Oligodendroglioma 

Updated: Oct 01, 2019
Author: ABM Salah Uddin, MD; Chief Editor: Stephen A Berman, MD, PhD, MBA 

Overview

Background

Oligodendrogliomas (ODs) are primary glial brain tumors that are divided into grade II and anaplastic grade III tumors (World Health Organization [WHO] criteria). 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 chemotherapy, a recently discovered finding based on genetic characteristics.

Pathophysiology

Oligodendrogliomas arise in the cerebral hemispheres and are distributed among the frontal, parietal, temporal, and occipital lobe, in approximately a 3:2:2:1 ratio. Rarely, they can arise in the cerebellum, brain stem, and spinal cord.[1] They usually occur in the cerebral white matter and are very cellular, with uniform nuclei. They react with glial fibrillary acidic protein on immunostaining.

Epidemiology

Frequency

The incidence of oligodendrogliomas ranges from 5–19% of all intracranial tumors. The newer studies showed incidence of oligodendrogliomas to be around 25% of all gliomas. This may be explained by the improvements in the treatment of oligodendrogliomas, prompting neuropathologists to favor the diagnosis.

Mortality/Morbidity

The morbidity and mortality profile for oligodendrogliomas is much better than for astrocytic tumors. However, it also depends on tumor location and pressure effects, as with any other intracranial lesion. The median survival from initial diagnosis of all low-grade oligodendrogliomas (LGOs) is 4–10 years, but it is only 3–4 years for anaplastic oligodendrogliomas.

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, with a median age at diagnosis of 40–50 years. In children, only 6% of gliomas are diagnosed as oligodendrogliomas.

Prognosis

Combined loss of 1p/19q is a significant predictor of overall survival in anaplastic oligodendroglioma and is also significantly associated with longer recurrence-free survival and chemosensitivity.[2]

The phosphatase and tensin homologue deleted by chromosome 10 (PTEN) alteration is associated with a poor prognosis.

Other variables, including age of the patient at time of diagnosis, location and extent of surgical resection, postoperative performance status, histologic features of the tumor, and use of adjuvant therapies and early presentation with seizures, determine the prognosis for an individual patient. Overall, as many as three fourths of patients with nonanaplastic tumors can be expected to survive 5 years from the time of diagnosis, with a median reported survival duration of 6-10 years. For those with anaplastic oligodendrogliomas, median survival is more likely to be 3–4 years. Late progression of disease is common, so the usual 5-year survival time used to indicate "cure" in other cancers is not relevant for oligodendrogliomas.

 

Presentation

History

In prior years, a long delay occurred between symptom onset and diagnosis (as long as 29 y in some series). Because of earlier and better imaging availability, oligodendrogliomas have been diagnosed much earlier in recent years.

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 are 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. Occasionally they may be multifocal, like other gliomas.

The most common presenting symptom is seizure, observed at diagnosis in as many as half of patients. As many as 80% of patients have seizures at some time during their illness. Depending on the location of the tumor, the seizure can be simple partial, complex partial, or generalized. Previously undiagnosed oligodendrogliomas may be identified with medically refractory epilepsy.

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). Rarely, they can metastasize outside the nervous system, especially the anaplastic oligodendroglioma.

In long-surviving patients with 1p/19q co-deletion, indolent leptomeningeal disease may be a complication of oligodendroglioma, which may have implications for the treatment.[3, 4]

Occasional patients present with strokelike transient ischemic attacks or with intracerebral hemorrhage.

Physical

Physical findings depend on the location of the tumor.

Frontal, parietal, and temporal lobe tumors most commonly present with seizures. Seizures may be simple, complex partial, and even generalized. Frontoparietal tumors may present with hemiparesis and sensory neglect. Sensory neglect is pronounced in right hemispheric lesions. Temporal lobe tumors rarely may present with visual field defects, although patients may be unaware of hemianopsia.

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, well-documented cases are described in children and may present with cerebellar ataxia and increased intracranial pressure.

Causes

No causes or risk factors are known. Occasional clustering occurs in some families, although the mode of inheritance is unknown. Patients with anaplastic oligodendrogliomas who have loss of heterozygosity on 1p or combined loss of heterozygosity on 1p and 19q survive substantially longer (mean, 10 y) than patients whose tumors lack these genetic changes (mean, 2 y).

 

DDx

 

Workup

Laboratory Studies

Routine laboratory workup is not helpful. If seizures are noted, include EEG, serum electrolyte studies, and if necessary a lumbar puncture in the metabolic workup for seizure, after excluding intracranial pathology with an imaging study. These routine tests help exclude other causes of seizure (eg, electrolyte imbalance, metabolic abnormalities).

Imaging Studies

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, the LGO generally does not enhance, while an anaplastic oligodendroglioma does enhance. These tumors also tend toward calcification. See the image below.

      Sagittal gadolinium-enhanced T1-weighted magnetic 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 with those without 1p/19q loss. Tumors with 1p/19q loss 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 oligodendroglioma 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.

    • As with contrast MRI, the tumor does not enhance unless it is behaving unusually aggressively or has an anaplastic astrocytic component. See the images below.

      Contrast-enhanced computed tomography scan in a 44 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 oligodendr Computed tomography scan of a low-grade oligodendroglioma. This image reveals a well-demarcated, left frontal hypoattenuating lesion with a small calcification.

Other Tests

Definite diagnosis in confirmed by stereotactic or open biopsy of the lesion. Currently, MR spectroscopy is performed regularly in some centers to differentiate the tumor from other benign lesions and to define the aggressiveness of the tumor, although this is in the investigational phase. In the future, it may offer another noninvasive modality of investigation.

Histologic Findings

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 and in some patients may be massive and responsible for sudden death.

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. The classic appearance of the Oligodendrogliomas. The classic appearance of the oligodendroglioma is that of a round to oval, water-clear cytoplasm ringing about round to lobulated nuclei. The chromatin appearance is finely threadlike to smudgy, often associated with pointlike basophilic chromocenters, rather than nucleoli.
Classic histologic image of oligodendroglioma. Thi Classic histologic image of oligodendroglioma. This image shows monomorphous tumoral proliferation that consists of round, regular cells with a small, central, hyperchromatic nucleus surrounded by clear cytoplasm. Few calcifications are present.
 Oligodendrogliomas. The cellular density is moder Oligodendrogliomas. The cellular density is moderate to high, and the fried-egg appearance dominates the histologic features.

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. Many oligodendrogliomas have some component of astrocytoma within them; however, distinguishing neoplastic astrocytes from reactive astrocytes may be very difficult. Clearly, some tumors are truly mixed oligoastrocytic tumors; both cell types are believed to arise from a common oligodendrocyte precursor termed the oligodendrocyte type-2 astrocyte.

Oligodendrogliomas. This tumor exhibits oligodendr Oligodendrogliomas. This tumor exhibits oligodendroglial-type nuclei and scanty eosinophilic fibrillar cytoplasm amidst a mucinous background. Such tumors may be considered oligoastrocytomas.

To call a tumor a mixed oligoastrocytoma, the minimum proportion of astrocyte is variable but ranges from 10–25%. In most instances, the diagnosis of oligodendroglioma is apparent. Confusion can arise with intraventricular oligodendrogliomas, which can appear similar to central neurocytoma. Under light microscopy, neuronal differentiation (eg, Homer Wright rosette formation) can indicate a diagnosis of central neurocytoma, but immunohistochemical markers such as synaptophysin may be necessary to confirm the diagnosis.[7]

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 tumors and as anaplastic oligodendroglioma if several of the malignant features are present.[8] See the images below.

Oligodendrogliomas. Oligodendrogliomas with vascul Oligodendrogliomas. Oligodendrogliomas with vascular proliferation and significant mitotic activity are best considered to be anaplastic oligodendrogliomas (World Health Organization [WHO] grade III).
Smear preparation of anaplastic oligodendroglioma. Smear preparation of anaplastic oligodendroglioma. This image reveals increased nuclear pleomorphism and vascular proliferation.
Oligodendrogliomas. Anaplastic oligodendrogliomas Oligodendrogliomas. Anaplastic oligodendrogliomas frequently take on eosinophilic cytoplasm and hyperchromasia of the nuclei. Such tumors may demonstrate necrosis among its diagnostic features.
 

Treatment

Medical Care

Individualize treatment of an oligodendroglioma depending on the presence or absence of symptoms, location and biological aggressiveness of the tumor, extent of possible surgical resection, 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. Because most patients either develop or present with seizures, anticonvulsive therapy is recommended once the patient is diagnosed with oligodendroglioma. See Brain Cancer Treatment Protocols for summarized information.

Chemotherapy

The role of chemotherapy for the treatment of oligodendroglioma was well established by several studies using nitrosourea-based therapy.{re8} Most used procarbazine, lomustine (CCNU), and vincristine, a combination chemotherapy regimen (ie, PCV) developed by Levin and coworkers.[9] Patients with pure and mixed oligoastrocytic tumors, newly diagnosed, and recurrent mixed tumors responded to this therapy before receiving radiotherapy. Despite prolonged responses, most patients experience disease relapse and ultimately die of progressive disease. The median time for recurrence was at least 16 months in partial responders and at least 25 months in complete responders. Recurrent tumors are not cured by PCV, and the intensity of treatment may be limited by the bone marrow reserve.[10]

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.[11]

An interim analysis of a phase II study of intensified chemotherapy (I-PCV) alone for newly diagnosed anaplastic oligodendroglioma showed that median progression-free survival for all patients is 19.5 months, similar to the median progression-free survival for patients receiving radiotherapy alone in the RTOG and EORTC trials. These findings suggest that the patient care is not compromised by initiating treatment with chemotherapy alone and delay of radiotherapy may have a beneficial impact on quality of life.[12]

A phase III study preliminary findings reported by Cairncross et al, comparing radiation therapy versus chemotherapy plus radiation in patients with newly diagnosed anaplastic OD and mixed OD, 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).[13]

New agents are needed for further improvements of survival in OD.

Radiation therapy

Various studies compared the effects of radiation therapy before and after the maximal surgical resection. The studies showed that the immediate postoperative irradiation in patients with LOG increases the median progression-free survival by 2 years without affecting the overall survival. This result suggests that radiation therapy can be withheld until a clinical or radiologic progression occurs to delay the sequelae of cranial irradiation.

The RTOG study compared the effects of pre–radiation therapy dose-intensified PCV chemotherapy followed by radiation therapy versus radiation therapy alone in newly diagnosed oligodendroglioma and anaplastic oligodendroglioma. No difference in overall survival was noted. However, the progression-free survival rate was longer after radiation therapy plus PCV.

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.[14]

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).[15]  

Surgical Care

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 total gross resection, no further treatment may be necessary, but the patient must be followed up for clinical or radiologic recurrence.

The optimal use of radiotherapy in the treatment of oligodendroglioma is not entirely clear. Although differences of opinion exist regarding the efficacy of radiotherapy for oligodendrogliomas, radiation is used routinely at diagnosis in patients who have undergone incomplete removal of nonanaplastic oligodendrogliomas and generally is recommended for patients with anaplastic oligodendrogliomas regardless of the extent of resection. Radiotherapy also is used at recurrence in previously untreated patients. As systemic therapies are becoming available and more effective, delaying radiotherapy in many patients may be prudent to avoid the toxic side effects of radiation to the nervous system.

 

Medication

Medication Summary

The standard chemotherapeutic treatment for oligodendrogliomas is combination chemotherapy with PCV. While modifications of the timing and dosage of this regimen (increasing dose, decreasing time interval to every 6 wk), are beyond the scope of this article, interested readers can review the references cited in Bibliography. Physicians prescribing chemotherapy should be aware of the treatment regimens and monitoring required. PCV chemotherapy is administered every 6 weeks or 8 weeks for a total of 6 cycles. If the treatment should fail, radiation therapy, other clinical trials for recurrent gliomas, or other drugs may be considered.

PCV chemotherapy

Class Summary

This combination of agents inhibits cell growth and differentiation.

Procarbazine, lomustine (CCNU), vincristine

Oral chemotherapy drugs administered in combination (PCV) on a specific chemotherapeutic schedule.

 

Follow-up

Further Outpatient Care

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.

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).

Complications

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

Patient Education

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.