Molecular profiling and clinico-pathological characteristics of vulvar and vaginal melanomas

Vulvar and vaginal melanomas are infrequent malignancies characterized by an aggressive behaviour and a poor prognosis. Surgery is the treatment of choice for primary tumors and loco-regional metastases. As target therapies have emerged as effective treatments both in the advanced and adjuvant settings, molecular profiling of primary tumors and/or metastases is mandatory in order to choose the proper treatment in melanoma patients harbouring specific mutations. Recently, some studies have analyzed the molecular profile of urogenital melanomas, but limited to few specimens and ending with a lack of general agreement. We evaluated a cohort of vulvar and vaginal melanomas for clinical-pathological parameters and molecular profile of the most frequently mutated genes in melanomas, KIT, BRAF and NRAS. Our study population was composed of 23 cases, including 14 vulvar, 7 vaginal and 2 cases of concomitant vulvar and vaginal melanomas. We analyzed clinical-pathological parameters such as histotype, number of mitoses, presence of ulceration, regression, vascular invasion and metastasis, in addition to recurrence and overall survival. Molecular analyses were performed by bi-directional Sanger sequencing for KIT (exons 9, 11, 13 and 17), BRAF (exons 11 and 15) and NRAS (exons 2 and 3). We applied multivariate models to assess the associations of KIT, BRAF and NRAS status with prognostic factors, adjusting for age. KIT mutations were found in 4 samples (17%), 3 vulvar and 1 vaginal melanoma. NRAS alterations were observed in 2 of 15 available samples (13%) equally distributed between the two categories; BRAF mutations were detected in 1 vulvar melanoma of 19 available samples (5%). KIT mutation was associated with significantly lower number of mitosis and lower Breslow thickness (P=0.01 and P=0.05, respectively, adjusting for age and site). Thicker melanomas were found to be associated with a worse progression free and overall survival (P=0.01 and P=0.03, respectively, adjusting for age). In conclusion in our cohort, melanomas of female genital tract harboured mutations in all the three genes tested, with KIT and NRAS most commonly mutated. KIT status was found to be significantly associated with prognostic factors. Since melanoma patients carrying mutations of KIT, NRAS or BRAF might benefit from target therapy such as imatinib, MEK inhibitor or anti-BRAF drugs, we suggest that even in these rare melanomas molecular analysis should be performed in order to drive proper therapeutic treatment.