title: Interobserver Agreement in Endometrial Carcinoma Histotype Diagnosis Varies Depending on The Cancer Genome Atlas (TCGA)-based Molecular Subgroup.
abstract: The Cancer Genome Atlas recently identified a genomic-based molecular classification of endometrial carcinomas, with 4 molecular categories: (1) ultramutated (polymerase epsilon [POLE] mutated), (2) hypermutated (microsatellite instability), (3) copy number abnormalities-low, and (4) copy number abnormalities-high. Two studies have since proposed models to classify endometrial carcinomas into 4 molecular subgroups, modeled after The Cancer Genome Atlas, using simplified and more clinically applicable surrogate methodologies. In our study, 151 endometrial carcinomas were molecularly categorized using sequencing for the exonuclease domain mutations (EDM) of POLE, and immunohistochemistry for p53 and mismatch repair (MMR) proteins. This separated cases into 1 of 4 groups: (1) POLE EDM, (2) MMR-D, (3) p53 wildtype (p53 wt), or (4) p53 abnormal (p53 abn). Seven gynecologic pathologists were asked to assign each case to one of the following categories: grade 1 to 2 endometrioid carcinoma (EC), grade 3 EC, mucinous, serous carcinoma (SC), clear cell, dedifferentiated, carcinosarcoma, mixed, and other. Consensus diagnosis among all 7 pathologists was highest in the p53 wt group (37/41, 90%), lowest in the p53 abn group (14/36, 39%), and intermediate in the POLE EDM (22/34, 65%) and MMR-D groups (23/40, 58%). Although the majority of p53 wt endometrial carcinomas are grade 1 to 2 EC (sensitivity: 90%), fewer than half of grade 1 to 2 EC fell into the p53 wt category (positive predictive value: 42%). Pure SC almost always resided in the p53 abn group (positive predictive value: 96%), but it was insensitive as a marker of p53 abn (sensitivity 64%) and the reproducibility of diagnosing SC was suboptimal. The limitations in the precise histologic classification of endometrial carcinomas highlights the importance of an ancillary molecular-based classification scheme.
authors.affiliation: *Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY †Department of Pathology and Laboratory Medicine, and Genetic Pathology Evaluation Center, Vancouver General Hospital, University of British Columbia **Department of Gynecology and Obstetrics, University of British Columbia, Vancouver, BC ‡Department of Pathology, Saskatoon City Hospital, Saskatoon, SK §Department of Pathology, Laval University, Quebec City #Department of Human Genetics, McGill University, Research Institute of the McGill University Health Network, Montreal, QC ∥Department of Laboratory Medicine and Pathology, Royal Alexandra Hospital, University of Alberta, Edmonton ¶Department of Pathology and Laboratory Medicine, Calgary Laboratory Services, University of Calgary, Calgary, AB, Canada.
authors.forename: Lien N
authors.initials: LN
authors.lastname: Hoang
authors.forename: Mary A
authors.initials: MA
authors.lastname: Kinloch
authors.forename: Joyce M
authors.initials: JM
authors.lastname: Leo
authors.forename: Katherine
authors.initials: K
authors.lastname: Grondin
authors.forename: Cheng-Han
authors.initials: CH
authors.lastname: Lee
authors.forename: Carol
authors.initials: C
authors.lastname: Ewanowich
authors.forename: Martin
authors.initials: M
authors.lastname: Köbel
authors.forename: Angela
authors.initials: A
authors.lastname: Cheng
authors.forename: Aline
authors.initials: A
authors.lastname: Talhouk
authors.forename: Melissa
authors.initials: M
authors.lastname: McConechy
authors.forename: David G
authors.initials: DG
authors.lastname: Huntsman
authors.forename: Jessica N
authors.initials: JN
authors.lastname: McAlpine
authors.forename: Robert A
authors.initials: RA
authors.lastname: Soslow
authors.forename: C Blake
authors.initials: CB
authors.lastname: Gilks
mesh_terms: D014408:Biomarkers, Tumor / Q000032:analysis*; D004257:DNA Polymerase II / Q000235:genetics; D016889:Endometrial Neoplasms / Q000145:classification* / Q000473:pathology*; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D009154:Mutation; D015588:Observer Variation; D000075223:Poly-ADP-Ribose Binding Proteins; D016133:Polymerase Chain Reaction; D015203:Reproducibility of Results; D012680:Sensitivity and Specificity; D016159:Tumor Suppressor Protein p53 / Q000032:analysis / Q000096:biosynthesis
chemical_list: D014408:Biomarkers, Tumor; D000075223:Poly-ADP-Ribose Binding Proteins; D016159:Tumor Suppressor Protein p53; D004257:DNA Polymerase II; C119525:POLE protein, human