R. Kate Kelley, MD: Cholangiocarcinoma is one of the more complicated and heterogeneous cancers that we deal with. As you alluded to, it’s not really a single entity. The first place to start is looking at the anatomic heterogeneity of the disease. As Sameek introduced, we’ve got parts of the bile ducts that occur arise within the liver. We call those intrahepatic cholangiocarcinomas when they develop a cancer. Akin to your tree analogy, those are the little twigs that bear the leaves of the tree high up. Those little twigs can form a cancer. The bigger branches can form a more intraductal but large duct cancer. Right where those big branches converge to form the big trunk of the tree itself, those are some of the most difficult cancers, called hilar or perihilar cholangiocarcinoma, occurring at the bifurcation of the intrahepatic right and left hepatic ducts where they join into becoming the main hepatic duct. Both hilar cholangiocarcinomas were formerly known by the eponym Klatskin carcinoma. Even our nomenclature is confusing, with 3 different names—hilar, perihilar, and Klatskin—referring to the same thing.

Below the hilar claim to carcinomas, we have what we call distal cholangiocarcinoma. Anatomically, those are the cancers that arise distal to the cystic duct where the common bile duct meets the pancreas. Those 3 locations have very different clinical presentations based on both their location and genetics, which we’ll talk about in a moment. From location alone, those that are inside the liver have a lot of room to grow and spread before they cause symptoms often. An intrahepatic cholangiocarcinoma might become quite large before it starts to press on the capsule or obstruct the duct; unfortunately, they can be very advanced at the time of diagnosis.

Conversely, as cholangiocarcinomas start to grow in the distal bile duct or hilar locations, they will cause obstruction; people get yellow or dark urine and present with obstructive jaundice at an earlier stage. Their stage, complications, and requirements for percutaneous or endoscopic drainage differ widely, but patients’ experiences differ quite a bit, whether it’s intrahepatic, hilar, or distal.

You also asked about the biology, and this is where it gets interesting. This is a renaissance in the disease in that just in the past few years, we’ve learned that these anatomic locations are not only structurally and anatomically different but also seem to have different biologies. With the advent of available next-generation sequencing that can perform genomic analysis, even with small amounts of tissue, we’ve seen that intrahepatic cholangiocarcinomas have very different hilar and distal mutation profiles on the whole. As we start talking about treatments later, we’ll discuss some that are targetable by therapy.ut We see driver mutations, like FGFR2 fusions and IDH1 mutations, occurring in around 15% of intrahepatic cholangiocarcinomas but almost never occurring in the distals. The distals and hilars are more likely to have a KRAS or HER2 [human epidermal growth factor receptor 2] driver, so they’re genomically and anatomically different. Lastly, this probably reflects a different cell of origin, whereas the intrahepatic cholangiocarcinomas arise from those little twig-like ducts and form a cholangiole cellular carcinoma-type histology and may arise from hepatic progenitor stem cells. The more hilar and distal seem to arise from more epithelial cells.

John L. Marshall, MD: This makes no sense to me. I went into GI [gastrointestinal] cancer because it was easy. I could just give everybody FOLFOX [5-fluororacil, leucovorin, oxaliplatin], and I was good, right? It was right- vs left-sided colon cancers. Now you’re telling me that the same pathway has different biology depending on if it’s intrahepatic, gallbladder. They kept throwing curve balls at us when we were bundling these cancers. I like what you’re saying, that somehow these lining cells have different functions, maybe different characteristics and, therefore, different vulnerabilities. Does anybody else know why this might be, why we’re seeing these differences? I like your answer, but does anyone have any other explanation?

Milind Javle, MD: Embryologically, these cancers derive differently. You have the perihilar, or the distal cholangiocarcinoma, developing along with the pancreas. I think of this as the entire continuum of the GI tract. Esophageal cancer is not the same as gastric cancer, just as it’s not the same as colon cancer. The biliary tract can be regarded as a continuum that has developed differentially during embryogenesis and development. I think of perihilar and distal more akin to pancreatic cancer in terms of genetic profile, as well as actionable or non-actionable. Intrahepatic cholangiocarcinoma is really its own entity, almost like a different disease. Gallbladder cancer, at times, looks more like breast cancer, with 15% HER2 amplification. We have been confusing ourselves and patients. Patients ask me, “What do I have? Do I have biliary cancer, bile duct cancer, or cholangiocarcinoma? What exactly do I have?” We need time; granularity will come in terms of these being different entities.

John L. Marshall, MD: I’ve been very interested in the colon cancer world with the microbiome and the interface between what’s outside the body and what’s inside the body. This might have something to do with this as well, that the carcinogenic insight, or instigating problem, may be different along that pathway, too. What you’re exposed to in the lower common bile duct and the gallbladder… Different exposures may lead to different kinds of cancers. Sameek, any other thoughts from your angle?

Sameek Roychowdhury, MD, PhD: The genetic characterization of these cancer types throughout the biliary tree supports our clinical diagnosis, the clinical and embryologic distinctions. What you said about the microbiome having a potential impact on the local inflammatory environment, certainly, the bile ducts are not without bacteria. Many of the cholangiocarcinomas that we see have some connection to some inflammatory disorder, but many don’t. That doesn’t mean it’s not a lack of inflammation in the bile duct and the tree. It’s particularly challenging for patients to understand that it’s 1 disease that’s really 10 diseases. The granularity will come with time as we learn more about these cancer types.

Transcript Edited for Clarity