Skin Pathology & Melanoma

The skin is the most common site of human malignancy. For NEET PG, the high-yield triad is basal cell carcinoma (BCC), squamous cell carcinoma (SCC) and malignant melanoma, with Merkel cell carcinoma as a favourite "neuroendocrine of skin" add-on. Master the histological signatures, premalignant precursors, BRAF V600E in melanoma, and Breslow depth — these are the repeat-offender facts.

Overview & classification

Cutaneous neoplasms are broadly divided by the cell of origin:

Category	Cell of origin	Key tumours
Keratinocytic (non-melanoma skin cancer, NMSC)	Basal/squamous keratinocytes	BCC, SCC, actinic keratosis (premalignant), Bowen disease (SCC in situ)
Melanocytic	Melanocyte (neural crest)	Benign nevus, dysplastic nevus, malignant melanoma
Neuroendocrine	Merkel cell (mechanoreceptor)	Merkel cell carcinoma
Adnexal / appendageal	Sweat gland, sebaceous, hair follicle	Sebaceous carcinoma, etc.

High-yield: BCC is the commonest human malignancy overall; SCC is the second commonest skin cancer; melanoma is the deadliest (most skin-cancer deaths despite being far less common).

The dominant carcinogen for all three NMSC/melanoma is chronic ultraviolet (UVB) radiation, which causes characteristic C→T and CC→TT "UV-signature" transitions (pyrimidine dimers). Defective repair (xeroderma pigmentosum) massively accelerates all three.

Basal cell carcinoma (BCC)

Etiology & pathophysiology

• Arises from the basal layer of the epidermis / follicular bulge stem cells.
• Driven by aberrant Hedgehog (Hh) signalling — loss-of-function of PTCH1 (tumour suppressor) or activating SMO mutation → unchecked GLI transcription.
• Germline PTCH1 mutation → Gorlin syndrome (Nevoid BCC / basal-cell nevus syndrome): multiple BCCs, odontogenic keratocysts of the jaw, palmar/plantar pits, calcified falx cerebri, medulloblastoma risk.

Clinical features

• Pearly/translucent papule or nodule with rolled, raised borders and overlying telangiectasia; central ulceration = "rodent ulcer".
• Sun-exposed skin, classically above a line from the angle of the mouth to the ear lobe (upper face, nose, inner canthus).
• Locally invasive and destructive but virtually never metastasises.

Histology — the exam signature

• Nests/islands of basaloid cells (small, dark, scant cytoplasm) budding off the epidermis.
• Peripheral palisading of nuclei at the edge of the nests.
• Retraction (clefting) artifact between tumour nests and the surrounding myxoid stroma — a classic clue.

High-yield: "Peripheral palisading of nuclei + retraction artifact + pearly telangiectatic nodule" = BCC. It metastasises essentially never.

Management

• Surgical excision is standard; Mohs micrographic surgery for high-risk/facial lesions (tissue-sparing, margin-controlled).
• Vismodegib / sonidegib (SMO inhibitors targeting the Hedgehog pathway) for locally advanced or metastatic/Gorlin-related disease — a high-yield targeted-therapy fact.
• Imiquimod / 5-fluorouracil for superficial BCC.

Squamous cell carcinoma (SCC)

Etiology & pathophysiology

• Malignancy of keratinocytes of the stratum spinosum.
• Key driver: cumulative UVB → p53 (TP53) mutations.
• Other risk factors are the heavily tested "anything chronically injured/immunosuppressed":
  • Actinic keratosis (premalignant precursor), arsenic exposure, ionising radiation, tar/soot (scrotal SCC — Pott, the first occupational cancer), chronic non-healing wounds and burn scars (Marjolin ulcer), HPV (types 16/18 — genital/periungual), and immunosuppression (transplant patients get aggressive multiple SCCs).

Premalignant / in-situ lesions

Lesion	Description	Significance
Actinic (solar) keratosis	Rough, scaly "sandpaper" patch on sun-exposed skin; parakeratosis + atypia of lower epidermis	Direct precursor of SCC
Bowen disease	Full-thickness epidermal atypia, intact basement membrane	SCC in situ
Erythroplasia of Queyrat	Bowen disease of glans penis	SCC in situ
Keratoacanthoma	Rapidly growing crateriform nodule with central keratin plug; may regress	Well-differentiated SCC variant

Clinical & histology

• Indurated, scaly, ulcerated nodule/plaque on sun-exposed skin (lower lip, ear, dorsum of hands).
• Histology: nests of atypical keratinocytes invading the dermis, intercellular bridges, and keratin pearls (concentric whorls of keratin = degree of differentiation).

High-yield: Keratin pearls + intercellular bridges = SCC. SCC can metastasise (unlike BCC), most often to regional lymph nodes; risk is higher for lip, ear, Marjolin ulcer and immunosuppressed patients.

Management

• Surgical excision (Mohs for high-risk facial/recurrent lesions); radiotherapy for non-surgical candidates.
• Actinic keratosis treated with cryotherapy, topical 5-FU, imiquimod, or photodynamic therapy.

Malignant melanoma

The single most exam-dense topic of this set. A malignant neoplasm of melanocytes (neural-crest derived) — uncommon but the cause of most skin-cancer mortality.

Risk factors

• Fair skin, intense intermittent sun exposure / blistering sunburns, multiple/atypical (dysplastic) nevi, family history, xeroderma pigmentosum, prior melanoma.
• Familial: CDKN2A (p16) germline mutation.
• The strongest single phenotypic risk = large number of melanocytic nevi.

Molecular genetics (very high-yield)

• BRAF V600E activating mutation — present in ~40–60% of cutaneous melanomas; activates the MAPK (RAS-RAF-MEK-ERK) pathway. Most common in melanomas on intermittently sun-exposed skin of younger patients.
• NRAS, KIT (acral/mucosal melanomas), GNAQ/GNA11 (uveal melanoma).

High-yield: BRAF V600E is the most commonly tested melanoma mutation. It is the target of BRAF inhibitors (vemurafenib, dabrafenib), usually combined with MEK inhibitors (trametinib, cobimetinib) to delay resistance.

Clinical subtypes

Subtype	Frequency / site	Growth & note
Superficial spreading	Most common (~70%); trunk (men), legs (women)	Long radial growth phase
Nodular	~15–30%; any site	Vertical growth from the outset → worst prognosis early
Lentigo maligna	Elderly, sun-damaged face	Best prognosis; long in-situ (Hutchinson freckle) phase
Acral lentiginous	Palms, soles, subungual	Commonest type in dark-skinned / Indian / Asian patients; KIT mutations

High-yield: Acral lentiginous melanoma is the commonest variant in pigmented (Indian) skin — examine soles, palms and nail beds. Subungual melanoma → Hutchinson sign (pigment spreading onto the nail fold).

Clinical recognition — ABCDE rule

Asymmetry → Border irregular → Colour variegation → Diameter >6 mm → Evolution/elevation. Use this as a stepwise screening flow.

Two growth phases (mechanistic concept)

1. Radial growth phase — horizontal spread within epidermis/papillary dermis; no metastatic capacity.
2. Vertical growth phase — invasion deep into dermis; acquires metastatic potential (clonal expansion). The transition is the key prognostic event.

Diagnosis & staging

• Investigation of choice: excisional biopsy with narrow margins for histopathology (incisional/punch only if lesion too large). Shave biopsy is avoided because it destroys depth assessment.
• Histology: atypical melanocytes with prominent nucleoli, upward (pagetoid) spread into the epidermis; immunohistochemistry S-100 (sensitive), HMB-45, Melan-A/MART-1, SOX10.

Prognostic measures — Breslow vs Clark

System	What it measures	Use
Breslow thickness	Vertical depth in millimetres, from granular layer to deepest tumour cell	Single most important prognostic factor; drives T-staging
Clark level	Anatomical level of invasion (I epidermis → V subcutaneous fat)	Older, more subjective; largely superseded

High-yield: Breslow thickness (in mm) is the most powerful prognostic indicator in localised melanoma — deeper = worse. Clark level is the anatomical-layer system but is less predictive and now secondary.

Other adverse prognostic factors: ulceration, high mitotic rate, nodular type, male sex, axial location, sentinel-node positivity.

• Sentinel lymph node biopsy (SLNB) is recommended for melanomas ≥0.8 mm thick or with ulceration — the most important staging step for nodal disease.

Management — staged approach

Wide local excision (margin based on Breslow thickness: in-situ ~0.5 cm; ≤1 mm → 1 cm; 1–2 mm → 1–2 cm; >2 mm → 2 cm) → SLNB if indicated → systemic therapy for advanced/metastatic disease.

• Targeted therapy: BRAF + MEK inhibitor combination if BRAF V600E positive.
• Immunotherapy: immune checkpoint inhibitors — anti-PD-1 (nivolumab, pembrolizumab) and anti-CTLA-4 (ipilimumab); these have transformed metastatic melanoma survival.
• Melanoma is classically radioresistant; chemotherapy (dacarbazine) is now largely historical.

High-yield: Surgical margins are dictated by Breslow thickness. For systemic disease, choice = BRAF/MEK inhibitors (if mutated) ± checkpoint immunotherapy.

Merkel cell carcinoma (MCC)

• Aggressive neuroendocrine carcinoma of the skin arising from Merkel cells (touch mechanoreceptors).
• Strongly associated with the Merkel cell polyomavirus (MCPyV) and with UV exposure / immunosuppression; elderly, sun-exposed head & neck.
• Presents as a rapidly growing, painless, red-violaceous nodule.
• Histology: sheets of small round blue cells with "salt-and-pepper" chromatin; IHC positive for cytokeratin-20 (CK20) in a characteristic perinuclear "dot-like" pattern and neuroendocrine markers (chromogranin, synaptophysin, NSE); CK20+ / TTF-1 negative (distinguishes it from metastatic small-cell lung carcinoma which is CK20−/TTF-1+).
• Highly aggressive, early nodal/distant spread; managed with wide excision + SLNB + radiotherapy; avelumab (anti-PD-L1) for advanced disease.

High-yield: MCC = CK20 dot-like positivity + Merkel cell polyomavirus, neuroendocrine small-blue-cell tumour. Differentiate from small-cell lung cancer by CK20+/TTF-1−.

Key differentials & comparisons

Feature	BCC	SCC	Melanoma
Cell of origin	Basal keratinocyte	Spinous keratinocyte	Melanocyte
Key mutation	PTCH1 / Hedgehog	TP53 (p53)	BRAF V600E
Premalignant lesion	—	Actinic keratosis / Bowen	Dysplastic nevus / lentigo maligna
Histology clue	Palisading + retraction	Keratin pearls	Pagetoid atypical melanocytes, S-100
Metastasis	Almost never	Yes (LN)	Yes (early, wide)
Prognosis driver	Local destruction	Differentiation, site	Breslow depth

Pigmented-lesion differentials of melanoma: seborrhoeic keratosis (stuck-on, "horn cysts"), benign/dysplastic nevus, pigmented BCC, blue nevus, and subungual haematoma (vs subungual melanoma — Hutchinson sign helps).

Complications

• BCC: local tissue destruction, disfigurement (rodent ulcer eroding nose/orbit); recurrence if incompletely excised.
• SCC: regional lymph-node metastasis; higher metastatic risk for lip, ear, Marjolin ulcer, immunosuppressed, perineural invasion.
• Melanoma: wide haematogenous and lymphatic spread (lung, liver, brain, bone, GI tract); melanoma + breast cancer are classic causes of metastasis to unusual sites (e.g., the small bowel, heart, and the eye/choroid). Brain metastases are common and a leading cause of death.
• MCC: rapid nodal and distant spread; high recurrence.

Recently asked / exam angle

• "Peripheral palisading of nuclei" image/description → BCC (and remember it does NOT metastasise).
• "Keratin pearls" / "intercellular bridges" → SCC; precursor = actinic keratosis; Marjolin ulcer = SCC in a chronic burn scar.
• Breslow thickness = single most important prognostic factor in melanoma; expressed in mm. Clark = anatomical level.
• BRAF V600E mutation in melanoma → treated with vemurafenib/dabrafenib (+ MEK inhibitor) — recurrent NEET PG oncology-pharmacology crossover.
• Acral lentiginous = commonest melanoma in Indian/dark skin; nodular = worst early prognosis; lentigo maligna = best.
• Vismodegib targets the Hedgehog/SMO pathway in advanced BCC.
• Merkel cell carcinoma → CK20 dot-like + MCPyV, neuroendocrine.
• IHC for melanoma: S-100 (most sensitive), HMB-45, Melan-A, SOX10.
• Investigation of choice for a suspicious pigmented lesion = excisional biopsy (never shave).
• Gorlin syndrome (PTCH1) → multiple BCCs + jaw keratocysts + falx calcification.

Rapid revision

1. BCC = commonest human cancer, "pearly nodule with telangiectasia / rodent ulcer", palisading nuclei + retraction artifact, basically never metastasises.
2. BCC driver = Hedgehog pathway (PTCH1/SMO); advanced disease → vismodegib.
3. SCC = keratin pearls + intercellular bridges, can metastasise to lymph nodes.
4. Actinic keratosis → precursor of SCC; Bowen disease = SCC in situ; Marjolin ulcer = SCC in a chronic scar/burn.
5. Melanoma = deadliest skin cancer; recognise with ABCDE.
6. BRAF V600E is the key melanoma mutation → BRAF + MEK inhibitors; checkpoint inhibitors (nivolumab/pembrolizumab/ipilimumab) for metastatic disease.
7. Breslow thickness (mm) = most important prognosis factor; Clark level = anatomical layer, secondary.
8. Radial growth phase = no metastasis; vertical growth phase = metastatic potential.
9. Acral lentiginous melanoma is commonest in dark/Indian skin; nodular worst, lentigo maligna best prognosis.
10. Excisional biopsy is the investigation of choice; melanoma IHC = S-100, HMB-45, Melan-A, SOX10.
11. SLNB indicated for melanoma ≥0.8 mm or ulcerated; melanoma is radioresistant.
12. Merkel cell carcinoma = neuroendocrine, CK20 dot-like positive + Merkel cell polyomavirus, CK20+/TTF-1− distinguishes it from small-cell lung cancer.