Integration of HPV-16 and HPV-18 DNA in vulvar intraepithelial neoplasia

Objective.Vulvar intraepithelial neoplasia (VIN) is a premalignant disease of the lower genital tract. The increased occurrence of high-risk human papillomavirus (HPV) infection seems to be associated with the increasing frequency of VIN. Integration of HPV DNA into host chromosome has been hypothesized to be a critical step in the carcinogenesis of cervical neoplasia resulting in altered expression of two viral transforming genes E6 and E7.Method.We analyzed HPV-16 and HPV-18 DNA, and integrated transcripts of HPV-16 and HPV-18 genomes in 30 VIN cases with 53 lesions using a PCR-based protocol for the amplification of papillomavirus oncogene transcripts (APOT).Result.24 of 30 VIN lesions (80%) harbored HPV-16 (in 23 cases) and HPV-18 DNA. Integration of HPV-16 and HPV-18 genome was observed in eight (38.1%) of 21 HPV-16/18 positive VIN III cases. All eight VIN were multifocal and had multicentric disease (CIN/VAIN) including one case that progressed to vulvar carcinoma. Five of eight lesions were found to have E7 specific viral–cellular fusion transcripts only, two of eight showed E7–E4 viral–cellular fusion transcripts, and one of eight had both episomally derived and E7–E4 viral–cellular fusion transcripts. In 10 (83.3%) of 12 multifocal VIN III patients, all specimens derived from the same patient harbored the same HPV type and HPV transcript pattern suggesting monoclonality.Conclusion.HPV-16 is the most prevalent type among VIN II/III. HPV-16 and HPV-18 DNA integration into host cell genome seems to be related to the progression stage of vulvar dysplasia and, therefore, may be necessary for development of HPV-associated invasive vulvar carcinoma.