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

Abstract

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 p16INK4A expression as marker of HPV activity, and presence and integration of highrisk HPV DNA. Results: Usual vulvar intraepithelial neoplasia was present adjacent to vulvar squamous cell carcinoma in 25 of 130 cases. Usual vulvar intraepithelial neoplasiaassociated 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 neoplasiaassociated tumors is highly unlikely. The diseasespecific 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.

Differentiated vulvar intraepithelial neoplasia is often found in lesions, previously diagnosed as lichen sclerosus, which have progressed to vulvar squamous cell carcinoma

“…The nuclear chromatin is vesicular rather than coarse, and the nuclei have prominent nucleoli (Figure 3e), usually most prominently in the basal and parabasal keratinocytes. 8 Although differentiated VIN is seen adjacent to B80% of vulvar squamous cell carcinomas, 2 it is seldom diagnosed as a solitary lesion, 10 which may be explained by underdiagnosis due to its difficult recognition [11][12][13] or due to its short intraepithelial phase. 10 It has been hypothesized that differentiated VIN may develop from lichen sclerosus and that it carries a higher malignant potential than lichen sclerosus does, 3,13-17 but its role as a premalignant lesion has not been accepted by all pathologists.…”

Patients with usual vulvar intraepithelial neoplasia-related vulvar cancer have an increased risk of cervical abnormalities

“…A subdivision on the basis of the histology of the adjacent VIN lesion (we adopted the new ISSVD Classification (Sideri et al, 2005)) was considered the most appropriate method to subdivide the vulvar SCCs into a pathway (van de Nieuwenhof et al, 2009b). Every original surgical specimen was revised for the presence of LS and/or VIN lesions, based on the current histopathological characteristics (Hart, 2001).…”

“…The other type, accounting for B20%, is human papillomavirus (HPV) related, occurs in younger patients, and has usual VIN (uVIN) as premalignancy (van der Avoort et al, 2006). Recently, we found that uVIN-associated vulvar SCC patients had a significantly better disease-free survival than dVIN-associated vulvar SCC patients (van de Nieuwenhof et al, 2009b). The majority of uVIN-related vulvar SCCs are caused by HPVs 16, 18 and 33 (Toki et al, 1991;Hording et al, 1994;Iwasawa et al, 1997;Pinto et al, 2004;Hampl et al, 2006).…”

“…High-risk HPV presence does not per se indicate a causal role in the carcinogenesis and may represent a non-significant or transient infection. A better method of subdividing the two types of vulvar SCC is on the basis of the histology of the adjacent VIN lesion (Vilmer et al, 1998;Rouzier et al, 2001;van de Nieuwenhof et al, 2009b).…”

Tumor Proteomics by Multivariate Analysis on Individual Pathway Data for Characterization of Vulvar Cancer Phenotypes

“…INK4A and p14 ARF (11)(12)(13)(14). HPV negative VSCC is on the other hand often associated with low expression of p16 INK4A and p14 ARF and a higher frequency of p53 mutations or deletions (14 -16).…”