Gastrointestinal Stromal Tumors (GISTs)

Updated: Jan 10, 2020
  • Author: Michael A Choti, MD, MBA, FACS; Chief Editor: N Joseph Espat, MD, MS, FACS  more...
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Overview

Practice Essentials

Gastrointestinal stromal tumors (GISTs) account for less than 1% of GI tumors, but they are the most common mesenchymal neoplasms of the GI tract. [1] GISTs are usually found in the stomach or small intestine but can occur anywhere along the GI tract and rarely have extra-GI involvement. See the image below.

Shown here is a gastric gastrointestinal stromal t Shown here is a gastric gastrointestinal stromal tumor (GIST). This is a gross specimen following partial gastrectomy. Note the submucosal tumor mass with the classic features of central umbilication and ulceration.

Signs and symptoms

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 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:

  • Vague, nonspecific abdominal pain or discomfort (most common)
  • Early satiety or a sensation of abdominal fullness
  • Palpable abdominal mass (rare)
  • Malaise, fatigue, or exertional dyspnea with significant blood loss
  • Focal or widespread signs of peritonitis (with perforation)

Obstructive signs and symptoms of GISTs can be site-specific, as follows:

  • Dysphagia with an esophageal GIST
  • Constipation and a distended, tender abdomen with a colorectal GIST
  • Obstructive jaundice with a duodenal GIST

See Presentation for more detail.

Diagnosis

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 such as hemorrhage, obstruction, or perforation:

  • Complete blood cell count
  • Coagulation profile
  • Serum chemistry studies
  • BUN and creatinine
  • Liver function tests, amylase and lipase values
  • Type, screen, and crossmatch
  • Serum albumin

Imaging studies

Plain abdominal radiography:

  • Nonspecific
  • May be part of an emergent workup
  • Abnormal gas patterns, including dilated loops of bowel or free extraluminal air, may be seen with bowel obstruction or perforation

Barium and air (double-contrast) series:

  • Frequently provides only limited information
  • Can usually detect GISTs that have grown to a size sufficient to produce symptoms
  • Barium swallow for patients with dysphagia
  • Barium enema for patients with constipation, decreased stool caliber, or colonic manifestations
  • GISTs appear as an elevated, sharply demarcated filling defect
  • The overlying mucosa typically has a smooth contour unless ulceration has developed

Computed tomography scans of the abdomen and pelvis:

  • Essential for the diagnosis and staging of GISTs
  • Provides comprehensive information regarding the size and location of the tumor and its relationship to adjacent structures
  • Can also be used to detect the presence of multiple tumors and of metastatic spread

CT characteristics of small GISTs (< 5 cm) are as follows [2] :

  • Sharply demarcated
  • Homogeneous density
  • Mainly exhibit intraluminal growth patterns

CT characteristics of intermediate GISTs (5-10 cm) are as follows [2] :

  • Irregular shape
  • Heterogeneous density
  • An intraluminal and extraluminal growth pattern
  • Signs of biological aggression, sometimes including adjacent organ infiltration [2]

CT characteristics of large GISTs (>10 cm) are as follows [2] :

  • Irregular margins
  • Heterogeneous densities
  • Locally aggressive behavior
  • Distant and peritoneal metastases

CT criteria associated with high-grade histology and increased mortality:

  • Tumor larger than 11.1 cm
  • Irregular surface contours
  • Indistinct margins
  • Adjacent organ invasion
  • Heterogeneous enhancement
  • Hepatic or peritoneal metastasis

Magnetic resonance imaging:

  • Like CT scanning, MRI can depict tumors and yield information about surrounding structures
  • Can also be used to detect the presence of multiple tumors and metastases
  • Less well studied than CT for diagnosing GISTs, but appears equally sensitive [3]
  • GISTs may appear hypointense on T2-weighted images

Positron emission tomography scanning with 2-[F-18]-fluoro-2-deoxy-D-glucose has the following uses:

  • Detection of metastatic disease
  • Monitoring of response to adjuvant therapy (eg, imatinib mesylate)

Endoscopy:

  • Frequently performed early in the workup of patients with GI bleeding, abdominal pain, or GI obstructive symptoms from GISTs
  • Endoscopic features of GISTs include the suggestion of a smooth submucosal mass displacing the overlying mucosa
  • Ulceration or bleeding of the overlying mucosa from pressure necrosis may be present
  • Problematic for biopsy specimen collection because of the submucosal location of GISTs
  • Endoscopic biopsy results yield a diagnosis in less than 50% of cases
  • Obtaining a repeat biopsy in the same site as a prior biopsy may increase the diagnostic yield

Endoscopic ultrasonography (EUS):

  • Allows localization of lesions and their characterization by ultrasonography
  • Fine-needle aspiration biopsy specimens may be obtained under sonographic guidance
  • GISTs typically appear as a hypoechoic mass in the layer corresponding to the muscularis propria
  • Complementary with CT
  • More accurate than CT in differentiating benign from malignant lesions
  • Allows a more comprehensive evaluation of the mass and the surrounding structures than CT

EUS characteristics of malignant GISTs include the following:

  • Size larger than 4 cm (the only independent predictor)
  • Heterogeneous echogenicity
  • Internal cystic areas
  • Irregular borders on the extraluminal surfaces

EUS features that may help differentiate gastric GISTs from leiomyomas are as follows [4] :

  • Inhomogenicity
  • Hyperechogenic spots
  • A marginal halo
  • Higher echogenicity than the surrounding muscle layer

Aspects of EUS-guided biopsy are as follows:

  • Biopsy provides definitive diagnosis
  • Biopsy may be required when preoperative therapy is needed in cases where the tumor is unresectable or only marginally resectable
  • Biopsy may not be necessary if the tumor is surgically resectable and preoperative medical therapy is not required

See Workup for more detail.

Management

Surgery is the definitive therapy for patients with GISTs, as follows:

  • 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 is contemplated
  • Laparoscopic resection has improved and is a more frequently considered option

Imatinib mesylate is used in GIST as follows:

  • Adjuvant therapy post complete surgical resection in patients with high-risk tumors
  • Neoadjuvant therapy with the goal of tumor shrinkage prior to surgical resection

Other tyrosine kinase inhibitors are used when imatinib is not tolerated or is not effective are as follows:

  • Sunitinib: Less specific than imatinib; approved as a second-line agent for advanced GIST
  • Sorafenib: Investigational second-generation agent
  • Dasatinib: Investigational second-generation agent
  • Nilotinib: Investigational second-generation agent

See Treatment and Medication for more detail.

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Background

Gastrointestinal stromal tumors (GISTs) account for less than 1% of GI tumors, with only about 5000 new cases expected annually in the United States. GISTs rank a distant third in prevalence behind adenocarcinomas and lymphomas among the histologic types of GI tract tumors. However, GISTs are the most common mesenchymal neoplasms of the GI tract. See the image below.

Shown here is a gastric gastrointestinal stromal t Shown here is a gastric gastrointestinal stromal tumor (GIST). This is a gross specimen following partial gastrectomy. Note the submucosal tumor mass with the classic features of central umbilication and ulceration.

GISTs are usually found in the stomach or small intestine but can occur anywhere along the GI tract. Rarely, GISTs have extra-GI involvement. [5]

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 found little evidence of 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 and 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. [6] 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. [6]

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. [7]

Activating KIT mutations are seen in 85-95% of GISTs. About 3-5% of the remainder of KIT-negative GISTs contain PDGFR-alpha mutations. [8, 9, 10]

 The PDGFR alpha mutation seems to leave the PDGFRalpha receptor constitutively active and may represent an alternate pathway with activation of similar downstream signaling as the KIT receptor. The discovery of these receptor mutations has redefined the classification and management of the disease.

The discovery in 2000 that the tyrosine kinase inhibitor (TKI) imatinib, initially used to treat chronic myeloid leukemia, is effective in treating metastatic GISTs revolutionized the care of patients with GISTs. [11] Imatinib has been shown to target KIT and PDGFR alpha in KIT receptor-positive GIST. [12, 13, 14, 15, 16]

This discovery has been celebrated as the example of the power of targeted, individualized therapy and has helped focus a great deal of attention on this orphan disease. The US Food and Drug Administration (FDA) approved imatinib for treatment of metastatic GIST in 2002 and for the adjuvant therapy of primary resected GIST in 2008. [5] The FDA has also approved the newer tyrosine kinase inhibitors sunitinib and regorafenib for treatment of GISTs that are unresponsive to imatinib.

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Pathophysiology

GISTs are typically diagnosed as solitary lesions, although in rare cases (ie, pediatric type), multiple lesions can be found. These tumors have been reported to range in size from smaller than 1 cm to as large as 40 cm in diameter. [17] GISTs can grow intraluminally or extraluminally toward adjacent structures. When the growth pattern is extraluminal, patients can harbor the disease symptom free for an extended period and present with very large exogastric masses.

Approximately 50-70% of GISTs originate in the stomach. Of those, 15% occur in the cardia and fundus, 70% in the body, and 15% in the antrum). [18] 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. [19]

Distant metastases tend to appear late in the course of the disease in most cases. In contrast to other soft tissue tumors, the common metastatic sites of GISTs are the liver and peritoneum. Lymph node involvement is rare, occurring in only 0-8% of cases. However, in rare cases of pediatric GIST, lymph nodes are commonly involved, and distant metastasis is present at diagnosis. [20] Despite these metastases, these variant GISTs have an indolent clinical course.

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Etiology

Most GISTs are associated with gain-of-function mutations in exon 11 of the c-kit proto-oncogene., which encodes the transmembrane tyrosine kinase KIT. [21]  The c-kit proto-oncogene is located on chromosome arm 4q11-12. Most of these mutations are of the in-frame type, which allows preservation of c-kit expression and activation.

Stem cell factor, also called Steel factor or mast cell growth factor, is the ligand for KIT. 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 occurs, exposing binding sites for intracellular signal transduction molecules.

What follows is activation of a signaling cascade that involves phosphorylation of several downstream target proteins, including MAP kinase, RAS, and others. Ultimately, the signal is transduced into the nucleus, resulting in mitogenic activity and protein transcription.

In the majority of GISTs, KIT is constitutively phosphorylated and does not require stem cell factor for initiation of 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. [22]

Although 95% of GISTs are KIT positive, 5% of GISTs have no detectable KIT expression. In a proportion of these 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. Initial studies suggest that GISTs from BRAF mutations have a predilection for the small bowel and are not associated with a high risk of malignancy. [23]  Mutations of the NF2 gene have also been reported in GISTs, but these mutations do not seem to be an integral part of GIST pathogenesis. [24]

A small minority of GISTs are associated with hereditary syndromes. Familial GISTs are characterized by inherited germline mutations in KIT or PDGFRA and additional findings such as the following:

  • Cutaneous hyperpigmentation
  • Irritable bowel syndrome
  • Dysphagia
  • Diverticular disease

Of individuals with these germline mutations, 90% may develop GISTs by 70 years of age. Patients with germline autosomal dominant mutations of KIT may present with multiple GISTs at an early age. [25]  However, familial GISTs have favorable outcomes and do not appear to be associated with shortened survival. No data support preventive therapy in patients with these germline mutations.

In addition, the following syndromes are linked to GISTs [25] :

  • Carney triad - gastric GISTs, paraganglioma, and pulmonary chondromas (these may occur at different ages); primarily affects young women [26]
  • Carney-Stratakis syndrome - GIST and paraganglioma
  • Neurofibromatosis type 1 - Wild-type, often multicentric GIST, predominantly located in the small bowel
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Epidemiology

Frequency

Roughly 5000 new cases of GISTs are diagnosed annually in the United States. According to the Surveillance, Epidemiology, and End Results (SEER) database, the annual age-adjusted incidence of GISTs rose from 0.55 per 100,000 population in 2001 to 0.78/100,000 in 2011. [27]

Data on worldwide frequency are limited, but in general, GISTs constitute 1-3% of all gastric malignancies. Population-based studies from Iceland, the Netherlands, Spain, and Sweden report annual incidence rates ranging from 6.5 to 14.5 cases per million. [28, 29, 30, 31]

Mortality/Morbidity

According to 2001-2011 SEER data, 5-year overall survival rates for patients with GISTs are 77% for those with localized disease at diagnosis, 64% for those with regional disease, and 41% for those with metastatic disease. [27]

Gastric GISTs carry a better prognosis than small bowel GISTs of similar size and mitotic rate. In general, gastric GISTs portend a much better prognosis than adenocarcinoma of the stomach.

Even after complete resection of primary GIST, at least 50% of patients develop recurrence or metastasis, at a median time to recurrence of 2 years. This high rate of recurrence is in the setting of an overall 5-year survival rate of 50%.

Larger GISTs are associated with complications such as GI hemorrhage, GI obstruction, and bowel perforation. Patients with advanced GISTs who are receiving tyrosine kinase inhibitor therapy may develop tumor-related intraluminal or intraperitoneal hemorrhage, rupture, fistula, or obstruction requiring emergent surgery.

Race-, Sex-, and Age-related Demographics

A review of the SEER database from 2001-2011 found that GISTs were more common in non-Hispanics than Hispanics (rate ratio [RR]=1.23) and in blacks (RR=2.07) or Asians/Pacific Islanders (RR=1.50) than in whites. GISTs were also more common in males than females (RR=1.35). The incidence of GISTs increased with age, peaking among 70-79 year olds. [27]

Older age at diagnosis, male sex, black race, and advanced stage at diagnosis were independent risk factors of worse overall survival, on multivariate analysis. Those characteristics, along with earlier year of diagnosis, were also independent risk factors of worse GIST-specific survival. [27]

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Prognosis

GISTs manifest a wide variety of clinical behavior, from slow-growing indolent tumors to aggressive malignant cancers with the propensity to invade 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 biopsy or operative specimens provides objective measures for diagnosis and helps predict clinical behavior.

The predominant prognostic factors in patients with GISTs include the size of the tumor, location of the tumor, and the mitotic rate. [32, 33, 34]  To these may be added the ability or inability to achieve completely negative resection margins. The following characteristics appear to be the most predictive of aggressive behavior in GISTs:

  • Mitotic rate greater than 5 mitoses per 50 high-power fields (HPFs)
  • Size larger than 5 cm and 10 cm, which pose moderate and high malignant potential, respectively [17]
  • Location (small bowel GISTs of comparable size and mitotic rate are generally more aggressive than gastric GISTs)

Because no standardized staging system exists for stromal tumors of the GI tract and most series are small and heterogeneous, comparison of the different published survival rates is difficult. However, various reports of 5-year survival rates after R0 resection for GISTs range from 32-93%. In large series, this rate is about 50-60%.

The median survival after palliative resection is about 10 months, with a 5-year survival rate as high as 10%. These rates improve with the addition of imatinib. [35, 36, 32, 33]  The 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) is large.

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 the following classification system to define the risk of aggressive or malignant behavior in GISTs [37] :

  • Very low risk: size < 2 cm and < 5 mitoses/50 HPFs
  • Low risk: 2-5 cm and < 5/50 HPFs
  • Intermediate risk: < 5 cm and 6-10/50 HPFs  or 5-10 cm and < 5/50 HPFs
  • High risk: >5 cm and >5/50 HPFs  or   >10 cm and any mitotic rate  or any size and >10/50 HPFs

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. [38]

The NCCN criteria for risk stratification of primary GIST have not been incorporated into the AJCC staging but may be more helpful in determining individual risk for progressive disease, after margin-negative resection. The stratification is by mitotic index (≤5 versus >5 per 50 HPF) and then further divided by tumor size (≤2 cm vs >2 cm; ≤5 cm vs >5 cm; ≤10 cm vs >10 cm) and tumor location (gastric and non-gastric). [39]  

Gastric GISTs greater than 10 cm but less than or equal to 5/50 HPF mitotic index have only a 12% risk of progressive disease despite 34-52% risk of progressive disease in the other tumor locations. Gastric GISTs greater than 10 cm and a high mitotic index (>5/50 HPFs), however, have an equally high risk of progressive disease (86%) as GISTs in other locations (71-90%). [39]

Mutational status has both prognostic significance and impact on 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 KIT exon 9 mutant GISTs. The risk for progression and death were increased in patients with no detectable KIT or PDG-FRA mutations. [12]

Other factors found to have a negative impact on prognosis are as follows:

  • Tumor rupture during operation
  • Involvement of histologic margins
  • Lymph node involvement

In an analysis of 4,694 patients with localized GISTs from the National Cancer Data Base, Sineshaw and colleagues found that patients treated with adjuvant therapy had a 46% lower risk of death than patients treated with surgery alone, This survival benefit was significant for patients with GISTs larger than 10 cm. [40]

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Patient Education

Patients should be educated about as many aspects of the disease as possible, including diagnostic and therapeutic measures and options. GIST Support International has produced a patient education booklet entitled Understanding Your GIST Pathology Report.

Most importantly, patients should be apprised of the need for lifelong close clinical follow-up, even after complete resection of disease. Emphasize that GISTs have a propensity to recur.

For patient education resources, see the Cancer Center.

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