Ependymal Tumors

2024-11-05 Scott Ryall, PhD Affiliation

1.Brigham and Women's Hospital, Harvard Medical School, Boston , MA (USA)

Classification

Definition

Ependymal tumors are classified according to a combination of histopathological findings, molecular features, and anatomical site. ^1,2 This includes two molecularly defined subtypes 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 an alteration absent from the above classifications (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 remains unclear. ¹

Additional details are described in the 2021 WHO Classification of Tumors of the Central Nervous System.

Ependymal Tumors	Genetic Event(s)
Supratentorial ependymoma	The median age of supratentorial ependymoma is approximately 8 years (0-85 years). Its incidence decreases with age: 41% in children, 27% in adolescents, 12% in young adults, and 11% in adults aged > 45 years. ³ 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 ^4,5. 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) ⁶.
Supratentorial ependymoma, ZFTA fusion-positive	The median age at diagnosis of supratentorial ependymoma, ZFTA fusion-positive is approximately 6 years (0-41 years) with its incidence decreasing with age. ^7-9 The principle oncogenic event in these tumors are fusions of ZFTA (formerly C11orf95), primarily with RELA, as a result of a chromothriptic event on chromosome 11. ⁷ The ZFTA::RELA fusion has been shown to result in activation of NF-κB signaling as its primary oncogenic function. ^7,8 Homozygous deletions of CDKN2A co-occurring with a ZFTA::RELA fusion is indicative of a dismal prognosis. ^10-12 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	The median age at diagnosis of supratentorial ependymoma, YAP1 fusion-positive is 1 year (0-51 years). ¹³. These tumors are defined by genomic fusions of YAP1, most commonly with MAMLD1, but with other partners as well. ¹³ YAP1::MAMLD1 functions as an oncogenic driver via the recruitment of nuclear factor I (NFIC) and TEA domain (TEAD). ^14,15. 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. ¹⁶
Posterior fossa ependymoma	The median age at diagnosis of posterior fossa ependymoma is 6 years (0-70 years). ^17-19 Posterior fossa ependymoma is the diagnosis reserved for tumors lacking further molecular specificity to subgroup into either PFA, PFB, or subependymoma. ¹³ The standard by which this sub-classification is completed is via DNA methylation profiling. ^13,16 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 should include the suffix "NOS" (not otherwise specified). ⁶
Posterior fossa group A (PFA) ependymoma	The median age at diagnosis of posterior fossa group A (PFA) ependymoma is 3 years (0-58 years). ^13,18,20-22 Classification as 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. ^16,23,24 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 ^21,25-28. Rarely, PFA ependymomas will harbour EZHIP alterations (~10%) or H3 p.K27M (~5%), which are mutually exclusive with one another ^21,29-31. 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. ^21,32-34. DNA methylation analysis of ependymomas identified 2 molecular subgroups and 9 molecular subtypes of PFA ependymomas ^16,21.
Posterior fossa group B (PFB) ependymoma	Posterior fossa group B (PFB) ependymoma, unlike PFA ependymoma tends to arise in older patients with a median age at diagnosis of 30 years (1-72 years), despite isolated cases arising in children. ^{13,18,20,21,35,36} Classification as a PFB ependymoma is contingent on demonstrating the retention of H3 p.K27me3 by immunohistochemistry or assignment to the PFB group by DNA methylation analysis. ^16,23,24 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. ^13,23,35,37
Spinal ependymoma	The median age at diagnosis of spinal ependymoma ranges from 25-45 years (10-60 years) depending on the cohort's inclusion criteria. ^13,38 These tumors carry frequent losses of chromosome 22q and mutations in NF2, whilst MYCN amplification, by definition, is absent. ^13,39 Spinal ependymoma are readily distinguished from myxopapillary ependymomas, subependymomas, and MYCN-amplified spinal ependymoma by DNA methylation analysis, ^13,16,40, although not always concordant. ⁴¹
Spinal ependymoma, MYCN-amplified	The median age at diagnosis of spinal ependymoma, MYCN-amplified is 31 years (12-56 years), with isolated cases arising in children. ^40,42-44 These tumors are defined by high level amplifications of MYCN. ^40,42-44 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. ⁴⁵. Additional cytogenetic alterations including monosomy 10 (~30%) and focal losses on chromosome 11q (~25%). ^40,42-44 DNA methylation analysis distinguishes spinal ependymoma, MYCN-amplified from other ependymal tumour types, as well as from other MYCN amplified tumors. ^16,43,44
Myxopapillary ependymoma	The median age at diagnosis of myxopapillary ependymoma is 39 years (12-78 years). ^46,47 These tumors 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. ^41,48 Myxopapillary ependymoma have a unique DNA methylation profile, which may unintentionally include classic ependymoma dependent on the extent of myxoid change. ^13,41,49

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	32642681	2020	Comparison of epidemiology, treatments, and outcomes in pediatric versus adult ependymoma.	Elsamadicy AA et al
4	30027327	2019	MRI Phenotype of RELA-fused Pediatric Supratentorial Ependymoma.	Nowak J et al
5	30514397	2018	Significance of molecular classification of ependymomas: C11orf95-RELA fusion-negative supratentorial ependymomas are a heterogeneous group of tumors.	Fukuoka K et al
6	29372318	2018	cIMPACT-NOW update 1: Not Otherwise Specified (NOS) and Not Elsewhere Classified (NEC).	Louis DN et al
7	24553141	2014	C11orf95-RELA fusions drive oncogenic NF-κB signalling in ependymoma.	Parker M et al
8	24562983	2014	Supratentorial ependymomas of childhood carry C11orf95-RELA fusions leading to pathological activation of the NF-κB signaling pathway.	Pietsch T et al
9	34389065	2021	Supratentorial non-RELA, ZFTA-fused ependymomas: a comprehensive phenotype genotype correlation highlighting the number of zinc fingers in ZFTA-NCOA1/2 fusions.	Tauziède-Espariat A et al
10	11763427	2001	CDKN2A/p16 in ependymomas.	Bortolotto S et al
11	20516456	2010	Molecular staging of intracranial ependymoma in children and adults.	Korshunov A et al
12	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
13	25965575	2015	Molecular Classification of Ependymal Tumors across All CNS Compartments, Histopathological Grades, and Age Groups.	Pajtler KW et al
14	31477715	2019	YAP1 subgroup supratentorial ependymoma requires TEAD and nuclear factor I-mediated transcriptional programmes for tumorigenesis.	Pajtler KW et al
15	32404936	2020	YAP1/TAZ drives ependymoma-like tumour formation in mice.	Eder N et al
16	29539639	2018	DNA methylation-based classification of central nervous system tumours.	Capper D et al
17	19061350	2009	Incidence patterns for ependymoma: a surveillance, epidemiology, and end results study.	McGuire CS et al
18	21840481	2011	Delineation of two clinically and molecularly distinct subgroups of posterior fossa ependymoma.	Witt H et al
19	31675094	2019	CBTRUS Statistical Report: Primary Brain and Other Central Nervous System Tumors Diagnosed in the United States in 2012-2016.	Ostrom QT et al
20	27269943	2016	Therapeutic Impact of Cytoreductive Surgery and Irradiation of Posterior Fossa Ependymoma in the Molecular Era: A Retrospective Multicohort Analysis.	Ramaswamy V et al
21	29909548	2018	Molecular heterogeneity and CXorf67 alterations in posterior fossa group A (PFA) ependymomas.	Pajtler KW et al
22	34944845	2021	Molecular Classification and Therapeutic Targets in Ependymoma.	Larrew T et al
23	27881822	2016	Lowered H3K27me3 and DNA hypomethylation define poorly prognostic pediatric posterior fossa ependymomas.	Bayliss J et al
24	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
25	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
26	31086175	2019	PFA ependymoma-associated protein EZHIP inhibits PRC2 activity through a H3 K27M-like mechanism.	Jain SU et al
27	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
28	31451685	2019	EZHIP constrains Polycomb Repressive Complex 2 activity in germ cells.	Ragazzini R et al
29	23592488	2013	Exomic sequencing of four rare central nervous system tumor types.	Bettegowda C et al
30	27539613	2016	Evidence of H3 K27M mutations in posterior fossa ependymomas.	Gessi M et al
31	28623522	2017	H3 K27M mutations are extremely rare in posterior fossa group A ependymoma.	Ryall S et al
32	11953826	2002	Genetic abnormalities detected in ependymomas by comparative genomic hybridisation.	Carter M et al
33	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
34	22526017	2012	Distinct disease-risk groups in pediatric supratentorial and posterior fossa ependymomas.	Godfraind C et al
35	30019219	2018	Heterogeneity within the PF-EPN-B ependymoma subgroup.	Cavalli FMG et al
36	31727173	2019	Improved risk-stratification for posterior fossa ependymoma of childhood considering clinical, histological and genetic features - a retrospective analysis of the HIT ependymoma trial cohort.	Jünger ST et al
37	24553142	2014	Epigenomic alterations define lethal CIMP-positive ependymomas of infancy.	Mack SC et al
38	22961356	2012	Spinal cord ependymomas in children and adolescents.	Benesch M et al
39	11112826	2000	Neoplasms of the spinal cord and filum terminale: radiologic-pathologic correlation.	Koeller KK et al
40	31373367	2019	Spinal Cord Ependymomas With MYCN Amplification Show Aggressive Clinical Behavior.	Swanson AA et al
41	30053291	2018	DNA methylation-based classification of ependymomas in adulthood: implications for diagnosis and treatment.	Witt H et al
42	11303789	2001	Low frequency of chromosomal imbalances in anaplastic ependymomas as detected by comparative genomic hybridization.	Scheil S et al
43	31414211	2019	MYCN amplification drives an aggressive form of spinal ependymoma.	Ghasemi DR et al
44	32641156	2020	High level MYCN amplification and distinct methylation signature define an aggressive subtype of spinal cord ependymoma.	Raffeld M et al
45	24705254	2014	Genomic analysis of diffuse intrinsic pontine gliomas identifies three molecular subgroups and recurrent activating ACVR1 mutations.	Buczkowicz P et al
46	27306443	2016	Myxopapillary ependymoma: a SEER analysis of epidemiology and outcomes.	Bates JE et al
47	33624261	2021	Clinical characteristics and long-term surgical outcome of spinal myxopapillary ependymoma: a French cohort of 101 patients.	Montero AS et al
48	29402569	2018	Unusual paediatric spinal myxopapillary ependymomas: Unique molecular entities or pathological variations on a theme?	Rogers S et al
49	31679042	2020	Molecular characterization of histopathological ependymoma variants.	Neumann JE et al

External Links

Citation

Scott Ryall

Ependymal Tumors

Atlas Genet Cytogenet Oncol Haematol. 2024-11-05

Online version: http://atlasgeneticsoncology.org/solid-tumor/209294