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 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]
Laboratory Studies
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:
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Interphase Fluorescence In-Situ Hybridization (FISH): Detects chromosomal abnormalities through fluorescent DNA probes [52]
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Reverse Transcription Polymerase Chain Reaction (RT-PCR): Can measure gene expression by quantifying the amount of mRNA corresponding to a specific gene of interest
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Next Generation Sequencing: High coverage, high sensitivity, and high-throughput method to sequence genes and detect low-frequency variants
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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]
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. [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.
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].
Procedures
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.
Histologic Findings
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.
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.
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.
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CT scan without contrast. Fourth ventricle ependymoma.
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CT scan without contrast. Fourth ventricle ependymoma. Note blood in the fourth ventricle.
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CT scan without contrast in the patient with fourth ventricle ependymoma. Blood has refluxed into the third and lateral ventricles.
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CT scan without contrast in the patient with fourth ventricle ependymoma. Note blood traversing foramina.
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T1-weighted MRI. Rare case of a fourth ventricle ependymoma presenting as an intraventricular bleed.
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T1-weighted MRI without contrast demonstrating ependymoma located in the fourth ventricle.
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T2-weighted MRI demonstrating ependymoma in the fourth ventricle.
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Coronal T1-weighted MRI with contrast demonstrating ependymoma of the fourth ventricle.
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Gross surgical specimen of a fourth ventricle ependymoma.
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Histologic study of a classic ependymoma. Note the characteristic perivascular pseudorosettes.
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Cellular ependymoma. Cells with a high nuclear-cytoplasmic ratio. Few pseudorosettes or paucicellular areas are present.
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Myxopapillary ependymoma. Clusters of loosely arranged cuboidal cells separated by pools of mucin.
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Clear cell ependymoma. Round cells with cytoplasmic clearing. This may mimic an oligodendroglioma.
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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].
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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].
Tables
Supratentorial ependymomas |
ZFTA (C11orf95): Zinc Finger Translocation Associated gene |
YAP1: Yes-Associated Protein 1 |
|
Posterior fossa ependymomas |
Posterior Fossa Group A molecular profile |
Posterior Fossa Group B molecular profile |
|
Spinal ependymomas |
NF2: Neurofibromatosis 2 gene |
MYCN Proto-oncogene |
|
MYCN Non-amplified |
|
Subependymoma |
Supratentorial |
Posterior fossa |
|
Spinal |
