Molecular GBM versus Histopathological GBM: Radiology-Pathology-Genetic Correlation and the New WHO 2021 Definition of Glioblastoma

Left frontal lobe mass in a 39-year-old man with histologic low grade (WHO grade 2) and positive chromosomal 7 and 10 mutations (+7/−10) supporting the molecular profile of “Glioblastoma, IDH-wild-type (CNS WHO grade 4).” H&E slide reveals moderate cytoplasm with eosinophilic processes and lack of palisading necrosis or MVP. The infiltrating glioma cells are negative for IDH1-R132H (B) and for H3 K27M(C) on immunohistochemistry. The cells showed retained expression of ATRX with no significant overexpression. Chromosomal microarray analysis performed by using molecular inversion probes on a whole genome array reveals combined gain of chromosome 7 (including EGFR amplification) and loss of chromosome 10 (D, arrow). There are no features of IDH-mutant gliomas such as 1p/19q codeletion and no reportable alterations are identified in the targeted regions of the IDH1 and IDH2 genes. Neuro-oncology expanded gene panel by using next-generation sequencing was also performed to evaluate for microsatellite instability status, somatic mutations, and rearrangements (fusions and abnormal transcript variants) involving 160 genes associated with tumors of the CNS, which confirmed the change seen on chromosomal microarray. Despite the absence of MVP and tumor necrosis, this molecular profile is now considered to be diagnostic of glioblastoma (CNS WHO grade 4) in the IDH-wild-type setting, according to the 2021 WHO Classification of CNS Tumors. Tumor tissue was negative for MGMT promoter methylation.

Left frontal lobe mass in a 65-year-old woman with characteristic MR imaging and histopathological features of glioblastoma, IDH-wild-type (CNS WHO grade 4). Axial T2-weighted (A) and contrast-enhanced (B) images reveal a heterogenous T2-signal cortical-subcortical mass centered in the left frontal operculum with areas of necrosis and heterogeneous peripheral enhancement. H&E slide reveals the classic “pseudopalisading” necrosis characterized by a “garlandlike” arrangement of hypercellular tumor nuclei (C, arrows) lining up around a central clear zone of tumor necrosis (C, arrowhead). Microvascular proliferation is noted with delicate capillary-like microvessels resembling classic angiogenesis, multi-layered stratification of the endothelial cells and occlusion of the vessel lumen (D, arrows). The infiltrating glioma cells were negative for IDH1-R132H and for H3 K27M on immunohistochemistry. Chromosomal microarray analysis was performed by the by using molecular inversion probes on a whole genome array revealing genomic alterations include loss of 2q22.1 (including LRP1B), 2 copy gain of chromosome 7, loss of 9p21.3 (including CDKN2A and CDKN2B), and loss of 10p15.3p11.1. Tumor tissue was negative for MGMT promoter methylation. Final integrated diagnosis was “Glioblastoma, IDH-wild-type (CNS WHO grade 4).”