Two pathways leading to vulvar squamous cell carcinoma (SCC) exist. The expression of proliferation-and cell-cycle-related biomarkers and the presence of high-risk (hr) HPV might be helpful to distinguish the premalignancies in both pathways. Seventy-five differentiated vulvar intra-epithelial neoplasia (VIN)-lesions with adjacent SCC and 45 usual VIN-lesions (32 solitary and 13 with adjacent SCC) were selected, and tested for hr-HPV DNA, using a broad-spectrum HPV detection/genotyping assay (SPF 10 -LiPA), and the immunohistochemical expression of MIB1, p16 INK4A and p53. All differentiated VIN-lesions were hr-HPV-and p16-negative and in 96% MIB1-expression was confined to the parabasal layers. Eighty-four percent exhibited high p53 labeling indices, sometimes with parabasal extension. Eighty percent of all usual VIN-lesions were hr-HPV-positive, p16-positive, MIB1-positive and p53-negative. Five (of seven) HPV-negative usual VIN lesions, had an expression pattern like the other HPV-positive usual VIN lesions. In conclusion, both pathways leading to vulvar SCC have their own immunohistochemical profile, which can be used to distinguish the 2 types of VIN, but cannot explain differences in malignant potential. 1,2 Both types of vulvar cancer are preceded by their own type of vulvar intra-epithelial neoplasia (VIN). On the basis of histopathological characteristics, VIN lesions can be divided into usual VIN (also known as Bowenoid or classic VIN, basaloid or warty subtype) and differentiated VIN (formerly named simplex VIN or well-differentiated VIN).3 Recently, the International Society for Vulvovaginal Disease (ISSVD) has proposed a revised nomenclature for vulvar lesions.
2,3The majority of vulvar SCCs occur in elderly patients with lichen sclerosus and develops following an human papillomavirus (HPV)-negative pathway.4,5 Its premalignancy, differentiated VIN, can be difficult to distinguish from a benign vulvar lesion (e.g. chronic inflammation) or normal epithelium. 5,6 It is assumed that differentiated VIN is highly proliferative and might rapidly progress into an invasive neoplasm, because it is seldom found without (micro-invasive) vulvar carcinoma and often adjacent to HPV-negative vulvar SCC. 2,5,6 Since differentiated VIN is often unifocal and the amount of skin involved is limited, surgical treatment by means of a wide local excision probably reduces the risk of progression to invasive carcinoma.
7Usual VIN is often multifocal, occurs in younger women and is associated with smoking and HPV, predominantly HPV-16 and -18, and can lead to HPV-positive vulvar SCC. 8 One third of all vulvar SCCs is associated with HPV. 9 The risk of malignant transformation of usual VIN to an invasive carcinoma appears to be 3-4%. The viral gene products E6 and E7 interfere with 2 pathways of cell cycle regulation. HPV E6 can interact with p53, leading to p53 dysfunction, which allows for an absence of cell cycle arrest.6,10 HPV E7 can inactivate pRb which can result in an overexpression of p16 INK4A and hyperproliferation...