The 2021 WHO Classification of Tumors of the Central Nervous System: a summary

Abstract

The fifth edition of the WHO Classification of Tumors of the Central Nervous System (CNS), published in 2021, is the sixth version of the international standard for the classification of brain and spinal cord tumors. Building on the 2016 updated fourth edition and the work of the Consortium to Inform Molecular and Practical Approaches to CNS Tumor Taxonomy, the 2021 fifth edition introduces major changes that advance the role of molecular diagnostics in CNS tumor classification. At the same time, it remains wedded to other established approaches to tumor diagnosis such as histology and immunohistochemistry. In doing so, the fifth edition establishes some different approaches to both CNS tumor nomenclature and grading and it emphasizes the importance of integrated diagnoses and layered reports. New tumor types and subtypes are introduced, some based on novel diagnostic technologies such as DNA methylome profiling. The present review summarizes the major general changes in the 2021 fifth edition classification and the specific changes in each taxonomic category. It is hoped that this summary provides an overview to facilitate more in-depth exploration of the entire fifth edition of the WHO Classification of Tumors of the Central Nervous System.

Keywords: World Health Organization; brain tumor; central nervous system; classification; diagnosis.

Fig. 1

Polymorphous low-grade neuroepithelial tumor of the young (PLNTY) is a glial neoplasm associated with a history of epilepsy in young people, diffuse growth patterns, frequent presence of oligodendroglioma-like components, calcification, CD34 immunoreactivity, and MAPK pathway-activating genetic abnormalities. (A) Common oligodendroglioma-like appearance (H&E, ×200), but (B) histological appearances can vary greatly within tumors (H&E, ×400). (C) CD34 immunostaining is typically strong and diffuse in the tumor (×100); and (D) is often found in the peritumoral cortex (×200).

Fig. 2

Diffuse hemispheric glioma, H3 G34-mutant, is a malignant, infiltrative glioma, typically of the cerebral hemispheres and with a missense mutation in the H3F3A gene that results in a G34R/V substitution of histone H3. (A) High-grade anaplastic features, sometimes with an embryonal appearance (H&E, ×200) and (B) positive nuclear staining with H3 G34R/V immunohistochemistry (×100).

Fig. 3

Myxoid glioneuronal tumor is a tumor typically arising in the septal region and involving the lateral ventricle. It is characterized by a proliferation of oligodendrocyte-like tumor cells embedded in a prominent myxoid stroma, often including admixed floating neurons, neurocytic rosettes, and/or perivascular neuropil, and by a dinucleotide mutation in the PDGFRA gene. (A) Common septal location (magnetic resonance imaging, T1 with contrast) and (B) characteristic histological features with small round cells and myxoid stroma (H&E, ×200).

Fig. 4

Multinodular and vacuolating neuronal tumor is a benign tumor comprising monomorphous neuronal elements in discrete and coalescent nodules, with vacuolar changes both in tumor cells and the neuropil. (A) Multinodular appearance (H&E, ×40). (B) Vacuolar change in tumor cells and in neuropil (H&E, ×200).

Fig. 5

CNS tumor with BCOR internal tandem duplication is a neoplasm with a mostly solid growth pattern, uniform oval or spindle-shaped cells, a dense capillary network, focal pseudorosette formation, and an internal tandem duplication (ITD) in exon 15 of the BCOR gene. (A) High-grade neoplasm with perivascular rosettes (H&E, ×200) and (B) strong, diffuse nuclear staining on BCOR immunohistochemistry (×100).

Fig. 6

Desmoplastic myxoid tumor of the pineal region, SMARCB1-mutant is a rare pineal-region tumor that features desmoplasia and myxoid changes (H&E, ×200) (A) as well as loss of INI1 staining (×200) (B).

Fig. 7

Newly recognized mesenchymal, non-meningothelial tumors of uncertain histogenesis. (A) Intracranial mesenchymal tumor, FET-CREB fusion-positive (H&E, ×200); these tumors have variable morphology and a fusion of an FET RNA-binding protein family gene and a member of the CREB family of transcription factors. (B, C) CIC-rearranged sarcoma, with (B) poorly differentiated cells (H&E, ×200) and (C) with ETV4 frequently being upregulated in these tumors (×200). (D) Primary intracranial sarcoma, DICER1-mutant with characteristic eosinophilic cytoplasmic droplets (H&E, ×200).

Fig. 8

Pituitary blastoma is a malignant embryonal sellar neoplasm composed of primitive blastemal cells, neuroendocrine cells, and Rathke epithelium, typically occurring in young children and linked to germline or somatic variants in the DICER1 gene. (A) Neuroendocrine cells arranged in lobules, rosettes, and glands, interspersed with small undifferentiated, blastemal cells (H&E, ×100) and with (B) ACTH immunoreactivity in some cells (×200).