Ependymoma

Ependymomas are glial cell tumors arising from CSF-producing ependymal cells lining the ventricular system. Ependymomas most commonly occur within the posterior fossa in contact with the 4th ventricle, or within the intramedullary spinal cord. The clinical presentation of ependymomas varies depending on the location of the tumor. Magnetic resonance imaging is the imaging modality of choice, but histologic confirmation is required for diagnosis. The mainstay of treatment for intracranial ependymoma is surgical resection and adjuvant radiation therapy; young patients receive chemotherapy instead. Spinal cord ependymomas are treated with maximal surgical resection.

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Overview

Definition

Ependymomas are glial cell tumors in the CNS arising from ependymal cells.

  • Glial cells are supportive tissues within the brain and nervous system.
  • Ependymal cells produce CSF.
  • May arise anywhere in the ventricular system (intracranial ependymoma) or spinal canal (spinal ependymoma), but most commonly:
    • Children: the posterior fossa at the floor of the 4th ventricle 
    • Adults: lumbosacral spinal cord or filum terminale

Classification of nervous system tumors

Table: Classification of nervous system tumors
CategoriesSpecific tumors
Neuroepithelial tumors in the CNS
  • Astrocytoma, including glioblastoma multiforme
  • Oligodendroglioma
  • Ependymoma and choroid-plexus tumor
  • Medulloblastoma (embryonal tumor)
Meningeal tumors
  • Meningioma
  • Hemangioblastoma
Sellar-region tumors
  • Craniopharyngioma
  • Pituitary adenoma
  • Pinealoma/pinealoblastoma
Primary CNS lymphomaPrimary CNS lymphoma
Metastasis to the brain (5x more common than primary brain tumors)Most commonly arising from:
  • Lung, breast, and renal cell carcinomas
  • Melanoma
Peripheral tumors
  • Schwannoma, including acoustic neuroma
  • Neuroblastoma

Epidemiology

Intracranial ependymoma:

  • Incidence: 
    • < 6%–9% of primary tumors arising in the CNS
    • 30% of primary CNS neoplasms in children < 3 years old
    • In children, 90% of ependymomas are intracranial.
    • 3rd most common pediatric brain tumor (behind medulloblastoma and pilocytic astrocytoma)
  • Age: 
    • More common in children than adults
    • Median age at diagnosis: 4–5 years old
    • 25%–40% of patients are < 2 years old.
    • Intracranial ependymoma in adults usually occurs prior to age 40.
  • Sex: slight predominance in men
  • Location: most commonly occurs in the posterior fossa

Spinal ependymoma:

  • Incidence: 
    • Approximately 25% of primary spinal cord tumors
    • In adults, 75% of ependymomas are in the spinal cord.
  • Age: 
    • More common in adults
    • Median age at diagnosis: 30–40 years of age 
  • Location: 
    • Approximately 50% occur in the lumbosacral cord or filum terminale.
    • Approximately 50% occur elsewhere in the cervical or thoracic spinal cord.

Etiology

  • No known cause of ependymoma
  • Clustering of the disease within families has been noted.
  • Increased incidence of spinal ependymoma in neurofibromatosis 2 (NF2)

Pathophysiology

  • Arises from ependymal cells:
    • The cells line the cerebral ventricles and passageways in the brain and spinal cord.
    • Derived from radial glial cells in the subventricular zone
  • Transformation from normal ependymal cells into neoplastic cells:
    • Genetic mutations
    • Epigenetic alterations
  • Can be locally invasive and spread through the spinal cord
  • Tumor characteristics:
    • Usually well demarcated 
    • Multiple areas of calcification, hemorrhage, and cysts
    • Tumor cells often form ependymal rosettes (perivascular pseudorosettes are the histologic hallmark of ependymomas).
  • Several molecular “profiles” have been identified based on specific combinations of genetic and epigenetic abnormalities within tumor cells:
    • Ependymomas can be classified into the following subgroups according to the profiles:
      • Posterior fossa ependymoma group A (PF-EPN-A)
      • Posterior fossa ependymoma group B (PF-EPN-B)
      • Supratentorial ependymoma with RELA fusion (ST-EPN-RELA)
      • Supratentorial ependymoma with YAP fusion (ST-EPN-YAP)
    • RELA fusion: 
      • Oncogenic fusion between RELA and C11orf95
      • RELA is the principal effector of NF-κB signaling.
    • Subgroup classification is still emerging and requires further study to understand prognostic and therapeutic implications.

Clinical Presentation

The clinical presentation depends on the location of the ependymoma and the age of the patient. Most patients have symptoms for approximately 3–6 months prior to diagnosis.

  • Posterior fossa ependymoma:
    • Signs of increased intracranial pressure due to obstructive hydrocephalus:
      • Headache (frequently worse in the morning)
      • Nausea and potentially significant vomiting
      • Ataxia
      • Vertigo
      • Papilledema
      • Nystagmus
    • Cranial nerve palsies
    • Personality, mood, and cognitive changes
  • Supratentorial ependymomas:
    • Seizures
    • Focal neurologic deficit
  • Spinal cord ependymoma:
    • Motor and sensory deficits involving descending nerve tracts, ascending nerve tracts, and exiting peripheral nerves
    • Specific deficits depend on the level of the tumor

Diagnosis

Imaging

Imaging is obtained 1st as part of the diagnostic work-up, but histologic evaluation is required for diagnosis. Imaging findings may suggest an ependymoma and guide surgery.

  • MRI:
    • Imaging modality of choice for both the brain and spinal cord
    • Hypointense masses on T1-weighted MRI
    • Hyperintense masses on T2-weighted or proton density MRI
    • Gadolinium enhancement is usually prominent.
  • CT findings:
    • Hyperdense with homogenous enhancement
    • Cysts and calcifications are commonly seen.
  • General findings suggestive of ependymoma (distinguishable from other posterior fossa tumors):
    • Tumor arising from the 4th ventricle
    • Tumor extending down to the craniocervical junction
    • Pronounced extension through the foramina of Luschka
    • Restricted diffusion on diffusion-weighted images
    • Calcifications in the 4th ventricle 
MRI scan reveals an anaplastic ependymoma

Magnetic resonance imaging scan reveals an anaplastic ependymoma extending from the brainstem to the 4th ventricle.

Image: “Giant duodenal ulcers after neurosurgery for brainstem tumors that required reoperation for gastric disconnection: a report of two cases” by BMC Surgery. License: CC BY 4.0

Histologic classification

Ependymoma is based on a histologic diagnosis; therefore, the gold standard for diagnosis is pathologic evaluation of a tissue specimen. Ependymomas are classified by histologic grades according to the WHO.

  • World Health Organization grade I: 
    • Subependymoma: 
      • Rare, benign tumors of the 4th or lateral ventricles in adults
      • Hypocellular tissue consisting of a coarse, glial matrix containing clusters of cells with uniform nuclei and microcysts
    • Myxopapillary ependymoma: 
      • Mostly benign tumors arising in the conus medullaris and filum terminale of the spinal cord
      • Pseudopapillary structures with mucin-rich microcysts
      • Cuboidal cells surrounding a myxoid stroma
  • World Health Organization grade II: classic ependymoma:
    • May arise anywhere in the ventricular system or spinal canal
    • Potential variants include:
      • Papillary variant
      • Clear-cell variant
      • Tanycytic variant
    • Findings include:
      • Solid or papillary mass 
      • Perivascular pseudorosettes: tumor cells appear as a gland surrounding the vasculature (diagnostic of ependymoma)
      • Cells with regular, round-to-oval nuclei and an abundance of granular chromatin
      • Dense fibrillary background
  • World Health Organization grade III: anaplastic ependymoma:
    • Abundant mitotic cells
    • Pseudopalisading necrosis
  • RELA fusion-positive ependymoma: 
    • A new piece of the WHO classification
    • Can include grades II and III
    • Determined based on genetic testing
WHO grade III intracranial ependymoma

World Health Organization grade III intracranial ependymoma:
Perivascular pseudorosettes are seen as well as brisk, mitotic activity, which classifies the tumor as an anaplastic ependymoma.

Image: “Exomic sequencing of four rare central nervous system tumor types” by Bettegowda C., et al. License: CC BY 2.5

Other testing

  • CSF cytology:
    • Important in the work-up to evaluate for metastasis
    • Ideally done prior to surgery (debris from surgery can make interpretation difficult)
    • Often contraindicated at presentation due to obstructive hydrocephalus
  • EEG:
    • Not required for diagnosis
    • In patients with supratentorial lesions, diffuse slowing and/or epileptogenic spikes are noted in areas around the tumor.

Management and Prognosis

Management

  • Refer to specialized centers when possible.
  • Intracranial ependymoma:
    • Maximal safe resection
    • Adjuvant radiation therapy
    • Chemotherapy:
      • > 1 year of age: may be used post-radiation for some patients
      • < 1 year of age: used to delay radiation therapy (sparing adverse effects of radiation)
  • Spinal ependymoma:
    • Optimal management includes complete surgical resection. 
    • The role of adjuvant radiation therapy is unclear.
    • No proven role for chemotherapy
  • Corticosteroids: to reduce edema surrounding the tumor
  • Anticonvulsants: to treat seizures in patients with intracranial ependymoma

Prognosis

  • Survival rates: 
    • Children:
      • 10-year survival: up to 70% in patients with totally resected tumors
      • 10-year survival: 30%–40% in patients with partially resected tumors 
    • Adults:
      • 5-year survival: 67%–85%
      • 10-year survival: 50%–77%
  • Factors affecting survival:
    • Extent of resection (most important factor)
    • Histologic grade and molecular genetic subgroup
    • Location of the tumor
    • Children diagnosed at an older age have a better prognosis.
    • Karnofsky performance status (measures functional status) in adults
  • Long-term survivors of treatment have increased risk of:
    • Neurocognitive deficits
    • Focal neurologic deficits
    • Sensorineural hearing loss
    • Growth and endocrine abnormalities
    • Vasculopathy
    • 2nd malignancy

Differential Diagnosis

  • Medulloblastoma: a tumor arising in the posterior fossa. Medulloblastoma is the most common malignant brain tumor in children. Patients present with symptoms of increased intracranial pressure and cerebellar signs worsening over time. Treatment is with a combination of surgery, radiation, and chemotherapy. Unlike ependymomas, medulloblastomas rarely have foraminal extension and primary tumors do not occur in the spinal cord.
  • Pilocytic astrocytoma: the 2nd most common brain tumor in children. Magnetic resonance imaging can help distinguish pilocytic astrocytoma from other tumors. A pilocytic astrocytoma is usually cystic with a mural module, or has central necrosis with a thick rim of enhancing tissue. In contrast, ependymomas often arise from the 4th ventricle and are usually accompanied by restricted diffusion on diffusion-weighted images. 
  • Choroid plexus tumors: rare, primary CNS tumors arising from the choroid plexus within the ventricles. Choroid plexus tumors usually present in children with signs and symptoms of hydrocephalus. Histologically, choroid plexus tumors resemble adenocarcinomas and may be associated with Li-Fraumeni syndrome.
  • Oligodendroglioma: a CNS tumor arising from oligodendrocytes. Oligodendroglioma commonly develops in the cerebral hemisphere (usually the frontal lobe). Presentation may include focal neurological deficits, seizures, and personality changes. Diagnosis is by MRI and biopsy. Management involves surgical resection and may be accompanied by radiation and/or chemotherapy.

References

  1. Capodano, A.M. (2001). Nervous system: Ependymomas. Atlas Genet Cytogenet Oncol Haematol. 5(3), 208–210. 
  2. DeAngelis, L.M., Wen, P.Y. (2018). Primary and metastatic tumors of the nervous system. In Jameson, J., et al. (Eds.), Harrison’s Principles of Internal Medicine, 20e. McGraw-Hill. https://accessmedicine-mhmedical-com.aucmed.idm.oclc.org/content.aspx?bookid=2129&sectionid=192016511
  3. Genetic and Rare Disease Information Center. (2021). Ependymoma. Retrieved April 19, 2021, from https://rarediseases.info.nih.gov/diseases/6353/ependymoma
  4. Mayo Clinic. (2019). Embryonal tumors. Retrieved April 19, 2021, from https://www.mayoclinic.org/diseases-conditions/embryonal-tumor/
  5. National Cancer Institute Center for Cancer Research. (2021). Choroid Plexus Tumors Diagnosis and Treatment. Retrieved April 19, 2021, from https://www.cancer.gov/rare-brain-spine-tumor/tumors/choroid-plexus-tumors
  6. National Cancer Institute. (2020). Childhood Ependymoma Treatment (PDQ®)–Patient Version. Retrieved April 19, 2021, from https://www.cancer.gov/types/brain/patient/child-ependymoma-treatment-pdq
  7. National Cancer Institute. (2021). Ependymoma Diagnosis and Treatment. Retrieved April 19, 2021, from https://www.cancer.gov/rare-brain-spine-tumor/tumors/ependymoma
  8. Upadhyaya, S.A., Tinkle, C. (2020). Intracranial ependymoma and other ependymal tumors. UpToDate. Retrieved April 19, 2021, from https://www.uptodate.com/contents/intracranial-ependymoma-and-other-ependymal-tumors
  9. Welch, W.C., Schiff, D., Gerszten, P.C. (2020). Spinal cord tumors. UpToDate. Retrieved April 19, 2021, from https://www.uptodate.com/contents/spinal-cord-tumors

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