Cholangiocarcinoma (CCA) comprises a heterogeneous group of rare malignant tumors that originate from cells of the biliary tree.1
CCA is responsible for about 15% of all primary liver tumors and is the second most common primary malignancy of the liver, following hepatocellular carcinoma (HCC). It is also responsible for about 3% of gastrointestinal tumors.1 CCA incidence has been increasing, even though data points to 0.3-6 per 100,000 inhabitants per year.1
Geographic differences are observed for CCA incidence that are associated with risk factors, since the different CCA subtypes present distinct potential triggers of tumor formation.1,2 Globally recognized risk factors for CCA are non-controlled alcohol consumption and tobacco smoking but also disorders such as metabolic syndrome, nonalcoholic fatty liver disease, and viral infections caused by hepatitis virus may predispose tumor development.1
Subtypes of CCA
CCA are aggressive epithelial tumors with diversified anatomical origins, resulting in three different subtypes of tumor: intrahepatic (iCCA), perihilar (pCCA) and distal (dCCA). pCCA and dCCA are also known as extrahepatic malignancies (eCCA).1 In addition to their distinct anatomic location, these CCA differ in etiology, pathogenesis, epidemiology, clinical presentation, prognosis and treatment.1,2 pCCA is the most common subtype of CCA, corresponding up to 60% of all CCAs in the US.1
iCCA are located inside the hepatic parenchyma and can occur at any location in the intrahepatic biliary tree, while pCCA are localized in the biliary tree, proximal to the origin of the cyst duct.1 iCCA has been proposed to arise from biliary epithelial cells or from hepatic progenitor cells.2 Incidence of iCCA has increased during the last few years and mortality is particularly high with low rates of survival after 5 years of diagnosis.2,3 Indeed, cancer associated fibroblasts (CAF) are part of the tumor environment of CCAs, facilitating tumor progression and growth, while reducing rates of survival.1,2
The anatomical distinction between pCCA and dCCA is made through the insertion of the cystic duct.2 Both pCCA and dCCA are considered to develop from cells of the biliary epithelium and peribiliary glands.4
CCA Symptoms and Diagnosis
The clinical presentation of CCA depends on the tumor subtype. Typically, CCA presents with weight loss and malaise. When the tumor is extrahepatic, symptoms include jaundice, pale stools, pruritus, dark urine and changes in liver function. Intrahepatic tumors tend to result in abdominal pain.3 CCA is typically symptomatic only in advanced stages, therefore diagnosis is commonly reached when the therapeutic options available are less efficient and when resection is no longer an option.1,3
Diagnosis of CCA can be made through non-invasive and invasive techniques. Radiologic imaging with ultrasound is important for assessing normal liver function and is a first option for examination, however, there is no diagnostic imaging criteria clearly defined. Computer tomography (CT) can be also used for differentiating extrahepatic and intrahepatic tumors. Magnetic resonance imaging (MRI) is used with cholangiopancreatography to observe the extension of the tumor and possibility of ressection.5
Read more about CCA diagnosis.
Studies such as endoscopic ultrasound (EUS) and endoscopic retrograde cholangiopancreatography (ERCP) allow the collection of tumor samples that will facilitate diagnosis or allow draining bile ducts.3 The risk of tumor seeding is unknown; however, histologic confirmation of the tumor is required for a correct diagnosis.6
Treatment options for CCA are limited. Treatment is typically carried out with surgical intervention and adjuvant therapies such as targeted radiation therapy. Surgical options are the only ones that can provide a probability of treatment success, but the usual late diagnosis of the disease typically positions up to 45% of patients in a non-resectable stage of the disease. Recurrence is also a significant problem, occurring in 2 to 3 years after surgery with an intrahepatic presentation.7
Even though surgery is the first treatment option, for iCCA there are many contraindications to the procedure, such as metastatic disease. Postoperative mortality has decreased through the years, but there are still major complications that can also occur after surgery, such as intra abdominal abscesses and bile duct leaks.7 Orthotopic liver transplantation may be performed but is associated with elevated recurrence rates and a long-term survival not reaching 20%.7 Patients with pCCA may benefit from liver transplantation but they can only be candidates for the procedure when presenting a tumor size smaller than 3 centimeters with no metastatic disease and no history of endoscopic biopsy.2
Read more about CCA treatment.
Nonsurgical treatments have reduced effect, since CCA is considered resistant to chemotherapy. Chemotherapeutic treatment of advanced iCCA is done with gemcitabine and cisplatin.5 Patients presenting with unresectable CCA and cholestasis may see survival increase after a drainage of more than 50% of the hepatic parenchyma.7 Locoregional therapy such as transarterial chemoembolization and radiofrequency ablation, may represent a therapeutic option for patients with iCCA that are not candidates for surgery.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
- 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
- Doherty B, Nambudiri VE, Palmer WC. Update on the Diagnosis and Treatment of Cholangiocarcinoma. Curr Gastroenterol Rep. 2017 Jan;19(1):2. doi: 0.1007/s11894-017-0542-4
- Nakanuma Y, Sato Y, Harada K, Sasaki M, Xu J, Ikeda H. Pathological classification of intrahepatic cholangiocarcinoma based on a new concept. World J Hepatol. 2010 Dec 27;2(12):419-27. doi:10.4254/wjh.v2.i12.419
- Vilgrain V. Staging cholangiocarcinoma by imaging studies. HPB (Oxford). 2008;10(2):106-9. doi:10.1080/13651820801992617
- 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 7;26(25):3542-3561. doi:10.3748/wjg.v26.i25.3542
- Blechacz B. Cholangiocarcinoma: Current Knowledge and New Developments. Gut Liver. 2017 Jan 15;11(1):13-26. doi:10.5009/gnl15568
Reviewed by Harshi Dhingra, MD, on 7/1/2021.