Ependymoma

Ependymomas are glial tumors that arise from ependymal cells within the central nervous system (CNS). They were first described by Bailey in 1924. Ependymomas can arise anywhere along the neuraxis. and their location varies by age. 90% of ependymomas in children are located intracranially, while 50-60% of adult ependymomas arise in the spine.[12, 13, 14]  They are a relatively rare subtype of CNS tumor, making up about 3% of all CNS tumors diagnosed in the United States.[15]

For all ependymomas, the 10-year relative survival rate is noted to be over 85%.[15]  This survival rate varies by location. Studies comparing survival rates between supratentorial and posterior fossaependymoma are mixed, but both generally confer a worse prognosis than spinal ependymoma.[12, 16, 17, 18]

Ependymomas are a heterogenous class of CNS tumor and encompass neoplasms that vary widely in their features. Molecular characterization of ependymomas has provided evidence that the classification may encompass tumors with very distinct biological profiles. Incorporating this insight, the 2021 WHO Guidelines subdivided the neoplasm into the types listed below.

Supratentorial ependymoma:

• ZFTA fusion-positive
• YAP1 fusion-positive
• Supratentorial ependymoma not otherwise specified (NOS)

Posterior fossa ependymoma:

• PF-A
• PF-B
• Posterior fossa ependymoma NOS

Spinal ependymoma:

• MYC-N amplified
• MYC-N nonamplified
• Myxopapillary ependymoma
• Spinal ependymoma NOS

Subependymoma:

• Supratentorial
• Posterior fossa
• Spinal

Each ependymoma anatomic category includes subtypes associated with molecular characteristics of the tumor. Each anatomic category also includes a catch-all category for tumors with histologic features suggestive of ependymoma, but without any of hallmark molecular features.

Myxopapillary ependymomas are considered a biologically and morphologically distinct variant of ependymoma, occurring almost exclusively in the region of the cauda equina. The most recent WHO guidelines elevated myxopapillary tumors from grade 1 to grade 2 in light of new evidence suggesting that these tumors recur at a higher rate than previously believed.[19, 20]

Subependymomas are uncommon, benign lesions that are characterized by slow growth and can arise in any compartment of the CNS. They are considered separately from other ependymoma types and are stratified by location.  

Ependymoblastomas are now considered a primitive neuroectodermal tumor (PNET) and are distinct from ependymoma.

See the image below.

Gross surgical specimen of a fourth ventricle ependymoma.

Supratentorial ependymomas present in the cerebral hemispheres or within ventricles and are more commonly found in children than adults.

Posterior fossa ependymomas are the most common type of ependymoma overall (though rare in adults,) and are often found in close proximity to cranial nerves and other vital structures, complicating their management.

Spinal ependymomas are most commonly found in adults and are typically considered to have a benign prognosis. They often present as intramedullary masses and can impinge upon nerve roots arising from the terminal spinal cord.

Ependymomas are traditionally thought to arise from oncogenetic events that transform normal ependymal cells into tumor phenotypes. Some evidence now suggests that radial glia may be the cells of origin.[21, 22]  Significant progress has been made toward delineating mutations that segregate with various tumor phenotypes.  While ependymomas exhibit molecular alterations that vary by subtype, some common molecular characteristics include: a loss of loci on chromosome 22, a mutation of p53 in malignant ependymoma,[23]  a recurring breakpoint at band 11q13,[24]  abnormal karyotypes with frequent involvement of chromosome 6 and/or 16,[25]  and NF2 mutations. 

Clustering of ependymomas has been reported in some families, with segregation analysis in one family suggesting the presence of an ependymoma tumor suppressor gene in the region of the chromosome 22 locus loss (22pter-22q11.2).[26, 27, 28, 29, 30, 31]

The pathophysiology of ependymoma varies based on the location and molecular characteristics of the tumor. 

Supratentorial Ependymomas 

ZFTA-Fusion positive: characterized by gene fusion that interferes with inflammatory pathways, carries a poor prognosis

Yap1-fusion positive: represents the minority of supratentorial ependymomas, characterized by a gene fusion more commonly observed in younger patients and is thought to carry a favorable prognosis.[32]

Posterior Fossa Ependymomas

PF-A: The most common and aggressive subgroup, these occur in young children and appear to lack recurrent somatic mutations.

PF-B: – These tumors tend to present in older children and adolescents. They display frequent large-scale copy number gains and losses but have favorable clinical outcomes.

Spinal Ependymomas

MYCN-amplified: Contains an amplified oncogene that drives rapid proliferation; aggressive subtype with higher likelihood for dissemination and worse prognosis than other spinal subtypes.[33]

Myxopapillary ependymoma: relatively slow-growing tumor with favorable prognosis, but recur at a rate similar to other spinal tumors[20] ; the vast majority arise in the conus medullaris and cauda equina; primarily occur in young adults.[34]

Ependymomas have no known environmental cause. A number of genetic mutations have been associated with ependymomas, but a causal relationship between these mutations and tumor progression has not yet been determined. A population based study in Denmark observed that germline mutations in NF1 and NF2 were associated with the development of childhood ependymoma, but fewer than 4% of observed ependymomas were associated with germline mutations.[35]

Ependymomas are a relatively uncommon form of CNS neoplasm, representing about 3% of CNS tumors diagnosed in the United States overall. However, ependymomas comprise approximately 17% of all spinal tumors.[15]

Some studies have noted a slightly increased incidence of ependymoma in males vs. females. Ependymoma incidence is higher in white people than in other races.[15]

Epidemiological characteristics vary by ependymoma subtype. Intracranial ependymomas, particularly posterior fossa ependymomas, generally present in young children with a median age at diagnosis of 2.5 years.[36]  In one large retrospective population study, 66% of spinal tumors occurred in adults over the age of 45, and 39% of all intracranial tumors occurred in children under the age of 12.[37]

The most recent 10-year relative survival rate for ependymoma is 86.7%.[15]  This figure varies by age, with patients diagnosed with ependymoma under the age of 14% having a 10 year relative survival of 72%. However, reported 10 year event free survival rates for intracranial pediatric cases are around 60%.[16, 38]   These overall rates may therefore reflect differences in prognoses between ependymoma subtypes, which also vary in incidence with age. Supratentorial and posterior fossa ependymomas, which are more common in children, carry a worse prognosis than spinal cord ependymomas, which are more common in adults.

Comparisons between the relative survival rates of supratentorial and infratentorial ependymomas are mixed. Some studies indicate that supratentorial ependymomas are associated with worse mortality than posterior fossa ependymomas in adults, but that these two subtypes have comparable mortality rates in children.[18]  Other studies indicate that pediatric patients with posterior fossa ependymomas had improved overall survival compared to supratentorial ependymomas.81 These conclusions are complicated by the fact that ependymomas are rare overall and that posterior fossa ependymomas are more common than supratentorial ependymomas in pediatric patients.[18]

Predictors of long-term survival include extent of resection made at surgery and amount of residual tumor on postoperative imaging.[39]  A number of studies[40, 41, 42, 43, 44, 45, 46, 47]  support the suggestion that the extent of resection is the most important predictor of outcome, independent of the histologic grade of the tumor. Patients with totally resected tumors, primarily of the posterior fossa, had an overall 5-year, progression-free survival rate of nearly 70% compared with 30-40% for those patients with partially resected tumors.

Molecular characteristics of ependymomas have also been proposed as relevant prognostic factors. Ependymomas of the posterior fossa can be further classified into PF-A and PF-B based on their DNA methylome profile. With respect to overall survival at 10 years, patients with PF-A ependymomas have a relatively poor prognosis compared to PF-B (18% vs 51%.)[48]  Chromosome 1q gains and 6q deletions are other molecular characteristics that have been associated with worse outcomes within PF-A class ependymomas.[49]

Recurrent tumors are also suggestive of a poor prognosis. One meta analysis of recurrent pediatric ependymomas noted an overall survival of 11 months following recurrence.[50]

The clinical history associated with ependymomas varies depending upon the age of the patient and the location of the lesion. The duration of symptoms prior to diagnosis usually varies from 1-36 months; most patients have symptoms from 3-6 months. In one retrospective study of adult ependymoma patients, the most common presenting symptom of both intracranial and spinal ependymoma was pain. Changes in personality, mood, and concentration can be early indicators or may be the only abnormalities observed. Seizures are a presenting symptom in 20% of patients, and focal neurologic deficits may also be prominent.

Because they produce few specific symptoms, ependymomas cannot be diagnosed based on history alone. Clinical suspicion for a brain or spinal neoplasm should be confirmed with neuroimaging.  

Supratentorial Ependymoma

Supratentorial ependymomas may be associated with increased intracranial pressure that manifests as headache, nausea, vomiting, and cognitive impairment. Headaches can vary in intensity and quality and are frequently more severe in the early morning or upon first awakening. In children who present prior to closure of cranial sutures, enlarging head circumference secondary to obstructive hydrocephalus also may be part of the clinical history.

Posterior Fossa Ependymoma

Children or adults with masses in the fourth ventricle may have a history of progressive lethargy, headache, nausea, and vomiting secondary to increased intracranial pressure from obstructive hydrocephalus. As the tumor extends along the floor of the fourth ventricle, it may cause multiple cranial-nerve palsies (primarily VI-X), as well as cerebellar dysfunction.

Spinal Ependymoma

Spinal ependymomas are usually associated with a history of progressive neurologic deficit related to involvement of ascending or descending nerve tracts, exiting peripheral nerves, and pain that correlates with the level of the lesion.

Myxopapillary ependymoma, which primarily affects terminal areas of the spine, primarily presents with low back pain, but can present with bowel or bladder symptoms in around 30% of patients64. They can also be associated with cauda equina syndrome, which can present with lower limb dysfunction, saddle anesthesia, and/or bladder/bowel dysfunction.

Subependymoma

Subependymomas are typically asymptomatic and are often identified incidentally on neuroimaging, but symptoms may resemble those above depending on location. Given their prevalence in the fourth ventricle, they may present with symptoms of increased intracranial pressure.  

In patients with supratentorial ependymomas, neurologic symptoms and signs can be either general or focal, and they reflect the location of the tumor. Patients can present with cranial nerve symptoms. Hemiparesis, sensory loss, visual loss, aphasia, and cognitive impairment are common

Findings in patients with posterior fossa ependymomas including the following:

• Hydrocephalus secondary to obstruction is a common complication.
• General symptoms of increased intracranial pressure (headache, nausea, papilledema) are also common.
• At diagnosis, common symptoms include papilledema, ataxia, and nystagmus.

Patients with spinal ependymomas are more likely to present with sensory changes than with weakness. Signs and symptoms will vary by level of the tumor, as follows:

• Cervical levels: Weakness or motor dysfunction in upper limbs
• Thoracic levels: Sensory symptoms, such as loss of cutaneous sensation below level of the lesion; motor symptoms may not be evident 
• Lumbar levels: Radicular pain, weakness/motor dysfunction in the lower limbs

Myxopapillary ependymomas typically arise in the conus medullaris and cauda equina and therefore can lead to saddle anesthesia, bladder dysfunction, or impotence

Patients with subependymomas are most often asymptomatic. However, patients with intraventricular tumors can present with some symptoms of hydrocephalus.

Complications resulting from ependymoma vary by location and typically arise secondary to tumor mass effect. Nonspecific complications that can occur in any location of tumor include hemorrhage, infection, and worsening of neurologic deficit.

Children who undergo resection of a posterior fossa lesion are at risk for postoperative cerebellar mutism. Intracranial complications can include seizures. 

Although computed tomography (CT) is often the first imaging study performed in patients with possible central nervous system lesions, contrast-enhanced magnetic resonance imaging (MRI) of the brain or spine is the gold standard imaging study for ependymoma. CT lacks the resolution of MRI, especially in the posterior fossa, but can be used in patients who cannot have an MRI.[3]

Gross total resection, if feasible, is indicated to confirm the histologic diagnosis and to initiate treatment. Patients in whom gross total resection is not feasible should undergo biopsy (stereotactic or open) or subtotal resection.[3]

The most recent WHO 2021 Classification of CNS Tumors emphasizes the use of DNA methylation profiling to further determine the ependymal tumor subtype. By revealing epigenetic modifications in gene expression, methylation profiling can often serve as the first step in distinguishing molecular subtypes of ependymoma that arise in the same anatomical location. Building evidence suggests that subtypes defined by differences in their methylation profile may represent distinct disease processes and characteristics.[3, 51]  While these molecular subtypes often have similar treatment approaches, classification into subtypes can help provide patients with the most specific information regarding the prognosis of their disease and may guide subsequent planning.

For example, methylation profiling is required to further classify posterior fossa ependymomas into groups A and B. Although immunohistochemistry can also provide insight into this distinction, it is a less specific approach. Furthermore, in spinal ependymomas, methylation profiling can provide key insight in the distinction between myxopapillary ependymomas, subependymomas, and MYC-N amplified spinal ependymomas. MYC-N ependymomas are more lethal than other spinal ependymoma subtypes and potentially warrant a more aggressive surgical approach to resection.[32]

Other laboratory tests, such as genetic testing, can also have utility. For example, in spinal ependymomas, other genetic testing approaches can identify mutations in NF2 and a loss in chromosome 22q, each of which represent more dangerous subtypes. The 2021 WHO guidelines recommend identifying the status ZFTA and YAP1 mutations within a supratentorial ependymoma. Laboratory studies that can aid in screens such as these include:

• Interphase Fluorescence In-Situ Hybridization (FISH): Detects chromosomal abnormalities through fluorescent DNA probes ^[52]
• Reverse Transcription Polymerase Chain Reaction (RT-PCR): Can measure gene expression by quantifying the amount of mRNA corresponding to a specific gene of interest
• Next Generation Sequencing: High coverage, high sensitivity, and high-throughput method to sequence genes and detect low-frequency variants
• Molecular inversion profiling (ZFTA only): Can identify specific biomarkers through the use of ssDNA probes to hybridize to a specific sequence of interest (corresponding to a gene) ^[53]

Ependymomas have some characteristic features on CT scan and MRI that help narrow the differential diagnosis. Whenever possible, patients in whom an ependymoma is suspected should undergo MRI with and without administration of intravenous contrast.[54]

For complete discussion, see Imaging in Brain Ependymoma and Imaging in Spine Ependymoma.

Supratentorial Ependymoma

On precontrast and postcontrast MRI, supratentorial ependymomas often appear heterogeneous secondary to necrosis, hemorrhage, and calcification. Variable signal intensity is noted on T1- and T2-weighted images, although intracranial ependymomas are usually hypointense to isointense on T1-weighted images and hyperintense compared with gray matter, on T2-weighted images.

MRI images of an ependymoma in the left ventricle. Courtesy of figshare.com [El Majdoub, Faycal; Elawady, Moataz; Blau, Tobias; Bührle, Christian; Hoevels, Mauritius; Runge, Matthias; et al. (2016): Intracranial Ependymoma: Long-Term Results in a Series of 21 Patients Treated with Stereotactic 125Iodine Brachytherapy. PLOS ONE. Dataset. Available at: https://figshare.com/articles/dataset/Intracranial_Ependymoma_Long_Term_Results_in_a_Series_of_21_Patients_Treated_with_Stereotactic_125_Iodine_Brachytherapy__/117659].

T1 and T2 MRI images of an ependymoma in the left ventricle

Posterior Fossa Ependymoma

The radiographic features of posterior fossa ependymomas resemble that of supratentorial ependymomas. They can be identified based on their tendency to invade inferiorly through the foramen of Magendie and impinge the cervical spinal cord.[55]  

T1-weighted MRI without contrast demonstrating ependymoma located in the fourth ventricle.

T2-weighted MRI demonstrating ependymoma in the fourth ventricle.

Coronal T1-weighted MRI with contrast demonstrating ependymoma of the fourth ventricle.

Spinal Ependymoma

Most intramedullary tumors are isointense or slightly hypointense to the surrounding spinal cord on T1-weighted images. Often, only subtle spinal cord enlargement is evident. T2-weighted images are more sensitive because most tumors are hyperintense to the spinal cord on these pulse sequences. T2 studies are not particularly specific and may not distinguish the solid tumor from polar cysts. Nearly all intramedullary neoplasms enhance on T1-weighted contrast examinations.

Ependymomas usually demonstrate uniform contrast enhancement and are located symmetrically within the spinal cord. Polar cysts are identified in the majority of cases, particularly in the setting of cervical or cervicothoracic tumors. Heterogeneous enhancement from intratumoral cysts or necrosis can also be observed.

In some cases, contrast enhancement of a cystic ependymoma may be minimal. In these cases, distinguishing these tumors from intramedullary astrocytomas is difficult.

MRI image of the sagittal neck with an ependymoma. Modification of a figure from nl-wiki, without author annotations. Courtesy of Wikimedia Commons [Author Lucien Monfils, available at: https://commons.wikimedia.org/wiki/File:Ependymoma.png].

Lumbar puncture (LP) may be performed to aid in the differential diagnosis. However, LP is generally contraindicated in the setting of a posterior fossa tumor because of the risk of herniation. Cerebrospinal fluid (CSF) studies do not aid significantly in the diagnosis of ependymomas, with the possible exception of determining leptomeningeal spread in children with posterior fossa tumors. Dissemination of the tumor through the CSF is observed in fewer than 10% of patients at diagnosis. The incidence is higher with infratentorial ependymomas than with supratentorial tumors (9% vs 1.6%).

Yet even in the case of leptomeningeal spread, spinal MRI performed with and without contrast enhancement is preferable for such a determination. In patients with spinal ependymoma, CSF obtained from LP may show elevated protein levels.

As histopathological features of ependymoma tend to be present across multiple subtypes that differ in their clinical and molecular characteristics, histopathological classification of ependymoma has been deemphasized in the 2021 WHO guidelines. The presence of characteristic histologic features may have utility in supporting a diagnosis of ependymoma. Ependymomas that have characteristic histology, but do not have any of the canonical molecular features defined in the WHO guidelines, can be classified into a general category of ependymoma that is further stratified by compartment.

The characteristic histologic finding in ependymoma is perivascular pseudorosettes with glial fibrillary acidic protein (GFAP)–positive processes tapering toward blood vessels. Other histologic variants (epithelial, tanycytic (fibrillar), subependymoma, myxopapillary) also occur and were previously used to guide staging of ependymoma. Histologic differentiation of ependymoma from astrocytoma may be difficult, but the presence of perivascular pseudorosettes or true rosettes establishes the diagnosis.

See the images below.

Histologic study of a classic ependymoma. Note the characteristic perivascular pseudorosettes.

Gross surgical specimen of a fourth ventricle ependymoma.

A variety of histologic ependymoma subtypes may be encountered. The cellular ependymoma is the most common, but epithelial, tanycytic (fibrillar), subependymoma, myxopapillary, or mixed examples also occur. Histologic differentiation from astrocytoma may be difficult. Most spinal ependymomas are histologically benign, although necrosis and intratumoral hemorrhage are frequent. Although unencapsulated, these glial-derived tumors are usually well circumscribed and do not infiltrate adjacent spinal cord tissue.

Attempts to correlate the expression of MIB-1 antigen with malignancy of ependymomas have been confounded by tumor heterogeneity. Myxopapillary ependymoma histology consists of a papillary arrangement of cuboidal or columnar tumor cells surrounding a vascularized core of hyalinized and poorly cellular connective tissue.

Cellular ependymoma. Cells with a high nuclear-cytoplasmic ratio. Few pseudorosettes or paucicellular areas are present.

Myxopapillary ependymoma. Clusters of loosely arranged cuboidal cells separated by pools of mucin.

Clear cell ependymoma. Round cells with cytoplasmic clearing. This may mimic an oligodendroglioma.

No conventional staging criteria exist for intracranial or spinal ependymomas. Postoperative MRI is recommended within 48 hours of tumor resection to assess presence of residual tumor and to facilitate adjuvant treatment planning. In the case of children with ependymomas of the fourth ventricle, a surveillance spinal MRI is often recommended to rule out seeding.

Electroencephalography (EEG) performed on a patient with a supratentorial ependymoma may show generalized, diffuse slowing and/or epileptogenic spikes over the area of the tumor. However, no findings on EEG are specific for ependymoma.

The extent of tumor resection is the most important prognostic factor associated with long-term survival for patients with nonmalignant forms of ependymoma, regardless of location. Thus, a gross total resection (GTR) is optimal. The feasibility and extent of the resection will vary with the location of the tumor and the clinical characteristics of the patient.

Resection is typically followed by histologic analysis and molecular testing to classify the tumor and guide prognostic estimates. Depending on the type of tumor, adjuvant treatment with radiation may be indicated. Currently, there are no ependymoma-specific molecular therapies, but this is an area of active research.  

Due to the risk of ependymoma recurrence, MRI surveillance typically follows treatment.

Though surgical treatment is the primary treatment for ependymoma, medical management also plays a role. General medical management may include steroids for treatment of peritumoral edema and anticonvulsants.[4]  In the case of incomplete tumor resection or recurrence, radiation is central to medical management.[56] Chemotherapy has shown potential in some prospective studies to delay radiotherapy in young children with intracranial ependymoma following resection but is not a mainstay of treatment.[57]  

Supratentorial Ependymoma

Following incomplete resection, adjuvant conformal radiation treatment is the mainstay of medical treatment for supratentorial ependymoma for patients over the age of 18 months.[58]  Because it spares many normal tissues and reduces the integral dose, proton therapy (PT) may be preferred to treat childhood cancer, however a systematic review of clinical outcome studies on PT published between 2007 and 2015 found insufficient evidence to either support or refute PT for treatment of ependymoma in children.[54]  

Posterior Fossa Ependymoma

Resection of ependymomas located in the posterior fossa can be limited by the presence of nearby cranial nerves and other vital structures. Subtotal resection can be associated with increased rates of local recurrence, but adjuvant radiation therapy may be useful in limiting this effect, and the current standard of care for posterior fossa ependymomas includes conformal radiation therapy.[59]  Adjuvant radiation therapy has been shown to be significantly associated with progression free and overall survival in posterior fossa ependymoma, but this effect may be isolated to the PF-A subtype. Some studies have proposed that PF-B subtype ependymomas can be treated with surgery alone, but this has yet to be studied in trials.[60]

Spinal Ependymoma

Adjuvant radiation therapy for spinal ependymoma varies based on the grade and recurrence status of the tumor. Adjuvant radiation therapy is not required if the spinal ependymoma if there is no evidence of metastasis and the grade of the tumor is WHO grade 2 or less. All grade 3 spinal ependymomas receive radiation therapy.[3]  For patients who have postoperative residual tumor or early recurrence, radiation is considered on the basis of the individual patient's medical condition and neurological status.[61, 62]

Though no treatments targeting molecular subtypes of ependymoma are currently recommended, this is an area of active research. The relevance of molecular subtypes to the clinical characteristics of ependymomas is potentially suggestive of therapeutic targets related to these mutations.[13]

Regardless of subtype or molecular characteristics, the primary treatment modality for ependymoma is surgical resection. Across subtypes, extent of resection is one of the strongest predictors of overall survival. Other treatment modalities are usually only considered in cases where residual tumor is present following resection or when gross total resection is not feasible. Second look surgery is also considered in such cases. 

Postoperative imaging is recommended to determine the extent of surgical resection. If not performed preoperatively, complete evaluations by consulting physicians, including a neurooncologist and radiation oncologist, should be considered.

Supratentorial Ependymoma

The surgical approach to supratentorial lesions varies by location of the tumor, but the consistent goal is to achieve maximal resection. 

Hydrocephalus can be managed with a perioperative external ventricular drain, ventriculoperitoneal shunt, or, more rarely, third ventriculostomy. A reasonable algorithm of management affords the opportunity to assess the need for permanent CSF diversion after tumor resection. This can be accomplished by clamping the external ventricular drain postoperatively and monitoring intracranial pressure and/or clinical signs.

Posterior Fossa Ependymoma

Children with posterior fossa lesions usually undergo surgery via a midline suboccipital approach. Despite the survival advantage of GTR, lesions of the posterior fossa are in close proximity to cranial nerves. This makes aggressive GTR risky and fraught with the possibility of long-term neurologic dysfunction and disability. Posterior fossa syndrome, also referred to as cerebellar mutism, is a recognized complication of posterior fossa surgery and most common when brainstem invasion is observed.[63, 64]  Mutism can have a latency range of 1-7 days and duration of 6-365 days. Thus, consideration must be given to the balance between improved survival with GTR and potential postoperative morbidity.

The management of hydrocephalus in posterior fossa ependymoma resembles management in supratentorial ependymoma as described above.

Spinal Ependymoma

Intramedullary tumors are approached via standard laminectomy with the patient in the prone position. The strategies for intramedullary tumor removal depend upon the relationship of the tumor to the spinal cord. Most ependymomas are intramedullary and are not apparent upon inspection of the surface. Intraoperative ultrasound may be used to localize the tumor and to determine the rostrocaudal tumor borders.

Resection in the caudal spinal cord involves some further considerations. The role of surgery for filum terminale ependymoma depends on the size of the tumor and its relationship to the surrounding roots of the cauda equina. Gross total en bloc resection should be attempted whenever possible. This usually can be accomplished for small and moderate-sized tumors, which remain well circumscribed within the fibrous coverings of the filum terminale and easily separable from the cauda equina nerve roots. Recurrences following successful en bloc resection are rare. 

A team of specialists including a neurologist, neurosurgeon, neurooncologist, and radiation oncologist should evaluate patients with ependymomas to develop a coordinated treatment strategy. At some institutions, transferring the patient to another facility may be necessary if the proper consultations cannot be obtained. In most cases, surgical resection can be performed on an urgent, but not emergent, basis.

Postoperative consultations should include physical therapy and rehabilitative medicine representatives to facilitate recovery.

No restrictions of diet are required for patients with ependymomas.

No universal restrictions on activity are required for patients with ependymomas. Patients' activity depends on their overall neurological status.

In the case of patients with supratentorial ependymomas, a history of seizures may preclude operation of motor vehicles.

Long-term monitoring of ependymoma patients with periodic brain/spine MRI is recommended following gross total resection. Current NCCN recommendations specify tumor site MRI once every 3-4 months during the first year following resection, then every 4-6 months during the second year, and every 6-12 months for 5-10 years. 

Surveillance is motivated by the risk of recurrent disease, which carries a poor prognosis. Most recurrences are local, but distant recurrences have also been reported. The rate of recurrence varies by ependymoma subtype. Following recurrence, repeat resection is recommended if possible. Depending on the extent of this resection, either system or craniospinal radiation therapy is recommended.

Spinal ependymoma recurrence is less common than in intracranial cases, but still of concern, especially in cases of subtotal resection.

Supratentorial Ependymoma

Some retrospective studies have reported recurrence rates of over 50% in intracranial ependymoma following gross total resection and radiation treatment, most of which recurred locally.[65, 66]

Posterior Fossa Ependymoma

Studies have suggested that recurrence rate in posterior fossa ependymoma varies significantly by subtype: PF-A ependymomas recurred in over 50% of patients, while no recurrences were observed in patients with PF-B tumors.[67]  

Spinal Ependymoma

Spinal ependymoma recurs less frequently than other types of ependymoma, but recurrence is still associated with worse survival and post-surgical surveillance is recommended.[3]

The National Comprehensive Cancer Network (NCCN) recommends the following for treatment of adults with ependymoma[3] :

• Following suspicion for ependymoma on neuroimaging, maximal safe resection should be performed
• Following diagnosis of grade 2 or grade 3 ependymoma after resection/biopsy, conduct brain and spine MRI, plus LP to assess for leptomeningeal spread (LP contraindicated with posterior fossa masses) 
• If post-resection neuroimaging is negative for metastasis, administer standard conformal radiation therapy  (to tumor area plus 1-2cm margins). If metastasis detected, administer whole craniospinal radiation therapy (or proton therapy to reduce toxicity.) Spinal ependymomas < WHO Grade 2 do not require radiation therapy if gross total resection was performed and neuroimaging/LP are negative.
• MRI surveillance for recurrence following resection for 5-10 years
• For recurrent ependymoma, patients who have not received radiation therapy should receive radiation therapy, and if a patient has received radiation therapy, then chemotherapy, radiation therapy, or supportive care should be considered.

The European Association of Neuro-oncology (EANO) recommends a similar treatment approach to the NCCN, advocating for maximal safe resection followed by post operative radiation and monitoring for recurrence. However, the EANO recommends adjuvant chemotherapy (exact regimen varies) instead of radiation in patients less than 12 months old to avoid harmful side effects of radiotherapy. On the contrary, in the NCCN guidelines, chemotherapy is not recommended as a monotherapy and is only considered in recurrent cases where resection and radiation have failed.[68]

No specific medications exist to treat ependymomas. Conventional chemotherapeutic agents that have shown efficacy in other CNS neoplasms, such as temozolomide, have shown some promise in treating patients with recurrent ependymoma, but are not routinely recommended.[69]

However, there are a number of active clinical trials that are exploring the use of a variety of drug classes for their efficacy in ependymoma, particularly in pediatric patients with recurrent disease. Immunotherapies, tyrosine kinase inhibitors, and angiogenesis inhibitors have shown promising results in preclinical experiments, but have not demonstrated benefit in any clinical trials to date.[13]    

 While medications are not a central part of curative treatment for ependymoma, they play a role in managing associated symptoms. For seizure control in supratentorial ependymomas, patients are usually started on levetiracetam (Keppra), phenytoin (Dilantin), or carbamazepine (Tegretol). Levetiracetam is often used because it lacks the effects on the P450 system seen with phenytoin and carbamazepine, which can interfere with antineoplastic therapy. Vasogenic cerebral edema is treated with corticosteroids (eg, dexamethasone), generally in combination with an anti-ulcer agent. Corticosteroids also are effective to treat edema associated with intramedullary tumors in the preoperative and postoperative settings.

Class Summary

These agents are used to treat and to prevent seizures.

Levetiracetam (Keppra)

Used as adjunct therapy for partial seizures and myoclonic seizures. Also indicated for primary generalized tonic-clonic seizures. Mechanism of action is unknown.

Phenytoin (Dilantin)

Blocks sodium channels and prevents repetitive firing of action potentials. Effective anticonvulsant and first-line agent in treating partial and generalized tonic-clonic seizures.

Carbamazepine (Tegretol)

Like phenytoin, interacts with sodium channels and blocks repetitive neuronal firing. First-line agent to treat partial seizures and may be used for tonic-clonic seizures as well. Extended release form available, which is administered bid. Serum drug levels should be monitored (ideal range is 4-8 mcg/mL).

Class Summary

These agents reduce peritumoral edema, frequently leading to symptomatic and objective improvement.

Dexamethasone (Decadron)

Postulated mechanisms of action in brain tumors include reduction in vascular permeability, cytotoxic effects on tumors, inhibition of tumor formation, and decreased CSF production.