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40 years!
Last updated:
4/12/2024
Years published: 2004, 2014, 2020, 2024
NORD gratefully acknowledges Jason K. Sicklick, MD, FACS, Associate Professor of Surgery, Division of Surgical Oncology, Moores Cancer Center, UC San Diego Health Sciences, for assistance in the preparation of this report.
Summary
Gastrointestinal stromal tumors (GISTs) are in a group of cancers known as sarcomas. The number of new cases in the United States each year has been estimated at 5,000–6,000. These tumors arise from nerve cells in the wall of the gastrointestinal (GI) tract and can occur anywhere from the esophagus to the rectum. However, most arise in the stomach (55%) and the small intestine (29%), while the colon/rectum (3%) and esophagus (0.5%) are less common sites of the disease. There have also been rare reports of tumors arising in the appendix, pancreas, gallbladder and lining of the abdominal cavity.
These tumors most commonly present with non-specific symptoms, including feeling full sooner than normal after eating (early satiety) and abdominal pain, but may also present with bleeding or signs of intestinal obstruction. They spread most commonly to sites within the abdominal cavity and to the liver, although certain subtypes spread to lymph nodes and very rare cases spread to the lungs and bone. Although it was previously believed that some cases of GIST are benign (do not spread), it is now understood that all GISTs have some potential to metastasize, with risk ranging from very low to high. A better understanding of GIST biology has also revealed that its prevalence varies across racial and ethnic groups.
Most GISTs result from a non-inherited change (variant) in one of two genes, KIT or PDGFRA, which leads to inappropriate and ongoing division of tumor cells. However, approximately 10%–15% of cases of GIST in adults and 85% of cases in children are not associated with variants in either the KIT or PDGFRA genes. These previously uncategorized cases were originally grouped under the umbrella terms “wild-type GIST” and “pediatric-like GIST.” Advances in research have since revealed that these tumors have variants in as many as 20 other genes, and defining the specific variants in individual patients can help guide further research and treatment.
Most GIST-causing variants arise randomly and are not inherited. However, there are rare cases in which a gene variant is inherited, for example in succinate dehydrogenase (SDH)-deficient GIST associated with Carney–Stratakis syndrome (CSS; also known as GIST-paraganglioma syndrome). Though most GIST arise in older adults, these rarer cases of inherited GIST often present in children, adolescents and young adults.
GIST is most commonly diagnosed by pathological analysis of biopsy tissue taken during an endoscopy or through the skin. Computed tomography (CT) and magnetic resonance (MR) imaging are also used to diagnose GIST and determine the location and extent of the tumor. Molecular characterization of the tumor, through identification of specific gene variants or the presence of markers on the tumor surface, provides further information for diagnosis and can help guide treatment.
Surgical removal is the most common treatment for GIST that has not spread, and an operation provides the best chance of a cure if the tumor is completely removed. In cases where the tumor has spread, oral chemotherapy (i.e., pills) is usually indicated in conjunction with surgery. The most frequently used drugs are tyrosine kinase inhibitors (e.g., Gleevec), which target the commonly observed variants in KIT and PDFGRA. Patients respond differently to the range of available tyrosine kinase inhibitors, so it can be useful to test for specific variants in the tumor when selecting a course of therapy. Clinical trials are also underway to target subtypes of GIST with rare genetic variants. Finally, it is noteworthy that there is no role for radiation therapy in the management of GIST.
Introduction
GISTs belong to the group of cancers called sarcomas, which are malignant tumors that arise from various tissues, including fat, muscle, nerves, cartilage, bone, blood vessels and lymphatic vessels. This distinguishes sarcomas from carcinomas, which arise from the lining of organs/tissues (e.g., lung, colon, breast, prostate and pancreas), lymphomas, which arise from immune cells in lymph nodes and leukemias, which arise from immune cells in the bone marrow.
Until the late 1990s, the diagnosis of GIST did not exist. We now know that GISTs are the most common sarcomas and that these tumors arise from the interstitial cells of Cajal (ICC), pacemaker cells in the wall of the bowel that regulate the muscular contractions that help propel food through the digestive system (peristalsis). Recently, cells called telocytes have been suggested as an additional source of some GISTs. Overall, GISTs are molecularly heterogeneous, with their genetic variants linked to tumor location, prognosis and pattern of spread, as well as drug sensitivity and resistance.
GIST can present with a wide spectrum of subjective symptoms, such as nausea, early satiety, bloating and weight loss. Patients can also experience objective signs of a tumor, such as anemia (low red blood cell count) or a lump in the abdomen. These signs and symptoms depend on the tumor location (e.g., stomach versus rectum), size and pattern of growth.
The most common site of origin is in the stomach (~55%), and these tumors are often associated with pain, GI bleeding and/or a mass that can be seen or felt (palpable). Other primary sites are the small intestine (~29%), the colon and rectum (~3%) and the esophagus (~0.5%). Rarely, cases of so-called extra-intestinal GIST (E-GIST) have been reported to occur outside the bowel, along the lining of the abdomen or within the abdominal fat. Tumors present visually as discrete masses. GI bleeding can lead to anemia, which can cause paleness, lightheadedness, fatigue and other symptoms. Patients presenting with tumors of these sites may also experience weight loss, fever, abscess and/or urinary symptoms. There are rare cases presenting in the lowest third of the esophagus, which can cause difficulty with swallowing and resultant weight loss.
The primary site of the tumor may affect prognosis, with small intestinal GIST having a poorer survival rate than that originating in the stomach (though this notion has been questioned in recent studies). In addition, intestinal location has been correlated with a high risk of spread (metastases). Approximately 75%–90% of GISTs are limited to one site upon diagnosis. GIST spreads 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. GIST rarely spreads to the lymph nodes. Although some cases of GIST were previously thought to be benign, it is now known that all GISTs have the potential to spread. This risk is dependent on the tumor location and size, as well as the number of cells that are dividing (i.e., mitotic index), as counted by a pathologist using a microscope.
GIST in children and adolescents
GIST is extremely rare in children and adolescents, and the symptoms and pathology in these age groups are different from those in most adults. These cases generally present in the stomach, are more likely to show lymph node involvement and are more likely to spread to the liver and abdominal lining. They are usually not associated with the KIT or PDGFRA gene variants found in most adults, and about 80% of these cases have a variant in the gene for the succinate dehydrogenase (SDH) enzyme complex. Patients with these SDH-deficient tumors most often have an accompanying diagnosis of hormone-secreting paraganglioma in a condition known as Carney–Stratakis syndrome (CSS). Thus, patients should be screened for neck and chest paragangliomas, and also assessed for the presence of specific hormone metabolites in urine (catecholamines and metanephrines). It was previously believed that age was a determining factor in the differences between cases of GIST affecting adults versus children, and cases in children were distinguished as “pediatric-type” GIST or “wild-type” GIST. However, some adult cases of GIST share the distinct characteristics found in most pediatric cases, rendering the separation of these cases based on age unwarranted and somewhat of a misnomer. It is now best to discuss GIST subtypes based upon the specific characteristics of the tumor.
Current research suggests that disease-causing gene variants underlie the processes by which cells become cancerous. Specifically, malignancies most often develop due to variants in genes known as “oncogenes” or “tumor suppressor genes.” Oncogenes promote cell division, while tumor suppressor genes block cell division and ensure that cells die at the proper time; abnormalities of either type of gene can contribute to cancer development. In the case of GIST, most tumors have variants in the KIT oncogene and a minority have variants in the PDGFRA oncogene. Both genes encode proteins called tyrosine kinases, a finding that has been critical for better understanding and treating the disease. Most of these cancer-causing variants are acquired during life, rather than being inherited, and are found only in the cancerous cells.
There is no environmental exposure or infection that is known to predispose individuals to GIST and the relevant gene variants most often happen randomly (sporadically) rather than being inherited. There are also common sites for variants for each. For the KIT gene, the most common variant site is in exon 11, but can also involve exons 9, 13/14, and 17/18. Variants in the PDGFRA gene involve exon 12 or 18. The term exon refers to the regions of a gene that contain the code for producing the gene’s protein and are used to delineate different regions of a gene.
Though very rare, a few families with inherited variants of the KIT gene have been described. They experience early onset of GIST in adolescence or young adulthood. Some of these families have altered skin pigmentation or difficult swallowing (dysphagia). In addition, at least one family has been described with an inherited variant of the PDGFRA gene. Inherited cases are rare and are known as familial GIST.
There are also instances of GIST that do not have variants of the KIT or PDGFRA genes. Most of these cases have been linked to variants in the genes that encode the succinate dehydrogenase (SDH) enzyme complex (i.e., SDHA, SDHB, SDHC, or SDHD). These variants lead to loss of the SDH complex and lack of SDHB protein staining in tumors. These SDH-deficient GISTs are clinically distinct in that they generally affect younger patients and are associated with additional tumors in two syndromes known as Carney–Stratakis syndrome (CSS) and Carney triad. CSS is a hereditary condition associated with variants in the SDH gene. Carney triad, on the other hand, is a non-hereditary condition in which the DNA code is not affected, but the DNA structure of the SDHC gene is modified by a process called methylation (also known as epigenetic variation). Because SDH-deficient GISTs are not caused by KIT or PDGFRA variants, they are generally resistant to tyrosine kinase inhibitors.
Additional gene variants have also been linked to GIST, including in the BRAF, KRAS, and NF1 genes of the RAS/MAPK pathway. While BRAF and KRAS are not associated with inherited GIST, inherited variants in the NF1 gene lead to a disorder called neurofibromatosis type 1, which is associated with greater risk of GIST. These cases usually present as multiple tumors in the small intestine. There is also emerging evidence that, even in the absence of inherited NF-1variants, specific BRAF and NF1 variants frequently occur in GISTs of the proximal small bowel (known as the duodenal-jejunal flexure or ligament of Treitz). These findings are important because these variants do not respond to standard drug treatments.
Some cases of GIST were previously called “quadruple wild type” GIST, as they lacked variants in the KIT, PDGFRA, RAS pathway (KRAS, NF1, BRAF), and SDH genes. Because this designation was based on the absence of identifiable gene variants, it was believed that additional genes were responsible for these “unclassified” cases. In recent years, studies have identified several new genetic abnormalities associated with GIST. These include gene fusions, in which a hybrid forms from two previously independent genes. Various GIST-associated fusions have been identified that include the FGFR1 gene, the ETV6–NTRK3 fusion, and the BRAF gene. Importantly, these GIST subtypes respond differently to the available drug treatments, highlighting the importance of understanding the specific biology of individual tumors.
The exact incidence and prevalence of GIST are unknown, but estimates range from 3.2–19 people per million in the general population. GISTs are the most common sarcomas of the GI tract, though they account for only a small fraction of all GI cancers. The typical GIST patient presents in the fifth to seventh decade of life, with some studies suggesting that males are affected more often than females. Children have also been found to present with GIST, but these cases are very rare and usually occur as SDH-deficient GIST in the setting of CSS (males or females) or Carney triad (females only). The disease in children may have a slower time course, but this is not always so; in rare cases, the disease may be more aggressive. As a better understanding of GIST biology has emerged, and potential links between the incidence of GIST and ethnic backgrounds have been revealed. In the U.S., the highest rate is within the black population, followed by Asian/Pacific Islanders, whites and Hispanics.
GIST diagnosis can be confirmed by biopsy during endoscopy or by percutaneous biopsy (through the skin). The use of endoscopic ultrasound for lesions in the stomach can be helpful, as these tumors can be below the surface of the stomach and therefore not seen by standard endoscopy. If tumors are larger than 2 cm, a biopsy suggesting a benign lesion should be interpreted with caution.
Most patients undergo a computed tomography (CT) or magnetic resonance imaging (MRI) scan 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. PET/CT scanning may be helpful as an additional test in cases where there is diagnostic uncertainty; however, it is not routinely performed.
The molecular characteristics of a tumor can also help identify it as GIST. As indicated above, variants in the KIT, PDGFRA, or SDH genes are present in most cases of GIST and their presence can be used for diagnosis. A growing number of rarer variants have also been discovered, meaning that gene-based diagnosis of GIST is becoming increasingly sensitive. In addition, markers (antigens) on the surface of cancer cells can help classify them as GIST. For example, researchers have discovered that most GIST cells have the marker CD117 on their surface. CD117 is the protein product of the KIT gene, which is commonly mutated in GIST. A different marker, DOG1 (named because it was Discovered On GIST), is also present on the vast majority of GISTs, but not always overlapping with CD117. As a result, a tumor that is positive for both CD117 and DOG1 has over 97% likelihood of being GIST.
Treatment
Tumors that are confined to one site without evidence of spread (i.e., localized) are treated by surgical removal. There is no clear benefit for radiation therapy before/after surgery for this type of sarcoma. Surgery offers the best chance of cure if a localized tumor is completely removed without rupturing the tumor (i.e., breaking the tumor into pieces and spilling tumor cells). However, not all patients are diagnosed at an early stage; 10%–25% of patients present with metastatic disease. Patients with tumors that have spread, are more aggressive or are locally advanced may benefit from chemotherapy in combination with surgery.
Older generations of intravenous chemotherapies are not effective for this type of sarcoma, with less than 5% of patients responding. In 2002, however, the tyrosine kinase inhibitor Gleevec (imatinib), which inhibits the proteins encoded by the KIT and PDGRFA oncogenes, was granted accelerated approval by the FDA for the treatment of advanced or metastatic GIST. It is very effective in controlling disease that has spread and most patients will have their tumors decrease in size or stabilize for many months. It is also effective in patients with recurrent tumors. Although Gleevec is effective at controlling GIST, patients who have disease that has spread from the initial site (metastatic disease) rarely experience the complete disappearance of all tumors. In addition, some individuals eventually develop resistance to Gleevec, with about half of patients experiencing this after 20 months of treatment. Surgery may be combined with Gleevec to control metastatic disease.
A subsequent accelerated approval for Gleevec was received in 2008 for adjuvant (post-operative) use in patients with GIST who have potentially curative resection (surgical removal) of GISTs, but who are at increased risk for 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 GIST. There is an increase in overall patient survival when the drug is taken for 36 months rather than the standard 12 months of treatment. Studies are ongoing to evaluate the use of imatinib for longer periods of time. Concerns have been raised over the cost of long-term imatinib treatment, but the recent availability of generic versions has reduced these costs.
In 2006, another tyrosine kinase inhibitor, sunitinib (Sutent) was approved by the FDA for the treatment of GIST in individuals in whom the disease had progressed, despite therapy with Gleevec, or in patients who cannot take Gleevec. 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). Stivarga inhibits the activity of numerous tyrosine kinases that promote cancer growth. In 2018, the FDA approved Larotrectinib, also a tyrosine kinase inhibitor, for the treatment of any tumor bearing a fusion of the NTRK3 gene (not only in GIST). This was only the second drug to be approved for treatment of cancers with a specific variant, regardless of tissue type, underscoring the importance of categorizing GISTs by their specific biology.
In 2020, the FDA approved a drug known as avapritinib (Avyaki) for treatment of unresectable metastatic GIST with variants in the PDGFRA gene that are not sensitive to imatinib, sunitinib or regorafenib. The clinical trial showed a remarkable response rate of 84% in these cases, indicating that targeting specific patient variants could be key for developing new therapies.
Iin 2020, ripretinib (Qinlock) was FDA approved as the first new drug to be used specifically as a fourth-line treatment for advanced GIST. It is an inhibitor of the kinases encoded by the KIT and PDGFRA genes.
Alternative approaches to surgery and chemotherapy include treatments directed at sites of liver involvement. Bland, radio-, 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 microwave ablation, uses localized microwaves to burn tumors in the liver.
Additional tyrosine kinase inhibitors have been 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 as dabrafenib, which acts against the B-raf serine/threonine kinase (distinct from tyrosine kinases), has demonstrated prolonged antitumor activity in an individual with GIST associated with a variant 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.
A new mode of treatment called immunotherapy is currently under investigation for cases of GIST that are resistant, or respond poorly, to tyrosine kinase inhibitors. Immunotherapy is based on the principle that the body’s immune system can identify and kill cancer cells, but cancers normally inhibit this process. Treatments that remove this inhibition can therefore activate the immune system to destroy cancer cells. While such immunotherapies that have shown promise in many other cancers, nivolumab alone, nivolumab with ipilimumab, or dasatinib with ipilimumab have shown limited success against refractory GIST.
GISTs that are not associated with variants in the KIT or PDGFRA genes often do not respond effectively to treatment with tyrosine kinase inhibitors such as Gleevec or Sutent. Recently, the NIH evaluated guadecitabine for treatment of SDH-deficient GIST (i.e., CSS or Carney triad), but the drug failed to improve outcomes. Researchers are now studying other treatment avenues to find effective treatments for these types of GIST. One such treatment is the drug temolozomide (Temodar) which is currently in phase II clinical trials for patients with SDH-deficient GIST. This drug is already FDA-approved for glioblastoma and anaplastic astrocytoma cancers, but its potential efficacy in SDH-deficient tumors would expand the use of personalized, variant-specific therapies for 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 website.
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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Email: prpl@cc.nih.gov
Some current clinical trials also are posted on the following page on the NORD website: https://rarediseases.org/living-with-a-rare-disease/find-clinical-trials/
For information about clinical trials sponsored by private sources, contact www.centerwatch.com
For more information about clinical trials conducted in Europe, contact https://www.clinicaltrialsregister.eu
JOURNAL ARTICLES
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INTERNET
Gastrointestinal Stromal Tumor; GIST. Online Mendelian Inheritance in Man (OMIM). Entry Number; 606764: Last Edit Date: 12/09/2019. Available at: http://omim.org/entry/606764 Accessed March 27, 2024.
FDA approves larotrectinib for solid tumors with NTRK gene fusions. Last Edit Date: 12/14/2018. Available at: https://www.fda.gov/drugs/fda-approves-larotrectinib-solid-tumors-ntrk-gene-fusions-0 Accessed March 27, 2024.
FDA approves avapritinib for gastrointestinal stromal tumor with a rare mutation. Last Edit Date: 1/9/2020. Available at: https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-avapritinib-gastrointestinal-stromal-tumor-rare-mutation Accessed March 27, 2024.
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