In this talk, we're going to cover
gastrointestinal stromal tumors,
otherwise known as GISTS.
Let's cover first epidemiology.
Overall, this is not anywhere near
the most common GI malignancy.
Only about 1-2% of the total of all
GI cancers are going to be GIST.
However, it's important that we
recognize them, be aware of them,
and diagnose them appropriately because
we have some very good therapies for them.
There's an interesting
in how the incidence of this
is expressed around the world.
And for reasons that
may be partly genetic,
but partly and mostly unknown.
There's a very high incidence in Hong
Kong and Shanghai and Taiwan, and Norway.
What's the relationship?
I have no clue.
But also in China in the Shanxi
province, very low incidence.
In the Czech Republic as a
very low incidence, go figure.
Men and women are
So it's the same
in both genders.
It typically does
occur in older age,
although that's the peak incidence,
it can occur in younger individuals.
Of the locations where
GIST are located,
the stomach is about 50% of
the total between 40 and 60%.
The jejunum and ileum,
between a quarter and a third,
and less commonly, we will find
GIST in the esophagus, the duodenum,
the colon, the rectum, the anus.
So everywhere from top to
bottom we can find them,
just stomach and small
bowel are more common.
So how does this all work?
Well remarkably, we know quite
a bit about the pathophysiology.
The interstitial cells of Cajal are
the origin of these GI stromal tumors.
Those cells normally sit in the muscular
layer in the muscularis propria,
and are responsible for helping to
coordinate the one way, hopefully,
from top to bottom.
These cells have
on their surface,
a receptor called CD117,
or the c-kit receptor.
And normally, this is separated
the receptor two separate monomers.
And when stem cell factor
binds to the receptor,
we get a conformational change within
the cytoplasmic face of the protein
that will allow ATP
to be hydrolyzed.
And we can phosphorylate a
variety of intracellular proteins
leading to cellular activation.
That's the normal scenario.
In GI stromal tumors,
these interstitial cells of
Cajal now have a mutation
that leads to constitutive
dimerization of the mutant c-kit.
And that leads to tyrosine kinase
activity that goes all the time,
even in the absence
of stem cell factor.
So that means the cells are being driven to
proliferate and do all the various things,
even though there is no
ligand bound to the receptor.
So C-KIT activation,
either in the normal circumstance
or abnormally in the mutant form
of the tyrosine kinase
improves cellular survival,
Interestingly, for these GI stromal
tumors, mutations can also occur
in a different receptor tyrosine
kinase on the surface of cells,
that is the platelet-derived growth factor
receptor A abbreviated here, PDGFRA.
The clinical presentation
is as you might expect,
early on with small tumors,
patients are entirely asymptomatic.
However, as the tumor gets larger and you
may have erosion of the overlying mucosa,
then you may get bleeding and
the patient may become anemic.
And that may be presenting with
Melena, dark, tarry stools.
The patient may be vomiting
blood, have hematemesis.
And because of the irritation
of blood within the GI tract,
you can also get ileus,
the dilation of the bowel.
To make the diagnosis,
we would initially use imaging modalities
such as CT or MRI to find the tumors
and then we would go in by endoscopy.
To do biopsy to verify exactly
what it is that we're dealing with.
Take a little bit,
send it off to pathology, that's me,
where we will do immunohistochemistry
and other studies
to verify that we are dealing
with a GI stromal tumor.
Specifically we want to
do molecular testing.
We want to demonstrate
that we either have c-KIT
or platelet-derived growth
factor receptor A mutations,
because those specific mutations
in a GIST give us the opportunity
to apply tyrosine
This is just showing you an
example of a GI stromal tumor,
the epithelium overlying
it on the left hand side,
completely normal, the lamina
appropriate, completely normal,
normal but deep to that
we have a uniform collection
of stromal like cells,
long spindly cells that
represent our tumor.
And just on the right hand side,
we're seeing what they look
like it's kind of nondescript.
To me, I can say that's
malignant GI stromal tumor.
For you, trust your pathologist.
We will do specifically though
to look for the mutations or
overexpression of some of the markers.
In this case, CD117, the secret molecule
is shown by immunohistochemistry
is a brown staining in a
membrane localized pattern.
How do we manage these?
Well, because they are very responsive
to tyrosine kinase inhibitors,
such as imatinib or dasatinib we can treat
these quite easily with chemotherapy.
We would also in general, debulk,
remove the vast majority of the tumor,
because we can take out segments
of bow that have the GIST
and then send those
off to pathology.
But the major mainstay, at least
in terms of the medical management
are going to be the
tyrosine kinase inhibitors.
With that we've covered everything
you want to know about GIST.