Expression Characteristics of 3-Marker Panel (PAX2, PTEN, and β-Catenin) in Benign Interval and Secretory Endometrium and Secretory Endometrial Precancer

<b>Background/Objectives</b>: 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. <b>Methods</b>: In this study, a total of 69 AH/EIN within secretory endometrium were analyzed using this panel. Benign interval endometrium (<i>n</i> = 57) and secretory phase endometrium (<i>n</i> = 71) were also analyzed for PAX2, PTEN, and β-catenin expression as controls. <b>Results</b>: 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. <b>Conclusions</b>: 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.