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Current epidemiology of cholangiocarcinoma in Western countries

  • Mathew Vithayathil
    Affiliations
    Liver Unit, Division of Digestive Diseases, Imperial College London and Imperial College Healthcare NHS Trust, United Kingdom
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  • Shahid A. Khan
    Correspondence
    Corresponding author. Address: Division of Digestive Diseases, Imperial College London, London, United Kingdom. Tel: +44 (0)20 3312 6254.
    Affiliations
    Liver Unit, Division of Digestive Diseases, Imperial College London and Imperial College Healthcare NHS Trust, United Kingdom
    Search for articles by this author
Open AccessPublished:August 14, 2022DOI:https://doi.org/10.1016/j.jhep.2022.07.022

      Summary

      Cholangiocarcinomas are cancers arising from bile ducts, either found within the liver (intrahepatic) or outside the liver (extrahepatic). In Western countries, deaths due to intrahepatic cancers are rising at a higher rate than deaths due to extrahepatic cancers. This may be due to rising cases of liver disease and misclassification of the different cancer types.

      Keywords

      Epidemiology of cholangiocarcinoma

      Cholangiocarcinoma (CCA) encompasses a rare group of primary neoplasms arising from the biliary tree.
      • Khan S.A.
      • Tavolari S.
      • Brandi G.
      Cholangiocarcinoma: epidemiology and risk factors.
      CCAs have traditionally been classified as intrahepatic (iCCA) or extrahepatic (eCCA) based on their anatomical origin within the biliary tree. eCCAs can be further sub-classified into perihilar (pCCA) and distal (dCCA), based on their location relative to the cystic duct
      • Blechacz B.
      • Komuta M.
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      • Gores G.J.
      Clinical diagnosis and staging of cholangiocarcinoma.
      ,
      • Rizvi S.
      • Gores G.J.
      Pathogenesis, diagnosis, and management of cholangiocarcinoma.
      (Fig. 1). iCCAs are the second most common cause of primary liver cancer, after hepatocellular carcinoma.
      • Khan S.A.
      • Tavolari S.
      • Brandi G.
      Cholangiocarcinoma: epidemiology and risk factors.
      ,
      • Welzel T.M.
      • McGlynn K.A.
      • Hsing A.W.
      • O’Brien T.R.
      • Pfeiffer R.M.
      Impact of classification of hilar cholangiocarcinomas (Klatskin tumors) on the incidence of intra- and extrahepatic cholangiocarcinoma in the United States.
      pCCAs account for up to 60% of all CCAs, with iCCAs accounting for less than 10% of primary biliary tree tumours.
      • Nakeeb A.
      • Pitt H.A.
      • Sohn T.A.
      • Coleman J.
      • Abrams R.A.
      • Piantadosi S.
      • et al.
      Cholangiocarcinoma. A spectrum of intrahepatic, perihilar, and distal tumors.
      ,
      • DeOliveira M.L.
      • Cunningham S.C.
      • Cameron J.L.
      • Kamangar F.
      • Winter J.M.
      • Lillemoe K.D.
      • et al.
      Cholangiocarcinoma: thirty-one-year experience with 564 patients at a single institution.
      iCCA and eCCA show distinct epidemiological, clinical, molecular and genetic characteristics.
      • Petrick J.L.
      • Yang B.
      • Altekruse S.F.
      • Van Dyke A.L.
      • Koshiol J.
      • Graubard B.I.
      • et al.
      Risk factors for intrahepatic and extrahepatic cholangiocarcinoma in the United States: a population-based study in SEER-Medicare.
      • Tyson G.L.
      • El-Serag H.B.
      Risk factors for cholangiocarcinoma.
      • Cardinale V.
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      • Torrice A.
      • Gatto M.
      • Napoli C.
      • Bragazzi M.C.
      • et al.
      Intra-hepatic and extra-hepatic cholangiocarcinoma: new insight into epidemiology and risk factors.
      • Vij M.
      • Puri Y.
      • Rammohan A.
      • Gowripriya G.
      • Rajalingam R.
      • Kaliamoorthy I.
      • et al.
      Pathological, molecular, and clinical characteristics of cholangiocarcinoma: a comprehensive review.
      Resection is the mainstay of curative treatment for both iCCA and eCCA, with anatomical location influencing the surgical techniques employed.
      • Sano T.
      • Shimizu Y.
      • Senda Y.
      • Kinoshita T.
      • Nimura Y.
      Assessing resectability in cholangiocarcinoma.
      Locoregional and, in particular, systemic therapy play a significant role in both curative and palliative cohorts, with precision strategies based on DNA profiling increasingly utilised for both iCCA and eCCA.
      • Vithayathil M.
      • Bridegwater J.
      • Khan S.A.
      Medical therapies for intra-hepatic cholangiocarcinoma.
      ,
      • Manne A.
      • Woods E.
      • Tsung A.
      • Mittra A.
      Biliary tract cancers: treatment updates and future directions in the era of precision medicine and immuno-oncology.
      Figure thumbnail gr1
      Fig. 1Classification of cholangiocarcinoma based on anatomical location in the biliary tract.
      CCA, cholangiocarcinoma.
      Previous studies have demonstrated the distinct, worldwide, epidemiological trends in iCCA and eCCA.
      • Patel T.
      Worldwide trends in mortality from biliary tract malignancies.
      • Khan 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.
      • Taylor-Robinson S.D.
      • Toledano M.B.
      • Arora S.
      • Keegan T.J.
      • Hargreaves S.
      • Beck A.
      • et al.
      Increase in mortality rates from intrahepatic cholangiocarcinoma in England and Wales 1968-1998.
      • Bertuccio P.
      • Malvezzi M.
      • Carioli G.
      • Hashim D.
      • Boffetta P.
      • El-Serag H.B.
      • et al.
      Global trends in mortality from intrahepatic and extrahepatic cholangiocarcinoma.
      These distinct epidemiological profiles reflect specific risk factors, treatment options and previous misclassification of tumours.
      • Welzel T.M.
      • McGlynn K.A.
      • Hsing A.W.
      • O’Brien T.R.
      • Pfeiffer R.M.
      Impact of classification of hilar cholangiocarcinomas (Klatskin tumors) on the incidence of intra- and extrahepatic cholangiocarcinoma in the United States.
      ,
      • Petrick J.L.
      • Yang B.
      • Altekruse S.F.
      • Van Dyke A.L.
      • Koshiol J.
      • Graubard B.I.
      • et al.
      Risk factors for intrahepatic and extrahepatic cholangiocarcinoma in the United States: a population-based study in SEER-Medicare.
      • Tyson G.L.
      • El-Serag H.B.
      Risk factors for cholangiocarcinoma.
      • Cardinale V.
      • Semeraro R.
      • Torrice A.
      • Gatto M.
      • Napoli C.
      • Bragazzi M.C.
      • et al.
      Intra-hepatic and extra-hepatic cholangiocarcinoma: new insight into epidemiology and risk factors.
      ,
      • Selvadurai S.
      • Mann K.
      • Mithra S.
      • Bridgewater J.
      • Malik H.
      • Khan S.A.
      Cholangiocarcinoma miscoding in hepatobiliary centres.
      Herein, we examine the most recent trends in iCCA and eCCA mortality in Western countries and review the key factors which may be underlying these trends.

      Mortality data acquisition

      Mortality data for males and females for iCCA and eCCA were obtained from the World Health Organisation (WHO) Mortality Database
      WHO. World Health Organization (WHO)
      Mortality Database Health statistics and information systems.
      using the International Classification of Disease 10th Revision (ICD-10) codes 22.1 and 24.0. Mortality data for males and females from individual countries were included for the years 2008, 2010, 2012, 2014, 2016 and 2018 where available. Western countries with consistent reporting of annual mortality rates were included: European Union (EU) (Austria, Belgium, Croatia, Czech Republic, Denmark, France, Germany, Hungary, Ireland, Italy, Latvia, Lithuania, Malta, Netherlands, Poland, Portugal, Romania, Slovakia, Spain and Sweden); Non-EU Europe (Norway, Switzerland, the UK); North America (Canada and the USA); and Oceania (Australia and New Zealand). Age-stratified population data (for age strata: 0-4, 5-9, 10-14, 15-19, 20-24, 25-29, 30-34, 35-39, 40-44, 45-49, 50-54, 55-59, 60-64, 65-69, 70-74, 75-79, 80-84, 85-89, 90-94, 95+) were obtained from the census data for Canada

      Canada S. Census of Population n.d. https://www12.statcan.gc.ca/census-recensement/index-eng.cfm?MM=1 (accessed March 22, 2022).

      and the USA,

      Bureau USC. U.S. Census Bureau, Current Population Survey, Annual Social and Economic Supplement n.d. https://www.census.gov/data/datasets/time-series/demo/cps/cps-asec.html (accessed March 22, 2022).

      and the WHO mortality database for all other countries.
      WHO. World Health Organization (WHO)
      Mortality Database Health statistics and information systems.
      The age-standardised mortality rate (ASMR) per 100,000 people was calculated for each year for individual countries using the WHO standard population.
      • Ahmad O.B.
      • Boschi-pinto C.
      • Lopez A.D.
      Age standardization of rates: a new WHO standard.
      Average annual percentage change (AAPC) was calculated for each country for iCCA and eCCA. iCCA:eCCA ratio was calculated for all countries for 2018 where available. For countries where 2018 mortality data were unavailable, 2016 mortality data were used.
      Mortality rates for intrahepatic cholangiocarcinoma are greater than for extrahepatic cholangiocarcinoma for most Western countries, based on the current classification of cancers.

      Current trends in mortality

      The annual male and female ASMRs for iCCA in individual Western countries between 2008 and 2018 are shown in Table 1. In Europe, the highest most recent mortality rates were seen in Malta, Ireland and Spain for males and Ireland, the UK and Switzerland for females, with Romania, Hungary and Poland reporting the lowest rates for both sexes. Canada and Australia had higher mortality rates in males and females compared to the USA and New Zealand, respectively. 53.8% of countries had male mortality rates greater than 1 in 100,000, which increased to 71.4% of countries in 2018. Similarly, the proportion of countries with female mortality rates greater than 1 in 100,000 increased from 26.9% to 66.7% between 2008 and 2018. 2018 mortality rates were greater than 2 in 100,000 in Ireland, Portugal, Spain, Australia, Canada, the UK and Belgium for males, and in Hungary for females. All Western countries showed an increase in iCCA mortality in males over the 10-year period with increasing mortality seen in females in all but 2 countries (Austria and New Zealand). The largest increases in AAPCs were observed in the Eastern European countries of Lithuania, Latvia and Poland for males and in Latvia, Lithuania and Slovakia for females.
      Table 1Age-standardised (WHO World Standard population) mortality rates for intrahepatic cholangiocarcinoma (ICD-10 code 22.1) per 100,000 person-years for male and females from Western countries.
      MaleFemale
      200820102012201420162018AAPC %200820102012201420162018AAPC %
      Europe
      EU
      Austria1.762.151.661.991.811.941.731.151.301.411.470.891.00-0.09
      Belgium1.201.611.371.632.012.006.160.921.161.131.231.031.294.15
      Croatia1.231.201.521.111.291.690.570.400.681.100.677.71
      Czech Republic0.500.670.540.800.680.897.930.310.430.460.530.590.658.15
      Denmark0.480.740.801.371.011.0110.850.460.960.911.121.021.1513.10
      France1.621.822.022.064.261.041.101.191.202.49
      Germany1.271.381.261.391.471.511.850.911.020.940.871.021.162.79
      Hungary0.340.260.590.600.670.539.610.200.290.240.470.420.4411.43
      Ireland1.931.842.674.021.621.742.666.05
      Italy0.891.061.201.201.325.260.680.680.840.830.883.64
      Latvia0.260.510.861.111.150.9818.140.060.340.700.520.481.0164.69
      Lithuania0.360.650.980.681.681.5323.740.240.510.850.741.150.8018.87
      Malta2.172.571.892.323.8710.170.650.381.291.040.4815.18
      Netherlands0.650.891.241.231.551.248.230.580.650.921.001.251.319.13
      Poland0.090.140.220.260.320.3416.010.110.130.170.190.190.269.59
      Portugal0.941.401.382.082.402.5812.190.600.870.701.121.271.209.24
      Romania0.280.390.490.460.570.6710.120.170.190.260.310.380.4510.88
      Slovakia0.520.711.040.870.868.310.330.280.550.590.9117.66
      Spain1.531.791.992.042.404.861.021.131.141.211.312.58
      Sweden0.580.680.750.980.841.117.700.450.640.790.700.630.715.59
      Non-EU
      UK1.411.511.731.871.932.033.831.301.441.671.731.861.914.05
      Norway0.861.011.191.361.578.100.941.001.291.011.133.22
      Switzerland1.501.371.381.621.585.170.991.061.251.041.446.78
      North America
      Canada1.361.431.751.791.872.054.411.021.201.451.561.611.665.25
      USA1.061.121.201.261.371.483.440.770.880.970.971.101.174.34
      Oceania
      Australia1.531.761.711.972.132.203.861.251.251.501.671.661.763.66
      New Zealand1.111.031.101.362.960.860.951.240.55-1.75
      AAPC, average annual percentage change.
      ASMRs for males and females with eCCA in Western countries are shown in Table 2. In Europe, Hungary, Austria, Germany and Sweden had the highest most recent mortality rates for both sexes, with Malta, Ireland and the UK reporting the lowest rates. In contrast to iCCA, the USA reported higher mortality rates for eCCA than Canada, and New Zealand reported higher rates than Australia. Unlike iCCA, no countries had mortality rates for eCCA greater than 1 in 100,000 for either males or females in 2008, rising to only 14.2% and 4.8% of all countries in 2018 for males and females, respectively. No countries had mortality rates greater than 2 in 100,000. Regarding AAPCs, Norway, Spain and Hungary showed the highest positive increase in AAPCs in Europe. In contrast to iCCA, negative AAPCs were observed in several countries, including Denmark, Ireland, Italy, Netherlands, Portugal and the UK for males and Croatia, Denmark, Ireland, Italy, Latvia, Netherlands, Portugal, Slovakia and the UK for females. Canada and Australia showed negative AAPCs compared to positive AAPCs seen in the USA and New Zealand.
      Table 2Age-standardised (WHO World Standard population) mortality rates for extrahepatic cholangiocarcinoma (ICD-10 code 24.0) per 100,000 person-years for male and females from Western countries.
      MaleFemale
      200820102012201420162018AAPC %200820102012201420162018AAPC %
      Europe
      EU
      Austria0.840.900.740.731.031.214.640.670.610.560.660.750.670.45
      Belgium0.080.180.140.120.150.109.090.050.110.060.070.040.0813.78
      Croatia0.400.570.740.770.759.070.490.510.480.480.44-1.22
      Czech Republic0.440.640.410.760.600.638.080.470.530.280.450.410.452.63
      Denmark0.210.180.140.090.160.11-2.740.350.310.350.130.230.18-0.72
      France0.080.080.070.091.790.050.060.050.064.53
      Germany0.460.590.791.001.011.1510.440.340.460.650.740.780.789.39
      Hungary0.300.340.421.611.691.7732.960.310.310.321.091.131.2425.92
      Ireland0.150.160.07-4.270.190.210.03-7.54
      Italy0.300.280.220.220.22-3.640.170.190.140.140.13-2.33
      Latvia0.610.140.470.580.550.2010.980.340.330.220.400.220.16-2.83
      Lithuania0.400.160.350.420.230.4211.520.300.240.300.120.160.200.45
      Malta0.320.600.267.71
      Netherlands0.500.370.440.590.380.34-2.030.420.330.330.460.430.32-1.49
      Poland0.150.140.200.160.130.151.130.130.150.140.130.110.130.57
      Portugal0.760.490.690.100.150.16-2.210.450.440.290.120.100.09-12.52
      Romania0.350.380.380.380.380.390.920.170.280.230.260.310.214.32
      Slovakia0.240.270.360.570.4810.960.320.320.330.260.29-0.94
      Spain0.050.070.070.210.220.1621.860.040.030.040.100.1426.15
      Sweden0.660.460.670.800.830.813.490.830.800.660.730.850.810.21
      Non-EU
      UK0.060.070.080.050.070.05-0.750.040.050.030.040.040.04-0.60
      Norway0.080.140.030.080.1632.020.080.110.020.070.0927.39
      Switzerland0.330.310.490.370.430.820.220.350.350.280.382.87
      North America
      Canada0.090.080.090.080.090.07-1.630.110.090.070.060.060.07-3.52
      USA0.140.140.130.140.160.182.650.110.090.090.100.120.142.83
      Oceania
      Australia0.120.120.090.040.040.04-7.040.090.120.080.030.050.01-5.86
      New Zealand0.330.310.210.343.020.210.160.090.184.64
      AAPC, average annual percentage change.
      Mortality rates for 2018 for iCCA and eCCA in males and females are shown in Fig. 2, Fig. 3, respectively. ASMRs were higher for iCCA compared to eCCA for all countries except Hungary (for both sexes) and Sweden (for females). iCCA:eCCA mortality ratios were greater than 10 for Australia, Ireland, the UK, Canada, Belgium, and Portugal for both sexes and for Spain for males and Norway for females.
      Figure thumbnail gr2
      Fig. 2Age-standardised mortality rates for intrahepatic and extrahepatic cholangiocarcinoma per 100,000 person-years for males from Western countries for 2018.∗
      ∗2016 Age-standardised mortality rates reported for Croatia, Italy, Norway and New Zealand.
      Figure thumbnail gr3
      Fig. 3Age-standardised mortality rates for intrahepatic and extrahepatic cholangiocarcinoma per 100,000 person-years for females from Western countries for 2018.∗
      ∗2016 Age-standardised mortality rates reported for Croatia, Italy, Norway and New Zealand.

      Drivers of variation in mortality trends

      Based on the most recent WHO mortality data, mortality rates were higher for iCCA than eCCA in the majority of Western countries, with higher ASMRs seen in males compared to females. There has been a general increase in iCCA-related mortality for both sexes over the last decade in all countries. In comparison, eCCA-related mortality increases were modest, with multiple countries showing a decrease in eCCA-related mortality.
      Previous studies have demonstrated that mortality rates for iCCA are rising. Taylor-Robinson et al. first reported rising mortality rates in the UK.
      • Taylor-Robinson S.D.
      • Toledano M.B.
      • Arora S.
      • Keegan T.J.
      • Hargreaves S.
      • Beck A.
      • et al.
      Increase in mortality rates from intrahepatic cholangiocarcinoma in England and Wales 1968-1998.
      The same authors observed decreasing rates of eCCA-related mortality. These trends have been observed globally in subsequent population studies.
      • Patel T.
      Worldwide trends in mortality from biliary tract malignancies.
      ,
      • Khan 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.
      ,
      • Bertuccio P.
      • Malvezzi M.
      • Carioli G.
      • Hashim D.
      • Boffetta P.
      • El-Serag H.B.
      • et al.
      Global trends in mortality from intrahepatic and extrahepatic cholangiocarcinoma.
      Bertuccio et al. observed rising global mortality rates for iCCA between 1995 and 2016, with rates for eCCA remaining stable across the same time period,
      • Bertuccio P.
      • Malvezzi M.
      • Carioli G.
      • Hashim D.
      • Boffetta P.
      • El-Serag H.B.
      • et al.
      Global trends in mortality from intrahepatic and extrahepatic cholangiocarcinoma.
      in line with current trends. There are several drivers underlying the differing trends in iCCA and eCCA, including misclassification of CCAs, varying risk factors, early diagnosis and surveillance, and access to specialist care.
      Mortality rates for intrahepatic cholangiocarcinoma are consistently rising across Western countries.

      Misclassification and coding

      The classification of CCAs has been subject to repeated change. Though the currently accepted subtype classification of CCA is iCCA, pCCA and dCCA,
      • Banales J.M.
      • Cardinale V.
      • Carpino G.
      • Marzioni M.
      • Andersen J.B.
      • 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).
      ,
      • Bridgewater J.
      • Galle P.R.
      • Khan S.A.
      • Llovet J.M.
      • Park J.-W.
      • Patel T.
      • et al.
      Guidelines for the diagnosis and management of intrahepatic cholangiocarcinoma.
      pCCAs currently do not have a separate ICD-10 code. pCCAs account for up to 60% of all CCAs,
      • Nakeeb A.
      • Pitt H.A.
      • Sohn T.A.
      • Coleman J.
      • Abrams R.A.
      • Piantadosi S.
      • et al.
      Cholangiocarcinoma. A spectrum of intrahepatic, perihilar, and distal tumors.
      ,
      • DeOliveira M.L.
      • Cunningham S.C.
      • Cameron J.L.
      • Kamangar F.
      • Winter J.M.
      • Lillemoe K.D.
      • et al.
      Cholangiocarcinoma: thirty-one-year experience with 564 patients at a single institution.
      and misclassification of these malignancies has been demonstrated to greatly influence the accuracy of reported iCCA and eCCA mortality rates. The second edition International Classification of Diseases for Oncology (ICD-O-2) previously assigned pCCA a histological code assigned to the iCCA rather than the eCCA grouping.
      World Health Organization
      International classification of diseases for oncology.
      Though the more recent third edition (ICD-O-3) established in 2013
      Organization WH
      International classification of diseases for oncology.
      allows assignment of pCCA to either iCCA or eCCA, different countries adopt classifications at different time points.
      • Khan S.A.
      • Emadossadaty S.
      • Ladep N.G.
      • Thomas H.C.
      • Elliott P.
      • Taylor-Robinson S.D.
      • et al.
      Rising trends in cholangiocarcinoma: is the ICD classification system misleading us?.
      A retrospective review of the US Surveillance, Epidemiology and End Results (SEER) database demonstrated that a change from the ICD-O-2 classification of pCCAs to the ICD-O-3 classification resulted in a decreasing trend in iCCA and an increasing trend in eCCA incidence.
      • Khan S.A.
      • Emadossadaty S.
      • Ladep N.G.
      • Thomas H.C.
      • Elliott P.
      • Taylor-Robinson S.D.
      • et al.
      Rising trends in cholangiocarcinoma: is the ICD classification system misleading us?.
      ICD-O-2 classifications from the SEER database resulted in 91% of pCCAs being incorrectly classified as iCCAs, leading to a 13% overestimation of iCCA incidence and a 15% underestimation of eCCA incidence.
      • Welzel T.M.
      • McGlynn K.A.
      • Hsing A.W.
      • O’Brien T.R.
      • Pfeiffer R.M.
      Impact of classification of hilar cholangiocarcinomas (Klatskin tumors) on the incidence of intra- and extrahepatic cholangiocarcinoma in the United States.
      The impact of misclassification on our epidemiological understanding of CCAs has been demonstrated in further studies,
      • Selvadurai S.
      • Mann K.
      • Mithra S.
      • Bridgewater J.
      • Malik H.
      • Khan S.A.
      Cholangiocarcinoma miscoding in hepatobiliary centres.
      ,
      • Tyson G.L.
      • Ilyas J.A.
      • Duan Z.
      • Green L.K.
      • Younes M.
      • El-Serag H.B.
      • et al.
      Secular trends in the incidence of cholangiocarcinoma in the USA and the impact of misclassification.
      ,
      • Walter D.
      • Ferstl P.
      • Waidmann O.
      • Trojan J.
      • Hartmann S.
      • Schnitzbauer A.A.
      • et al.
      Cholangiocarcinoma in Germany: epidemiologic trends and impact of misclassification.
      and the rising iCCA and declining eCCA mortality rates in the West may be reflective of this misclassification.
      In a recent study from the UK, original clinical notes of cases coded as hepatobiliary carcinoma using WHO ICD-10 criteria (C22.1/Intrahepatic Bile Duct carcinoma, C24.0/Extrahepatic Bile Duct carcinoma, C23X/Malignant Neoplasm Gall Bladder, C22.0/Malignant Neoplasm Liver Cell Carcinoma) at 3 independent UK regional hepatopancreatobiliary centres over a 2-year period were reviewed by independent clinicians.
      • Selvadurai S.
      • Mann K.
      • Mithra S.
      • Bridgewater J.
      • Malik H.
      • Khan S.A.
      Cholangiocarcinoma miscoding in hepatobiliary centres.
      The agreed final diagnosis was compared to the originally allocated ICD-10 code. Of all the cases originally coded as C22.1/iCCA, only 43% were deemed to be true iCCA and thus coded correctly, while 34% cases were actually pCCA. Furthermore, 92% all pCCA cases were incorrectly coded as iCCA.
      • Selvadurai S.
      • Mann K.
      • Mithra S.
      • Bridgewater J.
      • Malik H.
      • Khan S.A.
      Cholangiocarcinoma miscoding in hepatobiliary centres.
      Given all countries use the same coding system with its inherent errors, and show similar trends, this systemic error may well be occurring on a large scale. Future epidemiological studies where more accurate classifications are adopted universally may highlight different trends in CCA subtypes. It is also important to encourage adoption of the next version of ICD (ICD-11) which will, for the first time, have a unique code for pCCA.
      Mortality rates for extrahepatic cholangiocarcinoma show a more modest rise compared to intrahepatic cholangiocarcinoma, with a decrease observed in many Western countries.

      Risk factors and mutational biology

      Though misclassification of CCAs may account for some of the divergence of iCCA and eCCA mortality trends, the underlying aetiology and risk factors for the different subtypes could be contributory. iCCA and eCCA have common and differing risk factors. Liver flukes are an established risk factor for both iCCA and eCCA in Eastern Asia.
      • Sripa B.
      • Kaewkes S.
      • Sithithaworn P.
      • Mairiang E.
      • Laha T.
      • Smout M.
      • et al.
      Liver fluke induces cholangiocarcinoma.
      Primary sclerosing cholangitis (PSC) is a strong risk factor for both iCCA and eCCA and affected patients represent a high-risk cohort.
      • Petrick J.L.
      • Yang B.
      • Altekruse S.F.
      • Van Dyke A.L.
      • Koshiol J.
      • Graubard B.I.
      • et al.
      Risk factors for intrahepatic and extrahepatic cholangiocarcinoma in the United States: a population-based study in SEER-Medicare.
      In Western countries, risk factors associated with chronic liver disease including viral hepatitis, alcohol consumption and non-alcoholic fatty liver disease are all associated with iCCA but not eCCA.
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      In contrast, biliary diseases (including gallstone disease) are more strongly associated with eCCA.
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      The rising trend in iCCA-related mortality could be reflective of increasing rates of chronic liver disease, in particular non-alcoholic fatty liver disease and alcohol-related liver disease.
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      By contrast, the increasing application of biliary interventions, such as cholecystectomy for gallstone disease,
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      may be leading to a reduction in the risk of eCCA.
      Though there are established risk factors for CCA, the majority of cases are sporadic, with no identified cause. Though some genetic polymorphisms have been linked to CCA, no genome-wide association studies have been conducted.
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      Carcinogenesis is mediated by the interaction between multiple cellular processes, involving pro-inflammatory cytokines, bile acids, aberrant activation of cell signalling receptors and increased cell proliferation.
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      ,
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      Though activation of pathways such as RAS-MAPK are common to CCA subtypes, there is heterogeneity in other signalling protein expression. In iCCA, identification of aberrant expression of key proteins (including IDH [isocitrate dehydrogenase] and FGFR2 [fibroblast growth factor receptor 2]) has led to the development of novel targeted therapies.
      • Vithayathil M.
      • Bridegwater J.
      • Khan S.A.
      Medical therapies for intra-hepatic cholangiocarcinoma.
      Conversely, pCCA and dCCA demonstrate higher frequencies of mutations in KRAS, TP53 and ELF3 mutations.
      • Banales J.M.
      • Marin J.J.G.
      • Lamarca A.
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      This variation in underlying mutational biology may contribute to the disparity in mortality trends between subtypes. Further understanding of these pathways and identification of actionable mutations will help to guide the development of targeted therapies with the potential to improve patient survival.

      Early diagnosis and surveillance

      CCAs are mainly asymptomatic, with diagnosis usually made at more advanced stages. Less than one-third of cases have single lesions less than 3 cm at diagnosis, with regional lymph node invasion present in almost half of patients and distant metastases present in a quarter.
      • Izquierdo-Sanchez L.
      • Lamarca A.
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      • Buettner S.
      • Utpatel K.
      • Klümpen H.-J.
      • et al.
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      As a consequence, curative resection is possible in less than 30% of patients.
      • van Vugt J.L.A.
      • Gaspersz M.P.
      • Coelen R.J.S.
      • Vugts J.
      • Labeur T.A.
      • de Jonge J.
      • et al.
      The prognostic value of portal vein and hepatic artery involvement in patients with perihilar cholangiocarcinoma.
      Early diagnosis is important for early intervention and improving patient survival. pCCAs and dCCAs appear to be detected at earlier stages, while patients with iCCA tend to present with multiple, larger and more poorly differentiated lesions at diagnosis.
      • Izquierdo-Sanchez L.
      • Lamarca A.
      • La Casta A.
      • Buettner S.
      • Utpatel K.
      • Klümpen H.-J.
      • et al.
      Cholangiocarcinoma landscape in Europe: diagnostic, prognostic and therapeutic insights from the ENSCCA Registry.
      This is due to extrahepatic lesions causing biliary obstruction and hence earlier clinical presentation compared to iCCAs. This earlier clinical presentation may contribute to the divergent trends in mortality rates between iCCA and eCCA subtypes; efforts to increase the rates of early detection could lead to significant survival improvements.
      Inaccurate coding, the misclassification of perihilar cholangiocarcinoma, subtype-specific risk factors and variations in national surveillance and cancer treatment may contribute to the divergence in observed mortality rates.
      PSC is an autoimmune disorder characterised by inflammation and stricturing of intra- and extrahepatic bile ducts.
      • Karlsen T.H.
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      • Thorburn D.
      • Vesterhus M.
      Primary sclerosing cholangitis - a comprehensive review.
      The underlying mechanisms behind PSC remain poorly understood and there are currently no effective disease-modifying therapies. Patients with PSC are at high risk (up to 600-fold greater than the general population) of developing CCA.
      • Bergquist A.
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      Data from the US SEER database demonstrated autoimmune cholangitis was associated with a significantly increased risk of both iCCA (odds ratio [OR] 21.52; 95% CI 7.21-26.90) and eCCA (OR 40.80; 95% CI 34.96-47.60).
      • Petrick J.L.
      • Yang B.
      • Altekruse S.F.
      • Van Dyke A.L.
      • Koshiol J.
      • Graubard B.I.
      • et al.
      Risk factors for intrahepatic and extrahepatic cholangiocarcinoma in the United States: a population-based study in SEER-Medicare.
      Data on 2,234 patients with CCA from 11 countries in the European Network for the Study of Cholangiocarcinoma demonstrate that PSC is more strongly associated with pCCA than with iCCA or eCCA, based on the current classification systems.
      • Izquierdo-Sanchez L.
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      • et al.
      Cholangiocarcinoma landscape in Europe: diagnostic, prognostic and therapeutic insights from the ENSCCA Registry.
      Given the elevated risk of CCA in patients with PSC, surveillance has been advocated in this cohort. However, there is a paucity of studies demonstrating the effectiveness of biomarker- and imaging-based surveillance in reducing CCA-related mortality. However, 3 retrospective studies provide evidence for the potential survival benefit of CCA imaging surveillance in PSC.
      • Bergquist A.
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      A study of 830 patients with PSC from the Mayo Clinic reported that patients who underwent imaging surveillance had significantly increased overall survival if diagnosed with CCA compared to those in whom surveillance was not performed (hazard ratio 0.22, 95% CI 0.12-0.41; p <0.001).
      • Ali A.H.
      • Tabibian J.H.
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      Surveillance for hepatobiliary cancers in patients with primary sclerosing cholangitis.
      Similarly, yearly imaging was associated with a 2-fold reduction in hepatopancreatobiliary cancers in patients with PSC and concurrent inflammatory bowel disease.
      • Trivedi P.J.
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      Bergquist et al. assessed the effects of imaging surveillance strategies in 27 centres from 12 Western countries.
      • Bergquist A.
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      Impact on follow-up strategies in patients with primary sclerosing cholangitis.
      The authors found scheduled imaging surveillance was associated with a lower risk of overall mortality (hazard ratio 0.61; 95% CI 0.47-0.80) and improved survival after CCA diagnosis compared to no scheduled imaging. Though these studies are suggestive of regular surveillance improving CCA outcomes, due to the retrospective design they are limited by selection bias, lead-time bias and the potential for confounder factors. Serum biomarkers carcinoembryonic antigen and carbohydrate antigen 19-9 (CA19-9) are associated with CCAs.
      • Macias R.I.R.
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      Diagnostic and prognostic biomarkers in cholangiocarcinoma.
      However, the clinical performance of these biomarkers for detecting early CCA is inconsistent, with the sensitivity of CA19-9 varying between 68%-97%
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      A 3-year prospective study on serum tumor markers used for detecting cholangiocarcinoma in patients with primary sclerosing cholangitis.

      Torzilli G, Makuuchi M, Ferrero A, Takayama T, Hui A-M, Abe H, et al. Accuracy of the preoperative determination of tumor markers in the differentiation of liver mass lesions in surgical patients. Hepatogastroenterology n.d.;49:740–745.

      • Qin X.-L.
      • Wang Z.-R.
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      Utility of serum CA19-9 in diagnosis of cholangiocarcinoma: in comparison with CEA.
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      and that of carcinoembryonic antigen between 63.3-68.6%.
      • Qin X.-L.
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      • Shi J.-S.
      • Lu M.
      • Wang L.
      • He Q.-R.
      Utility of serum CA19-9 in diagnosis of cholangiocarcinoma: in comparison with CEA.
      ,
      • Kau S.Y.
      • Shyr Y.M.
      • Su C.H.
      • Wu C.W.
      • Lui W.Y.
      Diagnostic and prognostic values of CA 19-9 and CEA in periampullary cancers.
      However, these markers are also elevated in other diseases, including biliary obstruction and acute cholangitis,

      Ker CG, Chen JS, Lee KT, Sheen PC, Wu CC. Assessment of serum and bile levels of CA19-9 and CA125 in cholangitis and bile duct carcinoma. J Gastroenterol Hepatol n.d.;6:505–508. https://doi.org/10.1111/j.1440-1746.1991.tb00896.x.

      ,
      • Shiozawa K.
      • Ishii K.
      • Mori T.
      • Takamura N.
      • Ikehara T.
      • Shinohara M.
      • et al.
      Heterochronous development of intrahepatic cholangiocellular carcinoma following hepatocellular carcinoma in a hepatitis B virus carrier.
      and like imaging-based strategies there is limited prospective evidence demonstrating their role in surveillance in patients with PSC. There is a need for high-quality prospective randomised studies to assess both the clinical and economic effectiveness of different surveillance strategies. However, given patients with PSC often require imaging due to cholestasis and infection during their natural disease course, conducting any potential prospective longitudinal studies is challenging.
      Due to the lack of robust prospective evidence, currently there is no internationally agreed standard for screening for CCA. According to the recommendations of the American College of Gastroenterology, clinicians can consider screening for CCA with regular cross-sectional imaging (ultrasound or MRI) with serial CA19-9 every 6-12 months.
      • Lindor K.D.
      • Kowdley K.V.
      • Harrison M.E.
      American College of Gastroenterology
      ACG clinical guideline: primary sclerosing cholangitis.
      Both the American Association for the Study of Liver Diseases
      • Chapman R.
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      Diagnosis and management of primary sclerosing cholangitis.
      and the European Association for the Study of Liver
      European Association for the Study of the Liver
      EASL Clinical Practice Guidelines: management of cholestatic liver diseases.
      guidelines state there is insufficient evidence to formally recommend regular biochemical or radiological screening, but that it should be used if there is a clinical deterioration in patients with PSC. This lack of consensus guidance means there is a wide variation in surveillance strategies in clinical practice. A retrospective study including 2,975 patients with PSC from 10 European countries, the USA and Canada showed there was a wide variation of surveillance strategies adopted within centres both within the same and across different countries.
      • Bergquist A.
      • Weismüller T.J.
      • Levy C.
      • Rupp C.
      • Joshi D.
      • Nayagam J.S.
      • et al.
      Impact on follow-up strategies in patients with primary sclerosing cholangitis.
      There was further variation in the choice of surveillance, with ultrasound, MRI, CA19-9 and endoscopic retrograde cholangiopancreatography all being employed based on local centre protocols. This lack of standardisation in surveillance could potentially contribute to the variation of CCA trends in different countries; more in-depth studies looking at national surveillance strategies are needed.
      Future epidemiological studies where more accurate classifications are adopted universally may highlight different trends in cholangiocarcinoma subtypes.

      Access to specialist care

      There are multiple treatment strategies available for CCAs dependent on cancer stage. For localised disease, curative resection is the gold standard for iCCA and eCCA. For iCCA lesions, hepatectomy with neoadjuvant chemotherapy is associated with improved survival,
      • Primrose J.N.
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      Capecitabine compared with observation in resected biliary tract cancer (BILCAP): a randomised, controlled, multicentre, phase 3 study.
      whilst pCCA and dCCA may require more extensive hepatopancreatobiliary resection.
      • Valle J.W.
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      • Huguet F.
      • Gruenberger T.
      • Arnold D.
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      ,
      • de Jong M.C.
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      • Bauer T.W.
      • Marsh J.W.
      • Ribero D.
      • et al.
      The impact of portal vein resection on outcomes for hilar cholangiocarcinoma: a multi-institutional analysis of 305 cases.
      Promising outcomes have been achieved with liver transplantation in patients with pCCA
      • Murad S.D.
      • Kim W.R.
      • Therneau T.
      • Gores G.J.
      • Rosen C.B.
      • Martenson J.A.
      • et al.
      Predictors of pretransplant dropout and posttransplant recurrence in patients with perihilar cholangiocarcinoma.
      ,
      • Darwish Murad S.
      • Kim W.R.
      • Harnois D.M.
      • Douglas D.D.
      • Burton J.
      • Kulik L.M.
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      Efficacy of neoadjuvant chemoradiation, followed by liver transplantation, for perihilar cholangiocarcinoma at 12 US centers.
      or iCCA
      • Sapisochin G.
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      and localised disease, but its application is limited by organ availability. As mentioned, curative resection is possible in less than 30% of patients,
      • van Vugt J.L.A.
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      The prognostic value of portal vein and hepatic artery involvement in patients with perihilar cholangiocarcinoma.
      hence, non-curative management with biliary intervention and medical pharmacotherapy is the mainstay of treatment. Combination systemic chemotherapy with cisplatin and gemcitabine is associated with improved survival in patients with unresectable disease.
      • Izquierdo-Sanchez L.
      • Lamarca A.
      • La Casta A.
      • Buettner S.
      • Utpatel K.
      • Klümpen H.-J.
      • et al.
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      ,
      • Valle J.
      • Wasan H.
      • Palmer D.H.
      • Cunningham D.
      • Anthoney A.
      • Maraveyas A.
      • et al.
      Cisplatin plus gemcitabine versus gemcitabine for biliary tract cancer.
      The advent of DNA profiling has identified targetable somatic mutations and the development of precision-based cancer pharmacotherapy, such as the FDA-approved fibroblast growth factor receptor antagonist pemigatinib for unresectable iCCA.
      • Vithayathil M.
      • Bridegwater J.
      • Khan S.A.
      Medical therapies for intra-hepatic cholangiocarcinoma.
      ,
      • Abou-Alfa G.K.
      • Sahai V.
      • Hollebecque A.
      • Vaccaro G.
      • Melisi D.
      • Al-Rajabi R.
      • et al.
      Pemigatinib for previously treated, locally advanced or metastatic cholangiocarcinoma: a multicentre, open-label, phase 2 study.
      Furthermore, the advent and efficacy of immunotherapy in multiple cancer types has spurred clinical interest in CCA.
      • Le D.T.
      • Uram J.N.
      • Wang H.
      • Bartlett B.R.
      • Kemberling H.
      • Eyring A.D.
      • et al.
      PD-1 blockade in tumors with mismatch-repair deficiency.
      These different treatment modalities are delivered by highly specialised secondary and tertiary care centres. Treatment in specialist high-volume centres is associated with improved survival in general cancer care.
      • Birkmeyer J.D.
      • Siewers A.E.
      • Finlayson E.V.A.
      • Stukel T.A.
      • Lucas F.L.
      • Batista I.
      • et al.
      Hospital volume and surgical mortality in the United States.
      ,
      • Stitzenberg K.B.
      • Sigurdson E.R.
      • Egleston B.L.
      • Starkey R.B.
      • Meropol N.J.
      Centralization of cancer surgery: implications for patient access to optimal care.
      These findings are replicated in CCA: surgical resection in academic centres is associated with significantly increased overall survival and R0 resection margins
      • Lee G.C.
      • Gamblin T.C.
      • Fong Z.V.
      • Ferrone C.R.
      • Goyal L.
      • Lillemoe K.D.
      • et al.
      Facility type is associated with margin status and overall survival of patients with resected intrahepatic cholangiocarcinoma.
      ,
      • Wu L.
      • Tsilimigras D.I.
      • Paredes A.Z.
      • Mehta R.
      • Hyer J.M.
      • Merath K.
      • et al.
      Trends in the incidence, treatment and outcomes of patients with intrahepatic cholangiocarcinoma in the USA: facility type is associated with margin status, use of lymphadenectomy and overall survival.
      ; furthermore, non-curative chemotherapy for patients with CCA is associated with increased overall survival when delivered in referral centres.
      • Sutton T.L.
      • Walker B.S.
      • Nabavizadeh N.
      • Grossberg A.
      • Thomas C.R.
      • Lopez C.D.
      • et al.
      Geographic disparities in referral rates and oncologic outcomes of intrahepatic cholangiocarcinoma: a population-based study.
      There is large intra- and inter-country variation in access to specialist cancer services, which is influenced by public policies and national health systems.
      • Prager G.W.
      • Braga S.
      • Bystricky B.
      • Qvortrup C.
      • Criscitiello C.
      • Esin E.
      • et al.
      Global cancer control: responding to the growing burden, rising costs and inequalities in access.
      This inequality in access may partly account for the variation in CCA mortality rates observed between countries, and focused studies at the local and national levels are needed to examine the magnitude of this effect.

      Conclusion

      iCCA-related mortality has increased consistently across Western countries over the last decade. Mortality rates for eCCA have increased more slowly. These differences may reflect the different genetic and environmental drivers of the cancer subtypes, as well as variations in disease surveillance, early diagnosis and management in different countries. Further epidemiological studies looking at regional variations within countries and more accurate coding and sub-classification of CCAs are crucial to monitor and better understand the underlying factors driving mortality trends over time.

      Abbreviations

      AAPC, average annual percentage change; ASMR, age-standardised mortality rate; CCA, cholangiocarcinoma; eCCA, extrahepatic cholangiocarcinoma; iCCA, intrahepatic cholangiocarcinoma; ICD, International Classification of Disease; ICD-O, International Classification of Diseases for Oncology; PSC, primary sclerosing cholangitis; SEER, Surveillance, Epidemiology and End Results; WHO, World Health Organisation.

      Financial support

      No financial support was given for completion of the manuscript.

      Authors’ contributions

      SK and MV conceived the article structure, drafted the manuscript and reviewed and approved the final version of the manuscript.

      Data availability statement

      All data is available upon request from the corresponding author.

      Conflict of interest

      The authors have no conflicts of interests or disclosures.
      Please refer to the accompanying ICMJE disclosure forms for further details.

      Acknowledgments

      We are grateful for support from the UK National Institutes for Health Research (NIHR) Biomedical Facilities at Imperial College London .

      Supplementary data

      The following are the supplementary data to this article:

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