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Mixed and Ambiguous Endometrial Carcinomas: A Heterogenous Group of Tumors With Different Clinicopathologic and Molecular Genetic Features

Espinosa, Iñigo MD, PhD; D’Angelo, Emanuela MD, PhD; Palacios, José MD, PhD; Prat, Jaime MD, PhD, FRCPath

The American Journal of Surgical Pathology: July 2016 - Volume 40 - Issue 7 - p 972–981
doi: 10.1097/PAS.0000000000000640
Original Articles

Besides endometrioid, serous, and clear cell carcinomas, there are endometrial carcinomas exhibiting mixed and ambiguous morphologic features. We have analyzed the immunophenotype (p53, p16, β-catenin, ER, HNF-1B, MLH1, and Ki-67) and mutational status (PTEN, KRAS, PIK3CA, and POLE) of 7 mixed carcinomas and 13 ambiguous carcinomas, all of them classified initially as mixed carcinomas. Only 2 of the 7 (28%) mixed carcinomas showed different immunophenotypes in different components. All but 2 tumors (5/7, 71%) overexpressed p53 and p16 and were negative for ER. Both carcinomas (2/7, 28%) showed a prominent micropapillary component that resembled an ovarian low-grade serous carcinoma and merged with villoglandular endometrioid carcinoma. The ambiguous carcinomas exhibited glandular architecture, high nuclear grade, and overlapping features of endometrioid and serous carcinomas. All tumors overexpressed p53 and p16, and the majority of cases (12/13, 92%) were negative for ER. KRAS mutations were identified in 3 of 7 (42%) mixed carcinomas, including the 2 cases with a “low-grade” serous–like component. PIK3CA mutations occurred in 2 (2/13, 15%) ambiguous carcinomas and PTEN mutations in 1 (1/7, 14%) mixed and 1 (1/13, 8%) ambiguous carcinoma. POLE exonuclease domain mutations were encountered in a case of mixed undifferentiated and well-differentiated (dedifferentiated) carcinoma. Two of the 7 (29%) mixed endometrial carcinomas and 5 of the 13 (38%) ambiguous carcinomas had extended beyond the pelvis (stages III and IV). Two of the 7 (29%) patients with mixed endometrial carcinoma and 6 of 12 (50%) patients with ambiguous endometrial carcinoma were alive with disease or had died of tumor. Our results show that, biologically, many so-called mixed carcinomas represent serous carcinomas with ambiguous morphology. Our series include 2 true mixed endometrial carcinomas with a “low-grade serous”–like component, microcystic, elongated, or fragmented features, KRAS mutations, and aggressive behavior.

*Department of Pathology, Hospital de la Santa Creu i Sant Pau, Institute of Biomedical Research (IIB Sant Pau), Autonomous University of Barcelona, Barcelona

Department of Pathology, Hospital Universitario Ramón y Cajal, Madrid, Spain

Supported by Grants FIS PI11-01561 and RTICC RD06/0020/0015, RD12/0036/0013, Department of Health, Spain, Fundación AECC-Grupos Estables. Tumor samples were obtained with the support of Xarxa Banc de Tumors de Catalunya (XBTC).

Conflicts of Interest and Source of Funding: The authors have disclosed that they have no significant relationships with, or financial interest in, any commercial companies pertaining to this article.

Correspondence: Jaime Prat, MD, PhD, FRCPath, Department of Pathology, Hospital de la Santa Creu i Sant Pau, Autonomous University of Barcelona, Sant Quiti 87-89, Barcelona 08041, Spain (e-mail:

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