Incidence

Childhood ependymoma comprises approximately 9% of all childhood brain and spinal cord tumors, representing about 200 cases per year in the United States.[4,5]

Anatomy

Ependymomas arise from ependymal cells that line the ventricles and passageways in the brain and the center of the spinal cord (see Figure 1). Ependymal cells produce cerebrospinal fluid (CSF). These tumors are classified as supratentorial, posterior fossa (infratentorial), or spinal. In children, 65% to 75% of ependymomas arise in the posterior fossa around the fourth ventricle.[6] Less commonly, ependymomas present in the supratentorial compartment. Spinal ependymomas are rare in childhood.

Figure 1. Anatomy of the inside of the brain, showing the pineal and pituitary glands, optic nerve, ventricles (with cerebrospinal fluid shown in blue), and other parts of the brain. The tentorium separates the cerebrum from the cerebellum. The infratentorium (posterior fossa) is the region below the tentorium that contains the brain stem, cerebellum, and fourth ventricle. The supratentorium is the region above the tentorium and denotes the region that contains the cerebrum.

Clinical Features

The clinical presentation of ependymoma is dependent on tumor location.

• Posterior fossa (infratentorial) ependymomas: Children with posterior fossa ependymomas may present with signs and symptoms of obstructive hydrocephalus caused by obstruction at the level of the fourth ventricle. They may also present with ataxia, neck pain, and/or cranial nerve palsies.
• Supratentorial ependymomas: Supratentorial ependymomas may result in headaches, seizures, or location-dependent focal neurological deficits.
• Spinal cord ependymomas: Spinal cord ependymomas, which are often the myxopapillary variant, tend to cause back pain, lower extremity weakness, and/or bowel and bladder dysfunction.

Diagnostic Evaluation

Every patient suspected of having an ependymoma is evaluated with diagnostic imaging of the whole brain and spinal cord. The most sensitive method available for evaluating spinal cord subarachnoid metastasis is spinal magnetic resonance imaging (MRI) performed with gadolinium. This is ideally done before surgery to avoid confusion with postoperative blood. If MRI is used, the entire spine is generally imaged in at least two planes with contiguous MRI slices performed after gadolinium enhancement.

If feasible, CSF cytological evaluation is conducted.[7] Despite the frequent finding of disseminated disease at the time of recurrence, metastatic disease at initial presentation is rare.[8][Level of evidence C2]

Prognostic Factors

Unfavorable factors affecting outcome (except as noted) include the following:

• Molecular characteristics.
  Posterior fossa ependymomas are divided into the following two primary molecular groups on the basis of distinctive patterns of gene expression.[9-12]

  1. Posterior fossa A ependymoma (PF-EPN-A).

     • PF-EPN-A occurs primarily in young children and is characterized by a largely balanced genomic profile, with an increased occurrence of chromosome 1q gain [13-16] and expression of genes and proteins previously shown to be associated with poor prognosis, such as tenascin C and epidermal growth factor receptor.[13,17,18]
     • Gain of 1q confers a very poor prognosis despite complete resection and postoperative radiation therapy (5-year event-free survival rate, 81.5% for balanced 1q vs. 35.7% for gain 1q).[19][Level of evidence B4]
     • A combined retrospective analysis of 663 patients from five nonoverlapping cohorts identified loss of 6q as a poor prognostic factor for patients with PF-EPN-A.[20] Loss of 6q was observed in 8.6% of PF-EPN-A cases, and it is more common in tumors with 1q gain. The subset of patients (n = 22) with both 1q gain and 6q loss had a particularly poor prognosis.
     • A retrospective multi-institutional study compared patient-matched primary tumors with recurrent tumors. The study reported that the high-risk features of 1q gain and 6q loss were more frequent in recurrent tumors than in primary tumors, and these features remained associated with a poor prognosis.[21]
  2. Posterior fossa B ependymoma (PF-EPN-B).

     • PF-EPN-B occurs primarily in older children and adults and is characterized by a more favorable prognosis and by numerous cytogenetic abnormalities involving whole chromosomes or chromosomal arms.[9,12,22]
     • Patients with PF-EPN-B have a favorable outcome when compared with patients with PF-EPN-A. Patients with PF-EPN-B have a 5-year progression-free survival (PFS) rate of 73% and an overall survival (OS) rate exceeding 90%.[11,12]
     • Gain of 1q is not a prognostic feature in patients with PF-EPN-B, whereas loss of chromosome 13q may confer a poor prognosis.[22]
  Supratentorial ependymomas can be divided into the following two primary molecular groups on the basis of their gene fusion status:

  1. Supratentorial ependymoma, ZFTA fusion–positive (ST-EPN-ZFTA) (formerly termed RELA fusion–positive).

     • While a retrospective analysis suggested that the RELA fusion predicted poorer prognosis,[11] subsequent reports suggest that patients with RELA fusions who undergo a complete resection and postoperative radiation have relatively favorable survival rates that are in the range of 80% at 5 years.[11,19,23,24] Retrospective studies suggest a poor outcome for patients who undergo complete surgical resections but do not receive postoperative radiation therapy.[11]
     • Homozygous deletion of CDKN2A has been associated with a poor prognosis in patients with ST-EPN-ZFTA.[25][Level of evidence B4] CDKN2A deletion has also been reported as a secondary event in recurrent ependymoma.[26]
  2. Supratentorial ependymoma with YAP1 fusions (ST-EPN-YAP1).

     • Patients with ST-EPN-YAP1 have a favorable prognosis (although based on small numbers), with 5-year survival rates approaching 100%.[11,23,27]
  Spinal ependymomas can be separated by methylome studies, but molecular classification does not provide any clinicopathological advantage over histopathological classification for myxopapillary ependymoma and subependymoma. However, molecular classification is useful for identifying spinal ependymoma with MYCN amplification, which has been associated with a poor prognosis. There is a paucity of data on the optimal risk stratification of spinal ependymoma in children, although inferring from adults, a complete resection confers a favorable prognosis.

  1. Spinal ependymoma, MYCN-amplified (SP-EPN-MYCN).

     • This is a rare and aggressive ependymoma that predominantly affects young adults.
     • SP-EPN-MYCN tumors are typically grade 3, and they are characterized by aggressive behavior, with frequent leptomeningeal dissemination and high rate of recurrence.[28-31]
• Younger age at diagnosis. Younger age at diagnosis has historically been a poor prognostic factor, although this could partially result from the common practice of avoiding or deferring radiation in children younger than 3 years. In a prospective Children’s Oncology Group (COG) trial (ACNS0121 [NCT00027846]), immediate postoperative radiation therapy was given to all children older than 1 year after gross-total resection or near-total resection. The study demonstrated that there was no significant difference in 5-year PFS or OS between patients aged 1 to 3 years and patients aged 3 to 21 years.[19]
• Anaplastic histology. Anaplastic histology has been associated with a poor prognosis.[32][Level of evidence B4]; [33-36]; [37][Level of evidence C1]; [38][Level of evidence C2] However, the distinction between grade 2 and grade 3 disease has significant interobserver variability, confounding the use of anaplasia as a prognostic factor.[39] The 2021 WHO Classification of Tumors of the CNS no longer uses the term anaplastic ependymoma and allows only a histologically defined diagnosis of ependymoma in the integrated diagnosis. Within the layered report, a pathologist can still choose to assign either CNS WHO grade 2 or 3 to a tumor on the basis of its histological features.[2,3]
• Subtotal resection. Subtotal resection confers a very poor prognosis.[19,35,36]; [32][Level of evidence B4]
• Lower doses of radiation. Lower doses of radiation or chemotherapy-only protocols confer a poor prognosis.[12,23,40,41]

Follow-Up After Treatment

Surveillance neuroimaging, coupled with clinical assessments, is generally recommended after treatment for ependymoma. In a report of 198 patients with ependymoma, 90 experienced a relapse. Patients whose relapsed tumor was detected by routine surveillance imaging had superior second PFS than patients whose relapsed tumor was detected by clinical symptomology. The latter were more likely to have metastatic disease at relapse. It is not known whether these patients also had more biologically aggressive disease, although the median time to relapse and the median time from last surveillance imaging was the same in both groups.[42]

Most practitioners obtain MRI of the brain and/or spinal cord at the following intervals:[43][Level of evidence B4]

• First 2 to 3 years after treatment: Every 3 to 4 months.
• Four to 5 years after treatment: Every 6 months.
• More than 5 years after treatment: Annually because of the high incidence of late recurrences.

References

1. Louis DN, Ohgaki H, Wiestler OD: WHO Classification of Tumours of the Central Nervous System. 4th rev.ed. IARC Press, 2016.
2. Louis DN, Perry A, Wesseling P, et al.: The 2021 WHO Classification of Tumors of the Central Nervous System: a summary. Neuro Oncol 23 (8): 1231-1251, 2021. [PMC free article: PMC8328013] [PubMed: 34185076]
3. WHO Classification of Tumours Editorial Board, ed.: WHO Classification of Tumours: Central Nervous System Tumours. Vol. 6. 5th ed. IARC Press; 2021.
4. Gurney JG, Smith MA, Bunin GR: CNS and miscellaneous intracranial and intraspinal neoplasms. In: Ries LA, Smith MA, Gurney JG, et al., eds.: Cancer incidence and survival among children and adolescents: United States SEER Program 1975-1995. National Cancer Institute, SEER Program, 1999. NIH Pub.No. 99-4649, Chapter 3, pp 51-63. Also available online. Last accessed February 9, 2024.
5. Ostrom QT, Gittleman H, Truitt G, et al.: CBTRUS Statistical Report: Primary Brain and Other Central Nervous System Tumors Diagnosed in the United States in 2011-2015. Neuro Oncol 20 (suppl_4): iv1-iv86, 2018. [PMC free article: PMC6129949] [PubMed: 30445539]
6. Andreiuolo F, Puget S, Peyre M, et al.: Neuronal differentiation distinguishes supratentorial and infratentorial childhood ependymomas. Neuro Oncol 12 (11): 1126-34, 2010. [PMC free article: PMC3098029] [PubMed: 20615923]
7. Moreno L, Pollack IF, Duffner PK, et al.: Utility of cerebrospinal fluid cytology in newly diagnosed childhood ependymoma. J Pediatr Hematol Oncol 32 (6): 515-8, 2010. [PubMed: 20463607]
8. Benesch M, Mynarek M, Witt H, et al.: Newly Diagnosed Metastatic Intracranial Ependymoma in Children: Frequency, Molecular Characteristics, Treatment, and Outcome in the Prospective HIT Series. Oncologist 24 (9): e921-e929, 2019. [PMC free article: PMC6738295] [PubMed: 30850560]
9. Wani K, Armstrong TS, Vera-Bolanos E, et al.: A prognostic gene expression signature in infratentorial ependymoma. Acta Neuropathol 123 (5): 727-38, 2012. [PMC free article: PMC4013829] [PubMed: 22322993]
10. Witt H, Mack SC, Ryzhova M, et al.: Delineation of two clinically and molecularly distinct subgroups of posterior fossa ependymoma. Cancer Cell 20 (2): 143-57, 2011. [PMC free article: PMC4154494] [PubMed: 21840481]
11. Pajtler KW, Witt H, Sill M, et al.: Molecular Classification of Ependymal Tumors across All CNS Compartments, Histopathological Grades, and Age Groups. Cancer Cell 27 (5): 728-43, 2015. [PMC free article: PMC4712639] [PubMed: 25965575]
12. Ramaswamy V, Hielscher T, Mack SC, et al.: Therapeutic Impact of Cytoreductive Surgery and Irradiation of Posterior Fossa Ependymoma in the Molecular Era: A Retrospective Multicohort Analysis. J Clin Oncol 34 (21): 2468-77, 2016. [PMC free article: PMC4962737] [PubMed: 27269943]
13. Mendrzyk F, Korshunov A, Benner A, et al.: Identification of gains on 1q and epidermal growth factor receptor overexpression as independent prognostic markers in intracranial ependymoma. Clin Cancer Res 12 (7 Pt 1): 2070-9, 2006. [PubMed: 16609018]
14. Korshunov A, Witt H, Hielscher T, et al.: Molecular staging of intracranial ependymoma in children and adults. J Clin Oncol 28 (19): 3182-90, 2010. [PubMed: 20516456]
15. Kilday JP, Mitra B, Domerg C, et al.: 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). Clin Cancer Res 18 (7): 2001-11, 2012. [PubMed: 22338015]
16. Godfraind C, Kaczmarska JM, Kocak M, et al.: Distinct disease-risk groups in pediatric supratentorial and posterior fossa ependymomas. Acta Neuropathol 124 (2): 247-57, 2012. [PMC free article: PMC3554251] [PubMed: 22526017]
17. Korshunov A, Golanov A, Timirgaz V: Immunohistochemical markers for intracranial ependymoma recurrence. An analysis of 88 cases. J Neurol Sci 177 (1): 72-82, 2000. [PubMed: 10967185]
18. Andreiuolo F, Le Teuff G, Bayar MA, et al.: Integrating Tenascin-C protein expression and 1q25 copy number status in pediatric intracranial ependymoma prognostication: A new model for risk stratification. PLoS One 12 (6): e0178351, 2017. [PMC free article: PMC5472261] [PubMed: 28617804]
19. Merchant TE, Bendel AE, Sabin ND, et al.: Conformal Radiation Therapy for Pediatric Ependymoma, Chemotherapy for Incompletely Resected Ependymoma, and Observation for Completely Resected, Supratentorial Ependymoma. J Clin Oncol 37 (12): 974-983, 2019. [PMC free article: PMC7186586] [PubMed: 30811284]
20. Baroni LV, Sundaresan L, Heled A, et al.: Ultra high-risk PFA ependymoma is characterized by loss of chromosome 6q. Neuro Oncol 23 (8): 1360-1370, 2021. [PMC free article: PMC8328032] [PubMed: 33580238]
21. Donson AM, Bertrand KC, Riemondy KA, et al.: Significant increase of high-risk chromosome 1q gain and 6q loss at recurrence in posterior fossa group A ependymoma: A multicenter study. Neuro Oncol 25 (10): 1854-1867, 2023. [PMC free article: PMC10547517] [PubMed: 37246777]
22. Cavalli FMG, Hübner JM, Sharma T, et al.: Heterogeneity within the PF-EPN-B ependymoma subgroup. Acta Neuropathol 136 (2): 227-237, 2018. [PMC free article: PMC6373486] [PubMed: 30019219]
23. Upadhyaya SA, Robinson GW, Onar-Thomas A, et al.: Molecular grouping and outcomes of young children with newly diagnosed ependymoma treated on the multi-institutional SJYC07 trial. Neuro Oncol 21 (10): 1319-1330, 2019. [PMC free article: PMC6784269] [PubMed: 30976811]
24. Fukuoka K, Kanemura Y, Shofuda T, et al.: Significance of molecular classification of ependymomas: C11orf95-RELA fusion-negative supratentorial ependymomas are a heterogeneous group of tumors. Acta Neuropathol Commun 6 (1): 134, 2018. [PMC free article: PMC6278135] [PubMed: 30514397]
25. Jünger ST, Andreiuolo F, Mynarek M, et al.: CDKN2A deletion in supratentorial ependymoma with RELA alteration indicates a dismal prognosis: a retrospective analysis of the HIT ependymoma trial cohort. Acta Neuropathol 140 (3): 405-407, 2020. [PMC free article: PMC7423858] [PubMed: 32514758]
26. Milde T, Pfister S, Korshunov A, et al.: Stepwise accumulation of distinct genomic aberrations in a patient with progressively metastasizing ependymoma. Genes Chromosomes Cancer 48 (3): 229-38, 2009. [PubMed: 19025795]
27. Andreiuolo F, Varlet P, Tauziède-Espariat A, et al.: Childhood supratentorial ependymomas with YAP1-MAMLD1 fusion: an entity with characteristic clinical, radiological, cytogenetic and histopathological features. Brain Pathol 29 (2): 205-216, 2019. [PMC free article: PMC7379249] [PubMed: 30246434]
28. Ghasemi DR, Sill M, Okonechnikov K, et al.: MYCN amplification drives an aggressive form of spinal ependymoma. Acta Neuropathol 138 (6): 1075-1089, 2019. [PMC free article: PMC6851394] [PubMed: 31414211]
29. Swanson AA, Raghunathan A, Jenkins RB, et al.: Spinal Cord Ependymomas With MYCN Amplification Show Aggressive Clinical Behavior. J Neuropathol Exp Neurol 78 (9): 791-797, 2019. [PubMed: 31373367]
30. Scheil S, Brüderlein S, Eicker M, et al.: Low frequency of chromosomal imbalances in anaplastic ependymomas as detected by comparative genomic hybridization. Brain Pathol 11 (2): 133-43, 2001. [PMC free article: PMC8098350] [PubMed: 11303789]
31. Raffeld M, Abdullaev Z, Pack SD, et al.: High level MYCN amplification and distinct methylation signature define an aggressive subtype of spinal cord ependymoma. Acta Neuropathol Commun 8 (1): 101, 2020. [PMC free article: PMC7346356] [PubMed: 32641156]
32. Massimino M, Miceli R, Giangaspero F, et al.: Final results of the second prospective AIEOP protocol for pediatric intracranial ependymoma. Neuro Oncol 18 (10): 1451-60, 2016. [PMC free article: PMC5035526] [PubMed: 27194148]
33. Merchant TE, Jenkins JJ, Burger PC, et al.: Influence of tumor grade on time to progression after irradiation for localized ependymoma in children. Int J Radiat Oncol Biol Phys 53 (1): 52-7, 2002. [PubMed: 12007941]
34. Korshunov A, Golanov A, Sycheva R, et al.: The histologic grade is a main prognostic factor for patients with intracranial ependymomas treated in the microneurosurgical era: an analysis of 258 patients. Cancer 100 (6): 1230-7, 2004. [PubMed: 15022291]
35. Tamburrini G, D'Ercole M, Pettorini BL, et al.: Survival following treatment for intracranial ependymoma: a review. Childs Nerv Syst 25 (10): 1303-12, 2009. [PubMed: 19387655]
36. Massimino M, Barretta F, Modena P, et al.: Second series by the Italian Association of Pediatric Hematology and Oncology of children and adolescents with intracranial ependymoma: an integrated molecular and clinical characterization with a long-term follow-up. Neuro Oncol 23 (5): 848-857, 2021. [PMC free article: PMC8099475] [PubMed: 33135735]
37. Amirian ES, Armstrong TS, Aldape KD, et al.: Predictors of survival among pediatric and adult ependymoma cases: a study using Surveillance, Epidemiology, and End Results data from 1973 to 2007. Neuroepidemiology 39 (2): 116-24, 2012. [PMC free article: PMC3470871] [PubMed: 22846789]
38. Tihan T, Zhou T, Holmes E, et al.: The prognostic value of histological grading of posterior fossa ependymomas in children: a Children's Oncology Group study and a review of prognostic factors. Mod Pathol 21 (2): 165-77, 2008. [PubMed: 18084249]
39. Ellison DW, Kocak M, Figarella-Branger D, et al.: Histopathological grading of pediatric ependymoma: reproducibility and clinical relevance in European trial cohorts. J Negat Results Biomed 10: 7, 2011. [PMC free article: PMC3117833] [PubMed: 21627842]
40. Vaidya K, Smee R, Williams JR: Prognostic factors and treatment options for paediatric ependymomas. J Clin Neurosci 19 (9): 1228-35, 2012. [PubMed: 22840355]
41. Zapotocky M, Beera K, Adamski J, et al.: Survival and functional outcomes of molecularly defined childhood posterior fossa ependymoma: Cure at a cost. Cancer 125 (11): 1867-1876, 2019. [PMC free article: PMC6508980] [PubMed: 30768777]
42. Klawinski D, Indelicato DJ, Hossain J, et al.: Surveillance imaging in pediatric ependymoma. Pediatr Blood Cancer 67 (11): e28622, 2020. [PubMed: 32743915]
43. Massimino M, Barretta F, Modena P, et al.: Pediatric intracranial ependymoma: correlating signs and symptoms at recurrence with outcome in the second prospective AIEOP protocol follow-up. J Neurooncol 140 (2): 457-465, 2018. [PubMed: 30109673]

Molecular Subgroups of Ependymoma

Molecular characterization studies have previously identified nine molecular subgroups of ependymoma, six of which predominate in childhood. The subgroups are determined by their distinctive DNA methylation and gene expression profiles and unique spectrum of genomic alterations (see Figure 2).[1-4]

One new molecularly defined ependymoma was added to the 2021 World Health Organization (WHO) Classification of Tumours of the Central Nervous System: spinal ependymoma with MYCN amplification. The 2021 classification further described ependymal tumors defined by anatomical location and histology but not by molecular alteration. These tumors are called posterior fossa ependymoma (PF-EPN), supratentorial ependymoma (ST-EPN), and spinal ependymoma (SP-EPN). These tumors either contain a unique molecular alteration (not elsewhere classified [NEC]) or their molecular analysis failed or was not obtained (not otherwise specified [NOS]).[5]

• Infratentorial tumors.

  -

  Posterior fossa ependymoma (PF-EPN).

  -

  Posterior fossa A (PF-EPN-A), loss of H3 K27 trimethylation mark.

  -

  Posterior fossa B (PF-EPN-B), retained H3 K27 trimethylation mark.

• Supratentorial tumors.

  -

  Supratentorial ependymoma (ST-EPN).

  -

  ZFTA fusion–positive ependymoma (ST-EPN-ZFTA). This was previously called RELA fusion–positive ependymoma (ST-EPN-RELA), but it was renamed because ZFTA is the new designation for C11orf95, and ZFTA may be fused with a partner gene other than RELA.[6]

  -

  YAP1 fusion–positive ependymoma (ST-EPN-YAP1).

• Spinal tumors.

  • Spinal ependymoma (SP-EPN).
  • Spinal ependymoma, MYCN-amplified (SP-EPN-MYCN).
  • Myxopapillary ependymoma (SP-EPN-MPE).

Subependymoma—whether supratentorial, infratentorial, or spinal—accounts for the remaining three molecular variants, and it is rarely, if ever, seen in children.

Figure 2. Graphical summary of key molecular and clinical characteristics of ependymal tumor subgroups. Schematic representation of key genetic and epigenetic findings in the nine molecular subgroups of ependymal tumors as identified by methylation profiling. CIN, Chromosomal instability. Reprinted from Cancer Cell, Volume 27, Kristian W. Pajtler, Hendrik Witt, Martin Sill, David T.W. Jones, Volker Hovestadt, Fabian Kratochwil, Khalida Wani, Ruth Tatevossian, Chandanamali Punchihewa, Pascal Johann, Juri Reimand, Hans-Jorg Warnatz, Marina Ryzhova, Steve Mack, Vijay Ramaswamy, David Capper, Leonille Schweizer, Laura Sieber, Andrea Wittmann, Zhiqin Huang, Peter van Sluis, Richard Volckmann, Jan Koster, Rogier Versteeg, Daniel Fults, Helen Toledano, Smadar Avigad, Lindsey M. Hoffman, Andrew M. Donson, Nicholas Foreman, Ekkehard Hewer, Karel Zitterbart, Mark Gilbert, Terri S. Armstrong, Nalin Gupta, Jeffrey C. Allen, Matthias A. Karajannis, David Zagzag, Martin Hasselblatt, Andreas E. Kulozik, Olaf Witt, V. Peter Collins, Katja von Hoff, Stefan Rutkowski, Torsten Pietsch, Gary Bader, Marie-Laure Yaspo, Andreas von Deimling, Peter Lichter, Michael D. Taylor, Richard Gilbertson, David W. Ellison, Kenneth Aldape, Andrey Korshunov, Marcel Kool, and Stefan M. Pfister, Molecular Classification of Ependymal Tumors across All CNS Compartments, Histopathological Grades, and Age Groups, Pages 728–743, Copyright (2015), with permission from Elsevier.

References

1. Pajtler KW, Witt H, Sill M, et al.: Molecular Classification of Ependymal Tumors across All CNS Compartments, Histopathological Grades, and Age Groups. Cancer Cell 27 (5): 728-43, 2015. [PMC free article: PMC4712639] [PubMed: 25965575]
2. Witt H, Mack SC, Ryzhova M, et al.: Delineation of two clinically and molecularly distinct subgroups of posterior fossa ependymoma. Cancer Cell 20 (2): 143-57, 2011. [PMC free article: PMC4154494] [PubMed: 21840481]
3. Mack SC, Witt H, Piro RM, et al.: Epigenomic alterations define lethal CIMP-positive ependymomas of infancy. Nature 506 (7489): 445-50, 2014. [PMC free article: PMC4174313] [PubMed: 24553142]
4. Pajtler KW, Mack SC, Ramaswamy V, et al.: The current consensus on the clinical management of intracranial ependymoma and its distinct molecular variants. Acta Neuropathol 133 (1): 5-12, 2017. [PMC free article: PMC5209402] [PubMed: 27858204]
5. WHO Classification of Tumours Editorial Board, ed.: WHO Classification of Tumours: Central Nervous System Tumours. Vol. 6. 5th ed. IARC Press; 2021.
6. Zschernack V, Jünger ST, Mynarek M, et al.: Supratentorial ependymoma in childhood: more than just RELA or YAP. Acta Neuropathol 141 (3): 455-466, 2021. [PMC free article: PMC7882569] [PubMed: 33481105]
7. Ramaswamy V, Hielscher T, Mack SC, et al.: Therapeutic Impact of Cytoreductive Surgery and Irradiation of Posterior Fossa Ependymoma in the Molecular Era: A Retrospective Multicohort Analysis. J Clin Oncol 34 (21): 2468-77, 2016. [PMC free article: PMC4962737] [PubMed: 27269943]
8. Korshunov A, Witt H, Hielscher T, et al.: Molecular staging of intracranial ependymoma in children and adults. J Clin Oncol 28 (19): 3182-90, 2010. [PubMed: 20516456]
9. Merchant TE, Bendel AE, Sabin ND, et al.: Conformal Radiation Therapy for Pediatric Ependymoma, Chemotherapy for Incompletely Resected Ependymoma, and Observation for Completely Resected, Supratentorial Ependymoma. J Clin Oncol 37 (12): 974-983, 2019. [PMC free article: PMC7186586] [PubMed: 30811284]
10. Baroni LV, Sundaresan L, Heled A, et al.: Ultra high-risk PFA ependymoma is characterized by loss of chromosome 6q. Neuro Oncol 23 (8): 1360-1370, 2021. [PMC free article: PMC8328032] [PubMed: 33580238]
11. Panwalkar P, Clark J, Ramaswamy V, et al.: Immunohistochemical analysis of H3K27me3 demonstrates global reduction in group-A childhood posterior fossa ependymoma and is a powerful predictor of outcome. Acta Neuropathol 134 (5): 705-714, 2017. [PMC free article: PMC5647236] [PubMed: 28733933]
12. Chapman RJ, Ghasemi DR, Andreiuolo F, et al.: Optimizing biomarkers for accurate ependymoma diagnosis, prognostication, and stratification within International Clinical Trials: A BIOMECA study. Neuro Oncol 25 (10): 1871-1882, 2023. [PMC free article: PMC10547510] [PubMed: 36916248]
13. Pajtler KW, Wen J, Sill M, et al.: Molecular heterogeneity and CXorf67 alterations in posterior fossa group A (PFA) ependymomas. Acta Neuropathol 136 (2): 211-226, 2018. [PMC free article: PMC6105278] [PubMed: 29909548]
14. Hübner JM, Müller T, Papageorgiou DN, et al.: EZHIP/CXorf67 mimics K27M mutated oncohistones and functions as an intrinsic inhibitor of PRC2 function in aggressive posterior fossa ependymoma. Neuro Oncol 21 (7): 878-889, 2019. [PMC free article: PMC6620627] [PubMed: 30923826]
15. Jain SU, Do TJ, Lund PJ, et al.: PFA ependymoma-associated protein EZHIP inhibits PRC2 activity through a H3 K27M-like mechanism. Nat Commun 10 (1): 2146, 2019. [PMC free article: PMC6513997] [PubMed: 31086175]
16. Gessi M, Capper D, Sahm F, et al.: Evidence of H3 K27M mutations in posterior fossa ependymomas. Acta Neuropathol 132 (4): 635-7, 2016. [PubMed: 27539613]
17. Ryall S, Guzman M, Elbabaa SK, et al.: H3 K27M mutations are extremely rare in posterior fossa group A ependymoma. Childs Nerv Syst 33 (7): 1047-1051, 2017. [PubMed: 28623522]
18. Cavalli FMG, Hübner JM, Sharma T, et al.: Heterogeneity within the PF-EPN-B ependymoma subgroup. Acta Neuropathol 136 (2): 227-237, 2018. [PMC free article: PMC6373486] [PubMed: 30019219]
19. Parker M, Mohankumar KM, Punchihewa C, et al.: C11orf95-RELA fusions drive oncogenic NF-κB signalling in ependymoma. Nature 506 (7489): 451-5, 2014. [PMC free article: PMC4050669] [PubMed: 24553141]
20. Pietsch T, Wohlers I, Goschzik T, et al.: Supratentorial ependymomas of childhood carry C11orf95-RELA fusions leading to pathological activation of the NF-κB signaling pathway. Acta Neuropathol 127 (4): 609-11, 2014. [PubMed: 24562983]
21. Pagès M, Pajtler KW, Puget S, et al.: Diagnostics of pediatric supratentorial RELA ependymomas: integration of information from histopathology, genetics, DNA methylation and imaging. Brain Pathol 29 (3): 325-335, 2019. [PMC free article: PMC7379587] [PubMed: 30325077]
22. Jünger ST, Andreiuolo F, Mynarek M, et al.: CDKN2A deletion in supratentorial ependymoma with RELA alteration indicates a dismal prognosis: a retrospective analysis of the HIT ependymoma trial cohort. Acta Neuropathol 140 (3): 405-407, 2020. [PMC free article: PMC7423858] [PubMed: 32514758]
23. Milde T, Pfister S, Korshunov A, et al.: Stepwise accumulation of distinct genomic aberrations in a patient with progressively metastasizing ependymoma. Genes Chromosomes Cancer 48 (3): 229-38, 2009. [PubMed: 19025795]
24. Sievers P, Henneken SC, Blume C, et al.: Recurrent fusions in PLAGL1 define a distinct subset of pediatric-type supratentorial neuroepithelial tumors. Acta Neuropathol 142 (5): 827-839, 2021. [PMC free article: PMC8500895] [PubMed: 34355256]
25. Sturm D, Orr BA, Toprak UH, et al.: New Brain Tumor Entities Emerge from Molecular Classification of CNS-PNETs. Cell 164 (5): 1060-72, 2016. [PMC free article: PMC5139621] [PubMed: 26919435]
26. Fukuoka K, Kanemura Y, Shofuda T, et al.: Significance of molecular classification of ependymomas: C11orf95-RELA fusion-negative supratentorial ependymomas are a heterogeneous group of tumors. Acta Neuropathol Commun 6 (1): 134, 2018. [PMC free article: PMC6278135] [PubMed: 30514397]
27. Ghasemi DR, Sill M, Okonechnikov K, et al.: MYCN amplification drives an aggressive form of spinal ependymoma. Acta Neuropathol 138 (6): 1075-1089, 2019. [PMC free article: PMC6851394] [PubMed: 31414211]
28. Swanson AA, Raghunathan A, Jenkins RB, et al.: Spinal Cord Ependymomas With MYCN Amplification Show Aggressive Clinical Behavior. J Neuropathol Exp Neurol 78 (9): 791-797, 2019. [PubMed: 31373367]
29. Scheil S, Brüderlein S, Eicker M, et al.: Low frequency of chromosomal imbalances in anaplastic ependymomas as detected by comparative genomic hybridization. Brain Pathol 11 (2): 133-43, 2001. [PMC free article: PMC8098350] [PubMed: 11303789]
30. Raffeld M, Abdullaev Z, Pack SD, et al.: High level MYCN amplification and distinct methylation signature define an aggressive subtype of spinal cord ependymoma. Acta Neuropathol Commun 8 (1): 101, 2020. [PMC free article: PMC7346356] [PubMed: 32641156]

References

1. WHO Classification of Tumours Editorial Board, ed.: WHO Classification of Tumours: Central Nervous System Tumours. Vol. 6. 5th ed. IARC Press; 2021.
2. Louis DN, Ohgaki H, Wiestler OD: WHO Classification of Tumours of the Central Nervous System. 4th rev.ed. IARC Press, 2016.
3. Pajtler KW, Mack SC, Ramaswamy V, et al.: The current consensus on the clinical management of intracranial ependymoma and its distinct molecular variants. Acta Neuropathol 133 (1): 5-12, 2017. [PMC free article: PMC5209402] [PubMed: 27858204]
4. Louis DN, Perry A, Wesseling P, et al.: The 2021 WHO Classification of Tumors of the Central Nervous System: a summary. Neuro Oncol 23 (8): 1231-1251, 2021. [PMC free article: PMC8328013] [PubMed: 34185076]
5. Ellison DW, Kocak M, Figarella-Branger D, et al.: Histopathological grading of pediatric ependymoma: reproducibility and clinical relevance in European trial cohorts. J Negat Results Biomed 10: 7, 2011. [PMC free article: PMC3117833] [PubMed: 21627842]
6. Taylor MD, Poppleton H, Fuller C, et al.: Radial glia cells are candidate stem cells of ependymoma. Cancer Cell 8 (4): 323-35, 2005. [PubMed: 16226707]
7. Andreiuolo F, Puget S, Peyre M, et al.: Neuronal differentiation distinguishes supratentorial and infratentorial childhood ependymomas. Neuro Oncol 12 (11): 1126-34, 2010. [PMC free article: PMC3098029] [PubMed: 20615923]
8. Grill J, Bergthold G, Ferreira C: Pediatric ependymomas: will molecular biology change patient management? Curr Opin Oncol 23 (6): 638-42, 2011. [PubMed: 21892086]
9. Mack SC, Pajtler KW, Chavez L, et al.: Therapeutic targeting of ependymoma as informed by oncogenic enhancer profiling. Nature 553 (7686): 101-105, 2018. [PMC free article: PMC5993422] [PubMed: 29258295]
10. Mack SC, Witt H, Piro RM, et al.: Epigenomic alterations define lethal CIMP-positive ependymomas of infancy. Nature 506 (7489): 445-50, 2014. [PMC free article: PMC4174313] [PubMed: 24553142]
11. Pajtler KW, Witt H, Sill M, et al.: Molecular Classification of Ependymal Tumors across All CNS Compartments, Histopathological Grades, and Age Groups. Cancer Cell 27 (5): 728-43, 2015. [PMC free article: PMC4712639] [PubMed: 25965575]
12. Johnson RA, Wright KD, Poppleton H, et al.: Cross-species genomics matches driver mutations and cell compartments to model ependymoma. Nature 466 (7306): 632-6, 2010. [PMC free article: PMC2912966] [PubMed: 20639864]

References

1. Villano JL, Parker CK, Dolecek TA: Descriptive epidemiology of ependymal tumours in the United States. Br J Cancer 108 (11): 2367-71, 2013. [PMC free article: PMC3681017] [PubMed: 23660944]
2. Fassett DR, Pingree J, Kestle JR: The high incidence of tumor dissemination in myxopapillary ependymoma in pediatric patients. Report of five cases and review of the literature. J Neurosurg 102 (1 Suppl): 59-64, 2005. [PubMed: 16206735]
3. Bandopadhayay P, Silvera VM, Ciarlini PDSC, et al.: Myxopapillary ependymomas in children: imaging, treatment and outcomes. J Neurooncol 126 (1): 165-174, 2016. [PubMed: 26468139]
4. Raffeld M, Abdullaev Z, Pack SD, et al.: High level MYCN amplification and distinct methylation signature define an aggressive subtype of spinal cord ependymoma. Acta Neuropathol Commun 8 (1): 101, 2020. [PMC free article: PMC7346356] [PubMed: 32641156]

References

1. Smith MA, Altekruse SF, Adamson PC, et al.: Declining childhood and adolescent cancer mortality. Cancer 120 (16): 2497-506, 2014. [PMC free article: PMC4136455] [PubMed: 24853691]
2. National Cancer Institute: NCCR*Explorer: An interactive website for NCCR cancer statistics. Bethesda, MD: National Cancer Institute. Available online. Last accessed August 23, 2024.
3. Surveillance Research Program, National Cancer Institute: SEER*Explorer: An interactive website for SEER cancer statistics. Bethesda, MD: National Cancer Institute. Available online. Last accessed September 5, 2024.

References

1. Fassett DR, Pingree J, Kestle JR: The high incidence of tumor dissemination in myxopapillary ependymoma in pediatric patients. Report of five cases and review of the literature. J Neurosurg 102 (1 Suppl): 59-64, 2005. [PubMed: 16206735]
2. Bagley CA, Kothbauer KF, Wilson S, et al.: Resection of myxopapillary ependymomas in children. J Neurosurg 106 (4 Suppl): 261-7, 2007. [PubMed: 17465358]
3. Louis DN, Perry A, Wesseling P, et al.: The 2021 WHO Classification of Tumors of the Central Nervous System: a summary. Neuro Oncol 23 (8): 1231-1251, 2021. [PMC free article: PMC8328013] [PubMed: 34185076]
4. Akyurek S, Chang EL, Yu TK, et al.: Spinal myxopapillary ependymoma outcomes in patients treated with surgery and radiotherapy at M.D. Anderson Cancer Center. J Neurooncol 80 (2): 177-83, 2006. [PubMed: 16648988]
5. Bagley CA, Wilson S, Kothbauer KF, et al.: Long term outcomes following surgical resection of myxopapillary ependymomas. Neurosurg Rev 32 (3): 321-34; discussion 334, 2009. [PubMed: 19221818]
6. Pica A, Miller R, Villà S, et al.: The results of surgery, with or without radiotherapy, for primary spinal myxopapillary ependymoma: a retrospective study from the rare cancer network. Int J Radiat Oncol Biol Phys 74 (4): 1114-20, 2009. [PubMed: 19250760]
7. Agbahiwe HC, Wharam M, Batra S, et al.: Management of pediatric myxopapillary ependymoma: the role of adjuvant radiation. Int J Radiat Oncol Biol Phys 85 (2): 421-7, 2013. [PMC free article: PMC4613753] [PubMed: 22713833]
8. Jeibmann A, Egensperger R, Kuchelmeister K, et al.: Extent of surgical resection but not myxopapillary versus classical histopathological subtype affects prognosis in lumbo-sacral ependymomas. Histopathology 54 (2): 260-2, 2009. [PubMed: 19207953]
9. Bandopadhayay P, Silvera VM, Ciarlini PDSC, et al.: Myxopapillary ependymomas in children: imaging, treatment and outcomes. J Neurooncol 126 (1): 165-174, 2016. [PubMed: 26468139]
10. Looi WS, Indelicato DJ, Mailhot Vega RB, et al.: Outcomes following limited-volume proton therapy for multifocal spinal myxopapillary ependymoma. Pediatr Blood Cancer 68 (3): e28820, 2021. [PubMed: 33226179]
11. Liu KX, Indelicato DJ, Paulino AC, et al.: Multi-institutional Characterization of Outcomes for Pediatric and Young Adult Patients With High-Risk Myxopapillary Ependymoma After Radiation Therapy. Int J Radiat Oncol Biol Phys 117 (5): 1174-1180, 2023. [PubMed: 37437812]

References

1. Oh MC, Ivan ME, Sun MZ, et al.: Adjuvant radiotherapy delays recurrence following subtotal resection of spinal cord ependymomas. Neuro Oncol 15 (2): 208-15, 2013. [PMC free article: PMC3548580] [PubMed: 23229996]
2. Volpp PB, Han K, Kagan AR, et al.: Outcomes in treatment for intradural spinal cord ependymomas. Int J Radiat Oncol Biol Phys 69 (4): 1199-204, 2007. [PubMed: 17689025]
3. Merchant TE, Kiehna EN, Thompson SJ, et al.: Pediatric low-grade and ependymal spinal cord tumors. Pediatr Neurosurg 32 (1): 30-6, 2000. [PubMed: 10765136]
4. Indelicato DJ, Ioakeim-Ioannidou M, Grippin AJ, et al.: Bicentric Treatment Outcomes After Proton Therapy for Nonmyxopapillary High-Grade Spinal Cord Ependymoma in Children. Int J Radiat Oncol Biol Phys 112 (2): 335-341, 2022. [PubMed: 34597719]

Surgery

Surgery is performed in an attempt at maximal tumor reduction. Evidence suggests that more extensive surgical resection is related to an improved rate of survival.[1-5]; [6,7][Level of evidence C2] Magnetic resonance imaging (MRI) is performed postoperatively to confirm the extent of resection. If not obtained preoperatively, MRI of the entire neuraxis and cerebrospinal fluid cytopathology is performed to evaluate for disease dissemination.

Patients across all molecular subgroups who have residual tumor or disseminated disease are considered at high risk of relapse and may be treated on clinical trials specifically designed for them. Patients with no evidence of residual tumor still have an approximate 20% to 40% relapse risk despite receiving postoperative radiation therapy.[8][Level of evidence B4]

Anecdotal experience suggests that surgery alone for completely resected supratentorial World Health Organization (WHO) grade 2 tumors and spinal ependymomas may, in select cases, be an appropriate approach to treatment.[9-13][Level of evidence C2]

Evidence (surgery):

1. A prospective multi-institutional cooperative group trial (Children's Oncology Group [COG] ACNS0121 [NCT00027846]) included patients with newly diagnosed intracranial ependymomas (N = 356). Surgery alone was used for the treatment of supratentorial, WHO grade 2, gross-totally resected ependymomas (n = 11).[8][Level of evidence B4]

   • The 5-year event-free survival (EFS) rate was 61.4%, and the overall survival (OS) rate was 100%.
   • Local failure occurred in four patients (36%), and local and distant failure occurred in one patient (9%).
   • In this study, the number of patients eligible for a surgery-alone approach was very small. Only a subset of these patients successfully avoided additional treatment.

Retrospective analysis of the outcome for patients with posterior fossa B ependymoma suggests that these patients might be sufficiently treated with gross-total resection alone,[7] but this approach has not been tested in a prospective randomized clinical trial.

Adjuvant Therapy

Treatment Options Under Clinical Evaluation for Childhood Ependymoma

Early-phase therapeutic trials may be available for selected patients. These trials may be available via the COG, the Pediatric Brain Tumor Consortium, or other entities. Information about National Cancer Institute (NCI)–supported clinical trials can be found on the NCI website. For information about clinical trials sponsored by other organizations, see the ClinicalTrials.gov website.

References

1. van Veelen-Vincent ML, Pierre-Kahn A, Kalifa C, et al.: Ependymoma in childhood: prognostic factors, extent of surgery, and adjuvant therapy. J Neurosurg 97 (4): 827-35, 2002. [PubMed: 12405370]
2. Abdel-Wahab M, Etuk B, Palermo J, et al.: Spinal cord gliomas: A multi-institutional retrospective analysis. Int J Radiat Oncol Biol Phys 64 (4): 1060-71, 2006. [PubMed: 16373081]
3. Kothbauer KF: Neurosurgical management of intramedullary spinal cord tumors in children. Pediatr Neurosurg 43 (3): 222-35, 2007. [PubMed: 17409792]
4. Zacharoulis S, Ji L, Pollack IF, et al.: Metastatic ependymoma: a multi-institutional retrospective analysis of prognostic factors. Pediatr Blood Cancer 50 (2): 231-5, 2008. [PubMed: 17610266]
5. Merchant TE, Li C, Xiong X, et al.: Conformal radiotherapy after surgery for paediatric ependymoma: a prospective study. Lancet Oncol 10 (3): 258-66, 2009. [PMC free article: PMC3615425] [PubMed: 19274783]
6. Cage TA, Clark AJ, Aranda D, et al.: A systematic review of treatment outcomes in pediatric patients with intracranial ependymomas. J Neurosurg Pediatr 11 (6): 673-81, 2013. [PubMed: 23540528]
7. Ramaswamy V, Hielscher T, Mack SC, et al.: Therapeutic Impact of Cytoreductive Surgery and Irradiation of Posterior Fossa Ependymoma in the Molecular Era: A Retrospective Multicohort Analysis. J Clin Oncol 34 (21): 2468-77, 2016. [PMC free article: PMC4962737] [PubMed: 27269943]
8. Merchant TE, Bendel AE, Sabin ND, et al.: Conformal Radiation Therapy for Pediatric Ependymoma, Chemotherapy for Incompletely Resected Ependymoma, and Observation for Completely Resected, Supratentorial Ependymoma. J Clin Oncol 37 (12): 974-983, 2019. [PMC free article: PMC7186586] [PubMed: 30811284]
9. Volpp PB, Han K, Kagan AR, et al.: Outcomes in treatment for intradural spinal cord ependymomas. Int J Radiat Oncol Biol Phys 69 (4): 1199-204, 2007. [PubMed: 17689025]
10. Hukin J, Epstein F, Lefton D, et al.: Treatment of intracranial ependymoma by surgery alone. Pediatr Neurosurg 29 (1): 40-5, 1998. [PubMed: 9755311]
11. Little AS, Sheean T, Manoharan R, et al.: The management of completely resected childhood intracranial ependymoma: the argument for observation only. Childs Nerv Syst 25 (3): 281-4, 2009. [PubMed: 19153750]
12. Venkatramani R, Dhall G, Patel M, et al.: Supratentorial ependymoma in children: to observe or to treat following gross total resection? Pediatr Blood Cancer 58 (3): 380-3, 2012. [PubMed: 21370439]
13. Ghia AJ, Mahajan A, Allen PK, et al.: Supratentorial gross-totally resected non-anaplastic ependymoma: population based patterns of care and outcomes analysis. J Neurooncol 115 (3): 513-20, 2013. [PubMed: 24085643]
14. Koshy M, Rich S, Merchant TE, et al.: Post-operative radiation improves survival in children younger than 3 years with intracranial ependymoma. J Neurooncol 105 (3): 583-90, 2011. [PubMed: 21637963]
15. Combs SE, Kelter V, Welzel T, et al.: Influence of radiotherapy treatment concept on the outcome of patients with localized ependymomas. Int J Radiat Oncol Biol Phys 71 (4): 972-8, 2008. [PubMed: 18337022]
16. Schroeder TM, Chintagumpala M, Okcu MF, et al.: Intensity-modulated radiation therapy in childhood ependymoma. Int J Radiat Oncol Biol Phys 71 (4): 987-93, 2008. [PubMed: 18258381]
17. Merchant TE, Mulhern RK, Krasin MJ, et al.: Preliminary results from a phase II trial of conformal radiation therapy and evaluation of radiation-related CNS effects for pediatric patients with localized ependymoma. J Clin Oncol 22 (15): 3156-62, 2004. [PubMed: 15284268]
18. Patteson BE, Baliga S, Bajaj BVM, et al.: Clinical outcomes in a large pediatric cohort of patients with ependymoma treated with proton radiotherapy. Neuro Oncol 23 (1): 156-166, 2021. [PMC free article: PMC7849993] [PubMed: 32514542]
19. Indelicato DJ, Ioakeim-Ioannidou M, Bradley JA, et al.: Proton Therapy for Pediatric Ependymoma: Mature Results From a Bicentric Study. Int J Radiat Oncol Biol Phys 110 (3): 815-820, 2021. [PubMed: 33508372]
20. Peters S, Merta J, Schmidt L, et al.: Evaluation of dose, volume, and outcome in children with localized, intracranial ependymoma treated with proton therapy within the prospective KiProReg Study. Neuro Oncol 24 (7): 1193-1202, 2022. [PMC free article: PMC9248402] [PubMed: 34964901]
21. Indelicato DJ, Flampouri S, Rotondo RL, et al.: Incidence and dosimetric parameters of pediatric brainstem toxicity following proton therapy. Acta Oncol 53 (10): 1298-304, 2014. [PubMed: 25279957]
22. Sato M, Gunther JR, Mahajan A, et al.: Progression-free survival of children with localized ependymoma treated with intensity-modulated radiation therapy or proton-beam radiation therapy. Cancer 123 (13): 2570-2578, 2017. [PubMed: 28267208]
23. Indelicato DJ, Bradley JA, Rotondo RL, et al.: Outcomes following proton therapy for pediatric ependymoma. Acta Oncol 57 (5): 644-648, 2018. [PubMed: 29239262]
24. Ritzmann TA, Chapman RJ, Kilday JP, et al.: SIOP Ependymoma I: Final results, long-term follow-up, and molecular analysis of the trial cohort-A BIOMECA Consortium Study. Neuro Oncol 24 (6): 936-948, 2022. [PMC free article: PMC9159435] [PubMed: 35018471]
25. Zacharoulis S, Levy A, Chi SN, et al.: Outcome for young children newly diagnosed with ependymoma, treated with intensive induction chemotherapy followed by myeloablative chemotherapy and autologous stem cell rescue. Pediatr Blood Cancer 49 (1): 34-40, 2007. [PubMed: 16874765]
26. Massimino M, Solero CL, Garrè ML, et al.: Second-look surgery for ependymoma: the Italian experience. J Neurosurg Pediatr 8 (3): 246-50, 2011. [PubMed: 21882914]
27. Wahab SH, Simpson JR, Michalski JM, et al.: Long term outcome with post-operative radiation therapy for spinal canal ependymoma. J Neurooncol 83 (1): 85-9, 2007. [PubMed: 17206474]
28. Garvin JH, Selch MT, Holmes E, et al.: Phase II study of pre-irradiation chemotherapy for childhood intracranial ependymoma. Children's Cancer Group protocol 9942: a report from the Children's Oncology Group. Pediatr Blood Cancer 59 (7): 1183-9, 2012. [PubMed: 22949057]
29. Upadhyaya SA, Robinson GW, Onar-Thomas A, et al.: Molecular grouping and outcomes of young children with newly diagnosed ependymoma treated on the multi-institutional SJYC07 trial. Neuro Oncol 21 (10): 1319-1330, 2019. [PMC free article: PMC6784269] [PubMed: 30976811]
30. Grill J, Kalifa C, Doz F, et al.: A high-dose busulfan-thiotepa combination followed by autologous bone marrow transplantation in childhood recurrent ependymoma. A phase-II study. Pediatr Neurosurg 25 (1): 7-12, 1996. [PubMed: 9055328]
31. Venkatramani R, Ji L, Lasky J, et al.: Outcome of infants and young children with newly diagnosed ependymoma treated on the "Head Start" III prospective clinical trial. J Neurooncol 113 (2): 285-91, 2013. [PMC free article: PMC4119804] [PubMed: 23508296]
32. Merchant TE, Boop FA, Kun LE, et al.: A retrospective study of surgery and reirradiation for recurrent ependymoma. Int J Radiat Oncol Biol Phys 71 (1): 87-97, 2008. [PubMed: 18406885]
33. Bouffet E, Capra M, Bartels U: Salvage chemotherapy for metastatic and recurrent ependymoma of childhood. Childs Nerv Syst 25 (10): 1293-301, 2009. [PubMed: 19360417]
34. Duffner PK, Horowitz ME, Krischer JP, et al.: The treatment of malignant brain tumors in infants and very young children: an update of the Pediatric Oncology Group experience. Neuro-oncol 1 (2): 152-61, 1999. [PMC free article: PMC1920752] [PubMed: 11554387]
35. Duffner PK, Horowitz ME, Krischer JP, et al.: Postoperative chemotherapy and delayed radiation in children less than three years of age with malignant brain tumors. N Engl J Med 328 (24): 1725-31, 1993. [PubMed: 8388548]
36. Geyer JR, Sposto R, Jennings M, et al.: Multiagent chemotherapy and deferred radiotherapy in infants with malignant brain tumors: a report from the Children's Cancer Group. J Clin Oncol 23 (30): 7621-31, 2005. [PubMed: 16234523]
37. Grill J, Le Deley MC, Gambarelli D, et al.: Postoperative chemotherapy without irradiation for ependymoma in children under 5 years of age: a multicenter trial of the French Society of Pediatric Oncology. J Clin Oncol 19 (5): 1288-96, 2001. [PubMed: 11230470]
38. Strother DR, Lafay-Cousin L, Boyett JM, et al.: Benefit from prolonged dose-intensive chemotherapy for infants with malignant brain tumors is restricted to patients with ependymoma: a report of the Pediatric Oncology Group randomized controlled trial 9233/34. Neuro Oncol 16 (3): 457-65, 2014. [PMC free article: PMC3922508] [PubMed: 24335695]
39. Grundy RG, Wilne SA, Weston CL, et al.: Primary postoperative chemotherapy without radiotherapy for intracranial ependymoma in children: the UKCCSG/SIOP prospective study. Lancet Oncol 8 (8): 696-705, 2007. [PubMed: 17644039]
40. Snider CA, Yang K, Mack SC, et al.: Impact of radiation therapy and extent of resection for ependymoma in young children: A population-based study. Pediatr Blood Cancer 65 (3): , 2018. [PubMed: 29115718]
41. Zapotocky M, Beera K, Adamski J, et al.: Survival and functional outcomes of molecularly defined childhood posterior fossa ependymoma: Cure at a cost. Cancer 125 (11): 1867-1876, 2019. [PMC free article: PMC6508980] [PubMed: 30768777]
42. von Hoff K, Kieffer V, Habrand JL, et al.: Impairment of intellectual functions after surgery and posterior fossa irradiation in children with ependymoma is related to age and neurologic complications. BMC Cancer 8: 15, 2008. [PMC free article: PMC2254428] [PubMed: 18208613]
43. MacDonald SM, Safai S, Trofimov A, et al.: Proton radiotherapy for childhood ependymoma: initial clinical outcomes and dose comparisons. Int J Radiat Oncol Biol Phys 71 (4): 979-86, 2008. [PubMed: 18325681]
44. Merchant TE, Lee H, Zhu J, et al.: The effects of hydrocephalus on intelligence quotient in children with localized infratentorial ependymoma before and after focal radiation therapy. J Neurosurg 101 (2 Suppl): 159-68, 2004. [PubMed: 15835103]

Surgery

The utility of further surgical intervention is individualized, based on the extent and location of the tumor. A study of 53 patients with recurrent ependymoma demonstrated an improved 5-year overall survival (OS) rate of 48.7% for patients who had gross-total or near-total resections at the time of surgery, compared with 5.3% for patients with less than gross-total or near-total resections.[4][Level of evidence B4]

In some cases, surgically accessible lesions may be treated alternatively with radiation therapy.

Radiation Therapy and/or Chemotherapy

Patients with recurrent ependymomas should be considered for treatment with the following modalities:[5][Level of evidence C1]

1. Focal retreatment with various radiation modalities, including stereotactic radiosurgery,[6-8][Level of evidence C1]; [9-11][Level of evidence C2]; [12] intensity-modulated photon therapy, and proton therapy.[13]; [14][Level of evidence C1]
2. Craniospinal irradiation for both local and distant (spinal) recurrence could be considered.[15] A study of 101 reirradiated patients conducted at St. Jude Children's Research Hospital observed the following results:[13][Level of evidence C2]

   • The median duration of OS was 75.1 months, and the median freedom from progression was 27.3 months.
   • The 1-, 2-, and 5-year estimates of OS rates were 95.5%, 74.9%, and 57.3%, respectively.
   • Among the 46 patients who received focal reirradiation for local failure, 13 had local failures, and 11 had distant-only failures.
   • Among the ten patients who received craniospinal irradiation for local failure, six had local failures, and none had distant-only failures.
   • Patients with distant-only failure who were treated with craniospinal irradiation had improved OS compared with individuals with local failure who were treated with focal radiation therapy (hazard ratio [HR], 0.37; 95% confidence interval [CI], 0.16–0.87).
   • The 10-year cumulative incidence of greater than grade 3 radiation necrosis after repeat radiation therapy was 7.9%.
   • Gain of chromosome 1q was associated with poorer OS (HR, 3.5; 95% CI, 1.1–10.6) for patients with distant failure (but not local failure) after initial radiation therapy. Other variables associated with reduced OS and freedom from progression included male sex, anaplastic histology at recurrence, and a short interval from initial radiation therapy to recurrence.
3. In a study of 31 children with locally recurrent ependymomas, patients received local (conformal) radiation at recurrence. They received various fractionation schemes using radiation doses similar to those used at initial diagnosis.[16]

   • The median local recurrence-free survival was 31 months (range, 2–63 months), and the median OS was 34 months (range, 3–63 months).
   • Patients who underwent surgery first had significantly higher survival rates than did patients who received reirradiation only.
4. In contrast, a study of 53 patients with recurrent ependymomas treated with radiation therapy after surgery showed no advantage with the addition of radiation therapy after a gross-total or near-total resection.[4][Level of evidence B4]

   • There was an improvement in the 5-year OS rate (22% vs. 7%) for patients treated with radiation therapy who had less than gross-total or near-total resections.
5. Three, and even four, courses of radiation therapy for patients with recurrences can prolong survival with acceptable minimal toxicity.[13][Level of evidence C2]
6. Active anticancer agents, including cyclophosphamide, cisplatin, carboplatin, lomustine, and etoposide, have been used in the recurrence setting. While older single-agent studies have demonstrated chemoresponsiveness with these agents, response is rarely durable.[17,18]

Regardless of treatment strategy, the prognosis for patients with recurrence is poor.[1] Entry into studies of novel therapeutic approaches should be considered.

Treatment Options Under Clinical Evaluation for Recurrent Childhood Ependymoma

Early-phase therapeutic trials may be available for selected patients. These trials may be available via the Children's Oncology Group (COG), the Pediatric Brain Tumor Consortium, or other entities. Information about National Cancer Institute (NCI)–supported clinical trials can be found on the NCI website. For information about clinical trials sponsored by other organizations, see the ClinicalTrials.gov website.

References

1. Zacharoulis S, Ashley S, Moreno L, et al.: Treatment and outcome of children with relapsed ependymoma: a multi-institutional retrospective analysis. Childs Nerv Syst 26 (7): 905-11, 2010. [PubMed: 20039045]
2. Ritzmann TA, Rogers HA, Paine SML, et al.: A retrospective analysis of recurrent pediatric ependymoma reveals extremely poor survival and ineffectiveness of current treatments across central nervous system locations and molecular subgroups. Pediatr Blood Cancer 67 (9): e28426, 2020. [PubMed: 32614133]
3. Wu J, Armstrong TS, Gilbert MR: Biology and management of ependymomas. Neuro Oncol 18 (7): 902-13, 2016. [PMC free article: PMC4896548] [PubMed: 27022130]
4. Adolph JE, Fleischhack G, Mikasch R, et al.: Local and systemic therapy of recurrent ependymoma in children and adolescents: short- and long-term results of the E-HIT-REZ 2005 study. Neuro Oncol 23 (6): 1012-1023, 2021. [PMC free article: PMC8168820] [PubMed: 33331885]
5. Messahel B, Ashley S, Saran F, et al.: Relapsed intracranial ependymoma in children in the UK: patterns of relapse, survival and therapeutic outcome. Eur J Cancer 45 (10): 1815-23, 2009. [PubMed: 19427780]
6. Kano H, Yang HC, Kondziolka D, et al.: Stereotactic radiosurgery for pediatric recurrent intracranial ependymomas. J Neurosurg Pediatr 6 (5): 417-23, 2010. [PubMed: 21039163]
7. Bouffet E, Hawkins CE, Ballourah W, et al.: Survival benefit for pediatric patients with recurrent ependymoma treated with reirradiation. Int J Radiat Oncol Biol Phys 83 (5): 1541-8, 2012. [PubMed: 22245198]
8. Desrousseaux J, Claude L, Chaltiel L, et al.: Respective Roles of Surgery, Chemotherapy, and Radiation Therapy for Recurrent Pediatric and Adolescent Ependymoma: A National Multicentric Study. Int J Radiat Oncol Biol Phys 117 (2): 404-415, 2023. [PubMed: 37437811]
9. Merchant TE, Boop FA, Kun LE, et al.: A retrospective study of surgery and reirradiation for recurrent ependymoma. Int J Radiat Oncol Biol Phys 71 (1): 87-97, 2008. [PubMed: 18406885]
10. Kano H, Niranjan A, Kondziolka D, et al.: Outcome predictors for intracranial ependymoma radiosurgery. Neurosurgery 64 (2): 279-87; discussion 287-8, 2009. [PubMed: 19190457]
11. Lin YY, Wu HM, Yang HC, et al.: Repeated gamma knife radiosurgery enables longer tumor control in cases of highly-recurrent intracranial ependymoma. J Neurooncol 148 (2): 363-372, 2020. [PubMed: 32405998]
12. Kano H, Su YH, Wu HM, et al.: Stereotactic Radiosurgery for Intracranial Ependymomas: An International Multicenter Study. Neurosurgery 84 (1): 227-234, 2019. [PubMed: 29608701]
13. Tsang DS, Burghen E, Klimo P, et al.: Outcomes After Reirradiation for Recurrent Pediatric Intracranial Ependymoma. Int J Radiat Oncol Biol Phys 100 (2): 507-515, 2018. [PubMed: 29229328]
14. Eaton BR, Chowdhry V, Weaver K, et al.: Use of proton therapy for re-irradiation in pediatric intracranial ependymoma. Radiother Oncol 116 (2): 301-8, 2015. [PubMed: 26243681]
15. Tsang DS, Murray L, Ramaswamy V, et al.: Craniospinal irradiation as part of re-irradiation for children with recurrent intracranial ependymoma. Neuro Oncol 21 (4): 547-557, 2019. [PMC free article: PMC6422429] [PubMed: 30452715]
16. Régnier E, Laprie A, Ducassou A, et al.: Re-irradiation of locally recurrent pediatric intracranial ependymoma: Experience of the French society of children's cancer. Radiother Oncol 132: 1-7, 2019. [PubMed: 30825956]
17. Bouffet E, Capra M, Bartels U: Salvage chemotherapy for metastatic and recurrent ependymoma of childhood. Childs Nerv Syst 25 (10): 1293-301, 2009. [PubMed: 19360417]
18. Jakacki RI, Foley MA, Horan J, et al.: Single-agent erlotinib versus oral etoposide in patients with recurrent or refractory pediatric ependymoma: a randomized open-label study. J Neurooncol 129 (1): 131-8, 2016. [PubMed: 27287856]

Purpose of This Summary

This PDQ cancer information summary for health professionals provides comprehensive, peer-reviewed, evidence-based information about the treatment of childhood ependymoma. It is intended as a resource to inform and assist clinicians in the care of their patients. It does not provide formal guidelines or recommendations for making health care decisions.

Reviewers and Updates

This summary is reviewed regularly and updated as necessary by the PDQ Pediatric Treatment Editorial Board, which is editorially independent of the National Cancer Institute (NCI). The summary reflects an independent review of the literature and does not represent a policy statement of NCI or the National Institutes of Health (NIH).

Board members review recently published articles each month to determine whether an article should:

• be discussed at a meeting,
• be cited with text, or
• replace or update an existing article that is already cited.

Changes to the summaries are made through a consensus process in which Board members evaluate the strength of the evidence in the published articles and determine how the article should be included in the summary.

The lead reviewers for Childhood Ependymoma Treatment are:

• Kenneth J. Cohen, MD, MBA (Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins Hospital)
• Louis S. Constine, MD (James P. Wilmot Cancer Center at University of Rochester Medical Center)
• Roger J. Packer, MD (Children's National Hospital)
• D. Williams Parsons, MD, PhD (Texas Children's Hospital)
• Malcolm A. Smith, MD, PhD (National Cancer Institute)

Any comments or questions about the summary content should be submitted to Cancer.gov through the NCI website's Email Us. Do not contact the individual Board Members with questions or comments about the summaries. Board members will not respond to individual inquiries.

Levels of Evidence

Some of the reference citations in this summary are accompanied by a level-of-evidence designation. These designations are intended to help readers assess the strength of the evidence supporting the use of specific interventions or approaches. The PDQ Pediatric Treatment Editorial Board uses a formal evidence ranking system in developing its level-of-evidence designations.

Permission to Use This Summary

PDQ is a registered trademark. Although the content of PDQ documents can be used freely as text, it cannot be identified as an NCI PDQ cancer information summary unless it is presented in its entirety and is regularly updated. However, an author would be permitted to write a sentence such as “NCI’s PDQ cancer information summary about breast cancer prevention states the risks succinctly: [include excerpt from the summary].”

The preferred citation for this PDQ summary is:

PDQ® Pediatric Treatment Editorial Board. PDQ Childhood Ependymoma Treatment. Bethesda, MD: National Cancer Institute. Updated <MM/DD/YYYY>. Available at: https://www.cancer.gov/types/brain/hp/child-ependymoma-treatment-pdq. Accessed <MM/DD/YYYY>. [PMID: 26389373]

Images in this summary are used with permission of the author(s), artist, and/or publisher for use within the PDQ summaries only. Permission to use images outside the context of PDQ information must be obtained from the owner(s) and cannot be granted by the National Cancer Institute. Information about using the illustrations in this summary, along with many other cancer-related images, is available in Visuals Online, a collection of over 2,000 scientific images.

Disclaimer

Based on the strength of the available evidence, treatment options may be described as either “standard” or “under clinical evaluation.” These classifications should not be used as a basis for insurance reimbursement determinations. More information on insurance coverage is available on Cancer.gov on the Managing Cancer Care page.

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