Endometrial carcinoma stands as the most prevalent gynecological cancer and the fourth most common cancer affecting women. The incidence of endometrial cancer has been steadily increasing over the past decade, posing a significant threat to public health. The early detection of its precancers remains a critical and evolving concern to reduce mortality associated with endometrial carcinoma. In the last decade, our understanding of endometrial carcinoma and its precancers has advanced through systematic investigations into the molecular genetics of endometrial carcinoma and its precancers. In this review, we focus on advances in precancers associated with the endometrioid subtype, by far the most common histologic variant of endometrial adenocarcinoma. Recent investigations have led to the identification of new biomarkers, and the proposed incorporation of these biomarkers or biomarker panels into the diagnostic framework of endometrial carcinoma precancers. Here, we review these recent advances and their relevance to the histopathologic diagnosis of endometrial carcinoma precancers.

Background/Objectives: Despite advancements in treatment options, endometrial cancer remains a significant threat to women, underscoring the importance of early detection of atypical hyperplasia/endometrioid intraepithelial neoplasia (AH/EIN), the widely accepted histological precursor to endometrial carcinoma. Even with refinements in morphological criteria for the diagnosis of AH/EIN, accurate diagnosis remains challenging for pathologists, particularly in cases with secretory changes. Morphological alterations resulting from secretory-related changes further complicate the application of diagnostic criteria, emphasizing the need for reliable biomarkers. Previous studies have demonstrated that a panel consisting of three immunohistochemical markers, PAX2, PTEN, and β-catenin, can be effectively utilized for the identification of AH/EIN in various non-secretory scenarios. Methods: In this study, a total of 69 AH/EIN within secretory endometrium were analyzed using this panel. Benign interval endometrium (n = 57) and secretory phase endometrium (n = 71) were also analyzed for PAX2, PTEN, and β-catenin expression as controls. Results: The 3-marker panel successfully identified 93% of secretory AH/EIN, comparable to its performance in identifying non-secretory bona fide AH/EIN (92.8%) and AH/EIN within endometrial polyps (92.4%). Of note, β-catenin expression in benign interval endometrium commonly displayed weak nuclear staining (67%), which could pose a diagnostic pitfall when using the 3-marker panel. Overall, the results demonstrate the diagnostic utility of the 3-marker panel in clinical practice in identifying AH/EIN within challenging secretory phase endometrium cases. Conclusions: Combined with previous research highlighting its effectiveness in other challenging contexts—such as AH/EIN in polyps, small-sized EIN (subdiagnostic EIN), and progestin-treated EIN—this study provides strong evidence supporting the panel’s broad applicability in resolving major diagnostic challenges related to the precise diagnosis of AH/EIN.

The Indian Journal of Cancer is an official publication of the Indian Cancer Society and Indian Society of Oncology.