Astrocytoma 

Updated: Dec 21, 2018
Author: Benjamin C Kennedy, MD; Chief Editor: Herbert H Engelhard, III, MD, PhD, FACS, FAANS 

Overview

Practice Essentials

Astrocytomas (see the image below) are CNS neoplasms in which the predominant cell type is derived from an immortalized astrocyte.[1] Survival correlates most highly with the intrinsic properties of the astrocytoma and typically ranges from approximately 10 years from the time of diagnosis for patients with pilocytic astrocytomas to less than 1 year for patients with glioblastoma.

Axial T2-weighted MRI shows a low-grade astrocytom Axial T2-weighted MRI shows a low-grade astrocytoma of the inferior frontal lobe with mild mass effect and no surrounding edema.

Signs and symptoms

Neurologic symptoms from astrocytoma development depend foremost on the site and extent of tumor growth in the CNS but may include any of the following:

  • Altered mental status

  • Cognitive impairment

  • Headaches

  • Nausea and vomiting

  • Visual disturbances

  • Motor impairment

  • Seizures

  • Sensory anomalies

  • Ataxia

Astrocytomas of the spinal cord or brainstem are less common and present as motor/sensory or cranial nerve deficits referable to the tumor's location.

On physical examination, patients may demonstrate signs of increased ICP or localizing and lateralizing signs such as the following:

  • Cranial nerve palsies

  • Hemiparesis

  • Sensory levels

  • Alteration of deep tendon reflexes (DTRs)

  • Pathologic reflexes (eg, Hoffman sign, Babinski sign)

See Presentation for more detail.

Diagnosis

No laboratory studies are diagnostic of astrocytoma, but the following baseline laboratory studies may be obtained for general metabolic surveillance and preoperative assessment:

  • Basic metabolic profile

  • CBC

  • Prothrombin time (PT)

  • Activated partial thromboplastin time (aPTT)

MRI

  • MRI is considered the criterion standard imaging study

  • Astrocytomas are generally 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

  • The possibility of metastatic disease must be considered in cases in which a cortically based enhancing mass is discovered, particularly if multiple lesions are identified

  • High-resolution MRI is now often used to provide intraoperative image guidance

CT scanning

  • A CT scan may be useful in the acute setting or when MRI is contraindicated

  • On CT, 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

  • 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

  • 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

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 is usually observed with both low-grade and high-grade lesions

  • In rare instances, a tumor blush may be observed with high-grade lesions

Radionuclide scans

  • PET, SPECT, or 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 of a lesion can be used to determine tumor grade; hypermetabolic lesions often correspond to higher-grade tumors

Other studies

  • EEG may be used to evaluate and monitor epileptiform activity

  • ECG and chest radiographs are indicated to evaluate operative risk

  • CSF studies may be used to rule out other diagnoses (eg, metastasis, lymphoma, medulloblastoma)

See Workup for more detail.

Management

There is no accepted standard of treatment for low-grade or anaplastic astrocytoma. Treatment decisions are generally best made through a team approach, including input from the involved neurosurgeon, radiation oncologist, and medical oncologist or neurologist.

Typically, anaplastic astrocytomas are treated with the following:

  • Surgery

  • Radiotherapy

  • Adjuvant temozolomide

  • Some practitioners add concomitant temozolomide[2, 3]

  • Some smaller survival benefit has been shown with adjuvant carmustine[4]

Treatment of low-grade astrocytomas remains more controversial. The role of maximal surgical resection, timing of radiotherapy, and the role, timing, and appropriate agents of chemotherapy are not clear.

Surgical care

  • Stereotactic biopsy is a safe and simple method for establishing a tissue diagnosis

  • Tumor resection can be performed safely and is generally undertaken with the intent to cause the least possible neurologic injury to the patient

  • Surgical resection provides improved survival advantage and histologic diagnosis of the tumor rather than offering a cure

  • Total resection of an astrocytoma is often impossible because the tumors often invade eloquent regions of the brain and exhibit tumor infiltration that is only detectable on a microscopic scale

  • Diversion of CSF by external ventricular drain (EVD) or ventriculoperitoneal shunt (VPS) may be required to decrease ICP

Symptomatic therapy

  • Patients with an astrocytoma and a history of seizures should receive anticonvulsant therapy, with monitoring of the serum drug concentration; levetiracetam (Keppra) is often used

  • Prophylactic use of anticonvulsants 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; patients receiving corticosteroids should have concurrent prophylaxis for gastrointestinal ulcers

Brainstem gliomas

Treatment and prognosis for brainstem gliomas typically depends on whether the tumor is diffuse or focal. Treatment of diffuse brainstem gliomas is as follows:

  • No benefit of surgical resection has been shown

  • Corticosteroids may provide temporary benefit by reduction of edema

  • Irradiation and chemotherapy are sometimes used, but neither has been shown to cure or prolong survival, and radiation necrosis and chemotherapy side effects can be significant

Treatment of focal brainstem gliomas is as follows:

  • Surgery is often the primary treatment, although the decision to operate, the surgical approach, and the extent of resection depend on location, patient factors, and the surgeon's judgment

  • Obstructive hydrocephalus is common and usually treated by a separate procedure, either endoscopic third ventriculostomy or shunt placement[5]

See Treatment and Medication for more detail.

Background

Astrocytomas are central nervous system (CNS) neoplasms in which the predominant cell type is derived from an immortalized astrocyte.[1] 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 following:

  • 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

  • An intrinsic tendency to progress to more advanced grades

See the image below.

Gross specimen of a low-grade astrocytoma. Gross specimen of a low-grade astrocytoma.

Numerous grading schemes based on histopathologic characteristics have been devised, including the following:

  • Bailey and Cushing grading system
  • Kernohan grades I-IV
  • World Health Organization (WHO) grades I-IV
  • St. Anne/Mayo grades 1-4

The regions of a tumor that demonstrate 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 article focuses on the widely accepted WHO grading scheme. The 2016 update of this scheme introduced the use of molecular parameters in addition to histology to define many tumor entities. Classification of astrocytoma relies on assessments of nuclear atypia—in particular, presence of isocitrate dehydrogenase (IDH) mutation—mitotic activity, cellularity, vascular proliferation, and necrosis.[6] The WHO scheme is as follows:

  • Grade I - Corresponds to pilocytic astrocytoma

  • Grade II - Corresponds to low-grade (diffuse) astrocytoma

  • Grade III - Corresponds to anaplastic astrocytoma

  • 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 article (for more information, see Glioblastoma Multiforme). For discussion of astrocytomas in children, see Pediatric Astrocytoma.

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.[7]

Infiltrating low-grade astrocytomas grow slowly than 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 series estimated the interval to be approximately 3.5 years.

The clinical course is marked by a gradual deterioration in 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 half of patients with low-grade astrocytoma.

For patients with anaplastic astrocytomas,[8] 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 is frequently reported. Seizures are less common in patients with anaplastic astrocytomas than in those with low-grade lesions. Initial presenting symptoms most commonly are headache, depressed mental status, and focal neurological deficits.

Epidemiology

The annual incidence of glioma in the United States is 5.4 cases per 100,000 population. Incidence differences are not significant between the United States and other countries.

Mortality/Morbidity

Morbidity and mortality, as defined by the length of a patient's history and the odds of recurrence-free survival, correlate most highly with the intrinsic properties of the astrocytoma in question. Typical ranges of survival from the time of diagnosis are as follows:

  • Pilocytic astrocytomas (WHO grade I): >10 years
  • Low-grade diffuse astrocytomas (WHO grade II) [9] : >5 years
  • Anaplastic astrocytomas (WHO grade III): 2-5 years
  • Glioblastoma (WHO grade IV): ~1 year

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

In most cases, patients with 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.

 

Presentation

History

The type of neurological symptoms that result from an astrocytoma depends foremost on the site and extent of tumor growth in the central nervous system (CNS). Onset of any of the following symptoms should alert the clinician to the presence of a neurological disorder and indicate a requirement for further investigation (in particular, with imaging studies such as magnetic resonance imaging [MRI] or computed tomography [CT] scan, with and without contrast):

  • Altered mental status
  • Cognitive impairment
  • Headaches
  • Visual disturbances
  • Motor impairment
  • Seizures
  • Sensory anomalies
  • Ataxia

Astrocytomas of the spinal cord or brainstem are less common. Patients with these neoplasms 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 manifestations of increased intracranial pressure (ICP), such as the following, to determine the risk of mass effect, hydrocephalus, and herniation:

  • Headache
  • Nausea and vomiting
  • Decreased alertness
  • Cognitive impairment
  • Papilledema
  • Ataxia

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.[10] With the exception of therapeutic irradiation[11] and, perhaps, nitroso compounds (eg, nitrosourea), the identification of specific causal environmental exposures or agents has been unsuccessful. Although concern has been raised regarding cell phone use as a potential risk factor for development of gliomas, studies have yielded conflicting results.[12, 13, 14, 15, 16]

Children receiving prophylactic irradiation for acute lymphoblastic leukemia (ALL) have a 22-fold increased risk of developing CNS neoplasms, including 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.[17]

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. Two-thirds of low-grade astrocytomas have p53 mutations.[18]

 

DDx

 

Workup

Laboratory Studies

No laboratory studies are diagnostic of astrocytoma. Baseline laboratory studies that may be obtained for general metabolic surveillance and preoperative assessment include the following:

  • Basic metabolic profile

  • Complete blood cell count (CBC)

  • Prothrombin time (PT)

  • Activated partial thromboplastin time (aPTT)

Imaging Studies

Computed tomography (CT) and magnetic resonance imaging (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 (see the image below). However, slight enhancement, calcification, and cystic changes may be evident early in the course of the disease.

Axial CT scan, precontrast and postcontrast, shows Axial CT scan, precontrast and postcontrast, shows a low-grade astrocytoma of the left frontal lobe. The tumor is nonenhancing.

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.

Like low-grade astrocytomas, 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.[19, 20]

Astrocytomas are generally isointense on T1-weighted images and hyperintense on T2-weighted images. (See the images below.) 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.

Coronal postcontrast T1-weighted MRI shows a low-g 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.
Axial T2-weighted MRI shows a low-grade astrocytom Axial T2-weighted MRI shows a low-grade astrocytoma of the inferior frontal lobe with mild mass effect and no surrounding edema.

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 is usually 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 on a larger role in the operating room, as many procedures are now performed with intraoperative image guidance based on 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.

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

The following studies may be indicated in patients with astrocytoma:

  • Electroencephalography (EEG) may be employed to evaluate and monitor epileptiform activity in patients with seizures associated with astrocytoma

  • 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

  • An electrocardiogram (ECG) and chest radiograph are indicated to evaluate operative risk

Procedures

Although cerebrospinal fluid analysis is not part of the diagnosis of astrocytoma, it may help in ruling out other possible diagnoses, such as metastasis, lymphoma, or medulloblastoma. However, lumbar puncture (LP) should be approached with extreme caution in patients with cerebral astrocytomas, because of the risk of downward cerebral herniation secondary to elevated intracranial pressure.

Histologic Findings

Four histological variants of low-grade astrocytomas are recognized: protoplasmic, gemistocytic, fibrillary, and mixed.[21]

Gemistocytic astrocytomas are generally 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.

Diffuse astrocytomas, the most common 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.

Compared with 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.

See the images below.

Low-grade diffuse astrocytoma and low cellularity Low-grade diffuse astrocytoma and low cellularity with minimal nuclear atypia.
Diffuse astrocytoma with microcyst formation. Diffuse astrocytoma with microcyst formation.
Gemistocytic astrocytoma tumor cells have eosinoph Gemistocytic astrocytoma tumor cells have eosinophilic cytoplasm with nuclei displaced to the periphery.
Characteristic pilocytic astrocytoma, long bipolar Characteristic pilocytic astrocytoma, long bipolar tumor cells, and Rosenthal fibers.

 

Staging

Staging is not performed or described for patients with astrocytoma. Astrocytomas can be described as low grade (grades I and II; eg, pilocytic astrocytomas, and diffuse astrocytomas) or high grade (grades III and IV; eg, anaplastic astrocytomas and glioblastoma).[22]

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

Approach Considerations

Treatment options in astrocytomas include operative intervention and the use of chemotherapy and radiation therapy. Treatment decisions are generally best made by a team approach, including input from the involved neurosurgeon, radiation oncologist, and medical oncologist or neurologist. Generally, care is primarily directed by a neurologist or specialist in neurooncology.

Treatment of low-grade astrocytomas has been controversial. The role of maximal surgical resection, timing of radiotherapy, and the role, timing, and appropriate agents of chemotherapy are not clear. The controversy due to a lack of strong data is compounded by the relatively young age of the patients, the relatively indolent natural history of low-grade astrocytomas, and the morbidity associated with these interventions.[23, 24]

A study by Ishkanian et al found that adjuvant radiotherapy for pilocytic astrocytoma (ie, grade I) significantly prolonged progression-free survival (PFS) at both 5 years and 10 years compared with observation alone. However, the overall survival was equivalent. [25]

For adult patients with grade 2 astrocytoma, radiation therapy plus adjuvant chemotherapy has been found superior to radiation therapy alone. In a phase III trial that included patients with grade 2 astrocytoma who were younger than 40 years of age and had undergone subtotal resection or biopsy or who were 40 years of age or older and had undergone tumor biopsy or resection, treatment with procarbazine, lomustine, and vincristine after radiation therapy at the time of initial diagnosis resulted in longer progression-free survival at 10 years—51%, versus 21% with radiation therapy only—and overall at 10 years of 60% versus 40%, respectively.[26]

Typically, anaplastic astrocytomas are treated with surgery, radiotherapy, and adjuvant temozolomide. Some practitioners add concomitant temozolomide, though no data from controlled trials exist to support concomitant temozolomide.[2, 3]  

In a retrospective study of 165 adult patients with anaplastic astrocytoma who were receiving adjuvant radiation, concurrent treatment with temozolomide were associated with improved survival, as was isocitrate dehydrogenase (IDH) mutation. On univariable analysis, improved 5-year survival was independently associated with concurrent temozolomide  (46.2 vs. 29.3%, P = 0.02) and IDH mutation (78.9 vs. 22.0%, P < 0.001).[27]

Anaplastic astrocytomas are usually more responsive to chemotherapy than glioblastomas.[28, 29] For recurrent anaplastic astrocytomas previously treated with nitrosoureas, temozolomide showed a 35% response rate, and compared to therapies with lower response rates, temozolomide provided an increased 6-month survival rate (46% vs 31%).[30, 31] Some smaller survival benefit has been shown with adjuvant carmustine.[4]

Patients with an astrocytoma and a history of seizures should receive anticonvulsant therapy with monitoring of the drug concentration in the blood. 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.

See Brain Cancer Treatment Protocols for summarized information.

Brainstem gliomas

Brainstem tumors account for 10-20%[32] of all central nervous system (CNS) tumors in the pediatric population, and are typically diagnosed in children 7-9 years old.[33, 34] Though many classification schemes exist, treatment and prognosis for brainstem gliomas typically depend on whether the tumor is diffuse or focal.

Diffuse brainstem gliomas

Diffuse brainstem gliomas make up 58-75%[35] of all brainstem tumors, typically arise in the pons, and are noncircumscribed on MRI. They are often malignant fibrillary astrocytomas (WHO grade III or IV) that infiltrate along white-matter tracts into the midbrain and thalamus and have a rapidly progressive and fatal course.

Clinical presentation of these tumors often involves ataxia, cerebellar signs, and long tract signs.[36] When clinical and radiographic evidence suggests diffuse brainstem glioma, biopsy is of limited use as tumor histology does not often alter treatment.[35, 37, 38, 39, 40, 41, 42, 43]

No treatment has been shown to cure or prolong survival in these patients, and radiation necrosis and chemotherapy side effects can be significant. No benefit of surgical resection has been shown, largely due to the eloquence of the region and diffuse and aggressive nature of the tumor.[36, 44] Corticosteroids may provide temporary benefit by reducing edema.

Irradiation has been shown to provide temporary clinical improvement and is sometimes employed, but a large phase III trial showed no benefit.[45] Even with radiation therapy, 1-year survival has been shown to be 35-46%, and 3-year survival 11-17%.[46, 47]

Chemotherapy is also sometimes used.[48] Convection-enhanced delivery of chemotherapy offers one potential avenue for improving the prognosis of these patients, and studies are ongoing.

Focal brainstem gliomas

Focal brainstem gliomas are usually WHO grade I or II, well-circumscribed on MRI with variable contrast enhancement, are more often found in the medulla and midbrain and have a much better prognosis than diffuse brainstem gliomas. Surgery is often the primary treatment for focal brainstem gliomas as well as dorsal exophytic brainstem gliomas, though the decision to operate, surgical approach, and extent of resection depend on location, patient factors, and the surgeon's judgment.

Obstructive hydrocephalus is common. It is usually treated by a separate procedure, either endoscopic third ventriculostomy or shunt placement.[5]

In a study of 39 children (median age, 10 years) with low-grade glioma, treatment with intensity-modulated radiotherapy (IMRT) after incomplete resection or disease progression was found to provide local control rates comparable to those provided by 2-dimensional and 3-dimensional radiotherapy. The 8-year progression-free and overall survival rates with IMRT were 78.2% and 93.7%, respectively.[49, 50]

The researchers used three approaches to identify the target area for IMRT: The first method (n=19) was to delineate the gross tumor volume (GTV) and add a 1-cm margin to create the clinical target volume. In the second method (n=6), a 0.5-cm margin was added around the GTV to create the clinical target volume. For both methods, the prescribed GTV dose was the same as the clinical treatment volume: a median dose of 50.4 Gy.

Method 3 (n=14) was dose painting: the GTV was delineated and a second target volume was created by adding 1 cm to the GTV. The second target volume was treated with a lower radiation dose than the GTV (median, 41.4 Gy versus 50.4 Gy). Multivariate analysis showed no difference in progression according to the method of target delineation, suggesting that a 1-cm margin may not be necessary.[49, 50]

For a complete discussion of this topic, see Brainstem Gliomas.

 

Surgical Care

The roles of surgery in the patient with astrocytoma are (1) to remove or debulk the tumor and (2) to provide tissue for histological diagnosis, permitting tailoring of adjuvant therapy and assessment of prognosis.[51] 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 adjacent regions of the brain and exhibit tumor infiltration that is detectable only on a microscopic scale. Therefore, surgical resection 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.

Complete resection (>98% based on volumetric MRI) has been shown to improve median survival compared with subtotal resection (13 vs 8.8 mo).[52] For low-grade gliomas, some data support supratotal resection (ie, removal of tissue beyond the MRI-defined abnormalities), suggesting an increase in overall survival with this strategy.[53]

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 the patient's symptoms with the findings on anatomic and functional imaging. This physician also may manage antiepileptic medication for patients who are having seizures.

A neurosurgeon should be consulted to assess the risks and benefits of surgical resection, stereotactic biopsy, stereotactic radiosurgery, and cerebrospinal fluid 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

Medication Summary

No specific drug treatment exists for low-grade glioma. Certain conditions (eg, low-grade astrocytoma) typically require treatment. For seizures, the patient is usually started on levetiracetam, phenytoin, or carbamazepine. Levetiracetam is often used because it lacks the effects on the P450 system seen with phenytoin and carbamazepine, which can interfere with antineoplastic therapy. Steroid therapy, usually combined with a gastroprotectant, is initiated for vasogenic edema around tumor.

Anticonvulsants

Class Summary

These agents prevent seizure recurrence and terminate clinical and electrical seizure activity.

Levetiracetam (Keppra)

Used as adjunct therapy for partial seizures and myoclonic seizures. Also indicated for primary generalized tonic-clonic seizures. Mechanism of action is unknown.

Phenytoin (Dilantin)

Effective in partial and generalized tonic-clonic seizures. Blocks sodium channel and prevents repetitive firing of action potentials.

Carbamazepine (Tegretol)

Similar to phenytoin. Effective in partial and generalized tonic-clonic seizures. Blocks sodium channel and prevents repetitive firing of action potentials.

Corticosteroids

Class Summary

These drugs reduce edema around the tumor, frequently leading to symptomatic and objective improvement.

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.

Antineoplastic Agent, Alkylating Agent

Class Summary

These agents inhibit cell growth and proliferation.

Temozolomide (Temodar)

Oral alkylating agent converted to MTIC at physiologic pH; 100% bioavailable; approximately 35% crosses the blood-brain barrier.

 

Follow-up

Further Outpatient Care

Outpatient management includes the following:

  • 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 MRIs is determined by both the neurosurgeon and other physicians involved in the ongoing care of the patient, including the neurooncologist and radiation oncologist

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 therapy 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.

Inpatient & Outpatient Medications

 

 

Transfer

See the list below:

  • 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 are possible sequelae of operative intervention, 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 low-grade lesions, the mean survival time after surgical intervention has been reported as 6-8 years. For those patients who undergo surgical resection, the prognosis depends on whether the neoplasm progresses to a higher-grade lesion.

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.

Irradiation of incompletely resected tumors can increase 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).

Attempts have been made to determine prognosis and response to various treatment modalities based on the individual pattern of genetic changes in a particular tumor. For example, patients with oligodendrogliomas that exhibit chromosomal changes at band 1p19q are known to have better responses to the procarbazine, lomustine (CCNU), vincristine (PCV) regimen of chemotherapy.

Efforts are under way 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.[54]

In high-grade astrocytoma, elevations in glioblastoma kallikrein 6 (KLK6), kallikrein 7 (KLK7), and kallikrein 9 (KLK9) proteins may have prognostic utility as markers of patient survival. Kallikrein levels and associated outcomes were as follows[55] :

  • Elevated KLK6- or KLK7-IR – Poor patient prognosis
  • Increased percent of tumor immunoreactive for KLK6 or KLK9  – Decreased survival
  • KLK6 immunoreactivity score < 10, KLK6 < 3% tumor core stained, or KLK7 immunoreactivity score < 9 – Significantly improved survival

Survivors of pediatric astrocytoma are at high risk for long-term complications of the disease and its treatment. An evaluation of 1182 astrocytoma survivors by Effinger et al found that at 30 years after diagnosis, compared with their siblings, survivors were at increased risk of serious chronic conditions and reported higher rates of poor general health, poor mental health, functional impairment, and activity limitation, as well as lower rates of college graduation, marriage, employment, and household income.[56]

 

Questions & Answers

Overview

What is the prognosis of astrocytomas?

What are the signs and symptoms of astrocytomas?

Which physical findings are characteristic of astrocytomas?

What is the role of lab testing in the workup of astrocytoma?

What is the role of MRI in the workup of astrocytoma?

What is the role of CT scan in the workup of astrocytoma?

What is the role of angiography in the workup of astrocytoma?

What is the role of radionuclide scans in the workup of astrocytoma?

What is the role of EEG in the workup of astrocytoma?

What is the role of ECG in the workup of astrocytoma?

What is the role of CSF analysis in the workup of astrocytoma?

How are astrocytomas treated?

Which surgical interventions are used in the treatment of astrocytoma?

How are the symptoms of astrocytomas managed?

How are brainstem gliomas treated?

What are astrocytomas?

What are the histopathologic schemes used to grade astrocytomas?

What is the WHO grading scheme for astrocytomas?

What is the pathophysiology of astrocytoma?

What is the annual incidence of astrocytoma in the US?

What is the typical survival for patients with astrocytomas?

What are the racial predilections of astrocytoma?

What are the sexual predilections of astrocytoma?

Which age groups have the highest incidence of astrocytomas?

Presentation

Which clinical history findings are characteristic of astrocytoma?

What is included in physical exam for astrocytoma?

Which physical findings suggest increased intracranial pressure (ICP) in patients with astrocytoma?

What causes astrocytoma?

DDX

What are the differential diagnoses for Astrocytoma?

Workup

Which lab tests are performed in the workup of astrocytoma?

What is the role of imaging studies in the workup of astrocytoma?

Which studies may be beneficial in the workup of astrocytoma?

What is the role of lumbar puncture in the workup of astrocytoma?

Which histologic findings are characteristic of astrocytoma?

How are astrocytomas staged?

Treatment

How are focal brainstem gliomas treated?

What is the efficacy of treatments for astrocytoma?

How are anaplastic astrocytomas treated?

How are low-grade astrocytomas treated?

What is the prevalence of brainstem gliomas among children?

How are diffuse brainstem gliomas treated?

What is the role of surgery in the treatment of astrocytomas?

Which specialist consultations are beneficial to patients with astrocytoma?

Which activity modifications are used in the treatment of astrocytoma?

Medications

What is the role of medications in the treatment of astrocytoma?

Which medications in the drug class Antineoplastic Agent, Alkylating Agent are used in the treatment of Astrocytoma?

Which medications in the drug class Corticosteroids are used in the treatment of Astrocytoma?

Which medications in the drug class Anticonvulsants are used in the treatment of Astrocytoma?

Follow-up

What is included in the outpatient care of patients with astrocytoma?

What is the role of radiation therapy in the treatment of astrocytomas?

When is patient transfer indicated for the treatment of astrocytomas?

What are the possible complications of surgery to treat astrocytoma?

What is the post-treatment prognosis of astrocytomas?

What is the role of kallikrein levels in determining the prognosis of high-grade astrocytoma?