2019 NPB-12

This case was originally published in 2019. The information provided in this case was accurate and correct at the time of initial program release. Any changes in terminology since the time of initial publication may not be reflected in this case.

The patient is a 55-year-old woman who complained of episodes of involuntary head shaking, progressively worsening over the past six months. MRI revealed a large mass (Image A and Image B). A debulking operation was performed.

Tissue Site
Right frontal lobe mass

The whole slide image provided is an H&E-stained image of the right frontal lobe of the brain from a resection.

The lesion in this case is a large, bifrontal neoplasm that crosses the corpus callosum and has focal contrast enhancement (Image A and Image B). This radiographic appearance would be most characteristic of a glioblastoma. The H&E photomicrographs (Image C, Image D, Image E, and Image F) show a high-grade glioma with areas of tumor necrosis (Image C), focal microcyst formation (Image D), endothelial proliferation (Image E), nuclear pleomorphism (Image D, Image E, and Image F) and mitoses (Image F). IHC studies show the tumor is negative for the IDH1 R132H mutation (Image G) and has both loss of ATRX expression (Image H) and p53 overexpression in more than 50% of the tumor cell nuclei (Image I).

The fact that this glioma crosses the midline might raise the possibility of diffuse midline glioma, H3 K27M-mutant. This is unlikely since those tumors are predominantly seen in children or young adults, and the location is most commonly brainstem or diencephalon. IHC staining eliminates this possibility since the tumor is negative for the H3 K27M mutation-specific antibody (Image J).

The major point to be made in this case is that the lack of IDH1 R132H staining is unexpected given the ATRX loss and overexpression of p53. This staining pattern for ATRX and p53 suggests the presence of mutations in their respective genes, which are very commonly seen in conjunction with IDH1 or IDH2 mutations. TP53 mutations occur in less than one third of IDH-wildtype glioblastomas, and ATRX mutations are rare. In contrast, TP53 mutations occur in over 80% of IDH-mutated glioblastomas, and ATRX mutations are present in more than two-thirds. Therefore, without actual sequencing of the IDH genes in this neoplasm, it is unjustified to conclude that the tumor is "IDH-wildtype." The diagnosis of anaplastic oligodendroglioma is very unlikely in that such tumors almost always have retained ATRX expression. Because this astrocytoma has endothelial proliferation and necrosis, it cannot be an anaplastic astrocytoma. While loss of ATRX and overexpression of p53 can be seen in diffuse midline gliomas, negativity for the mutation-specific antibody means this cannot be a diffuse midline glioma, H3 K27M-mutant. Overall, with the information available, the best diagnosis would be glioblastoma, NOS, until molecular studies of IDH1/2 have been completed.

Indeed, molecular studies revealed that the neoplasm had a noncanonical IDH1 mutation: IDH1 R132C. The currently available commercial antibodies for IDH1 R132H will not detect such mutations or mutations in the IDH2 gene. In addition, FISH revealed intact 1p/19q. The final diagnosis in this case is glioblastoma, IDH-mutant, WHO grade IV. Such glioblastomas commonly correspond clinically to "secondary glioblastomas" based on a clinical history of a prior lower grade neoplasm. This might be suggested by the histological appearance in Image D and the scanned image slide.

It is important to distinguish IDH-wildtype from IDH-mutant glioblastomas since the latter have a more favorable survival and therapeutic response rate. When IHC staining results are equivocal or atypical, IDH1/2 molecular studies are required. The pattern of ATRX and p53 staining can assist with the decision to pursue molecular testing or not, as well as the older age of the patient. Patients age 55 and older do not normally require reflex sequencing, but in this case the lack of ATRX staining is a clue to the presence of a noncanonical IDH mutation. Regardless of IDH1/2 mutation status, MGMT promoter methylation testing is standard of care for all glioblastomas as it has a direct bearing on patient management; if methylation is present, then the tumor may respond favorably to alkylating agents (eg, temozolomide).

• While the IDH1 R132H mutation is present in over 90% of IDH-mutant gliomas, other mutations in IDH1 or IDH2 are possible.
• The IDH1 R132H mutation is detected by commercially available antibodies; other IDH1/2 mutations are not.
• Lack of staining with antibodies to IDH1 R132H should not automatically lead to a diagnosis of IDH-wildtype glioma.
• The presence of mutations in ATRX (or loss of nuclear staining) is a strong indicator that there could be an IDH1/2 mutation in the tumor.

1. Ahmadipour Y, Jabbarli R, Gembruch O, et al. Impact of multifocality and molecular markers on survival of glioblastoma [Epub ahead of print]. World Neurosurg. 2018 Oct 19;S1878-8750(18)32372-6.
2. Kessler T, Sahm F, Sadik A, et al. Molecular differences in IDH wildtype glioblastoma according to MGMT promoter methylation. Neuro Oncol. 2018 Feb 19;20(3):367-79.
3. Louis DN, Brat DJ, Ohgaki H, et al. Glioblastoma, IDH-wildtype. In: Louis DN, Ohgaki H, Wiestler OD, et al, eds. WHO Classification of Tumours of the Central Nervous System. Revised 4th ed. France: IARC; 2016:28-45.
4. Ohgake H, Kleihues P, von Deming A, et al. Glioblastoma, IDH-mutant. In: Louis DN, Ohgaki H, Wiestler OD, et al, eds. WHO Classification of Tumours of the Central Nervous System. Revised 4th ed. France: IARC; 2016:52-6.