NORD gratefully acknowledges Ernest C. Borden, MD, Taussig Cancer Institute. Cleveland Clinic Foundation, for assistance in the preparation of this report.
Gastrointestinal stromal tumors (GISTs) belong to a group of cancers known as soft tissue sarcomas. The number of new cases in the United States annually has been estimated to be 5,000-6,000. Tumors usually arise from the intestinal tract with the most common site being the stomach, followed by the small intestine, and then the colon/rectum with rare cases arising in the esophagus. There are also tumors that appear to arise in the membranous tissue lining the wall of the stomach (peritoneum) or in a fold of such membranous tissue (the omentum). There are also case reports of tumors arising in the appendix and/or pancreas. These tumors most commonly present with abdominal pain, bleeding or signs of intestinal obstruction. They spread most commonly to sites within the abdominal cavity and to the liver, although there are rare cases of spread to the lungs and bone. Some GISTs are noncancerous (benign) and do not spread (indolent); others are aggressive with extensive local invasion as well as distant metastases. Most cases result from a change (mutation) in one of two genes, KIT or PDGFR, which leads to continued growth and division of tumor cells. There are a few reported cases of families in which a gene mutation is inherited; however, the majority of tumors occur randomly for no apparent reason (sporadically) and not inherited (acquired mutation). Most cases arise in older adults.
Approximately 10-15% of cases of GIST in adults and 85% of cases in children are not associated with mutations in either the KIT or PDGFR genes. These cases are known as wild type GISTs and are sometimes grouped together under the umbrella term pediatric-like GIST. They may be associated with other genes or have no identifiable gene mutation.
GISTs were initially believed to be a single entity, but recent research has shown that there are several molecular subtypes with different characteristics including different prognoses, clinical symptoms, and different associated genes. that respond differently to various treatment options. Broadly, GISTs are classified as a soft tissue sarcoma. Sarcomas are malignant tumors that arise from the connective tissue, which connects, supports, and surrounds various structures and organs in the body. Soft tissue includes fat, muscle, nerves, tendons, and blood and lymph vessels.
The most common site of origin is in the stomach (39-70%), often presenting with pain, GI bleeding and/or a mass that can be seen or felt (palpable). GI bleeding can lead to anemia, which can lead to paleness, lightheadedness, and fatigue. Other symptoms may include a vague feeling of abdominal discomfort, a feeling of abdominal fullness or bloating, or feeling full sooner than normal after eating (early satiety). Other primary sites are the small intestine (31-45%), colon and rectum (10-16%), and mesentery (membranous folds that attach various organs to the body wall) or membranous lining of the abdomen (peritoneum) (8%). Patients presenting with tumors of the small intestine may also experience weight loss, fever, abscess, and/or urinary symptoms. There are rare cases presenting in the lowest third of the esophagus causing difficulty with swallowing and weight loss.
The primary site of the tumor may be a prognostic factor with small intestinal GISTs having a poorer survival than those originating in the stomach. In addition, intestinal location has been correlated with a high risk of spread (metastases). GISTs can also arise in the omentum and mesentery, not in association with a component of the gastrointestinal tract. Tumors present as large masses; some appear to develop in association with cysts.
Approximately 80-85% of GISTs are limited to one site upon diagnosis. GISTs spread most commonly to sites within the abdominal cavity and to the liver, although there are rare cases that have spread to the lungs and bone. GISTs rarely spread to the lymph nodes.
PEDIATRIC-LIKE GASTROINTESTINAL TUMOR
GISTs are extremely rare in children and adolescents. The symptoms and pathology of GISTs in these age groups is different from these tumors in most adults. Generally, pediatric GISTs present in the stomach, affect girls more often than boys, and usually are not associated with mutations in the KIT or PDGFR genes (wild type GIST). In addition, pediatric cases are more likely to show lymph node involvement and more likely to spread to the liver and abdomen. Usually, these tumors are more indolent than adult GISTs.
Initially, it was believed that age was a determining factor in the differences between cases of GIST in adults and children. However, some adult cases with wild type GIST share the distinct characteristic findings found in most pediatric cases. Thus, separating these cases based on age is unwarranted. Collectively, these cases are known as under the umbrella designation, pediatric-like GIST.
Also included in this umbrella category are cases associated with neoplastic syndromes such as Carney triad (gastric GISTs, paragangliomas, and pulmonary chondromas) and Carney-Stratakis syndrome (GISTs and familial paraganglioma).
There is no exposure or infection that is known to predispose to GISTs. It is known that the majority of tumors will have mutations in the KIT gene, and a minority, in the PDGFR gene. There are common sites for mutations. For the KIT gene, the most common mutation site is in exon 11, but can also involve exon 9, 13, and 17. Mutations in the PDGFR gene involve exon 12 or 18. Exon refers to the region of a gene that contains the code for producing the gene’s protein. Each of these mutations is on the long arm of chromosome 4 (4q12).
Chromosomes, which are present in the nucleus of human cells, carry the genetic information for each individual. Human body cells normally have 46 chromosomes. Pairs of human chromosomes are numbered from 1 through 22 and the sex chromosomes are designated X and Y. Males have one X and one Y chromosome and females have two X chromosomes. Each chromosome has a short arm designated “p” and a long arm designated “q”. Chromosomes are further sub-divided into many bands that are numbered. For example, “chromosome 4q12” refers to band 12 on the long arm of chromosome 4. The numbered bands specify the location of the thousands of genes that are present on each chromosome.
Current research suggests that abnormalities of DNA (deoxyribonucleic acid), which is the carrier of the body’s genetic code, are the underlying basis for cellular malignant transformation. In individuals with cancer, malignancies most often develop due to abnormalities in the structure of genes within the nuclei of cells known as “oncogenes” or “tumor suppressor genes.” Oncogenes control cell growth; tumor suppressor genes control cell division and ensure that cells die at the proper time. The KIT and PDGFR genes are oncogenes. Mutations of these genes lead to unrestricted growth of cancer cells. Most of these genetic mutations are acquired during life, are found only in cancer cells, and are not passed on to an affected individual’s children. A few families with inherited mutations of the KIT gene have been described. They have early onset of GISTs in adolescence or young adulthood. Some families have altered skin pigmentation or difficult swallowing (dysphagia). At least one family has been described with an inherited mutation of the PDGFR gene. Inherited cases are extremely rare and are known as familial GIST.
Familial GIST is believed to be inherited as an autosomal dominant trait. Genetic diseases are determined by the combination of genes for a particular trait that are on the chromosomes received from the father and the mother. Dominant genetic disorders occur when only a single copy of an abnormal gene is necessary for the appearance of the disease. The abnormal gene can be inherited from either parent, or can be the result of a new mutation (gene change) in the affected individual. The risk of passing the abnormal gene from affected parent to offspring is 50% for each pregnancy regardless of the sex of the resulting child.
As stated above, wild type GISTs do not have mutations of the KIT or PDGFR genes. Some of these cases have been linked to genes involved in the succinate dehydrogenase (SDH) enzyme complex (i.e. SDHA, SDHB, SDHC or SDHD genes). These genes create (encode) enzymes involved in the formation of succinate dehydrogenase. Many pediatric patients are referred to as succinate dehydrogenase deficient because they have low levels of this enzyme.
Additional genes have been linked to wild type GISTs including BRAF, KRAS, and NRAS mutations. Many cases are also associated with overexpression of insulin-like growth factor 1, although the significance of this finding is not fully understood. Some cases have no identifiable gene mutation suggesting that additional genes can cause GISTs.
GISTs can also occur as part of a larger cancer predisposition syndrome such as Carney-Stratakis syndrome (CSS) and Carney’s triad. CSS is a genetic disorder that is believed to be caused by mutations in the genes of the succinate dehydrogenase enzyme complex. It is inherited as an autosomal dominant trait. The exact, underlying cause of Carney triad is unknown. Individuals with neurofibromatosis type 1, a genetic disorder caused by mutations to the NF1 gene, are at a greater risk than the general population of developing a pediatric-like GIST, which usually presents as multiple tumors in the small intestine.
GISTs are believed to arise from specific cells known as interstitial cells of Cajal (ICC) or the undifferentiated precursor cells that ultimately develop into these cells. ICCs are the “pacemaker” cells of the gastrointestinal tract and are critical for proper GI motility. They help to generate and maintain electrical rhythmic activity within the GI tract including the series of muscular contractions that help propel food through the digestive system (peristalsis).
Researchers have also discovered that most GISTs are positive for CD117, a characteristic marker or antigen found on the surface of cancer cells. The discovery of CD117 can aid in the diagnosis of GISTs and can be an important factor in developing new treatments.
The typical patient with a GIST presents in the fifth to seventh decade of life, with some studies suggesting a male predominance. Children have also been found to present with GISTs. The disease in children may have a slower time course. Pediatric cases occur more often in females. There does not appear to be a link to a particular ethnic background. Individuals with familial GIST usually do not present with tumors until the mid-40s.
The exact incidence and prevalence of GISTs are unknown and estimates vary ranging from 9-19 people per 1 million in the general population. GISTs are the most common sarcoma of the gastrointestinal tract, but are estimated to account for only .1-3% of all gastrointestinal cancers.
Diagnosis can be by biopsy. Some tumors are diagnosed by endoscopy. The use of endoscopic ultrasound for lesions in the stomach can be helpful as these tumors can be below the surface of the stomach. If tumors are larger than 2-3 cm, a biopsy suggesting a benign lesion should be interpreted with caution.
Most patients undergo computed tomography (CT) scans to determine the extent of the tumor involved. It is most important to image the abdomen and pelvis as the most common sites of spread are within the abdominal cavity and the liver. If patients complain of bone pain, a bone scan should be considered, to determine if there is disease in the bones. PET scanning has been shown to be a helpful additional test; however, at this time it is not routinely covered by insurance companies.
Tumors that are confined to one site without evidence of spread (localized) are treated by surgical removal. There is no clear benefit for radiation therapy after surgery for this type of sarcoma. Surgery can cure most patients if the tumor is completely removed.
Standard chemotherapies are not effective for this type of sarcoma, with a less than 5% response rate. Imatinib mesylate (Gleevec®), a tyrosine kinase inhibitor that inhibits the KIT or PDGRF proteins responsible for tumor growth, has been found to be very effective in controlling disease that has spread. The majority of patients will have their tumors decrease in size or stabilize for many months. Although imatinib mesylate has been very effective at controlling disease, patients who have disease that has spread from the initial site (metastatic disease) rarely experience the complete disappearance of all disease. In addition, some individuals eventually develop resistance to imatinib mesylate. Surgery may be combined with imatinib mesylate to control metastatic disease.
Gleevec, which is manufactured by Novartis Pharmaceuticals Corporation, was granted accelerated approval by the Food and Drug Administration (FDA) for the treatment of advanced or metastatic GIST in 2002. Imatinib is an oral drug that inhibits the function of both KIT and PDGFR proteins. It has been shown to have significant activity in patients with recurrent tumors.
A subsequent accelerated approval was received in 2008 for adjuvant use by patients with GIST who have potentially curative resection (surgical removal) of GIST tumors, but who are at increased risk for a recurrence. This accelerated approval program provided earlier patient access to Gleevec while the confirmatory clinical trials were being conducted. In 2008, regular approval for the metastatic GIST indication was also granted.
Gleevec was granted regular approval by the FDA in 2012 as a treatment for use in adult patients following surgical removal of CD117-positive gastrointestinal stromal tumors. There is an increase in overall patient survival when the drug is taken for 36 months rather than the standard 12 months of treatment.
In 2006, another tyrosine kinase inhibitor, known as sunitinib malate (Sutent®), was approved by the FDA for the treatment of GIST in individuals in whom the disease had progressed despite therapy with Gleevec or who cannot take Gleevec. Sutent appears to be particularly effective in certain individuals with wild type GIST. Sutent is manufactured by Pfizer Inc.
In 2013, a third type of tyrosine kinase inhibitor known as regorafenib (Stivarga®) was approved by the FDA for the treatment of GIST, specifically for individuals with advanced GIST that cannot be treated surgically and who no longer respond to other FDA-approved treatments (i.e. Gleevec and Sutent). Regorafenib is a multi-kinase inhibitor that blocks the activity of several enzymes that promote cancer growth.
Alternative approaches include treatments directed at sites of liver involvement. Embolization or chemoembolization are ways of decreasing blood supply to the tumor sites within the liver and can control disease for some time. Another approach called radiofrequency ablation uses localized radiation; this overcomes the problem of side effects from treating the whole liver with radiation, as normally the liver is very sensitive to radiation.
Additional tyrosine kinase inhibitors are being studied for individuals with GIST including sorafenib, dasatinib, motesanib, nilotinib, masitinib, and crenolanib. These drugs differ in their ability to inhibit one or more tyrosine kinases. An inhibitor known dabrafenib that acts against the protein B-raf protein demonstrated prolonged antitumor activity in an individual with GIST associated with a mutation of the BRAF gene. More research is necessary to determine the long-term safety and effectiveness of these drugs and whether they have a role in the treatment of individuals with GIST.
GIST that are not associated with mutations in the KIT or PDGFR genes (i.e. wild type or pediatric-like GIST) do not respond effectively to treatment with tyrosine kinase inhibitors such as Gleevec or Sutent. Researchers are studying other treatment avenues to find effective treatments for these types of GIST.
Information on current clinical trials is posted on the Internet at www.clinicaltrials.gov. All studies receiving U.S. government funding, and some supported by private industry, are posted on this government web site.
For information about clinical trials being conducted at the NIH Clinical Center in Bethesda, MD, contact the NIH Patient Recruitment Office:
Toll-free: (800) 411-1222
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For information about clinical trials sponsored by private sources, contact:
For more information about clinical trials conducted in Europe, contact: https://www.clinicaltrialsregister.eu/
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