Mutational Profile in Vulvar, Vaginal, and Urethral Melanomas: Review of 37 Cases With Focus on Primary Tumor Site

Abstract

Melanomas of female genital tract are rare tumors with poor prognosis. While BRAF-V600E is the most common pathogenic mutation seen in cutaneous sun-exposed melanomas, mucosal and anogenital melanomas usually lack BRAF mutations and instead they harbor KIT alterations. The American Joint Committee on Cancer staging guideline (AJCC eighth edition) recommends using cutaneous melanoma guidelines for vulvar melanoma staging and does not provide any recommendations for vaginal melanoma staging. The aim of this study is to investigate the mutational status of invasive melanomas arising from different anatomic sites in lower female genital tract (vulvar hair-bearing skin, glabrous skin, vagina and urethra) in a group of 37 patients. Tumors were analyzed using a DNA targeted next-generation sequencing panel covering the 21 most common genes and mutation hotspots in melanomas. The most common genetic alterations in invasive melanomas of lower female genital tract are KIT (32%), TP53 (22%), and NF1 (19%). Overall 66% (21/32) of cases showed a pathogenic alteration in at least one of the MAPK pathway genes. No statistical significance seen between different primary tumor sites and the frequency of the oncogenic mutations, nor were any significant differences found by mutation status. Only one case of urethral melanoma showed a BRAF non-V600E mutation (D594G). Our results suggest a similar molecular pathogenesis and overall survival in melanomas arising from lower female genital tract, irrespective of their exact location in the urogenital area. Future classifications of melanoma should consider grouping vulvar melanomas with mucosal rather than cutaneous melanomas.

Comparative mRNA/micro-RNA co-expression network drives melanomagenesis by promoting epithelial–mesenchymal transition and vasculogenic mimicry signaling

“…PS-PLA1, the sole substrate of LysoPS, is detectable across several physiological states and is restricted to the inner surface of cellular membranes, apoptotic cells, antigen-activated lymphocytes, and immunological escape of melanoma cells [69] . It is clear that the cause of MM is mostly associated with mutagenesis, with the involvement of several oncogenes, including BRAF and NRAS [70] . It is possible that PLA1A , with the highest sensitivity, specificity, and AUC, could be used as a single indispensable biomarker for the diagnosis, screening, and prognosis of BRAF mutation melanoma.…”

Vulvar Melanoma: Molecular Characteristics, Diagnosis, Surgical Management, and Medical Treatment

“…Similarly, Omholt et al reported eight c-KIT mutations in 23 women with VM vs no mutations in seven women with vaginal melanomas [ 24 ]. No difference in the mutational profile between the hair-bearing and glabrous skin of the vulva appears to be present [ 25 ]. KIT activates downstream signaling cascades of the Ras/Raf/MEK/ERK pathway, a key regulator of melanoma cell regulation [ 26 ].…”

Successful treatment with avapritinib in patient with mucosal metastatic melanoma

“…Vulvar melanoma can arise from the hairy or from the glabrous part of the vulva. The significance of tumor location, although controversial, 4 could account for the particular behavior and the molecular characteristics of this disease that make it a distinct entity from cutaneous and other mucosal melanomas. 5 …”

“…2,3 Vulvar melanoma can arise from the hairy or from the glabrous part of the vulva. The significance of tumor location, although controversial, 4 could account for the particular behavior and the molecular characteristics of this disease that make it a distinct entity from cutaneous and other mucosal melanomas. 5 In the metastatic disease, survival is usually poor, due either to the aggressive biological behavior or to the lack of efficacy of novel therapeutic strategies.…”

“…5 In the metastatic disease, survival is usually poor, due either to the aggressive biological behavior or to the lack of efficacy of novel therapeutic strategies. Vulvar melanoma only seldomly presents BRAF V600 mutations (3-26% of cases), 4,5 and, consequently, target therapy with BRAF and MEK inhibitors is a rare therapeutic option. Immunotherapy with anti-PD1 antibodies seems to have a weak effect on mucosal melanoma, with a median progression-free survival (PFS) and overall survival (OS) of 3.9 and 12.4 months, respectively.…”