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Primary brain tumors, including ependymomas, are a diverse group of diseases that together constitute the most common solid tumor of childhood. Immunohistochemical analysis, cytogenetic and molecular genetic findings, and measures of mitotic activity are increasingly used in tumor diagnosis and classification. Brain tumors are classified according to histology, but tumor location, extent of spread, molecular features, and age are important factors that affect treatment and prognosis.
Ependymomas arise from ependymal cells that line the ventricles and passageways in the brain and the center of the spinal cord. Ependymal cells produce cerebrospinal fluid (CSF). These tumors are classified as supratentorial, infratentorial, or spinal. In children, most ependymomas are infratentorial tumors that arise in or around the fourth ventricle and, less commonly, in the supratentorial space. Spinal ependymomas are rare in childhood. According to the 2016 revision to the World Health Organization (WHO) classification of tumors of the central nervous system, ependymal tumors are classified into the following five main subtypes:
The location of the tumor determines the clinical presentation. Treatment begins with surgery. The type of adjuvant therapy given, such as a second surgery, chemotherapy, or radiation therapy, depends on the following:
The PDQ childhood brain tumor treatment summaries are organized primarily according to the WHO classification of nervous system tumors. For a full description of the classification of nervous system tumors and a link to the corresponding treatment summary for each type of brain tumor, refer to the PDQ summary on Childhood Brain and Spinal Cord Tumors Treatment Overview.
Childhood ependymoma comprises approximately 9% of all childhood brain and spinal cord tumors, representing about 200 cases per year in the United States.[2,3]
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.
Molecular characterization studies have identified nine molecular subgroups of ependymoma, six of which predominate in childhood, on the basis of their distinctive DNA methylation and gene expression profiles and on their distinctive spectrum of genomic alterations (refer to Figure 2).[4,5,6,7]
Subependymoma—whether supratentorial, infratentorial, or spinal—accounts for the other 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.
Posterior fossa A ependymoma (PF-EPN-A)
The most common posterior fossa ependymoma subgroup is PF-EPN-A and is characterized by the following:
A study that included over 600 cases of PF-EPN-A used methylation array profiling to divide this population into two distinctive subgroups, PFA-1 and PFA-2. Gene expression profiling suggested that these two subtypes may arise in different anatomic locations in the hindbrain. Within both of the PFA-1 and PFA-2 groups, distinctive minor subtypes could be identified, suggesting the presence of heterogeneity. Additional study will be required to define the clinical significance of these subtypes.
Posterior fossa B ependymoma (PF-EPN-B)
The PF-EPN-B subgroup is less common than the PF-EPN-A subgroup, representing 15% to 20% of all posterior fossa ependymomas in children, and is characterized by the following:
The largest subset of pediatric supratentorial ependymomas is characterized by gene fusions involving RELA (ST-EPN-RELA),[14,15] a transcriptional factor important in NF-κB pathway activity. ST-EPN-RELA is characterized by the following:
A second, less common subset of supratentorial ependymomas has fusions involving YAP1 on chromosome 11 (ST-EPN-YAP1) and are characterized by the following:
Supratentorial ependymomas without RELA or YAP1 fusions (on chromosome 11) are an undefined entity, and it is unclear what these samples represent. By DNA methylation analysis, these samples often cluster with other entities such as high-grade gliomas and embryonal tumors, and caution should be taken when diagnosing a supratentorial ependymoma that does not harbor a fusion involving chromosome 11.[16,17]
The clinical presentation of ependymoma is dependent on tumor location.
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.
Unfavorable factors affecting outcome (except as noted) include the following:
Posterior fossa ependymomas are divided into the following two groups on the basis of distinctive patterns of gene expression.[4,5,8,20]
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.
Supratentorial tumors can be divided into subtypes on the basis of their gene fusion status:
Follow-up After Treatment
Surveillance neuroimaging, coupled with clinical assessments, are generally recommended after treatment for ependymoma. The frequency and duration have been arbitrarily determined and the utility is uncertain. Most practitioners obtain MRI imaging of the brain and/or spinal cord every 3 to 4 months for the first 2 to 3 years after treatment. After 3 years, imaging every 6 months for the next 2 years is often undertaken and frequently yearly thereafter. After 5 years of follow-up treatment, yearly MRIs are typically recommended because of the high incidence of late recurrences and evidence showing better outcomes if relapsed ependymomas are identified on surveillance MRI (5-year OS, 37%) compared with cases identified because of the development of symptoms (5-year OS, 8%).[Level of evidence: 2A]
For the first time, the 2016 World Health Organization (WHO) Classification of Tumors of the Central Nervous System (CNS) incorporated the addition of genotypic findings in the classification of select CNS tumors. This integrated classification is intended to define more homogeneous entities that will improve the accuracy of diagnoses, refine prognoses, and more reliably reach conclusions regarding treatment strategies.
Ependymal tumors are now classified into the following five main subtypes:
The true incidence of subependymomas (WHO grade I) is difficult to determine. These tumors are frequently asymptomatic and may be found incidentally at autopsy. Subependymomas probably comprise less than 5% of all ependymal tumors. A diagnosis of subependymoma in a child is questionable and further review or molecular analysis should be considered.
Subependymomas and myxopapillary ependymomas are usually considered to be clinically and pathologically distinct from the grade II and grade III ependymomas.
Although supratentorial and infratentorial ependymomas are believed to arise from radial glia cells, they have different genomics, genomic landscapes, gene expression, and immunohistochemical signatures.[5,6,7,8] Supratentorial tumors are more often characterized by neuronal differentiation. It is clear that supratentorial and infratentorial ependymomas should be considered as separate biological entities.[5,8,9,10,11]
Ependymoblastoma is no longer recognized in the WHO classification and is now classified as an embryonal tumor with multilayered rosettes (refer to the PDQ summary on Childhood Medulloblastoma and Other Central Nervous System Embryonal Tumors Treatment for more information).
Although there is no formal staging system, ependymomas can be divided into supratentorial, infratentorial, and spinal tumors. Approximately 20% of childhood ependymomas arise in the spine and 80% arise in the brain (30% in the supratentorial region and 70% in the infratentorial region). Ependymomas usually originate in the ependymal linings of ventricles or central canal or ventriculus terminalis of the spinal cord and have access to the cerebrospinal fluid. Therefore, these tumors may spread throughout the neuraxis, although dissemination is noted in less than 10% of patients with grade II and grade III ependymomas. Considering the rarity of disseminated disease in posterior fossa and supratentorial ependymoma, it is crucial that imaging of the neuraxis be performed presurgically; alternatively, spinal imaging should be repeated before initiating radiation therapy to re-evaluate whether metastatic disease is present (as opposed to postoperative blood/vascular congestion).
Myxopapillary ependymomas may disseminate to the nervous system early in the course of illness,[2,3] and imaging of the brain is recommended.
Many of the improvements in survival in patients with childhood cancer have been made as a result of clinical trials that have attempted to improve on the best available, accepted therapy. Clinical trials in pediatrics are designed to compare new therapy with therapy that is currently accepted as standard. This comparison may be done in a randomized study of two treatment arms or by evaluating a single new treatment and comparing the results with those previously obtained with existing therapy.
Because of the relative rarity of cancer in children, all patients with aggressive brain tumors should be considered for entry into a clinical trial. To determine and implement optimum treatment, treatment planning by a multidisciplinary team of cancer specialists who have experience treating childhood brain tumors is required. Radiation therapy of pediatric brain tumors is technically demanding and should be performed in centers that have experience in that area to ensure optimal results.
Table 1 describes the standard treatment options for newly diagnosed and recurrent childhood ependymoma.
Dramatic improvements in survival have been achieved for children and adolescents with cancer. Between 1975 and 2010, childhood cancer mortality decreased by more than 50%. Childhood and adolescent cancer survivors require close monitoring because cancer therapy side effects may persist or develop months or years after treatment. (Refer to the PDQ summary Late Effects of Treatment for Childhood Cancer for specific information about the incidence, type, and monitoring of late effects in childhood and adolescent cancer survivors.)
Myxopapillary ependymomas, considered to be a histologic subtype of ependymoma, have a relatively high incidence of central nervous system tumor dissemination at diagnosis and at follow-up. Imaging of the complete craniospinal axis at the time of diagnosis and during follow-up is indicated.[1,2]
Standard treatment options for newly diagnosed childhood myxopapillary ependymoma (World Health Organization [WHO] grade I) include the following:
Historically, the management of myxopapillary ependymoma (WHO grade I) consisted of an attempt at en bloc resection of the tumor with no further treatment in the case of a gross-total resection.; [Level of evidence: 3iiiDi] However, based on the finding that dissemination of these tumors to other parts of the neuraxis can occur, particularly when complete resection is not obtained, and evidence that focal radiation therapy may improve progression-free survival, many practitioners now favor the use of radiation therapy after surgical resection of the primary mass.[1,3]; [Level of evidence: 3iiiDi]; [6,7][Level of evidence: 3iiiDiii]
Standard treatment options for newly diagnosed childhood ependymoma (World Health Organization [WHO] grade II), anaplastic ependymoma (WHO grade III), or RELA fusion–positive ependymoma (WHO grade II or grade III) include the following:
Typically, all patients undergo surgery to remove the tumor. Whether additional treatment is given depends on the extent of tumor resection and whether there is disseminated disease.
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.[1,2,3,4,5]; [6,7][Level of evidence: 3iDii] Magnetic resonance imaging (MRI) is performed postoperatively to confirm the extent of resection. If not performed preoperatively, MRI of the entire neuraxis to evaluate disease dissemination and cerebrospinal fluid cytopathology is performed.
Patients across all molecular subgroups who have residual tumor or disseminated disease should be considered at high risk of relapse and may be treated on protocols specifically designed for them. Patients with no evidence of residual tumor still have an approximate 20% to 40% relapse risk despite postoperative radiation therapy.[Level of Evidence: 2Di]
Anecdotal experience suggests that surgery alone for completely resected supratentorial nonanaplastic tumors and intradural spinal cord ependymomas may, in select cases, be an appropriate approach to treatment.[9,10][Level of evidence: 3iiiDi]; [11,12,13][Level of evidence: 3iiiDiii]
In a prospective multi-institutional cooperative group trial (Children's Oncology Group [COG] ACNS0121 [NCT00027846]) for patients with newly diagnosed intracranial ependymomas (N = 356), surgery alone was used for the treatment of supratentorial, nonanaplastic, gross-totally resected ependymomas (n = 11), which resulted in a 5-year event-free survival (EFS) of 61.4% and an overall survival (OS) of 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 and only a subset of these patients successfully avoided additional treatment.[Level of evidence: 2Di and 2A]
Retrospective analysis of the outcome for patients with posterior fossa ependymoma suggests that these patients might be sufficiently treated with gross-total resection alone, but this approach has not been tested in a prospective, randomized clinical trial.
Treatment options for no residual disease, no disseminated disease
The standard postsurgical treatment for these patients has been radiation therapy consisting of 54 Gy to 59.4 Gy to the tumor bed for children aged 3 years and older.[5,14] The ACNS0121 (NCT00027846) study extended the use of radiation therapy (54 Gy) to patients as young as 1 year, resulting in similar EFS and OS rates when compared with children older than 3 years.[Level of Evidence: 2Di] It is not necessary to treat the entire CNS (whole brain and spine) because these tumors usually recur initially at the local site, although posterior fossa ependymomas may disseminate at recurrence, particularly in tumors with 1q gain.; [Level of evidence: 3iiiA] When possible, patients should be treated in a center experienced with the delivery of highly conformal radiation therapy (including intensity-modulated radiation therapy or charged-particle radiation therapy [e.g., proton radiation therapy]) to pediatric patients with brain tumors.
Evidence (radiation therapy):
Concerns of brain stem toxicity in very young children (aged <3 years) after proton therapy to the posterior fossa have prompted the use of more conservative doses in these children at some centers.[18,20,21]
There is no evidence that adjuvant chemotherapy, including the use of myeloablative chemotherapy, improves the outcome for patients with totally resected, nondisseminated ependymoma. For this reason, current treatment approaches do not include chemotherapy as a standard component of primary therapy for children with newly diagnosed ependymomas that are completely resected.
Treatment options for residual disease, no disseminated disease
Second-look surgery should be considered because patients who have complete resections followed by irradiation have better disease control. In some cases, further surgery can be undertaken after the initial attempted resection if the pediatric neurosurgeon believes that a gross-total resection could be obtained by an alternate surgical approach to the tumor. In other cases, further up-front surgery is not anticipated to result in a gross-total resection, therefore, adjuvant therapy is initiated with future consideration of second-look surgery.
The rationale for radiation therapy, as described in the Treatment options for no residual disease, no disseminated disease subsection above, also pertains to the treatment of children with residual, nondisseminated ependymoma. In patients with a subtotal resection, treatment with radiation therapy results in a 5-year PFS rate of 25% and is particularly poor in PF-EPN-A subgroups, although the outcome for patients with residual tumor within the spinal canal may be better.
The rationale for using chemotherapy in patients with residual tumor is to attempt to achieve a state of no evidence of disease before undergoing radiation therapy, either by achieving a complete response (CR) to chemotherapy alone or by facilitating the likelihood of a gross-total resection at the time of second-look surgery after chemotherapy. The benefit of chemotherapy for residual tumor after up-front surgery is still being investigated.
There is no evidence that high-dose chemotherapy with stem cell rescue is of any benefit.; [Level of evidence: 2A]
Treatment options for CNS disseminated disease
Regardless of the degree of surgical resection, these patients generally receive radiation therapy to the whole brain and spine, along with boosts to local disease and bulk areas of disseminated disease. The traditional local postsurgical radiation doses in these patients have been 54 Gy to 55.8 Gy. Doses of approximately 36 Gy to the entire neuraxis (i.e., the whole brain and spine) are also administered but may be modulated depending on the age of the patient. Boosts between 41.4 Gy and 50.4 Gy to bulk areas of spinal disease are administered, with doses depending on the age of the patient and the location of the tumor. However, there are no contemporary studies published to support this approach.
The role of chemotherapy in the management of children with disseminated ependymoma is unproven.
Treatment options for children younger than 1 year
Some, but not all, chemotherapy regimens induce objective responses in children younger than 3 years with newly diagnosed ependymoma.[31,32,33,34] The goal of chemotherapy is to avoid radiation, defer radiation until the child is older, or achieve a state of no evidence of disease before undergoing radiation therapy (either by a CR to chemotherapy or by a gross-total resection at time of second-look surgery after chemotherapy). Up to 25% of infants and young children with totally resected disease may achieve long-term survival. These studies have not been molecularly characterized and it is unclear which patients may benefit from chemotherapy-only regimens. Survivors of chemotherapy-only protocols may eventually receive salvage radiation therapy.; [Level of evidence: 2Di]
Deferred radiation therapy
Historically, postoperative radiation therapy was omitted for children younger than 3 years with ependymoma. The previous two COG studies and many recent trials have lowered the age limit for postoperative radiation therapy to age 1 year in an effort to improve outcomes for these younger children. The first of these two studies (ACNS0121 [NCT00027846]) has shown that conformal radiation in children with completely resected tumors resulted in significantly improved outcomes compared with patients who received chemotherapy alone.[Level of evidence: 2Di]
It is unclear which patients can benefit from radiation-sparing approaches; however, comparison of results of the POG-9233 trial with the results of the ACNS0121 (NCT00027846) trial suggests a 50% to 60% improvement in survival for patients who were treated with radiation therapy.[8,35] A prospective evaluation of molecular markers may identify the infants who can be safely treated with radiation-sparing approaches and/or patients who may benefit from chemotherapy.
Conformal radiation approaches, including 3-dimensional conformal radiation therapy that minimizes damage to normal brain tissue and charged-particle radiation therapy, such as proton-beam therapy, are under evaluation for infants and children with ependymoma.[17,40] When analyzing neurologic outcomes after treatment of young children with ependymoma, it is important to consider that not all long-term deficits can be ascribed to radiation therapy because deficits may be present in young children before therapy begins. For example, the presence of hydrocephalus at diagnosis is associated with a lower intelligence quotient, as measured after surgical resection and before administration of radiation therapy.
Treatment Options Under Clinical Evaluation for Newly Diagnosed Childhood Ependymoma or Anaplastic 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, refer to the ClinicalTrials.gov website.
Current Clinical Trials
Use our advanced clinical trial search to find NCI-supported cancer clinical trials that are now enrolling patients. The search can be narrowed by location of the trial, type of treatment, name of the drug, and other criteria. General information about clinical trials is also available.
Recurrence is not uncommon for all grades of ependymoma and may develop many years after initial treatment. Late recurrence beyond 10 to 15 years has been reported. Disease generally recurs at the primary tumor site, although concomitant neuraxis dissemination may also be seen. Systemic relapse is extremely rare. At time of relapse, a complete evaluation for extent of recurrence is indicated for all patients.
Treatment options for recurrent childhood ependymoma include the following:
The utility of further surgical intervention is individualized, based on the extent and location of the tumor.
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:[Level of evidence: 3iiiB]
Regardless of treatment strategy, the prognosis for patients with recurrence is poor. 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, refer to the ClinicalTrials.gov website.
The following is an example of a national and/or institutional clinical trial that is currently being conducted:
Tumor tissue from progressive or recurrent disease must be available for molecular characterization. Patients with tumors that have molecular variants addressed by treatment arms included in the trial will be offered treatment on Pediatric MATCH. Additional information can be obtained on the NCI website and ClinicalTrials.gov website.
The PDQ cancer information summaries are reviewed regularly and updated as new information becomes available. This section describes the latest changes made to this summary as of the date above.
This summary was comprehensively reviewed.
This summary is written and maintained by the PDQ Pediatric Treatment Editorial Board, which is editorially independent of NCI. The summary reflects an independent review of the literature and does not represent a policy statement of NCI or NIH. More information about summary policies and the role of the PDQ Editorial Boards in maintaining the PDQ summaries can be found on the About This PDQ Summary and PDQ® - NCI's Comprehensive Cancer Database pages.
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 who care for cancer 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:
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:
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Levels of Evidence
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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]
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Last Revised: 2019-09-09
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