Glioblastoma is the most common malignant primary brain tumour in adults, characterised histologically by pseudopalisading necrosis and/or microvascular proliferation, and radiologically by a typically heterogeneous contrast-enhancing diffusion-restricting mass in the cerebral hemispheres, often with central necrosis and surrounding oedema.
Description
Glioblastoma, formerly known as glioblastoma multiforme, is a high-grade glioma originating from glial cells, most commonly astrocytes. It is the most aggressive and malignant form of glioma, characterised by rapid growth, invasiveness, and a poor prognosis. Most frequently, it arises in the cerebral hemispheres, although it can occur anywhere in the brain or spinal cord.
Classified as a diffuse astrocytoma, glioblastoma is marked histopathologically by highly invasive cells that infiltrate surrounding brain tissues. This infiltration occurs at the microscopic level, where individual tumuor cells spread into adjacent brain structures, intermingling with normal cells and crossing anatomic boundaries such as brain lobes and the corpus callosum. This diffuse infiltration is facilitated by the tumor cells’ ability to disrupt normal brain architecture, degrade extracellular matrix, and form secondary structures away from the primary mass. The presence of these invasive cells throughout the brain tissue makes it challenging to clearly define the margins of the tumor, complicating surgical removal and contributing to the likelihood of recurrence
Pathogenesis
The development of glioblastoma is a complex, multi-step process involving several genetic alterations. The most common genetic abnormalities include alterations in the EGFR gene, loss of the tumour suppressor genes PTEN and TP53, and loss of heterozygosity at chromosome 10q. These genetic changes lead to increased cell proliferation, reduced apoptosis, and enhanced angiogenesis, thereby contributing to the aggressive nature of this tumour.
Subtypes
Glioblastomas are currently classified into two main subtypes based on the isocitrate dehydrogenase (IDH) mutation status:
- IDH-wildtype glioblastoma: Represents the vast majority of glioblastomas and usually develops de novo without a precursor lesion.
- IDH-mutant glioblastoma: Less common, develops from lower-grade astrocytomas or oligodendrogliomas, and is associated with a better prognosis compared to the IDH-wildtype.
Epidemiology, Risk Factors & Associations
- The most common malignant primary brain tumour in adults (45% of all primary malignant brain tumours).
- Median age at diagnosis is around 64 years.
- Slightly more common in males.
- No established environmental risk factors, although prior ionising radiation is a known risk.
- Associated with inherited tumour syndromes, such as p53 mutation-related syndromes (neurofibromatosis type 1 and Li-Fraumeni syndrome), Turcot syndrome, Ollier disease, and Maffucci syndrome.
Clinical Features
Typically presents with symptoms related to increased intracranial pressure (headaches, nausea, vomiting, and altered consciousness) and focal neurological deficits depending on the location of the tumour (motor weakness, sensory loss, language dysfunction, etc.).
Complications
Being a malignant tumour, glioblastoma can infiltrate the surrounding brain tissue, making complete surgical resection challenging. The risk of malignant transformation is inherent in its diagnosis. Metastasis outside of the CNS is rare, but when it occurs, it most commonly involves the lungs.
Pathological Features
Histopathology
- Macroscopic: Typically large, poorly defined, necrotic and haemorrhagic masses often seen as a reddish-gray rind of tissue around a necrotic core
- Microscopic: Characterised by cellular polymorphism, nuclear atypia, mitotic activity, necrosis with pseudopalisading, and microvascular proliferation.
Serology
- No specific serological markers for glioblastoma.
Biochemistry
- Molecular markers such as MGMT promoter methylation, EGFR amplification, and IDH1/2 mutations may have prognostic and therapeutic implications.
Radiological Features
General Features
- Typically located in the cerebral hemispheres, possibly crossing the corpus callosum to involve both hemispheres (‘butterfly glioma’).
- Intra-axial mass that is typically heterogeneous due to cysts, haemorrhage, and necrosis. Heterogenously enhanced.
- Subependymal spread
- Pitfalls: Extent of enhancement or adjacent T2 abnormality signal abnormality often understate the true extent of infiltrating tumour
CT
- Non-contrast: Irregular mass lesion with variable density and surrounding oedema, may demonstrate calcifications.
- C+ Arterial & C+ Venous: Intense and heterogeneous enhancement, central necrosis.
MRI
- T1: Hypointense or isointense heterogenous intra-axial mass.
- T2 & FLAIR: Peritumoural T2/FLAIR represents an admixture of infiltrative tumour and vasogenic oedema.
- DWI/ADC: Variable diffusion restriction.
- T1 Gad+: Intense and heterogeneous enhancement, often with a ring-enhancing pattern due to central necrosis.
- SWI/GRE/T2*: May show blooming due to haemorrhage.
- Perfusion: Elevated maximum rCBV relative to lower grade gliomas.
- MRS: Elevated choline, lipid/lactate peaks. Decreased NAA and myoinositol levels.
NM
- PET FDG: High FDG uptake.
Grading and Staging
According to the WHO Classification of Tumours of the CNS, glioblastoma is a grade IV tumour.
Diagnosis
The diagnosis is primarily made by neuroimaging studies (CT and MRI) and confirmed by histopathological examination of the tumour tissue obtained by biopsy or resection.
Differential Diagnosis
Imaging-based
Other lesions which ring-enhance
- Metastatic brain tumours: Typically multiple and located at the grey-white junction, although they can mimic the appearance of glioblastoma.
- Cerebral abscess: Typically T2 hypointense rim, central restricted diffusion, peripheral enhancement is smoother than GBM.
- Anaplastic astrocytoma: May be indistinguishable, though may have less necrosis and may contain significant nonenhancing components.
Other lesions which involve the corpus callosum
- Tumefactive Multiple Sclerosis: Seen in younger patients. MR shows other demyelinating lesions.
- Tumefactive Demyelinating Lesion: Similar in appearance to tumefactive and multiple sclerosis.
- Primary CNS lymphoma: Typically located in the periventricular white matter, more commonly seen in immunocompromised patients (steroids, HIV, transplant, chemotherapy). Absolute tumour blood flow (aTBF), relative tumour blood flow (rTBF) and ADCmin typically higher in GBM compared to CNSL. SUV typically lower in GBM.1
Management
Neuro-oncology referral is essential. The standard treatment involves maximal safe surgical resection, followed by radiotherapy and chemotherapy with temozolomide. Molecular profiling of the tumour, including IDH mutation status, may guide specific targeted therapies.
References
- Yamashita, K., Yoshiura, T., Hiwatashi, A., Togao, O., Yoshimoto, K., Suzuki, S.O., Abe, K., Kikuchi, K., Maruoka, Y., Mizoguchi, M. and Iwaki, T., 2013. Differentiating primary CNS lymphoma from glioblastoma multiforme: assessment using arterial spin labeling, diffusion-weighted imaging, and 18 F-fluorodeoxyglucose positron emission tomography. Neuroradiology, 55, pp.135-143.
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