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Gastrointestinal Stromal Tumors Clinical Presentation

  • Author: Nancy S Behazin, MD; Chief Editor: BS Anand, MD  more...
 
Updated: Mar 30, 2015
 

History

In adult GISTs, the stomach (60%) and small intestine (30%) are the most common primary sites. Duodenum (5%) and colorectum (< 5%) are less common primary sites. Only a small number of cases (< 1%) have been reported in the esophagus and appendix. On rare occasions, GISTs develop outside the gastrointestinal tract in the mesentery, omentum, or retroperitoneum.

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. 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.[4]

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, GIST is an unexpected finding during emergency surgery for a perforated viscus.

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Physical

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.

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Causes

Most 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.[5]

This discovery by Hirota and colleagues in 1998 was a landmark elucidation of the etiology of a disease on a molecular level.[12] 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.

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 70 years of age. Familial GISTs have favorable outcomes and do not appear to be associated with shortened survival. There is 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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Contributor Information and Disclosures
Author

Nancy S Behazin, MD Fellow, Department of Gastroenterology, Scott and White Hospital, Texas A&M Health Science Center College of Medicine

Nancy S Behazin, MD is a member of the following medical societies: American College of Gastroenterology, American College of Physicians, American Medical Association, American Society for Gastrointestinal Endoscopy, Texas Medical Association

Disclosure: Nothing to disclose.

Specialty Editor Board

Francisco Talavera, PharmD, PhD Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Received salary from Medscape for employment. for: Medscape.

Noel Williams, MD, FRCPC FACP, MACG, 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, FRCPC is a member of the following medical societies: Royal College of Physicians and Surgeons of Canada

Disclosure: Nothing to disclose.

Chief Editor

BS Anand, MD Professor, Department of Internal Medicine, Division of Gastroenterology, Baylor College of Medicine

BS Anand, MD is a member of the following medical societies: American Association for the Study of Liver Diseases, American College of Gastroenterology, American Gastroenterological Association, American Society for Gastrointestinal Endoscopy

Disclosure: Nothing to disclose.

Acknowledgements

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.

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: Merck Honoraria Speaking and teaching; Ikaria Pharmaceuticals Honoraria Board membership

Michael AJ Sawyer, MD Consulting Staff, Department of Surgery, Southwestern Medical Center; Consulting Staff, Department of Surgery, Comanche County Memorial Hospital; Consulting Staff, Great Plains Surgical Clinic, Inc

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.

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