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Back to Oncology Diseases
Gastrointestinal stromal tumor
In medical oncology, gastrointestinal stromal tumors (GIST) are a
rare malignancy of the gastrointestinal tract.
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.
History
Until the 1990's, 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.
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 diagnosing GISTs. Although some
families with hereditary GISTs have been described, most cases are
sporadic.
Signs and symptoms
Patients present with trouble swallowing, intestinal obstruction,
gastrointestinal hemorrhage or metastases (mainly in the liver).
Often, there is vague abdominal pain or discomfort.
Generally, surgery is required to obtain a biopsy for investigation.
To the surgeon, GISTs appear as circumscribed masses without a
capsule. They originate from the wall of the gut.
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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 independant 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.
Diagnosis
As part of the analysis, blood tests and CT scanning are often
undertaken.
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 between the muscular layers of the intestinal wall,
while larger ones have usually disrupted normal anatomy. There are
usually mild signs of inflammation.
When GIST is suspected?as opposed to other causes for similar
tumors?the histopathologist can use immunohistochemistry (specific
antibodies that stain the molecule CD117?see below). Virtually all
GISTs are CD117-positive. Other cells that show CD117 positivity are
mast cells.
Treatment
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, imatinib (Glivec?/Gleevec?),
a drug initially marketed for chronic myelogenous leukemia, turned out
to inhibit the c-kit tyrosine kinase, leading to a 40-70% response
rate in metastatic or inoperable GISTs.
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