 2006;30:436)

Report as “DFSP with areas of fibrosarcoma”, indicate extent of fibrosarcomatous change, nuclear grade, level of mitotic activity

Case reports: 42 year old woman with abdominal mass (Archives 2006;130:882)

Treatment: wide local excision

Micro: in fibrosarcomatous areas, spindle cells intersect at acute angles, chromatin is coarser than usual, increased mitotic activity

Micro images: fibrosarcoma arising in DFSP - DFSP cells trap fat cells, fibrosarcoma cells are more uniform #1#2#3fibrosarcoma cells are spindled, uniform and hyperchromatic and arranged in herringbone pattern #1#2uncommon finding is myoid nodules containing cells with eosinophilic cytoplasm, present in DFSP or fibrosarcomatous areas, cells are actin+, CD34-, desmin-H&E and FISH

pleomorphic sarcoma arising in DFSP - tumor cells are pleomorphic and have granular chromatin

 

 

Dermatomyofibroma

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Also called cutaneous myofibroma

See Soft Tissue chapter - Part 1

 

Endometriosis

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Umbilical or groin lesions in women of reproductive age, or elsewhere associated with surgical scar

Micro: endometrial glands, endometrial stroma and hemorrhage; may have marked decidual changes

DD: sweat gland tumor, metastatic adenocarcinoma

 

Epithelial sheath neuroma

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Proliferation of nerve fibers coated by squamous epithelium

 

Granular cell tumor of skin

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Micro: infiltrative tumor composed of large polyhedral cells with abundant granular cytoplasm and small, central nuclei; often pseudoepitheliomatous hyperplasia

Positive stains: PAS, S100

 

Hamartoma of scalp with ectopic meningothelial elements

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Also called rudimentary meningocele

Related to meningioma of skin

Scalp nodule that appears during infancy

Micro: whorls or dissecting pattern of meningothelial cells in dermis and subcutis; often psammoma bodies and cartilage; center of lesion may have long cleft

Positive stains: vimentin, EMA

Negative stains: CD31, factor VIII related antigen

 

Histiocytoma - Skin-Tumor chapter

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Tumor of true histiocytic origin, not fibrohistiocytic

By definition, excludes Langerhans cell histiocytosis

Occurs in children, most tumors are benign

Micro: closely packed histiocytes with eosinophilic cytoplasm and variable lipid droplets, often inflammatory cells; minimal stroma; older lesions have fibrosis but no active fibroblastic proliferation

Negative stains: CD1a

EM: no Birbeck granules

 

Variants of histiocytoma

Solitary epithelioid histiocytoma - Skin-tumor chapter

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Solitary or multifocal, often with articular involvement

May have malignant behavior

Formerly called reticulohistiocytoma

Micro: usually upper dermis; mononuclear and multinuclear epithelioid histiocytes with eosinophilic to glassy cytoplasm, often with spike-like cytoplasmic extensions; nuclei are round/oval with distinct nucleoli and variable nuclear grooves and multinucleation; frequent lymphocytes and neutrophils

Micro images: dermis contains multinucleated formsdermal tumor contains mild atypia, and pushes against epidermisgiant cell reticulohistiocytoma #1#2#3 

Positive stains: vimentin, CD163, Factor XIIIa (focal), CD68 (may be focal)

Negative stains: S100, keratin, MelanA

References: AJSP 2006;30:521

 

Generalized eruptive histiocytoma - Skin-tumor chapter

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Definition: benign, papular, self-healing histiocytosis characterized by recurrent crops of small, firm, tan to red papules that appear in a symmetrical fashion on the face, trunk and arms, and may regress spontaneously

Rare, <50 cases described, most in adults

Part of spectrum of non-Langerhans cell histiocytosis

Case reports: successful treatment with PUVA (J Dtsch Dermatol Ges 2007;5:131)

Treatment: local excision, excellent prognosis

Positive stains: CD68, MAC387, alpha-1-antichymotrypsin, lysozyme

Negative stains: S100, CD1a

EM: no Birbeck granules

 

Inclusion body fibromatosis

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See Soft Tissue Chapter-Part 1

 

Inflammatory pseudotumor

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Probably does not represent an inflammatory myofibroblastic tumor

Gross: small, deep dermal nodule

Micro: central fibrosis and hyalinized vascular center with plasma cells and lymphoid follicles; usually spares epidermis

 

Keloid

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Abnormal dermal reaction to injury

Usually in blacks in earlobe

High rate of recurrence

Micro: wide bands of collagen with large, brightly eosinophilic, glassy fibers; also parallel fibroblasts and myofibroblasts; mucinous pools after steroid injection

DD: hyperplastic scar, keloidal dermatofibroma, complication of acne

 

Langerhans cell histiocytosis

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Also called histiocytosis X

Langerhans cells are derived from bone marrow, circulate freely from skin to regional lymph nodes

Solitary or multiple lesions (papules, nodules, plaques)

In infants, resembles seborrheic keratosis

Micro: (1) diffuse dermal infiltrate of Langerhans cells (large, ovoid, pale pink cytoplasm, indented bland nuclei) or

(2) clusters of Langerhans cells which resemble granulomas or (3) dermal infiltrate of cells with more foamy cytoplasm

Micro images: #1, #2, #3, #4, #5, #6

Positive stains: S100, CD1a

EM: Birbeck granules (resemble lollipops) next to nuclear membrane

 

Leiomyoma

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Divided into lesions of nipple or scrotum, pilar leiomyoma or solitary angioleiomyoma (vascular leiomyoma) usually in subcutis

May be very painful

Familial cutaneous leiomyomatosis: may be associated with renal cell carcinoma

Micro: intersecting smooth muscle fascicles; may have scattered bizarre hyperchromatic nuclei (symplastic leiomyoma); no atypia, no mitotic activity, no necrosis

Pilar leiomyoma: dermal intersecting fascicles of eosinophilic spindle cells with plump, cigar-shaped nuclei with dermal collagen bundles

Micro images: contributed by Angel Fernandez-Flores, MD, PhD, Hospital El Bierzo and Clinica Ponferrada, Spain - #1#2#3#4 

Positive stains: desmin, variable keratin and EMA

Negative stains: S100, GFAP

DD: myoepithelioma (desmin-, S100+)

 

Leiomyosarcoma

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Larger than leiomyomas

Recur, but only rarely metastasize

May be associated with HIV infection

Micro: cellular lesions of smooth muscle type cells with atypia, necrosis and mitotic activity; may have prominent vascular pattern, clear cell features, desmoplasia

 

Malignant Fibrous Histiocytoma (MFH)

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See discussion in Soft Tissue Chapter-Parts 1 and 2 under MFH-giant cell type, MFH-inflammatory, MFH-pleomorphic, myxofibrosarcoma, benign fibrous histiocytoma-angiomatoid subtype

 

Malignant peripheral nerve sheath tumor (MPNST)

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More common in deep soft tissue but also present in skin

May be associated with neurofibromatosis type I

 

Meningioma

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Nodule of scalp or vertebral axis

 

Meningioma-like tumor of skin

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Whorled spindle cells, some arranged around blood vessels

 

Neurofibroma

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Dermal tumors may cause proliferation of entrapped sweat glands or folliculosebaceous structures

Diffuse variant involves scalp as a thick plaque

Variants: localized or diffuse, intraneural, myxoid, pigmented, plexiform

 

Neurothekeoma

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Also called nerve sheath myxoma

Benign, despite atypia and mitotic figures; rarely recurs

Children or teenagers with tumors of central face, arms and shoulders; 80% female

 

Myxoid variant of neurothekeoma

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Micro: encapsulated or sharply circumscribed, nests or cords of large epithelioid cells with mild/moderate atypia in myxoid or sclerotic background; tumor cells may be close to small nerves; variable mitotic figures

Positive stains: usually NKI/C3 and microphthalmia transcription factor, type 4 collagen+, variable S100

Negative stains: usually EMA, keratin

 

Cellular variant of neurothekeoma

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Head and neck of young women

Micro: dermal or subcutaneous proliferation of nests and fascicles of tumor cells filling and expanding superficial and deep dermis; cells are epithelioid with abundant eosinophilic or amphophilic cytoplasm and overlapping cell membranes; nuclear are vesicular with dispersed chromatin; variable hyperchromatism; also spindled cells; no involvement of epidermis or junctional melanocytic proliferation; no mucinous stroma, no maturation, no circumscription

Micro images: a: H&E shows dense dermal nests of epithelioid tumor cells; b: microphthalmia transcription factor+; c: NKI/C3+

Positive stains: NKI/C3, smooth muscle actin, microphthalmia transcription factor, PGP 9.5, NSE, Leu7

Negative stains: S100, HMB45

DD: melanoma

References: Mod Path 2004;17:230 (microphthalmia transcription factor and NKI/C3)

 

Palisaded encapsulated neuroma

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Also called solitary circumscribed neuroma

Common, usually due to trauma or surgery

Small solitary papule, often in face

Micro: spindle lesion with palisading, occasionally epithelioid cells

Positive stains: S100

DD: neurofibroma, leiomyoma

 

Perineurioma

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Micro: may be epithelioid or sclerotic

Positive stains: EMA

DD: epithelioid histiocytoma, fibroma

 

Pleomorphic fibroma

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Definition: polypoid or dome-shaped cutaneous nodule with sparse cellularity and cytologic atypia of fibroblasts

Not a WHO diagnosis

First described in 1989 (AJSP 1989;13:107)

Usually trunk, extremity or head (Clin Exp Dermatol 1998;23:22)

Case reports: 66 year old woman with subungual tumor (J Cutan Pathol 2003;30:569)

Micro: resembles fibroepithelial polyp but with enlarged, bizarre, smudged, hyperchromatic nuclei, thick collagen bundles and rare mitotic figures; may be sclerotic (Am J Dermatopathol 2002;24:54) or have myxoid foci (Am J Dermatopathol 1998;20:502)

Micro images: large pleomorphic cells separated by collagenatypical cells have smudged chromatin, mitoses are absent/rare, compare to sarcomas with abnormal (but not degenerative) nuclei and frequent mitotic figures, some atypicalanal skin #1#2various images

Positive stains: vimentin, actin, CD34

Negative stains: S100

DD: atypical fibrous histiocytoma (more cellular, foam cells, hemosiderin laden macrophages, Am J Dermatopathol 1999;21:414), atypical fibroxanthoma (more cellular, more mitotic figures), giant cell fibroblastoma (young children)

 

Schwannoma

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Relatively rare in skin

Variants: intraneural, plexiform, degenerative (with ancient change), granular cell tumor, congenital neural hamartoma

 

Sclerosing fibroma

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Solitary lesions known as circumscribed storiform collagenoma

Some cases may represent folliculitis

May be associated with Cowden’s disease

Case reports: 60 year old woman with clinical basal cell carcinoma (Case of Week #190)

Micro: well circumscribed hypocellular lesion with focal heavy collagen deposition

Positive stains: CD34

 

Sinus histiocytosis with massive lymphadenopathy

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Also called Rosai-Dorfman disease

May involve skin

Usually prominent cervical lymphadenopathy

 

Striated muscle hamartoma

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Also called rhabdomyosarcomatous mesenchymal hamartoma

Benign process in infants, usually on chin or near ala of nose

May be associated with other congenital anomalies

May be multiple

Micro: central core has bundles or individual skeletal muscle fibers; also other mesenchymal elements

 

Supernumerary digit

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Acral neuroma, also called rudimentary polydactyly

On radial side of fifth digit

Micro: haphazard nerves with displaced Meissner bodies

 

Xanthoma

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Non-neoplastic

Often periarticular; also trunk or extremities of males

Associated with hyperlipidemia (primary or secondary to diabetes, hypothyroidism, myeloma, lymphoma, leukemia, obstructive liver disease)

Eruptive xanthoma: abrupt onset of crops of yellow papules with erythematous halos on extremities, which wax and wane with triglyceride and cholesterol levels

Plane xanthoma: linear yellow lesions in skinfolds, including palmar creases; associated with primary biliary cirrhosis

Tuberous/tendinous xanthoma: yellow nodules on Achilles tendon and extensor tendons of fingers

Verruciform xanthoma: papillomatous, verruca-like change of overlying epidermis

Xanthelasma: soft yellow papules and plaques in eyelid; some cases lack lipid abnormalities

Gross: nodules

Micro: fat-laden histiocytes in dermis or subcutis; also tendons, synovium and bone

 

Xanthogranuloma

Juvenile xanthogranuloma

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Also called nevoxanthoendothelioma

Proliferative disorder of dendrocytes

Uncommon (0.5% in one tumor registry), less common than Langerhans cell histiocytosis (3% incidence), the other principal histiocytic disorders of childhood

Usually infants (median age 5 months) with a congenital mark, although 10-30% occur in adults; male/female = 1.4:1

May spontaneously regress

Skin, often face or trunk, but may affect any site; less commonly in subcutis, skeletal muscle, eye, peripheral nerve, testis

20% have multiple lesions (>90% are males, usually age 6 years or less)

May be associated with glaucoma and ambylopia due to involvement of iris and ciliary body

Also associated with neurofibromatosis type I, Niemann-Pick disease, urticaria pigmentosa, CMV infection

Neonates may develop systemic disease and death due to hepatic failure (giant cell hepatitis and tumor in liver and viscera)

Treatment: excision; some lesions may involute spontaneously; relapse rate of 7%; systemic cases need multiagent chemotherapy

Gross: yellow-red, papulonodular lesions; solitary or multicentric, 1 mm to 2 cm

Micro: initially dense lymphohistiocytic proliferation of dermis with no/rare giant cells; then foamy and Touton giant cells (giant cells are often lacking in extracutaneous lesions) or other types of giant cells; also short fascicles of spindle cells; late - short fascicles of fibrohistiocytic cells and fibrosis; usually poorly circumscribed, thin epidermis with elongated rete ridges, preservation of adnexae, variable storiform pattern, lymphocytes, eosinophils, prominent vasculature; no/scattered mitotic figures, may have mild nuclear atypia

Positive stains: CD68, alpha-1-antichymotrypsin, lysozyme, vimentin, Factor XIIIa

Negative stains: S100, CD1a

EM: no Birbeck granules, may have cytoplasmic lipid

DD: Langerhans cell histiocytosis (nuclear grooves, S100+, CD1a+, Birbeck granules by EM), hyperlipidemia associated xanthomas (more uniform foamy histiocytes), reticulohistiocytoma (random distribution of multinucleated histiocytes with eosinophilic or ground glass cytoplasm), dermatofibroma (dense collagenous stroma, storiform growth pattern, pseudoepitheliomatous hyperplasia), lipoma, atheroma

References: AJSP 2003;27:579, AJSP 2005;29:21

 

Necrobiotic xanthogranulomas:

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Destructive lesions of dermis and subcutis, often involving face and trunk, and accompanied by monoclonal gammopathy or cryoglobulins

 

End of Skin - Nonmelanocytic tumors chapter