Department of Obstetrics and Gynecology, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands.
Hum Pathol. 2010 Oct;41(10):1475-85. doi: 10.1016/j.humpath.2009.12.015. Epub 2010 Jul 24.
The molecular pathogenesis of human papilloma virus-unrelated vulvar squamous cell carcinoma is not well known. Whether malignant progression of lichen sclerosus and differentiated vulvar intraepithelial neoplasia to vulvar squamous cell carcinoma could be accompanied by altered DNA content has not been studied extensively. DNA content in isolated nuclei of microdissected normal vulvar epithelium (n = 2), lichen sclerosus (n = 9), differentiated vulvar intraepithelial neoplasia (n = 13), and squamous cell carcinoma (n = 17) from 22 patients was measured via DNA image cytometry. For additional analysis, 6 differentiated vulvar intraepithelial neoplasia lesions were selected, bringing the number of patients to 28. p53 expression was determined by immunohistochemistry on consecutive tissue sections. Thirty-eight percent (5/13) of differentiated vulvar intraepithelial neoplasia lesions and 65% (11/17) of squamous cell carcinomas were DNA aneuploid or tetraploid. In lesions that contained differentiated vulvar intraepithelial neoplasia and adjacent squamous cell carcinoma, the ploidy status of differentiated vulvar intraepithelial neoplasia did not exceed that of squamous cell carcinoma. We observed a strong correlation between high p53 expression and DNA aneuploidy. This relation was also present at the level of a single nucleus, measured by sequential image cytometry of p53 immunohistochemistry followed by DNA image cytometry on formalin-fixed tissue sections. Similarly, we found p53-positive nonproliferating cells with increased DNA content in the superficial compartment of 6 additional solitary differentiated vulvar intraepithelial neoplasia lesions that were not associated with squamous cell carcinoma, indicating ascending aneuploid cells from the basal compartment. DNA ploidy measurements suggest that differentiated vulvar intraepithelial neoplasia has a higher malignant potential than lichen sclerosus and thus is a more likely precursor of squamous cell carcinoma. Furthermore, high p53 expression correlates with increased DNA content and aneuploidy; but it requires further research to unveil a possible causal relation.
人乳头瘤病毒无关的外阴鳞癌的分子发病机制尚不清楚。外阴硬化性苔藓和分化型外阴上皮内瘤变恶变为外阴鳞癌时是否伴随着 DNA 含量的改变尚未被广泛研究。通过 DNA 图像细胞术测量了 22 名患者的微切割正常外阴上皮（n = 2）、硬化性苔藓（n = 9）、分化型外阴上皮内瘤变（n = 13）和鳞状细胞癌（n = 17）的分离核 DNA 含量。为了进一步分析，选择了 6 个分化型外阴上皮内瘤变病变，使患者数量增加到 28 个。通过连续组织切片的免疫组织化学法测定 p53 表达。38%（5/13）的分化型外阴上皮内瘤变和 65%（11/17）的鳞状细胞癌为 DNA 非整倍体或四倍体。在包含分化型外阴上皮内瘤变和相邻鳞状细胞癌的病变中，分化型外阴上皮内瘤变的倍性状态未超过鳞状细胞癌。我们观察到高 p53 表达与 DNA 非整倍体之间存在很强的相关性。这种关系在单个核水平上也存在，通过 p53 免疫组织化学的连续图像细胞术测量 followed 甲醛固定组织切片的 DNA 图像细胞术来测量。同样，我们发现 6 个额外的孤立分化型外阴上皮内瘤变病变的浅层区域中存在 p53 阳性非增殖细胞，这些细胞具有增加的 DNA 含量，但与鳞状细胞癌无关，表明从基底区域上升了非整倍体细胞。DNA 倍性测量表明，分化型外阴上皮内瘤变的恶性潜能高于硬化性苔藓，因此更有可能是鳞状细胞癌的前身。此外，高 p53 表达与 DNA 含量增加和非整倍体相关；但需要进一步的研究来揭示可能的因果关系。
