Ependymal Tumors
2023-07-27 Scott Ryall, PhD Affiliation1.Brigham and Women's Hospital, Harvard Medical School, Boston , MA (USA)
Classification
Definition
The 2021 WHO guidelines for CNS tumor classification aims to classify ependymal tumors according to a combination of histopathological and molecular features and anatomical site. 1,2 This includes two molecularly defined types of supratentorial ependymoma: i) Supratentorial ependymoma, ZFTA fusion-positive, and ii) Supratentorial ependymoma, YAP1 fusion-positive, two molecularly defined posterior fossa ependymoma: i) Posterior fossa group A (PFA) ependymoma, and ii) Posterior fossa group B (PFB) ependymoma, and Spinal ependymoma, MYCN-amplified. Also included in the 2021 WHO guidelines are anatomical ependymomas without molecular features to be used when molecular analysis reveals a different alteration than the one in the classification (specified by the suffix “not elsewhere classified [NEC]”) or when molecular analysis fails or is unfeasible (specified by “not otherwise specified [NOS]”). Myxopapillary ependymoma and subependymoma remain molecularly unspecified, as additional clinicopathological utility in these tumor types is currently not observed. 1
| Ependymal Tumors | Genetic Event(s) |
|---|---|
| Supratentorial ependymoma | Supratentorial ependymoma is the diagnosis reserved for tumors that lack definitive ZFTA and YAP1 rearrangement status, which allows for a diagnsotic refinement. However, in 20-30% of supratentorial ependymomas, a ZFTA or YAP1 rearrangement is not detected 3,4. In these cases, a diagnosis of supratentorial ependymoma can be made. If the tumor harbors an alteration not involving ZFTA or YAP1, the tumor should be designated with suffix “NEC” (not elsewhere classified) while the inability to perform molecular interrogation prompts the addition of “NOS” (not otherwise specified) 5. |
| Supratentorial ependymoma, ZFTA fusion-positive | The principle oncogenic event in these supratentorial ependymoma are fusions of ZFTA (formerly C11orf95), primarily with RELA, as a result of a chromothriptic event on chromosome 11. 6 The ZFTA::RELA fusion has been shown to result in activation of NF-κB signaling as its primary oncogenic function. 6,7 Homozygous deletions of CDKN2A co-occurring with a ZFTA::RELA fusion is indicative of a dismal prognosis. 8-10 DNA methylation analysis classifies supratentorial ependymomas based on their molecular driver and can therefore be useful for identifying the presence or absence of a ZFTA rearrangement. |
| Supratentorial ependymoma, YAP1 fusion-positive | These supratentorial ependymoma are defined by genomic fusions of YAP1, most commonly with MAMLD1, but with other partners as well. 11 YAP1::MAMLD1 functions as an oncogenic driver via the recruitment of nuclear factor I (NFIC) and TEA domain (TEAD). 12,13. DNA methylation analysis classifies supratentorial ependymomas based on their molecular driver and can therefore be useful for identifying the presence or absence of a YAP1 rearrangement. 14 |
| Posterior fossa ependymoma | Posterior fossa ependymoma is the diagnosis reserved for tumors lacking further molecular specificity to subgroup into either PFA, PFB, or subependymoma. 11 The standard by which this sub-classification is completed is via DNA methylation profiling. 11,14 If molecular testing was successfully performed but unable to assign a molecular group, the diagnosis should include the suffix "NEC" (not elsewhere classified). If testing is not feasible, the diangosis shoul include the suffix "NOS" (not otherwise specified). 5 |
| Posterior fossa group A (PFA) ependymoma | Classification as a posterior fossa group A (PFA) ependymoma is contingent on demonstrating the loss of H3 p.K27me3 by immunohistochemistry or assignment to the PFA group by DNA methylation analysis. 14-16 The H3p.K27me3 loss is caused by overexpression of EZHIP, a phenotypic mimic of H3 p.K27M that acts by binding to EZH2 and inhibiting the function of the PRC2 complex 17-21. Rarely, PFA ependymomas will harbour EZHIP alterations (~10%) or H3 p.K27M (~5%), which are mutually exclusive with one another 17,22-24. Cytogenetically, PFA ependymomas may habor a gain of chromosome 1q, which is a negative prognostic indicator, though its absence is not a defintive indicator of an improved prongosis. 17,25-27. DNA methylation analysis of ependymomas identified 2 molecular subgroups and 9 molecular subtypes of PFA ependymomas 14,17. |
| Posterior fossa group B (PFB) ependymoma | Classification as a posterior fossa group B (PFB) ependymoma is contingent on demonstrating the retention of H3 p.K27me3 by immunohistochemistry or assignment to the PFB group by DNA methylation analysis. 14-16 Importantly, H3 p.K27me3 retention is not specific to PFB ependymoma. Cyotgenetically, PFB ependymoma harbor many many chromosomal aberrations, the most common of which are monosomy 6, trisomy 18, and loss of chromosome 22q. 11,15,28,29 |
| Spinal ependymoma | Spinal ependymoma carry frequent losses of chromosome 22q and mutations in NF2, whilst MYCN amplification, by definition, is absent. 11,30 Spinal ependymoma are readily distinguished from myxopapillary ependymomas, subependymomas, and MYCN-amplified spinal ependymoma by DNA methylation analysis, 11,14,31, although not always concordant. 32 |
| Spinal ependymoma, MYCN-amplified | Spinal ependymoma, MYCN-amplified are defined by high level amplifications of MYCN. 31,33-35 Importantly, MYCN amplification is not specific to spinal ependymoma, and evaluating H3 p.K27me3 loss by immunohistochemistry can be used to differentiate it from diffuse midline gliomas with H3 p.K27M. 36. Additional cytogenetic alterations including monosomy 10 (~30%) and focal losses on chromosome 11q (~25%). 31,33-35 DNA methylation analysis distinguishes spinal ependymoma, MYCN-amplified from other ependymal tumour types, as well as from other MYCN amplified tumors. 14,34,35 |
| Myxopapillary ependymoma | Myxopapillary ependymoma harbor a variety of recurring chromosomal copy-number abnormalities including gains of chromosome 16 and losses of chromosome 10, but no consistent structural variants or driving mutations have been uncovered. 32,37 Myxopapillary ependymoma have a unique DNA methylation profile, which may unintentionally include classic ependymoma dependent on the extent of myxoid change. 11,32,38 |
| Subependymoma | Cyogenetically, subependymoma harbor recurrent monosomy 19 and partial losses of chromosome 6, primarily in infratentorial tumors. 32 Mutations in TRPS1 have also been reported. 39 DNA methylation analysis has shown that subependymomas have distinct methylation profiles contingent on their location; supratentorial, posterior fossa, or spinal cord. 11,32,38 |
Article Bibliography
| Reference Number | Pubmed ID | Last Year | Title | Authors |
|---|---|---|---|---|
| 1 | 32502305 | 2020 | cIMPACT-NOW update 7: advancing the molecular classification of ependymal tumors. | Ellison DW et al |
| 2 | 34185076 | 2021 | The 2021 WHO Classification of Tumors of the Central Nervous System: a summary. | Louis DN et al |
| 3 | 30027327 | 2019 | MRI Phenotype of RELA-fused Pediatric Supratentorial Ependymoma. | Nowak J et al |
| 4 | 30514397 | 2018 | Significance of molecular classification of ependymomas: C11orf95-RELA fusion-negative supratentorial ependymomas are a heterogeneous group of tumors. | Fukuoka K et al |
| 5 | 29372318 | 2018 | cIMPACT-NOW update 1: Not Otherwise Specified (NOS) and Not Elsewhere Classified (NEC). | Louis DN et al |
| 6 | 24553141 | 2014 | C11orf95-RELA fusions drive oncogenic NF-κB signalling in ependymoma. | Parker M et al |
| 7 | 24562983 | 2014 | Supratentorial ependymomas of childhood carry C11orf95-RELA fusions leading to pathological activation of the NF-κB signaling pathway. | Pietsch T et al |
| 8 | 11763427 | 2001 | CDKN2A/p16 in ependymomas. | Bortolotto S et al |
| 9 | 20516456 | 2010 | Molecular staging of intracranial ependymoma in children and adults. | Korshunov A et al |
| 10 | 32514758 | 2020 | CDKN2A deletion in supratentorial ependymoma with RELA alteration indicates a dismal prognosis: a retrospective analysis of the HIT ependymoma trial cohort. | Jünger ST et al |
| 11 | 25965575 | 2015 | Molecular Classification of Ependymal Tumors across All CNS Compartments, Histopathological Grades, and Age Groups. | Pajtler KW et al |
| 12 | 31477715 | 2019 | YAP1 subgroup supratentorial ependymoma requires TEAD and nuclear factor I-mediated transcriptional programmes for tumorigenesis. | Pajtler KW et al |
| 13 | 32404936 | 2020 | YAP1/TAZ drives ependymoma-like tumour formation in mice. | Eder N et al |
| 14 | 29539639 | 2018 | DNA methylation-based classification of central nervous system tumours. | Capper D et al |
| 15 | 27881822 | 2016 | Lowered H3K27me3 and DNA hypomethylation define poorly prognostic pediatric posterior fossa ependymomas. | Bayliss J et al |
| 16 | 28733933 | 2017 | Immunohistochemical analysis of H3K27me3 demonstrates global reduction in group-A childhood posterior fossa ependymoma and is a powerful predictor of outcome. | Panwalkar P et al |
| 17 | 29909548 | 2018 | Molecular heterogeneity and CXorf67 alterations in posterior fossa group A (PFA) ependymomas. | Pajtler KW et al |
| 18 | 30923826 | 2019 | EZHIP/CXorf67 mimics K27M mutated oncohistones and functions as an intrinsic inhibitor of PRC2 function in aggressive posterior fossa ependymoma. | Hübner JM et al |
| 19 | 31086175 | 2019 | PFA ependymoma-associated protein EZHIP inhibits PRC2 activity through a H3 K27M-like mechanism. | Jain SU et al |
| 20 | 31281901 | 2019 | CATACOMB: An endogenous inducible gene that antagonizes H3K27 methylation activity of Polycomb repressive complex 2 via an H3K27M-like mechanism. | Piunti A et al |
| 21 | 31451685 | 2019 | EZHIP constrains Polycomb Repressive Complex 2 activity in germ cells. | Ragazzini R et al |
| 22 | 23592488 | 2013 | Exomic sequencing of four rare central nervous system tumor types. | Bettegowda C et al |
| 23 | 27539613 | 2016 | Evidence of H3 K27M mutations in posterior fossa ependymomas. | Gessi M et al |
| 24 | 28623522 | 2017 | H3 K27M mutations are extremely rare in posterior fossa group A ependymoma. | Ryall S et al |
| 25 | 11953826 | 2002 | Genetic abnormalities detected in ependymomas by comparative genomic hybridisation. | Carter M et al |
| 26 | 22338015 | 2012 | Copy number gain of 1q25 predicts poor progression-free survival for pediatric intracranial ependymomas and enables patient risk stratification: a prospective European clinical trial cohort analysis on behalf of the Children's Cancer Leukaemia Group (CCLG), Societe Francaise d'Oncologie Pediatrique (SFOP), and International Society for Pediatric Oncology (SIOP). | Kilday JP et al |
| 27 | 22526017 | 2012 | Distinct disease-risk groups in pediatric supratentorial and posterior fossa ependymomas. | Godfraind C et al |
| 28 | 24553142 | 2014 | Epigenomic alterations define lethal CIMP-positive ependymomas of infancy. | Mack SC et al |
| 29 | 30019219 | 2018 | Heterogeneity within the PF-EPN-B ependymoma subgroup. | Cavalli FMG et al |
| 30 | 11112826 | 2000 | Neoplasms of the spinal cord and filum terminale: radiologic-pathologic correlation. | Koeller KK et al |
| 31 | 31373367 | 2019 | Spinal Cord Ependymomas With MYCN Amplification Show Aggressive Clinical Behavior. | Swanson AA et al |
| 32 | 30053291 | 2018 | DNA methylation-based classification of ependymomas in adulthood: implications for diagnosis and treatment. | Witt H et al |
| 33 | 11303789 | 2001 | Low frequency of chromosomal imbalances in anaplastic ependymomas as detected by comparative genomic hybridization. | Scheil S et al |
| 34 | 31414211 | 2019 | MYCN amplification drives an aggressive form of spinal ependymoma. | Ghasemi DR et al |
| 35 | 32641156 | 2020 | High level MYCN amplification and distinct methylation signature define an aggressive subtype of spinal cord ependymoma. | Raffeld M et al |
| 36 | 24705254 | 2014 | Genomic analysis of diffuse intrinsic pontine gliomas identifies three molecular subgroups and recurrent activating ACVR1 mutations. | Buczkowicz P et al |
| 37 | 29402569 | 2018 | Unusual paediatric spinal myxopapillary ependymomas: Unique molecular entities or pathological variations on a theme? | Rogers S et al |
| 38 | 31679042 | 2020 | Molecular characterization of histopathological ependymoma variants. | Neumann JE et al |
| 39 | 28528424 | 2017 | TRPS1 gene alterations in human subependymoma. | Fischer SB et al |
Citation
Scott Ryall, PhD
Ependymal Tumors
Atlas Genet Cytogenet Oncol Haematol. 2023-07-27
Online version: http://atlasgeneticsoncology.org/solid-tumor/209197/ependymal-tumors
