Astrocytoma

Updated: Dec 08, 2020
  • Author: Benjamin C Kennedy, MD; Chief Editor: Herbert H Engelhard, III, MD, PhD, FACS, FAANS  more...
  • Print
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.

For patient education information, see Brain Cancer.

Next:

Background

Astrocytomas are a form of glioma (ie, a neoplasm of the glial cells, which constitute the supportive tissue of the brain and nervous system). In astrocytomas, 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.

Previous
Next:

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.

Previous
Next:

Etiology

The etiology of diffuse astrocytomas has been the subject of analytic epidemiological studies that have yielded associations with various disorders and exposures. [9]  With the exception of therapeutic irradiation [10]  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. [11, 12, 13, 14, 15]

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. [16]

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 ifound 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. [17]

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). [18]

Previous
Next:

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.

The American Cancer Society estimated that in 2020, 23,890 cases of brain and other nervous system tumors will be diagnosed and over 18,000 deaths will occur. Brain and other nervous system tumors are the second leading cause of cancer death among males younger than 40 years old and females younger than 20 years old. [19]

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) [20] : >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.

Previous
Next:

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. [21]

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 [22] :

  • 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. [23]

Previous