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Melanoma in special populations

TL;DR — Four populations sit outside the evidence base that governs standard melanoma care. Solid organ transplant recipients have roughly twice the melanoma incidence (SIR 2.29, 95% CI 2.07–2.49), present at more advanced stage (adjusted OR 4.29, 2.04–9.00 for stage II–IV) and have higher melanoma-specific mortality (adjusted HR 1.93, 1.03–3.63) (Park 2020, PMID 32111554); giving them checkpoint inhibitors carries a 36.2% one-year acute-rejection rate and 18.4% graft loss against a 31.6% objective response (Saleem 2025, PMID 40545616). Pregnancy-associated melanoma is diagnosed at greater thickness during pregnancy than postpartum (median 0.75 vs 0.60 mm, P = .002), and the incidence rise over time was fully explained by maternal age (Bannister-Tyrrell 2015, PMID 25349945). Paediatric melanoma is dominated by spitzoid (31%) and superficial spreading (26%) histology with a 46% sentinel-node positivity rate and 7% fatality — a combination that inverts the usual relationship between nodal positivity and outcome (Hawryluk 2024, PMID 38040338). People with skin of colour are diagnosed at more advanced stages with worse survival and a different subtype mix (Brunsgaard 2023, PMID 35533771). None of these groups was represented in the registrational trials.

Solid organ transplant recipients and the immunosuppressed

Question Evidence
Incidence and stage Ontario population-based cohort, adults receiving a first solid organ transplant 1991–2012 followed to 2013: 51 transplant recipients with melanoma versus 11,369 without and 255 matched non-transplant melanoma patients. Melanoma SIR 2.29 (95% CI 2.07–2.49); adjusted OR 4.29 (2.04–9.00) for stage II–IV at diagnosis; melanoma-specific mortality adjusted HR 1.93 (1.03–3.63); all-cause mortality after melanoma raised even for T1/T2 disease (adjusted HR 2.18, 1.13–4.21) (Park 2020, PMID 32111554)
Checkpoint inhibitors — the central dilemma Systematic review and individual-participant-data meta-analysis: 128 of 140 studies, 343 transplant recipients treated with checkpoint inhibitors; 76.9% male, 70.9% kidney recipients, median age 63 years, 72.9% receiving PD-1 inhibitors. Within 3 years 52.8% (43.9–61.6) died of cancer; acute rejection in 36.2% (30.7–41.7) at 1 year; graft loss in 18.4% (13.7–23.1) at 1 year; objective response 31.6% (25.0–37.7) at 1 year (Saleem 2025, PMID 40545616)
Kidney recipients specifically Single-centre retrospective series of 6 kidney transplant recipients with metastatic cancer (2 melanoma): 3 of 6 developed acute kidney injury, 2 biopsy-proven rejection with graft failure; 5 of 6 progressed, 1 remission (Venkatachalam 2020, PMID 31415036)
Broader syntheses Systematic reviews of checkpoint inhibitor use in transplant recipients (PMID 35390767; PMID 30992053); safety of immunotherapy after liver transplantation under a prospective standardised protocol (PMID 41082711); a case report of acute renal transplant rejection after nivolumab for metastatic melanoma (PMID 33558380)
Prospective strategy trial A recruiting single-group phase 1/2 study is testing nivolumab–ipilimumab with sirolimus and prednisone in 16 kidney-transplant recipients with selected unresectable or metastatic cutaneous cancers, explicitly including non-uveal melanoma (NCT05896839). No outcome results were available in the registry on 2026-09-01
Donor-transmitted melanoma A recognised and separately reviewed phenomenon (PMID 32328846)

The transplant trade-off is quantified and stark: a ~32% chance of tumour response against a ~36% chance of acute rejection and ~18% chance of graft loss within a year, with over half dying of cancer within three years regardless (PMID 40545616). No randomised evidence exists and none is likely. Nicotinamide chemoprevention has been tested in transplant recipients for keratinocyte cancers, not melanoma (PMID 36856616). Immunotherapy in patients with altered immune systems has been reviewed as a category (PMID 41461997; PMID 28241095).

Pregnancy

Finding Detail
Incidence and trend 577 pregnancy-associated melanomas in New South Wales 1994–2008 (195 during pregnancy, 382 within 12 months postpartum). Crude incidence rose from 37.1 to 51.84 per 100,000 maternities; adjusting for maternal age accounted for the entire trend (Bannister-Tyrrell 2015, PMID 25349945)
Thickness Melanomas diagnosed during pregnancy were thicker than those diagnosed postpartum (median 0.75 vs 0.60 mm, P = .002) (PMID 25349945)
Obstetric outcomes Associated with increased risk of a large-for-gestational-age infant, but not with preterm birth, planned birth, caesarean section or stillbirth. Parity was inversely associated: ≥3 previous pregnancies gave 0.59 times the odds versus nulliparity (0.42–0.84, P = .003) (PMID 25349945)
Placental and fetal metastasis Literature review identified 87 patients with placental or fetal metastasis from any cancer; 27 (31%) were melanoma — the commonest single cause. The fetus was affected in 6 of 27 melanoma cases (22%), and 5 of those 6 infants died of disease (Alexander 2003, PMID 12775744)
Systematic review of fetal/placental metastases Across pregnant patients with cancer generally (PMID 35182890); maternal and perinatal outcomes in pregnancy-associated melanoma reviewed separately (PMID 28527349); recent syntheses of mechanisms, risks and management (PMID 42089033; PMID 41975782)
Uveal melanoma in reproductive-age women Pregnancy and survival outcomes after brachytherapy have been reported (PMID 39333941)

Melanoma is the most frequent cancer to metastasise to placenta and fetus, which makes placental examination after delivery in a woman with metastatic melanoma a defined clinical action rather than a precaution (PMID 12775744).

Children and adolescents

Finding Detail
Presentation 317 patients under 20 diagnosed 1995–2015 across 11 academic centres: 73% diagnosed in adolescence (≥11 years); spitzoid 31% and superficial spreading 26% the commonest subtypes; 11% arose from congenital nevi. Adolescents with melanoma more often had a family history of melanoma than controls (P = .046) (Hawryluk 2024, PMID 38040338)
Nodal and outcome paradox Sentinel node biopsy performed in 68% and positive in 46%, yet fatality was 7% (PMID 38040338) — a nodal positivity rate several-fold higher than adult melanoma with far lower mortality
Atypical spitzoid tumours 76 histologically equivocal tumours analysed by array CGH (median age 16, median follow-up 90 months): chromosomal aberrations in 59%; the initial histological diagnosis changed after aCGH in 47% of cases; final classification 61% benign, 18% ambiguous, 21% malignant. Positive sentinel nodes (6 of 29) occurred at similar rates across all diagnostic groups (P = .83) and were not associated with unfavourable outcome; two local recurrences and no metastasis beyond the sentinel node (Gassenmaier 2022, PMID 35104769)
Other series Prepubertal versus adolescent outcomes (PMID 21451389); clinical features and outcomes of spitzoid proliferations in children and adolescents (PMID 30467833); a UK twenty-year tertiary-centre review (PMID 40926920); paediatric incidence trends in Texas and SEER-13 (PMID 30729662) and geographic trends in US paediatric melanoma (PMID 37285703)
Trial inclusion KEYNOTE-716 enrolled patients from age 12 with paediatric-adjusted dosing (Luke 2022, PMID 35367007) — one of the few adjuvant trials to do so

The paediatric sentinel-node paradox is the central interpretive problem: 46% nodal positivity with 7% mortality means nodal status carries a different meaning in children, and the spitzoid data show that a positive node in an atypical spitzoid tumour predicts nothing (PMID 38040338; PMID 35104769). Applying adult nodal-based staging and adjuvant-eligibility rules to children is therefore not justified by the available data.

Older adults

Adjuvant anti-PD-1 in 885 patients aged ≥65 (280 aged ≥75) with resected stage III/IV melanoma in the nationwide Dutch Melanoma Treatment Registry 2018–2022 found grade ≥3 immune-related adverse events in 15.5% of those aged 65–74 and 13.9% of those ≥75, with no significant correlation between age and grade ≥3 events; increasing comorbidity count was associated with higher risk (multivariable OR 1.83, 95% CI 0.99–3.40), and 1-year recurrence-free survival of 80.0% matched registration trials and other real-world data (Özkan 2024, PMID 39368226). Age itself is therefore not the risk variable; comorbidity is. Related work has examined immunotherapy outcomes by age (PMID 32097116), early cessation of anti-PD-1 in patients ≥80 (PMID 38838764) and prognostic scoring in older patients with solid tumours (PMID 36291861).

Older age nonetheless carries independent prognostic weight: rapid tumour growth occurs more often in people ≥70 (geometric mean ratio 2.8) (Liu 2006, PMID 17178980), KIT mutation is commoner with age (Gong 2018, PMID 29746316), and melanoma incidence continues to rise in older cohorts while falling in younger ones (Helgadottir 2024, PMID 39245436; O'Sullivan 2026, PMID 41932245).

Skin of colour

Melanoma is about 30 times more common in White than Black people in the US, but people with darker skin are diagnosed at later stages when treatment is harder (Mangione 2023, PMID 37071089). The subtype mix differs — acral lentiginous and mucosal melanoma account for a larger share of diagnoses — and anatomical distribution and dermatoscopic patterns differ enough that distinguishing physiological from pathological pigmentation is a specific skill (Brunsgaard 2023, PMID 35533771). Survival gaps persist within stage: in CONCORD-3, distant-stage one-year net survival improved in both Black and White patients but remained consistently lower in Black patients (Di Carlo 2020, PMID 33409455). Acral melanoma disparities attenuate but do not disappear after adjustment for socioeconomic status and stage (Yan 2022, PMID 34363907) — see acral and mucosal melanoma.

HIV infection and pre-existing autoimmune disease

Both groups were excluded from the registrational checkpoint-inhibitor trials.

Group Evidence
People with HIV A PRISMA-guided systematic review identified 73 patients (90.4% male, mean age 56.1 years) from 13 articles (11 case reports, 2 case series) and 4 meeting abstracts, most treated with anti-PD-1 (Cook 2019, PMID 30730549). A multicentre real-world study of 54 people with HIV treated with checkpoint inhibitors for skin cancer — 64.8% melanoma, 22.2% cutaneous squamous cell carcinoma — found 89% male, 92.6% with suppressed viral load, 81.5% receiving first-line anti-PD-(L)1 monotherapy, and immune-related adverse events in 42.6% at a median onset of 43.5 days (IQR 20.5–126), with maximum grade 1/2 in 39% (de Givry 2025, PMID 41396687)
Pre-existing autoimmune disorders Approximately a quarter of cancer patients carry a concomitant autoimmune diagnosis, and the majority of checkpoint-inhibitor trials excluded them; a retrospective analysis assessed incidence of autoimmune-disease worsening, all immune-related events, time to worsening and survival difference (Kumar 2022, PMID 35671576)
Both, reviewed together Checkpoint inhibitors in challenging populations (Johnson 2017, PMID 28241095); immunotherapy for melanoma in patients with altered immune systems (Peacker 2026, PMID 41461997)

The evidence base for both groups is case series and registry data. For people with HIV the toxicity signal appears comparable to the general population and mostly low-grade; for autoimmune disease the question of disease worsening remains inadequately quantified. Neither supports a confident recommendation.

Melanoma of unknown primary

Finding Detail
Genomic and clinical character In 727 patients with melanoma of unknown primary from the prospective multicentre German ADOREG registry and the Essen tumour database (1999–2022), compared against 587 stage III/IV patients with known primary from the same centre, with next-generation sequencing of available samples and survival adjusted for age, sex and stage: melanoma of unknown primary showed an oncogenic pattern and clinical course resembling sun-exposed melanoma (Lodde 2026, PMID 41719057). Median follow-up 3.5 years
Survival in the modern era Population-based retrospective analysis reports improved survival outcomes for melanoma of unknown primary in the era of novel therapies (Tupper 2024, PMID 38458569)
Comparative outcomes Advanced melanoma of unknown primary versus known primary outcomes have been compared directly (PMID 39206786), and single-institution and review series describe management (PMID 28746931; PMID 30481368; PMID 33383207; PMID 39410614)

Melanoma of unknown primary accounts for a meaningful share of stage III and IV presentations and is not a distinct biological entity on current evidence — which is itself the useful finding, since it means the cutaneous evidence base applies.

The retinoblastoma survivor population

Survivors of heritable retinoblastoma carry substantially increased melanoma risk; survivors of non-heritable retinoblastoma do not. Across 1,851 White long-term survivors diagnosed 1914–2006 and 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 a median age at diagnosis about 20 years younger in heritable survivors; sun sensitivity and phenotype did not vary by skin-cancer status, pointing to a genetic rather than exposure mechanism (Kleinerman 2021, PMID 34153328). Any-cancer figures come from a separate cohort: SIR 11.9 (95% CI 10.4–13.5) for heritable versus 0.8 (0.5–1.2) for non-heritable survivors, with the frequently quoted 3.1–17 figure being a range across melanoma, CNS, oral cavity and breast subsequent neoplasms rather than a melanoma-specific estimate (Schonfeld 2021, PMID 33473166). RB1 is not on standard melanoma germline panels (Goldstein 2026, PMID 42201696). Detail lives at retinoblastoma second cancers and survivorship and in germline predisposition; it is not restated here.

Interpretation rules for this page

  • "Retinoblastoma survivors" is never a single risk group — heritable and non-heritable differ by 4.5% versus 0.7% 50-year melanoma incidence (PMID 34153328).
  • In transplant recipients, quantify both arms of the trade-off — response rate and rejection/graft-loss rate (PMID 40545616).
  • Pregnancy-associated melanoma incidence trends are age-confounded (PMID 25349945).
  • Nodal positivity means something different in children and in atypical spitzoid tumours (PMID 38040338; PMID 35104769).
  • Age is not the toxicity variable in older adults; comorbidity count is (PMID 39368226).
  • Registrational trial populations were overwhelmingly White and cutaneous, which bounds every effect size on this page (PMID 35293617).

Open questions

  • Can checkpoint inhibition be given to transplant recipients with modified immunosuppression that preserves the graft? A 16-patient phase 1/2 strategy trial is recruiting, but no prospective outcome result is available (PMID 40545616; NCT05896839).
  • Why are pregnancy-diagnosed melanomas thicker than postpartum ones — delay, or biology (PMID 25349945)?
  • What does a positive sentinel node mean in a child, and should paediatric adjuvant eligibility be defined by it (PMID 38040338; PMID 35104769)?
  • Should array CGH or methylation profiling be standard for histologically equivocal spitzoid tumours, given a 47% diagnosis-change rate (PMID 35104769; PMID 35737508)?
  • Are RB1-carrier retinoblastoma survivors reached by melanoma surveillance pathways built around CDKN2A, MC1R and BAP1 (PMID 34153328; PMID 42201696)?
  • Does the skin-of-colour survival gap persist after full adjustment for stage, subtype and treatment access (PMID 33409455; PMID 34363907)?

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