Multiple primary and familial melanoma as distinct high-risk phenotypes: a retrospective cohort study

Introduction: Patients with multiple primary melanoma (MPM) and familial melanoma (FM) are commonly grouped as a single high-risk category, although they may represent biologically distinct entities reflecting different contributions of genetic susceptibility and environmental exposure. The aim of this study was to compare clinical, phenotypic, environmental, histopathological, and genetic features among patients with MPM only, FM only, and combined MPM+FM, as well as to identify independent predictors of MPM phenotype. Methods: In this retrospective observational study, 333 high-risk melanoma patients were stratified into MPM only, FM only, and MPM+FM. Clinical and histopathological variables were analyzed using appropriate statistical tests. Univariate and multivariate logistic regression models were used to identify independent predictors of MPM, comparing patients with MPM only versus those with FM only. Results: Age at first melanoma diagnosis differed significantly across groups (p < 0.001), with MPM patients presenting older age compared with FM and MPM+FM. Early-onset melanoma (<40 years) was more frequent in FM (40.7%) and MPM+FM (43.1%) than in MPM (21.0%; p = 0.001). A family history of melanoma-associated cancers was observed exclusively in FM and MPM+FM (p < 0.001). Tanning bed use was more frequent in patients with a familial component (p = 0.02). Histopathological features and nevus burden were comparable across groups. In both univariate and multivariate logistic regression analyses, increasing age (OR 1.04, 95% CI 1.02–1.07; p = 0.003) and male sex (OR 2.90, 95% CI 1.41–5.99; p = 0.004) were independently associated with MPM. Discussion: MPM and FM represent distinct high-risk melanoma phenotypes. MPM is associated with older age and male sex, suggesting a predominant role of cumulative environmental exposure, whereas FM is characterized by earlier onset and broader cancer susceptibility. These findings support phenotype-driven risk stratification and tailored surveillance strategies.