August 2022 – Neuropathology

Is associated with a poor outcome.

Posterior fossa (PF) ependymomas are circumscribed glial neoplasms that arise in the fourth ventricle and affect predominantly children, with a slight male predominance. Histologically, they typically show prominent perivascular pseudorosettes with tumor cells radially arranged around blood vessels with an intervening anucleate zone. True ependymal rosettes are present only in a minority of cases. Tumor cells show indistinct borders and uniform round-to-ovoid nuclei with speckled chromatin. Nuclear pleomorphism, vascular hyalinization, calcification, and microcystic change can be seen. Although clear cell change can be present, this is more frequently seen in supratentorial ependymomas. PF ependymomas can be assigned CNS WHO grades 2 or 3. Although grading criteria in ependymomas are not clearly defined, brisk mitotic activity and microvascular proliferation are considered high-grade histological features that carry greater prognostic significance over nuclear pleomorphism and tumor necrosis. PF ependymomas are positive for S100 and GFAP immunohistochemistry, while OLIG2 expression is usually focal to absent. EMA immunoreactivity can be seen in a paranuclear dot-like fashion. Focal keratin expression can also be seen. 

According to the 2021 WHO Classification of CNS Tumors, PF ependymomas are currently divided into two groups based on their clinical, histopathological, and molecular features, and DNA methylation profiling: posterior fossa group A (PFA) and posterior fossa group B (PFB) ependymomas. The diagnosis of PF ependymoma should be used when molecular analysis either is not feasible (not otherwise specified, NOS) or cannot assign a molecular group (not elsewhere classified, NEC).

Posterior fossa group A (PFA) ependymomas arise more frequently from the roof or lateral aspect of the fourth ventricle. They predominantly affect infants and young children with a median age of 3 years, in contrast to PFB ependymomas, which more frequently occur in older children and adolescents. Microscopically, PFA ependymomas show the histopathological features and immunoprofile described for PF ependymomas. High-grade features may be present in up to two-thirds of cases, and CNS grades 2 or 3 are assigned based on these features. 

PFA ependymomas show global reduction of H3 p.K28me3 (K27me3), but only approximately 4% of these tumors harbor H3 p.K28M (K27M) mutations. Reduction of H3 K27me3 can be assessed by surrogate immunohistochemistry as loss of expression in tumor cell nuclei, and retained H3 K27me3 expression in endothelial cells can be used as an internal control. Since variability in the proportion of tumor cells showing H3 K27me3 nuclear expression loss can be seen, a cut-off value of 80% positivity has been proposed, with tumors above this cut-off more likely to fall into the PFB group. 

Essential diagnostic criteria for PFA ependymomas include the histological features and immunoprofile of ependymoma, along with either reduction/loss of H3 K27me3 in tumor cell nuclei or a DNA methylation profile aligned with this molecular group. By genome-wide copy number analysis, PFA ependymomas usually show a stable genome. However, given its prognostic significance across all PF ependymomas, assessment for gain of chromosome 1q is recommended. Nonetheless, PFA ependymomas appear to be associated with a worse prognosis regardless of the chromosome 1q status. PFA ependymomas carry a poor outcome when compared to PFB ependymomas, and extent of surgical resection appears to be significantly associated with prognosis. 

References

1. Sriram V, Pietsch T, Aldape KD, et al. Posterior fossa group A (PFA) ependymoma. In: WHO Classification of Tumours Editorial Board. Central nervous system tumours [Internet]. Lyon (France): International Agency for Research on Cancer; 2021. (WHO classification of tumours series, 5th ed.; vol. 6). Available from: https://tumourclassification.iarc.who.int/chapters/45.
2. Pajtler KW, Wen J, Sill M, et al. Molecular heterogeneity and CXorf67 alterations in posterior fossa group A (PFA) ependymomas. Acta Neuropathol. 2018 Aug;136(2):211-226.
3. 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 Nov;134(5):705-714. 
4. Godfraind C, Kaczmarska JM, Kocak M, et al. Distinct disease-risk groups in pediatric supratentorial and posterior fossa ependymomas. Acta Neuropathol. 2012 Aug;124(2):247-57.5.
5. 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 May 11;27(5):728-43.