by Richard Mitchell, MD, PhD

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    00:01 Hello there. In this talk, we're going to cover another primary tumor of the liver.

    00:07 But much rarer than a hepatocellular carcinoma and this is cholangiocarcinoma.

    00:12 This is cancer of the biliary tree. In terms of the epidemiology, it is the second most common primary malignant liver tumor after hepatocellular carcinoma.

    00:23 But just think for a minute, the most common tumor of the liver is metastatic cancer and that's 30 times more common than the hepatocellular carcinoma and this one is an order of magnitude less common than hepatocellular.

    00:39 So, although, it's the second most common, not that common.

    00:43 It is the United States relatively uncommon, about one per 100,000 population but interestingly, in the worldwide population, largely due to infections and certain kind of environmental exposures and diet, about 8% of the cancer deaths worldwide are attributable to cholangiocarcinoma.

    01:01 So, it's very common in Southeast Asian countries and it's associated with liver flukes and also, dietary nitrosamines. Risk factors for cholangiocarcinoma.

    01:12 Mainly related to chronic inflammation of the biliary tree.

    01:16 In Southeast Asia, this is the liver fluke but you can have primary sclerosing cholangitis or ascending cholangitis as an etiology. Certain environmental or dietary exposures can also do this.

    01:28 It's already indicated. And then, if there are defects in, say, mismatch repair, as in Lynch syndrome, hereditary non-polyposis choli syndrome, then, that may also put you at increased risk for cholangiocarcinoma.

    01:45 The pathophysiology then, kind of is self-explanatory.

    01:48 If you have proliferation of bile duct epithelium in the setting of potentially mutagenic exposures that can cause accumulated mutations, that will increase the risk of cancer.

    02:00 So, inflammatory mediators in particular things like reactive oxygen species will cause DNA breaks and point mutations..

    02:11 The environmental exposures, nitrosamines can also cause mutations and in the setting where there's ongoing proliferation, we cement new mutations into the genome of the epithelium lining, the gallbladder tree.

    02:28 There is a particular kind of tumor, the characteristic cholangiocarcinoma is a klatskin tumor.

    02:35 It's an extrahepatic tumor that arises right at the junction of the right and the left hepatic ducts.

    02:40 That's about 70% of all extrahepatic cholangiocarcinomas.

    02:45 The common bile duct is going to be a location for the remaining majority of the extrahepatic tumors.

    02:53 The microscopic appearance, it's an adenocarcinoma. It's usually well to moderately differentiated.

    02:58 It tends to induce a rather prominent desmoplastic response.

    03:02 That is to say it induces a fibrous stroma.

    03:05 So, these tend to be firm fibrotic tumors. Invasion, particularly, perineural and lymphovascular are quite common and the tumor tends to be fairly aggressive.

    03:15 We can also see tumors that are difficult to sort out between a primary hepatocellular versus a primary cholangiocarcinoma and they're probably cells that sit at that interface can be the original causal cell in tumors.

    03:33 The clinical presentation is patients will have biliary tract obstruction that there are lots of causes for that and it doesn't mean you have cholangiocarcinoma if you have jaundice and/or pruritus due to the accumulation of bile salts. Weight loss is nonspecific.

    03:49 It's a common finding in tumors not otherwise specified.

    03:53 And a patient may describe right upper quadrant discomfort and/or a palpable mass.

    03:57 In making the diagnosis, yes, you can do a bunch of laboratories.

    04:01 So, this is going to end up being an obstructive tumor, so, alkaline phosphatase is going to be elevated.

    04:07 Gamma-glutamyltransferase, GGT is also going to be elevated because it's a very sensitive marker of hepatocyte damage.

    04:13 We would expect bilirubin to be elevated and it's probably total bilirubin is up and a combination of direct and indirect are all up because the obstruction is post hepatic.

    04:24 It's outside the liver. The AST and ALT may be normal or only minimally elevated because there's not much damage to the hepatocytes.

    04:33 Other biomarkers such as CA 19-9 and carcinoembryonic antigen are okay.

    04:40 They are not going to be something that you would screen with.

    04:43 However, once you made the diagnosis and you want to follow the progression of the tumor or the response to the therapy, you can measure these as a way to give a rough index of how well the tumor is growing or not growing.

    04:57 On imaging, we can do ultrasound to exclude other benign causes of obstruction such as a gallstone, going to be much more common.

    05:04 We can do endoscopic retrograde cholangiopancreatography, so, actually going up and looking for areas of obstruction.

    05:10 And clearly, if the imaging is not conclusive, we'll want to do pathology.

    05:15 We'll do a biopsy, send it off to your favorite gastrointestinal pathologist.

    05:21 To manage this disease, surgical resection is the way to go. You want to get rid of the tumor.

    05:27 You may give chemotherapy up front, neoadjuvant or you may give therapy afterwards, probably both.

    05:33 Because overall, this tumor has a generally poor prognosis, five-year survival for all comers, even after a successful surgical resection, it's still only 20 to 40%.

    05:45 If metastatic disease is present at the time of presentation, so, to porta hepatis lymph nodes or to liver, then, the prognosis is much worse and unfortunately, 50 to 60% of patients will present with that.

    06:04 Recurrences are very common after surgery. That's why you would give adjuvant chemotherapy.

    06:09 So, cholangiocarcinoma, not super common but something you should be aware of and certainly, in terms of the risk factors.

    About the Lecture

    The lecture Cholangiocarcinoma by Richard Mitchell, MD, PhD is from the course Disorders of the Biliary Tract.

    Included Quiz Questions

    1. Acute diverticulitis
    2. Chronic inflammation of the biliary tree
    3. Primary sclerosing cholangitis
    4. Lynch syndrome
    1. 60%
    2. 20%
    3. 15%
    4. 10%
    5. 5%
    1. CEA
    2. Alkaline phosphatase
    3. Gamma-glutamyl transferase
    4. Bilirubin
    5. AST

    Author of lecture Cholangiocarcinoma

     Richard Mitchell, MD, PhD

    Richard Mitchell, MD, PhD

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