2019 NPB-13

This case was originally published in 2019. The information provided in this case was accurate and correct at the time of initial program release. Any changes in terminology since the time of initial publication may not be reflected in this case.

A previously healthy 17-month-old girl presented to the emergency department with new-onset head tilt and unsteady gait. MRI revealed a 4-cm posterior fossa mass centered at the right cerebellar-medullary junction with extension through the right foramen of Luschka. There was patchy gadolinium enhancement and no associated restricted diffusion. The patient underwent suboccipital craniotomy for gross total resection of the lesion.

Tissue Site
Posterior fossa

The whole slide image provided is an H&E-stained image of a cerebellum from a resection.

Posterior fossa (infratentorial) ependymomas are more common in children than adults and often cause hydrocephalus secondary to obstruction of or around the fourth ventricle. After pilocytic astrocytoma and medulloblastoma, ependymoma is the third most common pediatric brain tumor of the posterior fossa and is thought to derive from radial glial cells in the developing brain. The tumor is named after the ependymal lining cells of the brain, with which it often shares the common feature of apical cilia or microvilli.

Posterior fossa ependymomas commonly have a heterogeneous appearance on MRI with gadolinium enhancement. They characteristically lack diffusion restriction, which helps to differentiate them from embryonal tumors such as medulloblastoma, atypical teratoid/rhabdoid tumor (AT/RT), and embryonal tumor with multilayered rosettes (ETMR). Cystic or calcified areas can also be seen. Extension through the foramina of Magendie or Luschka is a feature highly suggestive of the diagnosis of ependymoma (Image A). Ependymomas often extend through these structures into the cerebellopontine cistern or inferiorly through the foramen magnum. MR imaging of the spine is conducted as part of the staging process, but tumor dissemination is less common in ependymoma than in medulloblastoma.

Ependymomas throughout the central nervous system can display similar histologic features. One hallmark finding is the arrangement of tumor nuclei a short circumferential distance away from the intratumoral vessels, known as a perivascular pseudorosette; this feature is seen in the majority of ependymomas (Image C). A less common but more specific feature is the presence of tubules and canals of tumor cells with an ependymal appearance, often with apical cilia or microvilli (true ependymal rosettes, Image B). Ependymomas are generally S100 positive and GFAP positive, and the latter is accentuated in the cell processes composing the perivascular pseudorosettes. These tumors also display EMA staining at the surfaces of ependymal rosettes/canals, as well as in a dot-like or ring-like pattern adjacent to tumor nuclei (Image D). Neurofilaments, synaptophysin, OLIG2, SOX10, and NeuN are usually negative. Nuclear expression of INI1 (SMARCB1) is retained in ependymomas, whereas this pattern is lost in AT/RTs.

Recent studies have shown that pediatric posterior fossa ependymomas are composed of two subgroups with distinct methylation patterns and clinical outcomes: posterior fossa ependymoma type A (PF-EPN-A) and type B (PF-EPN-B). Type A tumors characteristically occur in young children (median age 3 years) and are associated with a poor prognosis, including high risk of recurrence and high incidence of metastasis. Type B tumors are more common in adolescents and adults and have a good prognosis with a high probability of overall survival at 10 years after diagnosis, nearing 100% for patients with gross total resection and adjuvant radiation.

The markedly different biologic behaviors for these two subtypes of posterior fossa ependymoma make it important to distinguish them at the time of initial diagnosis. H3K27me3 IHC is useful in the identification of type A tumors where nuclear staining is lost (Image E). Type B tumors display retained nuclear H3K27me3 immunoexpression. Normal background structures, such as vascular endothelial cells, retain H3K27me3 immunoexpression and serve as a useful internal positive control.

It is important to note that loss of H3K27me3 immunoexpression is also a feature of H3-K27M mutant diffuse midline glioma (DMG), which commonly occurs in the brainstem. The distinction between DMG and ependymoma is usually based on histologic features, with the former having the appearance of a diffuse astrocytoma and lacking perivascular pseudorosettes and true rosettes. DMG is defined by the presence of recurrent somatic variants in the histone genes H3F3A or HIST1H3B, typically stains with OLIG2, and occurs in the midline. In addition to DMG and PF-EPN-A, malignant peripheral nerve sheath tumors can also show loss of H3K27me3 immunoexpression.

Molecular genetic testing is commonly employed in the evaluation of pediatric brain tumors. Posterior fossa ependymoma type A tumors are characterized by a stable copy number profile (balanced genome) and generally show no recurrent single nucleotide variants of significance.

• Posterior fossa ependymomas commonly show MRI evidence of extension into the recesses of the fourth ventricle.
• Two distinct subtypes of posterior fossa ependymoma have been identified by methylation profiling and have a marked difference in prognosis.
• PF-EPN-A tumors occur in young children, have a balanced "silent" genome with no recurrent somatic variants, display loss of nuclear H3K27me3 immunoexpression, and have a poor prognosis.
• PF-EPN-B tumors occur in older adolescents and adults, more commonly harbor chromosomal gains/losses, display retained nuclear H3K27me3 immunoexpression, and have a good prognosis.

1. Mack SC, Witt H, Piro RM, et al. Epigenomic alterations define lethal CIMP-positive ependymomas of infancy. Nature. 2014;506(7489):445-50.
2. Panwalkar P, Clark J, Ramaswamy V, et al. Immunohistochemical analysis of H3K27me3 demonstrates global reduction in group-A childhood posterior fossa ependymoma and is a powerful predictor of outcome. Acta Neuropathol. 2017;134(5):705-14.
3. Ramaswamy V, Hielscher T, Mack SC, et al. Therapeutic impact of cytoreductive surgery and irradiation of posterior fossa ependymoma in the molecular era: a retrospective multicohort analysis. J Clin Oncol. 2016;2468-77.
4. Witt H, Mack SC, Ryzhova M, et al. Delineation of two clinically and molecularly distinct subgroups of posterior fossa ependymoma. Cancer Cell. 2011;20:143-57.