Molecular Pathogenesis of Gastrointestinal Neoplasia
Moderators: Dr. Wataru Yasui and Dr. Jeremy Jass
Section 2 -
Gastrointestinal Stromal Tumors (GISTs)
University of Washington
While GISTs were originally thought to be very rare, it is now apparent that they
are much more common than previously thought, with as many as 4,500-6,000 new cases in the USA each
year.  They have an equal sex predilection and although they arise over a wide age range, from
pediatric to elderly patients, 75% of GISTs occur in individuals over the age of 50.  Overall,
the median age is 58 years.  GISTs can arise anywhere along the gastrointestinal (GI) tract.
Approximately 5% arise within the esophagus, 50% in the stomach, 25% in the small bowel, and 10% in the
colon and rectum. Most of the colorectal lesions are found within the rectum. In approximately 10% of
patients, GISTs arise outside of the tubal gut, within the mesentery, omentum, retroperitoneum, or pelvis
and are known collectively as EGISTs.  Presenting symptoms include early satiety, bloating,
gastrointestinal bleeding, or fatigue related to anemia.  Clinically aggressive GISTs
metastasize to the liver or disseminate diffusely throughout the abdomen.  GISTs rarely
(<<1%) metastasize to lymph nodes or spread outside of the abdomen.
GIST can be identified as incidental lesions identified at
routine endoscopy or in resection specimens that are removed for other reasons (ie-gastric carcinoma).
GISTs vary in size from less than 1 cm to very large lesions measuring more than 35 cm. The median size
is approximately 5 cm.  GISTs are usually centered on the bowel wall but may extend inward
towards the mucosa, outwards towards the bowel wall, or have a dumbbell configuration with both mucosal
and serosal based masses. They are usually uninodular but may present as multiple/numerous nodules. On
cut section, GISTs are usually fleshy and solid but may have central cystic degeneration, hemorrhage, or
GISTs can exhibit either epithelioid or spindle cell cytomorphology and mixed spindle cell and
epithelioid GISTs are common.  Spindle cell GISTs are usually arranged in fascicles while
epithelioid lesions may be arranged in nests or sheets. The stroma can be hyalinized or myxoid and blood
vessels can be very prominent, mimicking solitary fibrous tumor/hemangiopericytoma. Cytologically, GISTs
are very monomorphic, with rounded to elongated nuclei with fine chromatin and inconspicuous nucleoli,
and abundant pale pink fibrillary cytoplasm. They can also exhibit prominent paranuclear vacuoles,
extensive nuclear palisading, and hyaline eosinophilic cytoplasmic structures known as "skenoid"
fibers.  Mitotic activity is usually very minimal (<1 mitotic figure/10 HPF). Necrosis can
be seen. Pleomorphism is very rare; present in approximately 2% of all GISTs.  Diffuse
pleomorphism involving entire resection specimens, is virtually never seen in GISTs.
Approximately 95% of GISTs are positive for KIT (CD117), 60-70% are positive for CD34,
30-40% for smooth muscle actin (SMA), 5% are positive for S-100 protein, and 1-2% are positive for desmin
or keratin.  KIT positivity is usually diffuse and strong and can have a cytoplasmic,
membranous, or paranuclear "dot-like" distribution. Approximately 5% of GISTs are negative for
KIT.  Identification of KIT or PDGFRA
mutations can be helpful in confirming the diagnosis of GIST in morphologically unusual or KIT
GISTs tend to have relatively simple karyotypes. Loss of
chromosome 14 followed by losses of 1p, 9p, 11p, or 22q are the most common cytogenetic
findings.  High-grade lesions typically, have at least three cytogenetic changes. Loss of 9p
is associated with aggressive/malignant behavior and appears to represent loss of the p16Ink4a tumor suppressor gene. 
KIT is a receptor tyrosine kinase that is involved in the
development and maintenance of germ cells, hematopoietic cells, melanocytes, and interstitial cells of
Cajal.  GISTs are believed to arise from interstitial cell of Cajal precursors through
activating KIT or platelet derived growth factor receptor A gene (PDGFRA) mutations.
KIT mutations are
identified in 85-90% of GISTs regardless of size. Studies have shown that these mutations result in
ligand independent activation of KIT.  Approximately 3-4% of GISTs have mutations within PDGFRA.  These mutations are very similar to KIT
mutations and also result in ligand independent kinase activation. A small number of families,
with familial GISTs, inherited with an autosomal dominant pattern of inheritance, harbor germline
activating KIT or PDGFRA mutations identical to
those seen in sporadic (non-familial) GISTs.
Interestingly, all patients that harbor
germline activating KIT or PDGFRA mutations
develop ICC hyperplasias and GISTs. Recently, two mouse GIST models have been developed by transgenic
"knock-in" technology that harbor germline activating KIT mutations of the
type seen in sporadic and familial GISTs.
s is seen in
humans, mice harboring the activated KIT alleles develop ICC hyperplasia
and/or GISTs with 100% penetrance.
Prognostic Factors and Risk Stratification:
The most important prognostic factors are size and mitotic
count.  However, low mitotic rate and small size does not absolutely guarantee a benign
clinical course. Small GISTs with a low mitotic rate have been known to metastasize.  This
prompted the development of guidelines for defining risk of aggressive behavior based on size and mitotic
rate.  Central to these guidelines is the idea that all GISTs have potential for aggressive
clinical behavior. The guidelines were developed during a consensus conference at the United States
National Institutes of Health in April, 2001. The guidelines are summarized in Table 1.
Table 1 – Proposed Guidelines for Defining Risk of Aggressive Behavior in
| ||Size ||Mitotic Count|
|Very Low Risk ||< 2 cm ||< 5 per 50 HPF|
|Low Risk ||2-5 cm ||< 5 per 50 HPF|
|Intermediate Risk ||< 5 cm|
|6-10 per 50 HPF|
< 5 per 50 HPF
|High Risk ||> 5 cm|
> 10 cm
|> 5 per 50 HPF|
Any mitotic rate
> 10 per 50 HPF
The revelation that most GISTs harbor activating KIT mutations spawned the hypothesis that targeting KIT
might be useful in treating GISTs.  This was particularly important since prior to the
onset of targeted therapy, GISTs did not respond to any known chemotherapy or radiation therapy.
However, with the availability of imatinib mesylate (Gleevec®, Glivec®), a small molecule inhibitor that
binds to the kinase domain of KIT and PDFRA, cooperative group studies were initiated to study the
efficacy in GIST. These studies have shown that GIST responds well to imatinib, although the response is
dependent on the location of the KIT mutation within the KIT gene.  While primary resistance to imatinib does occur, the
majority of KIT mutations are responsive to imatinib and a proportion of
PDGFRA mutations also respond. Imatinib has largely been studied as salvage
therapy for recurrent/metastatic GISTs but ongoing studies are looking at using imatinib in the
neoadjuvant and adjuvant setting. Finally, acquired, secondary resistance to imatinib is an emerging
problem.  The mechanism of resistance is due to acquisition of a second site mutation within
KIT or PDGFRA that disrupts the interaction
The main differential diagnosis of conventional GIST includes
true smooth muscle tumors (leiomyomas and leiomyosarcomas), schwannoma, inflammatory fibroid polyp, and
desmoid fibromatosis. Immunohistochemical studies are extremely helpful in sorting out this differential
diagnosis. True smooth muscle tumors are positive for smooth muscle actin and desmin and are negative
for KIT. Schwannomas are positive for S-100 protein and are negative for KIT. Inflammatory fibroid
polyps can be positive for CD34. However, they are negative for KIT and contain inflammatory cells
including eosinophils. There is some controversy about whether or not desmoid fibromatosis is positive
for KIT. However, reports of KIT immunoreactivity in desmoids seem to be related to overzealous antigen
retrieval. For this reason, we do not use antigen retrieval with KIT immunohistochemistry and have found
KIT to be negative in fibromatosis. However, care should be taken in the use of KIT immunohistochemistry
since melanomas, germ cell tumors, angiosarcomas and some carcinomas are also positive for KIT.
Fortunately, these lesions can usually be excluded on the basis of their characteristic morphologic
features and immunoreactivity for other antibodies that are not positive in GIST.
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