Gastrointestinal Stromal Tumors (GIST)

00:01 Welcome.

00:02 In this talk, we're going to cover gastrointestinal stromal tumors, otherwise known as GISTS.

00:09 Let's cover first epidemiology.

00:12 Overall, this is not anywhere near the most common GI malignancy.

00:17 Only about 1-2% of the total of all GI cancers are going to be GIST.

00:22 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.

00:31 There's an interesting heterogeneity in how the incidence of this is expressed around the world.

00:39 And for reasons that may be partly genetic, partly environmental, but partly and mostly unknown.

00:45 There's a very high incidence in Hong Kong and Shanghai and Taiwan, and Norway.

00:51 What's the relationship? I have no clue.

00:53 But also in China in the Shanxi province, very low incidence.

00:58 In the Czech Republic as a very low incidence, go figure.

01:01 Men and women are equally represented.

01:03 So it's the same in both genders.

01:07 It typically does occur in older age, although that's the peak incidence, it can occur in younger individuals.

01:17 Of the locations where GIST are located, the stomach is about 50% of the total between 40 and 60%.

01:26 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.

01:37 So everywhere from top to bottom we can find them, just stomach and small bowel are more common.

01:43 So how does this all work? Well remarkably, we know quite a bit about the pathophysiology.

01:50 The interstitial cells of Cajal are the origin of these GI stromal tumors.

01:56 Those cells normally sit in the muscular layer in the muscularis propria, and are responsible for helping to coordinate the one way, hopefully, peristaltic movement from top to bottom.

02:11 These cells have on their surface, a receptor called CD117, or the c-kit receptor.

02:19 And normally, this is separated the receptor two separate monomers.

02:25 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.

02:39 And we can phosphorylate a variety of intracellular proteins leading to cellular activation.

02:45 That's the normal scenario.

02:48 In GI stromal tumors, these interstitial cells of Cajal now have a mutation that leads to constitutive dimerization of the mutant c-kit.

03:00 And that leads to tyrosine kinase activity that goes all the time, even in the absence of stem cell factor.

03:07 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.

03:16 So C-KIT activation, either in the normal circumstance or abnormally in the mutant form of the tyrosine kinase causes proliferation, improves cellular survival, ultimately invasion.

03:31 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.

03:49 The clinical presentation is as you might expect, early on with small tumors, patients are entirely asymptomatic.

03:58 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.

04:08 And that may be presenting with Melena, dark, tarry stools.

04:13 The patient may be vomiting blood, have hematemesis.

04:18 And because of the irritation of blood within the GI tract, you can also get ileus, the dilation of the bowel.

04:26 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.

04:36 To do biopsy to verify exactly what it is that we're dealing with.

04:41 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.

04:51 Specifically we want to do molecular testing.

04:53 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 kinase inhibitors.

05:10 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, the submucosa, normal but deep to that we have a uniform collection of stromal like cells, long spindly cells that represent our tumor.

05:32 And just on the right hand side, we're seeing what they look like it's kind of nondescript.

05:36 To me, I can say that's malignant GI stromal tumor.

05:39 For you, trust your pathologist.

05:43 We will do specifically though immunohistochemical staining to look for the mutations or overexpression of some of the markers.

05:51 In this case, CD117, the secret molecule is shown by immunohistochemistry is a brown staining in a membrane localized pattern.

06:03 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.

06:16 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.

06:27 But the major mainstay, at least in terms of the medical management are going to be the tyrosine kinase inhibitors.

06:35 With that we've covered everything you want to know about GIST.