Ependymomas arise from the ependymal lining of the ventricles and central canal of the spinal cord. They occur at any age but with characteristic location preferences: supratentorial in young children, posterior fossa in older children, and spinal in adults. The 2021 WHO Classification reorganized ependymomas around molecular subgroups defined largely by chromosomal alterations and signature gene fusions, with prognostic implications that override classical histologic features. This page covers ependymoma pathology, molecular subgroups, and clinical-pathologic correlations.

Classical Histology

  • Perivascular pseudorosettes: ependymal cells radiate from blood vessels with intervening fibrillary processes. Most characteristic feature.
  • True ependymal rosettes: ependymal cells forming a small lumen (less common but pathognomonic).
  • Cellular density: moderate to high.
  • Cilia / blepharoplasts: on luminal surfaces (visible on EM; can detect with EMA dot-like positivity).
  • Mitoses: variable; grade-related.
  • Necrosis: in higher-grade tumors.
  • Microvascular proliferation: in higher-grade.

Immunohistochemistry

  • GFAP: positive in fibrillary processes.
  • EMA: dot-like cytoplasmic positivity (paranuclear) — highly characteristic.
  • S100, vimentin: positive.
  • OLIG2: usually negative (distinguishes from astrocytoma).
  • NeuN, synaptophysin: negative.

2021 WHO Molecular Subgroups

Supratentorial Ependymomas

  • Supratentorial ependymoma, ZFTA fusion-positive (formerly RELA fusion): most common supratentorial; children. Often more aggressive.
  • Supratentorial ependymoma, YAP1 fusion-positive: less common; better prognosis.

Posterior Fossa Ependymomas

  • Posterior fossa ependymoma, group A (PFA): young children; aggressive; loss of H3K27me3 trimethylation (similar mechanism to H3 K27-altered diffuse midline glioma but without H3 mutations). Poor prognosis.
  • Posterior fossa ependymoma, group B (PFB): older children, young adults; better prognosis.

Spinal Ependymomas

  • Spinal ependymoma: adults; intramedullary cord lesions; surgery often curative.
  • Spinal ependymoma, MYCN-amplified: aggressive variant; rare.

Subependymomas

  • CNS WHO grade 1; benign; usually intraventricular; often incidental in adults.

Myxopapillary Ependymoma

  • Conus medullaris, filum terminale.
  • Mucinous matrix, papillary architecture.
  • NKX6-1, GFAP positive.
  • Now considered CNS WHO grade 2 (was grade 1).
  • Surgical resection; recurrence possible if incomplete.

Grading

  • CNS WHO grade 2: classical ependymoma.
  • CNS WHO grade 3: anaplastic features (mitoses, microvascular proliferation, necrosis).
  • Note: Grade is somewhat secondary to molecular subgroup in current classification — molecular subtype is more prognostic than histologic grade.

Anatomic Distribution

  • Supratentorial: cerebral hemispheres (lateral or third ventricle, or extra-ventricular).
  • Posterior fossa (most common in children): fourth ventricle; can extend through outlet foramina.
  • Spinal cord: intramedullary; cervical and thoracic most common; myxopapillary at conus / filum.

Clinical Features

  • Posterior fossa: vomiting, ataxia, cranial nerve palsies, hydrocephalus.
  • Supratentorial: focal deficits, seizures, headache.
  • Spinal: back pain, sensory level, motor weakness, bladder dysfunction.
  • Myxopapillary: cauda equina syndrome, low back pain.

Imaging

  • Heterogeneous enhancement.
  • Calcification common.
  • Cystic change common.
  • Extension through fourth ventricle outlets (“plastic ependymoma” — molds through foramina).
  • Spinal: cord enlargement with mass effect.

Treatment

  • Surgery: extent of resection is the most important prognostic factor for most subgroups.
  • Radiation: standard adjuvant for most. Proton therapy increasingly used in pediatrics to spare developing brain.
  • Chemotherapy: limited role; trials of various agents ongoing.
  • Targeted therapies: investigational based on molecular subgroup.
  • Long-term surveillance for recurrence.

Prognosis

  • Highly dependent on molecular subgroup, location, and extent of resection.
  • 5-year survival: 60-80% overall but ranges from < 50% (PFA, ZFTA-positive) to > 90% (spinal, subependymoma).
  • Recurrence is common, often locally.

🔍 Did You Know?

The classification of ependymomas underwent one of the most dramatic transformations in the 2021 WHO update. Previously, ependymomas were classified by histology and grade — and pathologic predictions of behavior were often inaccurate. The discovery of recurrent molecular alterations defining distinct subgroups changed everything. Each anatomic compartment (supratentorial, posterior fossa, spinal) has its own characteristic molecular subgroups, and the molecular subgroup is more prognostic than the histologic grade. The PFA (posterior fossa group A) ependymoma, for example, is biologically defined by global loss of H3K27me3 trimethylation — a mechanism similar to (but distinct from) the H3 K27M mutation of diffuse midline glioma. PFA ependymomas can look low-grade microscopically but behave aggressively; PFB ependymomas can look high-grade but have better prognosis. The clinical implications are direct: molecular subgrouping now influences treatment decisions, surgical aggressiveness, radiation field design, and clinical trial enrollment. Identifying the molecular subgroup is as important as making the histologic diagnosis. The lesson: ependymomas illustrate the broader transformation of CNS tumor classification — from a histologic taxonomy to an integrated molecular taxonomy, with prognostic and therapeutic implications baked into the modern classification.

Pitfalls and Pearls

  • Perivascular pseudorosettes + true ependymal rosettes + EMA dot-like positivity: ependymoma.
  • Supratentorial ZFTA-fusion ependymoma: common in children; aggressive.
  • Supratentorial YAP1-fusion: better prognosis.
  • PFA ependymoma: young children; loss of H3K27me3; aggressive.
  • PFB ependymoma: older children/young adults; better prognosis.
  • Spinal ependymoma: adults; surgery often curative.
  • Myxopapillary ependymoma: conus/filum terminale; mucinous + papillary; now grade 2.
  • Subependymoma: intraventricular; grade 1; often incidental.
  • Extent of resection: most important prognostic factor.
  • Plastic ependymoma: extends through fourth ventricle outlets.
  • OLIG2 negative: distinguishes from astrocytoma.
  • Synaptophysin negative: distinguishes from neuronal tumors.
  • Molecular subgroup > histologic grade for prognosis in 2021 WHO.
  • Proton radiation: increasingly used in pediatric ependymoma to spare developing brain.

References

  1. Louis DN, Perry A, Wesseling P, et al. The 2021 WHO Classification of Tumors of the Central Nervous System: a summary. Neuro Oncol. 2021;23(8):1231-1251.
  2. Pajtler KW, Witt H, Sill M, et al. Molecular classification of ependymal tumors across all CNS compartments, histopathological grades, and age groups. Cancer Cell. 2015;27(5):728-743.
  3. Parker M, Mohankumar KM, Punchihewa C, et al. C11orf95-RELA fusions drive oncogenic NF-κB signalling in ependymoma. Nature. 2014;506(7489):451-455.
  4. Mack SC, Witt H, Piro RM, et al. Epigenomic alterations define lethal CIMP-positive ependymomas of infancy. Nature. 2014;506(7489):445-450.
  5. Merchant TE, Bendel AE, Sabin ND, et al. Conformal radiation therapy for pediatric ependymoma. J Clin Oncol. 2019;37(12):974-983.