Ependymoma 

Updated: Jul 21, 2021
Author: Jeffrey N Bruce, MD; Chief Editor: Herbert H Engelhard, III, MD, PhD, FACS, FAANS 

Overview

Practice Essentials

Ependymomas are glial tumors that arise from ependymal cells within the central nervous system (see the image below). These tumors tend to be intracranial in children and spinal in adults.[1]

CT scan without contrast. Fourth ventricle ependym CT scan without contrast. Fourth ventricle ependymoma.

The World Health Organization (WHO) divides ependymomas into the following types[2] :

  • Subependymoma (WHO Grade I)
  • Myxopapillary ependymoma (WHO Grade I)
  • Ependymoma (with papillary, clear cell, and tanycytic variants; WHO Grade II)
  • RELA fusion–positive ependymoma (WHO Grade II or Grade III with change in the RELA gene)
  • Anaplastic ependymoma (WHO Grade III)

Signs and symptoms

The clinical history associated with ependymomas varies according to the age of the patient and the location of the lesion. Reported symptoms may include the following:

  • Masses in the fourth ventricle: Progressive lethargy, headache, nausea, and vomiting; multiple cranial-nerve palsies (primarily VI-X), as well as cerebellar dysfunction
  • In children who present before closure of cranial sutures, enlarging head circumference secondary to obstructive hydrocephalus
  • Supratentorial ependymomas: Increased intracranial pressure manifested as headache, nausea, vomiting, and cognitive impairment
  • Changes in personality, mood, and concentration; seizures; focal neurologic deficits
  • Spinal ependymomas: Progressive neurologic deficit

Physical findings with intracranial ependymomas may include the following:

  • General or focal neurologic signs reflecting the location of the tumor
  • Infratentorial ependymomas: Papilledema ataxia; nystagmus
  • Supratentorial ependymomas: Hemiparesis, sensory loss, visual loss, aphasia, and cognitive impairment

Physical findings with cervical or thoracic ependymomas may include the following:

  • Spinal tumors in the upper cervical cord: Occipital or cervical pain or paresthesia, neck stiffness, and weakness and wasting of neck muscles
  • Spastic tetraplegia or hemiplegia and weakness ventrolaterally below the lesion
  • Altered cutaneous sensation below the lesion
  • Characteristic findings associated with specific cervical and upper thoracic levels (eg, C4, C5, C6, C7, C8, T1)

Physical findings with thoracic ependymomas may include the following:

  • These tumors are localized more by the sensory (as opposed to motor) examination
  • Localizing upper thoracic lesions by testing intercostal muscle strength is difficult
  • Beevor sign localizes lesions below T10
  • Abdominal skin reflexes usually are absent below the lesion

Physical findings with lumbar ependymomas may include the following:

  • These lesions are localized from the root level of sensory loss and motor weakness
  • Nerve root compression: Radicular pain and weakness
  • Lesions compressing only the first and second lumbar segments: Lost cremasteric reflexes, preserved abdominal reflexes, and increased knee and ankle jerks
  • Lesions affecting the third and fourth lumbar segments: If the roots of the cauda equina are not affected, weakness of the quadriceps, loss of the patellar reflexes, and hyperactive Achilles reflexes may be present; if they are affected, flaccid paralysis of the legs and loss of knee and ankle reflexes may occur
  • Lesions affecting spinal cord and cauda equina concurrently: Spastic paralysis of one leg with increased ankle reflexes ipsilaterally may occur, as well as flaccid paralysis with loss of reflexes contralaterally

Physical findings with myxopapillary ependymomas of the conus and cauda equina may include the following:

  • Presenting symptom is pain in the back, rectal area, or both lower legs
  • Spontaneous pain is rare with conus lesions but prominent with cauda equina lesions
  • Motor dysfunction is symmetric for conus lesions and asymmetric for cauda equina lesions
  • Autonomic dysfunction is typically an early sign with conus lesions but a late finding with cauda equina lesions

See Clinical Presentation for more detail.

Diagnosis

No laboratory studies are helpful in making the diagnosis of ependymoma. On CT and MRI, e pendymomas have some characteristic features that help narrow the differential diagnosis, including the following:

  • Intracranial ependymoma: Typically isodense on unenhanced CT, with minimal to moderate enhancement on contrast administration; on precontrast and postcontrast MRI, usually hypointense to isointense on T1-weighted images and hyperintense (compared with gray matter) on T2-weighted images
  • Spinal ependymoma: Most intramedullary tumors are isointense or slightly hypointense to the surrounding spinal cord on T1-weighted images; most tumors are hyperintense to the spinal cord on T2-weighted images

Other diagnostic modalities that may be helpful include the following:

See Workup for more detail.

Management

Treatment of patients with ependymomas depends upon neurosurgical intervention to facilitate definitive diagnosis and to decrease tumor burden. Postoperative adjuvant therapy can include brain or spine radiation, chemotherapy, and radiosurgery.[3, 4, 5, 6]  Medical management of ependymomas includes the following[7, 8] :

  • Adjuvant therapy (ie, conventional radiation therapy, radiosurgery, chemotherapy)
  • Steroids for treatment of peritumoral edema
  • Anticonvulsants in patients with supratentorial ependymoma

The National Comprehensive Cancer Network (NCCN) suggests the following for adults[9] :

  • After gross total resection (GTR) of an intracranial WHO grade II ependymoma, limited field fractionated external beam radiotherapy (LFFEBRT) can be considered
  • Postoperative LFFEBRT is recommended for WHO grade II ependymoma when subtotal resection is noted on postoperative MRI and for grade III anaplastic ependymoma regardless of extent of resection [10] ; if postoperative spinal MRI or LP findings are positive, craniospinal radiation therapy is indicated regardless of grade or extent of resection
  • For recurrent ependymoma, if a patient has not received radiation therapy, such therapy should be administered; if a patient has received radiation therapy, then chemotherapy, radiation therapy, or supportive care should be considered [9]

In terms of surgical care, a GTR is optimal. Approaches include the following:

  • Children with posterior fossa lesions: Midline suboccipital approach; hydrocephalus can be managed with a perioperative external ventricular drain, ventriculoperitoneal shunt, or, more rarely, third ventriculostomy
  • Intramedullary tumors: Standard laminectomy with the patient prone; laminoplasty is performed in children but does not guarantee long-term stability
  • Filum terminale ependymoma: Gross total en bloc resection whenever possible

See Treatment and Medication for more detail.

Background

Ependymomas are glial tumors that arise from ependymal cells within the central nervous system (CNS). They were first described by Bailey in 1924. The World Health Organization (WHO) classification scheme for these tumors includes 4 divisions based on histologic appearance: WHO grade I, myxopapillary ependymoma and subependymoma; WHO grade II, ependymoma (with cellular, papillary, and clear cell variants); WHO grade III, anaplastic ependymoma.

Myxopapillary ependymomas are considered a biologically and morphologically distinct variant of ependymoma, occurring almost exclusively in the region of the cauda equina and behaving in a more benign fashion than grade II ependymoma. Subependymomas are uncommon lesions that share the benign features of myxopapillary ependymomas. 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 epen Gross surgical specimen of a fourth ventricle ependymoma.

Intracranial ependymomas present as intraventricular masses with frequent extension into the subarachnoid space,[11] while spinal ependymomas present as intramedullary masses arising from the central canal or exophytic masses at the conus and cauda equina.

The anatomic distinction between intracranial and spinal locations has an epidemiologic and clinical correlate. In children, approximately 90% of ependymomas are intracranial, with the majority of these usually arising from the roof of the fourth ventricle (infratentorial). In adults and adolescents, 75% of ependymomas arise within the spinal canal, with a significant minority occurring intracranially in the supratentorial compartment.[12]

Pathophysiology

Ependymomas are traditionally thought to arise from oncogenetic events that transform normal ependymal cells into tumor phenotypes. Significant progress has been made toward delineating mutations that segregate with various tumor phenotypes. Some evidence now suggests that radial glia may be the cells of origin.[13, 14]

In 1988, Dal Chin and colleagues described cytogenetic studies on a supratentorial ependymoma from a 3-year-old girl that showed a t(10;11;15)(p12.2;q13.1;p12) and loss of one X chromosome.[15] This relatively simple karyotypic change was not observed in the analysis of 4 ependymomas published 1 year later. In 1 of the 4 ependymomas studied, translocations involving chromosomes 9, 17, and 22 were observed together with loss of the normal chromosome 17. A second ependymoma had many chromosomal alterations that included a translocation between chromosomes 1 and 2 and rearrangements involving chromosome 17. Consistent genetic alterations were not detected in the remaining 2 cases.

These initial studies underscore the molecular heterogeneity that can exist among histologically identical tumors. Subsequent studies have identified more consistent genetic defects as follows: a loss of loci on chromosome 22, a mutation of p53 in malignant ependymoma,[16] a recurring breakpoint at band 11q13,[17] abnormal karyotypes with frequent involvement of chromosome 6 and/or 16,[18] 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).[19, 20, 21, 22, 23, 24]

Intracranial ependymomas can be classified on the basis of anatomical location (supratentorial region or posterior fossa) and according to molecular subgroups, which reflect differences in the age of onset, gender predominance, and response to therapy. The grouping is as follows[25] :

  • Posterior fossa ependymoma group A (PF-EPN-A) – The most common and aggressive subgroup; these occur in young children and appear to lack recurrent somatic mutations.
  • Posterior fossa ependymoma group B (PF-EPN-B) – These tumors display frequent large-scale copy number gains and losses but have favorable clinical outcomes.
  • Posterior fossa ependymoma group subependymoma (PF-EPN-SE) – This subgroup is comprised of rare grade I subependymomas occurring almost exclusively in adults. [26]   
  • Supratentorial ependymomas  – More than 70% of these are defined by highly recurrent gene fusions in the NF-κB subunit gene RELA (ST-EPN-RELA); a smaller number involve fusion of the gene encoding the transcriptional activator YAP1 (ST-EPN-YAP1)

Spinal cord ependymomas are classified into three subgroups as follows[27] :

  • Spinal cord (classic) ependymoma group (SP-EPN) –  These are generally grade II tumors; neurofibromatosis type 2 (NF2) is frequently mutated with a high frequency of 22q homozygous loss. These tumors have a more indolent clinical course and a generally favorable prognosis. [28]   A minority of aggressive SP-EPN grade III tumors characterized by  MYCN amplification, an absence of  NF2 alterations or other recurrent pathogenic mutations, and a unique methylation classifier profile have been identified. [29]   
  • Spinal cord myxopapiliary ependymoma group (SP-MPE) – These tumors are generally grade 1 tumors occurring primarily in adults.
  • Spinal cord subependymoma ependymoma group (SP-SE) – These are very rare low grade tumors 

Etiology

Ependymomas have no known environmental cause. As noted in Pathophysiology, a number of genetic mutations have been associated with ependymomas. However, a causal relationship between these mutations and tumor progression has not yet been determined.

Intramedullary ependymomas have been associated with neurofibromatosis type I.

Epidemiology

Worldwide, intracranial ependymomas represent 6-9% of primary CNS neoplasms and account for 30% of primary CNS neoplasms in children younger than 3 years.[30]

In the United States, grade II and III ependymoma are more common in blacks than in whites.[31]

The incidence of ependymoma is approximately equal in males and females.

Ependymomas generally present in young children with a mean age of diagnosis of 4 years, yet 25-40% of patients are younger than 2 years. Spinal ependymomas are most common in patients aged 15-40 years, most of which are of a myxopapillary subtype. Intracranial tumors are seen more often in children, particularly in the infratentorial compartment.

Prognosis

Predictors of long-term survival include extent of resection made at surgery and amount of residual tumor on postoperative imaging.[32]  Although lower WHO tumor grade, infratentorial location in children, absence of tumor invasion within the brainstem, absence of metastases,[33]  improved performance status, and older age (for childhood ependymoma) have been associated with a survival advantage in isolated, retrospective series,[34]  these factors are not significantly correlated with long-term survival.[35, 36]

Children who undergo resection of a posterior fossa lesion are at risk for postoperative cerebellar mutism. Nonspecific complications that can occur in any location of tumor include hemorrhage, infection, and worsening of neurological deficit.

In general, brain tumor resection has an overall mortality rate of 1-2%; 40% of patients remain healthy or have minimal deficits after surgery, 30% manifest no postoperative change relative to preoperative deficits, and 25% of patients sustain increased postoperative deficits that most often improve.

A number of studies [37, 38, 33, 39, 40, 41, 42, 43]  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.

Depending on the patient population, the reported 10-year overall survival rate for ependymoma can vary from 45-55%. The current 5-year survival rate for patients with intracranial ependymomas is approximately 50%, when rates from children and adults are combined.[44]  Stratification based on age reveals 5-year survival rates of 76% in adults and 14% in children.

 

 

Presentation

History

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. 

Children 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.

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.

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.

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.

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.

Physical Examination

Intracranial ependymoma findings are as follows:

  • Neurologic symptoms and signs affecting patients with intracranial ependymoma can be either general or focal, and they reflect the location of the tumor.

  • At the time of diagnosis, the most common signs of infratentorial ependymomas include papilledema and ataxia. Nystagmus is present in 40-50% of patients at the time of diagnosis.

  • Supratentorial lesions often present as hemiparesis, sensory loss, visual loss, aphasia, and cognitive impairment.

Cervical/thoracic ependymoma findings are as follows:

  • Patients with spinal tumors in the upper segments of the cervical cord can present with pain or paresthesia in the occipital or cervical region, stiffness of the neck, and weakness and wasting of neck muscles.

  • Below the lesion, a spastic tetraplegia or hemiplegia and weakness of the ventrolateral region may occur.

  • Cutaneous sensation may be affected below the lesion with concurrent involvement of the descending trigeminal nucleus.

  • When considering radicular symptoms associated with cervical tumors, note that nerve roots in the cervical region exit above the pedicle of the like-numbered vertebra. Anatomically, the cervical nerve root exits in close relation to the undersurface of the pedicle through the neural foramen.

Characteristic findings associated with various cervical and upper thoracic levels are outlined as follows:

  • C4 (paralysis of the diaphragm)

  • C5 (atrophic paralysis of the deltoid, biceps, supinator longus, rhomboid, and spinate muscles): The upper arms hang limp at the side. The sensory level extends to the outer surface of the arm. The biceps and supinator reflexes are lost.

  • C6 (paralysis of triceps and wrist extensors): The forearm is held semiflexed, and a partial wrist drop is present. The triceps reflex is lost. Sensory impairment extends to a line running down the middle of the arm slightly to the radial side.

  • C7 (paralysis of the flexors of the wrist and of the flexors and extensors of the fingers): Efforts to close the hands result in extension of the wrist and slight flexion of the fingers (ie, preacher's hand). The sensory level is similar to that of the sixth cervical segment but slightly more to the ulnar side of the arm.

  • C8 (atrophic paralysis of the small muscles of the hand with resulting clawhand [main-en-griffe]): Horner syndrome, unilateral or bilateral, results from lesions at this level and is characterized by the triad of ptosis, small pupil (ie, miosis), and loss of sweating on the face. Sensory loss extends to the inner aspect of the arm and involves the fourth and fifth fingers and the ulnar aspect of the middle finger.

  • T1: Lesions rarely cause motor symptoms because this nerve root provides little functional innervation of the small hand muscles. Other signs of cervical tumors include nystagmus, especially with tumors in the upper segment. This condition is presumably caused by damage to the descending portion of the median longitudinal fasciculus. Horner syndrome may be found with intramedullary lesions in any portion of the cervical cord if the descending sympathetic pathways are affected.

Thoracic ependymoma findings are as follows:

  • Unlike the cervical or lumbar region of the cord, where motor dysfunction is easily discernible, tumors in the thoracic region are localized more by the sensory examination.

  • Determining the location of lesions in the upper half of the thoracic cord by testing the strength of intercostal muscles is difficult.

  • The Beevor sign, in which the umbilicus moves upward when the supine patient attempts to flex the head on the chest against resistance, can be used to localize lesions below T10.

  • Abdominal skin reflexes usually are absent below the lesion.

Lumbar ependymoma findings are as follows:

  • The location of a lumbar lesion can be deduced easily from the patient's root level of sensory loss and associated motor weakness.

  • Radicular pain and weakness are associated with nerve root compression. In the lumbar region, the nerve root exits below and in close proximity to the pedicle of its like-numbered vertebra with the intervertebral disc space situated well below the pedicle.

  • Tumors that compress only the first and second lumbar segments cause loss of the cremasteric reflexes. The abdominal reflexes are preserved, while knee and ankle jerks are increased.

  • If the tumor affects the third and fourth segments of the lumbar cord and does not involve the roots of the cauda equina, weakness of the quadriceps, loss of the patellar reflexes, and hyperactive Achilles reflexes occur. More commonly, lesions at this level also involve the cauda equina with resulting flaccid paralysis of the legs as well as loss of knee and ankle reflexes.

  • If the spinal cord and cauda equina are affected concurrently, spastic paralysis of one leg with increased ankle reflexes ipsilaterally and flaccid paralysis with loss of reflexes contralaterally may occur.

Myxopapillary ependymoma of the conus and cauda equina

The presenting symptom of tumors that involve the conus or cauda equina is pain in the back, rectal area, or both lower legs, often leading to a misdiagnosis of sciatica. Although the two regions are related anatomically, the following clinical features can serve to distinguish lesions of the conus from those of the cauda equine:

  • Spontaneous pain is rarely associated with conus lesions, whereas it is usually the most prominent symptom in patients who have cauda equina lesions

  • The pain of a cauda equina lesion is severe and radicular in nature, involving the perineum, thighs, and legs, often asymmetrically, whereas the pain of a conus lesion is usually bilateral and symmetric

  • Symmetric saddle anesthesia and dissociation mark the sensory deficit of a conus lesion secondary to the compromise of crossing fibers; patients with sensory deficits attributable to cauda equina lesions do not have dissociation and often present with unilateral or asymmetric findings

  • Motor dysfunction is symmetric for conus lesions and asymmetric for cauda equina lesions

  • Autonomic dysfunction, such as bladder dysfunction and impotence, is typically an early sign in patients with conus medullaris lesions, whereas it is a late finding in patients with cauda equina lesions

Patients with spinal tumors in the conus and cauda equina can have a combination of symptoms. As the tumor grows, flaccid paralysis of the legs, atrophy of the leg muscles, and foot drop may occur. Fasciculations may be observed in the atrophied muscles. Sensory loss may affect the perianal or saddle area as well as the remaining sacral and lumbar dermatomes. This loss may be slight, or it may be so severe that a trophic ulcer develops over the lumbosacral region, buttocks, hips, or heels. Signs of raised intracranial pressure may be observed with ependymomas of this region if the cerebrospinal fluid (CSF) protein content is high.

 

DDx

Diagnostic Considerations

With intracranial (posterior fossa) ependymoma, the differential diagnosis includes the following:

With intracranial (supratentorial) ependymoma, the differential diagnosis includes the following:

With spinal (intramedullary) ependymoma, the differential diagnosis includes the following:

Other diagnostic considerations include the following:

Differential Diagnoses

 

Workup

Approach Considerations

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 should be used in patients who cannot have an MRI.[9] No laboratory studies are helpful in making the diagnosis of ependymoma.

Gross total resection, if feasible, is indicated to confirm the histologic diagnosis and initiates treatment. Patients in whom gross total resection is not feasible should undergo biopsy (stereotactic or open) or subtotal resection.[9]

Imaging Studies

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.[45]

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

Intracranial ependymoma

Intracranial ependymomas are typically isodense on unenhanced CT scans with minimal to moderate enhancement upon contrast administration. Calcification can be noted on unenhanced CT scans in approximately one half of cases. Cyst formation is common in these tumors, and foraminal spread can be observed in posterior fossa lesions through the foramina of Luschka and Magendie.

On precontrast and postcontrast MRI, tumors 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. See the images below.

CT scan without contrast. Fourth ventricle ependym CT scan without contrast. Fourth ventricle ependymoma.
CT scan without contrast. Fourth ventricle ependym CT scan without contrast. Fourth ventricle ependymoma. Note blood in the fourth ventricle.
CT scan without contrast in the patient with fourt CT scan without contrast in the patient with fourth ventricle ependymoma. Blood has refluxed into the third and lateral ventricles.
CT scan without contrast in the patient with fourt CT scan without contrast in the patient with fourth ventricle ependymoma. Note blood traversing foramina.
T1-weighted MRI. Rare case of a fourth ventricle e T1-weighted MRI. Rare case of a fourth ventricle ependymoma presenting as an intraventricular bleed.
T1-weighted MRI without contrast demonstrating epe T1-weighted MRI without contrast demonstrating ependymoma located in the fourth ventricle.
T2-weighted MRI demonstrating ependymoma in the fo T2-weighted MRI demonstrating ependymoma in the fourth ventricle.
Coronal T1-weighted MRI with contrast demonstratin 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.

Procedures

Lumbar puncture (LP) is generally contraindicated in the setting of a brain tumor because of the risk of transtentorial herniation secondary to increased intracranial pressure. 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 when ependymoblastomas are excluded. 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 patiens with spinal ependymoma, CSF obtained from LP may show elevated protein levels.

Histologic Findings

Ependymoma (WHO grade II) pathology includes papillary,clear cell, and tanycytic variants, as well as anaplastic ependymomas (WHO grade III), myxopapillary ependymomas (WHO grade I), and subependymomas (WHO grade I) (see the images below). Histologically, ependymomas are characterized by ependymal pseudorosettes with glial fibrillary acidic protein (GFAP)–positive processes tapering toward blood vessels. Myxopapillary ependymomas are located at the cauda equina and conus, while subependymoma and anaplastic ependymomas are described at intramedullary locations. See the images below.

Gross surgical specimen of a fourth ventricle epen Gross surgical specimen of a fourth ventricle ependymoma.
Histologic study of a classic ependymoma. Note the Histologic study of a classic ependymoma. Note the characteristic perivascular pseudorosettes.
Cellular ependymoma. Cells with a high nuclear-cyt Cellular ependymoma. Cells with a high nuclear-cytoplasmic ratio. Few pseudorosettes or paucicellular areas are present.
Myxopapillary ependymoma. Clusters of loosely arra Myxopapillary ependymoma. Clusters of loosely arranged cuboidal cells separated by pools of mucin.
Clear cell ependymoma. Round cells with cytoplasmi Clear cell ependymoma. Round cells with cytoplasmic clearing. This may mimic an oligodendroglioma.

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, but the presence of perivascular pseudorosettes or true rosettes establishes the diagnosis. 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.

Staging

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

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.

 

Treatment

Medical Care

Medical management of patients with ependymomas includes adjuvant therapy (ie, conventional radiation therapy, radiosurgery, chemotherapy), steroids for treatment of peritumoral edema, and anticonvulsants in patients with supratentorial ependymoma.[7, 8]

Adjuvant treatment of histologically confirmed intracranial ependymoma remains an actively debated topic.

The National Comprehensive Cancer Network (NCCN) suggests the following for adults: After a gross total resection of an intracranial WHO grade II ependymoma, limited field fractionated external beam radiotherapy (LFFEBRT) can be considered versus observation. Postoperative LFFEBRT is recommended for WHO grade II ependymoma when subtotal resection is noted on postoperative MRI, and for grade III anaplastic ependymoma regardless of the extent of resection.[10] If postoperative spinal MRI or LP findings are positive, craniospinal radiation therapy is indicated regardless of grade or extent of resection.

For recurrent ependymoma, the NCCN suggests radiation therapy for patients who have not previously received it. If the patient has received radiation therapy, then chemotherapy, radiation therapy, or supportive care should be considered.[9]

For children younger than 3 years, the use of chemotherapy has historically been fostered by the desire to avoid adverse radiation effects. Combination chemotherapy regimens comprising cisplatin, etoposide, carboplatin, vincristine, and mechlorethamine; or ifosfamide, carboplatin, and etoposide (ICE), have been administered with variable success.

In older children and adults, radiotherapy is the standard treatment following resection for most patients with WHO grade II ependymoma. While surgery alone has been piloted for a very select group of patients (those with supratentorial tumors who undergo gross total resection with a wide resection margin), most tumors of the posterior fossa cannot be fully resected and are likely to recur without postoperative radiation.[46, 47]

Because it spares many normal tissues and reduces the integral dose, proton therapy (PT) is the preferred tumor irradiation technique for treating 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.[48]

Early attempts at defining appropriate treatment paradigms for intracranial ependymoma have depended heavily upon single-institution retrospective reviews.

In 1990, Goldwein and colleagues reviewed 36 children (aged 0.8-16.8 y) with recurrent intracranial ependymoma who were treated for a total of 52 separate relapses from 1970-1989.[49]  They concluded that some patients with histologically benign ependymoma at first relapse could benefit from aggressive therapy, with occasional long-term, progression-free survival possible. In contrast, patients with malignant lesions or patients who relapsed a second time were less likely to benefit from conventional therapy.

In their study, initial therapy for relapse consisted of surgery in 33 cases and chemotherapy in 38 cases. Twelve patients received radiation at the time of first relapse, and 5 of these 12 who initially had been treated with surgery and chemotherapy alone were irradiated to full dose.

The 2-year actuarial survival and progression-free survival rates were 29% and 23%, respectively. The 2-year survival rate after treatment of first relapse was 39%. Of the 52, 44 subsequent relapses (and 1 septic death) occurred, 3 of which occurred in the 5 patients treated with definitive radiation. Twenty-seven relapses occurred exclusively with local disease. Eight patients had relapse outside of as well as in the primary site. Survival rate was better for patients who had histologically benign lesions at relapse (53% vs 9%, P< 0.02), and for patients in the first versus subsequent relapse (P< 0.005). Cisplatin and VP-16 appeared to be the most active chemotherapeutic agents.

In 1992, Chiu and colleagues evaluated the clinical courses of 25 children aged 2 weeks to 15 years treated for intracranial ependymoma at M. D. Anderson Cancer Center.[35]

Nine patients had supratentorial primaries (5 high grade, 4 low grade), and 16 patients had infratentorial primaries (9 high grade, 7 low grade). Five patients underwent gross complete resection, and 20 patients had incomplete resection. Seven patients received craniospinal irradiation (25-36 Gy to the neuro-axis, 45-55 Gy to tumor bed), and 12 received local field irradiation (29-60 Gy, median 50 Gy). Five infants had adjuvant chemotherapy without radiotherapy, 6 children had postradiotherapy adjuvant chemotherapy, and 12 patients had salvage chemotherapy with various agents and number of courses.

Eight patients were alive, disease free, and without relapse from 1-12.5 years after diagnosis (median 42 mo). The primary failure pattern was local recurrence.

The data presented in this study suggested that the long-term cure rate of children with ependymoma is suboptimal; histologic grade may be of prognostic importance for supratentorial tumors; prognosis appears worse for girls and infants younger than 3 years; in well-staged patients, routine spinal irradiation could be omitted; and the role of adjuvant chemotherapy is unclear.

In 1998, an extensive review and analysis of all published literature on the topic of intracranial ependymoma highlighted the difficulty associated with extrapolating data from single-institution studies.[11]  Forty-five series were reviewed, including more than 1400 children. The largest series reported on 92 patients, and the accrual rate ranged from 0.32-12 patients per year. Notably, the extent of surgical resection was the only reported prognostic factor in these series that was consistently found to be a valid predictor of outcome.

These findings were confirmed by a prospectively randomized trial published that same year evaluating Children's Cancer Group Protocol 921. Predictors of long-term survival included an estimate of the extent of resection made at surgery (total compared with less than total, P =0.0001) and the amount of residual tumor on postoperative imaging as verified by centralized radiologic review. Other factors, including centrally reviewed tumor histopathologic type, location, metastasis, and tumor (M and T) stages, patient age, race, sex, and chemotherapy treatment regimen were not found to be correlated significantly with long-term survival.

More recently, in 2000, Stafford and colleagues evaluated the efficacy of stereotactic radiosurgery (SRS) for locally recurrent ependymoma and found that this technique may allow a high salvage rate in selected patients. In 12 patients (with a total of 17 tumors) treated with SRS, a medial survival of 3.4 years was achieved. In-field local control was achieved in 14 of the 17 tumor sites, and the estimated 3-year local control rate was 68%. Two patients developed treatment-related complications following therapy.[50]

Currently, no role exists for adjuvant therapy of spinal ependymoma after complete surgical resection. 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.

However, Agbahiwe et al report that in pediatric myxopapillary ependymoma, which typically follows a more aggressive course, adjuvant radiotherapy resulted in better local control compared with surgery alone; these authors recommended that radiotherapy be considered after surgical resection in these children.[51] A case report by Fujiwara et al describes successful use of temozolomide for relapsed spinal myxopapillary ependymoma with multiple recurrence  and cerebrospinal dissemination despite surgery and radiotherapy.[52]

Conventional chemotherapy has yet to effect any improvement in outcome for ependymoma,[53, 54] and radiotherapy to the developing brain is to be avoided due to its substantial neurocognitive effects. Therefore, recent emphasis has been placed on molecular subclassification of these tumors. hTERT negativity is associated with a 5-year survival rate of 84% compared to 41% for hTERT positive tumors.[55] Several genes have been identified as having associations with risk of relapse, age of onset, and location of tumor.[56, 57] As more information regarding molecular signatures of ependymomas is gathered, more individualized therapies may be realized.[14, 25]

 

Surgical Care

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.

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 making 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.[58, 59] 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.

Hydrocephalus can be managed with a perioperative external ventricular drain, ventriculoperitoneal shunt, or, more rarely, third ventriculostomy. A reasonable algorithm of management affords the medical team 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.

Although the approach to supratentorial lesions varies according to location, the goal of gross total resection should be the same as in infratentorial surgery.

Intramedullary tumors are approached via standard laminectomy with the patient in the prone position. Considerations include the following:

  • Although somatosensory evoked potentials and direct motor evoked potentials are employed routinely, only rarely do they influence surgical decisions or technique.
  • Laminoplasty is performed in children but does not guarantee long-term stability.
  • The strategies for intramedullary tumor removal depend upon the relationship of the tumor to the spinal cord. Most tumors are totally 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.
  • The extent of tumor resection is guided by the anatomy of the lesion, intraoperative monitoring, the surgeon's experience, and the preliminary frozen-section histologic diagnosis.
  • The plane between an ependymoma and surrounding spinal cord is usually well defined and easily developed.
  • Large tumors may require internal decompression with an ultrasonic aspirator or laser.
  • A competent dural closure is essential to prevent CSF leaks.

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. Considerations include the following:

  • 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.
  • A portion of uninvolved filum terminale is generally present between the tumor and spinal cord.
  • Amputation of the afferent and efferent filum segments is required for tumor removal.
  • Internal decompression is not used for small and moderate-sized tumors because this may increase the risk of CSF dissemination.
  • Recurrences following successful en bloc resection are rare.

Postoperative Care

Patients with ependymomas who undergo surgical resection typically spend the night after surgery in an intensive care unit followed by an inpatient stay of 3-5 days. The final length of stay depends on each patient's neurological condition as well as tumor location and extent of resection.

Postoperative antibiotics are usually continued for 24 hours, and deep vein thrombosis prophylaxis is continued until patients are ambulatory. Anticonvulsants are maintained at therapeutic levels throughout the inpatient stay for supratentorial ependymoma, while steroid dose is tailored to each patient's clinical status and gradually tapered pending improvement. Many patients benefit from occupational therapy and physical therapy/rehabilitation.

While patients are still in the hospital, they should undergo postoperative imaging to determine the extent of surgical resection. This is best evaluated within 3 days of surgery by a contrast-enhanced MRI of the brain because contrast enhancement during this period accurately reflects residual tumor. In addition, patients should have an MRI of the entire spine with and without gadolinium to rule out seeding.

If not performed preoperatively, complete evaluations by consulting physicians, including a neurooncologist and radiation oncologist, should be considered.

Consultations

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.

Diet

No restrictions of diet are required for patients with ependymomas.

Activity

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

Follow-up care with a rehabilitative medicine team is recommended for patients who sustain neurological deficits after spinal tumor resection. 

For patients with supratentorial tumors, postoperative anticonvulsant medication is continued upon discharge. Steroids are usually tapered in accordance with the patient's clinical status and degree of edema documented on postoperative imaging.

Children with posterior fossa tumors must be monitored for signs of hydrocephalus, and all patients with supratentorial tumors should have serum levels of anticonvulsant drugs checked on a regular basis.

 

Guidelines

Guidelines Summary

The National Comprehensive Cancer Network (NCCN) recommends the following for treatment of adults with ependymoma[9] :

  • After a gross total resection (GTR) of an intracranial WHO grade II ependymoma, limited field fractionated external beam radiotherapy (LFFEBRT) can be considered versus mere observation.
  • Postoperative LFFEBRT for WHO grade II ependymoma when subtotal resection is noted on postoperative MRI, and for grade III anaplastic ependymoma regardless of the extent of resection.  
  • If postoperative spinal MRI or LP findings are positive, craniospinal radiation therapy is indicated regardless of grade or extent of resection.
  • 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. 

 

 

Medication

Medication Summary

No specific medications exist to treat ependymomas; however, supratentorial ependymomas require medical treatment. For seizures, the patient is 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.

Anticonvulsants

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).

Corticosteroids

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.