Cholangiocarcinoma (CCA)


Cholangiocarcinoma (CCA) is a malignant disease with a poor prognosis.1 CCA can be classified based on the anatomic location of the tumor into intrahepatic CCA (iCCA), perihilar CCA (pCCA) and distal CCA (dCCA).2 

Many patients with CCA are asymptomatic until advanced stages of the disease are reached. This is particularly relevant in many cases of iCCA where the absence of symptoms results in locally advanced disease or in metastases presentation at the time of the diagnosis.3 Surgical resection is the only effective potential cure for CCA but it requires an early diagnosis so localized tumors can be identified and effectively treated.1 Even when surgery is an option based on a pre-operative assessment, between 20% to 50% of patients are found with unresectable tumors at the time of the procedure.4,5

There are several tests that can be used in the diagnosis, monitoring and management of CCA.

Blood Workup and Tumor Markers

An evaluation of the patient’s liver function should be performed during the initial diagnosis. Patients with CCA typically present with an affected liver panel with levels of alkaline phosphatase, gamma-glutamyl transpeptidase, transaminases and bilirubin elevated.6,7 

There are also a few potential tumor markers that can be followed in CCA; however, they have a limited value in clinics due to their low sensitivity and specificity.8 These include the serum carbohydrate antigen 19-9 (CA 19-9), and the carcinoembryonic antigen (CEA).7 Both tumor markers can be found increased in other diseases as well in addition to CCA.9 Even though they cannot be used alone for establishing a diagnosis, they can be used for monitoring recurrence.8

Imaging Studies

Patients with a suspected liver mass or biliary obstruction are ideal candidates for ultrasonography (US). US is a noninvasive test that can help detect bile duct dilatations. Its sensitivity and specificity to detect pCCA reaches up to 96%.10,11 A preoperative workup for CCA may include a contrast-enhanced US for visualizing the tumor vasculature and to allow the differential diagnosis of lesions in the liver. Endoscopic US (EUS) can also be performed to evaluate possible biliary strictures or to stage the involvement of the lymph nodes and portal vein.1

MRI is the most accurate imaging technique used for CCA diagnosis.12 MRI not only allows visualization of the malignant lesions, but also to perform their characterization and study their progression through the bile duct and liver. It also allows the staging of the disease according to the involvement of the vascular, ductal and lymphatic structures.13 A different type of MRI, magnetic resonance cholangiopancreatography (MRCP), allows the observation of the bile ducts and to assess how far the tumor has extended, without the use of an endoscope or a contrast agent.13,14 

CT is a different non-invasive imaging modality with high resolution that can be used for studying liver masses, to observe stenosis and to look for signs of metastatic disease.15 CT is capable of distinguishing CCA from other liver diseases such as hepatocellular carcinoma (HCC).16 PET CT imaging may be used to help diagnose iCCA with a sensitivity up to 90%.9 It can also aid in predicting survival.17

A cholangiography allows the evaluation of the bile ducts and to assess the extension of the tumor around them. It can also allow the identification of bile duct strictures.18 There are different types of cholangiograms. An Endoscopic retrograde cholangiopancreatography (ERCP) and Percutaneous transhepatic cholangiography (PTC) may be used for additional retrieval of cellular samples for improving diagnosis.14,19 These cholangiograms can also be used for CCA management as they allow the placing of stents into bile ducts for therapeutic drainage.14 A Magnetic resonance cholangiopancreatography (MRCP) is performed instead when no biopsy samples are needed.14

Angiography

An angiography is an x-ray imaging test where the liver and bile duct blood vessels are visualized.13 Abnormalities of the blood vessels as well as potential blood flow blockages can be observed. This test can be performed coupled to a CT scan or an MRI (CT angiography and MRI angiography, respectively).13

Biopsy

A biopsy is mandatory when confirming a CCA diagnosis.20 Cell samples or samples of the bile duct tissue can be obtained during an ERCP or PTC test. In these examinations, a small brush is passed through an endoscope or a needle that scrapes small portions of the tissue to be sampled.14 Sensitivity of the brushing cytology may be increased with fluorescence in situ hybridization (FISH) for detection of chromosomal abnormalities.9,21

Cell samples can be also collected using a thin and hollow needle that is guided with US or with a CT scan into the sampling point.14 Endoscopic ultrasound -guided fine needle aspiration (EUS-FNA) can allow the detection of a malignant tumor with a sensitivity up to 83%. Potential tumor seeding should be taken care of when performing EUS-FNA.22

References

1. Yang CM, Shu J. Cholangiocarcinoma evaluation via imaging and artificial intelligence. Oncology. 2021;99(2):72-83. doi:10.1159/000507449

2. Blechacz B. Cholangiocarcinoma: current knowledge and new developments. Gut Liver. 2017 Jan 15;11(1):13-26. doi:10.5009/gnl15568

3. Mejia JC, Pasko J. Primary liver cancers: intrahepatic cholangiocarcinoma and hepatocellular carcinoma. Surg Clin North Am. 2020 Jun;100(3):535-549. doi:10.1016/j.suc.2020.02.013

4. Rocha FG, Matsuo K, Blumgart LH, Jarnagin WR. Hilar cholangiocarcinoma: the memorial sloan-kettering cancer center experience. J Hepatobiliary Pancreat Sci. 2010 Jul;17(4):490-6. doi:10.1007/s00534-009-0205-4 

5. Nagino M, Ebata T, Yokoyama Y, et al. Evolution of surgical treatment for perihilar cholangiocarcinoma: a single-center 34-year review of 574 consecutive resections. Ann Surg. 2013 Jul;258(1):129-40. doi:10.1097/SLA.0b013e3182708b57

6. 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

7. Buckholz AP, Brown RS Jr. Cholangiocarcinoma: diagnosis and management. Clin Liver Dis. 2020 Aug;24(3):421-436. doi:10.1016/j.cld.2020.04.005

8. Entezari P, Riaz A. Intrahepatic cholangiocarcinoma. Semin Intervent Radiol. 2020 Dec;37(5):475-483. doi:10.1055/s-0040-1719188. 

9. 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

10. Honickman SP, Mueller PR, Wittenberg J, et al. Ultrasound in obstructive jaundice: prospective evaluation of site and cause. Radiology. 1983 May;147(2):511-5. doi:10.1148/radiology.147.2.6836132

11. Robledo R, Muro A, Prieto ML. Extrahepatic bile duct carcinoma: US characteristics and accuracy in demonstration of tumors. Radiology. 1996 Mar;198(3):869-73. doi:10.1148/radiology.198.3.8628885

12. Jhaveri KS, Hosseini-Nik H. MRI of cholangiocarcinoma. J Magn Reson Imaging. 2015 Nov;42(5):1165-79. doi:10.1002/jmri.24810

13. Fowler KJ, Saad NE, Linehan D. Imaging approach to hepatocellular carcinoma, cholangiocarcinoma, and metastatic colorectal cancer. Surg Oncol Clin N Am. 2015 Jan;24(1):19-40. doi:10.1016/j.soc.2014.09.002

14. Tests for bile duct cancer. American Cancer Society. Accessed June 8, 2021.

15. Ciresa M, De Gaetano AM, Pompili M, et al. Enhancement patterns of intrahepatic mass-forming cholangiocarcinoma at multiphasic computed tomography and magnetic resonance imaging and correlation with clinicopathologic features. Eur Rev Med Pharmacol Sci. 2015 Aug;19(15):2786-97.

16. Sano S, Yamamoto Y, Sugiura T, et al. The radiological differentiation of hypervascular intrahepatic cholangiocarcinoma from hepatocellular carcinoma with a focus on the CT value on multi-phase enhanced CT. Anticancer Res. 2018 Sep;38(9):5505-5512. doi:10.21873/anticanres.12884

17. Sabaté-Llobera A, Gràcia-Sánchez L, Reynés-Llompart G, et al. Differences on metabolic behavior between intra and extrahepatic cholangiocarcinomas at 18F-FDG-PET/CT: prognostic implication of metabolic parameters and tumor markers. Clin Transl Oncol. 2019 Mar;21(3):324-333. doi:10.1007/s12094-018-1926-0

18. Choi JY, Kim MJ, Lee JM, et al. Hilar cholangiocarcinoma: role of preoperative imaging with sonography, MDCT, MRI, and direct cholangiography. AJR Am J Roentgenol. 2008 Nov;191(5):1448-57. doi:10.2214/AJR.07.3992

19. Voigtländer T, Lankisch T,O. Endoscopic diagnosis of cholangiocarcinoma: from endoscopic retrograde cholangiography to bile proteomics. Best Pract Res Clin Gastroenterol. 2015 Apr;29(2):267-75. doi:10.1016/j.bpg.2015.02.005

20. Bridgewater J, Galle PR, Khan SA, et al. Guidelines for the diagnosis and management of intrahepatic cholangiocarcinoma. J Hepatol. 2014 Jun;60(6):1268-89. doi:10.1016/j.jhep.2014.01.021 

21. Smoczynski M, Jablonska A, Matyskiel A, et al. Routine brush cytology and fluorescence in situ hybridization for assessment of pancreatobiliary strictures. Gastrointest Endosc. 2012 Jan;75(1):65-73. doi:10.1016/j.gie.2011.08.040

22. Levy MJ, Heimbach JK, Gores GJ. Endoscopic ultrasound staging of cholangiocarcinoma. Curr Opin Gastroenterol. 2012 May; 28(3):244-52. doi:10.1097/MOG.0b013e32835005bc 

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