eMedicine Specialties > Gastroenterology > Stomach

Gastrointestinal Stromal Tumors

Author: Sandeep Mukherjee, MB, BCh, MPH, FRCPC, Associate Professor, Department of Internal Medicine, Section of Gastroenterology and Hepatology, University of Nebraska Medical Center; Consulting Staff, Section of Gastroenterology and Hepatology, Veteran Affairs Medical Center
Coauthor(s): Michael AJ Sawyer, MD, Director, Videoendoscopic Surgical Institute of Oklahoma, Consulting Staff, Department of Surgery, Comanche County Memorial Hospital; Consulting Staff, Great Plains Surgical Clinic, Lawton, Oklahoma; Robert A Decker, MD, Clinical Assistant Professor, Department of Medicine, University of Hawaii at Manoa: Chief, Gastroenterology Service, Kaiser Permanente Medical Center of Honolulu
Contributor Information and Disclosures

Updated: Mar 4, 2008

Introduction

Background

Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal neoplasms of the gastrointestinal tract. GISTs can also originate in the mesentery and omentum. Overall, GISTs are rare and 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.

Since the term GIST was introduced by Mazur and Clark in 1983, laboratory investigations aimed at the subcellular and molecular levels have demonstrated that GISTs do not possess the ultrastructural and immunohistochemical features characteristic of smooth muscle differentiation, as are seen in leiomyomas and leiomyosarcomas.1 Therefore, the determination was made that GISTs do not arise from smooth muscle cells, but from another mesenchymal derivative such as the progenitors of spindle and epithelioid cells.

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.2 These are GI pacemaker cells and are largely responsible for initiating and coordinating GI motility. This finding led Kindblom and coworkers to suggest the term GI pacemaker cell tumors.2 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 by Hirota and colleagues in 1998.3

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.

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. 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 omental or mesenteric GISTs have been reported but are very rare.

Frequency

United States

Approximately 10-20 persons per million population are diagnosed with GISTs each year.

International

The international prevalence of GISTs is comparable to that reported in the United States. Retrospective reviews from Western Europe, Asia, and Africa have produced similar rates of disease.

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 and mitotic activity. The implications of these tumor characteristics are discussed in Prognosis and Histologic Findings.

Race

GISTs have no known racial proclivity.

Sex

Slightly more males are diagnosed with GISTs than females, although many reviews have reported no sex predilection.

Age

GISTs are most commonly diagnosed in the latter half of the sixth and the first half of the seventh decades of life (ie, 55-65 y). On occasion, they are discovered in younger adults. GISTs are extremely uncommon in children.

Clinical

History

  • 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 endoscopic or surgical procedures or during radiologic studies performed to investigate protean manifestations of gastrointestinal tract disease or to treat an emergent condition such as hemorrhage or obstruction. Lesions greater than 4 cm in diameter are more likely to be symptomatic.
  • 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. 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, the GIST is an unexpected finding during emergency surgery for a perforated viscus.

Physical

  • No physical findings specifically suggest the presence of a GIST. Some patients present with a palpable abdominal mass. Others may present with nonspecific physical findings associated with 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 are present.

Causes

  • Gain-of-function mutations in exon 11 of the c-kit proto-oncogene are associated with most GISTs. 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.
    • This discovery by Hirota and colleagues in 1998 was a landmark elucidation of the etiology of a disease on a molecular level.3 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 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 instances, 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.
    • Studies have reported a small subset of KIT-negative GISTs in which mutations of platelet-derived growth factor receptor-alpha (PDGFA), protein kinase C, and FLJ10261 were detected. These mutations and c-kit mutations appear to be mutually exclusive according to the 2003 work of Heinrich and associates. These investigators discovered PDGFA mutations in 14 of 14 subjects with GISTs who lacked c-kit mutations.
  • A small minority of GISTs are associated with hereditary syndromes.
    • One is characterized by multiple GISTs with or without the presence of dermal and mucous membrane hyperpigmentation, numerous nevi, and urticaria pigmentosa. Mast cell dysfunction and diffuse hyperplasia of GI spindle cells are other features of this syndrome.
    • GISTs occur with a higher than expected frequency in patients with type 1 neurofibromatosis.
    • GISTs are also a feature of the rare Carney triad, which is observed predominantly in young women. This triad consists of epithelioid gastric stromal tumors, pulmonary chondromas, and extra-adrenal paragangliomas.

More on Gastrointestinal Stromal Tumors

Overview: Gastrointestinal Stromal Tumors
Differential Diagnoses & Workup: Gastrointestinal Stromal Tumors
Treatment & Medication: Gastrointestinal Stromal Tumors
Follow-up: Gastrointestinal Stromal Tumors
References
[ CLOSE WINDOW ]

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Further Reading

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Keywords

GI stromal tumor, GIST, GISTs, gastrointestinal mesenchymal neoplasm, GI mesenchymal neoplasm, leiomyoma, leiomyosarcoma, pacemaker cell tumor, GI pacemaker cell tumor, gastrointestinal pacemaker cell tumor, GI tumor, gut tumor, gastrointestinal neoplasm, GI neoplasm

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Contributor Information and Disclosures

Author

Sandeep Mukherjee, MB, BCh, MPH, FRCPC, Associate Professor, Department of Internal Medicine, Section of Gastroenterology and Hepatology, University of Nebraska Medical Center; Consulting Staff, Section of Gastroenterology and Hepatology, Veteran Affairs Medical Center
Sandeep Mukherjee, MB, BCh, MPH, FRCPC is a member of the following medical societies: Royal College of Physicians and Surgeons of Canada
Disclosure: Nothing to disclose.

Coauthor(s)

Michael AJ Sawyer, MD, Director, Videoendoscopic Surgical Institute of Oklahoma, Consulting Staff, Department of Surgery, Comanche County Memorial Hospital; Consulting Staff, Great Plains Surgical Clinic, Lawton, Oklahoma
Michael AJ Sawyer, MD is a member of the following medical societies: American College of Surgeons, Society for Surgery of the Alimentary Tract, Society of American Gastrointestinal and Endoscopic Surgeons, and Society of Laparoendoscopic Surgeons
Disclosure: Nothing to disclose.

Robert A Decker, MD, Clinical Assistant Professor, Department of Medicine, University of Hawaii at Manoa: Chief, Gastroenterology Service, Kaiser Permanente Medical Center of Honolulu
Disclosure: Nothing to disclose.

Medical Editor

Sandeep Mukherjee, MB, BCh, MPH, FRCPC, Associate Professor, Department of Internal Medicine, Section of Gastroenterology and Hepatology, University of Nebraska Medical Center; Consulting Staff, Section of Gastroenterology and Hepatology, Veteran Affairs Medical Center
Sandeep Mukherjee, MB, BCh, MPH, FRCPC is a member of the following medical societies: Royal College of Physicians and Surgeons of Canada
Disclosure: Nothing to disclose.

Pharmacy Editor

Francisco Talavera, PharmD, PhD, Senior Pharmacy Editor, eMedicine
Disclosure: Nothing to disclose.

Managing Editor

Noel Williams, MD, Professor Emeritus, Department of Medicine, Dalhousie University, Halifax, Nova Scotia, Canada; Professor, Department of Internal Medicine, Division of Gastroenterology, University of Alberta, Edmonton, Alberta, Canada
Noel Williams, MD is a member of the following medical societies: Royal College of Physicians and Surgeons of Canada
Disclosure: Nothing to disclose.

CME Editor

Alex J Mechaber, MD, FACP, Assistant Dean for Medical Curriculum, Associate Professor of Medicine, Division of General Internal Medicine, University of Miami Miller School of Medicine
Alex J Mechaber, MD, FACP is a member of the following medical societies: Alpha Omega Alpha, American College of Physicians-American Society of Internal Medicine, and Society of General Internal Medicine
Disclosure: Nothing to disclose.

Chief Editor

Julian Katz, MD, Clinical Professor of Medicine, Drexel University College of Medicine; Consulting Staff, Department of Medicine, Section of Gastroenterology and Hepatology, Hospital of the Medical College of Pennsylvania
Julian Katz, MD is a member of the following medical societies: American College of Gastroenterology, American College of Physicians, American Gastroenterological Association, American Geriatrics Society, American Medical Association, American Society for Gastrointestinal Endoscopy, American Society of Law Medicine and Ethics, American Trauma Society, Association of American Medical Colleges, and Physicians for Social Responsibility
Disclosure: Nothing to disclose.

 
 
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