title: Molecular classification of endometrial carcinoma on diagnostic specimens is highly concordant with final hysterectomy: Earlier prognostic information to guide treatment.
abstract: Categorization and risk stratification of endometrial carcinomas is inadequate; histomorphologic assessment shows considerable interobserver variability, and risk of metastases and recurrence can only be derived after surgical staging. We have developed a Proactive Molecular Risk classification tool for Endometrial cancers (ProMisE) that identifies four distinct prognostic subgroups. Our objective was to assess whether molecular classification could be performed on diagnostic endometrial specimens obtained prior to surgical staging and its concordance with molecular classification performed on the subsequent hysterectomy specimen.
  
  
  
  Sequencing of tumors for exonuclease domain mutations (EDMs) in POLE and immunohistochemistry for mismatch repair (MMR) proteins and p53 were applied to both pre- and post-staging archival specimens from 60 individuals to identify four molecular subgroups: MMR-D, POLE EDM, p53 wild type, p53 abn (abnormal). Three gynecologic subspecialty pathologists assigned histotype and grade to a subset of samples. Concordance of molecular and clinicopathologic subgroup assignments were determined, comparing biopsy/curetting to hysterectomy specimens.
  
  
  
  Complete molecular and pathologic categorization was achieved in 57 cases. Concordance metrics for pre- vs. post-staging endometrial samples categorized by ProMisE were highly favorable; average per ProMisE class sensitivity(0.9), specificity(0.96), PPV(0.9), NPV(0.96) and kappa statistic 0.86(95%CI, 0.72-0.93), indicating excellent agreement. We observed the highest level of concordance for 'p53 abn' tumors, the group associated with the worst prognosis. In contrast, grade and histotype assignment from original pathology reports pre- vs. post-staging showed only moderate levels of agreement (kappa=0.55 and 0.44 respectively); even with subspecialty pathology review only moderate levels of agreement were observed.
  
  
  
  Molecular classification can be achieved on diagnostic endometrial samples and accurately predicts the molecular features in the final hysterectomy specimens, demonstrating concordance superior to grade and histotype. This biologically relevant information, available at initial diagnosis, has the potential to inform management (surgery, adjuvant therapy) from the earliest time point in cancer care.
authors.affiliation: Department of Pathology and Laboratory Medicine, University of British Columbia and BC Cancer Agency, Vancouver, British Columbia, Canada.
authors.forename: Aline
authors.initials: A
authors.lastname: Talhouk
authors.affiliation: Department of Pathology and Laboratory Medicine, University of British Columbia and Vancouver General Hospital, Vancouver, British Columbia, Canada; Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY, United States.
authors.forename: Lien N
authors.initials: LN
authors.lastname: Hoang
authors.affiliation: Department of Pathology and Laboratory Medicine, University of British Columbia and BC Cancer Agency, Vancouver, British Columbia, Canada; Department of Human Genetics, McGill University, Research Institute of the McGill University Health Network, Montreal, Quebec, Canada.
authors.forename: Melissa K
authors.initials: MK
authors.lastname: McConechy
authors.affiliation: Department of Pathology and Laboratory Medicine, University of British Columbia and Vancouver General Hospital, Vancouver, British Columbia, Canada.
authors.forename: Quentin
authors.initials: Q
authors.lastname: Nakonechny
authors.affiliation: Department of Pathology and Laboratory Medicine, University of British Columbia and Vancouver General Hospital, Vancouver, British Columbia, Canada.
authors.forename: Joyce
authors.initials: J
authors.lastname: Leo
authors.affiliation: Genetic Pathology Evaluation Centre, Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, British Columbia, Canada.
authors.forename: Angela
authors.initials: A
authors.lastname: Cheng
authors.affiliation: Genetic Pathology Evaluation Centre, Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, British Columbia, Canada.
authors.forename: Samuel
authors.initials: S
authors.lastname: Leung
authors.affiliation: Department of Pathology and Laboratory Medicine, University of British Columbia and BC Cancer Agency, Vancouver, British Columbia, Canada.
authors.forename: Winnie
authors.initials: W
authors.lastname: Yang
authors.affiliation: Department of Pathology and Laboratory Medicine, University of British Columbia and BC Cancer Agency, Vancouver, British Columbia, Canada.
authors.forename: Amy
authors.initials: A
authors.lastname: Lum
authors.affiliation: Department of Pathology and Laboratory Medicine, Calgary Laboratory Services and University of Calgary, Calgary, Alberta, Canada.
authors.forename: Martin
authors.initials: M
authors.lastname: Köbel
authors.affiliation: Department of Laboratory Medicine and Pathology, Royal Alexandra Hospital and University of Alberta, Edmonton, Canada.
authors.forename: Cheng-Han
authors.initials: CH
authors.lastname: Lee
authors.affiliation: Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY, United States.
authors.forename: Robert A
authors.initials: RA
authors.lastname: Soslow
authors.affiliation: Department of Pathology and Laboratory Medicine, University of British Columbia and BC Cancer Agency, Vancouver, British Columbia, Canada.
authors.forename: David G
authors.initials: DG
authors.lastname: Huntsman
authors.affiliation: Department of Pathology and Laboratory Medicine, University of British Columbia and Vancouver General Hospital, Vancouver, British Columbia, Canada.
authors.forename: C Blake
authors.initials: CB
authors.lastname: Gilks
authors.affiliation: Department of Gynecology and Obstetrics, Division of Gynecologic Oncology, University of British Columbia, 2775 Laurel St., 6th Floor, Vancouver, British Columbia V5Z 1M9, Canada. Electronic address: jessica.mcalpine@vch.ca.
authors.forename: Jessica N
authors.initials: JN
authors.lastname: McAlpine
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D015331:Cohort Studies; D016889:Endometrial Neoplasms / Q000145:classification / Q000235:genetics* / Q000401:mortality / Q000601:surgery; D005260:Female; D006801:Humans; D007044:Hysterectomy; D008875:Middle Aged; D011379:Prognosis