Background/Objectives: The clinical, histopathological, and dermoscopic features may be associated with melanoma mutational status. The aims of the study were to assess the clinical, histopathological, and dermoscopic features of melanoma to identify their correlation with BRAF, NRAS, and cell cycle genes’ mutational status in melanoma. Methods: The clinical, histopathological information, dermoscopic images, and genomic DNA of 55 histopathologically diagnosed primary cutaneous melanomas were retrospectively analyzed. Next-generation sequencing (NGS) assays were conducted on the Ion GeneStudio S5 platform (Thermo Fisher Scientific, Waltham, MA, USA), using the Ion AmpliSeqTM Italian Melanoma Intergroup Somatic Panel. Results: Overall, 55 melanomas, including 30 superficial spreading, 24 nodular, and 1 naevoid, were analyzed. BRAF mutation was more frequently observed in ulcerated melanoma (16/23; 69.6%), with mitotic rate ≥ 5 n/mm2 (8/11; 72.7%), while NRAS mutation was more common in amelanotic/hypomelanotic (8/17; 70.0%) and nodular melanoma (10/24; 41.7%). Dermoscopically, shiny white structures (OR = 3.50; 95% confidence interval: 1.13–10.84) were associated with BRAF-mutated melanomas, whereas a homogeneous disorganized pattern was associated with NRAS-mutated melanomas (OR = 6.96; 1.49–32.53). The risk of diagnosing cell cycle gene-mutated melanomas was significantly increased in presence of vascular patterns (OR = 4.50; 1.33–15.20), linear irregular (OR = 3.75; 1.18–11.92), polymorphous vessels (OR = 4.05; 1.27–12.97), and milky red globules/areas (OR = 3.14; 1.00–9.89). The blue-white veil was significantly associated with P53 mutation (OR = 35.84; 2.01–640.2). Conclusions: Conversely to Wild Type, BRAF, NRAS, and cell cycle gene-mutated melanomas were significantly associated with clinical and dermoscopic features underlying a more aggressive melanoma phenotype. The vascular pattern, linear irregular, polymorphous vessels, and milky-red globules/areas may be considered predictors of cell cycle mutated melanomas.
