Gastrointestinal stromal tumor (GIST) is the most common sarcoma of the gastrointestinal tract. The tumor can originate anywhere from the esophagus to the rectum, but most often comes from the stomach or small intestine. Uncommonly, GIST arises elsewhere in the abdomen outside of the gastrointestinal tract. GIST is a distinct entity from gastrointestinal leiomyosarcoma.
The exact incidence of GIST in the United States is unknown. Previously, the diagnosis was often missed because GIST was not widely recognized and the average pathologist had little to no experience with the tumor. Within the last 10 years, pathologists began using a certain test (CD117 or KIT staining) on tumors suspected to be GIST and this has made it easier to identify GIST. Currently, it is estimated that 3,000 patients in the United States are found to have GIST each year.
GIST affects slightly more males than females. Most patients are between 40 and 80 years of age at diagnosis. In nearly all patients, there is no apparent reason why GIST has developed. GIST has been found to run in only a dozen or so families in the world.
Historically, the 5 year survival of patients after removal of a primary GIST is approximately 50-60%. However, survival has now been markedly improved by the development of targeted chemotherapy (see below). In fact, patients with metastatic GIST treated with imatinib mesylate now have a 2 year survival of about 80% from the time of metastasis.
The prognosis of a patient with primary GIST depends on tumor size, location, and cellular division. Generally, patients with tumors that are 10 cm or greater in size have a high chance of developing tumor recurrence. Meanwhile, those with tumors less than 2 cm are more likely to be cured by surgical resection. Patients with tumors between 2 and 10 cm have an intermediate risk of having the tumor come back after surgery. The location of a primary GIST is also thought to influence outcome. Patients with stomach GIST fare better than those with small intestine GIST. The rate of cellular division (known as mitotic rate) of GIST is determined by examining the tumor under a microscope. Patients with a mitotic rate of 5 or greater per 50 high power microscopic fields have a higher chance of tumor recurrence after removal of a primary GIST. Another important factor in predicting outcome is the presence of tumor spread (metastasis) at the time of diagnosis of a primary GIST; these patients have a worse prognosis.
A primary GIST may be discovered in a variety of ways. Some patients lack symptoms and the tumor is detected during a radiologic examination, abdominal operation, or endoscopy performed for another reason. Other patients have abdominal discomfort or pain, or feel a mass. About 20% of patients will have slow bleeding in their gastrointestinal tract which they will not notice. Others have obvious gastrointestinal bleeding. Occasionally, a patient will develop intense abdominal pain and bleeding due to rupture of a GIST.
Like many sarcomas, GIST tends to push, and not invade, nearby structures. GIST also tends to be very vascular; in other words, it has many blood vessels supplying it. Nevertheless, GIST is often not diagnosed before it is removed. Under microscopic examination, the cells have a characteristic appearance and about 95% of tumors have stain for the KIT protein. It must be emphasized that an expert pathologist should be consulted whenever there is a possibility that a tumor may be a GIST but the diagnosis is uncertain. In particular, it is difficult to recognize the 5% of GIST that do not demonstrate KIT staining.
Treatment and Follow up for Local Disease
The treatment for primary GIST is surgical resection whenever possible. The goal of the surgeon is to remove the entire tumor without rupturing it. This may require removing parts of adjacent organs if the tumor adheres to them. During the operation, the surgeon should look carefully throughout the abdomen for the presence of tumor spread to other sites. It is unclear whether any other therapy should be given after successful removal of a primary GIST (see below). Outside of a clinical trial, the current recommendation is that patients should undergo surveillance for tumor recurrence by having a CT scan of the abdomen and pelvis with oral and intravenous contrast every 3-6 months for several years.
In some patients with primary GIST, the tumor may be too large to remove or may require extensive resection of other organs. In this setting, imatinib mesylate may be given for a few months to shrink the tumor and make surgery possible or to reduce the extent of the operation.
Treatment and Follow-up for Metastatic Disease
GIST tends to spread (metastasize) initially to the liver or to the lining of the abdomen (called the peritoneum). The initial treatment for metastatic GIST is currently imatinib mesylate (see below). Within 1-2 months, the tumors will shrink or stabilize in size in over 80% of patients. Other agents are available for patients who do not respond to imatinib. In patients who respond to imatinib, consideration should be given to removing their residual tumors whenever possible. Unlike targeted therapy, traditional chemotherapy has almost no effect on GIST and has mostly been abandoned.
Targeted therapies for GISTs
Imatinib mesylate (also known as Gleevec or STI571) was developed by Novartis Pharmaceuticals (Basel, Switzerland). Imatinib is a selective inhibitor of KIT and PDGFRA. These 2 proteins are involved in cell growth. Over 80% of patients with GIST have a mutation in the KIT gene, and about 5% have a mutation in the PDGFRA gene. Imatinib also inhibits another protein that is involved in a type of leukemia. The first patient with metastatic GIST was treated with imatinib in the year 2000. Imatinib is a pill that is taken daily. Unlike traditional chemotherapy, it is generally well-tolerated. The most common side effects are swelling around the eyes or in the legs, a skin rash, and minor stomach discomfort or diarrhea. Remarkably, imatinib provides benefit to over 80% of patients with metastatic GIST. George Demetri from the Dana Farber Cancer Institute and colleagues have shown that about 30% will have their tumor stop growing and another 50% will have their tumor shrink to less than half the original size. Rarely, imatinib may cause a small tumor to disappear completely. Imatinib has dramatically affected the outcome of patients with metastatic GIST. As stated above, the 2 year survival in metastatic GIST from the time of imatinib therapy is about 80%. In contrast, other chemotherapy agents used in the past provided almost no benefit.
The best dose of imatinib for metastatic GIST is currently being evaluated in 2 large studies. The initial data from the United States study show that the doses of 400 mg per day and 800 mg per day appear to be equivalent. It is generally recommended that imatinib be continued in patients with metastatic GIST unless the tumor becomes resistant to it. About half of the patients treated with imatinib will have their tumor start to grow again by 2 years. For this reason, we recommend that patients who respond to imatinib should be considered for complete surgical resection of their metastatic disease whenever possible. Postoperatively, imatinib should be resumed due to the likelihood of residual microscopic disease.
While it is clear that imatinib is useful for metastatic GIST, it is uncertain whether it should be used in patients following the complete resection of primary GIST. This is called adjuvant therapy. Adjuvant therapy is performed to reduce or eliminate the chance of a tumor coming back after its removal. Adjuvant imatinib is being studied in 2 clinical trials in this country and Canada. One trial (American College of Surgeons Oncology Group (ACOSOG) Z9000) of 106 patients with high risk primary GIST has completed accrual and the other trial (ACOSOG Z9001) in patients with a GIST 3 cm or greater in size has accrued over 300 patients so far. In both trials, 1 year of imatinib at a dose of 400 mg per day is given. In ACOSOG Z9001, half the patients receive a placebo. Because GIST is a relatively uncommon disease, both trials have required the participation of multiple cooperative groups of physicians. Data should become available in the next few years as to whether adjuvant imatinib is beneficial.
There are other targeted agents that are currently being tested for GIST. The most developed drug is SU11248, which was originally made by SUGEN, Inc. and is now owned by Pfizer, Inc. It inhibits KIT and PDGFRA as well as 2 other proteins called VEGFR and Flt3. So far, it has only been used in patients who have failed imatinib therapy and the agent will likely be approved shortly for use outside of a clinical trial.