β-catenin, Pax2, and Pten Panel Identifies Precancers Among Histologically Subdiagnostic Endometrial Lesions

Abstract

Despite refinements in histologic criteria for the diagnosis of endometrioid precancers, many challenging cases are encountered in daily practice, creating diagnostic uncertainty and suboptimal patient management. Recently, an immunohistochemical 3-marker panel consisting of β-catenin, Pax2, and Pten was identified as a useful diagnostic adjunct. However, previous studies focused either on cancers or diagnostically unambiguous precancers, leaving questions about the applicability and utility of the panel in endometria with architectural features near or below the threshold of accepted histologic criteria for endometrioid precancers. Here, in a retrospective study of 90 patients, we evaluated the performance of the 3-marker panel. Notably, the panel detected a subset of disordered proliferative endometria (8/44, 18%), nonatypical hyperplasias (19/40, 48%), and cases with ambiguous features (3/6, 50%) with aberrancy for ≥1 markers. Marker-aberrant cases were more likely to progress to endometrioid precancer or cancer (P=0.0002). Patterns of marker aberrancy in the index and progressor cases from individual patients provided evidence for origin in a common precursor, and next-generation sequencing of the progressor cases rationalized marker aberrancy for β-catenin and Pten. The results unequivocally demonstrate that some lesions that do not approach current histologic thresholds are bona fide neoplastic precursors with clinically-relevant driver events that can be detected by the 3-marker panel. The findings provide further validation for the diagnostic utility of the panel in clinical practice and its application in difficult or ambiguous cases.

Utility of a PAX2, PTEN, and β-catenin Panel in the Diagnosis of Atypical Hyperplasia/Endometrioid Intraepithelial Neoplasia in Endometrial Polyps

“…15 Third, the panel can help in the detection of precancers among some histologically subdiagnostic endometrial lesions. 13 In summary, our study demonstrated that the panel of 3 IHC markers (PAX2, PTEN, and β-catenin) is a useful tool in the diagnosis of AH/EIN within EMP. This study adds EMPs to the list of confounding variables "secretory phase, concurrent progestin administration, and minute lesions", where the 3-marker panel can be of diagnostic utility.…”

“…Second, IHC markers may help to identify residual AH/EIN after progestin treatment since many women with AH/EIN undergo conservative management with long-term progestin administration 15 . Third, the panel can help in the detection of precancers among some histologically subdiagnostic endometrial lesions 13 …”

“…Recently, the World Health Organization 2020 Classification system for the first time recommended the incorporation of biomarkers into the diagnostic workflows for AH/EIN 3 . Our recent studies demonstrated the reliable identification of the majority of AH/EIN (92.8%) using an immunohistochemical (IHC) marker panel comprised of PAX2, PTEN, and β-catenin 9–13 . In this study, we systematically investigated the performance of the 3-marker panel (PAX2, PTEN, and β-catenin) in aiding the diagnosis of AH/EIN within EMP (AH/EIN in EMP) and other putative polypoid precancers.…”

Biomarkers in the Diagnosis of Endometrial Precancers. Molecular Characteristics, Candidate Immunohistochemical Markers, and Promising Results of Three-Marker Panel: Current Status and Future Directions

“…Pathologists can reliably identify MMR protein deficiency in AH/EIN using the standard scoring system in Lynch syndrome screening for newly diagnosed endometrial cancers [ 73 , 74 , 75 , 76 ]. Studies investigating MMR expression in unselected biopsies with AH/EIN report that less than 5% of AH/EIN cases demonstrate loss of MMR expression, a surprisingly low number given the high incidence of MMRd in invasive cancers [ 24 , 26 , 77 , 78 ]. While highly specifically differentiating AH/EIN from non-neoplastic mimics, the utility of MMR in diagnosing AH/EIN remains debatable due to the low prevalence of MMR deficiency in AH/EIN.…”

“…In our practice, we have found that appropriately applying this criterion, combining marker aberrancy with morphological “clonal” demarcation from the background effectively differentiates between clonal alteration and sporadic alterations in isolated glands (illustrated in Figure 5 A–C). While a comprehensive large-scale study validating the utility of the three-marker panel in small-sized AH/EIN is yet to be conducted, our preliminary study, though limited in cases, suggests its effectiveness in this context [ 78 , 90 ].…”