by Brian Keller MD PhD and John Woulfe MD PhD
July 6, 2023
An IDH wildtype glioblastoma is an aggressive type of brain and spinal cord cancer and the most common type of cancerous brain tumour in adults. The tumour is made up of cells called astrocytes that are normally found throughout the brain and spinal cord. Another name for this tumour is glioblastoma multiforme (GBM).
IDH (isocitrate dehydrogenase) is a gene that provides instructions for making a protein involved in cellular metabolism (energy production). “IDH-wildtype” means that the glioblastoma tumour cells contained two normal copies of the IDH gene or that the tumour cells were found to be producing a normal amount of the IDH protein. Pathologists can look for IDH by performing immunohistochemistry, polymerase chain reaction (PCR), or next-generation sequencing (NGS). The IDH status of a tumour is important because it helps distinguish glioblastoma from other brain and spinal cord tumours such as a grade 4 astrocytoma that typically contain an altered or “mutated” IDH gene.
All central nervous system (CNS) tumours are given a grade from 1 to 4 based on how much the tumour cells look and behave like the cells normally found in the CNS and the grading system used by most pathologists is called the WHO grade because the World Health Organization developed it. According to this grading system, all glioblastomas are considered grade 4 because the cell in the tumour look and behave very differently than normal astrocytes.
The symptoms of glioblastoma depend on the location of the tumour, however common symptoms include weakness, vision changes, confusion, and difficulty speaking or understanding language. Larger tumours can cause nausea, vomiting, and headache. Seizures occur in up to half of all people with glioblastoma.
At present doctors do not know what causes most glioblastomas. However, some genetic tumour syndromes such as Li-Fraumeni, Lynch, and neurofibromatosis type-1 (NF-1) are associated with an increased risk of developing glioblastoma. Prior radiation to the head and neck (often as a child) is also associated with an increased risk of developing glioblastoma later in life.
The diagnosis of glioblastoma is made after some of the tumour is examined under a microscope by a pathologist. The diagnosis can be made after only a small sample of the tumour is removed in a procedure called a biopsy or after the entire tumour is removed in a procedure called an excision or resection.
The histologic diagnosis is your pathologist’s initial assessment or opinion of the tumour after examining the slides under the microscope. This examination usually involves looking at an H&E stained slide (often called the ‘routine stain’ by pathologists) although it may also involve looking at some slides stained using a test called immunohistochemistry. The histologic diagnosis is not a final diagnosis. However, your doctors may use the histologic diagnosis to start planning your treatment. Later, the histologic diagnosis is combined with the results of other tests to reach the final ‘integrated diagnosis’.
The integrated diagnosis is your pathologist’s assessment or opinion of the tumour after examining the tumour under the microscope and performing additional tests such as immunohistochemistry, polymerase chain reaction (PCR), and next-generation sequencing (NGS). For this reason, the integrated diagnosis provides information about both how the tumour looks and any genetic alterations inside the tumour cells. Because the integrated diagnosis includes more complex tests, it can take several weeks to get this result. The integrated diagnosis is considered the ‘final diagnosis’ and it is important because your doctors will use it to determine which treatment options are best for you.
When examined under the microscope, glioblastoma is made up of abnormal astrocytes that look very little like the astrocytes normally found throughout the central nervous system (CNS). Pathologists use the word atypical to describe abnormal-looking cells. The tumour cells may also be described as pleomorphic because they show considerable variation in shape and size. Necrosis (dead or dying tumour cells) and mitotic figures (tumour cells dividing to create new tumour cells) are also typically seen. Small, newly formed blood vessels which pathologists describe as ‘microvascular proliferation’ is also commonly seen throughout the tumour.
ATRX is a gene that provides instructions for making a protein involved in normal cell development. Pathologists perform a test called immunohistochemistry to look for the ATRX protein inside tumour cells. When this test is performed, most glioblastomas show normal ATRX protein in a part of the cell called the nucleus. Your report may describe this result as ‘retained’. This result is important because it helps distinguish glioblastoma from other types of brain and spinal cord tumours such as a grade 4 astrocytoma that typically show a loss of ATRX.
MGMT is a gene that provides instructions for making a protein involved in the repair of damaged DNA (genetic material). A promoter is an area of DNA that provides instructions for turning the gene on and off. When the promoter region of the MGMT gene becomes methylated, the gene is less likely to turn on, resulting in damaged DNA going unrepaired. Pathologists test for MGMT promoter methylation because patients with tumours that show “methylation” have a better prognosis and are more likely to respond well to chemotherapy compared to patients with ‘unmethylated’ tumours.
TERT is a gene that provides instructions for making a protein involved in keeping the DNA (genetic material) in a cell stable over time. A promoter is an area of DNA that provides instructions for turning the gene on and off. When the promoter region of the TERT gene becomes mutated (altered), the gene is more likely to turn on which allows the tumour cells to survive longer and create new tumour cells. TERT is important because tumours with mutated TERT promoters have been shown to behave in a more aggressive manner.
Most of the DNA in cells is found on small structures called chromosomes and normal cells have 23 pairs of chromosomes. The tumour cells in glioblastoma can gain (“+”) or lose (“- “) chromosomes. The most common gain is chromosome 7 (“+7”) while the most common loss is chromosome 10 (“-10”). Pathologists test for the number of chromosomes in the tumour cells to help confirm the diagnosis of glioblastoma.
p53 is a gene that provides instructions for making a protein called a ‘tumour suppressor’. Tumour suppressor genes are important because they stop cells from dividing (creating new cells) uncontrollably and they provide a way to remove damaged cells from the body. Some pathologists perform a test called immunohistochemistry to look for the p53 protein inside cells. Many glioblastomas have an altered or mutated p53 gene and this results in either too much protein in a cell or the complete loss of the protein. Pathologists describe too much protein as “overexpressed” and no protein as “null”. Testing for p53 is not required to make the diagnosis of glioblastoma, however, it can be useful for identifying genetic syndromes associated with p53 such Li-Fraumeni syndrome.