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.
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.