A paradigm shift in understanding vulvovaginal melanoma as a distinct tumor type compared with cutaneous melanoma

• Published in: Gynecologic oncology Vol. 188; pp. 13 - 21
• Main Authors: Wilhite, Annelise M., Wu, Sharon, Xiu, Joanne, Gibney, Geoffrey T., Phung, Thuy, In, Gino K., Herzog, Thomas J., Khabele, Dineo, Erickson, Britt K., Brown, Jubilee, Rocconi, Rodney P., Pierce, Jennifer Y., Scalici, Jennifer M., Jones, Nathaniel L.
• Format: Journal Article
• Language: English
• Published: Elsevier Inc 01.09.2024
• Subjects: Immune checkpoint inhibitor therapy; Molecular profiles; Tumor microenvironment; Vulvovaginal melanoma; Molecular profiles; Tumor microenvironment; Immune checkpoint inhibitor therapy; Vulvovaginal melanoma
• ISSN: 0090-8258; 1095-6859; 1095-6859
• DOI: 10.1016/j.ygyno.2024.06.002

Our goal was to compare molecular and immune profiles of vulvovaginal melanoma (VVM) with cutaneous melanoma (CM) and explore the significance of immune checkpoint inhibitor (ICI) agents on survival. Samples from VVM and CM tumors underwent comprehensive molecular and immune profiling. Treatment and survival data were extracted from insurance claims data and OS was calculated from time of ICI treatment to last contact. Statistical significance was determined using chi-square and Wilcoxon rank sum test and adjusted for multiple comparisons. Molecular analysis was performed on 142 VVM and 3823 CM tumors. VVM demonstrated significantly (q < 0·01) less frequent BRAF and more frequent KIT, ATRX, and SF3B1 mutations. Alterations in pathways involving DNA damage and mRNA splicing were more common in VVM, while alterations in cell cycle and chromatin remodeling were less common. Immunogenicity of VVM was lower than CM, with an absence of high TMB (0% vs 46.9%) and lower PD-L1 positivity (18·0% vs 29·5%). Median immune checkpoint gene expression was lower in VVM, as were cell fractions for type I macrophages and CD8+ T-cells(q < 0·01). Myeloid dendritic cells were increased in VVM(q < 0·01). Median OS was shorter for VVM than for CM patients treated with ICIs (17·6 versus 37·9 months, HR:1·65 (95% CI 1·02–2·67) p = 0·04). VVM has a distinct molecular and immune profile compared to CM, which may contribute to the worse survival in VVM compared to CM patients treated with ICI therapy. Though ICIs have been a mainstay of treatment in recent years, our findings suggest that new therapeutic strategies are needed. •Vulvovaginal melanoma is a rare disease, with minimal available data on molecular and immunologic characteristics.•Vulvovaginal melanoma has less frequent BRAF and more frequent KIT, ATRX, and SF3B1 mutations than cutaneous melanoma.•High tumor mutation burden was absent in vulvovaginal melanoma tumors, compared with 50% TMB-H cutaneous melanomas.•Vulvovaginal melanoma patients receiving immune checkpoint inhibitor therapy had a shorter OS compared to cutaneous patients.