Lattanzi M, et al. - In view of the observation that two primary histologic subtypes, superficial spreading melanoma (SSM) and nodular melanoma (NM), comprise the majority of all cutaneous melanomas, researchers examined if primary melanoma histologic subtype could predict the survival and could influence response to treatment in the metastatic setting. Examining the most recent Surveillance, Epidemiology, and End Results (SEER) cohort (n = 118,508) and the New York University (NYU) cohort (n = 1621) with available protocol-driven follow-up, they noted NM to be an independent risk factor for death, controlling for thickness, ulceration, stage, and other variables. For death, NM continued to be an independent risk factor upon treatment with BRAF-targeted therapy in the metastatic setting but exhibited no statistically marked difference with immune checkpoint inhibition. They identified a higher rate of NRAS mutation in correlation with NM. Performing high-throughput sequencing, NM-specific genomic alterations in NOTCH4, ANK3, and ZNF560 were identified, which were independently validated.