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.

Anorectal and Genital Mucosal Melanoma: Diagnostic Challenges, Current Knowledge and Therapeutic Opportunities of Rare Melanomas

“…Unfortunately, the acquired resistance through the reactivation of the MAPK pathway may also occur for MM patients treated with both the MEK inhibitor or the MEK inhibitor plus the BRAF inhibitor [ 21 , 145 ]. To overcome this resistance, it could be useful to inhibit downstream proteins like ERK or develop new molecules targeting aberrant MAPK signaling [ 3 , 146 ]. Moreover, MEK inhibitors have also been studied in combination with mTOR1/2, AKT or CDK4/6 inhibitors in preclinical models or in clinical trials of MM [ 147 , 148 ].…”

“…Differently from cutaneous melanoma (CM), the aetiology, risk factors and pathogenesis of MM are poorly understood, thus explaining the lack of effective treatment options, the undesirable response rates and the extremely poor prognosis. Indeed, due to the rarity and the consequent paucity of literature data about efficient therapeutic strategies, as well as the deferred diagnosis often at an advanced stage, this melanoma subtype is characterized by a worse prognosis than melanoma arising from the skin [ 3 ]. Here, we summarize the current state of knowledge regarding anorectal and genital MM (penis, vulva, vagina) as models of rare melanomas deserving of a multidisciplinary approach, with the involvement of experts in the field of CM, urogenital and anorectal malignancies.…”

An Unusual Polypoid Septal Mucosal Melanoma: Overview and Diagnostic Pitfalls

“…UV-radiation-derived mutations of the BRAF gene are only detected in 0-3% of all MM, whereas rare c-KIT somatic mutations are encountered more frequently than in CM, as in our case. The immunohistochemical identity of our patient’s tumor is in accordance with its mucosal origin [ 4 , 5 ].…”

“…The sinonasal mucosa is characterized by high melanocyte density and is the most common location for exposure to carcinogens like formaldehyde which was for decades considered to be a risk factor for MM development. However, many studies have failed to confirm this hypothesis [ 4 ]. Sunlight does not seem to predispose to MM unlike cutaneous melanoma (CM), as they occur in sun-shielded surfaces.…”

“…However, in patients unfit for combination immunotherapy, nivolumab or pembrolizumab monotherapy is opted. In the presence of certain mutations [ 4 ], BRAF or c-KIT targeted therapy is indicated in urgently desired symptomatic benefit or in case of failure of immunotherapy [ 1 , 3 , 14 ].…”