Liver Tumors and Transplantation: Liver Tumors and Transplantation: Biliary Cancer

0:00Welcome to Board Pearls. This is episode three of four of the Liver Tumors and Transplantation chapter, in the Liver Disease module. This episode is cholangiocarcinoma. The man from episode two, whose liver mass turned out not to be hepatocellular carcinoma, shows why the tumor's location decides everything, how imaging separates it from hepatocellular carcinoma, who's at risk, why carbohydrate antigen 19-9, CA 19-9, can't be trusted, why a transplant can't cure him, and which molecular tests change his drugs. A man with sclerosing cholangitis and a hilar stricture shows the one setting where transplant can cure cholangiocarcinoma, and why the way his tissue was taken decides whether he keeps that chance. A woman with painless jaundice from a distal tumor shows what can imitate it.

0:45Here's the patient. He's the fifty-eight-year-old man from episode two, with alcohol-related cirrhosis and a three-centimeter liver mass. His magnetic resonance imaging, MRI, showed rim enhancement and a targetoid pattern, LR-M, and his biopsy showed intrahepatic cholangiocarcinoma. His computed tomography, CT, of the chest and abdomen shows two enlarged nodes near the liver and two small lung nodules. He asks whether a transplant could cure him, since it would treat his cirrhosis too.

1:17He has intrahepatic cholangiocarcinoma, a cancer of the bile duct epithelium, with nodal spread and probable lung metastases. The answer to his question depends on where the tumor sits, because cholangiocarcinoma comes in three anatomic types, each managed differently. Intrahepatic cholangiocarcinoma arises within the liver itself, upstream of the second-order bile ducts. Perihilar cholangiocarcinoma, the Klatskin tumor, arises at the confluence of the hepatic ducts. Distal cholangiocarcinoma arises between the insertion of the cystic duct and the ampulla. His is a mass inside the liver, so it's intrahepatic.

1:56Perihilar tumors are further classified by Bismuth-Corlette, by how far they extend into the confluence and the ducts above it. Type one is below the confluence, and type two reaches it. Type three-a extends into the right hepatic duct and type three-b into the left. Type four involves both the right and left intrahepatic ducts, or is multifocal.

2:16His imaging had already pointed away from hepatocellular carcinoma. On contrast-enhanced CT or MRI, intrahepatic cholangiocarcinoma shows progressive enhancement through the venous and delayed phases without washout, while hepatocellular carcinoma washes out in the portal venous phase. The reason is the tumor's dense desmoplastic stroma, which traps contrast and holds it, while the abnormal capillaries of hepatocellular carcinoma clear it quickly. That difference is the key discriminator between the two cancers. Positron emission tomography, PET, has limited specificity for the primary tumor, about fifty percent, but it helps stage nodes and distant metastases. Endoscopic ultrasound, EUS, adds local staging and tissue sampling in perihilar and distal tumors.

3:06His cirrhosis is one of several risk factors, and knowing them identifies whose new mass or stricture to suspect. Primary sclerosing cholangitis carries a lifetime risk of ten to fifteen percent, and cholangiocarcinoma is the leading cause of cancer death in that disease. Chronic hepatitis B and C raise the risk, mainly for intrahepatic tumors. So do hepatolithiasis, choledochal cysts and Caroli disease, the liver flukes Opisthorchis viverrini and Clonorchis sinensis in East and Southeast Asia, and historically the contrast agent Thorotrast. A patient from Thailand with recurrent cholangitis and intrahepatic stones has two risk factors. A patient with hepatitis B and a progressively enhancing mass without washout should raise intrahepatic cholangiocarcinoma rather than hepatocellular carcinoma.

3:56His CA 19-9 would have added little. It's raised in about seventy-five percent of patients with cholangiocarcinoma, but it also rises with any benign biliary obstruction or cholangitis, so it isn't specific for cancer. And about five to ten percent of people are Lewis-negative, lacking the antigen they need to make CA 19-9, so their level stays normal even with active cancer. It's one piece of evidence alongside imaging and tissue, never the deciding test.

4:24The answer to his question is no. Intrahepatic cholangiocarcinoma larger than two centimeters is a contraindication to transplant, because survival after transplant is poor, driven by occult metastatic disease. Transplant doesn't solve two problems at once here as it does for hepatocellular carcinoma in cirrhosis. Surgical resection is the only curative option for intrahepatic and distal cholangiocarcinoma, and his three-centimeter tumor with nodes and lung nodules is beyond that too. Had it been found at one point eight centimeters without spread, he'd have been assessed for resection.

4:59So his treatment is systemic. First-line therapy for advanced cholangiocarcinoma is gemcitabine plus cisplatin plus durvalumab. Intrahepatic tumors also get molecular testing, because two targets have approved drugs. Fusions of fibroblast growth factor receptor two, FGFR2, found in about ten to fifteen percent of intrahepatic tumors, are treated with the FGFR inhibitors pemigatinib or futibatinib. Mutations of isocitrate dehydrogenase one, IDH1, found in about ten to twenty percent, are treated with ivosidenib. Mutated IDH1 produces the oncometabolite 2-hydroxyglutarate, which disrupts epigenetic regulation, and ivosidenib reverses its accumulation. His tissue goes for FGFR2 and IDH1 testing, and he starts gemcitabine, cisplatin, and durvalumab, with the molecular results guiding his options at progression.

5:56The second patient shows how differently a hilar tumor is treated. A fifty-two-year-old man has primary sclerosing cholangitis and ulcerative colitis. His surveillance is a yearly magnetic resonance cholangiopancreatography, MRCP, with a CA 19-9, and this year's MRCP shows a new dominant hilar stricture. A dominant stricture in sclerosing cholangitis is assumed to be cholangiocarcinoma until proven otherwise, so he goes to endoscopic retrograde cholangiopancreatography, ERCP. Brushings for cytology and fluorescence in situ hybridization, FISH, which detects chromosomal polysomy, are followed by cholangioscopy with directed biopsy, and the tissue shows adenocarcinoma.

6:41He has a two-and-a-half-centimeter perihilar cholangiocarcinoma involving both hepatic ducts, Bismuth-Corlette type four, which can't be resected. But he may be curable by transplant. The Mayo Clinic protocol takes highly selected patients with unresectable perihilar tumors of three centimeters or less, no intrahepatic metastases, and no lymph node involvement. They receive neoadjuvant external-beam radiation with concurrent fluorouracil, a brachytherapy boost, and capecitabine maintenance. A staging laparotomy then looks for regional spread, and only then comes the transplant. He meets the criteria.

7:17The protocol's results justify that sequence. Selected protocols report about sixty-five percent survival at five years, and after transplant for cholangiocarcinoma, survival at one year is about ninety percent, with recurrence in about twenty percent by five years. The staging laparotomy is a real checkpoint, and regional spread found there stops the transplant. His listing goes through the National Liver Review Board, covered in episode four.

7:42How his tissue was taken decided whether he stayed eligible. A biopsy of a hilar primary through the skin, or by EUS with fine-needle aspiration, passes through the peritoneal cavity and can seed tumor along the tract, creating the extrahepatic disease that disqualifies him. Brushings and biopsies from inside the duct at ERCP sample the tumor without entering the peritoneum, which is why his came that way. A suspicious regional node is a different matter and is biopsied, because positive nodes rule out transplant however the diagnosis is made, and sampling one doesn't create spread that wasn't already there. His tumor's location is the reason it can be transplanted while the first man's can't.

8:21The third patient has a distal tumor. A sixty-nine-year-old woman has painless jaundice and weight loss. She has a stricture of the distal common bile duct, between the cystic duct and the ampulla, with no spread on imaging. EUS shows a mass, and the biopsy shows adenocarcinoma. Resection is the only cure for distal cholangiocarcinoma, so she's referred for surgery.

8:43Her diagnosis needed tissue because something else imitates it. Sclerosing cholangitis related to immunoglobulin G4, IgG4, often alongside autoimmune pancreatitis, can produce a distal stricture in an older patient with painless jaundice and mimic distal cholangiocarcinoma on imaging. Without tissue, an IgG4 level and a look for that disease come first. Her adenocarcinoma settles it. Chapter twenty-six covers IgG4-related disease.

9:12Here are the traps the boards set in these patients. A mass that enhances progressively without washout is cholangiocarcinoma until shown otherwise, not hepatocellular carcinoma. CA 19-9 misleads in cholangitis and is useless in a Lewis-negative patient. An intrahepatic cholangiocarcinoma larger than two centimeters isn't transplanted. A selected unresectable hilar tumor may still be cured under the Mayo protocol.

9:41The traps around tissue and treatment are just as specific. A hilar primary in a possible transplant candidate isn't biopsied through the skin or by EUS, though a suspicious node can be. Every intrahepatic tumor needs testing for FGFR2 fusions and IDH1 mutations. And a distal stricture in an older patient can be IgG4-related disease rather than cancer.

10:05So, start to finish. Locate the cholangiocarcinoma first, because location decides treatment. Intrahepatic tumors enhance progressively without washout, unlike hepatocellular carcinoma, because their fibrous stroma traps contrast. CA 19-9 is nonspecific and absent in Lewis-negative patients.

10:26Resection is the only cure for intrahepatic and distal tumors, and intrahepatic tumors larger than two centimeters aren't transplanted. Selected unresectable hilar tumors of three centimeters or less, without nodes or intrahepatic metastases, qualify for neoadjuvant chemoradiation and transplant under the Mayo protocol, with tissue taken from inside the duct. Give gemcitabine, cisplatin, and durvalumab for advanced disease, and test intrahepatic tumors for FGFR2 fusions and IDH1 mutations.

10:59Episode four is liver transplant: the evaluation and the Model for End-Stage Liver Disease, MELD, three point zero score, exception points and donor types, complications after transplant, and recurrent disease.

11:14For the full chapter, the practice vignettes, and the topic-tagged question bank, head to board pearls dot com. You'll find the rest of the series on Apple Podcasts, Spotify, or wherever you listen to podcasts. That brings us to the end of episode three of four of chapter twenty-four, and I'll see you in the next one.