Table 3. Childhood Astrocytomas and Other Tumors of Glial Origin and Preferential Central Nervous System (CNS) Location continued...
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.[2,4,10,11,12] In general, treatment is not required for incidental tumors found with surveillance scans. Symptomatic lesions or those that have radiographically progressed may require treatment.
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.[14,15,16,17,18] This fusion is seen in the majority of infratentorial and midline pilocytic astrocytomas, but is present at lower frequency in supratentorial (hemispheric) tumors.[14,15,19,20,21,22,23] 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. 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).[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.[26,27,28]