Skip to main content
SpringerLink
Log in

Molecular Pathology of Gallbladder Cancer

  • Chapter
  • First Online:
Molecular Surgical Pathology

  • 2328 Accesses

Abstract

Gallbladder cancer is relatively rare worldwide, but constitutes an important health problem in certain parts of the globe. In Chile, it is the leading cause of cancer deaths among women. The reasons for this stark geographic variation in the incidence of GBC is not well understood, but attributed to both genetic as well as environmental factors. Perhaps more so than any other organ, the association of inflammation/injury with cancer of the gallbladder is very evident: Gallstones, infections, and inflammation secondary to anomalies of the distal biliary tract are well-established causes of cancerous transformation of GB epithelium. While most GBC arise in association with flat intraepithelial neoplasia, and their precursors of metaplasia, it is being recognized increasingly that an adenoma–carcinoma sequence (invasive cancers arising from mass-forming preinvasive neoplasia) also in play in a small percentage of cases. A variety of molecular and genetic alterations have been identified in GBC in the past decade, some associated with prognosis as well. In the ensuing chapter, a detailed analysis of the current literature on the molecular/genetic carcinogenesis in the gallbladder is provided. These alterations have the potential to serve not only as diagnostic and prognostic markers, but as potential targets for the management of these tumors which often show dismal prognosis otherwise.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 169.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 219.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

References

  • Aldridge MC, Bismuth H. Gallbladder cancer: the polyp-cancer sequence. Br J Surg. 1990;77:363–4.

    Article  PubMed  CAS  Google Scholar 

  • Bertran E, Heise K, Andia M, et al. Gallbladder cancer: incidence and survival in a high-risk area of Chile. Int J Cancer. 2010;127:2446–54.

    Article  PubMed  CAS  Google Scholar 

  • Buch S, Schafmayer C, Volzke H, et al. A genome-wide association scan identifies the hepatic cholesterol transporter ABCG8 as a susceptibility factor for human gallstone disease. Nat Genet. 2007;39:995–9.

    Article  PubMed  CAS  Google Scholar 

  • Chang XZ, Yu J, Zhang XH, et al. Enhanced expression of trophinin promotes invasive and metastatic potential of human gallbladder cancer cells. J Cancer Res Clin Oncol. 2009;135:581–90.

    Article  PubMed  CAS  Google Scholar 

  • Chijiiwa K, Kimura H, Tanaka M, et al. Malignant potential of the gallbladder in patients with anomalous pancreaticobiliary ductal junction. The difference in risk between patients with and without choledochal cyst. Int Surg. 1995;80:61–4.

    PubMed  CAS  Google Scholar 

  • Dixon E, Vollmer Jr CM, Sahajpal A, et al. An aggressive surgical approach leads to improved survival in patients with gallbladder cancer: a 12-year study at a North American Center. Ann Surg. 2005;241:385–94.

    Article  PubMed  Google Scholar 

  • Dutta U, Garg PK, Kumar R, et al. Typhoid carriers among patients with gallstones are at increased risk for carcinoma of the gallbladder. Am J Gastroenterol. 2000;95:784–7.

    Article  PubMed  CAS  Google Scholar 

  • Fox JG, Dewhirst FE, Shen Z, et al. Hepatic Helicobacter species identified in bile and gallbladder tissue from Chileans with chronic cholecystitis. Gastroenterology. 1998;114:755–63.

    Article  PubMed  CAS  Google Scholar 

  • Garcia P, Manterola C, Araya JC, et al. Promoter methylation profile in preneoplastic and neoplastic gallbladder lesions. Mol Carcinog. 2009;48:79–89.

    Article  PubMed  CAS  Google Scholar 

  • Ghosh M, Kamma H, Kawamoto T, et al. MUC 1 core protein as a marker of gallbladder malignancy. Eur J Surg Oncol. 2005;31:891–6.

    Article  PubMed  CAS  Google Scholar 

  • Giatromanolaki A, Sivridis E, Simopoulos C, et al. Hypoxia inducible factors 1alpha and 2alpha are associated with VEGF expression and angiogenesis in gallbladder carcinomas. J Surg Oncol. 2006;94:242–7.

    Article  PubMed  CAS  Google Scholar 

  • Hart J, Modan B, Shani M. Cholelithiasis in the aetiology of gallbladder neoplasms. Lancet. 1971;1:1151–3.

    Article  PubMed  CAS  Google Scholar 

  • Hsing AW, Gao YT, Rashid A, et al. Gallstones and the risk of biliary tract cancer: a population-based study in China. Br J Cancer. 2007;97:1577–82.

    Article  PubMed  CAS  Google Scholar 

  • Itoi T, Watanabe H, Ajioka Y, et al. APC, K-ras codon 12 mutations and p53 gene expression in carcinoma and adenoma of the gall-bladder suggest two genetic pathways in gall-bladder carcinogenesis. Pathol Int. 1996;46:333–40.

    Article  PubMed  CAS  Google Scholar 

  • Juvonen T, Savolainen MJ, Kairaluoma MI, et al. Polymorphisms at the apoB, apoA-I, and cholesteryl ester transfer protein gene loci in patients with gallbladder disease. J Lipid Res. 1995;36:804–12.

    PubMed  CAS  Google Scholar 

  • Kashiwagi H, Kijima H, Dowaki S, et al. MUC1 and MUC2 expression in human gallbladder carcinoma: a clinicopathological study and relationship with prognosis. Oncol Rep. 2001;8:485–9.

    PubMed  CAS  Google Scholar 

  • Kaufman M, Mehrotra B, Limaye S, et al. EGFR expression in gallbladder carcinoma in North America. Int J Med Sci. 2008;5:285–91.

    Article  PubMed  CAS  Google Scholar 

  • Kawamoto T, Krishnamurthy S, Tarco E, et al. HER receptor family: novel candidate for targeted therapy for gallbladder and extrahepatic bile duct cancer. Gastrointest Cancer Res. 2007;1:221–7.

    PubMed  Google Scholar 

  • Kim JH, Kim HN, Lee KT, et al. Gene expression profiles in gallbladder cancer: the close genetic similarity seen for early and advanced gallbladder cancers may explain the poor prognosis. Tumour Biol. 2008;29:41–9.

    Article  PubMed  CAS  Google Scholar 

  • Kornprat P, Rehak P, Lemmerer M, et al. Analysis of trefoil factor family protein 1 (TFF1, pS2) expression in chronic cholecystitis and gallbladder carcinoma. Virchows Arch. 2005;446:505–10.

    Article  PubMed  CAS  Google Scholar 

  • Kozuka S, Tsubone N, Yasui A, et al. Relation of adenoma to carcinoma in the gallbladder. Cancer. 1982;50:2226–34.

    Article  PubMed  CAS  Google Scholar 

  • Lammert F, Miquel JF. Gallstone disease: from genes to evidence-based therapy. J Hepatol. 2008;48 Suppl 1:S124–35.

    Article  PubMed  CAS  Google Scholar 

  • Lazcano-Ponce EC, Miquel JF, Muñoz N, et al. Epidemiology and molecular pathology of gallbladder cancer. CA Cancer J Clin. 2001;51:349–64.

    Article  PubMed  CAS  Google Scholar 

  • Legan M, Luzar B, Marolt VF, et al. Expression of cyclooxygenase–2 is associated with p53 accumulation in premalignant and malignant gallbladder lesions. World J Gastroenterol. 2006;12:3425–9.

    PubMed  CAS  Google Scholar 

  • Li Q, Yang Z. Expression of phospho–ERK1/2 and PI3-K in benign and malignant gallbladder lesions and its clinical and pathological correlations. J Exp Clin Cancer Res. 2009;28:65.

    Article  PubMed  Google Scholar 

  • Li SH, Li CF, Sung MT, et al. Skp2 is an independent prognosticator of gallbladder carcinoma among p27(Kip1)-interacting cell cycle regulators: an immunohistochemical study of 62 cases by tissue microarray. Mod Pathol. 2007;20:497–507.

    Article  PubMed  CAS  Google Scholar 

  • Luzar B, Poljak M, Cor A, et al. Expression of human telomerase catalytic protein in gallbladder carcinogenesis. J Clin Pathol. 2005;58:820–5.

    Article  PubMed  CAS  Google Scholar 

  • Ma HB, Hu HT, Di ZL, et al. Association of cyclin D1, p16 and retinoblastoma protein expressions with prognosis and metastasis of gallbladder carcinoma. World J Gastroenterol. 2005;11:744–7.

    PubMed  Google Scholar 

  • Misra S, Chaturvedi A, Misra NC, et al. Carcinoma of the gallbladder. Lancet Oncol. 2003;4:167–76.

    Article  PubMed  Google Scholar 

  • Nakashima T, Kondoh S, Kitoh H, et al. Vascular endothelial growth factor-C expression in human gallbladder cancer and its relationship to lymph node metastasis. Int J Mol Med. 2003;11:33–9.

    PubMed  CAS  Google Scholar 

  • Nakazawa K, Dobashi Y, Suzuki S, et al. Amplification and overexpression of c-erbB-2, epidermal growth factor receptor, and c-met in biliary tract cancers. J Pathol. 2005;206:356–65.

    Article  PubMed  CAS  Google Scholar 

  • Nemeth Z, Szasz AM, Tatrai P, et al. Claudin-1, -2, -3, -4, -7, -8, and -10 protein expression in biliary tract cancers. J Histochem Cytochem. 2009;57:113–21.

    Article  PubMed  CAS  Google Scholar 

  • Nomoto M, Izumi H, Ise T, et al. Structural basis for the regulation of UDP-N-acetyl-alpha-d-galactosamine: polypeptide N-acetylgalactosaminyl transferase-3 gene expression in adenocarcinoma cells. Cancer Res. 1999;59:6214–22.

    PubMed  CAS  Google Scholar 

  • Ooi A, Suzuki S, Nakazawa K, et al. Gene amplification of Myc and its coamplification with ERBB2 and EGFR in gallbladder adenocarcinoma. Anticancer Res. 2009;29:19–26.

    PubMed  Google Scholar 

  • Pai R, Soreghan B, Szabo IL, et al. Prostaglandin E2 transactivates EGF receptor: a novel mechanism for promoting colon cancer growth and gastrointestinal hypertrophy. Nat Med. 2002;8:289–93.

    Article  PubMed  CAS  Google Scholar 

  • Paigen BC, Carey MC. Gallstones. In: King RA, editor. Rotter JI. Motulsky AG (eds): Genetic basis of common diseases. Oxford University Press; 2002. p. 298–335.

    Google Scholar 

  • Patel S, Roa JC, Tapia O, et al. Hyalinizing cholecystitis and associated carcinomas. Am J Surg Pathol. 2011;35:1104–13.

    Article  PubMed  Google Scholar 

  • Randi G, Franceschi S, La Vecchia C, et al. Gallbladder cancer worldwide: geographical distribution and risk factors. Int J Cancer. 2006;118:1591–602.

    Article  PubMed  CAS  Google Scholar 

  • Roa I, Araya JC, Shiraishi T, et al. DNA content in gallbladder carcinoma: a flow cytometric study of 96 cases. Histopathology. 1993;23:459–64.

    Article  PubMed  CAS  Google Scholar 

  • Roa I, Araya JC, Villaseca M, et al. Preneoplastic lesions and gallbladder cancer: an estimate of the period required for progression. Gastroenterology. 1996;111:232–6.

    Article  PubMed  CAS  Google Scholar 

  • Roa I, Araya JC, Villaseca M, et al. Gallbladder cancer in a high risk area: morphological features and spread patterns. Hepatogastroenterology. 1999;46:1540–6.

    PubMed  CAS  Google Scholar 

  • Roa JC, Anabalon L, Araya J, et al. Promoter methylation profile in gallbladder cancer. J Gastroenterol. 2006;41:269–75.

    Article  PubMed  CAS  Google Scholar 

  • Roa JC, Roa I, Correa P, et al. Microsatellite instability in preneoplastic and neoplastic lesions of the gallbladder. J Gastroenterol. 2005;40:79–86.

    Article  PubMed  CAS  Google Scholar 

  • Roa JC, Vo Q, Roa I, et al. Inactivation of CDKN2A gene (p16) in gallbladder carcinoma. Rev Med Chil. 2004;132:1369–76.

    PubMed  Google Scholar 

  • Roa JC, Tapia O, Cakir A, et al. Squamous cell and adenosquamous carcinomas of the gallbladder. Mod Pathol. 2011;24:1069–78.

    Article  PubMed  Google Scholar 

  • Saetta A, Lazaris AC, Davaris PS, et al. Detection of ras oncogene point mutations and simultaneous proliferative fraction estimation in gallbladder cancer. Pathol Res Pract. 1996;192:532–40.

    Article  PubMed  CAS  Google Scholar 

  • Sasatomi E, Tokunaga O, Miyazaki K, et al. Precancerous conditions of gallbladder carcinoma: overview of histopathologic characteristics and molecular genetic findings. J Hepatobiliary Pancreat Surg. 2000;7:556–67.

    Article  PubMed  CAS  Google Scholar 

  • Shi YZ, Hui AM, Li X, et al. Overexpression of retinoblastoma protein predicts decreased survival and correlates with loss of p16INK4 protein in gallbladder carcinomas. Clin Cancer Res. 2000;6:4096–100.

    PubMed  CAS  Google Scholar 

  • Shibata T, Kokubu A, Gotoh M, et al. Genetic alteration of Keap1 confers constitutive Nrf2 activation and resistance to chemotherapy in gallbladder cancer. Gastroenterology. 2008;135:1358–68.

    Article  PubMed  CAS  Google Scholar 

  • Srivastava A, Tulsyan S, Pandey SN, et al. Single nucleotide polymorphism in the ABCG8 transporter gene is associated with gallbladder cancer susceptibility. Liver Int. 2009;29:831–7.

    Article  PubMed  CAS  Google Scholar 

  • Strom BL, Soloway RD, Rios-Dalenz JL, et al. Risk factors for gallbladder cancer. An international collaborative case–control study. Cancer. 1995;76:1747–56.

    Article  PubMed  CAS  Google Scholar 

  • Takahashi T, Shivapurkar N, Riquelme E, et al. Aberrant promoter hypermethylation of multiple genes in gallbladder carcinoma and chronic cholecystitis. Clin Cancer Res. 2004;10:6126–33.

    Article  PubMed  CAS  Google Scholar 

  • Tang M, Baez S, Pruyas M, et al. Mitochondrial DNA mutation at the D310 (displacement loop) mononucleotide sequence in the pathogenesis of gallbladder carcinoma. Clin Cancer Res. 2004;10:1041–6.

    Article  PubMed  CAS  Google Scholar 

  • Tian Y, Ding RY, Zhi YH, et al. Analysis of p53 and vascular endothelial growth factor expression in human gallbladder carcinoma for the determination of tumor vascularity. World J Gastroenterol. 2006;12:415–9.

    PubMed  CAS  Google Scholar 

  • Wang JW, Peng SY, Li JT, et al. Identification of metastasis-associated proteins involved in gallbladder carcinoma metastasis by proteomic analysis and functional exploration of chloride intracellular channel 1. Cancer Lett. 2009;281:71–81.

    Article  PubMed  CAS  Google Scholar 

  • Wistuba II, Albores-Saavedra J. Genetic abnormalities involved in the pathogenesis of gallbladder carcinoma. J Hepatobiliary Pancreat Surg. 1999;6:237–44.

    Article  PubMed  CAS  Google Scholar 

  • Wistuba II, Ashfaq R, Maitra A, et al. Fragile histidine triad gene abnormalities in the pathogenesis of gallbladder carcinoma. Am J Pathol. 2002;160:2073–9.

    Article  PubMed  CAS  Google Scholar 

  • Wistuba II, Miquel JF, Gazdar AF, et al. Gallbladder adenomas have molecular abnormalities different from those present in gallbladder carcinomas. Hum Pathol. 1999;30:21–5.

    Article  PubMed  CAS  Google Scholar 

  • Wu XS, Akiyama Y, Igari T, et al. Expression of homeodomain protein CDX2 in gallbladder carcinomas. J Cancer Res Clin Oncol. 2005;131:271–8.

    Article  PubMed  CAS  Google Scholar 

  • Xu LN, Zou SQ, Wang JM, et al. Action and mechanism of Fas and Fas ligand in immune escape of gallbladder carcinoma. World J Gastroenterol. 2005;11:3719–23.

    PubMed  CAS  Google Scholar 

  • Yamagiwa H, Tomiyama H. Intestinal metaplasia-dysplasia-carcinoma sequence of the gallbladder. Acta Pathol Jpn. 1986;36:989–97.

    PubMed  CAS  Google Scholar 

  • Yamamoto S, Kitadai Y, Tsuchida A, et al. Expression of platelet-derived endothelial cell growth factor/thymidine phosphorylase in human gallbladder lesions. Eur J Cancer. 2000;36:257–63.

    Article  PubMed  CAS  Google Scholar 

  • Yokoyama N, Watanabe H, Ajioka Y, et al. Genetic alterations in gallbladder carcinoma: a review. Nippon Geka Gakkai Zasshi. 1998;99:687–95.

    PubMed  CAS  Google Scholar 

  • Yue SQ, Yang YL, Zhou JS, et al. Relationship between urokinase-type plasminogen activator receptor and vascular endothelial growth factor expression and metastasis of gallbladder cancer. World J Gastroenterol. 2004;10:2750–2.

    PubMed  CAS  Google Scholar 

  • Zhang M, Pan JW, Ren TR, et al. Correlated expression of inducible nitric oxide synthase and P53, Bax in benign and malignant diseased gallbladder. Ann Anat. 2003;185:549–54.

    Article  PubMed  CAS  Google Scholar 

  • Zong H, Yin B, Chen J, et al. Over-expression of c-FLIP confers the resistance to TRAIL-induced apoptosis on gallbladder carcinoma. Tohoku J Exp Med. 2009;217:203–8.

    Article  PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Departamento de Anatomia Patologica, Universidad de La Frontera, Temuco, Chile

    Juan Carlos Roa M.D.

  2. Department of Pathology and Laboratory Medicine, Emory University, Atlanta, GA, USA

    N. Volkan Adsay M.D.

Authors
  1. Juan Carlos Roa M.D.
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. N. Volkan Adsay M.D.
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to N. Volkan Adsay M.D. .

Editor information

Editors and Affiliations

  1. , Molecular Pathology Laboratory, Indiana University School of Medicine, 350 West 11th Street, Rm 4010, Indianapolis, 46202, Indiana, USA

    Liang Cheng

  2. Department of Pathology, and Laboratory Medicine, Indiana University School of Medicine, 635 Barnhill Drive, Room 128, Indianapolis, 46202, Indiana, USA

    John N. Eble

Rights and permissions

Reprints and permissions

Copyright information

© 2013 Springer Science+Business Media New York

About this chapter

Cite this chapter

Roa, J.C., Adsay, N.V. (2013). Molecular Pathology of Gallbladder Cancer. In: Cheng, L., Eble, J. (eds) Molecular Surgical Pathology. Springer, New York, NY. https://doi.org/10.1007/978-1-4614-4900-3_4

Download citation

  • DOI: https://doi.org/10.1007/978-1-4614-4900-3_4

  • Published:

  • Publisher Name: Springer, New York, NY

  • Print ISBN: 978-1-4614-4899-0

  • Online ISBN: 978-1-4614-4900-3

  • eBook Packages: MedicineMedicine (R0)

Publish with us

Policies and ethics

Search

Navigation