Endometrial Cancer Characteristics and Risk of Recurrence

The Role of Epigenetic Silencing of MLH1

Lindsay E. Borden, MD; Tonja M. Locklear, PhD; Douglas J. Grider, MD; Janet L. Osborne, MD; Erin J. Saks, MD; Fidel A. Valea, MD; David A. Iglesias, MD


Am J Clin Pathol. 2022;157(1):90-97. 

In This Article

Abstract and Introduction


Objectives: To describe clinicopathologic characteristics and survival outcomes of endometrial adenocarcinomas stratified by mismatch repair (MMR) status.

Methods: Single-institution, retrospective study of all women with endometrioid adenocarcinomas treated from January 2012 through December 2017. Patients were categorized into one of three groups based on MMR testing: intact MMR expression (MMR+), probable MMR mutation (MMR–), or MLH1 hypermethylation (hMLH1+). Demographics, pathologic characteristics, recurrence rates, and survival differences were analyzed.

Results: In total, 316 women were included in the analysis: 235 (74.4%) patients in the MMR+ group, 10 (3.1%) in the MMR– group, and 71 (22.5%) in the hMLH1+ group. Patients with hMLH1+ were significantly older, exhibited higher-grade histology and presence of lymphovascular space invasion, and were more likely to have received adjuvant treatment. The early stage hMLH1+ patients were more likely to recur (15.3% hMLH1+ vs 2.3% MMR+ vs 12.5% MMR–, P < .001). Hypermethylation remained a significant predictor of recurrence in multivariable analysis (odds ratio, 5.09; 95% confidence interval [CI], 1.54–16.86; P = .008). Recurrence-free survival was significantly reduced in early stage hMLH1+ (hazard ratio, 7.40; 95% CI, 2.80–21.62; P < .001).

Conclusions: Women with hMLH1+ endometrial cancer have worse prognostic features and recur more frequently, even in patients traditionally considered low risk for recurrence.


Endometrial cancer is the most common gynecologic malignancy in the United States, with 61,880 estimated new cases in 2019 and 12,160 estimated deaths.[1] Approximately 3% to 5% of endometrial cancers may be attributable to Lynch syndrome, characterized by a deleterious germline mutation in a gene coding for mismatch repair (MMR) proteins, which results in an increased lifetime risk of endometrial, colon, and breast cancers, as well as other malignancies.[2] Identification of these higher-risk patients and families has the advantage of allowing for appropriate patient counseling and informing decisions related to cancer screening, possible risk reduction strategies, and therapeutic options. Historically, higher-risk individuals who would be candidates for germline genetic testing were identified based on the patient's personal and family history. However, given the concern for possibly missing a proportion of at-risk individuals and their families based on history alone, many centers have adopted universal tumor-based screening of patients diagnosed with endometrial and/or colon cancers. MMR testing is a critical step in the identification of the Lynch syndrome proband and sporadic microsatellite-unstable endometrial carcinomas. The current study focuses on the clinical characteristics and survival outcomes of sporadic high microsatellite instability (MSI-H) endometrial carcinomas secondary to hypermethylation of the MLH1 promoter (hMLH1+) region resulting in epigenetic silencing of the MLH1 and PMS2 genes.

Further understanding of the characteristics and behaviors of these tumors is necessary given the introduction and emphasis of personalized cancer care. This study aims to describe the unique characteristics and long-term outcome data of a cohort of hMLH1+ tumors and compare them with tumors with intact MMR expression (MMR+) and germline-deficient MMR expression (MMR–).