Neurosurgery Service, Alicante University General Hospital, Alicante Institute for Health and Biomedical Research (ISABIAL - FISABIO Foundation), Alicante, Spain.

Now the diagnosis requires the lack of isocitrate dehydrogenase 1 and 2 mutations (IDH-wildtype) as well as a lack of mutation in Histone H3 (H3-wildtype)

Glioblastomas are hierarchically organized tumors driven by glioma stem cells that retain partial differentiation potential.

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 1).

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.

They are comprised of a heterogeneous population of tumor cells, immune cells, and extracellular matrix.

Interactions among these different cell types and pro-/anti-inflammatory cytokines may promote tumor development and progression.

Histologically, they are characterized by hypercellularity, nuclear pleomorphism, microvascular proliferation, and pseudopalisading necrosis.

Glioblastomas are among the most vascularized tumors in humans. There is also an abnormal vascular remodeling process that leads to microvascular proliferation that is a histopathological hallmark of glioblastoma.

In these tumors, angiogenesis appears to be triggered by expression of vascular endothelial growth factor, an important regulator of tumor blood vessel permeability 2).

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).

see Glioblastoma Genetics.

see Glioblastoma growth.

It generally presents with epilepsy, cognitive decline, headache, dysphasia, or progressive hemiparesis. 4).

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.

A 57-year-old man presented with seizures. Until the seizure onset, he had been treated for thyroid cancer and its metastases to the thoracic vertebral body with the multi-receptor tyrosine kinase inhibitor (RTK) lenvatinib for 4 years. MRI revealed a slightly high intensity lesion in the left frontal base area on T2-weighted or fluid-attenuated inversion recovery (FLAIR) images, and the lesion showed only faint enhancement on T1-weighted images after gadolinium administration. Total resection was performed and the histopathological diagnosis was glioblastoma. However, grade IV histology was observed in only a limited area, and the majority of the specimen showed lower grade histology with moderate vascularization that lacked microvascular proliferation.

Lenvatinib, which is anti-angiogenic, might have affected the radiological characteristics, as well as the pathology of the tumor. Brain tumors arising during treatment with RTKs for other cancers could show atypical imaging findings 6).

59-year-old female patient with previous history of Type 2 diabetes mellitus.Dyslipidemia. Obesity, active smoking, 1 pack / day. Proteinuria> 300 mg / gr with preserved renal function . Chronic anemia. Shoulder capsulitis. Glaucoma,

Admitted from the emergency room due to the finding of a frontoparietal lesion during the study of paresthesias. Self-limited episodes of 1-2 min duration of paresthesia in the right side of the face located in the mouth corner and right nasolabial fold to the eye with a sensation of “tic”. He also presents paresthesias and numbness in the 1st-2nd and 3rd right hands.

Left frontoparietal LOE that appears to be a primary neoplasm, probably of a high-grade glial type, as a first diagostic trait without being able to completely rule out a single mtx. Incidental finding of a well-defined intraconal LOE of the left orbit, which on the image shows a cavernous hemangioma

Postoperative complication: Wound dehiscence.

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.
Thomas AA, Omuro A. Current role of antiangiogenic strategies for glioblas- toma. Curr Treat Options Oncol. 2014;15:551–66.
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.
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.
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.
Arai N, Sasaki H, Tamura R, Obara K, Yoshida K. Unusual magnetic resonance imaging findings of a glioblastoma arising during treatment with lenvatinib for thyroid cancer. World Neurosurg. 2017 Aug 10. pii: S1878-8750(17)31314-1. doi: 10.1016/j.wneu.2017.08.017. [Epub ahead of print] PubMed PMID: 28804045.
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