The Etiologic Role of HPV in Vulvar Squamous Cell Carcinoma Fine Tuned

Purpose: High-risk human papilloma virus (HPV) plays a role in the development of a subset of vulvar squamous cell carcinomas. Uncertainty exists about the true impact of HPV in this tumor type because conflicting reports have been published with diverging prevalence rates. This study was done to fine tune the role of high-risk HPV infection in vulvar squamous cell carcinoma development in relation to clinical prognosis. Experimental Design: 130 vulvar squamous cell carcinomas of patients with known survival data were analyzed for histology of the adjacent lesion (differentiated or HPV-associated usual vulvar intraepithelial neoplasia), in relation to p16(INK4A) expression as marker of HPV activity, and presence and integration of high-risk HPV DNA. Results: Usual vulvar intraepithelial neoplasia was present adjacent to vulvar squamous cell carcinoma in 25 of 130 cases. Usual vulvar intraepithelial neoplasia-associated squamous cell carcinomas had high p16(INK4A) expression, and 24 of 25 squamous cell carcinomas contained integrated high-risk HPV DNA. Differentiated vulvar intraepithelial neoplasia was found adjacent to 105 of 130 vulvar squamous cell carcinomas. High-risk HPV was detected in 11 (10.5%) differentiated vulvar intraepithelial neoplasia-associated vulvar squamous cell carcinoma but correlated with high p16(INK4A) expression in only one case. Integration of viral DNA was never observed in differentiated vulvar intraepithelial neoplasia-associated squamous cell carcinomas, which suggests that a causal relationship of high-risk HPV in differentiated vulvar intraepithelial neoplasia-associated tumors is highly unlikely. The disease-specific survival of the differentiated vulvar intraepithelial neoplasia-associated vulvar squamous cell carcinoma patients was significantly worse compared with patients with a usual vulvar intraepithelial neoplasia-associated tumor. Conclusions: High-risk HPV is causally associated with the development of usual vulvar intraepithelial neoplasia associated squamous cell carcinomas, which comprise 19% of all vulvar squamous cell carcinomas, but not with differentiated vulvar intraepithelial neoplasia-associated vulvar squamous cell carcinomas. Differentiated vulvar intraepithelial neoplasia-associated vulvar squamous cell carcinomas have a significantly worse prognosis. (Cancer Epidemiol Biomarkers Prev 2009;18(7):2061-7)