Cutaneous melanoma

Meet the patient

A 52-year-old man points to a dark mole on his back that "wasn't there six months ago". It is asymmetric, the border is notched, it mixes tan, dark brown and black, and it has grown to 9 mm. His wife noticed it first. He has fair skin that burns, several dozen naevi, and one blistering sunburn every summer of his youth.[1][6]

That lesion carries every lesson of melanoma in one image: it is new, it is changing, and it is the ugly duckling — the mole that does not match its neighbours. The two decisions that follow are the two that follow every melanoma: biopsy it properly (full-thickness excisional, never shaved) and read the Breslow thickness, because that single number in millimetres sets the margin, the sentinel-node decision, and the prognosis.[3][5]

What melanoma is — a melanocyte tumour with six faces

Melanoma is a malignant tumour of melanocytes — neural-crest-derived pigment cells — most often in the skin, but also the mucosa, nail apparatus, conjunctiva and uveal tract. Histology defines it by architectural disorder, cytological atypia and pagetoid scatter; the basement membrane separates in situ from invasive disease.[3]

Six subtypes you must recognise, because site and morphology change the trap:[3][5]

How common, who, and why it is rising

Incidence keeps climbing worldwide, disproportionately in white populations; Australia and New Zealand carry the highest global incidence, where lifetime risk approaches 1 in 25.[3][6]

The risk-factor list, grouped:[2]

• Host factors: fair skin (Fitzpatrick I–II), red hair (MC1R variants), 50 or more common naevi or 5 or more atypical naevi, personal or family history of melanoma, large congenital naevi, xeroderma pigmentosum, solid-organ transplant or immunosuppression, prior melanoma.
• Genetics: CDKN2A (p16) germline mutations — familial atypical multiple mole melanoma (FAMMM) syndrome — CDK4, and inherited telomere biology syndromes; a minority of cases, but they warrant genetic counselling and intensive surveillance.
• Exposure: intermittent intense UV (sunburn history, indoor tanning) drives SSM; chronic cumulative UV drives lentigo maligna. Sunscreen reduces invasive melanoma incidence (randomised evidence in high-risk adults).
• Prevention — sun protection, avoiding indoor tanning, self-examination — is the cornerstone of public-health melanoma control. [2]

The MAPK and PI3K pathways — and why BRAF matters

Two oncogenic engines and one immune escape — know them because each is a drug target. UV produces C to T pyrimidine-dimer transitions concentrated in key oncogenes. The MAPK pathway is the dominant driver: BRAF V600E in about 50 percent of cutaneous melanomas (V600K in 5–10 percent, commoner in older, sun-damaged patients), NRAS in about 15 percent, NF1 loss in about 15 percent — and combined BRAF plus MEK inhibition exploits that dependency.[4][8]

The rest of the molecular map:[3]

• PI3K-AKT-mTOR is co-activated through PTEN loss (about 30 percent), promoting invasion and resistance.
• TERT promoter mutations and CDKN2A loss confer replicative immortality, accumulating as a naevus moves through dysplasia and radial to vertical growth.
• Immune evasion — melanoma is among the most immunogenic solid tumours, and engagement of the PD-1/PD-L1 and CTLA-4 checkpoints disables cytotoxic T cells. Blocking those checkpoints (anti-PD-1, anti-CTLA-4, anti-LAG-3) restores anti-tumour immunity and is the basis of modern advanced-disease therapy.
• Progression model: benign naevus, atypical or dysplastic naevus, melanoma in situ (radial growth), invasive melanoma (vertical growth), then regional and distant metastasis — lymphatic first, then haematogenous to lung, liver, brain, bone and gut. [5]

Recognise the lesion — ABCDE, the ugly duckling, and the traps

The single most reliable sign is a new or changing pigmented lesion. Apply ABCDE plus the ugly duckling — the naevus that looks different from the patient's own crowd of naevi:[1][6]

• Asymmetry, Border irregularity, Colour variegation (three or more colours, including blue, black, red or white), Diameter over 6 mm (low specificity alone), Evolving (change in size, shape or symptom).
• Nodular melanoma is the classic trap — a vertically growing, often symmetrical nodule that may be pink (amelanotic) and skip the ABCDE entirely. It is why a rapidly growing pink papule gets biopsied, not watched.
• Atypical presentations examiners love: acral melanoma on a sole or under a nail (longitudinal melanonychia that widens, takes a triangular shape, and shows Hutchinson's sign — pigment onto the proximal or lateral nailfold); amelanotic pink papule mimicking BCC, pyogenic granuloma or keratoacanthoma; desmoplastic scar-like plaque with neuropathic pain; mucosal ulceration or bleeding; uveal melanoma with visual change; and metastatic disease of unknown primary (in-transit, nodal or visceral disease with a regressed cutaneous primary). [3][5]

The mimics — and the discriminator that separates each

The discriminator line: an ugly duckling — the one mole that does not match its neighbours — is melanoma until dermoscopy and histology prove otherwise. A subungual haematoma grows out with the nail and carries no Hutchinson's sign; melanoma does not grow out.[1]

Dermoscopy — chaos and clues

Dermoscopy lifts melanoma sensitivity and specificity. Run the two-step algorithm — first benign versus melanocytic, then benign versus malignant melanocytic — and look for the melanoma-specific criteria:[7]

• Atypical pigment network (thickened, irregular lines).
• Irregular streaks (pseudopods or radial streaming) at the periphery.
• Irregular blotches and multiple colours — five or six colours is highly specific.
• Regression — scar-like white areas with peppering (blue-grey dots).
• Blue-white veil over a raised invasive component; highly specific.
• Atypical (polymorphous) vessels — dotted, linear-irregular, milky-red areas, chrysalis.
• Chaos and clues — an asymmetric lesion with at least one clue; the practical short algorithm for the non-expert. [7]

Histopathology — Breslow is the number that runs the show

The histology report sets staging and management — read every line of it.[3][5]

• Breslow thickness (mm) — the single most important prognostic factor; measured from the top of the granular layer to the deepest invasive cell.
• Ulceration — adverse; defines the "b" subcategory.
• Mitotic rate (per mm²) — adverse; required on every report.
• Lymphovascular invasion, microsatellites (0.05 mm or more, within 1–2 cm of the primary; equals N1c), perineural (neurotropic) invasion.
• Regression — pathological regression present.
• Clark level — superseded for staging except in thin (T1) melanomas where thickness and ulceration are borderline.
• Margins and histological subtype (SSM, nodular, LM, ALM, desmoplastic, Spitzoid). [1]

The bedside round — examine the whole skin, including the parts patients forget

• Examine the whole skin — scalp (part the hair), retro-auricular, oral mucosa, conjunctiva, neck, axillae, trunk (use a chaperone), genitals and perianal skin, palms, soles, interdigital web spaces, and all nails.[6]
• Palpate the regional nodes — cervical, axillary, inguinal.
• Use total-body photography and sequential digital dermoscopy for high-risk patients (dysplastic naevus syndrome, personal or family history); hand-held dermatoscopy at every visit. [3]

Investigations — biopsy it properly, or you cannot stage it

• Biopsy technique is critical: a full-thickness excisional biopsy with 1–3 mm clinical margins, oriented vertically (to preserve lymphatic drainage and allow accurate Breslow measurement). Never shave or scoop a suspected melanoma — it cannot be staged and it distorts the thickness. A punch suffices for a small lesion. For a large lesion such as lentigo maligna, an incisional biopsy of the most atypical area is acceptable for diagnosis, followed by definitive excision.[6][5]
• Staging is driven by stage and symptoms. Localised (clinical stage I–II): no routine imaging or bloods, and LDH is not required. Stage III or IV: whole-body CT or PET-CT and brain MRI (more sensitive than CT for brain metastases), plus LDH (an independent M-category prognostic factor).[3][5]
• Sentinel lymph node biopsy (SLNB) is offered for pathological stage T1b or deeper (0.8 mm or more, or under 0.8 mm with ulceration); it is discussed selectively for thin (T1a) melanomas with adverse features (mitoses, regression, lymphovascular invasion, young age). Performed with lymphoscintigraphy and blue dye and/or radiotracer.[3]
• Gene-expression profiling (DecisionDx-Melanoma, CP-GEP) is an emerging adjunct to refine SLNB decisions in borderline-thickness tumours; not yet universal. [3]

AJCC 8th edition staging — T by thickness, N by node burden

The T1 split is the most examined number in melanoma — memorise the 0.8 mm cut-off.[3]

N (regional nodes): N1 (1 node), N2 (2–3 nodes), N3 (4 or more, or matted); suffix (a) clinically occult or sentinel-detected, (b) clinically detected, (c) in-transit, satellite or microsatellite metastases without nodal involvement (N1c).[3]

M (distant) — anatomy plus LDH, the independent prognostic marker:[1]

[3] [5]

Each M category is further split by LDH — normal (0) versus elevated (1) — and an elevated LDH is an independent adverse marker that, in the AJCC 8th edition, roughly halves the 5-year survival within its category.[3]

Biopsy and surgery — the margins follow the Breslow

Wide local excision margins are set by Breslow thickness — learn the ladder:[5][6]

• Sentinel lymph node biopsy for T1b or deeper disease provides staging and prognostic information.[3]
• Completion lymph node dissection versus observation after a positive SLNB: MSLT-II and DeCOG-SLT showed no melanoma-specific survival benefit from immediate completion dissection, with only a small absolute reduction in regional nodal recurrence. CLND is now reserved for bulky or clinically apparent nodal disease, with ultrasound surveillance the alternative.[3][5]
• Lentigo maligna may be excised with Mohs micrographic surgery (or staged mapped excision) for tissue conservation on the face. [1]

Adjuvant systemic therapy — resected IIB/IIC and stage III

Adjuvant therapy improves recurrence-free survival in resected high-risk melanoma, regardless of BRAF status:[5]

• Anti-PD-1 — pembrolizumab (KEYNOTE-054) or nivolumab (CheckMate 238) for about 1 year, for resected IIB, IIC or III regardless of BRAF status.
• BRAF plus MEK — dabrafenib plus trametinib (COMBI-AD) for about 1 year, for BRAF V600-mutated resected stage III.
• Choice between anti-PD-1 and BRAF plus MEK in BRAF-positive patients is individualised — efficacy comparable, toxicity profiles different. [1]

Advanced and metastatic disease — the algorithm immunotherapy transformed

Modern first-line therapy has turned stage IV melanoma into a disease a subset of patients survive for a decade. The choice rests on tempo, symptom burden, BRAF status and performance status.[5][3]

The doses the examiner expects you to know — name the drug, the dose and the trial:[1]

• Anti-PD-1 monotherapy (flat, weight-independent dosing): pembrolizumab 200 mg IV every 3 weeks or 400 mg every 6 weeks (KEYNOTE-006); nivolumab 240 mg every 2 weeks or 480 mg every 4 weeks. First-line for most patients regardless of BRAF status.
• Nivolumab plus ipilimumab induction (CheckMate 067): nivolumab 1 mg/kg plus ipilimumab 3 mg/kg IV every 3 weeks for four doses, then nivolumab 240 mg every 2 weeks or 480 mg every 4 weeks. The reverse schedule (ipilimumab 1 mg/kg plus nivolumab 3 mg/kg, CheckMate 511) halves the grade 3–5 immune-related adverse-event rate with comparable efficacy, and is now preferred in many patients. Reserve the combination for symptomatic, bulky, rapidly progressing or brain-metastatic disease that can tolerate the toxicity.
• Nivolumab plus relatlimab (RELATIVITY-047): nivolumab 480 mg plus relatlimab 160 mg IV every 4 weeks — anti-PD-1 plus anti-LAG-3, improved progression-free survival over nivolumab alone.
• BRAF plus MEK for BRAF V600-mutant disease (confirm V600E, K or D by validated assay — IHC screens, sequencing or NGS confirms):
  • Dabrafenib 150 mg orally twice daily plus trametinib 2 mg orally once daily (COMBI-d, COMBI-v).
  • Encorafenib 450 mg orally once daily plus binimetinib 45 mg orally twice daily (COLUMBUS).
  • Vemurafenib 960 mg orally twice daily plus cobimetinib 60 mg orally once daily for 21 days of each 28-day cycle (coBRIM; vemurafenib monotherapy was the historical BRIM-3 regimen, now superseded by the combination).
  • Targeted therapy gives rapid disease control (responses within 1–2 weeks) — ideal for symptomatic, bulky or brain disease — but resistance typically emerges within 9–12 months on combination.
• Intratumoural T-VEC (talimogene laherparepvec) — a modified oncolytic herpes simplex virus type 1 expressing GM-CSF, injected into cutaneous, subcutaneous or nodal lesions at 10⁶ PFU/mL for the first dose (to seroconvert) then 10⁸ PFU/mL every 2 weeks, for injectable locally advanced or low-burden cutaneous disease (OPTiM).
• Brain metastases: nivolumab plus ipilimumab has intracranial activity; stereotactic radiosurgery for limited disease; whole-brain radiotherapy reserved for diffuse symptomatic disease.
• In-transit or regionally advanced disease: isolated limb infusion or perfusion with melphalan (with or without actinomycin D or TNF-alpha), electrochemotherapy, or intralesional T-VEC.
• Uveal melanoma (HLA-A*02:01-positive): tebentafusp — a gp100-by-CD3 TCR-CD3 bispecific — 20 mcg IV on day 1, 30 mcg on day 8, then 30 mcg weekly; the first systemic agent to improve overall survival in metastatic uveal melanoma.
• PET-CT and multidisciplinary tumour-board review is standard for stage III or IV. [1]

Treatment selection in one line: anti-PD-1 monotherapy for most patients with favourable tempo; ipi plus nivo for symptomatic, bulky, rapidly progressing or brain-met disease that can tolerate it; BRAF plus MEK first-line in BRAF V600-mutant disease needing a fast response or when checkpoint inhibitors are contraindicated.[5][8]

[1]

A practical timeline for advanced BRAF-mutant melanoma:[1]

[3] [5]

The landmark trials — name them, and what each changed

The fellowship viva tests both the trial name and the regimen. Commit them as one bundle.[3][5]

CheckMate 067 randomised treatment-naive unresectable stage III or IV melanoma to nivolumab plus ipilimumab, nivolumab, or ipilimumab. At 6.5 years the median overall survival was 72.1 months with the combination versus 36.9 with nivolumab versus 19.9 with ipilimumab; at 10 years (2024) overall survival was 43 percent, 37 percent and 19 percent — the longest survival ever reported in a phase 3 advanced-melanoma trial. A substantial fraction of durable responders stayed off any systemic therapy beyond five years, the strongest evidence that cure is achievable in a subset. Treatment-related grade 3–4 events ran 59 percent in the combination arm, with treatment-related deaths around 1.4 percent (mostly colitis, pneumonitis and myocarditis).[5]

KEYNOTE-054 (EORTC 1325) — adjuvant pembrolizumab 200 mg every 3 weeks for up to 12 months versus placebo in resected stage IIIA–IIIC; at 3.5 years relapse-free survival hazard ratio 0.59, 5-year RFS 55.4 percent versus 38.3 percent, with benefit regardless of BRAF status. It established adjuvant anti-PD-1 for resected stage III.[5]

COMBI-AD — adjuvant dabrafenib 150 mg twice daily plus trametinib 2 mg daily for 12 months versus placebo in resected BRAF V600-mutant stage III; at 5 years relapse-free survival 52 percent versus 36 percent. It established BRAF plus MEK as an alternative to anti-PD-1 for BRAF-mutant resected stage III.[5]

MSLT-II and DeCOG-SLT showed no melanoma-specific survival benefit from immediate completion lymph node dissection after a positive sentinel node — surveillance is acceptable, and CLND is reserved for bulky or clinically apparent disease. BRIM-3 established vemurafenib; COLUMBUS established encorafenib plus binimetinib; RELATIVITY-047 established nivolumab plus relatlimab.[3][5]

[1]

Radiotherapy — a narrow but defined role

Radiotherapy is never curative alone, but it has two jobs:[5]

• Adjuvant after therapeutic lymph node dissection for high-risk nodal disease (multiple involved nodes, extracapsular extension) to cut regional recurrence — especially desmoplastic and head or neck sites.
• Palliative for symptomatic brain, bone and soft-tissue metastases. [1]

Special populations — children, pregnancy, transplant, familial

• Paediatric melanoma is rare; Spitzoid histology is commoner and biologically distinct, and congenital melanocytic naevi carry a small lifetime risk. Management mirrors adults with age-adjusted dosing.[3]
• Pregnancy: it is safe to biopsy and excise melanoma during pregnancy; sentinel-node mapping with radiotracer is generally avoided in the first trimester but feasible later. Systemic immunotherapy decisions weigh maternal benefit against fetal risk and are individualised.
• Immunosuppressed (transplant): melanoma behaves more aggressively, and immunotherapy is complicated by allograft rejection — anti-PD-1 carries graft-rejection risk.
• Familial (CDKN2A): refer for genetic counselling, intensive whole-skin surveillance from early adulthood, and consider pancreatic-cancer screening (the associated risk). [3]

Prognosis and surveillance — from near-certain cure to a chronic disease

Five-year survival by AJCC 8th stage (approximate):[3][5]

Prognostic factors are stage (Breslow thickness, ulceration, sentinel-node status, LDH), mitotic rate, site (acral, mucosal and uveal worse), BRAF status, age and male sex. Surveillance is stage-stratified (NCCN, ESMO, Cancer Council Australia): typically every 3–12 months for 5 years with skin and node examination, imaging reserved for stage III or IV or symptoms, and lifelong whole-skin surveillance because new primaries arise in 5–10 percent.[5]

Prevention — sun, self-examination, and the high-risk clinic

• Sun protection: shade, protective clothing, broad-spectrum SPF 30-plus applied adequately and frequently; avoid indoor tanning. Sunscreen reduces invasive melanoma incidence.[2]
• Self-examination and professional surveillance for high-risk individuals — dysplastic naevus syndrome, personal or family history, immunosuppression, CDKN2A carriers.
• No proven chemoprevention; nicotinamide and retinoids are investigational. [2]

The mantra

The mantra: new or changing, ugly duckling — excise it full-thickness, read the Breslow, cut to the margin it dictates, and send for a sentinel node at T1b or deeper.[1]

Ward-round test — three stems, thirty seconds each

Stem 1 — the changing mole on the back (answer)

A 52-year-old man has a new, asymmetric, 9 mm dark mole on his back with colour variegation and a notched border, noticed by his wife six months ago. What is the clinical sign, and what is the correct biopsy? Model: This is the ugly duckling — a new, changing, ABCDE-positive lesion that does not match the patient's other naevi, the single most reliable clue to melanoma (likely superficial spreading). The correct biopsy is a full-thickness excisional biopsy with 1–3 mm margins, oriented vertically — never a shave or scoop, because Breslow thickness (the single most important prognostic factor, measured from the granular layer to the deepest invasive cell) cannot be assessed on a shaved specimen. The thickness then sets the wide-local-excision margin and the sentinel-node decision (T1b or deeper).[1]

Stem 2 — the pigmented nail band in an adult (answer)

A 60-year-old man has a dark longitudinal band on his great toenail that has widened over a year; pigment now extends onto the proximal nailfold. What is the sign, the diagnosis to exclude, and what do you do? Model: This is Hutchinson's sign — pigment onto the proximal or lateral nailfold — and in an adult a widening, triangular longitudinal melanonychia with Hutchinson's sign is acral lentiginous melanoma until histology excludes it. Biopsy the nail matrix (the most atypical, widest part of the band). Acral melanoma is the commonest type in darker skin and is frequently delayed because it is mistaken for trauma; a subungual haematoma, by contrast, grows out with the nail and carries no Hutchinson's sign.[3]

Stem 3 — the 4 mm ulcerated melanoma with a positive sentinel node (answer)

A 65-year-old has a 4.0 mm ulcerated melanoma on the calf; sentinel node biopsy is positive in one node. What is the stage, the wide-local-excision margin, and the adjuvant therapy? Model: Breslow 4.0 mm with ulceration is T4b; a single positive sentinel node is stage IIIA–IIIC depending on node burden. The wide-local-excision margin for over-4 mm disease is 2 cm. After a positive sentinel node, immediate completion lymph node dissection is not required (MSLT-II, DeCOG-SLT showed no survival benefit) — ultrasound surveillance is acceptable unless the node is bulky or clinically apparent. Adjuvant therapy for resected stage III is a year of anti-PD-1 (pembrolizumab, KEYNOTE-054, or nivolumab, CheckMate 238) regardless of BRAF status, or dabrafenib plus trametinib (COMBI-AD) if BRAF V600-mutated.[5]

[1]

References

1. [1]Ahmed B, Qadir MI, Ghafoor S. Malignant Melanoma: Skin Cancer-Diagnosis, Prevention, and Treatment Crit Rev Eukaryot Gene Expr, 2020.PMID 32894659
2. [2]Dzwierzynski WW. Melanoma Risk Factors and Prevention Clin Plast Surg, 2021.PMID 34503715
3. [3]Tasdogan A, Sullivan RJ, Katalinic A, et al. Cutaneous melanoma Nat Rev Dis Primers, 2025.PMID 40180935
4. [4]Guo W, Wang H, Li C. Signal pathways of melanoma and targeted therapy Signal Transduct Target Ther, 2021.PMID 34924562
5. [5]Joshi UM, Kashani-Sabet M, Kirkwood JM. Cutaneous Melanoma: A Review JAMA, 2025.PMID 40853557
6. [6]Lauters R, Brown AD, Harrington KA. Melanoma: Diagnosis and Treatment Am Fam Physician, 2024.PMID 39418569
7. [7]Marghoob NG, Liopyris K, Jaimes N. Dermoscopy: A Review of the Structures That Facilitate Melanoma Detection J Am Osteopath Assoc, 2019.PMID 31135866
8. [8]Castellani G, Buccarelli M, Arasi MB, et al. BRAF Mutations in Melanoma: Biological Aspects, Therapeutic Implications, and Circulating Biomarkers Cancers (Basel), 2023.PMID 37627054