The 2021 WHO Classification of Tumors of the Central Nervous System: An update on pediatric low-grade gliomas and glioneuronal tumors

Abstract

The 2021 5th edition of the WHO Classification of Tumors of the Central Nervous System reflects the discovery of genetic alterations underlying many central nervous system (CNS) neoplasms. Insights gained from technologic advances and novel applications in molecular diagnostics, including next-generation sequencing and DNA methylation-based profiling, coupled with the recognition of clinicopathologic correlates, have prompted substantial changes to CNS tumor classification; this is particularly true for pediatric low-grade gliomas and glioneuronal tumors (pLGG/GNTs). The 2021 WHO now classifies gliomas, glioneuronal tumors and neuronal tumors into 6 families, three of which encompass pLGG/LGNTs: "Pediatric type diffuse low-grade gliomas," "circumscribed astrocytic gliomas," and "glioneuronal and neuronal tumors." Among these are six newly recognized tumor types: "diffuse astrocytoma, MYB or MYBL1-altered"; "polymorphous low grade neuroepithelial tumor of the young (PLNTY)"; "diffuse low-grade glioma-MAPK altered"; "Diffuse glioneuronal tumor with oligodendroglioma-like features and nuclear clusters (DGONC)"; "myxoid glioneuronal tumor (MGT)"; and "multinodular and vacuolating neuronal tumor (MVNT)." We review these newly recognized entities in the context of general changes to the WHO schema, discuss implications of the new classification for treatment of pLGG/LGNT, and consider strategies for molecular testing and interpretation.

Keywords: 2021 CNS WHO; glioneuronal tumors; low-grade gliomas.

FIGURE 1

Newly defined pLGG/GNT entities in the 2021 WHO often demonstrate overlapping histologic features with other glial and glioneuronal tumors: Myxoid/mucinous component in a diffuse astrocytoma, MYB‐altered (bearing MYB‐QKI fusion, A), a diffuse low‐grade glioma, FGFR1‐mutant, (FGFR1 p.N546K mutant, B), and myxoid glioneuronal tumor (septal location, PDGFRA p.K385L mutant, C). Oligodendroglioma‐like cells in the same diffuse low‐grade glioma, FGFR1‐mutant, (FGFR1 p.N546K mutant, D) and a PLNTY with microcalcification (bearing FGFR2‐CTNNA3 fusion, E and F). A tumor showing histologic features of DGONC, but lacking monosomy 14, did not match to a known methylation class, and was instead found to be NTRK2‐fusion positive (G). Vacuolization of cells and nodular growth pattern in an MVNT, (MAP2K1‐mutant, H, I). Scale bars in A, C, D, E, G and H = 100 μm; Scale bars in B, F, I = 200 μm