John L. Marshall, MD: This disease has changed. You are experts in this disease; you can carve out a career in bile duct cholangiocarcinomas. That suggests that there’s more of it out there and that we’re seeing an increase in the number of patients diagnosed with this disease. It’s mostly intrahepatic cholangiocarcinomas that we’re diagnosing. I’m very interested in your reflections on this. When I started, the cancer textbook had a big, thick, “unknown primary” chapter. That chapter has gotten skinnier and skinnier with molecular profiling and better understanding of the disease. This initial presentation of a large lesion in the liver with satellite lesions,we used to call it “metastatic unknown primary.” Now we recognize this pattern of when you have this large thing up in the top of the tree and some others scattered around; that may be cholangiocarcinoma. It’s a shift in just diagnosis. Katie, do you think that’s right, or is there something else going on here?

R. Kate Kelley, MD: That’s part of it, but I also think there’s a true incident. There’s an interesting paper from an immuno-oncologist, Shoop Saha and team at Harvard, where they looked at the incidence in SEER [Surveillance, Epidemiology, and End Results] database of cholangiocarcinoma and cancer of “unknown primary,” and they found an almost identical scope or scale of decrease in cancer of “unknown primary” diagnosis and increase of intrahepatic cholangiocarcinoma. On top of that, there was a greater increase just beyond that amount in the intrahepatics. We think the risk factors for intrahepatic cholangiocarcinoma are quite similar to HCC [hepatocellular carcinoma]. Many of those, including nonalcoholic fatty liver disease and the tale of the hepatitis C virus epidemic, are still relevant in increasing the intrahepatic component as they are for HCC.

John L. Marshall, MD: Are there other habits that we are doing? Who’s your typical patient you’re seeing with this? Younger, older? Men, women? No one?

Milind Javle, MD: I’d say the age is somewhat lower than what you expect for many of the GI [gastrointestinal] cancers. The typical patients we see nowadays have intrahepatic cholangiocarcinoma. I want to reflect on something you said earlier, John, about making a career in this disease. I asked my colleagues in Boston years ago, “Can I make a career in biliary tract cancer?” He said, “That’s never happened,” and here we are. Going forward, in terms of why there are changes in the spectrum of these diseases, we have to reflect on the fact that lifestyles are changing. Obesity is an epidemic, particularly in Texas. We have one of the highest incidences of obesity in the nation and a correspondingly higher incidence of HCC and intrahepatic cholangiocarcinoma. I agree with Katie that part of it is this reclassification, but a lot of it is an increase from lifestyle changes that have led to an increase in intrahepatic cholangiocarcinoma.

R. Kate Kelley, MD: I’d like to interject to say that there’s also regional and geographic heterogeneity at play. In certain parts of the world, this intrahepatic increase may be because of nonalcoholic fatty liver disease and risk factors like obesity. One other risk factor we didn’t talk about that’s highly prevalent in Asia is fluke infection: Opisthorchis- and Clonorchis-type infections in freshwater fish. That’s the dominant cause in other parts of the world. While we may see an increase due to exposure to certain lifestyle risk factors here, in other places—Asia in particular—there can be fluke infections, and the waxing or waning public health measures may impact whether that risk factor comes into play.

John L. Marshall, MD: Sameek, I always think about the classic board question of the inflammatory bowel disease, with cholangitis and getting cholangiocarcinomas. All that is still true, but this is outside that, right? We’re not seeing more IBD [irritable bowel disease] necessarily leading to this?

Sameek Roychowdhury, MD, PhD: Any type of inflammatory state with constant healing and remodeling of the liver parenchyma can contribute, like in other sites of the body through inflammation and carcinogenesis. The fluke example is a good example of a different etiology in some parts of the world that genetically also looks different from what we see in North American intrahepatic cholangiocarcinoma. We don’t see the same pattern of some of the driver genes here that we’ve seen in other parts of the world at the same prevalence. They may still occur but at a different rate. That speaks to the intrinsic differences that can drive carcinogenesis. That also makes the epidemiology, and the associations among obesity, inflammation, geographic differences make the epidemiology harder to make these connections. That plays into the phenotype we see in our patients.

Milind Javle, MD: Sorry, John. I never answered your question about the typical patient I see. The typical patient with intrahepatic cholangiocarcinoma, which is the most common that we see now, is middle-aged, presenting with some metabolic syndrome-type feature often discovered incidentally—liver enzyme elevation with statins, investigation of reflux, or something nonspecific. I see like a dimorphic type of picture. There’s another group of younger people who, often women, who have advanced disease at presentation with abdominal pain, back pain, or jaundice. I see both types of disease presentations.

Transcript Edited for Clarity