About 50% of melanomas harbour a BRAF mutation. Of these 50%, 10% have a V600K mutation. Although it is the second most common driver mutation after V600E, no specific studies have been conducted to identify a clinical and therapeutic gold standard for this patient subgroup. We analysed articles, including registrative clinical trials, to identify common clinical and biological traits of the V600K melanoma population, including different adopted therapeutic strategies. Melanoma V600K seems to be more frequent in Caucasian, male and elderly populations with a history of chronic sun damage and exposure. Prognosis is poor and no specific prognostic factor has been identified. Recent findings have underlined how melanoma V600K seems to be less dependent on the ERK/MAPK pathway, with a higher expression of PI3KB and a strong inhibition of multiple antiapoptotic pathways. Both target therapy with BRAF inhibitors + MEK inhibitors and immunotherapy with anti-checkpoint blockades are effective in melanoma V600K, although no sufficient evidence can currently support a formal recommendation for first line treatment choice in IIIC unresectable/IV stage patients. Still, melanoma V600K represents an unmet medical need and a marker of poor prognosis for cutaneous melanoma.

The etiology of melanoma is multifactorial and arises from the interplay of genetic, phenotypic, and environmental factors. The genetic predisposition to melanoma is influenced by a complex interaction among genes exhibiting varying levels of penetrance (high, moderate, and low), each contributing differently to the susceptibility of the disease. Furthermore, penetrance may vary based on the incidence of melanoma across diverse populations and geographical regions. Advances in genetic sequencing technologies have facilitated the identification of novel genes potentially associated with melanoma, as well as the characterization of relevant germline variants. While the most extensively researched variant is CDKN2A, recent studies have highlighted other variants unrelated to CDKN2A as significant areas of investigation. Among them, high-penetrance genes encompass CDK4, BAP1, POT1, TERT, ACD, and TERF2IP. In contrast, moderate-penetrance genes include MC1R, MITF, and SLC45A2, while low-penetrance genes consist of OCA2, TYRP1, and TYR. In addition to elevating the risk of melanoma, these genetic alterations may also predispose individuals to internal neoplasms. This review aims to provide a comprehensive overview of the definitions of sporadic, multiple primary, familial, and hereditary melanoma, with a particular emphasis on non-CDKN2A germline variants and their dermoscopic and phenotypic features.

Locally advanced (laBSCs) and metastatic basosquamous carcinomas (mBSCs) represent a therapeutic challenge. By definition, these forms are not amenable to surgery or radiotherapy, but according to literature reports, sonic hedgehog pathway inhibitors (HHIs), anti‐programmed death 1 receptor antibodies (anti‐PD‐1), and other treatment approaches involving chemotherapy, surgery, and radiotherapy have been used. This work features 5 real‐life cases of advanced BSCs, treated at the Dermato‐Oncology Unit of Trieste (Maggiore Hospital, University of Trieste). In addition, a review of the current treatment options reported in the literature for laBSC and mBSC is provided, collecting a total of 17 patients. According to these preliminary data, HHIs such as sonidegib and vismodegib could represent a safe and effective first line of treatment, while the anti‐PD‐1 cemiplimab may be useful as a second‐line option. Chemotherapy and combined approaches involving surgery and radiotherapy have been also reported to be suitable in some patients.