Mucosal Melanoma: Pathological Evolution, Pathway Dependency and Targeted Therapy

Abstract

Mucosal melanoma (MM) is a rare melanoma subtype that originates from melanocytes within sun-protected mucous membranes. Compared with cutaneous melanoma (CM), MM has worse prognosis and lacks effective treatment options. Moreover, the endogenous or exogenous risk factors that influence mucosal melanocyte transformation, as well as the identity of MM precursor lesions, are ambiguous. Consequently, there remains a lack of molecular markers that can be used for early diagnosis, and therefore better management, of MM. In this review, we first summarize the main functions of mucosal melanocytes. Then, using oral mucosal melanoma (OMM) as a model, we discuss the distinct pathologic stages from benign mucosal melanocytes to metastatic MM, mapping the possible evolutionary trajectories that correspond to MM initiation and progression. We highlight key areas of ambiguity during the genetic evolution of MM from its benign lesions, and the resolution of which could aid in the discovery of new biomarkers for MM detection and diagnosis. We outline the key pathways that are altered in MM, including the MAPK pathway, the PI3K/AKT pathway, cell cycle regulation, telomere maintenance, and the RNA maturation process, and discuss targeted therapy strategies for MM currently in use or under investigation.

Keywords: melanocytic lesions; mucosal melanocytes; mucosal melanoma; mutations; signaling dependency; targeted therapy.

Figure 1

Mucosal melanocytic benign lesions and malignant OMM. Benign hyperpigmented lesions (A, B) and malignant OMM in situ (C, D). Benign macule in gingiva (A) and its HE staining pictures (E, F). Benign intramucosal nevus on the hard palate (B) and its HE staining pictures (G, H). HE staining of blue nevus (I, J). HE staining of junctional nevus (K, L). Lentigo maligma melanoma on mandibular gingiva (C) and its HE staining figures (M, N). Ulcerated malignant MM on the hard palate (D) and its HE staining pictures (O, P).

Figure 2

Molecular pathways involved in the development of mucosal melanoma. Red-filled rectangles indicate genes experiencing activating mutation or amplification, while blue-filled rectangles genes undoing suppressing mutation or deletion. Black figures suggest mutation rates, whereas red and blue percentages are respectively amplification and deletion proportions in the test cohort. Created with BioRender.com (2021). Retrieved from https://app.biorender.com/biorender-templates.