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Non-neoplastic epithelial lesions of the vulva (NNEDV) lichen sclerosus (LS) and squamous hyperplasia (SH) have been implicated in the pathogenesis of squamous cell carcinoma of the vulva (SCC). To date, there have been no recognisable precursor lesions for SCC associated with NNEDV. TP53 is the most frequent genetic change in human cancers and can indicate both aetiology and molecular pathogenesis of tumours. A total of 27 SCC patients underwent immunohistochemistry (IHC) and TP53 mutational analysis using microdissection and direct sequencing. There were 19 patients with areas of adjacent epidermis: 17 had NNEDV (four SCCs had more than one adjacent lesion) and two had normal epidermis. In all, 70.4% of the SCCs, 40% LS and 22.2% SH demonstrated overexpression of p53. In total, 77.8% of SCCs, 46.7% of LS and 22.2% SH demonstrated mutations in TP53, with the majority of lesions having a mutation in codon 136. Eight cases were identified where the same mutation was identified in the SCC and in the adjacent area. These data suggest that TP53 mutations develop in NNEDV and are intrinsic to the clonal evolution that leads to SCC. The type of mutation detected is more likely to occur due to endogenous cellular changes rather than exogenous carcinogen exposure.

Objectives: We compared microvessel density (MVD) in normal, benign, preneoplastic, and neoplastic (squamous cell carcinoma (SCC)) vulvar disease to ascertain if this parameter could identify cases with lichen sclerosus (LS) and high-grade vulvar intraepithelial neoplasia (VIN3) at risk of developing malignancy., Methods: Microvessels were immunohistochemically stained in paraffin wax-embedded vulvar tissue sections with anti-von Willebrand factor (vWF) antibody using the streptavidin-biotin-horseradish peroxidase complex technique. Three "hot spots" with the greatest MVD were identified within 200 microm of the subepithelial dermis under low magnification (x 40 and x 100). The highest (HVD) and average (AVD) MVDs were quantified for each sample under high magnification (x 200) using an image analysis system., Results: HVD and AVD showed similar significant differences. SCC had significantly the highest MVD followed by VIN3, normal vulva, and LS. LS had significantly the lowest MVD, even lower than that of normal vulva. Two cases of VIN3 had much higher HVD (9.16 and 9.61) and AVD (6.89 and 7.71) compared with the main cluster of cases., Conclusion: In vulvar LS, MVD, as assessed by HVD/AVD, is not a useful parameter in determining potential malignant progression, while in VIN3 this parameter could be valuable in identifying cases at greatest risk of progression to invasive disease.

Background: Topical corticosteroids have become the treatment of choice for genital lichen sclerosus (LS) and are believed to be required for long-term relief of symptoms., Objective: To compare vulval LS that had been treated with topical corticosteroids, vulval LS that had not received topical corticosteroids, and histologically normal vulval skin., Methods: We used immunohistochemistry to look for Ki67 expression and abnormal p53 expression., Results: We found a statistically significant difference for p53 overexpression, with increased levels seen when comparing corticosteroid-treated LS with normal genital skin (P = 0.011). Ki67 expression was also significantly higher in the corticosteroid-treated group compared with normal genital skin (P = 0.001), and increased levels were also found in the treated group compared with untreated LS (P = 0.05)., Conclusions: Our data suggest that topical corticosteroids have an effect on cell cycle proteins in genital skin and, in particular, genital skin with LS changes.

Abnormalities in the cell cycle are associated with tumorigenesis but have not yet been identified in squamous cell carcinoma (SCC) of the vulva or in adjacent vulvar lesions. The purpose of this study was to identify cell cycle protein expression (cyclin D1 and retinoblastoma protein [pRb]) in vulvar SCC and in adjacent potentially premalignant lesions: lichen sclerosis (LS), squamous cell hyperplasia (SH), and vulvar intraepithelial neoplasia (VIN). Using immunohistochemical techniques, 57 SCCs were analyzed with 19 adjacent areas showing LS, 13 showing SH, 11 VIN, and six normal epithelium. Fifty-one percent of SCCs showed abnormal cyclin D1 expression and 37% showed abnormal pRb. Abnormal cyclin D1 expression in the adjacent areas was as follows: 53% in LS, 31% in SH, 18% in VIN, and 0% in normal. Abnormal pRb expression was as follows: 42% in LS, 62% in SH, 46% in VIN, and 33% in normal. Only 10 lesions showed abnormal expression of both proteins. Abnormal expression of cyclin D1 in SCC was statistically significant compared with adjacent normal epithelium. In SCC lesions, abnormal cyclin D1 expression was associated with greater depth of invasion. Abnormal pRb in SCC was associated with poor tumor grade. Cyclin D1 and pRb are separately involved in the progression of vulvar cancer, and changes in the expression of these proteins may represent an early stage of malignant transformation in vulvar disease.

Lichen sclerosus (LS) has a known association with the development of squamous cell carcinoma of the vulva. The purpose of this study was to investigate molecular markers, which could indicate premalignant changes. Multiple sequential vulvar biopsies were taken over a period of 11 years from a patient with longstanding LS. Immunohistochemical staining was used to demonstrate a range of molecular markers. Increased expression of p53 and Ki67 was found in areas of squamous hyperplasia (SH) and differentiated vulvar intraepithelial neoplasia (dVIN) which correlated with the subsequent development of invasive squamous cell carcinoma (SCC). Molecular changes have been found to accompany histologic changes in the progression of vulvar LS to malignancy. Such markers may prove a useful addition in the clinical management of these conditions.

Objective: To investigate the presence of angiogenic factors in benign, premalignant and malignant vulvar lesions., Study Design: Immunohistochemical demonstration of vascular endothelial growth factor (VEGF) and platelet-derived endothelial cell growth factor (PD-ECGF) in normal vulvar skin, lichen sclerosus, vulvar intraepithelial neoplasia (VIN) and vulvar cancer., Results: VEGF was found in the majority of vulvar cancers but only a minority of VIN lesions. PD-ECGF was found in the majority of lesions., Conclusion: Demonstration of angiogenesis may suggest which preinvasive lesions will progress to invasive cancer.