Gastrointestinal stromal tumor (GIST) is a rare malignancy of the gastrointestinal (GI) tract. Unlike the vast majority of GI cancers such as esophagus, stomach, and colon cancers, which come from epithelial cells (cells that form the inner lining of the GI tract), GIST derives from cells in the mesenchymal tissue (nonepithelial cells) and thus falls into the broad family of tumors called soft-tissue sarcomas.
GISTs represent less than 1 percent of all primary GI cancers. A study using the National Cancer Institute Surveillance, Epidemiology, and End Results (SEER) registry reported less than one case (0.68 case) of GIST per 100,000 people, or about 4,500 to 6,000 total cases annually, in the United States between 1992 and 2000.
Prior to the 1990s, there was much debate as to the type of cell in the GI tract that gave rise to GISTs. In the early 1990s, a significant breakthrough was made when almost all GISTs were discovered to express a protein called c-Kit (also known as CD117). C-Kit belongs to a class of proteins known as kinases that perform crucial functions in regulating the growth of cells. The c-Kit protein is found on the surface of malignant cells that form GISTs. Furthermore, in 80 percent of GISTs, the c-Kit protein contains mutations that render it more active, ultimately resulting in the uncontrolled growth of the malignant cells. The recognition of c-Kit expression as a common feature of GISTs now allows these tumors to be more readily distinguished from other malignancies of the GI tract, such as leiomyosarcomas.
It is now believed that GIST originates from cells in the mesenchymal tissue of the GI tract known as the interstitial cells of Cajal. These cells, which also produce c-Kit, are sometimes described as the “pacemaker” cells of the gut. They have characteristics of both smooth muscle cells and nerve cells and are important in regulating gut contractility (peristalsis), which helps move food through the gastrointestinal tract.
How It Spreads GISTs most frequently occur in the stomach, followed by the small intestine, omentum or mesentery (lining of the abdomen), colon, and esophagus. GISTs usually start in the second layer of the bowel wall and may grow inward (toward the cavity, or lumen, of the bowel, where food passes through) or outward. GISTs typically invade the local surrounding tissues by extension of the primary tumor and metastasize (spread) to distant sites such as the liver and abdominal cavity. GISTs rarely metastasize to the lymph nodes.
What Causes It The exact cause of GIST is unknown. Almost all GISTs express (make) the c-Kit protein on the surface of their cells. In 80 percent of GISTs, a mutation is found in the c-Kit protein that makes it much more active than the normal c-Kit protein. Most often, a mutation is found in a position of the c-Kit gene known as exon 11; less often, a mutation is found in exon 9, 13, or 17. Although the exact mechanism is unknown, it is believed the widespread expression of c-Kit and the presence of c-Kit mutations play a large role in the pathogenesis of GISTs. In rare cases, GISTs do not express the c-Kit protein and instead make a protein called platelet-derived growth factor receptor (PDGFR).
Risk Factors
There are no known risk factors for GIST. The vast majority of GISTs are sporadic (no evidence of inheritance from one generation to the next). However, a few families whose members have a predisposition to developing multiple GISTs have been described. These families were found to have germ line mutations in the c-Kit gene, which get passed on from one generation to the next.
Screening
Due to the low incidence of the disease and the fact that there are no known risk factors, there are no screening programs or recommendations for GIST.
Common Signs and Symptoms
The most common symptom caused by GIST—occurring in 40 percent of cases—is gastrointestinal bleeding, which is manifested as vomiting blood, passage of black tarry stools, or passage of bloody stools, depending on whether the tumor is in the stomach or further down in the intestines. Gastrointestinal bleeding usually causes anemia. When GISTs are large, they can result in bowel obstruction, which causes nausea, vomiting, severe abdominal pain, and constipation.
Diagnosis
The diagnosis of GIST depends on where the tumor is located.
Physical Examination There are few findings on physical examination.
• Paleness, due to anemia.
• Abdominal tenderness, due to bowel obstruction.
• An abdominal mass that can be palpated (felt).
• An enlarged liver (hepatomegaly).
• Fluid in the abdominal cavity (ascites).
Blood and Other Tests
• Fecal occult blood test (test for hidden blood in the stool).
• Complete blood count, which may indicate anemia due to gastrointestinal bleeding.
• Liver function blood tests (transaminases, alkaline phosphatase, bilirubin, and LDH), which may indicate tumor in the liver.
• Levels of serum iron and ferritin, which may indicate anemia.
Imaging
• X-rays of the upper gastrointestinal tract (upper GI series) by standard and double-contrast methods may find GISTs in the esophagus, stomach, and small intestine.
• Chest X-ray can detect tumors that have metastasized to the lungs and the midchest area (mediastinum).
• CT scan of the abdomen detects tumors in the liver and abdominal cavity and, less often, in the stomach, small intestine, and colon. CT scan of the chest detects tumors in the lung and midchest. CT scans define the size and lateral extent of tumors.
• PET scan is a nuclear medicine study that can distinguish whether a mass seen on CT is a GIST, and can occasionally detect tumors that are missed by CT scan. Tumors appear as bright spots on PET scan because they take up the radioactive sugar that is injected into the vein.
• MRI of the abdomen is sometimes used when CT scan with contrast (dye) cannot be used because of allergy to contrast or kidney failure.
Endoscopy and Biopsy
• Esophagoduodenoscopy (EGD) is the key test in the diagnosis of GIST found in the stomach or esophagus. A flexible fiber-optic tube with a camera at the end is passed through the esophagus into the stomach. The entire esophagus and stomach can be visualized with this technique to look for a GIST. If a mass is found in the stomach or esophagus, a piece of tissue from the mass can be biopsied using forceps located at the end of the fiber-optic scope.
• Colonoscopy is similar to EGD except that the flexible fiber-optic scope is passed through the rectum into the colon and is used to visualize the entire colon to look for masses. As in the case of EGD, biopsy of any colonic masses can be obtained during colonoscopy.
• Endoscopic ultrasound is a newer technique that uses an ultrasound probe at the end of an endoscope (such as an EGD) to evaluate the extent of a mass in the stomach or esophagus and to evaluate for any abnormal lymph nodes that may be affected by cancer near the stomach or esophagus.
• CT-guided biopsy is a technique in which a CT scan is used to locate a mass in the chest or abdomen while a needle is simultaneously used to biopsy the mass under the guidance of the CT image. This technique can be used to biopsy a mass in the abdominal cavity that is suspicious for a GIST.
• Pathology review of the tumor samples obtained by biopsy is done by looking at thin sections of the tumor tissue under the microscope. Immunohistochemistry, wherein the tumor tissue is stained by an antibody that recognizes the c-Kit protein, is also performed. Since almost all GISTs express the c-Kit protein, positive staining of the tumor tissue for c-Kit confirms the diagnosis of GIST.
Staging
There is no current staging system for GIST. However, two parameters are often used after removal of a GIST by surgery to determine its aggressiveness and to predict how likely it is to recur. The two parameters are the size of the tumor and its mitotic rate (the number of dividing tumor cells seen under the microscope). Using these two parameters, GISTs are divided into very low risk, low risk, intermediate risk, and high risk.
* HPF denotes high-powered field seen under the microscope.
Treatment Overview
The most important initial treatment decision for patients with GIST is to determine whether the tumor can be completely removed by surgery. If the GIST is not removable by surgery, other treatment options, including targeted therapy, may be considered.
Surgery Surgery is the only realistic means of cure in patients with GIST. Surgery is an option for patients with localized GISTs that have not metastasized to distant sites or invaded adjacent organs or vital structures (such as major blood vessels). When the tumor originates from the omentum or mesentery (lining of the abdominal cavity), surgery may be difficult, since the tumor usually spreads to multiple places in the abdominal cavity. Other factors determine whether a patient with GIST is a candidate for surgery. These include the overall health of the patient and whether the patient can tolerate an extensive operation.
The goal of surgery is complete resection of the tumor, whether it is in the esophagus, stomach, colon, omentum, or mesentery. During surgery, the rest of the abdominal cavity and the liver are explored to make sure there are no residual tumors or occult tumors that were not seen on preoperative imaging studies. GIST is usually encased by a sheath of tissue called a pseudocapsule, so care is taken during surgery to ensure that the tumor does not rupture. Even when GISTs are extending into adjacent organs (for example, a GIST that arises in the stomach and extends to the pancreas), they usually only displace these organs and do not invade them. Therefore, it is often possible to lift the tumor off the adjacent organs during surgery. For tumors in the esophagus or colon, surgery usually involves removing the tumor and portions of the esophagus or colon. For tumors in the stomach, either the entire stomach or a part of it is removed, depending on the size of the tumor. In all cases, the goal is to obtain a negative resection margin—a border of normal tissue surrounding the tumor that does not contain any cancer.
Most GISTs that are localized to one area are removable by surgery. For example, in a large series of patients with GIST published by the Memorial Sloan-Kettering Cancer Center, 85 percent of patients with localized GIST were able to undergo complete resection. Nearly 45 percent of these patients remained free of disease recurrence five years after their surgery.
In general, the likelihood of recurrence after complete resection of a GIST depends on two factors: the size and the mitotic rate (number of dividing cells) of the original tumor. As described in the table above, tumors that are greater than 4 inches (10 cm) in dimension or have a mitotic rate greater than ten per fifty high-powered fields are at high risk of relapse (greater than 50 percent at five years). Tumors that are smaller than 2 inches (5 cm) and have a mitotic rate of less than ten per fifty high-powered fields have a less than 10 percent chance of recurrence at five years. Several studies are investigating the value of administering a drug called imatinib mesylate (Gleevec) following surgery to try to decrease the risk of tumor recurrence (see “Targeted Therapy,” below). In some instances, patients may also receive this same drug prior to their planned surgery, with the goal of shrinking the tumor to allow for a safer operation.
Chemotherapy Traditional chemotherapy agents, in contrast to newer targeted therapies such as imatinib mesylate (Gleevec) and sunitinib (Sutent), are not effective in the treatment of GIST.
Targeted Therapy Metastatic GISTs or locally advanced GISTs that have invaded (grown into) adjacent organs are not resectable by surgery. Prior to the year 2000, there was no known effective treatment for patients with these unresectable tumors. However, the discovery in the late 1990s that almost all GISTs express the c-Kit protein and that the c-Kit protein is abnormally activated in the tumor cells led to the development of a very effective treatment for unresectable GIST.
In the early 2000s, imatinib mesylate (Gleevec) was discovered to specifically bind to (target) the c-Kit molecule and block its function. Imatinib is a small molecule that comes in the form of an oral pill and is easily absorbed by the bowel. It belongs to a new class of drugs called receptor tyrosine kinase inhibitors (RTKIs). Imatinib is a prototype of so-called targeted therapy, in which drugs are designed to specifically target and inactivate proteins (in this case, c-Kit) that are thought to be responsible for the uncontrolled growth of the cancer cells. Imatinib was originally approved for the treatment of chronic myelogenous leukemia (CML) when it was found to effectively block the activity of another protein, called BCR/ABL, which causes CML. In clinical trials, most patients with CML who took imatinib had complete remission of their disease.
Due to its ability to block the activity of c-Kit, imatinib was studied in patients with GIST. In a large multinational clinical trial comparing two doses of imatinib in patients with unresectable GIST, 66 percent of patients had marked shrinkage of their tumors, and another 16 percent had tumors that remained stable on treatment. The median duration of response was twenty-seven months. There was no difference in response rates between the two doses tested (400 mg and 600 mg daily). Based on these positive results, imatinib was approved by the FDA in 2002 for the treatment of unresectable or metastatic GIST.
Imatinib is generally very well tolerated by patients. Its most common side effects are swelling of the area around the eyes, generalized swelling, mild skin rash on the face, and mild decrease in blood counts (decreased red blood count, called anemia, and decreased platelet count). Other side effects include nausea, abdominal bloating and cramping, and diarrhea. All of these side effects are usually mild.
Interestingly, it appears that the type of c-Kit mutation found in a patient’s GIST determines how well the patient responds to imatinib treatment. In a large clinical trial in which patients with unresectable GIST were treated with imatinib, patients whose GIST contained a c-Kit mutation at exon 11 did much better than patients whose tumor contained a c-Kit mutation at exon 9 or no c-Kit mutation at all. A higher percentage of patients with an exon 11 mutation had tumor shrinkage with imatinib treatment; these patients also lived longer than patients with an exon 9 mutation or no mutation. While these sorts of mutational analyses are useful, they are not a part of routine testing at most pathology laboratories.
Despite the effectiveness of imatinib, most advanced GISTs eventually become resistant to imatinib treatment. For patients whose GIST has progressed despite imatinib treatment, another drug, called sunitinib (Sutent), has been found to be effective. Similar to imatinib, sunitinib is a tyrosine kinase inhibitor that targets and blocks the c-Kit protein, in addition to other proteins. Sunitinib also comes in the form of a pill that is taken orally. In a clinical trial comparing sunitinib to placebo in patients whose GIST had progressed despite imatinib, patients who took sunitinib had a longer period of tumor control (shrinkage or stable tumor) compared to those who took placebo. Patients whose GIST contained an exon 9 mutation in c-Kit did much better on sunitinib than patients whose tumor contained an exon 11 mutation. This is opposite of the effect seen with imatinib.
Sunitinib is also generally well tolerated by patients. Its most common side effects include diarrhea, skin discoloration, mouth sores, fatigue, high blood pressure, and decreased blood counts (red blood count and platelet count). Based on its efficacy, sunitinib was approved by the FDA in January of 2006 for the treatment of patients with GIST after disease progression on, or intolerance to, imatinib.
Because of the effectiveness of imatinib in patients with advanced GIST, this agent is being studied in patients whose GIST has been completely removed by surgery, to determine if it can increase the chance of cure in these patients. This type of therapy given after surgery is called adjuvant treatment. Two large clinical trials, one in Europe and the other in the United States, are currently evaluating imatinib as adjuvant therapy for GIST. Both trials are comparing imatinib treatment to no adjuvant treatment in patients with intermediate or high-risk GIST (determined by tumor size and mitotic rate) that has been completely removed by surgery. Results from these studies are not yet available. Furthermore, potentially operable patients whose tumors are very large at the time of diagnosis, may initially start treatment with imatinib for a period of time, with the goal of shrinking the tumor to make eventual surgical resection safer and easier (referred to as neoadjuvant therapy).
Assessing Treatment Response
Two types of scans are usually used to determine whether a patient with GIST is responding to treatment with imatinib or sunitinib—CT and PET scans. Either scan is obtained every three to six months while the patient is on treatment. A CT scan often shows shrinkage of tumors if they are responding to therapy. However, GISTs can sometimes increase in size or remain the same size on the CT scan in early treatment, due to bleeding in the tumor or death and degeneration of tumor cells; thus, this is not indicative of treatment failure. Often, GISTs that are responding to treatment become less bright on CT scan (hypodense) and PET scan (decreased uptake).
Treatment by Stage
Localized
The standard for patients with localized GIST that has not metastasized to distant organs or invaded adjacent organs is surgery. For GISTs in the stomach, the tumor and either part of the stomach or the entire stomach are removed (gastrectomy). For tumors in the esophagus, small intestine, or colon, portions of the esophagus, intestine, or colon are removed along with the tumor. In all cases, the goal is to achieve a negative margin around the tumor.
Five-Year Survival 35 to 87 percent, depending on the size of the tumor and the mitotic rate
Investigational The adjuvant treatment of patients with completely resected GIST is currently being evaluated in two Phase III clinical trials, one in the United States and the other in Europe. Both trials are comparing imatinib treatment to no adjuvant treatment in patients with intermediate or high-risk GIST (determined by tumor size and mitotic rate) that has been completely removed by surgery. The goal of adjuvant therapy is to reduce the risk of disease recurrence. Results from these studies are not yet available. As noted above, neoadjuvant therapy with imatinib is also a strategy frequently used for GISTs that are very large at initial presentation.
Localized Advanced or Metastatic
The standard treatment of patients with locally advanced or metastatic GIST is targeted therapy with imatinib. The rate of tumor shrinkage with imatinib is in the range of 60 to 70 percent. If patients progress on imatinib, the dose of imatinib is increased or the patients are switched to treatment with sunitinib (Sutent). Patients who exhibit an excellent response to treatment and have isolated sites of residual disease may benefit from surgical exploration to resect these areas, but the long-term advantages of such an approach have yet to be proven.
Five-Year Survival 10 to 20 percent
Investigational Other novel targeted-therapy agents are being evaluated in clinical trials in patients with unresectable GIST that is resistant to imatinib treatment. These include sorafenib (Nexavar) and PTK/ZK (vatalanib), both of which are tyrosine kinase inhibitors that block vascular endothelial growth factor (VEGF). VEGF plays a key role in tumor blood vessel formation, which in turn is important in tumor growth and metastasis. Another clinical trial is evaluating the combination of imatinib and bevacizumab (Avastin), which is an antibody directed against VEGF.
Recurrent Cancer
Patients whose GIST recurs after surgery may undergo a repeat operation if the recurrence is localized and the individual is a good candidate for surgery. If the recurrent disease is more extensive, patients are typically treated with imatinib mesylate (Gleevec) and sunitinib (Sutent) as in the case of metastatic disease.
Prevention
Because GIST is so rare and is not associated with any known risk factors, there are no recommended preventive measures against GIST.
The Most Important Questions You Can Ask
• Is my GIST removable by surgery? If not, why not?
• Is there a role for imatinib either before or after my planned surgery to remove the tumor?
• Based on the pathology of the tumor, is my GIST high, low, or intermediate risk and what does that mean?
• Does my GIST express the c-Kit protein?
• Can the tumor be analyzed for its mutational status (e.g., exon 11 or 9 mutation)?
• If the tumor is not removable by surgery, can I take imatinib or sunitinib (Sutent)?
• Is there a clinical trial available for my condition?
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