Adult intracranial ependymoma-relevance of DNA methylation profiling for diagnosis, prognosis, and treatment

Abstract

Background: A methylation-based classification of ependymoma has recently found broad application. However, the diagnostic advantage and implications for treatment decisions remain unclear. Here, we retrospectively evaluate the impact of surgery and radiotherapy on outcome after molecular reclassification of adult intracranial ependymomas.

Methods: Tumors diagnosed as intracranial ependymomas from 170 adult patients collected from 8 diagnostic institutions were subjected to DNA methylation profiling. Molecular classes, patient characteristics, and treatment were correlated with progression-free survival (PFS).

Results: The classifier indicated an ependymal tumor in 73.5%, a different tumor entity in 10.6%, and non-classifiable tumors in 15.9% of cases, respectively. The most prevalent molecular classes were posterior fossa ependymoma group B (EPN-PFB, 32.9%), posterior fossa subependymoma (PF-SE, 25.9%), and supratentorial ZFTA fusion-positive ependymoma (EPN-ZFTA, 11.2%). With a median follow-up of 60.0 months, the 5- and 10-year-PFS rates were 64.5% and 41.8% for EPN-PFB, 67.4% and 45.2% for PF-SE, and 60.3% and 60.3% for EPN-ZFTA. In EPN-PFB, but not in other molecular classes, gross total resection (GTR) (P = .009) and postoperative radiotherapy (P = .007) were significantly associated with improved PFS in multivariable analysis. Histological tumor grading (WHO 2 vs. 3) was not a predictor of the prognosis within molecularly defined ependymoma classes.

Conclusions: DNA methylation profiling improves diagnostic accuracy and risk stratification in adult intracranial ependymoma. The molecular class of PF-SE is unexpectedly prevalent among adult tumors with ependymoma histology and relapsed as frequently as EPN-PFB, despite the supposed benign nature. GTR and radiotherapy may represent key factors in determining the outcome of EPN-PFB patients.

Keywords: DNA methylation; adult; ependymoma; intracranial; radiotherapy.

Figure 1.

Reassessment of histologically diagnosed supratentorial (A) and infratentorial (B) ependymoma in adults by DNA methylation profiling. Molecular analyses resulted in the classification of tumors as either belonging to an ependymal class (ependymoma and subependymoma, green), or cases were reclassified into other defined molecular brain tumor classes (yellow) or were not classifiable (gray/black). Abbreviations: A IDH = astrocytoma, IDH-mutant, C-NC = central neurocytoma, CNS BCOR = neuroepithelial tumor with BCOR alteration, CPP = choroid plexus papilloma A, EPN-PFA = ependymoma posterior fossa group A, EPN-PFB = ependymoma posterior fossa group B, GBM IDHwt = glioblastoma IDH wild type, HGG NEC = high-grade glioma not elsewhere classified, HGNET MN1 = high grade neuroepithelial tumor with MN1 alteration, PF-SE = posterior fossa subependymoma, PTPR = papillary tumor of the pineal region, PXA = pleomorphic xanthoastrocytoma, RGNT = rosette-forming glioneuronal tumor, EPN-ZFTA = supratentorial ZFTA fusion-positive ependymoma, spinal EPN = spinal ependymoma, ST-SE = supratentorial subependymoma.

Figure 2.

Kaplan–Meier curves showing progression-free survival (PFS, left) and overall survival (OS, right). Above diagrams show survival by histological tumor grade for the whole cohort of adult patients with diagnosis of ependymoma prior to DNA methylation profiling (A and B) and for the group of ependymal tumors confirmed by DNA methylation profiling (C and D). Notably, histological tumor grade was no longer a predictor of survival after exclusion of tumors that were non-ependymal and non-classifiable after DNA-methylation profiling. Panels (E and F) show that PFS and OS did not differ significantly between the three major molecular classes of adult intracranial ependymoma. Panels (G and H) show that confirmed ependymal tumors generally had a better PFS and OS in comparison to the groups of other tumor types and non-classifiable tumors as indicated by the classifier demonstrating the clinical importance of DNA methylation profiling. Abbreviations: EPN-PFB = posterior fossa ependymoma group B, EPN-ZFTA = supratentorial ZFTA fusion-positive ependymoma, PF-SE/E = posterior fossa subependymoma molecular class with ependymoma histology.

Figure 3.

Kaplan–Meier diagrams showing progression-free survival (PFS) for EPN-PFB tumors. No difference in PFS was seen by histological tumor grade in this molecular class (A). In EPN-PFB patients receiving only surgery gross total resection was associated with improved PFS (B). Use of postoperative radiotherapy showed a tendency to a longer PFS in EPN-PFB tumors regardless of resection status (C). In the subgroup of incompletely resected EPN-PFB tumors, adjuvant radiotherapy was significantly associated with PFS (D).

Figure 4.

Kaplan–Meier diagrams showing progression-free survival (PFS) of PF-SE tumors in a combined data analysis of the current series and the series by Thomas et al. PFS is shorter in the presence of pure ependymoma histology (A), TERT promoter mutation (B) and, with borderline significance, loss of chromosome 6 (C). The absence of all these factors is associated with a favorable prognosis (D). The changes were more common in elderly patients. This correlation was significant for TERT promoter mutations (P < .001*, E).