Ependymoma Pathology

Updated: Jan 05, 2018
  • Author: Christine Fuller, MD; Chief Editor: Adekunle M Adesina, MD, PhD  more...
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Ependymomas, as their name implies, are glial tumors that exhibit ependymal differentiation. [1, 2] This group of neoplasms includes the following tumor categories: subependymoma (World Health Organization [WHO] grade I), myxopapillary ependymoma (WHO grade I), ependymoma (WHO grade II), and anaplastic ependymoma (WHO grade III). Ependymoma, RELA fusion-positive, is a newly-recognized entity codified in the revised fourth edition of the WHO classification; these aggressive tumors include the majority of supratentorial ependymomas occurring in children and young adults. [1]



Ependymomas are the most common primary tumor of the spinal cord (especially in adults) and the third most common pediatric central nervous system (CNS) tumor. Although as a group they represent less than 10% of all neuroepithelial tumors, ependymomas account for nearly one third of intracranial tumors in children younger than 3 years. The age distribution for ependymomas is bimodal; the first peak incidence occurs around age 5-6 years when infratentorial lesions predominate; a second, later, peak occurs in the third and fourth decades, at which time spinal examples are most common.

In general, most pediatric ependymomas arise intracranially, whereas well over one half of adult ependymomas arise from the spinal cord. [3] Ependymomas have double the rate of occurrence in white individuals compared with black individuals, whereas these tumors are equally distributed between the sexes. Although most ependymomas are sporadic, they may also be encountered in the context of neurofibromatosis type 2, a hereditary cancer predisposition syndrome with germline mutation of NF2/MerlinRELA fusion-positive ependymoma accounts for approximately 70% of pediatric supratentorial ependymomas, although it may also occasionally be encountered in adults. [4, 5]

Representing approximately 10% of ependymal tumors, subependymomas most often "present" as incidental autopsy findings in the brains of the elderly. [6] Myxopapillary ependymomas similarly arise most frequently in adults; approximately 20% occur in children, in whom there is a 2:1 male-to-female bias and a greater tendency for dissemination through cerebrospinal fluid (CSF) pathways. [7, 8] Anaplastic ependymomas, however, are far more common in the pediatric age group, frequently arising in a supratentorial location.



To theorize the "cell of origin" of ependymomas and related tumors, one needs only to look back through the stages of normal ependymal cell development. The "stem cell" theory of tumorigenesis has it roots in the classic literature of neuropathology, dating back to early perspectives from Bailey and Cushing. [9] Radial glia, multipotent progenitor cells derived from the neuroepithelium of the primitive neural tube, give rise to multiple differing populations of elongated unipolar and bipolar cells termed tanycytes; fetal ependymal tanycytes directly give rise to mature ependymocytes, whereas other tanycytic populations mature and remain as ependymal tanycytes within selective regions of the ventricular system, particularly the hypothalamic region of the third ventricle and within circumventricular organs. Specialized ependyma of the circumventricular organs and choroid plexus cells are additional highly specialized ependymal cells that ultimately derive from this developmental pathway.

Not only do choroid plexus tumors and ependymomas (including the various histologic subtypes) clearly recapitulate specific cell types found at various stages in this ontologic sequence, so too do a variety of other uncommon and/or relatively recently recognized entities. These include astroblastoma, papillary tumor of the pineal region, chordoid glioma, angiocentric glioma, and pilomyxoid glioma. [10] In addition, gene expression profiling studies support the concept that radial glial cells from different neuroanatomic sites may be predisposed to acquiring particular genetic aberrations that result in ependymomas with site-specific genetic signatures and biologic potential. [11] This may well explain why phenotypically identical ependymomas from supratentorial, posterior fossa, and spinal locations may exhibit notably different clinical behaviors.



Supratentorial ependymal tumors (including ependymomas and subependymomas) more frequently arise in the lateral ventricles compared to the third ventricle. In children, ependymal tumors occur most commonly within the fourth ventricle (posterior fossa), [2] followed by supratentorial locations, the latter including both a mix of primarily paraventricular and intraparenchymal-centered tumors and a tendency toward anaplasia (World Health Organization [WHO] grade III). [12]  However, an extraventricular localization does not negate the possibility of an ependymoma, especially in the pediatric age group. Rare intracranial extraaxial examples have been described. [13, 14] Pure cortical ependymoma represents a rare type of supratentorial ependymoma that occurs in the superficial cortex of young adults, is often associated with seizures, tends to be low grade, and is curable by resection. [15, 16, 17]

Ependymal tumors may arise at any level of the spinal cord, where they are much more common in the adult population, as noted earlier. Interestingly, certain histologic subtypes have preferred spinal locations. Classic (WHO grade II) ependymomas, including the tanycytic variant, generally present as centrally situated intramedullary tumors within the thoracic/cervicothoracic cord, [18] whereas spinal subependymomas more often arise as eccentric masses. [19, 20] Anaplastic (WHO grade III) spinal ependymomas are exceedingly rare.

The prototypical location of myxopapillary ependymoma is the region of the conus medullaris/cauda equina/filum terminale; infrequently, these may arise at other cord levels, intracranial sites (both intraparenchymal and intraventricular), and subcutaneous sacrococcygeal areas. [21, 22, 23, 24, 25, 26] The ovaries and mediastinum are other rare sites of ependymal tumors.


Clinical Features and Imaging

Ependymomas arising intracranially typically come to clinical attention when their growth results in blockage of cerebrospinal fluid (CSF) pathways, resulting in hydrocephalus and increased intracranial pressure. Signs and symptoms related to this include headache, nausea/vomiting, ataxia, strabismus, irritability, and altered mental status; infants may exhibit macrocephaly and bulging fontanelles. In this context, anaplastic ependymomas elicit a similar constellation of signs/symptoms as grade II ependymomas, although in the former, these tend to develop in a more rapid fashion. Back pain as well as motor and/or sensory deficits may be encountered with spinal ependymomas, irrespective of subtype; the clinical presentation correlates with specific anatomic involvement.

Classic ependymomas arising in the spinal cord typically involve multiple contiguous segments and grow as well-demarcated central intramedullary tumors. On magnetic resonance imaging (MRI), these tumors are iso- to hypointense on T1-weighted images and hyperintense on T2-weighted images (see the image below) [27] ; the majority are hyperdense on computer tomography (CT) scans. Ependymomas invariably show uniform enhancement following contrast administration and, in approximately 90% of cases, they will have intramedullary cysts at their rostral and/or caudal aspects. [28, 29]

T1-weighted post contrast sagittal magnetic resona T1-weighted post contrast sagittal magnetic resonance image of a conventional ependymoma of the cervical spinal cord.

Intracranial ependymomas are likewise sharply demarcated, are often at least partially cystic, and typically arise within or near the ventricular system with accompanying hydrocephalus. Extraventricular examples are well described, the bulk of these being anaplastic ependymomas arising supratentorially in children. Similar to their spinal counterparts, intracranial ependymomas are isointense on T1-weighted MRI and iso- to hyperintense on T2-weighted MRI; however, postcontrast enhancement may be variable and heterogeneous (see the following images). Calcifications and/or intratumoral hemorrhage are not uncommon. [3, 30] Infiltration of the surrounding central nervous system (CNS) parenchyma is a feature that may be encountered in anaplastic ependymomas, making differentiation from infiltrative glioma problematic from a radiographic standpoint.

T1-weighted axial magnetic resonance image of a po T1-weighted axial magnetic resonance image of a posterior fossa ependymoma.
T2-weighted axial magnetic resonance image of a po T2-weighted axial magnetic resonance image of a posterior fossa ependymoma.
T1-weighted postcontrast sagittal magnetic resonan T1-weighted postcontrast sagittal magnetic resonance image of a posterior fossa ependymoma.

Subependymomas show variable signal characteristics on CT scans and MRIs and, unlike other ependymomas, postcontrast enhancement is rare. These lesions may present either as a sharply demarcated nodule bulging into the ventricle or as arising eccentrically within the spinal cord (in contrast to classic spinal ependymomas, which tend to arise centrally). Intratumoral calcification or hemorrhage may be encountered. [19, 20, 30, 31, 32]

Myxopapillary ependymomas are well-circumscribed and arise in the conus medullaris/cauda equina/filum region; these tumors are characteristically hyperintense on both T1- and T2- weighted MRIs due to their high mucin content (see the first image below). [31] Similar to other ependymomas, myxopapillary ependymomas also show uniform postcontrast enhancement (see the second image below). Cystic change or hemorrhage may be encountered on occasion.

T1-weighted sagittal magnetic resonance image of a T1-weighted sagittal magnetic resonance image of a myxopapillary ependymoma arising from the region of the filum terminale.
T1-weighted postcontrast magnetic resonance image T1-weighted postcontrast magnetic resonance image of myxopapillary ependymoma.



Gross Findings

Surgical biopsy/resection specimens of ependymal tumors are composed of tan to gray soft tissue; they may contain cystic areas, hemorrhage, necrosis, and/or calcification. Myxopapillary ependymomas are often encapsulated and tend to be more lobulated, whereas subependymoma tissue tends to be more firm and multinodular. When anaplastic ependymomas are encountered in the setting of an autopsy, these lesions may show evidence of frank intraparenchymal invasion. Subependymomas, myxopapillary ependymomas, and grade II ependymomas are generally well-demarcated from the surrounding central nervous system tissues. [1]


Microscopic Findings

Ependymal tumors are composed of a number of graded tumor categories as well as specific variants, all definable by their unique histologic appearance (with the exception of RELA fusion-positive ependymomas which are genetically defined). Common features shared by the majority of these lesions include sharp demarcation from surrounding tissue and perivascular pseudorosettes.

Classic ependymomas (World Health Organization [WHO] grade II) make up the bulk of ependymal tumors. At the most biologically aggressive end of the spectrum are anaplastic ependymomas, given a WHO grade III designation, whereas subependymoma and myxopapillary ependymoma are both considered WHO grade I lesions and tend to behave in a more indolent manner. The recognized histopathologic variants of tanycytic, papillary, and clear cell ependymoma may present as prominant components in both classic and anaplasitc ependymoma. [1] The microscopic features of each will be presented below, together with their typical intraoperative cytology/smear preparation findings.

Ependymoma (WHO grade II)

Classic (conventional) ependymomas typically present as moderately cellular glial tumors. Unlike infiltrative astrocytomas and oligodendroglial tumors, ependymomas show distinct demarcation from the surrounding brain parenchyma. The cells composing ependymomas may display variable cytomorphologic characteristics, some exhibiting elongated fibrillary glial-type properties, whereas others display more epithelioid features that are reminiscent of ependymocyte ventricular lining cells.

Key histologic features of conventional ependymomas include the following:

  • Solid, noninfiltrative growth pattern

  • Perivascular pseudorosettes (anuclear zones formed by radially arranged tumor cell processes surrounding central blood vessels), as shown in the following image

    Typical perivascular pseudorosettes in a conventio Typical perivascular pseudorosettes in a conventional ependymoma. (Hematoxylin and eosin, ×200.)
  • True ependymal rosettes and canals (epithelioid cuboidal to columnar cells arranged around a central, open lumen), as seen in the image below. Ependymal rosettes contain a small round lumen, whereas canals have larger, more elongated lumens that are reminiscent of small ventricles.

    Ependymal true rosettes and canals in a convention Ependymal true rosettes and canals in a conventional ependymoma. (Hematoxylin and eosin, ×100.)

Whereas perivascular pseudorosettes are a nearly universal finding, ependymal canals and rosettes are more specific diagnostic features of ependymomas, although these are present in only a minority of cases. Mitotic figures are usually difficult to detect. Zones of geographic necrosis without surrounding pseudopalisades of tumor cells are not uncommon in grade II ependymomas; however, endothelial proliferation and pseudopalisading necrosis should be absent. [10, 33]

Nuclear pleomorphism may be encountered, but this feature alone does not warrant an anaplastic (grade III) designation. Degenerative changes that may be present include hemorrhage, calcification, myxoid degeneration, and vascular hyalinization. Cartilage, bone, fat, neuropil-like islands, and cells with a signet ring, oncocytic, or giant cell morphology or containing melanin or eosinophilic intracytoplasmic inclusions have all been described. [34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45]

Intraoperative smear preparations of ependymomas generally contain cohesive clusters of cells with bland oval-to-round nuclei within a fibrillary background, with unipolar elongated cytoplasmic processes extending from the periphery of tissue fragments. [46] Epithelioid cells may be present in some cases. [3, 47] Perivascular pseudorosettes and, much less frequently, true rosettes, are encountered on these cytologic samples. [46]

Well-characterized histopathologic variants of classic ependymoma

The WHO 2016 central nervous system (CNS) tumor classification recognizes three distinct histologic variants of grade II ependymoma: tanycytic ependymoma, papillary ependymoma, and clear cell ependymoma, all described below. Although present in previous versions of the WHO classification, "cellular ependymoma" is no longer considered a distinct ependymoma variant as areas of hypercellularity may be encountered to a greater or lesser extent within otherwise classic ependymomas. Despite appearing superficially worrisome, these areas are differentiated from anaplastic ependymoma by virtue of their lack of microvascular proliferation, pseudopalisading necrosis, and an elevated mitotic rate. [1]  

Ependymoma. Note the hypercellularity but lack of Ependymoma. Note the hypercellularity but lack of elevated mitotic activity or microvascular proliferation. (Hematoxylin and eosin, ×100.)

Tanycytic ependymoma has a predilection for the spinal cord. This uncommon ependymoma variant is composed of elongated, spindle-shaped cells with thin eosinophilic fibrillary processes (see the following image); it is by virtue of these bipolar cells and their resemblance to radial glia-like tanycytes that this lesion derives its name. [10, 48]

Tanycytic ependymoma. Note the spindled morphology Tanycytic ependymoma. Note the spindled morphology and vague perivascular pseudorosettes. This example contains scattered cells with striking nuclear atypia. (Hematoxylin and eosin, ×100.)

Tanycytic ependymomas also display a predominantly fascicular architecture, and as true ependymal rosettes are lacking and perivascular pseudorosettes are often inconspicuous, these tumors pose a diagnostic challenge as they may resemble a variety of other CNS lesions (especially pilocytic astrocytoma and schwannoma). [18, 48, 49] Nuclear pleomorphism, representing a degenerative feature similar to the nuclear pleomorphism of "ancient schwannomas," may be prominent in some cases.

Cytologic smear preparations often yield confusing findings, containing cells with long, thin processes quite similar to those encountered in pilocytic astrocytoma. [50] As noted in the Immunohistochemistry section below, ancillary testing including immunohistochemistry and/or electron microscopy is frequently needed to accurately differentiate tanycytic ependymoma from a number of other lesions.

Papillary ependymoma is a rare variant of ependymoma that is typified by single or multiple layers of cuboidal to columnar cells resting upon central fingerlike projections of glial fibrillary "stroma," as seen in the following image. True fibrovascular cores are not seen, and the epithelial-like surfaces tend to be smooth in contour. [3, 51] Cytologic smear preparations likewise tend to contain cells of an epithelioid appearance.

Papillary ependymoma. Note the elongated glial pro Papillary ependymoma. Note the elongated glial processes within these papillary structures. (Hematoxylin and eosin, ×200.)

Clear cell ependymomas are composed of sheets of cells with round nuclei and abundant surrounding clear cytoplasm, and these tumors may closely mimic oligodendroglioma (see the image below). Similar to other ependymomas, however, this uncommon variant forms a discrete margin with surrounding brain parenchyma (unlike oligodendrogliomas, which are infiltrative), and perivascular pseudorosettes can nearly always be identified. True rosettes are absent. [52, 53]

Clear cell ependymoma. Note the vague perivascular Clear cell ependymoma. Note the vague perivascular pseudorosettes and superficial resemblance to oligodendroglioma. (Hematoxylin and eosin, ×200.)

Preferentially arising in a supratentorial location in children, a significant proportion of clear cell ependymomas exhibit notably aggressive biologic behavior as well as histologic features of anaplasia (including endothelial proliferation, hypercellularity, and frequent mitoses), necessitating a grade III designation. [52]  

Anaplastic ependymoma (WHO grade III)

The histologic grading of ependymomas and determination of what role this grading plays in the assessment of clinical prognosis has long been a contentious issue. The WHO 2016 classification puts forth high nuclear-to-cytoplasmic ratio and high mitotic count as essential diagnostic features of anaplastic ependymoma. Diffuse microvascular proliferation and necrosis are accompanying histologic features. [1]  Nuclear pleomorphism is less commmon. Interestingly, despite their malignant designation, anaplastic ependymomas still tend to be well-delineated and solid, with any infiltration limited to the edges of the lesion. By definition, true embryonal/primitive neuroectodermal tumor (PNET)-like components and ependymoblastic rosettes are absent. Cytologic smear preparations of anaplastic ependymomas also harbor nuclear pleomorphism, mitoses, vascular proliferation, and necrosis. [46]

Anaplastic ependymoma. Note the numerous mitoses a Anaplastic ependymoma. Note the numerous mitoses and vascular proliferation. (Hematoxylin and eosin, ×100). Courtesy of Surgical Neurology International [Ng DWK, King NKK, Foo ASC, et al. Anaplastic supratentorial cortical ependymoma presenting as a butterfly lesion. Surg Neurol Int. 2012 Sept 13; 3:107.]

In many instances, these histologic criteria provide for a straightforward and rapid assignment of WHO grade III status [1, 54, 55] ; however, a subset of ependymomas contain few to multiple small zones of "focal anaplasia" with hypercellularity, numerous mitotic figures and, sometimes, vascular proliferation. [56]  Given the inherent subjectivity of ependymoma grading and the lack of definitive correlation with patient outcomes, [54, 57, 58]  it is likely that molecular subgrouping of ependymomas may replace histologic grading for providing appropriate patient prognostication and therapeutic planning. 

Ependymoma, RELA-fusion positive

The WHO 2016 CNS classification recognizes ependymoma, RELA fusion-positive as a new genetically-defined ependymoma variant. [1]  This lesion accounts for approximately 70% of pediatric supratentorial ependymomas, although it may on occasion be encountered in adults. [4, 5]  The C11orf95-RELA oncogenic fusion, a result of chromothripsis, drives aberrant activation of the NF-κB signaling pathway. [4, 5, 59]  Both C11orf95 or RELA may fuse with other partners on occasion and, therefore, the current method of choice for detection of possible fusions is fluorescence in situ hybridization (FISH) using breakapart probe sets shouldering the two gene regions. [5]

There is no specific histopathologic correlate with RELA fusion-positivity, although some have reported a tendency for these tumors to exhibit a clear cell morpholopgy and branching capillaries. [60]  Grading is dependent upon the presence (grade III) or absence (grade II) of anaplastic features. [1]  Detection of L1CAM by immunohistochemistry is usual in RELA fusion-positive supratentorial ependymomas, although such positivity may be seen with a variety of other brain tumors as well. [5]  A single large multi-institutional study suggests that of three molecularly distinct supratentorial ependymal tumor groups (also including supratentorial subependymomas and supratentorial Yes-associated protein 1 (YAP1) fusion-positive ependymoma), RELA fusion-positive ependymomas represents the most biologically aggressive. [61]  

RELA fusion ependymoma. RELA fusion-positive epend RELA fusion ependymoma. RELA fusion-positive ependymoma with branched capillaries. (Hematoxylin & eosin, x200).

Subependymoma (WHO grade I)

Subependymomas tend to have a nodular appearance at low power (as seen in the image below). These hypocellular tumors are composed of bland cells with round to oval nuclei set within a delicate fibrillar matrix. The lesional cells have a tendency to cluster and, although microcysts are commonly encountered, the perivascular pseudorosettes so typical of other ependymal tumors are generally poorly formed or totally lacking. Areas of hemorrhage (and/or hemosiderin-laden macrophages) and calcifications are common, and vessels with sclerotic walls have also been described. [62, 63]

Subependymoma. At low power, these lesions charact Subependymoma. At low power, these lesions characteristically have a nodular appearance. (Hematoxylin and eosin, ×20.)

Focal nuclear pleomorphism and rarely necrosis may be encountered, although these features do not hold any prognostic relevance. [6, 63, 64] Of note, however, up to 20% of subependymomas will also contain significant areas of conventional or even anaplastic ependymoma; these "combined" tumors should be graded according to the highest-grade component present, be it WHO grade II or III. [1]

Lastly, the cytologic features of subependymoma, as demonstrated in smear/squash preparations, mirror the histologic features described above: bland nuclei within a fibrillar background, sometimes with visible microcysts (see the image below). [65]

Subependymoma. These lesions are hypocellular with Subependymoma. These lesions are hypocellular with clusters of cells with bland nuclei set within abundant glial matrix. (Hematoxylin and eosin, ×100.)

Myxopapillary ependymoma (WHO grade I):

As the name implies, myxopapillary ependymomas display a variably papillary architecture with cuboidal to elongated glial cells radially arranged around Alcian blue-positive myxoid stroma with a central blood vessel (see the following images).

Myxopapillary ependymoma. Typical appearance with Myxopapillary ependymoma. Typical appearance with papillary structures containing central blood vessel surrounded by myxoid stroma and cells with elongated glial processes. (Hematoxylin and eosin, ×100.)
Myxopapillary ependymoma. This image contains cell Myxopapillary ependymoma. This image contains cells with a more epithelioid appearance. (Hematoxylin and eosin, ×200.)

Some lesions are not particularly papillary at all, instead exhibiting a more compact or reticular architecture with mucin-rich microcysts and occasional perivascular pseudorosettes. Collagen balls/"balloons" are a finding unique to this ependymoma variant; these structures may be highlighted with periodic acid-Schiff (PAS) and collagen stains. Vascular hyalinization and fibrosis represent degenerative changes that may be quite prominent, masking the typical myxoid and papillary nature of this lesion. [1, 66] Necrosis and vascular proliferation are typically absent, and mitotic figures are rare. Cytologic squash/crush preparations often contain mucin-rich papillary structures, similar to histologic sections. [46]



The typical immunohistochemical staining pattern shared by the majority of ependymal neoplasms is positivity for S100, glial fibrillary acidic protein (GFAP) (see the first image below), and vimentin. [3, 67, 68] Cytokeratin, OLIG2, and SOX10 are generally negative, although rarely focal staining may be encountered. [59] Epithelial membrane antigen (EMA) staining often shows a punctuate, dotlike positivity (see the second image below); ringlike EMA staining is less common. [3, 52, 67]  CD99 and D2-40 are also frequently positive, with variable membranous or dotlike staining. [69] Stains for neural markers are typically negative; however, the solid nature of these tumors can be well demonstrated by a lack of intratumoral neurofilament staining.

Glial fibrillary acidic protein (GFAP) highlights Glial fibrillary acidic protein (GFAP) highlights cell processes in perivascular pseudorosettes. (GFAP, ×400.)
Epithelial membrane antigen (EMA) staining in a cl Epithelial membrane antigen (EMA) staining in a clear cell ependymoma demonstrating a characteristic dot type pattern. (EMA, ×400.)

In addition to the above immunoprofile, myxopapillary ependymomas will frequently be positive for COX2 or p53. [21, 23, 70] Myxopapillary ependymomas are also EMA negative. Subependymomas are positive for both GFAP and S100, and these tumors may show weak positivity for neuronal markers neural cell adhesion molecule (NCAM) and neuron-specific enolase (NSE). In terms of proliferation index, Ki67 labeling is lowest in subependymoma and myxopapillary ependymoma, with WHO grades II and III showing higher labeling indices that are correlative with their respective higher grades. [21, 71]

Electron microscopy

All ependymal tumors show ultrastructural characteristics of ependymal differentiation, including intracellular intermediate filaments, desmosomes, occasional cilia, and microvilli; the latter are present within microlumina and on the cell surface. [39, 48, 49] Interdigitating cell processes and microtubular aggregates bound by rough endoplasmic reticulum are additional features typical of myxopapillary ependymoma. [27]



From a molecular standpoint, evidence continues to mount supporting the concept that ependymomas represent multiple genetically distinct tumor subsets in terms of patient age, site of occurrence, and biologic potential. [11, 72]  For example, genome-wide screening studies have detected a number of chromosomal copy number alterations, including gains on chromosomes 1q, 5q, 7q, 9, 12, and 15, as well as losses on chromosomes 6q, 16, 17p, and 22. [73, 74, 75, 76]  Chromosome 22q loss is frequently detected in adult spinal ependymomas, many of these tumors harboring concomitant mutation of NF2; this is not the case for intracranial ependymomas with 22q deletions. [11, 77, 78] In contrast, intracranial ependymomas are more likely to show 1q gain, irrespective of patient age. [79]  At the gene expression level, homeobox-containing genes tend to be expressed at high levels in extracranial ependymomas, whereas high expression of Notch is more frequent in intracranial examples. [80]

A number of alterations have been found to be associated with more biologically aggressive ependymomas. For example, gain of chromosome 1q and deletion of CDKN2A are not only more frequently encountered in pediatric intracranial ependymomas, these alterations likewise tend to correlate with anaplastic histology, increased recurrence, and shortened survival. [74, 81, 82, 83, 84, 85]  In pediatric posterior fossa ependymomas, activatiation of the Notch pathway as well as tenascin-C expression may be associated with tumor progression, whereas overexpression of neurofilament light popypeptide 70 (NEFL) may correlate with longer progression-free survival in pediatic supratentorial ependymomas. [86, 87]  Altered expression of telomerase, p53, bcl2, MMP2 and 14, EZH2, EVI1, PDGFRα, cyclin D1, nestin, nucleolin, and claudin-5 have all been implicated as potential prognostic markers; additional testing will be required to establish any of these as clinically relavent ependymoma biomarkers. [88, 89, 90, 91, 92, 93, 94, 95, 96, 97]  Micro-RNAs have likewise been found to be differentially expressed in ependymomas, with several individual miRNAs implicated to have potential prognostic significance. [98, 99]

More recently, high-resolution genetic/epigenetic profiling platforms have been instrumental in helping define biologically distinct ependymoma subgroups. As noted above, supratentorial ependymal tumors include the biologically banal subependymoma, as well as two molecularly-defined subgroups (ependymoma with YAP1 fusions, and the much more biologically aggressive ependymoma, RELA fusion-positive). [4, 5, 61]  Similarly, there is evidence that posterior fossa ependymomas can be divided into prognostically distint groups. Posterior fossa group A ependymomas are notable for a balanced genome and aggressive biologic behavior/shorter survial; these tumors tend to be laterally situated, arising mostly in infants/young children, and exhibit frequent recurrence and metastases. By comparison, posterior fossa group B ependymomas are typified by frequent chromosomal copy number alterations and significantly better patient outcomes, these tumors tending to arise in older children and adults. [61, 83, 100, 101]  Epigenetic silencing of tumor suppressor genes via hypermethylation may represent an important mechanism in the pathogenesis of pediatric ependymomas of supratentorial and spinal origin, [102]  and it appears that posterior fossa group A ependymomas also tend to exhibit a CpG island methylator or "CIMP" phenotype. [103]  

Myxopapillary ependymomas are frequently polyploid/aneuploid, harboring gains in chromosomes 5, 7, 9, 16, and 18, and/or losses involving 22q and 1p. [75, 104]  Overexpression of HOXB13, NEFL, and PDGFRα have been detected in pediatric cases. [105]  NF2 alterations have not been documented in subependymomas, [6]  whereas expression of HIF-1α, pSTAT3, nucleolin, and topoisomerase IIβ have been described. [106]


Tumor Spread and Staging

Both World Health Organization (WHO) grade II and III (anaplastic) ependymomas may metastasize along cerebrospinal fluid (CSF) pathways in the subarachnoid space to seed other spinal and intracranial regions; rare extracranial/extraneural metastases have been described. [52, 107, 108] Although myxopapillary ependymomas don't typically metastasize/disseminate in the adult population, their pediatric counterparts exhibit a significant rate of dissemination through the CSF pathways. [8]  Subependymomas do not exhibit metastatic potential; however, they may rarely recur. [6]


Prognosis and Predictive Factors

Adults with ependymomas tend to fare far better than their pediatric counterparts, due in part to the much higher incidence of anaplastic histology and posterior fossa localization in children, thus making complete resection technically difficult. [109] Adults with ependymomas experiencing the poorest outcomes include those whose tumors have a supratentorial location, tumor anaplasia, and high proliferative index. [110, 111, 112, 113, 114]  Postoperative radiation therapy may afford improved progression-free and overall survival for pediatric ependymomas, including the very young. [115, 116] Nonetheless, children acquiring ependymomas within the first few years of life have exceptionally poor outcomes, given the significant morbidity generated from administering radiotherapy to these immature brains. [54]  Studies have indicated that chemotherapy may represent a beneficial therapy in children with residual postsurgery tumor burden. [117, 118, 119, 120]

Overall, adequacy of tumor excision has proven to be a reliable predictor of both recurrence-free and overall survival in patients from all age groups with intracranial ependymomas. [3, 54, 57, 113, 121, 122, 123, 124]  Similarly, incomplete resection represents the only independent predictor of recurrence for spinal cord ependymomas. [125] Demonstration of tumor invasion from a microscopic standpoint on the original resection specimen may be an indicator of poor prognosis. [126] The vast majority of first recurrences are at the site of the resection cavity, and radiation therapy may enhance recurrence-free survival in those tumors that are incompletely excised, including spinal ependymomas. [57, 115, 116, 122, 127] Adjuvant chemotherapy appears to be less beneficial, except as noted above. [128]  Cerebrospinal fluid (CSF) dissemination portends a poor prognosis.

Histologic grading (grade II vs grade III) has been found to significantly correlate with overall and/or recurrence-free survival in some ependymoma series, [33, 54, 56, 57, 121, 122, 124, 129, 130] but not others. [117, 123, 126]  By immunohistochemistry, elevated Ki67 proliferation index likewise correlates well with anaplastic ependymoma status and aggressive biologic behavior. [109, 123, 57, 131, 132]  Detection of cyclin D1, telomerase, nestin, or PDGFR-alpha overexpression in ependymomas has also been found to correlate with poor prognosis. [109, 133, 134, 135]  

Aside from histologic grading, particular ependymoma subgroups/histologies are associated with fairly predictable clinical outcomes. For example, clear cell ependymomas tend to represent more aggressive tumors, often displaying histologic features coinciding with grade III status. These tumors have been documented to exhibit the unusual capacity for transdural invasion into venous sinus spaces or metastasis into lymph nodes and soft tissue. [52]  As noted elsewhere, high-resolution genetic/epigentic methods have been instrumental in identifying multiple molecularly-defined ependymoma subgroups; the most biologically aggressive of these are the posterior fossa group A and supratentorial RELA fusion-positive ependymoma, both of which predominate in the pediatric population. [61]

Myxopapillary ependymomas tend to be slow-growing with prolonged overall survival. Unfortunately, almost one half of these patients will experience local recurrence, regardless of the extent of surgical excision. Encapsulated myxopapillary ependymomas tend to have a lower recurrence rate, and adjuvant radiation therapy helps reduce tumor recurrence. [7, 136] As noted elsewhere neuraxis recurrence/metastasis may be encountered with myxopapillary ependymomas, mainly in the pediatric age group; these children require complete neuraxis screening both at the time of diagnosis and during follow-up. [8, 137, 138, 139, 140, 141] Expression of EGFR has been found by some to correlate with myxopapillary ependymoma recurrence. [142, 143]

Lastly, the vast majority of subependymomas remain clinically silent through life, detected only at autopsy as an incidental finding. When these tumors do come to clinical attention due to symptomatology, complete resection is generally curative. The exception to this rule occurs in subependymomas harboring other ependymoma components, in which case these tumors tend to follow a clinical course similar to the higher-grade component. [6, 64]

Diagnostic considerations

A wide variety of central nervous system (CNS) neoplasms may be confused with ependymomas. A solid growth pattern, as evidenced by lack of significant intratumoral neurofilament-positive processes, is a reliable feature of ependymomas that differentiates them from the various infiltrative gliomas. Ependymal canals/rosettes are another useful histologic signature, although these are only encountered in a subpopulation of ependymomas. As noted elsewhere, perivascular pseudorosettes are much more commonly encountered, although these features are unfortunately much less specific than ependymal canals in verifying an ependymoma identity. IDH1 mutation, a frequent feature of most low-grade infiltrative astrocytomas and oligodendrogliomas, has not been encountered in ependymomas. [144, 145]

Pilocytic and pilomyxoid astrocytoma may both harbor perivascular pseudorosette-like formations; however, ependymomas do not possess the Rosenthal fibers and eosinophilic granular bodies typical of the former, nor do conventional ependymomas exhibit the abundant myxoid microcystic background of the latter. BRAF alterations (fusions or mutations) are also not a feature of ependymomas, although are detectable in the majority of pilocytic and pilomyxoid astrocytomas. [146]

Astroblastoma, an exceedingly uncommon lesion of unknown lineage, also contains perivascular pseudorosettes, although these areas contain characteristically short, wide processes in contrast to the delicate long processes in ependymomas. Angiocentric glioma may likewise contain perivascular pseudorosettes; however, these lesions also show variable infiltrative features and exhibit a longitudinal orientation of perivascular arrangements, both features not present in ependymomas. [147]

A number of specific ependymoma variants may pose significant diagnostic challenges. For example, tanycytic ependymoma with its spindled fascicular appearance may closely resemble schwannoma or meningioma. GFAP positivity may be quite variable in the tanycytic ependymoma and may also be infrequently encountered in schwannomas. Collagen IV is therefore, a more reliable marker for schwannoma, typically showing a diffuse intercellular positivity; this pattern is not present in ependymomas. [18]

Clear cell ependymoma may resemble a number of primary CNS lesions with "clear cells" (oligodendroglioma, neurocytoma, and hemangioblastoma) as well as metastatic clear cell carcinomas. Identification of perivascular pseudorosettes is key to the diagnosis of clear cell ependymoma; immunohistochemistry findings (especially dotlike EMA positivity), electron microscopic features of ependymal differentiation, and molecular findings (lack of 1p/19q deletion or IDH1 mutation) are additional supportive features confirming this diagnosis. [52, 53]

Choroid plexus tumors, papillary meningiomas, papillary tumor of the pineal gland, and metastatic carcinomas may mimic papillary ependymoma; however, strong positivity for GFAP and lack of diffuse cytokeratin staining are diagnostic of the latter, and electron microscopic confirmation is usually not necessary. [3]

Lastly, myxopapillary ependymoma has a number of potential diagnostic mimics including chordoma, renal cell carcinoma, myxoid chondrosarcoma, and paraganglioma. Immunohistochemistry will typically solve this conundrum, with myxopapillary ependymoma exhibiting a pattern of positivity distinct from the other entities (positive for vimentin, S100, and GFAP; negative for cytokeratin). [148]