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Skin Tumours - Robbins & Cotran Pathologic Basis of Disease

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OVERVIEW - Classification

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I. DISORDERS OF PIGMENTATION & MELANOCYTES

1. Freckle (Ephelis)

• Most common pigmented lesion of childhood in lightly pigmented individuals
• Small (1 mm to several mm), tan-red or light brown macules appearing after sun exposure
• Morphology: Hyperpigmentation results from increased melanin in basal keratinocytes - melanocytes are normal in density (may be slightly enlarged)
• Fade in winter, darken in summer - due to changes in degree of pigmentation, NOT number of melanocytes
• Note: Café au lait spots of neurofibromatosis type 1 resemble freckles histologically but are larger, arise independently of sun, and contain macromelanosomes

2. Lentigo

• Common benign localised hyperplasia of melanocytes
• Equal in both sexes, all skin types; most common in infants and children
• Small (5-10 mm), oval, tan-brown macules or patches; can involve mucous membranes
• Morphology: Linear (nonnested) melanocytic hyperplasia restricted to the cell layer immediately above the basement membrane - produces a hyperpigmented basal cell layer
• Unlike freckles, lentigines do NOT darken on sun exposure

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3. Melanocytic Nevus (Pigmented Nevus / Mole)

• Benign neoplasms associated with acquired activating mutations in RAS or BRAF (the kinase immediately downstream of RAS)
• Oncogene-induced senescence: the initial activating mutation causes a burst of proliferation followed by permanent cell cycle arrest - this is why nevi grow to a certain size and stop

• Small (<6 mm), rounded, well-demarcated lesion with uniform pigmentation
• Early: nests of round-to-oval nevus cells at DEJ (junctional component)
• Progression: cells drop off into dermis; junctional activity disappears with age
• Mature intradermal nevi: upper dermal cells may be large and pigmented; deeper cells smaller, spindle-shaped, may form neural-like structures ("neurotization")
• Maturation (cells smaller with depth) distinguishes benign nevi from melanoma

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4. Dysplastic Nevi

• Larger than common acquired nevi (>5 mm, often >10 mm)
• Irregular, pebbly surface; variable pigmentation; irregular, indistinct borders
• May occur sporadically or in familial clusters (Familial Dysplastic Nevus Syndrome / B-K mole syndrome)
• Patients with familial dysplastic nevi + family history of melanoma have a nearly 100% lifetime risk of developing melanoma

• Architectural disorder: nests of melanocytes that bridge adjacent rete ridges (confluent growth)
• Cytologic atypia: enlarged melanocytes with abundant cytoplasm and large nuclei with prominent nucleoli
• Stromal reaction: lamellar fibroplasia around elongated rete ridges and lymphocytic infiltrate
• Lentiginous proliferation: single melanocytes proliferating along the basal layer beyond the lateral margins of the compound component ("shouldering")

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5. Melanoma

• UV radiation is the main environmental cause; C→T transitions at dipyrimidine sites are the UV mutational signature
• UV suppresses cutaneous immunity (transient defect in innate immunity), reducing elimination of sun-damaged cells

• Asymmetry
• Border irregularity
• Color variation (shades of brown, black, red, white, blue)
• Diameter >6 mm
• Evolution (change over time)

1. Radial growth phase (RGP): Horizontal spread within epidermis and superficial dermis; low metastatic potential; melanoma cells lack ability to form tumour masses in dermis
2. Vertical growth phase (VGP): Invasion into deeper dermis as an expanding mass; acquisition of metastatic potential; cells have different antigenic profile from RGP cells

• Radial growth: atypical melanocytes (large cells, prominent red nucleoli, irregular nuclear contours) spreading upward (pagetoid spread) and laterally
• Vertical growth: nodular aggregates of cells with mitotic figures invading dermis
• Regression areas: fibrosis, melanophages, lymphocytes

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II. BENIGN EPITHELIAL TUMOURS

6. Seborrheic Keratosis

• Extremely common, usually in older individuals; rarely seen before age 30
• Appear suddenly in large numbers (Leser-Trélat sign) may indicate internal malignancy (usually GI adenocarcinoma)

• Round, flat-to-raised coin-like lesions with a "stuck-on" greasy appearance; tan to dark brown; sharply demarcated
• Microscopically: proliferation of basaloid (basosquamous) cells with variable melanin; formation of keratin-filled cysts (horn cysts) and pseudo-horn cysts (invaginations of surface keratin)
• Dermatosis papulosa nigra: a variant seen in ~1/3 of African American adults (clinically and histologically identical to seborrheic keratosis)
• Pathogenesis: activating mutations in FGFR3 (identical receptor mutated in achondroplasia) and/or PIK3CA in most sporadic lesions; FGFR3 also mutated in acanthosis nigricans

7. Acanthosis Nigricans

• Thickened, hyperpigmented, velvety skin in flexural areas (axillae, neck folds, groin, anogenital)
• Two types:
  • Benign (~80%): childhood/puberty onset; associated with obesity, diabetes (hyperinsulinemia → IGF1R activation), endocrine tumours, or autosomal dominant inheritance (FGFR3 germline mutation)
  • Malignant (~20%): middle-aged/older; paraneoplastic - most commonly with GI adenocarcinoma (possibly via TGF-α → EGFR activation)
• Morphology: Undulating epidermal peaks and valleys (papillomatosis), hyperkeratosis, slight basal layer hyperpigmentation - NO melanocytic hyperplasia

8. Fibroepithelial Polyp (Acrochordon / Skin Tag / Squamous Papilloma)

• One of the most common cutaneous lesions; middle-aged and older individuals
• Soft, flesh-coloured polypoid growths on neck, axillae, eyelids, groin
• Covered by normal-appearing epidermis; fibrovascular core

9. Epithelial/Follicular Inclusion Cyst

• Intradermal or subcutaneous cyst lined by stratified squamous epithelium containing laminated keratin
• Rupture causes intense foreign-body inflammatory reaction

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III. ADNEXAL (APPENDAGE) TUMOURS

• Cylindroma: lobules of basaloid cells in a "jigsaw puzzle" pattern; thought to arise from eccrine or apocrine glands
• Syringoma: small ducts lined by flattened epithelium in a dense fibrous stroma; eccrine differentiation; common on lower eyelids
• Most adnexal tumours are benign and locally excised

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IV. PREMALIGNANT & MALIGNANT EPIDERMAL TUMOURS

10. Actinic Keratosis (Solar Keratosis)

• The most common precancerous skin lesion; risk of progression to SCC is low for any individual lesion but significant in aggregate
• Caused by UV-induced DNA damage; strongly associated with cumulative sun exposure in lightly pigmented individuals
• Morphology:
  • Sandpaper-like rough, scaly erythematous lesions on sun-exposed areas
  • Atypical (dysplastic) keratinocytes in the lower epidermis with cytoplasmic pink (dyskeratotic) cells, alternating ortho- and parakeratosis
  • Elastosis (solar elastosis) in the dermis
  • Atypia confined to the lower portion of the epidermis (unlike full-thickness change of CIS/Bowen disease)
  • Bowenoid actinic keratosis: full-thickness epidermal atypia = carcinoma in situ (Bowen disease)

11. Squamous Cell Carcinoma (SCC) of Skin

• UV radiation (most important) - TP53 mutations at pyrimidine dimers are early events
• Immunosuppression (chemotherapy, organ transplantation) - reduces surveillance; HPV subtypes 5 & 8 suspected
• Industrial carcinogens (tars, oils)
• Chronic ulcers, burn scars, draining osteomyelitis
• Arsenical ingestion
• Ionizing radiation
• Xeroderma pigmentosum (defective nucleotide excision repair → rapid mutation accumulation)
• Oral: tobacco, betel nut chewing

• In situ (Bowen disease): sharp, red, scaling plaques; full-thickness epidermal atypia - atypical cells with enlarged hyperchromatic nuclei at ALL levels of epidermis
• Invasive: nodular lesions, variable keratin production (hyperkeratotic scale), may ulcerate
• Variable differentiation: well-differentiated forms make keratin pearls (squamous eddies); poorly differentiated forms show anaplastic cells with rare keratinization
• Desmosomes (intercellular bridges) may be identified

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12. Basal Cell Carcinoma (BCC)

• UV radiation + Hedgehog (HH) signalling pathway is central
• Loss of PTCH1 (Patched) function → constitutive activation of Smoothened (SMO) → Gli transcription factor activation
• PTCH1 mutations in ~90% of sporadic BCCs (often UV signature mutations)
• Gorlin syndrome (Basal Cell Nevus Syndrome): germline PTCH1 mutation → hundreds of BCCs, jaw cysts, skeletal anomalies, medulloblastoma
• Hedgehog inhibitor vismodegib (SMO inhibitor) is effective in advanced BCC

• Arise on hair-bearing skin; most on face (nose most common site)
• Pearly or translucent papules with telangiectatic vessels; may show central ulceration ("rodent ulcer")
• Microscopically: nests of basaloid cells with large oval nuclei and scant cytoplasm arising from the epidermis
• Characteristic peripheral palisading of nuclei in tumour nests + retraction artefact (clefting) between tumour nests and stroma
• Stromal mucin between tumour nests
• Subtypes: nodular (most common), superficial, morpheaform/sclerosing (most aggressive - infiltrative cords in a dense fibrous stroma; high recurrence)

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13. Merkel Cell Carcinoma

• Rare but highly aggressive neuroendocrine carcinoma of the skin
• Arises from Merkel cells (mechanoreceptors in basal epidermis) or their precursors
• Associated with Merkel cell polyomavirus (MCV) integration in ~80% of cases; UV-related TP53 mutations in most MCV-negative cases
• Seen predominantly in elderly, immunocompromised patients
• Morphology: Small blue cells with scant cytoplasm, vesicular nuclei, numerous mitoses; perinuclear dot-like cytokeratin 20 (CK20) positivity on immunostaining (paranuclear dot pattern - pathognomonic)
• High rates of lymph node metastasis; poor prognosis

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V. TUMOURS OF THE DERMIS

14. Benign Fibrous Histiocytoma (Dermatofibroma)

• Common benign dermal tumour; most common on legs of women
• Triggered by minor trauma or insect bite in some cases
• Morphology: Firm, tan-brown papule/nodule; overlying epidermis often hyperpigmented
  • Histology: whorled proliferation of spindle-shaped fibroblasts/histiocytes with collagen trapping at the periphery
  • Overlying epidermis shows basilar hyperpigmentation and pseudoepitheliomatous hyperplasia
  • "Dirty finger" pattern - irregular collagen trapping

15. Dermatofibrosarcoma Protuberans (DFSP)

• Low-grade malignant fibrous tumour of the dermis; locally aggressive, rarely metastasizes
• Pathogenesis: characteristic translocation t(17;22) creating COL1A1-PDGFB fusion gene → constitutive PDGFR-β signalling; imatinib (PDGFR inhibitor) is effective in unresectable cases
• Morphology:
  • Indurated, flesh-coloured plaque that may develop protuberant nodules
  • On sectioning: firm, fibrotic nodule
  • Histology: storiform (cartwheel/swirling) pattern of spindled cells
  • Infiltrates subcutis in a "Swiss cheese" pattern (tumour cords surrounding fat lobules) - accounts for high local recurrence after simple excision

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VI. TUMOURS OF CELLULAR MIGRANTS TO THE SKIN

16. Mycosis Fungoides (Cutaneous T-Cell Lymphoma / CTCL)

• Lymphoma of skin-homing CD4+ helper T cells; part of a spectrum of CTCLs
• Most commonly affects persons >40 years old; involves truncal areas

1. Eczema-like patches - scaly, red-brown patches (early; may persist for years)
2. Plaques - raised, scaling, indurated erythematous plaques resembling psoriasis
3. Tumour nodules - fungating, may ulcerate; correlates with systemic spread

• Infiltrate of atypical lymphocytes accumulating beneath and invading the epidermis
• Pautrier microabscesses: small intraepidermal aggregates of atypical lymphocytes (pathognomonic)
• Atypical cells have highly convoluted ("cerebriform") nuclei

17. Mastocytosis

• A spectrum of disorders characterised by accumulation of mast cells in the skin and other organs
• Most common form: urticaria pigmentosa - multiple small, reddish-brown macules and papules that urticate when rubbed (Darier sign - localized urticaria/whealing on stroking a lesion)
• Pathogenesis: Majority caused by activating mutations in c-KIT (CD117), the receptor for stem cell factor (SCF), which is the major growth factor for mast cells; most common mutation is D816V point mutation in KIT
• Morphology: Dense dermal infiltrates of mast cells with round/oval nuclei and abundant pale cytoplasm; metachromatic granules on Giemsa stain; CD117+ on immunohistochemistry
• Systemic mastocytosis can involve bone marrow, liver, spleen; may cause mediator release symptoms (flushing, hypotension, GI symptoms)

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Key Comparison Table: BCC vs SCC vs Melanoma

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Benign Epithelial Tumours of the Skin

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1. Seborrheic Keratosis

• Activating mutations in FGFR3 (a receptor tyrosine kinase) drive tumour growth in most sporadic cases
• Leser-Trélat sign: sudden appearance of large numbers of seborrheic keratoses as a paraneoplastic sign, likely due to TGF-α from tumour cells (most commonly GI carcinoma)

• Round to oval, flat, waxy, tan-to-dark-brown plaque with a velvety/granular surface; mm to several cm
• "Stuck-on" greasy appearance; sharp demarcation from adjacent epidermis
• In dark-skinned individuals: appears as multiple small dark lesions on the face - called dermatosis papulosa nigra (present in ~35% of African American adults)
• Hand lens shows small pore-like ostia filled with keratin - helps distinguish from melanoma

• Exophytic, sharply demarcated from normal epidermis
• Sheets of small basaloid cells (resembling normal basal cells) with variable melanin
• Horn cysts: small keratin-filled cysts - characteristic
• Invagination cysts: invaginations of keratin into the main tumour mass
• If irritated: whirling squamous differentiation ("eddy currents")

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2. Acanthosis Nigricans

• Undulating epidermal peaks and valleys (papillomatosis)
• Hyperkeratosis
• Slight basal layer hyperpigmentation - but NO melanocytic hyperplasia (unlike lentigines)

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3. Fibroepithelial Polyp (Acrochordon / Skin Tag / Squamous Papilloma)

• One of the most common cutaneous lesions
• Soft, flesh-coloured, pedunculated (polypoid) growths on neck, axillae, eyelids, groin
• Microscopically: normal-appearing epidermis overlying a loose fibrovascular core - no atypia

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4. Epithelial / Follicular Inclusion Cyst

• Intradermal or subcutaneous cyst lined by stratified squamous epithelium filled with laminated keratin
• Rupture of the cyst wall → intense foreign-body giant cell inflammatory reaction

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Premalignant & Malignant Epidermal Tumours

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5. Actinic Keratosis (Solar Keratosis) - Premalignant

• Caused by cumulative UV-induced DNA damage in lightly pigmented individuals
• Feels like sandpaper; rough, scaly, erythematous lesion on sun-exposed skin

• Atypical (dysplastic) keratinocytes confined to the lower layers of the epidermis (unlike SCC in situ where atypia is full-thickness)
• Dyskeratotic (pink) cells, alternating ortho- and parakeratosis
• Solar elastosis in dermis (degenerated elastic fibres due to UV)
• When atypia becomes full-thickness → Bowen disease (SCC in situ)

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6. Squamous Cell Carcinoma (SCC)

• UV radiation (most important) - TP53 mutations at pyrimidine dimers are early events
• Immunosuppression (organ transplant, chemotherapy)
• Industrial carcinogens (tars, oils)
• Chronic ulcers, burn scars, draining osteomyelitis
• Arsenical ingestion, ionizing radiation
• Xeroderma pigmentosum (defective nucleotide excision repair → rapid mutation accumulation)
• HPV subtypes 5 & 8 in epidermodyplasia verruciformis

• In situ (Bowen disease): sharply defined red scaling plaque; full-thickness epidermal atypia - enlarged hyperchromatic nuclei at ALL layers of epidermis
• Invasive SCC: nodular, hyperkeratotic scale (variable keratin production), may ulcerate
• Well-differentiated: keratin pearls (squamous eddies); intercellular bridges (desmosomes) visible
• Poorly differentiated: anaplastic cells, rare keratinization

• <5% metastasize to regional nodes
• Despite low metastatic rate, causes ~8,000 deaths/year in the US (comparable to metastatic melanoma) due to sheer frequency

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7. Basal Cell Carcinoma (BCC)

• PTCH1 (Patched-1) normally inhibits Smoothened (SMO)
• Loss-of-function mutations in PTCH1 (~90% of BCCs) → constitutive SMO activation → Gli transcription → tumour growth
• UV signature mutations in PTCH1
• Gorlin syndrome (Basal Cell Nevus Syndrome): germline PTCH1 mutation → hundreds of BCCs + jaw cysts + skeletal anomalies + medulloblastoma
• Vismodegib (SMO inhibitor) effective in advanced/unresectable BCC

• Arises on hair-bearing skin; most common site = face (especially nose)
• Grossly: pearly or translucent papule with telangiectatic vessels; may develop central ulceration ("rodent ulcer")
• Histology: nests and cords of basaloid cells (large oval nuclei, scant cytoplasm) emanating from the epidermis
• Peripheral palisading of nuclei at the edge of tumour nests
• Retraction artefact (clefting) between tumour nests and surrounding stroma - characteristic
• Mucin-rich stroma between nests

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8. Merkel Cell Carcinoma

• Rare, highly aggressive neuroendocrine carcinoma of the skin
• Arises from Merkel cells (mechanoreceptors in basal epidermis)
• ~80% associated with Merkel cell polyomavirus (MCV) integration into the tumour genome; remaining ~20% have UV-related mutations
• Predominantly in elderly and immunocompromised patients
• Histology: small blue cells, scant cytoplasm, vesicular nuclei, many mitoses
• CK20 immunostain: paranuclear dot-like positivity - pathognomonic
• High rates of lymph node metastasis; poor prognosis

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Quick Comparison: Benign vs Malignant Epithelial Tumours

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