title: The Genomic Heterogeneity of FIGO Grade 3 Endometrioid Carcinoma Impacts Diagnostic Accuracy and Reproducibility.
abstract: The Cancer Genome Atlas (TCGA) identified 4 groups of endometrial carcinomas based on an integrated genomic characterization: POLE ultramutated (POLE), microsatellite instability-high, copy number-low (CN-L), and copy number-high (CN-H). In that study, CN-H comprised all of the serous carcinoma cases and 25% of all International Federation of Gynecology and Obstetrics (FIGO) Grade 3 endometrioid carcinoma cases. In this study, 2 expert gynecologic pathologists undertook a morphologic reassessment of the FIGO Grade 3 endometrioid carcinoma subset of the TCGA study cohort, including an analysis for evidence of serous differentiation. Interobserver variability κvalues are reported for the histologic evaluation of all 4 genomic clusters, and diagnostic discrepancies are discussed. Overall, there were 55 agreements, 6 disagreements, and 14 deferrals. Of the 75 cases analyzed, 6 cases had a consensus morphologic diagnosis of serous carcinoma, but only 2 of these cases had a serous carcinoma genotype, whereas the remaining 4 cases were genotypically endometrioid carcinoma. For the CN-H group, 2 of 15 cases were serous carcinoma by morphology and genotype, whereas at least 1 pathologist interpreted the remaining 13 cases as endometrioid carcinoma. The interobserver agreement rate was highest in the CN-L group (90%; κ=0.9), compared with the other genomic groups (POLE: 62%, κ=0.55; microsatellite instability-high: 78%, κ=0.74; and CN-H: 53%, κ=0.48). Our review confirms that most high-grade endometrial carcinomas diagnosed by TCGA as FIGO Grade 3 endometrioid carcinoma are indeed endometrioid carcinomas by morphology and genotype, and that the reproducibility of histologic diagnosis between pathologists varies between the TCGA-integrated genomic clusters.
authors.affiliation: Department of Pathology (Y.R.H., B.W., R.A.S.) Gynecology Service, Department of Surgery (D.A.L.), Memorial Sloan Kettering Cancer Center, New York, New York Department of Pathology (R.B.), MD Anderson Cancer Center, Houston, Texas.
authors.forename: Yaser R
authors.initials: YR
authors.lastname: Hussein
authors.forename: Russell
authors.initials: R
authors.lastname: Broaddus
authors.forename: Britta
authors.initials: B
authors.lastname: Weigelt
authors.forename: Douglas A
authors.initials: DA
authors.lastname: Levine
authors.forename: Robert A
authors.initials: RA
authors.lastname: Soslow
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D014408:Biomarkers, Tumor / Q000235:genetics; D018269:Carcinoma, Endometrioid / Q000145:classification / Q000473:pathology*; D015331:Cohort Studies; D018284:Cystadenocarcinoma, Serous / Q000145:classification / Q000473:pathology*; D016889:Endometrial Neoplasms / Q000145:classification / Q000473:pathology*; D005260:Female; D023281:Genomics; D006801:Humans; D053842:Microsatellite Instability; D008875:Middle Aged; D060787:Neoplasm Grading; D009367:Neoplasm Staging; D015588:Observer Variation; D015203:Reproducibility of Results; D012189:Retrospective Studies
chemical_list: D014408:Biomarkers, Tumor