Cholangiocarcinoma (CCA)


Cholangiocarcinoma (CCA) is a rare group of fatal malignancies that can develop in the biliary tract.1 CCA represents about 2% of the total reported malignant tumors and 3% of all gastrointestinal cancers.1,2 It is also the second most common malignancy of the liver.1

CCAs are subdivided into three subtypes, depending on where the tumor is originally formed: intrahepatic (iCCA), perihilar (pCCA) and distal (dCCA).3,4 pCCA and dCCA are referred to as extrahepatic presentations (eCCA).5

iCCA and eCCA have distinct clinical presentations as these are dependent on where the tumor is located. CCA symptoms may start with jaundice when there is an obstruction of the biliary tree such as in eCCA, or as an initial symptom in iCCA when biliary duct drainage is compromised.6,7 Other symptoms can include pruritus, pale stools, dark urine, fatigue, weight loss and abdominal pain.8 CCA is, however, an asymptomatic disease in most cases and symptoms appear when the tumor is already in an advanced and unresectable stage, with limited treatment options available.9,10 

CCA occur in both male and female genders and the average age for presentation is 65 years old in the Western countries.10 Risk factors include age, diseases of the liver and bile ducts (such as hepatolithiasis), parasitic and viral infections and a personal history of primary sclerosing cholangitis (PSC).1 The overall mortality of hepatobiliary malignancies reaches 13%10 and the 5-year survival rate after diagnosis is about 10%.11 The 5-year survival rate for patients that are diagnosed with unresectable tumors is close to 0%. Death typically results from cachexia, malnutrition, biliary sepsis and liver failure.12 

The prognosis for this disease is partially dependent on the location of the tumor and how it affects the possibility of resection.13 Tumors are staged following the tumor, node, and metastasis (TMN) classification system and staging is performed separately for iCCA and eCCA.14 Curative surgery is the only hypothesis for long-term survival in CCA15,16 with only few patients considered candidates for the procedure.17,18 As the tumors are forming close to major blood vessels and progressing into the liver, resection may be difficult.13 Preoperative staging strategies may not be sufficient to predict long term prognosis for the patients that are selected for surgery.19

Prognosis of iCCA and eCCA

Patients diagnosed with iCCA have the worst prognosis. When diagnosed with no possibility of surgical resection, these patients frequently present with multiple intrahepatic or extrahepatic metastases or peritoneal carcinomatosis.20 Patients with unresectable iCCA typically live up to 24 months after diagnosis.17 In advanced stages of the disease, iCCA is refractory to chemotherapy and radiotherapy treatments.17  Few recent studies point to a survival improvement with the use of adjuvant chemotherapy after tumor resection.21,22

Studies show that metastasis to the lymph nodes, vascular invasion, the presence of multifocal lesions, the size of the tumor, cirrhosis and an advanced age are poor prognosis for iCCA.23-25 A simultaneous diagnosis of primary sclerosing cholangitis is also associated with a poor prognosis.13 A negative lymph node status and a tumor-free resection margin have been reported to have important role on disease free survival.26,27

Data on eCCA prognosis is scarce, however, chemotherapy was shown to be potentially important for survival.18 The presence of dysplasia was also considered a prognostic factor in survival.18,28 Impact of tumor size in pCCA survival is still in debate with reports suggesting an association of smaller tumors with better prognosis but contradicting reports suggest that there is no association between tumor size and survival.29,30 Surgical resection on pCCA is associated with long-term survival.31

Factors Affecting CCA Prognosis After Surgical Resection

The success rate of the surgical interventions contributes to a five-year survival rate of 25% to 35%.32 Surgery may prolong patient’s life for 12 to 15 months17 but recurrence is high.33 The 5-year survival rate of dCCA after surgery can reach up to 40%,34 while for pCCA the survival rate can reach 30%.31

After surgical resection, several factors may point towards a poor survival outcome. These include a positive resection margin, vascular or perineural invasion, metastasis within the liver or in the lymph nodes.35 Complete resection with negative surgical margins can positively impact prognosis.13

Recurrence of CCA

There is limited data on the recurrence of CCA after a surgical curative resection. Surgical treatment of the tumor, a gross appearance of mass-forming type tumors, and also no bile duct invasion at the time of the primary tumor diagnosis may be favorable prognostic factors in iCCA.36 The remnant liver is commonly the site of recurrence37 and median survival for patients that undergo surgery for iCCA recurrence ranges between 18.9 to 45.1 months.38,39 Radiofrequency and radiotherapy may be important to extend survival.40 Other studies suggest that pancreatic secretory trypsin inhibitor (PSTI) and insulin-like growth factor-II mRNA-binding protein 3 (IMP3) can potentially act as immunohistochemical markers involved in predicting early recurrence of iCCA.41,42

Locoregional lymph node metastasis has been suggested as a significant prognostic factor for overall survival and disease-free survival linked to pCCA.43

References

1. 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

2. Vauthey JN, Blumgart LH. Recent advances in the management of cholangiocarcinomas. Semin Liver Dis. 1994 May;14(2):109-14. doi:10.1055/s-2007-1007302

3. Banales JM, Cardinale V, Carpino G, Marzioni M, Andersen JB, Invernizzi P et al. Expert consensus document: cholangiocarcinoma: current knowledge and future perspectives consensus statement from the european network for the study of cholangiocarcinoma (ENS-CCA). Nat Rev Gastroenterol Hepatol. 2016 May;13(5):261-80. doi:10.1038/nrgastro.2016.51

4. Rizvi S, Khan SA, Hallemeier CL, Kelley RK, Gores GJ. Cholangiocarcinoma – evolving concepts and therapeutic strategies. Nat Rev Clin Oncol. 2018 Feb;15(2):95-111. doi:10.1038/nrclinonc.2017.157

5. 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

6. 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.

7. Endo I, Gonen M, Yopp AC, 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

8. 7. Khan SA, Davidson BR, Goldin R, Pereira SP, Rosenberg WM, Taylor-Robinson SD 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

9. 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

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

11. Patel T. Worldwide trends in mortality from biliary tract malignancies. BMC Cancer. 2002 May ;2:10. doi:10.1186/1471-2407-2-10 

12. Cholangiocarcinoma. Orpha.net. Accessed 18 Jun 2021

13. Bile duct cancer (cholangiocarcinoma) treatment. cancer.gov. Accessed June 18, 2021

14. Rahnemai-Azar AA, Weisbrod A, Dillhoff M, Schmidt C, Pawlik TM. Intrahepatic cholangiocarcinoma: Molecular markers for diagnosis and prognosis. Surg Oncol. 2017 Jun;26(2):125-137. doi:10.1016/j.suronc.2016.12.009

15. Sakamoto Y, Kosuge T, Shimada K, et al. Prognostic factors of surgical resection in middle and distal bile duct cancer: an analysis of 55 patients concerning the significance of ductal and radial margins. Surgery. 2005 Apr;137(4):396-402. doi:10.1016/j.surg.2004.10.008

16. Bahra M, Jacob D, Langrehr JM, Neumann UP, Neuhaus P. Carcinoma of the distal and middle bile duct: surgical results, prognostic factors, and long-term follow-up. J Hepatobiliary Pancreat Surg. 2008;15(5):501-7. doi:10.1007/s00534-007-1308-4

17. Sirica AE, Dumur CI, Campbell DJ, Almenara JA, Ogunwobi OO, Dewitt JL. Intrahepatic cholangiocarcinoma progression: prognostic factors and basic mechanisms. Clin Gastroenterol Hepatol. 2009 Nov;7(11 Suppl):S68-78. doi:10.1016/j.cgh.2009.08.023

18. Choe JW, Kim HJ, Kim JS. Survival improvement and prognostic factors in recent management of extrahepatic cholangiocarcinoma: a single-center study. Hepatobiliary Pancreat Dis Int. 2020 Apr;19(2):153-156. doi:10.1016/j.hbpd.2019.12.011

19. Briggs CD, Neal CP, Mann CD, Steward WP, Manson MM, Berry DP. Prognostic molecular markers in cholangiocarcinoma: a systematic review. Eur J Cancer. 2009 Jan;45(1):33-47. doi:10.1016/j.ejca.2008.08.024

20. Lin XH, Luo JC. The risk factors and prognostic factors of intrahepatic cholangiocarcinoma. J Chin Med Assoc. 2017 Mar;80(3):121-122. doi:10.1016/j.jcma.2016.12.001

21. Lee GC, Ferrone CR, Tanabe KK, Lillemoe KD, Blaszkowsky LS, Zhu AX et al. Predictors of adjuvant treatment and survival in patients with intrahepatic cholangiocarcinoma who undergo resection. Am J Surg. 2019 Nov;218(5):959-966. doi:10.1016/j.amjsurg.2019.02.036

22. Ebata T, Hirano S, Konishi M, et al. Bile duct cancer adjuvant trial (BCAT) study group. randomized clinical trial of adjuvant gemcitabine chemotherapy versus observation in resected bile duct cancer. Br J Surg. 2018 Feb;105(3):192-202. doi:10.1002/bjs.10776

23. de Jong MC, Nathan H, Sotiropoulos GC, et al. Intrahepatic cholangiocarcinoma: an international multi-institutional analysis of prognostic factors and lymph node assessment. J Clin Oncol. 2011 Aug 10;29(23):3140-5. doi:10.1200/JCO.2011.35.6519

24. Hyder O, Marques H, Pulitano C, Marsh JW, Alexandrescu S, Bauer TW et al. A nomogram to predict long-term survival after resection for intrahepatic cholangiocarcinoma: an Eastern and Western experience. JAMA Surg. 2014 May;149(5):432-8. doi:10.1001/jamasurg.2013.5168

25. Nuzzo G, Giuliante F, Ardito F, et al. Improvement in perioperative and long-term outcome after surgical treatment of hilar cholangiocarcinoma: results of an Italian multicenter analysis of 440 patients. Arch Surg. 2012 Jan;147(1):26-34. doi:10.1001/archsurg.2011.771

26. Yoshida T, Matsumoto T, Sasaki A, Morii Y, Aramaki M, Kitano S. Prognostic factors after pancreatoduodenectomy with extended lymphadenectomy for distal bile duct cancer. Arch Surg. 2002 Jan;137(1):69-73. doi:10.1001/archsurg.137.1.69

27. Murakami Y, Uemura K, Hayashidani Y, Sudo T, Ohge H, Sueda T. Pancreatoduodenectomy for distal cholangiocarcinoma: prognostic impact of lymph node metastasis. World J Surg. 2007 Feb;31(2):337-42; discussion 343-4. doi:10.1007/s00268-006-0224-0

28. Courtin-Tanguy L, Rayar M, Bergeat D, Merdrignac A, Harnoy Y, Boudjema K et al. The true prognosis of resected distal cholangiocarcinoma. J Surg Oncol. 2016 Apr;113(5):575-80. doi:10.1002/jso.24165

29. Regimbeau JM, Fuks D, Pessaux P, et al. Tumour size over 3 cm predicts poor short-term outcomes after major liver resection for hilar cholangiocarcinoma. By the HC-AFC-2009 group. HPB (Oxford). 2015 Jan;17(1):79-86. doi:10.1111/hpb.12296.

30. Zhang Y, Wu Z, Wang X, Li C, Chang J, Jiang W et al. Development and external validation of a nomogram for predicting the effect of tumor size on survival of patients with perihilar cholangiocarcinoma. BMC Cancer. 2020 Oct 30;20(1):1044. doi:10.1186/s12885-020-07501-0

31. Juntermanns B, Kaiser GM, Reis H, et al. Long-term Survival after resection for perihilar cholangiocarcinoma: Impact of UICC staging and surgical procedure. Turk J Gastroenterol. 2019 May;30(5):454-460. doi:10.5152/tjg.2019.18275

32. Adeva J, Sangro B, Salati M, Edeline J, La Casta A, Bittoni A et al. Medical treatment for cholangiocarcinoma. Liver Int. 2019 May;39 Suppl 1:123-142. doi:10.1111/liv.14100

33. Okusaka T, Nakachi K, Fukutomi A, Mizuno N, Ohkawa S, Funakoshi A, et al. Gemcitabine alone or in combination with cisplatin in patients with biliary tract cancer: a comparative multicentre study in Japan. Br J Cancer. 2010 Aug 10;103(4):469-74. doi:10.1038/sj.bjc.6605779

34. Murakami Y, Uemura K, Sudo T, et al. Prognostic factors after surgical resection for intrahepatic, hilar, and distal cholangiocarcinoma. Ann Surg Oncol. 2011 Mar;18(3):651-8. doi:10.1245/s10434-010-1325-4

35. Tanaka S, Sugimachi K, Kameyama T, et al. Human WISP1v, a member of the ccn family, is associated with invasive cholangiocarcinoma. Hepatology. 2003 May;37(5):1122-9. doi:10.1053/jhep.2003.50187

36. Ohira M, Kobayashi T, Hashimoto M, Tazawa H, Abe T, Oshita A et al. Prognostic factors in patients with recurrent intrahepatic cholangiocarcinoma after curative resection: A retrospective cohort study. Int J Surg. 2018 Jun;54(Pt A):156-162. doi:10.1016/j.ijsu.2018.04.058

37. Endo I, Gonen M, Yopp AC, 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

38. Song SC, Heo JS, Choi DW, Choi SH, Kim WS, Kim MJ. Survival benefits of surgical resection in recurrent cholangiocarcinoma. J Korean Surg Soc. 2011 Sep;81(3):187-94. doi:10.4174/jkss.2011.81.3.187

39. Sulpice L, Rayar M, Boucher E, Pracht M, Meunier B, Boudjema K. Treatment of recurrent intrahepatic cholangiocarcinoma. Br J Surg. 2012 Dec;99(12):1711-7. doi:10.1002/bjs.8953

40. Ercolani G, Vetrone G, Grazi GL, Aramaki O, Cescon M, Ravaioli M et al. Intrahepatic cholangiocarcinoma: primary liver resection and aggressive multimodal treatment of recurrence significantly prolong survival. Ann Surg. 2010 Jul;252(1):107-14. doi:10.1097/SLA.0b013e3181e462e6

41. Chen YL, Jeng YM, Hsu HC, Lai HS, Lee PH, Lai PL et al. Expression of insulin-like growth factor II mRNA-binding protein 3 predicts early recurrence and poor prognosis in intrahepatic cholangiocarcinoma. Int J Surg. 2013;11(1):85-91. doi:10.1016/j.ijsu.2012.11.021

42. Tonouchi A, Ohtsuka M, Ito H, et al. Relationship between pancreatic secretory trypsin inhibitor and early recurrence of intrahepatic cholangiocarcinoma following surgical resection. Am J Gastroenterol. 2006 Jul;101(7):1601-10. doi:10.1111/j.1572-0241.2006.00612.x

43. Geers J, Jaekers J, Topal H, et al. Predictors of survival after surgery with curative intent for perihilar cholangiocarcinoma. World J Surg Oncol. 2020 Nov 3;18(1):286. doi:10.1186/s12957-020-02060-x

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

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