Melanoma

Rising incidence in young adults, BRAF/NRAS/NF1 landscape, sentinel node staging, and the immunotherapy + targeted therapy revolution

Key Points

• Melanoma accounts for only ~1% of skin cancers but causes ~80% of skin cancer deaths; ~100,640 new invasive cases annually in the US.
• UV radiation is the primary carcinogen; indoor tanning before age 35 increases melanoma risk by 75%.
• BRAF V600E/K mutations occur in ~50% of cutaneous melanomas; BRAF + MEK inhibitor combination (dabrafenib + trametinib, encorafenib + binimetinib) achieves high response rates.
• The ABCDE mnemonic (Asymmetry, Border, Color, Diameter, Evolution) aids early clinical recognition.
• Sentinel lymph node biopsy (SLNB) is the standard staging procedure for melanomas ≥0.8 mm (or <0.8 mm with high-risk features).
• Adjuvant immunotherapy (pembrolizumab, nivolumab) and targeted therapy (dabrafenib + trametinib for BRAF-mutated) significantly reduce recurrence for stage III–IV resected disease.
• Unresectable stage III or IV melanoma is treated with anti-PD-1 ± anti-CTLA-4 (ipilimumab + nivolumab — highest response rate but significant toxicity) or BRAF + MEK inhibition for BRAF-mutated tumors.

Epidemiology & Incidence

Melanoma is the most serious form of skin cancer. In 2024, approximately 100,640 new invasive melanomas and ~8,290 deaths were projected in the US. Despite representing only ~1% of skin cancers, melanoma accounts for the vast majority of skin cancer deaths. The lifetime risk is ~2.6% (1 in 38) for Americans. Incidence has been rising globally for decades, though the rate of increase has slowed recently. Melanoma is disproportionately common in young adults — it is one of the most common cancers in adults under 40. The overall male-to-female incidence ratio is 1.5:1, though in adults under…

Genetic Predispositions & Risk Factors

UV radiation (both UVA and UVB) is the primary environmental carcinogen, causing mutations in BRAF, RAS, and other oncogenes. Cumulative lifetime UV exposure drives risk; intermittent intense exposure with sunburns (particularly in childhood) is especially associated with melanoma. Somatic driver mutations in cutaneous melanoma: • BRAF V600E (~40–50% of cutaneous melanoma): Targetable with vemurafenib, dabrafenib, encorafenib + MEK inhibitors • BRAF V600K (~5–10%): Also targetable • NRAS (~20%): Activates MAPK and PI3K pathways; MEK inhibitors have limited activity; binimetinib approved •…

Clinical Presentation

The ABCDE criteria aid recognition of early melanoma: • A — Asymmetry: One half does not match the other • B — Border: Irregular, ragged, notched, or blurred edges • C — Color: Variation in color within a lesion (tan, brown, black, red, white, blue — "multiple colors") • D — Diameter: Larger than 6 mm (pencil eraser); though early melanomas may be smaller • E — Evolution: Any change in size, shape, color, or onset of new symptoms (bleeding, crusting, itching) The "ugly duckling" sign: A lesion that looks different from a patient's other nevi should be viewed with suspicion, even if not…

Staging Overview

Melanoma is staged using AJCC 8th Edition: Stage I: T1–2 N0 M0 (localized, Breslow depth ≤2 mm, no ulceration for IA) Stage II: T2b–T4b N0 M0 (localized, depth >2 mm or ulceration) Stage III: Any T, N1–3 M0 (regional nodal involvement, satellite/in-transit, microsatellitosis) Stage IV: Any T, Any N, M1 (distant metastases — M1a: skin/soft tissue; M1b: lung; M1c: other viscera; M1d: brain) Sentinel lymph node biopsy (SLNB) is indicated for melanomas ≥0.8 mm, or ULN significantly impacts prognosis and treatment selection).

Stage I–II Treatment

Wide local excision (WLE) with histologically confirmed clear margins is the primary treatment. Excision margins are standardized by Breslow depth: • In situ: 0.5–1 cm margins • ≤1.0 mm: 1 cm margins • 1.01–2.0 mm: 1–2 cm margins • >2.0 mm: 2 cm margins (maximum feasible; often limited by anatomy) SLNB is performed at the time of WLE for T1b (≥0.8 mm) and above. For T1a with favorable features, SLNB is individualized. Adjuvant systemic therapy for stage IIB–IIC (high-risk stage II — ulcerated T3–T4 or thick melanomas with SLN-negative status): • Pembrolizumab × 1 year (KEYNOTE-716 trial):…

Stage III Treatment (Resected & Unresectable)

Resected stage III melanoma (node-positive, in-transit, satellite, or microsatellitosis): Adjuvant immunotherapy: • Pembrolizumab × 1 year (KEYNOTE-054): 5-year RFS 59.8% vs. 49.2% for placebo; OS benefit shown for high-risk subset • Nivolumab × 1 year (CheckMate 238): Superior to ipilimumab 10 mg/kg; improved RFS with significantly better tolerability For BRAF V600E/K-mutated resected stage III: • Adjuvant dabrafenib + trametinib × 1 year (COMBI-AD): 5-year RFS 52% vs. 36%; OS 65% vs. 54%; particularly for BRAF-mutated high-risk stage III • Choice between immunotherapy and targeted therapy:…

Stage IV (Metastatic) Treatment

Stage IV melanoma management has been revolutionized by immunotherapy and targeted therapy — 5-year OS has risen from <10% (pre-2011) to ~50% in landmark trials. Immunotherapy (PD-1/CTLA-4 blockade) — preferred for BRAF wild-type and for most BRAF-mutated patients (durable benefit): • Nivolumab + ipilimumab (CheckMate 067 — 10-year follow-up): ORR 58%; 10-year OS 52% — unprecedented long-term survival in unresectable/metastatic melanoma. Standard for high-burden disease in fit patients (PS 0–1). • Anti-PD-1 monotherapy (nivolumab, pembrolizumab): ORR 33–40%; preferred for older patients,…