Epidemiology

Ependymomas constitute approximately 5% of adult intracranial gliomas and up to 10% of childhood CNS tumors. Ependymomas are the third most common childhood brain tumor. There is a peak incidence at age 5 years and then again at age 34 years.

Pathology

Ependymomas are tumors that resemble normal ependymal cells and tend to occur along the surfaces of the ventricles. They may also occur in the parenchyma adjacent to the ventricle or anywhere along the entire length of the spinal canal and the filum terminale. More than 60% of ependymomas occur infratentorially, most of which occur in the posterior fossa, and arising predominantly from the fourth ventricle. Most supratentorial ependymomas are parenchymal rather than intraventricular in location, and occur most frequently in the frontal and parietal lobes. Tumor extension may occur along the leptomeninges, around the medulla and upper cervical cord to the conus, and along nerve roots; ependymal cells may be found in the CSF.

Ependymomas are classified as either differentiated (low-grade or grade II) or anaplastic (malignant or grade III) tumors. Most are cellular tumors consisting of uniform polygonal cells in a collagenous background with well-defined cytoplasmic borders. They may also contain areas of cysts, calcifications, and occasional hemorrhage. Some groups of cells form clusters around a circumscribed central space (ependymal rosette). Anaplastic ependymomas have features that resemble GBM. These lesions may have high mitotic activity, endothelial proliferation, and necrosis. A very highly cellular, embryonal form of ependymal tumor occurring in infants and children younger than age 5 years is the ependymoblastoma.¹⁷⁴ This tumor is biologically and pathologically distinct from the other types of ependymomas. The ependymoblastoma often disseminates along the CSF pathways and requires irradiation of the craniospinal axis (CSA). Children with this tumor rarely live more than 2 to 3 years. Ependymoblastomas are most likely a form of PNET with ependymal differentiation, and are treated in the same fashion as medulloblastoma. This variant of ependymoma should be regarded as distinct from malignant (anaplastic) ependymoma in terms of treatment.

Prognostic Factors

One of the most important prognostic variables is the amount of residual tumor after resection.¹⁷⁵ Children with low-grade nondisseminated ependymomas that have been completely resected have the best prognosis, whereas incomplete resection or dissemination carries a poor prognosis. The retrospective series by Horn and colleagues evaluated the outcome of 83 children with ependymoma treated at 11 institutions between the years 1987 and 1991.¹⁷⁵ This is an important contemporary review and the data is useful as a baseline from which to compare new trials. In this review, the overall survival at 5 and 7 years was 57% and 46%, respectively; event-free survival for the same periods was 42% and 33%. Patients younger than age 3 years had significantly worse outcome. Univariate analysis revealed that young age, subtotal resection, and grade III histology were important adverse risk factors for event-free survival. Overall survival was negatively influenced by the same factors, with high-grade histology having only borderline significance (p = .05) in a multivariate analysis. Most patients (89%) progressed at the original tumor location. Adjuvant chemotherapy or CSA irradiation did not significantly influence outcome. The authors concluded that improvement of local control is an important goal for future studies.

There are conflicting data concerning the prognostic implications of anaplasia in these tumors.^176,177 Ross and Rubinstein reviewed a series of 15 patients classified as having anaplastic ependymomas (excluding cases of ependymoblastoma) in an attempt to correlate pathology with survival; postoperative survival was not found to correlate with anaplastic histology. The median survival for 10 patients with malignant tumors was 8.8 years; 5 patients who had tumor recurrence died within 13 months to 6 years (median 2.5 years). In their review, Horn and colleagues found WHO grade III histology a significant adverse risk factor for overall survival and event-free survival in univariate analyses, but only of borderline significance in overall survival when correcting for other factors, such as extent of disease.¹⁷⁵

Clinical Presentation

Clinically, patients may present with subtle signs and symptoms for years before the diagnosis is made or may present abruptly with obstructive hydrocephalus or an expanding ependymoma of the spinal cord. Other focal findings include visual field defects, focal seizures, headache, nausea, and vomiting.

Diagnostic Neuroimaging

The neuroimaging of ependymomas is nonspecific, but some findings are useful that suggest the diagnosis, including calcification associated with a fourth ventricular tumor. They tend to extend out of the fourth ventricle into the cerebellum, foramen magnum, cerebellopontine angle, and upper cervical arachnoid space. The MRI appearance of ependymomas is heterogeneous. The solid portions are hypointense on T1WI and hyperintense on T2WI. Almost all ependymomas are contrast enhancing, although the enhancement is often irregular and patchy. Intratumoral cysts are more common in supratentorial ependymomas and usually have slightly higher intensity signal than CSF on T1WI. Because many lesions may be confused with ependymomas (such as PNETs), treatment should not proceed without histologic verification of the tumor and an assessment of the degree of anaplasia.

Treatment

The goal of surgery for ependymoma should be to achieve a GTR as often and as safely as possible. Unfortunately, extensive resection is often impossible, particularly for lesions of the posterior fossa or for spinal cord ependymomas involving the cauda equina. Supratentorial lesions are more amenable to GTR. In patients older than age 3 years with GTRs of low-grade nondisseminated ependymomas, deferring further adjuvant therapy may be a viable option. In one study, all 5 patients with the above tumor profile were alive after a median follow-up of 44 months, with a median progression-free survival over 38 months.¹⁷⁸ Low-grade ependymoma of the spine may be managed with surgery alone if the resection is complete. Staging is a critical aspect in the management of ependymomas. This involves an MRI of the brain and the entire spinal cord with contrast, as well as CSF cytology to rule out neuraxis dissemination.

Several retrospective series strongly suggest an advantage to the addition of radiation therapy in improving survival.^179–181 In the series by Ernestus and colleagues, patients with supratentorial grade II ependymomas treated with radiation had a median survival 185 months. The benefit of postoperative irradiation was even more striking in patients who underwent only a partial resection: the median disease-free survival was 9 months in patients undergoing surgery only, but was more than 108 months in those who received postoperative radiation therapy. Survival was only 21 months for those with grade III tumors despite irradiation. Other trials have documented the radiosensitivity of ependymomas. The literature does not identify, however, the optimal perimeters of the radiation field for treating ependymomas in specified locations or whether the craniospinal axis should always be included in the field. The risk of spinal subarachnoid metastasis is greatest with infratentorial anaplastic ependymomas (approximately 30%) and is least likely with supratentorial low-grade ependymomas (5% to 10%). There is also a risk of intraventricular and intracranial spread from a malignant supratentorial lesion. For these reasons, the extent of the irradiated field is an important issue. Salazar and colleagues reported a local control rate of 12% using small-volume fields, as compared to 78% control with whole-brain irradiation in a group of patients with low-grade ependymomas.¹⁸⁰ The 5-year survival rate was 12% with partial-brain and 67% with whole-brain treatment. Other series show no benefit to craniospinal irradiation.^{175,177,182,183} Because the primary site of recurrence of both low- and high-grade ependymomas is usually within the local radiation field, whole-brain or craniospinal irradiation is probably not indicated. Staging is a critical aspect in the management of ependymomas. The consensus management approach is to give focal irradiation after maximal resection to the resection cavity and to the surrounding tissue area, rather than CSA irradiation if there is no evidence of dissemination.

Chemotherapy unfortunately has only a minor role in these tumors, and may be most useful in the treating of recurrent ependymoma. Adjuvant chemotherapy does not improve overall survival in ependymoma patients. Despite their frequent posterior fossa location, ependymomas, unlike PNETs, are fairly chemoresistant. These tumors are occasionally sensitive to several agents, including the nitrosoureas and platinum compounds. A CCG study randomized pediatric patients with newly diagnosed posterior fossa ependymomas into two groups: those who received CSA irradiation, and those who received CSA irradiation and an adjuvant chemotherapy regimen of CCNU, vincristine, and prednisone for 1 year. There was no difference in outcome between the two groups, suggesting that this chemotherapy regimen does not improve survival of infratentorial ependymoma patients.¹⁸⁴ Much more research is needed to find new agents to treat ependymoma.