Vulval intraepithelial neoplasia : cellular markers of progression and novel immunotherapy
Squamous intraepithelial neoplasia can develop at several sites in the lower genital tract and is associated with a risk of malignant progression. Women with vulval intraepithelial neoplasia (VIN) usually undergo treatment, not only to reduce the risk of subsequent carcinoma but also in an attempt to alleviate symptoms. Current therapies are often unpleasant and frequently ineffective, with many patients requiring multiple treatments for recurrent, recalcitrant disease. The central role of human papillomaviruses (HPVs) in the pathogenesis of cervical squamous neoplasia is now accepted. However, the potential mechanisms underlying disease progression in VIN are poorly understood making it difficult to define a high-risk group of patients in whom treatment would be most urgent. In the work presented in this thesis, viral and genetic events of potential importance in the pathogenesis of vulval neoplasia have been identified. Using polymerase chain reaction (PCR) oncogenic HPVs were found within pre invasive VIN lesions often, but not exclusively, as viral integrants. It would appear that viral integration might therefore be an early event in vulval oncogenesis. RNA in situ hybridisation has shown that the HPV is transcriptionally active and could therefore contribute to the subversion of normal cellular growth control mechanisms. Comparative genomic hybridisation (CGH) has identified chromosomal alterations occurring in a non- random fashion within VIN lesions. Several of these aberrations show striking similarities to those seen in invasive disease of both the vulva and cervix and may help to define a high-risk group of patients. Finally, the use of a novel viral vector vaccine to induce cell-mediated immune responses to non-structural HPV proteins in women with VIN is described. Vaccination can be associated with disease regression suggesting that development of effective immunostimulation could become an additional therapy for women with VIN.