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. 2011 May 31:10:7.
doi: 10.1186/1477-5751-10-7.

Histopathological grading of pediatric ependymoma: reproducibility and clinical relevance in European trial cohorts

David W Ellison  1 , Mehmet Kocak, Dominique Figarella-Branger, Giangaspero Felice, Godfraind Catherine, Torsten Pietsch, Didier Frappaz, Maura Massimino, Jacques Grill, James M Boyett, Richard G Grundy
Affiliations

Histopathological grading of pediatric ependymoma: reproducibility and clinical relevance in European trial cohorts

David W Ellison et al. J Negat Results Biomed. .

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.

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Figures

Figure 1
Figure 1
Progression-free (PFS) and overall survival (OS) in four European trials. (a) PFS and (b) OS by trial. Black line = SFOP; red line = CNS9204; blue line = CNS9904; and green line = AIEOP.
Figure 2
Figure 2
Novel grading scheme for pediatric intracranial classic (grade II) and anaplastic (grade III) ependymomas, in which "nodules" are regions of high cell density.
Figure 3
Figure 3
Specific histopathological characteristics of ependymoma. (a) A nodule of moderately high cell density against a low cell density background. (H&E, × 40). (b) The tumor vasculature here shows mural cell hyperplasia and qualifies as microvascular proliferation (H&E, ×100).
Figure 4
Figure 4
Grading of ependymomas in three European trials by five neuropathologists (phase 1 of study). (a) Proportions of tumors classified as grade II (dark gray) or grade III (light gray) by neuropathologists A-E in phase 1 of the study, grouped by trial. (b) Proportions of tumors classified by each neuropathologist (Path-A, Path-B etc.) in phase 1 of the study as grade II (dark gray) or grade III (light gray).
Figure 5
Figure 5
Proportions of tumors in the three trial cohorts for which there was 4/5 or 5/5 agreement on grade among five pathologists during phase 1 of the study.
Figure 6
Figure 6
Percentages of tumors from the CNS9204 cohort for which each neuropathologist's independent grade assignment (phase 1) matched the consensus grade after joint review by all pathologists (phase 2); e.g. pathologist A independently classified 22/84 tumors as grade II and 62/84 tumors as grade III during phase 1, while in phase 2, joint review classified 17/22 and 54/62 as grade II and grade III tumors, respectively, producing an overall "match" on 71/84 tumors.
Figure 7
Figure 7
Grading of ependymomas in three European trials by five neuropathologists (phase 3 of study). (a) Proportions of tumors classified as grade II (dark gray) or grade III (light gray) among trial cohorts. (b) Proportions of tumors classified as grade II (dark gray) or grade III (light gray) in two trial cohorts (SFOP & CNS9904) before (phase 1; pre-TR) or after (phase 3; post-TR) review of CNS9204 cohort in phase 2 of study (TR). (c) Proportions of tumors in three trial cohorts for which at least 4 of the 5 neuropathologists agreed on grade.
Figure 8
Figure 8
Strength of consensus among neuropathologists on histological variables. Consensus on (a) cell density, (b) mitotic activity, (c) microvascular proliferation, and (d) necrosis was closely matched across studies during phase 3, but was lower for angiogenesis than for other variables.
Figure 9
Figure 9
Progression-free (PFS) and overall survival (OS) in AIEOP trial cohort patients split according to histological grade and extent of surgical resection, showing significantly different survival curves (PFS p = 0.0004; OS p < 0.0001). (a) PFS and (b) OS. CR = complete resection; STR = subtotal resection; black line = CR-Gd. II; red line = STR-Gd. II; blue line = CR-Gd. III; green line = STR-Gd. III
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