AUTHOR AND EDITOR INFORMATION

Section 1 of 10  

• Authors and Editors
• Introduction
• Clinical
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

INTRODUCTION

Section 2 of 10  

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• Introduction
• Clinical
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
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• References

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.

CLINICAL

Section 3 of 10  

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• Introduction
• Clinical
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
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• References

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.

Physical

• A detailed neurological examination is required for the proper evaluation of any patient with an astrocytoma. Because these tumors may affect any part of the CNS, including the spinal cord, and may spread to distant regions of the CNS, a thorough physical examination referable to the entire neuraxis is necessary to define the location and extent of disease.
• Special attention should be paid to signs of increased ICP, such as headache, nausea and vomiting, decreased alertness, cognitive impairment, papilledema, or ataxia, to determine the likelihood of mass effect, hydrocephalus, and herniation risk. Localizing and lateralizing signs, including cranial nerve palsies, hemiparesis, sensory levels, alteration of deep tendon reflexes (DTRs), and the presence of pathological reflexes (eg, Hoffman and Babinski signs), should be noted. Once neurological abnormalities are identified, imaging studies should be sought for further evaluation.

Causes

• The etiology of diffuse astrocytomas has been the subject of analytic epidemiological studies that have yielded associations with various disorders and exposures. With the exception of therapeutic irradiation and, perhaps, nitroso compounds (eg, nitrosourea), the identification of specific causal environmental exposures or agents has been unsuccessful.
• Children receiving prophylactic irradiation for acute lymphatic leukemia (ALL), for example, have a 22-fold increased risk of developing CNS neoplasms in WHO grade II, III, and IV astrocytomas, with an interval for onset of 5-10 years. Furthermore, irradiation of pituitary adenomas has been demonstrated to carry a 16-fold increased risk of glioma formation.
• Evidence exists for genetic susceptibility to glioma development. For example, familial clustering of astrocytomas is well described in inherited neoplastic syndromes, such as Turcot syndrome, neurofibromatosis type 1 (NF1) syndrome, and p53 germ line mutations (eg, Li-Fraumeni syndrome).
• Biological investigation has implicated that mutations in specific molecular pathways, such as the p53-MDM2-p21 and p16-p15-CDK4-CDK6-RB pathways, are associated with astrocytoma development and progression. In addition, inherited elements of the immune response known as human leukocyte antigens (HLA) have been both positively and negatively associated with an increased risk for the development of glioblastoma multiforme.
• Recently, attempts have been made to determine prognosis and response to various treatment modalities based on the individual pattern of genetic changes in a particular patient. For example, patients with oligodendrogliomas that exhibit chromosomal changes at band 1p19q are known to have improved responses to the procarbazine, CCNU, vincristine (PCV) regimen of chemotherapy. Efforts are underway to identify similar unique susceptibilities associated with other commonly altered genes and proteins in astrocytomas. Other groups are working on developing models that will allow for a more accurate assessment of prognosis based on a combination of molecular profiling of the tumors and clinical characteristics of the patient.

WORKUP

Section 4 of 10  

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• Clinical
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
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• References

Lab Studies

• No laboratory studies diagnostic of astrocytoma currently exist. Baseline laboratory studies, including Chem 7, CBC, prothrombin time (PT), and activated partial thromboplastin time (aPTT), may be obtained for general metabolic surveillance and preoperative assessment.

Imaging Studies

• CT scans and MRI (with and without contrast) are helpful in the diagnosis, grading, and pathophysiological evaluation of astrocytomas. MRI is considered the criterion standard, but a CT scan may be useful in the acute setting or when MRI is contraindicated.
• On a CT scan, low-grade astrocytomas appear as poorly defined, homogeneous, low-density masses without contrast enhancement. However, slight enhancement, calcification, and cystic changes may be evident early in the course of the disease. In cases where a cortically based enhancing mass is discovered, particularly in cases where multiple lesions are identified, the possibility of metastatic disease must be considered. Systemic imaging, generally consisting of a contrast-enhanced CT scan of the chest, abdomen, and pelvis, may be warranted to evaluate for the possibility of an alternate primary lesion.
• Similarly, anaplastic astrocytomas may appear as low-density lesions or inhomogeneous lesions, with areas of both high and low density within the same lesion. Unlike low-grade lesions, partial contrast enhancement is common.
• Astrocytomas generally are isointense on T1-weighted images and hyperintense on T2-weighted images. While low-grade astrocytomas uncommonly enhance on MRI, most anaplastic astrocytomas enhance with paramagnetic contrast agents. New methods are being developed to assess tumor vascularity by MRI, including techniques such as arterial-spin labeling (ASL) and dynamic contrast-enhanced MRI.
• Angiography may be used to rule out vascular malformations and to evaluate tumor blood supply. A normal angiographic pattern or a pattern consistent with an avascular mass that displaces normal vessels usually is observed with both low-grade and high-grade lesions. In rare instances, a tumor blush may be observed with high-grade lesions.
• Imaging has also taken a larger role in the operating room, as many procedures are now performed with intraoperative image guidance based upon high-resolution MRIs. In addition, intraoperative MRI and CT scans are being tested for utility in guiding the extent of resection and presence of residual tumor during the surgical procedure.
• Ultimately, the boundaries of infiltrating tumors extend far beyond what can be seen by imaging studies. New methods of tumor imaging are being developed to specifically tag or label tumor cells so they may be visualized in the operating room. Such methods include pretreatment of the patient with dyes or tumor-specific proteins tagged with fluorescent molecules.

Other Tests

• Because seizure activity often is associated with astrocytomas, EEG may be employed to evaluate and monitor epileptiform activity.
• Radionuclide scans, such as positron emission tomography (PET), single-photon emission tomography (SPECT), and technetium-based imaging, can permit study of tumor metabolism and brain function. PET and SPECT may be used to distinguish a solid tumor from edema, to differentiate tumor recurrence from radiation necrosis, and to localize structures.
• Metabolic activity determined by radionuclide scans can be used to determine the grade of a lesion. Hypermetabolic lesions often correspond to higher-grade tumors.
• ECG and chest radiographs are indicated to evaluate operative risk.

Procedures

• A lumbar puncture (LP) in patients with cerebral astrocytomas should be approached with extreme caution because of the risk of downward cerebral herniation secondary to elevated ICP. Although CSF studies are not employed in the diagnosis of astrocytomas, they may be employed to rule out other possible diagnoses, such as metastasis, lymphoma, or medulloblastoma.

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.

TREATMENT

Section 5 of 10  

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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.

• Patients with an astrocytoma and a history of seizures should receive anticonvulsant therapy with monitoring of the drug concentration in the blood stream. The use of anticonvulsants prophylactically in astrocytoma patients with no prior history of seizures has been reported but remains controversial.
• The use of corticosteroids, such as dexamethasone, yields rapid improvement in most patients secondary to a reduction of tumor mass effect. Concurrent prophylaxis for gastrointestinal ulcers should be prescribed with corticosteroid administration.

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.

Consultations

• A neurologist should be consulted to document a patient's detailed neurological examination. This establishes a baseline and partly assesses the possibility of occult disease. Employing multiple modalities, the neurologist must correlate symptomatology with anatomic and functional imaging. This physician also may manage antiepileptic medication for patients manifesting seizures.
• A neurosurgeon should be consulted to assess the risks and benefits of surgical resection, stereotactic biopsy, stereotactic radiosurgery, and CSF diversion.
• A neurooncologist may be consulted to help coordinate a comprehensive therapeutic plan. Once a histological diagnosis is determined, the neurooncologist should be consulted to provide comprehensive adjunctive therapy, including the use of chemotherapy and radiation.

Activity

• No broad restrictions on activity are prescribed, other than those dictated by the nature and the extent of neurological symptoms and disability.
• Seizures, if uncontrolled, may preclude driving.
• Physical and occupational therapy may be required for recovery of full or partial function.

MEDICATION

Section 6 of 10  

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• Treatment
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• Follow-up
• Miscellaneous
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• References

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 Category: Corticosteroids

Reduce edema around the tumor, frequently leading to symptomatic and objective improvement.

FOLLOW-UP

Section 7 of 10  

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• Follow-up
• Miscellaneous
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• References

Further Inpatient Care

• Management of low-grade astrocytomas is controversial. The tumors may be radiographically stable and clinically quiescent for long periods after the initial presentation.
• Therapeutic options include observation, radiation, and resection with and without radiation. Unless an astrocytoma is resected completely, radiation therapy should be considered.
• In higher-grade lesions, even if gross total resection is confirmed radiographically, postoperative radiation is indicated because microscopic disease remains.
• If no resection is undertaken and radiation is contemplated, a stereotactic biopsy is recommended to establish the histological grade of the tumor definitively.

Further Outpatient Care

• Patients should consult a neurologist to observe the progression of neurological signs and symptoms and to manage steroid and anticonvulsant regimens.
• Outpatient neurosurgery observation is necessary for tumor monitoring and management of hydrocephalus if a shunt has been placed.
• Postoperative and postirradiation chemotherapy trials using nitrosourea and other agents are likely to benefit patients with malignant astrocytomas, but the benefit for patients with well-differentiated astrocytomas is questionable.
• Frequency of postoperative MRI is determined by both the neurosurgeon and other physicians involved in the ongoing care of the patient, including the neurooncologist and radiation oncologist.

In/Out Patient Meds

• Corticosteroids, antiepileptic agents, and GI prophylaxis should be employed.

Transfer

• If surgery is anticipated, patients should be transferred to institutions with an appropriately equipped and adequately staffed neurosurgical intensive care unit for postoperative monitoring.
• Patients may require extensive or focused postoperative rehabilitation that may necessitate transfer to specialized institutions dedicated to physical and occupational therapy.

Complications

• Although neurological injury (potentially devastating) and death must be mentioned, neurosurgery for astrocytomas is generally intended to decrease tumor bulk while avoiding permanent neurological injury. Transient deficits due to local swelling or injury may occur, but they often improve after a course of physical therapy and rehabilitation.

Prognosis

• Prognosis for survival after operative intervention and radiation therapy can be favorable for low-grade astrocytomas.
• For those patients who undergo surgical resection, the prognosis depends on whether the neoplasm progresses to a higher-grade lesion.
• For low-grade lesions, the mean survival time after surgical intervention has been reported as 6-8 years.
• In the case of anaplastic astrocytoma, symptomatic improvement or stabilization is the rule after surgical resection and irradiation. High-quality survival is observed in 60-80% of these patients. Factors such as youth, functional status, extent of resection, and adequate irradiation affect the duration of postoperative survival.
• Recent reports indicated that irradiation of incompletely resected tumors increased 5-year postoperative survival rates from 0-25% for low-grade astrocytomas and from 2-16% for anaplastic astrocytomas. Furthermore, the median survival rate of patients with anaplastic astrocytoma who undergo both resection and irradiation has been reported to be twice that of patients receiving only operative therapy (5 y vs 2.2 y).

MISCELLANEOUS

Section 8 of 10  

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• Introduction
• Clinical
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• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

Medical/Legal Pitfalls

• Failure to make an appropriate diagnosis of astrocytoma is a pitfall that should be avoided by adhering to a systematic diagnostic approach, including imaging studies and obtaining adequate tissue for analysis.
• Timing of diagnosis is particularly important when lesions abut crucial brain nuclei or eloquent cortex. The extent of lesion resectability may be affected by delay.
• Clear explanation of all therapeutic options and prognosis once a diagnosis is established is essential.

MULTIMEDIA

Section 9 of 10  

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• Miscellaneous
• Multimedia
• References

Media file 1:  Low-grade fibrillary astrocytoma and low cellularity with minimal nuclear atypia
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Media file 2:  Fibrillary astrocytoma with microcyst formation
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Media file 3:  Gemistocytic astrocytoma Tumor cells have eosinophilic cytoplasm with nuclei displaced to the periphery.
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Media file 4:  Characteristic pilocytic astrocytoma, long bipolar tumor cells, and Rosenthal fibers
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Media file 5:  Anaplastic astrocytoma with high cellularity with marked nuclear atypia
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Media file 6:  Gross specimen of a low-grade astrocytoma
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Media file 7:  Axial CT scan, precontrast and postcontrast, shows a low-grade astrocytoma of the left frontal lobe. The tumor is nonenhancing.
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Media file 8:  Coronal postcontrast T1-weighted MRI shows a low-grade astrocytoma in the right inferior frontal lobe just above the sylvian fissure. No enhancement is present post–gadolinium administration.
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Media file 9:  Axial T2-weighted MRI shows a low-grade astrocytoma of the inferior frontal lobe with mild mass effect and no surrounding edema.
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Media type:  MRI

REFERENCES

Section 10 of 10

• Authors and Editors
• Introduction
• Clinical
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

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• Kleihues P, Davis RL, Ohgaki H. Low-grade diffuse astrocytoma. In: Kleihues P, Cavenee WK, eds. Pathology and Genetics: Tumours of the Nervous System. Lyon, France:. International Agency for Cancer Research;1997:10-14.
• Laws ER Jr, Taylor WF, Clifton MB. Neurosurgical management of low-grade astrocytoma of the cerebral hemispheres. J Neurosurg. Oct 1984;61(4):665-73. [Medline].
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• Zhou YH, Hess KR, Liu L, et al. Modeling prognosis for patients with malignant astrocytic gliomas: quantifying the expression of multiple genetic markers and clinical variables. Neuro-oncol. Oct 2005;7(4):485-94. [Full Text].

Article Last Updated: Aug 7, 2006