Expression of the CDK inhibitor p27kip1 and oxidative DNA damage in non-neoplastic and neoplastic vulvar epithelial lesions

Abstract

Vulvar cancer represents an important medical problem worldwide whose incidence is increasing at an alarming rate in young females. Several factors have been linked to vulvar cancer development, but its exact pathogenesis remains to be determined. Vulvar tumorigenesis proceeds through intermediate dysplastic lesions, known as vulvar intraepithelial neoplasias, frequently associated with non-neoplastic epithelial disorders of the vulva, such as lichen sclerosus and squamous cell hyperplasia. In this study, the expression of the CDK inhibitor p27 Kip1 and the extent of endogenous oxidative DNA damage were evaluated in vulvar specimens, including normal tissues, lichen sclerosus, squamous cell hyperplasia, vulvar intraepithelial neoplasias and invasive squamous cell carcinomas. We found that p27 Kip1 was constantly expressed in normal vulvar epithelium cells while a progressive significant reduction in the percentage of p27 Kip1 -positive cells was observed in vulvar intraepithelial neoplasias (77%) and in invasive carcinomas (64%). Mean percentage of positive cells in invasive carcinomas, but not in vulvar intraepithelial neoplasias, was also significantly lower than squamous cell hyperplasia lesions (78%) while lichen sclerosus displayed a percentage of positive cells (45%) significantly lower than both vulvar intraepithelial neoplasias and invasive carcinomas. 8-hydroxydeoxyguanosine (8-OHdG) is considered a sensitive biomarker for oxidative stress. We observed a progressive significant increase in the levels of 8-OHdG and in the percentage of positive cells from normal vulvar epithelium to vulvar intraepithelial neoplasias (25%) and to invasive carcinomas (64%). Squamous cell hyperplasia displayed an intermediate percentage of positive cells comparable to vulvar intraepithelial neoplasias 2 but significantly higher than vulvar intraepithelial neoplasias 1 and lower than invasive carcinomas. Lichen sclerosus staining was significantly lower than carcinomas but higher than vulvar intraepithelial neoplasias and squamous cell hyperplasia. These results demonstrate that expression of p27 Kip1 is downregulated while oxidative DNA damage increases from early non-neoplastic epithelial alterations through vulvar intraepithelial neoplasias to invasive vulvar carcinomas. Thus, both parameters might play an important role in the development of this cancer and their study might contribute to our understanding of human vulvar carcinogenesis. Keywords: vulvar cancer; tumorigenesis; cell cycle; oxidative DNA damage Squamous cell carcinoma of the vulva accounts for 4% of all gynecologic malignancies and although its incidence rates in older women have remained relatively stable over the past few decades, diagnosed cases of vulvar cancer are increasing at an alarming rate in young females worldwide. 1 The type of vulvar squamous cell carcinoma usually found in younger women appears to be associated with human papillomavirus (HPV) infection. Indeed, specific genital HPV types, in particular HPV 16, are strongly implicated in the ...

Medical treatment of vulvar squamous cell hyperplasia

“…In contrast subsequent investigations revealed that some cases of squamous hyperplasia were found not only be monoclonal but also to show increased expression of p53 and allelic imbalance [17–20]. In another recent study, it was demonstrated that expression of p27 (Kipl) was down‐regulated while oxidative DNA damage increased from non‐neoplastic epithelial disorder through vulvar epithelial neoplasia to invasive vulvar carcinoma [21]. These findings may support the hypothesis that there may be a pathway of neoplastic transformation from SH to invasive carcinoma.…”

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Increased expression of CD133 and reduced dystroglycan expression are strong predictors of poor outcome in colon cancer patients

“…Immunohistochemical analyses were performed on routinely processed, formalin-fixed, paraffin-embedded tissues employing an avidin–biotin complex immunoperoxidase technique, as previously described [12,13]. A specific polyclonal anti-CD133 antibody (Santa Cruz Biotechnology, Santa Cruz, CA, USA; 1:100) was used for the staining.…”