Astrocytoma pathophysiology
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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1];Associate Editor(s)-in-Chief: Shivali Marketkar, M.B.B.S. [2]
Overview
Astrocytomas have a predilection for the cerebrum, cerebellum, hypothalamus, pons, and optic nerve and chiasm. Although astrocytomas have many different histological characteristics, the most common type is the well-differentiated fibrillary astrocytoma. These tumors express glial fibrillary acidic protein (GFAP), which possibly functions as a tumor suppressor[1], and is a useful diagnostic marker in a tissue biopsy. [2]
Pathophysiology
Gross Pathology
- Astrocytoma causes regional effects by compression, invasion, and destruction of brain parenchyma, arterial and venous hypoxia, competition for nutrients, release of metabolic end products (e.g., free radicals, altered electrolytes, neurotransmitters), and release and recruitment of cellular mediators e.g., cytokines) that disrupt normal parenchymal function. Secondary clinical sequelae may be caused by elevated intracranial pressure (ICP) attributable to direct mass effect, increased blood volume, or increased cerebrospinal fluid (CSF) volume.
Microscopic Pathology
- Histologic diagnosis with tissue biopsy will normally reveal an infiltrative character suggestive of the slow growing nature of the tumor. The tumor may be cavitating, pseudocyst-forming, or noncavitating. Appearance is usually white-gray, firm, and almost indistinguishable from normal white matter.
Genetics
Low-Grade Gliomas
- Genomic alterations involving BRAF activation 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 KIAA1549-BRAF gene fusion, producing a fusion protein that lacks the BRAF regulatory domain.[3][4][5][6] This fusion is seen in most 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.[28] However, other factors such as p16 deletion and tumor location may modify the impact of BRAF mutation on outcome.[29] Progression to high-grade glioma is rare for pediatric low-grade glioma with the BRAF-KIAA1549fusion.[30]
- 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.[20,22,23,31] BRAF V600E point mutations 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.[32-34] One retrospective study of 53 children with gangliogliomas demonstrated BRAF V600E staining in approximately 40% of tumors. Five-year recurrence-free survival was worse in the V600E-mutated tumors (about 60%) than in the tumors that did not stain for V600E (about 80%).[35] The frequency of the BRAF V600E mutation was significantly higher in pediatric low-grade glioma that transformed to high-grade glioma (8 of 18 cases) than was the frequency of the mutation in cases that did not transform (10 of 167 cases).[30]
- 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.[26]
- Activating mutations in FGFR1 and PTPN11, as well as NTRK2 fusion genes, have also been identified in noncerebellar pilocytic astrocytomas.[36] 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.[37,38]
- Most children with tuberous sclerosis have a mutation in one of two tuberous sclerosis genes (TSC1/hamartin or TSC2/tuberin). Either of these mutations results in an overexpression of the mTOR complex 1. These children are at risk of developing subependymal giant cell astrocytomas, in addition to cortical tubers and subependymal nodules.
High-Grade Astrocytomas
- Pediatric high-grade gliomas, especially glioblastoma multiforme, are biologically distinct from those arising in adults.[39-42] Pediatric high-grade gliomas, compared with adult tumors, less frequently have PTEN and EGFRgenomic alterations, and more frequently have PDGF/PDGFR genomic alterations and mutations in histone H3.3genes. 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.[43-45]
- 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.[45]
- 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). The subgroups are the following:
- 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. Thalamic high-grade gliomas in older adolescents and young adults also show a high rate of H3F3A K27 mutations.[46
- 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.[47] Both mutations induce distinctive DNA methylation patterns compared with the patterns observed in IDH-mutated tumors, which occur in young adults.[43-45,47,48]
- 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.[45]
- Childhood secondary high-grade glioma (high-grade glioma that is preceded by a low-grade glioma) is uncommon (2.9% in a study of 886 patients). No pediatric low-grade gliomas with the BRAF-KIAA1549 fusion transformed to a high-grade glioma, whereas low-grade gliomas with the BRAF V600E mutations were associated with increased risk of transformation. Approximately 40% of patients (7 of 18) with secondary high-grade glioma had BRAF V600E mutations, with CDKN2A alterations present in 57% of cases (8 of 14).[30]
Oligodendroglioma
- The molecular profile of pediatric patients with oligodendrogliomas rarely demonstrates deletions of 1p and 19q, as found in 40% to 80% of adult cases. When 1p19q codeletion is observed in pediatric oligodendroglioma, it is primarily in patients older than 15 years. Similarly, IDH1 mutations are uncommon in pediatric oligodendroglioma, but when present, are observed primarily in patients older than 15 years.[37,49,50] Like other diffuse pediatric low-grade gliomas, pediatric oligodendrogliomas were noted to have FGFR1 tyrosine kinase domain duplications (3 of 5 cases studied), with an MYB fusion gene observed in one of the two remaining cases.[37]
Histopathological Video
Video
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References
- ↑ M Toda; et al. (1994). "Cell growth suppression of astrocytoma C6 cells by glial fibrillary acidic protein cDNA transfection". Journal of Neurochemistry. 63 (5): 1975–1978. PMID 7931355.
- ↑ JHN Deck; et al. (1978). "The role of glial fibrillary acidic protein in the diagnosis of central nervous system tumors". Acta Neuropathologica. Springer Berlin / Heidelberg. 42 (3): 183–190. doi:10.1007/BF00690355.
- ↑ Bar EE, Lin A, Tihan T, Burger PC, Eberhart CG (2008). "Frequent gains at chromosome 7q34 involving BRAF in pilocytic astrocytoma". J Neuropathol Exp Neurol. 67 (9): 878–87. doi:10.1097/NEN.0b013e3181845622. PMID 18716556.
- ↑ Forshew T, Tatevossian RG, Lawson AR, Ma J, Neale G, Ogunkolade BW; et al. (2009). "Activation of the ERK/MAPK pathway: a signature genetic defect in posterior fossa pilocytic astrocytomas". J Pathol. 218 (2): 172–81. doi:10.1002/path.2558. PMID 19373855.
- ↑ Jones DT, Kocialkowski S, Liu L, Pearson DM, Bäcklund LM, Ichimura K; et al. (2008). "Tandem duplication producing a novel oncogenic BRAF fusion gene defines the majority of pilocytic astrocytomas". Cancer Res. 68 (21): 8673–7. doi:10.1158/0008-5472.CAN-08-2097. PMC 2577184. PMID 18974108.
- ↑ Jones DT, Kocialkowski S, Liu L, Pearson DM, Ichimura K, Collins VP (2009). "Oncogenic RAF1 rearrangement and a novel BRAF mutation as alternatives to KIAA1549:BRAF fusion in activating the MAPK pathway in pilocytic astrocytoma". Oncogene. 28 (20): 2119–23. doi:10.1038/onc.2009.73. PMC 2685777. PMID 19363522.