Gastrointestinal stromal tumor
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In medical oncology, gastrointestinal stromal tumors (GIST) are a rare malignancy of the gastrointestinal tract (1-3% of all gastrointestinal malignancies).
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Introduction
GISTs are non-epithelial tumors, diagnostically separate from more common forms of bowel cancer. 70% occur in the stomach, 20% in the small intestine and less then 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.
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 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—as opposed to other causes for similar tumors—the histopathologist can use immunohistochemistry (specific antibodies that stain the molecule CD117 (a.k.a. c-kit)—see below). Virtually all GISTs are CD117-positive. Other cells that show CD117 positivity are mast cells.
Tumors of the stomach and small bowel referred to in older texts as leiomyosarcomas would most likely be reclassified as GISTs today on the basis of immunohistochemical staining.
Radiology
Barium fluoroscopic examinations ("upper GIs", "small bowel series" or "small bowel follow-through") and CT are commonly used to evaluate the patient with upper abdominal pain. Both are able to make the diagnosis of GIST, although small tumors may be missed, expecially 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 seen. In distinction to gastric adenocarcinoma or gastric/small bowel lymphoma, malignant adenopathy is uncommon (<10%).
Pathophysiology
Investigators agree that GISTs probably arise from ICC cells (Interstitial Cajal Cells), 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 scf (stem cell factor). The c-kit/CD117 receptor 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 transcellular 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. It is likely that additional mutations are "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, please see below.
Genetics
Although some families with hereditary GISTs have been described, most cases are sporadic.
Epidemiology
GISTs occur in 10-20 per one million people; one out of 3-4 is malignant. The true incidence might be higher, as novel laboratory methods are much more sensitive in diagosing GISTs.
Therapy
Most small GISTs (<5 and especially <2 cm) with a low rate of mitosis (<5 dividing cells per 50 high-power fields) are benign and—after surgery—do not require adjuvant therapy.
Larger GISTs (>5 cm), and especially when the cell division rate is high (>6 mitoses/50 HPF), may disseminate and/or recur.
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.
Patients who become refractory on imatinib may respond to the experimental tyrosine kinase inhibitor SU11248, which is undergoing trials.
History
Until the 1990s, all non-epithelial tumors of the gastrointestinal tract were called "gastrointestinal stromal tumors" from smooth muscle origin. Histopathologists generally didn't distinguish between the types, as this did affect neither therapy nor prognosis. Subsequently, CD34, and later CD117 were identified as markers that could distinguish the various types.
Sources
- De Silva MV, Reid R. Gastrointestinal stromal tumors (GIST): c-kit mutations, CD117 expression, differential diagnosis and targeted cancer therapy with imatinib. Pathol Oncol Res 2003;9:13-9. PMID 12704441.
- Kitamura Y, Hirota S, Nishida T. Gastrointestinal stromal tumors (GIST): a model for molecule-based diagnosis and treatment of solid tumors. Cancer Sci 2003:94:325-20. PMID 12824897.de:Gastrointestinaler Stromatumor