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Acral and mucosal melanoma

TL;DR — Acral and mucosal melanoma are genomically and clinically distinct from cutaneous melanoma and are systematically under-represented in the trials that set the standard of care. Mucosal melanoma has a low point-mutation burden with high numbers of structural variants including recurrent rearrangements targeting TERT, CDK4 and MDM2, with NRAS, BRAF, NF1, KIT, SF3B1, TP53, SPRED1, ATRX, HLA-A and CHD8 significantly mutated (Newell 2019, PMID 31320640). GWAS finds acral melanoma "uniquely unrelated to pigmentation" among melanoma subtypes (Landi 2020, PMID 32341527). The efficacy gap is large and consistent: across 1,135 patients treated with anti-PD-1 monotherapy at five institutions in the US, Australia and China, White patients had objective response 54% (95% CI 50–57) versus 20% (13–28) for East Asian, Hispanic and African patients in non-acral cutaneous and unknown-primary melanoma, with White ethnicity independently associated with higher response (OR 4.10, 2.48–6.81) (Bai 2022, PMID 35293617). A Spanish registry comparison of 69 acral against 724 cutaneous melanomas found first-line immunotherapy response 15.0% versus 39.1% (P = .0033) and median overall survival 17.3 versus 43.0 months (P = .007) (Gonzalez-Cao 2026, PMID 40841506). Acral lentiginous histotype carries independently worse disease-free survival after full adjustment (adjusted HR 1.25, 1.02–1.52) (Mandalà 2022, PMID 35421840).

Distinct genomics

Subtype Genomic signature
Mucosal 67 whole genomes with 45 exomes for driver validation: low point-mutation burden, high structural-variant burden with recurrent rearrangements targeting TERT, CDK4 and MDM2. Significantly mutated: NRAS, BRAF, NF1, KIT, SF3B1, TP53, SPRED1, ATRX, HLA-A, CHD8. SF3B1 mutations commoner in female genital and anorectal melanomas; CTNNB1 mutations implicate WNT-signalling defects; TERT aberrations and ATRX mutations associate with telomere-length alterations. Mutation profiles suggest potential susceptibility to CDK4/6 and/or MEK inhibition (Newell 2019, PMID 31320640)
Acral Whole-genome sequencing and SNP arrays of five metastatic tumours with matched normals, combined with published data, defined recurrently mutated driver genes and contrasted the acral genomic landscape against mucosal, uveal and cutaneous melanoma (Furney 2014, PMID 24913711). East Asian acral melanoma has its own characterised mutational landscape (PMID 39798666), and comparative whole-genome analysis of in situ versus invasive acral lentiginous melanoma links copy-number gains of GAB2, PAK1, UCP2 and CCND1 to invasion (PMID 38916228)
Both, in a Japanese cohort Acral (n = 52): BRAF 9%, NRAS 17%, KRAS 8%, KIT 19%, NF1 7%. Mucosal (n = 15): drivers in NRAS, KRAS, NF1, PTEN, GNAQ, KIT. Median tumour mutational burden across all melanoma types 4.6 mutations/Mb with no significant difference between cutaneous and acral/mucosal in this cohort (Hida 2024, PMID 39564955)
Germline architecture Acral melanoma is uniquely unrelated to pigmentation across regional and host-factor analyses of 36,760 melanoma cases (Landi 2020, PMID 32341527)

KIT is the one actionable recurrent driver. Across 32 studies and 5,224 patients, KIT mutation occurred in 9.5% overall and associated with mucosal site (OR 1.363, 1.094–1.697, P = .006), acral site (OR 1.374, 1.123–1.682, P = .02), chronically sun-damaged skin (OR 1.880, 1.127–3.136, P = .016) and older age, and negatively with non-CSD skin (OR 0.562, 0.392–0.805, P = .002) (Gong 2018, PMID 29746316).

Epidemiology

Measure Value Source
Acral lentiginous melanoma, US age-adjusted incidence 2006–2015 2.0 per million person-years (1,724 cases vs 87,442 non-acral cutaneous) Huang 2020, PMID 32208196
Acral melanoma, Sweden 1990–2020 1,000 cases; no significant change in standardised incidence 1996–2020 despite rising absolute counts Helkkula 2024, PMID 39140487
Acral 5-year melanoma-specific survival, Sweden 75.8–77.9% (women), 62.4–71.7% (men) across three diagnostic eras PMID 39140487
Acral 5-year disease-specific survival, SEER 2000–2016 77.8% (95% CI 75.9–79.9), n = 2,245 Yan 2022, PMID 34363907
Mucosal melanoma, SEER 1988–2010 2,755 cases; incidence rises exponentially with age, unlike cutaneous Bishop 2014, PMID 24272143
Mucosal 5-year relative survival 34% aggregate, range 3–69% by site PMID 24272143
Cutaneous 5-year relative survival, same series 89% PMID 24272143

The stability of acral incidence against a steeply rising cutaneous incidence is the strongest population-level evidence that the cutaneous rise is UV- or detection-driven rather than a general melanocytic phenomenon (PMID 39140487) — see screening and overdiagnosis.

The efficacy gap

Comparison Result
Anti-PD-1 monotherapy by ethnicity, 1,135 patients, 5 institutions, US/Australia/China, 2009–2019 (Bai 2022, PMID 35293617) In non-acral cutaneous and unknown-primary melanoma: objective response 54% (50–57) in White vs 20% (13–28) in East Asian/Hispanic/African patients (adjusted P < .001); median PFS 14.2 (10.7–20.3) vs 5.4 months (4.5–7.0) (adjusted P < .001). White ethnicity independently associated with higher response (OR 4.10, 2.48–6.81, adjusted P < .001)
Acral vs cutaneous, Spanish registry (Gonzalez-Cao 2026, PMID 40841506) 69 acral (17 stage III, 52 stage IV) vs 724 cutaneous, predominantly non-Hispanic White. Stage IV acral patients older (median 73.6 vs 66.6 years, P = .001), less often BRAF-mutant (9.6% vs 60.7%, P = .0001). First-line immunotherapy: response 15.0% vs 39.1% (P = .0033), median PFS 5.5 vs 15.3 months (P = .001), median OS 17.3 vs 43.0 months (P = .007). Stage III acral deeper (T4b 52.9% vs 25.3%, P = .02). Adjuvant anti-PD-1: median RFS 10.2 months vs not reached (P = .017), 5-year OS 36.1% vs 75.8% (P = .034)
Mucosal melanoma checkpoint inhibitors, systematic review of 41 studies (Li 2020, PMID 32489431) Ipilimumab monotherapy: response 0–17%, median PFS <5 months, median OS <10 months in most studies. Nivolumab or pembrolizumab monotherapy: response >15% and median OS >11 months in most studies
Acral histotype, adjusted (Mandalà 2022, PMID 35421840) Adjusted DFS HR 1.25 (1.02–1.52, P = .028) vs superficial spreading melanoma after adjustment for age, sex, Breslow thickness, ulceration and sentinel-node status; nodular histotype showed no independent effect

The Spanish registry finding is the most informative single comparison because its acral and cutaneous populations are both predominantly non-Hispanic White, which separates subtype from ethnicity — two variables the international observational data cannot disentangle (PMID 40841506; PMID 35293617).

Recognising it

Acral melanoma is missed because acral melanocytic nevi are common and the standard pigment rules do not apply at these sites.

Feature Evidence
Parallel ridge pattern A band-like pigmentation on the ridges of the skin markings, described as highly specific for melanoma in situ on acral volar skin, with dermoscopic–histopathological correlation in 22 acral melanocytic lesions (Ishihara 2006, PMID 16456320)
In acral lentiginous melanoma in situ 21 patients with available dermoscopic images, mean age 58.5 years, 90.5% on the sole, mean maximal diameter 19.9 ± 13.7 mm; dermoscopic features compared between small (<15 mm) and large (≥15 mm) lesions, with the parallel ridge pattern prominent (Han 2020, PMID 33239715)
Brazilian plantar cohort (n = 48, 15 years) Mean age 62.54, 62.5% women. Amelanotic tumours were more prevalent in lighter phototypes (20% vs 7.7%); polychromia was the commonest finding (94.4%); parallel ridge pattern prevalence 78%; a serrated pattern was associated with lower Breslow thickness (P = .041); ulceration on histopathology (P = .013) or dermoscopy (P = .047) associated with greater thickness (Garcia 2025, PMID 39616094)
Mimics Acral melanoma has been reported simulating warts (PMID 16918571), and subcorneal haematoma on palms and soles has distinguishing dermoscopic features (PMID 38651845)
Reviews Clinical presentation, diagnosis and management of acral melanoma foot lesions (PMID 29235153); diagnosis and management of acral pigmented lesions (PMID 37556446); clinical presentation correlated with mutational status (PMID 29512974); a clinic-to-guidelines synthesis (PMID 41219165)

The functional cost of treating these sites is distinctive. Reconstruction after wide excision on the sole, hand and nail unit has its own literature — glabrous-skin closure of plantar defects (PMID 25749930), synthetic dermal matrix with split-thickness grafts and functional podiatry outcomes (PMID 37724606), perforator flaps for foot melanoma (PMID 41294367), and conservative or functional approaches to subungual melanoma (PMID 21812768; PMID 24322643; PMID 40083617). Margin trials excluded palms and soles by design (Hayes 2016, PMID 26790922), so the margin evidence on which these operations rest is extrapolated.

Subtype-directed therapy

Approach Evidence
c-KIT inhibition Systematic review and one-arm meta-analysis of 19 single-arm studies, 601 patients: imatinib (8 studies), nilotinib (7), dasatinib (3), sunitinib (1). Pooled objective response 15% (95% CI 12–18); highest for nilotinib at 20% (14–26). By subtype: mucosal 14% (6–24), acral lentiginous 22% (14–30). At least one severe adverse event in 42% (34–50) (Steeb 2021, PMID 34562816)
Anti-PD-1 plus VEGFR inhibition (mucosal) Toripalimab plus axitinib in metastatic mucosal melanoma, 3-year update at median 42.5 months' follow-up in 29 chemotherapy-naive patients: median OS 20.7 months (95% CI 9.7–32.7), median PFS 7.5 months (3.8–14.8), median duration of response 13.4 months (5.5–20.6); 1-, 2- and 3-year OS 62.1%, 44.8%, 31.0%. PD-L1 expression and TMB were not associated with benefit; a 12-gene expression signature correlated with improved PFS (Li 2022, PMID 35193932); the phase 1 report is PMID 31403867
Neoadjuvant in mucosal melanoma Phase 2 trial of neoadjuvant toripalimab plus axitinib in resectable mucosal melanoma (PMID 37956739)
Isolated limb perfusion/infusion for acral in-transit disease In 364 patients treated 2002–2023, response rates did not differ between acral (n = 84) and non-acral (n = 280) on multivariable analysis, but median PFS was shorter for acral (5.6 vs 7.7 months, P = .02), as were out-of-field PFS (9.6 vs 15.3 months, P = .02) and disease-specific survival (3.5 vs 7.8 years, P = .008) (Dugan 2025, PMID 40413325)
Salvage anti-PD-1 in a Chinese population Five-year follow-up of the POLARIS-01 phase 2 trial of toripalimab monotherapy (PMID 38547052)

Disparities, and what drives them

Acral melanoma disproportionately affects people with darker skin, and its outcomes are worse for reasons that are only partly biological.

  • Socioeconomic status and race. Among 2,245 SEER acral lentiginous melanoma patients 2000–2016, 5-year disease-specific survival was 77.8% (75.9–79.9). After adjustment, patients in the lowest and second-lowest SES quintiles had 1.33 (0.90–1.96) and 1.42 (1.03–1.97) times the risk of death versus the highest quintile; Hispanic White and Black patients had 1.48 (1.10–1.99) and 1.25 (0.88–1.79) times the risk versus non-Hispanic White patients. Hazard ratios decreased after adjusting for SES and stage at diagnosis (Yan 2022, PMID 34363907).
  • Beyond delayed diagnosis. Disparities in acral lentiginous melanoma have been analysed as extending beyond diagnostic delay (PMID 40562077), and treatment and survival disparities examined in the National Cancer Database (PMID 40773363).
  • Patterns of care. Whether the acral subtype accounts for differences in patterns of care in Black patients has been directly examined (PMID 33461732), as have dermatologic surgeons' approaches to the subtype (PMID 38059993).
  • Skin of colour generally. Melanoma in skin of colour is diagnosed at more advanced stages with worse survival, and acral lentiginous and mucosal melanoma represent a larger share of diagnoses (Brunsgaard 2023, PMID 35533771).
  • Amelanotic acral melanoma is diagnosed later than pigmented melanoma (Wu 2024, PMID 37690705).

Staging and surgical constraints

Mucosal melanoma has its own contested staging systems — mucosal-melanoma TNM, Ballantyne/Prasad and squamous-cell TNM — with disagreement about which correlates best with survival (Moya-Plana 2019, PMID 31421470; Michel 2014, PMID 23729399); see staging. Anatomically, standard excision margins are frequently unachievable at acral and mucosal sites, and margin trials excluded palms and soles by design (Hayes 2016, PMID 26790922) — see surgical management and margins.

Interpretation rules for this page

  • Do not apply cutaneous effect sizes to these subtypes. First-line immunotherapy response was 15.0% (acral) versus 39.1% (cutaneous) in one registry (PMID 40841506).
  • Distinguish subtype from ethnicity. The international observational data confound them; the Spanish registry does not (PMID 35293617; PMID 40841506).
  • Report mucosal site. Five-year relative survival ranges 3–69% across mucosal sites (PMID 24272143).
  • Structural variation, not point mutation, is the mucosal genomic signature — a mutational-burden framing misdescribes the disease (PMID 31320640).
  • A 15% pooled KIT-inhibitor response rate is a real but modest option, not a targeted-therapy equivalent of BRAF inhibition (PMID 34562816).
  • Disparity estimates attenuate after adjustment for SES and stage, which locates part of the effect in access rather than biology (PMID 34363907).

Open questions

  • Do standard-of-care effect sizes hold in acral and mucosal melanoma, and can any pooled registry analysis with subtype recorded answer this without dedicated trials (PMID 40841506; PMID 35293617)?
  • Why is acral melanoma genetically unrelated to pigmentation while sharing the melanoma diagnosis (PMID 32341527)?
  • Do the CDK4/6 and MEK susceptibilities predicted from mucosal genomics translate clinically (PMID 31320640)?
  • Is anti-PD-1 plus VEGFR inhibition superior to anti-PD-1 alone in mucosal melanoma? The evidence is single-arm (PMID 35193932).
  • How much of the acral survival disparity is access and how much is biology, given that adjustment for SES and stage attenuates but does not eliminate it (PMID 34363907)?
  • Which mucosal staging system should be standard (PMID 31421470; PMID 23729399)?
  • Should acral lentiginous histotype be a stage modifier, given its independent adverse effect after full adjustment (PMID 35421840)?

References

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