Glioblastoma Multiforme (GBM)

What is glioblastoma multiforme (GBM)?

Glioblastoma multiforme (GBM) is a fast-growing type of tumour of the brain or spinal cord. It is the most common type of primary malignant brain tumour in adults.

GBMs almost never spread outside of the brain, spine or central nervous system to other parts of the body. They are very challenging to treat because of their complex nature, which is why a great deal of research in the UK and around the world is focused on this tumour type.

GBMs are highly varied tumours that contain a mixture of different types of "glial" brain cells, hence the name glioblastoma and “multiforme” meaning “highly variable”. Cell types within these tumours are variably specialised and they closely interact with normal brain cells such as astrocytes, oligodendrocytes, microglia and cells of the blood vessels.

The makeup of the tumour cells varies both in terms of genetic mutations (lesions affecting the DNA in specific genes) and the resulting activity of the affected genes. This is called “heterogeneity”, which translates as “diversity”, “variability” or “composed of dissimilar cells”.

Glioblastoma is a grade 4 brain tumour - a classification assigned by the World Health Organisation (WHO) - on the basis of the histology (how it looks under the microscope) of a tumour sample (biopsy). The way that a tumour looks on a brain scan can also indicate the type and grade of a tumour, but is not as reliable as looking at the cells themselves.

A small percentage of patients are diagnosed with multifocal and multicentric glioblastoma, meaning there is more than one focal point within the brain for the tumour.

Latest research indicates that GBMs are unlikely to develop from fully formed brain cells but instead develop from immature cells or stem cells which suffered DNA damage at some point in their life during their development from a stem cell to a progenitor cell and/or a mature brain cell. 

The complexity, diversity and rapid growth of a GBM tumour means it is very difficult for researchers to develop treatments that can be effective for a patient with this diagnosis.

Molecular profiling

Pathologists can undertake genetic profiling of GBM tumours. This examination can provide a unique profile of the individual tumour.

The following information can be gleaned as a result of molecular profiling:

IDH status - IDH stands for “Isocitrate Dehydrogenase.” This is an enzyme involved in the production of energy by brain tumour cells, and in GBM it may have a mutation which confers a better prognosis. Research has indicated that different forms of GBMs have differences between these enzymes, though their role in tumour initiation (how a tumour first begins) and tumour growth is still being explored. As part of this research, a number of drugs that can potentially influence IDH enzymes are being investigated.

IDH 'wild' type status - This occurs in about 90% of GBM brain tumours and usually indicates that the tumour formed as glioblastoma since the very beginning (primary GBM) and carries a worse prognosis than those classified as being IDH mutant.

IDH mutant - This represents approximately 10% of GBMs, and indicates a secondary glioblastoma tumour, meaning that it was previously a lower grade glioma and carries a better prognosis than a 'wild' type status.

IDH NOS - This stands for “Not Otherwise Specified”, meaning that in rare cases, it cannot be determined whether a GBM is 'wild' type or mutant for IDH.

MGMT methylation - This is short for O6-methylguanine-DNA methyltransferase and whether it is 'methylated' or 'unmethylated' indicates how effectively the tumour cells can repair the damage inflicted on them by certain chemotherapy drugs, such as Temozolomide. Patients with higher levels of MGMT methylation respond better to Temozolomide treatment. Methylation means the transfer of a methyl group (CH3) from one molecule to another, which affects the way the tumour behaves.

1p/19q deletion - The word “deletion” refers to the fact that when you look at one of the chromosomes, the genes at positions 1p and 19q are missing. Tumours with a 1p/19q deletion may respond better to certain chemotherapy drugs such as Temozolomide or Carmustine, than other tumours without the deletion.

What is the main cause of glioblastoma multiforme (GBM)?

Currently, we do not know what causes glioblastoma. The main contributing factor appears to be an accumulation of genetic mutations, which lead normal cells to develop into cancerous cells, and these grow further to become a tumour. We do not know what causes these mutations. Research is identifying some of the genes that become mutated in glioblastoma, which we hope will improve our ability to detect, diagnose and treat it. There is no substantial evidence linking lifestyle factors such as smoking, alcohol consumption or use of mobile phones to the development of glioblastoma. 

Multifocal and multicentric glioblastoma

Multifocal Glioblastoma

On an MRI scan, this type of glioblastoma can be seen to have multiple areas of high-grade cancerous formations joined together by other abnormal brain tissue. This type of GBM accounts for 2-20% of all glioblastoma tumours.

Multicentric Glioblastoma

A multicentric glioblastoma is considered to be more than one GBM tumour that has arisen in the brain at the same time, or within a very short timeframe. It shows up on an MRI scan as more than one area of active brain tumour with areas of apparently normal brain tissue between them.

What are the first symptoms of glioblastoma (GBM)?

Glioblastoma is a type of brain tumor that can cause a wide range of symptoms, depending on its location and size. Some common symptoms of glioblastoma include:

Headaches - Glioblastoma can cause persistent or severe headaches that may worsen over time.

Seizures: Glioblastoma can cause seizures that may be focal or generalized, depending on the location of the tumor.

Weakness or numbness - Glioblastoma can cause weakness or numbness in one side of the body or in one limb.

Nausea and vomiting - Glioblastoma can cause nausea and vomiting, which may be related to increased pressure within the skull.

Cognitive changes - Glioblastoma can cause cognitive changes such as confusion, memory loss, or difficulty with language.

Vision or hearing changes - Glioblastoma can cause changes in vision or hearing, such as blurred vision or ringing in the ears.

Weakness or numbness - Glioblastoma can cause weakness or numbness in one side of the body or in one limb.

What are the worsening symptoms of glioblastoma multiforme (GBM)?

The symptoms of glioblastoma depend on what part of the brain the tumour is located. For example, it can grow in areas of the brain that lead to difficulties in moving limbs or in forming words. Growing tumours increase pressure within the skull, leading to headaches. Other worsening symptoms include loss of appetite; nausea and vomiting; loss of balance; mood swings; problems speaking or with memory or concentration; seizures; impaired vision. 

Glioblastoma stage 4 - what to expect?

The diagnosis of glioblastoma normally involves a neurological exam, imaging tests (MRI) to help determine the location and size of the tumour and, where possible, taking a biopsy, which involves removing a sample of tissue for testing.

Treatment normally involves surgery to remove as much of the tumour as is possible and safe. Unfortunately the diffuse nature of glioblastoma means that some tumour cells will almost always be left behind and continue to grow. For this reason, radiotherapy and chemotherapy are the next stages of treatment. Usually, people are offered the chemotherapy drug temozolomide alongside radiotherapy, and then further doses of temozolomide afterwards.

What is the treatment for glioblastoma multiforme (GBM)?

Surgery is the first option for the treatment of a GBM, usually followed by radiotherapy and chemotherapy.

The surgical operation to remove a GBM is a delicate balancing act between removing as much of the tumour as possible and protecting the function of the healthy brain, so the location of your brain tumour is very important with regard to both the potential impact of surgery and the symptoms that you experience (because different areas of the brain control different mental and physical processes). 

A neurosurgeon is limited as to how much of a glioblastoma they can remove because GBMs are “diffuse”, meaning that tumour cells invade healthy areas of the brain adjacent to the tumour.

Part of the skill of a neurosurgeon is for them to judge how much of a tumour is safe to remove without damaging the healthy brain, which is why clinicians may sometimes recommend that part or all of the operation be undertaken as an awake craniotomy.

Unfortunately, the diffuse nature of GBM explains why some tumour cells will almost always be left behind and hence will continue to grow. 

For this reason, radiotherapy and chemotherapy are the next stages of treatment for a GBM. Usually, people are offered the chemotherapy drug Temozolomide alongside radiotherapy, and then further doses of Temozolomide afterwards.

What is the prognosis for glioblastoma multiforme (GBM)?

The average survival time is devastatingly short – just 12-18 months. However, 25% of glioblastoma patients survive more than one year and 5% of patients survive more than five years. The reason why some people survive so much longer than others is not yet clear. 

Frequently asked questions

Is Glioblastoma always fatal?

Glioblastoma multiforme (GBM) is the most common type of primary malignant brain tumour in adults. It is also the most aggressive and lethal. Less than 1% of all patients with a glioblastoma live for more than ten years, so in the majority of cases, it is fatal.

Is glioblastoma curable?

Glioblastoma is a highly aggressive and malignant form of brain cancer, and at present, it is generally considered to be incurable.

The standard treatment for glioblastoma typically involves surgery to remove as much of the tumour as possible, followed by radiation therapy and chemotherapy to help slow the growth of any remaining cancer cells. While this treatment approach can help to extend survival and improve the quality of life for some patients, cancer typically returns and continues to progress despite treatment.

Research into new treatments, such as immunotherapy and targeted therapies, is ongoing, and these treatments may offer hope for improved outcomes in the future. However, at present, there is no known cure for glioblastoma.

What is the life expectancy of a person with glioblastoma?

It varies - the average survival time is devastatingly short – just 12-18 months. Only 25% of glioblastoma patients survive more than one year and 5% of patients survive more than five years. Less than 1% of all patients with a glioblastoma live for more than ten years, so in the majority of cases, it is fatal.

How can we find a cure for glioblastoma?

Research we are funding across all of our Centres of Excellence will help lead towards finding a cure for GBM.

Pioneering research at our Brain Tumour Research Centre of Excellence at Queen Mary University of London is focused on using GBM stem cells to help develop unique, patient-specific treatments.

The team of researchers and clinical experts at our Centre of Excellence at Imperial College, London, are part of a global collaboration looking at how the ketogenic diet can influence GBM metabolism and help in the effective treatment and management of living with this brain tumour. They are also studying the influence of arginine deprivation on GBM cells and are working towards a clinical trial to investigate this further.

 Our team at the University of Plymouth Centre of Excellence has identified a range of mutations in brain tumour cells that initiate tumour progression and drive growth, potentially transforming slow-growing low-grade gliomas into more immediately life threatening high-grade gliomas, which include GBM.

We also fund BRAIN UK at Southampton University, the country’s only national tissue bank registry providing crucial access to brain tumour samples for researchers from all clinical neuroscience centres in the UK, effectively covering about 90% of the UK population, and an essential component in the fight to find a cure for GBM.