General Information

Clinicopathologic Classification of Childhood Astrocytomas and Other Tumors of Glial Origin
Prognosis
        Low-grade astrocytomas
        High-grade astrocytomas
Disease Presentation

The PDQ childhood brain tumor treatment summaries are organized primarily according to the World Health Organization 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 has decreased by more than 50%.[3] 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.

The pathologic classification of pediatric brain tumors is a specialized area that is undergoing evolution; review of the diagnostic tissue by a neuropathologist who has particular expertise in this area is strongly recommended.

Childhood astrocytomas and other tumors of glial origin are classified according to clinicopathologic and histologic subtype and are histologically graded from grade I to IV according to the World Health Organization’s (WHO) histologic typing of central nervous system (CNS) tumors.[1] 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) and neuronal tumors (with or without an astrocytic component).

WHO histologic grades are commonly referred to as low-grade gliomas or high-grade gliomas (see Table 1).

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 a more aggressive variant and may be more likely to disseminate, and it was reclassified by the WHO as a grade II tumor (see Table 2).[1,2,4]

Childhood astrocytomas and other tumors of glial origin can occur anywhere in the CNS, although each tumor type tends to have preferential CNS locations (see Table 3).

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 has been used retrospectively to predict event-free survival for pilocytic astrocytomas arising in the cerebellum or other location.[5-7]

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.[8,9] 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).[8,9]

Children with neurofibromatosis type 1 (NF1) have an increased propensity to develop WHO grade I and 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.[2,4,10-12] In general, treatment is not required for incidental tumors found with surveillance scans. Symptomatic lesions or those that have radiographically progressed may require treatment.[13]

Genomic alterations involving BRAF are very common in sporadic cases of pilocytic astrocytoma, resulting in activation of the ERK/MAPK pathway. 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.[14-18] This fusion is seen in the majority of infratentorial and midline pilocytic astrocytomas, but is present at lower frequency in supratentorial (hemispheric) tumors.[14,15,19-23] 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.[15,17,18,24] 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.[21] 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.[23] However, other factors such as p16 deletion and tumor location may modify the impact of BRAF mutation on outcome.[25] BRAF activation through the KIAA1549-BRAF fusion has also been described in other pediatric low-grade gliomas (e.g., pilomyxoid astrocytoma).[22,23] 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.[26-28]

Molecular features of pediatric high-grade astrocytomas show some similarities to the genetic aberrations seen in adult glioblastomas that arise from pre-existing lower-grade gliomas (so-called secondary glioblastoma).[29-31] These include a high incidence of TP53 mutations, a low incidence of PTEN and P16^INK4A mutations, and the presence of PDGF/PDGFR overexpression. However, the IDH1 mutations that have been identified in a high proportion of adults with secondary glioblastoma are rarely seen in pediatric glioblastoma.[32,33] While the incidence of IDH1 mutations is low in children, it increases with age in the adolescent and young adult population.[32] Mutations in histone H3.3 (H3F3A) are present in approximately one-third of non–brain stem pediatric high-grade astrocytomas,[33,34] and most of these cases also have TP53 mutations.[33] Pediatric high-grade astrocytomas with H3F3A mutations often additionally have somatic mutations in ATRX, a gene coding for a protein involved in chromatin remodeling.[33] Diffuse intrinsic pontine gliomas show an even higher frequency of H3F3A mutations than do non–brain stem pediatric high-grade astrocytomas, with approximately three-fourths of cases showing mutations.[34,35] Diffuse intrinsic pontine gliomas show a comparably high frequency of TP53 mutations, but IDH1 and IDH2 mutations are rare.[35] These findings suggest that a substantial proportion of pediatric high-grade astrocytomas are associated with processes required for establishing normal chromatin architecture.

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.[36]

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.[1] It rarely arises in the cerebellum and spreads rostrally.[37] 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.[38]

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.[39-44] Tumor spread, when it occurs, is usually by contiguous extension; dissemination to other CNS sites is uncommon, but does occur.[45,46] Although metastasis is uncommon, tumors may be of multifocal origin, especially when associated with NF1.

Unfavorable prognostic features include young age, fibrillary histology, and inability to obtain a complete resection.[47] Elevated MIB-1 labeling index, a marker of cellular proliferative activity, is associated with shortened PFS in patients with pilocytic astrocytoma.[7] A BRAF-KIAA fusion, found in pilocytic tumors, confers a better clinical outcome.[23]

Oligodendrogliomas are rare in children and have a relatively favorable prognosis, with the exception of children younger than 3 years who have less than a gross total resection.[48]

High-grade astrocytomas are often locally invasive and extensive and tend to occur above the tentorium.[39,42] 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. Biologic markers, such as p53 overexpression and mutation status, may be useful predictors of outcome in patients with high-grade gliomas.[4,49,50] 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.[51] Although high-grade astrocytoma carries a generally poor prognosis in younger patients, those with anaplastic astrocytoma and those in whom a gross total resection is possible may fare better.[43,52,53]

Presenting symptoms for childhood astrocytomas depend not only on CNS location, but also size of tumor, rate of growth, and chronologic and developmental age of the child.

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