Gastrointestinal stromal tumour (GIST)

by Jason Wasserman MD PhD FRCPC
August 9, 2024


Background:

A gastrointestinal stromal tumour, or GIST, is a type of cancer that starts in the digestive tract. The most common places for GISTs to develop are the stomach and small intestine, but they can occur anywhere along the digestive tract. GISTs are different from other types of tumours because they start in special cells called interstitial cells of Cajal (ICCs), which help coordinate the movement of the digestive tract.

What are the symptoms of a gastrointestinal stromal tumour?

The symptoms of a GIST can vary depending on the size and location of the tumour. Some people with GIST may not experience any symptoms, especially if the tumour is small and slow-growing. However, as the tumour grows, it can cause a variety of symptoms, including:

  • Abdominal pain or discomfort: This is the most common symptom and can range from mild discomfort to severe pain.
  • A feeling of fullness: Some people may feel full after eating only a small amount of food, especially if the tumour is located in the stomach.
  • Nausea and vomiting: These symptoms may occur if the tumour causes a blockage in the digestive tract.
  • Bleeding: GISTs can cause bleeding into the digestive tract, which might show up as blood in the stool (which can appear black and tarry) or vomiting blood.
  • Fatigue or weakness: If the tumour causes chronic bleeding, these symptoms can result from anemia (low red blood cell count).

What causes a gastrointestinal stromal tumour?

GISTs are caused by genetic mutations that occur in the cells of the digestive tract, specifically in a type of cell called the interstitial cell of Cajal (ICC). These cells help regulate the movement of food through the digestive tract. The most common mutations associated with GISTs involve the KIT gene or the PDGFRA gene. These mutations cause the cells to grow uncontrollably, leading to the development of a tumour.

Most GISTs occur sporadically, meaning the mutations happen by chance and are not inherited. However, in rare cases, GISTs can be part of a genetic syndrome that runs in families, such as neurofibromatosis type 1 (NF1) or Carney-Stratakis syndrome. People with these syndromes have a higher risk of developing GISTs and other types of tumours.

Histologic types

GISTs can look different under the microscope, and pathologists divide them into three main types based on how the tumour cells appear:

  • Epithelioid type: In this type, the tumour cells are round and look like the cells that line organs.
  • Spindled type: This type of GIST has long and thin cells resembling a spindle or a piece of thread. It is the most common type of GIST.
  • Mixed type: This type has features of both epithelioid and spindled cells.

Grade

Pathologists grade GISTs to determine how aggressive the tumour is. The grade is based on the number of dividing cells, called mitotic figures, that are visible under the microscope in a specific area of the tumour.

  • Low grade: This means that there are 5 or fewer mitotic figures in an area of 5 mm² (or in 50 high-powered fields under the microscope). Low-grade GISTs are less likely to grow quickly or spread to other body parts.
  • High grade: This means that there are more than 5 mitotic figures in an area of 5 mm². High-grade GISTs are more aggressive and have a higher chance of growing quickly or spreading.

Tumour size

The size of the tumour is very important because it helps determine the risk of the tumour returning or spreading after treatment. However, the tumour size can only be accurately measured after it has been completely removed by surgery.

Necrosis

Necrosis is the death of cells or tissue. In the context of GISTs, necrosis can happen when parts of the tumour do not get enough blood supply, causing the cells in that area to die. The presence of necrosis in a tumour can be a sign that the tumour is more aggressive.

Risk assessment score

The risk assessment score for GIST helps predict the likelihood of developing metastatic disease (spread of the tumour to other parts of the body) or death related to the tumour. The risk assessment score is typically only reported after the entire tumour has been surgically removed.

This score is based on three factors:

  • Tumour size: Larger tumours have a higher risk of coming back.
  • Tumour location: Tumours in certain parts of the digestive tract, like the small intestine, may have a higher risk than those in other locations. Tumours in the stomach are generally associated with the lowest risk of progressive disease.
  • Mitotic count: The number of mitotic figures in the tumour is stratified into two groups: 5 or fewer mitotic figures per 5 mm² and more than 5 mitotic figures per 5 mm². The risk of developing progressive disease is lower when there are 5 over fewer mitotic figures.

Based on these factors, the tumour can be classified into one of four risk levels:

  • No risk of progressive disease.
  • Low risk of progressive disease.
  • Moderate risk of progressive disease.
  • High risk of progressive disease.

Immunohistochemistry

Immunohistochemistry (IHC) is a special test that pathologists use to help identify the type of tumour. In this test, they apply special markers to the tissue sample that stick to certain proteins in the tumour cells. For GISTs, the most common markers are CD117 (also called KIT), DOG1, and CD34. These markers are usually positive in GISTs, which helps confirm the diagnosis. Some GISTs may also show other markers like SMA (smooth muscle actin) or S100, while markers like desmin are usually negative.

Succinate dehydrogenase B (SDHB)

Succinate dehydrogenase B (SDHB) is a protein that is important in producing energy in cells. In some cases, GISTs may show a loss of this protein. When this happens, it suggests that the patient has an inherited syndrome, which increases the risk of developing GISTs and possibly other types of tumours. Pathologists can screen for the loss of SDHB using a special test called immunohistochemistry (IHC). Patients with SDHB-deficient tumours should be referred to a specialist for further genetic testing.

Molecular tests

Molecular tests may be performed on GISTs to assess for changes (mutations) in specific genes, particularly KIT and PDGFRA. These genes are important because mutations in them can drive the growth of the tumour. Approximately 75% of GISTs have mutations involving the KIT gene, while about 10% have mutations involving the PDGFRA gene. Knowing whether a GIST has a mutation in one of these genes helps doctors decide on the best treatment plan, as certain therapies are more effective against tumours with specific mutations.

One of the most common methods used to assess these genes is called next-generation sequencing (NGS). NGS is a technique that allows scientists to look at the DNA in tumour cells and identify specific mutations or changes. It works by breaking the DNA into small pieces, reading the sequence of each piece, and then using a computer to assemble these sequences to identify any genetic changes. This technology allows for a comprehensive analysis of the tumour’s genetic makeup, which can provide valuable information for treatment decisions.

Molecular testing for KIT and PDGFRA is particularly important for patients being considered for treatment with specific drugs called tyrosine kinase inhibitors (TKIs). TKIs are targeted therapies that block the signals that tell cancer cells to grow. Because these drugs are more effective in tumours with certain mutations, testing for these genetic changes is recommended before starting treatment to ensure the most appropriate therapy is selected.

Margins

In pathology, a margin is the edge of tissue removed during tumour surgery. The margin status in a pathology report is important as it indicates whether the entire tumour was removed or if some was left behind. This information helps determine the need for further treatment.

Pathologists typically assess margins following a surgical procedure, like an excision or resection, that removes the entire tumour. Margins aren’t usually evaluated after a biopsy, which removes only part of the tumour. The number of margins reported and their size—how much normal tissue is between the tumour and the cut edge—vary based on the tissue type and tumour location.

Pathologists examine margins to check if tumour cells are present at the tissue’s cut edge. A positive margin, where tumour cells are found, suggests that some cancer may remain in the body. In contrast, a negative margin, with no tumour cells at the edge, suggests the tumour was fully removed. Some reports also measure the distance between the nearest tumour cells and the margin, even if all margins are negative.

Margin

Pathologic stage (pTNM)

The pathologic stage for gastrointestinal stromal tumours (GISTs) is based on the TNM staging system, an internationally recognized system originally created by the American Joint Committee on Cancer (AJCC). This staging system is not used for children or adults who are known to have a genetic syndrome that is associated with GIST.

The AJCC system uses information about the primary tumour (T), lymph nodes (N), and distant metastatic disease (M)  to determine the complete pathologic stage (pTNM). Your pathologist will examine the tissue submitted and give each part a number. Generally, a higher number means a more advanced disease.

Tumour stage (pT)

GISTs are given a tumour stage between 1 and 4 based solely on the tumour size.

  • T1 – The tumour is smaller than or equal to 2 cm in maximum dimension.
  • T2 – The tumour measures more than 2 cm but not more than 5 cm.
  • T3 – The tumour measures more than 5 cm but not more than 10 cm.
  • T4 – The tumour is larger than 10 cm in maximum dimension.​
Nodal stage (pN)

GISTs are given a nodal stage of 0 or 1 based on the absence or presence of tumour cells in a lymph node.

  • N0 – No tumour cells were found in any of the lymph nodes examined.
  • N1 – Tumour cells were found in at least one lymph node.
  • NX – No lymph nodes were sent for pathologic examination.
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