Glioblastoma

Glioblastoma

While glioblastoma was historically classified as isocitrate dehydrogenase (IDH)-wildtype and IDH-mutant groups, the Consortium to Inform Molecular and Practical Approaches to CNS Tumor Taxonomy (cIMPACT-NOW) and the World Health Organization Classification of Tumors of the Central Nervous System 2021 clearly updated the nomenclature to reflect glioblastoma to be compatible with wildtype IDH status only. Therefore, glioblastoma is now defined as “a diffuse, astrocytic glioma that is IDH-wildtype and H3-wildtype and has one or more of the following histological or genetic features: microvascular proliferationnecrosisTERT promoter mutationEpidermal growth factor receptor gene amplification, +7/-10 chromosome copy-number changes (CNS WHO grade 4) 1).

see Glioblastoma History.

see Glioblastoma epidemiology.

Prior malignancies in patients harboring glioblastoma

Patients who develop GBM following a prior malignancy constitute ~8% of patients with GBM. Despite significant molecular differences these two cohorts appear to have a similar overall prognosis and clinical course. Thus, whether or not a patient harbors a malignancy prior to diagnosis of GBM should not exclude him or her from aggressive treatment or for consideration of novel investigational therapies 2).

see Glioblastoma classification.

Genome-wide profiling studies have shown remarkable genomic diversity among glioblastomas.

Molecular studies have helped identify at least 3 different pathways in the development of glioblastomas.

● 1st pathway: dysregulation of growth factor signaling through amplification and mutational activation of receptor tyrosine kinase (RTK) genes. RTKs are transmembrane proteins that act as receptors for an epidermal growth factor (EGF), vascular endothelial growth factor (VEGF) & platelet-derived growth factor (PDGF). They can also act as receptors for cytokines, hormones, and other signaling pathways

● 2nd pathway: activation of the Phosphoinositide 3 kinase (PI3K)/AKT/mTOR, which is an intracellular signaling pathway that is essential in regulating cell survival

● 3rd pathway: inactivation of the p53 and retinoblastoma (Rb) tumor suppressor pathways

Glioblastomas are intrinsic brain tumors thought to originate from a neuroglial stem or progenitor cells. More than 90% of glioblastomas are isocitrate dehydrogenase (IDH)-wildtype tumors. Incidence increases with age, males are more often affected. Beyond rare instances of genetic predisposition and irradiation exposure, there are no known glioblastoma risk factors.

Glioblastoma biomarker.

see Glioblastoma pathogenesis

Vessels with different microcirculation patterns are required for glioblastoma (GBM) growth. However, details of the microcirculation patterns in GBM remain unclear.

Mei et al. examined the microcirculation patterns of GBM and analyzed their roles in patient prognosis together with two well-known GMB prognosis factors (O6 -methylguanine DNA methyltransferase [MGMT] promoter methylation status and isocitrate dehydrogenase [IDH] mutations).

Eighty GBM clinical specimens were collected from patients diagnosed between January 2000 and December 2012. The microcirculation patterns, including endothelium-dependent vessels (EDVs), extracellular matrix-dependent vessels (ECMDVs), GBM cell-derived vessels (GDVs), and mosaic vessels (MVs), were evaluated by immunohistochemistry (IHC) and immunofluorescence (IF) staining in both GBM clinical specimens and xenograft tissues. Vascular density assessments and three-dimensional reconstruction were performed. MGMT promoter methylation status was determined by methylation-specific PCR, and IDH1/2 mutations were detected by Sanger sequencing. The relationship between the microcirculation patterns and the patient prognosis was analyzed by the Kaplan-Meier method.

All 4 microcirculation patterns were observed in both GBM clinical specimens and xenograft tissues. EDVs was detected in all tissue samples, while the other three patterns were observed in a small number of tissue samples (ECMDVs in 27.5%, GDVs in 43.8%, and MVs in 52.5% tissue samples). GDV-positive patients had a median survival of 9.56 months versus 13.60 months for GDV-negative patients (P = 0.015). In MGMT promoter-methylated cohort, GDV-positive patients had a median survival of 6.76 months versus 14.23 months for GDV-negative patients (P = 0.022).

GDVs might be a negative predictor for the survival of GBM patients, even in those with MGMT promoter methylation 3).

Glioblastoma Pathology.

see Glioblastoma Genetics.

see Glioblastoma growth.

It generally presents with epilepsycognitive declineheadachedysphasia, or progressive hemiparesis4).

Seizures as the presenting symptom of glioblastoma predicted longer survival in adults younger than 60 years. The IDH1 R132H mutation and p53 overexpression (>40%) were associated with seizures at presentation. Seizures showed no relationship with the tumor size or proliferation parameters 5).

see Glioblastoma diagnosis.

Glioblastoma Differential Diagnosis

SHORT score.

see Glioblastoma treatment.

see Glioblastoma outcome

see Ketogenic Diet in glioblastoma

see Glioblastoma complications.

see Glioblastoma case series.

Glioblastoma case reports


1)

Chen J, Han P, Dahiya S. Glioblastoma: Changing concepts in the WHO CNS5 classification. Indian J Pathol Microbiol. 2022 May;65(Supplement):S24-S32. doi: 10.4103/ijpm.ijpm_1109_21. PMID: 35562131.
2)

Zacharia BE, DiStefano N, Mader MM, Chohan MO, Ogilvie S, Brennan C, Gutin P, Tabar V. Prior malignancies in patients harboring glioblastoma: an institutional case-study of 2164 patients. J Neurooncol. 2017 May 27. doi: 10.1007/s11060-017-2512-y. [Epub ahead of print] Review. PubMed PMID: 28551847.
3)

Mei X, Chen YS, Zhang QP, Chen FR, Xi SY, Long YK, Zhang J, Cai HP, Ke C, Wang J, Chen ZP. Association between glioblastoma cell-derived vessels and poor prognosis of the patients. Cancer Commun (Lond). 2020 May 2. doi: 10.1002/cac2.12026. [Epub ahead of print] PubMed PMID: 32359215.
4)

Thomas DGT,Graham DI, McKeran RO,Thomas DGT. The clinical study of gliomas. In: Brain tumours: scientific basis, clinical investigation and current therapy. In: Thomas DGT, Graham DI eds. London: Butterworths, 1980:194–230.
5)

Toledo M, Sarria-Estrada S, Quintana M, Maldonado X, Martinez-Ricarte F, Rodon J, Auger C, Aizpurua M, Salas-Puig J, Santamarina E, Martinez-Saez E. Epileptic features and survival in glioblastomas presenting with seizures. Epilepsy Res. 2016 Dec 26;130:1-6. doi: 10.1016/j.eplepsyres.2016.12.013. [Epub ahead of print] PubMed PMID: 28073027
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