Exploring the immune landscape of melanoma of the lower female genital tract

Vulvovaginal melanoma (VVM) is a rare malignancy with poor prognosis and limited evidence to guide immunotherapy selection. This study aimed to assess the expression and interrelationships of programmed death-1 (PD-1), programmed death ligand-1 (PD-L1), cytotoxic T-lymphocyte-associated protein 4 (CTLA-4), cluster of differentiation 4 (CD4), and cluster of differentiation 8 (CD8), and their associations with clinicopathological features and outcomes. Fifteen VVM cases were analysed using immunohistochemistry. PD-L1 was evaluated using tumour proportion score (TPS), immune cell score (IS), and combined positive score (CPS), CTLA-4, CD4, and CD8 were scored. Continuous marker values were analysed using Pearson correlation, with additional descriptive and spatial assessment of marker distribution. Survival and treatment data were reviewed when available. Most tumours showed high expression of PD-1, PD-L1 (IS/CPS), CTLA-4, CD4, and CD8, whereas PD-L1 (TPS) was comparatively lower. Significant positive correlations were observed between PD-1 and CD8, PD-1 and PD-L1 (IS/CPS), CD8 and PD-L1 (CPS), and between CTLA-4 and PD-L1 (TPS/CPS), indicating coordinated immune-checkpoint activation. PD-L1 expression was frequently enriched at the tumour-stroma interface. High CD4 expression correlated with increased mitotic rate, while CD8 and CTLA-4 expression correlated with melanin status. Higher PD-1, PD-L1, and CTLA-4 expression generally associated with longer overall survival following immunotherapy. In a case with serial recurrences, PD-1, PD-L1 (TPS, CPS), CTLA-4 expression increased while PD-L1 (IS) and CD4 + /CD8 + ratio decreased, suggesting a progressively immunosuppressive tumour microenvironment. These findings suggest that integrated immune profiling of PD-1, PD-L1, CTLA-4, and T-cell subsets may serve as predictive markers for immunotherapy in VVM.