Advertisement

Carcinogenesis of the Biliary Tract in PBM

  • Yuichi Nagakawa
  • Yatsuka Sahara
  • Chie Takishita
  • Akihiko TsuchidaEmail author
Chapter

Abstract

Pancreaticobiliary maljunction (PBM) complicates biliary tract cancer at a high rate because of continuous biliary reflux of pancreatic juice. Pathological findings suggest a hyperplasia-dysplasia-carcinoma sequence in carcinogenesis of PBM. This appears to be a different mechanism from that of usual gallbladder cancer without PBM, which develops by an adenoma-carcinoma sequence or by de novo carcinogenesis. Molecular biological analysis revealed a high incidence of cellular proliferation-activating factors, such as COX-2, in the hyperplasia stage. In addition, cellular proliferative activity including Ki-67 was significantly higher in normal gallbladder mucosa without PBM. Furthermore, a high incidence of K-ras gene mutation was seen in hyperplasia (13–63%), and microsatellite instability was observed in 60% of cases with dysplasia. In cancerous lesions, a high rate of cyclin D1 and p53 overexpression and p53 gene mutation have been recognized. These results suggest that a multistep carcinogenetic process contributes to the carcinogenesis of PBM. Overexpression of COX-2 is observed in PBM. Therefore, COX-2 inhibitors, such as NSAIDs, may play an important role in preventing carcinogenesis.

Keywords

Pancreaticobiliary maljunction Congenital biliary dilatation Carcinogenesis K-ras p53 Cyclooxygenase-2 

References

  1. 1.
    Aoki T, Tsuchida A, Kasuya K, Endo M, Kitamura K, Koyanagi Y. Is preventive resection of the extrahepatic duct necessary in cases of pancreaticobiliary maljunction without dilatation of the bile duct? Jpn J Clin Oncol. 2001;31:107–11.CrossRefPubMedPubMedCentralGoogle Scholar
  2. 2.
    Reveille RM, VanStiegmann G, Everson GT. Increased secondary bile acids in choledochal cyst; possible role in biliary metaplasia and carcinoma. Gastroenterology. 1990;99:525–7.CrossRefPubMedPubMedCentralGoogle Scholar
  3. 3.
    Narita H, Hashimoto T, Suzuki T, Kamiya Y, Murata Y, Hayashi S, Tsuruga N, Yura J. Clinical and experimental studies on the activation mechanism of pancreatic enzymes refluxing into the biliary tract with an anomoalous pancreatico-biliary ductal junction (in Japanese). J Jpn Soc Pediatr Surg. 1990;26:609–15.Google Scholar
  4. 4.
    Narisawa T. Bile acids and colon cancer (in Japanese). Igaku no Ayumi. 1988;147:395–8.Google Scholar
  5. 5.
    Tokiwa K, Iwai N. Early mucosal changes of the pancreaticobiliary duct. Gastroenterology. 1996;110:1614–8.CrossRefPubMedPubMedCentralGoogle Scholar
  6. 6.
    Masuhara S, Kasuya K, Aoki T, Yoshimatsu A, Tsuchida A, Koyanagi Y. Relation between K-ras codon mutation and p53 protein overexpression in gallbladder cancer and biliary ductal epithelia in patients with pancreaticobiliary maljunction. J Hepato-Biliary-Pancreat Surg. 2000;7:198–205.CrossRefGoogle Scholar
  7. 7.
    Kamisawa T, Kuruma S, Chiba K, Tabata T, Koizumi S, Kikuyama MJ. Biliary carcinogenesis in pancreaticobiliary maljunction. Gastroenterology. 2017;52:158–63.Google Scholar
  8. 8.
    Hanada K, Itoh M, Fujii K, Tsuchida A, Hirata M, Ishimaru S, Iwao T, Eguchi N, Kajiyama G. Pathology and cellular kinetics of gallbladder with an anomalous junction of the pancreaticobiliary duct. Am J Gastroenterol. 1996;91:1007–11.PubMedGoogle Scholar
  9. 9.
    Itoi T, Itokawa F, Takei K, Kasuya K, Watanabe H, Nakamura K, Sofuni A, Tsuchida A, Aoki T. Clinicopathological aspects of carcinogenesis of pancreaticobiliary maljunction. In: Koyanagi Y, Aoki T, editors. Pancreaticobiliary maljunction. Tokyo: Igaku Tosho; 2002. p. 261–8.Google Scholar
  10. 10.
    Matsubara T, Sakurai Y, Sasayama Y, et al. K-ras point mutations in cancerous and noncancerous biliary epithelium in patients with pancreaticobiliary maljunction. Cancer. 1996;77:1752–7.CrossRefPubMedGoogle Scholar
  11. 11.
    Iwase T, Nakazawa S, Yamao K, Yoshino J, Inui K, Yamachika H, Kanemaki N, Fujimoto M, Okushima K, Miyoshi H, Taki N, Nakamura Y, Mizutani S, Horibe Y, Masui T, Tatematsu M. Ras gene point mutations in gallbladder lesions associated with anomalous connection of pancreaticobiliary ducts. Hepato-gastroenterol. 1997;44:1457–62.Google Scholar
  12. 12.
    Tomishige H, Kishikawa T, Hara F, Nishikawa O, Nishida Y, Kongo M, Li SF. Point mutations of K-ras gene in children with congenital biliary dilatation. J Jpn Soc Pediatr Surg. 1999;35:215–20.Google Scholar
  13. 13.
    Hanada K, Itoh M, Fujii K, Tsuchida A, Ooishi H, Kajiyama G. K-ras and p53 mutations in stage I gallbladder carcinoma with an anomalous junction of the pancreaticobiliary duct. Cancer. 1996;77:452–8.CrossRefPubMedGoogle Scholar
  14. 14.
    Hui AM, Li X, Shi YZ, Takayama T, Torzilli G, Makuuchi M. Cyclin D1 overexpression in a critical event in gallbladder carcinogenesis and independently predicts decreased survival for patients with gallbladder carcinoma. Clin Cancer Res. 2000;6:4272–7.PubMedGoogle Scholar
  15. 15.
    Itoi T, Shinohara Y, Takeda K, Nakamura K, Takei K, Sanada J, Horibe T, Saito T, Kasuya K, Ebihara Y. Nuclear cyclin D1 overexpression is a critical event associated with cell proliferation and invasive growth in gallbladder carcinogenesis. J Gastroenterol. 2000;35:142–9.CrossRefPubMedGoogle Scholar
  16. 16.
    Filmus J, Robles AI, Shi W, Wong MJ, Colombo LL, Conti CJ. Induction of cyclin D1 overexpression by activated ras. Oncogene. 1994;9:3627–33.PubMedGoogle Scholar
  17. 17.
    Tsuchida A, Nagakawa Y, Kasuya K, Itoi T, Endo M, Ozawa T, Aoki T, Koyanagi Y. Immunohistochemical analysis of cyclooxygenase-2 and vascular endothelial growth factor in pancreaticobiliary maljunction. Oncol Rep. 2003;10:339–42.PubMedGoogle Scholar
  18. 18.
    Tsuchida A, Itoi T. Carcinogenesis and chemoprevention of biliary tract cancer in pancreaticobiliary maljunction. World J Gastrointest Oncol. 2010;2:130–5.CrossRefPubMedPubMedCentralGoogle Scholar
  19. 19.
    Nagai M, Kawarada Y, Watanabe M, Iwase T, Muneyuki T, Yamao K, Fukutome K, Yatani R. Analysis of microsatellite instability, TGF-beta type II receptor gene mutations and hMSH2 and hMSH1 allele losses in pancreaticobiliary maljunction-associated biliary tract tumors. Anticancer Res. 1999;19:1765–8.PubMedGoogle Scholar

Copyright information

© Springer Nature Singapore Pte Ltd. 2018

Authors and Affiliations

  • Yuichi Nagakawa
    • 1
  • Yatsuka Sahara
    • 1
  • Chie Takishita
    • 1
  • Akihiko Tsuchida
    • 1
    Email author
  1. 1.Department of Gastrointestinal and Pediatric SurgeryTokyo Medical UniversityShinjuku-kuJapan

Personalised recommendations