eMedicine Specialties > Pediatrics: General Medicine > Oncology

Astrocytoma

Author: Tobey MacDonald, MD, Clinical Director of Neuro-Oncology, Children's Hospital National Medical Center; Associate Professor, Department of Pediatric Hematology-Oncology, George Washington University
Coauthor(s): Roger J Packer, MD, Executive Director, Neuroscience and Behavioral Medicine, Director, Brain Tumor Institute, Children's National Medical Center; Professor of Neurology and Pediatrics, The George Washington University
Contributor Information and Disclosures

Updated: Feb 11, 2009

Introduction

Background

Brain tumors comprise approximately 20% of all childhood malignancies, second only to acute lymphoblastic leukemia in frequency. Astrocytoma is the most common brain tumor, accounting for more than half of all primary CNS malignancies.

Astrocytomas comprise a wide range of neoplasms that differ in their location within the CNS, growth potential, extent of invasiveness, morphological features, tendency for progression, and clinical course. The following clinicopathologic entities can be distinguished: pilocytic astrocytoma (World Health Organization [WHO] grade I), diffuse astrocytoma (WHO grade II), anaplastic astrocytoma (WHO grade III), and glioblastoma multiforme (WHO grade IV).

Most astrocytomas are indolent low-grade (ie, WHO grade I-II) tumors that predominantly arise in midline locations, such as the cerebellum and diencephalic region, including the visual pathway and hypothalamus. Those remaining are malignant high-grade (ie, WHO grade III-IV) tumors that are generally found in the cerebral hemispheres or pontine areas of the brain stem. Patients with hemispheric astrocytomas clinically present with seizures; however, these tumors are more likely to be low-grade. Astrocytomas of the midbrain and medulla are also more likely to be low-grade. Spinal cord astrocytomas are less common and may be either high-grade or low-grade.

Most cases occur in the first decade of life, with the peak age at 5-9 years. Surgical resection alone is sufficient to cure most low-grade astrocytomas; however, the prognosis remains poor for high-grade astrocytomas in spite of the addition of radiotherapy and chemotherapy.

Pathophysiology

Increasing evidence indicates that the differences between the clinicopathologic entities of astrocytoma (ie, WHO grades I-IV) reflect the type and sequence of genetic alterations acquired during the process of transformation.

Pilocytic astrocytomas (ie, WHO grade I) arise throughout the neuraxis, but preferred sites include the optic nerve, optic chiasm/hypothalamus, thalamus and basal ganglia, cerebral hemispheres, cerebellum, and brain stem. These tumors show low cellularity, low proliferative and mitotic activity, and rarely metastasize or undergo malignant transformation. In general, they do not aggressively infiltrate surrounding tissue and regressive changes in long-standing lesions are common. These tumors are the principle CNS neoplasm of neurofibromatosis type 1 (NF1). Findings on cytogenetic analysis are typically normal, although gains of chromosomes 7 and 8 are observed in one third of tumors. Mutational inactivation of the TP53 gene does not appear to play a role in the evolution of this tumor.

Pilomyxoid astrocytoma (PMA) is a recently defined variant of pediatric low-grade astrocytoma. PMAs have been classified with pilocytic astrocytomas but have been found to have different histologic features and to behave more aggressively than pilocytic astrocytomas. PMAs have a tendency to disseminate and, in some reports, have a worse prognosis compared with pilocytic astrocytomas.

Diffuse astrocytomas (ie, WHO grade II) may arise in any area of the CNS but most commonly develop in the cerebrum, particularly the frontal and temporal lobes. The brain stem and spinal cord are the next most frequently affected sites, whereas the cerebellum is a distinctly uncommon site. These tumors are moderately cellular, infiltrative, and often enlarging, which distorts but does not destroy neighboring anatomical structures. Mitotic activity is generally absent. TP53 mutations and overexpression of the platelet-derived growth factor receptor are the principal associated genetic alterations, although these findings are more frequently observed in adults than in children.

Anaplastic astrocytoma (ie, WHO grade III) arises in the same locations as diffuse astrocytomas, with a preference for the cerebral hemispheres. These tumors show increased cellularity, distinct nuclear atypia, marked mitotic activity, and a tendency to infiltrate through neighboring tissue. A high frequency of TP53 and PTEN mutations has been recognized in adult tumors, with pediatric tumors showing much less.

Glioblastoma multiforme (ie, WHO grade IV) tumors occur most often in the subcortical white matter of the cerebral hemispheres. Combined frontotemporal location with infiltration into the adjacent cortex, basal ganglia, and contralateral hemisphere is typical. Glioblastoma is the most frequent tumor of the brain stem in children, while the cerebellum and spinal cord are rare sites. These tumors are highly cellular, with high proliferative and mitotic activity. Although rapid and extensive invasion of surrounding tissue is common, distant metastasis within or outside the CNS is rare.

Pediatric glioblastomas have a pattern of genetic alterations different from that in adults. Although TP53 mutations and loss of heterozygosity (LOH) on 17p is observed in pediatric tumors, the frequency is much less. Overexpression of p53 protein has been associated with worse clinical outcome in pediatric high-grade astrocytomas. Other studies have shown that overexpression of the epidermal growth factor receptor (EGFR) is observed in most pediatric high-grade astrocytomas, but this does not appear to be associated with outcome. EGFR amplification, which is commonly seen in adult high-grade astrocytomas, has been described in diffuse pontine gliomas of childhood but is otherwise a rare event in the pediatric tumors. However, LOH on chromosome 10 occurs at a high frequency in both adults and children, supporting the view that LOH on chromosome 10 is instrumental to the development of glioblastoma.

Frequency

United States

Astrocytoma is the most common brain tumor of childhood. Researchers report that the annual incidence is approximately 14 new cases per million children younger than 15 years.

Mortality/Morbidity

In low-grade astrocytomas, complete surgical resection is associated with 5-year survival rates as high as 95-100% without further treatment. Patients with subtotal resections may have only a 60-80% survival rate over similar periods; however, after partial resection, long-term progression-free intervals may ensue. Current operative mortality rates are less than 1%. Morbidity depends largely on tumor location and is highest in diencephalic tumors, in which the incidence of hemiparesis or visual field deficits may be 10-20%. Cortical-based tumors may be associated with seizures.

In high-grade astrocytomas, the most recent 5-year survival rate is 15-30% for supratentorial lesions and less than 10% for pontine tumors. Neurologic morbidity, such as neurocognitive impairment, neuroendocrinologic deficiency, motor and coordination impairment, and cranial nerve dysfunction may occur from tumor invasion, surgical resection, and/or treatment with radiation and chemotherapy. Seizure disorders may develop depending on the tumor location.

Race

No specific racial predisposition is observed.

Sex

The male-to-female ratio is approximately 1:1, except for supratentorial low-grade gliomas, in which it is approximately 2:1.

Age

Most cases occur in the first decade of life, with the peak incidence occurring in children aged 5-9 years. High-grade supratentorial tumors occur slightly later, with a median age at diagnosis of 9-10 years.

Clinical

History

Patients often report a history of illness for more than 3 months prior to diagnosis.

• Increased intracranial pressure
  • Initial symptoms are usually nonspecific, nonlocalizing, and related to increased intracranial pressure (ICP). These signs occur in as many as 75% of patients regardless of tumor location.
  • The classic triad of a raised ICP consists of morning headaches, vomiting, and lethargy. The headache is characterized by pain upon arising that is relieved by vomiting and lessens during the day.
  • School-aged children more commonly report vague intermittent headaches and fatigue. They may have a declining academic performance and may exhibit personality changes.
  • Infants may present with irritability, anorexia, developmental delay, or regression.
• Seizures: Seizures are present at diagnosis in at least 25% of patients with supratentorial astrocytomas. They may precede diagnosis by several months to 1-2 years.
• Signs related to tumor location
  • Focal motor deficits occur in as many as 60% of patients with hemispheric and central diencephalic tumors. They are more common in individuals with high-grade gliomas.
  • Seizures occur in 30-50% of children, may be focal, and are a more common presenting finding in low-grade gliomas.
  • Hypothalamic tumors may be associated with neuroendocrine abnormalities, growth hormone deficiency, diabetes insipidus, and precocious pubertal development. These tumors may also impinge on the optic chiasm, resulting in optic atrophy and visual deficits.
  • Patients with diencephalic tumors may present with the classic diencephalic syndrome (ie, emesis, emaciation, unusual euphoria), but the syndrome is rare in children older than 3 years.
  • Patients with astrocytomas of the cerebellum may present with weakness, dysmetria, tremor, and ataxia.
  • Astrocytomas of the brain stem are characterized by the presence of isolated cranial nerve deficits and contralateral hemiparesis.
  • Astrocytomas of the visual pathways may be brought to medical attention because of strabismus, proptosis, nystagmus, or developmental delay. Young children rarely report the slow and progressive visual loss characteristic of these tumors. Infants frequently display head tilt, head bobbing, and nystagmus. Astrocytomas in children with neurofibromatosis type 1 (NF1) may be asymptomatic at the time of diagnosis and may be detected on screening studies.
  • Patients with astrocytomas of the spinal cord most frequently present with pain (70% of patients have pain localized to the vertebral segments adjacent to the tumor), weakness, gait disturbance, and sphincter dysfunction. Paresthesias and loss of sensation occur later in the disease course.

Physical

• Increased intracranial pressure
  • A funduscopic examination reveals papilledema. Infants may have only optic pallor.
  • Palsy of cranial nerve VI is common and results in the inability to abduct one or both eyes.
  • Infants may demonstrate the setting sun sign, observed as an impaired upgaze and a forced downward deviation of both eyes. Measurement of head circumference in infants with open sutures may reveal macrocephaly.
• Other signs
  • Strength and motor testing may reveal weakness and monoplegia or hemiplegia.
  • Localized deficits in truncal steadiness, upper extremity coordination, and gait may be observed with tumors of the posterior fossa and basal ganglia.
  • Multiple and bilateral cranial nerve deficits, especially VI and VII; long tract signs; and ataxia are associated with brainstem tumors.
  • Visual acuity is frequently reduced to less than 20/200 with optic gliomas. The pattern of visual loss in those patients with intraorbital tumors is most commonly a decrease in central vision, whereas bitemporal hemianopsia is most often noted in those patients with chiasmatic tumors. The involved eye generally shows optic pallor and nystagmus. Mild proptosis is usually present with primary intraorbital tumors.
  • Spinal astrocytomas often cause weaknesses of a variable extent and severity, ranging from monoparesis to quadriparesis. Pain along the involved vertebral segment may occur when the patient sneezes or coughs. Papilledema and hydrocephaly are present in 15% of patients and are attributed to increased cerebrospinal fluid (CSF) viscosity from an elevated protein content.

Causes

• Epidemiologic studies investigating parental occupational exposure, environmental exposure, and maternal nutritional intake failed to identify linkages with any of the childhood brain tumors.
• An association with NF1 is present in 50-80% of patients with isolated optic nerve astrocytomas and in as many as 20% of those with chiasmal or deeper optic tract tumors. NF1 and tuberous sclerosis are also associated with other low-grade astrocytomas. Twenty percent of children with NF1 have low-grade gliomas, especially visual pathway tumors.
• Astrocytoma is the most frequent CNS tumor in people with the Li-Fraumeni syndrome (germline mutation of the p53 tumor suppressor gene on the short arm of chromosome 17).
• Ionizing radiation to the head for prior malignancies causes secondary supratentorial malignant astrocytomas in a small number of patients.

• Search for CME/CE on This Topic »

• Astrocytoma (Oncology)
• Juvenile Pilocytic Astrocytoma (Radiology)
• Astrocytoma, Brain (Radiology)
• Low-Grade Astrocytoma (Neurology)

• Glioblastoma Multiforme Has 4 Distinct Molecular Subtypes

• Role of Stereotactic Radiosurgery and Fractionated Stereotactic Radiotherapy for the Treatment of Recurrent Glioblastoma Multiforme
• Resistance: Aggravating the Aggressor
• A Novel Target for Glioblastoma Therapy

• Brain Cancer Resource Center