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PA33.1-3 | Skin Cancers: BCC, SCC & Melanoma — SDL Guide (Part 2)

Basal Cell Carcinoma (BCC) — Pathogenesis and Pathology (PA33.2)

Basal cell carcinoma (BCC) is the most common malignant tumour in humans — accounting for approximately 75–80% of all skin cancers. It arises from the pluripotent basal keratinocytes (or the outer root sheath of hair follicles).

Risk factors:

Risk Factor	Notes
UV/sun exposure	Most important — especially intermittent intense exposure
Fitzpatrick type I–II	Fair skin, blue eyes, burns easily
Gorlin syndrome (naevoid BCC syndrome)	Autosomal dominant; PTCH1 germline mutation; hundreds of BCCs from childhood
Immunosuppression	10× increased risk
Arsenic exposure	Produces multiple superficial BCCs
Prior radiation therapy	BCCs arise in the radiation field after a latency of years

Pathogenesis — the Hedgehog pathway:

This is one of the most clearly understood carcinogenic pathways in oncology.

The normal Hedgehog (Hh) signalling pathway:
1. PTCH1 (Patched 1) — a membrane receptor that normally inhibits Smoothened (SMO)
2. When the Hedgehog ligand binds PTCH1, the inhibition of SMO is relieved
3. SMO activates transcription factors GLI1/GLI2 → gene expression promoting cell proliferation

In BCC:
• UV-induced inactivating mutation in PTCH1 (the tumour suppressor) → PTCH1 cannot suppress SMO → constitutive, ligand-independent activation of Hh signalling → uncontrolled GLI-driven proliferation
• Less commonly: activating mutation in SMO itself
• Clinical importance: Vismodegib and sonidegib are small-molecule SMO inhibitors — FDA-approved targeted therapy for locally advanced or metastatic BCC (rare but exists)

Hedgehog Signalling Pathway: Normal Skin vs Basal Cell Carcinoma

Histological patterns of BCC:

(1) Nodular BCC — the most common subtype (~60–70%):

Nodular Basal Cell Carcinoma — Histological Features

• Basaloid cells — small, uniform cells with scant cytoplasm and oval, hyperchromatic nuclei; resemble the basal layer cells (hence the name)
• Peripheral palisading — at the edge of every tumour nest, cells line up perpendicular to the basement membrane, like a picket fence; highly characteristic of BCC
• Stromal retraction (clefting) — a clear space appears between the tumour nests and the stroma; this is a fixation artifact (the mucin-rich stroma shrinks away from the nests during processing) but it is a diagnostically important artifact
• Minimal mitoses; minimal nuclear pleomorphism — BCC is a 'slow grower' cytologically
• Mucin (myxoid stroma) — blue-grey mucinous material in the stroma

(2) Morphoeic (sclerosing/infiltrative) BCC — the most dangerous subtype:
• Thin cords and strands of basaloid cells embedded in a dense desmoplastic fibrous stroma
• No peripheral palisading; no retraction clefts
• Poorly defined clinical margins → highest recurrence rate after excision
• Clinical appearance: flat, scar-like, indurated plaque (easily missed)

(3) Superficial BCC:
• Buds of basaloid cells attached to the undersurface of the epidermis, extending only superficially
• Seen on the trunk; multiple lesions common in arsenic exposure

Morphoeic BCC — Histology and Gross Appearance

Gross appearance:

• Nodular BCC ("rodent ulcer"): Pearly, translucent nodule with rolled (pearlescent) edges and central ulceration; overlying telangiectasias (superficial blood vessels) visible through the thinned epidermis; classically on the face, nose, or periorbital area
• The term 'rodent ulcer' historically described the central ulceration that can progressively enlarge and erode underlying tissue (like a rodent gnawing)

Natural history — locally destructive, almost never metastasises:

This is the most clinically important fact about BCC:

• Metastatic rate: <0.01–0.1% — extraordinarily rare; BCC is therefore classified as a locally invasive malignancy, not a metastatic one
• Local destruction is the key threat: untreated BCC can erode deeply into subcutaneous tissue, cartilage (nose, ear), and bone (skull, orbit) — hence the 'rodent ulcer' metaphor
• Recurrence after incomplete excision is common, especially morphoeic subtype
• Why doesn't BCC metastasise? Several theories: (1) tumour cells require specific stromal signals (paracrine dependence) that are not available at distant sites; (2) lack of efficient lymphovascular invasion machinery; (3) slow growth rate

Management: Surgical excision with clear margins is the standard. Mohs micrographic surgery for high-risk/morphoeic lesions. Vismodegib for locally advanced/unresectable disease.

BCC vs SCC vs Melanoma — Comparison Table

Feature	BCC	SCC	Melanoma
Cell of origin	Basal keratinocyte / hair follicle outer root sheath	Suprabasal keratinocyte	Melanocyte
Frequency	Most common skin cancer (~75%)	Second most common (~20%)	~5% but most deadly
Key mutation	PTCH1 (Hedgehog pathway)	TP53 (UV-induced)	BRAF V600E (~50%), NRAS
Main UV type	UVB (intense/intermittent)	UVB (cumulative, chronic)	UVA + UVB
Gross appearance	Pearly nodule, rolled edges, telangiectasias	Indurated ulcerated plaque/nodule	Pigmented, irregular, asymmetric
Key histology	Basaloid nests, peripheral palisading, retraction cleft	Keratin pearls, atypical squamous cells	Atypical melanocytes, pagetoid spread, radial/vertical growth phases
Premalignant lesion	None clearly defined (AK is SCC precursor, not BCC)	Actinic keratosis, Bowen's disease	Dysplastic naevus
Metastatic potential	Almost none (<0.1%)	Low (2–5%), higher in high-risk SCC	High; can metastasise early
Prognosis	Excellent (local control)	Good (localised); poor (metastatic)	Poor once metastatic
Key prognostic measure	Completeness of excision	Depth, grade, LVI, perineural invasion	Breslow depth, Clark level, ulceration, mitoses
IHC markers	BerEP4+, EMA−, S100−	CK5/6+, p40+, EMA+, S100−	S100+, HMB-45+, Melan-A+

Clinical Comparison of Common Skin Malignancies: BCC, SCC, and Melanoma

Melanocytic Naevus — The Benign Baseline

Before understanding melanoma, you must understand what it is NOT — the benign melanocytic naevus (common mole).

Melanocytic naevus (plural: naevi) is a benign proliferation of naevus cells (melanocytes that have aggregated into clusters called nests).

Types of common acquired naevi:

• Junctional naevus — nests of naevus cells at the dermo-epidermal junction (DEJ); flat, uniformly pigmented macule; seen in children and adolescents
• Compound naevus — nests at the DEJ and in the dermis; slightly raised, pigmented papule
• Intradermal naevus — nests entirely within the dermis; flesh-coloured or lightly pigmented dome-shaped papule; seen in adults

This sequence (junctional → compound → intradermal) represents the natural progression of naevi as the naevus cells 'mature' and migrate downwards — this is called naevus maturation.

Histological features of benign naevi (features that say 'don't worry'):
• Maturation — naevus cells in the superficial dermis are larger; those deeper are smaller (opposite of what malignant cells do)
• Orderly nests — regular, similar-sized nests with equal spacing
• No pagetoid spread — naevus cells do not migrate upward through the epidermis (epidermal levels above the DEJ are free of naevus cells)
• No significant mitoses in the dermis
• No ulceration

Compound Melanocytic Naevus — Histological Features

Dysplastic naevus (Clark's naevus):
A dysplastic naevus is an architecturally and cytologically atypical naevus that is considered a precursor lesion and marker for increased melanoma risk. Features: size >5 mm, irregular border, variable pigmentation ('fried egg' appearance clinically). Histology: bridging of rete ridges, shouldering, lamellar fibroplasia, mild–moderate cytological atypia. Patients with dysplastic naevus syndrome (>50 atypical moles, family history of melanoma) have a lifetime melanoma risk approaching 100%.