Gastrointestinal stromal tumors (GISTs) account for less than 1% of gastrointestinal tumors, but they are the most common mesenchymal neoplasms of the gastrointestinal tract. GISTs are usually found in the stomach or small intestine but can occur anywhere along the gastrointestinal (GI) tract and may rarely have extra-GI involvement.
Up to 75% of GISTs are discovered when they are less than 4 cm in diameter and are either asymptomatic or associated with nonspecific symptoms. They are frequently diagnosed incidentally during radiologic studies or during endoscopic or surgical procedures performed to investigate the GI tract disease or to treat an emergent condition such as hemorrhage, obstruction, or perforated viscus. Clinical manifestations of GISTs are as follows[1] :
Obstructive signs and symptoms of GISTs can be site-specific, as follows:
See Clinical Presentation for more detail.
No laboratory test can specifically confirm or rule out the presence of a GIST. The following tests are generally ordered in the workup of patients who present with nonspecific abdominal symptoms; abdominal pain; or complications of a GIST-like hemorrhage, obstruction, or perforation:
Imaging studies
Plain abdominal radiography:
Barium and air (double-contrast) series:
Computed tomography scans of the abdomen and pelvis:
Can also be used to detect the presence of multiple tumors and of metastatic spread. Computed tomography (CT) scan characteristics of small GISTs (< 5 cm) are as follows[3] :
CT scan characteristics of intermediate GISTs (5-10 cm) are as follows[3] :
CT scan characteristics of large GISTs (>10 cm) are as follows[3] :
CT scan criteria associated with high-grade histology and increased mortality[4] :
Magnetic resonance imaging (MRI):
Positron emission tomography (PET) scanning with 2-[F-18]-fluoro-2-deoxy-D-glucose (FDG) has the following uses:
Endoscopy:
Endoscopic ultrasonography (EUS):
EUS characteristics of malignant GISTs include the following[9] :
EUS features that may help differentiate gastric GISTs from leiomyomas are as follows[10] :
Aspects of EUS-guided biopsy are as follows:
See Workup for more detail.
Surgery is the definitive therapy for patients with GISTs, as follows:
Imatinib mesylate is used in GIST as follows:
Other tyrosine kinase inhibitors are used when imatinib is not tolerated or is not effective are as follows:
See Treatment and Medication for more detail.
Gastrointestinal stromal tumors (GISTs) account for less than 1% of gastrointestinal (GI) tumors, however, they are the most common mesenchymal neoplasms of the gastrointestinal tract.[1, 11] GISTs are usually found in the stomach or small intestine but can occur anywhere along the GI tract and may rarely have extra-GI involvement.[12] GISTs rank a distant third in prevalence behind adenocarcinomas and lymphomas among the histologic types of GI tract tumors.
Historically, these lesions were classified as leiomyomas or leiomyosarcomas because they possessed smooth muscle features when examined under light microscopy. In the 1970s electron microscopy studies found little evidence of the smooth muscle origin of these tumors. In the 1980s, with the advent of immunohistochemistry, it was shown that these tumors did not have immunophenotypic features of smooth muscle cells but rather expressed antigens related to neural crest cells. Mazur and Clark in 1983, and Schaldenbrand and Appleman in 1984 were the first to describe "stromal tumors" as a separate entity.
According to the work of Kindblom and associates reported in 1998, the actual cell of origin of GISTs is a pluripotential mesenchymal stem cell programmed to differentiate into the interstitial cell of Cajal.[13] These are GI pacemaker cells found in the muscularis propria and around the myenteric plexus and are largely responsible for initiating and coordinating GI motility. This finding led Kindblom and coworkers to suggest the term "GI pacemaker cell tumors."[13] Additional studies found that interstitial cells of Cajal express KIT and are developmentally dependent on stem cell factor, which is regulated through KIT kinase. Perhaps the most critical development that distinguished GISTs as a unique clinical entity was the discovery of c-kit proto-oncogene mutations in these tumors in by Hirota and colleagues in 1998.[14]
These advances led to the classification of GISTs as an entity separate from smooth muscle tumors, helped elucidate their etiology and pathogenesis at a molecular level, and led to the development of molecular-targeted therapy for this disease.
Gastrointestinal stromal tumors (GISTs) can occur anywhere in the gastrointestinal tract. They are submucosal lesions, which most frequently grow endophytically in parallel with the lumen of the affected structure. GISTs may also manifest as exophytic extraluminal excrescences. These tumors have been reported to range in size from smaller than 1 cm to as large as 40 cm in diameter.[15]
Approximately 50-70% of GISTs originate in the stomach. The small intestine is the second most common location, with 20-30% of GISTs arising from the jejunoileum. Less frequent sites of occurrence include the colon and rectum (5-15%) and esophagus (<5%). Primary pancreatic, omental, or mesenteric GISTs have been reported but are very rare.[12]
Most gastrointestinal stromal tumors (GISTs) are associated with gain-of-function mutations in exon 11 of the c-kit proto-oncogene. These mutations lead to constitutive overexpression and autophosphorylation of c-Kit, provoking a cascade of intracellular signaling that propels cells toward proliferation or away from apoptotic pathways.[6]
This 1998 discovery by Hirota and colleagues was a landmark elucidation of the etiology of a disease on a molecular level.[14] Most of these mutations are of the in-frame type, which allows preservation of c-kit expression and activation. The c-kit proto-oncogene is located on chromosome arm 4q11-12. It encodes KIT, which is a transmembrane tyrosine kinase. Stem cell factor, also called Steel factor or mast cell growth factor, is the ligand for KIT and exists primarily in dimeric form.
Under normal circumstances, KIT activation is initiated when stem cell factor binds to the extracellular domain of c-Kit. The result is homodimerization of the normally inactive c-Kit monomers. Autophosphorylation of intracellular tyrosine residues then transpires. This exposes binding sites for intracellular signal transduction molecules. What follows is activation of a signaling cascade that involves phosphorylation of several downstream target proteins, including mitogen-activated protein (MAP) kinase, RAS, and others. Ultimately, the signal is transduced into the nucleus, resulting in mitogenic activity and protein transcription.
KIT is constitutively phosphorylated in the majority of GISTs. In these cases, stem cell factor is not required to initiate the sequence of c-Kit homodimerization and autophosphorylation. This is termed ligand-independent activation. The increased transduction of proliferative signals to the nucleus favors cell survival and replication over dormancy and apoptosis, leading to tumorigenesis.
Although 95% of GISTs are KIT positive, 5% of GISTs are truly negative for detectable KIT expression, referred to as the "KIT-negative GISTs".
In a proportion of KIT-negative GISTs, mutations occur in the PDGFRA gene rather than KIT. Immunostaining with PDGFRA has been shown to be helpful in discriminating between KIT-negative GISTs and other gastrointestinal mesenchymal lesions.
BRAF mutations and protein kinase C theta (PKCtheta) have also been reported in a small proportion of GISTs lacking KIT/PDGFRA.
A small minority of GISTs are associated with hereditary syndromes. Familial GISTs are characterized by inherited germline mutations in KIT or PDGFRA and have additional findings such as cutaneous hyperpigmentation, irritable bowel syndrome, dysphagia, or diverticular disease. 90% of patients with these germline mutations are at risk of being diagnosed with GIST by age 70 years. Familial GISTs have favorable outcomes and do not appear to be associated with shortened survival. There are no data to support preventative therapy in patients with these germline mutations.
GIST is one of several malignancies that may occur with neurofibromatosis type 1 (NF-1), with gliomas and neurofibromas being more common.
The Carney triad, observed predominantly in young women, consists of epithelioid gastric stromal tumors, pulmonary chondromas, and extra-adrenal paragangliomas.
An estimated 4000 to 5000 new cases of gastrointestinal stromal tumors (GISTs) are diagnosed annually in the United States.[16]
Previous population-based studies from Iceland,[17] the Netherlands,[18] Spain,[19] and Sweden[5] reported annual incidence rates ranging from 6.5 to 14.5 cases per million.
In a 2016 systematic review (2000-2014) of the global epidemiology of GISTs that included data from 29 studies comprising 13,550 patients from 19 countries, the incidence was predominantly 10-15 cases per million annually.[20] Overall, China had the lowest incidence with 4.3 million per year; the highest incidences were in Hong Kong and Shanghai, China; Taiwan; and northern Norway, with a an estimated 19-22 cases per million per year.
GISTs have no known racial proclivity. However, Cheung et al reported that of 3795 patients diagnosed with mesenchymal tumors from the Surveillance, Epidemiology, and End Results (SEER) database from 1992-2005, more than 88% of tumors were identified as GIST with patient demographics as follows: 72.2% white, 15.6% black, and 9.1% Hispanic individuals.[2] More recent SEER data (2001-2013; follow-up in 2015) also showed that white patients were predominantly affected (about 69.4%).[21]
SEER data from 1992-2000 reported a slightly higher prevalence in males versus females, at 54% and 46%, respectively.[3] Similarly, more recent SEER data (2001-2013; follow-up in 2015) revealed a slightly higher male prevalence of approximately 52%.[21]
GISTs have been reported in all age groups including infants, but it is most common in patients older than 40 years.[11] A systematic review of the global epidemiology of GISTs found that the median age was in the mid 60s.[21] It is extremely rare in patients younger than 30 years. Previously, a study of 1765 gastric GISTs reported the median age at diagnosis was 63 years,[15] and in a series consisting of 906 jejunal and ileal GISTs, the mean age was 59 years.[4] In the latter two series, only 2.7% of gastric GISTs and 0.6% of small bowel GISTs were detected in patients younger than 21 years.
The predominant prognostic factors in patients with gastrointestinal stromal tumors (GISTs) include the size of the tumor, location of the tumor, and the mitotic rate. To these may be added the ability or inability to achieve completely negative resection margins. In addition to being prognostic factors, tumor size and location, and mitotic rate as well as tumor rupture are independent risk factors for metastasis.[1]
Previously reported 5-year disease-specific survival rates were 30-60% according to the results reported by many studies,[22, 23, 24, 25] with a large disparity between patients presenting with localized primary disease (median survival of 5 y) and those presenting with metastasis or recurrent disease (median survival of 10-20 mo).
A 2015 population-based data trend analysis of overall and cancer-specific survival in 5138 patients with GIST from the Surveillance, Epidemiology, and End Results (SEER) database (1998-2011) showed a statistically significant and clinically relevant rise in overall and cancer-specific survival between 1998 and 2008, for resected and metastatic GIST.[26] The 3-year overall survival and cancer-specific survival for nonmetastatic disease rose from 68.5% to 88.6% and from 75.3% to 92.2%, respectively, in the 11-year study period. For metastatic GIST, the 3-year overall survival rose from 15.0% to 54.7% and the cancer-specific survival increased from 15.0% to 61.9% in the same time period.[26]
Location is also significant. Patients with gastric GISTs tend to fare better than those with extragastric GISTs.
Dougherty et al demonstrated the importance of the mitotic count as a prognostic factor and predictor of malignant behavior was illustrated by.[27] Even after curative resections, patients with a mitotic rate of 10 or greater per 50 high-power fields (HPFs) had a median survival rate of 18 months, compared with an 80%, 8-year disease-free survival rate in patients who had curative resections and tumors with a mitotic rate less than 10/50 HPFs.
Fletcher et al stratified the risk of aggressive or malignant behavior in GISTs, based on size and mitotic rate, as follows[28] :
In 2009, Gold et al from Memorial Sloan-Kettering Cancer Center (MSKCC) developed a nomogram that uses tumor size, site, and mitotic index to predict relapse-free survival after resection of localized primary GIST.[29]
Mutational status has both prognostic significance and impact on the response to tyrosine kinase inhibitor therapy. In randomized clinical trials, the presence of a KIT exon 11 mutation was associated with better response, progression-free survival, and overall survival rates than that of KIT exon 9 mutant GISTs. The risk for progression and death were increased in patients with no detectable KIT or PDGFRA mutations.[6]
Outcomes in patients with GISTs are highly dependent on the clinical presentation and the histopathologic features of the tumor. The overall 5-year survival rate ranges from 28% to 60%. This can be stratified for patients presenting with localized primary disease and those presenting with metastatic or recurrent disease. The median survival rate in the former group is 5 years, whereas the median survival in the latter group is approximately 10-20 months. Larger GISTs are associated with complications such as gastrointestinal (GI) hemorrhage, GI obstruction, and bowel perforation. This is discussed further in Surgical Care.
Tumors can be classified into high and low-risk categories based on size, location, and mitotic activity. The implications of these tumor characteristics are also discussed in Histologic Findings.
Complications can be divided into preoperative and postoperative categories. Preoperative tumor-related complications usually occur with tumors larger than 4 cm.
Major preoperative complications include the following:
The range of postoperative complications is similar to that for major abdominal and GI surgery. The following is a representative but not exhaustive list:
Patients should be educated about as many aspects of the disease as possible, including diagnostic and therapeutic measures and options. Most importantly, they should be apprised of the need for lifelong close clinical follow-up, even after complete resection of disease. Emphasize that gastrointestinal stromal tumors (GISTs) have a propensity to recur.
For patient education resources, see the Cancer Center, as well as Stomach Cancer (Gastric Cancer) and Cancer of the Small Intestine (Adenocarcinoma).
In adult gastrointestinal stromal tumors (GISTs), the stomach (55.6-59%) and small intestine (primarily jejunum/ileum, 25-31.8%) are the most common primary sites, followed by colorectal (3-6.0%), other sites (3-5.5%), and the esophagus (0.7%).[20, 26] Only a small number of cases (<1%) have been reported in the appendix. On rare occasions, GISTs develop outside the gastrointestinal tract, in the mesentery, omentum, or retroperitoneum.
The rate of incidental diagnosis is 18% on average (range, 5-40%).[20] Up to 75% of GISTs are discovered when they are smaller than 4 cm in diameter and are either asymptomatic or associated with nonspecific symptoms. They are frequently diagnosed incidentally during endoscopic or surgical procedures or during radiologic studies performed to investigate protean manifestations of gastrointestinal (GI) tract disease or to treat an emergent condition such as hemorrhage or obstruction. In a population-based study, the median tumor size of GISTs that were detected based on symptoms, incidental findings, and during an autopsy were 8.9, 2.7, and 3.4 cm, respectively.[5]
The most common symptoms associated with GISTs are vague, nonspecific abdominal pain or discomfort. Patients also describe early satiety or a sensation of abdominal fullness. Rarely, an abdominal mass is palpable.
GISTs may also produce symptoms secondary to obstruction or hemorrhage. GI bleeding is produced by pressure necrosis and ulceration of the overlying mucosa with resultant hemorrhage from disrupted vessels. It can occur as a slow intraluminal GI bleed or massive intraperitoneal hemorrhage due to rupture of the tumor.[11] Patients who have experienced significant blood loss may report malaise, fatigue, or exertional dyspnea.
Obstruction can result from intraluminal growth of an endophytic tumor or from luminal compression from an exophytic lesion. The obstructive symptoms can be site-specific (eg, dysphagia with an esophageal GIST, constipation with a colorectal GIST, obstructive jaundice with a duodenal tumor).
In some cases, GIST is an unexpected finding during emergency surgery for a perforated viscus.
Some patients with gastrointestinal stromal tumors (GISTs) present with a palpable abdominal mass. Others may present with nonspecific physical findings associated with gastrointestinal (GI) blood loss, bowel obstruction, or bowel perforation and abscess formation.
Patients presenting with significant GI bleeding can manifest vital sign abnormalities or overt shock. In others, fecal occult blood testing may be positive.
Physical findings associated with bowel obstruction can include a distended, tender abdomen. Duodenal obstruction involving the ampulla may be associated with jaundice and, rarely, even a distended palpable gallbladder.
If perforation has occurred, focal or widespread signs of peritonitis may be present.
No laboratory test can specifically confirm or rule out the presence of a gastrointestinal stromal tumor (GIST). The following tests are generally ordered in the workup of the patient who presents with nonspecific abdominal symptomatology; abdominal pain; or complications of a GIST-like hemorrhage, obstruction, or perforation:
Findings of gastrointestinal stromal tumors (GISTs) on plain abdominal radiography are nonspecific, but it may be ordered as part of the workup of a patient presenting emergently with a possible bowel obstruction or perforation. Abnormal gas patterns, including dilated loops of bowel or free extraluminal air, are examples of findings that may be detected in these clinical situations.
Double-contrast radiographic series can usually detect GISTs that have grown to a size sufficient to produce symptoms.
The choice of performing a barium swallow, barium enema, or both depends on the patient's clinical presentation. For example, patients whose primary symptomatology includes dysphagia should have a barium swallow. Those presenting with constipation, decreased stool caliber, or other signs and symptoms referable to the colon should have a barium enema.
In these contrast studies, GISTs appear as a filling defect that is sharply demarcated and is elevated compared with the surrounding mucosa.[30] Typically, the contour of the overlying mucosa is smooth unless ulceration has developed because of growth of the underlying tumor.
Although these contrast studies can produce striking images, frequently the information they provide is limited. Other modalities discussed below have equal or greater sensitivity and can provide more information about the status of the surrounding structures.
As is frequently the case with other small bowel lesions, GISTs in the small intestine can be difficult to diagnose and localize. Enteroclysis allows delivery of contrast into the small bowel so it does not become too diluted by the time it reaches the area in question. This may help to better define small intestinal GISTs.
The ultrasonographic appearance of GISTs varies depending on the size of the lesion and the presence or absence of necrosis within the mass. In addition, ulceration or necrosis of the overlying mucosa can change the ultrasonographic characteristics of the tumor.
Transcutaneous ultrasonography is probably not the optimum choice for imaging these lesions unless the mass has reached quite a large size. Because GISTs are associated with air-filled viscera, image quality is often degraded by intervening bowel gas.
The best ultrasonographic images of these lesions are acquired during endoscopic ultrasonography. This is discussed in Procedures.
CT scanning is an important radiographic modality in the diagnosis and staging of GISTs.[1, 31] It provides comprehensive information regarding the size and location of the tumor and its relationship to the adjacent structures. CT scanning can also be used to detect the presence of multiple tumors as well as provide evidence of metastatic spread. Findings on CT scan that are more likely to indicate metastatic disease include the following[1] :
Advantages of CT enterography over standard CT scanning include evaluation of the entire small-bowel wall thickness, improved visualization of deep ileal loops, and assessment of the surrounding mesentery.[1]
Ghanem and colleagues described CT scanning characteristics on patients with histologically confirmed primary (n = 20) or recurrent (n = 16) GISTs by dividing the tumors into small (<5 cm), intermediate (5-10 cm), and large (>10 cm) tumors.[7] Small GISTs were sharply demarcated, homogeneous masses, mainly exhibiting intraluminal growth patterns. Intermediate GISTs were characterized by irregular shape, heterogeneous density, an intraluminal and extraluminal growth pattern, and signs of biologic aggression, including adjacent organ infiltration in nine primary and two recurrent lesions. Large GISTs featured irregular margins, heterogeneous densities, locally aggressive behavior, and distant and peritoneal metastases.[7]
Tateishi and coworkers correlated CT findings with histologic tumor grade and mortality rates in patients with low-grade (n = 44) and high-grade (n = 25) GISTs who underwent dual-phase CT scanning.[9] The investigators found that CT criteria associated with high-grade histology and increased mortality included a tumor larger than 11.1 cm with irregular surface contours, indistinct margins, adjacent organ invasion, heterogeneous enhancement, and hepatic or peritoneal metastasis.
CT scanning can also be used to assess treatment response to adjuvant therapies (eg, imatinib therapy).[31]
Similar to CT scanning, MRI can depict the tumor(s) and provide information about the surrounding structures, particularly the anorectal region.[31] It can also be used to detect the presence of multiple tumors and metastases.
MRI has not been studied as intensively as CT scanning in the application of diagnosing GISTs. It appears to be just as sensitive as CT scanning.[8] However, MRI is more accurate than CT scanning for defining rectal GISTs and identifying liver metastasis, hemorrhage, and necrosis.[1, 31]
As with CT scan features, small GISTs are generally round, with strong homogeneous arterial enhancement, whereas larger tumors are often lobulated, with mild, heterogeneous, gradual enhancement.[31] T1-weighted images of solid GISTs typically show low signal intensity, whereas T2-weighted images have high signal intensity; the tumors enhance when contrast medium is used.[31]
PET scanning provides functional information that may help in staging the tumors and may be used as an adjunct to CT scanning to identify viable lesions from necrotic tissue, benign from malignant tissue, and scar tissue from recurrent tumor.[31] PET scanning is also a sensitive modality to monitor early clinical responses to adjuvant therapies such as imatinib mesylate.[32, 31]
As a result of gastrointestinal (GI) bleeding, abdominal pain, or GI obstructive symptoms, endoscopy is frequently performed early in the workup of patients with GISTs.
Endoscopic features of GISTs include the suggestion of a smooth submucosal mass displacing the overlying mucosa. Some tumors may be associated with ulceration or bleeding of the overlying mucosa from pressure necrosis.[33]
Obtaining reliable biopsy specimens by traditional endoscopic means is fraught with difficulty because of the submucosal location of these tumors. This is a major reason why endoscopic biopsy results yield a diagnosis in less than 50% of cases. Obtaining a repeat biopsy at the same site as a previous biopsy may increase the diagnostic yield.
EUS is a modality that allows localization of lesions, particularly those smaller than 2 cm, and their characterization.[31] Fine-needle aspiration biopsy specimens also may be obtained via the endoscope under sonographic guidance.
The typical EUS appearance of a GIST is a hypoechoic mass situated in the layer corresponding to the muscularis propria.
Chak and coinvestigators described EUS characteristics of malignant GISTs to include size larger than 4 cm, heterogeneous echogenicity, internal cystic areas, and irregular borders on the extraluminal surfaces.[34]
Belloni and colleagues compared computed tomography (CT) scanning and EUS in the diagnosis of GIST and in their ability to discriminate benign from malignant disease and found that EUS is more accurate in differentiating benign from malignant lesions but that CT scanning allows a more comprehensive evaluation of the mass and the surrounding structures.[35] The authors concluded that the techniques are complementary and helpful in planning operative therapy.
Kim et al reported that EUS may be able to differentiate gastric GISTs from leiomyomas in a study of 53 patients.[36] The findings of inhomogenicity, hyperechogenic spots, a marginal halo, and higher echogenicity as compared with the surrounding muscle layer appeared more frequently in the GISTs than in the leiomyomas (P <0.05). The presence of at least two of these four features had a sensitivity of 89.1% and a specificity of 85.7% for predicting GISTs. Except for tumor size and irregularity of the border, most of the EUS features were not helpful in predicting the malignant potential of GISTs. On multivariate analysis, only the maximal diameter of the GISTs was an independent predictor. The investigators also reported that once GISTs are suspected, surgery should be considered if the size is greater than 3.5 cm.[36]
It has been suggested that definitive diagnosis of GIST requires tissue acquisition through EUS-guided fine needle aspiration. However, biopsy may not be necessary if the tumor is surgically resectable and preoperative medical therapy is not required. Biopsy may be required when preoperative therapy is needed in cases in which the tumor is unresectable or only marginally resectable.
Angiography is rarely used in the diagnosis or management of GISTs. It may be used during diagnostic dilemmas or for urgent treatment of complications such as GI hemorrhage. Therefore, much of the literature on GISTs and angiography is limited to case reports, including the following:
Gastrointestinal stromal tumors (GISTs) manifest a wide variety of clinical behavior, from slow-growing indolent tumors to aggressive malignant cancers with the propensity to invade the adjacent organs, metastasize to the liver, and recur locally within the abdomen. Clinical presentation provides the most overt evidence for distinguishing benign from malignant behavior. Histologic analysis of the biopsy or operative specimens provides objective measures for diagnosis and helps to predict clinical behavior.
The morphologic features that appear to be the most predictive of outcome and biologic behavior are tumor size and the mitotic rate. Unfortunately, no absolute determinations can be made, because even small lesions with low mitotic rates can metastasize or behave in a locally aggressive fashion. In 2002, Fletcher and colleagues proposed a classification system to define the relative risk for the malignant behavior in GISTs.[28] See the Fletcher et al stratification of risk in Prognosis.
GISTs typically stain intensely for the CD117 molecule, which is an epitope of KIT. In contrast, desmoids, schwannomas (S-100–positive, KIT-negative), leiomyomas, and leiomyosarcomas (desmin-positive, KIT-negative) do not. In GISTs, CD117 appears diffusely in the cytoplasm in a punctate or Golgi-like pattern.[28] CD34 staining results are also positive in approximately 60% of GISTs. Koh et al concluded that the lack of CD34 expression may be the result of cystic degeneration following treatment with imatinib.[45]
Woodall et al created a TGM (tumor, grade, metastasis) staging system based on Surveillance, Epidemiology, and End Results (SEER) data (1977-2004) from 2537 patients with GISTs.[46] Median follow-up time was 21 months, 47.6% of patients were men, and the median age was 64 years. The investigators noted that 5% had lymph node involvement and 22.6% had distant metastasis. Tumor size (T1, ≤70 mm; T2, >70 mm; P <0.001), grade (G1, grades I and II; G2, grades III and IV; P <0.001), and the presence of metastases (M0, no; M1, yes; P <0.001) affected the overall survival. When combined in a TGM staging system, the grade and the presence of metastasis were the factors most predictive of survival.[46]
Surgical resection, often laparoscopically, is first-line treatment for primary and localized gastrointestinal stromal tumors (GISTs), although management of the tumors is generally based on findings on endoscopic ultrasonography and computed tomography (CT) scanning and includes the adjunct use of tyrosine kinase inhibitors.[1]
Preoperative care focuses on managing the acute complications of GISTs (ie, hemorrhage, bowel obstruction, perforation) or on preparing the patient for surgery. Proper postoperative care also helps ensure complete and uneventful patient recovery. Features of preoperative and postoperative care in patients with GIST are summarized below.
Patients with GIST-related hemorrhage require intravenous fluid resuscitation. Those with massive hemorrhage may require transfusion of blood products. Postoperatively, resuscitative and maintenance intravenous fluids are provided. Most commonly, a balanced salt solution such as lactated Ringer is used.
Specific electrolyte abnormalities can be directly measured and replaced as appropriate.
Early postoperative activity is encouraged.
Patients receive nothing by mouth for varying durations, depending on the preference of the operating surgeon.
Following nasogastric tube removal, patients can be started on a liquid diet and advanced to a full diet as tolerated. Postgastrectomy diet counseling by a registered dietitian is helpful in patients undergoing subtotal or total gastrectomies.
Depending on the patient's preoperative nutritional status, a period of specialized nutritional support might be indicated. This can range from enteral tube feedings to peripheral hyperalimentation to total parenteral nutrition. Multivitamin and iron supplementation may be indicated.
Depending on the type of resection, a nasogastric tube is left in place postoperatively. Ensuring that the tube is continuously functional and remains unclogged is crucial. Criteria for removal of a nasogastric tube vary by clinician.
A urinary Foley catheter remains in place in the early postoperative period or during the preoperative resuscitative period in patients who have sustained major hemorrhage or other complications. The catheter aids monitoring of hydration status and serves as a guide for fluid resuscitation. Once the patient is stabilized and no additional major fluid shifts are anticipated, the catheter can be removed.
Instruct patients to cough and to take frequent deep breaths. The incentive spirometer is an important adjunct for this and should be used by the patient every 1-2 hours while awake. Early mobilization of the patient assists with maintaining good pulmonary toilet.
Vital signs are monitored per protocol. Intake and output records are kept. Pulse oximetry is used when appropriate to measure oxygen saturation.
Unless bowel perforation or other septic complications have occurred, a single dose of intravenous antibiotic prophylaxis against wound infection is usually sufficient.
Patients with abdominal catastrophes such as bowel perforation or infarction require a full therapeutic course of intravenous antibiotics that cover the spectrum of gut flora.
An epidural catheter can be placed by anesthesia personnel for postoperative pain control. Alternatively, a patient-controlled anesthesia schedule can be ordered.
Prophylaxis against deep venous thrombosis is crucial because it and pulmonary embolism are significant sources of postoperative morbidity and mortality. Available modalities include subcutaneous heparin, subcutaneous fractionated heparin preparations, and sequential compression stockings.
The head of the bed can be kept elevated 30°-45°, or sometimes higher for elderly patients or during sleep, to help prevent aspiration.
Imatinib is a selective small molecule inhibitor of a family of structurally similar tyrosine kinase signaling enzymes, including KIT, PDGFRA, and chronic myelogenous leukemia specific BCR-ABL protein. In laboratory studies, imatinib was shown to inhibit the proliferation of BCR-ABL leukemic cells and gastrointestinal stromal tumor (GIST) cells with KIT mutations.
Imatinib mesylate is indicated in patients with advanced GISTs. It is indicated as adjuvant therapy after complete surgical resection in patients with tumors that are stratified to be high risk (see Prognosis) and as neoadjuvant therapy, with the goal of tumor shrinkage prior to surgical resection.
In a study that randomly assigned patients with metastatic or unresectable GIST to either 400 mg or 600 mg of imatinib, imatinib induced an objective response in more than half of the patients.[47] The early favorable results of this study led the US Food and Drug Administration (FDA) to approve imatinib for the treatment of KIT-positive unresectable or metastatic GIST in February 2002.[47]
In a randomized, double-blind, placebo-controlled study DeMatteo et al showed adjuvant imatinib therapy was safe and improved recurrence-free survival compared with placebo after resection of a GIST.[48]
In another randomized, placebo-controlled trial, Joensuu et al reported that patients assigned to 36 months of imatinib had longer recurrence-free survival compared to those assigned to 12 months of treatment (hazard ratio, 0.46; 95% confidence interval, 0.32-0.65; P <0.001; 5-year recurrence-free survival was 65.6% and 47.9%, respectively.[49] Note that in some patients, imatinib fails immediately after initiation (primary resistance); in others, an initially show response to imatinib is seen but progressive disease develops later (secondary resistance).[50]
Imatinib resistance may be managed by increasing the dose to 800 mg per day or switching directly to sunitinib,[50] another tyrosine kinase receptor inhibitor that is less specific than imatinib. Sunitinib inhibits KIT and PDGFRA as well as vascular endothelial growth factor receptors (VEGFR1-3), Fms-related tyrosine kinase 3, colony-stimulating factor (CSF), and RET. Thus, sunitinib has both antiangiogenic and anti-tumor potential.[50]
In a phase III, double-blind study evaluating sunitinib versus placebo in patients with advanced GIST who were intolerant or refractory to imatinib, the time to disease progression was four times longer in those receiving sunitinib (27.3 vs 6.4 weeks for placebo; P <0.0001).[51] Progression-free survival and overall survival were better for patients treated with sunitinib.[51]
In January 2006, the FDA approved sunitinib as a second-line agent for patients with advanced GIST.
In a study that evaluated the safety and efficacy of sunitinib in patients with advanced GIST after imatinib failure, the results suggested that continuous daily dosing of sunitinib was an effective alternative with acceptable safety for patients with imatinib resistant GIST.[52]
Regorafenib (Stivarga) received FDA approval in 2013 for locally advanced, unresectable GISTs that no longer responded to imatinib or sunitinib.[53] The pivotal phase III GRID (efficacy and safety of regorafenib for advanced GISTs after failure of imatinib and sunitinib) trial of 199 patients with metastatic or unresectable GIST showed that regorafenib plus best supportive care (BSC) significantly improved the progression-free survival compared to placebo plus BSC.[54, 55] Patients were treated with BSC and randomized in a 2:1 ratio to either regorafenib (160 mg daily for 3 weeks, followed by a 1-week break) or placebo. Median progression-free survival was 4.8 months for regorafenib and 0.9 months for placebo.[54, 55]
Investigational agents for patients with progressive disease despite imatinib and sunitinib use include the second-generation tyrosine kinase inhibitors sorafenib, dasatinib, pazopanib, and nilotinib. Other drugs under investigation include onalespib (AT13387), a second-generation non-ansamycin heat-shock protein 90 (HSP90) inhibitor; ponatinib, a third-generation tyrosine kinase inhibitor; vatalanib (PTK787/ZK222584), a novel VEGFR tyrosine-kinase inhibitor; dovitinib (TAKI-258, CHIR-258), a tyrosine kinase-receptor inhibitor; and cabozantinib (XL184), a novel MET and VEGFR2 inhibitor.
The management of GISTs requires the participation of a multidisciplinary team. The team should include a surgeon, gastroenterologist, medical oncologist, pathologist, and radiologist.[1]
Surgery is the definitive therapy for patients with gastrointestinal stromal tumors (GISTs). Radical and complete surgical extirpation offers the only chance for cure. Surgery is also indicated in symptomatic patients with locally advanced or metastatic disease. Debulking large lesions is helpful when adjuvant therapy with imatinib mesylate is contemplated.
In a retrospective study (1995-2002) involving 57 patients who underwent surgical treatment of GISTs with either curative intent (n = 28; 49%) or after operative treatment at other institutions for metastatic disease (n = 29; 51%), 22 patients (79%) in the curative-intent group had resections with completely negative margins.[56] In three of the patients with complete resections, metastatic disease was totally resected along with the primary tumor. An additional two patients had subsequent complete resection after favorable clinical responses to imatinib mesylate therapy. CD117 staining was positive in 96% of the resected specimens. In total, 34 patients were diagnosed with metastatic disease during the initial evaluation and treatment or at some point during follow-up. The most common sites of metastatic disease were the liver (71%) and peritoneum (53%).[56]
The investigators monitored the entire cohort for a median duration of 18 months and found that 23 patients (40%) remained alive and free of disease.[56] An additional 22 patients (39%) were alive with disease. Of the remainder, seven were known to have died and five were lost to follow-up. Treatment with imatinib effected disease stabilization or regression in 22 (85%) of the 26 patients treated, with a median duration of response of 19 months.[56]
The study authors concluded that complete resection with negative margins remains the only potentially curative treatment of GISTs. Furthermore, imatinib therapy for metastatic disease is associated with good clinical response rates, but the true therapeutic efficacy of this drug will not be known until prospective trials are completed.
Besana-Ciani et al were able to achieve complete resection in 78.9% of 19 patients.[57] The mean tumor size was 8.4 cm. These patients received long-term follow-up. Using the Fletcher et al histologic classification,[28] tumors were divided into 2 groups, with one group comprising those classified as very low, low, and intermediate risk, and the second consisting of tumors classified as high risk. The 5-year survival rates were 63% in the former group and 34% in the latter group. As might be expected, complete resection was also a significant predictor of superior survival compared with incomplete resection. These investigators also concluded that radical complete resection offers the only chance for long-term survival in patients with GISTs.[57]
Laparoscopic resection has improved and is a more frequently considered option for patients with a GIST. In a retrospective study (2005-2010) of 58 patients diagnosed with GISTs of whom 16 underwent laparoscopic surgery and 42 underwent open surgery, Chen et al concluded that laparoscopic surgery was technically possible for GISTs no larger than 5 cm, located at the stomach and small bowel.[58] The patients benefited from fewer days until resuming a normal diet, shorter postoperative hospital stays, and less analgesia use. The patients in the laparoscopy group experienced the same short-term oncology result as the patients who underwent open surgery.[58]
El-Gendi et al evaluated 12 patients who underwent limited duodenal resection for primary nonmetastatic duodenal GIST and concluded that limited resection is a reliable option for disease-free survival depending on tumor size, adjacent organ involvement, and location.[59]
Preoperative imatinib should be considered if surgical morbidity would be improved by cytoreducing the size of the tumor.
Postoperative imatinib has been shown to increase recurrence-free survival after complete resection of localized GIST.[60] Joensuu et al showed that compared with 12 months of adjuvant imatinib, 36 months of imatinib improved recurrence-free survival and overall survival of GIST patients with a high risk of GIST recurrence.[49] In an interim analysis of 908 patients with localized, high-, or intermediate-risk GIST assigned in equal numbers to 2 years of adjuvant imatinib or observation following R0-R1 surgery, Casali et al found the greatest difference in relapse-free survival at 3 years (84% vs 66%, respectively). At 5 years, relapse-free survival was 69% in the imatinib group versus 63% in the observation group, whereas overall survival was 100% and 99%, respectively. The imatinib failure-free survival was similar in both groups at 5 years, with 87% in the imatinib group and 84% in the observation group.
Comprehensive follow-up is extremely important in all but the smallest and lowest-grade gastrointestinal stromal tumors (GISTs). A follow-up plan should include the following measures:
Imatinib mesylate is the only available drug that has made a significant impact in the treatment of GISTs.
Clinical Context: Also known as STI-571, imatinib first received attention as an inhibitor of the BCR-ABL fusion protein, which induces uncontrolled tyrosine kinase activity in CML.
Clinical Context: Sunitinib is a multikinase inhibitor that targets several tyrosine kinase inhibitors implicated in tumor growth, pathologic angiogenesis, and metastatic progression. It inhibits platelet-derived growth factor receptors (ie, PDGFR-alpha, PDGFR-beta), vascular endothelial growth factor receptors (ie, VEGFR1, VEGFR2, VEGFR3), stem cell factor receptor (KIT), Fms-like tyrosine kinase-3 (FLT3), colony-stimulating factor receptor type 1 (CSF-1R), and the glial cell-line–derived neurotrophic factor receptor (RET).
It is indicated in persons with gastrointestinal stromal tumors (GISTs) whose disease has progressed or who are unable to tolerate treatment with imatinib (Gleevec). It delays the median time to tumor progression.
Clinical Context: Regorafenib is a tyrosine kinase inhibitor. It is indicated for locally advanced, unresectable gastrointestinal stromal tumors that no longer respond to other treatments (eg, imatinib, sunitinib).
Imatinib mesylate (STI 571) is a selective tyrosine kinase inhibitor with action against mutant c-Kit as occurs in association with gastrointestinal stromal tumors (GISTs). It represented a breakthrough in antineoplastic drug therapy because it is targeted against a specific molecular derangement.
Druker et al were the first to report this effect in laboratory experiments in 1996.[61] In 2001, Druker, Talpaz, and coworkers reported the results of clinical trials demonstrating over 90% complete clinical response rates.[62]
Following the 1998 Hirota et al landmark report on the role of c-kit proto-oncogene mutations in the pathogenesis of GISTs, involving activation of KIT tyrosine kinase, it was hypothesized that KIT inhibition might be a successful treatment strategy for GISTs. Druker et al,[61] Buchdunger et al,[63] and Heinrich et al[64] demonstrated such activity in the laboratory in various cell lines.[61]
Tuveson et al proved in vivo efficacy against human GIST cells, showing that STI-571 produced cell cycle arrest and apoptosis.[65] Results from 35 patients with GISTs receiving imatinib doses of 400-1000 mg/day showed partial responses were achieved in 54%, and the disease remained stable in an additional 37%.[66] The most common adverse effects were periorbital edema (40%), peripheral edema (37%), fatigue (30%), rash (30%), and nausea and vomiting (25%). Late severe myelosuppression was uncommon. The highest well-tolerated dose in this study was 400 mg bid. At doses of 500 mg bid, severe nausea, vomiting, edema, and rashes were common. After a minimum follow-up of 10 mo, 82% of subjects continued to have a partial disease response (51%) or no evidence of disease progression (31%).[66]
In a gene expression study using oligonucleotide microarrays on tumor samples obtained before and after imatinib mesylate therapy, 38 genes were expressed at significantly lower levels in the pretreatment biopsy samples from tumors that significantly responded to 8-12 weeks of imatinib mesylate (ie, >25% tumor reduction).[67] Eighteen of these genes encoded Krüppel-associated box (KRAB) domain containing zinc finger (ZNF) transcriptional repressors. Ten KRAB-ZNF genes mapped to a single locus on chromosome 19p, and a subset predicted likely response to imatinib mesylate-based therapy in a naïve panel of GIST. This gene signature includes KRAB-ZNF 91 subfamily members that may be both predictive of, and functionally associated with, likely response to short-term imatinib mesylate treatment.