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Two separate pathways leading to vulvar carcinoma have been suggested. First, a human papillomavirus (HPV)-dependent pathway, in which premalignant stages of vulvar cancer are the classic vulvar intraepithelial neoplasia (VIN) lesions. Second, an HPV-independent pathway, associated with differentiated VIN III lesions and/or lichen sclerosus. To obtain insight into the mechanisms underlying these pathways, we determined the relationship between HPV DNA and the expression of p14(ARF) and p16(INK4A) in non- and (pre)malignant vulvar lesions. Seventy-three archival samples of non- and (pre)neoplastic vulvar lesions were selected and tested for hr-HPV DNA using a broad-spectrum HPV detection/genotyping assay (SPF(10)-LiPA) and the expression of p14(ARF) and p16(INK4A). The prevalence of HPV increased with the severity of the classic VIN lesions; in VIN I no hr-HPV was detected, in VIN II 43%, and in VIN III 71% of the samples were hr-HPV-positive. Roughly the same was true for the expression of p14(ARF) and p16(INK4A). The simultaneous expression of p14(ARF) and p16(INK4A) was highly associated with the presence of hr-HPV DNA. Hr-HPV was detected in only a single case of the differentiated VIN III lesions, whereas no expression of p14(ARF) was found and 16(INK4A) was present in only two cases. All 16 samples of vulvar cancer were hr-HPV DNA- negative, although in respectively 63% and 25%, p14(ARF) and p16(INK4A) was expressed. No relation was found between hr-HPV and the expression of p14(ARF) and p16(INK4A) in the 20 nonneoplastic vulvar lesions. Our results provide further evidence that vulvar squamous cell carcinoma is a multifactorial disease that develops from two different pathways. First, an HPV-dependent pathway with a remarkable resemblance to CIN lesions and cervical carcinoma and second, an HPV-independent pathway in which differentiated VIN III lesions that are hr-HPV-negative may be precursors.

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...

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Lichen sclerosus, high-grade usual vulvar intraepithelial neoplasia (VIN) and differentiated VIN have a different malignant potential. The objective of this study was to quantify the proliferative activity in the basal region of the epithelium of vulvar premalignancies. Furthermore, we investigated whether MIB1 expression in the basal region of vulvar epithelium can be helpful in diagnosing differentiated VIN, which may be hard to discern from normal epithelium. MIB1 was used to immunohistochemically visualise proliferating cells within formalin-fixed, paraffin-embedded, archival tissue sections of different vulvar premalignancies (N ¼ 48) and normal vulvar epithelium (N ¼ 16). Automatic digital image analysis software was developed to quantify the proliferating fraction in different parts of the epithelium (MIB1 positivity index). MIB1 expression differed among the various vulvar premalignancies; a MIB1-negative basal cell layer was a distinct feature of normal vulvar epithelium. No MIB1-negative basal cell layer was noted in differentiated VIN or other vulvar premalignancies. Owing to this negative cell layer, the MIB1 proliferation index in normal vulvar epithelium was significantly lower than in vulvar premalignancies. In conclusion, MIB1 expression can be a helpful tool in diagnosing a premalignancy and has additional value especially to distinguish differentiated VIN neoplasia from normal vulvar epithelium, but cannot explain the differences in malignant potential.

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