Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

Gallbladder cancer

A Publisher Correction to this article was published on 18 November 2022

This article has been updated

Abstract

Gallbladder cancer (GBC) is the most common cancer of the biliary tract, characterized by a very poor prognosis when diagnosed at advanced stages owing to its aggressive behaviour and limited therapeutic options. Early detection at a curable stage remains challenging because patients rarely exhibit symptoms; indeed, most GBCs are discovered incidentally following cholecystectomy for symptomatic gallbladder stones. Long-standing chronic inflammation is an important driver of GBC, regardless of the lithiasic or non-lithiasic origin. Advances in omics technologies have provided a deeper understanding of GBC pathogenesis, uncovering mechanisms associated with inflammation-driven tumour initiation and progression. Surgical resection is the only treatment with curative intent for GBC but very few cases are suitable for resection and most adjuvant therapy has a very low response rate. Several unmet clinical needs require to be addressed to improve GBC management, including discovery and validation of reliable biomarkers for screening, therapy selection and prognosis. Standardization of preneoplastic and neoplastic lesion nomenclature, as well as surgical specimen processing and sampling, now provides reproducible and comparable research data that provide a basis for identifying and implementing early detection strategies and improving drug discovery. Advances in the understanding of next-generation sequencing, multidisciplinary care for GBC, neoadjuvant and adjuvant strategies, and novel systemic therapies including chemotherapy and immunotherapies are gradually changing the treatment paradigm and prognosis of this recalcitrant cancer.

This is a preview of subscription content, access via your institution

Access options

Buy article

Get time limited or full article access on ReadCube.

$32.00

All prices are NET prices.

Fig. 1: Gallbladder anatomy and histology.
Fig. 2: Worldwide incidence of GBC.
Fig. 3: Model of gallbladder cancer progression.
Fig. 4: Metaplasia–dysplasia–carcinoma sequence.
Fig. 5: GBC T stage.
Fig. 6: Adenoma–carcinoma sequence.
Fig. 7: Proposed algorithm for management of GBC.
Fig. 8: Extended cholecystectomy.

Change history

References

  1. Roa, I., Ibacache, G., Munoz, S. & de Aretxabala, X. Gallbladder cancer in Chile: pathologic characteristics of survival and prognostic factors: analysis of 1366 cases. Am. J. Clin. Pathol. 141, 675–682 (2014).

    Article  PubMed  Google Scholar 

  2. Kapoor, V. K. Gallbladder neck cancer and perihilar cholangiocarcinoma - siblings, cousins or look alikes? Korean J. Hepatobiliary Pancreat. Surg. 19, 86–88 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  3. Roa, J. C., Basturk, O. & Adsay, V. Dysplasia and carcinoma of the gallbladder: pathological evaluation, sampling, differential diagnosis and clinical implications. Histopathology 79, 2–19 (2021). Complete review that sets the basis for morphology nomenclature of preneoplastic and neoplastic gallbladder lesions.

    Article  PubMed  Google Scholar 

  4. Roa, J., Adsay, N. V., Arola, J., Tsu, W. & Zen, Y. in Digestive System Tumours Vol. 1 WHO Classification of Tumours (ed. WHO Classification of Tumours Editorial Board) Ch. 9, 283–288 (IARC, 2019).

  5. Sharma, A., Sharma, K. L., Gupta, A., Yadav, A. & Kumar, A. Gallbladder cancer epidemiology, pathogenesis and molecular genetics: recent update. World J. Gastroenterol. 23, 3978–3998 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  6. Espinoza, J. A. et al. The inflammatory inception of gallbladder cancer. Biochim. Biophys. Acta 1865, 245–254 (2016). This review describes the evidence linking inflammation to the generation of GBC and delineates the implications for carcinogenesis and cancer prevention.

    CAS  PubMed  PubMed Central  Google Scholar 

  7. Nepal, C. et al. Integrative molecular characterisation of gallbladder cancer reveals micro-environment-associated subtypes. J. Hepatol. 74, 1132–1144 (2021). One of the first comprehensive molecular characterizations of gallbladder cancer.

    Article  CAS  PubMed  Google Scholar 

  8. Jiao, Y. et al. Exome sequencing identifies frequent inactivating mutations in BAP1, ARID1A and PBRM1 in intrahepatic cholangiocarcinomas. Nat. Genet. 45, 1470–1473 (2013). First article including GBC information and as a separate entity from cholangiocarcinoma.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Javle, M., Zhao, H. & Abou-Alfa, G. K. Systemic therapy for gallbladder cancer. Chin. Clin. Oncol. 8, 15 (2019).

    Article  Google Scholar 

  10. Javle, M. M. et al. Pertuzumab + trastuzumab for HER2-positive metastatic biliary cancer: preliminary data from MyPathway. J. Clin. Oncol. 35, 402–402 (2017).

    Article  Google Scholar 

  11. Sung, H. et al. Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J. Clin. 71, 209–249 (2021).

    Article  PubMed  Google Scholar 

  12. Huang, J. et al. Worldwide distribution, associated factors, and trends of gallbladder cancer: a global country-level analysis. Cancer Lett. 521, 238–251 (2021). This paper describes worldwide gallbladder cancer incidence and mortality, and ecological associations with risk factors.

    Article  CAS  PubMed  Google Scholar 

  13. Miranda-Filho, A. et al. Gallbladder and extrahepatic bile duct cancers in the Americas: incidence and mortality patterns and trends. Int. J. Cancer 147, 978–989 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Van Dyke, A. L. et al. Biliary tract cancer incidence and trends in the United States by demographic group, 1999–2013. Cancer 125, 1489–1498 (2019).

    Article  PubMed  Google Scholar 

  15. Malhotra, R. K., Manoharan, N., Shukla, N. K. & Rath, G. K. Gallbladder cancer incidence in Delhi urban: A 25-year trend analysis. Indian. J. Cancer 54, 673–677 (2017).

    Article  PubMed  Google Scholar 

  16. Dutta, U., Bush, N., Kalsi, D., Popli, P. & Kapoor, V. K. Epidemiology of gallbladder cancer in India. Chin. Clin. Oncol. 8, 33 (2019).

    Article  PubMed  Google Scholar 

  17. Koshiol, J., Ferreccio, C., Devesa, S. S., Roa, J. C. & Fraumeni, J. F. Jr. in Cancer Epidemiology and Prevention (eds Thun, M. J. et al.) Ch. 34, 661–670 (Oxford Univ. Press, 2017).

  18. Henley, S. J., Weir, H. K., Jim, M. A., Watson, M. & Richardson, L. C. Gallbladder cancer incidence and mortality, United States 1999–2011. Cancer Epidemiol. Biomark. Prev. 24, 1319–1326 (2015).

    Article  Google Scholar 

  19. Lemrow, S. M. et al. Gallbladder cancer incidence among American Indians and Alaska Natives, US, 1999-2004. Cancer 113, 1266–1273 (2008).

    Article  PubMed  Google Scholar 

  20. Randi, G., Franceschi, S. & La Vecchia, C. Gallbladder cancer worldwide: geographical distribution and risk factors. Int. J. Cancer 118, 1591–1602 (2006).

    Article  CAS  PubMed  Google Scholar 

  21. Mhatre, S. S. et al. Place of birth and risk of gallbladder cancer in India. Indian. J. Cancer 53, 304–308 (2016).

    Article  CAS  PubMed  Google Scholar 

  22. Hundal, R. & Shaffer, E. A. Gallbladder cancer: epidemiology and outcome. Clin. Epidemiol. 6, 99–109 (2014). This paper describes the prevalence of gallstones relative to the prevalence of GBC.

    PubMed  PubMed Central  Google Scholar 

  23. Lazcano-Ponce, E. C. et al. Epidemiology and molecular pathology of gallbladder cancer. CA Cancer J. Clin. 51, 349–364 (2001).

    Article  CAS  PubMed  Google Scholar 

  24. Shaffer, E. A. Epidemiology and risk factors for gallstone disease: has the paradigm changed in the 21st century? Curr. Gastroenterol. Rep. 7, 132–140 (2005).

    Article  PubMed  Google Scholar 

  25. Hsing, A. W. et al. Gallstones and the risk of biliary tract cancer: a population-based study in China. Br. J. Cancer 97, 1577–1582 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Shrikhande, S. V., Barreto, S. G., Singh, S., Udwadia, T. E. & Agarwal, A. K. Cholelithiasis in gallbladder cancer: coincidence, cofactor, or cause. Eur. J. Surgical Oncol. 36, 514–519 (2010).

    Article  CAS  Google Scholar 

  27. Mhatre, S. et al. Mustard oil consumption, cooking method, diet and gallbladder cancer risk in high- and low-risk regions of India. Int. J. Cancer 147, 1621–1628 (2020).

    Article  CAS  PubMed  Google Scholar 

  28. Tamrakar, D., Paudel, I., Adhikary, S., Rauniyar, B. & Pokharel, P. Risk factors for gallbladder cancer in nepal a case control study. Asian Pac. J. Cancer Prev. 17, 3447–3453 (2016).

    CAS  PubMed  Google Scholar 

  29. Barahona Ponce, C. et al. Gallstones, body mass index, C-reactive protein, and gallbladder cancer: Mendelian randomization analysis of Chilean and European genotype data. Hepatology 73, 1783–1796 (2021).

    Article  CAS  PubMed  Google Scholar 

  30. Mhatre, S. et al. The role of gallstones in gallbladder cancer in India: a Mendelian randomization study. Cancer Epidemiol. Biomark. Prev. 30, 396–403 (2021).

    Article  Google Scholar 

  31. Wang, J. et al. RNA sequencing revealed signals of evolution from gallbladder stone to gallbladder carcinoma. Front. Oncol. 10, 823 (2020).

    Article  PubMed  PubMed Central  Google Scholar 

  32. Grimaldi, C. H. et al. Increased mortality with gallstone disease: results of a 20-year population-based survey in Pima Indians. Ann. Intern. Med. 118, 185–190 (1993).

    Article  CAS  PubMed  Google Scholar 

  33. Maringhini, A. et al. Gallstones, gallbladder cancer, and other gastrointestinal malignancies. An epidemiologic study in Rochester, Minnesota. Ann. Intern. Med. 107, 30–35 (1987).

    Article  CAS  PubMed  Google Scholar 

  34. Boekstegers, F. et al. ABCB1/4 gallbladder cancer risk variants identified in India also show strong effects in Chileans. Cancer Epidemiol. 65, 101643 (2020).

    Article  PubMed  Google Scholar 

  35. Gudbjartsson, D. F. et al. Large-scale whole-genome sequencing of the Icelandic population. Nat. Genet. 47, 435–444 (2015).

    Article  CAS  PubMed  Google Scholar 

  36. Mhatre, S. et al. Common genetic variation and risk of gallbladder cancer in India: a case-control genome-wide association study. Lancet Oncol. 18, 535–544 (2017).

    Article  PubMed  Google Scholar 

  37. IARC Working Group on the Evaluation of Carcinogenic Risks to Humans. in A Review of Human Carcinogens. Part F: Chemical Agents and Related Occupations Vol. 100F 225–244 (IARC, 2012).

  38. Koshiol, J. et al. Association of aflatoxin and gallbladder cancer. Gastroenterology 153, 488–494.e481 (2017).

    Article  CAS  PubMed  Google Scholar 

  39. Nogueira, L. et al. Association of aflatoxin with gallbladder cancer in Chile. JAMA 313, 2075–2077 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  40. Singh, P., Callicott, K. A., Orbach, M. J. & Cotty, P. J. Molecular analysis of S-morphology aflatoxin producers from the United States reveals previously unknown diversity and two new taxa. Front. Microbiol. 11, 1236 (2020).

    Article  PubMed  PubMed Central  Google Scholar 

  41. Groopman, J. D. et al. Aflatoxin exposure during the first 1000 days of life in rural South Asia assessed by aflatoxin B(1)-lysine albumin biomarkers. Food Chem. Toxicol. 74, 184–189 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Diaz de Leon-Martinez, L. et al. Evaluation of acute and chronic exposure to aflatoxin B1 in indigenous women of the Huasteca Potosina, Mexico. Env. Sci. Pollut. Res. Int. 27, 30583–30591 (2020).

    Article  CAS  Google Scholar 

  43. Leroy, J. L., Wang, J. S. & Jones, K. Serum aflatoxin B(1)-lysine adduct level in adult women from Eastern Province in Kenya depends on household socio-economic status: a cross sectional study. Soc. Sci. Med. 146, 104–110 (2015).

    Article  PubMed  Google Scholar 

  44. Boyd, M. L. & Cotty, P. J. Aspergillus flavus and aflatoxin contamination of leguminous trees of the Sonoran Desert in Arizona. Phytopathology 91, 913–919 (2001).

    Article  CAS  PubMed  Google Scholar 

  45. Hemminki, K., Forsti, A., Hemminki, O., Liska, V. & Hemminki, A. Long-term incidence and survival trends in cancer of the gallbladder and extrahepatic bile ducts in Denmark, Finland, Norway and Sweden with etiological implications related to Thorotrast. Int. J. Cancer 151, 200–208 (2022).

    Article  CAS  PubMed  Google Scholar 

  46. Iyer, P. et al. Non-typhoidal Salmonella DNA traces in gallbladder cancer. Infect. Agent. Cancer 11, 12 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  47. Kapoor, V. K. in A Pictorial Treatise on Gall Bladder Cancer (ed. Kapoor, V. K.) 35–55 (Springer, 2021).

  48. Di Ciaula, A. et al. The role of diet in the pathogenesis of cholesterol gallstones. Curr. Med Chem. 26, 3620–3638 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  49. Rebholz, C., Krawczyk, M. & Lammert, F. Genetics of gallstone disease. Eur. J. Clin. Invest. 48, e12935 (2018).

    Article  PubMed  Google Scholar 

  50. Lammert, F. et al. Gallstones. Nat. Rev. Dis. Primers 2, 16024 (2016).

    Article  PubMed  Google Scholar 

  51. Doherty, G. et al. The need for standardizing diagnosis, treatment and clinical care of cholecystitis and biliary colic in gallbladder disease. Medicina 58, 388 (2022).

    Article  PubMed  PubMed Central  Google Scholar 

  52. Kanoh, K. et al. Significance of contracted cholecystitis lesions as high risk for gallbladder carcinogenesis. Cancer Lett. 169, 7–14 (2001).

    Article  CAS  PubMed  Google Scholar 

  53. Carotti, S. et al. Effect of ursodeoxycholic acid on inflammatory infiltrate in gallbladder muscle of cholesterol gallstone patients. Neurogastroenterol. Motil. 22, 866–873 (2010).

    Article  CAS  PubMed  Google Scholar 

  54. Mukhopadhyay, S. & Landas, S. K. Putative precursors of gallbladder dysplasia: a review of 400 routinely resected specimens. Arch. Pathol. Lab. Med. 129, 386–390 (2005).

    Article  PubMed  Google Scholar 

  55. Seretis, C. et al. Metaplastic changes in chronic cholecystitis: implications for early diagnosis and surgical intervention to prevent the gallbladder metaplasia-dysplasia-carcinoma sequence. J. Clin. Med. Res. 6, 26–29 (2014).

    PubMed  Google Scholar 

  56. Rege, R. V. & Prystowsky, J. B. Inflammation and a thickened mucus layer in mice with cholesterol gallstones. J. Surg. Res. 74, 81–85 (1998).

    Article  CAS  PubMed  Google Scholar 

  57. van Erpecum, K. J. et al. Gallbladder histopathology during murine gallstone formation: relation to motility and concentrating function. J. Lipid Res. 47, 32–41 (2006).

    Article  PubMed  Google Scholar 

  58. Rosa, L. et al. Evaluation of the chemopreventive potentials of ezetimibe and aspirin in a novel mouse model of gallbladder preneoplasia. Mol. Oncol. 14, 2834–2852 (2020). This work describes a new mouse model that recapitulates the metaplasia–dysplasia sequence observed in humans and demonstrates that a lithogenic high-cholesterol diet induces the development of cholecystolithiasis, chronic inflammation and preneoplastic lesions.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Barreto, S. G., Dutt, A. & Chaudhary, A. A genetic model for gallbladder carcinogenesis and its dissemination. Ann. Oncol. 25, 1086–1097 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Pandey, A. et al. Integrated genomic analysis reveals mutated ELF3 as a potential gallbladder cancer vaccine candidate. Nat. Commun. 11, 4225 (2020). This paper reports a comprehensive analysis of GBCs from three geographically different regions and identifies ELF3 as a potential gallbladder cancer vaccine candidate.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Ohnishi, S. et al. DNA damage in inflammation-related carcinogenesis and cancer stem cells. Oxid. Med. Cell Longev. 2013, 387014 (2013).

    Article  PubMed  PubMed Central  Google Scholar 

  62. Neganova, M., Liu, J., Aleksandrova, Y., Klochkov, S. & Fan, R. Therapeutic influence on important targets associated with chronic inflammation and oxidative stress in cancer treatment. Cancers 13, 6062 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Moreno, M., Pimentel, F., Gazdar, A. F., Wistuba, I. I. & Miquel, J. F. TP53 abnormalities are frequent and early events in the sequential pathogenesis of gallbladder carcinoma. Ann. Hepatol. 4, 192–199 (2005).

    Article  CAS  PubMed  Google Scholar 

  64. Iyer, P. et al. ERBB2 and KRAS alterations mediate response to EGFR inhibitors in early stage gallbladder cancer. Int. J. Cancer 144, 2008–2019 (2019).

    Article  CAS  PubMed  Google Scholar 

  65. Ajani, J. A. et al. Gastric adenocarcinoma. Nat. Rev. Dis. Primers 3, 17036 (2017).

    Article  PubMed  Google Scholar 

  66. Ong, C. K. et al. Exome sequencing of liver fluke-associated cholangiocarcinoma. Nat. Genet. 44, 690–693 (2012).

    Article  CAS  PubMed  Google Scholar 

  67. Chan-On, W. et al. Exome sequencing identifies distinct mutational patterns in liver fluke-related and non-infection-related bile duct cancers. Nat. Genet. 45, 1474–1478 (2013).

    Article  CAS  PubMed  Google Scholar 

  68. Shah, S. C. & Itzkowitz, S. H. Colorectal cancer in inflammatory bowel disease: mechanisms and management. Gastroenterology 162, 715–730.e3 (2022).

    Article  PubMed  Google Scholar 

  69. Abdel-Wahab, R. et al. Genomic profiling reveals high frequency of DNA repair genetic aberrations in gallbladder cancer. Sci. Rep. 10, 22087 (2020). This is the first and the most comprehensive study to date evaluating the frequency of DNA repair genetic aberrations in GBC, hopefully incentivizing clinical trials for this patient subgroup.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Alhmoud, J. F., Woolley, J. F., Al Moustafa, A. E. & Malki, M. I. DNA damage/repair management in cancers. Cancers 12, 1050 (2020).

    Article  CAS  PubMed Central  Google Scholar 

  71. Jain, K. et al. Sequential occurrence of preneoplastic lesions and accumulation of loss of heterozygosity in patients with gallbladder stones suggest causal association with gallbladder cancer. Ann. Surg. 260, 1073–1080 (2014).

    Article  PubMed  Google Scholar 

  72. Wistuba, I. I. et al. Fragile histidine triad gene abnormalities in the pathogenesis of gallbladder carcinoma. Am. J. Pathol. 160, 2073–2079 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. Priya, T. P., Kapoor, V. K., Krishnani, N., Agrawal, V. & Agarwal, S. Fragile histidine triad (FHIT) gene and its association with p53 protein expression in the progression of gall bladder cancer. Cancer Invest. 27, 764–773 (2009).

    Article  CAS  PubMed  Google Scholar 

  74. Priya, T. P., Kapoor, V. K., Krishnani, N., Agrawal, V. & Agrawal, S. Role of E-cadherin gene in gall bladder cancer and its precursor lesions. Virchows Arch. 456, 507–514 (2010).

    Article  CAS  PubMed  Google Scholar 

  75. House, M. G. et al. Progression of gene hypermethylation in gallstone disease leading to gallbladder cancer. Ann. Surg. Oncol. 10, 882–889 (2003).

    Article  PubMed  Google Scholar 

  76. Takahashi, T. et al. Aberrant promoter hypermethylation of multiple genes in gallbladder carcinoma and chronic cholecystitis. Clin. Cancer Res. 10, 6126–6133 (2004).

    Article  CAS  PubMed  Google Scholar 

  77. Garcia, P. et al. Promoter methylation profile in preneoplastic and neoplastic gallbladder lesions. Mol. Carcinog. 48, 79–89 (2009).

    Article  CAS  PubMed  Google Scholar 

  78. Bragelmann, J. et al. Epigenome-wide analysis of methylation changes in the sequence of gallstone disease, dysplasia, and gallbladder cancer. Hepatology 73, 2293–2310 (2021).

    Article  CAS  PubMed  Google Scholar 

  79. Das, D., Karthik, N. & Taneja, R. Crosstalk between inflammatory signaling and methylation in cancer. Front. Cell Dev. Biol. 9, 756458 (2021).

    Article  PubMed  PubMed Central  Google Scholar 

  80. Zhao, H. et al. Inflammation and tumor progression: signaling pathways and targeted intervention. Signal Transduct. Target. Ther. 6, 263 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  81. Landskron, G., De la Fuente, M., Thuwajit, P., Thuwajit, C. & Hermoso, M. A. Chronic inflammation and cytokines in the tumor microenvironment. J. Immunol. Res. 2014, 149185 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  82. Basturk, O., Aishima, S. & Esposito, I. in Digestive System Tumours Vol. 1 WHO Classification of Tumours (ed. WHO Classification of Tumours Editorial Board) 276–278 (IARC, 2019).

  83. Fukumura, Y. et al. Precursor lesions of gallbladder carcinoma: disease concept, pathology, and genetics. Diagnostics 12, 341 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  84. Muraki, T. et al. Reflux-associated cholecystopathy: analysis of 76 gallbladders from patients with supra-oddi union of the pancreatic duct and common bile duct (pancreatobiliary maljunction) elucidates a specific diagnostic pattern of mucosal hyperplasia as a prelude to carcinoma. Am. J. Surg. Pathol. 41, 1167–1177 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  85. Muraki, T. et al. Pancreatobiliary maljunction-associated gallbladder cancer is as common in the West, shows distinct clinicopathologic characteristics and offers an invaluable model for anatomy-induced reflux-associated physio-chemical carcinogenesis. Ann. Surg. 276, e32–e39 (2022).

    Article  PubMed  Google Scholar 

  86. Fukuzawa, H. et al. Mechanism of pancreatic juice reflux in pancreaticobiliary maljunction: a fluid dynamics model experiment. J. Hepatobiliary Pancreat. Sci. 27, 265–272 (2020).

    Article  PubMed  Google Scholar 

  87. Kamisawa, T. et al. Biliary carcinogenesis in pancreaticobiliary maljunction. J. Gastroenterol. 52, 158–163 (2017).

    Article  CAS  PubMed  Google Scholar 

  88. Otani, K. et al. Immunohistochemical detection of 8-hydroxy-2′-deoxyguanosine in gallbladder epithelium of patients with pancreaticobiliary maljunction. Eur. J. Gastroenterol. Hepatol. 13, 1363–1369 (2001).

    Article  CAS  PubMed  Google Scholar 

  89. Kuraishi, Y. et al. Impact of DNA double-strand breaks on pancreaticobiliary maljunction carcinogenesis. Diagn. Pathol. 16, 72 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  90. Kawakami, S. et al. Stepwise correlation of TP53 mutations from pancreaticobiliary maljunction to gallbladder carcinoma: a retrospective study. BMC Cancer 21, 1245 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  91. Akita, M. et al. Intracholecystic papillary neoplasms are distinct from papillary gallbladder cancers: a clinicopathologic and exome-sequencing study. Am. J. Surg. Pathol. 43, 783–791 (2019).

    Article  PubMed  Google Scholar 

  92. Javle, M. et al. Molecular characterization of gallbladder cancer using somatic mutation profiling. Hum. Pathol. 45, 701–708 (2014). The first comprehensive descriptive molecular genetic cohort of GBC using exome sequencing.

    Article  CAS  PubMed  Google Scholar 

  93. Li, M. et al. Genomic ERBB2/ERBB3 mutations promote PD-L1-mediated immune escape in gallbladder cancer: a whole-exome sequencing analysis. Gut 68, 1024–1033 (2019).

    Article  CAS  PubMed  Google Scholar 

  94. Yang, P. et al. Somatic genetic aberrations in gallbladder cancer: comparison between Chinese and US patients. Hepatobiliary Surg. Nutr. 8, 604–614 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  95. Li, M. et al. Whole-exome and targeted gene sequencing of gallbladder carcinoma identifies recurrent mutations in the ErbB pathway. Nat. Genet. 46, 872–876 (2014).

    Article  CAS  PubMed  Google Scholar 

  96. Ebata, N. et al. Molecular classification and tumor microenvironment characterization of gallbladder cancer by comprehensive genomic and transcriptomic analysis. Cancers 13, 733 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  97. Alexandrov, L. B. et al. The repertoire of mutational signatures in human cancer. Nature 578, 94–101 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  98. Nakamura, H. et al. Genomic spectra of biliary tract cancer. Nat. Genet. 47, 1003–1010 (2015).

    Article  CAS  PubMed  Google Scholar 

  99. Roa, J. C. et al. Microsatellite instability in preneoplastic and neoplastic lesions of the gallbladder. J. Gastroenterol. 40, 79–86 (2005).

    Article  CAS  PubMed  Google Scholar 

  100. Goeppert, B. et al. Low frequency of mismatch repair deficiency in gallbladder cancer. Diagn. Pathol. 14, 36 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  101. Weinberg, B. A. et al. Molecular profiling of biliary cancers reveals distinct molecular alterations and potential therapeutic targets. J. Gastrointest. Oncol. 10, 652–662 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  102. Javle, M. M. et al. Precision medicine for gallbladder cancer using somatic copy number amplifications (SCNA) and DNA repair pathway gene alterations. J. Clin. Oncol. 35, 4076–4076 (2017).

    Article  Google Scholar 

  103. Roa, I. et al. Overexpression of the HER2/neu gene: a new therapeutic possibility for patients with advanced gallbladder cancer. Gastrointest. Cancer Res. 7, 42–48 (2014). The first description of HER2 as a potential target for therapy in GBC.

    PubMed  PubMed Central  Google Scholar 

  104. Zhang, Y. et al. Single-cell RNA-sequencing atlas reveals an MDK-dependent immunosuppressive environment in ErbB pathway-mutated gallbladder cancer. J. Hepatol. 75, 1128–1141 (2021).

    Article  CAS  PubMed  Google Scholar 

  105. Dixit, R., Pandey, M., Tripathi, S. K., Dwivedi, A. N. & Shukla, V. K. Comparative analysis of mutational profile of sonic hedgehog gene in gallbladder cancer. Dig. Dis. Sci. 62, 708–714 (2017).

    Article  CAS  PubMed  Google Scholar 

  106. Xie, F. et al. Aberrant activation of Sonic hedgehog signaling in chronic cholecystitis and gallbladder carcinoma. Hum. Pathol. 45, 513–521 (2014).

    Article  CAS  PubMed  Google Scholar 

  107. Bizama, C. et al. Targeting specific molecular pathways holds promise for advanced gallbladder cancer therapy. Cancer Treat. Rev. 41, 222–234 (2015).

    Article  CAS  PubMed  Google Scholar 

  108. Mishra, S. et al. Genomic profiling of gallbladder carcinoma: targetable mutations and pathways involved. Pathol. Res. Pract. 232, 153806 (2022).

    Article  CAS  PubMed  Google Scholar 

  109. Aggarwal, V., Montoya, C. A., Donnenberg, V. S. & Sant, S. Interplay between tumor microenvironment and partial EMT as the driver of tumor progression. iScience 24, 102113 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  110. Deshmukh, A. P. et al. Identification of EMT signaling cross-talk and gene regulatory networks by single-cell RNA sequencing. Proc. Natl Acad. Sci. USA 118, e2102050118 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  111. Romeo, E., Caserta, C. A., Rumio, C. & Marcucci, F. The vicious cross-talk between tumor cells with an EMT phenotype and cells of the immune system. Cells 8, 460 (2019).

    Article  CAS  PubMed Central  Google Scholar 

  112. Chen, P. et al. Diversity and intratumoral heterogeneity in human gallbladder cancer progression revealed by single-cell RNA sequencing. Clin. Transl Med. 11, e462 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  113. Bagci, P. et al. Cellular phenotypes in gallbladder dysplasia: diagnostic significance and clinical associations in an analysis of 318 cases [abstract 1663]. Lab. Invest. 93 (Suppl. 1), 398A (2013).

    Google Scholar 

  114. Dursun, N. et al. Metaplasia in the gallbladder: an analysis of clinicopathologic associations in 1218 cholecystectomies [abstract 618]. Mod. Pathol. 24 (Suppl. 1), 147A (2011).

    Google Scholar 

  115. Memis, B. et al. Frequency of dysplasia/carcinoma and foveolar atypia associated with gallbladder cancer risk: Comparative analysis in mapped/totally sampled gallbladders from high-risk versus low-risk regions [abstract]. Lab. Invest. 32 (Suppl. 2), 1699 (2019).

    Google Scholar 

  116. de Aretxabala, X. et al. Gallbladder cancer: an analysis of a series of 139 patients with invasion restricted to the subserosal layer. J. Gastrointest. Surg. 10, 186–192 (2006).

    Article  PubMed  Google Scholar 

  117. Adsay, V. et al. Epithelial atypia in the gallbladder: diagnosis and classification in an international consensus study [abstract 1738]. Lab. Invest. 96 (Suppl. 1), 438A–439A (2016).

    Google Scholar 

  118. Vieth, M., Riddell, R. H. & Montgomery, E. A. High-grade dysplasia versus carcinoma: east is east and west is west, but does it need to be that way? Am. J. Surg. Pathol. 38, 1453–1456 (2014).

    Article  PubMed  Google Scholar 

  119. Adsay, V. et al. Intracholecystic papillary-tubular neoplasms (ICPN) of the gallbladder (neoplastic polyps, adenomas, and papillary neoplasms that are >/=1.0 cm): clinicopathologic and immunohistochemical analysis of 123 cases. Am. J. Surg. Pathol. 36, 1279–1301 (2012).

    Article  PubMed  Google Scholar 

  120. Nakanuma, Y. et al. Characterization of high-grade biliary intraepithelial neoplasm of the gallbladder in comparison with intracholecystic papillary neoplasm. Hum. Pathol. 116, 22–30 (2021).

    Article  PubMed  Google Scholar 

  121. Kang, J. S. et al. A comparison of outcomes in patients with intracholecystic papillary neoplasms or conventional adenocarcinomas of the gallbladder. HPB 23, 746–752 (2021).

    Article  PubMed  Google Scholar 

  122. Mochidome, N. et al. Prognostic implications of the coexisting precursor lesion types in invasive gallbladder cancer. Hum. Pathol. 114, 44–53 (2021).

    Article  PubMed  Google Scholar 

  123. Shindoh, J. et al. Tumor location is a strong predictor of tumor progression and survival in T2 gallbladder cancer: an international multicenter study. Ann. Surg. 261, 733 (2015). This article shows the importance of tumour location and patient management for GBC survival.

    Article  PubMed  Google Scholar 

  124. Roa, J. C. et al. Early gallbladder carcinoma has a favorable outcome but Rokitansky-Aschoff sinus involvement is an adverse prognostic factor. Virchows Arch. 463, 651–661 (2013).

    Article  PubMed  Google Scholar 

  125. Memis, B. et al. Not all T2 gallbladder carcinomas (GBC) are equal: proposal for sub-staging of T2 GBC with significant prognostic value [abstract]. Mod. Pathol. 29 (Suppl. 2), 438–451 (2016).

    Google Scholar 

  126. DeSimone, M. S. et al. T2 gallbladder cancer shows substantial survival variation between continents and this is not due to histopathologic criteria or pathologic sampling differences. Virchows Arch. 478, 875–884 (2021).

    Article  CAS  PubMed  Google Scholar 

  127. Kapoor, V. K. et al. Anticipatory extended cholecystectomy: the ‘Lucknow’ approach for thick walled gall bladder with low suspicion of cancer. Chin. Clin. Oncol. 5, 8 (2016).

    PubMed  Google Scholar 

  128. Hamdani, N. & Kapoor, V. K. in Dilemmas in Abdominal Surgery: A Case-Based Approach (eds da Piedade Barreto, S.G.A & Shrikhande, S.V.) Ch. 28 (CRC Press, 2020).

  129. Hawkins, W. G. et al. Jaundice predicts advanced disease and early mortality in patients with gallbladder cancer. Ann. Surg. Oncol. 11, 310–315 (2004).

    Article  PubMed  Google Scholar 

  130. Mishra, P. K. et al. Predictors of curative resection and long term survival of gallbladder cancer-a retrospective analysis. Am. J. Surg. 214, 278–286 (2017).

    Article  PubMed  Google Scholar 

  131. Tran, T. B. et al. Gallbladder cancer presenting with jaundice: uniformly fatal or still potentially curable? J. Gastrointest. Surg. 21, 1245–1253 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  132. Corvera, C. U. et al. 18F-fluorodeoxyglucose positron emission tomography influences management decisions in patients with biliary cancer. J. Am. Coll. Surg. 206, 57–65 (2008).

    Article  PubMed  Google Scholar 

  133. Povoski, S. P., Ouellette, J. R., Chang, W. W. & Jarnagin, W. R. Axillary lymph node metastasis following resection of abdominal wall laparoscopic port site recurrence of gallbladder cancer. J. Hepatobiliary Pancreat. Surg. 11, 197–202 (2004).

    Article  PubMed  Google Scholar 

  134. Goel, S. et al. 18-FDG PET-CT should be included in preoperative staging of gall bladder cancer. Eur. J. Surgical Oncol. 46, 1711–1716 (2020).

    Article  Google Scholar 

  135. Behari, A. & Kapoor, V. K. Incidental gall bladder cancer. Adv. Surg. 47, 227–249 (2013).

    Article  PubMed  Google Scholar 

  136. Duffy, A. et al. Gallbladder cancer (GBC): 10-year experience at Memorial Sloan-Kettering Cancer Centre (MSKCC). J. Surg. Oncol. 98, 485–489 (2008).

    Article  CAS  PubMed  Google Scholar 

  137. Gamboa, A. C. & Maithel, S. K. The landmark series: gallbladder cancer. Ann. Surg. Oncol. 27, 2846–2858 (2020).

    Article  PubMed  Google Scholar 

  138. Goel, S. et al. Multimodality management of gallbladder cancer can lead to a better outcome: experience from a tertiary care oncology centre in North India. World J. Gastroenterol. 27, 7813–7830 (2021).

    Article  PubMed  PubMed Central  Google Scholar 

  139. Butte, J. M. et al. The role of laparoscopic staging in patients with incidental gallbladder cancer. HPB 13, 463–472 (2011).

    Article  PubMed  PubMed Central  Google Scholar 

  140. Ethun, C. G. et al. Pathologic and prognostic implications of incidental versus nonincidental gallbladder cancer: a 10-institution study from the United States Extrahepatic Biliary Malignancy Consortium. Am. Surg. 83, 679–686 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  141. Zaidi, M. Y. et al. Evaluation and management of incidental gallbladder cancer. Chin. Clin. Oncol. 8, 37 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  142. Qadan, M. & Kingham, T. P. Technical aspects of gallbladder cancer surgery. Surg. Clin. North Am. 96, 229–245 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  143. Agarwal, A. K., Kalayarasan, R., Javed, A., Gupta, N. & Nag, H. H. The role of staging laparoscopy in primary gall bladder cancer-an analysis of 409 patients: a prospective study to evaluate the role of staging laparoscopy in the management of gallbladder cancer. Ann. Surg. 258, 318–323 (2013).

    Article  PubMed  Google Scholar 

  144. Kang, J. S. et al. Limits of serum carcinoembryonic antigen and carbohydrate antigen 19-9 as the diagnosis of gallbladder cancer. Ann. Surg. Treat. Res. 101, 266–273 (2021).

    Article  PubMed  PubMed Central  Google Scholar 

  145. Chapman, R. et al. Diagnosis and management of primary sclerosing cholangitis. Hepatology 51, 660–678 (2010).

    Article  CAS  PubMed  Google Scholar 

  146. European Association for the Study of the Liver. EASL Clinical Practice Guidelines: management of cholestatic liver diseases. J. Hepatol. 51, 237–267 (2009).

    Article  Google Scholar 

  147. Lindor, K. D., Kowdley, K. V. & Harrison, M. E., American College of Gastroenterology. ACG Clinical Guideline: Primary Sclerosing Cholangitis. Am. J. Gastroenterol. 110, 646–659 (2015).

    Article  CAS  PubMed  Google Scholar 

  148. Bodmer, M., Brauchli, Y. B., Krahenbuhl, S., Jick, S. S. & Meier, C. R. Statin use and risk of gallstone disease followed by cholecystectomy. JAMA 302, 2001–2007 (2009).

    Article  CAS  PubMed  Google Scholar 

  149. Erichsen, R., Froslev, T., Lash, T. L., Pedersen, L. & Sorensen, H. T. Long-term statin use and the risk of gallstone disease: a population-based case-control study. Am. J. Epidemiol. 173, 162–170 (2011).

    Article  PubMed  Google Scholar 

  150. Tsai, C. J., Leitzmann, M. F., Willett, W. C. & Giovannucci, E. L. Statin use and the risk of cholecystectomy in women. Gastroenterology 136, 1593–1600 (2009).

    Article  CAS  PubMed  Google Scholar 

  151. Liu, Z. et al. Statin use and reduced risk of biliary tract cancers in the UK Clinical Practice Research Datalink. Gut 68, 1458–1464 (2019).

    Article  CAS  PubMed  Google Scholar 

  152. Marcano-Bonilla, L. et al. Aspirin, statins, non-aspirin NSAIDs, metformin and the risk of biliary cancer: a Swedish population-based cohort study. Cancer Epidemiol. Biomark. Prev. 31, 804–810 (2022).

    Article  CAS  Google Scholar 

  153. Health Ministries & Chilean Government. Clinical Guide: Preventive Cholecystectomy in Adults between the Age of 35 and 49 (2010).

  154. Behari, A. & Kapoor, V. K. Asymptomatic gallstones (AsGS) - To treat or not to? Indian J. Surg. 74, 4–12 (2012).

    Article  PubMed  Google Scholar 

  155. Nervi, F. et al. Gallbladder disease is associated with insulin resistance in a high risk Hispanic population. J. Hepatol. 45, 299–305 (2006).

    Article  CAS  PubMed  Google Scholar 

  156. Nogueira, L. et al. Gallstones, cholecystectomy, and risk of digestive system cancers. Am. J. Epidemiol. 179, 731–739 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  157. Ruhl, C. E. & Everhart, J. E. Relationship of non-alcoholic fatty liver disease with cholecystectomy in the US population. Am. J. Gastroenterol. 108, 952–958 (2013).

    Article  PubMed  Google Scholar 

  158. Jackson, S. S. et al. Aspirin use and survival from biliary tract cancer. JAMA Oncol. 5, 1802–1804 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  159. Liao, S. F. et al. Postdiagnosis aspirin use associated with decreased biliary tract cancer-specific mortality in a large nationwide cohort. Hepatology 74, 1994–2006 (2021).

    Article  CAS  PubMed  Google Scholar 

  160. Miyakawa, S. et al. Biliary tract cancer treatment: 5,584 results from the Biliary Tract Cancer Statistics Registry from 1998 to 2004 in Japan. J. Hepatobiliary Pancreat. Surg. 16, 1–7 (2009).

    Article  PubMed  Google Scholar 

  161. Sahara, K. et al. Defining and predicting early recurrence after resection for gallbladder cancer. Ann. Surg. Oncol. 28, 417–425 (2021).

    Article  PubMed  Google Scholar 

  162. Kapoor, V. K. Surgical procedures for gall bladder cancer. Surg. Update 2014, 127 (2014).

    Google Scholar 

  163. Shukla, H. S. et al. Indian Council of Medical Research consensus document for the management of gall bladder cancer. Indian J. Med. Paediatr. Oncol. 36, 79–84 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  164. Kapoor, V. K. Is gall bladder cancer a bad cancer per se? World J. Gastrointest. Surg. 7, 107–109 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  165. Ozer, M. et al. A propensity score analysis of chemotherapy use in patients with resectable gallbladder cancer. JAMA Netw. Open 5, e2146912 (2022).

    Article  PubMed  PubMed Central  Google Scholar 

  166. Benson, A. B. et al. Hepatobiliary cancers, version 2.2021, NCCN clinical practice guidelines in oncology. J. Natl Compr. Cancer Netw. 19, 541–565 (2021).

    Article  Google Scholar 

  167. Khan, T. M. et al. Perioperative versus adjuvant chemotherapy in the management of incidentally found gallbladder cancer (OPT-IN). Ann. Surg. Oncol. 29, 37–38 (2022).

    Article  PubMed  Google Scholar 

  168. Pawlik, T. M. et al. Incidence of finding residual disease for incidental gallbladder carcinoma: implications for re-resection. J. Gastrointest. Surg. 11, 1478–1486 (2007).

    Article  PubMed  Google Scholar 

  169. Aloia, T. A. et al. Gallbladder cancer: expert consensus statement. HPB 17, 681–690 (2015). A consolidated report of morphological and surgical issues important in GBC management.

    Article  PubMed  PubMed Central  Google Scholar 

  170. Agarwal, A. K., Kalayarasan, R., Javed, A. & Sakhuja, P. Role of routine 16b1 lymph node biopsy in the management of gallbladder cancer: an analysis. HPB 16, 229–234 (2014).

    Article  PubMed  Google Scholar 

  171. Nagino, M. et al. Clinical practice guidelines for the management of biliary tract cancers 2019: The 3rd English edition. J. Hepatobiliary Pancreat. Sci. 28, 26–54 (2021).

    Article  PubMed  Google Scholar 

  172. Lee, S. E. et al. Practical guidelines for the surgical treatment of gallbladder cancer. J. Korean Med. Sci. 29, 1333–1340 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  173. Kalayarasan, R. et al. A prospective analysis of the preoperative assessment of duodenal involvement in gallbladder cancer. HPB 15, 203–209 (2013).

    Article  PubMed  PubMed Central  Google Scholar 

  174. Ethun, C. G. et al. Routine port-site excision in incidentally discovered gallbladder cancer is not associated with improved survival: a multi-institution analysis from the US Extrahepatic Biliary Malignancy Consortium. J. Surg. Oncol. 115, 805–811 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  175. Maker, A. V. et al. Is port site resection necessary in the surgical management of gallbladder cancer? Ann. Surg. Oncol. 19, 409–417 (2012).

    Article  PubMed  Google Scholar 

  176. Han, H. S. et al. Laparoscopic surgery for gallbladder cancer: an expert consensus statement. Dig. Surg. 36, 1–6 (2019).

    Article  CAS  PubMed  Google Scholar 

  177. Goel, M., Kurunkar, S. R., Kanetkar, A. & Patkar, S. Outcome of robot-assisted radical cholecystectomy in a high-volume tertiary cancer center in India. J. Laparoendosc. Adv. Surg. Tech. B Videoscop. 29, vor.208.0539 (2019).

    Google Scholar 

  178. Agarwal, A. K., Javed, A., Kalayarasan, R. & Sakhuja, P. Minimally invasive versus the conventional open surgical approach of a radical cholecystectomy for gallbladder cancer: a retrospective comparative study. HPB 17, 536–541 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  179. Kapoor, V. K. Jaundice in gall bladder cancer–the yellow signal. Clin. Med. Rev. Oncol. 5, 1–3 (2015).

    Article  Google Scholar 

  180. Goel, M. et al. Towards standardization of management of gallbladder carcinoma with obstructive jaundice: analysis of 113 cases over 10 years at a single institution. J. Surg. Oncol. 124, 572–580 (2021).

    Article  PubMed  Google Scholar 

  181. Valle, J. W. et al. Biliary cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann. Oncol. 27, v28–v37 (2016).

    Article  CAS  PubMed  Google Scholar 

  182. Schwartz, L. H. et al. Gallbladder carcinoma: findings at MR imaging with MR cholangiopancreatography. J. Comput. Assist. Tomogr. 26, 405–410 (2002).

    Article  PubMed  Google Scholar 

  183. Lee, H. et al. Optimal extent of surgery for early gallbladder cancer with regard to long-term survival: a meta-analysis. J. Hepatobiliary Pancreat. Sci. 25, 131–141 (2018).

    Article  PubMed  Google Scholar 

  184. Burasakarn, P., Thienhiran, A., Hongjinda, S. & Fuengfoo, P. The optimal extent of surgery in T2 gallbladder cancer and the need for hepatectomy: a meta-analysis. Asian J. Surg. 45, 33–38 (2022).

    Article  PubMed  Google Scholar 

  185. American Cancer Society. Key Statistics of Gallbladder Cancer. American Cancer Society https://www.cancer.org/cancer/gallbladder-cancer/about/key-statistics.html (2022).

  186. Zhang, W., Huang, Z., Wang, W. E. & Che, X. Survival benefits of simple versus extended cholecystectomy and lymphadenectomy for patients with T2 gallbladder cancer: a propensity-matched population-based study (2010 to 2015). Front. Oncol. 11, 705299 (2021).

    Article  PubMed  PubMed Central  Google Scholar 

  187. Horgan, A. M., Amir, E., Walter, T. & Knox, J. J. Adjuvant therapy in the treatment of biliary tract cancer: a systematic review and meta-analysis. J. Clin. Oncol. 30, 1934–1940 (2012).

    Article  PubMed  Google Scholar 

  188. Saluja, S. S., Nekarakanti, P. K., Mishra, P. K., Srivastava, A. & Singh, K. Prospective randomized controlled trial comparing adjuvant chemotherapy vs. no chemotherapy for patients with carcinoma of gallbladder undergoing curative resection. J. Gastrointest. Surg. 26, 398–407 (2022).

    Article  PubMed  Google Scholar 

  189. Takada, T. et al. Is postoperative adjuvant chemotherapy useful for gallbladder carcinoma? A phase III multicenter prospective randomized controlled trial in patients with resected pancreaticobiliary carcinoma. Cancer 95, 1685–1695 (2002).

    Article  PubMed  Google Scholar 

  190. Edeline, J. et al. Gemcitabine and oxaliplatin chemotherapy or surveillance in resected biliary tract cancer (PRODIGE 12-ACCORD 18-UNICANCER GI): a randomized phase III study. J. Clin. Oncol. 37, 658–667 (2019).

    Article  CAS  PubMed  Google Scholar 

  191. Primrose, J. N. et al. Capecitabine compared with observation in resected biliary tract cancer (BILCAP): a randomised, controlled, multicentre, phase 3 study. Lancet Oncol. 20, 663–673 (2019).

    Article  CAS  PubMed  Google Scholar 

  192. Stein, A. et al. Adjuvant chemotherapy with gemcitabine and cisplatin compared to observation after curative intent resection of cholangiocarcinoma and muscle invasive gallbladder carcinoma (ACTICCA-1 trial)-a randomized, multidisciplinary, multinational phase III trial. BMC Cancer 15, 564 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  193. Ben-Josef, E. et al. SWOG S0809: a phase II Intergroup trial of adjuvant capecitabine and gemcitabine followed by radiotherapy and concurrent capecitabine in extrahepatic cholangiocarcinoma and gallbladder carcinoma. J. Clin. Oncol. 33, 2617–2622 (2015).

    Article  CAS  PubMed  Google Scholar 

  194. Shroff, R. T. et al. Adjuvant therapy for resected biliary tract cancer: ASCO clinical practice guideline. J. Clin. Oncol. 37, 1015–1027 (2019).

    Article  PubMed  Google Scholar 

  195. Valle, J. et al. Cisplatin plus gemcitabine versus gemcitabine for biliary tract cancer. N. Engl. J. Med. 362, 1273–1281 (2010).

    Article  CAS  PubMed  Google Scholar 

  196. Sharma, A. et al. Best supportive care compared with chemotherapy for unresectable gall bladder cancer: a randomized controlled study. J. Clin. Oncol. 28, 4581–4586 (2010).

    Article  CAS  PubMed  Google Scholar 

  197. Sharma, A. et al. Modified gemcitabine and oxaliplatin or gemcitabine + cisplatin in unresectable gallbladder cancer: results of a phase III randomised controlled trial. Eur. J. Cancer 123, 162–170 (2019).

    Article  CAS  PubMed  Google Scholar 

  198. Azizi, A. A., Lamarca, A., McNamara, M. G. & Valle, J. W. Chemotherapy for advanced gallbladder cancer (GBC): a systematic review and meta-analysis. Crit. Rev. Oncol. Hematol. 163, 103328 (2021).

    Article  PubMed  Google Scholar 

  199. Sahai, V. et al. Nab-paclitaxel and gemcitabine as first-line treatment of advanced or metastatic cholangiocarcinoma: a phase 2 clinical trial. JAMA Oncol. 4, 1707–1712 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  200. Shroff, R. T. et al. Gemcitabine, Cisplatin, and nab-Paclitaxel for the treatment of advanced biliary tract cancers: a phase 2 clinical trial. JAMA Oncol. 5, 824–830 (2019). Important clinical trial showing the effect of conventional chemotherapy in patients with GBC.

    Article  PubMed  PubMed Central  Google Scholar 

  201. US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT03768414 (2021).

  202. Oh, D.-Y. et al. Durvalumab plus gemcitabine and cisplatin in advanced biliary tract cancer. NEJM Evid. 1, EVIDoa2200015 (2022).

    Article  Google Scholar 

  203. Lamarca, A. et al. Second-line FOLFOX chemotherapy versus active symptom control for advanced biliary tract cancer (ABC-06): a phase 3, open-label, randomised, controlled trial. Lancet Oncol. 22, 690–701 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  204. Ying, J. & Chen, J. Combination versus mono-therapy as salvage treatment for advanced biliary tract cancer: A comprehensive meta-analysis of published data. Crit. Rev. Oncol. Hematol. 139, 134–142 (2019).

    Article  PubMed  Google Scholar 

  205. Javle, M. et al. Pertuzumab and trastuzumab for HER2-positive, metastatic biliary tract cancer (MyPathway): a multicentre, open-label, phase 2a, multiple basket study. Lancet Oncol. 22, 1290–1300 (2021). This article shows the importance of HER2-targeted treatment in advanced GBC.

    Article  CAS  PubMed  Google Scholar 

  206. Meric-Bernstam, F. et al. Zanidatamab (ZW25) in HER2-positive biliary tract cancers (BTCs): results from a phase I study. J. Clin. Oncol. 39, 299–299 (2021).

    Article  Google Scholar 

  207. US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT04466891 (2022).

  208. Ngo-Huang, A. et al. Home-based exercise prehabilitation during preoperative treatment for pancreatic cancer is associated with improvement in physical function and quality of life. Integr. Cancer Ther. 18, 1534735419894061 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  209. Butte, J. M. et al. Residual disease predicts outcomes after definitive resection for incidental gallbladder cancer. J. Am. Coll. Surg. 219, 416–429 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  210. US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT04559139 (2022).

  211. Sirohi, B. et al. Neoadjuvant chemotherapy in patients with locally advanced gallbladder cancer. Future Oncol. 11, 1501–1509 (2015).

    Article  CAS  PubMed  Google Scholar 

  212. Chaudhari, V. A. et al. Outcome of neoadjuvant chemotherapy in “locally advanced/borderline resectable” gallbladder cancer: the need to define indications. HPB 20, 841–847 (2018).

    Article  PubMed  Google Scholar 

  213. Howell, D. et al. Patient-reported outcomes in routine cancer clinical practice: a scoping review of use, impact on health outcomes, and implementation factors. Ann. Oncol. 26, 1846–1858 (2015).

    Article  CAS  PubMed  Google Scholar 

  214. Cella, D. et al. Validity of the FACT Hepatobiliary (FACT-Hep) questionnaire for assessing disease-related symptoms and health-related quality of life in patients with metastatic pancreatic cancer. Qual. Life Res. 22, 1105–1112 (2013).

    Article  PubMed  Google Scholar 

  215. Friend, E. et al. Development of a questionnaire (EORTC module) to measure quality of life in patients with cholangiocarcinoma and gallbladder cancer, the EORTC QLQ-BIL21. Br. J. Cancer 104, 587–592 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  216. Kaupp-Roberts, S. D. et al. Validation of the EORTC QLQ-BIL21 questionnaire for measuring quality of life in patients with cholangiocarcinoma and cancer of the gallbladder. Br. J. Cancer 115, 1032–1038 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  217. Montazeri, A. Quality of life data as prognostic indicators of survival in cancer patients: an overview of the literature from 1982 to 2008. Health Qual. Life Outcomes 7, 102 (2009).

    Article  PubMed  PubMed Central  Google Scholar 

  218. Yoo, C. et al. Liposomal irinotecan plus fluorouracil and leucovorin versus fluorouracil and leucovorin for metastatic biliary tract cancer after progression on gemcitabine plus cisplatin (NIFTY): a multicentre, open-label, randomised, phase 2b study. Lancet Oncol. 22, 1560–1572 (2021).

    Article  CAS  PubMed  Google Scholar 

  219. Zhu, A. X. et al. Final overall survival efficacy results of ivosidenib for patients with advanced cholangiocarcinoma with IDH1 mutation: the phase 3 randomized clinical ClarIDHy trial. JAMA Oncol. 7, 1669–1677 (2021).

    Article  PubMed  Google Scholar 

  220. Jackson, S. S. et al. Associations between reproductive factors and biliary tract cancers in women from the Biliary Tract Cancers Pooling Project. J. Hepatol. 73, 863–872 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  221. Jackson, S. S. et al. Anthropometric risk factors for cancers of the biliary tract in the biliary tract cancers pooling project. Cancer Res. 79, 3973–3982 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  222. McGee, E. E. et al. Smoking, alcohol, and biliary tract cancer risk: a pooling project of 26 prospective studies. J. Natl Cancer Inst. 111, 1263–1278 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  223. Koshiol, J. et al. The Chile biliary longitudinal study (Chile BiLS): a gallstone cohort. Am. J. Epidemiol. 190, 196–206 (2021).

    Article  PubMed  Google Scholar 

  224. Koshiol, J. et al. Association of inflammatory and other immune markers with gallbladder cancer: results from two independent case-control studies. Cytokine 83, 217–225 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  225. Koshiol, J. et al. Circulating inflammatory proteins and gallbladder cancer: potential for risk stratification to improve prioritization for cholecystectomy in high-risk regions. Cancer Epidemiol. 54, 25–30 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  226. Liu, Z. et al. Circulating levels of inflammatory proteins and survival in patients with gallbladder cancer. Sci. Rep. 8, 5671 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  227. Liu, Z. et al. Association of circulating inflammation proteins and gallstone disease. J. Gastroenterol. Hepatol. 33, 1920–1924 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  228. Hofmann, J. N. et al. Intra-individual variability over time in serum cytokine levels among participants in the prostate, lung, colorectal, and ovarian cancer screening trial. Cytokine 56, 145–148 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  229. Koshiol, J. et al. Distribution of dysplasia and cancer in the gallbladder: an analysis from a high cancer-risk population. Hum. Pathol. 82, 87–94 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  230. Memis, B. et al. Prognosis of T2 gallbladder carcinomas: an analysis of 326 cases highlights a prognosis better than the current impression in the west, but incomparably worse than what is reported in Asia [abstract]. Mod. Pathol. 29 (Suppl. 2), 438–451 (2016).

    Google Scholar 

  231. Akkas, G. et al. Pathologic diagnosis as the reason for wide discrepancies in the literature regarding the incidence and behavior of T1 gallbladder cancer (GBC): an analysis of 473 GBC and comparison with literature [abstract]. Lab. Invest. 95 (Suppl. 1), 438A–439A (2015).

    Google Scholar 

  232. Ebata, T. et al. Review of hepatopancreatoduodenectomy for biliary cancer: an extended radical approach of Japanese origin. J. Hepatobiliary Pancreat. Sci. 21, 550–555 (2014).

    Article  PubMed  Google Scholar 

  233. Kang, S., El-Rayes, B. F. & Akce, M. Evolving role of immunotherapy in advanced biliary tract cancers. Cancers 14, 1748 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  234. Morizane, C. et al. Combination gemcitabine plus S-1 versus gemcitabine plus cisplatin for advanced/recurrent biliary tract cancer: the FUGA-BT (JCOG1113) randomized phase III clinical trial. Ann. Oncol. 30, 1950–1958 (2019).

    Article  CAS  PubMed  Google Scholar 

  235. Lee, J. et al. Gemcitabine and oxaliplatin with or without erlotinib in advanced biliary-tract cancer: a multicentre, open-label, randomised, phase 3 study. Lancet Oncol. 13, 181–188 (2012).

    Article  CAS  PubMed  Google Scholar 

  236. Zheng, Y. et al. A randomised phase II study of second-line XELIRI regimen versus irinotecan monotherapy in advanced biliary tract cancer patients progressed on gemcitabine and cisplatin. Br. J. Cancer 119, 291–295 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  237. Demols, A. et al. Regorafenib after failure of gemcitabine and platinum-based chemotherapy for locally advanced/metastatic biliary tumors: REACHIN, a randomized, double-blind, phase II trial. Ann. Oncol. 31, 1169–1177 (2020).

    Article  CAS  PubMed  Google Scholar 

  238. Javle, M. M. et al. Varlitinib plus capecitabine in second-line advanced biliary tract cancer: a randomized, phase II study (TreeTopp). ESMO Open 7, 100314 (2022).

    Article  CAS  PubMed  Google Scholar 

  239. Harding, J. J. et al. Targeting HER2 (ERBB2) mutation-positive advanced biliary tract cancers with neratinib: results from the phase II SUMMIT ‘basket’ trial. J. Clin. Oncol. 39, 320–320 (2021).

    Article  Google Scholar 

  240. Malka, D. et al. Gemcitabine and oxaliplatin with or without cetuximab in advanced biliary-tract cancer (BINGO): a randomised, open-label, non-comparative phase 2 trial. Lancet Oncol. 15, 819–828 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  241. Lee, S. et al. Phase II study of ramucirumab in advanced biliary tract cancer previously treated by gemcitabine-based chemotherapy. Clin. Cancer Res. 28, 2229–2236 (2022).

    Article  CAS  PubMed  Google Scholar 

  242. Valle, J. W. et al. Cediranib or placebo in combination with cisplatin and gemcitabine chemotherapy for patients with advanced biliary tract cancer (ABC-03): a randomised phase 2 trial. Lancet Oncol. 16, 967–978 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  243. Bang, Y.-J. et al. Pembrolizumab (pembro) for advanced biliary adenocarcinoma: Results from the KEYNOTE-028 (KN028) and KEYNOTE-158 (KN158) basket studies. J. Clin. Oncol. 37, 4079–4079 (2019).

    Article  Google Scholar 

  244. Kim, R. D. et al. A phase 2 multi-institutional study of nivolumab for patients with advanced refractory biliary tract cancer. JAMA Oncol. 6, 888–894 (2020).

    Article  PubMed  Google Scholar 

  245. Kelley, R. K. et al. Pembrolizumab (PEM) plus granulocyte macrophage colony stimulating factor (GM-CSF) in advanced biliary cancers (ABC): final outcomes of a phase 2 trial. J. Clin. Oncol. 40, 444–444 (2022).

    Article  Google Scholar 

  246. Klein, O. et al. Evaluation of combination nivolumab and ipilimumab immunotherapy in patients with advanced biliary tract cancers: subgroup analysis of a phase 2 nonrandomized clinical trial. JAMA Oncol. 6, 1405–1409 (2020).

    Article  PubMed  PubMed Central  Google Scholar 

  247. Ueno, M. et al. Nivolumab alone or in combination with cisplatin plus gemcitabine in Japanese patients with unresectable or recurrent biliary tract cancer: a non-randomised, multicentre, open-label, phase 1 study. Lancet Gastroenterol. Hepatol. 4, 611–621 (2019).

    Article  PubMed  Google Scholar 

  248. Ioka, T. et al. Evaluation of safety and tolerability of durvalumab (D) with or without tremelimumab (T) in patients (pts) with biliary tract cancer (BTC). J. Clin. Oncol. 37, 387–387 (2019).

    Article  Google Scholar 

  249. International Agency for Research on Cancer. Estimated age-standardized incidence rates (World) in 2020, gallbladder, both sexes, all ages. WHO https://gco.iarc.fr/today/online-analysis-map?v=2020&mode=population&mode_population=continents&population=900&populations=900&key=asr&sex=0&cancer=12&type=0&statistic=5&prevalence=0&population_group=0&ages_group%5B%5D=0&ages_group%5B%5D=17&nb_items=10&group_cancer=1&include_nmsc=0&include_nmsc_other=0&projection=natural-earth&color_palette=default&map_scale=quantile&map_nb_colors=5&continent=0&show_ranking=0&rotate=%255B10%252C0%255D (2020).

Download references

Acknowledgements

The authors thank D. Check for creating the bar chart figure of gallbladder disease prevalence and gallbladder cancer incidence. The work of J.K. is supported by general funds from the Intramural Research Program of the NIH, National Cancer Institute, Division of Cancer Epidemiology and Genetics. The work of J.C.R. and P.G. is supported by the European Union’s Horizon 2020 Research and Innovation programme under grant agreement No. 825510 (ESCALON), and from Agencia Nacional de Investigación y Desarrollo (ANID) Fondecyt 1221345 and Millennium Science Initiative Program: Millennium Institute on Immunology and Immunotherapy (ICN09_016/ICN 2021_045; former P09/016-F).

Author information

Authors and Affiliations

Authors

Contributions

Introduction (J.C.R. and P.G.); Epidemiology (J.K.); Mechanisms/pathophysiology (J.C.R. and P.G.); Diagnosis, screening and prevention (J.C.R., V.K.K., S.K.M., J.K. and M.J.); Management (V.K.K., S.K.M. and M.J.); Quality of life (M.J.); Outlook (J.K., J.C.R., M.J., V.K.K., S.K.M. and P.G.); Overview of Primer (J.C.R.).

Corresponding author

Correspondence to Juan C. Roa.

Ethics declarations

Competing interests

M.J. receives research funding (to Institution) from Merck, EMD Serono, Novartis, Eli Lilly, AstraZeneca, Genentech, Transthera, Meclun, BMS, Incyte, QED, Taiho, Servier, Oncosil, Basilea, Nucana; and to self or as advisory board/Data and Safety Monitoring Board member from Incyte, Zymeworks, Mundi Pharma, Nucana, MORE health and Origimed. Peer grant funding is provided from Department of Defense and NIH. S.K.M. receives research funding (to Institution) from BMS, QED/HELSINN, Natera. The other authors (J.C.R., P.G., J.K. and V.K.K.) declare no competing interests.

Peer review

Peer review information

Nature Reviews Disease Primers thanks S. V. Shrikhande, I. Endo, V. K. Shukla, M. Goel and M. McNamara for their contribution to the peer review of this work.

Additional information

Publisher’s note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary information

Glossary

Muscularis mucosa

Thin muscle layer that separates mucosa from submucosa in most segments of the digestive tract with the exception of the gallbladder.

Histogenic sequence

Sequence of histopathological entities that progress from preneoplastic to invasive neoplastic gallbladder lesion.

Lithiasic

Related to the formation of stony concretions (calculi) in the body, most often in the gallbladder or urinary system.

Non-lithiasic

Not associated with stones.

Pancreatobiliary maljunction

A congenital anomaly in which the pancreatic and common bile ducts join together outside the duodenal wall.

Mendelian randomization analysis

A method that uses germline genetic variation associated with the exposure but not the outcome to mimic randomization.

Aflatoxin B1

Considered the most potent carcinogen of the aflatoxins, a family of toxins that are products of fungal infection of agricultural crops.

Polypoid gallbladder lesions

Intraluminal projecting lesions attached to the surface by a stalk.

Primary sclerosing cholangitis

Progressive fibrosing inflammatory disorder of the intrahepatic and extrahepatic bile ducts.

Cholelithiasis

Stones in the gallbladder.

Fluke-related cholangiocarcinoma

Cases of cholangiocarcinoma associated with chronic exposure to parasitic flatworms (flukes).

Loss of heterozygosity

(LOH). Allelic imbalance caused by the loss of one of the two alleles present at a particular locus in a heterozygous somatic cell.

Microsatellite instability

(MSI). Genomic alteration characterized by deletions and/or insertions in microsatellite regions of the genome; correlated with deficiency of the DNA mismatch repair system.

Tumour mutational burden

(TMB). Approximate number of gene mutations occurring in the genome of a cancer cell, expressed as the number of mutations per megabase (muts/Mb).

Hot tumour

Immunogenic tumour that shows signs of inflammation and is infiltrated by tumour-specific CD8+ T lymphocytes, making it more responsive to immunotherapy treatment using checkpoint inhibitors.

Rokitansky–Aschoff sinuses

Pseudodiverticula into the gallbladder wall present in the muscle layer or even in the perimuscular connective tissue.

Mirizzi’s syndrome

Extrinsic compression of the common hepatic or bile duct by a large stone in the neck of the gallbladder.

Xanthogranulomatous cholecystitis

Severe chronic inflammation of the gallbladder with abundant foamy cells and granuloma formation resulting in thickening of the gallbladder wall.

Gallbladder fossa

Place in the liver undersurface where the gallbladder is normally embedded with absence of liver capsule.

Radiological response rates

A score that attempts to provide objective measurements via imaging of tumour response to therapy.

Nab-paclitaxel

Nanoparticle albumin-bound paclitaxel to increase the delivery to tumour cells.

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Roa, J.C., García, P., Kapoor, V.K. et al. Gallbladder cancer. Nat Rev Dis Primers 8, 69 (2022). https://doi.org/10.1038/s41572-022-00398-y

Download citation

  • Accepted:

  • Published:

  • DOI: https://doi.org/10.1038/s41572-022-00398-y

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing