Oligodendroglioma

Oligodendrogliomas are malignant CNS tumors arising from neural glial cell precursors. Oligodendrogliomas often arise in the frontal lobes of the brain and have a generally favorable prognosis when compared to other gliomas. Oligodendrogliomas are the 3rd most common CNS tumor. The most frequent presenting symptom is a seizure; other symptoms include headaches, visual loss, and focal neurologic deficits. Diagnosis is established by brain biopsy that demonstrates a classic “fried egg” appearance (round nuclei with clear cytoplasm). Oligodendrogliomas are slow-growing, but because they are life-limiting, they are managed with a combination of surgical resection, radiation, and chemotherapy.

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Overview

Definition

Oligodendrogliomas are malignant neuroepithelial tumors arising from neural glial cell precursors. These tumor cells appear histologically similar to oligodendrocytes, but lack the myelinating ability of oligodendrocytes. Oligodendrogliomas are a type of glioma:

  • Gliomas arise from glial cells, which are supportive tissues within the brain and spinal cord.
  • Oligodendrocytes are glial cells in the CNS that produce myelin.
  • Astrocytomas and ependymomas are the other common glial cell tumors.

Classification of nervous system tumors

Table: Classification of nervous system tumors
Categories Specific tumors
Neuroepithelial tumors in the CNS
  • Astrocytomas, including glioblastoma multiforme
  • Oligodendroglioma
  • Ependymoma and choroid-plexus tumors
  • Medulloblastomas (embryonal tumors)
Meningeal tumors
  • Meningiomas
  • Hemangioblastomas
Sellar region tumors
  • Craniopharyngioma
  • Pituitary adenoma
  • Pinealoma/pinealoblastoma
Primary CNS lymphoma Primary CNS lymphoma
Metastasis to the brain (5× more common than primary brain tumors) Most commonly arising from:
  • Lung, breast, and renal cell carcinomas
  • Melanoma
Peripheral tumors
  • Schwannomas, including acoustic neuroma
  • Neuroblastoma

Epidemiology

  • Incidence:
    • 3rd most common primary brain neoplasm (behind glioblastoma multiforme and low-grade diffuse astrocytoma)
    • Accounts for approximately 5% of primary CNS tumors
    • 0.2 per 100,000 population
    • Approximately 1000 patients diagnosed with oligodendrogliomas each year in the United States.
  • Median age at diagnosis: 25–45 years
  • Slightly more common in males than in females

Pathophysiology

Pathophysiology

  • Location: 
    • Usually arise in the cerebral hemispheres (cortical or subcortical)
    • Rarely can occur within the cerebellum, ventricles, or spinal cord
  • Regional effects on brain parenchyma include:
    • Compression
    • Invasion
    • Destruction
  • ↑ Intracranial pressure (ICP) may be due to:
    • Direct mass effect
    • Edema in surrounding brain tissue
    • ↑ Blood volume
    • ↑ CSF volume/hydrocephalus
  • Disruption of normal parenchymal functions are due to:
    • Hypoxia
    • Competition for nutrients
    • Release of metabolic end products:
      • Free radicals
      • Altered electrolytes
      • Neurotransmitters
    • Release and recruitment of cellular mediators (e.g., cytokines)

Pathogenesis

Oligodendrogliomas are histologically defined tumors that include both isocitrate dehydrogenase (IDH) 1 and 2 mutations and codeletions of chromosomal arms 1p and 19q.

  • Mutations in IDH1 (found in the cytosol) and/or IDH2 (found in the mitochondria):
    • IDH:
      • Catalyzes the reversible oxidative decarboxylation of isocitrate → α-ketoglutarate (α-KG) in the TCA cycle 
      • Primary producer of NADPH in most tissues, especially the brain
      • Also involved in mitigating oxidative damage
    • Mutations lead to production and buildup of 2-hydroxyglutarate (2-HG):
      • 2-HG inhibits enzymatic function of α-KG–dependent dioxygenases, which are involved in DNA demethylation.
      • ↑ 2-HG causes epigenetic dysregulation → can lead to tumor development
  • Codeletions of chromosomal arms 1p and 19q:
    • Leads to epigenetic changes and hypermethylation of the genome
    • Typically occur because of an unbalanced translocation between chromosomes 1 and 19
  • Other mutations:
    • Activating mutations in the telomerase reverse transcriptase (TERT) promoter:
      • TERT is a catalytic subunit in telomerase → activating mutations allow tumor cells to become “immortal”
      • A primary diagnostic marker for glioblastoma multiforme, though can also be present in oligodendrogliomas
    • Methylation (i.e., silencing) of the O-6-methylguanine-DNA methyltransferase (MGMT) promoter: MGMT is an enzyme involved in DNA repair.

Classification

Oligodendrogliomas are classified by the WHO according to their histology and the types of mutations they harbor. (Grade I tumors are considered benign, so, unlike astrocytomas, there are no grade I oligodendrogliomas.)

  • WHO grade II: 
    • Oligodendroglioma, IDH-mutant and 1p/19q-codeleted
    • Oligodendroglioma, not otherwise specified
  • WHO grade III: 
    • Anaplastic oligodendroglioma, IDH-mutant and 1p/19q-codeleted
    • Anaplastic oligodendroglioma, not otherwise specified
  • Tumors not otherwise specified underwent genetic testing that was inconclusive or genetic testing was not done.
  • The diagnosis of oligoastrocytoma is no longer preferred, as tumors with mixed histology should be classified according to their molecular signature as either astrocytomas or oligodendrogliomas. If the 1p/19q codeletion is absent, the tumor is typically classified as an astrocytoma.

Clinical Presentation

Most of the signs and symptoms depend on the exact location of the tumor. Oligodendrogliomas are slow-growing and often asymptomatic for years prior to diagnosis. The most common presenting symptom is a seizure.

  • Seizures: can be either partial or generalized
  • General symptoms: symptoms that can occur with tumors in any location
    • Headache (usually in the morning)
    • Nausea and/or vomiting 
    • Cognitive difficulties: 
      • Memory problems
      • Mood or personality changes (mostly seen in frontal lobe tumors)
    • Papilledema
  • Focal neurologic deficits: depends on particular location of tumor
    • Muscle weakness (damage to contralateral motor cortex)
    • Sensory abnormalities (damage to contralateral somatosensory cortex)
    • Apraxia 
    • Aphasia
    • Visual field deficits 
    • Hemiparesis

Diagnosis

Imaging

Head MRI is the imaging method of choice when evaluating for brain tumors.

  • MRI of the brain:
    • T2-weighted images: hyperintense or mixed signal intensity lesions
    • T1-weighted images: hypointense or mixed signal intensity lesions
    • More likely to have indistinct borders and nonuniform/heterogeneous signals compared to astrocytomas
    • Calcifications are also commonly seen.
    • Contrast enhancement:
      • Grade II lesions typically do not enhance.
      • Anaplastic lesions typically do show some enhancement.
  • Head CT:
    • Done when there are contraindications to MRI or in the acute care setting 
    • Findings include: 
      • Hypodense lesions with surrounding edema
      • Calcifications and hemorrhage can be seen.
      • Typically, only anaplastic lesions enhance.

Biopsy

  • Gross appearance: 
    • Well-circumscribed, gray, gelatinous mass 
    • Often with areas of cysts, hemorrhages, and calcifications
  • Microscopic appearance: 
    • Composed of well-differentiated cells resembling oligodendrocytes
    • Sheets of fried-egg cells (large cells with clear cytoplasm and round hyperchromatic nucleus)
    • Chicken-wire capillaries: networks of thin blood vessels throughout the tumor due to significant angiogenesis
    • Anaplastic tumors exhibit:
      • Higher cell density
      • Nuclear atypia
      • Mitotic activity
      • Microvascular proliferation
      • Necrosis
  • Molecular testing:
    • Presence of IDH1/2 mutations and 1p/19q codeletion:
      • Immunohistochemical staining for IDH1/2 mutations
      • FISH studies for 1p/19q codeletions
    • Lack myelin basic protein (MBP) found in normal myelin-producing oligodendrocytes and Schwann cells
    • May stain positive for oligodendrocyte transcription factor 2 (Olig2), a marker for oligodendrocyte progenitor cells that is involved in cell differentiation
    • May stain positive for glial fibrillary acidic protein (GFAP), a common marker of astrocytes
Oligodendroglioma

Oligodendroglioma:
Note the fried-egg cells with dark, round nuclei and chicken-wire capillaries throughout the tissue sample.

Image: “Morphologic spectrum of glial tumors: an increased trend towards oligodendroglial tumors in Pakistan” by Hashmi AA, Faridi N, Malik B, Edhi MM, Khurshid A, Khan M. License: CC BY 4.0

Management and Prognosis

Management

Oligodendrogliomas are infiltrative tumors that are commonly considered incurable owing to high risk of relapse/recurrence. Optimal management typically involves surgery, radiation, and chemotherapy.

  • Surgery: diagnostic and therapeutic roles
    • Confirms the diagnosis, which can guide adjuvant therapies
    • For best outcomes, the goal of surgery is a gross total resection; however, this is not always possible, depending on the region of the brain affected.
  • Radiation therapy:
    • Typically follows surgery
    • Administered to a restricted area around the surgical site to maximize therapeutic benefit while minimizing side effects
    • Typically withheld from very young children owing to serious comorbidity in that age group
  • Chemotherapy:
    • Typically given following radiation
    • Improves overall survival when combined with adjuvant radiation therapy
    • The standard regimen is PCV:
      • Procarbazine
      • Lomustine (CCNU)
      • Vincristine
    • Can also consider temozolomide as a 2nd-line agent in oligodendroglioma (it is 1st-line for astrocytomas)
  • Other therapies:
    • Anticonvulsant therapy in patients with seizures
    • Corticosteroids for brain edema

Prognosis

  • Average 5-year survival: 
    • Low-grade oligodendroglioma: 5–10 years 
    • Anaplastic oligodendroglioma: 3–4 years 
  • Factors affecting prognosis:
    • Age of the patient at diagnosis (younger patients do better)
    • Location of the tumor
    • Extent of surgical resection
    • Histologic grade of the tumor
    • Postoperative performance status

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Differential Diagnosis

  • Astrocytoma: CNS tumor arising from astrocytes. Aggressive, grade IV astrocytomas are called glioblastoma multiforme, while grade II astrocytomas are called low-grade diffuse astrocytomas. Astrocytomas can present similarly to oligodendrogliomas and are diagnosed using MRI and biopsy. Mutations in IDH and codeletion of 1p/19q are required to diagnose oligodendroglioma; if only IDH mutations are present, this likely represents a low-grade astrocytoma. Like oligodendrogliomas, treatment for astrocytomas includes surgical excision, radiation, and chemotherapy.
  • Meningioma: benign tumor arising from the meninges of the brain or the spinal cord. Meningiomas present with headache, vision disturbances, and possible seizures. Diagnosis is confirmed using MRI and biopsy, and meningiomas are treated with surgical excision. Unlike meningiomas, oligodendrogliomas are more commonly symptomatic and have no association with the dura. 
  • Metastatic tumor: neoplastic cells that have spread to the brain from primary tumors elsewhere in the body. Metastatic neoplasms are the most common neoplasms in the brain. Neuroimaging often shows multiple foci of the carcinoma, suggesting an origin outside the brain. Clinical presentation depends on the primary tumor and location and extent of brain metastasis. Treatment is directed at the underlying neoplasm and may involve surgical resection, radiation therapy, and chemotherapy.
  • Cerebral toxoplasmosis: infection with Toxoplasma gondii in the CNS in immunocompromised patients (e.g., HIV patients). This disease is usually symptomatic only in patients with CD4 counts < 100 cells/µL, and it presents with fever, headache, focal neurologic deficits, and/or seizures. Cerebral toxoplasmosis is diagnosed with serologic studies and brain MRI showing ring-enhancing lesions (which is unlike oligodendrogliomas). Cerebral toxoplasmosis is treated with pyrimethamine, sulfadiazine, and leucovorin, along with antiretroviral therapy. 

References

  1. Van den Bent, M. (2021). Clinical features, diagnosis, and pathology of IDH-mutant, 1p/19q-codeleted oligodendrogliomas. UpToDate. Retrieved May 21, 2021, from https://www.uptodate.com/contents/clinical-features-diagnosis-and-pathology-of-idh-mutant-1p-19q-codeleted-oligodendrogliomas 
  2. Van den Bent, M. (2021). Treatment and prognosis of IDH-mutant, 1p/19q-codeleted (grade II and III) oligodendrogliomas. UpToDate. Retrieved May 21, 2021, from https://www.uptodate.com/contents/treatment-and-prognosis-of-idh-mutant-1p-19q-codeleted-grade-ii-and-iii-oligodendrogliomas 
  3. Uddin, S. (2020). Oligodendroglioma. Medscape. Retrieved May 21, 2021, from https://emedicine.medscape.com/article/1156699-overview 
  4. Tork, C.A., Atkinson, C. (2020). Oligodendroglioma. StatPearls. Retrieved May 21, 2021, from https://www.ncbi.nlm.nih.gov/books/NBK559184/ 

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