Current Trends in Mucosal Melanomas: An Overview

Abstract

Primary mucosal melanomas (MMs) are uncommon tumors originating from melanocytes located in the mucous membranes at various anatomic sites within the body. MM significantly differs from cutaneous melanoma (CM) regarding epidemiology, genetic profile, clinical presentation, and response to therapies. Despite these differences, that have important implications for both disease diagnosis and prognosis, MMs are usually treated in the same way as CM but exhibit a lower response rate to immunotherapy leading to a poorer survival rate. Furthermore, a high inter-patient variability can be observed in relation to therapeutic response. Recently, novel "omics" techniques have evidenced that MM lesions have different genomic, molecular, and metabolic landscapes as compared with CM lesions, thus explaining the heterogeneity of the response. Such specific molecular aspects might be useful to identify new biomarkers aimed at improving the diagnosis and selection of MM patients who could benefit from immunotherapy or targeted therapy. In this review, we have focused on relevant molecular and clinical advancements for the different MM subtypes in order to describe the updated knowledge relating to main diagnostic, clinical, and therapeutic implications as well as to provide hints on likely future directions.

Keywords: cancer; diagnosis; genetic; immunotherapy; metabolism; mucosal melanomas; prognosis.

Figure 1

Main genes and their functional role in MM. ATRX, ATP-dependent helicase; BRAF, B-Raf proto-oncogene; CDK4/6, Cyclin-dependent kinase 4/6; CCND1, Cyclin D1; CDKN2A/B, Cyclin-dependent kinase inhibitor of kinase 2A/B; E2F, E2F transcription factor 2; ERK, Extracellular-related kinase; KIT, receptor tyrosine kinase; MDM2, mouse double minute 2 p53 binding protein homolog; MITF, Microphthalmia-associated transcription factor; MEK, Mitogen-activated protein kinase-extracellular related kinase; mTOR, mammalian target of rapamycin; NF1, neurofibromin 1; NRAS, neuroblastoma RAS viral oncogene homolog; PI3K, Phosphatidylinositol 3 kinase; PTEN, Phosphatase and tensin homologue; RB1, retinoblastoma 1; SF3B1, splicing factor 3b subunit 1; SPRED1, sprout-related EVH1 domain containing protein 1; TERT, telomerase reverse transcriptase; TP53, tumor protein p53.

Figure 2

Distribution of MM anatomical locations (head and neck, gastrointestinal, urinary, and genital) and correspondent mutation frequencies for the main driver oncogenes (BRAF, NRAS, and KIT). Mutation prevalence values were mainly derived by NGS-based approaches (for references, see text).