Melanoma of unknown primary: New perspectives for an old story

Melanoma of unknown primary site (MUP) comprises 3-4 % of all melanomas. It mostly presents in lymph nodes (LNs), followed by subcutaneous sites, and visceral organs; nevertheless, there is a trend of increase in the relative incidence of visceral counterpart in recent years. Spontaneous regression of the primary lesion is a well-established theory, based on the evidence that melanoma can undergo regression at the primary site. MUP and stage-matched melanoma of known primary site (MKP) share similar prognostic factors. The survival rate of patients with MUP has been compared to those with stage-matched MKP. Multiple studies conducted before the era of novel therapy with immune checkpoint or BRAF/MEK inhibitors found improved survival in favor of MUP, whereas others reported equivalent or poorer outcomes. Here, we discuss the genetic and molecular features, epidemiology, diagnosis, prognostic factors, survival, and treatment of MUP in comparison with MKP, in the pre- and post-novel therapy era.