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Oligodendroglioma, IDH mutant and 1p / 19q codeleted

Authors: Jared T. Ahrendsen, M.D., Ph.D., Sanda Alexandrescu, M.D.

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

Deputy Editor-in-Chief: Chunyu Cai, M.D., Ph.D.

Last author update: 25 April 2022

Last staff update: 6 October 2023

Copyright: 2018-2024, PathologyOutlines.com, Inc.

PubMed Search: Oligodendroglioma, IDH mutant, 1p / 19q codeleted

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Table of Contents

Cite this page: Ahrendsen JT, Alexandrescu S. Oligodendroglioma, IDH mutant and 1p / 19q codeleted. PathologyOutlines.com website. https://www.pathologyoutlines.com/topic/cnstumoroligodendrogliomaidhmutant.html. Accessed May 3rd, 2024.

Definition / general

CNS WHO 2021 definition: diffusely infiltrating glioma with IDH1 or IDH2 mutation and codeletion of chromosome arms 1p and 19q (CNS WHO grade 2 or 3)

Essential features

Diffusely infiltrating glial neoplasm with IDH1 or IDH2 mutation and 1p / 19q whole arm codeletion (both features are required for diagnosis)
Morphology resembles nonneoplastic oligodendrocytes with round monotonous nuclei and perinuclear halos
Chicken wire vasculature, microcalcifications and microcysts are characteristic (Neuro Oncol 2014;16:1244)
Astrocytic differentiation does not preclude diagnosis if molecular features are present
- Small gemistocytes (mini gemistocytes) with rounded bellies of eosinophilic, eccentrically placed cytoplasm are occasionally seen, especially in grade 3 tumors (Acta Neuropathol 1984;64:265)
Presence of other atypical features (including multinucleated giant cells, sarcomatous features, neurocytic differentiation or ganglion-like cells) does not preclude a diagnosis of oligodendroglioma if the requisite molecular features are present (Acta Neuropathol 2010;120:237, J Neuropathol Exp Neurol 2002;61:947, Neuropathology 2014;34:323)

ICD coding

ICD-O:
- 9450/3 - oligodendroglioma, NOS
- 9451/3 - oligodendroglioma, anaplastic

Epidemiology

Most epidemiologic data is based on histologic, rather than molecular, classification of oligodendroglioma
Incidence of 0.23 cases per 100,000 population in the United States (Neuro Oncol 2019;21:v1)
- Incidence of CNS WHO grade 3 oligodendroglioma is 0.11
Of all brain tumors in the United States:
- 0.9% are oligodendroglioma WHO grade 2
- 0.4% are oligodendroglioma WHO grade 3
Peak incidence in fourth and fifth decades of life (Neuro Oncol 2020;22:iv1)
Rare in infants and children (Am J Surg Pathol 2014;38:1058)
Slight male predominance (Neuro Oncol 2019;21:v1)

Sites

Infiltrative neoplasm involving the white and gray matter
Can occur anywhere in the neuraxis; most common locations (Neuro Oncol 2020;22:iv1):
- Frontal lobes: 59%
- Temporal lobes: 14%
- Parietal lobes: 10%
- Occipital lobes: 1%
Rarely observed in midline structures, brainstem, cerebellum or spinal cord
Leptomeningeal spread occasionally observed, particularly at recurrence (Neurology 2019;92:e2483)

Pathophysiology

Cell (or cells) of origin for oligodendroglioma remains unknown
IDH mutation is likely the initiating event (driver mutation), which precedes 1p / 19q codeletion (Adv Anat Pathol 2015;22:50, Biomed Res Int 2014;2014:540236)
IDH mutations give rise to metabolic alterations, with increased production of 2-hydroxyglutarate (2HG)
Increased 2HG inhibits histone demethylation, causing a hypermethylation phenotype in neoplastic cells: glioma CpG island methylated phenotype (G CIMP) (Nature 2012;483:479, Acta Neuropathol 2013;125:621)

Etiology

Generally sporadic without significant known risk factors
Rare instances of familial oligodendroglioma and genetic alterations with associated increased risk of developing oligodendroglioma (Neuro Oncol 2018;20:1625, Cancer 2005;103:2363, J Natl Cancer Inst 2014;107:384)

Clinical features

About 67% of patients present with seizure (PLoS One 2017;12:e0188419, Nat Rev Neurol 2017;13:340)
Other common presenting symptoms: headache, focal neurologic deficits or cognitive / mental status change, depending on anatomic location

Grading

WHO grade 2:
- Well differentiated tumor lacking anaplastic features (brisk mitotic activity, microvascular proliferation, necrosis)
WHO grade 3:
- Prominent anaplastic features (necrosis, microvascular proliferation or brisk mitotic activity) are compatible with anaplastic oligodendroglioma, IDH mutant and 1p / 19q codeleted, WHO grade 3
- Strict mitotic activity criteria do not currently exist
- Some authors suggest ≥ 6 mitotic figures per 10 high power fields in resection specimens for grade 3 designation (J Neuropathol Exp Neurol 2001;60:248)
- Fewer mitotic figures might be sufficient for grade 3 designation in small biopsy specimens if other anaplastic features (vascular proliferation or necrosis) or significant nuclear atypia are present
- CDKN2A homozygous deletion may serve as a molecular marker of CNS WHO grade 3 in IDH mutant and 1p / 19q codeleted oligodendrogliomas (Neuro Oncol 2019;21:1519)

Diagnosis

Magnetic resonance imaging (MRI), followed by stereotactic brain biopsy or surgical resection
Methods to detect IDH gene mutation:
- Immunohistochemistry for IDH1 R132H (positive in > 90% of tumors) (Acta Neuropathol 2009;118:599)
  - IDH2 mutations overrepresented in oligodendrogliomas compared with astrocytomas (Biomed Res Int 2014;2014:540236)
- Sanger sequencing
- Droplet digital polymerase chain reaction (ddPCR)
- Next generation sequencing
- MRI techniques to detect 2-hydroxyglutarate and therefore IDH mutation are under investigation (J Clin Invest 2013;123:3659)
Methods to detect 1p / 19q codeletion:
- Fluorescent in situ hybridization (FISH)
- Array comparative genomic hybridization
- Polymerase chain reaction (PCR)

Radiology description

Computed topography (CT):
- Mixed density (hypodense and isodense) located in cortex or subcortical white matter (Radiology 2017;284:316)
- High attenuation areas, likely from calcifications
MRI:
- Heterogeneous on T1 and T2 weighted imaging
- Typically no diffusion restriction
- Poorly circumscribed borders (AJNR Am J Neuroradiol 2017;38:678)
- Cystic changes are relatively common (Radiology 2017;284:316)
- Contrast enhancement present in < 20% of WHO grade 2 tumors and > 70% of WHO grade 3 tumors (AJNR Am J Neuroradiol 2012;33:852, Eur J Cancer 2019;107:15)
- Elevated 2HG by magnetic resonance spectroscopy could serve as radiologic surrogate of IDH mutation status (Nat Med 2012;18:624)

Radiology images

Contributed by Jared T. Ahrendsen, M.D., Ph.D. and John DeWitt, M.D., Ph.D.

MRI, brain: T1 post

MRI, brain: T2

MRI: frontal lobe tumor with cystic change

Images hosted on other servers:

Axial flair frontal lobe tumor

Axial flair large temporal lobe tumor

Prognostic factors

Slow growing and relatively long overall survival
- Median overall survival: 11.6 years; 10 year overall survival rate: 51 - 63% (J Neuropathol Exp Neurol 2005;64:479, Neuro Oncol 2020;22:iv1)
- Longer median survival compared with grade 2 IDH mutant astrocytoma (median overall survival: 10.9 years) (Acta Neuropathol 2015;129:867)
Favorable features (Crit Rev Oncol Hematol 2008;66:262):
- Younger age at diagnosis
- Tumor location in frontal lobe
- Presentation with seizures
- Macroscopically complete surgical resection
- CNS WHO grade 2 histology
- Higher postoperative Karnofsky score
Unfavorable features:
- Contrast enhancement on MRI
- CNS WHO grade 3 histology (Eur J Cancer 2020;137:10, Oncotarget 2014;5:1515)
- CDKN2A / CDKN2B homozygous deletion (J Neuropathol Exp Neurol 2004;63:314, Neuro Oncol 2019;21:1519)
Local recurrence and malignant transformation are common

Case reports

26 year old man presents with nausea, headache and rash (JAAD Case Rep 2019;6:1)
43 year old woman with headaches, blurry vision and a right parietal mass (Front Neurol 2018;9:700)
44 year old man with sudden right sided optic neuritis (BMJ Case Rep 2018;2018:bcr2018225318)
48 year old man presents with seizures (Front Oncol 2021;10:601452)
55 year old man with mass lesion in the superior left temporal gyrus (Brain Pathol 2019;29:693)

Treatment

Gross total resection, if possible
Adjuvant chemotherapy (temozolomide) and radiotherapy
- Given to patients with symptomatic or progressive tumors, tumors with CNS WHO grade 3 histology or those with large postoperative residual tumor
References: Crit Rev Oncol Hematol 2008;66:262, Lancet 2005;366:985

Gross description

Variably well defined, gray-pink mass
Mucoid change can give a gelatinous consistency
Areas of cystic degeneration, calcifications, hemorrhage or necrosis can be seen

Frozen section description

Moderately cellular, diffusely infiltrating neoplasm
Glia with mild to moderate nuclear atypia
Round nuclei with speckled chromatin
Calcifications, perineuronal satellitosis or perivascular accumulation of tumor cells may be seen
Will not see perinuclear halos on frozen section or smear preparations
Anaplastic features (necrosis, vascular proliferation, mitoses) may be seen in WHO grade 3 tumors
Reference: J Cytol 2011;28:147

Intraoperative frozen / smear cytology images

Contributed by Jared T. Ahrendsen, M.D., Ph.D.

Intraoperative smear preparation

Intraoperative frozen section

Microscopic (histologic) description

Closely packed cells with small, round, monotonous nuclei (slightly larger than a normal oligodendrocyte)
Perinuclear clearing (fried egg appearance)
- Formalin fixation artifact
- Will not be seen on frozen sections or smear preparations
Network of thin walled, branching blood vessels (chicken wire vasculature)
Microcalcifications (calcospherites) are characteristic
Presence of perineural, perivascular or subpial aggregates of tumor cells (secondary structures of Scherer)
Occasional mitoses and moderate nuclear atypia are still consistent with grade 2 designation (J Neuropathol Exp Neurol 2001;60:248)
Not uncommon to find well differentiated / fibrillary astrocytic morphology (Acta Neuropathol 1984;64:265)
Features of CNS WHO grade 3 oligodendroglioma:
- Presence of microvascular proliferation
- Presence of necrosis
- Presence of brisk mitotic activity
  - Strict mitotic figure cutoffs do not currently exist; some authors suggest ≥ 6 mitoses per 10 high power fields for WHO grade 3 designation in tumors without necrosis or vascular proliferation (Neuro Oncol 2014;16:1244, Neuro Oncol 2016;18:888)

Microscopic (histologic) images

Contributed by Jared T. Ahrendsen, M.D., Ph.D. and John DeWitt, M.D., Ph.D.

Diffusely infiltrating glial neoplasm

Microcalcifications

Perinuclear halos

Chicken wire vasculature

Secondary structures of Scherer

Cellularity and vascular proliferation

Focal necrosis

Brisk mitotic activity

Mixed astrocytic histology

IDH1 R132H

p53

ATRX

Virtual slides

Images hosted on other servers:

Oligodendroglioma,
resection

Oligodendroglioma,
IDH1 R132H,
resection

Positive stains

IDH1 (R132H)
- Positive in > 90% of oligodendrogliomas (Acta Neuropathol 2009;118:599)
- Negative staining is not incompatible with oligodendroglioma if 1p / 19q codeletion is present
Olig2, GFAP
ATRX (retained; wildtype pattern)
p53 (weak staining in rare cells; wildtype staining pattern)
Ki67:
- Grade 2 tumors: usually < 5% of tumor nuclei
- Grade 3 tumors: generally > 10% of tumor nuclei (Neuro Oncol 2014;16:1244, Neuro Oncol 2016;18:888)
Trio of IDH1 (R132H), ATRX and p53 is useful to distinguish oligodendroglioma from IDH mutant astrocytoma (Acta Neuropathol 2012;124:615)

Negative stains

Loss of H3K27 trimethylation (Acta Neuropathol 2020;139:597)
Keratins (although certain cytokeratin cocktails may demonstrate crossreactivity)

Electron microscopy description

Not routinely used for diagnostic purposes

Molecular / cytogenetics description

Oligodendroglioma is a molecularly defined diagnosis requiring demonstration of both:
- IDH1 or IDH2 mutation
- Unbalanced translocation between chromosome 1 and 19, resulting in whole arm loss of 1p and 19q chromosomal material (1p / 19q codeletion)
  - Incomplete or partial deletions are not compatible with oligodendroglioma diagnosis
Other common molecular alterations:
- TERT promotor mutation in vast majority (Nat Genet 2015;47:458)
  - Early (clonal) event in tumorogenesis (Oncotarget 2019;10:3641)
  - Often absent in teenagers with oligodendroglioma (Acta Neuropathol Commun 2018;6:95)
- CIC mutation in 70% (N Engl J Med 2015;372:2499)
- FUBP1 mutations in 20 - 30% (Science 2011;333:1453)
- NOTCH1 mutation in 15% (Nat Genet 2015;47:458)
- Loss of H3K27 trimethylation by immunohistochemistry (Acta Neuropathol 2020;139:597)
Molecular alterations associated with tumor progression:
- Increased copy number alterations (Neuro Oncol 2018;20:66)
- CDKN2A / CDKN2B deletions on chromosome 9p21 (PLoS One 2016;11:e0168728)
- PIK3CA mutation (Clin Cancer Res 2019;25:4375)
- TCF12 mutation (Nat Commun 2015;6:7207)
- MYC amplification (Nat Commun 2016;7:11263)
Epigenetic changes:
- Glioma CpG island methylator phenotype (G CIMP) (Cancer Cell 2010;17:510)
- MGMT promotor methylation is detectable in the majority of tumors (Int J Cancer 2005;113:379)

Sample pathology report

Brain, frontal lobe, left, tumor, resection:
- Integrated diagnosis: oligodendroglioma, IDH1 R132H mutant and 1p / 19q codeleted
- Histologic diagnosis: oligodendroglioma
- CNS WHO grade: 3
- Molecular information:
  - IDH1 R132H mutation
  - 1p / 19q codeletion
  - TERT promotor mutation

Differential diagnosis

Astrocytoma, IDH mutant:
- Lacks 1p / 19q codeletion and TERT promotor mutations
- Harbors p53 or ATRX mutations
  - p53 expression strong and diffuse in tumor cells
  - ATRX expression lost in tumor cells
Other tumors with oligo-like morphology:
- Dysembryoplastic neuroepithelial tumor (DNET)
- Central neurocytoma
- Polymorphous low grade neuroepithelial tumor of the young (PLNTY)
- Clear cell ependymoma
- Metastatic clear cell carcinomas
- These tumors lack IDH mutations and 1p / 19q codeletion and are generally circumscribed instead of infiltrative
Macrophage rich lesions:
- Stain positive with macrophage markers

Additional references

WHO Classification of Tumours Editorial Board: Central Nervous System Tumours, 5th Edition, 2022, Neuropathology 2017;37:465, Neurol Clin 2018;36:467

Board review style question #1

A 42 year old man presents to the emergency room with new onset seizures. Brain magnetic resonance imaging (MRI) reveals a nonenhancing infiltrative mass lesion in the right frontal lobe. A biopsy is performed, shown in the image above. What molecular features are most likely present?

BRAF V600E mutation
EGFR amplification
IDH mutation and 1p / 19q codeletion
IDH, p53 and ATRX mutations
Polysomy 7 and monosomy 10 (+7 / -10)

Board review style answer #1

C. IDH mutation and 1p / 19q codeletion. The image shows an oligodendroglioma, which is defined by the presence of IDH mutation and 1p / 19q codeletion.

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Reference: Oligodendroglioma, IDH mutant and 1p / 19q codeleted

Board review style question #2

Which of the following is a common genetic alteration in oligodendroglioma, IDH mutant and 1p / 19q codeleted?

ATRX mutation
BRAF V600E
EGFR amplification
p53 mutation
TERT promotor mutation

Board review style answer #2

E. TERT promotor mutation. TERT promotor mutations are commonly observed in oligodendroglioma.

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Reference: Oligodendroglioma, IDH mutant and 1p / 19q codeleted

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