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

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.