Each anatomical subtype of cholangiocarcinoma, intrahepatic (iCCA), perihilar (pCCA) and distal (dCCA), has a distinct epidemiology, biology, and prognosis, thus necessitating different management approaches
Fluorescence in situ hybridization (FISH) has improved the diagnostic performance of conventional cytology for the detection of pCCA and dCCA; several emerging diagnostic modalities, including liquid biopsy techniques, might further improve cholangiocarcinoma diagnosis
Neoadjuvant chemoradiotherapy followed by liver transplantation offers the best outcomes for a subset of patients with pCCA; liver transplantation might also be an option for patients with very early stage iCCA
Emerging evidence indicates that high-dose, conformal external-beam radiation therapy is a potential treatment option for patients with localized, unresectable iCCA
An enhanced understanding of the potential driver genetic aberrations in cholangiocarcinomas has heralded several novel drugs for advanced-stage disease, including FGFR inhibitors and IDH inhibitors; targeted therapy and immunotherapy combinations also hold promise
Cholangiocarcinoma is a disease entity comprising diverse epithelial tumours with features of cholangiocyte differentiation: cholangiocarcinomas are categorized according to anatomical location as intrahepatic (iCCA), perihilar (pCCA), or distal (dCCA). Each subtype has a distinct epidemiology, biology, prognosis, and strategy for clinical management. The incidence of cholangiocarcinoma, particularly iCCA, has increased globally over the past few decades. Surgical resection remains the mainstay of potentially curative treatment for all three disease subtypes, whereas liver transplantation after neoadjuvant chemoradiation is restricted to a subset of patients with early stage pCCA. For patients with advanced-stage or unresectable disease, locoregional and systemic chemotherapeutics are the primary treatment options. Improvements in external-beam radiation therapy have facilitated the treatment of cholangiocarcinoma. Moreover, advances in comprehensive whole-exome and transcriptome sequencing have defined the genetic landscape of each cholangiocarcinoma subtype. Accordingly, promising molecular targets for precision medicine have been identified, and are being evaluated in clinical trials, including those exploring immunotherapy. Biomarker-driven trials, in which patients are stratified according to anatomical cholangiocarcinoma subtype and genetic aberrations, will be essential in the development of targeted therapies. Targeting the rich tumour stroma of cholangiocarcinoma in conjunction with targeted therapies might also be useful. Herein, we review the evolving developments in the epidemiology, pathogenesis, and management of cholangiocarcinoma.
Subscribe to Journal
Get full journal access for 1 year
only $4.92 per issue
All prices are NET prices.
VAT will be added later in the checkout.
Tax calculation will be finalised during checkout.
Rent or Buy article
Get time limited or full article access on ReadCube.
All prices are NET prices.
Rizvi, S. & Gores, G. J. Pathogenesis, diagnosis, and management of cholangiocarcinoma. Gastroenterology 145, 1215–1229 (2013).
Saha, S. K., Zhu, A. X., Fuchs, C. S. & Brooks, G. A. Forty-year trends in cholangiocarcinoma incidence in the US: intrahepatic disease on the rise. Oncologist 21, 594–599 (2016).
Khan, S. A. et al. Changing international trends in mortality rates for liver, biliary and pancreatic tumours. J. Hepatol. 37, 806–813 (2002).
Taylor-Robinson, S. D. et al. Increase in mortality rates from intrahepatic cholangiocarcinoma in England and Wales 1968–1998. Gut 48, 816–820 (2001).
Cardinale, V. et al. Cholangiocarcinoma: increasing burden of classifications. Hepatobiliary Surg. Nutr. 2, 272–280 (2013).
Jarnagin, W. R. et al. Staging, resectability, and outcome in 225 patients with hilar cholangiocarcinoma. Ann. Surg. 234, 507–517 (2001).
Barr Fritcher, E. G. et al. An optimized set of fluorescence in situ hybridization probes for detection of pancreatobiliary tract cancer in cytology brush samples. Gastroenterology 149, 1813–1824 (2015).
Gonda, T. A. et al. Mutation profile and fluorescence in situ hybridization analyses increase detection of malignancies in biliary strictures. Clin. Gastroenterol. Hepatol. 15, 913–919 (2017).
Darwish Murad, S. et al. Efficacy of neoadjuvant chemoradiation, followed by liver transplantation, for perihilar cholangiocarcinoma at 12 US centers. Gastroenterology 143, 88–98 (2012).
Sapisochin, G. et al. Liver transplantation for “very early” intrahepatic cholangiocarcinoma: international retrospective study supporting a prospective assessment. Hepatology 64, 1178–1188 (2016).
Valle, J. et al. Cisplatin plus gemcitabine versus gemcitabine for biliary tract cancer. N. Engl. J. Med. 362, 1273–1281 (2010).
Razumilava, N. & Gores, G. J. Cholangiocarcinoma. Lancet 383, 2168–2179 (2014).
DeOliveira, M. L. et al. Cholangiocarcinoma: thirty-one-year experience with 564 patients at a single institution. Ann. Surg. 245, 755–762 (2007).
Nakeeb, A. et al. Cholangiocarcinoma. A spectrum of intrahepatic, perihilar, and distal tumors. Ann. Surg. 224, 463–473 (1996).
Sripa, B. & Pairojkul, C. Cholangiocarcinoma: lessons from Thailand. Curr. Opin. Gastroenterol. 24, 349–356 (2008).
Shaib, Y. & El-Serag, H. B. The epidemiology of cholangiocarcinoma. Semin. Liver Dis. 24, 115–125 (2004).
West, J., Wood, H., Logan, R. F., Quinn, M. & Aithal, G. P. Trends in the incidence of primary liver and biliary tract cancers in England and Wales 1971–2001. Br. J. Cancer 94, 1751–1758 (2006).
Patel, T. Worldwide trends in mortality from biliary tract malignancies. BMC Cancer 2, 10 (2002).
Shaib, Y. H., Davila, J. A., McGlynn, K. & El-Serag, H. B. Rising incidence of intrahepatic cholangiocarcinoma in the United States: a true increase? J. Hepatol. 40, 472–477 (2004).
Alvaro, D. et al. Descriptive epidemiology of cholangiocarcinoma in Italy. Dig. Liver Dis. 42, 490–495 (2010).
Bergquist, A. & von Seth, E. Epidemiology of cholangiocarcinoma. Best Pract. Res. Clin. Gastroenterol. 29, 221–232 (2015).
Bertuccio, P. et al. A comparison of trends in mortality from primary liver cancer and intrahepatic cholangiocarcinoma in Europe. Ann. Oncol. 24, 1667–1674 (2013).
Lepage, C. et al. Trends in the incidence and management of biliary tract cancer: a French population-based study. J. Hepatol. 54, 306–310 (2011).
Jepsen, P., Vilstrup, H., Tarone, R. E., Friis, S. & Sorensen, H. T. Incidence rates of intra- and extrahepatic cholangiocarcinomas in Denmark from 1978 through 2002. J. Natl Cancer Inst. 99, 895–897 (2007).
Altekruse, S. F. et al. Geographic variation of intrahepatic cholangiocarcinoma, extrahepatic cholangiocarcinoma, and hepatocellular carcinoma in the United States. PLoS ONE 10, e0120574 (2015).
Khan, S. A. et al. Rising trends in cholangiocarcinoma: is the ICD classification system misleading us? J. Hepatol. 56, 848–854 (2012).
Kilander, C., Mattsson, F., Ljung, R., Lagergren, J. & Sadr-Azodi, O. Systematic underreporting of the population-based incidence of pancreatic and biliary tract cancers. Acta Oncol. 53, 822–829 (2014).
Duberg, A. S. & Hultcrantz, R. Misleading figures on trends in mortality from hepatocellular carcinoma in Europe. Hepatology 49, 336 (2009).
Torner, A. et al. The underreporting of hepatocellular carcinoma to the cancer register and a log-linear model to estimate a more correct incidence. Hepatology 65, 885–892 (2017).
Hainsworth, J. D. et al. Molecular gene expression profiling to predict the tissue of origin and direct site-specific therapy in patients with carcinoma of unknown primary site: a prospective trial of the Sarah Cannon research institute. J. Clin. Oncol. 31, 217–223 (2013).
Varadhachary, G. R. & Raber, M. N. Cancer of unknown primary site. N. Engl. J. Med. 371, 757–765 (2014).
Bridgewater, J. et al. Guidelines for the diagnosis and management of intrahepatic cholangiocarcinoma. J. Hepatol. 60, 1268–1289 (2014).
Rimola, J. et al. Cholangiocarcinoma in cirrhosis: absence of contrast washout in delayed phases by magnetic resonance imaging avoids misdiagnosis of hepatocellular carcinoma. Hepatology 50, 791–798 (2009).
Iavarone, M. et al. Contrast enhanced CT-scan to diagnose intrahepatic cholangiocarcinoma in patients with cirrhosis. J. Hepatol. 58, 1188–1193 (2013).
Kim, S. H. et al. Typical and atypical imaging findings of intrahepatic cholangiocarcinoma using gadolinium ethoxybenzyl diethylenetriamine pentaacetic acid-enhanced magnetic resonance imaging. J. Comput. Assist. Tomogr. 36, 704–709 (2012).
Vilgrain, V. Staging cholangiocarcinoma by imaging studies. HPB 10, 106–109 (2008).
Charatcharoenwitthaya, P., Enders, F. B., Halling, K. C. & Lindor, K. D. Utility of serum tumor markers, imaging, and biliary cytology for detecting cholangiocarcinoma in primary sclerosing cholangitis. Hepatology 48, 1106–1117 (2008).
Levy, C. et al. The value of serum CA 19–19 in predicting cholangiocarcinomas in patients with primary sclerosing cholangitis. Dig. Dis. Sci. 50, 1734–1740 (2005).
Patel, A. H., Harnois, D. M., Klee, G. G., LaRusso, N. F. & Gores, G. J. The utility of CA 19–9 in the diagnoses of cholangiocarcinoma in patients without primary sclerosing cholangitis. Am. J. Gastroenterol. 95, 204–207 (2000).
Nehls, O., Gregor, M. & Klump, B. Serum and bile markers for cholangiocarcinoma. Semin. Liver Dis. 24, 139–154 (2004).
Choi, S. B. et al. The prognosis and survival outcome of intrahepatic cholangiocarcinoma following surgical resection: association of lymph node metastasis and lymph node dissection with survival. Ann. Surg. Oncol. 16, 3048–3056 (2009).
Endo, I. et al. Intrahepatic cholangiocarcinoma: rising frequency, improved survival, and determinants of outcome after resection. Ann. Surg. 248, 84–96 (2008).
Li, Y. Y. et al. Prognostic value of cirrhosis for intrahepatic cholangiocarcinoma after surgical treatment. J. Gastrointest. Surg. 15, 608–613 (2011).
Pascher, A., Jonas, S. & Neuhaus, P. Intrahepatic cholangiocarcinoma: indication for transplantation. J. Hepatobiliary Pancreat. Surg. 10, 282–287 (2003).
Robles, R. et al. Spanish experience in liver transplantation for hilar and peripheral cholangiocarcinoma. Ann. Surg. 239, 265–271 (2004).
Sapisochin, G. et al. “Very early” intrahepatic cholangiocarcinoma in cirrhotic patients: should liver transplantation be reconsidered in these patients? Am. J. Transplant 14, 660–667 (2014).
Kiefer, M. V. et al. Chemoembolization of intrahepatic cholangiocarcinoma with cisplatinum, doxorubicin, mitomycin C, ethiodol, and polyvinyl alcohol: a 2-center study. Cancer 117, 1498–1505 (2011).
Park, S. Y. et al. Transarterial chemoembolization versus supportive therapy in the palliative treatment of unresectable intrahepatic cholangiocarcinoma. Clin. Radiol. 66, 322–328 (2011).
Vogl, T. J. et al. Transarterial chemoembolization in the treatment of patients with unresectable cholangiocarcinoma: results and prognostic factors governing treatment success. Int. J. Cancer 131, 733–740 (2012).
Kuhlmann, J. B. et al. Treatment of unresectable cholangiocarcinoma: conventional transarterial chemoembolization compared with drug eluting bead-transarterial chemoembolization and systemic chemotherapy. Eur. J. Gastroenterol. Hepatol. 24, 437–443 (2012).
Hoffmann, R. T. et al. Transarterial hepatic yttrium-90 radioembolization in patients with unresectable intrahepatic cholangiocarcinoma: factors associated with prolonged survival. Cardiovasc. Intervent. Radiol. 35, 105–116 (2012).
Rafi, S. et al. Yttrium-90 radioembolization for unresectable standard-chemorefractory intrahepatic cholangiocarcinoma: survival, efficacy, and safety study. Cardiovasc. Intervent. Radiol. 36, 440–448 (2013).
Masselli, G., Manfredi, R., Vecchioli, A. & Gualdi, G. MR imaging and MR cholangiopancreatography in the preoperative evaluation of hilar cholangiocarcinoma: correlation with surgical and pathologic findings. Eur. Radiol. 18, 2213–2221 (2008).
Ruys, A. T. et al. Radiological staging in patients with hilar cholangiocarcinoma: a systematic review and meta-analysis. Br. J. Radiol. 85, 1255–1262 (2012).
Mohamadnejad, M. et al. Role of EUS for preoperative evaluation of cholangiocarcinoma: a large single-center experience. Gastrointest. Endosc. 73, 71–78 (2011).
Heimbach, J. K., Sanchez, W., Rosen, C. B. & Gores, G. J. Trans-peritoneal fine needle aspiration biopsy of hilar cholangiocarcinoma is associated with disease dissemination. HPB 13, 356–360 (2011).
Trikudanathan, G., Navaneethan, U., Njei, B., Vargo, J. J. & Parsi, M. A. Diagnostic yield of bile duct brushings for cholangiocarcinoma in primary sclerosing cholangitis: a systematic review and meta-analysis. Gastrointest. Endosc. 79, 783–789 (2014).
Dudley, J. C. et al. Next-generation sequencing and fluorescence in situ hybridization have comparable performance characteristics in the analysis of pancreaticobiliary brushings for malignancy. J. Mol. Diagn. 18, 124–130 (2016).
Tanaka, A. et al. Clinical features, response to treatment, and outcomes of IgG4-related sclerosing cholangitis. Clin. Gastroenterol. Hepatol. 15, 920–926 (2017).
Li, L. et al. Human bile contains microRNA-laden extracellular vesicles that can be used for cholangiocarcinoma diagnosis. Hepatology 60, 896–907 (2014).
Arbelaiz, A. et al. Serum extracellular vesicles contain protein biomarkers for primary sclerosing cholangitis and cholangiocarcinoma. Hepatology http://dx.doi.org/10.1002/hep.29291 (2017).
Severino, V. et al. Extracellular vesicles in bile as markers of malignant biliary stenoses. Gastroenterology 153, 495–504 (2017).
Wan, J. C. et al. Liquid biopsies come of age: towards implementation of circulating tumour DNA. Nat. Rev. Cancer 17, 223–238 (2017).
Yang, J. et al. Detection of cholangiocarcinoma by assay of methylated DNA markers in plasma. Gastroenterology 152, S1041–S1042 (2017).
Nagorney, D. M. & Kendrick, M. L. Hepatic resection in the treatment of hilar cholangiocarcinoma. Adv. Surg. 40, 159–171 (2006).
Hemming, A. W., Mekeel, K., Khanna, A., Baquerizo, A. & Kim, R. D. Portal vein resection in management of hilar cholangiocarcinoma. J. Am. Coll. Surg. 212, 604–613 (2011).
Hong, Y. K. et al. The efficacy of portal vein embolization prior to right extended hemihepatectomy for hilar cholangiocellular carcinoma: a retrospective cohort study. Eur. J. Surg. Oncol. 37, 237–244 (2011).
Schnitzbauer, A. A. et al. Right portal vein ligation combined with in situ splitting induces rapid left lateral liver lobe hypertrophy enabling 2-staged extended right hepatic resection in small-for-size settings. Ann. Surg. 255, 405–414 (2012).
Tschuor, C. et al. Salvage parenchymal liver transection for patients with insufficient volume increase after portal vein occlusion — an extension of the ALPPS approach. Eur. J. Surg. Oncol. 39, 1230–1235 (2013).
Rosen, C. B., Heimbach, J. K. & Gores, G. J. Liver transplantation for cholangiocarcinoma. Transpl. Int. 23, 692–697 (2010).
Valle, J. W. et al. Cisplatin and gemcitabine for advanced biliary tract cancer: a meta-analysis of two randomised trials. Ann. Oncol. 25, 391–398 (2014).
Okusaka, T. et al. Gemcitabine alone or in combination with cisplatin in patients with biliary tract cancer: a comparative multicentre study in Japan. Br. J. Cancer 103, 469–474 (2010).
Primrose, J. N. et al. Adjuvant capecitabine for biliary tract cancer: the BILCAP randomized study [abstract]. J. Clin. Oncol. 35 (Suppl. 15), 4006 (2017).
Edeline, J. et al. Gemox versus surveillance following surgery of localized biliary tract cancer: results of the PRODIGE 12-ACCORD 18 (UNICANCER GI) phase III trial. J. Clin. Oncol. 35, 225–225 (2017).
Crane, C. H. & Koay, E. J. Solutions that enable ablative radiotherapy for large liver tumors: fractionated dose painting, simultaneous integrated protection, motion management, and computed tomography image guidance. Cancer 122, 1974–1986 (2016).
Pan, C. C. et al. Radiation-associated liver injury. Int. J. Radiat. Oncol. Biol. Phys. 76, S94–S100 (2010).
Kavanagh, B. D. et al. Radiation dose-volume effects in the stomach and small bowel. Int. J. Radiat. Oncol. Biol. Phys. 76, S101–S107 (2010).
Hong, T. S. et al. Multi-institutional phase II study of high-dose hypofractionated proton beam therapy in patients with localized, unresectable hepatocellular carcinoma and intrahepatic cholangiocarcinoma. J. Clin. Oncol. 34, 460–468 (2016).
Tse, R. V. et al. Phase I study of individualized stereotactic body radiotherapy for hepatocellular carcinoma and intrahepatic cholangiocarcinoma. J. Clin. Oncol. 26, 657–664 (2008).
Tao, R. et al. Ablative radiotherapy doses lead to a substantial prolongation of survival in patients with inoperable intrahepatic cholangiocarcinoma: a retrospective dose response analysis. J. Clin. Oncol. 34, 219–226 (2016).
Patel, S., Ragab, O. & Kamrava, M. Another solution that enables ablative radiotherapy for large liver tumors: percutaneous interstitial high-dose rate brachytherapy. Cancer 122, 2766 (2016).
Mukewar, S. et al. Endoscopically inserted nasobiliary catheters for high dose-rate brachytherapy as part of neoadjuvant therapy for perihilar cholangiocarcinoma. Endoscopy 47, 878–883 (2015).
Hammad, A. Y. et al. Is Radiotherapy warranted following intrahepatic cholangiocarcinoma resection? The impact of surgical margins and lymph node status on survival. Ann. Surg. Oncol. 23, 912–920 (2016).
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).
Jia, A. Y. et al. Intensity-modulated radiotherapy following null-margin resection is associated with improved survival in the treatment of intrahepatic cholangiocarcinoma. J. Gastrointest. Oncol. 6, 126–133 (2015).
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).
Shinohara, E. T., Mitra, N., Guo, M. & Metz, J. M. Radiotherapy is associated with improved survival in adjuvant and palliative treatment of extrahepatic cholangiocarcinomas. Int. J. Radiat. Oncol. Biol. Phys. 74, 1191–1198 (2009).
Pollom, E. L. et al. Does radiotherapy still have a role in unresected biliary tract cancer? Cancer Med. 6, 129–141 (2017).
Foo, M. L., Gunderson, L. L., Bender, C. E. & Buskirk, S. J. External radiation therapy and transcatheter iridium in the treatment of extrahepatic bile duct carcinoma. Int. J. Radiat. Oncol. Biol. Phys. 39, 929–935 (1997).
Ghafoori, A. P. et al. Radiotherapy in the treatment of patients with unresectable extrahepatic cholangiocarcinoma. Int. J. Radiat. Oncol. Biol. Phys. 81, 654–659 (2011).
Mansour, J. C. et al. Hilar cholangiocarcinoma: expert consensus statement. HPB 17, 691–699 (2015).
Nakamura, H. et al. Genomic spectra of biliary tract cancer. Nat. Genet. 47, 1003–1010 (2015).
Borad, M. J. et al. Integrated genomic characterization reveals novel, therapeutically relevant drug targets in FGFR and EGFR pathways in sporadic intrahepatic cholangiocarcinoma. PLoS Genet. 10, e1004135 (2014).
Graham, R. P. et al. Fibroblast growth factor receptor 2 translocations in intrahepatic cholangiocarcinoma. Hum. Pathol. 45, 1630–1638 (2014).
Ross, J. S. et al. New routes to targeted therapy of intrahepatic cholangiocarcinomas revealed by next-generation sequencing. Oncologist 19, 235–242 (2014).
Wu, Y. M. et al. Identification of targetable FGFR gene fusions in diverse cancers. Cancer Discov. 3, 636–647 (2013).
Sia, D. et al. Massive parallel sequencing uncovers actionable FGFR2–PPHLN1 fusion and ARAF mutations in intrahepatic cholangiocarcinoma. Nat. Commun. 6, 6087 (2015).
Gingras, M. C. et al. Ampullary cancers harbor ELF3 tumor suppressor gene mutations and exhibit frequent WNT dysregulation. Cell Rep. 14, 907–919 (2016).
Yachida, S. et al. Genomic sequencing identifies ELF3 as a driver of ampullary carcinoma. Cancer Cell 29, 229–240 (2016).
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).
Farshidfar, F. et al. Integrative genomic analysis of cholangiocarcinoma identifies distinct IDH-mutant molecular profiles. Cell Rep. 18, 2780–2794 (2017).
Churi, C. R. et al. Mutation profiling in cholangiocarcinoma: prognostic and therapeutic implications. PLoS ONE 9, e115383 (2014).
Borger, D. R. et al. Frequent mutation of isocitrate dehydrogenase (IDH)1 and IDH2 in cholangiocarcinoma identified through broad-based tumor genotyping. Oncologist 17, 72–79 (2012).
Kipp, B. R. et al. Isocitrate dehydrogenase 1 and 2 mutations in cholangiocarcinoma. Hum. Pathol. 43, 1552–1558 (2012).
Rizvi, S. et al. A hippo and fibroblast growth factor receptor autocrine pathway in cholangiocarcinoma. J. Biol. Chem. 291, 8031–8047 (2016).
Javle, M. A phase 2 study of BGJ398 in patients (pts) with advanced or metastatic FGFR-altered cholangiocarcinoma (CCA) who failed or are intolerant to platinum-based chemotherapy [abstract]. J. Clin. Oncol. 34 (Suppl. 4), 335 (2016).
Perera, T. P. S. et al. Discovery and pharmacological characterization of JNJ-42756493 (erdafitinib), a functionally selective small-molecule FGFR family inhibitor. Mol. Cancer Ther. 16, 1010–1020 (2017).
Tabernero, J. et al. Phase I dose-escalation study of JNJ-42756493, an oral pan-fibroblast growth factor receptor inhibitor, in patients with advanced solid tumors. J. Clin. Oncol. 33, 3401–3408 (2015).
Whitesell, L. & Lindquist, S. L. HSP90 and the chaperoning of cancer. Nat. Rev. Cancer 5, 761–772 (2005).
Acquaviva, J. et al. FGFR3 translocations in bladder cancer: differential sensitivity to HSP90 inhibition based on drug metabolism. Mol. Cancer Res. 12, 1042–1054 (2014).
Gu, T. L. et al. Survey of tyrosine kinase signaling reveals ROS kinase fusions in human cholangiocarcinoma. PLoS ONE 6, e15640 (2011).
Saborowski, A. et al. Mouse model of intrahepatic cholangiocarcinoma validates FIG–ROS as a potent fusion oncogene and therapeutic target. Proc. Natl Acad. Sci. USA 110, 19513–19518 (2013).
Zhu, A. X. et al. Genomic profiling of intrahepatic cholangiocarcinoma: refining prognosis and identifying therapeutic targets. Ann. Surg. Oncol. 21, 3827–3834 (2014).
Bekaii-Saab, T. et al. Multi-institutional phase II study of selumetinib in patients with metastatic biliary cancers. J. Clin. Oncol. 29, 2357–2363 (2011).
Bridgewater, J. et al. A phase 1b study of selumetinib in combination with cisplatin and gemcitabine in advanced or metastatic biliary tract cancer: the ABC-04 study. BMC Cancer 16, 153 (2016).
Goeppert, B. et al. BRAF V600E-specific immunohistochemistry reveals low mutation rates in biliary tract cancer and restriction to intrahepatic cholangiocarcinoma. Mod. Pathol. 27, 1028–1034 (2014).
Hyman, D. M. et al. Vemurafenib in multiple nonmelanoma cancers with BRAF V600 mutations. N. Engl. J. Med. 373, 726–736 (2015).
Sia, D. et al. Integrative molecular analysis of intrahepatic cholangiocarcinoma reveals 2 classes that have different outcomes. Gastroenterology 144, 829–840 (2013).
Pant, S. et al. A phase I dose escalation study of oral c-MET inhibitor tivantinib (ARQ 197) in combination with gemcitabine in patients with solid tumors. Ann. Oncol. 25, 1416–1421 (2014).
Goyal, L. et al. A phase 2 and biomarker study of cabozantinib in patients with advanced cholangiocarcinoma. Cancer 123, 1979–1988 (2017).
El-Khoueiry, A. B. et al. S0941: a phase 2 SWOG study of sorafenib and erlotinib in patients with advanced gallbladder carcinoma or cholangiocarcinoma. Br. J. Cancer 110, 882–887 (2014).
O'Rourke, C. J., Munoz-Garrido, P., Aguayo, E. L. & Andersen, J. B. Epigenome dysregulation in cholangiocarcinoma. Biochim. Biophys. Acta http://dx.doi.org/10.1016/j.bbadis.2017.06.014 (2017).
Rohle, D. et al. An inhibitor of mutant IDH1 delays growth and promotes differentiation of glioma cells. Science 340, 626–630 (2013).
Wang, F. et al. Targeted inhibition of mutant IDH2 in leukemia cells induces cellular differentiation. Science 340, 622–626 (2013).
Burris, H. et al. The first reported results of AG-120, a first-in-class, potent inhibitor of the IDH1 mutant protein, in a phase I study of patients with advanced IDH1-mutant solid tumors, including gliomas. Mol. Cancer. Ther. 14 (12 Suppl. 2), PL04-05 (2015).
Amatangelo, M. D. et al. Enasidenib induces acute myeloid leukemia cell differentiation to promote clinical response. Blood 130, 732–741 (2017).
Kats, L. M. et al. A pharmacogenomic approach validates AG-221 as an effective and on-target therapy in IDH2 mutant AML. Leukemia 31, 1466–1470 (2017).
Thomas, D. & Majeti, R. Optimizing next-generation AML therapy: activity of mutant IDH2 inhibitor AG-221 in preclinical models. Cancer Discov. 7, 459–461 (2017).
Saha, S. K. et al. Isocitrate dehydrogenase mutations confer dasatinib hypersensitivity and SRC dependence in intrahepatic cholangiocarcinoma. Cancer Discov. 6, 727–739 (2016).
Kim, K. H. et al. SWI/SNF-mutant cancers depend on catalytic and non-catalytic activity of EZH2. Nat. Med. 21, 1491–1496 (2015).
Nakagawa, S. et al. Enhancer of zeste homolog 2 (EZH2) promotes progression of cholangiocarcinoma cells by regulating cell cycle and apoptosis. Ann. Surg. Oncol. 20 (Suppl. 3), S667–S675 (2013).
Tang, B. et al. EZH2 elevates the proliferation of human cholangiocarcinoma cells through the downregulation of RUNX3. Med. Oncol. 31, 271 (2014).
Nakagawa, S. et al. Epigenetic therapy with the histone methyltransferase EZH2 inhibitor 3-deazaneplanocin A inhibits the growth of cholangiocarcinoma cells. Oncol. Rep. 31, 983–988 (2014).
Fujimoto, A. et al. Whole-genome mutational landscape of liver cancers displaying biliary phenotype reveals hepatitis impact and molecular diversity. Nat. Commun. 6, 6120 (2015).
Jiao, Y. et al. Exome sequencing identifies frequent inactivating mutations in BAP1, ARID1A and PBRM1 in intrahepatic cholangiocarcinomas. Nat. Genet. 45, 1470–1473 (2013).
Luchini, C. et al. PBRM1 loss is a late event during the development of cholangiocarcinoma. Histopathology 71, 375–382 (2017).
Sasaki, M., Nitta, T., Sato, Y. & Nakanuma, Y. Loss of ARID1A expression presents a novel pathway of carcinogenesis in biliary carcinomas. Am. J. Clin. Pathol. 145, 815–825 (2016).
Baradari, V., Hopfner, M., Huether, A., Schuppan, D. & Scherubl, H. Histone deacetylase inhibitor MS-275 alone or combined with bortezomib or sorafenib exhibits strong antiproliferative action in human cholangiocarcinoma cells. World J. Gastroenterol. 13, 4458–4466 (2007).
Dawson, M. A. & Kouzarides, T. Cancer epigenetics: from mechanism to therapy. Cell 150, 12–27 (2012).
Kwak, T. W., Kim, D. H., Jeong, Y. I. & Kang, D. H. Antitumor activity of vorinostat-incorporated nanoparticles against human cholangiocarcinoma cells. J. Nanobiotechnol. 13, 60 (2015).
Sriraksa, R. & Limpaiboon, T. Histone deacetylases and their inhibitors as potential therapeutic drugs for cholangiocarcinoma — cell line findings. Asian Pac. J. Cancer Prev. 14, 2503–2508 (2013).
Wang, B. et al. Sodium valproate inhibits the growth of human cholangiocarcinoma in vitro and in vivo. Gastroenterol. Res. Pract. 2013, 374593 (2013).
Iwahashi, S. et al. Effects of valproic acid in combination with S-1 on advanced pancreatobiliary tract cancers: clinical study phases I/II. Anticancer Res. 34, 5187–5191 (2014).
Kawamata, F. et al. Intracellular localization of mesothelin predicts patient prognosis of extrahepatic bile duct cancer. Int. J. Oncol. 41, 2109–2118 (2012).
Nomura, R. et al. Mesothelin expression is a prognostic factor in cholangiocellular carcinoma. Int. Surg. 98, 164–169 (2013).
Golan, T. et al. Overall survival and clinical characteristics of BRCA-associated cholangiocarcinoma: a multicenter retrospective study. Oncologist 22, 804–810 (2017).
Martin-Liberal, J. et al. The expanding role of immunotherapy. Cancer Treat. Rev. 54, 74–86 (2017).
Feldman, S. A., Assadipour, Y., Kriley, I., Goff, S. L. & Rosenberg, S. A. Adoptive cell therapy — tumor-infiltrating lymphocytes, T-cell receptors, and chimeric antigen receptors. Semin. Oncol. 42, 626–639 (2015).
Palmer, W. C. & Patel, T. Are common factors involved in the pathogenesis of primary liver cancers? A meta-analysis of risk factors for intrahepatic cholangiocarcinoma. J. Hepatol. 57, 69–76 (2012).
Santana-Davila, R., Bhatia, S. & Chow, L. Q. Harnessing the immune system as a therapeutic tool in virus-associated cancers. JAMA Oncol. 3, 106–112 (2017).
Ott, P. A. & Hodi, F. S. The B7-H1/PD-1 pathway in cancers associated with infections and inflammation: opportunities for therapeutic intervention. Chin. Clin. Oncol. 2, 7 (2013).
Tashiro, H. & Brenner, M. K. Immunotherapy against cancer-related viruses. Cell Res. 27, 59–73 (2017).
Brivio, S., Cadamuro, M., Strazzabosco, M. & Fabris, L. Tumor reactive stroma in cholangiocarcinoma: the fuel behind cancer aggressiveness. World J. Hepatol. 9, 455–468 (2017).
Raggi, C., Invernizzi, P. & Andersen, J. B. Impact of microenvironment and stem-like plasticity in cholangiocarcinoma: molecular networks and biological concepts. J. Hepatol. 62, 198–207 (2015).
Hasita, H. et al. Significance of alternatively activated macrophages in patients with intrahepatic cholangiocarcinoma. Cancer Sci. 101, 1913–1919 (2010).
Mertens, J. C. et al. Therapeutic effects of deleting cancer-associated fibroblasts in cholangiocarcinoma. Cancer Res. 73, 897–907 (2013).
Rizvi, S. et al. Platelet-derived growth factor primes cancer-associated fibroblasts for apoptosis. J. Biol. Chem. 289, 22835–22849 (2014).
Mantovani, A., Marchesi, F., Malesci, A., Laghi, L. & Allavena, P. Tumour-associated macrophages as treatment targets in oncology. Nat. Rev. Clin. Oncol. 14, 399–416 (2017).
El-Khoueiry, A. B. et al. Nivolumab in patients with advanced hepatocellular carcinoma (CheckMate 040): an open-label, non-comparative, phase 1/2 dose escalation and expansion trial. Lancet 389, 2492–2502 (2017).
Aguiar, P. N. et al. PD-L1 expression as a predictive biomarker in advanced non-small-cell lung cancer: updated survival data. Immunotherapy 9, 499–506 (2017).
Carbognin, L. et al. Differential activity of nivolumab, pembrolizumab and MPDL3280A according to the tumor expression of programmed death-ligand-1 (PD-L1): sensitivity analysis of trials in melanoma, lung and genitourinary cancers. PLoS ONE 10, e0130142 (2015).
Garon, E. B. et al. Pembrolizumab for the treatment of non-small-cell lung cancer. N. Engl. J. Med. 372, 2018–2028 (2015).
Bang, Y. J. et al. Safety and efficacy of pembrolizumab (MK-3475) in patients (pts) with advanced biliary tract cancer: interim results of KEYNOTE-028 [abstract]. Eur. J. Cancer 51 (Suppl. 3), S112 (2015).
Gani, F. et al. Program death 1 immune checkpoint and tumor microenvironment: implications for patients with intrahepatic cholangiocarcinoma. Ann. Surg. Oncol. 23, 2610–2617 (2016).
Fontugne, J. et al. PD-L1 expression in perihilar and intrahepatic cholangiocarcinoma. Oncotarget 8, 24644–24651 (2017).
Le, D. T. et al. PD-1 blockade in tumors with mismatch-repair deficiency. N. Engl. J. Med. 372, 2509–2520 (2015).
Naboush, A., Roman, C. A. & Shapira, I. Immune checkpoint inhibitors in malignancies with mismatch repair deficiency: a review of the state of the current knowledge. J. Investig. Med. 65, 754–758 (2017).
Silva, V. W. et al. Biliary carcinomas: pathology and the role of DNA mismatch repair deficiency. Chin. Clin. Oncol. 5, 62 (2016).
Rizvi, N. A. et al. Cancer immunology. Mutational landscape determines sensitivity to PD-1 blockade in non-small cell lung cancer. Science 348, 124–128 (2015).
Snyder, A. et al. Genetic basis for clinical response to CTLA-4 blockade in melanoma. N. Engl. J. Med. 371, 2189–2199 (2014).
Rosenberg, J. E. et al. Atezolizumab in patients with locally advanced and metastatic urothelial carcinoma who have progressed following treatment with platinum-based chemotherapy: a single-arm, multicentre, phase 2 trial. Lancet 387, 1909–1920 (2016).
Le, D. T. et al. Mismatch repair deficiency predicts response of solid tumors to PD-1 blockade. Science 357, 409–413 (2017).
Andresen, K. et al. Four DNA methylation biomarkers in biliary brush samples accurately identify the presence of cholangiocarcinoma. Hepatology 61, 1651–1659 (2015).
Lankisch, T. O. et al. Bile proteomic profiles differentiate cholangiocarcinoma from primary sclerosing cholangitis and choledocholithiasis. Hepatology 53, 875–884 (2011).
Metzger, J. et al. Urine proteomic analysis differentiates cholangiocarcinoma from primary sclerosing cholangitis and other benign biliary disorders. Gut 62, 122–130 (2013).
The authors thank Ms Courtney Hoover for her excellent secretarial support. The work of the authors is supported by the US NIH (grants DK59427 to G.J.G., 1R03CA212877-01 to R.K.K., and DK84567 to the Mayo Center for Cell Signalling in Gastroenterology), and by the Mayo Foundation. S.R. has also received support from the Cholangiocarcinoma Foundation and from the Mayo Center for Cell Signalling in Gastroenterology (Pilot & Feasibility Award P30DK084567).
R.K.K has received research support from Agios, Eli Lilly, Merck, and Novartis, via her institution, for conduct of clinical trials in cholangiocarcinoma. S.R., S.A.K., C.L.H., and G.J.G. declare no competing interests.
About this article
Cite this article
Rizvi, S., Khan, S., Hallemeier, C. et al. Cholangiocarcinoma — evolving concepts and therapeutic strategies. Nat Rev Clin Oncol 15, 95–111 (2018). https://doi.org/10.1038/nrclinonc.2017.157
HMGA1-TRIP13 axis promotes stemness and epithelial mesenchymal transition of perihilar cholangiocarcinoma in a positive feedback loop dependent on c-Myc
Journal of Experimental & Clinical Cancer Research (2021)
Identification of tumor antigens and immune subtypes of cholangiocarcinoma for mRNA vaccine development
Molecular Cancer (2021)
LncRNA MT1JP plays a protective role in intrahepatic cholangiocarcinoma by regulating miR-18a-5p/FBP1 axis
BMC Cancer (2021)
Fibrinogen/albumin ratio index is an independent predictor of recurrence-free survival in patients with intrahepatic cholangiocarcinoma following surgical resection
World Journal of Surgical Oncology (2021)
Comprehensive analysis of genomic mutation signature and tumor mutation burden for prognosis of intrahepatic cholangiocarcinoma
BMC Cancer (2021)