Astrocytoma pathophysiology

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Fahimeh Shojaei, M.D., Shivali Marketkar, M.B.B.S. [2], Ammu Susheela, M.D. [3]

Overview[edit | edit source]

The exact pathogenesis of astrocytoma is not completely understood but it is believed that this tumor has a close association with genetic mutations. Microscopic pathologic findings in pilocytic astrocytoma include normal cells with slow growth rate, biphasic pattern (dense fibrillar tissue within loose myxoid tissue), calcification, vascular hyalinization, and nested fibrotic pattern. In diffuse astrocytoma, we may see atypical cells, relatively slow mitosis rate, diffusely infiltrate neuropil and poorly defined cytoplasm. In anaplastic astrocytoma, we may see pleomorphic and malignant cells, high mitosis rate, hyperchromatosis, and prominent small vessels. In glioblastoma multiform, we may see pleomorphic cells, naked nuclei, multi-focal necrosis, pseudopalisading pattern, scattered pyknotic nuclear debris in the center, micro-vascular proliferation, and vascular thrombi.

Pathophysiology[edit | edit source]

• The exact pathogenesis of astrocytoma is not completely understood but it is believed that this tumor has a close association with genetic mutations.^[1]
• The origin of this tumor is from neuroepithelial cells.

Associated conditions[edit | edit source]

• There are no conditions associated with astrocytoma.

Genetics[edit | edit source]

Low-Grade Astrocytomas[edit | edit source]

• Genomic alterations involving BRAF activation are very common in sporadic cases of pilocytic astrocytoma, resulting in activation of the ERK/MAPK pathway.^[2][3][4][5]
• BRAF activation in pilocytic astrocytoma occurs most commonly through a KIAA1549-BRAF gene fusion, producing a fusion protein that lacks the BRAF regulatory domain.
• This fusion is seen in most infratentorial and midline pilocytic astrocytomas, but is present at lower frequency in supratentorial (hemispheric) tumors.^{[6][7][8][9][10]}
• 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.^[11]
• Other factors such as p16 deletion and tumor location may modify the impact of BRAF mutation on outcome.
• Progression to high-grade glioma is rare for pediatric low-grade glioma with the BRAF-KIAA1549 fusion.^[12]
• BRAF activation through the KIAA1549-BRAF fusion has also been described in other pediatric low-grade gliomas (e.g.,pilomyxoid astrocytoma).
• Other genomic alterations in pilocytic astrocytomas that may 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.^[13]
• BRAF V600E point mutations are observed in nonpilocytic pediatric low-grade gliomas as well, including approximately two-thirds of pleomorphic xanthoastrocytoma patients and in ganglioglioma and desmoplastic infantile ganglioglioma patients.
• A 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%).
• 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) compared to the frequency of the mutation in cases that did not transform (10 of 167 cases).^[14]
• 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 non-cerebellar 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.^[15]

High-Grade Astrocytomas[edit | edit source]

• Pediatric high-grade gliomas, especially glioblastoma multiforme, are biologically distinct from those arising in adults.^{[16][17][18][19]}
• Pediatric high-grade gliomas, compared with adult tumors, are more frequently associated with PDGF/PDGFR genomic alterations and mutations in histone H3.3genes and less frequently with PTEN and EGFR genomic alterations.
• Although, it was believed that pediatric glioblastoma multiforme tumors were more closely related to adult secondary glioblastoma multiforme tumors in which there is step-wise transformation from lower-grade into higher-grade gliomas with tumors having IDH1 and IDH2 mutations, the latter mutations are rarely observed in childhood glioblastoma multiforme tumors.^[20][21]
• 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.^[22]
• 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.
  • H3F3A mutation at G34: The second H3F3A mutation tumor cluster, the G34 grouping, is found in older children and young adults (median age, 18 years), arises exclusively in the cerebral cortex, and carries a 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.^[23] Both mutations induce distinctive DNA methylation patterns compared with the patterns observed in IDH-mutated tumors, which occur in young adults.^[24]
• 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.
• 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).

Gross Pathology[edit | edit source]

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 sequel may be caused by elevated intracranial pressure (ICP) attributable to direct mass effect, increased blood volume, or increased cerebrospinal fluid (CSF) volume.[25]

Microscopic Pathology[edit | edit source]

Pathological findings diagnostic of astrocytoma include:^{[26][27][28][29]}

Pilocytic Cells appearance is normal and growth rate is slow. Biphasic pattern (dense fibrillar tissue within loose myxoid tissue) Calcification Vascular hyalinization Nested fibrotic pattern
Diffuse There might be some atypical cells inside tumor Mitosis rate is relatively slow Diffusely infiltrate neuropil Poorly defined cytoplasm
Anaplastic: Tumor cells are pleomorphic and malignant High mitosis rate Hyperchromatosis Prominent small vessels
Glioblastoma Pleomorphic cells Naked nuclei Multi-focal necrosis Pseudopalisading pattern Scattered pyknotic nuclear debris in the center Micro-vascular proliferation Vascular thrombi

Histopathological Video[edit | edit source]

Video[edit | edit source]

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References[edit | edit source]

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