Adult type diffuse gliomas in the new 2021 WHO Classification

Abstract

Adult-type diffuse gliomas represent a group of highly infiltrative central nervous system tumors with a prognosis that significantly varies depending on the specific subtype and histological grade. Traditionally, adult-type diffuse gliomas have been classified based on their morphological features with a great interobserver variability and discrepancy in patient survival even within the same histological grade. Over the last few decades, advances in molecular profiling have drastically changed the diagnostic approach and classification of brain tumors leading to the development of an integrated morphological and molecular classification endowed with a more clinically relevant value. These concepts were largely anticipated in the revised fourth-edition of WHO classification of central nervous system tumors published in 2016. The fifth-edition (WHO 2021) moved molecular diagnostics forward into a full integration of molecular parameters with the histological features into an integrative diagnostic approach. Diagnosis of adult type diffuse gliomas, IDH mutant and IDH-wildtype has been simplified by introducing revised diagnostic and grading criteria. In this review, we will discuss the most recent updates to the classification of adult-type diffuse gliomas and summarize the essential diagnostic keys providing a practical guidance to pathologists.

Keywords: IDH mutant; IDH-WT; astrocytoma; glioblastoma.

Figure 1.

(A) Astrocytoma, IDH-mutant, WHO grade 2. Images show a diffusely infiltrating astrocytoma with low cell density and low mitotic rate (left panel; H&E). Tumor cells display elongated irregularly shaped hyperchromatic nuclei with scarce cytoplasm; perineuronal satellitosis is evident (upper and lower insets, respectively; H&E). Tumor cells are diffusely immunoreactive for GFAP, IDH1-R132H and p53 (upper right panels), while exhibiting loss of ATRX expression, confirmed by double immunostaining revealing positive nuclei of resident cells (blue), while IDH1-R132H positive tumor cells are ATRX negative (brown) (lower left panel and inset). OLIG2 is usually expressed both in tumor cells and in normal oligodendrocytes (middle panel and inset). Tumor display a low proliferating index and no CDKN2A/B deletion, as assayed by FISH analysis (rigth panels). (B) Astrocytoma, IDH-mutant, WHO grade 3. Increased cell density, atypia and higher mitotic rate characterize these tumors (left panel and insets; H&E). Immunohistochemical stains are positive for IDH1 R132H, negative for ATRX and reveal an elevated proliferation index (middle and right panels). (C) Astrocytoma, IDH-mutant, WHO grade 4. Increased cell density, pleomorphism, anaplasia, necrosis and/or glomeruloid microvascular proliferation are typical features of WHO grade 4 tumors (left panel and insets; H&E), along with immunoreactivity for IDH1-R132H and homozygous deletion of CDKN2A/B, considered sufficient to grade the tumor as WHO grade 4 (right panels). All images are from 40x and 60x original magnification.

Figure 2.

Flowchart shows the diagnostic algorithm of adult-type diffuse glioma, based on the most relevant histopathological features and molecular markers.

Figure 3.

(A) Oligodendroglioma, IDH-mutant and 1p/19q codeleted, WHO grade 2. Representative images showing a diffusely infiltrating tumor characterized by round-to-oval monomorphic nuclei with perinuclear clearing. Microcalcifications and perineuronal satellitosis is a common feature (left panel and insets; H&E). Immunostains for GFAP is negative, while IDH1-R132H is diffusely positive (upper right panels). Tumor cells retain expression of ATRX and are diffusely immunoreactive for OLIG2 (lower left and middle panel). Proliferation index is low and FISH analysis reveals 1p/19q codeletion (right panels). (B) Oligodendroglioma, IDH-mutant and 1p/19q codeleted, WHO grade 3. Increased cellularity with nuclear anaplasia, mitotic figures, microvascular proliferation and/or necrosis are distinctive features of grade 3 tumors (left panel and insets; H&E). Immunohistochemistry reveals intense and diffuse IDH1-R132H immunoreactivity and a high proliferation index (middle and right panels). All images are from 40x and 60x original magnification.

Figure 4.

(A) Glioblastoma, IDH-wildtype. Photomicrograph showing neoplastic astrocytes with nuclear pleomorphism and areas of necrosis and microvascular proliferation (left panel and insets; H&E). As described, GBM may have areas of sarcomatous transformation composed of a spindle cell with round to spindled vesicular nuclei, pleomorphism and mitotic figures. Osteoid tissue with prominent osteoblastic rimming and occasional scattered osteoclastic giant cells are shown ((right panel; H&E). (B) FISH analysis with fluorescent probes for EGFR (red) and chromosome 7 centromere (green) reveals numerous and merged EGFR signals in interphase nuclei of neoplastic cells, indicative of EGFR amplification (left panel). A representative FISH analysis of interphase nuclei of histologically WHO grade 2 diffuse astrocytoma IDH wildtype are shown. Nuclei shows three signals detected with the chromosome 7 and one signal with chromosome 10 centromeric probes (middle and right panels, respectively), molecular features associated to aggressive behavior and diagnosis of glioblastoma, IDH-wildtype.