Cholangiocarcinoma (CCA)


Cholangiocarcinoma (CCA) is a rare malignant disease with a poor prognosis and the second most common primary hepatic cancer, after hepatocellular carcinoma (HCC).1 Tumors can develop from the cells in the liver parenchyma (intrahepatic tumor) or from the bile ducts that are outside the liver parenchyma (extrahepatic tumor).2 

CCA is commonly asymptomatic in early stages, leading to late diagnoses.3 In advanced stages typical CCA symptoms include malaise and weight loss. Other symptoms that can be associated with these tumors, include abdominal pain, and decreased appetite for intrahepatic presentations, and jaundice, pale stools, pruritus and dark urine as consequence from the cholestasis caused by extrahepatic tumors.3,4 Several risk factors contributing to CCA development have been identified.5 These risk factors contribute not only for the geographical differences observed in CCA incidence worldwide but also impact the formation of either intra- or extrahepatic tumors.6 Most of these risk factors induce chronic inflammation and irritation of the biliary tree that further supports cholangiocarcinogenesis.7

Diagnosis of CCA is a challenging task due to the initial absence of symptoms. There are also other medical conditions that can mimic CCA symptoms and delay the diagnosis. The differential diagnosis of CCA include bile duct strictures, bile duct tumors, biliary obstruction, liver tumors, cholangitis, xanthogranulomatous cholecystitis, choledochal cysts and cholelithiasis.8

Bile Duct Stricture

Bile duct strictures correspond to an intrahepatic or extrahepatic narrowing of the ductal system. The narrowing of the biliary system leads to a proximal dilatation due to an abnormal bile flow, resulting in obstructive jaundice.9 This condition may be asymptomatic and can significantly impact liver function causing secondary biliary cirrhosis or cholangitis.10 Biliary strictures may result from different benign conditions, such as chronic pancreatitis and papillary stenosis,8 but can also develop as a consequence of CCA.11

Liver Tumors

The differential diagnosis for intrahepatic CCA includes primary liver neoplasms, specifically hepatocellular carcinoma (HCC), epithelioid hemangioendothelioma and metastatic carcinoma.12 A combined HCC and CCA, cholangiohepatocellular carcinoma, and metastatic adenocarcinomas of the liver are other differentials.8 

Bile Duct Tumors

Malignant tumors may form in the bile duct, cystic duct, perihilar region and common hepatic duct.13 Even though these tumors mimic CCA, they however, tend to develop in young women, are less aggressive and can be surgically treated.13 

Benign biliary tumors such as papillomas and adenomas are also commonly formed in the bile duct.8

Biliary Obstruction

CCA patients commonly present with biliary obstruction as the primary tumor grows into a mass in the liver.13 However, intrahepatic tumors invade and obstruct the portal vein leading to lobar or segmental atrophy.8 Other diseases such as bile duct lymphomas can also cause biliary obstruction with similar imaging findings of CCA.14,15 

Mirizzi syndrome should also be a differential diagnosis to investigate. In this condition, a gallstone is impacted in the cystic duct or neck of the gallbladder. An obstruction results from the compression of the common hepatic duct.13 The inflammation that forms around the common bile duct in this syndrome can induce the formation of a bile duct stricture and mimic CCA with periductal-infiltrating abilities.13 

Cholangitis

Differential diagnosis for CCA should include primary sclerosing cholangitis (PSC). The chronic inflammation induced by PSC contributes to bile duct benign strictures and to fibrosis of the bile ducts, mimicking CCA.12,13,16 Predisposition of PSC patients to CCA development is due to the chronic inflammation. Indeed, about 60% to 80% of the PSC patients also present inflammatory bowel disease and about 10% of PSC patients develop CCA.8,13,17

Other secondary cholangitis such as recurrent pyogenic cholangitis may lead to biliary obstruction and result in abdominal pain, fever, and jaundice. Between 2% to 6% of patients showing recurrent pyogenic cholangitis may develop CCA.13

Xanthogranulomatous Cholecystitis

Xanthogranulomatous cholecystitis (XGC) is a severe and chronic infection of the gallbladder.13 Several factors may contribute to the development of this infection such as gallstones and diabetes mellitus.18 In this condition, there is an obstruction of the cystic duct with damage of the mucosa, cellular activation and fibrosis.18,19 Imaging of XGC may resemble gallbladder carcinoma with local invasion.13

Choledochal Cyst

Choledochal cystic diseases, such as Caroli’s disease, are malformations of the pancreatic and biliary ducts.20 The cysts resulting from a dilatation of the biliary tree are either intra-or extrahepatic and are classified into five types.21 Type I and type IV cysts have been associated with CCA development.21,22

Cholelithiasis

Even though considered a typically benign disease, the presence of gallstones (cholelithiasis) may cause symptoms due to the blockage of the bile flow after obstruction of the cystic duct. This blockage may result in cholecystitis.23 When the gallstone is located in the bile duct patients develop jaundice and abdominal pain due to the duct obstruction.23 Cholelithiasis has been observed in CCA patients.24 

References

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

3. 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

4. Cholangiocarcinoma. Orpha.net. Accessed June 07, 2021.

5. Khan SA, Tavolari S, Brandi G. Cholangiocarcinoma: epidemiology and risk factors. Liver Int. 2019 May;39 Suppl 1:19-31. doi:10.1111/liv.14095

6. Tyson GL, El-Serag HB. Risk factors for cholangiocarcinoma. Hepatology. 2011 Jul;54(1):173-84. doi:10.1002/hep.24351. 

7. Krasinskas AM. Cholangiocarcinoma. Surg Pathol Clin. 2018 Jun;11(2):403-429. doi:10.1016/j.path.2018.02.005

8. Lee WJ, Lim HK, Jang KM, Kim SH, Lee SJ, Lim JH et al. Radiologic spectrum of cholangiocarcinoma: emphasis on unusual manifestations and differential diagnoses. Radiographics. 2001 Oct;21 Spec No:S97-S116.  doi:10.1148/radiographics.21.suppl_1.g01oc12s97

9. Katabathina VS, Dasyam AK, Dasyam N, Hosseinzadeh K. Adult bile duct strictures: role of MR imaging and MR cholangiopancreatography in characterization. Radiographics. 2014 May-Jun;34(3):565-86. doi:10.1148/rg.343125211

10. Hanau LH, Steigbigel NH. Acute (ascending) cholangitis. Infect Dis Clin North Am. 2000 Sep;14(3):521-46. doi:10.1016/s0891-5520(05)70119-7

11. Lee HJ, Cho KB. Diagnosis of malignant biliary stricture: more is better. Clin Endosc. 2018 Mar;51(2):115-117. doi:10.5946/ce.2018.035

12. Oliveira IS, Kilcoyne A, Everett JM, Mino-Kenudson M, Harisinghani MG, Ganesan K. Cholangiocarcinoma: classification, diagnosis, staging, imaging features, and management. Abdom Radiol (NY). 2017 Jun;42(6):1637-1649. doi:10.1007/s00261-017-1094-7

13. Menias CO, Surabhi VR, Prasad SR, Wang HL, Narra VR, Chintapalli KN. Mimics of cholangiocarcinoma: spectrum of disease. Radiographics. 2008 Jul-Aug;28(4):1115-29. doi:10.1148/rg.284075148

14. Eliason SC, Grosso LE. Primary biliary malignant lymphoma clinically mimicking cholangiocarcinoma: a case report and review of the literature. Ann Diagn Pathol. 2001 Feb;5(1):25-33. doi:10.1053/adpa.2001.21483

15. Das K, Fisher A, Wilson DJ, dela Torre AN, Seguel J, Koneru B. Primary non-Hodgkin’s lymphoma of the bile ducts mimicking cholangiocarcinoma. Surgery. 2003 Sep;134(3):496-500. doi:10.1067/s0039-6060(03)00149-1

16. Pang L, Hu S, Dai W, Wu S, Kong J. Dilemma of the differential diagnosis of hilar cholangiocarcinoma and benign diseases: a single-center retrospective study. Carcinogenesis. 2021 Apr;42(3):442-447. doi:10.1093/carcin/bgaa125

17. 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

18. Kwon AH, Matsui Y, Uemura Y. Surgical procedures and histopathologic findings for patients with xanthogranulomatous cholecystitis. J Am Coll Surg. 2004 Aug;199(2):204-10. doi:10.1016/j.jamcollsurg.2004.03.018

19. Goodman ZD, Ishak KG. Xanthogranulomatous cholecystitis. Am J Surg Pathol. 1981 Oct;5(7):653-9. doi:10.1097/00000478-198110000-00007

20. Rizvi S, Gores GJ. Pathogenesis, diagnosis, and management of cholangiocarcinoma. Gastroenterology. 2013 Dec;145(6):1215-29. doi:10.1053/j.gastro.2013.10.013

21. Söreide K, Körner H, Havnen J, Söreide JA. Bile duct cysts in adults. Br J Surg. 2004 Dec;91(12):1538-48. doi:10.1002/bjs.4815

22. Yoshida H, Itai Y, Minami M, Kokubo T, Ohtomo K, Kuroda A. Biliary malignancies occurring in choledochal cysts. Radiology. 1989 Nov;173(2):389-92. doi:10.1148/radiology.173.2.2678253

23. Jones MW, Weir CB, Ghassemzadeh S. Gallstones (cholelithiasis). In: StatPearls. Treasure Island (FL): StatPearls Publishing; March 26, 2021.

24. Callea F, Sergi C, Fabbretti G, Brisigotti M, Cozzutto C, Medicina D. Precancerous lesions of the biliary tree. J Surg Oncol Suppl. 1993;3:131-3. doi:10.1002/jso.2930530535

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

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