Gastrointestinal stromal tumour (GIST)

by Jason Wasserman MD PhD FRCPC
February 25, 2025

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 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 mitotic figures (dividing tumour cells) visible under the microscope in a specific tumour area.

• Low grade: This means 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 there are more than 5 mitotic figures in an area of 5 mm². High-grade GISTs are more aggressive and likely to grow quickly or spread.

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.

Molecular tests

Molecular tests may be performed on GISTs to assess for 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 PDGFRA gene mutations. 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 doctors 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.

SDH-deficient gastrointestinal stromal tumours

Some gastrointestinal stromal tumours do not have mutations in the KIT or PDGFRA genes. Instead, they have changes in a group of genes called SDH subunit genes. These tumours are known as SDH-deficient GISTs, and they make up about 5 to 10% of all GISTs.

In about 60% of cases, SDH-deficient GISTs occur because of a mutation in one of the SDH genes. This type of mutation is usually germline, which means it is present from birth and can sometimes run in families. The most commonly mutated gene is SDHA, followed by SDHB, SDHC, and SDHD.

In the remaining 40% of cases, there is no DNA mutation but a chemical change called SDHC promoter methylation (also called an epimutation). This change prevents the SDHC gene from working properly and leads to SDH-deficient GIST.

People with SDH-deficient GISTs tend to be younger than those with other types of GIST. In fact, almost all GISTs in children are SDH-deficient. Some patients with a rare condition called Carney triad—which includes GIST, lung tumors, and adrenal tumors—often have SDHC epimutation rather than a gene mutation.

When examined under the microscope, most SDH-deficient GISTs have an epithelioid (rounded cell) appearance. These tumours often form multiple nodules and show plexiform mural involvement, meaning they grow in a pattern that spreads throughout the layers of the gastrointestinal wall.

Unlike conventional GISTs, lymphovascular invasion (cancer cells spreading into blood vessels and lymphatic channels) and lymph node metastases (spread to nearby lymph nodes) are common in SDH-deficient GISTs. This is an important difference because lymph node involvement is rare in other types of GIST.

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 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.

Pathologic stage (pTNM)

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

Prognosis

The prognosis for a person with a gastrointestinal stromal tumour (GIST) depends on several factors, including the tumour’s size, location, and mitotic activity (how quickly the cells are dividing). These factors are assessed as part of the GIST risk assessment score (see the above section for more details).

Factors that influence prognosis

1. Mitotic activity: Pathologists count how often tumour cells are dividing in a specific area of the tumour. A higher mitotic count can indicate a more aggressive tumour, but some high-mitotic count tumours remain slow-growing for many years.
2. Tumour size: Larger tumours are more likely to spread than smaller ones.
3. Location: GISTs in the stomach tend to have a better prognosis than those in the small intestine. SDH-deficient GISTs are more unpredictable in their behaviour.
4. Tumour rupture: If the tumour has ruptured, there is a higher risk of spread.

How does mutation status affect prognosis?

The genetic mutation present in the tumour also plays a role in prognosis and response to treatment:

• KIT-mutant GISTs tend to behave more aggressively than PDGFRA-mutant or wild-type (no KIT, PDGFRA, or BRAF mutations) GISTs.
• Best prognosis: Tumours with PDGFRA exon 12, BRAF, or KIT exon 11 mutations tend to have a better outcome.
• Worst prognosis: Tumours with KIT exon 9, KIT exon 11, or PDGFRA exon 18 (except D842V) mutations tend to be more aggressive.

How does mutation status affect treatment response?

Mutation status can also predict how well a tumour will respond to imatinib (a targeted therapy):

• KIT exon 11-mutant tumours respond best to imatinib.
• PDGFRA exon 18 (D842V) mutations are resistant to imatinib and may require other treatments.
• KIT exon 9-mutant tumours may benefit from a higher dose of imatinib (800 mg instead of 400 mg).
• Some wild-type GISTs (including NF1-associated GISTs) do not respond well to imatinib.

Prognosis for SDH-deficient GISTs

SDH-deficient GISTs behave differently from other types. Some people with SDH-deficient GISTs and liver metastases can live for many years or even decades without needing specific treatment, while metastatic KIT/PDGFRA-mutant GISTs tend to grow and spread much more quickly.

Because GISTs vary widely in behaviour, doctors use prognostic tools that consider tumour size, mitotic count, and location to help estimate the risk of recurrence and guide treatment decisions.