RELA Fusion in Supratentorial Extraventricular Ependymomas: A Morphologic, Immunohistochemical, and Molecular Study of 43 Cases

Abstract

Supratentorial extraventricular ependymomas (STEEs) are relatively rare ependymomas, and their pathologic and genetic characteristics are still poorly understood. The aim of this study was to determine the histologic, immunohistochemical, and RELA fusion features, as well as to clarify in more detail the clinical courses of STEEs. Data from a total of 43 patients with STEEs was analyzed retrospectively. The status of RELA fusion was evaluated using fluorescence in situ hybridization. The expression levels of L1CAM, p65, cyclin D1, and p53 were assessed using immunohistochemistry. Progression-free survival and overall survival were calculated via Kaplan-Meier estimation using the log-rank test. Among all 43 STEEs, 65.1% (28/43) are positive for RELA fusion. Interestingly, almost half of the patients with RELA fusion–positive ependymomas are adults (13/28), and 89.3% (25/28) cases are anaplastic ependymomas, which suggests that RELA fusion testing is necessary in adults with STEEs. We investigated the immunohistochemical status of p65, L1CAM and CCND1 protein expression for their ability to predict RELA fusion status. RELA fusion–positive STEEs are frequently associated with expression of p65 (85.2%), L1CAM (85.2%), and CCND1 (81.5%). The accuracy of predicting RELA fusion status was much higher when the expression of p65 and L1CAM was combined, that is, when both were immunopositive. The status of RELA fusion, p53 overexpression, and extent of tumor resection are significantly associated with prognosis.

The Survival and Prognostic Factors of Supratentorial Cortical Ependymomas: A Retrospective Cohort Study and Literature-Based Analysis

“…RELA fusion-positive ependymoma has been considered as a novel entity according to the 2016 WHO classification of CNS tumors (14). Previous studies depicted that incidence of C11orf95-RELA fusions in STE ranging from 65.1 to 70% (15)(16)(17). However, the incidence of C11orf95-RELA fusions in CEs has rarely been investigated before.…”

“…Matsumoto et al (11) found all CEs (5/5, 100%) had RELA fusions in their study. RELA fusion positive had been considered as a negative prognostic factor in ependymomas (16). However, Figarella-Branger et al (18) and Lillard et al (17) did not find that RELA fusion-positive STE had a poorer outcome; they hold GTR or near total resection (NTR) may overcome the deleterious effects of RELA fusion on survival (17)(18)(19).…”

Ependymoma‐like tumor with mesenchymal differentiation harboring C11orf95‐NCOA1/2 or ‐RELA fusion: A hitherto unclassified tumor related to ependymoma

“…Parker et al reported that the fusion genes resulted from clustered genomic rearrangements occurring in localized genomic regions, known as chromothripsis, at chromosome 11q12.1–11q13.3, and that the fusion proteins led to NF‐κB pathway activation with nuclear accumulation of p65/RelA (4). In addition, L1CAM, which was originally identified as a neural adhesion molecule essential for axonogenesis (9), was reported to be overexpressed in ST ependymomas with C11orf95 ‐ RELA (4,10,11), suggesting that L1CAM is a target of aberrant signaling of the fusion proteins (4). Overexpression of both p65/RelA and L1CAM is identifiable by immunohistochemistry (4,10,11).…”

The role of clinical factors and immunocheckpoint molecules in the prognosis of patients with supratentorial extraventricular ependymoma: a single-center retrospective study

“…Several studies have shown that the outcomes of patients with C11orf95-RELA fusion-positive ependymoma are worse than those of patients with the other two subtypes (Pajtler et al 2015;Malgulwar et al 2018;Wang et al 2019). Malgulwar et al (2018) and Wang et al (2019) found that L1CAM was consistent with the RELA fusion gene by more than 80%. In our study, amazingly, the PFS and OS of all patients were analyzed by Kaplan-Meier and Cox analyses, which revealed no difference between patients with L1CAM positivity and patients with L1CAM negativity (P > 0.05; Tables 2 and 3).…”

“…The reason for this inconsistent result might be the poor consistency of the application of L1CAM alone in the detection of the C11orf95-RELA fusion gene when we analyzed the data from our study and the recent literature. Several studies have suggested that markers such as P65 could also be included in tests to assess the presence of the C11orf95-RELA fusion gene (Gessi et al 2019;Wang et al 2019). In addition, although the presence of the RELA fusion gene is associated with poor outcomes, the difference might not be significant.…”