Institute of Pathology, Department of Gynaecology, University Medical Centre Hamburg-Eppendorf, Martinistrasse 52, Hamburg, Germany.
Int J Gynecol Pathol. 2011 Sep;30(5):497-504. doi: 10.1097/PGP.0b013e3182184c7a.
Human papillomavirus (HPV)-independent development of vulvar carcinomas is common and the disruption of the TP53 pathway seems to play a key role in these tumors. Overexpression of TP53 in precursor lesions (differentiated VIN) and associated invasive carcinomas is regarded as an important diagnostic feature of this subtype of vulvar cancer. To determine the relationship of TP53 mutation status with clinicopathologic parameters, HPV status, and patient outcome, 18 squamous cell carcinomas of the vulva with TP53 overexpression along with 21 immunohistochemically TP53-negative tumors were analyzed. TP53 mutations were found in 17 (43.6%) of vulvar cancers, 18 (46.2%) tumors were HPV associated, and 8 (20.5%) carcinomas showed no relation to HPV infection or TP53 mutations. The presence of TP53 mutations was significantly linked to TP53 overexpression (P=0.002) and negative HPV status (P=0.012). The specificity of TP53 protein overexpression for the occurrence of TP53 mutations was 68.2%, with a positive predictive value of 66.7%. The most frequent mutation types were C:G →T:A transitions (57.9%). This mutation pattern strongly indicates the important role of oxidative stress in vulvar carcinogenesis. There were no relationships between TP53 mutation status and tumor stage, grading, nodal status, depth of invasion, or patient prognosis. In summary, TP53 mutations play a crucial role in a substantial proportion of vulvar carcinomas and are probably associated to cellular oxidative stress in chronically degenerative diseases of the vulva, such as lichen sclerosus. These data support the potential utility of restoring TP53 function as a therapeutic alternative in vulvar cancer. Further studies are necessary to clarify the prognostic implications of TP53 mutations in vulvar carcinomas.
人乳头瘤病毒（HPV）不相关的外阴癌的发生很常见，TP53 通路的破坏似乎在外阴癌中起着关键作用。在外阴癌前病变（分化型 VIN）和相关的浸润性癌中，TP53 的过度表达被认为是这种外阴癌亚型的一个重要诊断特征。为了确定 TP53 突变状态与临床病理参数、HPV 状态和患者预后的关系，我们分析了 18 例伴有 TP53 过表达的外阴鳞癌和 21 例免疫组化 TP53 阴性肿瘤。在外阴癌中发现了 17 例（43.6%）TP53 突变，18 例（46.2%）肿瘤与 HPV 相关，8 例（20.5%）癌与 HPV 感染或 TP53 突变无关。TP53 突变的存在与 TP53 过表达显著相关（P=0.002）和 HPV 阴性状态相关（P=0.012）。TP53 蛋白过表达发生 TP53 突变的特异性为 68.2%，阳性预测值为 66.7%。最常见的突变类型是 C:G→T:A 转换（57.9%）。这种突变模式强烈表明氧化应激在外阴癌发生中的重要作用。TP53 突变状态与肿瘤分期、分级、淋巴结状态、浸润深度或患者预后之间无关系。总之，TP53 突变在外阴癌中起着至关重要的作用，并且可能与慢性退行性疾病如硬化性苔藓中外阴细胞的氧化应激有关。这些数据支持恢复 TP53 功能作为外阴癌治疗选择的潜在应用。需要进一步的研究来阐明 TP53 突变在外阴癌中的预后意义。
