Clinical, dermoscopic and confocal microscopy features of multiple primary melanomas according to pathogenic germline variant status: a retrospective, hospital-based study

Background Familial melanoma comprises approximately 10% of cutaneous melanomas. Individuals with pathogenic germline variants have a higher risk of developing multiple primary melanomas (MPMs) than individuals who lack these variants. However, differences in clinical, dermoscopic and reflectance confocal microscopy (RCM) features between variant carriers and noncarriers are not well established. Objectives To compare the clinical, dermoscopic and RCM characteristics of patients with MPMs with or without the pathogenic germline variants associated with familial melanoma. Methods This retrospective study included 45 patients with MPMs who underwent Sanger sequencing and/or custom next-generation sequencing (NGS) panels between 2020 and 2023. Clinical, dermoscopic and RCM images were reviewed and compared between pathogenic germline variant-positive and pathogenic germline variant-negative groups. Results Pathogenic germline variants in moderate-risk to high-risk melanoma genes were found in 15 patients. Carriers were diagnosed at a younger age than noncarriers [mean (SD) 41.8 years (10.1) vs. 53.5 (10.4); P < 0.001], more frequently had a family history of melanoma (P = 0.02), had more melanomas arising from pre-existing naevi (P < 0.001) and less actinic damage (P = 0.05). CDKN2A carriers were younger [38.9 years (11.4) vs. 45.3 (7.8)] and had fewer melanomas [2.7 (1.3) vs. 4.1 (1.2); P = 0.05] than MITF or POT1 carriers. CDKN2A carriers had low (n = 5), medium (n = 1) or high (n = 2) naevus counts, while MITF carriers had medium (n = 1) to high (n = 4) counts. Dermoscopically, pathogenic germline variant carriers showed fewer regression structures (8.3% vs. 39.8%; P = 0.01). RCM findings indicated a nonsignificant trend toward more dendritic cell-type melanomas in noncarriers (33.9% vs. 19.4%). Conclusions Patients with MPMs who carry pathogenic germline variants demonstrate distinct clinical and imaging profiles compared with patients who do not carry these variants. These findings support personalized surveillance of individuals at high risk of developing MPMs and the integration of genetic testing into melanoma management. Further studies with larger cohorts are needed to refine genotype-phenotype associations.