Zannoni Gian F, Faraglia Beatrice, Tarquini Elisabetta, Camerini Andrea, Vrijens Karen, Migaldi Mario, Cittadini Achille, Sgambato Alessandro
Istituto di Anatomia Patologica, Università Cattolica del Sacro Cuore, Rome, Italy.
Mod Pathol. 2006 Apr;19(4):504-13. doi: 10.1038/modpathol.3800532.
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 p27Kip1 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 p27Kip1 was constantly expressed in normal vulvar epithelium cells while a progressive significant reduction in the percentage of p27Kip1-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 p27Kip1 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.
外阴癌是一个全球性的重要医学问题，其在年轻女性中的发病率正以惊人的速度上升。多种因素与外阴癌的发生有关，但其确切发病机制仍有待确定。外阴肿瘤发生过程中会出现中间发育异常病变，即外阴上皮内瘤变，常与外阴非肿瘤性上皮疾病相关，如硬化性苔藓和鳞状细胞增生。在本研究中，我们评估了细胞周期蛋白依赖性激酶（CDK）抑制剂p27Kip1的表达以及内源性氧化DNA损伤的程度，研究对象包括正常组织、硬化性苔藓、鳞状细胞增生、外阴上皮内瘤变和浸润性鳞状细胞癌的外阴标本。我们发现，p27Kip1在正常外阴上皮细胞中持续表达，而在外阴上皮内瘤变（77%）和浸润性癌（64%）中，p27Kip1阳性细胞的百分比逐渐显著降低。浸润性癌中阳性细胞的平均百分比显著低于鳞状细胞增生病变（78%），但外阴上皮内瘤变中并非如此，而硬化性苔藓中阳性细胞的百分比（45%）显著低于外阴上皮内瘤变和浸润性癌。8-羟基脱氧鸟苷（8-OHdG）被认为是氧化应激的敏感生物标志物。我们观察到，从正常外阴上皮到外阴上皮内瘤变（25%）再到浸润性癌（64%），8-OHdG水平和阳性细胞百分比逐渐显著增加。鳞状细胞增生中阳性细胞的百分比处于中间水平，与外阴上皮内瘤变2相当，但显著高于外阴上皮内瘤变1且低于浸润性癌。硬化性苔藓的染色显著低于癌，但高于外阴上皮内瘤变和鳞状细胞增生。这些结果表明，从早期非肿瘤性上皮改变到外阴上皮内瘤变再到浸润性外阴癌，p27Kip1的表达下调，而氧化DNA损伤增加。因此，这两个参数可能在这种癌症的发生中起重要作用，对它们的研究可能有助于我们理解人类外阴癌的发生机制。
