title: Histopathological grading of pediatric ependymoma: reproducibility and clinical relevance in European trial cohorts.
abstract: BACKGROUND
  Histopathological grading of ependymoma has been controversial with respect to its reproducibility and clinical significance. In a 3-phase study, we reviewed the pathology of 229 intracranial ependymomas from European trial cohorts of infants (2 trials - SFOP/CNS9204) and older children (2 trials - AIEOP/CNS9904) to assess both diagnostic concordance among five neuropathologists and the prognostic utility of histopathological variables, particularly tumor grading.
  
  
  RESULTS
  In phase 1, using WHO criteria and without first discussing any issue related to grading ependymomas, pathologists assessed and independently graded ependymomas from 3 of 4 trial cohorts. Diagnosis of grade II ependymoma was less frequent than grade III, a difference that increased when one cohort (CNS9204) was reassessed in phase 2, during which the pathologists discussed ependymoma grading, jointly reviewed all CNS9204 tumors, and defined a novel grading system based on the WHO classification. In phase 3, repeat independent review of two cohorts (SFOP/CNS9904) using the novel system was associated with a substantial increase in concordance on grading. Extent of tumor resection was significantly associated with progression-free survival (PFS) in SFOP and AIEOP, but not in CNS9204 and CNS9904. Strength of consensus on grade was significantly associated with PFS in only one trial cohort (AIEOP). Consensus on the scoring of individual histopathological features (necrosis, angiogenesis, cell density, and mitotic activity) correlated with PFS in AIEOP, but in no other trial.
  
  
  CONCLUSIONS
  We conclude that concordance on grading ependymomas can be improved by using a more prescribed scheme based on the WHO classification. Unfortunately, this appears to have utility in limited clinical settings.
authors.affiliation: Dept, of Pathology, St, Jude Children's Research Hospital, Memphis, USA. David.Ellison@stjude.org
authors.forename: David W
authors.initials: DW
authors.lastname: Ellison
authors.forename: Mehmet
authors.initials: M
authors.lastname: Kocak
authors.forename: Dominique
authors.initials: D
authors.lastname: Figarella-Branger
authors.forename: Giangaspero
authors.initials: G
authors.lastname: Felice
authors.forename: Godfraind
authors.initials: G
authors.lastname: Catherine
authors.forename: Torsten
authors.initials: T
authors.lastname: Pietsch
authors.forename: Didier
authors.initials: D
authors.lastname: Frappaz
authors.forename: Maura
authors.initials: M
authors.lastname: Massimino
authors.forename: Jacques
authors.initials: J
authors.lastname: Grill
authors.forename: James M
authors.initials: JM
authors.lastname: Boyett
authors.forename: Richard G
authors.initials: RG
authors.lastname: Grundy
mesh_terms: D014408:Biomarkers, Tumor; D001932:Brain Neoplasms / Q000473:pathology*; D002648:Child; D002986:Clinical Trials as Topic; D015331:Cohort Studies; D018572:Disease-Free Survival; D004806:Ependymoma / Q000473:pathology*; D006801:Humans; D007223:Infant
chemical_list: D014408:Biomarkers, Tumor