astrocytoma

Introduction

Background

Astrocytomas are 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 ability to arise at any site in the CNS, with a preference for the cerebral hemispheres; clinical presentation usually in adults; heterogeneous histopathological properties and biological behavior; diffuse infiltration of contiguous and distant CNS structures, regardless of histological stage; and an intrinsic tendency to progress to more advanced grades.

Gross specimen of a low-grade astrocytoma.

Gross specimen of a low-grade astrocytoma.

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

This article focuses on the widely accepted WHO grading scheme that relies on assessments of nuclear atypia, mitotic activity, cellularity, vascular proliferation, and necrosis.2 WHO grade I corresponds to pilocytic astrocytoma, WHO grade II corresponds to low-grade (diffuse) astrocytoma, WHO grade III corresponds to anaplastic astrocytoma, and WHO grade IV corresponds to glioblastoma multiforme (GBM). This article is confined to low-grade and anaplastic astrocytomas. GBM and pilocytic astrocytoma are not discussed in this article (for more information, see Glioblastoma Multiforme).

Pathophysiology

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

Infiltrating low-grade astrocytomas grow slowly compared to their malignant counterparts. Doubling time for low-grade astrocytomas is estimated at 4 times that of anaplastic astrocytomas. Several years often intervene between the initial symptoms and the establishment of a diagnosis of low-grade astrocytoma. One recent series estimated the interval to be approximately 3.5 years. The clinical course is marked by a gradual deterioration in 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,3 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. Compared to low-grade lesions, seizures are less common among patients with anaplastic astrocytomas. Initial presenting symptoms most commonly are headache, depressed mental status, and focal neurological deficits.

Frequency

United States

The annual incidence of glioma in the United States is 5.4 cases per 100,000 population.

International

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, are correlated most highly with the intrinsic properties of the astrocytoma in question. Typical ranges of survival are approximately 10 years from the time of diagnosis for pilocytic astrocytomas (WHO grade I), more than 5 years for patients with low-grade diffuse astrocytomas (WHO grade II),4 2-5 years for those with anaplastic astrocytomas (WHO grade III), and less than 1 year for patients with glioblastoma (WHO grade IV).

Race

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

Sex

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

Age

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

Clinical

History

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

Physical

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

Causes

  • The etiology of diffuse astrocytomas has been the subject of analytic epidemiological studies that have yielded associations with various disorders and exposures.5 With the exception of therapeutic irradiation6 and, perhaps, nitroso compounds (eg, nitrosourea), the identification of specific causal environmental exposures or agents has been unsuccessful.  Although some concern has been raised regarding cell phone use as a potential risk factor for development of gliomas, the largest studies have not supported this.7,8,9,10,11
  • Children receiving prophylactic irradiation for acute lymphatic leukemia (ALL), for example, have a 22-fold increased risk of developing CNS neoplasms in WHO grade II, III, and IV astrocytomas, with an interval for onset of 5-10 years. Furthermore, irradiation of pituitary adenomas has been demonstrated to carry a 16-fold increased risk of glioma formation.12
  • 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.13
  • Recently, attempts have been made to determine prognosis and response to various treatment modalities based on the individual pattern of genetic changes in a particular patient. For example, patients with oligodendrogliomas that exhibit chromosomal changes at band 1p19q are known to have improved responses to the procarbazine, CCNU, vincristine (PCV) regimen of chemotherapy. Efforts are underway to identify similar unique susceptibilities associated with other commonly altered genes and proteins in astrocytomas. Other groups are working on developing models that will allow for a more accurate assessment of prognosis based on a combination of molecular profiling of the tumors and clinical characteristics of the patient.

http://emedicine.medscape.com/article/283453-overview

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