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Melanoma — overview

TL;DR — Melanoma is a malignancy of melanocytes that behaves as at least four diseases: cutaneous (UV-driven, BRAF/RAS/NF1, checkpoint-responsive), uveal (GNAQ/GNA11, hepatotropic, checkpoint-refractory), acral and mucosal (structural-variant-driven, under-represented in trials). Worldwide in 2020 there were an estimated 325,000 new cases and 57,000 deaths, with age-standardised incidence varying more than fortyfold — 42 per 100,000 person-years in Australian and New Zealand men against commonly under 1 per 100,000 across Africa and Asia — and, on unchanged rates, projected to reach 510,000 cases and 96,000 deaths by 2040 (Arnold 2022, PMID 35353115). It is the disease in which checkpoint immunotherapy first proved durable: CheckMate 067's ten-year results give median overall survival 71.9 months with nivolumab plus ipilimumab against 19.9 months with ipilimumab, and among patients alive and progression-free at three years, ten-year melanoma-specific survival was 96% (Wolchok 2025, PMID 39282897). Yet the same period produced the field's central controversy: incidence has risen several-fold while mortality has been flat or falling, and an estimated 59–60% of US melanoma diagnoses in White patients in 2014 may have been overdiagnosis (Adamson 2022, PMID 35293957). Melanoma is simultaneously the best solved and the least well-defined common cancer.

Four diseases under one name

Cutaneous Uveal Acral Mucosal
Dominant drivers BRAF, RAS, NF1, triple-WT (Cancer Genome Atlas Network 2015, PMID 26091043) GNAQ/GNA11 in 83% (Van Raamsdonk 2010, PMID 21083380) KIT 19%, NRAS 17%, BRAF 9% in one Japanese series (Hida 2024, PMID 39564955) Structural variants targeting TERT, CDK4, MDM2; low point-mutation burden (Newell 2019, PMID 31320640)
UV aetiology Yes — signature present from benign precursor to invasion (Shain 2015, PMID 26559571) No GWAS finds it unrelated to pigmentation (Landi 2020, PMID 32341527) No
5-year relative survival (SEER 1988–2010) 89% 78% (ocular) 77.8% (SEER 2000–2016) (Yan 2022, PMID 34363907) 34% aggregate, range 3–69% by site
Survival trend over the immunotherapy era Improved (metastatic 5-year 16% → 35%) (Siegel 2026, PMID 41528114) No change — 82.8% flat 1975–2016 (Weinberger 2025, PMID 40225965) Incidence and survival broadly flat (Helkkula 2024, PMID 39140487) No improvement 1988–2010 (Bishop 2014, PMID 24272143)
First-line advanced therapy Checkpoint blockade (PMID 39282897) Tebentafusp, HLA-A*02:01-restricted (Nathan 2021, PMID 34551229) Checkpoint blockade with markedly lower response (Gonzalez-Cao 2026, PMID 40841506) Checkpoint blockade with lower response (Li 2020, PMID 32489431)

Details: molecular subtypes and genomics, uveal melanoma, acral and mucosal melanoma.

The burden, and why the numbers are contested

Measure Estimate Source
New cases worldwide, 2020 325,000 PMID 35353115
Deaths worldwide, 2020 57,000 PMID 35353115
Projected cases, 2040 510,000 (≈+50%) PMID 35353115
Projected deaths, 2040 96,000 (+68%) PMID 35353115
Highest incidence (male, Australia/NZ) 42 per 100,000 person-years PMID 35353115
Africa and most of Asia commonly <1 per 100,000 PMID 35353115
Estimated overdiagnosis, US White women 2014 59% (95% CI 45–70) PMID 35293957
Estimated overdiagnosis, US White men 2014 60% (32–75) PMID 35293957
County-level correlation, incidence vs melanoma mortality (US) r = 0.09, P = .05 Adamson 2022, PMID 36190719
County-level correlation, lung cancer incidence vs mortality (same counties) r = 0.96, P < .001 PMID 36190719

The last two rows are the sharpest statement of the problem: in the same counties, lung cancer incidence predicts lung cancer death almost perfectly and melanoma incidence barely predicts melanoma death at all. Meanwhile, cohorts born from roughly the mid-1960s onward show falling age-specific incidence in Australia, Sweden, the US, Canada and Italy — the first population-scale evidence that prevention changed the disease (Aitken 2018, PMID 29105744; Helgadottir 2024, PMID 39245436). Both readings live in epidemiology and global burden and screening and overdiagnosis.

What is settled

  • UV exposure and phenotype drive cutaneous melanoma risk. Nevus count is the largest single relative risk (RR 6.89 for 101–120 nevi vs <15) with ~42% of melanomas attributable to ≥25 common nevi (Gandini 2005, PMID 15617989; Olsen 2010, PMID 20086181), and Mendelian randomisation supports causality for childhood sunburn (Liu 2024, PMID 37712456).
  • Excision margins do not need to be wide. Seven randomised trials in 4,579 patients show no significant difference between narrow (1–2 cm) and wide (3–5 cm) margins on any outcome (Hanna 2021, PMID 33722422), and 2 cm was as safe as 4 cm at a median 19.6 years (Utjés 2019, PMID 31280965).
  • Completion lymph-node dissection does not improve survival. MSLT-II and DeCOG-SLT agree (Faries 2017, PMID 28591523; Leiter 2019, PMID 31557067).
  • Checkpoint blockade produces a durable plateau. Ipilimumab's survival curve flattens around year three at ~21% (Schadendorf 2015, PMID 25667295); combination therapy reaches far higher (PMID 39282897).
  • In BRAF-mutant disease, start with immunotherapy. DREAMseq: 2-year overall survival 71.8% versus 51.5% (P = .010) (Atkins 2023, PMID 36166727).

What is contested

Question The two positions
Is the incidence rise disease or detection? Overdiagnosis estimated at 29–60% across studies (Bjørch 2024, PMID 37793786) versus continued increases in thick and advanced disease including in low-SES men (Clarke 2017, PMID 28736233)
Should populations be screened? USPSTF I statement three times (Mangione 2023, PMID 37071089) versus national programs; Germany's produced no mortality difference against neighbouring countries (P = .42) (Hübner 2026, PMID 42268621)
What is sentinel node status for? A staging and trial-eligibility instrument, or therapeutic in some patients (Crystal 2022, PMID 35921122)
Neoadjuvant or adjuvant in resectable stage III? NADINA's 12-month event-free survival 83.7% vs 57.2% (Blank 2024, PMID 38828984) versus unresolved time-bias criticisms of S1801 and no overall-survival endpoint (Olivier 2024, PMID 38621314)
Adjuvant therapy in stage IIB/IIC and IIIA? 48-month recurrence-free survival 71.3% vs 58.3% (Luke 2025, PMID 40198940) versus 43.2% chronic toxicity (Patrinely 2021, PMID 33764387), a narrowed PRFS2 signal, and stage IIIA survival exceeding stage IIB and IIC (Kanaki 2019, PMID 31401470)
Why does checkpoint blockade fail in uveal melanoma? Mutational burden and driver divergence — described but never tested as a predictive framework (Piulats 2024, PMID 38048850)

How the treatment landscape arrived

Era What defined it Anchor
Before 2011 Surgery, high-dose interleukin-2 with a 16% response rate and a durable tail, dacarbazine, and adjuvant interferon with a 3.0% absolute 5-year survival difference Atkins 1999, PMID 10561265; Ives 2017, PMID 28692949
2011–2014 BRAF inhibition (63% relative reduction in risk of death vs dacarbazine) and ipilimumab, whose survival curve plateaus at ~21% from year three Chapman 2011, PMID 21639808; Schadendorf 2015, PMID 25667295
2014–2017 Anti-PD-1 monotherapy superior to ipilimumab; BRAF/MEK combination superior to BRAF alone; MSLT-II removes completion dissection Schachter 2017, PMID 28822576; Robert 2015, PMID 25399551; Faries 2017, PMID 28591523
2017–2022 Adjuvant therapy in stage III; TIL therapy randomised; relatlimab as a third checkpoint; tebentafusp in uveal melanoma Eggermont 2021, PMID 33857412; Rohaan 2022, PMID 36477031; Tawbi 2022, PMID 34986285; Nathan 2021, PMID 34551229
2022–2026 Adjuvant therapy extends to node-negative stage IIB/IIC; neoadjuvant sequencing reaches phase 3; ten-year checkpoint data mature Luke 2025, PMID 40198940; Kirkwood 2023, PMID 37845511; Blank 2024, PMID 38828984; Wolchok 2025, PMID 39282897

Population mortality followed with a lag. US White melanoma mortality rose 7.5% from 1986 to 2013 and then fell 17.9% from 2013 to 2016 (annual percent change −6.2%, 95% CI −8.7 to −3.7), the largest sustained improvement observed in the disease (Berk-Krauss 2020, PMID 32191523), and US 5-year relative survival for metastatic melanoma rose from 16% to 35% between the mid-1990s and 2015–2021 (Siegel 2026, PMID 41528114).

Map of this condition

Section Pages
Foundations epidemiology and global burden · risk factors and prevention · germline predisposition
Mechanism molecular subtypes and genomics
Diagnosis and staging clinical diagnosis and dermoscopy · histopathology and prognostic factors · staging · sentinel node and nodal management
Controversy screening and overdiagnosis
Treatment surgical management and margins · adjuvant therapy · neoadjuvant therapy · immunotherapy in advanced disease · targeted therapy · cellular therapy and resistance · brain metastases
Safety immune-related adverse events · red flags and safety concerns
Subtypes uveal melanoma · acral and mucosal melanoma
Populations and follow-up special populations · surveillance and survivorship
Reference and frontier guidelines · clinical trials landscape · patient experience and advocacy

The border with retinoblastoma

Survivors of heritable retinoblastoma carry increased melanoma risk; survivors of non-heritable retinoblastoma do not, and "retinoblastoma survivors" must never be written as one risk group. Across 1,851 White long-term survivors followed to 2016, melanoma occurred in 33 of 1,020 heritable and 7 of 831 non-heritable survivors, with 50-year cumulative incidence 4.5% versus 0.7% and skin cancers arising about 20 years earlier in heritable survivors (Kleinerman 2021, PMID 34153328). Any-cancer figures come from a separate cohort: SIR 11.9 (95% CI 10.4–13.5) versus 0.8 (0.5–1.2), with the frequently quoted 3.1–17 figure being a range across melanoma, CNS, oral-cavity and breast subsequent neoplasms, not a melanoma-specific estimate (Schonfeld 2021, PMID 33473166). Both conditions contain an intraocular malignancy — retinoblastoma in children, uveal melanoma in adults — separated by age and biology. Evidence lives once, in retinoblastoma; this condition cross-links rather than restating it. See germline predisposition and special populations.

Interpretation rules for this condition

  • Name the subtype before quoting any number. Cutaneous, uveal, acral and mucosal melanoma differ in driver, tropism, treatment and trend.
  • Incidence is not occurrence. In US counties, incidence and melanoma mortality correlate at r = 0.09 (PMID 36190719).
  • State whether in situ disease is included — it rises faster than invasive disease everywhere (Sacchetto 2018, PMID 29395684).
  • Recurrence-free survival is not overall survival, and trial-level surrogacy between them is only moderate (R² = 0.59, 95% CI 0.08–1.00) (Coart 2020, PMID 32777716).
  • Registrational trial populations were overwhelmingly White and cutaneous; effect sizes do not transport automatically (Bai 2022, PMID 35293617).
  • Give the diagnosis-year window for any stage IV survival figure — the denominator changed after 2011 (PMID 41528114; Berk-Krauss 2020, PMID 32191523).
  • This is a research knowledge base, not medical advice.

Open questions

The tiered set with stable IDs is in OPEN-QUESTIONS.md. The largest are: how much of the projected 2040 burden is disease rather than detection; what sentinel node status is for now that completion dissection has no survival benefit; whether neoadjuvant sequencing improves overall survival or only the endpoints trials measure; why checkpoint blockade transforms cutaneous but not uveal melanoma, and whether that explanation predicts anything; and whether standard-of-care effect sizes hold in the acral, mucosal and skin-of-colour populations that the registrational trials barely included.

Every page in this condition is listed in the map above; the literature layer is at ../literature/BIBLIOGRAPHY.md, the guideline registry at ../literature/guidelines/REGISTRY.md, the statistics sheet at ../literature/statistics/STATISTICS.md, and the patient-voice layer at ../literature/patient-voice/README.md.

References

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