Molecularly Classified Uterine FIGO Grade 3 Endometrioid Carcinomas Show Distinctive Clinical Outcomes But Overlapping Morphologic Features.

Publisher: Wolters Kluwer Health, Inc Country of Publication: United States NLM ID: 7707904 Publication Model: Print Cited Medium: Internet ISSN: 1532-0979 (Electronic) Linking ISSN: 01475185 NLM ISO Abbreviation: Am J Surg Pathol Subsets: MEDLINE

Publication: <2015- > : Philadelphia, PA : Wolters Kluwer Health, Inc.
Original Publication: New York, Masson.

DNA Mutational Analysis* ; Immunohistochemistry*; Biomarkers, Tumor/*deficiency ; Biomarkers, Tumor/*genetics ; Carcinoma, Endometrioid/*genetics ; Endometrial Neoplasms/*genetics; Adult ; Aged ; Aged, 80 and over ; Carcinoma, Endometrioid/classification ; Carcinoma, Endometrioid/mortality ; Carcinoma, Endometrioid/pathology ; DNA Mismatch Repair ; DNA Polymerase II/genetics ; DNA Repair Enzymes/deficiency ; Endometrial Neoplasms/classification ; Endometrial Neoplasms/mortality ; Endometrial Neoplasms/pathology ; Female ; Humans ; Middle Aged ; Mutation ; Neoplasm Grading ; PAX8 Transcription Factor/analysis ; Poly-ADP-Ribose Binding Proteins/genetics ; Predictive Value of Tests ; Tumor Suppressor Protein p53/genetics ; beta Catenin/genetics

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.
Competing Interests: 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.
(Copyright © 2020 Wolters Kluwer Health, Inc. All rights reserved.)

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0 (Biomarkers, Tumor)
0 (CTNNB1 protein, human)
0 (PAX8 Transcription Factor)
0 (PAX8 protein, human)
0 (Poly-ADP-Ribose Binding Proteins)
0 (TP53 protein, human)
0 (Tumor Suppressor Protein p53)
0 (beta Catenin)
EC 2.7.7.7 (DNA Polymerase II)
EC 2.7.7.7 (POLE protein, human)
EC 6.5.1.- (DNA Repair Enzymes)

Date Created: 20201006 Date Completed: 20210330 Latest Revision: 20210330

20250114

10.1097/PAS.0000000000001598

33021522