Sections View Full Chapter Figures Tables Videos Annotate Full Chapter Figures Tables Videos Supplementary Content + Download Section PDF Listen ++ For further information, see CMDT Part 39-07: Carcinoma of the Biliary Tract + Key Features Download Section PDF Listen +++ +++ Essentials of Diagnosis ++ Obstructive jaundice, usually painless, often with dilated biliary tract Pain is more common in gallbladder carcinoma than cholangiocarcinoma A dilated gallbladder may be detected (Courvoisier sign) Diagnosis by cholangiography with biopsy and brushings for cytology +++ General Considerations +++ Gallbladder carcinoma ++ The diagnosis is often made unexpectedly at surgery Cholelithiasis (often large, symptomatic stones) is usually present Risk factors Chronic infection of the gallbladder with Salmonella typhi Gallbladder polyps over 1 cm in diameter (particularly with hypoechoic foci on endoscopic ultrasonography [EUS]) Mucosal calcification of the gallbladder (porcelain gallbladder) Anomalous pancreaticobiliary ductal junction Aflatoxin exposure Genetic factors include k-ras and TP53 mutations TNM staging for gallbladder carcinoma Tis, carcinoma in situ T1a, tumor invades lamina propria T1b, tumor invades muscle layer T2, tumor invades perimuscular connective tissue with no extension beyond serosa (visceral peritoneum) (T2a) or into liver (T2b) T3, tumor perforates the serosa or directly invades the liver or adjacent organ or structure T4, tumor invades the main portal vein or hepatic artery or invades two or more extrahepatic organs or structures N1, metastasis to one to three regional lymph nodes N2, metastasis to four or more regional lymph nodes M1, distant metastasis +++ Carcinoma of the bile ducts (cholangiocarcinoma) ++ About 50% arise at the confluence of the hepatic ducts (perihilar or so-called Klatskin tumors), and 40% arise in the distal extrahepatic bile duct (the incidence of which has risen since 1990); the remainder are intrahepatic or peripheral (the incidence of which rose dramatically from the 1970s to early 2000s) TNM staging for perihilar cholangiocarcinoma Tis, carcinoma in situ/high-grade dysplasia T1, tumor confined to bile duct T2, tumor invades beyond the wall of the bile duct to surrounding adipose tissue T3, tumor invades to liver, gallbladder, or pancreas or a single vein or artery in the liver T4, tumor invades the main portal vein or its branches bilaterally, common hepatic artery, second-order biliary radicals and contralateral portal vein or hepatic artery N1, metastasis to one to three regional lymph nodes N2, metastasis to four or more regional lymph nodes M1, distant metastasis TNM staging for intrahepatic cholangiocarcinoma T1a, solitary tumor ≤ 5 cm T1b, solitary tumor > 5 cm without vascular invasion T2, solitary tumor with intrahepatic vascular invasion or multiple tumors ≤ 5 cm with or without vascular invasion T3, tumor perforating the visceral peritoneum T4, tumor invading adjacent organ (except gallbladder) N1, regional lymph node metastasis M1, distant metastasis Risk factors for intrahepatic cholangiocarcinoma Hepatitis C virus infection Cirrhosis HIV infection Nonalcoholic fatty liver disease Diabetes mellitus Obesity Tobacco smoking Mixed hepatocellular carcinoma-cholangiocarcinoma is being increasingly recognized In southeast Asia, hepatolithiasis and infection of the bile ducts with helminths (Clonorchis sinensis, Opisthorchis viverrini) is associated with chronic cholangitis and an increased risk of cholangiocarcinoma +++ Demographics +++ Carcinoma of the bile ducts ++ Accounts for 10–25% of all hepatobiliary malignancies and for 3% of all cancer deaths in the United States, and the incidence and mortality rates have increased dramatically in the past 2 decades More prevalent in individuals aged 50–70, with slight male predominance and more common in Asia Increased incidence in patients with Bile duct adenoma Biliary papillomatosis Caroli disease Biliary-enteric anastomosis Ulcerative colitis, especially those with primary sclerosing cholangitis Biliary cirrhosis Diabetes mellitus Hyperthyroidism Chronic pancreatitis Heavy alcohol consumption Past exposure to Thorotrast, a contrast agent + Clinical Findings Download Section PDF Listen +++ +++ Symptoms and Signs ++ Progressive jaundice is most common symptom Pain in the right upper abdomen with radiation into the back Usually present early in the course of gallbladder carcinoma However, occurs later in the course of bile duct carcinoma Anorexia and weight loss are common and often associated with fever and chills due to cholangitis Rarely, hematemesis or melena results from erosion of the tumor into a blood vessel (hemobilia) Fistula formation between the biliary system and adjacent organs may also occur The course is usually one of rapid deterioration, with death occurring within a few months A palpable gallbladder with obstructive jaundice is said to signify malignant disease (Courvoisier law); however, this clinical generalization has proved to be only 50% accurate Hepatomegaly is usually present and is associated with liver tenderness Ascites may occur with peritoneal implants Pruritus and skin excoriations +++ Differential Diagnosis ++ Biliary stricture Hepatocellular or pancreatic carcinoma Primary sclerosing cholangitis Primary biliary cirrhosis Choledocholithiasis + Diagnosis Download Section PDF Listen +++ +++ Laboratory Tests ++ With biliary obstruction, predominantly conjugated hyperbilirubinemia, with total serum bilirubin values ranging from 5 mg/dL to 30 mg/dL There are usually concomitant elevations of the serum alkaline phosphatase and cholesterol Serum aspartate aminotransferase (AST) is normal or minimally elevated Serum CA 19-9 level Elevated in up to 85% of patients May help distinguish cholangiocarcinoma from a benign biliary stricture (in the absence of cholangitis) Otherwise, test is neither sensitive nor specific for biliary tract carcinoma +++ Imaging Studies ++ MRI with magnetic resonance cholangiopancreatography is imaging procedure of choice Permits visualization of the biliary tract Detects vascular invasion Obviates the need for angiography Ultrasonography and contrast-enhanced, triple-phase, helical CT may show Gallbladder mass in gallbladder carcinoma Intrahepatic mass or biliary dilation in carcinoma of the bile ducts CT may also show involved regional lymph nodes Positron emission tomography (PET) may detect cholangiocarcinomas as small as 1 cm +++ Diagnostic Procedures ++ Most helpful diagnostic studies before surgery Endoscopic retrograde cholangiography or percutaneous transhepatic cholangiography with biopsy and cytologic specimens However, false-negative biopsy and cytology results are common Fine-needle aspiration (FNA) of tumors under endoscopic ultrasonographic guidance, peroral cholangioscopy, confocal laser endomicroscopy, and intraductal ultrasonography may confirm diagnosis of cholangiocarcinoma in patients with bile duct stricture and an otherwise indeterminate evaluation However, FNA can result in tumor seeding and should be avoided if the tumor is potentially resectable + Treatment Download Section PDF Listen +++ +++ Medications ++ There is limited response to chemotherapy such as with gemcitabine alone However, the combination of cisplatin and gemcitabine or capecitabine and gemcitabine prolongs survival in patients with locally advanced or metastatic cholangiocarcinoma +++ Surgery ++ In young and fit patients, curative surgery for gallbladder carcinoma may be attempted if the tumor is well localized If the tumor is unresectable at laparotomy, biliary-enteric bypass can be performed Liver transplantation or resection Cholangiocarcinoma is generally considered a contraindication However, a 5-year survival rate of up to 75% has been reported in those with stage I and II perihilar cholangiocarcinoma undergoing chemoradiation and exploratory laparotomy followed by liver transplantation +++ Therapeutic Procedures ++ When disease progresses despite treatment, meticulous efforts at palliative care are essential Palliation can be achieved by placing a self-expandable metal stent via an endoscopic or percutaneous transhepatic route Covered metal stents may be more cost-effective than uncovered metal stents because of a lower risk of stent occlusion However, they are not associated with longer survival Plastic stents Less expensive but more prone to occlude than metal ones (particularly covered metal stents) Suitable for patients expected to survive only a few months Photodynamic therapy in combination with stent placement prolongs survival when compared with stent placement alone in patients with nonresectable cholangiocarcinoma ERCP-directed radiofrequency ablation, transcatheter arterial chemoembolization (TACE) and transarterial radioembolization (TARE) are additional emerging options Radiotherapy may relieve pain and contribute to biliary decompression + Outcome Download Section PDF Listen +++ +++ Prognosis ++ The 5-year survival rate For localized carcinoma of the gallbladder (stage 1, T1a, N0, M0) is as high as 80% with laparoscopic cholecystectomy But if there is muscular invasion (stage T2), it is only 60%, even with a more extended open resection Carcinoma of the bile ducts Curable by surgery in < 10% of cases Few patients survive more than 24 months after surgery Factors predicting shorter survival for intrahepatic cholangiocarcinoma include large tumor size, multiple tumors, lymph node metastasis, and vascular invasion +++ Prevention ++ The frequency of carcinoma developing in choledochal cysts is over 14% at 20 years, and thus early surgical excision is recommended +++ When to Refer ++ All patients with carcinoma of the biliary tract should be referred to a specialist +++ When to Admit ++ Biliary obstruction Cholangitis + References Download Section PDF Listen +++ + +Baiu I et al. JAMA patient page. Gallbladder cancer. JAMA. 2018 Sep 25;320(12):1294. [PubMed: 30264121] + +Bertuccio P et al. Global trends in mortality from intrahepatic and extrahepatic cholangiocarcinoma. J Hepatol. 2019 Jul;71(1):104–14. [PubMed: 30910538] + +Brooks C et al. Role of fluorescent in situ hybridization, cholangioscopic biopsies, and EUS-FNA in the evaluation of biliary strictures. Dig Dis Sci. 2018 Mar;63(3):636–44. [PubMed: 29353443] + +Conio M et al. Covered versus uncovered self-expandable metal stent for palliation of primary malignant extrahepatic biliary strictures: a randomized multicenter study. Gastrointest Endosc. 2018 Aug;88(2):283–91. [PubMed: 29653120] + +Goldaracena N et al. Current status of liver transplantation for cholangiocarcinoma. Liver Transpl. 2018 Feb;24(2):294–303. [PubMed: 29024405] + +Liu Z et al. Statin use and reduced risk of biliary tract cancers in the UK Clinical Practice Research Datalink. Gut. 2019 Aug;68(8):1458–64. [PubMed: 30448774] + +Petrick JL et al. Body mass index, diabetes and intrahepatic cholangiocarcinoma risk: the Liver Cancer Pooling Project and meta-analysis. Am J Gastroenterol. 2018 Oct;113(10):1494–505. [PubMed: 30177781] + +Sirica AE et al. Intrahepatic cholangiocarcinoma: continuing challenges and translational advances. Hepatology. 2019 Apr;69(4):1803–15. [PubMed: 30251463] + +Torre LA et al. Worldwide burden of and trends in mortality from gallbladder and other biliary tract cancers. Clin Gastroenterol Hepatol. 2018 Mar;16(3):427–37. [PubMed: 28826679]