Herbert B. Newton, MD, FAAN
DESCRIPTION
- Oligodendrogliomas (oligos) are an uncommon group of glial neoplasms that typically occur in young and middle-age adults. They have variable growth potential and can be quite infiltrative, depending on whether they are typical low-grade oligodendrogliomas (LGO) or the more aggressive anaplastic oligodendrogliomas (AO). Survival is prolonged in most patients and ranges between 4 and 10 years.
EPIDEMIOLOGY
Incidence/Prevalence
- Oligodendrogliomas comprise approximately 4–5% of primary brain tumors in adults; this corresponds to roughly 700 new cases each year in North America. The incidence of LGO and AO are relatively equal, similar to the incidence of pure and mixed oligos.
- All races and ethnic groups affected. Caucasians are affected more commonly than Blacks, Latinos, and Asians. Typical presentation is between 40 and 50 years of age for all forms of oligo. Incidence is slightly higher in males than females (1.5:1).
RISK FACTORS
- The only known risk factors for oligos are prior cranial radiation exposure and those rare families in which oligos are genetically transmitted.
Genetics
- Oligodendrogliomas are usually sporadic and do not have an underlying genetic predilection; rarely, oligos can be familial.
GENERAL PREVENTION
- No preventive measures are known.
PATHOPHYSIOLOGY/ETIOLOGY
- The World Health Organization classifies LGO as grade II, AO as grade III, and mixed anaplastic oligoastrocytoma (AOA) as grade III.
- Oligodendrogliomas are most likely derived from transformed oligodendrocytes. They have a predilection for the subcortical white matter of the cerebral hemispheres. Molecular genetic studies of oligos have noted that the two most common abnormalities are deletion of chromosomes 19q (50–80%) and 1p (40–65%). Loss of 1p and 19q are associated with chemosensitivity and prolonged survival of LGO and AO. Overexpression (without amplification) of epidermal growth factor receptors (EGFR) and platelet-derived growth factor receptors (PDGFR) is present in over 50% of oligos. Other abnormalities include loss of chromosomal material on 9p and 10q, mutation or deletion of the tumor suppressor genes p53 and p16, and overexpression of vascular endothelial growth factor (VEGF).
HISTORY
- The median duration from onset of symptoms to diagnosis ranges from 6 to 12 months in AO to 18 to 30 months for LGO. The most common symptom at presentation is seizure activity (50–70%). Seizures can be simple partial, complex partial, generalized tonic-clonic, or a combination. Other presenting symptoms include headache and other signs of increased intracranial pressure (e.g., nausea, emesis, diplopia), focal weakness, speech dysfunction, cognitive decline, and behavioral changes; rarely, patients can have acute symptoms from intra-tumoral hemorrhage.
PHYSICAL EXAM
- The common findings on neurological examination include hemiparesis, papilledema, dysphasia, impaired memory and cognition, hemianopsia, and sensory loss. Many patients with LGO have non-focal neurological examinations.
DIAGNOSTIC TESTS AND INTERPRETATION
Lab
Initial Lab Tests
- General lab tests are not helpful except for pre-surgical screening and to check anticonvulsant levels.
Imaging
Initial Approach
- MRI, with and without gadolinium contrast, is the most sensitive diagnostic test. MRI is more sensitive than CT for oligos that are small or within the posterior fossa. On T1 images, the tumor is usually infiltrative and appears hypo- or isointense compared to brain. On T2 images, the mass is hyperintense. Foci of hemorrhage or calcification may be noted. With gadolinium administration, most LGO do not enhance while AO/AOA show either patchy or ring-like enhancement. Peritumoral edema and mass effect are usually mild to moderate. CT demonstrates an ill-defined region of hypodensity with variable enhancement; edema and mass effect are mild. CT may show calcification of some oligos but this is not a specific finding.
Diagnostic Procedures/Other
- Fluorodeoxyglucose-positron emission tomography (FDG-PET) may be of benefit to assess the metabolism of oligos to differentiate from non-neoplastic lesions and to maximize targeting for biopsy; on PET imaging, LGO appear hypometabolic and AO appear hypermetabolic; magnetic resonance spectroscopy (MRS) can also be used for metabolic screening to differentiate oligos from other lesions; MRS reveals an elevated choline peak, moderately reduced N-acetyl aspartate (NAA) peak, the presence of a lactate peak, and a reduced NAA/choline ratio.
Pathological Findings
- Pathological evaluation of LGO reveals a moderately cellular tumor with rounded, homogeneous cells that have a “fried-egg appearance” on paraffin sections. Other features include microcalcifications, dense branching capillaries, mild nuclear atypia, and low-level mitotic activity; AO will have similar features with the addition of higher cellular density, cellular and nuclear atypia, high mitotic rate, endothelial proliferation, and necrosis.
- Molecular analysis of chromosome 1p and/or 19q loss is of prognostic significance in patients with AO and LGO.
DIFFERENTIAL DIAGNOSIS
- Other mass lesions that may or may not enhance should be considered, including abscess, subacute infarct, tumefactive regions of demyelination, and evolving hematoma.
MEDICATION
First Line
- Seizures are a common problem in patients with LGO and AO; appropriate anticonvulsant choices (e.g., phenytoin, carbamazepine, levetiracetam) and management will be critical. Dexamethasone is used at the lowest dose able to control symptoms related to intracranial pressure.
ADDITIONAL TREATMENT
General Measures
- The management of LGO and AO requires a multi-modality approach to cytoreduction that may require surgery, radiotherapy, and chemotherapy (chemo). Treatment must be individualized, and input from neurosurgeons, neuro-oncologists, and radiation oncologists is necessary for optimal therapy. Patients with small, indolent tumors (i.e., presentation with seizures, normal neurological examination, no evidence on CT/MRI of increased intracranial pressure) may be followed without treatment for evidence of growth.
Additional Therapies
- External beam radiation therapy (RT) should be considered for carefully selected oligo patients after subtotal resection or at progression; it is appropriate to consider delaying RT for patients with clean post-operative margins on follow-up MRI.
- Most patients with AO should be considered for RT after surgery, although it may be delayed until after chemotherapy (chemo) in patients with deletion of 1p and 19q. The majority of phase II clinical trial data suggest an extension of median and 5-year survival by RT after subtotal resection and at recurrence. The recommended RT dose is 50 to 60 Gy over six weeks, in 180 to 200 cGy daily fractions; focal three-dimensional treatment planning and conformal techniques should be used whenever possible to minimize radiation exposure to normal brain.
- Stereotactic radiosurgery (SRS) has recently been used for recurrent oligos that were less than 4 cm in size. Larger tumors will not benefit from SRS due to infiltration beyond the treatment field. Median doses range from 15 to 17 Gy in one fraction. SRS may improve survival in carefully selected patients with small oligos.
- Oligodendrogliomas are the most chemosensitive type of primary brain tumor. The use of chemo should be delayed after complete surgical resection. Chemo should be considered first-line treatment for subtotally resected LGO or AO with 1p/19q deletion status (100% response rate, survival >120 months) or 1p deletion/p53 mutation (100% response rate, survival >71 months). Patients with oligos that retain 1p and/or 19q may still respond to chemo, but with lower response rates and shorter median survival. The most active regimens are temozolomide, PCV (procarbazine, CCNU [lomustine] vincristine), BCNU [carmustine], and melphalan.
SURGERY/OTHER PROCEDURES
- Surgery should be considered in all patients to make a histological diagnosis, reduce tumor bulk and intracranial pressure, and alleviate symptoms. Maximal surgical resection is the treatment of choice for accessible LGO and AO, preferably by computer-assisted volumetric resection techniques (e.g., stealth apparatus). For patients with deep, inaccessible lesions or tumors in eloquent cortex, stereotactic biopsy should be performed. Several studies suggest that median and 5-year survival of LGO and AO are improved with complete or sub-total resection versus biopsy.
IN-PATIENT CONSIDERATIONS
Initial Stabilization
- Will often be for seizure control or raised intracranial pressure, or for pre-surgical evaluation. Dexamethasone (4–16 mg/d) may be of benefit to reduce peritumoral edema and swelling.
Admission Criteria
- Patients with LGO and AO are often admitted for seizure control or neurological deterioration due to elevated intracranial pressure and tumor growth; maximizing anticonvulsant doses, resolving metabolic disturbances, and reducing intracranial pressure will be required before discharge.
Discharge Criteria
- After stabilization of seizures or intracranial pressure, or recovery from surgical intervention.
FOLLOW-UP RECOMMENDATIONS
- Will be variable depending on the status of seizure control and the need for further active treatment.
Patient Monitoring
- Patients are followed with serial MRI scans and neurological examinations every 4 to 6 months. Patients receiving chemotherapy may require more frequent follow-up; anticonvulsant levels need to be monitored carefully.
PATIENT EDUCATION
PROGNOSIS
- The median survival of patients with LGO is 6 to 10 years, with a 5-year survival rate of 75%; median survival of patients with AO is 3 to 4 years; survival of AO patients is affected by 1p and 19q status; tumors with deletion of both 1p and 19q are very chemosensitive, with patient survival of 8 to 10 years; tumors which maintain both 1p and 19q are treatment resistant, with patient survival of 2 to 5 years.
- Prognosis is improved with young age (<40 years), LGO histology, high Karnofsky performance status, and deletion of 1p and/or 19q; prognosis is worse with age >50 years, poor Karnofsky performance status, AO histology, and presence of 1p and 19q.
COMPLICATIONS
- Most often include continued seizure activity, and neurological deficits caused by the tumor and/or active treatment.
ICD9
191.9 Malignant neoplasm of brain, unspecified site