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

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.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.Ependymoma is the third most common neuroepithelial tumor of the central nervous system (CNS) in childhood, after astrocytoma and medulloblastoma [1,2]. It currently presents a considerable therapeutic challenge, being incurable in more than half of cases. In contrast to the mainly spinal tumors of adults, childhood disease is dominated by intracranial tumors [1]. Treatment of pediatric intracranial ependymomas principally involves surgery and adjuvant radiotherapy, extent of surgical resection being a critical determinant of outcome [3]. The role of chemotherapy is controversial, but its use alongside radiotherapy has been the focus of several clinical trials, especially in the setting of attemp