Department of Pathology, Hospital de la Santa Creu i Sant Pau, Institute of Biomedical Research (IIB Sant Pau), Autonomous University of Barcelona, 08041 Barcelona, Spain.
Department of Pathology, Università degli Studi di Bologna, 40126 Italia.
Hum Pathol. 2018 Feb;72:100-106. doi: 10.1016/j.humpath.2017.11.006. Epub 2017 Nov 11.
Undifferentiated endometrial carcinoma is an aggressive type of uterine cancer, which is occasionally associated with a low-grade endometrioid carcinoma component. This combination is referred to as "dedifferentiated endometrioid endometrial carcinoma." Neuroendocrine expression may occur in undifferentiated endometrial carcinoma, but its significance in dedifferentiated endometrial carcinomas is unknown. To gain insight into the pathogenesis of these tumors we have analyzed the immunophenotype (ARID1A, MLH1, PMS2, MSH2, MSH6, p53, β-catenin, SMARCB1, synaptophysin, chromogranin A, and CD56) and mutational status (PTEN, KRAS, PIK3CA, TP53 and POLE) of 4 dedifferentiated endometrial carcinomas with strong and diffuse neuroendocrine expression. All tumors demonstrated neuroendocrine expression in ≥70% of the cells in the undifferentiated carcinoma areas. Loss of expression of at least 1 DNA mismatch repair protein was observed in 2 cases, and p53 immunoreaction was aberrant (mutated/inactivated) in one case. All carcinomas were negative for β-catenin and maintained nuclear SMARCB1 (INI1) and ARID1A expression. Three tumors shared identical endometrioid molecular profile (PTEN and/or PIK3CA mutations) in both components. One tumor had POLE exonuclease domain mutation in the undifferentiated component. In one case, TP53 mutation was found exclusively in the undifferentiated component. Two patients died with peritoneal carcinomatosis and abdominal metastases, respectively; one patient died of a renal failure without evidence of disease, and the last patient is alive and free of disease at 3.3 years. Dedifferentiated endometrial carcinomas with neuroendocrine features are clinically and molecularly heterogeneous tumors. Probably, these carcinomas might acquire undifferentiated phenotype through mutations in TP53 and POLE.
未分化子宫内膜癌是一种侵袭性的子宫癌，偶尔与低级别子宫内膜样癌成分相关。这种组合被称为“去分化的子宫内膜样癌”。未分化子宫内膜癌中可能出现神经内分泌表达，但在去分化的子宫内膜癌中的意义尚不清楚。为了深入了解这些肿瘤的发病机制，我们分析了 4 例具有强烈弥漫性神经内分泌表达的去分化子宫内膜癌的免疫表型（ARID1A、MLH1、PMS2、MSH2、MSH6、p53、β-连环蛋白、SMARCB1、突触素、嗜铬粒蛋白 A 和 CD56）和突变状态（PTEN、KRAS、PIK3CA、TP53 和 POLE）。所有肿瘤在未分化癌区域的≥70%细胞中均显示神经内分泌表达。在 2 例中观察到至少 1 种 DNA 错配修复蛋白表达缺失，在 1 例中 p53 免疫反应异常（突变/失活）。所有癌均为β-连环蛋白阴性，并维持核 SMARCB1（INI1）和 ARID1A 表达。3 个肿瘤在两个成分中具有相同的子宫内膜样分子谱（PTEN 和/或 PIK3CA 突变）。一个肿瘤在未分化成分中具有 POLE 外切酶结构域突变。在 1 例中，仅在未分化成分中发现 TP53 突变。2 例患者分别死于腹膜癌病和腹部转移，1 例患者死于肾衰竭而无疾病证据，最后 1 例患者在 3.3 年后仍然存活且无疾病。具有神经内分泌特征的去分化子宫内膜癌是临床和分子上具有异质性的肿瘤。可能这些癌通过 TP53 和 POLE 的突变获得未分化表型。
