HPV-related vulvar diseases and perspectives of p16INK4a immunochemistry: a review of the literature

Introduction: Two different types of vulvar intraepithelial neoplasia (VIN), HPV-related and HPV-unrelated, should be considered as two separate entities with different management options. The incidence of HPV-related VIN is increasing worldwide and is implicated in carcinogenesis. Our objective is to investigate the use of p16(INK4a) immunostaining or p16(INK4a)/p53 double staining for the detection of HPV-related disease to overcome the problem that histological criteria often have significant overlap. Methods: A systematic literature search was carried out in the online databases PubMed, EMBASE, Cochrane Library, Clincaltrials.gov and Scopus. The key search terms were HPV, VIN, p16(INK4a) immunochemistry and p53. Results: We found that nuclear and cytoplasmic immunostaining for p16(INK4a) was intense and diffuse in HPV-associated lesions and weak and focal in normal vulvar epithelium, nondysplastic lesions, lichen sclerosus and keratinizing vulvar squamous cell carcinoma. p53 nuclear immunostaining was always negative in HPV-related disease. Conclusions: Our findings indicated that p16(INK4a) or p16(INK4a)/p53 immunoreactivity, along with histological diagnosis, could be a convenient means to adequately classify VIN and its connection to HPV infection. Therefore, the clear recognition of HPV-associated VIN would lead to an appropriate strategy of treatment and follow-up.