Glioblastoma multiforme pathophysiology: Difference between revisions

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Revision as of 04:21, 28 February 2019

Glioblastoma multiforme Microchapters

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]Associate Editor(s)-in-Chief: Marjan Khan M.B.B.S.[2]

Overview

Genes involved in the pathogenesis of glioblastoma multiforme include Mdm2, PTEN, IDH1, p53, EGFR, PDGFRA, and chromosomes 10p, 10q, 17p, and 19q. On gross pathology, the characteristic findings of glioblastoma multiforme include a poorly-marginated, diffusely infiltrating, firm or gelatinous mass with a central necrotic core. On microscopic histopathological analysis, the characteristic findings of glioblastoma multiforme include pleomorphic astrocytes with marked atypia, mitosis, necrosis, and microvascular proliferation.

Pathophysiology

Pathogenesis

Molecular alterations

  • There are four subtypes of glioblastoma multiforme.[1]
  • Tumors in the "classical" subtype is characterized by mutations in EGFR.
  • The "proneural" subtype often has high rates of alterations in TP53, PDGFRA, and IDH1.
  • The "mesenchymal" subtype is characterized by mutations in NF1, and EGFR.
  • The "neural" subtype has several mutations in many of the same genes as the other groups.
  • Majority of the genetic alterations in glioblastoma multiforme are clustered in three pathways: p53, Rb, and PI3K/AKT.
  • Another important alteration is methylation of MGMT, a suicide DNA repair enzyme. Methylation is described to impair DNA transcription and therefore, expression of the MGMT enzyme. Since MGMT can only repair one DNA alkylation due its suicide repair mechanism, reverse capacity is low and methylation of the MGMT gene promoter greatly affects DNA repair capacity. Hence, MGMT methylation is associated with an improved response to treatment with DNA-damaging chemotherapeutics, such as temozolomide.

Glioblastoma multiforme stem-like cells

  • Cancer cells with stem cell-like properties have been found to be a cause of resistance to conventional treatment and high recurrence rate of glioblastoma multiforme.
  • A biomarker that exhibits cancer stem cell properties, Hes3, has been shown to regulate cells of glioblastoma multiforme when placed in culture.

Metabolism

  • The IDH1 gene is frequently mutated in glioblastoma multiforme (primary: 5%, secondary: 80%). By producing very high concentrations of the oncometabolite D-2-hydroxyglutarate and dysregulating the function of the wild-type IDH1-enzyme, it induces profound changes to the metabolism of IDH1-mutated glioblastoma multiforme compared with IDH1 wild-type glioblastoma multiforme or healthy astrocytes.
  • The IDH1 mutation increases the dependence of glioblastoma multiforme on glutamine or glutamate as an energy source. Since healthy astrocytes excrete glutamate, IDH1-mutated glioblastoma multiforme cells do not favor dense tumor structures but instead migrate, invade and disperse into healthy parts of the brain where glutamate concentrations are higher. This may explain the invasive behaviour of these IDH1-mutated glioblastoma multiforme.

Ion channels

  • Glioblastoma multiforme exhibits numerous alterations in genes that encode for ion channels, including upregulation of gBK potassium channels and ClC-3 chloride channels.
  • Upregulating these ion channels, the tumor cells can facilitate increased ion movement over the cell membrane, thereby increasing H2O movement through osmosis, which aids the tumor cells in changing cellular volume very rapidly. This is helpful in their extremely aggressive invasive behavior, because quick adaptations in cellular volume can facilitate movement through the extracellular matrix of the brain.

Genetics

  • Development of glioblastoma multiforme is the result from multiple genetic mutations.
  • Genes involved in the pathogenesis of glioblastoma multiforme include the following:[2]
Types of glioblastoma multiforme Genes
Primary​
Secondary
  • IDH1
  • p53
  • Gene on chromosome 10q
  • Gene on chromosome 17p
  • Gene on chromosome 19q
Classic
Proneural
Mesenchymal

Associated Conditions

Glioblastoma multiforme may be associated with:[2]

Pathology

Gross Pathology

On gross pathology, the characteristic findings of glioblastoma multiforme include:[2][3]

Microscopic Pathology

On microscopic histopathological analysis, the characteristic findings of glioblastoma multiformes include:[2][3]

According to WHO classification of brain tumors, glioblastoma multiforme is termed as grade IV tumor.[2]

Immunohistochemistry

Glioblastoma multiforme is demonstrated by positivity to tumor markers such as GFAP.[2]

References

  1. Verhaak RG, Hoadley KA, Purdom E, Wang V, Qi Y, Wilkerson MD; et al. (2010). "Integrated genomic analysis identifies clinically relevant subtypes of glioblastoma multiforme characterized by abnormalities in PDGFRA, IDH1, EGFR, and NF1". Cancer Cell. 17 (1): 98–110. doi:10.1016/j.ccr.2009.12.020. PMC 2818769. PMID 20129251.
  2. 2.0 2.1 2.2 2.3 2.4 2.5 Pathology of Glioblastoma multiforme. Dr Dylan Kurda and Dr Frank Gaillard et al. Radiopaedia 2015. http://radiopaedia.org/articles/Glioblastoma
  3. 3.0 3.1 Pathology of Glioblastoma multiforme. Libre Pathology. http://librepathology.org/wiki/index.php/Glioblastoma


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