Cancer Causes & Control

, Volume 19, Issue 1, pp 33–41 | Cite as

Risk factors of biliary tract cancer in a large-scale population-based cohort study in Japan (JPHC study); with special focus on cholelithiasis, body mass index, and their effect modification

  • Seiji Ishiguro
  • Manami Inoue
  • Norie Kurahashi
  • Motoki Iwasaki
  • Shizuka Sasazuki
  • Shoichiro Tsugane
Original Paper



We examined the association of potential risk factors with the incidence of biliary tract cancer in a large-scale population-based cohort study. Particular focus was placed on a history of cholelithiasis, body mass index (BMI), and their effect modification, and whether risk differs by cancer subsite, namely by gallbladder cancer and extrahepatic bile duct cancer.


We investigated 101,868 middle-aged and older Japanese subjects (48,681 men and 53,187 women) during 1,200,386 person-years of follow-up.


A total of 235 cases of biliary tract cancer (93 gallbladder cancer and 142 extrahepatic bile duct cancer) were newly diagnosed. Cholelithiasis was associated with an increased risk of biliary tract cancer [HR, 2.53; 95% CI, 1.56–4.12]. This association was similarly observed for both gallbladder [HR, 3.01; 95% CI, 1.56–6.19] and extrahepatic bile duct cancer [HR, 2.12; 95% CI, 1.08–4.18]. Body mass index was associated with an increased risk of extrahepatic bile duct cancer (P for trend = 0.03) and this effect was not modified by a history of cholelithiasis.


Cholelithiasis was confirmed to be associated with the risk of biliary tract cancer, both gallbladder and extrahepatic bile duct cancer. Obesity may increase the risk of extrahepatic bile duct cancer only, independent of cholelithiasis.


Cholelithiasis Body mass index Biliary tract cancer Population-based cohort study 



The authors thank all staff members in each study area for their unfailing efforts in the conduct of the baseline and follow-up surveys. We also thank the Iwate, Aomori, Ibaraki, Niigata, Osaka, Kochi, Nagasaki and Okinawa Cancer Registries for providing the incidence data. This work was supported by a Grant-in-Aid for Cancer Research and for the Third Term Comprehensive Control Research for Cancer from the Ministry of Health, Labour, and Welfare of Japan. This study was supported by a Grant-in-Aid for Cancer Research and for the Third-Term Comprehensive Control Research for Cancer from the Ministry of Health, Labour, and Welfare of Japan.


  1. 1.
    Plesko I, Somogyi J, Dimitrova E, Kiss J, Vlasak V (1985) Epidemiological features of biliary tract cancer incidence in Slovakia. Neoplasma 32:125–134PubMedGoogle Scholar
  2. 2.
    Nectoux J, Coleman MP (1993) Trends in biliary tract cancer. Rev Epidemiol Sante Publique 41:113–122PubMedGoogle Scholar
  3. 3.
    Tominaga S, Kuroishi T (1994) Biliary tract cancer. Cancer Surv 19–20:125–137PubMedGoogle Scholar
  4. 4.
    Okusaka T (2002) Chemotherapy for biliary tract cancer in Japan. Semin Oncol 29:51–53PubMedGoogle Scholar
  5. 5.
    Ueno H, Okusaka T, Ikeda M, Takezako Y, Morizane C (2004) Phase II study of S-1 in patients with advanced biliary tract cancer. Br J Cancer 91:1769–1774PubMedCrossRefGoogle Scholar
  6. 6.
  7. 7.
    Kato K, Akai S, Tominaga S, Kato I (1989) A case–control study of biliary tract cancer in Niigata Prefecture, Japan. Jpn J Cancer Res 80:932–938PubMedGoogle Scholar
  8. 8.
    Zatonski WA, Lowenfels AB, Boyle P et al (1997) Epidemiologic aspects of gallbladder cancer: a case–control study of the SEARCH Program of the International Agency for Research on Cancer. J Natl Cancer Inst 89:1132–1138PubMedCrossRefGoogle Scholar
  9. 9.
    Khan ZR, Neugut AI, Ahsan H, Chabot JA (1999) Risk factors for biliary tract cancers. Am J Gastroenterol 94:149–152PubMedCrossRefGoogle Scholar
  10. 10.
    Chow WH, McLaughlin JK, Menck HR, Mack TM (1994) Risk factors for extrahepatic bile duct cancers: Los Angeles County, California (USA). Cancer Causes Control 5:267–272PubMedCrossRefGoogle Scholar
  11. 11.
    Caroli-Bosc FX, Deveau C, Harris A et al (1999) Prevalence of cholelithiasis: results of an epidemiologic investigation in Vidauban, southeast France. General Practitioner’s Group of Vidauban. Dig Dis Sci 44:1322–1329PubMedCrossRefGoogle Scholar
  12. 12.
    Tsugane S, Sasaki S, Tsubono Y (2002) Under- and overweight impact on mortality among middle-aged Japanese men and women: a 10-y follow-up of JPHC study cohort I. Int J Obes Relat Metab Disord 26:529–537PubMedCrossRefGoogle Scholar
  13. 13.
    Inoue M, Sobue T, Tsugane S (2004) Impact of body mass index on the risk of total cancer incidence and mortality among middle-aged Japanese: data from a large-scale population-based cohort study—the JPHC study. Cancer Causes Control 15:671–680PubMedCrossRefGoogle Scholar
  14. 14.
    World Health Organization (2000) International classification of diseases for oncology, 3rd edn. WHO, GenevaGoogle Scholar
  15. 15.
    Shaib YH, El-Serag HB, Nooka AK et al (2007) Risk factors for intrahepatic and extrahepatic cholangiocarcinoma: a hospital-based case–control study. Am J Gastroenterol 102:1016–1021PubMedCrossRefGoogle Scholar
  16. 16.
    Hsing AW, Gao YT, McGlynn KA et al (2007) Biliary tract cancer and stones in relation to chronic liver conditions: a population-based study in Shanghai, China. Int J Cancer 120:1981–1985PubMedCrossRefGoogle Scholar
  17. 17.
    Welzel TM, McGlynn KA, Hsing AW, O’Brien TR, Pfeiffer RM (2006) Impact of classification of hilar cholangiocarcinomas (Klatskin tumors) on the incidence of intra- and extrahepatic cholangiocarcinoma in the United States. J Natl Cancer Inst 98:873–875PubMedCrossRefGoogle Scholar
  18. 18.
    Stata Corporation (2005) Stata statistical software VCS. Stata Corporation, TxGoogle Scholar
  19. 19.
    Strom BL, Hibberd PL, Soper KA, Stolley PD, Nelson WL (1985) International variations in epidemiology of cancers of the extrahepatic biliary tract. Cancer Res 45:5165–5168PubMedGoogle Scholar
  20. 20.
    Renard P, Boutron MC, Faivre J et al (1987) Biliary tract cancers in Cote-d’Or (France): incidence and natural history. J Epidemiol Community Health 41:344–348PubMedCrossRefGoogle Scholar
  21. 21.
    Maringhini A, Moreau JA, Melton LJ 3rd, Hench VS, Zinsmeister AR, DiMagno EP (1987) Gallstones, gallbladder cancer, and other gastrointestinal malignancies. An epidemiologic study in Rochester, Minnesota. Ann Intern Med 107:30–35PubMedGoogle Scholar
  22. 22.
    Zatonski WA, La Vecchia C, Przewozniak K, Maisonneuve P, Lowenfels AB, Boyle P (1992) Risk factors for gallbladder cancer: a Polish case–control study. Int J Cancer 51:707–711PubMedCrossRefGoogle Scholar
  23. 23.
    Chow WH, Johansen C, Gridley G, Mellemkjaer L, Olsen JH, Fraumeni JF Jr (1999) Gallstones, cholecystectomy and risk of cancers of the liver, biliary tract and pancreas. Br J Cancer 79:640–644PubMedCrossRefGoogle Scholar
  24. 24.
    Yamagiwa H (1989) Mucosal dysplasia of gallbladder: isolated and adjacent lesions to carcinoma. Jpn J Cancer Res 80:238–243PubMedGoogle Scholar
  25. 25.
    Dowling GP, Kelly JK (1986) The histogenesis of adenocarcinoma of the gallbladder. Cancer 58:1702–1708PubMedCrossRefGoogle Scholar
  26. 26.
    Duarte I, Llanos O, Domke H, Harz C, Valdivieso V (1993) Metaplasia and precursor lesions of gallbladder carcinoma. Frequency, distribution, and probability of detection in routine histologic samples. Cancer 72:1878–1884PubMedCrossRefGoogle Scholar
  27. 27.
    Ziegler U, Palme G, Merker HJ (1982) Morphological alterations in epithelial cells of the mouse gallbladder 30 hours after treatment with lithogenic diet. Pathol Res Pract 174:116–130PubMedGoogle Scholar
  28. 28.
    Skar V, Skar AG, Stromme JH (1988) Beta-glucuronidase activity related to bacterial growth in common bile duct bile in gallstone patients. Scand J Gastroenterol 23:83–90PubMedCrossRefGoogle Scholar
  29. 29.
    Abayli B, Colakoglu S, Serin M et al (2005) Helicobacter pylori in the etiology of cholesterol gallstones. J Clin Gastroenterol 39:134–137PubMedGoogle Scholar
  30. 30.
    Bulajic M, Maisonneuve P, Schneider-Brachert W et al (2002) Helicobacter pylori and the risk of benign and malignant biliary tract disease. Cancer 95:1946–1953PubMedCrossRefGoogle Scholar
  31. 31.
    Zhang XH, Andreotti G, Gao YT et al (2006) Tea drinking and the risk of biliary tract cancers and biliary stones: a population-based case–control study in Shanghai, China. Int J Cancer 118:3089–3094PubMedCrossRefGoogle Scholar
  32. 32.
    Strom BL, Soloway RD, Rios-Dalenz JL et al (1995) Risk factors for gallbladder cancer. An international collaborative case–control study. Cancer 76:1747–1756PubMedCrossRefGoogle Scholar
  33. 33.
    Serra I, Yamamoto M, Calvo A et al (2002) Association of chili pepper consumption, low socioeconomic status and longstanding gallstones with gallbladder cancer in a Chilean population. Int J Cancer 102:407–411PubMedCrossRefGoogle Scholar
  34. 34.
    Yagyu K, Lin Y, Obata Y et al (2004) Bowel movement frequency, medical history and the risk of gallbladder cancer death: a cohort study in Japan. Cancer Sci 95:674–678PubMedCrossRefGoogle Scholar
  35. 35.
    Kimura W, Shimada H, Kuroda A, Morioka Y (1989) Carcinoma of the gallbladder and extrahepatic bile duct in autopsy cases of the aged, with special reference to its relationship to gallstones. Am J Gastroenterol 84:386–390PubMedGoogle Scholar
  36. 36.
    World Health Organization (2003) WHO Technical Reports Series 916. Diet NatPoCDRoaJWFECG, Switzerland: World Health Organization (2003) WHO Technical Reports Series 916. Diet, Nutrition and the Prevention of Chronic Disease. Report of a Joint WHO/FAO Expert ConsultationGoogle Scholar
  37. 37.
    Oh SW, Yoon YS, Shin SA (2005) Effects of excess weight on cancer incidences depending on cancer sites and histologic findings among men: Korea National Health Insurance Corporation Study. J Clin Oncol 23:4742–4754PubMedCrossRefGoogle Scholar
  38. 38.
    Yang F, Huang X, Yi T, Yen Y, Moore DD, Huang W (2007) Spontaneous development of liver tumors in the absence of the bile acid receptor farnesoid X receptor. Cancer Res 67:863–867PubMedCrossRefGoogle Scholar
  39. 39.
    St George CM, Russell JC, Shaffer EA (1994) Effects of obesity on bile formation and biliary lipid secretion in the genetically obese JCR:LA-corpulent rat. Hepatology 20:1541–1547PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media B.V. 2007

Authors and Affiliations

  • Seiji Ishiguro
    • 1
    • 2
  • Manami Inoue
    • 1
  • Norie Kurahashi
    • 1
  • Motoki Iwasaki
    • 1
  • Shizuka Sasazuki
    • 1
  • Shoichiro Tsugane
    • 1
  1. 1.Epidemiology and Prevention Division, Research Center for Cancer Prevention and ScreeningNational Cancer CenterTokyoJapan
  2. 2.Division of Surgical Oncology, Department of SurgeryNagoya University Graduate School of MedicineNagoyaJapan

Personalised recommendations