Genetically Enriched Melanoma: Predictive Value of Clinicopathological Characteristics in a Single-Center Cohort

Background/Objectives: Cutaneous melanoma is predominantly sporadic, although a subset of patients presents clinical features suggestive of inherited susceptibility. We introduced the pragmatic concept of genetically enriched (GE) melanoma, defined by the presence of early-onset melanoma, familial melanoma, or multiple primary melanomas. Methods: Its clinicopathological characteristics and prognosis were compared with those of sporadic melanoma. Demographic, clinicopathological, and survival data were analyzed using descriptive statistics, survival analysis, and Cox regression models. Results: In this retrospective single-center study, 1,874 patients were classified as having GE (n = 796, 42.5%) or sporadic melanoma (n = 1,078, 57.5%). Patients with GE melanoma were significantly younger at diagnosis (median age, 37 years [IQR 32–43] vs 57 years [IQR 50–66], p < 0.001) and were more frequently females than those with sporadic melanoma (56.8% vs. 51.4%, p = 0.024). The GE cohort also showed a distinct clinicopathological profile, with a higher proportion of melanoma in situ (20.2% vs. 15.2%), lower proportions of acral lentiginous (3.5% vs. 1.1%) and lentigo maligna (5.2% vs. 1.4%) melanoma, and a lower prevalence of previous malignancies. After a median follow-up of 8 years, disease-free survival did not differ significantly between the two cohorts (log-rank p = 0.23). Within the GE cohort, older age and male sex were associated with a higher risk of recurrence. Conclusions: Overall, patients fulfilling clinical criteria suggestive of inherited melanoma susceptibility appear to represent a distinct clinicopathological subgroup without evidence of poorer prognosis. The concept of GE melanoma may offer a pragmatic framework for identifying patients who may benefit from genetic counseling and tailored surveillance strategies.