Endometrial cancer is the most common gynecologic malignancy in developed countries with a slow but constant rise in both incidence and mortality [1,2]. Most patients present with early stage disease and have an excellent prognosis, yet a subset of low grade and early stage endometrioid endometrial cancers will recur following initial treatment. Significant research has been dedicated to better understand risk factors for recurrence of endometrial cancer.

Historically, endometrial cancer has been classified into two clinicopathological types: (i) the common type I (80–90%), including grade 1 and 2 endometrioid adenocarcinomas, and (ii) the less common type II (10–20%), which comprises high-grade endometrioid, serous, clear cell, undifferentiated and carcinosarcoma histologies [3]. Well-established clinicopathological risk factors for recurrence have been defined and include age, depth of myometrial invasion, grade, and lympho-vascular space invasion (LVSI) [2,3]. Early molecular data have supported the dualistic type I/ II classification to some extent; however, it was noted that considerable molecular heterogeneity exists within both type I and II [4]. Therefore, in 2013 The Cancer Genome Atlas (TCGA) suggested four distinct molecular categories of endometrial cancer based on somatic mutational burden and copy number alterations. Subsequently, multiple studies showed that surrogate parameters can be used to incorporate this molecular classification into the pathological routine workup, abrogating the need for extensive sequencing but using immunohistochemistry stains for mismatch repair proteins and p53 as well as targeted POLE sequencing instead [[5], [6], [7], [8]].

It was noted in the initial TCGA study that 52% of the endometrial cancers in the microsatellite-stable, low-copy number group, the so-called no specific molecular profile (NMSP) group, harbored a mutation in the β-catenin gene (CTNNB1) [4]. β-catenin is a “moonlighting protein” with two functions in (i) the cell adhesion complex E cadherin and (ii) the canonical Wnt/β-catenin signaling pathway. Most mutations in endometrioid adenocarcinomas were found in exon 3 of CTNNB1. Mutations in this gene location result in stabilization of the β-catenin protein, which in turn results in re-distribution of β-catenin from the plasma membrane into the cancer cell nucleus in steady-state – a process that can be detected by immunohistochemistry [9]. This protein redistribution within the cell, not its expression level, differentiates normal and cancer. The redistribution into the cancer cell nucleus is associated with an increased activity of the canonical Wnt/β-catenin signaling pathway, which may result in enhanced cancer cell proliferation [10].

Data on β-catenin as a prognosticator in endometrial cancer are limited and mixed [[11], [12], [13]]. The majority of available studies indicate that a CTNNB1 mutation is associated with a higher risk of recurrence in low grade and low-stage endometrioid endometrial cancers [2,3]. The objective of this retrospective cohort study was to investigate the impact of aberrant β-catenin distribution as assessed by immunohistochemistry on disease recurrence in endometrioid endometrial cancers over a four-year period at a single academic institution. We hypothesized that aberrant β-catenin staining is associated with an increased risk of endometrial cancer recurrence.