Gastrointestinal Stromal Tumors

Other Names: Gastrointestinal Stromal Sarcoma; GIST Gastrointestinal stromal tumors (GIST) are a type of soft tissue tumor that usually begin in specialized nerve cells in the wall of the stomach, intestines, or rectum, known as interstitial cells of Cajal.

GIST may be noncancerous (benign) or cancerous (malignant). If cancerous, the tumor may also be called a soft tissue sarcoma.

Cause

Genetic changes in one of several genes are involved in the formation of GISTs. About 80 percent of cases are associated with a mutation in the KIT gene, and about 10 percent of cases are associated with a mutation in the PDGFRA gene. Mutations in the KIT and PDGFRA genes are associated with both familial and sporadic GISTs. A small number of affected individuals have mutations in other genes.

The KIT and PDGFRA genes provide instructions for making receptor proteins that are found in the cell membrane of certain cell types and stimulate signaling pathways inside the cell. Receptor proteins have specific sites into which certain other proteins, called ligands, fit like keys into locks. When the ligand attaches (binds), the KIT or PDGFRA receptor protein is turned on (activated), which leads to activation of a series of proteins in multiple signaling pathways. These signaling pathways control many important cellular processes, such as cell growth and division (proliferation) and survival.

Mutations in the KIT and PDGFRA genes lead to proteins that no longer require ligand binding to be activated. As a result, the proteins and the signaling pathways are constantly turned on (constitutively activated), which increases the proliferation and survival of cells. When these mutations occur in ICCs or their precursors, the uncontrolled cell growth leads to GIST formation

Inheritance

Most cases of GIST are not inherited. Sporadic GIST is associated with somatic mutations, which are genetic changes that occur only in the tumor cells and occur during a person's lifetime.

In some cases of familial GIST, including those associated with mutations in the KIT and PDGFRA genes, mutations are inherited in an autosomal dominant pattern, which means one copy of the altered gene in each cell is sufficient to increase a person's chance of developing tumors.

When familial GIST is associated with mutations in other genes, it can have an autosomal recessive pattern of inheritance, which means alterations in both copies of the gene in each cell increase a person's chance of developing tumors.

Risk factors

The risk of GIST is increased in people who have a certain variations (mutations) in the KIT gene, PDGFRA genes, and possibly a few other genes.

Symptoms

Symptoms depend on the location, size, and aggressiveness of the tumors, but may include vomiting of blood, bloody or tarry bowel movements, or anemia caused by chronic bleeding. Other symptoms may include painful and swollen abdomen, appendicitis-like pain, or complications due to gastrointestinal obstruction or tumor rupture.

For most diseases, symptoms will vary from person to person. People with the same disease may not have all the symptoms listed.

80%-99% of people have these symptoms

• Gastrointestinal stroma tumor
• Neoplasm of the stomach
• Stomach tumor
• Sarcoma(Cancer of connective tissue)

30%-79% of people have these symptoms

• Constipation
• Dysphagia(Poor swallowing)
• Fatigue(Tired)
• Gastrointestinal hemorrhage(Gastrointestinal bleeding)
• Intestinal obstruction(Bowel obstruction)
• Nausea and vomiting

5%-29% of people have these symptoms

• Abnormality of the liver(Abnormal liver)
• Anemia(Low number of red blood cells or hemoglobin)
• Esophageal neoplasm(Esophageal tumor)
• Irregular hyperpigmentation
• Neoplasm of the colon(Colon tumor)
• Neoplasm of the rectum(Rectal tumor)
• Neoplasm of the small intestine(Small intestine tumor)
• Skin rash

Diagnosis

Endoscopic image of GIST in fundus of stomach, seen on retroflexion.

Same GIST seen on forward view of the endoscope showing overlying clot.

CT scanning is often undertaken (see the radiology section). The definitive diagnosis is made with a biopsy, which can be obtained endoscopically, percutaneously with CT or ultrasound guidance or at the time of surgery. A biopsy sample will be investigated under the microscope by a pathologist physician. The pathologist examines the histopathology to identify the characteristics of GISTs (spindle cells in 70-80%, epitheloid aspect in 20-30%). Smaller tumors can usually be confined to the muscularis propria layer of the intestinal wall. Large ones grow, mainly outward, from the bowel wall until the point where they outstrip their blood supply and necrose (die) on the inside, forming a cavity that may eventually come to communicate with the bowel lumen. When GIST is suspected—as opposed to other causes for similar tumors—the pathologist can use immunohistochemistry (specific antibodies that stain the molecule CD117 [also known as c-kit] —see below). 95% of all GISTs are CD117-positive (other possible markers include CD34, DOG-1, desmin, and vimentin). Other cells that show CD117 positivity are mast cells.

If the CD117 stain is negative and suspicion remains that the tumor is a GIST, the newer antibody DOG-1 (Discovered On GIST-1) can be used. Also sequencing of Kit and PDGFRA can be used to prove the diagnosis.

The purpose of radiologic imaging is to locate the lesion, evaluate for signs of invasion and detect metastasis. Features of GIST vary depending on tumor size and organ of origin. The diameter can range from a few millimeters to more than 30 cm. Larger tumors usually cause symptoms in contrast to those found incidentally which tend to be smaller and have better prognosis. Plain radiographs are not very helpful in the evaluation of GISTs. Barium fluoroscopic examinations and CT are commonly used to evaluate the patient with abdominal complaints. Barium swallow images show abnormalities in 80% of GIST cases. Preferred imaging modalities in the evaluation of GISTs are CT and MRI.

Treatment

Image showing Gastrointestinal Stromal Tumor after surgical removal

Treatment may include surgery to remove the tumors, and/or medication with tyrosine kinase inhibitors (TKI) depending on the extent of disease and tumor sensitivity to TKI.

For patients with primary, localized gastrointestinal stromal tumors (GIST), surgery with complete excision is often the first line of treatment. However, surgery may not be as successful in the treatment of recurrent and metastatic GIST. The TKI imatinib mesylate (imatinib) may be used as the first treatment option for tumors which cannot be removed completely by surgery (unresectable), cancerous GIST that has spread (metastatic), or recurrent GIST. TKI sunitinib malate (sunitinab) is generally given to people if treatment with imatinib has not been successful. KIT and PDGFRA genetic testing may help predicting tumor responses to kinase inhibitors. The medication(s) listed below have been approved by the Food and Drug Administration (FDA) as orphan products for treatment of this condition.

• Imatinib mesylate (Brand name: Gleevec®)Treatment of patients with Kit (CD117) positive unresectable and/or metastatic malignant gastrointestinal stromal tumors (GIST)
• Regorafenib (Brand name: Stivarga)Treatment of patients with locally advanced, unresectable or metastatic gastrointestinal stromal tumor (GIST) who have been previously treated with imatinib mesylate and sunitinib malate.
• Pazopanib (Brand name: Votrient)Advanced soft tissue sarcoma (STS) who have received prior chemotherapy.

NIH genetic and rare disease info

• NIH info on Gastrointestinal Stromal Tumors

Gastrointestinal Stromal Tumors is a rare disease.

Gastrointestinal Stromal Tumors Resources
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