CNS tumor
Diffuse astrocytic and oligodendroglial tumors
Glioblastoma, IDH mutant

Editorial Board Member: Maria Martinez-Lage, M.D.
Editor-in-Chief: Debra Zynger, M.D.
Meaghan Morris, M.D., Ph.D.
Fausto J. Rodriguez, M.D.

Topic Completed: 26 March 2019

Revised: 29 March 2019

Copyright: 2019, PathologyOutlines.com, Inc.

PubMed Search: Glioblastoma IDH mutant[TIAB]

Meaghan Morris, M.D., Ph.D.
Fausto J. Rodriguez, M.D.
Page views in 2019 to date: 3,712
Cite this page: Morris M, Rodriguez FJ. Glioblastoma, IDH mutant. PathologyOutlines.com website. http://www.pathologyoutlines.com/topic/cnstumorglioblastomaidhmutant.html. Accessed December 5th, 2019.
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
ICD coding
  • ICD-O: 9445 / 3 - Glioblastoma, IDH mutant
  • ICD-10: C71.1 - Malignant neoplasm of frontal lobe
Sites
Pathophysiology
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
Case reports
Treatment
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
Negative stains
Molecular / cytogenetics description
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 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?



  1. BRAF
  2. Isocitrate dehydrogenase 1 (IDH1)
  3. Lactate dehydrogenase (LDH)
  4. SMARCB1 (INI1)
  5. Succinate dehydrogenase B (SDHB)
Board review 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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Board review question #2
In glioblastomas, an IDH mutation is associated with

  1. High grade brainstem glioma in children
  2. Improved prognosis
  3. Mismatch repair deficiency syndrome
  4. Older age of onset (average seventh decade)
  5. Poor response to chemoradiation
Board review 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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