Melanoma

Malignant tumour of melanocytes — the deadliest skin cancer, responsible for the majority of dermato-oncology deaths despite accounting for a minority of skin cancers. NEET PG loves the ABCDE rule, Breslow thickness, sentinel node biopsy, BRAF-targeted therapy, and checkpoint inhibitor immunotherapy.

Definition & basic biology

Melanoma is a malignant neoplasm arising from melanocytes — neural-crest–derived dendritic cells that synthesise melanin and normally reside in the basal layer of the epidermis. Although most common in skin, melanocytes also populate the uveal tract of the eye, leptomeninges, and mucosal surfaces (oral, nasal, anorectal, vulvovaginal), giving rise to extracutaneous melanomas.

The lethality of melanoma stems from its early propensity for lymphatic and haematogenous metastasis once it transitions from the radial (horizontal) to the vertical growth phase, where tumour cells invade the dermis as expansile nests.

High-yield: Melanoma is the leading cause of death among skin cancers. Basal and squamous cell carcinomas are far more common but rarely fatal.

Major risk factors

Risk factor	Notes
Intermittent intense UV / blistering sunburns	Especially childhood sunburn; UVB > UVA for initiation
Fair skin (Fitzpatrick I–II), red hair, freckling	MC1R gene variants
Multiple / atypical (dysplastic) naevi	>50 naevi or ≥5 atypical naevi raises risk
Family history / familial melanoma	CDKN2A (p16) germline mutation
Giant congenital melanocytic naevus	Lifetime risk ~5–10%
Immunosuppression	Transplant recipients, HIV
Xeroderma pigmentosum	Defective nucleotide-excision repair
Prior melanoma	Strong risk for a second primary

High-yield: CDKN2A (chromosome 9p21, encodes p16^INK4a^) is the classic familial melanoma gene. BRAF V600E is the commonest somatic driver mutation in sporadic melanoma.

Clinical subtypes (classification)

Four classical clinicopathological subtypes are tested repeatedly. The key conceptual divide is radial-growth-phase dominant (better prognosis) versus early vertical growth (nodular, worse).

Subtype	Frequency	Site	Key features
Superficial spreading	~70% (commonest overall)	Trunk (men), legs (women)	Long radial growth phase, irregular borders, variegated colour
Nodular	~15–20%	Trunk, head, neck	Vertical growth from outset, worst prognosis, may be amelanotic
Lentigo maligna melanoma	~5–10%	Sun-damaged face of elderly	Arises in lentigo maligna (Hutchinson freckle); best prognosis
Acral lentiginous	~5% overall, but commonest in dark-skinned / Asians	Palms, soles, subungual	Hutchinson sign (nail-fold pigment); poor prognosis (late diagnosis)

High-yield: Superficial spreading = commonest type overall. Acral lentiginous = commonest type in dark-skinned populations (Indians, Africans, Asians) and is UV-independent. Nodular = most aggressive. Lentigo maligna melanoma = best prognosis but the in-situ precursor (lentigo maligna) is the slowest growing.

Other variants: amelanotic melanoma (no pigment — easily missed, mimics pyogenic granuloma/BCC), desmoplastic melanoma (spindled, neurotropic), mucosal and uveal (ocular) melanoma.

High-yield: Uveal (choroidal) melanoma is the commonest primary intraocular malignancy in adults and characteristically metastasises to the liver via haematogenous spread (no lymphatics in the eye). It is associated with monosomy 3 and GNAQ/GNA11 mutations, not BRAF.

Clinical features — the ABCDE rule

The classic screening mnemonic for a suspicious pigmented lesion:

• A — Asymmetry
• B — Border irregularity (notched, scalloped)
• C — Colour variegation (black, brown, blue, red, white)
• D — Diameter >6 mm (size of a pencil eraser)
• E — Evolution / Elevation (change in size, shape, colour, symptoms — itch, bleed)

High-yield: The "ugly duckling" sign — a naevus that looks distinctly different from a patient's other moles — is a useful complementary clue. E (evolution) is considered the single most important feature in early detection.

Subungual melanoma clue: Hutchinson's sign = pigment spilling onto the proximal/lateral nail fold from a longitudinal melanonychia — strongly suggests acral lentiginous melanoma (vs benign causes of nail pigmentation).

Diagnosis & investigation of choice

Stepwise approach:

Suspicious lesion → Dermoscopy (non-invasive triage) → Excisional biopsy with narrow (1–3 mm) margins (investigation/diagnosis of choice) → Histopathology + Breslow thickness → Sentinel lymph node biopsy if indicated → Staging imaging for advanced disease → Molecular testing (BRAF).

• Excisional biopsy taking the full depth is the diagnostic gold standard — it allows accurate measurement of Breslow thickness, which drives staging and surgical margins. Incisional/punch biopsy is reserved for very large lesions or cosmetically sensitive sites (face, acral).
• Shave biopsy is avoided because it transects the lesion and prevents accurate depth measurement.

High-yield: The single most important prognostic factor in localised cutaneous melanoma is Breslow thickness (measured in mm from the granular layer of the epidermis to the deepest tumour cell). Ulceration and mitotic rate are the next most important.

Breslow thickness vs Clark level

Parameter	What it measures	Clinical use
Breslow thickness	Vertical depth in mm (granular layer → deepest tumour cell)	Best prognostic indicator; drives T-staging & excision margins
Clark level	Anatomical level of dermal invasion (I–V)	Older system; now largely superseded by Breslow

Clark levels: I = epidermis (in situ) · II = papillary dermis · III = fills papillary dermis · IV = reticular dermis · V = subcutaneous fat.

High-yield: Breslow has replaced Clark level in AJCC staging because depth in mm correlates better with outcome than anatomical layer. Remember: Breslow = millimetres; Clark = layers.

Histology & immunohistochemistry

Melanoma cells show atypical melanocytes with pagetoid (upward) spread, nuclear pleomorphism, and prominent nucleoli.

IHC marker	Comment
S-100	Most sensitive (but not specific)
HMB-45	More specific; marks active/junctional melanocytes
Melan-A / MART-1	Sensitive and fairly specific
SOX10	Sensitive nuclear marker, useful in desmoplastic types

Staging (AJCC TNM essentials)

• T — based on Breslow thickness and ulceration (T1 ≤1 mm, T2 >1–2 mm, T3 >2–4 mm, T4 >4 mm).
• N — regional nodes; sentinel lymph node status is pivotal.
• M — distant metastasis; serum LDH is incorporated (elevated LDH → M1c/poorer prognosis).

High-yield: Elevated serum LDH is an independent poor prognostic marker in metastatic (stage IV) melanoma and is built into the M category.

Sentinel lymph node biopsy (SLNB)

A staging procedure to identify occult nodal metastasis by mapping the first draining ("sentinel") node using blue dye + radiocolloid (technetium-99m).

• Indicated for Breslow ≥0.8 mm, or thinner lesions with adverse features (ulceration, high mitotic rate).
• Not routinely done for thin (<0.8 mm) non-ulcerated melanoma (low yield) or for in-situ disease.
• A positive SLNB upstages the patient and guides adjuvant therapy. Note: completion lymph-node dissection after a positive SLNB is no longer routine (MSLT-II) — nodal observation with ultrasound is often preferred.

High-yield: SLNB is the most accurate method for staging the regional nodal basin and is the strongest predictor of survival after Breslow thickness. Threshold for offering SLNB = Breslow ≥0.8 mm or any ulceration.

Management & drug of choice

Surgery — the mainstay for localised disease

Wide local excision with margins dictated by Breslow thickness:

Breslow thickness	Recommended excision margin
In situ (Tis)	0.5–1.0 cm
≤1.0 mm	1 cm
1.01–2.0 mm	1–2 cm
2.01–4.0 mm	2 cm
>4.0 mm	2 cm

High-yield: Margin rule of thumb — thin (≤1 mm) → 1 cm; thick (>2 mm) → 2 cm. Margins are NOT increased beyond 2 cm regardless of thickness. For lentigo maligna of the face, Mohs micrographic surgery offers margin-controlled excision.

Systemic therapy — metastatic / advanced disease

Modern melanoma therapy is built on two pillars: immune checkpoint inhibitors and BRAF/MEK targeted therapy.

1. Targeted therapy (for BRAF V600E/K-mutant tumours, ~40–50%):

• BRAF inhibitors: vemurafenib, dabrafenib, encorafenib.
• MEK inhibitors: trametinib, cobimetinib, binimetinib.
• Given as a combination (BRAF + MEK inhibitor) to delay resistance and reduce paradoxical squamous proliferation.

2. Immune checkpoint inhibitors (regardless of BRAF status):

• Anti-PD-1: nivolumab, pembrolizumab.
• Anti-CTLA-4: ipilimumab.
• Combination nivolumab + ipilimumab gives higher response rates at the cost of more immune-related adverse events.

High-yield: BRAF-targeted therapy (e.g. vemurafenib) only works in BRAF V600E-mutant melanoma — so molecular BRAF testing is mandatory before starting it. Checkpoint inhibitors work irrespective of BRAF status.

High-yield: Ipilimumab = anti-CTLA-4; nivolumab/pembrolizumab = anti-PD-1. Immune-related adverse effects include colitis, hepatitis, dermatitis, hypophysitis and thyroiditis — managed with steroids.

3. Older/adjuvant agents: high-dose interferon-α and IL-2 are now largely historical, replaced by checkpoint inhibitors in the adjuvant setting. Dacarbazine was the classic cytotoxic chemotherapy but has poor response rates and is no longer first line. Talimogene laherparepvec (T-VEC) is an oncolytic herpesvirus injected intralesionally for unresectable cutaneous/nodal disease.

Approach to advanced melanoma:

Confirm metastatic melanoma → test BRAF status → if BRAF-mutant = BRAF + MEK inhibitor OR checkpoint inhibitor; if BRAF wild-type = checkpoint inhibitor (anti-PD-1 ± anti-CTLA-4) → consider radiotherapy/stereotactic RT for brain or bone metastases.

Complications & metastasis

• Regional nodal and in-transit metastases (satellite lesions between primary and node).
• Distant metastasis: lung, liver, brain, bone, and — characteristically — gastrointestinal tract and any organ; melanoma is notorious for late and unusual metastatic sites.
• Brain metastases are common and a major cause of death; melanoma is one of the haemorrhagic brain-met tumours (mnemonic "MR/CT B-RECT" for haemorrhagic mets — Renal, Choriocarcinoma, Thyroid, Melanoma, etc.).
• Treatment toxicities: immune-related adverse events (colitis, endocrinopathy), BRAF-inhibitor-induced secondary cutaneous SCC/keratoacanthomas, arthralgia and pyrexia.

High-yield: Melanoma can metastasise to virtually any organ, including the GI tract and heart, and is one of the classic tumours producing haemorrhagic brain metastases. It is also a cause of amelanotic secondary deposits.

Key differentials

Lesion	Distinguishing feature
Benign / dysplastic naevus	Symmetric, uniform colour, stable; ABCDE-negative
Seborrhoeic keratosis	"Stuck-on" greasy plaque, horn cysts on dermoscopy
Pigmented basal cell carcinoma	Pearly border, telangiectasia, rolled edge
Pyogenic granuloma	Rapidly growing vascular nodule — mimics amelanotic/nodular melanoma
Blue naevus	Stable, uniformly blue dermal lesion
Subungual haematoma	Migrates distally with nail growth; no Hutchinson sign
Spitz naevus	Pink dome-shaped lesion in children; histologically tricky

High-yield: An amelanotic nodular melanoma is a great mimic of pyogenic granuloma and BCC — a non-healing or bleeding "vascular" nodule warrants biopsy. A subungual haematoma migrates distally with nail growth, whereas melanonychia/melanoma stays fixed and may show Hutchinson's sign.

Recently asked / exam angle

• ABCDE criteria — direct single-best-answer questions; know that E = Evolution and D = Diameter >6 mm.
• Breslow vs Clark — "Most important prognostic factor in melanoma?" → Breslow thickness. "Which measures depth in mm?" → Breslow. "Which uses anatomical levels I–V?" → Clark.
• Commonest subtype → superficial spreading (overall); acral lentiginous in dark-skinned/Indian patients; nodular = worst prognosis; lentigo maligna melanoma = best prognosis.
• SLNB threshold → Breslow ≥0.8 mm or ulceration; mapping with technetium-99m + blue dye.
• BRAF V600E → targeted therapy (vemurafenib/dabrafenib + MEK inhibitor); must test before starting.
• Checkpoint inhibitor mechanisms → ipilimumab (anti-CTLA-4), nivolumab/pembrolizumab (anti-PD-1).
• IHC → S-100 most sensitive, HMB-45 most specific.
• Excision margins by Breslow thickness (1 cm for ≤1 mm; 2 cm for >2 mm).
• Uveal melanoma → commonest primary intraocular malignancy in adults; liver metastasis; monosomy 3.
• Familial gene → CDKN2A (p16); somatic driver → BRAF.
• Hutchinson sign → distinguishes acral/subungual melanoma; Hutchinson freckle = lentigo maligna (different "Hutchinson"!).
• Serum LDH → poor prognosis in stage IV; part of M staging.

High-yield: Beware the two "Hutchinsons": Hutchinson's sign = nail-fold pigment spread (subungual melanoma); Hutchinson's melanotic freckle = lentigo maligna on sun-damaged skin.

Mnemonics

• ABCDE — Asymmetry, Border, Colour, Diameter, Evolution.
• Checkpoint targets: "Ipi hits CTLA-4, Nivo/Pembro hit PD-1."
• Breslow = mm, Clark = layers.
• Haemorrhagic brain mets: "Melanoma bleeds" (also choriocarcinoma, renal, thyroid).

Rapid revision

1. Melanoma = malignant melanocyte tumour; highest mortality among skin cancers.
2. Superficial spreading = commonest overall; acral lentiginous = commonest in dark/Indian skin and UV-independent.
3. Nodular melanoma = vertical growth from start = worst prognosis; lentigo maligna melanoma = best prognosis.
4. ABCDE screening + ugly-duckling sign; E (evolution) is most important early clue.
5. Excisional biopsy = diagnostic procedure of choice; never shave-biopsy a suspected melanoma.
6. Breslow thickness (mm) = single most important prognostic factor; ulceration + mitotic rate next.
7. Clark level = anatomical depth I–V; superseded by Breslow.
8. SLNB (Tc-99m + blue dye) if Breslow ≥0.8 mm or ulceration; strongest predictor after Breslow.
9. Excision margins: ≤1 mm → 1 cm; >2 mm → 2 cm (never beyond 2 cm).
10. BRAF V600E mutant → BRAF + MEK inhibitor (vemurafenib + trametinib); test before treating.
11. Checkpoint inhibitors: ipilimumab (anti-CTLA-4), nivolumab/pembrolizumab (anti-PD-1) — work regardless of BRAF.
12. IHC: S-100 most sensitive, HMB-45 most specific; CDKN2A familial gene; uveal melanoma → liver mets; raised LDH = poor prognosis.