Oligodendroglioma, IDH Mutant: Grade 2-3

Oligodendroglioma, IDH Mutant and 1p/19q Codeleted

• Defined as a diffusely infiltrating glioma with IDH1 or IDH2 mutation and codeletion of chromosome arms 1p and 19q.
• Classified as CNS WHO grade 2 or 3.

Essential Features

• Requires both IDH1 or IDH2 mutation and 1p/19q whole arm codeletion for diagnosis.
• Exhibits morphology similar to nonneoplastic oligodendrocytes, including round, monotonous nuclei and perinuclear halos.
• Characterized by chicken wire vasculature, microcalcifications, and microcysts.
• Astrocytic differentiation does not rule out diagnosis if molecular features are present, including small gemistocytes, especially in grade 3 tumors.

Additional Considerations

• The presence of atypical features such as multinucleated giant cells or sarcomatous features doesn't preclude diagnosis if molecular features are present.

ICD Coding

• 9450/3: Oligodendroglioma, NOS (Not Otherwise Specified).
• 9451/3: Anaplastic oligodendroglioma.

Epidemiology

• Incidence in the United States stands at 0.23 cases per 100,000 population.
• CNS WHO grade 3 oligodendroglioma incidence is 0.11.
• 0.9% of all brain tumors are oligodendroglioma WHO grade 2 and 0.4% are oligodendroglioma WHO grade 3.
• Peak incidence occurs in the fourth and fifth decades of life.
• Rare in infants and children.
• Slight male predominance.

Sites

• Typically involves white and gray matter.
• Can occur anywhere in the neuraxis, but most commonly in the frontal lobes (59%), temporal lobes (14%), and parietal lobes (10%).
• Rarely found in midline structures, brainstem, cerebellum, or spinal cord.

Pathophysiology

• The cell of origin for oligodendroglioma is unknown.
• IDH mutation is likely the initiating event, preceding 1p/19q codeletion.
• IDH mutations lead to increased production of 2-hydroxyglutarate (2HG).
• Elevated 2HG inhibits histone demethylation, causing a hypermethylation phenotype (G-CIMP).

Etiology

• Generally sporadic without significant known risk factors.
• Rare familial instances and genetic alterations are associated with increased risk.

Clinical Features

• Approximately 67% of patients present with seizures.
• Other symptoms include headache, focal neurologic deficits, or cognitive/mental status changes, depending on the tumor location.

Grading

• WHO grade 2 tumors lack anaplastic features.
• WHO grade 3 tumors exhibit prominent anaplastic features like necrosis, microvascular proliferation, or brisk mitotic activity.
• CDKN2A homozygous deletion may indicate CNS WHO grade 3.

Diagnosis

• Diagnosed via MRI, followed by stereotactic brain biopsy or surgical resection.
• Methods to detect IDH gene mutation: Immunohistochemistry for IDH1 R132H, Sanger sequencing, ddPCR, Next generation sequencing.
• Methods to detect 1p / 19q codeletion: FISH, array comparative genomic hybridization, PCR.

Radiology Description

• CT scans show mixed density (hypodense and isodense) in cortex or subcortical white matter, with high attenuation areas from calcifications.
• MRI shows heterogeneous appearance on T1 and T2 weighted imaging, poorly defined borders, and cystic changes.
• Contrast enhancement is present in < 20% of WHO grade 2 and > 70% of WHO grade 3 tumors.

Prognostic Factors

Favorable features:

• Younger age at diagnosis.
• Frontal lobe location.
• 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.
• CDKN2A / CDKN2B homozygous deletion.
• Median overall survival is 11.6 years, with a 10 year survival rate of 51 - 63%.
• Local recurrence and malignant transformation are common.

Gross Description

• Variably well defined, gray-pink mass.
• May have a gelatinous consistency due to mucoid change.
• Cystic degeneration, calcifications, hemorrhage, or necrosis may be present.

Frozen Section Description

• Moderately cellular, diffusely infiltrating neoplasm.
• Mild to moderate nuclear atypia.
• Round nuclei with speckled chromatin.
• Calcifications, perineuronal satellitosis, or perivascular accumulation may be seen.
• Perinuclear halos are not seen on frozen sections or smear preparations.
• Anaplastic features may be seen in WHO grade 3 tumors.

Microscopic (Histologic) Description

• Closely packed cells with small, round, monotonous nuclei.
• Perinuclear clearing (fried egg appearance) is a formalin fixation artifact.
• Network of thin walled, branching blood vessels (chicken wire vasculature).
• Microcalcifications (calcospherites) are characteristic.
• Perineural, perivascular, or subpial aggregates of tumor cells (secondary structures of Scherer).
• Occasional mitoses and moderate nuclear atypia are consistent with grade 2.
• Well differentiated / fibrillary astrocytic morphology may be present.

Features of CNS WHO grade 3:

• Microvascular proliferation.
• Necrosis.
• Brisk mitotic activity.

Positive Stains

• IDH1 (R132H) is positive in > 90% of oligodendrogliomas.
• Olig2, GFAP.
• ATRX (retained; wildtype pattern).
• p53 (weak staining in rare cells; wildtype staining pattern).
• Ki67: Grade 2 tumors typically show < 5% positive nuclei, while Grade 3 tumors generally show > 10%.
• The trio of IDH1 (R132H), ATRX, and p53 distinguishes oligodendroglioma from IDH mutant astrocytoma.

Molecular / Cytogenetics Description

• Requires demonstration of both IDH1 or IDH2 mutation and 1p/19q codeletion for diagnosis.
• Incomplete or partial deletions are not compatible with oligodendroglioma diagnosis.
• Common molecular alterations include TERT promotor mutation, CIC mutation, FUBP1 mutations, and NOTCH1 mutation.
• Molecular alterations associated with tumor progression: increased copy number alterations, CDKN2A / CDKN2B deletions, PIK3CA mutation, TCF12 mutation, MYC amplification.
• Epigenetic changes: Glioma CpG island methylator phenotype (G-CIMP), MGMT promotor methylation.

Sample Pathology Report

• Includes integrated diagnosis, histologic diagnosis, CNS WHO grade, and molecular information (IDH1 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.
• 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.
• Macrophage rich lesions: Stain positive with macrophage markers.