Pathology

Ependymomas are found throughout the neuraxis; however, anatomic distribution typically varies by age. Supratentorial tumors are usually diagnosed in older children.14 The 2007 World Health Organization (WHO) classification recognized three grades of ependymomas: grade I, subependymoma and myxopapillary ependymoma; grade II, differentiated ependymoma lacking malignant features; and grade III, anaplastic ependymoma. These tumors, whether supratentorial or infratentorial, are typically well defined and have monomorphic round-to-oval nuclei with dispersed chromatin. In higher grade tumors, the nuclei are irregularly shaped and polymorphic with condensed chromatin. Other features of malignant ependymoma include brisk mitotic activity, vascular proliferation, and pseudopalisading necrosis. Histological hallmarks include perivascular and ependymal rosettes15 ( Figs. 18.1 and 18.2; Table 18.1 ).

Immunohistochemically, all ependymal tumors demonstrate glial fibrillary acidic protein (GFAP) immunoreactivity. Unlike neoplasms of the choroid plexus, ependymomas also demonstrate neural cell adhesion molecule (NCAM; CD56) immunoreactivity. Immunoreactivity toward epithelial membrane antigen (EMA) may also be useful in diagnosis.16 Interestingly, a recent comparison of immunohistochemical markers in ependymoma noted increased neurofilament light polypeptide 70 (NEFL) immunoreactivity in supratentorial tumors, indicating some degree of neuronal differentiation in comparison to infratentorial tumors.17

Clear-cell ependymoma and subependymoma are the most common histological variants of ependymoma seen in the supratentorial brain. Clear-cell variants typically resemble oligodendroglioma, with regularly distributed cells with clear cytoplasm and inconspicuous perivascular rosettes. High mitotic index and vascular proliferation may grant these neoplasms a WHO grade III designation, which is further supported by the observation that this tumor subtype has a predilection for extraneural metastases and early recurrence.18 Subependymomas are solid, sometimes calcified, slow-growing nodules attached to the ependymal lining and intruding into the ventricle. This variant exhibits clumps of ependymal-appearing nuclei, scattered in a dense, finely fibrillar background.19

Genetics

Although ependymomas from the supratentorial and infratentorial compartments share histological features, the assumption that neoplasms in different anatomic locations share similar molecular biology may be incorrect. Anatomically distinct chromosomal abnormalities suggest that ependymomas of different locations are in fact diverse at the molecular level. 20–22 Distinct patterns of chromosomal gain or loss and unique gene expression signatures have been noted based on tumor location. Recent comparative genomic hybridization studies have confirmed regions of recurrent low-level chromosome 1q gain, which significantly correlated with high-grade intracranial tumors in pediatric patients.23,24

Gene expression profiling of supratentorial ependymomas has shown the distinct overexpression of several components of the EPHB–EPHRIN and NOTCH cell signaling pathways responsible for regulating cell proliferation and differentiation, namely elevated expression of EPHBEPHB2/3/4, EPHRINA3/4, JAGGED1/2, and CYCLINB2/D1/G.23 Indeed, a recent study demonstrates that aberrant EPHB2 signaling and deletion of Ink4a/Arf disrupt key neural differentiation pathways in embryonic stem cells during the formation of supratentorial ependymomas.25 In addition, the genomic loss of 9p occurs preferentially in pediatric supratentorial ependymomas containing deletions in CDNKN2A/p161Nk4.23,24,26 CDKN2A, a tumor suppressor gene located at 9p21.3, regulates neural stem cell proliferation; its deletion has been shown to rapidly expand progenitor cell numbers in developing neural tissue.27 Although gene expression analysis has revealed that CDKN2A is upregulated in spinal tumors, it is downregulated to much greater magnitude in supratentorial tumors.24 Furthermore, although epigenetic analysis has shown a significant difference in the methylation of neighboring CD-KN2B between spinal and supratentorial tumors, fluorescent in-situ hybridization has shown that CDKN2A deletion is virtually exclusive to supratentorial ependymomas.23,28 Other genes on 9p that seem to be downregulated exclusively in supratentorial ependymal tumors include FREM1, C9orf24, and KIAA116.26 Supratentorial ependymomas also express significantly higher amounts of the adenosine triphosphate (ATP)-binding cassette transporter G1, a protein central to chemotherapeutic resistance, relative to ependymomas elsewhere in the central nervous system.29 Thus, inhibitors of ATP-binding cassette transporters may prove to be useful therapeutic agents to increase the sensitivity of ependymoma cells to conventional treatments.

Overall, gene expression patterns in ependymoma have demonstrated similarity to those of radial glial cells, suggesting that this cell line may be a stem cell precursor population.23 In comparison with normal human brain samples, however, the specific gene expression patterns perturbed in supratentorial ependymomas have proven elusive.26 Furthermore, although numerous candidate genes have been investigated, few actual mutations have been identified in pediatric intracranial ependymal neoplasms.30–34 Although genomic hybridization and expression profiling studies have distinguished ependymomas based on tumor location and suggested gene pathways that may be dysregulated, focal genetic events or aberrant epigenetic mechanisms involved in the pathogenesis of supratentorial ependymoma remain unknown.

Imaging Characteristics

Whereas computed tomography (CT) provides superior demonstration of calcification within tumors, magnetic resonance imaging (MRI) is the preferred modality for the diagnosis and evaluation of supratentorial ependymomas. CT scanning reveals isodense or mildly hyperdense soft tissue components, often displaying heterogeneous enhancement postcontrast. On MRI, intracranial ependymomas generally demonstrate T1 hypointensity, T2 hyperintensity, and fluid-attenuated inversion recovery (FLAIR) hyperintensity relative to brain parenchyma. Of note, however, is that both T1 and T2 signal intensity may be heterogeneous within the supratentorial tumor. This is due, in part, to the greater propensity for cyst formation and myxoid accumulation than in infratentorial tumors.35,36 These cystic areas may remain isointense to water on T2 and FLAIR sequences or may even appear hyperintense on FLAIR because of the protein content. Classically, strong enhancement of the soft tissue portions of the tumor are noted on T1-weighted images obtained after gadolinium administration, although these areas may be intermixed with nonenhancing components ( Fig. 18.3; Table 18.2 ).

Although infrequently used, perfusion MRI of ependymomas usually demonstrates markedly elevated cerebral blood volume with poor return to baseline. Proton MRI spectroscopy usually demonstrates elevated choline and reduced N-acetylaspartate, as may be found in many other brain tumors. Diffusion-weighted imaging demonstrates diffusion restriction within the soft tissue components of ependymomas because of high cellularity; however, diffusivity values may be unreliable and thus are not recommended for histological diagnosis.

Unlike infratentorial ependymomas, most supratentorial tumors are extraventricular in origin (70%), arising within the cerebral parenchyma. These extraventricular ependymomas are thought to originate from rests of ependymal cells retained within the brain during embryonic development. However, supratentorial ependymomas are often located near ventricular margins and may extend into the ventricular system. Hydrocephalus occurs relatively late in comparison to ependymomas of the posterior fossa, usually as a result of significant subfalcine herniation. By this time, the tumor is typically large, with a diameter than may exceed 4 cm at presentation.35,36 Intraventricular ependymomas, comprising 30% of supratentorial tumors, generally arise along the surfaces of the septum pellucidum or lateral ventricles. Ependymomas arising within the third ventricle are considered exceptionally rare.37,38

Complete contrast-enhanced, biplanar spinal imaging should be done preoperatively to assess for spinal metastases. If done postoperatively, it should be delayed for at least 1 to 2 weeks as blood products and inflammation from surgery can make the interpretation of the imaging difficult.

Surgical Management

Complete surgical resection is undoubtedly the most important treatment modality for supratentorial ependymoma. Patients with gross total resection (GTR) of tumors defined by postoperative MRI have a much better prognosis (69–83% five-year survival) than do patients with incompletely resected supratentorial lesions (21–46% five-year survival).12,13,39–41 However, complete resections are achieved in only 40 to 60% of patients.12,39,42 GTR is more easily accomplished with supratentorial ependymomas compared with infratentorial ependymomas and is usually associated with fewer postoperative deficits because of lack of adherence to the brainstem and cranial nerve involvement.43 Indeed, GTR of the primary tumor has even shown prognostic significance in children with metastatic disease.44

Because of the significant impact on survival, second-look surgery is warranted to achieve GTR.43,45 The decision to proceed with second-look surgery and GTR is not always easy and may leave the patient with significant neurologic deficits. Thus, some authors have suggested preoperative use of chemotherapy in facilitating resection of residual tumor in a second operation.46,47 This is particularly useful in young infants with very vascular tumors as chemotherapy may markedly reduce the vascularity and facilitate re-resection.

To achieve GTR in supratentorial tumors, careful presurgical planning is essential. Because hypercellularity on initial MRI may suggest the diagnosis of ependymoma, intraoperative biopsy is needed for confirmation. Careful examination of pre-operative imaging is of paramount importance, as heterogeneous gadolinium enhancement may make comparison of pre- and postoperative imaging difficult. Postoperative MRI should be obtained within 24 to 48 hours to minimize postsurgical artifact and accurately estimate residual tumor, if any. In the case of supratentorial lesions, the tumor is usually quite distinct from normal brain, allowing for clear margins. Occasionally, pre-operative magnetic resonance (MR) angiogram is useful for determining vascular supply, particularly with intraventricular tumors. In those patients with tumors within or near eloquent cortex, physiological mapping or monitoring techniques should be considered in conjunction with special modalities such as functional MRI and tractography (diffusion tensor imaging [DTI]) to reduce the risk of postoperative morbidity.