Classification of adult-type diffuse gliomas: Impact of the World Health Organization 2021 update

Abstract

Over the last decade, developments in molecular profiling have radically altered the diagnosis, classification, and management of numerous cancer types, with primary brain tumors being no exception. Although historically brain tumors have been classified based on their morphological characteristics, recent advances have allowed refinement of tumor classification based on molecular alterations. This shift toward molecular classification of primary brain tumors is reflected in the 2021 5^th edition of the WHO classification of central nervous system tumors (WHO 2021). In this review, we will discuss the most recent updates to the classification of adult-type diffuse gliomas, a group of highly infiltrative and largely incurable CNS malignancies. It is our hope continued that refinement of molecular criteria will improve diagnosis, prognostication, and eventually treatment of these devastating tumors.

Keywords: IDH; astrocytoma; glioblastoma; glioma; oligodendroglioma.

FIGURE 1

Schematic showing how the disease entities from WHO 2016 is now defined in WHO 2021. Solid lines denote strong correlations between the two classifications, while dotted lines denote how a WHO 2016 disease entity would likely, but not definitively, be defined

FIGURE 2

Astrocytoma, IDH‐mutant, WHO grade 2. H & E‐stained sections reveal an infiltrating glial neoplasm composed of pleomorphic tumor cells (A). Microvascular proliferation, necrosis, and mitotic activity are inapparent. Immunohistochemical stains reveal that the tumor cells express IDH1 R132H (B), while exhibiting loss of nuclear ATRX expression (C; note retained expression in background normal cellular constituents). p53 immunostaining is positive in tumor cells (D). (200X magnification)

FIGURE 3

Astrocytoma, IDH‐mutant, WHO grade 3. H & E‐stained sections reveal a cellular astrocytic neoplasm (A). Immunohistochemical stains are positive for IDH1 R132H (B) and negative for ATRX (C; loss of nuclear expression). MIB1 (Ki‐67) immunostaining demonstrates an elevated proliferation index (D), consistent with WHO grade 3 classification. (200X magnification)

FIGURE 4

Oligodendroglioma, IDH‐mutant and 1p/19q codeleted, WHO grade 2. H & E‐stained sections reveal a diffusely infiltrating glial neoplasm characterized by round‐to‐oval nuclear monomorphism and perinuclear halos (A). Immunostaining is positive for IDH1 R132H (B). (200X magnification). Array‐based comparative genomic hybridization (aCGH) demonstrates whole‐arm loss of chromosomes 1p and 19q (arrows) consistent with 1p/19q codeletion (C)

FIGURE 5

Oligodendroglioma, IDH‐mutant, and 1p/19q codeleted, WHO grade 3. H & E‐stained sections reveal a densely cellular oligodendroglial neoplasm with obvious glomeruloid microvascular proliferation (A; arrow; 200X magnification). Mitotic activity is readily apparent (B; arrow; 400X magnification)

FIGURE 6

Glioblastoma, IDH‐wild type, WHO grade 4. H & E‐stained sections reveal a cellular, pleomorphic, glial neoplasm with glomeruloid microvascular proliferation (A; arrow; 200X magnification). Atypical mitotic figures (B; arrow; 400X magnification) are prominent. H & E‐stained sections of another case demonstrating notable nuclear pleomorphism and giant cell features (C; arrow; 100X magnification), along with pseudopalisading necrosis (D; arrow; 200X magnification)

FIGURE 7

Flowchart showing the diagnostic progression of diffuse glioma in adults, based on the most relevant molecular markers. IDH mutation is used initially to divide diffuse gliomas into IDH‐mutant and IDH‐wildtype tumors. The IDH‐wildtype tumors are they subdivided into 1p/19q‐codeleted oligodendroglioma and 1p/19q‐non‐codeleted astrocytoma, based on both 1p/19q and ATRX status. CDKN2A then provides further prognostic value. IDH‐wildtype tumors will be classified as glioblastoma if they possess any one of five markers: (1) histologic evidence of necrosis, (2) histologic evidence of microvascular proliferation, (3) TERT promoter mutation, (4) EGFR amplification, and/or (5) whole gain of chromosome 7 and whole loss of chromosome 10. IDH‐wildtype tumors which do not possess any of these “rule‐in” criteria must be further examined for appropriate diagnosis