Herbert B. Newton, MD, FAAN

DESCRIPTION

Low-grade gliomas (LGG) are a diverse group of pathologically distinct neoplasms that usually occur in children and young adults. The most common LGG are of astrocytic and oligodendroglial origin. These tumors have a reduced growth potential and are often less infiltrative when compared to malignant gliomas. Survival is typically prolonged, greater than 5 years in most patients.

EPIDEMIOLOGY

Incidence/Prevalence

• LGG comprise approximately 10–15% of primary brain tumors in adults. This corresponds to roughly 1,900 new cases of LGG each year in North America. The majority of LGG consist of grade II astrocytomas, oligodendrogliomas, and mixed tumors.
• All races and ethnic groups equally affected. Typical presentation is between 30 and 45 years of age, with a mean of 37 years. Incidence is slightly higher in males than females.

RISK FACTORS

• The only known risk factors for LGG are prior cranial radiation exposure and genetic diseases with a predilection for gliomas, such as Turcot's syndrome, neurofibromatosis (NF) types I and II, Li-Fraumeni syndrome, basal cell nevus syndrome, and tuberous sclerosis. Rarely, LGG can be familial.

Genetics

• LGG are usually sporadic and do not have an underlying genetic predilection. Rarely, LGG can manifest as part of a genetically mediated syndrome (i.e., NF).

GENERAL PREVENTION

• There are no preventive measures against LGG.

PATHOPHYSIOLOGY/ETIOLOGY

• LGG are a heterogeneous group of neoplasms that include pilocytic astrocytoma (PCA; WHO grade I), diffuse astrocytoma (WHO grade II), WHO grade II oligodendroglioma, WHO grade II mixed oligoastrocytoma, subependymoma, subependymal giant cell astrocytoma, pleomorphic xanthoastrocytoma, ganglioglioma, central neurocytoma, and dysembryoblastic neuroepithelial tumors.
  • Cells of origin of LGG are variable depending on tumor type. Pathological evaluation of LGG reveals mild to moderate cellularity without anaplasia or severe nuclear atypia, minimal mitotic activity and endothelial proliferation, no necrosis. Tumor cells often stain for glial fibrillary acidic protein. Diffuse astrocytomas can undergo anaplastic degeneration in up to 75% of cases.
  • Molecular genetic studies of LGG reveal frequent allelic deletions of chromosome 17p, often with loss or mutation of the tumor suppressor gene, p53. The presence of abnormal p53 protein in LGG is associated with shorter survival. Amplification of MDM2 or CDK2 and deletion of the tumor suppressors p16 and retinoblastoma may be present in some tumors. Deletion of 1p and 19q may be noted in oligodendrogliomas and is associated with chemosensitivity and extended survival.

COMMONLY ASSOCIATED CONDITIONS

• NF type I, NF type II, Turcot's syndrome, Li-Fraumeni syndrome, basal cell nevus syndrome, tuberous sclerosis.

HISTORY

• The median duration from onset of symptoms to diagnosis ranges from 6 to 17 months. The most common symptom at presentation is seizure, which occurs in 60–65% of patients. Focal seizures are more likely than generalized seizures. Headache and focal weakness each occur in approximately one quarter of patients. Cognitive changes, speech deficits, and visual abnormalities are noted in less than 15% of patients.

PHYSICAL EXAM

• The neurological examination is normal in about 50% of patients; neurological abnormalities that may be noted include focal motor deficits (45%), sensory alterations (40%), mental status alterations (25%), papilledema (20%), dysphasia (20%), and memory deficits (18%).

DIAGNOSTIC TESTS AND INTERPRETATION

Lab

Initial Lab Tests

• Lab testing is generally not helpful, except to measure anticonvulsant levels and for pre-operative screening.

Imaging

Initial Approach

• MRI, with and without gadolinium contrast, is the most sensitive diagnostic test. MRI is more sensitive than CT for tumors that are small or within the posterior fossa. On T1 images, the tumor is usually somewhat circumscribed and appears hypo- or isointense compared to brain. On T2 images, the mass is hyperintense. Cystic regions are often present in PCA. With gadolinium administration, most LGG show minimal or no enhancement. PCA can show variable enhancement, often within a cyst-associated mural nodule. Peritumoral edema and mass effect are usually mild to moderate. Calcification may be noted. CT demonstrates an ill-defined region of hypodensity with minimal enhancement. More than one-third of tumors that appear to be LGG by MRI/CT criteria are higher grade tumors, usually anaplastic astrocytoma.

Diagnostic Procedures/Other

• Molecular analysis of chromosome 1p and/or 19q loss may be of prognostic significance in patients with oligodendroglioma. Electroencephalography should be considered in patients with atypical or unusual seizures.

Pathological Findings

• LGG will demonstrate low cellularity, minimal cellular or nuclear atypia, minimal vascularity, no necrosis, and a lack of mitotic activity.

DIFFERENTIAL DIAGNOSIS

• Other mass lesions that may or may not enhance should be considered, including immature abscess, subacute infarct, tumefactive regions of demyelination, and evolving hematoma.

MEDICATION

First Line

• Seizures are a common problem in patients with LGG; appropriate anticonvulsant choices and management will be critical. Dexamethasone is used at the lowest dose able to control symptoms related to intracranial pressure.
• All patients should be on an H2 blocking drug while receiving chronic dexamethasone.

ADDITIONAL TREATMENT

General Measures

• The management of LGG remains controversial. Some authors recommend observation and serial MRI scans for proof of growth potential before initiation of treatment (i.e., surgery, irradiation). Other authors suggest immediate tissue diagnosis with biopsy or resection, followed by irradiation or chemotherapy. Observation is most appropriate for small, deep tumors that are asymptomatic except for seizure activity.

Additional Therapies

• External beam radiation therapy (RT) should be considered for all non-pilocytic LGG after incomplete surgical resection. Post-operative RT can be postponed for patients with PCA until growth potential is demonstrated. Retrospective studies suggest that time-to-progression and overall survival are improved with RT (5-year survival 32% with RT versus 10% with surgery alone). Timing of RT remains controversial, some authors advocate immediate post-operative treatment while others suggest waiting till tumor progression; however, the timing of RT does not appear to be critical, since overall survival is similar in the immediate and delayed treatment groups. RT for LGG is more beneficial for older patients (40 years or older). Conformal techniques should be used whenever possible to minimize radiation exposure to normal brain. Recommended RT doses are 50 to 55 Gy over 6 weeks. Irradiation should be delayed post-operatively in young children until proof of growth by MRI and/or neurological examination.
  • Stereotactic radiosurgery is a more recent RT option. Several studies have used doses of 15 to 50 Gy, for LGG up to 40 mm in size. Objective responses have been noted in over 50% of patients, although follow-up has been brief.
  • Chemotherapy does not have a clear role in most patients with LGG. Young children may respond to cisplatin-based regimens in order to delay the need for RT. A Southwest Oncology Group phase III trial of LGG in adults did not demonstrate a survival benefit for lomustine in combination with RT. Phase II studies suggest nitrosoureas (lomustine, carmustine), alone or in combination with platinum (cisplatin, carboplatin) drugs, may have benefit for patients with LGG. PCV (procarbazine, lomustine, vincristine) has demonstrated activity against LGG, especially oligodendrogliomas. Objective responses range from 30 to 45% in some studies. Temozolomide has demonstrated activity similar to PCV against LGG in recent phase II studies. Progressive or recurrent PCA may respond to cisplatin-based multiagent chemotherapy regimens.

SURGERY/OTHER PROCEDURES

• Surgery should be considered in all patients to make a histological diagnosis and alleviate symptoms; maximal surgical resection is the treatment of choice for accessible LGG, 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. Some studies suggest that overall and 5-year survival are improved with complete or sub-total resection versus biopsy.

IN-PATIENT CONSIDERATIONS

Initial Stabilization

• Usually related to seizure control and adjustment of anticonvulsants.

Admission Criteria

• Patients with LGG are most often admitted for seizure control or to reduce elevated intracranial pressure; maximizing anticonvulsant doses and resolving metabolic disturbances will be required before discharge.

Discharge Criteria

• Appropriate after stabilization of seizure activity or raised intracranial pressure; or after recovery from surgical resection.

FOLLOW-UP RECOMMENDATIONS

• Will be variable, depending on the type of LGG and the need for further active treatment (e.g., RT, chemotherapy).

PATIENT MONITORING

• Patients are followed with serial MRI scans and neurological examinations every 4 to 6 months. Patients receiving chemotherapy will require more frequent follow-up. Anticonvulsant levels will need to be monitored, if appropriate.

PATIENT EDUCATION

• National Brain Tumor Foundation: www.braintumor.org
• American Brain Tumor Association: www.abta.org
• The Brain Tumor Society: www.tbts.org

PROGNOSIS

• The median survival after diagnosis of patients with LGG is 4.7 years for diffuse astrocytomas, 7.1 years for mixed oligoastrocytomas, and 9.8 years for oligodendrogliomas; the 10-year survival in these cohorts is 17, 33, and 49%, respectively.
• Prognosis is improved with oligodendroglial or pilocytic histology, young age, and seizures at presentation. Prognosis is worse with age >40 years, poor performance status, and diffuse astrocytic histology.

COMPLICATIONS

• Most likely related to continued seizure activity or focal neurological deficits secondary to tumor growth or surgical intervention.

• Brandes AA, Vastola F, Basso U. Controversies in the therapy of low-grade glioma: when and how to treat. Expert Rev Anticancer Ther 2002;2:529–536.
• Bourne FD, Schiff D. Update on the molecular findings, management and outcome in low-grade gliomas. Nat Rev Neurol 2010;6:695–701.
• Duffau H. Surgery of low-grade gliomas: towards a “functional neurooncology.” Curr Opin Oncol 2009;21:543–549.

SEE-ALSO

Brain Tumor—Oligodendroglioma.

ICD9

191.9 Malignant neoplasm of brain, unspecified site

• LGG are a diverse group of slow-growing brain tumors that often present with seizures.
• Long-term stabilization and growth control is possible with early diagnosis and appropriate treatment.