Melanoma

Melanoma is a malignant tumour of melanocytes, responsible for most skin cancer deaths.

• Incidence is rising: about 330,000 new cases per year worldwide. Risk factors: intermittent intense UV exposure, sunburns, fair skin, numerous or atypical naevi, family history (CDKN2A, CDK4), prior melanoma, immunosuppression, and xeroderma pigmentosum.
• Subtypes: superficial spreading (most common), nodular, lentigo maligna, acral lentiginous (the most common type in people with darker skin), mucosal, uveal, and desmoplastic.
• Key driver mutations: BRAF V600 (about 50% cutaneous), NRAS (20%), KIT (acral and mucosal), and NF1.
• Breslow thickness, ulceration, and nodal status are the main prognostic factors.

• ABCDE: Asymmetry, Border irregularity, Colour variegation, Diameter above 6 mm, Evolution; also the "ugly duckling" sign.
• Nodular melanoma: firm, rapidly growing, often amelanotic and bleeding nodule.
• Acral lentiginous melanoma: pigmented patch or nodule on palms, soles, and subungual area (Hutchinson sign: pigment extension to nail fold).
• Advanced disease: satellite or in transit metastases, lymphadenopathy, and distant spread to lungs, liver, brain, bone.

• Dermoscopy guided examination; full thickness excisional biopsy with 1 to 3 mm margins (avoid shave biopsies for suspected melanoma).
• Histopathology: Breslow thickness, ulceration, mitotic rate, regression, microsatellites, and margins; BRAF testing for stage III to IV (and increasingly stage IIB/C).
• Staging (AJCC 8th): sentinel lymph node biopsy for T1b (0.8 mm or ulcerated) and above; imaging (CT, PET-CT, or MRI brain) for stage III with high risk and stage IV; LDH.
• Exclude naevi, seborrhoeic keratosis, pigmented BCC, and haemangioma.

• Wide local excision margins: in situ 0.5 to 1 cm; Breslow up to 1 mm: 1 cm; 1.01 to 2 mm: 1 to 2 cm; over 2 mm: 2 cm.
• Sentinel node biopsy; completion lymph node dissection no longer routine, with ultrasound surveillance instead.
• Adjuvant therapy (stage IIB to IV resected):
  • Pembrolizumab 200 mg every 3 weeks or 400 mg every 6 weeks for 1 year.
  • Nivolumab 240 mg every 2 weeks or 480 mg every 4 weeks for 1 year.
  • Dabrafenib 150 mg twice daily plus trametinib 2 mg daily for 12 months (BRAF V600 mutated stage III).
• Metastatic or unresectable disease:
  • Nivolumab 1 mg/kg plus ipilimumab 3 mg/kg every 3 weeks for 4 doses, then nivolumab 480 mg every 4 weeks.
  • Nivolumab plus relatlimab (fixed dose combination).
  • Pembrolizumab or nivolumab monotherapy.
  • BRAF V600: encorafenib 450 mg daily plus binimetinib 45 mg twice daily, or dabrafenib plus trametinib, or vemurafenib plus cobimetinib.
  • Lifileucel (tumour infiltrating lymphocytes) after anti-PD-1 and BRAF/MEK failure; talimogene laherparepvec for injectable lesions; KIT inhibitors (imatinib) for KIT-mutated disease.
• Immune related adverse events: colitis, hepatitis, pneumonitis, endocrinopathy, and myocarditis; manage with steroids (prednisolone 1 to 2 mg/kg), infliximab, and specialist input.
• Surveillance: skin and node examination every 3 to 6 months for 5 years, then annually; imaging according to stage; sun protection education.