PRAME Expression in HPV-associated and Differentiated Vulvar Intraepithelial Neoplasia–associated Vulvar Squamous Neoplasia

Preferentially expressed antigen in melanoma (PRAME) immunohistochemistry was initially used diagnostically in melanoma but is increasingly evaluated across malignancies for diagnostic, prognostic, and therapeutic purposes. PRAME protein acts as a dominant repressor of retinoic acid signaling and may help stratify patients for retinoic acid-based therapy. Multiple PRAME-targeted immunotherapy trials are ongoing, supported by its selective tumor expression. Vulvar intraepithelial neoplasia (VIN) is an appealing setting for PRAME assessment because lesions are often multifocal or extensive, and treatment by excision can be disfiguring. Immunotherapy is also of rising interest in advanced vulvar squamous cell carcinoma (VSCC). We aimed to evaluate PRAME expression in HPV-associated and differentiated vulvar intraepithelial neoplasia (dVIN)-associated squamous lesions of the vulva. Full tissue sections from 106 vulvar squamous neoplasms (31 HSIL, 29 VSCC arising in HSIL, 20 dVIN, 26 VSCC arising in dVIN) were stained with PRAME antibody. Expression was recorded as the percentage of positive tumor cells, with intensity (0-3+) and staining localization documented, and an H-score was subsequently calculated. Groups were compared using the Wilcoxon rank-sum or Kruskal-Wallis tests. Most VSCCs (78%) expressed PRAME, with significantly higher expression in dVIN-associated lesions (P=0.006). Subgroup analysis showed the highest PRAME expression in dVIN-associated VSCC and the lowest in HSIL (P<0.00001). These findings suggest that distinct biological drivers of HPV-associated and dVIN-associated vulvar neoplasia contribute to differential PRAME expression. The strongest expression in dVIN-associated VSCC highlights a possible link between aggressive tumor behavior and PRAME. dVIN-associated lesions may therefore represent promising candidates for PRAME-targeted therapy.