Pathogenesis, Diagnosis, and Management of Cholangiocarcinoma

Cholangiocarcinomas (CCAs) are hepatobiliary cancers with features of cholangiocyte differentiation; they can be classified anatomically as intrahepatic CCA (iCCA), perihilar CCA (pCCA), or distal CCA. These subtypes differ not only in their anatomic location, but in epidemiology, origin, etiology, pathogenesis, and treatment. The incidence and mortality of iCCA has been increasing over the past 3 decades, and only a low percentage of patients survive until 5 years after diagnosis. Geographic variations in the incidence of CCA are related to variations in risk factors. Changes in oncogene and inflammatory signaling pathways, as well as genetic and epigenetic alterations and chromosome aberrations, have been shown to contribute to the development of CCA. Furthermore, CCAs are surrounded by a dense stroma that contains many cancer-associated fibroblasts, which promotes their progression. We have gained a better understanding of the imaging characteristics of iCCAs and have developed advanced cytologic techniques to detect pCCAs. Patients with iCCAs usually are treated surgically, whereas liver transplantation after neoadjuvant chemoradiation is an option for a subset of patients with pCCAs. We review recent developments in our understanding of the epidemiology and pathogenesis of CCA, along with advances in classification, diagnosis, and treatment. Cholangiocarcinomas (CCAs) are hepatobiliary cancers with features of cholangiocyte differentiation; they can be classified anatomically as intrahepatic CCA (iCCA), perihilar CCA (pCCA), or distal CCA. These subtypes differ not only in their anatomic location, but in epidemiology, origin, etiology, pathogenesis, and treatment. The incidence and mortality of iCCA has been increasing over the past 3 decades, and only a low percentage of patients survive until 5 years after diagnosis. Geographic variations in the incidence of CCA are related to variations in risk factors. Changes in oncogene and inflammatory signaling pathways, as well as genetic and epigenetic alterations and chromosome aberrations, have been shown to contribute to the development of CCA. Furthermore, CCAs are surrounded by a dense stroma that contains many cancer-associated fibroblasts, which promotes their progression. We have gained a better understanding of the imaging characteristics of iCCAs and have developed advanced cytologic techniques to detect pCCAs. Patients with iCCAs usually are treated surgically, whereas liver transplantation after neoadjuvant chemoradiation is an option for a subset of patients with pCCAs. We review recent developments in our understanding of the epidemiology and pathogenesis of CCA, along with advances in classification, diagnosis, and treatment. Cholangiocarcinoma (CCA) is the most common biliary malignancy and the second most common hepatic malignancy after hepatocellular carcinoma (HCC).1Welzel T.M. McGlynn K.A. Hsing A.W. et al.Impact of classification of hilar cholangiocarcinomas (Klatskin tumors) on the incidence of intra- and extrahepatic cholangiocarcinoma in the United States.J Natl Cancer Inst. 2006; 98: 873-875Crossref PubMed Scopus (259) Google Scholar CCAs are epithelial tumors with features of cholangiocyte differentiation. Intrahepatic cholangiocarcinomas (iCCAs) are located within the hepatic parenchyma. The second-order bile ducts serve as the point of separation between iCCAs and perihilar CCAs (pCCAs) or distal CCAs (dCCAs)—the cystic duct is the anatomic boundary between these latter 2 subtypes (Figure 1A).2Blechacz B. Komuta M. Roskams T. et al.Clinical diagnosis and staging of cholangiocarcinoma.Nat Rev Gastroenterol Hepatol. 2011; 8: 512-522Crossref PubMed Scopus (369) Google Scholar The Bismuth–Corlette classification stratifies perihilar tumors on the basis of biliary involvement. This classification recently was extended to also take into account arterial and venous encasement.3Deoliveira M.L. Schulick R.D. Nimura Y. et al.New staging system and a registry for perihilar cholangiocarcinoma.Hepatology. 2011; 53: 1363-1371Crossref PubMed Scopus (194) Google Scholar pCCA is the most common type of CCA. In a large series of patients with bile duct cancer, 8% had iCCA, 50% had pCCA, and 42% had distal CCA.4DeOliveira M.L. Cunningham S.C. Cameron J.L. et al.Cholangiocarcinoma: thirty-one-year experience with 564 patients at a single institution.Ann Surg. 2007; 245: 755-762Crossref PubMed Scopus (819) Google Scholar CCA has a poor prognosis; patients have a median survival of 24 months after diagnosis. The only curative treatment option is surgery, for early stage disease.5Blechacz BG, Gores, GJ. Tumors of the bile ducts, gallbladder, and ampulla. In: Feldman, ed. Sleisenger and Fordtran's gastrointestinal and liver disease. Volume 1. 9th ed. Philadelphia: Saunders, 2010:1171–1176.Google Scholar Cholangiocarcinoma accounts for 3% of all gastrointestinal tumors. Over the past 3 decades, the overall incidence of CCA appears to have increased.6Khan S.A. Davidson B.R. Goldin R.D. et al.Guidelines for the diagnosis and treatment of cholangiocarcinoma: an update.Gut. 2012; 61: 1657-1669Crossref PubMed Scopus (489) Google Scholar The percentage of patients who survive 5 years after diagnosis has not increased during this time period, remaining at 10%.7Everhart J.E. Ruhl C.E. Burden of digestive diseases in the United States part III: liver, biliary tract, and pancreas.Gastroenterology. 2009; 136: 1134-1144Abstract Full Text Full Text PDF PubMed Scopus (475) Google Scholar, 8Tyson G.L. El-Serag H.B. Risk factors for cholangiocarcinoma.Hepatology. 2011; 54: 173-184Crossref PubMed Scopus (531) Google Scholar In the United States, Hispanics and Asians have the highest incidence of CCA (2.8 per 100,000 and 3.3 per 100,000, respectively), whereas African Americans have the lowest incidence of CCA (2.1 per 100,000). African Americans also have lower age-adjusted mortality rates compared with whites (1.4 per 100,000 vs 1.7 per 100,000). Men have a slightly higher incidence of CCA and mortality from cancer than women.7Everhart J.E. Ruhl C.E. Burden of digestive diseases in the United States part III: liver, biliary tract, and pancreas.Gastroenterology. 2009; 136: 1134-1144Abstract Full Text Full Text PDF PubMed Scopus (475) Google Scholar With the exception of patients with primary sclerosing cholangitis (PSC), a diagnosis of CCA is uncommon before age 40 years. Globally, hepatobiliary malignancies account for 13% of cancer-related deaths; 10%–20% of these are attributable to CCA. The mean age at diagnosis of CCA is 50 years. The global incidence of iCCA varies widely, from rates of 113 per 100,000 in Thailand to 0.1 per 100,000 in Australia.9Shaib Y. El-Serag H.B. The epidemiology of cholangiocarcinoma.Semin Liver Dis. 2004; 24: 115-125Crossref PubMed Scopus (888) Google Scholar, 10Sripa B. Pairojkul C. Cholangiocarcinoma: lessons from Thailand.Curr Opin Gastroenterol. 2008; 24: 349-356Crossref PubMed Scopus (351) Google Scholar Differences in the prevalence of genetic and other risk factors presumably account for this extensive variation. Epidemiologic studies have indicated that the age-adjusted mortality rate for iCCA is increasing, whereas the mortality rate from pCCA and dCCA could be decreasing.9Shaib Y. El-Serag H.B. The epidemiology of cholangiocarcinoma.Semin Liver Dis. 2004; 24: 115-125Crossref PubMed Scopus (888) Google Scholar, 10Sripa B. Pairojkul C. Cholangiocarcinoma: lessons from Thailand.Curr Opin Gastroenterol. 2008; 24: 349-356Crossref PubMed Scopus (351) Google Scholar, 11Khan S.A. Taylor-Robinson S.D. Toledano M.B. Beck A. Elliott P. Thomas H.C. Changing international trends in mortality rates for liver, biliary and pancreatic tumours.J Hepatol. 2002; 37: 806-813Abstract Full Text Full Text PDF PubMed Scopus (446) Google Scholar, 12Khan S.A. Toledano M.B. Taylor-Robinson S.D. Epidemiology, risk factors, and pathogenesis of cholangiocarcinoma.HPB (Oxford). 2008; 10: 77-82Abstract Full Text Full Text PDF PubMed Scopus (301) Google Scholar, 13McGlynn K.A. Tarone R.E. El-Serag H.B. A comparison of trends in the incidence of hepatocellular carcinoma and intrahepatic cholangiocarcinoma in the United States.Cancer Epidemiol Biomarkers Prev. 2006; 15: 1198-1203Crossref PubMed Scopus (159) Google Scholar, 14Patel T. Increasing incidence and mortality of primary intrahepatic cholangiocarcinoma in the United States.Hepatology. 2001; 33: 1353-1357Crossref PubMed Scopus (817) Google Scholar A study of a World Health Organization database reported a substantial global increase in iCCA mortality, with a decreasing trend in mortality from pCCA plus dCCA.15Patel T. Worldwide trends in mortality from biliary tract malignancies.BMC Cancer. 2002; 2: 10Crossref PubMed Scopus (376) Google Scholar Although this observed increase in the incidence of CCA over the past 30 years has been recorded as an increase in iCCA, it could result from misclassification of perihilar tumors as iCCAs.16Khan S.A. Emadossadaty S. Ladep N.G. et al.Rising trends in cholangiocarcinoma: is the ICD classification system misleading us?.J Hepatol. 2012; 56: 848-854Abstract Full Text Full Text PDF PubMed Scopus (176) Google Scholar According to the US Surveillance, Epidemiology, and End Results database, the age-adjusted incidence rate for iCCA increased from 0.59 per 100,000 in 1990 to 0.91 per 100,000 in 2001. It subsequently decreased to 0.6 per 100,000 by 2007. Conversely, the incidence rate for pCCA plus dCCA remained around 0.8 per 100,000 until 2001, and then gradually increased to 0.97 per 100,000 by 2007. Perihilar tumors were coded as iCCAs before 2001 and subsequently were coded as pCCAs after implementation of the third edition of the International Classification of Disease for Oncology. This update likely influenced the aforementioned changes in incidence rates of both CCA subtypes. Similar trends in the incidence of CCA subtypes were noted in the United Kingdom after the change to the third edition of the International Classification of Disease for Oncology in 2008.6Khan S.A. Davidson B.R. Goldin R.D. et al.Guidelines for the diagnosis and treatment of cholangiocarcinoma: an update.Gut. 2012; 61: 1657-1669Crossref PubMed Scopus (489) Google Scholar, 16Khan S.A. Emadossadaty S. Ladep N.G. et al.Rising trends in cholangiocarcinoma: is the ICD classification system misleading us?.J Hepatol. 2012; 56: 848-854Abstract Full Text Full Text PDF PubMed Scopus (176) Google Scholar There are several established risk factors for CCA, and most cases are sporadic.6Khan S.A. Davidson B.R. Goldin R.D. et al.Guidelines for the diagnosis and treatment of cholangiocarcinoma: an update.Gut. 2012; 61: 1657-1669Crossref PubMed Scopus (489) Google Scholar, 8Tyson G.L. El-Serag H.B. Risk factors for cholangiocarcinoma.Hepatology. 2011; 54: 173-184Crossref PubMed Scopus (531) Google Scholar, 17Razumilava N. Gores G.J. Classification, diagnosis, and management of cholangiocarcinoma.Clin Gastroenterol Hepatol. 2013; 11 (quiz e3–e4): 13-21 e1Abstract Full Text Full Text PDF PubMed Scopus (182) Google Scholar Geographic variations in incidence rates of CCA are related in part to variations in risk factors. For example, in Southeast Asia, which has one of the highest incidence rates of CCA, infection with the hepatobiliary flukes Opisthorchis viverrini and Clonorchis sinensis has been associated with the development of CCA. Both parasites cause chronic inflammation and are considered carcinogens.8Tyson G.L. El-Serag H.B. Risk factors for cholangiocarcinoma.Hepatology. 2011; 54: 173-184Crossref PubMed Scopus (531) Google Scholar, 18Shin H.R. Oh J.K. Lim M.K. et al.Descriptive epidemiology of cholangiocarcinoma and clonorchiasis in Korea.J Korean Med Sci. 2010; 25: 1011-1016Crossref PubMed Scopus (65) Google Scholar Hepatolithiasis is another risk factor for CCA (mainly iCCA) in Asian countries.8Tyson G.L. El-Serag H.B. Risk factors for cholangiocarcinoma.Hepatology. 2011; 54: 173-184Crossref PubMed Scopus (531) Google Scholar Chronic biliary inflammation secondary to calculi has been proposed to increase the risk of malignancy. Moreover, infestation with hepatobiliary flukes has been shown to be more common in patients with hepatolithiasis.8Tyson G.L. El-Serag H.B. Risk factors for cholangiocarcinoma.Hepatology. 2011; 54: 173-184Crossref PubMed Scopus (531) Google Scholar, 19Huang M.H. Chen C.H. Yen C.M. et al.Relation of hepatolithiasis to helminthic infestation.J Gastroenterol Hepatol. 2005; 20: 141-146Crossref PubMed Scopus (28) Google Scholar The incidence and prevalence of CCA in patients with bile duct (choledochal) cysts are also higher in Asian than in Western countries.20Edil B.H. Cameron J.L. Reddy S. et al.Choledochal cyst disease in children and adults: a 30-year single-institution experience.J Am Coll Surg. 2008; 206 (discussion 1005–1008): 1000-1005Abstract Full Text Full Text PDF PubMed Scopus (74) Google Scholar, 21Mabrut J.Y. Bozio G. Hubert C. et al.Management of congenital bile duct cysts.Dig Surg. 2010; 27: 12-18Crossref PubMed Scopus (40) Google Scholar Choledochal cystic diseases, including Caroli's disease, are rare congenital abnormalities of the pancreatic and biliary ducts. Choledochal cysts can be intrahepatic or extrahepatic, and are diagnosed in patients at an average age of 32 years old.8Tyson G.L. El-Serag H.B. Risk factors for cholangiocarcinoma.Hepatology. 2011; 54: 173-184Crossref PubMed Scopus (531) Google Scholar, 17Razumilava N. Gores G.J. Classification, diagnosis, and management of cholangiocarcinoma.Clin Gastroenterol Hepatol. 2013; 11 (quiz e3–e4): 13-21 e1Abstract Full Text Full Text PDF PubMed Scopus (182) Google Scholar Thorotrast, a previously used contrast agent that is now banned, was found to increase risk for CCA by 300-fold in a Japanese study.22Kato I. Kido C. Increased risk of death in thorotrast-exposed patients during the late follow-up period.Jpn J Cancer Res. 1987; 78: 1187-1192PubMed Google Scholar In the West, PSC is the most common predisposing condition for CCA. Among patients with PSC, the annual risk of development of CCA is 0.5%–1.5%, with a lifetime prevalence of 5%–10%17Razumilava N. Gores G.J. Classification, diagnosis, and management of cholangiocarcinoma.Clin Gastroenterol Hepatol. 2013; 11 (quiz e3–e4): 13-21 e1Abstract Full Text Full Text PDF PubMed Scopus (182) Google Scholar; CCA is diagnosed within 2 years of PSC in most of these patients. A number of potential risk factors for CCA in patients with PSC have been studied, including smoking and alcohol, although definitive data are lacking.8Tyson G.L. El-Serag H.B. Risk factors for cholangiocarcinoma.Hepatology. 2011; 54: 173-184Crossref PubMed Scopus (531) Google Scholar Hepatitis B virus (HBV) or hepatitis C virus (HCV) infection and cirrhosis have been proposed as potential etiologies of iCCA.23Lee T.Y. Lee S.S. Jung S.W. et al.Hepatitis B virus infection and intrahepatic cholangiocarcinoma in Korea: a case-control study.Am J Gastroenterol. 2008; 103: 1716-1720Crossref PubMed Scopus (160) Google Scholar, 24Shaib Y.H. El-Serag H.B. Nooka A.K. et al.Risk factors for intrahepatic and extrahepatic cholangiocarcinoma: a hospital-based case-control study.Am J Gastroenterol. 2007; 102: 1016-1021Crossref PubMed Scopus (206) Google Scholar, 25Sorensen H.T. Friis S. Olsen J.H. et al.Risk of liver and other types of cancer in patients with cirrhosis: a nationwide cohort study in Denmark.Hepatology. 1998; 28: 921-925Crossref PubMed Scopus (256) Google Scholar A recent meta-analysis of 11 studies found that cirrhosis, HBV, and HCV were major risk factors for iCCA, with odds ratios (ORs) of 22.92, 5.1, and 4.8, respectively.26Palmer W.C. Patel T. Are common factors involved in the pathogenesis of primary liver cancers? A meta-analysis of risk factors for intrahepatic cholangiocarcinoma.J Hepatol. 2012; 57: 69-76Abstract Full Text Full Text PDF PubMed Scopus (293) Google Scholar A case-control study from Korea found a significant association between HBV (OR, 2.3) and CCA, but not HCV and CCA. Cirrhosis also was found to be a significant risk factor for CCA, with an OR of 13.6. HCV and cirrhosis were associated with iCCA in a US case-control study. Compared with controls, patients with iCCA had a higher prevalence of anti-HCV antibodies, with an OR of 7.9.24Shaib Y.H. El-Serag H.B. Nooka A.K. et al.Risk factors for intrahepatic and extrahepatic cholangiocarcinoma: a hospital-based case-control study.Am J Gastroenterol. 2007; 102: 1016-1021Crossref PubMed Scopus (206) Google Scholar CCA development has been associated with other risk factors, including inflammatory bowel disease independent of PSC, alcohol, smoking, fatty liver disease, diabetes, cholelithiasis, and choledocholithiasis.8Tyson G.L. El-Serag H.B. Risk factors for cholangiocarcinoma.Hepatology. 2011; 54: 173-184Crossref PubMed Scopus (531) Google Scholar, 27Shaib Y.H. El-Serag H.B. 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Risk factors for cholangiocarcinoma.Hepatology. 2011; 54: 173-184Crossref PubMed Scopus (531) Google Scholar Further studies are necessary to verify these potential associations. iCCA is a histologically diverse hepatobiliary malignancy considered to develop from biliary epithelial cells or hepatic progenitor cells (Figure 1B). A recently proposed classification of iCCAs subdivided these tumors into the conventional, bile ductular, or intraductal neoplasm type, or rare variants (combined hepatocellular CCA, undifferentiated type, squamous/adenosquamous type). The conventional type includes small-duct or peripheral type and large-duct or perihilar type.30Nakanuma Y. Sato Y. Harada K. et al.Pathological classification of intrahepatic cholangiocarcinoma based on a new concept.World J Hepatol. 2010; 2: 419-427Crossref PubMed Scopus (189) Google Scholar Neural cell adhesion molecule, a marker of hepatic progenitor cells, has been detected in the bile ductular and combined hepatocellular CCA types, so these might have originated from hepatic progenitor cells.30Nakanuma Y. Sato Y. Harada K. et al.Pathological classification of intrahepatic cholangiocarcinoma based on a new concept.World J Hepatol. 2010; 2: 419-427Crossref PubMed Scopus (189) Google Scholar, 31Komuta M. Spee B. Vander Borght S. et al.Clinicopathological study on cholangiolocellular carcinoma suggesting hepatic progenitor cell origin.Hepatology. 2008; 47: 1544-1556Crossref PubMed Scopus (269) Google Scholar, 32Tsuchiya A. Kamimura H. 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Vandecaveye V. et al.Histological diversity in cholangiocellular carcinoma reflects the different cholangiocyte phenotypes.Hepatology. 2012; 55: 1876-1888Crossref PubMed Scopus (198) Google Scholar A model in which iCCAs arise from transdifferentiation and subsequent neoplastic conversion of normal hepatocytes into malignant cholangiocytes has been proposed. Fan et al35Fan B. Malato Y. Calvisi D.F. et al.Cholangiocarcinomas can originate from hepatocytes in mice.J Clin Invest. 2012; 122: 2911-2915Crossref PubMed Scopus (279) Google Scholar showed in mice that overexpression of Notch1 and AKT resulted in the development of invasive cystadenocarcinomas via conversion of hepatocytes into cholangiocyte precursors of iCCA.35Fan B. Malato Y. Calvisi D.F. et al.Cholangiocarcinomas can originate from hepatocytes in mice.J Clin Invest. 2012; 122: 2911-2915Crossref PubMed Scopus (279) Google Scholar Sekiya and Suzuki36Sekiya S. Suzuki A. Intrahepatic cholangiocarcinoma can arise from Notch-mediated conversion of hepatocytes.J Clin Invest. 2012; 122: 3914-3918Crossref PubMed Scopus (210) Google Scholar also showed that in mice, Notch-mediated conversion of hepatocytes into biliary cells leads to macronodular cirrhosis and iCCAs. Therefore, iCCAs may not have a single lineage, but instead derive from different cells of origin. In support of this theory, a recent study showed that transformed hepatocytes, hepatoblasts, and hepatic progenitor cells can give rise to a broad spectrum of liver tumors, ranging from CCA to HCC.37Holczbauer A. Factor V.M. Andersen J.B. et al.Modeling pathogenesis of primary liver cancer in lineage-specific mouse cell types.Gastroenterology. 2013; 145: 221-231Abstract Full Text Full Text PDF PubMed Scopus (115) Google Scholar These studies indicate that multiple cell types, rather than only cholangiocytes, transform and develop into CCAs. Additional animal models of CCA and lineage tracing studies are necessary to help identify the cells of origin for CCA. CCAs frequently arises under conditions of inflammation, which is believed to contribute to pathogenesis. A variety of cytokines, growth factors, tyrosine kinases, and bile acids can contribute to alterations in proliferation, apoptosis, senescence, and cell-cycle regulation required for cholangiocarcinogenesis.5Blechacz BG, Gores, GJ. Tumors of the bile ducts, gallbladder, and ampulla. In: Feldman, ed. Sleisenger and Fordtran's gastrointestinal and liver disease. Volume 1. 9th ed. Philadelphia: Saunders, 2010:1171–1176.Google Scholar Inflammatory cytokines activate inducible nitric oxide synthase, leading to excess nitric oxide with resultant single-stranded, double-stranded, and oxidative DNA lesions, as well as inhibition of DNA repair enzymes.38Jaiswal M. LaRusso N.F. 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