Original ArticlesMolecularly Classified Uterine FIGO Grade 3 Endometrioid Carcinomas Show Distinctive Clinical Outcomes But Overlapping Morphologic FeaturesJoehlin-Price, Amy MD*; Van Ziffle, Jessica PhD†; Hills, Nancy K. MA, PhD‡; Ladwig, Nicholas MD†; Rabban, Joseph T. MD, MPH†; Garg, Karuna MD†Author Information *Department of Pathology, Cleveland Clinic, Cleveland, OH Departments of †Pathology ‡Neurology, Epidemiology and Biostatistics, University of California San Francisco, San Francisco, CA Conflicts of Interest and Source of Funding: The authors have disclosed that they have no significant relationships with, or financial interest in, any commercial companies pertaining to this article. Correspondence: Karuna Garg, MD, Department of Pathology, University of California San Francisco, 1825 4th Street, San Francisco, CA 94158 (e-mail: [email protected]). The American Journal of Surgical Pathology: March 2021 - Volume 45 - Issue 3 - p 421-429 doi: 10.1097/PAS.0000000000001598 Buy Metrics Abstract FIGO grade 3 endometrioid endometrial carcinoma (EEC) is a heterogenous group of tumors with variable molecular and clinicopathologic characteristics but is treated clinically as a single entity. There is a need for additional objective markers to help guide management. The aim of this study was to evaluate a cohort of FIGO grade 3 EEC to validate the prognostic impact of molecular classification using POLE mutation (POLE-mut) analysis and immunohistochemistry for p53 and mismatch repair proteins. A secondary aim was to assess for any morphologic or immunophenotypic correlates among the molecular groups. Ninety-five cases of FIGO grade 3 EEC who underwent a hysterectomy at our institution were identified. Ten tumors (11%) harbored POLE-mut, 35 tumors (37%) showed mismatch repair deficiency, 18 tumors (19%) showed aberrant p53 staining (p53-ab), and 26 cases (27%) lacked all of these findings and were classified as no specific molecular profile. Six separate cases harbored >1 abnormality (multiple classifier), 5 of which had POLE-mut. The POLE-mut group and multiple classifier group showed excellent clinical outcomes, the p53-ab group showed the worst clinical outcomes and the 2 remaining groups showed intermediate prognosis. While the POLE-mut tumors showed a statistically significant enrichment for morphologic features including serous-like atypia and lymphocytic infiltrates, these findings were seen across all 4 molecular groups. There was no correlation between molecular grouping and tumor immunophenotypic findings, but overall 18% and 24% of tumors were completely negative for PAX-8 and estrogen receptor, respectively. Five CTNNB1 mutations were identified, 3 of which occurred in the context of a POLE-mut (including 1 multiple classifier case with MLH1/PMS2 loss). Thus our study corroborates the prognostic impact of molecular classification of high-grade endometrioid carcinoma of the uterus, achieved by readily available immunohistochemical stains in addition to POLE-mut analysis. Copyright © 2020 Wolters Kluwer Health, Inc. All rights reserved.