Ependymal Tumors
Main Text
Preamble
Overall, ependymomas represent 2-3% of all primary CNS neoplasms. Approximately 30% affect children and adolescents, although ependymal neoplasms occur at all ages, encompass multiple tumor types and subtypes, and can develop along the entire neuraxis. Clinically, ependymomas are a heterogeneous group ranging from relatively benign subependymomas to the deadly early childhood ependymomas of the posterior fossa.
The 5th edition WHO recognizes ependymomas as a distinct family of tumors that are now classified according to a combination of (1) histopathologic features, (2) molecular features, and (3) anatomic site.
Ependymomas are divided into specific molecular groups in each of three anatomic sites, viz., the supratentorial, posterior fossa, and spinal compartments (SC). DNA methylation profiling results in distinct ependymoma subgroups divided among these three sites. Each molecular subgroup is genetically, transcriptionally, demographically, and clinically distinct.
In this chapter, we group and discuss CNS ependymomas by their respective anatomic compartments (22-1). Two additional tumors—subependymoma (SE) and myxopapillary ependymoma (MPE)—are not restricted to a specific anatomic location (e.g., SEs can occur in all three anatomic compartments) and are discussed separately at the end of this chapter.
Supratentorial Ependymomas
Preamble
Supratentorial ependymomas (ST-EPNs) represent 30% of all ependymomas. The 5th edition WHO includes two molecularly defined types of ST-EPN: One with ZFTA fusion and the other with YAP1 fusion. If no pathogenic gene fusion of ZFTA (formerly known as C11orf95) or YAP1 can be detected, the diagnosis ST-EPN, not elsewhere classified (NEC) is used.
Supratentorial Ependymoma, ZFTA Fusion-Positive
Terminology
ZFTA fusion-positive ependymoma is a circumscribed supratentorial neoplasm with ZFTA gene fusions with partner genes, mainly RELA. ZFTA fusion-positive is the new, updated designation for C11orf95, because fusion partners other than RELA (e.g., MAML2/MAML3, NCOA1/NCOA2, MN1, or CTNNA2) may also occur.
Etiology
ZFTA fusion-positive ST-EPNs probably arise from radial glia stem cells. Fusion of the ZFTA gene with a partner gene—usually RELA—is the principal oncogenic driver of the neoplasm.
Pathology
Grossly, ZFTA fusion-positive ependymomas are sharply demarcated extraventricular masses arising in the cerebral hemispheres, most commonly the frontal and parietal lobes. Less common reported sites include the thalamus and hypothalamus/third ventricle.
Perivascular pseudorosettes are a cornerstone histologic marker of ZFTA fusion-positive ependymomas. True ependymal rosettes are rare.
ZFTA fusion-positive ependymomas are usually positive for L1CAM immunostaining. ZFTA fusions with partners other than RELA are uncommon; these rare tumors have a highly variable morphologic spectrum, exhibiting features that can resemble pleomorphic xanthoastrocytoma or astroblastoma.
ZFTA fusion-positive ependymomas exhibit varying degrees of anaplasia and are designated CNS WHO grade 2 or 3.
Clinical Issues
ZFTA fusion-positive ependymomas account for nearly 70% of ST-EPNs in children and most of the hemispheric ependymomas in adults. The five-year survival is 50%. Notably, recent evidence suggests progression-free survival in non-ZFTA:: RELA-fused ependymomas is worse.
Imaging
ZFTA fusion-positive ependymomas appear as large, bulky, heterogeneous-appearing para- or extraventricular hemispheric masses. Completely intraventricular ST-EPNs are rare. In many cases, no direct connection to the lateral ventricles can be identified.
NECT shows a mixed-density mass with solid and cystic components and peritumoral edema (22-2A)(22-3A). Intratumoral hemorrhage and calcification are common. Heterogeneous enhancement on CECT is present in nearly all cases.
MR findings vary widely. Mixed solid with variable cystic components are typical. Signal intensity is quite variable with hypo- and isointense foci on T1WI and variably iso- to hyperintense foci on T2WI (22-2). Cyst fluid does not suppress on FLAIR. “Blooming” hemorrhagic foci on T2* sequences are common (22-3). Moderately cellular tumors may exhibit some restricted diffusion.
Over 85% exhibit strong, thick but inhomogeneous enhancement on T1 C+(22-3F). Cystic components usually exhibit an enhancing rim. Most ZFTA fusion-positive ependymomas show moderate restricted diffusion on DWI and elevated rCBV on pMR (22-5).
Differential Diagnosis
The main differential diagnosis includes MN1-altered astroblastoma and neoplasms with BCOR internal tandem duplication. In adults, glioblastoma and pleomorphic xanthoastrocytoma can mimic hemispheric ependymomas. Rare neoplasms, such as extraventricular neurocytoma, can be indistinguishable on imaging studies.
Supratentorial Ependymoma, YAP1 Fusion-Positive
The second subgroup of ST-EPNs is characterized by the absence of ZFTA alterations and presence of YAP1 gene fusions. The most frequent rearrangement is with the MAMLD1 gene, but other fusion partners occur.
These tumors are uncommon. Most occur in infants and young children, where they represent just 6-7% of pediatric ST-EPNs. Immunoreactivity for L1CAM is absent. YAP1-fused ST-EPNs are associated with a more favorable prognosis than ZFTA-fused ependymomas.
Posterior Fossa Ependymomas
Preamble
Approximately 60% of all ependymomas are infratentorial. Of these, 95% are found in the fourth ventricle. The remainder occur as cerebellopontine angle (CPA) lesions.
Posterior fossa ependymomas have morphologic and immunohistochemical features of ependymoma. Two subtypes are defined: Posterior fossa group A (PFA) ependymoma and posterior fossa group B (PFB) ependymoma. Although they appear similar at gross pathology and on imaging studies, they differ in both age at onset and biologic behavior and so are discussed separately.
Posterior Fossa Group A Ependymoma
Terminology
PFA ependymoma is sometimes referred to as infantile posterior fossa ependymoma.
Pathology
Gross Pathology
In general, posterior fossa ependymomas are reddish-tan or gray in color and form relatively well-demarcated, lobulated masses. They have a plastic appearance, extruding from the fourth ventricle through the foramina of Luschka and Magendie to fill the cisterns and encase cranial nerves and blood vessels (22-6)(22-7).
Calcification, cyst formation, and hemorrhage are common (22-11).
Microscopic Features
The most characteristic microarchitectural feature of ependymomas is the presence of perivascular pseudorosettes, in which tumor cells are arranged radially around blood vessels.
PFA ependymomas exhibit varying degrees of anaplasia. Nearly 2/3 exhibit high-grade features, including prominent mitotic activity and microvascular proliferation. Nuclear pleomorphism and necrosis have lesser prognostic significance.
PFA ependymomas are designated as CNS WHO grade 2 or 3 depending on the degree of anaplasia.
Diagnostic Molecular Pathology
Molecular characterization of posterior fossa ependymomas has a greater impact on risk stratification than histopathologic grading criteria. Therefore, posterior fossa ependymomas should be assigned to a specific molecular group (i.e., PFA, PFB, or SE). PFA is defined by its unique DNA methylation profile or reduced H3p.K28me3 in tumor cell nuclei.
Clinical Issues
Epidemiology
Overall, ependymoma is the third most common posterior fossa tumor of childhood (after medulloblastoma and astrocytoma). PFA ependymoma accounts for nearly 30% of all brain tumors in children under the age of three years.
Demographics
PFA ependymomas are almost exclusively found in young children (median age = three years), and male patients predominate, nearly 2:1.
Presentation
Fourth ventricle ependymomas—both PFA and PFB—commonly cause intraventricular obstructive hydrocephalus. Infants with PFA ependymomas can present with a rapidly growing head circumference. Older children present with nonspecific symptoms (headache, vomiting, and lethargy).
Natural History
PFA ependymomas are associated with a high recurrence rate and poor clinical outcome. Overall five-year survival for this subgroup is ~ 50%, whereas it approaches 85-90% for the PFB ependymoma subgroup.
Treatment Options
Maximum cytoreduction surgery followed by conformal radiotherapy—not cranial spinal irradiation—is the standard treatment. Adjuvant therapy is generally reserved for recurrent tumor.
Imaging
General Features
Infratentorial ependymomas (both PFA and PFB) are relatively well-delineated, “plastic” tumors that typically arise from the floor of the fourth ventricle and extrude through the outlet foramina. They extend laterally through the foramina of Luschka toward the CPA cistern (22-8) and posteroinferiorly through the foramen of Magendie into the cisterna magna (22-9).
Sagittal images disclose a mass that fills most of the fourth ventricle and extrudes inferiorly into the cisterna magna (22-10C). Axial and coronal images show lateral extension toward or into the CPA cisterns (22-9).
Obstructive hydrocephalus is a frequent accompanying feature of infratentorial ependymomas. Extracellular fluid often accumulates around the ventricles, giving the appearance of “blurred” margins.
CSF dissemination is a key factor in staging, prognosis, and treatment of ependymoma. The only statistically significant preoperative imaging predictor of patient outcome is evidence of tumor spread. Therefore, preoperative imaging of the entire cranial-spinal axis should be performed in any child with a posterior fossa neoplasm, especially if medulloblastoma or ependymoma is suspected.
CT Findings
Ependymomas are generally mixed density on NECT scans with hypodense intratumoral cysts intermixed with iso- and hyperdense soft tissue portions. Coarse calcification occurs in ~ 1/2 of all ependymomas (22-12A). Macroscopic hemorrhage can be identified in ~ 10% of cases.
Most ependymomas show mild to moderate heterogeneous enhancement.
MR Findings
Ependymomas are generally heterogeneously hypointense relative to brain parenchyma on T1WI and hyperintense on T2/FLAIR (22-9). Following contrast administration, most ependymomas enhance. Areas of strong, relatively homogeneous enhancement are intermixed with foci of minimal or even no enhancement (22-9D).
T2* imaging (GRE, SWI) commonly demonstrates “blooming” foci that can be caused by calcification (22-12B) &/or old hemorrhage. An ependymoma may bleed, causing nonaneurysmal subarachnoid hemorrhage and siderosis around the tumor and along the pial surfaces of the cerebellum.
Most ependymomas do not restrict on DWI, although foci of restricted diffusion can be identified in some cases.
General MRS metabolite ratios are nonspecific. Elevated choline and reduced NAA are common in ependymoma, as in many other brain tumors. pMR generally demonstrates markedly elevated CBV with poor return to baseline.
Differential Diagnosis
Differential diagnosis of ependymoma is location dependent.
The major differential diagnosis of infratentorial ependymoma is medulloblastoma. Medulloblastomas are more common and typically arise from the roof of the fourth ventricle (not from the floor, as is typical of ependymoma). Medulloblastomas are hyperdense on NECT, often demonstrate diffusion restriction, and more frequently show evidence of CSF dissemination at the time of initial diagnosis. Cysts, hemorrhage, and calcification are less common in medulloblastoma compared with ependymoma.
Posterior Fossa Group B Ependymoma
Terminology
PFB ependymomas are identified as such by DNA methylation profiling.
Pathology
Both the general macro- and microscopic features of PFB ependymomas are similar to PFA ependymomas. While PFB ependymomas can arise anywhere in the fourth ventricle, they more frequently arise from the floor rather than the roof or lateral recesses (22-11).
In contrast to PFA ependymomas, almost all PFB ependymomas retain nuclear expression of H3p.K28me3, which can be readily assessed by immunohistochemistry.
Similar to the PFA ependymomas, PFB ependymomas can be CNS WHO grade 2 or 3 tumors depending on the degree of anaplasia and other high-grade features, such as prominent mitotic activity and microvascular proliferation.
Clinical Issues
Frequency of PFB ependymomas compared to PFA ependymomas is highly age dependent. Median age at presentation is 30 years. Over 90% occur in adults or adolescents; < 5% occur in infants and children under five years.
DNA methylation profiling has identified five distinct PFB subtypes. PFB-1, PFB-2, and PFB-3 tumors tend to occur in patients aged 25-30 years, whereas the median age of PFB-4 tumors is 15 years. PFB-5 tumors occur in older adults where the median age at diagnosis is 40 years.
Imaging
Imaging findings in PFB ependymomas (22-10) (22-12)are identical to PFA ependymomas.
Differential Diagnosis
A posterior fossa ependymoma in an adult or adolescent older than eight years is either a PFB ependymoma or subependymoma (SE) (22-17).
The other main differential diagnosis of PFB ependymoma is medulloblastoma, which can also occur in adolescents and adults. Pilocytic astrocytoma also occurs in the fourth ventricle but is more common in the cerebellar hemispheres. High-grade astrocytoma with pilocytic features (HGAP)is in the differential diagnosis, especially in patients with neurofibromatosis type 1. HGAPs are more common in the cerebellar hemispheres and brainstem.
Subependymoma
Terminology
Subependymomas (SEs) are rare, benign, slow-growing, noninvasive tumors that are often found incidentally at imaging or autopsy. SE is a well-circumscribed glial tumor with small, uniform, cytologically bland nuclei.
Etiology
The origin of SEs is unclear. They may arise from pluripotential ependymal-glial precursor cells, astrocytes in the subependymal plate, or a preexisting hamartomatous lesion. A specific mutation on the TRPS1 gene may play a role in at least some cases.
Pathology
Location
While SEs can arise along the whole neuraxis, they are usually located within or adjacent to an ependyma-lined space. They occur in all three anatomic compartments (supratentorial, posterior fossa, and spinal).
The fourth ventricle is the most common site (50-60% of cases) (22-13)(22-15). The lateral ventricles account for ~ 1/3 of all cases. Most of these occur in the frontal horn of the lateral ventricle, near the foramen of Monro, where they are often attached to the septi pellucidi (22-18). SEs in the third ventricle and occipital horn of the lateral ventricle are rare. Parenchymal and intramedullary intraspinal SEs occur but are uncommon.
Size and Number
SEs are solitary tumors. Most are < 2 cm (22-14), although some tumors may reach several centimeters in diameter (22-16). A few cases of very large biventricular SEs that fill both lateral ventricles have been reported. Because the posterior fossa is more anatomically constrained, infratentorial tumors are generally smaller than their supratentorial counterparts.
Gross Pathology
SEs are solid, round to somewhat lobulated, well-delineated, gray-tan masses. Calcification, cysts, and hemorrhage are common in larger lesions.
Microscopic Features
Bland nuclei in a dense fibrillary stroma with variable microcystic degeneration is typical. Nuclear pleomorphism and nonpalisading necrosis are rare but may occur. Mitotic activity is absent or low level.
Diagnostic Molecular Pathology
Although SEs in the three anatomic compartments have distinct, site-specific epigenetic methylation profiles, they all cluster together and are not placed in separate molecular groups.
Staging, Grading, and Classification
SEs are designated as CNS WHO grade 1 neoplasms even if rare pleomorphic features are present. Anaplastic transformation is exceptionally rare.
Clinical Issues
Epidemiology
SEs are often clinically silent, so reliable incidence figures are lacking. SEs are found in 0.5-1.0% of autopsies. They account for 8% of all ependymomas and < 1% of intracranial neoplasms.
Demographics
SEs are tumors of middle-aged and older adults. They are very rare in children. There is a moderate male predominance.
Presentation
The majority of SEs are asymptomatic and discovered incidentally. Approximately 40% cause symptoms, mostly related to CSF obstruction or mass effect.
Natural History
SEs exhibit an indolent growth pattern, expanding slowly into a ventricular space. Larger tumors may cause obstructive hydrocephalus, but they rarely invade adjacent brain. Recurrence is rare even after subtotal resection. Cytologic pleomorphism, occasional mitoses, and even necrosis have not proved prognostically significant.
Treatment Options
“Watchful waiting” with serial imaging is appropriate in asymptomatic patients. Complete surgical resection of symptomatic SEs is the procedure of choice.
Imaging
General Features
SEs are well-demarcated nodular masses that may expand the ventricle but usually cause little mass effect. Almost all fourth ventricle SEs are centered below the body of the fourth ventricle and above the obex (22-14). Nearly 1/2 of these exhibit tumor extension into the foramen of Magendie or Luschka (22-16).
CT Findings
SEs are iso- to slightly hypodense compared with brain on NECT scans. Calcification and intratumoral cysts may be present (22-14A), especially in larger lesions. Hydrocephalus is variable, and hemorrhage is rare. Little or no enhancement is seen on CECT.
MR Findings
Most SEs are isointense or slightly hyperintense compared with brain on T1WI (22-16A). Intratumoral cysts are common in larger lesions. SEs are heterogeneously hyperintense on T2(22-19A) and hyperintense on FLAIR (22-19B). Peritumoral edema is usually absent. T2* (GRE, SWI) shows “blooming” foci, probably secondary to calcification. Hemorrhage is seen in 10-12%.
The majority of SEs exhibit some degree of enhancement on T1 C+ that varies from none or mild (22-16C)to moderate (22-19C). Typically only part of the tumor enhances. Avid enhancement is rare.
SEs do not restrict on DWI. MRS shows normal choline with mildly decreased NAA.
Differential Diagnosis
The differential diagnosis of SE varies with age and anatomic location. In older patients, the major differential is intraventricular metastasis. Most intraventricular metastases arise in the choroid plexus. In young to middle-aged adults, ST-EPNs and PFB ependymomas (22-17) as well as central neurocytoma might considered (22-20). Central neurocytoma is typically found in the body of the lateral ventricle, not the frontal horn or inferior fourth ventricle, and has a characteristic bubbly appearance.
In children, depending on age, PFA and PFB ependymomas and (in patients with tuberous sclerosis) subependymal giant cell astrocytoma are considerations. Choroid plexus papillomas in children are usually in the atrium of the lateral ventricle. Choroid plexus papilloma also has a frond-like appearance and typically shows intense uniform enhancement.
Spinal Ependymomas
Preamble
Ependymal tumors of the spinal cord are relatively uncommon, accounting for 2-6% of all CNS tumors. Spinal ependymomas (SP-EPNs) primarily affect adults between the ages of 20-40 years.
Four distinct spinal ependymal tumor types are recognized: SP-EPN, SP-EPN with MYCN amplification (SP-MYCN), myxopapillary ependymoma (MPE), and SE. We discuss two of these—MPE and SP-MYCN—in this closing section, as the 5th edition WHO made some significant changes in these entities.
Spinal Ependymoma, MYCN-Amplified
SP-MYCN was recognized in the 5th edition WHO as a novel, clinically aggressive type of ependymoma characterized by early metastases, rapid progression, leptomeningeal dissemination, and poor response to multimodal treatment strategies. In the most recent classification, MYCN-amplified high-grade glioma is one of the recognized subtypes of IDH- and H3-wildtype pediatric-type high-grade gliomas.
SP-MYCN is rare, accounting for 5% of all SP-EPNs. It has a distinct methylation profile that differs from all other ependymal tumor types. Practically all SP-MYCNs display microvascular proliferation, necrosis, and a high mitotic count. To date, no CNS WHO grade has been assigned, but investigators report these tumors are characterized by grade 3 histopathology. Reported median overall survival is 14 months.
More than 80% are found in the cervical or thoracic spinal cord. Unlike classic spinal cord ependymomas, MYCN-amplified tumors appear diffusely infiltrative on MR. Imaging shows extremely heterogeneous signal intensity on T1- and T2WIs with intermixed cystic and solid components (22-21). Hemorrhage with a hypointense cap sign is common. Enhancement is variable and leptomeningeal dissemination is frequent, so imaging the entire neuraxis is recommended prior to surgical intervention.
Myxopapillary Ependymoma
MPE is a very slow-growing type of ependymoma that occurs at all ages but mostly affects young adults. MPEs are almost exclusively tumors of the conus medullaris, cauda equina, and filum terminale (22-22).
Progressive lower back pain is the most common clinical presentation. Although disseminated tumor and recurrent or progressive disease after surgery are common, 10-year survival is > 90%.
In the typical MPE, MIB-1 labeling index is low (generally < 1%). MPEs are CNS WHO grade 2 tumors, a change from the 2016 edition.
MPEs are generally hypo- to isointense on T1WIs and hyperintense on T2WIs. Enhancement is typically strong and homogeneous (22-23). Although adults rarely have multiple lesions, nearly 1/2 of MPEs in children and adolescents have leptomeningeal disease on initial presentation, so complete neuraxis imaging should be performed prior to surgery (22-24).
IMAGING FEATURES OF EPENDYMOMAS BY ANATOMIC COMPARTMENT
Supratentorial Ependymomas
• Hemispheres (not ventricles)
Bulky, mixed cystic-solid
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