Gastrointestinal stromal tumor

In medicaloncology, gastrointestinal stromal tumors (GIST) are a raretumorof the gastrointestinal tract(1-3% of all gastrointestinal malignancies).

GISTs are non-epithelialtumors, diagnostically separate from more common forms of bowel cancer. 70% occur in the stomach, 20% in the small intestineand less then 10% in the esophagus. Small tumors are generally benign, especially when cell divisionrate is slow, but large tumors disseminate to the liver, omentumand peritoneal cavity. They rarely occur in other abdominal organs.

Signs and symptoms

Patients present with trouble swallowing, gastrointestinal hemorrhageor 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 painor 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 endoscopicallyor at the time of surgery.

Diagnosis

As part of the analysis, blood testsand CT scanningare often undertaken (see the radiology section).

A biopsysample will be investigated under the microscope. The histopathologistidentifies 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 antibodiesthat stain the molecule CD117 (also known as 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(malignant tumor of smooth muscle) 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 CTare 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, 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 calcificationsmay 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 CajalCells), that are normally part of the autonomic nervous systemof the intestine. They serve a pacemaker function in controlling motility.

Most (50-80%) GISTs arise because of a mutation in a genecalled c-kit. This gene encodes a transmembrane receptorfor 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 marrowcells, mast cells, melanocytesand 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 kinaseto 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 kinasefunction of c-kit is vital in the therapy for GISTs, please see below.

Genetics

Although some families with hereditaryGISTs 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 that do not have a mutated c-kit ("wild-type")have a mutation in another protein, PDGFR-alpha, which is very similar to kit. Mutations in the following exons of the c-kit gene are known to occur in GIST - Exon 11, Exon 9, and rarely, Exons 13 and 7. See 1and 2

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 kinaseinhibitor 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 multiple tyrosine kinase inhibitor sunitinib(marketed as Sutent).

History

Until the 1990s, all non-epithelialtumorsof the gastrointestinal tractwere called "gastrointestinal stromal tumors" from smooth muscleorigin. Histopathologistsgenerally did not 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 2003:94:315-20. PMID 12824897.

External links

Research Links

• American Society of Clinical Oncology "Other Gastrointestinal Cancer" Abstracts (2005)

Patient-Oriented Websites

• GIST Support International, an international organization for the support of GIST patients, families, and friends. Includes basic information, links to research, treatment options, GIST registry.
• GIST InfoPatient links, includes information on new clinical trials and research
• American Cancer SocietyPatient Guide to GIST tumors.
• Life RaftInternational GIST Support group.de:Gastrointestinaler Stromatumor

This article is licensed under the GNU Free Documentation License.
It uses material from the http://en.wikipedia.org/wiki/Gastrointestinal+stromal+tumor Wikipedia article Gastrointestinal stromal tumor.