OVERVIEW: What every practitioner needs to know

Ependymoma is a rare central nervous system tumor affecting 2.0-2.3/million people in the United States, and occurring more commonly in children than adults. Symptoms of ependymoma are dependent on the location of the tumor, with intracranial tumors causing increased intracranial pressure, headache, ataxia, seizures, and nausea and vomiting, and spinal tumors causing weakness and back pain. Definitive treatment includes surgery and radiotherapy (dependent on the location), whereas treatment with chemotherapy has not been found to provide durable control.

Are you sure your patient has ependymoma? What are the typical findings for this disease?

A careful history, detailing the length and pattern of symptoms, might provide the clinician with a hint to the aggressive nature of ependymoma. Most of these tumors, particularly those that are anaplastic, produce symptoms over months to weeks. Sometimes ependymoma growth can be slower and cause insidious symptoms. Signs and symptoms of ependymoma correspond to the central nervous system (CNS) compartment involved.

Spinal cord ependymoma tends to present in older children and adults with long-standing back pain, with or without motor or sensory deficits, and sometimes bladder or bowel symptoms.

Posterior fossa ependymoma presents in younger children and frequently includes symptoms and signs of increased intracranial pressure, such as headache, fatigue, diplopia, papilledema, nausea, vomiting, ataxia, vertigo, head tilt, or neck pain.

Supratentorial ependymoma may be associated with headache, seizures, focal neurologic deficits (e.g., hemiparesis, hemisensory symptoms), or behavioral changes.

What other disease/condition shares some of these symptoms?

The back pain associated with spinal ependymoma is often insidious because of the slow-growing nature of this tumor. Thus, the full differential diagnosis of subacute to chronic back pain may be invoked in this situation (e.g., spinal stenosis, disk herniation, other malignancies, or infection).

Posterior fossa symptoms may occur with other causes of increased intracranial pressure, such as other brain tumors (e.g., medulloblastoma, pilocytic astrocytoma, or brainstem glioma), aqueductal stenosis with hydrocephalus, hydrocephalus due to other causes, or intracerebral hemorrhage.

Supratentorial symptoms may occur with other tumors (e.g., astrocytoma, primitive neuroectodermal tumors), stroke, intracerebral hemorrhage, or infection.

What laboratory studies should you request to help confirm the diagnosis? How should you interpret the results?

Neuropathologic examination of the surgical specimen is key! This examination will reveal the precise histologic diagnosis and grade of the tumor. Ependymoma has three grades according to the World Health Organization (WHO), based on cellularity, presence of mitoses, microvascular proliferation, and pseudopalisading necrosis.

WHO I: myxopapillary and subependymoma. These tumors are molecularly distinct from grade II and grade III ependymomas. Subependymoma occurs typically in the fourth ventricle, whereas myxopapillary ependymoma is almost exclusive to the conus medullaris/cauda equina.

WHO II: well differentiated (sometimes subcategorized as cellular, papillary, clear cell, or tanycytic)

WHO III: anaplastic

Brain and spine magnetic resonance imaging (MRI) with and without gadolinium. See below.

Cerebrospinal fluid cytologic examination to rule out dissemination of disease. In general, dissemination at presentation is rare in ependymoma. Fluid must be sampled from the lumbar subarachnoid space, not the ventricular system, and should be taken 10-14 days after surgery, once surgical debris within the CSF has dissipated, so that cytologic analysis will not be confounded.

Would imaging studies be helpful? If so, which ones?

MRI of the brain with and without gadolinium

Ependymoma often manifests as a well-circumscribed lesion with varying degrees of heterogeneous enhancement on MRI. This tumor sometimes contains cystic components, hemorrhage, or calcification. Ependymoma is typically hypointense or isointense to gray matter on T1-weighted images, and enhances heterogeneously with gadolinium contrast. T2-weighted images reveal ependymoma as hyperintense to gray matter.

MRI of the spine with and without gadolinium

Spinal cord ependymoma induces cord expansion, reveals gadolinium enhancement, and may be associated with cysts. Because of alterations in CSF flow, this tumor can cause dilatation of the central canal, resulting in hydromyelia, or what many practitioners refer to as syrinx. Cauda equina ependymomas demonstrate hyperintensity on T2-weighted MRI imaging, with homogeneous gadolinium enhancement.

For ependymomas of the brain, MRI of the spine is required to rule out metastases. This imaging can be done preoperatively, or 10-14 days after surgery, once any postoperative changes have resolved.

Computed tomography (CT) of the brain

Ependymoma is usually isointense to brain parenchyma on CT of the head, with cystic components and calcifications seen in 50% of cases.

Confirming the diagnosis

Because ependymoma is a rare disease, there are no standard diagnostic algorithms.

If you are able to confirm that the patient has ependymoma, what treatment should be initiated?

As with any CNS tumor, the clinician should assess for increased intracranial pressure or spinal cord compression.

Patients should be referred immediately to a neurosurgeon for resection and then to a neurooncologist and radiation oncologist for appropriate treatment.

Treatment always begins with surgical resection. In some cases, (e.g., myxopapillary ependymoma at the conus medullaris, subependymoma, and supratentorial ependymoma sparing the ventricles), complete resection of the tumor is curative, but patients should be routinely monitored for recurrent disease.

Any ependymoma of the posterior fossa, ependymoma invading the ventricular system (except subependymoma), or ependymoma incompletely resected in the cerebral parenchyma requires local field radiotherapy of 5400 to 6000 cGy. Although a few investigators have advocated withholding radiotherapy after a gross total resection of cerebellar ependymoma, such is not standard of care and may lead to inferior outcome. Metastatic ependymoma always requires craniospinal irradiation.

Incompletely resected myxopapillary ependymoma may be observed or followed with irradiation. There is no clear consensus.

Chemotherapy has proved disappointing in ependymoma therapy. However, chemotherapy may be useful in infants as a means of decreasing disease before radiotherapy. Delaying radiotherapy for years has been associated with a higher rate of recurrence and death. The most effective chemotherapeutic agents have been vincristine, cyclophosphamide, cisplatin, and etoposide, the lattermost often administered orally.

Chemotherapy might be efficacious in children with postsurgical residual tumor compared with similar patients receiving radiotherapy alone. Children receiving chemotherapy for incompletely resected ependymoma are likely best managed on a cooperative group trial, such as those of the Children’s Oncology Group or the International Society of Pediatric Oncology. Chemotherapy is often used at time of recurrence, and again, the child may be best managed on an investigational protocol.

Endocrinologic assessment after surgery and before radiotherapy is important. Increased intracranial pressure, hydrocephalus, and cranial irradiation can all lead to hormone deficiency. Baseline assessment of serum insulin-like growth factor 1, insulin-like growth factor binding-protein 3, thyroid-stimulating hormone, and free T4 is indicated, or the child should be referred to an endocrinologist.

Infratemporal radiation can lead to hearing loss, and the child with posterior fossa ependymoma should undergo pure-tone audiometry before any adjuvant therapy.

What are the adverse effects associated with each treatment option?

Surgery: perioperative infection or stroke, cerebellar affective syndrome, cranial neuropathies and brainstem dysfunction

Chemotherapy: almost all chemotherapy acutely can cause alopecia, nausea and vomiting, pancytopenia, and loss of appetite and weight loss, and can lead to infection or kidney or hepatic dysfunction. Long-term effects include secondary malignancies, infertility, peripheral neuropathies, hearing loss, and seizures. Other late effects of chemotherapy are well detailed in the Children’s Oncology Group Long-Term Survivorship Follow-Up Guidelines at www.survivorshipguidelines.org.

Radiotherapy: endocrinopathies, secondary malignancies, stroke, vascular malformations, and neurocognitive changes, including dysfunction in short-term memory, spatial relations, calculations, and/or visuomotor processing

What are the possible outcomes of ependymoma?

Important factors for prognosis include the following:

Age of patient: Infants tend to fare worse than older children, and the outcome for adults with tumor outside the spine is worse than in children.

Tumor location: Infratentorial tumors have a worse prognosis. Spinal tumors have the most favorable outcomes.

Extent of surgical resection: Incomplete resection of a grade II or III ependymoma has the worst prognosis and might make the disease incurable.

Grade: There is controversy about whether grade II versus grade III affects prognosis.

For grade II and grade III ependymomas, the best chance for survival occurs with gross total resection followed by focal radiotherapy. The 5-year overall survival for completely resected ependymoma followed by irradiation is approximately 75%-90%, whereas for incompletely resected ependymoma it is roughly 30%-50%.

Ependymoma recurrence typically occurs near the primary site.

What causes this disease and how frequent is it?

The cause of this rare cancer is unknown. Overall incidence estimates for ependymoma range from 2.0-2.3/million people in the United States. Ependymoma represents 1.9% of all primary CNS tumors, yet in children it makes up 8%-10% of brain tumors. Ependymomas compose 24% of childhood and 33.5% of adult spinal cord and cauda equina tumors.

Detailed Epidemiology

Ependymoma occurs more commonly in children, in whom it is the third most common intracranial tumor. The incidence is slightly higher in male than in female patients. Racial differences exist, with the highest incidence in whites (2.1/million whites versus 1.4/million African Americans).

The location of ependymoma varies between age groups, with children typically having intracranial tumors and adults more commonly having spinal cord tumors.

Genetic analysis of ependymoma has not led to any definitive single gene as being causative. The most common genetic abnormalities found in ependymoma are monosomy or translocations of chromosome 22, detected in 30% of ependymomas. However, genomic studies show that supratentorial, infratentorial, and spinal tumors likely arise from different stem cell (radial glial) populations and, thus, different genetic mutations.

Neurofibromatosis type 2 confers an increased risk of ependymoma, with most neurofibromatosis-related ependymoma occurring in the spine.

What complications might you expect from the disease or treatment of the disease?

Complications may stem from surgery, radiotherapy, or chemotherapy, as noted above.

How can ependymoma be prevented?

At present, there are no known preventive strategies for these cancers.

What is the evidence?

Carter, M, Nicholson, J, Ross, F. “Genetic abnormalities detected in ependymomas by comparative genomic hybridization”. Br J Cancer. vol. 86. 2002. pp. 929-39.

Duffner, PK, Krischer, JP, Sanford, RA, Horowitz. “Prognostic factors in infants and very young children with intracranial ependymomas”. Pediatr Neurosurg. vol. 28. 1998. pp. 215-22.

Healey, EA, Barnes, PD, Kupsky, WJ. “The prognostic significance of postoperative residual tumor in ependymoma”. Neurosurgery. vol. 28. 1991. pp. 666-72.

Korshunov, A, Witt, H, Hielscher, T. “Molecular Staging of INtracranial Ependymoma in Children and Adults”. J Clin Oncol. vol. 28. 2010. pp. 3182-3190.

Kulozik, AE, Witt, O, von Deimling, A. “Molecular staging of intracranial ependymoma in children and adults”. J Clin Oncol. vol. 28. 2010. pp. 3182-90.

Louis, DN, Ohgaki, H, Wiestler, OT. “WHO classification of tumours of the central nervous system”.

Mack, SC, Taylor, MD. “The genetic and epigenetic basis of ependymoma”. Childs Nervs Syst. vol. 25. 2009. pp. 1195-1201.

McGuire, CS, Sainani, KL, Fisher, PG. “Incidence patterns for ependymoma: a surveillance, epidemiology, and end results study”. J Neurosurg. vol. 110. 2009. pp. 725-29.

Merchant, TE, Fouladi, M. “Ependymoma: new therapeutic approaches including radiation and chemotherapy”. J Neurooncol. vol. 75. 2005. pp. 287-99.

Merchant, TE, Li, C, Xiong, X. “Conformal radiotherapy after surgery for paediatric ependymoma: a prospective study”. Lancet Oncol. vol. 10. 2009. pp. 258-66.

Nazar, GB, Hoffman, HJ, Becker, LE. “Infratentorial ependymomas in childhood: prognostic factors and treatment”. J Neurosurg. vol. 72. 1990. pp. 408-17.

Needle, MN, Goldwein, JW, Grass, J. “Adjuvant chemotherapy for the treatment of intracranial ependymoma of childhood”. Cancer. vol. 80. 1997. pp. 341-47.

Robertson, PL, Zeltzer, PM, Boyett, JM. “Survival and prognostic factors following radiation therapy and chemotherapy for ependymomas in children: a report of the Children’s Cancer Group”. J Neurosurg. vol. 88. 1998. pp. 695-703.

Taylor, MD, Poppleton, H, Fuller, C. “Radial glia cells are candidate stem cells of ependymoma”. Cancer Cell. vol. 8. 2005. pp. 323

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