Toward an integrated histomolecular diagnosis of supratentorial ependymoma

In an editorial in the July 2016 issue of Neuro-Oncology, Dr. Kristian W. Pajtler -- from the Department of Pediatric Oncology at the University Hospital, Heidelberg, Germany -- reflects on the fact that ependymomas are no longer considered a single disease entity regardless of location or molecular profile. Three ependymoma subgroups have now been identified in the supratentorial (ST) compartment. Pajtler writes: "One subgroup was enriched for World Health Organization (WHO) grade I tumors, and termed “molecular” subependymoma (ST-SE), while the other 2 were characterized by mutually exclusive prototypic fusion genes involving YAP1 and RELA, and named ST-EPN-YAP1 and ST-EPN-RELA, respectively." The RELA fusion ependymoma is notable because it is recognized as a separate diagnostic entity in the latest WHO classification of CNS tumors. Pajtler goes on as follows: "The study by Figarella-Branger et al. published in this issue of Neuro-Oncology focuses on supratentorial clear cell ependymoma... The authors report on a rare series of 20 supratentorial clear cell ependymomas that all share an additional histopathological attribute, the appearance of branching capillaries... Interestingly, nuclear immunostaining with a p65/RELA antibody was detected in all cases. The authors identified a causative C11orf95-RELA fusion using reverse transcriptase (RT)-PCR primers for the most common subtype, RELA fusion type I, in 19 of 20 samples... Based on these findings, the authors concluded that supratentorial ependymomas, phenotypically appearing as clear cell tumors with branching capillaries, represent a subset of the molecularly defined ST-EPN-RELA group. Figarella-Branger et al. are the first to report a correlation between a defined histological appearance of supratentorial ependymoma and a recently described distinct molecular subgroup. Interestingly, 10-year overall survival in patients with this histologically homogeneous RELA-positive series identified by immunohistochemistry and/or RT-PCR was better compared with survival rates in 122 patients with supratentorial ependymomas from a recent molecular classification study [Pajtler KW, et al Cancer Cell 2015;27(5):728-3] that were subgrouped according to their DNA methylation profiles as ST-EPN-RELA (72.2% vs 49%). At this stage, it is... difficult to infer whether RELA-positive clear cell ependymoma with branching capillaries represents a subset of histomolecularly defined tumors that have a more favorable outcome compared with the cellular subtype harboring the same fusion event... An integrative approach including routine testing for the RELA fusion as a diagnostic marker in histologically identified supratentorial ependymomas and in cases with diagnostic uncertainty or ambiguous features will undoubtedly facilitate and improve tumor classification.

Branching capillaries in supratentorial ependymoma from paper by Figarella-Branger et al.

"The study by Figarella-Branger et al has now set the stage to further explore if and to what extent distinct morphological appearances reflect biological subgroups of supratentorial ependymoma. Analyses of bigger cohorts are needed to confirm whether clear cell morphology with branching capillaries is always associated with ST-EPN-RELA tumors or if this histology might also occur in ST-EPN-YAP1 tumors. Specialties involved in the treatment of these tumor types should now move forward quickly to elicit the prognostic aswell as predictive impact of the molecular subgroups ST-EPN-RELA and ST-EPN-YAP1 in more detail. Integrated histomolecular analyses of supratentorial ependymomas from histopathologically and clinically well annotated international trial cohorts as well as from single series with long-term follow-up, as in the Figarella-Branger et al study, are essential to answer this question. An interconnection of tissue-based information with more precise diagnostic aids gained from novel, unbiased, and observer independent molecular analyses as well as data from imaging methods, including central pathology and radiological review, is required to finally converge at a refined diagnostic setting and improve treatment strategies for ependymoma. For RELA-positive ependymoma there is a good chance that this theory will be turned into action, since these tumors will be considered as an entity in the update of the WHO classification."