Gastrointestinal stromal tumor



A gastrointestinal stromal tumor (GIST) is one of the most common mesenchymal tumors of the gastrointestinal tract (1-3% of all gastrointestinal malignancies). They are typically defined as tumors whose behavior is driven by mutations in the Kit gene or PDGFRA gene, and may or may not stain positively for Kit.

Signs and symptoms
Patients present with trouble swallowing, gastrointestinal hemorrhage or metastases (mainly in the liver). Intestinal obstruction is rare, due to the tumor's outward pattern of growth. Often, there is a history of vague abdominal pain or discomfort, and the tumor has become rather large by time the diagnosis is made.

Generally, 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.

Diagnosis
As part of the analysis, blood tests and CT scanning are often undertaken (see the radiology section).

A biopsy sample will be investigated under the microscope. The histopathologist identifies the characteristics of GISTs (spindle cells in 70-80%, epitheloid aspect in 20-30%). Smaller tumors can usually be found 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&mdash;as opposed to other causes for similar tumors&mdash;the pathologist can use immunohistochemistry (specific antibodies that stain the molecule CD117 (also known as c-kit) &mdash;see below). 95% of all GISTs are CD117-positive (other possible markers include CD34, DOG-1, desmin, vimentin and others). 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.

Radiology
Barium fluoroscopic examinations (upper GI series and small bowel series) and CT are commonly used to evaluate the patient with upper abdominal pain. Both are adequate to make the diagnosis of GIST, although small tumors may be missed, especially in cases of a suboptimal examination.

Small GISTs appear as intramural masses. When large (> 5 cm), they most commonly grow outward from the bowel. Internal calcifications may be present. As the tumor outstrips its blood supply, it can necrose internally, creating a central fluid-filled cavity that can eventually ulcerate into the lumen of the bowel or stomach.

The tumor can directly invade adjacent structures in the abdomen. The most common site of spread is to the liver. Spread to the peritoneum may be seen. In distinction to gastric adenocarcinoma or gastric/small bowel lymphoma, malignant adenopathy (swollen lymph nodes) is uncommon (<10%).

Pathophysiology
GISTs are tumors of connective tissue, i.e. sarcomas; unlike most gastrointestinal tumors, they are nonepithelial. About 70% occur in the stomach, 20% in the small intestine and less than 10% in the esophagus. Small tumors are generally benign, especially when cell division rate is slow, but large tumors disseminate to the liver, omentum and peritoneal cavity. They rarely occur in other abdominal organs.

Some tumors of the stomach and small bowel, referred to as leiomyosarcomas (malignant tumor of smooth muscle), would most likely be reclassified as GISTs today on the basis of immunohistochemical staining.

GISTs are thought to arise from interstitial cells of Cajal (ICC), that are normally part of the autonomic nervous system of the intestine. They serve a pacemaker function in controlling motility.

Most (50-80%) GISTs arise because of a mutation in a gene called c-kit. This gene encodes a transmembrane receptor for a growth factor termed stem cell factor (scf). The c-kit product/CD117 is expressed on ICCs and a large number of other cells, mainly bone marrow cells, mast cells, melanocytes and several others. In the gut, however, a mass staining positive for CD117 is likely to be a GIST, arising from ICC cells.

The c-kit molecule comprises a long extracellular domain, a transmembrane segment, and an intracellular part. Mutations generally occur in the DNA encoding the intracellular part (exon 11), which acts as a tyrosine kinase to activate other enzymes. Mutations make c-kit function independent of activation by scf, leading to a high cell division rate and possibly genomic instability. Additional mutations are likely "required" for a cell with a c-kit mutation to develop into a GIST, but the c-kit mutation is probably the first step of this process.

The tyrosine kinase function of c-kit is vital in the therapy for GISTs, as described below.

Heritability
Although some families with hereditary GISTs have been described, most cases are sporadic.

In GIST cells, the c-kit gene is mutated approximately 85% to 90% of the time. 35% of the GIST cells with wildtype (i.e. not mutated) c-kit instead have a mutation in another gene, PDGFR-α (platelet derived growth factor receptor alpha), which is a related tyrosine kinase.

Mutations in the exons 11, 9 and rarely 13 and 17 of the c-kit gene are known to occur in GIST. D816V point mutations in c-kit exon 17 are responsible for resistance to targeted therapy drugs like imatinib mesylate, a tyrosine kinase inhibitor. Mutations in c-kit and PDGFrA are mutually exclusive.

Therapy
Tumor size, mitotic rate, and location can be used to predict the risk of recurrence in GIST patients. Tumors <2 cm with a mitotic rate of <5/50 HPF have been shown to have lower risk of recurrence than larger or more aggressive tumors. Nevertheless, all GIST tumors should be considered to have malignant potential and no GIST tumor can be correctly classified as "benign."

Surgery is the mainstay of therapy for nonmetastatic GISTs. Lymph node metastases are rare, and routine removal of lymph nodes is typically not necessary. Laparoscopic surgery, a minimally invasive abdominal surgery using telescopes and specialized instruments, has been shown to be effective for removal of these tumors without needing large incisions.

Until recently, GISTs were notorious for being resistant to chemotherapy, with a success rate of <5%. Recently, the c-kit tyrosine kinase inhibitor imatinib (Glivec/Gleevec), a drug initially marketed for chronic myelogenous leukemia, was found to be useful in treating GISTs, leading to a 40-70% response rate in metastatic or inoperable cases.

The two year survival of patients with advanced disease has risen to 75–80% following imatinib treatment.

Data presented at the 2007 ASCO meeting showed adjuvant treatment with imatinib following surgical resection of GIST tumors can significantly reduce the risk of disease recurrence (6% recurrence on imatinib vs. 17% without therapy at 12 months). The optimal duration of adjuvant therapy is currently unknown; trials are ongoing evaluating treatment durations of 1, 2, and 3 years.

Patients who develop resistance to imatinib may respond to the multiple tyrosine kinase inhibitor sunitinib (marketed as Sutent).

The effectiveness of imatinib and sunitinib depend on the genotype.

Epidemiology
GISTs occur in 10-20 per one million people. The true incidence might be higher, as novel laboratory methods are much more sensitive in diagnosing GISTs. In all, there are approximately 3500-5000 cases of GIST per year in the United States. This makes GIST the most common form of sarcoma, which constitutes more than 70 types of cancer, but in all forms constitutes less than 1% of all cancer.

History
Until the 1990s, all nonepithelial tumors of the gastrointestinal tract were called "gastrointestinal stromal tumors" from smooth muscle origin. Histopathologists generally did not distinguish between the types, as this did not affect either therapy or prognosis. Subsequently, CD34, and later CD117 were identified as markers that could distinguish the various types.