Astrocytoma

Practice Essentials

Astrocytomas are a form of glioma (ie, a neoplasm of the glial cells, which constitute the supportive tissue of the brain and nervous system). The predominant cell type in these tumors is thought to be derived from an immortalized astrocyte.^[1] Astrocytomas can arise anywhere in the nervous system, but most commonly occur in the brain. (See the image below.) Astrocytomas can be indolent or aggressive, depending on tumor grade, which drives prognosis and clinical decision making.

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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 signs and symptoms from astrocytoma 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 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 standard imaging study.
• Astrocytomas are generally isointense on T1-weighted images and hyperintense on T2-weighted images.
• While low-grade astrocytomas (WHO grades 1-2) uncommonly enhance on MRI, many grade 3-4 astrocytomas enhance with gadolinium contrast agents.
• High-resolution MRI is now often used to provide intraoperative image guidance.

CT:

• 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.
• High-grade 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.
• 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.

Other studies:

• Angiography may be used to rule out vascular malformations and to evaluate tumor blood supply
• PET, SPECT, or technetium-based imaging can permit study of tumor metabolism and brain function
• EEG may be used to evaluate and monitor epileptiform activity
• ECG and chest radiographs are indicated to evaluate operative risk

Tissue diagnosis and WHO classification

Classification of astrocytomas is based on distinct histopathologic and molecular alterations, and drives treatment decision making. Therefore, tissue diagnosis (via biopsy or surgical resection) is often necessary prior to further treatment planning. This article focuses on the widely accepted updated World Health Organization (WHO) grading scheme,^[2] and is confined to adult-type diffuse isocitrate dehydrogenase (IDH)-mutant gliomas, including grades 2-4 IDH1-mutant astrocytoma. See Background.

Management

Treatment options in astrocytomas include operative intervention, chemotherapy and radiotherapy, and are guided in part by WHO Classification. Therefore, tissue diagnosis with histological and molecular characterization is essential. Treatment decisions are best made by a team approach, including input from the involved neurosurgeon, radiation oncologist, and medical oncologist or neurologist, as well as the patient and/or their family. See Treatment and Medication.

The multimodal treatment guidelines for IDH-mutated astrocytomas as recommended by the American Society of Clinical Oncology (ASCO) and Society of Neuro-Oncology (SNO) are summarized in the flow chart below:

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IDH-mutant astrocytoma treatment guidelines.

Surgical care

• Tumor resection is generally undertaken with the intent to cause the least possible neurologic injury to the patient.
• Surgical resection provides improved survival advantage as well as histopathologic/molecular diagnosis of the tumor but is not curative. Total resection of an astrocytoma is often impossible because the tumors often exhibit tumor infiltration that is detectable only on a microscopic scale and/or invade eloquent regions of the brain.
• New methods of tumor imaging are being developed to specifically fluorescently tag or label tumor cells so they may be visualized in the operating room, to guide surgical resection. Such methods used for astrocytomas include preoperative infusion of fluorescein or Gleolan (5-ALA/PPIX).^[3]
• Several imaging methods can be used preoperatively and intraoperatively to map functional areas of the brain, such as those that control speech, language, and motor and sensory functions, if the tumor abuts these regions, to ensure the safe resection of the lesion while avoiding eloquent brain structures. These methods include functional MRI (fMRI), diffusion tensor imaging (DTI) tractography, and intraoperative direct cortical/subcortical stimulation.
• Stereotactic biopsy can be utilized to establish a tissue diagnosis in cases where surgical resection is not possible or preferred.
• Diversion of CSF by external ventricular drain (EVD) or ventriculoperitoneal shunt (VPS) may be required to decrease intracranial pressure.

Radiation and Adjuvant chemotherapy

• External beam radiotherapy is a mainstay of treatment for patients with IDH-mutant astrocytoma after surgical resection, but can be deferred in the setting of positive prognostic factors in grade 2 IDH-mutant astrocytomas (see Guidelines/Guidelines Summary).
• Options for adjuvant chemotherapy include temozolomide (TMZ) as well as the combination of procarbazine, lomustine (CCNU), and vincristine (PCV), depending on the WHO grading (see Guidelines/Guidelines Summary).

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

For patient education information, see Brain Cancer.

• References

Background

Astrocytomas constitute a broad group of gliomas, and have historically been classified on the basis of distinct radiographic and histologic features. 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 1-4
• St. Anne/Mayo grades 1-4

Most recently, astrocytomas have been re-classified as part of the 2021 WHO Classification of Tumors of the Central Nervous System^[2] (see the image below). This edition of the WHO grading scheme revolutionized classification by incorporating and emphasizing key molecular alterations, in addition to histopathologic features, in the diagnostic criteria for each tumor subtype. 

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2021 WHO classification of gliomas.

Broadly, two classes of astrocytic tumors are recognized: those with narrow zones of infiltration and well circumscribed (eg, pilocytic astrocytoma, subependymal giant cell astrocytoma, pleomorphic xanthoastrocytoma) and those with diffuse zones of infiltration (eg, low-grade astrocytoma, anaplastic astrocytoma, glioblastoma). For a discussion of well-circumscribed astrocytomas, see Pediatric Astrocytoma.

Diffuse gliomas 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 histopathologic properties and biological behavior
• Diffuse infiltration of contiguous and distant CNS structures, regardless of histologic stage
• An intrinsic tendency to progress to more advanced grades

The updated WHO criteria also make a distinction between adult-type and pediatric-type diffuse gliomas. For a discussion of pediatric-type diffuse gliomas, see Pediatric Astrocytoma. The updated criteria emphasize the IDH mutational status as the primary molecular alteration used for stratification of adult-type diffuse gliomas, as mutations in either gene (IDH1 or IDH2) have been shown to alter disease progression, carry prognostic significance (the IDH1/2 mutation is associated with improved survival), and guide treatment decisions. The emphasis on this molecular marker, as demonstrated in the above flow chart, has led to two major changes in the classifications of astrocytoma:

• Elimination of the entitity of IDH-mutant glioblastoma (now called WHO Grade 4 IDH-mutant astrocytoma)
• Classification of any low-grade IDH-wildtype astrocytomas as primarily pediatric-type diffuse gliomas (in contrast, IDH-wildtype gliomas in adults tend to have one or more aggressive features, which allows them to be classified as glioblastoma WHO Grade 4; see Glioblastoma).

 Oligodendroglioma, also IDH mutated, is distinguished from astrocytoma molecularly via existence of the chromosomal co-deletion 1p-19q and retention of the ATRX gene. For a detailed discussion of IDH-mutant oligodendroglioma, see Oligodendroglioma

• References

Pathophysiology

Astrocytomas are a form of glial neoplasm that arises in the brain or spinal cord. Astrocytomas can be either well-circumscribed or diffusely infiltrating, which often drives the clinical manifestations, disease progression, treatment options, and prognosis.

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.

Neurologic signs and symptoms attributable to astrocytomas result from perturbation of CNS function. Focal neurologic deficits (eg, weakness, paralysis, sensory deficits, cranial nerve palsies) and seizures of various characteristics may permit localization of lesions.^[4]

Infiltrating low-grade astrocytomas grow more slowly than their malignant counterparts. Several years often intervene between the initial symptoms and the establishment of a diagnosis of low-grade astrocytoma. Higher-grade astrocytomas tend to produce more-pronounced symptoms, focal neurologic symptoms, and functional impairment.

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Etiology

The etiology of diffuse astrocytomas has been the subject of analytic epidemiological studies that have yielded associations with various disorders and exposures.^[5]  With the exception of therapeutic irradiation^[6]  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, these claims are largely unsubstantiated.^{[7, 8, 9, 10, 11, 12]}

Children receiving prophylactic irradiation for acute lymphoblastic leukemia (ALL) have a 22-fold increased risk of developing CNS neoplasms, including WHO grade 2, 3, and 4 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.^[13]

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 found evidence 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. Two-thirds of low-grade astrocytomas have p53 mutations.^[14]

In patients with glioma who do not have single-gene alterations, anywhere between 5-10% have a family history of glial neoplasm, and having a first-degree relative with glioma doubles the risk of developing glioma. Large genome-wide association studies (GWAS) have identifed 25 risk loci associated with increased risk of glioma. Genetic loci specifically associated with IDH-mutant astrocytoma include portions of the IDH1 gene, among others.^[15]

In addition, human leukocyte antigen (HLA) types have been associated with either increased or decreased risk for the development of brain gliomas. Machulla et al reported that, compared with a control population, patients positive for HLA-A*25 had a 3.0-fold increased risk of brain glioma (P = 0.04), patients positive for HLA-B*27, a 2.7-fold increased risk (P = 0.03), and patients positive for HLA-DRB1*15 had a 2.2-fold risk (P= 0.03), while those with HLA-DRB1*07 had a 0.4-fold decreased risk  (P = 0.02).^[16]

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Epidemiology

The American Cancer Society estimates that in 2024, approximately 25,400 malignant tumors of the brain or spinal cord will be diagnosed, and about 18,760 deaths will occur from those tumors.^[17] Brain and other nervous system tumors are the leading cause of cancer death in children and adolescents younger than 20 years.^[18]

The annual incidence of glioma in the United States is 6.0 cases per 100,000 population.^[8] The majority of these cases (61.5%) were classified as glioblastomas (according to 2016 WHO criteria), while 18.8% were non-glioblastoma astrocytomas and the remainder were non-astrocytoma gliomas.^[8] In an analysis of the Central Brain Tumor Registry of the United States (CBTRUS) from 2019, 19% of all adult-type diffuse gliomas were IDH1-mutant astrocytomas.^[15]

Age

While increasing age has been shown to be a very strong risk factor for the development of glioblastoma, IDH1-mutant gliomas tend to affect a younger population. The median age at diagnosis of IDH1-mutant gliomas has been reported to be around 36-38 years (36 years for grades 2-3, 38 years for grade 4), while the median age for IDH1-wildtype gliomas (including glioblastomas) is around 50-60 years.^[15]

Race

In the United States, the incidence of adult-type diffuse glioma is the highest in the non-Hispanic White population. Non-hispanic Whites have a 30% higher risk of glioma than Hispanic Whites, and double the risk of Black, Asian or Pacific Islander, and American Indian or Alaskan Native individuals.^[15]  However, demographic and socioeconomic factors, including health disparities and access to care, have been reported to influence measured distributions of disease incidence. 

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, has been reported for development of lower-grade astrocytomas. A more significant male predominance, with a male-to-female ratio of 1.87:1, has been reported for the development of higher-grade astrocytomas. Five-year survival in non-glioblastoma astrocytoma is lowest in non-Hispanic Whites (44.1%) as compared with all other groups (50.8%).^[15]

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Prognosis

IDH-mutant astrocytomas are considered incurable, although treatment can prolong survival. However, prognosis for patients with IDH-mutant astrocytomas is significantly better than those with tumors without the IDH1 mutation, which is why molecular classification of the tumor (specifically IDH status) is critical for decision making and patient education. 

While prognostic data are limited for tumors classified using the 2021 WHO criteria, median survival after diagnosis of IDH-mutant astrocytomas by grade is as follows^{[19, 20, 21, 22]} :

• WHO Grade 2: 10-12 years
• WHO Grade 3: 8-10 years
• WHO Grade 4: 3-4 years

Given the impact of the IDH mutation on prognosis, many attempts have been made to further elucidate prognosis and response to various treatment modalities based on tumor molecular profiling. For example, a homozygous deletion of the cyclin-dependent kinase inhibitor 2A/B (CDKN2A/B) gene portends a poor prognosis, and therefore automatically results in a WHO grade 4 classification in the 2021 criteria, independent of histopathologic criteria. 

Beyond WHO grade, the following factors, among others, have been reported to have a negative impact on survival of patients with astrocytomas^{[23, 24]} :

• Male sex
• Worse functional status
• Larger tumors (> 5 cm)

Survivors of pediatric astrocytoma remain at high risk for long-term complications of their disease and its treatment. These patients require lifelong monitoring for late effects.^[25]

• References

History

The type of neurologic signs and 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 should alert the clinician to the presence of a neurologic 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.

• References

Physical Examination

A detailed neurologic 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 neurologic abnormalities are identified, imaging studies should be obtained for further evaluation.

• References

Approach Considerations

Classification of astrocytomas is based on distinct histopathologic and molecular alterations, and drives prognostic relevance and treatment decision making. Therefore, while clinical picture and imaging are important, tissue diagnosis is often necessary (via biopsy or surgical resection) prior to further treatment planning. The most recent World Health Organization (WHO) Classification of gliomas from 2021 is shown in the flow chart below.

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2021 WHO classification of gliomas.

• References

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)

• References

Imaging Studies

Computed tomography (CT) and magnetic resonance imaging (MRI), with and without contrast, are helpful in the diagnosis and clinical decision making for patients with 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.

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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 alternative primary lesion.

Like low-grade astrocytomas, higher-grade astrocytomas may appear as low-density lesions or non-homogeneous lesions, with areas of both high and low density within the same lesion. Unlike low-grade lesions, partial contrast enhancement is common.^{[26, 27]}

Astrocytomas are generally isointense on T1-weighted images and hyperintense on T2-weighted images. (See the images below.) While lower-grade astrocytomas uncommonly enhance on MRI, most higher-grade astrocytomas enhance with paramagnetic contrast agents.

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Coronal postcontrast T1-weighted MRI shows a low-grade astrocytoma in the right inferior frontal lobe just above the sylvian fissure. No enhancement i....

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

New methods are being developed to assess tumor vascularity by MRI, including techniques such as arterial-spin labeling (ASL) and dynamic contrast-enhanced MRI. Proton MR spectroscopy may help discriminate between IDH-mutant and IDH-wildtype tumors in patients with high-grade diffuse astrocytoma.^[28]

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. 

Furthermore, other higher-dimensional preoperative imaging studies can be used to map functional areas such as those that control speech, language, and motor and sensory functions, if the tumor abuts these regions, to ensure the safe resection of the lesion while avoiding eloquent brain structures. These include functional MRI (fMRI) and diffusion tensor imaging (DTI) tractography.^[29]

For more information, see Astrocytoma Brain Imaging and Spinal Imaging in Astrocytoma.

• References

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

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Procedures

In addition to its therapeutic role (tumor removal or debulking), surgery in the patient with astrocytoma provides tissue for histologic/molecular diagnosis and grading, which permits tailoring of adjuvant therapy and assessment of prognosis.^[30] Stereotactic biopsy is a safe and simple method for establishing a tissue diagnosis, but can be limited by quantity of tissue obtained. See Treatment/Surgical Care. 

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.

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Histologic Findings

Traditionally, astrocytomas were diagnosed and graded via histologic findings alone. Astrocytomas are generally characterized as CNS neoplasms with markers of astrocytes, including glial fibrillary acidic protein (GFAP), along with some or all of the classic histologic features of neoplastic disease, including nuclear atypia, increased mitoses, microvascular proliferation, and/or necrosis.^[31]  See the images below.

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Low-grade diffuse astrocytoma and low cellularity with minimal nuclear atypia.

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Higher-grade IDH-mutant astrocytoma, with nuclear atypia and mitoses. Courtesy of Wikipedia (https://en.wikipedia.org/wiki/Anaplastic_astrocytoma).

Traditionally, four histologic variants of low-grade diffuse astrocytomas had been recognized: protoplasmic, gemistocytic, fibrillary, and mixed. However, those classifications have been de-emphasized as part of the updated World Health Organization (WHO) 2021 classification, which integrates histopathologic and molecular findings for a unified diagnosis (see flow chart below).^{[2, 32]}

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2021 WHO classification of gliomas.

The WHO grade of the tumor is of primary importance when determining prognosis and treatment (see Overview/Prognosis and Guidelines/Guidelines Summary). 

Broadly, two classes of astrocytic tumors are recognized: those with narrow zones of infiltration and well circumscribed (eg, pilocytic astrocytoma, subependymal giant cell astrocytoma, pleomorphic xanthoastrocytoma) and those with diffuse zones of infiltration (eg, low-grade astrocytoma, anaplastic astrocytoma, glioblastoma).

The updated WHO criteria also make a distinction between adult-type and pediatric-type diffuse gliomas. In the updated criteria, isocitrate dehydrogenase (IDH) gene mutational status is the primary molecular alteration used for stratification of adult-type diffuse gliomas, as mutations in either gene (IDH1 or IDH2) alter disease progression, carry prognostic relevance (the IDH1/2 mutation is associated with improved survival), and guide treatment decisions. The emphasis on this molecular marker, as demonstrated in the above flow chart, has led to two major changes in the classifications of astrocytoma:

• Elimination of the entitity of IDH-mutant glioblastoma (now called WHO Grade 4 IDH-mutant astrocytoma)
• Classification of any low-grade IDH-wildtype astrocytomas as primarily pediatric-type diffuse gliomas (IDH wild type gliomas in adults tend to have one or more aggressive features that classifies them as glioblastoma WHO Grade 4).

For a discussion of glioblastoma, IDH wildtype, see Glioblastoma.

IDH-mutant astrocytomas are now defined as a distinct disease process and pathology. Oligodendroglioma, also IDH-mutated, is distinguished from astrocytoma molecularly via existence of the chromosomal co-deletion 1p-19q and retention of the ATRX gene. For a detailed discussion of pathology of IDH-mutant oligodendroglioma, see Pathology of Oligodendrogliomas.

IDH-mutant diffuse astrocytomas are graded by WHO from 2-4 as described in the flow chart above (no grade 1 IDH-mutant diffuse astrocytomas exist), and can be summarized below:

• Grade 2: No CDKN2A/B deletion, no significant mitosis, microvascular proliferation, or necrosis
• Grade 3: No CDKN2A/B deletion, microvascular proliferation, or necrosis, but significant mitotic activity
• Grade 4: Existence of CDKN2A/B homozygous deletion, microvascular proliferation, or necrosis

For more information, see Pathology of Diffuse Astrocytomas and Pathology of Expansile Astrocytomas.

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Staging

Staging is not performed or described for patients with astrocytoma. IDH-mutant astrocytomas can be described as low grade (WHO grade 2) or high grade (grades 3 and 4).^[33]  See Workup/Histologic Findings for a complete classification via the WHO grading criteria.

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.

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Approach Considerations

Treatment options in astrocytomas include operative intervention, chemotherapy, and radiotherapy. Treatment decisions are generally best made through a team approach, including input from the involved neurosurgeon, radiation oncologist, and medical oncologist or neurologist, as well as the patient and/or their family.

The multimodal treatment guidelines for IDH-mutated astrocytomas from the American Society of Clinical Oncology (ASCO) and Society of Neuro-Oncology (SNO) are summarized in the flow chart below.

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IDH-mutant astrocytoma treatment guidelines.

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Surgical Care

Surgical resection is the mainstay of operative treatment for astrocytomas. The goals of surgery are to debulk the tumor and collect sufficient tissue for diagnosis, while avoiding or limiting complications such as further neurologic injury.^[30] Alternatively, stereotactic biopsy can be used for establishing a tissue diagnosis, but while it is safe and simple, it can be limited by the quantity of tissue obtained. The decision whether to perform surgical resection for astrocytoma necessitates a patient-specific discussion of risks and benefits and should be a shared decision between the neurosurgeon and the patient and/or family.

Surgical resection is often used for high-grade lesions, and in low-grade lesions if the neurosurgeon believes it can be done in a safe manner. Retrospective studies have reported that in patients with low-grade glioma, early surgical resection provides longer survival compared with watchful waiting.^[34] In addition, in patients with IDH-mutant low-grade gliomas, larger extent of resection is associated with improved survival.^[35]

Complete resection of astrocytoma is impossible, as the tumors often invade into adjacent regions of the brain, with diffuse microscopic tumor infiltration. Gross total resection (> 98% based on volumetric MRI) has been shown to improve median survival compared with subtotal resection (13 vs 8.8 mo).^[36] For low-grade gliomas, retrospective data suggest that supratotal resection (ie, removal of tissue beyond the MRI-defined abnormalities) may increase overall survival.^[37]

The boundaries of infiltrating tumors extend far beyond what can be seen on imaging studies. New methods of tumor imaging are being developed to specifically fluorescently tag or label tumor cells so they may be visualized in the operating room, to guide surgical resection. Such methods used for astrocytomas include preoperative infusion of fluorescein and Gleolan (5-ALA/PPIX).^[3]

Several methods can be used preoperatively and intraoperatively to map functional areas of the brain, such as those that control speech, language, and motor and sensory functions, if the tumor abuts these regions, to ensure the safe resection of the lesion while avoiding eloquent brain structures. Preoperative imaging studies that can assist in mapping critical motor and language areas include functional MRI (fMRI) and diffusion tensor imaging (DTI) tractography.^[29] Mapping of these eloquent structures can also be done intraoperatively using direct cortical and subcortical stimulation, often with the patient awake and under local anesthesia, to test whether a suspected brain region corresponds to a critical motor or language area,^[29] in a fashion similar to what is done in epilepsy surgery.

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.

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. A postoperative MRI scan is often performed, to assess the extent of resection and potentially guide future oncologic management.

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Medical Care

Radiotherapy and chemotherapy

In addition to surgical resection, external beam radiation therapy and adjuvant chemotherapy can be considered for patients with IDH-mutated astrocytomas, depending on extent of surgical resection and WHO grade. See Guidelines section for a summary of the recommendations by the American Society of Clinical Oncology (ASCO) and Society of Neuro-Oncology (SNO). 

Management of low-grade astrocytomas can be controversial, as tumors may be radiographically stable and clinically quiescent for long periods after the initial presentation.^{[38, 39]} For adult patients with low-grade astrocytoma, radiation therapy plus adjuvant chemotherapy has been found superior to radiation therapy alone. A phase II study of temozolomide-based chemoradiation therapy in 132 patients with high-risk low-grade astrocytomas reported median overall survival of 8.2 years. Long-term overall survival rates—73.5% at 3 years, 60.9% at 5 years, and 34.6% at 10 years—confirmed efficacy and exceeded historical survival rates of patients receiving radiation only.^[40]  

Tovorafenib was approved by the US Food and Drug Administration (FDA) in April 2024 for relapsed or refractory pediatric low-grade glioma (LGG) harboring a BRAF fusion or rearrangement, or BRAF V600 mutation in patients aged 6 months and older.^[41]  Another regimen approved by the FDA for pediatric LGG is trametinib plus dabrafenib in patients aged 1 year and older. 

In a phase III trial that included patients with low-grade 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 (CCNU), and vincristine (PCV) 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 survival at 10 years of 60% versus 40%, respectively.{ref31. It is important to note that these studies were performed on patients whose disease was classified using prior WHO grading, and thus the findings are not limited to IDH-mutated astrocytomas.^[42]

Typically, higher-grade astrocytomas are treated with surgery, radiotherapy, and adjuvant temozolomide. Furthermore, some practitioners add temozolomide concurrently with adjuvant radiation, which has been associated with improved survival in higher-grade astrocytomas.^[43]

Postoperative and symptomatic care

After undergoing surgical resection, most patients require initial admission to a neurologic or surgical intensive care unit for close monitoring of neurologic status, as well as management of any potential surgical complications. A postoperative MRI scan of the brain is often performed in the days to weeks following resection.

Patients with an astrocytoma and a history of seizures should receive anticonvulsant therapy, with monitoring of the drug concentration in the blood. 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. The use of anticonvulsants prophylactically in astrocytoma patients with no history of seizures has been reported but remains controversial.

The use of corticosteroids, such as dexamethasone, can yield rapid improvement in many patients secondary to a reduction of tumor-associated vasogenic edema. Concurrent prophylaxis for gastrointestinal ulcers should be prescribed with corticosteroid administration.

Investigational therapy

Prognosis is still poor for many types of astrocytomas and other brain tumors. Thousands of patients with astrocytomas enroll in clinical trials each year. Investigational treatments are wide ranging, and fall into the following categories:

• Novel methods of radiotherapy, such as proton beam therapy and photodynamic therapy.^{[44, 45]}
• New intracranial drug delivery strategies, such as convection-enhanced delivery and focused ultrasound.^{[46, 47]}
• Therapies directed at key molecular alterations, such as drugs that target the IDH mutation.^[48]
• Therapies targeted to engage the patient's own immune system to fight the tumor, such as cellular vaccines (eg, autologous tumor lysate–loaded dendritic cell vaccine), oncolytic viruses, chimeric antigen receptor (CAR) T-cell therapy, antibody-armed T cells, and immune checkpoint blockade.^{[49, 50, 51]}

• References

Consultations

Consultations for patients with astrocytoma include the following:

• A neurologist should be consulted to document a patient's detailed neurologic examination. This establishes a baseline and partly assesses the possibility of occult disease. 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 neuro-oncologist may be consulted to help coordinate a comprehensive therapeutic plan. Once a histologic diagnosis is determined, the neuro-oncologist should be consulted to provide comprehensive adjunctive therapy, including the use of chemotherapy and radiation.
• A radiation oncologist may be consulted for expertise on radiation therapy, including dosing and timing, and potential options for targeted radiation therapy.
• A neuroradiologist should be consulted to interpret cranial imaging, such as CT and MRI, to help narrow down a differential diagnosis and report any relevant anatomic considerations for surgical planning.

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Activity

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

• References

Complications

Neurologic injury (potentially devastating) and death are possible sequelae of operative intervention, neurosurgery for astrocytomas is intended to debulk tumor and to obtain tissue for diagnosis while minimizing neurologic injury. Several pre-operative and intraoperative studies can be used to map functional areas, such as those that control speech, language, motor and sensory functions, if the tumor abuts these regions, to ensure the safe resection of the lesion while avoiding eloquent brain structures.

Patients with astrocytomas often have significant vasogenic edema surrounding the tumor, which can cause mass effect and neurologic deficits. Corticosteroids, such as dexamethasone, can reduce tumor-associated vasogenic edema and produce rapid improvement in many patients. Steroids are often given first in a loading dose and subsequently tapered.^[52]

Patients with astrocytomas often have glioma-associated epilepsy and seizures, and therefore should be monitored with electroencephalography and treated with anti-epileptic drugs, if necessary. 

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Long-Term Monitoring

Outpatient management includes the following:

• Patients should follow up with a neuro-oncologist to observe for progression of neurologic signs and symptoms, obtain serial MRI scans, and manage chemotherapy, radiotherapy, and steroid and anticonvulsant regimens.
• Patients may follow with a radiation oncologist if they are undergoing radiotherapy.
• Outpatient neurosurgery observation is necessary for tumor monitoring and management of hydrocephalus if a shunt has been placed.
• The frequency of postoperative MRIs is determined by both the neurosurgeon and other physicians involved in the ongoing care of the patient, including the neuro-oncologist and radiation oncologist.

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Guidelines Summary

Treatment guidelines for diffuse astrocytic and oligodendroglial tumors in adults have been published by the American Society of Clinical Oncology (ASCO) and Society of Neuro-Oncology (SNO).^[53] The guidelines contain the following recommendations for treatment of astrocytomas:

• For IDH-mutant, 1p19q non-codeleted, central nervous system (CNS) World Health Organization (WHO) grade 2  astrocytoma (low-grade diffuse glioma), offer radiation therapy (RT) with adjuvant chemotherapy (temozolomide [TMZ] or procarbazine, CCNU, and vincristine  [PCV]).
• In IDH-mutant, 1p19q non-codeleted, CNS WHO grade 2 astrocytoma, given its natural history, initial therapy may be deferred until radiographic or symptomatic progression in some patients with positive prognostic factors (eg, complete resection, younger age) or concerns about short- and long-term toxicity.
• For IDH-mutant, 1p19q non-codeleted CNS WHO grade 3 astrocytoma, offer RT with adjuvant TMZ.
• IDH-mutant CNS WHO grade 4 astrocytoma may be treated like IDH-mutant, non-codeleted, CNS WHO grade 3 astrocytoma (formerly anaplastic astrocytoma); or like IDH-wildtype, CNS WHO grade 4 glioblastoma (formerly IDH-wildtype glioblastoma), with concurrent TMZ and RT.
• IDH-wildtype, CNS WHO grade 2 or 3 astrocytoma may be treated according to recommendations for IDH-wildtype, CNS WHO grade 4 glioblastoma.

See the image below.

View Image

IDH-mutant astrocytoma treatment guidelines.

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Medication Summary

Medications used for astrocytoma include the following:

• Tovorafenib or trametinib plus dabrafenib for relapsed/refractory pediatric low-grade glioma
• Antineoplastic agents (eg, temozolomide) for adjuvant chemotherapy
• Anticonvulsants (eg, levetiracetam) for seizure control and prevention
• Corticosteroids (eg, dexamethasone) for vasogenic edema surrounding the tumor

• References

Tovorafenib (Ojemda)

• Dosing, Interactions, etc.

Clinical Context:  Indicated for relapsed or refractory pediatric low-grade glioma (LGG) harboring a BRAF fusion or rearrangement, or BRAF V600 mutation in patients aged 6 months and older. 

• References

Dabrafenib (Tafinlar)

• Dosing, Interactions, etc.

Clinical Context:  Dabrafenib, in combination with trametinib, is indicated in pediatric patients aged 1 year and older for low-grade glioma (LGG) with a BRAF V600E mutation who require systemic therapy.

• References

Class Summary

BRAF V600E mutations activates the BRAF pathway, which includes MEK1 and MEK2. Mitogen-activated extracellular signal regulated kinase 1 (MEK1) and MEK2 activation and of MEK1 and MEK2 kinase activity are regulators of signal-related kinase (ERK) pathway, which promotes cellular proliferation. Inhibiting this pathway decreases tumor growth.

• References

Trametinib (Mekinist)

• Dosing, Interactions, etc.

Clinical Context:  Trametinib, in combination with dabrafenib, is indicated in pediatric patients aged 1 year and older for low-grade glioma (LGG) with a BRAF V600E mutation who require systemic therapy. 

• References

Class Summary

Mitogen-activated extracellular signal regulated kinase 1 (MEK1) and MEK2 activation and of MEK1 and MEK2 kinase activity are regulators of signal-related kinase (ERK) pathway, which promotes cellular proliferation. BRAF V600E mutations activates the BRAF pathway, which includes MEK1 and MEK2. Inhibiting this pathway decreases tumor growth. 

• References

Levetiracetam (Keppra)

• Dosing, Interactions, etc.

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

• References

Phenytoin (Dilantin)

• Dosing, Interactions, etc.

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

• References

Carbamazepine (Tegretol)

• Dosing, Interactions, etc.

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

• References

Class Summary

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

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Temozolomide (Temodar)

• Dosing, Interactions, etc.

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

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Procarbazine (Matulane)

• Dosing, Interactions, etc.

Clinical Context: 

• References

Lomustine (CCNU, Gleostine)

• Dosing, Interactions, etc.

Clinical Context: 

• References

Vincristine

• Dosing, Interactions, etc.

Clinical Context: 

• References

Class Summary

These agents inhibit cell growth and proliferation.

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Dexamethasone (Decadron, AK-Dex, Alba-Dex, Dexone, Baldex)

• Dosing, Interactions, etc.

Clinical Context:  Postulated mechanisms of action in brain tumors include reduction in vascular permeability, cytotoxic effects on tumors, inhibition of tumor formation, and decreased CSF production.

• References

Class Summary

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

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