Key Facts

Melanoma treatment has been revolutionised by immunotherapy and targeted therapy. Early detection remains critical for cure.

Epidemiology

• Fifth most common cancer in the UK (~16,700 new cases/year)
• ~2,300 deaths/year
• Incidence rising rapidly (UV exposure, sun-seeking behaviour)
• More common in fair-skinned populations
• Median age: 65 years; can affect younger adults

Aetiology

• UV radiation: most important environmental risk factor (intermittent intense exposure > chronic)
• Sunburn history: particularly childhood sunburns
• Fair skin, red/blonde hair, blue eyes (Fitzpatrick skin types I-II)
• Multiple naevi (>50 common naevi or >5 atypical naevi)
• Family history: 2× risk with first-degree relative
• Genetic: CDKN2A mutations (familial melanoma); BRAF, NRAS somatic mutations
• Previous melanoma: 3-5% risk of second primary
• Immunosuppression: transplant recipients have 3-5× risk

Pathophysiology

• Arises from malignant transformation of melanocytes (neural crest-derived)
• BRAF V600E mutation: constitutive activation of MAPK pathway (50% of cutaneous melanomas)
• NRAS mutations: 15-20%
• C-KIT mutations: mucosal and acral melanomas
• Subtypes: superficial spreading (70%), nodular (15-20%), lentigo maligna (5-10%), acral lentiginous (5%)
• Spread: lymphatic (regional nodes), haematogenous (lung, brain, liver, bone, skin)

ABCDE Criteria

• Asymmetry of shape
• Border irregularity
• Colour variation (multiple shades of brown, black, red, white, blue)
• Diameter >6mm
• Evolution (change in size, shape, colour, or new symptoms)

Subtypes

• Superficial spreading: most common; irregular border, colour variation, radial growth phase
• Nodular: rapidly growing dome-shaped/polypoid nodule; often amelanotic; worst prognosis (no radial growth phase)
• Lentigo maligna: on sun-damaged skin (face) in elderly; slow-growing
• Acral lentiginous: palms, soles, subungual; most common in dark-skinned individuals

Red Flags

• Rapidly changing pigmented lesion
• New pigmented lesion in an adult
• Amelanotic (non-pigmented) nodule that is growing
• Subungual pigmentation (Hutchinson's sign - periungual pigmentation suggests melanoma)
• Satellite lesions or in-transit metastases

Bedside

• Dermoscopy: essential for assessment of pigmented lesions (improves diagnostic accuracy by 30%)
• Full skin examination (check all sites including scalp, soles, nails, mucous membranes)
• Lymph node palpation (regional drainage basins)

Bloods

• LDH: elevated in metastatic melanoma (prognostic marker)
• FBC, U&Es, LFTs (baseline)
• S100B protein: monitoring marker in advanced disease

Imaging

• CT chest/abdomen/pelvis: staging for ≥stage IIB or symptomatic
• MRI brain: if neurological symptoms or stage III/IV
• PET-CT: for staging equivocal findings, recurrence detection
• USS of regional lymph nodes: if suspicious on examination

Special Tests

• Excision biopsy (full thickness, 2mm clinical margin): standard diagnostic procedure
  • Never shave biopsy or incisional biopsy of suspected melanoma (need full Breslow measurement)
• Sentinel lymph node biopsy (SLNB): offered for Breslow ≥0.8mm or <0.8mm with ulceration/high mitotic rate
  • Staging procedure; prognostic value (positive SLNB → stage III)
• BRAF mutation testing: all stage III/IV melanomas (guides targeted therapy)
• Gene expression profiling: emerging prognostic tools (DecisionDx-Melanoma)

Non-pharmacological

• Sun protection advice (sunscreen SPF 30+, protective clothing, avoid sunburn)
• Regular skin self-examination education
• Surveillance: clinical examination ± imaging per risk stratification

Pharmacological

• Adjuvant (stage III):
  • Nivolumab (CheckMate-238) or pembrolizumab (KEYNOTE-054) for 1 year
  • Dabrafenib + trametinib for BRAF-mutated (COMBI-AD)
• Metastatic (stage IV):
  • BRAF-mutated: dabrafenib 150mg BD + trametinib 2mg OD (COMBI-d/v trials)
  • BRAF wild-type or any: nivolumab 3mg/kg + ipilimumab 1mg/kg × 4 then nivolumab maintenance (CheckMate-067)
  • Alternative: pembrolizumab monotherapy
• Response rates: combination immunotherapy 50-60% ORR; BRAF-targeted 65-70% ORR but shorter duration

Surgical/Interventional

• Wide local excision (WLE): definitive primary treatment
  • In situ: 5mm margin
  • Breslow ≤1mm: 1cm margin
  • Breslow 1-2mm: 1-2cm margin
  • Breslow >2mm: 2cm margin
• SLNB: staging for ≥0.8mm Breslow
• Completion lymph node dissection (CLND): no longer routine for positive SLNB (DeCOG-SLT, MSLT-II trials)
• Metastasectomy: for oligometastatic disease (especially pulmonary, can be curative)
• Isolated limb perfusion: for in-transit metastases

Referral Criteria

• Suspected melanoma: 2-week wait referral to dermatology/skin cancer clinic
• All confirmed melanomas: skin cancer MDT
• Stage III/IV: medical oncology referral
• Family history/high risk: specialist dermatology surveillance

• Stage IA (≤0.8mm, no ulceration): 5-year survival >99%
• Stage IB (≤1mm with ulceration or 1-2mm without): 5-year survival >95%
• Stage II (>1mm with high-risk features): 5-year survival 70-90% (depending on thickness)
• Stage III (nodal involvement): 5-year survival 40-78% (depending on tumour burden)
• Stage IV (metastatic): 5-year survival ~50% with combination immunotherapy (from <10% pre-immunotherapy era)
• Overall 5-year survival: approximately 90% (reflecting majority early-stage diagnosis)
• Prognosis for metastatic disease has been transformed by immunotherapy

Breslow Thickness and Excision Margins

Key Trials in Melanoma