Age-Related Variations in Clinical, Histological, and Genetic Characteristics in Multiple and Familial Melanomas: A Study of 333 Patients

<b>Background/Objectives</b>: Melanoma is an aggressive cutaneous malignancy with a rising incidence. While most cases are sporadic, 5-10% are hereditary, especially in patients with multiple or familial melanomas. The aim of this study is to explore the epidemiological, clinical, histological, and genetic features of this class of patients to identify risk factors for better management and surveillance. <b>Methods</b>: Between 2021 and 2024, patients with multiple melanomas or a familial history of melanoma were recruited. Collected data included demographic, clinic-pathologic features, and genetic analyses. <b>Results</b>: Patients >60 years had a higher prevalence of multiple melanomas (>50%, <i>p</i> = 0.0002), while familial melanoma was more common in those <40 years (54.3%). UV exposure increased with age, while sunscreen use decreased (<i>p</i> = 0.0004). Younger patients showed the highest nevi counts (mean: 139.6) and density (<i>p</i> < 0.0001). Dermatologists more frequently detected subsequent melanomas in older patients (>60 years) (<i>p</i> = 0.001). Genetic testing and melanoma subtypes showed no significant age-related differences. <b>Conclusions</b>: melanoma can develop at any age, and early detection through regular screening is crucial. Older patients (>60 years) have a higher prevalence of multiple melanomas, influenced by UV exposure and genetics. Indeed, in our cohort, a history of sun exposure, sunburns, and tanning bed use emerged as key risk factors, particularly among older individuals. Genetic testing showed a 4.3% rate of pathogenic/likely pathogenic variants, mainly in <i>CDKN2A</i>. Family history and nevus burden are significant risk factors, highlighting the need for targeted surveillance in high-risk populations.