====== Glioblastoma ======

//[[J.Sales-Llopis]]//

//Neurosurgery Department, [[General University Hospital Alicante]], [[Spain]].//

{{ ::glioblastoma.jpg?300|}}

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===== Definition =====

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]] 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 proliferation]], [[necrosis]], [[TERT promoter mutation]], [[Epidermal growth factor receptor]] [[gene amplification]], +7/-10 [[chromosome]] copy-number changes (CNS WHO grade 4)
((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.)).

===== History =====

see [[Glioblastoma History]].

===== Epidemiology =====

see [[Glioblastoma epidemiology]].

**Prior malignancies in patients harboring glioblastoma**

Patients who develop Glioblastoma following a prior malignancy constitute ~8% of patients with Glioblastoma. 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 Glioblastoma should not exclude him or her from aggressive treatment or for consideration of novel investigational therapies
((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.)).

===== Classification =====

see [[Glioblastoma classification]].

===== Glioblastoma cell lines =====

[[Glioblastoma cell lines]].

===== Glioblastoma stem-like cells =====

[[Glioblastoma stem-like cells]]

===== Glioblastoma biology =====

[[Glioblastoma biology]].

===== Pathogenesis =====

see [[Glioblastoma pathogenesis]].

===== Pathophysiology =====

[[Glioblastoma Pathophysiology]].

===== Molecular pathways in the development of glioblastoma =====

[[Genome-wide profiling]] studies have shown remarkable [[genomic]] diversity among [[glioblastoma]]s.

[[Molecular]] studies have helped identify at least 3 different [[pathway]]s in the development of glioblastomas.

● 1st pathway: dysregulation of [[growth factor]] [[signalling]] through [[amplification]] and mutational activation of [[receptor tyrosine kinase]] (RTK) genes. [[RTK]]s are [[transmembrane protein]]s 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 [[cytokine]]s, [[hormone]]s, and other [[signaling pathway]]s

● 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

===== Risk factors =====
[[Glioblastoma]]s are [[intrinsic]] brain tumors thought to originate from a [[neuroglia]]l stem or [[progenitor cell]]s. 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.

===== Biomarkers =====

[[Glioblastoma biomarkers]].

==== Microcirculation patterns ====

[[Vessel]]s with different [[microcirculation]] patterns are required for [[glioblastoma]] (Glioblastoma) growth. However, details of the microcirculation patterns in Glioblastoma remain unclear. 

Mei et al. examined the microcirculation patterns of Glioblastoma 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 Glioblastoma 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), Glioblastoma cell-derived vessels (GDVs), and mosaic vessels (MVs), were evaluated by [[immunohistochemistry]] (IHC) and immunofluorescence (IF) staining in both Glioblastoma 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 Glioblastoma 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 Glioblastoma patients, even in those with MGMT promoter methylation
((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.
)).

===== Pathology =====

[[Glioblastoma Pathology]].

===== Genetics =====

see [[Glioblastoma Genetics]].

===== Growth =====

see [[Glioblastoma growth]].

===== Radioresistance =====

[[Glioblastoma Radioresistance]]

===== Clinical Features =====
It generally presents with [[epilepsy]], [[cognitive decline]], [[headache]], [[dysphasia]], or progressive [[hemiparesis]].
((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.)).

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
((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.
)).

===== Diagnosis =====

see [[Glioblastoma diagnosis]].

===== Differential diagnosis =====
[[Glioblastoma Differential Diagnosis]]

===== Scores =====

[[SHORT score]].

===== Treatment =====

see [[Glioblastoma treatment]].

===== Prognosis =====
see [[Glioblastoma prognosis]]


===== Diet =====
see [[Ketogenic Diet in glioma]].

===== Complications =====

see [[Glioblastoma complications]].

===== Glioblastoma Research =====
[[Glioblastoma Research]]

===== Systematic reviews =====

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===== Comprehensive reviews =====

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Although great efforts have been made by clinicians and researchers, no significant improvement in survival has been achieved since the [[Stupp protocol]] became the [[standard of care]] (SOC) in [[2005]]. Despite [[multimodality]] treatments, recurrence is almost universal with survival rates under 2 years after diagnosis. 
Obrador et al. from Scientia BioTech S.L discuss the recent progress in our understanding of [[glioblastoma pathophysiology]], in particular, the importance of [[glioma stem cell]]s (GSCs), the [[tumor microenvironment]] conditions, and [[epigenetic]] mechanisms involved in growth, aggressiveness, and [[glioblastoma recurrence]]. The [[discussion]] on therapeutic strategies first covers the SOC treatment and targeted therapies that have been shown to interfere with different [[signaling pathway]]s ([[pRB]]/[[CDK4]]/[[RB1]]/[[P16]]ink4, [[TP53]]/[[MDM2]]/[[P14arf]], [[PI3k]]/[[Akt]]-[[PTEN]], [[RAS]]/[[RAF]]/[[MEK]], [[PARP]]) involved in GB [[tumorigenesis]], [[pathophysiology]], and treatment resistance acquisition. 
They analyze several immunotherapeutic approaches (i.e., [[checkpoint inhibitor]]s, [[vaccine]]s, [[CAR]]-modified NK or [[T cell]]s, [[oncolytic virotherapy]]) that have been used in an attempt to enhance the [[immune response]] against GB, and thereby avoid recidivism or increase survival of GB patients. Finally, they present treatment attempts made using nanotherapies (nanometric structures having active anti-GB agents such as antibodies, chemotherapeutic/anti-angiogenic drugs or [[sensitizer]]s, [[radionuclide]]s, and molecules that target GB cellular receptors or open the [[blood-brain barrier]]) and non-ionizing energies ([[laser interstitial thermal therapy]], high/low intensity [[focused ultrasound]]s, [[photodynamic therapy]]/sonodynamic therapies and [[electroporation]])
((Obrador E, Moreno-Murciano P, Oriol-Caballo M, López-Blanch R, Pineda B, Gutiérrez-Arroyo JL, Loras A, Gonzalez-Bonet LG, Martinez-Cadenas C, Estrela JM, Marqués-Torrejón MÁ. [[Glioblastoma]] [[Therapy]]: Past, Present and Future. Int J Mol Sci. 2024 Feb 21;25(5):2529. doi: 10.3390/ijms25052529. PMID: 38473776.)).



===== Retrospective observational studies =====
The purpose of a study by Vivancos Sánchez et al. was to assess the clinical [[impact]] of [[next-generation sequencing]] (NGS), as an increasingly available and advantageous [[tool]], for [[glioblastoma]] patients.
[[Adult patient]]s aged less than 65, and surgically treated for glioblastoma between 2010-2021, were included. Tumor [[sample]]s were analyzed with NGS using the Oncomine Comprehensive v3 (OCA) panel and Ion Reporter Genexus v5.9.1 (Thermo Fisher Scientific). 
Thirty-two patients were included, with a median age of 47.7 years and a median [[overall survival]] of 25 months. Identification of mutations by NGS resulted in a change in diagnosis in two cases. In all patients but one, at least one genetic alteration was detected (median of three per patient), most commonly [[EGFR]] [[amplification]]. In 93.7% of patients, biomarkers that make them potentially eligible for a [[clinical trial]] were found. No [[survival]] differences were seen regarding genetic alterations, although a trend towards better survival for those patients without [[CDK4]] mutation was observed (p = 0.088). 
The use of NGS provides useful information for diagnosis, especially in young patients, and it will probably become valuable for clinical [[decision-making]] as more therapeutic targets and treatments emerge. For the moment, it is crucial for scientific progress to happen
((Vivancos Sánchez C, Esteban Rodríguez MI, Peláez García A, Taravilla-Loma M, Rodríguez-Domínguez V, Rodríguez-Antolín C, Rosas-Alonso R, Losantos-García I, Isla Guerrero A, Gandía-González ML. Clinical Impact of a Next-Generation Sequencing Approach for Glioblastoma Patients. Cancers (Basel). 2025 Feb 22;17(5):744. doi: 10.3390/cancers17050744. PMID: 40075591.)).
----
This study reinforces the diagnostic and research utility of NGS in GBM, particularly in identifying trial-eligible patients. However, its clinical impact remains marginal, as no clear therapeutic benefit is demonstrated. Future research should focus on larger, multi-center cohorts, integrative molecular profiling (RNA-seq, methylation, proteomics), and prospective studies linking NGS findings to actual therapeutic interventions.

===== Case series =====

see [[Glioblastoma case series]].

===== Case reports =====

[[Glioblastoma case reports]].

===== Case report from the HGUA =====

A 26-year-old woman with a history of smoking, childhood hiccup spasms, nephritic colics, and a diagnosis of fibromyalgia since adolescence. The patient experienced persistent right-sided hemibody sensory disturbance, including dysesthesias, hypoesthesia, and hyperalgesia, over the past 6 months. Initial evaluation revealed a left hemispheric lesion on neuroimaging, prompting differential diagnoses of neoplasia, venous infarction, and demyelinating lesion. The patient was admitted to the Neurology department for further evaluation. Brain MRI findings indicated a low-grade glial primary neoplasia, primarily located in the frontal region with extension to the left parietal and temporal regions. She subsequently underwent a craniotomy and probable subtotal resection of the left frontal lesion using (MNIO). The histological examination confirmed the diagnosis of glioblastoma. Follow-up MRI revealed a significant increase in the size of the lesion. Further evaluation and monitoring are recommended to assess disease progression and guide treatment decisions.

Introduction:
Glioblastoma is a malignant primary brain tumor that arises from glial cells, commonly exhibiting aggressive behavior and poor prognosis. Its occurrence in young adults, like our patient, is relatively uncommon. The combination of persistent hemibody sensory disturbances and the identification of a left hemispheric lesion on neuroimaging necessitated further investigations to establish an accurate diagnosis and determine appropriate management.

Case Presentation:
A 26-year-old woman with a history of smoking and childhood hiccup spasms, nephritic colics, and fibromyalgia since adolescence presented with a new onset of persistent right-sided hemibody sensory disturbances. These symptoms included abnormal sensations (dysesthesias), reduced sensitivity to touch or pain (hypoesthesia), and increased sensitivity to pain (hyperalgesia). The patient sought medical attention due to the progressive and distressing nature of her symptoms.

Clinical Course:
The patient was initially evaluated in a private clinic, and a brain MRI was performed, revealing a left hemispheric lesion. Given the atypical presentation and location of the lesion, a comprehensive differential diagnosis was considered, including neoplasia, venous infarction, and demyelinating lesion. As a result, she was referred to the Neurology department of our institution for further evaluation.

Investigations:
Brain MRI with contrast showed a low-grade glial primary neoplasia, predominantly located in the frontal region with extension into the left parietal and temporal regions. Given the patient's young age and the lesion's atypical appearance, the possibility of glioblastoma was considered.

Treatment and Outcome:
In consideration of the patient's clinical presentation and MRI findings, she underwent a craniotomy for the removal of the left frontal lesion. The procedure was performed using Minimally Non-Invasive Surgery (MNIO) techniques and was completed without any notable complications.

Histopathology:
Histological examination of the resected tissue confirmed the diagnosis of glioblastoma, a highly malignant and aggressive brain tumor.

Follow-up:
Follow-up MRI revealed a marked increase in the size of the left temporal lesion, measuring 2.5 cm compared to 1.1 cm in the previous control. The lesion showed characteristics of a solid cystic mass with surrounding edema. Additionally, there was a slight increase in the sensation of cortico-subcortical frontoparietal mass effect on the left. Hyperintensity on the FLAIR sequence was associated with minimal contrast enhancement, and perfusion sequence values were inconclusive, making infiltration difficult to rule out. Further evaluations and regular follow-up visits are recommended to monitor disease progression and inform treatment decisions.

Discussion:
Glioblastoma is a rare occurrence in young adults, and its diagnosis can be challenging due to atypical clinical presentations. The combination of persistent hemibody sensory disturbances and a left hemispheric lesion on neuroimaging raised suspicion for an underlying neoplastic process. The patient's history of smoking and fibromyalgia could have potential implications in the pathogenesis or management of glioblastoma, although further research is needed to explore these associations.

Conclusion:
We report a rare case of glioblastoma in a 26-year-old woman presenting with persistent hemibody sensory disturbances. The identification of a left hemispheric lesion on neuroimaging prompted further evaluation, leading to the diagnosis of glioblastoma. Surgical intervention was performed using MNIO techniques, and the patient's condition is being closely monitored to guide further treatment decisions. This case underscores the importance of considering glioblastoma in the differential diagnosis of young adults presenting with neurological symptoms and focal brain lesions. Early detection and management are crucial for improving patient outcomes in such cases.

===== References =====