Cholangiocarcinoma (CCA)

Cholangiocarcinoma (CCA) is a rare and aggressive biliary adenocarcinoma with origin in the epithelial cells of the biliary system.1

CCA clinical presentation can vary according to the type of tumor, but general symptoms include malaise and weight loss.1 In extrahepatic presentations (eCCA), jaundice is common due to hepatic obstruction.2 Pale stools, pruritus, dark urine, vomiting and changes in the liver function can also be observed.1,3 Patients that present an intrahepatic CCA (iCCA) can manifest abdominal pain4 while jaundice may appear in advanced stages of the disease.2 

CCA is asymptomatic in many cases, typically in early presentations,2,3 leading to a late diagnosis and a poor prognosis. About 20% to 25% of iCCA cases are detected with no indication of possible malignant disease.5 CCA develops usually between ages 50 and 70 and its incidence increases in older individuals.5

Diagnosis of CCA can be achieved through non-invasive and invasive techniques, however, the use of non-invasive techniques must be supported with an histological study that confirms the initial diagnosis.2 Patients presenting asymptomatic cholestatic elevation of liver enzymes, with imaging results that point to a tumor of the hepatobiliary system or that are diagnosed with ulcerative colitis or primary sclerosing cholangitis (PSC), should be further assessed for potential CCA development.5 Other factors such as family history, the co-existence of other clinical conditions, including inflammatory bowel disease and hepatitis, travel activities or substance abuse should be also investigated when a CCA diagnosis is suspected.6

Laboratory Workup, Imaging Techniques

Tumor markers may be tested for CCA. Serum carbohydrate antigen 19-9 (CA 19-9) is a tumor antigen sensitive for CCA in up to 70% cases.6 The carcinoembryonic antigen (CEA) can be also investigated but is less sensitive than CA 19-9.6 Both CA 19-9 and CEA have been found in higher quantities in 40% and 85% of CCA patients, respectively, but they can be increased in other diseases as well in addition to CCA.1 CA 19-9 isolated values cannot be used for establishing a CCA diagnosis.3 Other markers such as matrix metalloproteinase-7 and cytokeratin-19 fragments are also overexpressed in CCA.7

A liver panel in CCA patients commonly reveals elevated liver enzymes with alkaline phosphatase and gamma-glutamyl transferase increased, correlating with a cholestatic liver injury. The obstruction of the biliary system that is related with CCA may result in an increase in transaminases also.6

Regardless of the type of presentation, CCA diagnosis requires imaging techniques that allow performing an evaluation of the biliary tree.3 Ultrasound (US) can be used as an initial test to determine changes in liver function1,8 but it does not easily differentiate iCCA and eCCA.9 

Patients that present symptoms or a liver panel with altered enzymes are commonly subjected to a magnetic resonance imaging (MRI). An MRI is important for diagnosing CCA3 and a better approach when compared with computed tomography (CT) as it shows a high intrinsic contrast resolution.3 If a mass is found during imaging, a combination of MRI with cholangiopancreatography (MRCP) should be then performed, as well as a cytologic examination.6 

A fluorodeoxyglucose positron emission tomography (PET) scanning can be performed when diagnosing CCA. PET CT is also a diagnostic tool when other tests do not provide a conclusive answer.1 The sensitivity of the examination goes up to 90% in iCCA diagnosis.1 This PET CT may additionally help clinicians to identify metastases with a detection rate close to 100%.10 When investigating an iCCA, a CT scan of the chest should be performed in order to diagnose a metastatic disease.1,6 

Endoscopic Techniques

Endoscopic retrograde cholangiopancreatography (ERCP), percutaneous transhepatic cholangiography (PTC) and endoscopic ultrasound (EUS) can be used to sample suspected CCA primary lesions.1,8 In the endoscopic evaluation using ERCP, sampling can be done via brushing or fine needle aspiration (FNA).8 EUS examination can deliver the localization of the tumor in the biliary tree8 while allowing the collection of a tumor sample through FNA. Fluorescence in situ hybridization (FISH) combined with the endoscopic studies can aid increasing the diagnostic output up to 35% or more.6

Even though a cytologic examination helps in diagnosis in most of cases, there is an increased risk of seeding associated with tumor sampling.8  In addition, a negative result does not exclude the existence of a tumor and that will require a repeated sampling for diagnosis confirmation.11

Differential Diagnosis

Many other diseases can lead to symptoms that are shared with CCA.6 The presence of an intrahepatic mass is also not always associated with CCA development. CCA must be differentiated from other tumors such as the hepatocellular carcinoma (HCC) or pancreatic cancer.5,11 Other medical conditions, such as cholecystitis, choledochal cysts, cholangitis, cholelithiasis, PSC and biliary disease may induce liver enzyme elevation or biliary dilation and need also to be considered in the differential diagnosis of CCA.6


1. Doherty B, Nambudiri VE, Palmer WC. Update on the Diagnosis and Treatment of Cholangiocarcinoma. Curr Gastroenterol Rep. 2017 Jan;19(1):2. doi:10.1007/s11894-017-0542-4

2. Banales JM, Marin JJG, Lamarca A, Rodrigues PM, Khan SA, Roberts LR, et al. Cholangiocarcinoma 2020: the next horizon in mechanisms and management. Nat Rev Gastroenterol Hepatol. 2020 Sep;17(9):557-588. doi:10.1038/s41575-020-0310-z

3. Inchingolo R, Maino C, Gatti M, Tricarico E, Nardella M, Grazioli L, et al. Gadoxetic acid magnetic-enhanced resonance imaging in the diagnosis of cholangiocarcinoma. World J Gastroenterol. 2020 Aug;26(29):4261-4271. doi:10.3748/wjg.v26.i29.4261

4. Nakeeb A, Pitt HA, Sohn TA, Coleman J, Abrams RA, Piantadosi S et al. Cholangiocarcinoma. A spectrum of intrahepatic, perihilar, and distal tumors. Ann Surg. 1996 Oct;224(4):463-73; discussion 473-5. doi:10.1097/00000658-199610000-00005

5. Alvaro D, Bragazzi MC, Benedetti A, Fabris L, Fava G, Invernizzi P et al. AISF “Cholangiocarcinoma” committee. Cholangiocarcinoma in Italy: A national survey on clinical characteristics, diagnostic modalities and treatment. Results from the “Cholangiocarcinoma” committee of the Italian Association for the Study of Liver disease. Dig Liver Dis. 2011 Jan;43(1):60-5. doi:10.1016/j.dld.2010.05.002

6. Buckholz AP, Brown RS Jr. Cholangiocarcinoma: Diagnosis and Management. Clin Liver Dis. 2020 Aug;24(3):421-436. doi:0.1016/j.cld.2020.04.005

7. Grunnet M, Mau-Sørensen M. Serum tumor markers in bile duct cancer–a review. Biomarkers. 2014 Sep;19(6):437-43. doi:10.3109/1354750X.2014.923048

8. Dondossola D, Ghidini M, Grossi F, Rossi G, Foschi D. Practical review for diagnosis and clinical management of perihilar cholangiocarcinoma. World J Gastroenterol. 2020 Jul;26(25):3542-3561. doi:10.3748/wjg.v26.i25.3542

9. Chen LD, Xu HX, Xie XY, Xie XH, Xu ZF, Liu GJ et al. Intrahepatic cholangiocarcinoma and hepatocellular carcinoma: differential diagnosis with contrast-enhanced ultrasound. Eur Radiol. 2010 Mar;20(3):743-53. doi:10.1007/s00330-009-1599-8

10. Breitenstein S, Apestegui C, Clavien PA. Positron emission tomography (PET) for cholangiocarcinoma. HPB (Oxford). 2008;10(2):120-1. doi:10.1080/13651820801992583

11. Forner A, Vidili G, Rengo M, Bujanda L, Ponz-Sarvisé M, Lamarca A. Clinical presentation, diagnosis and staging of cholangiocarcinoma. Liver Int. 2019 May;39 Suppl 1:98-107. doi:10.1111/liv.14086

Reviewed by Harshi Dhingra, MD, on 7/1/2021.