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September 10, 2025Open Access

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

Key Points

Germline variants were found in 15 out of 45 patients with multiple primary melanomas, indicating a significant genetic influence.
Variant carriers were diagnosed at a younger age (41.8 vs. 53.5 years, P < .001) and had more melanomas from existing nevi than non-carriers.
Dermoscopy revealed fewer regression structures in variant carriers (8.3% vs. 39.8%, P = .010), indicating potential differences in melanoma progression.
These distinct clinical and imaging profiles underline the importance of personalized surveillance strategies for high-risk melanoma patients.

Abstract

Abstract Background Familial melanoma represents approximately 10% of cutaneous melanomas. Individuals with pathogenic germline variants have a higher risk of developing multiple primary melanomas (MPM). However, differences in clinical, dermoscopic, and reflectance confocal microscopy (RCM) features between variant carriers and non-carriers are not well established. Objective To compare clinical, dermoscopic, and RCM characteristics of MPM patients with and without germline variants associated with familial melanoma. Methods This retrospective study included 45 MPM patients 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 variant-positive and variant-negative groups. Results Germline variants in moderate- to high-risk melanoma genes were found in 15 patients. Carriers were diagnosed at a younger age (41.8 ± 10.1 vs. 53.5 ± 10.4; P .001), had a more frequent family history of melanoma (P = .015), more melanomas arising from pre-existing nevi (P .001), and less actinic damage (P = .045). CDKN2A carriers were younger (38.9 ± 11.4 vs. 45.3 ± 7.8) and had fewer melanomas (2.7 ± 1.3 vs. 4.1 ± 1.2; P = .05) than MITF or POT1 carriers. CDKN2A carriers had low (n=5), medium (n=1), or high (n=2) nevus counts, while MITF carriers had medium (n=1) to high (n=4) counts. Dermoscopically, variant carriers showed fewer regression structures (8.3% vs. 39.8%; P = .010). RCM findings indicated a non-significant trend toward more dendritic cell-type melanomas in non-carriers (33.9% vs. 19.4%). Conclusion MPM patients with germline variants demonstrate distinct clinical and imaging profiles compared to non-carriers. These findings support personalized surveillance in high-risk individuals and the integration of genetic testing into melanoma management. Further studies with larger cohorts are needed to refine genotype–phenotype associations.

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