Abstract
Worldwide, gallbladder cancer (GBC) is comparatively rare but highly fatal and the most common biliary tree malignancy with gender and geographical-specific predilections that associate with the incidence of cholelithiasis. Morphological feature and anatomic location of gallbladder along with asymptomatic and aggressive nature of the disease progression are ascribed to advance stage diagnosis, poor prognosis thereby compromising GBC patient’s survival rate. Only 20% of GBC patients are diagnosed early with cancer progression limited to gallbladder while rest of the patients are diagnosed with metastasis to adjacent or distant organs. Currently, the available treatment option includes surgical removal of the non-metastatic and small-sized tumor or radiation therapy and/or chemotherapy in advanced stages with various side effects accounting for global health burden. With the recent advancement in better understanding of GBC pathogenesis, several markers have been proposed and evaluated for diagnostic efficiency in GBC. However, none of the markers identified so far has been developed for routine screening examination for GBC and still, there is lack of appropriate molecular diagnostic markers for its early detection and improve prognoses. Till today the complete treatment of GBCs remains unsatisfactory and a major challenge facing a bottleneck. In this chapter, we will focus on the GBC pathogenesis, available diagnostic methods and recent development in the molecular diagnostic methods that may provide future research directions for early detection of this deadly disease.
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Sharma A, et al. Gallbladder cancer epidemiology, pathogenesis and molecular genetics: recent update. World J Gastroenterol. 2017;23(22):3978–98.
Randi G, Franceschi S, La Vecchia C. Gallbladder cancer worldwide: geographical distribution and risk factors. Int J Cancer. 2006;118(7):1591–602.
Wernberg JA, Lucarelli DD. Gallbladder cancer. Surg Clin North Am. 2014;94(2):343–60.
Kumar JR, et al. An objective assessment of demography of gallbladder cancer. J Surg Oncol. 2006;93(8):610–4.
Gabbi C, et al. Estrogen-dependent gallbladder carcinogenesis in LXRbeta−/− female mice. Proc Natl Acad Sci U S A. 2010;107(33):14763–8.
Hundal R, Shaffer EA. Gallbladder cancer: epidemiology and outcome. Clin Epidemiol. 2014;6:99–109.
Lai CH, Lau WY. Gallbladder cancer—a comprehensive review. Surgeon. 2008;6(2):101–10.
Tomita K, et al. Long-term survival of a recurrent gallbladder carcinoma patient with lymph node and peritoneal metastases after multidisciplinary treatments: a case report. Surg Case Rep. 2016;2(1):12.
Rai R, et al. A multiple interaction analysis reveals ADRB3 as a potential candidate for gallbladder cancer predisposition via a complex interaction with other candidate gene variations. Int J Mol Sci. 2015;16(12):28038–49.
Dwivedi AN, Jain S, Dixit R. Gall bladder carcinoma: aggressive malignancy with protean loco-regional and distant spread. World J Clin Cases. 2015;3(3):231–44.
Misra S, et al. Carcinoma of the gallbladder. Lancet Oncol. 2003;4(3):167–76.
Shrikhande SV, et al. Cholelithiasis in gallbladder cancer: coincidence, cofactor, or cause! Eur J Surg Oncol. 2010;36(6):514–9.
Nervi F, Duarte I, Gómez G, Rodríguez G, Del Pino G, Ferrerio O, et al. Frequency of gallbladder cancer in Chile, a high-risk area. Int J Cancer. 1988;41:657–60.
Hamdani NH, et al. Clinicopathological study of gall bladder carcinoma with special reference to gallstones: our 8-year experience from eastern India. Asian Pac J Cancer Prev. 2012;13(11):5613–7.
Lowenfels AB, et al. Gallstone growth, size, and risk of gallbladder cancer: an interracial study. Int J Epidemiol. 1989;18(1):50–4.
Roa I, et al. Gallstones and gallbladder cancer-volume and weight of gallstones are associated with gallbladder cancer: a case-control study. J Surg Oncol. 2006;93(8):624–8.
Biswas PK. Carcinoma gallbladder. Mymensingh Med J. 2010;19(3):477–81.
Espinoza JA, et al. The inflammatory inception of gallbladder cancer. Biochim Biophys Acta. 2016;1865(2):245–54.
Tazuma S, Kajiyama G. Carcinogenesis of malignant lesions of the gall bladder. The impact of chronic inflammation and gallstones. Langenbeck’s Arch Surg. 2001;386(3):224–9.
Li Y, Zhang J, Ma H. Chronic inflammation and gallbladder cancer. Cancer Lett. 2014;345(2):242–8.
Sharma V, et al. Role of bile bacteria in gallbladder carcinoma. Hepato-Gastroenterology. 2007;54(78):1622–5.
Andia ME, et al. Geographic variation of gallbladder cancer mortality and risk factors in Chile: a population-based ecologic study. Int J Cancer. 2008;123(6):1411–6.
Tewari M, Mishra RR, Shukla HS. Salmonella typhi and gallbladder cancer: report from an endemic region. Hepatobiliary Pancreat Dis Int. 2010;9(5):524–30.
Tyagi BB, Manoharan N, Raina V. Risk factors for gallbladder cancer: a population based case-control study in Delhi. Indian J Med Pediatr Oncol. 2008;29:16–26.
Shukla VK, et al. Carcinoma of the gallbladder—is it a sequel of typhoid? Dig Dis Sci. 2000;45(5):900–3.
Di Domenico EG, et al. Biofilm producing Salmonella typhi: chronic colonization and development of gallbladder cancer. Int J Mol Sci. 2017;18(9):1887.
Prieto AI, Ramos-Morales F, Casadesus J. Repair of DNA damage induced by bile salts in Salmonella enterica. Genetics. 2006;174(2):575–84.
Rai A, Mohapatra SC, Shukla HS. A review of association of dietary factors in gallbladder cancer. Indian J Cancer. 2004;41(4):147–51.
Makiuchi T, et al. The relationship between vegetable/fruit consumption and gallbladder/bile duct cancer: a population-based cohort study in Japan. Int J Cancer. 2017;140(5):1009–19.
Panda D, et al. Gall bladder cancer and the role of dietary and lifestyle factors: a case-control study in a North Indian population. Eur J Cancer Prev. 2013;22(5):431–7.
Li L, et al. Overweight, obesity and the risk of gallbladder and extrahepatic bile duct cancers: a meta-analysis of observational studies. Obesity (Silver Spring). 2016;24(8):1786–802.
Tan W, et al. Body mass index and risk of gallbladder cancer: systematic review and meta-analysis of observational studies. Nutrients. 2015;7(10):8321–34.
Wang F, Wang B, Qiao L. Association between obesity and gallbladder cancer. Front Biosci (Landmark Ed). 2012;17:2550–8.
Larsson SC, Wolk A. Obesity and the risk of gallbladder cancer: a meta-analysis. Br J Cancer. 2007;96(9):1457–61.
Liu H, et al. Body mass index can increase the risk of gallbladder cancer: a meta-analysis of 14 cohort studies. Med Sci Monit Basic Res. 2016;22:146–55.
Hsing AW, et al. Family history of gallstones and the risk of biliary tract cancer and gallstones: a population-based study in Shanghai, China. Int J Cancer. 2007;121(4):832–8.
Fernandez E, et al. Family history and the risk of liver, gallbladder, and pancreatic cancer. Cancer Epidemiol Biomark Prev. 1994;3(3):209–12.
Rai R, et al. p53: its alteration and gallbladder cancer. Eur J Cancer Prev. 2011;20(2):77–85.
Wistuba II, et al. p53 protein overexpression in gallbladder carcinoma and its precursor lesions: an immunohistochemical study. Hum Pathol. 1996;27(4):360–5.
Rashid A, et al. K-ras mutation, p53 overexpression, and microsatellite instability in biliary tract cancers: a population-based study in China. Clin Cancer Res. 2002;8(10):3156–63.
Wistuba II, et al. Allele-specific mutations involved in the pathogenesis of endemic gallbladder carcinoma in Chile. Cancer Res. 1995;55(12):2511–5.
Singh MK, et al. Mutational spectrum of K-ras oncogene among Indian patients with gallbladder cancer. J Gastroenterol Hepatol. 2004;19(8):916–21.
Saetta AA. K-ras, p53 mutations, and microsatellite instability (MSI) in gallbladder cancer. J Surg Oncol. 2006;93(8):644–9.
Roa I, et al. Preneoplastic lesions in gallbladder cancer. J Surg Oncol. 2006;93(8):615–23.
Segovia Lohse HA, Cuenca Torres OM. Prevalence and sequence of metaplasia-dysplasia-carcinoma of the gallbladder. A single centre retrospective study. Cir Esp. 2013;91(10):672–5.
Itoi T, 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(5):333–40.
Kozuka S, et al. Relation of adenoma to carcinoma in the gallbladder. Cancer. 1982;50(10):2226–34.
Wan X, et al. Clinicopathological features of gallbladder papillary adenocarcinoma. Medicine (Baltimore). 2014;93(27):e131.
Dursun N, et al. Mucinous carcinomas of the gallbladder: clinicopathologic analysis of 15 cases identified in 606 carcinomas. Arch Pathol Lab Med. 2012;136(11):1347–58.
Singh SK, et al. Mucinous carcinoma of the gall bladder—an incidental diagnosis of a rare variant. J Cancer Res Ther. 2015;11(4):1045.
Maharaj R, et al. A case report of the clear cell variant of gallbladder carcinoma. Int J Surg Case Rep. 2017;32:36–9.
Zhang C, et al. A clear cell adenocarcinoma of the gallbladder with hepatoid differentiation: case report and review of literature. Onco Targets Ther. 2016;9:5797–802.
Oohashi Y, et al. Adenosquamous carcinoma of the gallbladder warrants resection only if curative resection is feasible. Cancer. 2002;94(11):3000–5.
Rustagi T, Rai M, Menon M. Ruptured adenosquamous cell carcinoma of the gallbladder: case report and review of literature. Gastrointest Cancer Res. 2011;4(1):29–32.
Bazan F, et al. Metastatic gallbladder adenocarcinoma with signet-ring cells: a case report. J Med Case Rep. 2011;5:458.
Ahmad Z, Qureshi A. Primary signet ring cell carcinoma of gall bladder: report of an extremely rare histological type of primary gall bladder carcinoma. BMJ Case Rep. 2010;2010:bcr0420091782.
Guo KJ, Yamaguchi K, Enjoji M. Undifferentiated carcinoma of the gallbladder. A clinicopathologic, histochemical, and immunohistochemical study of 21 patients with a poor prognosis. Cancer. 1988;61(9):1872–9.
Eltawil KM, et al. Neuroendocrine tumors of the gallbladder: an evaluation and reassessment of management strategy. J Clin Gastroenterol. 2010;44(10):687–95.
Monier A, et al. Neuroendocrine tumor of the gallbladder. Pol J Radiol. 2015;80:228–31.
Mezi S, et al. Neuroendocrine tumors of the gallbladder: a case report and review of the literature. J Med Case Rep. 2011;5:334.
Carrera C, Kunk P, Rahma O. Small cell carcinoma of the gallbladder: case report and comprehensive analysis of published cases. J Oncol. 2015;2015:304909.
Adachi T, et al. Gallbladder small cell carcinoma: a case report and literature review. Surg Case Rep. 2016;2(1):71.
Lee H, Choi HJ, Park IY. Small cell carcinoma of the gallbladder: a case report. Ann Hepatobiliary Pancreat Surg. 2017;21(3):168–71.
Al-Daraji WI, et al. Primary gallbladder sarcoma: a clinicopathologic study of 15 cases, heterogeneous sarcomas with poor outcome, except pediatric botryoid rhabdomyosarcoma. Am J Surg Pathol. 2009;33(6):826–34.
Husain EA, et al. Gallbladder sarcoma: a clinicopathological study of seven cases from the UK and Austria with emphasis on morphological subtypes. Dig Dis Sci. 2009;54(2):395–400.
Miller G, Jarnagin WR. Gallbladder carcinoma. Eur J Surg Oncol. 2008;34(3):306–12.
Gourgiotis S, et al. Gallbladder cancer. Am J Surg. 2008;196(2):252–64.
Yang XW, et al. The prognostic importance of jaundice in surgical resection with curative intent for gallbladder cancer. BMC Cancer. 2014;14:652.
Feng FL, et al. Role of radical resection in patients with gallbladder carcinoma and jaundice. Chin Med J. 2012;125(5):752–6.
Wang YF, et al. Combined detection tumor markers for diagnosis and prognosis of gallbladder cancer. World J Gastroenterol. 2014;20(14):4085–92.
Rana S, et al. Evaluation of CA 242 as a tumor marker in gallbladder cancer. J Gastrointest Cancer. 2012;43(2):267–71.
Chaube A, et al. CA 125: a potential tumor marker for gallbladder cancer. J Surg Oncol. 2006;93(8):665–9.
Xu XS, et al. Model based on alkaline phosphatase and gamma-glutamyltransferase for gallbladder cancer prognosis. Asian Pac J Cancer Prev. 2015;16(15):6255–9.
Ong SL, et al. Ten-year experience in the management of gallbladder cancer from a single hepatobiliary and pancreatic centre with review of the literature. HPB (Oxford). 2008;10(6):446–58.
Singh TD, et al. Quantitative assessment of expression of lactate dehydrogenase and its isoforms 3 and 4 may serve as useful indicators of progression of gallbladder cancer: a pilot study. Indian J Clin Biochem. 2011;26(2):146–53.
Singh TD, et al. The liver function test enzymes and glucose level are positively correlated in gallbladder cancer: a cancer registry data analysis from north central India. Indian J Cancer. 2012;49(1):125–36.
Oikarinen H. Diagnostic imaging of carcinomas of the gallbladder and the bile ducts. Acta Radiol. 2006;47(4):345–58.
Recio-Boiles A, Babiker HM. Cancer, gallbladder. Treasure Island: StatPearls; 2018.
Inui K, Yoshino J, Miyoshi H. Diagnosis of gallbladder tumors. Intern Med. 2011;50(11):1133–6.
Kim HJ, et al. Diagnostic role of endoscopic ultrasonography-guided fine needle aspiration of gallbladder lesions. Hepato-Gastroenterology. 2012;59(118):1691–5.
Kumaran V, et al. The role of dual-phase helical CT in assessing resectability of carcinoma of the gallbladder. Eur Radiol. 2002;12(8):1993–9.
Tan CH, Lim KS. MRI of gallbladder cancer. Diagn Interv Radiol. 2013;19(4):312–9.
Andren-Sandberg A. Diagnosis and management of gallbladder cancer. N Am J Med Sci. 2012;4(7):293–9.
Vijayakumar A, et al. Early diagnosis of gallbladder carcinoma: an algorithm approach. ISRN Radiol. 2013;2013:239424.
Kapoor A, Kapoor A, Mahajan G. Differentiating malignant from benign thickening of the gallbladder wall by the use of acoustic radiation force impulse elastography. J Ultrasound Med. 2011;30(11):1499–507.
Kumar R, et al. Role of 18F-FDG PET/CT in detecting recurrent gallbladder carcinoma. Clin Nucl Med. 2012;37(5):431–5.
Ramos-Font C, et al. Ability of FDG-PET/CT in the detection of gallbladder cancer. J Surg Oncol. 2014;109(3):218–24.
Hennedige TP, Neo WT, Venkatesh SK. Imaging of malignancies of the biliary tract–an update. Cancer Imaging. 2014;14:14.
De Moura DTH, et al. Endoscopic retrograde cholangiopancreatography versus endoscopic ultrasound for tissue diagnosis of malignant biliary stricture: systematic review and meta-analysis. Endosc Ultrasound. 2018;7(1):10–9.
Wang SN, et al. Aberrant p53 expression and the development of gallbladder carcinoma and adenoma. Kaohsiung J Med Sci. 2006;22(2):53–9.
Asai T, et al. High frequency of TP53 but not K-ras gene mutations in Bolivian patients with gallbladder cancer. Asian Pac J Cancer Prev. 2014;15(13):5449–54.
Maurya SK, et al. Genetic aberrations in gallbladder cancer. Surg Oncol. 2012;21(1):37–43.
Kumari N, et al. Role of C-erbB2 expression in gallbladder cancer. Indian J Pathol Microbiol. 2012;55(1):75–9.
Pujani M, et al. Expression of human epidermal growth factor receptor (Her 2/neu) and proliferative marker Ki-67: association with clinicopathological parameters in gallbladder carcinoma. Asian Pac J Cancer Prev. 2016;17(8):3903–9.
Kanthan R, et al. Gallbladder cancer in the 21st century. J Oncol. 2015;2015:967472.
Ma HB, et al. Association of cyclin D1, p16 and retinoblastoma protein expressions with prognosis and metastasis of gallbladder carcinoma. World J Gastroenterol. 2005;11(5):744–7.
Srivastava V, et al. Cyclin D1, retinoblastoma and p16 protein expression in carcinoma of the gallbladder. Asian Pac J Cancer Prev. 2013;14(5):2711–5.
Kim K, et al. Expression of cell cycle-related proteins, p16, p53 and p63 as important prognostic markers in gallbladder adenocarcinoma. Pathol Oncol Res. 2014;20(2):409–15.
Roa JC, et al. Inactivation of CDKN2A gene (p16) in gallbladder carcinoma. Rev Med Chil. 2004;132(11):1369–76.
Feng Z, et al. The risk factor of gallbladder cancer: hyperplasia of mucous epithelium caused by gallstones associates with p16/CyclinD1/CDK4 pathway. Exp Mol Pathol. 2011;91(2):569–77.
Yao H, et al. The role of annexin A4 in cancer. Front Biosci (Landmark Ed). 2016;21:949–57.
Huang HL, et al. Proteomic identification of tumor biomarkers associated with primary gallbladder cancer. World J Gastroenterol. 2014;20(18):5511–8.
Yao HS, et al. Annexin A4-nuclear factor-kappaB feedback circuit regulates cell malignant behavior and tumor growth in gallbladder cancer. Sci Rep. 2016;6:31056.
Jagannath P, Callery M. Molecular prognostic markers in gallbladder carcinoma. HPB (Oxford). 2012;14(9):571–2.
Nagano M, et al. Nuclear expression of thioredoxin-1 in the invasion front is associated with outcome in patients with gallbladder carcinoma. HPB (Oxford). 2012;14(9):573–82.
Wu K, et al. ADAM-17 over-expression in gallbladder carcinoma correlates with poor prognosis of patients. Med Oncol. 2011;28(2):475–80.
Puhalla H, et al. E-cadherin and beta-catenin expression in normal, inflamed and cancerous gallbladder tissue. Anticancer Res. 2005;25(6B):4249–54.
Priya TP, et al. Role of E-cadherin gene in gall bladder cancer and its precursor lesions. Virchows Arch. 2010;456(5):507–14.
Yi S, et al. N-cadherin and P-cadherin are biomarkers for invasion, metastasis, and poor prognosis of gallbladder carcinomas. Pathol Res Pract. 2014;210(6):363–8.
Nakamura T, et al. Prognostic significance of S100A4 expression in gallbladder cancer. Int J Oncol. 2002;20(5):937–41.
Luo W, et al. Clinical correlation of calpain-1 and glypican-3 expression with gallbladder carcinoma. Oncol Lett. 2016;11(2):1345–52.
Saranga Bharathi R, et al. Female sex hormone receptors in gallbladder cancer. J Gastrointest Cancer. 2015;46(2):143–8.
Gupta P, et al. Expression and clinicopathological significance of estrogen and progesterone receptors in gallbladder cancer. Gastrointest Cancer Res. 2012;5(2):41–7.
Baskaran V, et al. Do the progesterone receptors have a role to play in gallbladder cancer? Int J Gastrointest Cancer. 2005;35(1):61–8.
Park JS, et al. Estrogen receptor alpha, estrogen receptor beta, and progesterone receptor as possible prognostic factor in radically resected gallbladder carcinoma. J Surg Res. 2009;152(1):104–10.
Sumi K, et al. Loss of estrogen receptor beta expression at cancer front correlates with tumor progression and poor prognosis of gallbladder cancer. Oncol Rep. 2004;12(5):979–84.
Chandra V, et al. MicroRNA aberrations: an emerging field for gallbladder cancer management. World J Gastroenterol. 2016;22(5):1787–99.
Li G, Pu Y. MicroRNA signatures in total peripheral blood of gallbladder cancer patients. Tumour Biol. 2015;36(9):6985–90.
Pang Q, et al. Platelet to lymphocyte ratio as a novel prognostic tool for gallbladder carcinoma. World J Gastroenterol. 2015;21(21):6675–83.
Zhang L, et al. Prognostic significance of neutrophil to lymphocyte ratio in patients with gallbladder carcinoma. HPB (Oxford). 2016;18(7):600–7.
Zhang Y, et al. Prognostic significance of preoperative neutrophil/lymphocyte ratio and platelet/lymphocyte ratio in patients with gallbladder carcinoma. Clin Transl Oncol. 2015;17(10):810–8.
Saqib R, et al. Prognostic significance of pre-operative inflammatory markers in resected gallbladder cancer: a systematic review. ANZ J Surg. 2018;88(6):554–9.
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Rai, R., Gosai, S., Rao, C.V., Chandra, V. (2019). Molecular Diagnosis of Gall Bladder Cancer. In: Shukla, K., Sharma, P., Misra, S. (eds) Molecular Diagnostics in Cancer Patients. Springer, Singapore. https://doi.org/10.1007/978-981-13-5877-7_2
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