The Molecular Pathology of Morules in Endometrial Carcinoma: Biological Significance and Clinical Implications

Morules were ordinally described as mulberry-like clusters of endometrial metaplasia with the potential to differentiate toward true squamous metaplasia (SqM). Although both morular and SqM lesions are categorized under "endometrial carcinoma (Em Ca) with squamous differentiation" in the WHO classification, they represent biologically distinct entities. Notably, morules are strongly associated with CTNNB1 (β-catenin) mutations. This review summarizes the molecular mechanisms driving the differentiation of Em Ca cells toward both morular and SqM phenotypes. Morules are frequently identified in younger Em Ca patients and display a unique immunophenotype characterized by nuclear β-catenin accumulation, a lack of expression of estrogen-α and progesterone receptor expression, and a low proliferative index. In Em Ca cells harboring CTNNB1 alterations, the PTEN/β-catenin axis suppresses cell proliferation and induces epithelial-to-mesenchymal transition, promoting morule-related cancer stem cell (CSC) properties. Conversely, p40 expression serves as the initial signaling event establishing SqM-related CSC features within the morule-SqM cascade. Furthermore, the ezrin-radixin-moesin-binding phosphoprotein 50/S100A4/myosin heavy chain 9 axis drives terminal squamous differentiation, particularly under hypoxic conditions. Clinically, histopathological evaluation of morular morphology and nuclear β-catenin status serves as a valuable tool for predicting progestin therapeutic efficacy in young Em Ca patients.