Departments of *Pathology §Gynecology and Obstetrics ∥Oncology, Johns Hopkins Medical Institutions, Baltimore, MD ‡Department of Pathology, Magee-Womens Hospital, University of Pittsburgh Medical Center, Pittsburg, PA †Department of Pathology, Seirei Mikatahara Hospital, Hamamatsu, Japan.
Am J Surg Pathol. 2014 May;38(5):660-5. doi: 10.1097/PAS.0000000000000166.
Uterine and ovarian undifferentiated carcinomas (UCs) are often associated with low-grade endometrioid carcinomas (EMCs) and are characterized by a solid growth pattern and a lack of appreciable features of differentiation. As compared with pure EMC, UC is highly malignant, and the molecular pathogenesis that leads to disease aggressiveness remains largely unknown. This study interrogates the molecular pathogenesis of UCs by comparing the molecular alterations between the UC and the EMC components. A total of 20 UCs were studied, 12 of which contained both UC and EMC components. Mutation analysis was performed for the genes commonly mutated in EMC, and immunohistochemistry was used to determine the expression pattern of β-catenin and PTEN. Sequencing analysis revealed that UCs harbored somatic mutations in PIK3CA (50%), CTNNB1 (30%), TP53 (30%), FBXW7 (20%), and PPP2R1A (20%). All somatic mutations detected in EMCs were also present in concurrent UCs. Moreover, additional somatic mutations were detected in the UC component in 5 (42%) cases with concurrent EMC and UC. Concordance of immunostaining pattern for β-catenin and PTEN was recorded in all 12 matched EMCs and UCs, except 4 cases in which nuclear accumulation of β-catenin staining was detected in one of the components but not in the other. Our findings support a clonal relationship between EMCs and their associated UCs. Additional molecular genetics alteration, including mutations of CTNNB1, PPP2R1A, and TP53, may contribute to tumor progression from EMC to UC.
子宫和卵巢未分化癌（UCs）常与低级别子宫内膜样癌（EMCs）相关，其特征为实性生长模式和缺乏明显的分化特征。与纯 EMC 相比，UC 恶性程度更高，导致疾病侵袭性的分子发病机制仍知之甚少。本研究通过比较 UC 和 EMC 成分的分子改变，探讨 UC 的分子发病机制。共研究了 20 例 UCs，其中 12 例同时包含 UC 和 EMC 成分。对 EMC 中常见突变的基因进行了突变分析，并通过免疫组化检测β-catenin 和 PTEN 的表达模式。测序分析显示，UC 中存在 PIK3CA（50%）、CTNNB1（30%）、TP53（30%）、FBXW7（20%）和 PPP2R1A（20%）的体细胞突变。在同时存在 UC 的病例中，EMCs 中检测到的所有体细胞突变也存在于 UC 中。此外，在 5 例（42%）同时存在 EMC 和 UC 的病例中，UC 成分中还检测到额外的体细胞突变。在所有 12 例配对的 EMC 和 UC 中，均记录到β-catenin 和 PTEN 的免疫染色模式一致，除了 4 例中一个成分的β-catenin 染色核内聚集而另一个成分没有。我们的研究结果支持 EMCs 与其相关的 UCs 之间存在克隆关系。其他分子遗传学改变，包括 CTNNB1、PPP2R1A 和 TP53 的突变，可能有助于 EMC 向 UC 的肿瘤进展。
