CNS tumor

Diffuse astrocytic and oligodendroglial tumors

Glioblastoma, IDH mutant

Authors: Meaghan Morris, M.D., Ph.D., Fausto J. Rodriguez, M.D.

Editorial Board Member: Maria Martinez-Lage, M.D.

Editor-in-Chief: Debra L. Zynger, M.D.

Topic Completed: 26 March 2019

Minor changes: 7 May 2021

Copyright: 2019-2021, PathologyOutlines.com, Inc.

PubMed Search: Glioblastoma IDH mutant[TIAB]

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Table of Contents

Cite this page: Morris M, Rodriguez FJ. Glioblastoma, IDH mutant. PathologyOutlines.com website. https://www.pathologyoutlines.com/topic/cnstumorglioblastomaidhmutant.html. Accessed December 7th, 2021.

Definition / general

High grade infiltrating glioma with a point mutation in isocitrate dehydrogenase 1 or 2 (IDH1 / 2), predominantly astrocytic differentiation, nuclear atypia, pleomorphism, elevated mitotic activity and necrosis or microvascular proliferation

Essential features

High grade infiltrating glioma with astrocytic differentiation, elevated mitotic activity and necrosis or vascular proliferation
IDH1 or IDH2 mutation present by immunohistochemistry or sequencing
Frequently arises from a diffuse astrocytoma (WHO grade II) or anaplastic astrocytoma (WHO grade III)

Terminology

Astrocytoma, IDH1 mutant, grade 4: proposed terminology encompassing both infiltrating IDH1 mutant astrocytomas with microvascular proliferation or necrosis (as outlined in this chapter), and infiltrating IDH1 mutant astrocytomas with CDKN2A/B homozygous deletion regardless of histologic grade (Acta Neuropathol 2020;139:603)
Secondary glioblastoma: IDH mutant glioblastomas constitute the majority of glioblastomas arising from either a diffuse astrocytoma (WHO grade II) or anaplastic astrocytoma (WHO grade III); term not currently in use in pathology (Clin Cancer Res 2009;15:6002, Science 2008;321:1807)

ICD coding

ICD-O: 9445 / 3 - Glioblastoma, IDH mutant
ICD-10: C71.1 - Malignant neoplasm of frontal lobe

Epidemiology

M:F = 1.05:1 (Louis: WHO Classification of Tumours of the Central Nervous System, 4th Edition, 2016)
Commonly presents in fifth decade (Clin Cancer Res 2009;15:6002, Science 2008;321:1807)
10% of all glioblastomas (Louis: WHO Classification of Tumours of the Central Nervous System, 4th Edition, 2016)

Sites

Frontal lobe (> 60%) > temporal lobe > parietal or occipital lobe > nonlobar CNS sites (J Clin Oncol 2011;29:4482)

Pathophysiology

IDH mutant glioblastoma is the final stage of malignant progression from an IDH mutant diffuse astrocytoma (WHO grade II) or IDH mutant anaplastic astrocytoma (WHO grade III) (J Clin Oncol 2011;29:4482)

Clinical features

Patients often present with symptoms attributable to mass effect, neurocognitive symptoms, behavioral symptoms, focal neurologic signs or seizures
May present with radiologic progression at the resection site of a prior lower grade glioma

Diagnosis

MRI with contrast is the preferred imaging modality
Diagnosis is by biopsy or surgical resection

Radiology description

T2 / FLAIR (fluid attenuation inversion recovery) hyperintense and T1 hypointense to isointense mass with necrosis
Contrast enhancing with irregular nodular or ring pattern of enhancement

Radiology images

Contributed by Meaghan Morris, M.D., Ph.D.

Bright on FLAIR

Contrast enhancing

Prognostic factors

Average survival twice as long as patients with IDH wildtype glioblastomas (N Engl J Med 2009;360:765)
Although MGMT promoter methylation is a favorable prognostic factor in glioblastoma, particularly in patients receiving temozolomide chemotherapy, it is uncertain whether it stands as a favorable prognostic factor in IDH mutant glioblastomas (Clin Cancer Res 2007;13:2606, N Engl J Med 2005;352:997, Neurology 2013;81:1515, Oncotarget 2015;6:40896)
Homozygous CDKN2A/B homozygous deletion may be associated with worse prognosis (Acta Neuropathol 2018;136:153, Neuropathol Appl Neurobiol 2019;45:108)

Case reports

28 year old man with widely metastatic IDH1 and TP53 mutant glioblastoma with atypical molecular features (Diagn Pathol 2019;14:16)
28 year old woman with symptoms of postpartum depression (J Med Case Rep 2018;12:374)

Treatment

Surgical resection, if possible, followed by radiation and temozolomide chemotherapy (J Oncol Pract 2017;13:629)

Gross description

Soft gray-tan tissue with variable yellow-tan necrotic material
Often fragmented
Interface of tumor with brain parenchyma is indistinct

Frozen section description

Cellular morphology can be highly variable
- Often predominantly tumor cells with oval hyperchromatic nuclei in a fibrillary background
- Variably present larger cells and pleomorphism
- Variable quantity of cells with eccentric nuclei and glassy eosinophilic cytoplasm (gemistocytes)
- Some show predominantly small cells with little pleomorphism and scant cytoplasm
Sections are hypercellular showing infiltrating neoplastic cells with edema
Variably present mitotic figures, necrosis and microvascular proliferation
Vascular thromboses and myxoid background may be present
Smear most commonly shows predominantly smaller cells with fine fibrillar processes, elongated nuclei, nuclear atypia and may show mitotic figures

Frozen section images

Contributed by Meaghan Morris, M.D., Ph.D.

Hypercellular tissue with edema

Microvascular proliferation

Smear

Microscopic (histologic) description

Histologic sections show infiltrating tumor cells with increased mitotic activity and variable cellularity
- Myxoid background and microcyst formation may be present
Cellular morphology is variable, even within a single tumor
- Commonly there is a mix of cells with elongated nuclei and fine fibrillar processes, cells with eccentric nuclei and glassy eosinophilic cytoplasm (gemistocytes), larger pleomorphic cells and small cells with scant cytoplasm
- May show oligodendroglioma-like areas more frequently than IDH wildtype glioblastoma (J Clin Oncol 2011;29:4482)
There must be either necrosis or microvascular proliferation
- IDH mutant glioblastomas show a lower amount of necrosis on histology compared to IDH wildtype glioblastoma (J Clin Oncol 2011;29:4482)
Tumor cells infiltrate in a diffuse single cell pattern, often with entrapped neurons and axons
IDH mutant glioblastoma cannot be distinguished from IDH wildtype glioblastoma on histology alone

Microscopic (histologic) images

Contributed by Meaghan Morris, M.D., Ph.D.

Variable morphology and necrosis

Microvascular proliferation

Entrapped neurons

Olig2

IDH

ATRX

p53

Ki67

Positive stains

GFAP, Olig2, S100, SOX10, IDH R132H (> 80%) (N Engl J Med 2009;360:765)
p53, Ki67 elevated
Neurofilament (highlights entrapped axons)

Negative stains

ATRX expression lost
CAM5.2, CD45, CD20, MelanA

Molecular / cytogenetics description

IDH1 R132 mutation or IDH2 R172 mutation present (N Engl J Med 2009;360:765)
- Most common mutation is IDH1 R132H (> 80%) (N Engl J Med 2009;360:765)
Frequent TP53 mutations (> 70%) (N Engl J Med 2009;360:765)
- TP53 mutations are more common in IDH mutant glioblastomas versus IDH wildtype glioblastomas (J Clin Oncol 2011;29:4482, N Engl J Med 2009;360:765)
Majority show ATRX mutations and alternative lengthening of telomeres (Acta Neuropathol 2012;124:615, Brain Pathol 2013;23:237)
Usually lack TERT promoter mutations
- TERT promoter mutations are much less common in IDH mutant glioblastomas compared to IDH wildtype glioblastoma and oligodendrogliomas (Acta Neuropathol 2017;133:1001)

Sample pathology report

Brain, frontal lobe, biopsy:
- Glioblastoma, IDH mutant (WHO grade IV)
Brain, frontal lobe, biopsy:
- Integrated diagnosis: glioblastoma, IDH mutant
- Histological diagnosis: glioblastoma
- WHO histological grade: IV
- Molecular information:
  - IDH1: mutant (R132H immunohistochemistry)
  - ATRX: nuclear expression lost (consistent with mutant)
  - p53: many positive cells (immunohistochemistry; consistent with mutant)

Differential diagnosis

Glioblastoma, IDH wildtype:
- High grade infiltrative glial neoplasm with astrocytic differentiation, nuclear atypia, pleomorphism, elevated mitotic activity and necrosis or microvascular proliferation
- IDH mutation is not present by immunohistochemistry or sequencing
Anaplastic oligodendroglioma, IDH mutant:
- High grade infiltrating glioma composed of round cells resembling oligodendrocytes, hyperchromatic rounded nuclei, perinuclear halos, increased mitotic activity, fine branching vasculature, scattered calcifications, variable microvascular proliferation and variable necrosis
- IDH1 / 2 mutation present by immunohistochemistry or sequencing, and whole arm codeletion of chromosomes 1p and 19q present by molecular testing
- ATRX alterations and TP53 mutations are typically absent (Acta Neuropathol 2012;124:615, N Engl J Med 2009;360:765)
Anaplastic astrocytoma, IDH mutant:
- Infiltrative glioma with astrocytic differentiation, nuclear atypia, moderate pleomorphism and elevated mitotic activity but lacks necrosis or microvascular proliferation
- IDH1 / 2 mutation present by immunohistochemistry or sequencing
- TP53 and ATRX alterations frequently present
Lymphoma:
- Parenchymal lymphomas in the central nervous system are typically diffuse large B cell lymphomas, which lack the fine fibrillar cell processes typical of glial cells
- Diffuse large B cell lymphoma in the central nervous system often shows a perivascular tumor distribution and is positive for CD45 and CD20 but negative for GFAP and Olig2 by immunohistochemistry
Metastatic disease:
- Morphology varies by the site of origin; however, typically they lack the fine fibrillar processes found in glial tumors and generally are negative for Olig2 and GFAP by immunohistochemistry

Board review style question #1

A 40 year old woman presents with an infiltrative frontal lobe mass with nodular enhancement on MRI. She has a history of a diffuse astrocytoma 5 years prior. The surgical resection shows an infiltrative neoplasm with abundant fibrillary processes and pseudopallisading necrosis. What enzyme is likely to be mutated in this tumor?

BRAF
Isocitrate dehydrogenase 1 (IDH1)
Lactate dehydrogenase (LDH)
SMARCB1 (INI1)
Succinate dehydrogenase B (SDHB)

Board review style answer #1

B. Isocitrate dehydrogenase 1 (IDH1). The histology shows glioblastoma, which is arising from a diffuse astrocytoma in this clinical scenario. IDH1 mutations are frequent in glioblastomas arising from diffuse astrocytomas and tend to present in the frontal lobe of patients in their fifth decade of life. SDH mutations are found in pheochromocytomas but are not associated with glioblastoma. LDH mutations are not associated with glioblastoma. SMARCB1 / INI1 mutations with loss of INI1 labeling by immunohistochemistry are associated with atypical teratoid / rhabdoid tumors but are not associated with glioblastoma. Mutations in BRAF are found in multiple types of CNS tumors, including epithelioid glioblastoma, but are not associated with glioblastoma arising from a diffuse astrocytoma.

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Reference: Glioblastoma, IDH mutant

Board review style question #2

In glioblastomas, an IDH mutation is associated with

High grade brainstem glioma in children
Improved prognosis
Mismatch repair deficiency syndrome
Older age of onset (average seventh decade)
Poor response to chemoradiation

Board review style answer #2

B. Improved prognosis. IDH mutation in glioblastomas is associated with an improved prognosis compared with IDH wildtype glioblastomas. IDH mutant glioblastomas occur predominantly in the frontal lobe of adults with a mean onset in the fifth decade. Onset in the seventh decade is typical of IDH wildtype glioblastoma. High grade brainstem gliomas in children are associated with the K27M mutation of histone H3. Mismatch repair deficiency syndrome is associated with an increased risk of glioblastoma but is not associated with IDH mutation. IDH mutant glioblastomas are not known to be less responsive to therapy than IDH wildtype glioblastomas.

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Reference: Glioblastoma, IDH mutant