Molecular Profiling and Novel Therapeutic Strategies for Mucosal Melanoma: A Comprehensive Review

Abstract

Mucosal melanoma is a rare and aggressive subtype of melanoma. Unlike its cutaneous counterpart, mucosal melanoma has only gained limited benefit from novel treatment approaches due to the lack of actionable driver mutations and poor response to immunotherapy. Over the last years, whole-genome and exome sequencing techniques have led to increased knowledge on the molecular landscape of mucosal melanoma. Molecular studies have underlined noteworthy findings with potential therapeutic implications, including the presence of KIT mutations, which are potential targets of tyrosine kinase inhibitors currently in use in the clinic (imatinib), but also SF3B1 mutation, CDK4 amplifications, and CDKN2A gene deletions, which are presently under investigation in clinical trials. Recent results from a pooled analysis of patients with mucosal melanoma treated with immunotherapy have suggested that the combination of immune checkpoint inhibitors might improve survival outcomes in this subset of patients, as compared with single-agent immunotherapy. However, these results are not confirmed across different studies, and combo-immunotherapy correlates with a higher rate of adverse events. In this review, we describe the clinical, biological, and genetic features of mucosal melanoma. We also provide an update on the results of approved systemic treatment in this setting and overview the therapeutic strategies currently under investigation in clinical trials.

Review: The Key Factors to Melanomagenesis

“…Mucosal (oral) melanoma risk factors—Mucosal melanoma is a very rare and aggressive melanoma subtype that arises from the oncogenic transformation of the mucous membranes’ melanocytes [ 71 ]. This type of melanoma is biologically, epidemiologically, and molecularly different from cutaneous melanoma [ 72 ]. The risk factors and causes of mucosal melanoma’s development are not fully understood and there is little information regarding its molecular markers [ 71 ].…”

“…The risk factors and causes of mucosal melanoma’s development are not fully understood and there is little information regarding its molecular markers [ 71 ]. Mucous melanoma develops most frequently in the head and neck cavities (including the oral/nasal cavity and accessory sinuses), followed by the rectum/anus and the feminine genital tract [ 72 ]. Oral melanoma often presents clinically as heavily melanin-pigmented lesions but may also appear amelanotic [ 56 ].…”

Case report: complete remission with crizotinib in ROS1 fusion-positive sinonasal mucosal melanoma

“…Furthermore, mucosal melanomas often have a cryptic origin and are often asymptomatic in their early stages. The presence of thick blood vessels at the site of the disease promoted the early metastasis and diffusion of tumor cells in lymphatic and vascular networks ( 4 ). These factors make mucosal melanoma more difficult to diagnose and treat than cutaneous melanoma.…”

Combinations of EGFR and MET inhibitors reduce proliferation and invasiveness of mucosal melanoma cells

“…14 Mutations in BRAF and NRAS observed in MM are substantially different from those occurring in CM. 4,7,15 BRAF mutation was present in 26% of patients with vulvar and vaginal melanoma; however, only half of them were V600 mutations, which significantly reduces the effectiveness of BRAF and MEK inhibitors therapy typically used in CM. 16 For the minority of metastatic MM patients who exhibit BRAF V600E mutations, combined anti-BRAF and anti-MEK therapy may represent an adequate therapeutic strategy.…”