Morules and ß-catenin predict POLE mutation status in endometrial cancer: A pathway to more cost-effective diagnostic procedures.

OBJECTIVES: The characterization of DNA polymerase epsilon (POLE) mutations has transformed the classification of endometrial endometrioid carcinomas (EECs), highlighting the need for efficient identification methods. This study aims to examine the relationship between distinct morphologic features-namely, squamous morules and squamous differentiation (SD), as well as ß-catenin expression-and the POLE mutation status in endometrial cancer (EC). METHODS: Our study included 35 POLE-mutated (POLEmut) EC cases and 395 non-POLEmut EEC cases. RESULTS: Notably, we observed no presence of morules in POLEmut cases, while SD was identified in 20% of instances. Conversely, morules and SD were identified in 12.7% and 26.1% of non-POLEmut EC cases, respectively, with morules consistently linked to a POLE wild-type status. The nuclear ß-catenin expression is typically absent in tumors with wild-type POLE (wt-POLE) status. CONCLUSIONS: Our findings suggest that the presence of either morules or nuclear ß-catenin expression in EEC could practically rule out the presence of POLE mutations. These morphologic and immunohistochemical features can be used as preliminary screening tools for POLE mutations, offering significant savings in time and resources and potentially enhancing clinical decision-making and patient management strategies. However, further validation in larger, multi-institutional studies is required to fully understand the implications of these findings on clinical practice.

Comparison of clinical characteristics and prognosis between type I and type II endometrial cancer: a single-center retrospective study.

OBJECTIVES: To explore the differences in clinical characteristics, prognosis, and risk factors between type I and type II endometrial cancer (EC). MATERIALS AND METHODS: We retrospectively collected EC patients diagnosed with type I or type II EC from 2009 to 2021 in the First Affiliated Hospital of Zhengzhou University. RESULTS: In total, 606 eligible EC patients (396 type I, and 210 type II) were included. Baseline analyses revealed that type II patients were older, had more advanced clinical stage, were more likely to receive chemoradiotherapy, and had higher incidence of myometrial infiltration, cervix involvement, lymph node metastasis and positive ascites cytology. Type II significantly favored poorer overall survival (OS) (HR = 9.10, 95%CI 4.79-17.28, P < 0.001) and progression-free survival (PFS) (HR = 6.07, 95%CI 2.75-13.37, P < 0.001) compared to type I. For all included EC, univariate and multivariate COX analyses revealed age, myometrial infiltration and pathological type were independent risk factors for OS and PFS. Subgroup analyses identified age, menopause, clinical stage, and lymph node metastasis as independent risk factors for type I regarding OS. While age, myometrial infiltration and chemoradiotherapy were identified as risk and protective factors for type II regrading OS. Age and cervix involvement were identified as independent risk factors for type I regarding PFS. Myometrial infiltration was identified as independent risk factor for type II regarding PFS. CONCLUSION: Type II patients shared different clinical characteristics and worse prognosis compared to type I, and their independent risk and protective factors also varied.

Mechanism of progestin resistance in endometrial precancer/cancer through Nrf2-survivin pathway.

Progestin is commonly used for young patients suffering from endometrial hyperplasia or cancer. However, there is approximately 30% failure rate with unclear mechanism. We investigated if Nrf2-survivin pathway contributes the progestin resistance (PR) in this setting. Current study detected Nrf2 and survivin protein expression in post progestin treated endometrial tissue samples by using immunohistochemistry. Transfection of Nrf2 and survivin into endometrial cancer cells in vitro was done to determine the roles of Nrf2 and survivin in progestin resistance. Silence of survivin was then performed to explore if Nrf2-driven progestin resistance is mediated by survivin. Medorxyprogesterone acetate (MPA) and metformin were applied to examine the cellular proliferations under the controlled conditions. Overexpression of survivin and Nrf2 were found in progestin-resistant endometrial samples as well as in those areas with only partial responses after MPA treatment. In contrast, all responded endometrial tissue with complete decidualization showed negative expression of these two biomarkers. Exogenous overexpression of Nrf2 and survivin resulted in progestin resistance. In addition, reduction of survivin in endometrial cancer cells overcame the Nrf2 overexpression induced progestin resistance. Furthermore, Nrf2 and survivin expressions were effectively suppressed after withdrawal of MPA. Interestingly, metformin increased the progestin sensitivity by down regulation of Nrf2 and survivin. The findings suggest that dysregulation of Nrf2-survivin may represent part of the molecular mechanisms of progestin resistance in endometrial cancer. Detecting survivin and Nrf2 may predict progestin resistance, while targeting Nrf2 and survivin may represent a promising prevention and treatment strategy for endometrial cancer.