Brain tumors comprise approximately 20% of all childhood malignancies, second only to acute lymphoblastic leukemia in frequency. Astrocytoma is the most common brain tumor (see image shown below), 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.
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. [1, 2]
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. Refer to the image below.
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.
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.
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.
No specific racial predisposition is observed.
The male-to-female ratio is approximately 1:1, except for supratentorial low-grade gliomas, in which it is approximately 2:1.
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.
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