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Cholangiocarcinoma (CCA)

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Comorbidities

Comorbidities are chronic conditions that have an impact in the patient’s quality of life. About 3 in 4 patients will have at least a single chronic disease pre-existent to the cancer disease.1 The management of these chronic conditions is important not only to improve the daily life of cancer patients but also to allow increase survival after potential and required surgeries.2 

The existence of comorbidities also influences the diagnosis of the malignancy. Symptoms associated with comorbidity may lead the patient to visit a doctor in time for an early diagnosis. This is crucial for controlling cancer and for improving survival.1 However, diagnosis may be also delayed when symptoms associated with a tumor are considered the result from a previous existing condition.3 The existence of comorbidities in cancer patients also negatively impacts treatment, as these patients may be less likely good candidates for a curative procedure.3 The treatment of certain chronic diseases may additionally influence the incidence and aggressiveness of the tumor.1

Different pre-existing diseases and medical conditions can increase the risk of cholangiocarcinoma (CCA) development. Additionally, CCA patients are at higher risk of developing comorbidities that in turn increase mortality and complicate both medical procedures and treatment.4

Even though the etiology of a significant number of CCA cases is unknown, conditions that lead to chronic inflammatory processes can promote tumor formation and also co-exist with the malignancy. Surgeries for resecting a tumor can also originate comorbid complications, such as pancreatic insufficiency or diabetes, and influence prognosis.2,5

Liver Disease

Intrahepatic tumors may develop when the patients already have a chronic liver disease, such as chronic viral infections (hepatitis B virus (HBV) and hepatitis C virus (HCV)) and cirrhosis. Both diseases are considered risk factors for CCA development.6 Secondary biliary cirrhosis can also occur as consequence of biliary obstruction caused by the tumor.7 There are therapeutic options available to treat hepatitis, however, when the liver damage is extent at the time CCA is diagnosed, that damage may be irreversible and further complicate the treatment of that patient.5 

Primary Sclerosis Cholangitis

Primary sclerosis cholangitis (PSC) is an autoimmune disease that affects the bile ducts. This disease is responsible for the development of chronic inflammation, cellular proliferation and further obstruction of the bile ducts.6,8 Tumor development can be potentiated by cell proliferation, mucinous metaplasia and dysplasia occurring in the biliary tree.6

Patients with PSC have a higher probability of developing bile duct cancer.9 When there is a pre-existing PSC diagnosis, CCA is typically diagnosed earlier than expected in life. Studies have also shown that about 30% to 50% of CCA cases are identified within the first year after a PSC diagnosis.10,11 Patients with worsening of symptoms such as jaundice, pain, pruritus, weight loss and fatigue should be evaluated for a possible CCA.11

Infections

Parasitic infections caused by liver flukes can be diagnosed in CCA patients. These infections are risk factors for CCA development, inducing a background of chronic inflammation, infection and fibrosis.12

In CCA patients, the obstruction of the bile ducts by a tumor may affect bile drainage. An infection may develop under this condition as well as liver dysfunction.13,14 This blockage can be alleviated by the placement of a stent.13

Non-alcoholic fatty acid liver disease (NAFLD) includes different liver diseases from fatty liver to cirrhosis and has been identified in CCA patients.8

Abnormalities Of The Biliary tract

CCA patients may present congenital defects of the biliary tract such as cystic dilations. Other developmental defects such as Caroli’s disease or congenital hepatic fibrosis can also exist.15

Hepatolithiasis, Cholelithiasis and Choledocholithiasis

The presence of calculi and gallstones in the biliary tract of CCA patients is fairly common. These conditions are associated with chronic inflammation, bile stasis and also to bacterial infection. The duration of the disease appears to have an impact in the risk of developing CCA.8

Inflammatory Bowel Disease

The presence of inflammatory bowel disease (IBD) has been pointed as potential trigger for CCA in PSC patients.CCA incidence is higher within the first year of an IBD diagnosis.8

Type II Diabetes and Obesity

Studies point that metabolic disorders can predispose patients to develop liver cancer.16 Pre-existing type II diabetes has been correlated to the development of both intrahepatic and extrahepatic tumors.17 A more recent study also highlights the impact of diabetes in patients with intrahepatic tumors.2 The risk of development of biliary stones can be increased when patients present with diabetes.8

Obesity has reached a pandemic level around the world and has been associated to an increased risk of developing several malignancies.18 In the case of CCA, data available is still limited, however, different studies indicate a possible association.8

References

1. Renzi C, Kaushal A, Emery J, et al. Comorbid chronic diseases and cancer diagnosis: disease-specific effects and underlying mechanisms. Nat Rev Clin Oncol. 2019. Dec;16(12):746-761. doi:10.1038/s41571-019-0249-6

2. Qu WF, Zhou PY, Liu WR, Tian MX, Jin L, Jiang XF et al. Age-adjusted charlson comorbidity Index predicts survival in intrahepatic cholangiocarcinoma patients after curative resection. Ann Transl Med. 2020. Apr;8(7):487. doi:10.21037/atm.2020.03.23

3. Fowler H, Belot A, Ellis L, et al. Comorbidity prevalence among cancer patients: a population-based cohort study of four cancers. BMC Cancer. 2020 Jan;20(1):2. doi:10.1186/s12885-019-6472-9

4. Suk WA, Bhudhisawasdi V, Ruchirawat M. The curious case of cholangiocarcinoma: opportunities for environmental health scientists to learn about a complex disease. J Environ Public Health. 2018 Aug;2018:2606973. doi:10.1155/2018/2606973

5. Keenan BP, Kelley RKK. Key challenges for drugs in clinical development for cholangiocarcinoma. Expert Opin Investig Drugs. 2021 Apr;30(4):285-290. doi:10.1080/13543784.2021.188056

6. 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

7. Chang JG, Yoon YI, Lee SG, Hwang S, Kim KH, Ahn CS et al. Single-center experience of living donor liver transplantation for patients With secondary biliary cirrhosis. Transplant Proc. 2021 Jan-Feb;53(1):98-103. doi:10.1016/j.transproceed.2020.10.044

8. 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

9. 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

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

11. Song J, Li Y, Bowlus CL, Yang G, Leung PSC, Gershwin ME. Cholangiocarcinoma in patients with primary sclerosing cholangitis (PSC): a comprehensive review. Clin Rev Allergy Immunol. 2020 Feb;58(1):134-149. doi:10.1007/s12016-019-08764-7

12. Sithithaworn P, Yongvanit P, Duenngai K, Kiatsopit N, Pairojkul C. Roles of liver fluke infection as risk factor for cholangiocarcinoma. J Hepatobiliary Pancreat Sci. 2014 May;21(5):301-8. doi:10.1002/jhbp.62

13. Palliative therapy for bile duct cancer. American Cancer Society. Accessed 08 July, 2021

14. Sapisochin G, Ivanics T, Subramanian V, Doyle M, Heimbach JK, Hong JC. Multidisciplinary treatment for hilar and intrahepatic cholangiocarcinoma: a review of the general principles. Int J Surg. 2020 Oct;82S:77-81. doi:10.1016/j.ijsu.2020.04.067

15. Braconi C, Patel T. Cholangiocarcinoma: new insights into disease pathogenesis and biology. Infect Dis Clin North Am. 2010 Dec;24(4):871-84, vii. doi:10.1016/j.idc.2010.07.006

16. Welzel TM, Graubard BI, Zeuzem S, El-Serag HB, Davila JA, McGlynn KA. Metabolic syndrome increases the risk of primary liver cancer in the united states: a study in the SEER-medicare database. Hepatology. 2011 Aug;54(2):463-71. doi:10.1002/hep.24397

17. Petrick JL, Yang B, Altekruse SF, Van Dyke AL, Koshiol J, Graubard BI et al. Risk factors for intrahepatic and extrahepatic cholangiocarcinoma in the united states: a population-based study in SEER-medicare. PLoS One. 2017 Oct 19;12(10):e0186643. doi:10.1371/journal.pone.0186643

18. Berger NA. Obesity and cancer pathogenesis. Ann N Y Acad Sci. 2014 Apr;1311:57-76. doi:10.1111/nyas.12416

Reviewed by Debjyoti Talukdar, MD, on 7/1/2021.

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