Astrocytoma IDH mutant CNS WHO grade 4

by Brian Keller MD PhD and John Woulfe MD PhD
August 16, 2022


What is an astrocytoma?

An astrocytoma is a type of brain and spinal cord cancer. The tumour is made up of cells called astrocytes that are normally found throughout the brain and spinal cord. IDH mutant astrocytomas are typically found in the brain and most patients are under 55 years of age.

What does IDH mutant mean?

IDH (isocitrate dehydrogenase) is a gene that provides instructions for making a protein involved in cellular metabolism (energy production). “IDH-mutant” means that the astrocytoma tumour cells contained an altered or “mutated” IDH gene. As a result, the tumour cells do not produce the IDH protein. Humans have three different IDH proteins (numbered 1 through 3) but almost all astrocytoma mutations involve IDH1 (more than 90% of all tumours) or IDH2 (less than 10% of all tumours). Pathologists look for an altered or mutated IDH gene by performing a test called immunohistochemistry. If no alteration is found using this test, another test such as polymerase chain reaction (PCR) or next generation sequencing (NGS) may be used. The IDH status of a tumour is important because it helps distinguish astrocytoma from other brain and spinal cord tumours such as glioblastoma that typically contain a normal or “wild-type” IDH gene. IDH mutant astrocytomas tend to grow much slower and are associated with longer overall survival than IDH-wildtype glioblastomas.

Immunohistochemistry for IDH in an astrocytoma. The dark brown tumour cells contain the mutated IDH gene and produce an abnormal protein.

Why is this tumour called CNS WHO grade 4?

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 astrocytomas are divided into 3 grades – grade 2, grade 3, and grade 4 – based on how the cells look and behave compared to normal astrocytes.

In order to be called CNS WHO grade 4, the tumour cells should look abnormal compared to the astrocytes normally found in the brain and spinal cord. Most of the changes take place in a part of the cell called the nucleus and pathologists describe these cells as showing “nuclear atypia”. The tumour cells may also be described as pleomorphic because they show considerable variation in shape and size.  More abnormal-looking cells are described as showing anaplasia. Mitotic figures (tumour cells dividing to create new tumour cells) are typically found throughout the tumour. Other features that are usually required to make the diagnosis of a grade 4 tumour include necrosis (dead or dying tumour cells) and microvascular proliferation (small new blood vessels). Both of these features are only seen in grade 4 tumours. An astrocytoma that does not show necrosis or microvascular proliferation can still be called grade 4 if the tumour cells show a loss or deletion in one of the genes CDKN2A or CDKN2B.

Astrocytoma IDH mutant CNS WHO grade 4. The picture on the left shows tumour cells (green arrow) surrounding an area of necrosis (yellow arrow). The picture on the right shows microvascular proliferation (blue arrows).

What are the symptoms of astrocytoma?

The symptoms of astrocytoma depend on the location of the tumour; however, common symptoms include weakness, vision changes, and difficulty speaking or understanding language. Seizures are common and for many patients, it is the first presenting symptom.

What causes astrocytoma?

At present doctors do not know what causes most astrocytomas. However, people with some genetic tumour syndromes like Li-Fraumeni or neurofibromatosis are known to have an increased risk of developing astrocytoma. Unlike glioblastoma, prior radiation to the head and neck (often as a child) is not associated with an increased risk of developing astrocytoma.

How is the diagnosis of astrocytoma made?

The diagnosis of astrocytoma 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.

What is a histological diagnosis for astrocytoma?

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’.

What is the integrated diagnosis for astrocytoma?

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.

What is CDKN2A loss and why is it important for astrocytoma?

CDKN2A is a gene that provides instructions for making a protein two proteins called “tumour suppressors”. 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 astrocytomas will have a genetic alteration that results in a loss or deletion of the CDKN2A gene and loss of protein production. The loss of CDNK2A is important because it allows the cells to grow and divide much more quickly than cells with a normal CDNK2A gene. All astrocytomas with a loss of the CDNK2A gene are considered WHO grade 4 tumours even if the other features of grade 4 tumours (such as necrosis and microvascular proliferation) are not seen.

Pathologists perform tests such as immunohistochemistry, polymerase chain reaction (PCR), or next-generation sequencing (NGS) to look for alterations or mutations in the CDNK2A genes. The alteration is described as a “loss” because it results in the loss of the normal proteins made by the gene. A related gene called CDKN2B also provides instructions for making tumour suppressor proteins and this gene may be altered in some tumours.

What is ATRX and why is it important for astrocytoma?

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 astrocytomas show a complete loss of ATRX protein in a part of the cell called the nucleus. Your report may describe this result as ‘mutated’. This result is important because it helps distinguish astrocytoma from other types of brain and spinal cord tumours such as glioblastoma that typically do not show a loss of ATRX.

What is p53 and why is it important for astrocytoma?

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. Pathologists perform a test called immunohistochemistry to look for the p53 protein inside cells. Most astrocytomas 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”.

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