Gastrointestinal Stromal Tumors

Updated: Mar 30, 2015
  • 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 GI tract and 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 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 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
  • 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 [1]
  • 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. 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 [3] :

  • 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 [4]
  • GISTs may appear hypointense on T2-weighted images [5]

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 [6]
  • 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 [7]
  • 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 [8] :

  • 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 [9] :

  • 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 tumors, however, 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 tract and rarely have extragastrointestinal involvement. [10] GISTs rank a distant third in prevalence behind adenocarcinomas and lymphomas among the histologic types of gastrointestinal 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 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 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. [11] 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. [11] 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. [12]

These advances have 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

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 ranging in size from smaller than 1 cm to as large as 40 cm in diameter. [13] 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. [10]

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Frequency

United States

Roughly 5000 new cases of gastrointestinal stromal tumors are diagnosed annually in the United States.

International

Population-based studies from Iceland, the Netherlands, Spain, and Sweden report annual incidence rates ranging from 6.5 to 14.5 cases per million.

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Mortality/Morbidity

Outcomes in patients with GISTs are highly dependent on the clinical presentation and the histopathological features of the tumor. The overall 5-year survival rate ranges from 28-60%. 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, while the median survival rate in the latter group is approximately 10-20 months. Larger GISTs are associated with complications such as GI hemorrhage, GI obstruction, and bowel perforation. This is discussed further in Surgical Care and Complications.

Tumors can be classified into high and low-risk categories based on size, location, and mitotic activity. The implications of these tumor characteristics are discussed in Prognosis and Histologic Findings.

Race

GISTs have no known racial proclivity. However, Cheung et al reported that out 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% Caucasians, 15.6% African Americans, and 9.1% Hispanics. [1]

Sex

SEER (Surveillance, Epidemiology, and End Results) data from 1992-2000 report a slightly higher prevalence in males versus females, at 54% and 46%, respectively. [2]

Age

GISTs have been reported in all age groups including infants. It is extremely rare in patients younger than 30 years. In a study of 1765 gastric GISTs, the median age at diagnosis was 63 years. [13] In a series consisting of 906 jejunal and ileal GISTs, the mean age was 59 years. [3] In the latter 2 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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