Gastrointestinal Stromal Tumors

Updated: May 05, 2017
  • Author: Nancy S Behazin, MD; Chief Editor: BS Anand, MD  more...
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Overview

Practice Essentials

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.

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 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] :

  • 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 Clinical 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 of a GIST-like hemorrhage, obstruction, or perforation:

  • Complete blood cell count
  • Coagulation profile
  • Serum chemistry studies
  • Blood urea nitrogen (BUN) and creatinine levels
  • Liver function tests, amylase and lipase measurements
  • Type, screen, and crossmatch
  • Serum albumin levels

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 [2]
  • The overlying mucosa typically has a smooth contour unless ulceration has developed

Computed tomography scans of the abdomen and pelvis:

  • Important in 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. Computed tomography (CT) scan characteristics of small GISTs (< 5 cm) are as follows [3] :

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

CT scan characteristics of intermediate GISTs (5-10 cm) are as follows [3] :

  • Irregular shape
  • Heterogeneous density
  • An intraluminal and extraluminal growth pattern
  • Signs of biological aggression, sometimes including adjacent organ infiltration [3]

CT scan characteristics of large GISTs (>10 cm) are as follows [3] :

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

CT scan criteria associated with high-grade histology and increased mortality [4] :

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

Magnetic resonance imaging (MRI):

  • 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 [5]
  • GISTs may appear hypointense on T2-weighted images [6]

Positron emission tomography (PET) scanning with 2-[F-18]-fluoro-2-deoxy-D-glucose (FDG) 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 [7]
  • 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 scanning [8]
  • More accurate than CT scanning in differentiating benign from malignant lesions
  • Allows a more comprehensive evaluation of the mass and the surrounding structures than CT scanning

EUS characteristics of malignant GISTs include the following [9] :

  • 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 [10] :

  • 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 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.

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Pathophysiology

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]

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Etiology

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.

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Epidemiology

United States data

An estimated 4000 to 5000 new cases of gastrointestinal stromal tumors (GISTs) are diagnosed annually in the United States. [16]

International data

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.

Race-related demographics

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]

Sex-related demographics

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]

Age-related demographics

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.

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Prognosis

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] :

  • Very low risk - Smaller than 2 cm and less than 5/50 HPFs
  • Low risk - From 2-5 cm and less than 5/50 HPFs
  • Intermediate risk - Either (1) smaller than 5 cm and 6-10/50 HPFs or (2) 5-10 cm and less than 5/50 HPFs
  • High risk - Includes (1) larger than 5 cm and more than 5/50 HPFs, (2) larger than 10 cm and any mitotic rate, or (3) any size and more than 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. [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]

Morbidity/mortality

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

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:

  • Hemorrhage
  • Bowel obstruction
  • Volvulus
  • Intussusception
  • Bowel perforation with peritonitis

The range of postoperative complications is similar to that for major abdominal and GI surgery. The following is a representative but not exhaustive list:

  • Wound infection
  • Wound dehiscence with or without evisceration
  • Urinary tract infection
  • Atelectasis
  • Pneumonia
  • Anastomotic disruption
  • Anastomotic stricture
  • Marginal ulceration
  • Intra-abdominal abscess formation
  • Cholangitis
  • Delayed gastric emptying or gastroparesis
  • Internal or enterocutaneous fistula
  • Small-bowel obstruction
  • Dumping syndrome
  • Alkaline reflux gastritis
  • Cardiac arrhythmias
  • Myocardial infarction
  • Deep venous thrombosis
  • Pulmonary embolism
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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. 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).

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