Gastrointestinal Stromal Tumors (GISTs) Clinical Presentation

Updated: Sep 28, 2016
  • Author: Michael A Choti, MD, MBA, FACS; Chief Editor: N Joseph Espat, MD, MS, FACS  more...
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Many gastrointestinal stromal tumors (GISTs) are discovered incidentally during endoscopic or surgical procedures. In Japan, mass screening for gastric adenocarcinoma with upper endoscopy has led to an increase in incidental findings of asymptomatic GISTs.

Other GISTs are detected on radiologic studies performed to investigate protean manifestations of GI tract disease or procedures performed to treat an emergent condition such as hemorrhage or obstruction. In a population-based study, the median tumor size of GISTs that were detected as incidental findings was 2.7 cm, versus 8.9 cm for those found on the basis of symptoms. [24]

GISTs may produce symptoms secondary to hemorrhage or obstruction. Upper GI bleeding is the most common clinical manifestation of GISTs, manifesting as hematemesis or melena in 40-65% of patients. Bleeding occurs because of 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). Other symptoms are generally associated with an enlarging abdominal mass and may include the following:

  • Abdominal pain
  • Anorexia
  • Nausea
  • Vomiting
  • Weight loss
  • Epigastric fullness
  • Early satiety

Physical Examination

Physical examination rarely demonstrates any significant findings. In some cases, examination may identify a palpable mass in the abdomen. Palpable masses are typically detected in patients with extraluminal tumor growth.

Other patients may present with nonspecific physical findings associated with GI blood loss, bowel obstruction, or bowel perforation and abscess formation.

Patients with significant GI bleeding may present with abnormal vital signs 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.



Most GISTs are associated with gain-of-function mutations in exon 11 of the c-kit proto-oncogene., which encodes the transmembrane tyrosine kinase KIT. [25] The c-kit proto-oncogene is located on chromosome arm 4q11-12. Most of these mutations are of the in-frame type, which allows preservation of c-kit expression and activation.

Stem cell factor, also called Steel factor or mast cell growth factor, is the ligand for KIT. 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 occurs, exposing 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.

In the majority of GISTs, KIT is constitutively phosphorylated and does not require stem cell factor for initiation of 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. [26]

Although 95% of GISTs are KIT positive, 5% of GISTs have no detectable KIT expression. In a proportion of these 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. Initial studies suggest that GISTs from BRAF mutations have a predilection for the small bowel and are not associated with a high risk of malignancy. [27] Mutations of the NF2 gene have also been reported in GISTs, but these mutations do not seem to be an integral part of GIST pathogenesis. [28]

A small minority of GISTs are associated with hereditary syndromes. Familial GISTs are characterized by inherited germline mutations in KIT or PDGFRA and additional findings such as the following:

  • Cutaneous hyperpigmentation
  • Irritable bowel syndrome
  • Dysphagia
  • Diverticular disease

Of individuals with these germline mutations, 90% may develop GISTs by 70 years of age. Patients with germline autosomal dominant mutations of KIT may present with multiple GISTs at an early age. [29] However, familial GISTs have favorable outcomes and do not appear to be associated with shortened survival. No data support preventive therapy in patients with these germline mutations.

In addition, the following syndromes are linked to GISTs [29] :

  • Carney triad - gastric GISTs, paraganglioma, and pulmonary chondromas (these may occur at different ages); primarily affects young women [30]
  • Carney-Stratakis syndrome - GIST and paraganglioma
  • Neurofibromatosis type 1 - Wild-type, often multicentric GIST, predominantly located in the small bowel