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.

Keywords: c-kit; immunotherapy; melanoma; mucosal; targeted therapy.

Figure 1

(A–C) Female, 76 years–Mucosal melanoma on the vulva (labia minora) characterized by atypical pigmented melanocytes in single units and nests with pagetoid spread; a brisk lymphocytic infiltrate with numerous melanophages is observed in the upper dermis; (D–F) Male, 86 years–Endoscopic biopsy reveals a bulky tumor diagnosed as amelanotic mucosal melanoma of the anal canal; the tumor shows diffuse proliferation of non-pigmented epithelioid cells; tumor cells show cytoplasmic and membranous CD117 staining (inset); (G–I) Female, 47 years–Highly pigmented conjunctival mucosal melanoma (left eye) with prominent melanin pigment in intracellular and extracellular location; both in situ (G) and invasive components (H,I) are shown. These images come from the pathology archive of patients with mucosal melanomas, as indicated in the “Materials and methods” section.

Figure 2

A 67-year-old patient came to our attention because of rectorrhagia; a PET/CT scan showed lung and abdominal lymph node metastases. A biopsy of the anal mass showed atypical epithelioid cells with pleomorphic features. Immunohistochemistry showed strong positivity for HMB45 and Melan A, whereas cytokeratins and S-100 expression were negative, consistent with the diagnosis of anal mucosal melanoma. c-KIT staining was positive in >75% of tumor cells, and DNA sequence analysis revealed a KIT-activating mutation (L576P) in exon 11. The patient received Imatinib 400 mg/die. Panel (A) shows the anal baseline lesion with a pathologic left inguinal lymph node. Panel (B) shows the PET/CT scan after 4 months of Imatinib treatment, showing a near-complete response in the anal lesion and the inguinal lymph node. The response lasted 3 years, then the patient progressed and died. These images come from the radiology archive of a patient with mucosal melanomas, as indicated in the “Materials and methods” section.