April 2022 – Neuropathology

A 55-year-old man presented with balance and coordination issues, and imaging showed a heterogeneously enhancing mass involving the right thalamus. Biopsy showed a hypercellular infiltrating glioma with atypia and mitotic activity, but no microvascular proliferation or tumor necrosis. By immunohistochemistry, tumor cells were positive for Olig2, negative for IDH1-R132H and H3K27M, and showed retained expression of ATRX. By sequencing and chromosomal microarray, TERT promoter mutation, gain of chromosome 7, monosomy 10, and homozygous deletion of CDKN2A/B on 9p21.3 were identified.

Figure 1: T1-weighted pre- (a) and post-contrast (b) MRI
Figure 2: (a) H&E, (b) Olig2, (c) IDH1-R132H, (d) H3K27M
Figure 3:  Chromosomal microarray analysis

Which of the following molecular features of this IDH-wildtype diffuse astrocytic glioma qualifies it for a diagnosis of “glioblastoma, IDH-wildtype (CNS WHO grade 4)” even in the absence of classic histologic high-grade features?

  • Codeletion of chromosomes 1p and 19q
  • Combined gain of chromosome 7 and loss of chromosome 10
  • MGMT promoter methylation
  • CDKN2A homozygous deletion

The correct answer is ...

Combined gain of chromosome 7 and loss of chromosome 10.

The diagnosis in this case is “Glioblastoma, IDH-wildtype (CNS WHO Grade 4)” according to the recently released 2021 World Health Organization Classification of Tumours of the Central Nervous System. Consistent with the previous classification, infiltrating gliomas without an IDH1 or IDH2 mutation are classified as WHO grade 4 if tumor necrosis or microvascular proliferation are identified histologically. However, in the updated 2021 classification, three molecular features associated with poor prognosis may qualify IDH-wildtype infiltrating gliomas as glioblastoma even in the absence of these high-grade histologic features: 1) EGFR amplification, 2) combined gain of chromosome 7 and loss of chromosome 10, and 3) TERT promoter mutation.1 Thus, this case meets the integrated histologic and molecular features of “Glioblastoma, IDH-wildtype” given that it is an infiltrating glioma with both a TERT promoter mutation and combined copy number gain of chromosome 7 and loss of chromosome 10.

Of note, H3 K27 alterations must be excluded in IDH-wildtype infiltrating gliomas involving the midline, and tumors with these molecular alterations are best classified “Diffuse midline glioma, H3 K27-altered.” In this case, such alterations were not detected by immunohistochemistry or sequencing analysis.

Homozygous deletion of CDKN2A and/or CDKN2B on chromosome 9p is detected in a variety of tumors of the central nervous system, and has increased significance in the 2021 CNS WHO classification. Similar to IDH-wildtype infiltrating astrocytomas, IDH-mutant infiltrating astrocytomas may also reach a grade 4 designation by either histologic criteria (tumor necrosis and microvascular proliferation) or molecular criteria. Specifically, the presence of homozygous deletion of 9p including CDKN2A and/or CDKN2B are sufficient to categorize an IDH-mutant infiltrating astrocytoma as “Astrocytoma, IDH-mutant (CNS WHO grade 4)” even in the absence of classic high-grade histologic features.1

MGMT promoter methylation is frequently detected in high-grade infiltrating gliomas, both IDH-mutant and IDH-wildtype, and is associated with a more favorable response to alkylating chemotherapy, such as temozolomide compared with non-methylated tumors.2 While MGMT promoter methylation is common and predictive of treatment response in glioblastoma, IDH-wildtype, it is neither specific, nor required for the diagnosis. Finally, codeletion of chromosome arms 1p and 19q is characteristic of oligodendrogliomas, and is now required for the diagnosis, the terminology of which has been updated to “Oligodendroglioma, IDH-mutant and 1p/19q-codeleted” in the 2021 WHO classification.1


  1. WHO Classification of Tumours Editorial Board. Central nervous system tumours [Internet]. Lyon (France): International Agency for Research on Cancer; 2021 [cited 2022 Jan 25]. (WHO classification of tumours series, 5th ed.; vol. 6). Available from: https://tumourclassification.iarc.who.int/chapters/45.
  2. Hegi ME, Diserens AC, Gorlia T, Hamou MF, de Tribolet N, Weller M, Kros JM, Hainfellner JA, Mason W, Mariani L, Bromberg JE, Hau P, Mirimanoff RO, Cairncross JG, Janzer RC, Stupp R. MGMT gene silencing and benefit from temozolomide in glioblastoma. N Engl J Med. 2005 Mar 10;352(10):997-1003. doi:10.1056/NEJMoa043331. PMID: 15758010.

Garrett Fitzpatrick, M.D.
Fellow, Neuropathology
Mayo Clinic

Jorge Trejo-Lopez,  M.D.
Senior Associate Consultant, Anatomic Pathology
Mayo Clinic
Assistant Professor of Laboratory Medicine and Pathology
Mayo Clinic College of Medicine and Science

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This post was developed by our Education and Technical Publications Team.