General Information About Childhood Astrocytomas
Clinicopathologic Classification of Childhood Astrocytomas and Other Tumors of Glial Origin
WHO histologic grade
Neurofibromatosis type 1 (NF1)
The PDQ childhood brain tumor treatment summaries are organized primarily according to the World Health Organization (WHO) classification of nervous system tumors.[1,2] For a full description of the classification of nervous system tumors and a link to the corresponding treatment summary for each type of brain tumor, refer to the PDQ summary on Childhood Brain and Spinal Cord Tumors Treatment Overview.
Dramatic improvements in survival have been achieved for children and adolescents with cancer. Between 1975 and 2002, childhood cancer mortality decreased by more than 50%. Childhood and adolescent cancer survivors require close follow-up because cancer therapy side effects may persist or develop months or years after treatment. Refer to the PDQ summary on Late Effects of Treatment for Childhood Cancer for specific information about the incidence, type, and monitoring of late effects in childhood and adolescent cancer survivors.
Primary brain tumors are a diverse group of diseases that together constitute the most common solid tumor of childhood. Brain tumors are classified according to histology, but tumor location and extent of spread are important factors that affect treatment and prognosis. Immunohistochemical analysis, cytogenetic and molecular genetic findings, and measures of mitotic activity are increasingly used in tumor diagnosis and classification.
Gliomas arise from glial cells that are present in the brain and spinal cord. Gliomas are named according to their clinicopathologic and histologic subtype. For example, astrocytomas originate from astrocytes, oligodendroglial tumors from oligodendrocytes, and mixed gliomas from a mix of oligodendrocytes, astrocytes, and ependymal cells. Astrocytoma is the most commonly diagnosed type of glioma in children. According to the WHO classification of brain tumors, gliomas are further classified into low-grade (grades I and II) and high-grade (grades III and IV) tumors. Children with low-grade tumors have a relatively favorable prognosis, especially when the tumors can be completely resected. Children with high-grade tumors generally have a poor prognosis, unless the tumor is an anaplastic astrocytoma that can be completely resected.Anatomy
Childhood astrocytomas can occur anywhere in the central nervous system (CNS). Refer to Table 3 for the preferential CNS location for each tumor type.Clinical Features
Presenting symptoms for childhood astrocytomas depend on CNS location, size of tumor, rate of growth, and chronologic and developmental age of the child.
In infants and young children, low-grade astrocytomas presenting in the hypothalamus may result in diencephalic syndrome, which is manifested by failure to thrive in an emaciated, seemingly euphoric child. Such children may have little in the way of other neurologic findings, but can have macrocephaly, intermittent lethargy, and visual impairment.Diagnostic Evaluation
The diagnostic evaluation for astrocytoma is often limited to a magnetic resonance imaging (MRI) of the brain or spine. Additional imaging, when clinically indicated, would consist of an MRI of the remainder of the neuraxis.Clinicopathologic Classification of Childhood Astrocytomas and Other Tumors of Glial Origin
The pathologic classification of pediatric brain tumors is a specialized area that is evolving. Examination of the diagnostic tissue by a neuropathologist who has particular expertise in this area is strongly recommended.
Tumor types are based on the glial cell type of origin:
- Astrocytomas (astrocytes).
- Oligodendroglial tumors (oligodendrocytes).
- Mixed gliomas (cell types of origin include oligodendrocytes, astrocytes, and ependymal cells).
- Mixed neuronal-glial tumors.
Childhood astrocytomas and other tumors of glial origin are classified according to clinicopathologic and histologic subtype and are histologically graded (grade I to IV) according to the WHO histologic typing of CNS tumors.
WHO histologic grades are commonly referred to as low-grade gliomas or high-grade gliomas (refer to Table 1).Table 1. World Health Organization (WHO) Histologic Grade and Corresponding Classification for Tumors of the Central Nervous System
|WHO Histologic Grade||Grade Classification|
Table 2. Histologic Grade of Childhood Astrocytomas and Other Tumors of Glial Origin
|Type||WHO Histologic Grade|
|Subependymal giant cell astrocytoma||I|
In 2007, the WHO further categorized astrocytomas, oligodendroglial tumors, and mixed gliomas according to histopathologic features and biologic behavior. It was determined that the pilomyxoid variant of pilocytic astrocytoma may be an aggressive variant that is more likely to disseminate, and it was reclassified as a grade II tumor (refer to Table 2) by the WHO.[1,2,5]CNS location
Childhood astrocytomas and other tumors of glial origin can occur anywhere in the CNS, although each tumor type tends to have preferential CNS locations (refer to Table 3).Table 3. Childhood Astrocytomas and Other Tumors of Glial Origin and Preferential Central Nervous System (CNS) Location
|Tumor Type||Preferential CNS Location|
|Pilocytic astrocytoma||Optic nerve, optic chiasm/hypothalamus, thalamus and basal ganglia, cerebral hemispheres, cerebellum, and brain stem; and spinal cord (rare)|
|Pleomorphic xanthoastrocytoma||Superficial location in cerebrum (temporal lobe preferentially)|
|Diffuse astrocytoma (including fibrillary)||Cerebrum (frontal and temporal lobes), brain stem, spinal cord, optic nerve, optic chiasm, optic pathway, hypothalamus, and thalamus|
|Anaplastic astrocytoma, glioblastoma||Cerebrum; occasionally cerebellum, brain stem, and spinal cord|
|Oligodendrogliomas||Cerebrum (frontal lobe preferentially followed by temporal, parietal, and occipital lobes), cerebellum, brain stem, and spinal cord|
|Oligoastrocytoma||Cerebral hemispheres (frontal lobe preferentially followed by the temporal lobe)|
|Gliomatosis cerebri||Cerebrum with or without brain stem involvement, cerebellum, and spinal cord|
More than 80% of astrocytomas located in the cerebellum are low grade (pilocytic grade I) and often cystic; most of the remainder are diffuse grade II astrocytomas. Malignant astrocytomas in the cerebellum are rare.[1,2] The presence of certain histologic features (e.g., MIB-1 rate, anaplasia) has been used retrospectively to predict event-free survival for pilocytic astrocytomas arising in the cerebellum or other location.[6-8]
Astrocytomas arising in the brain stem may be either high grade or low grade, with the frequency of either type being highly dependent on the location of the tumor within the brain stem.[9,10] Tumors not involving the pons are overwhelmingly low-grade gliomas (e.g., tectal gliomas of the midbrain), whereas tumors located exclusively in the pons without exophytic components are largely high-grade gliomas (e.g., diffuse intrinsic pontine gliomas).[9,10]
High-grade astrocytomas are often locally invasive and extensive and tend to occur above the tentorium in the cerebrum.[11,12] Spread via the subarachnoid space may occur. Metastasis outside of the CNS has been reported but is extremely infrequent until multiple local relapses have occurred.
Gliomatosis cerebri is a diffuse glioma that involves widespread involvement of the cerebral hemispheres in which it may be confined, but it often extends caudally to affect the brain stem, cerebellum, and/or spinal cord. It rarely arises in the cerebellum and spreads rostrally. The neoplastic cells are most commonly astrocytes, but in some cases, they are oligodendroglia. They may respond to treatment initially, but overall have a poor prognosis.Neurofibromatosis type 1 (NF1)
Children with NF1 have an increased propensity to develop WHO grade I and grade II astrocytomas in the visual pathway; approximately 20% of all patients with NF1 will develop a visual pathway glioma. In these patients, the tumor may be found on screening evaluations when the child is asymptomatic or has apparent static neurologic and/or visual deficits. Pathologic confirmation is frequently not obtained in asymptomatic patients, and when biopsies have been performed, these tumors have been found to be predominantly pilocytic (grade I) rather than fibrillary (grade II) astrocytomas.[2,5,15-17]
In general, treatment is not required for incidental tumors found with surveillance scans. Symptomatic lesions or those that have radiographically progressed may require treatment.Genomic alterations
Genomic alterations involving BRAF activation are very common in sporadic cases of pilocytic astrocytoma, resulting in activation of the ERK/MAPK pathway. These include the following:
- BRAF activation in pilocytic astrocytoma occurs most commonly through a gene fusion between KIAA1549 and BRAF, producing a fusion protein that lacks the BRAF regulatory domain.[19-23] This fusion is seen in the majority of infratentorial and midline pilocytic astrocytomas, but is present at lower frequency in supratentorial (hemispheric) tumors.[19,20,24-28] Presence of the BRAF-KIAA1549 fusion predicted for better clinical outcome (progression-free survival [PFS] and overall survival) in one report that described children with incompletely resected low-grade gliomas. However, other factors such as p16 deletion and tumor location may modify the impact of BRAF mutation on outcome. BRAF activation through the KIAA1549-BRAF fusion has also been described in other pediatric low-grade gliomas (e.g., pilomyxoid astrocytoma).[27,28]
- Other genomic alterations in pilocytic astrocytomas that can also activate the ERK/MAPK pathway (e.g., alternative BRAF gene fusions, RAF1 rearrangements, RAS mutations, and BRAF V600E point mutations) are less commonly observed.[20,22,23,30] BRAF point mutations (V600E) are observed in nonpilocytic pediatric low-grade gliomas as well, including approximately two-thirds of pleomorphic xanthoastrocytoma cases and in ganglioglioma and desmoplastic infantile ganglioglioma.[31-33]
As expected, given the role of NF1 deficiency in activating the ERK/MAPK pathway, activating BRAF genomic alterations are uncommon in pilocytic astrocytoma associated with NF1.
Activating mutations in FGFR1 and PTPN11, as well as NTRK2 fusion genes, have also been identified in noncerebellar pilocytic astrocytomas. In pediatric grade II diffuse astrocytomas, the most common alterations reported are rearrangements in the MYB family of transcription factors in up to 53% of tumors.[35,36]High-grade astrocytomas
Pediatric high-grade gliomas, especially glioblastoma multiforme, are biologically distinct from those arising in adults.[37-40] Pediatric high-grade gliomas, compared with adult tumors, less frequently have PTEN and EGFR genomic alterations, and more frequently have PDGF/PDGFR genomic alterations and mutations in histone H3.3 genes. Although it was believed that pediatric glioblastoma multiforme tumors were more closely related to adult secondary glioblastoma multiforme tumors in which there is stepwise transformation from lower-grade into higher-grade gliomas and in which most tumors have IDH1 and IDH2 mutations, the latter mutations are rarely observed in childhood glioblastoma multiforme tumors.[41-43]
Based on epigenetic patterns (DNA methylation), pediatric glioblastoma multiforme tumors are separated into relatively distinct subgroups with distinctive chromosome copy number gains/losses and gene mutations. Two subgroups have identifiable recurrent H3F3A mutations, suggesting disrupted epigenetic regulatory mechanisms, with one subgroup having mutations at K27 (lysine 27) and the other group having mutations at G34 (glycine 34).
- H3F3A mutation at K27: The K27 cluster occurs predominately in mid-childhood (median age, approximately 10 years), is mainly midline (thalamus, brainstem, and spinal cord), and carries a very poor prognosis. These tumors also frequently have TP53 mutations.
- H3F3A mutation at G34: The second H3F3A mutation tumor cluster, the G34 grouping, is found in somewhat older children and young adults (median age, 18 years), arises exclusively in the cerebral cortex, and carries a somewhat better prognosis. The G34 clusters also have TP53 mutations and widespread hypomethylation across the whole genome.
The H3F3A K27 and G34 mutations appear to be unique to high-grade gliomas and have not been observed in other pediatric brain tumors. Both mutations induce distinctive DNA methylation patterns compared with the patterns observed in IDH-mutated tumors, which occur in young adults.[41-45]
Other pediatric glioblastoma multiforme subgroups include the RTK PDGFRA and mesenchymal clusters, both of which occur over a wide age range, affecting both children and adults. The RTK PDGFRA and mesenchymal subtypes are comprised predominantly of cortical tumors, with cerebellar glioblastoma multiforme tumors being rarely observed; they both carry a poor prognosis.Oligodendroglioma
The molecular profile of pediatric patients with oligodendroglioma does not demonstrate deletions of 1p or 19q, as found in 40% to 80% of adult cases. Pediatric oligodendroglioma harbors MGMT gene promoter methylation in the majority of tumors.Prognosis
Low-grade astrocytomas (grade I [pilocytic] and grade II) have a relatively favorable prognosis, particularly for circumscribed, grade I lesions where complete excision may be possible.[11,12,47-50] Tumor spread, when it occurs, is usually by contiguous extension; dissemination to other CNS sites is uncommon, but does occur.[51,52] Although metastasis is uncommon, tumors may be of multifocal origin, especially when associated with NF1.
Unfavorable prognostic features include the following:
- Young age.
- Fibrillary histology.
- Inability to obtain a complete resection.
Elevated MIB-1 labeling index, a marker of cellular proliferative activity, is associated with shortened PFS in patients with pilocytic astrocytoma. A BRAF-KIAA fusion, found in pilocytic tumors, confers a better clinical outcome.
Children with isolated optic nerve tumors have a better prognosis than those with lesions that involve the chiasm or that extend along the visual pathway.[54-57]; [Level of evidence: 3iiC] Children with NF1 also have a better prognosis, especially when the tumor is found in asymptomatic patients at the time of screening.[54,59]High-grade astrocytomas
Biologic markers, such as p53 overexpression and mutation status, may be useful predictors of outcome in patients with high-grade gliomas.[5,60,61] MIB-1 labeling index is predictive of outcome in childhood malignant brain tumors. Both histologic classification and proliferative activity evaluation have been shown to be independently associated with survival.Oligodendrogliomas
Oligodendrogliomas are rare in children and have a relatively favorable prognosis; however, children younger than 3 years who have less than a gross-total resection have a less favorable prognosis.References
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