Also known as:
- Gastrointestinal stromal sarcoma
- Paediatric, Adolescent, Wild-type & Syndromic GIST (PAWS-GIST)
- Carney’s Triad
- Carney-Stratakis Syndrome (a rare inherited form)
How rare are gastrointestinal stromal sarcomas?
In the UK and Europe the usual definition of a rare cancer is one that occurs in less than 6 people out of every 100,00 each year. Because there are around 200 rare cancers, this means that they make up about 24% (nearly a quarter) of all cancers.
In the UK GIST is diagnosed in around 900 people a year, making it a rare cancer with an incidence of around 1.3 cases per 100,000 a year. Of these 60-100 are PAWS-GIST, found in children and young adults. In adults GIST is usually diagnosed between the ages of 50 and 60 and is slightly more common in men. PAWS-GIST is slightly more common in young women. About 60% of GISTS start in the stomach, around 30% in the small intestine and the rest at various sites in the gastrointestinal tract (digestive system). Only 0.2% of all tumours found in the gastro-intestinal region are GISTs.
What is GIST?
GIST is a type of sarcoma, a cancer that affects the cells that make up the soft tissues of the body.
Sarcomas can form in any soft tissue such as muscles, blood vessels, tendons, ligaments, parts of joints, fat, the lower layers of skin and the connective tissue that supports and fills the spaces between the more familiar organs of the body.
Why is it called GIST?
GI: stands for the gastro-intestinal system, which is the digestive system or gut.
S: stands for stromal. Stromal tissues are the ones that are found supporting and surrounding the organs of the body. For example, a GIST that forms in the stomach is not stomach cancer. Stomach cancer starts in the specialised cells that line the stomach and produce protective mucus. They are the functional cells of the stomach. A GIST in the stomach will have started in other cells that are not directly involved with digestion.
T: stands for tumour. A tumour is a lump in the body. They can be quite soft, or relatively firm, benign (non-cancerous) or malignant (cancerous).
So GISTs are malignant tumours of the supporting cells in the digestive system.
Symptoms of GIST
Because GISTs are found in the digestive system, most of the symptoms will be due to its impact on the part of the gut it has developed in. These are often blood in your poo or vomit, discomfort or pain in your stomach, feeling sick or vomiting, weight loss, a painless lump in the stomach as well as more general symptoms of tiredness/fatigue, anaemia (not enough red blood cells) and fever and night sweats.
Where do GISTs start?
GISTs can occur in any part of the digestive system. This includes the oesophagus, stomach, small intestine, large intestine and rectum. The diagram below shows all of the parts of the digestive system. The labels underneath each of the two types of intestine show how each has been divided into smaller sections which do different jobs. Most GISTs are found in the stomach and small intestine, whilst only a handful of cases have been found in the liver.
GIST is thought to start in a particular type of cell called the “interstitial cells of Cajal” (named after a scientist who studied them), they are called ICC for short. The ICCs are found in the layers of muscle that surround the whole digestive system.
These muscles contract to squeeze food through the digestive system, from the first swallow to the final exit. The job of the interstitial cells is to act like a pacemaker to the muscle cells of your digestive system, making sure that these contractions happen at the right place and the right time.
As these ICCs are needed to help control the whole digestive system and are found from the start to the end, so GISTs can form anywhere in the gut.
What type of GISTS are there?
The most common type of GIST is simply known as “GIST” or “gastric GIST”, but there are other, rarer types which are now grouped together as PAWS-GIST. These include the paediatric (childhood) and adolescent GISTs as well as a genetically different form called “wild-type” GIST and inherited forms of GIST.
Paediatric/Adolescent GIST is more common among girls and young women than among boys and young men. It usually starts in the stomach and there may be many tumours present. It is also more likely to develop metastatic tumours in the lymph nodes. These tend to be slower growing than other GISTS.
Wild-type GIST is seen in people of any age, although it is still common in younger adults.
Syndromic GIST includes Carney’s Triad and Carney-Stratakis Syndrome. These are very rare forms of GIST that also have tumours in other parts of the body.
Other than increasing age and the very rare inherited conditions there are no clear risk factors for GIST. This means that there is nothing in someone’s lifestyle that can be changed to help prevent GIST, nor can a diagnosis of GIST be put down to something a person has done.
How GIST starts – genes linked to GIST.
What happens to turn interstitial cells cancerous? As with many cancers, GISTs start with a genetic change, or mutation. There are two key mutations that have been found in many GISTs.
The most common is a mutation in a gene called KIT. Mutations in KIT are seen in about 80% of all GISTs.
The gene KIT is sometimes called c-KIT or proto-oncogene c-Kit. A proto-oncogene is a gene that is normally found in the body that is known to cause cancer if it becomes mutated.
The c-KIT is the instructions to make an important protein, also called KIT, (or CD117 or SCFR). Unfortunately many genes and proteins in biology have multiple names as they are often discovered and named by different research groups.
KIT is found on the surface of many cell types including ones involved in the production of blood cells as well as cells found in the brain, lung, reproductive organs and the interstitial cells of Cajal in the digestive system. Its job is to stick to, or bind a molecule called stem cell factor (SCF) and trigger changes in the cell. Proteins that do this are called receptors because they receive messages.
KIT is one of a family of proteins called tyrosine kinases. These are a family of proteins that send messages within cells, telling them to activate or divide. The message is normally only passed on when it binds a molecule such as stem cell factor which activates the KIT protein.
When the KIT gene is mutated in GIST the KIT protein becomes permanently activated, so the message to divide and produce more cells is constantly being sent to the cells. If cells are constantly being made to divide, a tumour forms.
PDGFRa (platelet derived growth factor alpha).
Around 10-15% of GISTs have a different mutation. This is in another receptor protein found on many cells including blood cells and stromal cells called PDGFRa. This receptor binds a substance called platelet derived growth factor which is important for the formation of blood vessels and the growth of many tissues. PDGFRa is also a tyrosine kinase and when activated will trigger cells to divide. In GIST mutations occur that again lead to PDGFRa being permanently activated and the “divide” message constantly being sent.
Mutations in Variants of GIST.
The very rare sub-variants of GIST have a different genetic makeup to the more common form. They don’t tend to have the KIT/PDGFRa mutations found in adult GIST. They are the group known as PAWS-GIST.
Paediatric/Adolescent GISTs may be caused by other mutations that lead to excess KIT or PDGFRa being made. Many of these tumours have another mutation in the gene for a protein involved in releasing energy from glucose, called SDH (succinate dehydrogenase). This mutation stops SDH working and it is thought to be the cells trying to survive without it that leads to the cancer developing.
Wild-Type GIST is used to describe the form of GIST in adults who do not have either of the KIT/PDGFRa mutations. Many of these tumours also have mutations in the SDH gene. Some have mutations in another important oncogene called b-raf. Understanding which mutations are present will affect the choice of treatment.
Syndromic (Carney’s Triad and Carney-Stratakis Syndrome). These are very rare forms of GIST. Carney’s triad is not inherited. It is a condition when three separate types of tumour, including GIST,are seen in the same child. It is now thought that it is caused by a change in way the SDH gene is controlled. In Carney Stratakis syndrome, patients also have paraganglioma tumours (affecting nerve cells), so it is also known as the Carney-Stratakis dyad. Dyad means two parts This condition is caused by inherited mutations of the SDH genes.
Why genetic analysis is important.
In GIST, it is not a single mutation that occurs in KIT and PDGFRa. Mutations have been seen at several different points in the protein. The type and location of each mutation affects the treatments that can be used. The same is true for the other types of GIST. Because the standard therapies use targeted drugs, knowing which mutations are present can make sure the right treatment is used, or spare patients from the side-effects if a treatment is unlikely to work.
Treatment for GIST
Surgery is usually the first choice. The tumour(s) along with a border of normal tissue is removed. The border is to help ensure that no tumour cells are missed and that all of the GIST has gone. Depending on how the disease develops several surgeries may be used to help deal with tumours.
Targeted drug treatment
Imatinib mesilate (Glivec®)
Glivec was one of the first targeted drugs to be made. This means that rather than simply being toxic to any dividing cell (chemotherapy) it very specifically switches off one, sometimes more, proteins in the cell. Targeted drugs rely on them being able to lock or bind onto a particular part of a protein because they are an exact fit. This stops that protein working. Glivec was originally developed for another cancer, CML, where it bound to a different protein, also a tyrosine kinase. The researchers tested it against other similar proteins and found it was active against both KIT and PDGFRa.
Glivec may be given before surgery to reduce the size of tumours if they are very large, or difficult to remove, or after surgery (adjuvant therapy) to help prevent the tumour returning.
Because not all tumours have KIT/PDGFRa mutations the cancer genes must be genetically analysed to be certain that Glivec will work. Depending on the mutation found it may be necessary to change the dose to make it effective. For example, a mutation in a part called exon 9 will need a higher dose. If Glivec works it will have to be taken for many years to prevent the tumours returning.
Whilst Glivec is the first choice of treatment for GIST, the tumour cells can become resistant to the drug. Further mutations change the shape of the KIT or PDGFRa proteins, so Glivec no longer fits and is less effective. Sometimes it is used when patients struggle with the side-effects of Glivec.
An alternative is a drug called Sutent. It is similar to Glivec because it also affects tyrosine kinases, but different ones. The proteins Sutent affects are ones involved in the development of the blood vessels that are essential to supply tumours with the oxygen and nutrients they need to grow.
Sutent works best for people with certain KIT mutations (in exon 9) or wild-type GIST.
This relatively new drug affects several other tyrosine kinases that are involved in sending messages involved in the production of extra blood vessels. It can be used when Glivec or Sutent no longer work or are not tolerated very well.
What are the current clinical trials for GIST?
There is only one clinical trial currently being recruited in the UK. This is a study testing the value of detecting circulating tumour DNA in the blood of patients as an alternative to gastroscopy for diagnosis.
In the US 16 ongoing trials are listed (November 2022) Included in this are trials of KIT and other tyrosine kinase inhibitors that may work when tumours are resistant to Glivec, some immunotherapies that could activate an immune response against the GIST cells and another looking at using an older chemotherapy drug.