Skin-Nonmelanocytic tumors

Last revised 20 December 2009 Last major update November 2008 Copyright (c) 2005-2009, PathologyOutlines.com, Inc. Printer Friendly Versions (HTML, PDF)

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, Bowens disease, Pagets disease

Carcinoma (non adnexal): adenoid cystic carcinoma, adenoid

squamous cell, adenosquamous, basal cell, lymphoepithelioma-like, Merkel cell, 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, Hodgkins, HTLV-1, intravascular, Jessners 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), WoringerKolopp disease

Vascular tumors: acquired angioma, angiokeratoma, angiosarcoma,

bacillary angiomatosis, benign hemangioendothelioma, benign lymphangioendothelioma, glomus, hemangioma, hemangioendothelioma and subtypes, intravascular papillary endothelial hyperplasia, Kaposis sarcoma,

Kimuras 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

Primary references
AJCC Cancer Staging Manual (6th 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: Ackermans 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
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

Children 0-3 years Gross: small white maculopapular lesions Micro: large pale cells (Tokers cells), single or in clusters Positive stains: CEA, EMA, low molecular weight keratin DD: Pagets disease

Cutaneous horn
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
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
top 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

top 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
top 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
top 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
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
top Usually face, solitary or multiple Lined by sweat duct-like epithelium which may have apocrine features

Bronchogenic cyst
top Lesion of suprasternal notch, discovered shortly after birth Probably derived from branchial clefts, not bronchi Micro: lined by bronchial (pseudostratified, ciliated columnar) epithelium

Cystadenoma
top 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
top Resemble keratinous cysts of epidermal type, but also have hair adnexae Usually face of children along embryonic closure lines

Hidrocystoma
top 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
top See below

Pigmented follicular cyst

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

Steatocystoma
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

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
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
Eccrine sweat gland tumors may exhibit apocrine differentiation Pure apocrine tumors are rare

Apocrine tubular adenoma

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

Hidradenoma papilliferum
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
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

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
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 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

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
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
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
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
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 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 Pagets 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), Bowens disease (more atypical keratinocytes, more severe architectural abnormalities), Pagets 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
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: 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

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

Mucinous carcinoma
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
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 Severe cytologic atypia and high mitotic rate

Papillary eccrine adenoma

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Usually distal extremities of blacks Recur locally, dont 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
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

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

Uncommon Usually adults Difficult to diagnose; may be life threatening Low grade: microcystic carcinoma, adenoid cystic carcinoma, mucinous carcinoma, extramammary Pagets 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
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 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 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
top 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

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
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; nonlamellated keratin within the cyst, often with nucleated cells, often calcified Micro images: Trichilemmal type #1; #2; #3

Keratoacanthoma
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 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
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
top 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
top Also called tricholemmoma Benign Cowdens 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 top 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
top 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 top 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
top 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
top 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 Dariers disease Micro: follicular acantholysis and dyskeratosis

Adnexal tumors-sebaceous glands

Nevus sebaceous of Jadassohn
top 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
top 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
top 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

top Most common sebaceous gland lesion Usually elderly patients on nose or cheeks Micro images: #1; #2

Premalignant or noninvasive
Carcinoma in situ-general
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 Bowens 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

top

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
top 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

Bowens disease

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

Pagets disease (extramammary)

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 Pagets 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 Bowens disease, pagetoid actinic keratosis, melanocytic lesions, metastatic epidermotropic carcinomas, clear cell papulosis Carcinoma (non-adnexal)
Adenoid cystic carcinoma
top Micro: cribriform and tubular structures in dermis DD: metastases from salivary gland tumors, basal cell carcinoma

Adenoid squamous cell carcinoma

top

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
top Rare, aggressive Micro: squamous differentiation and mucin production

Basal cell carcinoma

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)

Basal cell nevus syndrome: also called Gorlins 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) 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 Bowens 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
top 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

top 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 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, neuronspecific 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

Metastatic carcinoma to skin

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
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 welldifferentiated), metastatic salivary gland tumor (usually high grade), mucinous metaplasia

Small cell neuroendocrine carcinoma

May be a variant of Merkel cell carcinoma or a metastases

Spindle squamous cell carcinoma

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

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
top 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

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) 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 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: 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) NX: regional lymph nodes cannot be assessed N0: no regional lymph node metastasis N1: regional lymph node metastasis Distant metastasis (M) top MX: distant metastasis cannot be assessed M0: no distant metastasis M1: distant metastasis Stage grouping top Stage 0: Stage I: Stage II: Stage III: Tis N0 M0 T1 N0 M0 T2-T3 N0 M0 T4 N0 M0 or any T N1 M0

Stage IV: Any T, Any N, M1

Lymphoma and related disorders

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

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

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, Hodgkins-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
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

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

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
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)

Follicular lymphoma-primary cutaneous

Mean age 64 years; localized papulonodular lesions, often in head, neck and trunk, with excellent prognosis By definition, arises in skin with no known extracutaneous disease within 6 months of initial diagnosis; has follicular growth pattern and germinal center cytology ( AJSP 2001;25:875) In Scottish Highlands, cutaneous B cell lymphomas (all subtypes) are associated with Borrelia burgdorferi infection (Lyme disease, AJSP 2000;24:1279) Indolent behavior, although cutaneous relapses are common; similar relapse rate as stage 1 nodal follicular lymphoma, but more likely to attain complete remission (AJSP 2002;26:733) Gross: solitary or grouped papules, plaques or tumors Micro: nodular, diffuse or floral-like pattern (32%, with IgD+ mantle zone) of centrocytes (cleaved follicular cells) and centrocytes (large transformed cells) Positive stains: CD19, CD20, CD79a, bcl6+ and usually CD10+ centrocytes and centroblasts, usually bcl2+ in follicular and interfollicular/diffuse areas ( AJSP 2001;25:732); similar to follicular lymphoma otherwise Negative stains: CD5 Molecular: t(14;18)+ in only 20-30% by PCR (Mod Path 2001;14:913; Mod Path 2001;14:828, AJSP 2000;24:694); FISH may be more specific than PCR due to bystander cell positivity for t(14;18) (AJSP 2004;28:748) DD: secondary follicular lymphoma, cutaneous MALT lymphoma (bcl2+, usually negative for bcl6 and CD10 although colonized follicles [CD21+] are bcl6+, AJSP 2001;25:732)), lymphoid hyperplasia (bcl2 doesnt stain germinal centers) References: AJSP 2005;29:69

Hodgkins lymphoma of skin

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)

Rapid clinical course Micro: high grade, spares epidermis, may be angiocentric

Intravascular lymphoma
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

Jessners lymphocytic infiltration of skin

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
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; #4; CD45; CD43; CD117; CD68 Positive stains: myeloblasts - chloroacetate esterase (Leder stain), myeloperoxidase References: eMedicine

Lymphoid hyperplasia
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
top 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+, CD56type B: relatively small hyperchromatic lymphocytes with complex nuclear membranes; CD3+, CD4+, CD8-, CD20-, CD30-, CD56Micro images: contributed by Angel Fernandez-Flores, MD, PhD, Hospital El Bierzo and Clinica Ponferrada, Spain - type A - #1; #2; #3; CD30 Molecular: T cells are clonal, but this doesnt predict transformation to lymphoma DD: arthropod bite

Mantle zone lymphoma

top 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

top 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
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 top 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 top 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 Pautriers 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 top

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

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

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 Hodgkins 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: Hodgkins 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
< 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) 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, dont fit other categories References: AJSP 2004;28:719

Woringer-Kolopp disease
top 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 Pagets disease type pattern

Vascular tumors
Acquired (tufted) angioma
Also called Nakagawas 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
Micro images: contributed by Angel Fernandez-Flores, MD, PhD, Hospital El Bierzo and Clinica Ponferrada, Spain - #1; #2; #3

Angiosarcoma

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 Kaposis 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
top Due to infection by Bartonella henselae May involve soft tissue, lymph nodes, internal organs May coexist with Kaposis 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, Kaposis sarcoma

Benign (infantile) hemangioendothelioma

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

Benign lymphangioendothelioma
Also called acquired progressive lymphangioma

Gross: bruise-like lesion Micro: anastomosing vascular channels, but no atypia DD: angiosarcoma, Kaposis sarcoma

Glomus tumor
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
Childhood tumors are often malformations, not neoplasms Capillary hemangioma 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, Kaposis sarcoma, angiosarcoma, hemangioendothelioma Cavernous hemangioma Markedly dilated dermal vessels, may elevate overlying epidermis, which may be atrophic Associated with Maffuccis syndrome, blue rubber bleb nevus syndrome, Kasabach-Merritt syndrome Epithelioid hemangioma 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), Kimuras disease (usually Asians with elevated serum eosinophils and IgE, usually regional lymphadenopathy) Glomeruloid hemangioma Associated with Castlemans disease and POEMS syndrome (Polyneuropathy, Organomegaly, Endocrinopathy, Mprotein 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 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 Spontaneously involutes, not associated with Kasabach-Merritt phenomenon Positive stains: GLUT1+, LewisY+ DD: kaposiform hemangioendothelioma (doesnt involute, GLUT1-, LewisY-, often associated with Kasabach-Merritt phenomenon) Microvenular hemangioma 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, Kaposis sarcoma (irregularly anastomosing vascular spaces, plasma cells, hyaline globules, fascicles of spindle cells)

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

Hemangioendothelioma and subtypes

Epithelioid hemangioendothelioma top Superficial and soft tissues in adults Micro: nests and cords of cells with abundant eosinophilic cytoplasm and prominent intracytoplasmic lumina DD: carcinoma Kaposiform hemangioendothelioma top 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 Kaposis 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 top 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; #5; CD31 #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 Dermis and subcutis Frequent local recurrences, only rare metastases Micro: thin-walled, large cavernous blood vessels and spindle cells

Intravascular papillary endothelial hyperplasia

Also called Massons 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

Kaposis sarcoma

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 Castlemans disease, reactive angioendotheliomatosis, plasmacytic lymphoma Classic Kaposis 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 Kaposis 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 Castlemans 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 slitlike 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)

Kimuras disease
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
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
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
top 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
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
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
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

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

top 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)

top Micro images: exophytic cellular nodule with ulceration; fascicles of atypical spindle cells; tumor is limited to dermis but otherwise resembles MFH-pleomorphic with marked cellularity, prominent pleomorphism, mitotic figures and clumped chromatin; marked cellularity and pleomorphism; characteristic bizarre cells; spindle variant has less pleomorphism; spindle and epithelioid cells with atypia; ulcerated tumor #1; #2; #3; #4; #5; nodular spindle cell tumor #1; #2; 81 year old woman with lower leg lesion; fig 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 positive; figure 1: eyebrow primary, figures 2-4: facial metastasis (fig 4 is CD68); Factor XIIIa; p53 contributed by Dr. Angel Fernandez-Florez, Hospital El Bierzo, Spain - #1; #2; #3; CD68; CD117; CD10; AE1-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

Rarely presents as skin nodule Less common than dermoid cyst Micro: tissue components from all 3 germinal layers

Benign fibrous histiocytoma (superficial) - skin-tumor

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 dermis; basophilia is due to increased cellularity; sharp border between tumor and subcutis; some fat may be entrapped at edge of lesion (must differentiate from infiltration of DFSP); tumor cells are mostly fibrous in this focus; tumor cells in this focus are composed of histiocyte-like cells and foam cells; randomly arranged foam cells, fibroblasts and histiocyte-like cells, note that foam cells are somewhat specific for this lesion; foam cells with vacuolated cytoplasm; foam cells vary from none (top), mixed (middle) to predominating (bottom); fibroblastic cells with vacuolated cytoplasm in collagenous stroma; tumor with hyperplastic epithelium #1; #2; less common finding of predominantly foam cells and cholesterol clefts; hyperplastic epidermis and sclerotic stroma #1; #2; #3; epithelial hyperplasia-left side shows squamous/basaloid differentiation, right side shows follicular differentiation; spindle cell nodule; paucicellular dermal tumor; spindle cells in dense collagenous stroma; cellularity 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 dermis; low Ki-67 compared to DFSP and AFX 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: Kaposis sarcoma, dermatofibrosarcoma protuberans, leiomyoma or leiomyosarcoma (confusion based primarily on immunostaining of fibrous histiocytomas), malignant fibrous histiocytoma, atypical fibroxanthoma, RosaiDorman disease References: AJSP 2002;26:35 Variants of benign fibrous histiocytoma (superficial) Aneurysmal variant of benign fibrous histiocytoma - skin-tumor chapter top

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; #2; fibrohistiocytic cellular proliferation with numerous blood filled cysts #1; #2; cysts lack an endothelial lining; cysts have a squamous lining #1 (unusual finding); #2; hemangiopericytoma-like pattern #1; #2; large amounts of hemosiderin; hemosiderin 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: Kaposis sarcoma, angiosarcoma (APMIS 2006;114:744), melanoma References: Histopathology 1995;26:323 Angiomatoid fibrous histiocytoma - skin-tumor chapter top 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 tissue; chronic inflammatory cells are accompanied by nodules of cells with round/oval nuclei that surround hemorrhagic cystic spaces #1; #2; cells surrounding cystic spaces are uniform with round/oval nuclei; some tumors have moderate pleomorphism; mediastinal tumor; various 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) karyotype; diagram 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

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 pattern; storiform growth; spindled tumor resembles a leiomyoma; deep tumor extension; more cellular than classic tumor; tumor cells are more histiocytelike and foam cells are present; hyperplastic and acanthotic epithelium; DFSP (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 top 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; #3; epithelioid cells in hyalinized stroma; low power - #1; #2; high power - #3; #4; vimentin; Factor XIIIa+; CD68 negative; keratin negative; MelanA 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

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; #2; adult patient; low power; medium power #1; #2; high 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 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
top 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

top 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

top 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 fat; cellular tumor; tumor with more fibrous stroma; foam cells help distinguish from DFSP; focal storiform pattern and cellular uniformity; hemangiopericytomalike 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]

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) Bednars 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 ]
top 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) Micro images: small uniform cells radiating like pinwheels from central area that often has a blood vessel is characteristic; uniform cells with no significant pleomorphism, minimal intercellular collagen, no/rare foam cells or giant cells, which are characteristic of benign fibrous histiocytoma; fine strands of collagen are present; infiltration 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 histiocytoma; DFSP with diminished storiform pattern but CD34+ (not shown); pigmented cells are not common; variants-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
top 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

top 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

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; #3; fibrosarcoma cells are spindled, uniform and hyperchromatic and arranged in herringbone pattern #1; #2; uncommon 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
top Also called cutaneous myofibroma See Soft Tissue chapter - Part 1

Endometriosis
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
Proliferation of nerve fibers coated by squamous epithelium

Granular cell tumor of skin

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

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

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

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 forms; dermal tumor contains mild atypia, and pushes against epidermis; giant 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 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

See Soft Tissue Chapter-Part 1

Inflammatory pseudotumor
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
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

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 Positive stains: S100, CD1a EM: Birbeck granules (resemble lollipops) next to nuclear membrane

Leiomyoma
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
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)

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)

More common in deep soft tissue but also present in skin May be associated with neurofibromatosis type I

Meningioma
Nodule of scalp or vertebral axis

Meningioma-like tumor of skin

Whorled spindle cells, some arranged around blood vessels

Neurofibroma

Type I neurofibrom atosis (skin)

neoplasma

102

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
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

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 top 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

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
Micro: may be epithelioid or sclerotic Positive stains: EMA DD: epithelioid histiocytoma, fibroma

Pleomorphic fibroma
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 collagen; atypical cells have smudged chromatin, mitoses are absent/rare, compare to sarcomas with abnormal (but not degenerative) nuclei and frequent mitotic figures, some atypical; anal skin #1; #2; various 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
Relatively rare in skin Variants: intraneural, plexiform, degenerative (with ancient change), granular cell tumor, congenital neural hamartoma

Sclerosing fibroma
Solitary lesions known as circumscribed storiform collagenoma Some cases may represent folliculitis May be associated with Cowdens disease Micro: well circumscribed hypocellular lesion with focal heavy collagen deposition Positive stains: CD34

Sinus histiocytosis with massive lymphadenopathy

Also called Rosai-Dorfman disease May involve skin Usually prominent cervical lymphadenopathy

Striated muscle hamartoma

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
Acral neuroma, also called rudimentary polydactyly On radial side of fifth digit Micro: haphazard nerves with displaced Meissner bodies

Xanthoma
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

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

Melanocytic Nevus

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Definition
A localized, benign melanocytic proliferation of the skin.

Clinical Features

Usually acquired (clinically apparent after first year of life) Most appear between second and sixth years Nearly all manifest by age 20 years Every Caucasian has variable number (average 2030)1 Intradermal nevus: o common adult type of nevus Multiple lentigines in: o PeutzJeghers syndrome o centrofacial lentiginosis o Moynahan's syndrome o LEOPARD syndrome o Carney's syndrome o xeroderma pigmentosum2

Pathogenesis

Predictable evolution:

rarely upset by dramatic event, such as: spontaneous resolution activation malignant transformation3 o proliferative activity roughly correlates with age4 Straddle fence between malformation and neoplasia: o cellular blue nevi and Spitz nevi: morphologic and behavioral features consistent with true neoplastic process o usual compound nevi: distinctive organoid configuration (with adnexal participation) suggesting developmental abnormality5 (may represent atavistic structures) exhibit clonality and loss of heterozygosity (in favor of neoplastic nature)6,7 o ordinary compound mole may have dual origin from: intraepidermal melanoblasts (some of which become intradermal) deeper cells with features strongly suggesting differentiation toward specialized peripheral nerve structures (not necessarily schwannian related)812 supported by ultrastructural, histochemical, immunohistochemical, and experimental studies Lentigo simplex: o generally regarded as first phase in evolution of common nevi (nevi incipientes') o therefore a precursor of junctional nevus Percentage of nevi with junctional changes decreases as patient age increases13
o

Gross Pathology

Usually in skin: o most commonly head, neck, and trunk Also any mucosal membrane covered by squamous epithelium Every size, shape, and degree of pigmentation May be more or less hairy Junctional nevus: o flat or slightly elevated o nonhairy o fawn colored Intradermal nevus: o papillomatous, pedunculated, or flat o often hairy Clusters of benign nevus cells can be seen in capsule of lymph node: o most commonly axillary14,15 o do not penetrate node o should not be confused with metastatic malignant melanoma (particularly likely when specimen from axillary lymphadenectomy for cutaneous melanoma)

Histopathology
Classification

Variously classified Location of melanocytes: o best system definite relationship to likelihood of malignant transformation

Junctional Nevus

Melanocytic proliferation restricted to basal portion of epidermis (junctional area) Characterized by melanocytic nests (theques') on epidermal side of dermoepidermal junction (Fig. 1

Fig. 1: Typical junctional nevus. Two large theques of melanocytes expand the basal layer of the epidermis.
)

Lentigo Simplex

Consists of proliferation of melanocytes in epidermal basal layer Differs from junctional nevus because melanocytes are individually arranged rather than in thques

Intradermal Nevus

All melanocytes are in dermis Small nests or bundles of melanocytes: o in upper dermis o tend to concentrate around pilosebaceous units Degree of pigmentation and cellularity vary widely Lower half: o tends to be less cellular and less pigmented o composed of spindle cells with fibrillary cytoplasm arranged in bundles16 o sometimes structures resembling tactile (WagnerMeissner) corpuscles o immunohistochemically different from neurofibromas,17 but may represent neural component of nevus (hard to dismiss these highly organoid structures as result of atrophy)18 o occasionally, a storiform pattern of growth, establishing link with dermal tumor known as storiform neurofibroma19 Multinucleated melanocytes: o scattered throughout nevus, particularly upper half o often characteristic mulberry shape Ultrastructurally and immunohistochemically, cells surrounded by basement membrane components20,21

Compound Nevus

Combines features of junctional and intradermal nevi (i.e. epidermal and dermal components) Melanin deposition: o highly variable amount, as for other types of nevi o sometimes abundant (hypermelanotic nevus)22 o generally in superficial half, particularly intraepidermal portion Lymphocytes and other mononuclear cells:

o o

as with other nevi, may be at base23 tend to be in clusters (rather than bandlike quality more common in melanoma)

Variations Depending on Site

Palms and soles: o nearly always junctional24 o tend to remain junctional throughout life o most intraepidermal melanocytes concentrated in skin furrows25 Scalp: o often prominent neural component Vulvar skin (vulvar or genital nevi): o tend to have larger, more irregularly shaped, and more irregular theques than elsewhere o tend to be accompanied by lentiginous melanocytic hyperplasia o can be misdiagnosed as malignant melanomas26

Morphologic Variations in Typical Compound or Intradermal Nevi

Marked sclerosis (desmoplastic or sclerotic nevus)27 Nodular myxoid changes28 Amyloid deposition Elastosis Metaplastic bone in the stroma Folliculitis and abscess formation Association with keratinous cysts29 and psammoma bodies Cytoplasmic vacuolization (sometimes resulting in lipoblast-like cells) Oncocytic changes30 Eczematous or focal acantholytic keratotic changes in overlying epidermis31,32

Diagnosis

Nevus (L. naevus, birthmark): o can be properly applied to any circumscribed growth of skin of congenital origin o usually used as synonym for mole (L. moles, a shapeless mass) to designate localized benign abnormality of the melanocytic system

Malignant Melanoma

Definition
Malignant cutaneous neoplasm derived from dermal melanocytes and whose prognosis is related to depth of dermal invasion (thickness).

Clinical Features

Most: in head and neck area o on lower extremities (particularly in females1,2 Rarely: o subungual region (melanotic whitlow)36 o palms and soles Most: o white people: particularly if: fair complexion red hair tend to burn or develop freckles after exposure to sunlight7 o arise after puberty: Also occur in: children:5,812 same microscopic pattern as adults (so usually distinguishable from Spitz nevi)1315 black people: usually in: palms soles nail beds mucous membranes May be: multiple:1618 distinguish from nevus activation19 hereditary:20 often numerous atypical melanocytic lesions (dysplastic nevi)21,22 associated with: generalized melanosis23,24 lesions resembling vitiligo25
o

Pathogenesis

Most:
o o

associated with sunlight exposure thought to be due to ultraviolet radiation33 Immunologic factors probably play important but ill-understood role

Gross Pathology
Four Categories3945

Melanoma arising in Hutchinson's freckle (lentigo maligna melanoma) Superficially spreading melanoma Nodular melanoma Acral lentiginous melanoma

Histopathology

If typical, easily identified by: o junctional activity o prominent melanin pigmentation o invasion of surrounding tissue o marked cytologic atypia o nuclear grooves, folds, and pseudoinclusion o large eosinophilic nucleoli o abundant mitotic figures (some atypical)53 Notorious for great variability:54,55 o cells may be: epithelioid spindle shaped (Fig. 2

Fig. 2: Malignant melanoma in region of Achilles tendon showing prominent spindling. This is a common finding in tumors at this site.
)
extremely bizarre cell size can range from: small (lymphocyte-like)56 to giant multinucleated forms (Fig. 3

Fig. 3: Melanoma containing highly anaplastic tumor cells.

cytoplasm may be: eosinophilic basophilic foamy signet ring type57,58 rhabdoid5961 oncocytic completely clear (balloon cell melanoma)62 melanin may be: abundant: sometimes so massive as to obscure cellular details (animal type)63 scanty absent (amelanotic melanoma) pattern of growth may be: pseudoglandular pseudopapillary peritheliomatous hemangiopericytoma-like resembling Spitz nevus (spitzoid melanoma) trabecular (Fig. 4

Fig. 4: Prominent trabecular pattern of growth in melanoma.

)

verrucous (nevoid or pseudonevoid melanoma)55,6467 (Figs 5 and 6

Fig. 5: Malignant melanoma with nevoid pattern of growth. Low-power view showing a polypoid configuration suggestive of a benign intradermal nevus. (Slide contributed by Dr Paul Duray, Bethesda, MD)

Fig. 6: Malignant melanoma with nevoid pattern of growth. High-power view showing only minimal atypicality of the tumor cells. This tumor recurred locally and eventually metastasized to regional lymph nodes. (Slide contributed by Dr Paul Duray, Bethesda, MD)
)
o

may be: marked fibroblastic response myxoid changes68,69 (Fig. 7

Fig. 7: Myxoid changes in malignant melanoma. This secondary alteration is more common at metastatic sites, but can also be seen in the primary lesion.
)

metaplastic or neoplastic bone and cartilage70,71 osteoclast-like giant cells72,73 pseudoepitheliomatous hyperplasia of overlying epidermis74 occasionally formations suggesting differentiation toward: Schwann cells tactile corpuscles ganglion cells other neuroid structures7577 Sometimes lymph node and other metastases acquire appearance practically indistinguishable from that of malignant peripheral nerve sheath tumor78

Special Stains and Immunohistochemistry

Useful for distinguishing normal or neoplastic melanocytes from other cell types None of great use for distinguishing between benign and malignant melanocytic neoplasms Melanin stains: o silver based rely on reducing properties of melanin granules these argentaffin stains (FontanaMasson is most widely used) are particularly useful for: detecting finely dispersed granules not immediately apparent in H&E sections demonstrating (when used with iron stain) that brown pigment in routine sections is melanin rather than hemosiderin

Electron Microscopy

Contributes to confirmation of diagnosis through identification of: o melanosomes (Figs 1213

Fig. 12: Electron microscopy of superficially spreading melanoma of right ear demonstrating junctional melanocytes among keratinocytes. ( $3850). Inset: Stage 3 melanosomes in neoplastic cells. ( $25,270)

Fig. 13: Stage 2 and stage 3 melanosomes with characteristic lattice arrangement in malignant melanoma of skin metastatic to lung ( $81,000) )
o less specific premelanosomes8688 Occasionally well-developed microvilli similar to those in adenocarcinoma cells89