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Ependymomas in infancy: underlying genetic alterations, histological features, and clinical outcome
Stephanie T Jünger1,2, Felipe Andreiuolo1, Martin Mynarek3
1Department of Neuropathology, DGNN Brain Tumor Reference Center, University of Bonn, Bonn, Germany.
Insights
Infant ependymomas are biologically diverse, with posterior fossa types showing poor outcomes despite lacking adverse genetic markers. Supratentorial tumors with RELA or YAP fusions had better survival rates.
Area of Science:
- Pediatric neuro-oncology
- Molecular neuropathology
- Cancer genomics
Background:
- Infant ependymomas present unique treatment challenges due to limited therapeutic options and adverse prognostic implications of young age.
- Ependymomas are recognized as a biologically heterogeneous tumor group, necessitating detailed characterization for improved therapeutic strategies.
Purpose of the Study:
- To histologically and genetically characterize ependymomas in infants diagnosed before 18 months of age.
- To identify distinct biological subgroups within infant ependymomas to inform treatment approaches.
Main Methods:
- Analysis of 28 infant ependymomas using neuropathological review, immunohistochemistry, genome-wide copy number alteration (CNA) analysis, and detection of RELA and YAP1 fusions.
- Tumors were assessed for histological grade, location, resection status, and specific molecular alterations.
Main Results:
- All infant ependymomas were anaplastic (WHO grade III), with 75% located in the posterior fossa (PFA).
- PFA ependymomas showed loss of H3-K27me3 and a stable genome without chromosome 1q gain, yet exhibited high relapse (71%) and mortality (43%) rates.
- Supratentorial ependymomas (25%) with RELA or YAP1 fusions had a better prognosis, with no mortality observed despite relapses.
Conclusions:
- Infant ependymomas can be classified into at least three biological entities: supratentorial tumors with RELA/YAP fusions and PFA ependymomas.
- PFA ependymomas demonstrate a poor prognosis irrespective of the absence of chromosome 1q gain, highlighting distinct biological behavior.
- Molecular subtyping is crucial for understanding ependymoma biology and guiding therapeutic decisions in infants.
Introduction:
Young age is an adverse prognostic factor in children with ependymomas. Treatment of these infants is challenging since beneficial therapeutic options are limited. As ependymomas are considered a biologically heterogeneous group, we aimed to characterize infant ependymomas with regard to their histological and genetic features.
Materials And Methods:
We analyzed 28 ependymomas occurring in children younger than 18 months at diagnosis enrolled into the HIT2000-E protocols with the aim to postpone irradiation until the age of 18 months if possible. All cases underwent neuropathological review, including immunohistochemical characterization. Genome-wide copy number alterations (CNA) were assessed by molecular inversion probe assays, and RELA and YAP1 fusions were detected by RT-PCR and sequencing.
Results:
All infant ependymomas were anaplastic (WHO grade III). Twenty-one (75%) cases were located in the posterior fossa. Gross total resection was accomplished in 12 (57%) of these cases. All posterior fossa tumors showed loss of H3-K27me3 characteristic of PFA ependymomas. CNA analysis showed a stable genome in all cases with lack of chromosome 1q gain, an adverse prognostic marker in PFA ependymomas of older children. However, after a median follow-up of 5.4 years, 15 (71%) relapsed, and 9 (43%) died. Seven ependymomas (25%) occurred in the supratentorial region. Gross total resection could be achieved in only two of these cases. Four tumors carried C11orf95-RELA fusions, and two cases had typical YAP1-MAMLD1 fusions (one case was not analyzable). The RELA-fused cases did not display CDKN2A loss as an adverse indicator of prognosis in this disease entity. Although three infants (43%) with supratentorial ependymomas relapsed, all patients survived (median follow-up, 8.0 years).
Conclusion:
Infant ependymomas seem to fall into three biological entities, with supratentorial tumors carrying RELA or YAP fusions and PFA posterior fossa ependymomas. The latter showed a poor outcome even though chromosome 1q gain was absent.
