Cancer - melanoma
Description
- Malignancy of melanocytes; the solid tumour where immunotherapy was first proved
Subtypes
| Subtype | % | Features |
|---|---|---|
| Superficial spreading | ~70% | Intermittent sun exposure, trunk/legs, radial growth phase first |
| Nodular | ~15% | Vertical growth from the outset - thick at diagnosis, worst prognosis, often amelanotic |
| Lentigo maligna | ~10% | Chronically sun-damaged skin, elderly, face; long in-situ phase |
| Acral lentiginous | ~5% | Palms, soles, subungual; not sun-related, equal across ethnicities, often late |
| Desmoplastic | rare | Neurotropic, high local recurrence, high TMB - very immunotherapy-responsive |
Non-cutaneous
- Uveal - GNAQ/GNA11 driven, no BRAF; haematogenous spread to liver, not lymphatics; tebentafusp if HLA-A*02:01
- Mucosal - anorectal, vulvovaginal, sinonasal; KIT mutations; poor prognosis
- Both are biologically distinct - do not apply cutaneous algorithms
Epidemiology
- Australia has the highest incidence in the world - ~17,000/yr, ~1,300 deaths
- Lifetime risk ~1 in 17; 3rd commonest cancer in Australia
- Commonest cancer in Australians aged 20-39
- M>F overall; men present with thicker tumours (trunk/back), women more often legs
- Incidence falling in younger cohorts (SunSmart), rising in the elderly
Aetiopathogenesis
Risk factors
- Intermittent intense UV exposure and blistering sunburn, especially in childhood
- Fair skin, red hair, freckling, blue eyes (Fitzpatrick I-II), MC1R variants
- >100 naevi, or >5 atypical/dysplastic naevi - strongest phenotypic markers
- Personal or family history of melanoma
- CDKN2A (p16) germline mutation - familial melanoma-pancreatic cancer syndrome; also BAP1 (uveal), MITF, TERT promoter
- Immunosuppression (transplant, CLL), xeroderma pigmentosum
- Giant congenital melanocytic naevus
- Solarium use - banned commercially in Australia since 2015
Driver mutations
| Mutation | % | Context |
|---|---|---|
| BRAF (V600E ~3/4, V600K ~1/5) | 40-50% | Younger, little chronic sun damage, trunk |
| NRAS | ~20% | Older, chronically sun-damaged |
| NF1 | ~14% | Older, desmoplastic, very high mutation burden |
| KIT | ~2% | Acral and mucosal |
| GNAQ/GNA11 | - | Uveal only |
- BRAF -> constitutive MAPK (RAS-RAF-MEK-ERK) signalling
- *BRAF status predicts response to BRAF inhibitors but is not itself prognostic*
- High UV-induced mutational burden -> abundant neoantigens -> the reason melanoma responds to checkpoint blockade
Diagnosis
Recognition
- ABCDE - Asymmetry, Border irregularity, Colour variegation, Diameter >6 mm, Evolution
- The ugly duckling sign - a lesion unlike the patient's other naevi
- Dermoscopy improves sensitivity and specificity; sequential digital imaging in high-risk patients
- Amelanotic and nodular melanoma defeat ABCDE - any new, firm, growing, bleeding nodule needs biopsy
Biopsy
- Excisional biopsy with 2 mm margin, full thickness - allows accurate Breslow
- Never shave or punch a suspected melanoma from within the lesion - it destroys thickness measurement
Histopathology report - what drives everything
- Breslow thickness (mm) - the single most important prognostic factor
- Ulceration (upstages within each T category)
- Mitotic rate - second most important
- Clark level (superseded), LVI, perineural invasion, regression, margins
- Molecular: BRAF V600 in all stage III/IV (and stage IIB+ if adjuvant targeted therapy considered)
Staging (AJCC 8)
- T by Breslow + ulceration: T1 <=1.0, T2 >1-2, T3 >2-4, T4 >4 mm
- Sentinel node biopsy - staging, not therapeutic
- Offer if >=0.8 mm, or thinner with ulceration/high mitotic rate
- Completion lymph node dissection after a positive SLNB no longer improves survival (MSLT-II) - surveillance ultrasound instead
- Stage IV: LDH is part of the staging system and independently prognostic
- Imaging (CT/PET-CT, MRI brain) for stage III/IV; not indicated in stage I-II
Management
A. Primary excision - wide local excision margins
| Breslow | Margin |
|---|---|
| In situ | 5 mm (5-10 mm for lentigo maligna) |
| <=1 mm | 1 cm |
| >1-2 mm | 1-2 cm |
| >2 mm | 2 cm |
- Wider margins do not improve survival - they reduce local recurrence only
B. Stage I-IIA
- Excision alone; no adjuvant therapy, no staging imaging
- Skin surveillance + patient self-examination education
C. Stage IIB-IIC (thick, node-negative)
- Adjuvant pembrolizumab or nivolumab 12 months - improves recurrence-free survival (KEYNOTE-716, CheckMate 76K)
- A recent change - this group used to receive surgery alone
D. Stage III (nodal)
- Neoadjuvant is now preferred for macroscopic/palpable nodal disease
- Ipilimumab + nivolumab x2 before surgery (NADINA) - markedly better event-free survival than adjuvant nivolumab alone; those with a major pathological response may need no further therapy
- Or neoadjuvant pembrolizumab (SWOG S1801)
- Otherwise complete resection then adjuvant therapy 12 months:
- Pembrolizumab or nivolumab (any BRAF status; nivolumab > ipilimumab, CheckMate 238)
- Dabrafenib + trametinib if BRAF V600-mutant (COMBI-AD - 3-yr OS benefit)
- Adjuvant radiotherapy only for high-risk local/nodal recurrence risk (no survival benefit)
- Interferon is obsolete
E. Stage IV / unresectable
Immunotherapy is first line in almost everyone, regardless of BRAF status
- Nivolumab + ipilimumab - highest response rate (~58%) and best long-term plateau; substantial toxicity (grade 3-4 in ~55%)
- Nivolumab + relatlimab (anti-LAG-3) - better PFS than nivolumab alone with less toxicity than ipi/nivo
- Single-agent pembrolizumab or nivolumab - anti-PD-1 alone beats ipilimumab, which beats dacarbazine
- BRAF/MEK inhibitor (dabrafenib+trametinib, encorafenib+binimetinib, vemurafenib+cobimetinib) if BRAF-mutant
- Reserve for rapidly progressive, symptomatic, high-burden disease needing a fast response, or after immunotherapy failure
- Response ~68% combination vs ~48% BRAF alone vs ~5% dacarbazine
- Rapid deep response but median PFS ~12 months - resistance is the rule; immunotherapy responses are more durable
- Brain metastases - ipilimumab + nivolumab has genuine intracranial activity (CR ~26%, PR ~30%); combine with SRS
- Chemotherapy (dacarbazine, temozolomide) is a last resort
F. Targeted therapy toxicity
- BRAF inhibitor monotherapy -> paradoxical MAPK activation in BRAF-wild-type cells
- -> cutaneous SCC, keratoacanthoma, new primary melanomas, verrucal keratoses
- Adding a MEK inhibitor abolishes this (acts downstream) and prolongs time to resistance
- Dabrafenib + trametinib -> pyrexia (distinctive - can be severe, may need steroids), chills, nausea
- Vemurafenib + cobimetinib -> photosensitivity, rash, arthralgia, diarrhoea, transaminitis, QT prolongation
- MEK inhibitors -> rash, diarrhoea, peripheral oedema, retinopathy/CSR, dec LVEF (baseline echo + eye review)
G. Prevention and surveillance
- Sun protection, no solaria; no evidence for population skin screening, but targeted high-risk surveillance is standard
- High-risk (multiple primaries, dysplastic naevus syndrome, CDKN2A): 6-monthly total-body skin exam + dermoscopy + total-body photography
- Educate on self-examination - most recurrences are detected by the patient
Associations
- Dysplastic naevus syndrome, giant congenital naevus
- CDKN2A - familial melanoma + pancreatic cancer
- BAP1 tumour predisposition - uveal melanoma, mesothelioma, RCC
- Xeroderma pigmentosum
- Immunosuppression - solid organ transplant, CLL, HIV
- Parkinson disease (bidirectional epidemiological association)
- Vitiligo developing on immunotherapy - a good prognostic sign
- Paraneoplastic: melanoma-associated retinopathy
Natural history & complications
Prognosis
- Breslow thickness is the dominant factor - determines both recurrence risk and probability of occult nodal disease
- Mitotic rate second; ulceration upstages
- Stage I 5-yr survival >95%; stage IIC ~75%; stage III 40-80% (wide, node-dependent); stage IV historically ~10% at 3 yr, now ~50% at 5 yr with immunotherapy
Nodal involvement predicts systemic recurrence
- 1 involved node -> ~40-50%
- >1 node -> ~75%
Poor prognostic markers in metastatic disease
- Elevated LDH
- Brain metastases
- High tumour burden / extensive visceral disease
- These also predict poor immunotherapy response
Metastatic pattern
- Cutaneous: lymphatics first -> in-transit/satellite deposits, regional nodes -> lung, liver, brain, bone, bowel (can present as intussusception or obstruction)
- Uveal: haematogenous straight to liver - bypasses nodes
- Melanoma is the classic cause of very late recurrence - >10 years is well described
Survivorship
- ~5% develop a second primary melanoma - lifelong skin surveillance
- Ongoing risk of non-melanoma skin cancer
- Immunotherapy: permanent endocrinopathy; BRAF/MEK: cardiac and ocular monitoring
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