Part I
Overview & Epidemiology
What melanoma is, where it sits in the skin-cancer family, the size of the global burden, the geographical and demographic structure of incidence, and the modifiable risk factors that drive the rising trend.
1. What is Melanoma?
Cutaneous melanoma is a malignant tumour arising from melanocytes, the pigment- producing cells of neural-crest origin that reside primarily in the basal layer of the epidermis. Melanocytes manufacture melanin within specialised lysosome-related organelles (melanosomes) and donate it to surrounding keratinocytes; their malignant transformation produces a tumour that is at first confined to the epidermis (melanoma in situ), then invades the dermis, then accesses lymphatics and the bloodstream with characteristic ferocity.
- Cell of origin: the cutaneous melanocyte; rare variants arise from melanocytes of the eye (uveal melanoma), mucosal surfaces, and the leptomeninges.
- Pathological hallmark: atypical melanocytic proliferation with single-cell upward (pagetoid) migration and asymmetric architecture on histology.
- Molecular hallmark: a high mutational burden — among the highest in any solid tumour — dominated by C>T transitions at dipyrimidines, the COSMIC SBS7 UV signature.
- Behavioural hallmark: early lymphatic and haematogenous spread relative to other skin cancers, and an unusually broad metastatic tropism (skin, lymph node, lung, liver, brain, bowel).
2. Where Melanoma Sits in the Skin-Cancer Family
Skin cancer is the commonest cancer in fair-skinned populations — but “skin cancer” is a heterogeneous label dominated numerically by keratinocyte carcinomas, with melanoma a small minority that nonetheless drives most of the mortality:
| Cancer | Cell of origin | Approx. share | Behaviour |
|---|---|---|---|
| Basal-cell carcinoma (BCC) | Basal keratinocyte | ~70–80% | Locally invasive; metastasis rare (~0.05%) |
| Squamous-cell carcinoma (SCC) | Suprabasal keratinocyte | ~15–20% | Locally invasive; metastasis ~3–5% |
| Cutaneous melanoma | Melanocyte | ~2–3% | Early lymphatic/haematogenous spread |
| Merkel-cell carcinoma | Merkel cell (neuroendocrine) | <1% | Aggressive, polyomavirus-driven |
| Cutaneous lymphoma, sarcoma | Various | <1% | Variable |
Despite making up only ~2–3% of cases, melanoma accounts for ~80% of skin-cancer deaths. A patient with a 2 mm thick truncal melanoma faces a substantially higher 10-year mortality than a patient with a similar-sized SCC at the same site. The course focuses on melanoma; keratinocyte carcinomas are covered separately.
3. Global Incidence
~325 K
new cases / year worldwide (GLOBOCAN 2020)
~57 K
deaths / year worldwide
~1 in 50
lifetime risk in fair-skinned populations
~4×
rise in incidence since 1970s (high-income)
~510 K
projected cases / year by 2040
~5th
commonest cancer in USA (men & women combined)
Cutaneous melanoma incidence has risen ~3–6% per year in fair-skinned populations through most of the post-war period, a rise driven largely by changes in recreational sun exposure (holiday tanning, tanning beds) layered on rising life expectancy and improved detection. The age- standardised incidence in non-Hispanic Whites in the USA is ~32/100,000/year; in Australia it is ~54/100,000/year (men) and ~38 (women).
The very latest decade (2010s–2020s) shows the curve flattening in several high-income countries among adults <40, attributed to four decades of SunSmart-style public-health campaigns, sun-protection norms, and tanning-bed regulation — an early but real signal that primary prevention is finally measurable. Incidence in adults >60 continues to rise.
4. Mortality & Survival — the Immunotherapy Era
Melanoma mortality has shown two phases. Through the 1990s and 2000s, age- standardised mortality rose roughly in step with incidence in most countries. From ~2013 onwards, mortality rates began to flatten and then fall in countries with broad access to modern systemic therapy — a striking population-level signal of the BRAF and immune-checkpoint era.
| AJCC 8 stage | 5-year MSS | 10-year MSS | Comment |
|---|---|---|---|
| IA | ~99% | ~98% | ≤0.8 mm, no ulceration |
| IB | ~97% | ~94% | 0.8–1.0 mm or ulcerated <0.8 |
| IIA | ~94% | ~88% | 1.0–2.0 mm ulcerated, or 2.0–4.0 mm not |
| IIB | ~87% | ~82% | 2.0–4.0 mm ulcerated, or >4.0 mm not |
| IIC | ~82% | ~75% | >4.0 mm + ulceration |
| IIIA | ~93% | ~88% | SLN+, low burden, T1a–T2a |
| IIIB | ~83% | ~77% | — |
| IIIC | ~69% | ~60% | — |
| IIID | ~32% | ~24% | Highest-risk node-positive |
| IV (M1a–c) | ~30%* | ~20%* | Modern immunotherapy era |
| IV brain (M1d) | ~20%* | ~15%* | Worst metastatic site |
*Numbers from CheckMate-067 10-year follow-up (Wolchok et al., NEJM 2022) and post-approval registries; pre-immunotherapy stage IV 5-yr survival was ~5–10%.
The transformation of stage IV from a sub-1-year median survival (DTIC era) to ~40% 10-year survival on combination ipilimumab+nivolumab is among the most striking survival gains in modern oncology — the subject of Part VII.
5. Geographical Variation
Melanoma incidence varies more than 100-fold worldwide. Two factors dominate: ambient UV flux and the phototype distribution of the local population.
| Region | ASR (per 100 K, 2020) | Predominant phototype |
|---|---|---|
| Australia / New Zealand | ~36 | Fitzpatrick I–II under high UV |
| Norway | ~30 | I–II, low UV but high sun-seeking |
| Denmark, Sweden | ~28 | I–II |
| USA (non-Hispanic White) | ~32 | I–III |
| Western Europe | ~12–25 | II–III |
| Southern Europe | ~6–12 | III–IV |
| East Asia (China, Japan) | ~0.4–0.7 | IV–V; acral predominates |
| Sub-Saharan Africa | ~0.3–0.7 | V–VI; acral predominates |
In Australia — the global epicentre — the lifetime risk of cutaneous melanoma is ~1 in 18 for men and ~1 in 26 for women, roughly 5× the USA rate. Inversely, in populations with phototype V/VI, melanoma is rare overall and is dominated by acral subtype on palms, soles, and nail beds — a UV- independent subtype with distinct genetics (KIT, often non-CSD).
6. Age, Sex & Anatomic Site
- Age. Median age at diagnosis ~65; nonetheless, melanoma is one of the commonest cancers in adolescents and young adults — in US adults aged 25–29, melanoma is among the top three cancers by incidence in women.
- Sex. Male incidence is ~1.5× female in most populations, and male mortality ~2× female — the latter reflecting a worse prognosis at any given Breslow thickness, possibly mediated by anatomical site (truncal in men) and delayed presentation.
- Anatomic site (men). Trunk (back) dominates — the “intermittent intense” pattern of weekend / holiday sun exposure.
- Anatomic site (women). Lower limbs dominate, with truncal disease catching up over time.
- Older adults. Head and neck dominate, especially the lentigo maligna subtype on chronically sun-damaged skin.
- Pediatric. Melanoma is rare under 20 (~7 cases per 1,000,000); often arises within congenital nevi or in xeroderma pigmentosum, and may not follow ABCDE.
7. Risk Factors
Two broad axes drive cutaneous melanoma risk: a genetic axis (phototype, family history, predisposition syndromes) and a UV-exposure axis (intermittent intense sunburns and tanning-bed use being far more potent than chronic occupational exposure for cutaneous melanoma):
| Factor | Approx. RR | Mechanism / comment |
|---|---|---|
| Fitzpatrick I–II (fair, burns easily) | 2–4 | Pheomelanin-dominant, MC1R variants |
| Red hair / freckling | 2–4 | MC1R loss-of-function alleles |
| >100 common nevi | ~7 | Single strongest phenotypic risk marker |
| ≥5 atypical (dysplastic) nevi | ~6 | — |
| Personal history of melanoma | ~9 | ~5–10% lifetime risk of second primary |
| Family history (1st-degree) | ~2 | Up to ~10 if CDKN2A carrier |
| CDKN2A germline mutation | 30–70 lifetime risk | Familial atypical multiple-mole melanoma (FAMMM) |
| Xeroderma pigmentosum | ~1000 | NER deficiency — UV repair failure |
| ≥5 lifetime sunburns | ~2 | Intermittent intense pattern |
| Tanning-bed use (any) before age 35 | ~1.6 | IARC group 1 carcinogen since 2009 |
| Chronic immunosuppression (SOT) | ~3 | Solid-organ transplant recipients |
The classical childhood-sunburn observation (Whiteman et al., Cancer Causes Control 2001) shows that ≥5 severe sunburns before age 20 roughly doubles lifetime melanoma risk — childhood and adolescence are an especially vulnerable window. Tanning-bed exposure was reclassified as IARC group 1 carcinogenic to humans in 2009; subsequent legislation banning under-18 use in many jurisdictions is one of the few primary-prevention interventions with hard population-level evidence.
8. A Brief History
- ~5th century BC — Hippocrates describes “melas oma” (black tumour) in the Corpus Hippocraticum.
- 1787 — John Hunter excises what is now thought to be a metastatic melanoma; the specimen survives at the Hunterian Museum, London.
- 1820 — William Norris (Stourbridge) publishes the first English-language case series of “melanosis”, describing familial clustering and metastatic pattern.
- 1838 — Robert Carswell coins the term “melanoma”.
- 1907 — William Sampson Handley codifies wide local excision (5 cm margins) — a doctrine that persisted for >70 years.
- 1969 — Wallace Clark publishes “levels of invasion”: Clark levels I–V.
- 1970 — Alexander Breslow (Washington DC) demonstrates that tumour thickness in millimetres outperforms Clark level as a prognostic measure.
- 1974 — Australia’s SunSmart era begins (later formalised as the “Slip!Slop!Slap!” campaign, 1981).
- 1985 — Friedman et al. introduce the ABCD criteria (Asymmetry, Border, Colour, Diameter); “E” (Evolution) added later.
- 1992 — Morton describes lymphatic mapping and sentinel-node biopsy for melanoma.
- 1998 — High-dose interferon-α adjuvant therapy approved (modest benefit).
- 2002 — Davies, Futreal & colleagues identify BRAF V600E in ~50% of melanomas (Nature 2002).
- 2010 — Phase 3 of ipilimumab (anti-CTLA-4) shows the first OS benefit ever in stage IV melanoma (Hodi et al., NEJM).
- 2011 — Vemurafenib approved for BRAF V600E (BRIM-3, Chapman et al., NEJM).
- 2014 — Pembrolizumab and nivolumab (anti-PD-1) approved for advanced melanoma.
- 2015 — CheckMate-067 randomises ipilimumab + nivolumab vs single agents (Larkin et al., NEJM).
- 2018 — AJCC 8th edition staging (Gershenwald et al., CA 2017) implemented.
- 2018 — James Allison & Tasuku Honjo share the Nobel Prize for the discovery of immune-checkpoint blockade.
- 2022 — CheckMate-067 10-year follow-up: ~43% OS for ipi+nivo in stage IV (Wolchok et al., NEJM).
- 2024 — Lifileucel (TIL therapy) approved by FDA (first solid-tumour TIL approval).