Herbert B. Newton, MD, FAAN
DESCRIPTION 
- High-grade astrocytomas (HGA) are a group of malignant neoplasms that typically occur in middle-age and older adults; they have a high growth potential and are more infiltrative than low-grade gliomas; survival is limited in most patients and ranges between 1 and 5 years.
EPIDEMIOLOGY
Incidence/Prevalence
- HGA comprise approximately 33–45% of primary brain tumors in adults. This corresponds to roughly 7,500 new cases of HGA each year in North America. 50–80% of HGA are glioblastoma multiforme (GBM), 20–40% are anaplastic astrocytoma (AA); gliosarcoma and mixed anaplastic oligoastrocytoma (AOA) occur less frequently.
- All races and ethnic groups affected. Caucasians are affected more commonly than blacks, Latinos, and Asians. Typical presentation is between 50 and 65 years of age for GBM and gliosarcoma patients and between 30 and 50 years of age for AA and mixed AOA patients. Incidence is slightly higher in males than females (1.5:1).
RISK FACTORS
- The only known risk factors for HGA are prior cranial radiation exposure and genetic diseases with a predilection for astrocytomas, such as Turcot's syndrome, neurofibromatosis (NF) types I and II, and Li-Fraumeni syndrome; rarely, HGA can be familial.
Genetics
- HGA are usually sporadic and do not have an underlying genetic predilection; rarely, HGA can manifest as part of a genetically mediated syndrome (i.e., NF).
GENERAL PREVENTION
- No preventive measures are known.
PATHOPHYSIOLOGY/ETIOLOGY
- The World Health Organization classifies AA as grade III, GBM as grade IV, gliosarcoma as grade IV, and mixed AOA as grade III.
- HGA are derived from transformed astrocytes. Molecular genetic studies of HGA reveal frequent loss or mutation of the tumor suppressor gene, p53. Amplification of MDM2 or CDK2 and deletion or mutation of the tumor suppressor genes p16 and retinoblastoma may be present. Primary GBM have amplification of epidermal growth factor receptors and/or deletion of the PTEN tumor suppressor gene. Deletion of 1p and 19q may be noted in mixed AOA and is associated with improved survival.
COMMONLY ASSOCIATED CONDITIONS
- NF type I, NF type II, Turcot's syndrome, Li-Fraumeni syndrome.
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HISTORY
- The median duration from onset of symptoms to diagnosis ranges from less than 6 months in GBM to 6 to 8 months for AA. The most common symptoms at presentation include headache (70%), seizure activity (54% overall; partial motor, 23%; generalized tonic-clonic, 20%; partial complex, 9%), cognitive and personality changes (52%), focal weakness (43%), nausea and emesis (31%), speech disturbances (27%), and alterations of consciousness (25%).
PHYSICAL EXAM
- The common findings on neurological examination include hemiparesis (57%), cranial nerve palsies (54%), papilledema (53%), cognitive deficits and confusion (45%), depressed sensorium (37%), hemianopsia (29%), and dysphasia (25%).
DIAGNOSTIC TESTS AND INTERPRETATION
Lab
Initial Lab Tests
- Routine labs are not helpful except for in the setting of pre-surgical screening.
Follow-Up & Special Considerations
- Molecular analysis of chromosome 1p and/or 19q loss may be of prognostic significance in patients with mixed AOA.
Imaging
Initial Approach
- MRI, with and without gadolinium contrast, is the most sensitive diagnostic test; MRI is more sensitive than CT for HGA 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. With gadolinium administration, most HGA show either diffuse or ring-like enhancement. Peritumoral edema and mass effect are usually moderate to severe. Hemorrhage and regions consistent with necrosis may be noted. CT demonstrates an ill-defined region of hypodensity with moderate to severe enhancement, edema, and mass effect.
Diagnostic Procedures/Other
- Fluorodeoxyglucose-positron emission tomography (FDG-PET) may be of benefit to assess the metabolism of HGA to differentiate from non-neoplastic lesions and to maximize targeting for biopsy. HGA typically appear hypermetabolic on PET imaging. Magnetic resonance spectroscopy (MRS) can also be used for metabolic screening to differentiate HGA from other lesions. MRS of HGA often reveals an elevated choline peak, severely reduced N-acetyl aspartate (NAA) peak, the presence of a lactate peak, and a reduced NAA/choline ratio.
Pathological Findings
- Pathological evaluation reveals significant heterogeneity, with high cellularity, cellular and nuclear atypia, moderate to high mitotic rate, endothelial proliferation, and necrosis (GBM and gliosarcoma only); gliosarcomas show regions of sarcomatous differentiation admixed with separate areas of neoplastic glial cells; staining for glial fibrillary acidic protein is more variable in HGA and typically less than that of low-grade gliomas.
DIFFERENTIAL DIAGNOSIS
- Other mass lesions that enhance should be considered, including mature abscess, subacute infarct, tumefactive regions of demyelination, and evolving hematoma.
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MEDICATION
First Line
ADDITIONAL TREATMENT
General Measures
- The management of HGA requires a multi-modality approach to cytoreduction that includes surgery, radiotherapy, and chemotherapy; input from neurosurgeons, neuro-oncologists, and radiation oncologists is necessary for optimal treatment.
Additional Therapies
- External beam radiation therapy (RT) should be considered for all HGA after surgical resection. Phase III trials demonstrate that time-to-progression and overall survival are significantly improved with RT (overall survival 36 weeks with RT versus 16 weeks with surgery alone); the recommended RT dose is 60 Gy over 6 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, especially in younger patients. For elderly patients (>65 years) and those with poor Karnofsky performance status, a protracted course of RT may be appropriate—30 to 40 Gy in 10 fractions over 3 weeks.
- Stereotactic radiosurgery (SRS) has been used for HGA, as a boost after initial RT and at recurrence, for tumors up to 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 HGA.
- Chemotherapy should be considered for all patients with HGA after RT and at recurrence. Clinical trials and meta-analyses suggest a modest survival benefit after RT (10–15% extension in 1-year survival), especially in patients with AA and mixed AOA. For AA and GBM, the most active drugs and combinations include temozolomide, bevacizumab, BCNU, procarbazine, PCV (procarbazine, CCNU, vincristine), cisplatin, carboplatin, and etoposide. Mixed AOA may respond well to chemotherapy with PCV or temozolomide if chromosome 1p and 19q deletions are noted. At recurrence, local chemotherapy with BCNU impregnated wafers may add a modest survival benefit, as suggested in several phase III trials.
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 HGA, 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 1-year survival are improved with complete or sub-total resection versus biopsy.
IN-PATIENT CONSIDERATIONS
Initial Stabilization
- Dexamethasone (4–16 mg/d; intravenous, IV) may be of benefit to reduce peritumoral edema and swelling; in some patients, IV mannitol (12.5 to 25 g, q3-6h) may also be necessary to control severe edema, mass effect, and midline shift.
Admission Criteria
- Patients with HGA 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
- Will be appropriate after stabilization of acute issues such as modifying anticonvulsant medications, reducing intracranial pressure, and recovery from surgical procedures.
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FOLLOW-UP RECOMMENDATIONS
- Will be variable depending on the acute issues during the admission, and the plan for further active treatment.
Patient Monitoring
- Patients are followed with serial MRI scans and neurological examinations every 4 to 8 weeks. Patients receiving chemotherapy may require more frequent follow-up; anticonvulsant levels need to be monitored carefully.
PATIENT EDUCATION
PROGNOSIS
- The median survival after diagnosis of patients with HGA is 30 to 42 months for AA, 8 to 16 months for GBM and gliosarcoma, and 42 to 52 months for mixed AOA.
- Prognosis is improved with young age (<40 years), AOA or AA histology, and high Karnofsly performance status; prognosis is worse with age >50 years, poor Karnofsky performance status, and GBM or gliosarcoma histology.
COMPLICATIONS
- Will be variable but often include continued seizure activity and neurological dysfunction, such as weakness, difficulty with speech, and imbalance.
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ICD9
191.9 Malignant neoplasm of brain, unspecified site