Oligodendroglioma

Oligodendrogliomas are primary glial brain tumors that are divided into grade 2 and grade 3 tumors, with grade 3 tumors showing anaplastic features such as microvascular proliferation, necrosis, and increased mitotic rate; distinction between the two grades can be pathologically difficult. Oligodendrogliomas are molecularly defined by the presence of complete deletion of the short arm of chromosome 1 (1p) and the long arm of chromosome 19 (19q) (1p/19q co-deletion). Virtually all oligodendrogliomas also have a mutation in isocitrate dehydrogenase (IDH1 or IDH2). Typically, they have an indolent course, and patients may survive for many years after symptom onset. Their good prognosis relative to other parenchymal tumors probably stems from inherently less aggressive biological behavior and a favorable response to radiation and chemotherapy.

Oligodendrogliomas arise in the cerebral hemispheres and have a predilection for the frontal lobes. They can rarely arise infratentorially or in the spinal cord. Leptomeningeal spread can occur rarely in late stages of the disease. Oligodendrogliomas have a “fried egg” appearance under the microscope with sheets of round nuclei surrounded by clear cytoplasm.

Frequency

The incidence of oligodendrogliomas is around 5% of all central nervous system neuroepithelial tumors.[1] . About 1,000 oligodendrogliomas are diagnosed per year in the United States.

Demographics

Oligodendrogliomas occur in both sexes, with a male-to-female predominance of 2:1.

Oligodendrogliomas may be diagnosed at any age but occur most commonly in young and middle-aged adults between 25 and 45 years old. Grade 3 tumors have a median age at diagnosis that is 5–10 years older than grade 2 tumors.

Prior to the WHO 2016 classification of CNS tumors, grades 2 and 3 gliomas were not molecularly distinguished by 1p/19q codeletion status. The median survival of all low-grade gliomas was estimated at 4–10 years, and survival of grade 3 gliomas was estimated at 3–4 years after diagnosis. Recently, 1p/19q codeletion was independently validated as a favorable prognostic factor in low grade glioma.{ref35. Another factor that increases probability of survival in low-grade gliomas is a high performance status.[2]

Patients with low-grade gliomas can be conventionally stratified into “high risk” and “low risk” categories, with risk referring to risk of tumor progression or recurrence. “Low-risk” patients have a better prognosis than “high-risk” patients. “High-risk” patients are defined as age older than 40 years, or less than a gross total resection achieved at surgery; “low-risk” patients are those who are both younger than age 40 and underwent gross total resection of the tumor. “Low-risk” patients might defer treatment with radiation and chemotherapy and followed with surveillance only, while “high-risk” patients may benefit with upfront adjuvant treatment.[3] This risk classification may change in the future as our understanding of the contributions of genetic markers to survivability evolves.

Progression-free and overall survival of low grade gliomas in “high-risk” patients was studied in the RTOG-9802 trial. The trial compared outcomes in patients who received radiation therapy alone versus radiation therapy (RT) plus chemotherapy with procarbazine, CCNU, and vincristine (PCV). Progression-free and overall survival at 12 years were significantly increased in the RT+PCV group. The median overall survival was 13.3 years in the RT+PCV group versus 7.8 years in the RT alone group, and progression-free survival at 10 years was 51% in the RT+PCV group versus 21% in the RT alone group. In a subgroup analysis, oligodendroglioma diagnosis was a favorable prognostic factor resulting in increased overall and progression-free survival; however, oligodendrogliomas were classified histologically in this study, not by 1p/19q status.[4]

Throughout the entire process, educate the patient and family through regular follow-up care and involvement of support groups to cope with physical, emotional, and spiritual stress. With proper education, the patient and family can develop good insight into the course and prognosis of the tumor.

.

Like other intracranial space-occupying lesions, oligodendrogliomas present with focal cerebral dysfunction, depending on location, and rarely as increased intracranial pressure.

Most oligodendrogliomas present as a single lesion in the cerebral hemispheres. Typically, they arise from the white matter, but they can be cortical or subcortical; they rarely are found in deep gray structures, and occasionally they may be primarily intraventricular. Rarely, they can occur infratentorially or in the spinal cord. Leptomeningeal spread can occur as a late manifestation of the disease. Occasionally they may be multifocal, like other gliomas.

As these tumors are slow growing, they often are clinically silent for many years. Many are found incidentally during head imaging for other concerns. The most common presenting symptom is seizure,. The seizure can be focal or can secondarily generalize into a convulsive seizure.

Occasionally patients with oligodendrogliomas are brought to medical attention for headache, symptoms of increased intracranial pressure, or focal neurological deficits.

Tumors that arise within the ventricles may cause obstructive hydrocephalus and are more likely to disseminate through the cerebrospinal fluid (CSF).

Physical findings depend on the location of the tumor. Due to the slow growing nature of these tumors, patients may be asymptomatic at the time of diagnosis and have a normal neurological examination.

Frontal, parietal, and temporal lobe tumors most commonly present with seizures. Seizures may be focal or may secondarily generalize. Frontal tumors may present with personality changes, executive dysfunction, or hemiparesis. Parietal tumors may present with hemisensory loss, sensory neglect, or visuospatial impairment. Occipital lobe tumors may present with visual field deficits.

Rare intraventricular oligodendroglioma may present with signs and symptoms of increased intracranial pressure such as headache, visual disturbance, and papilledema.

Posterior fossa oligodendrogliomas are uncommon. However, cases are described in children and may present with cerebellar ataxia and increased intracranial pressure.

In general, there is no known cause for oligodendrogliomas. Rarely, familial cancer syndromes such as Rubinstein-Taybi syndrome increase a person’s risk of development of gliomas.

Closely observe the patient for any complications resulting from continuing treatment, such as radiation necrosis from radiation therapy or neuropathy from chemotherapy.

Routine laboratory workup is not helpful as there are no serum biomarkers for oligodendroglioma. The tumor also does not cause any alteration in electrolytes or blood counts. Routine laboratory studies are appropriate if a patient is receiving chemotherapy.

Diagnostic imaging studies are the most important part of the workup.

• MRI (with and without gadolinium) is the preferred modality.

  • T1 images generally demonstrate a hypointense or mixed hypointense and hyperintense mass.

  • T2 images reveal a hyperintense mass with or without surrounding edema.

  • With contrast administration, grade 2 oligodendroglioma generally does not enhance, while a grade 3 oligodendroglioma might. Calcification is also a common finding, potentially reflecting the slow growing nature of these tumors. See the image below.
  • Sagittal gadolinium-enhanced T1-weighted magnetic resonance image of a low-grade oligodendroglioma. This image demonstrates no contrast enhancement.

• A study by Megyesi et al compared the MRI characteristics of oligodendroglioma with 1p/19q loss (now called astrocytoma) with those without 1p/19q loss. Tumors with 1p/19q loss (now called oligodendroglioma) were significantly more likely to have indistinct borders, a mixed signal intensity on T1- and T2-weighted images, paramagnetic susceptibility effects, and intratumoral calcification compared with astrocytoma without 1p/19q loss, which more often had a distinct border and a uniform signal on T1- and T2-weighted images.[5]

• A study by Brown et al, using noninvasive quantitative MRI with and without contrast, reliably predicted the co-deletion of chromosomes 1p and 19q with high sensitivity and specificity in suspected low-grade glioma.[6]

• CT scans reveal a hypodense, reasonably well-demarcated mass with moderate surrounding edema.

  • Intratumoral calcification is common, and hemorrhage is noted occasionally.

  • Contrast-enhanced computed tomography scan in a 44-year-old man with a 3-year history of epileptic seizures. This image reveals a calcified hypoattenuating lesion that is invading the corpus callosum.
    Computed tomography scan of a low-grade oligodendroglioma. This image reveals a well-demarcated, left frontal hypoattenuating lesion with a small calcification.

Definitive diagnosis is made by surgical resection for histologic and molecular analysis. Maximal surgical resection is associated with improved outcomes.

Macroscopic

Grossly, oligodendrogliomas appear as well defined, solid, and pinkish grey, frequently with areas of calcification and sometimes with areas of necrosis and cystic degeneration. Intratumoral hemorrhage may be present.

Microscopic

Oligodendrogliomas are distinctive, consisting of homogeneous, compact, rounded cells with distinct borders and clear cytoplasm surrounding a dense central nucleus, giving them a "fried egg" appearance. See the image below.

Oligodendrogliomas usually arise in the subcortical location but infiltrate diffusely into cortex around normal neuronal elements and, in superficially located lesions, may extend to the leptomeninges. Within the tumor, branching blood vessels are highly characteristic and divide the cells into discrete clusters.

The WHO 2016 Classification of Tumors of the CNS abolished the previously used term “oligoastrocytoma.” To definitively diagnose a glial tumor as oligodendroglioma, the tumor must have both IDH-mutation and 1p/19q co-deletion. Notably, the WHO 2021 Classification of Tumors of the CNS removed the term “anaplastic” from the naming of glial tumors, instead simply referring to them as grade 3.

Most oligodendrogliomas are slow-growing indolent tumors; however, they occasionally behave in a more malignant manner when initially diagnosed, or an indolent tumor may evolve into an aggressive one. Malignant tumors demonstrate increased cellularity, nuclear pleomorphism, endothelial proliferation, mitotic activity, and necrosis. Different grading systems are available for malignant tumors, but most pathologists use a simple two-tier grading system, diagnosing tumors without anaplastic features as oligodendroglioma, grade 2 tumors and as anaplastic oligodendroglioma, grade 3 if several of the malignant features are present. See the images below.

Conventional “TMN” cancer staging does not apply to gliomas as they rarely spread outside the CNS. Instead, gliomas are graded via the World Health Organization (WHO) grading scale from 1 to 4, with 1 being the least aggressive and 4 being the most aggressive. Oligodendrogliomas by definition are either a grade 2 or grade 3 glioma. See the Histologic Findings section for more information on delineation between grades 2 and 3 oligodendrogliomas.

The treatment recommendations for oligodendrogliomas are based largely on studies completed prior to the use of 1p/19q as a definitive marker for the disease. Currently, the standard treatment is maximum safe surgical resection, followed by either observation in “low-risk” patients (patients with gross total resection who are younger than 40 years) and upfront radiation and chemotherapy with either PCV or temozolomide in “high-risk” patients (patients with either subtotal resection or age older than 40 years). These recommendations may change with newer studies as 1p/19q co-deletion may prove to be a factor contributing to “low risk” of recurrence.

Medical and surgical treatment of oligodendrogliomas depends on the presence or absence of symptoms, location and biological aggressiveness of the tumor, extent of possible surgical resection, age of the patient, and histopathology and degree of anaplasia. Treatment options vary from conservative treatment of some patients with serial imaging studies and no intervention to aggressive multimodal treatment including surgical resection, radiotherapy, and chemotherapy in others.

Patients with low-grade gliomas, which include grade 2 oligodendrogliomas, have classically been stratified into “high risk” and “low risk” categories, with risk referring to risk of tumor progression or recurrence. “Low-risk” patients have a better prognosis than “high-risk” patients. See Prognosis.

“Low-risk” patients can sometimes defer treatment with radiation and chemotherapy with radiographic and clinical surveillance only, while “high-risk” patients have shown benefit with upfront adjuvant treatment.[3] Notably, this risk stratification is debated, especially now in the era of precision medicine and genetic markers for diagnosis.

Anti-epileptic medications are used in patients who have had seizures; empiric anti-epileptic therapy is not recommended.

Radiation therapy

The CODEL trial is investigating patients with grade 3 oligodendrogliomas, 1p/19q co-deleted. Investigators initially compared treatment with RT alone, RT plus concomitant and adjuvant temozolomide, and temozolomide alone. Interim analysis revealed that patients who received RT had significantly increased survival compared to patients who received TMZ alone without RT. For this reason, radiotherapy in combination with chemotherapy rather than chemotherapy alone is recommended in patients undergoing upfront treatment.[7] However, this trial is currently ongoing comparing with modified treatment arms and should establish the comparative efficacy of RT plus adjuvant PCV versus RT plus concomitant and adjuvant temozolomide.

Shaw et al found that for oligodendroglioma patients with 2-year survival (more benign tumors), the probability of overall survival for an additional 5 years was 74% with combination therapy compared to 59% with radiotherapy alone.[8]

One study suggests that patients with oligodendroglioma are at higher risk of developing radiation necrosis (RN). Of the cohort of 319 patients, 41 patients were identified as having RN (12.9%): 28 patients (21.3%) with oligodendroglioma and 13 (6.9%) with astrocytoma (HR 3.42, p <  0.001). Patients with oligodendroglioma who received > 54 Gy had a higher incidence (31.2%) than those receiving ≤ 54 Gy (14.3%, HR 6.9, p = 0.002).[9]  

Chemotherapy

The role of chemotherapy for the treatment of oligodendroglioma was well established by several studies using nitrosourea-based therapy.[10] Most used procarbazine, lomustine (CCNU), and vincristine, a combination chemotherapy regimen (ie, PCV) developed by Levin and coworkers.[11] The RTOG 9802 trial investigated the use of radiation therapy alone versus radiation therapy followed by PCV in patients with grade 2 gliomas who were “high risk” as defined above (at the time, 1p/19q co-deletion status was not a requirement for differentiation of oligodendrogliomas from other gliomas). The rate of progression-free survival was 51% at 10 years in the radiation + PCV group versus 21% in the radiation only group.[4] For this reason, combination chemotherapy and radiation therapy is advised.

Several studies have evaluated the role of temozolomide as second-line chemotherapy for recurrent oligodendroglioma and showed a response rate of about 25% for patients relapsing after PCV therapy. The EORTC study evaluated temozolomide as a first-line chemotherapy for recurrent oligodendroglial tumors and showed a response rate of 54%, with 39% of patients remaining free from progression at 12 months.[12] . A subsequent EORTC study investigated the response rate of “high risk” grade 2 gliomas to either radiation therapy or neoadjuvant temozolomide and although there was a progression-free survival benefit for patients who received RT, this benefit did not reach statistical significance.[13] The more recent CODEL trial evaluated patients with grade 3 oligodendrogliomas, 1p/19q co-deleted. They initially compared treatment with RT alone, RT plus concomitant and adjuvant temozolomide, and temozolomide alone. Interim analysis revealed that patients who received RT had significantly increased survival compared to patients who received TMZ alone without RT. Future results from this trial will help guide chemotherapeutic treatment for these tumor types.[7]

Preliminary findings from a phase III study reported by Cairncross et al, comparing radiation therapy versus chemotherapy plus radiation in patients with newly diagnosed anaplastic glioma, showed overall similar survival in both groups (4.8 y for radiotherapy plus chemotherapy group vs 4.5 y for radiotherapy alone). However, disease progression-free interval was longer for the combined therapy group (2.6 y vs 1.9 y for radiotherapy alone group).[14]

Targeted therapy

As oligodendrogliomas are by definition IDH-mutated, investigations into IDH-targeted therapies have been undertaken. Enasidenib and ivosidenib are medications currently used for IDH-mutant acute myeloid leukemia. It is currently unclear how IDH mutations contribute to glioma formation and growth. Studies are currently ongoing investigating the use of this targeted therapy in IDH-mutated gliomas.

Historically, surgery has been the mainstay of treatment for oligodendrogliomas. The extent of resection depends in large part on the location of the tumor and its proximity to "eloquent" brain areas. If possible, the goal is total resection of the tumor. In patients who undergo gross total resection and have features of low risk for recurrence (age< 40), no further treatment may be necessary, but the patient must be followed closely for clinical or radiologic recurrence. In patients with high risk for recurrence (subtotal resection, age > 40), upfront treatment with radiation therapy and chemotherapy is advised.

Further inpatient care

After the initial surgical resection and rehabilitation, the patient may require further inpatient care depending on the development of complications from either therapy or tumor recurrence. Appropriate intervention also depends on the nature of complications (eg, surgery for recurrence, steroid therapy for increased vasogenic edema).

Inpatient and outpatient medications

Patients with seizures require appropriate seizure medications even after surgery. Over time, the dose of the medications can be reduced, depending on the frequency of seizures.

Transfer

Transfer depends on the residual neurological deficit. The patient may be fully ambulatory or may need appropriate transfer arrangements (eg, cane, wheelchair).

The standard chemotherapeutic treatment for oligodendrogliomas is combination chemotherapy with PCV, initiated about 4 weeks after radiation therapy, or temozolomide concomitant with radiation followed by adjuvantly about 4 weeks after radiation. The schedule and modifications for these regimens are beyond the scope of this article.

Class Summary

This combination of agents inhibits cell growth and differentiation.

After initial appropriate management, closely monitor the patient with the family for tumor recurrence or chemotherapy-induced adverse effects. Monitor with regular follow-up care and MRI scans every 3 months initially and then every 6 months to 1 year.

After the initial surgical resection and rehabilitation, the patient may require further inpatient care depending on the development of complications from either therapy or tumor recurrence. Appropriate intervention also depends on the nature of complications (eg, surgery for recurrence, steroid therapy for increased vasogenic edema).

Patients with seizures require appropriate seizure medications even after surgery. Over time, the dose of the medications can be reduced, depending on the frequency of seizures.

Transfer depends on the residual neurological deficit. The patient may be fully ambulatory or may need appropriate transfer arrangements (eg, cane, wheelchair).