Cholangiocarcinoma (CCA)

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Cholangiocarcinoma (CCA) is a group of rare tumors of the biliary tract and the second most common malignancy of the liver.1 CCA are classified according to their anatomical location as intrahepatic (iCCA), and extrahepatic (eCCA) and eCCA further includes 2 subtypes of cancer, perihilar (pCCA, commonly called “Klatskin tumor”) and distal (dCCA).1,2

There are many described risk factors accounting for tumor development.3 These include environmental and behavioral factors, as well as other clinical conditions that are linked to a chronic biliary inflammation and a high cellular turnover, such as primary sclerosing cholangitis (PSC).1 Many of CCA patients, however, do not present a known risk factor that could trigger suspicion toward the potential formation of a tumor.4 

CCA diagnosis requires the use of imaging studies combined with clinical findings and a cytology confirmation. After establishing a CCA diagnosis, it is also important to evaluate the extent of tumor progression beyond the liver and the biliary tree.4 

A diagnostic process is in many cases initiated after a blood workup showing changes in the liver enzymatic activity.1,5 These abnormalities found in liver function tests usually lead to a thorough investigation for determining the underlying causes since many other benign and malignant clinical conditions can induce modifications in the liver panel and must be excluded during diagnosis.1 The average age of diagnosis exceeds 50 years.6

Clinical presentation of CCA is dependent on the location of the tumor. When patients are diagnosed, typically a large mass in the liver is found or jaundice has already developed due to an obstruction of the biliary tract.1 CCA symptoms do not usually appear when the disease is in an early stage and it is common to find these tumors to be unresectable with the disease progressed to advanced stages.4 

Symptoms of Intrahepatic, Extrahepatic Cancers

Extrahepatic tumors present with symptoms that are caused by biliary obstruction. These are jaundice, pruritus, pale stools and dark urine. Advanced stages of the disease can lead to abdominal pain and weight loss, and are frequently associated with unresectable tumors.7 About 56% of patients with pCCA show symptoms, such as weight loss and asthenia, at the initial presentation.6 It is also important to differentiate dCCA from benign biliary strictures that may develop in patients with PSC.8 

iCCA typically presents as a mass lesion within the liver.9 iCCA is in most cases asymptomatic and often an incidental diagnosis in 20% to 25% of patients.1,10 Jaundice can be present as an initial symptom in about 10% to 15% of patients as a consequence of an obstruction of the liver hilum that does not allow draining of the biliary ducts.11,12 

Jaundice

Jaundice is the most common symptom in CCA and is identified when plasma bilirubin concentration exceeds 2 mg/dL.1 Patients with jaundice present a yellow or green pigmentation of both skin and mucosas. When bilirubin levels are not too elevated, the skin pigmentation may still be normal, and jaundice may be identified after observation of the palate and sclera.1 Patients older than age 50, with no abdominal pain, but who develop progressive jaundice with other symptoms, such as weight loss, should be examined for a malignant disease.1

Dark Urine

Elevated bilirubin levels can result from an increase in bilirubin’s unconjugated fraction, the conjugated fraction, or both. The unconjugated fraction, as fat-soluble, is not filtered by the kidney. The conjugated fraction, however, is water-soluble, and is eliminated in urine. The presence of biliary pigments in the urine (choluria) leads to a dark or black urine. This symptom is most usually present in extrahepatic presentations.1 

Pale Stools

Patients with CCA may present with light colored/pale stools. In iCCA, the biliary obstruction caused by the tumor located in the biliary ducts will lead to an increase of conjugated bilirubin. This bilirubin fraction does not go into the duodenum, leading to stools that have no color (acholic) or that have a lighter color (pale stools).1

Pruritus

Excess bile salts in the blood may trigger a skin sensation that leads to active scratching of the skin. Pruritus may occur associated with jaundice and typically affects palms and soles of the feet. The itching sensation can be most intense at night causing additional complications, including sleep deprivation and depression.1

Nonspecific Symptoms

The presence of a hepatic mass can lead to abdominal pain. This is usually a non-specific symptom that may point to a disease already in an advanced stage.3 Patients may also present other non-specific symptoms such as malaise, night sweats, fatigue and cachexia when the disease has progressed.1,6,9

References

1. 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

2. Rodrigues J, Diehl DL.  Cholangiocarcinoma: clinical manifestations and diagnosis. TIGE. 2016 April;18(2):75-82. doi:10.1016/j.tgie.2016.07.004

3. Banales JM, Marin JJG, Lamarca A, 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

4. Esnaola NF, Meyer JE, Karachristos A, Maranki JL, Camp ER, Denlinger CS. Evaluation and management of intrahepatic and extrahepatic cholangiocarcinoma. Cancer. 2016 May;122(9):1349-69. doi:10.1002/cncr.29692

5. Hammill CW, Wong LL. Intrahepatic cholangiocarcinoma: a malignancy of increasing importance. J Am Coll Surg. 2008 Oct;207(4):594-603. doi:10.1016/j.jamcollsurg.2008.04.031

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

7. Khan SA, Davidson BR, Goldin R, et al. Guidelines for the diagnosis and treatment of cholangiocarcinoma: consensus document. Gut. 2002 Nov;51 Suppl 6(Suppl 6):VI1-9. doi:10.1136/gut.51.suppl_6.vi1.

8. Hirohashi K, Uenishi T, Kubo S, Yamamoto T, Tanaka H, Shuto T, Kinoshita H. Macroscopic types of intrahepatic cholangiocarcinoma: clinicopathologic features and surgical outcomes. Hepatogastroenterology. 2002 Apr;49(44):326-9. 

9. 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

10. Alvaro D, Bragazzi MC, Benedetti A, Fabris L, Fava G, Invernizzi P et al. 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.

11. Shimada K, Sano T, Sakamoto Y, Esaki M, Kosuge T, Ojima H. Surgical outcomes of the mass-forming plus periductal infiltrating types of intrahepatic cholangiocarcinoma: a comparative study with the typical mass-forming type of intrahepatic cholangiocarcinoma. World J Surg. 2007 Oct;31(10):2016-22. doi:10.1007/s00268-007-9194-0.12. Endo I, Gonen M, Yopp AC, Dalal KM, Zhou Q, Klimstra D et al. Intrahepatic cholangiocarcinoma: rising frequency, improved survival, and determinants of outcome after resection.Ann Surg. 2008 Jul;248(1):84-96. doi:10.1097/SLA.0b013e318176c4d3

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

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