January 14, 2007


Synonyms and related keywords: low-grade astrocytoma, fibrillary astrocytoma, gemistocytic astrocytoma, protoplasmic astrocytoma, diffuse astrocytoma, pilocytic astrocytoma, pilocystic astrocytoma, juvenile pilocytic astrocytoma, anaplastic astrocytoma, glioblastoma multiforme, CNS neoplasm, immortalized astrocyte


Background: Astrocytomas are CNS neoplasms in which the predominant cell type is derived from an immortalized astrocyte. Two classes of astrocytic tumors are recognized—those with narrow zones of infiltration (eg, pilocytic astrocytoma, subependymal giant cell astrocytoma, pleomorphic xanthoastrocytoma) and those with diffuse zones of infiltration (eg, low-grade astrocytoma, anaplastic astrocytoma, glioblastoma). Members of the latter group share various features, including the ability to arise at any site in the CNS, with a preference for the cerebral hemispheres; clinical presentation usually in adults; heterogeneous histopathological properties and biological behavior; diffuse infiltration of contiguous and distant CNS structures, regardless of histological stage; and an intrinsic tendency to progress to more advanced grades.

Numerous grading schemes based on histopathologic characteristics have been devised, including the Bailey and Cushing grading system, Kernohan grades I-IV, World Health Organization (WHO) grades I-IV, and St. Anne/Mayo grades 1-4. Regions of a tumor demonstrating the greatest degree of anaplasia are used to determine the histologic grade of the tumor. This practice is based on the assumption that the areas of greatest anaplasia determine disease progression.

This chapter focuses on the widely accepted WHO grading scheme that relies on assessments of nuclear atypia, mitotic activity, cellularity, vascular proliferation, and necrosis. WHO grade I corresponds to pilocytic astrocytoma, WHO grade II corresponds to low-grade (diffuse) astrocytoma, WHO grade III corresponds to anaplastic astrocytoma, and WHO grade IV corresponds to glioblastoma multiforme (GBM). This article is confined to low-grade and anaplastic astrocytomas. GBM and pilocytic astrocytoma are not discussed in this chapter (for more information, see Glioblastoma Multiforme).

Pathophysiology: Regional effects of astrocytomas include compression, invasion, and destruction of brain parenchyma. Arterial and venous hypoxia, competition for nutrients, release of metabolic end products (eg, free radicals, altered electrolytes, neurotransmitters), and release and recruitment of cellular mediators (eg, cytokines) disrupt normal parenchymal function. Elevated intracranial pressure (ICP) attributable to direct mass effect, increased blood volume, or increased cerebrospinal fluid (CSF) volume may mediate secondary clinical sequelae. Neurological signs and symptoms attributable to astrocytomas result from perturbation of CNS function. Focal neurological deficits (eg, weakness, paralysis, sensory deficits, cranial nerve palsies) and seizures of various characteristics may permit localization of lesions.

Infiltrating low-grade astrocytomas grow slowly compared to their malignant counterparts. Doubling time for low-grade astrocytomas is estimated at 4 times that of anaplastic astrocytomas. Several years often intervene between the initial symptoms and the establishment of a diagnosis of low-grade astrocytoma. One recent series estimated the interval to be approximately 3.5 years. The clinical course is marked by a gradual deterioration in one half of cases, a stepwise decline in one third of cases, and a sudden deterioration in 15% of cases. Seizures, often generalized, are the initial presenting symptom in about one half of patients with low-grade astrocytoma.

For patients with anaplastic astrocytomas, the growth rate and interval between onset of symptoms and diagnosis is intermediate between low-grade astrocytomas and glioblastomas. Although highly variable, a mean interval of approximately 1.5-2 years between onset of symptoms and diagnosis frequently is reported. Compared to low-grade lesions, seizures are less common among patients with anaplastic astrocytomas. Initial presenting symptoms most commonly are headache, depressed mental status, and focal neurological deficits.

Mortality/Morbidity: Morbidity and mortality, as defined by the length of a patient's history and the odds of recurrence-free survival, are correlated most highly with the intrinsic properties of the astrocytoma in question. Typical ranges of survival are approximately 10 years from the time of diagnosis for pilocytic astrocytomas (WHO grade I), more than 5 years for patients with low-grade diffuse astrocytomas (WHO grade II), 2-5 years for those with anaplastic astrocytomas (WHO grade III), and less than 1 year for patients with glioblastoma (WHO grade IV).

Race: Although genetic determinants are recognized in astrocytoma development and progression, astrocytomas do not differ intrinsically in incidence or behavior among racial groups. Demographic and sociological factors, such as population, age, ethnic attitude toward disease, and access to care, have been reported to influence measured distributions.

Sex: No clear sex predominance has been identified in the development of pilocytic astrocytomas. A slight male predominance, with a male-to-female ratio of 1.18:1 for development of low-grade astrocytomas, has been reported. A more significant male predominance, with a male-to-female ratio of 1.87:1 for the development of anaplastic astrocytomas, has been identified.

Age: Most cases of pilocytic astrocytoma present in the first 2 decades of life. In contrast, the peak incidence of low-grade astrocytomas, representing 25% of all cases in adults, occurs in people aged 30-40 years. Ten percent of low-grade astrocytomas occur in people younger than 20 years; 60% of low-grade astrocytomas occur in people aged 20-45 years; and 30% of low-grade astrocytomas occur in people older than 45 years. The mean age of patients undergoing a biopsy of anaplastic astrocytoma is 41 years.


History: The type of neurological symptoms that result from astrocytoma development depends foremost on the site and extent of tumor growth in the CNS. Reports of altered mental status, cognitive impairment, headaches, visual disturbances, motor impairment, seizures, sensory anomalies, or ataxia in the patient's history should alert the clinician to the presence of a neurological disorder and should indicate a requirement for further studies. In this event, radiographic imaging, such as CT scan and MRI (with and without contrast), is indicated. Astrocytomas of the spinal cord or brainstem are less common and present with motor/sensory or cranial nerve deficits referable to the tumor's location.




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Histologic Findings: Four histological variants of low-grade astrocytomas are recognized—protoplasmic, gemistocytic, fibrillary, and mixed.
  1. Protoplasmic astrocytomas generally are cortically based, with cells containing prominent cytoplasm. Protoplasmic astrocytomas constitute approximately 28% of infiltrating astrocytomas.
  2. Gemistocytic astrocytomas generally are found in the cerebral hemispheres in adults and are composed of large round cells with eosinophilic cytoplasm and eccentric cytoplasm. Gemistocytic astrocytomas constitute 5-10% of hemispheric gliomas.
  3. Fibrillary astrocytomas, the most frequent histological variant, resemble cells from the cerebral white matter and are composed of small, oval, well-differentiated cells. The tumors are identified by a mild increase in cellularity and fibrillary background. Markers for glial fibrillary acidic protein (GFAP) are used to identify fibrillary astrocytomas.
  4. Compared to low-grade lesions, anaplastic astrocytomas show a marked tendency for regional or diffuse hypercellularity. Furthermore, anaplastic astrocytomas show increased anaplasia, demonstrated by increased nuclear complexity, the presence of mitoses, increased cytoplasmic variability, and increased endothelial cell proliferation.

Staging: Staging is not performed or described for patients with astrocytoma. The histologic grade of the tumor is of primary importance when determining prognosis. Unlike other systemic tumors, distant or extracranial metastasis of astrocytomas is exceedingly rare. Clinical decline and tumor-associated morbidity and mortality are almost always associated with local mass effects on the brain by a locally recurrent intracranial tumor.


Medical Care: Generally, care of patients with brain tumors is primarily directed by a neurologist or specialist in neurooncology. Decisions on operative intervention and the use of chemotherapy and radiation therapy are generally best made by a team approach, including input from the involved neurosurgeon, radiation oncologist, and medical oncologist or neurologist.

Surgical Care: The roles of surgery in the patient with astrocytoma are to (1) remove or debulk the tumor and (2) provide tissue for histological diagnosis, permitting tailoring of adjuvant therapy and assessment of prognosis. A stereotactic biopsy is a safe and simple method for establishing a tissue diagnosis. The use of stereotactic biopsy can be limited by sampling error and the risk of biopsy-induced intracerebral hemorrhage. Diversion of CSF by external ventricular drain (EVD) or ventriculoperitoneal shunt (VPS) may be required to decrease ICP as part of nonoperative management or prior to definitive surgical therapy if hydrocephalus is present.

Total resection of astrocytoma is often impossible because the tumors often invade into eloquent regions of the brain and exhibit tumor infiltration that is only detectable on a microscopic scale. Therefore, surgical resection only provides for improved survival advantage and histological diagnosis of the tumor rather than offering a cure. However, craniotomy for tumor resection can be performed safely and is generally undertaken with the intent to cause the least possible neurological injury to the patient.




No specific drug treatment exists for low-grade glioma. Certain conditions (eg, low-grade astrocytoma) typically require treatment. For seizures, phenytoin or carbamazepine therapy is initiated. Steroid therapy, usually combined with gastroprotectant, is initiated for vasogenic edema around tumor.

Drug Category: Anticonvulsants -- Prevent seizure recurrence and terminate clinical and electrical seizure activity.
Drug Name
Phenytoin (Dilantin) -- Effective in partial and generalized tonic-clonic seizures. Blocks sodium channel and prevents repetitive firing of action potentials.
Adult DoseLoading dose: 15 mg/kg (1000 mg) PO/IV over 4 h divided into 2 or 3 doses
Maintenance dose: 5 mg/kg/d (300 mg) PO/IV qd or divided tid, usually adjusted based on serum levels
Pediatric DoseLoading dose: 15 mg/kg PO/IV over 4 h divided bid/tid
Maintenance dose: 5 mg/kg/d PO/IV frequently divided tid, usually adjusted based on serum levels
ContraindicationsDocumented hypersensitivity; sinoatrial block; second- and third-degree AV block; sinus bradycardia; Adams-Stokes syndrome
InteractionsAmiodarone, benzodiazepines, chloramphenicol, cimetidine, fluconazole, isoniazid, metronidazole, miconazole, phenylbutazone, succinimides, sulfonamides, omeprazole, phenacemide, disulfiram, ethanol (acute ingestion), trimethoprim, and valproic acid may increase phenytoin toxicity; phenytoin effects may decrease when taken concurrently with barbiturates, diazoxide, ethanol (chronic ingestion), rifampin, antacids, charcoal, carbamazepine, theophylline, and sucralfate; phenytoin may decrease effects of acetaminophen, corticosteroids, dicumarol, disopyramide, doxycycline, estrogens, haloperidol, amiodarone, carbamazepine, cardiac glycosides, quinidine, theophylline, methadone, metyrapone, mexiletine, oral contraceptives, and valproic acid
Pregnancy D - Unsafe in pregnancy
PrecautionsPerform blood counts and urinalyses when beginning therapy and at monthly intervals for several months thereafter to monitor for blood dyscrasias; discontinue use if a skin rash appears, and do not resume use if rash is exfoliative, bullous, or purpuric; rapid IV infusion may result in death from cardiac arrest, marked by QRS widening; caution in acute intermittent porphyria and diabetes (may elevate blood sugars); discontinue use if hepatic dysfunction occurs; monitor for nystagmus, ataxia, and diplopia
Drug Name
Carbamazepine (Tegretol) -- Similar to phenytoin. Effective in partial and generalized tonic-clonic seizures. Blocks sodium channel and prevents repetitive firing of action potentials.
Adult Dose200-600 mg PO tid/qid (bid with ER); monitor serum levels, maintain in 4- to 8-mcg/mL range
Pediatric Dose15-25 mg/kg/d PO divided tid/qid (bid with ER)
ContraindicationsDocumented hypersensitivity; history of bone marrow depression; administration of MAOIs within last 14 d
InteractionsSerum levels may increase significantly within 30 d of danazol coadministration (avoid whenever possible); do not coadminister with MAOIs; cimetidine may increase toxicity, especially if taken in first 4 wk of therapy; carbamazepine may decrease primidone and phenobarbital levels (their coadministration may increase carbamazepine levels); increases metabolism of warfarin, valproic acid, and phenytoin
Pregnancy D - Unsafe in pregnancy
PrecautionsDo not use to relieve minor aches or pains; caution with increased intraocular pressure; obtain CBCs and serum-iron baseline before treatment, during first 2 mo, and yearly or every other year thereafter; can cause drowsiness, dizziness, and blurred vision; caution while driving or performing other tasks requiring alertness; occasional leukopenia (aplastic anemia) is more common in elderly persons
Drug Category: Corticosteroids -- Reduce edema around the tumor, frequently leading to symptomatic and objective improvement.
Drug Name
Dexamethasone (Decadron, AK-Dex, Alba-Dex, Dexone, Baldex) -- Postulated mechanisms of action in brain tumors include reduction in vascular permeability, cytotoxic effects on tumors, inhibition of tumor formation, and decreased CSF production.
Adult DoseSignificant peritumoral edema: 16 mg/d PO/IV divided q6h, continue until improvement then taper to termination or minimum effective dose
Pediatric Dose0.15 mg/kg/d PO/IV divided q6h
ContraindicationsDocumented hypersensitivity; active bacterial or fungal infection
InteractionsEffects decrease with coadministration of barbiturates, phenytoin, and rifampin; dexamethasone decreases effect of salicylates and vaccines used for immunization
Pregnancy C - Safety for use during pregnancy has not been established.
PrecautionsIncreases risk of multiple complications, including severe infections; monitor adrenal insufficiency when tapering drug; abrupt discontinuation of glucocorticoids may cause adrenal crisis; possible complications include hyperglycemia, edema, osteonecrosis, myopathy, peptic ulcer disease, hypokalemia, osteoporosis, euphoria, psychosis, myasthenia gravis, growth suppression, and infections; severe stress may require increasing dose; iatrogenic Cushing syndrome (acne, hirsutism, and facial plethora) may occur


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