PDF icon Download PDF
Semin Liver Dis 2018; 38(02): 160-169
DOI: 10.1055/s-0038-1655775
Review Article

Emerging Technologies for the Diagnosis of Perihilar Cholangiocarcinoma

Sumera I Ilyas
1   Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota
,
John Eaton
1   Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota
,
Ju Dong Yang
1   Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota
,
Vinay Chandrasekhara
1   Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota
,
Gregory J. Gores
1   Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota
› Author Affiliations
› Further Information
   Permissions and Reprints
Preview

Corrected by:

Erratum: Emerging Technologies for the Diagnosis of Perihilar CholangiocarcinomaSemin Liver Dis 2018; 38(02): e1-e1
DOI: 10.1055/s-0044-1786508

Abstract

The diagnosis of malignant biliary strictures remains problematic, especially in the perihilar region and in primary sclerosing cholangitis (PSC). Conventional cytology obtained during endoscopic retrograde cholangiography (ERC)-guided brushings of biliary strictures is suboptimal due to limited sensitivity, albeit it remains the gold standard with a high specificity. Emerging technologies are being developed and validated to address this pressing unmet patient need. Such technologies include enhanced visualization of the biliary tree by cholangioscopy, intraductal ultrasound, and confocal laser endomicroscopy. Conventional cytology can be aided by employing complementary and advanced cytologic techniques such as fluorescent in situ hybridization (FISH), and this technique should be widely adapted. Interrogation of bile and serum by examining extracellular vesicle number and cargo, and exploiting next-generation sequencing and proteomic technologies, is also being explored. Examination of circulating cell-free deoxyribonucleic acid (cfDNA) for differentially methylated regions is a promising test which is being rigorously validated. The special expertise required for these analyses has to date hampered their validation and adaptation. Herein, we will review these emerging technologies to inform the reader of the progress made and encourage further studies, as well as adaptation of validated approaches.

Keywords

cell-free DNA - differentially methylated regions - FISH


Publication History

Publication Date:
05 June 2018 (online)

© 2018. Thieme. All rights reserved.

Thieme Medical Publishers, Inc.
333 Seventh Avenue, 18th Floor, New York, NY 10001, USA

 

  • References

  • 1 Rizvi S, Gores GJ. Pathogenesis, diagnosis, and management of cholangiocarcinoma. Gastroenterology 2013; 145 (06) 1215-1229
    Search in Google Scholar
  • 2 Rizvi S, Gores GJ. Current diagnostic and management options in perihilar cholangiocarcinoma. Digestion 2014; 89 (03) 216-224
    Search in Google Scholar
  • 3 DeOliveira ML, Cunningham SC, Cameron JL. , et al. Cholangiocarcinoma: thirty-one-year experience with 564 patients at a single institution. Ann Surg 2007; 245 (05) 755-762
    Search in Google Scholar
  • 4 Boonstra K, Weersma RK, van Erpecum KJ. , et al; EpiPSCPBC Study Group. Population-based epidemiology, malignancy risk, and outcome of primary sclerosing cholangitis. Hepatology 2013; 58 (06) 2045-2055
    Search in Google Scholar
  • 5 Kornfeld D, Ekbom A, Ihre T. Survival and risk of cholangiocarcinoma in patients with primary sclerosing cholangitis. A population-based study. Scand J Gastroenterol 1997; 32 (10) 1042-1045
    Search in Google Scholar
  • 6 Everhart JE, Ruhl CE. Burden of digestive diseases in the United States Part III: liver, biliary tract, and pancreas. Gastroenterology 2009; 136 (04) 1134-1144
    Search in Google Scholar
  • 7 Rizvi S, Khan SA, Hallemeier CL, Kelley RK, Gores GJ. Cholangiocarcinoma - evolving concepts and therapeutic strategies. Nat Rev Clin Oncol 2018; 15 (02) 95-111
    Search in Google Scholar
  • 8 Barr Fritcher EG, Voss JS, Brankley SM. , et al. An optimized set of fluorescence in situ hybridization probes for detection of pancreatobiliary tract cancer in cytology brush samples. Gastroenterology 2015; 149 (07) 1813-1824.e1
    Search in Google Scholar
  • 9 Trikudanathan G, Navaneethan U, Njei B, Vargo JJ, Parsi MA. Diagnostic yield of bile duct brushings for cholangiocarcinoma in primary sclerosing cholangitis: a systematic review and meta-analysis. Gastrointest Endosc 2014; 79 (05) 783-789
    Search in Google Scholar
  • 10 Barr Fritcher EG, Kipp BR, Slezak JM. , et al. Correlating routine cytology, quantitative nuclear morphometry by digital image analysis, and genetic alterations by fluorescence in situ hybridization to assess the sensitivity of cytology for detecting pancreatobiliary tract malignancy. Am J Clin Pathol 2007; 128 (02) 272-279
    Search in Google Scholar
  • 11 Brooks C, Gausman V, Kokoy-Mondragon C. , et al. Role of fluorescent in situ hybridization, cholangioscopic biopsies, and EUS-FNA in the evaluation of biliary strictures. Dig Dis Sci 2018; 63 (03) 636-644
    Search in Google Scholar
  • 12 Navaneethan U, Njei B, Venkatesh PG, Vargo JJ, Parsi MA. Fluorescence in situ hybridization for diagnosis of cholangiocarcinoma in primary sclerosing cholangitis: a systematic review and meta-analysis. Gastrointest Endosc 2014; 79 (06) 943-950.e3
    Search in Google Scholar
  • 13 Jhaveri KS, Hosseini-Nik H. MRI of cholangiocarcinoma. J Magn Reson Imaging 2015; 42 (05) 1165-1179
    Search in Google Scholar
  • 14 Charatcharoenwitthaya P, Enders FB, Halling KC, Lindor KD. Utility of serum tumor markers, imaging, and biliary cytology for detecting cholangiocarcinoma in primary sclerosing cholangitis. Hepatology 2008; 48 (04) 1106-1117
    Search in Google Scholar
  • 15 Fevery J, Buchel O, Nevens F, Verslype C, Stroobants S, Van Steenbergen W. Positron emission tomography is not a reliable method for the early diagnosis of cholangiocarcinoma in patients with primary sclerosing cholangitis. J Hepatol 2005; 43 (02) 358-360
    Search in Google Scholar
  • 16 Alkhawaldeh K, Faltten S, Biersack HJ, Ezziddin S. The value of F-18 FDG PET in patients with primary sclerosing cholangitis and cholangiocarcinoma using visual and semiquantitative analysis. Clin Nucl Med 2011; 36 (10) 879-883
    Search in Google Scholar
  • 17 Ma KW, Cheung TT, She WH. , et al. Diagnostic and prognostic role of 18-FDG PET/CT in the management of resectable biliary tract cancer. World J Surg 2018; 42 (03) 823-834
    Search in Google Scholar
  • 18 Saluja SS, Sharma R, Pal S, Sahni P, Chattopadhyay TK. Differentiation between benign and malignant hilar obstructions using laboratory and radiological investigations: a prospective study. HPB 2007; 9 (05) 373-382
    Search in Google Scholar
  • 19 Chapman R, Fevery J, Kalloo A. , et al; American Association for the Study of Liver Diseases. Diagnosis and management of primary sclerosing cholangitis. Hepatology 2010; 51 (02) 660-678
    Search in Google Scholar
  • 20 Schramm C, Eaton J, Ringe KI, Venkatesh S, Yamamura J. ; MRI working group of the IPSCSG. Recommendations on the use of magnetic resonance imaging in PSC-A position statement from the International PSC Study Group. Hepatology 2017; 66 (05) 1675-1688
    Search in Google Scholar
  • 21 Mohamadnejad M, DeWitt JM, Sherman S. , et al. Role of EUS for preoperative evaluation of cholangiocarcinoma: a large single-center experience. Gastrointest Endosc 2011; 73 (01) 71-78
    Search in Google Scholar
  • 22 Téllez-Ávila FI, Bernal-Méndez AR, Guerrero-Vázquez CG, Martínez-Lozano JA, Ramírez-Luna MÁ. Diagnostic yield of EUS-guided tissue acquisition as a first-line approach in patients with suspected hilar cholangiocarcinoma. Am J Gastroenterol 2014; 109 (08) 1294-1296
    Search in Google Scholar
  • 23 Navaneethan U, Njei B, Venkatesh PG, Lourdusamy V, Sanaka MR. Endoscopic ultrasound in the diagnosis of cholangiocarcinoma as the etiology of biliary strictures: a systematic review and meta-analysis. Gastroenterol Rep (Oxf) 2015; 3 (03) 209-215
    Search in Google Scholar
  • 24 Heimbach JK, Sanchez W, Rosen CB, Gores GJ. Trans-peritoneal fine needle aspiration biopsy of hilar cholangiocarcinoma is associated with disease dissemination. HPB 2011; 13 (05) 356-360
    Search in Google Scholar
  • 25 El Chafic AH, Dewitt J, Leblanc JK. , et al. Impact of preoperative endoscopic ultrasound-guided fine needle aspiration on postoperative recurrence and survival in cholangiocarcinoma patients. Endoscopy 2013; 45 (11) 883-889
    Search in Google Scholar
  • 26 Levy MJ, Heimbach JK, Gores GJ. Endoscopic ultrasound staging of cholangiocarcinoma. Curr Opin Gastroenterol 2012; 28 (03) 244-252
    Search in Google Scholar
  • 27 Gleeson FC, Rajan E, Levy MJ. , et al. EUS-guided FNA of regional lymph nodes in patients with unresectable hilar cholangiocarcinoma. Gastrointest Endosc 2008; 67 (03) 438-443
    Search in Google Scholar
  • 28 Navaneethan U, Njei B, Lourdusamy V, Konjeti R, Vargo JJ, Parsi MA. Comparative effectiveness of biliary brush cytology and intraductal biopsy for detection of malignant biliary strictures: a systematic review and meta-analysis. Gastrointest Endosc 2015; 81 (01) 168-176
    Search in Google Scholar
  • 29 Meister T, Heinzow HS, Woestmeyer C. , et al. Intraductal ultrasound substantiates diagnostics of bile duct strictures of uncertain etiology. World J Gastroenterol 2013; 19 (06) 874-881
    Search in Google Scholar
  • 30 Lee JH, Salem R, Aslanian H, Chacho M, Topazian M. Endoscopic ultrasound and fine-needle aspiration of unexplained bile duct strictures. Am J Gastroenterol 2004; 99 (06) 1069-1073
    Search in Google Scholar
  • 31 Chen YK, Parsi MA, Binmoeller KF. , et al. Single-operator cholangioscopy in patients requiring evaluation of bile duct disease or therapy of biliary stones (with videos). Gastrointest Endosc 2011; 74 (04) 805-814
    Search in Google Scholar
  • 32 Navaneethan U, Hasan MK, Lourdusamy V, Njei B, Varadarajulu S, Hawes RH. Single-operator cholangioscopy and targeted biopsies in the diagnosis of indeterminate biliary strictures: a systematic review. Gastrointest Endosc 2015; 82 (04) 608-14.e2
    Search in Google Scholar
  • 33 Njei B, McCarty TR, Varadarajulu S, Navaneethan U. Cost utility of ERCP-based modalities for the diagnosis of cholangiocarcinoma in primary sclerosing cholangitis. Gastrointest Endosc 2017; 85 (04) 773-781.e10
    Search in Google Scholar
  • 34 Navaneethan U, Hasan MK, Kommaraju K. , et al. Digital, single-operator cholangiopancreatoscopy in the diagnosis and management of pancreatobiliary disorders: a multicenter clinical experience (with video). Gastrointest Endosc 2016; 84 (04) 649-655
    Search in Google Scholar
  • 35 Mounzer R, Austin GL, Wani S, Brauer BC, Fukami N, Shah RJ. Per-oral video cholangiopancreatoscopy with narrow-band imaging for the evaluation of indeterminate pancreaticobiliary disease. Gastrointest Endosc 2017; 85 (03) 509-517
    Search in Google Scholar
  • 36 Meining A, Shah RJ, Slivka A. , et al. Classification of probe-based confocal laser endomicroscopy findings in pancreaticobiliary strictures. Endoscopy 2012; 44 (03) 251-257
    Search in Google Scholar
  • 37 Talreja JP, Sethi A, Jamidar PA. , et al. Interpretation of probe-based confocal laser endomicroscopy of indeterminate biliary strictures: is there any interobserver agreement?. Dig Dis Sci 2012; 57 (12) 3299-3302
    Search in Google Scholar
  • 38 Peter S, Council L, Bang JY. , et al. Poor agreement between endoscopists and gastrointestinal pathologists for the interpretation of probe-based confocal laser endomicroscopy findings. World J Gastroenterol 2014; 20 (47) 17993-18000
    Search in Google Scholar
  • 39 Caillol F, Filoche B, Gaidhane M, Kahaleh M. Refined probe-based confocal laser endomicroscopy classification for biliary strictures: the Paris Classification. Dig Dis Sci 2013; 58 (06) 1784-1789
    Search in Google Scholar
  • 40 Slivka A, Gan I, Jamidar P. , et al. Validation of the diagnostic accuracy of probe-based confocal laser endomicroscopy for the characterization of indeterminate biliary strictures: results of a prospective multicenter international study. Gastrointest Endosc 2015; 81 (02) 282-290
    Search in Google Scholar
  • 41 Jailwala J, Fogel EL, Sherman S. , et al. Triple-tissue sampling at ERCP in malignant biliary obstruction. Gastrointest Endosc 2000; 51 (4 Pt 1): 383-390
    Search in Google Scholar
  • 42 Eaton JE, Gossard AA, Talwalkar JA. Recall processes for biliary cytology in primary sclerosing cholangitis. Curr Opin Gastroenterol 2014; 30 (03) 287-294
    Search in Google Scholar
  • 43 Eaton JE, Barr Fritcher EG, Gores GJ. , et al. Biliary multifocal chromosomal polysomy and cholangiocarcinoma in primary sclerosing cholangitis. Am J Gastroenterol 2015; 110 (02) 299-309
    Search in Google Scholar
  • 44 Barr Fritcher EG, Voss JS, Jenkins SM. , et al. Primary sclerosing cholangitis with equivocal cytology: fluorescence in situ hybridization and serum CA 19-9 predict risk of malignancy. Cancer Cytopathol 2013; 121 (12) 708-717
    Search in Google Scholar
  • 45 Furmanczyk PS, Grieco VS, Agoff SN. Biliary brush cytology and the detection of cholangiocarcinoma in primary sclerosing cholangitis: evaluation of specific cytomorphologic features and CA19-9 levels. Am J Clin Pathol 2005; 124 (03) 355-360
    Search in Google Scholar
  • 46 Bangarulingam SY, Bjornsson E, Enders F. , et al. Long-term outcomes of positive fluorescence in situ hybridization tests in primary sclerosing cholangitis. Hepatology 2010; 51 (01) 174-180
    Search in Google Scholar
  • 47 Barr Fritcher EG, Kipp BR, Voss JS. , et al. Primary sclerosing cholangitis patients with serial polysomy fluorescence in situ hybridization results are at increased risk of cholangiocarcinoma. Am J Gastroenterol 2011; 106 (11) 2023-2028
    Search in Google Scholar
  • 48 Levy C, Lymp J, Angulo P, Gores GJ, Larusso N, Lindor KD. The value of serum CA 19-9 in predicting cholangiocarcinomas in patients with primary sclerosing cholangitis. Dig Dis Sci 2005; 50 (09) 1734-1740
    Search in Google Scholar
  • 49 Ali AH, Tabibian JH, Nasser-Ghodsi N. , et al. Surveillance for hepatobiliary cancers in patients with primary sclerosing cholangitis. Hepatology 2017;
    Search in Google Scholar
  • 50 Eaton JE, McCauley BM, Atkinson EJ. , et al. Variations in primary sclerosing cholangitis across the age spectrum. J Gastroenterol Hepatol 2017; 32 (10) 1763-1768
    Search in Google Scholar
  • 51 Weismüller TJ, Trivedi PJ, Bergquist A. , et al; International PSC Study Group. Patient age, sex, and inflammatory bowel disease phenotype associate with course of primary sclerosing cholangitis. Gastroenterology 2017; 152 (08) 1975-1984.e8
    Search in Google Scholar
  • 52 Rizvi S, Eaton JE, Gores GJ. Primary sclerosing cholangitis as a premalignant biliary tract disease: surveillance and management. Clin Gastroenterol Hepatol 2015; 13 (12) 2152-2165
    Search in Google Scholar
  • 53 Boyd S, Tenca A, Jokelainen K. , et al. Screening primary sclerosing cholangitis and biliary dysplasia with endoscopic retrograde cholangiography and brush cytology: risk factors for biliary neoplasia. Endoscopy 2016; 48 (05) 432-439
    Search in Google Scholar
  • 54 Kinde I, Wu J, Papadopoulos N, Kinzler KW, Vogelstein B. Detection and quantification of rare mutations with massively parallel sequencing. Proc Natl Acad Sci U S A 2011; 108 (23) 9530-9535
    Search in Google Scholar
  • 55 Dudley JC, Zheng Z, McDonald T. , 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 2016; 18 (01) 124-130
    Search in Google Scholar
  • 56 Hirsova P, Ibrahim SH, Verma VK. , et al. Extracellular vesicles in liver pathobiology: small particles with big impact. Hepatology 2016; 64 (06) 2219-2233
    Search in Google Scholar
  • 57 Li L, Masica D, Ishida M. , et al. Human bile contains microRNA-laden extracellular vesicles that can be used for cholangiocarcinoma diagnosis. Hepatology 2014; 60 (03) 896-907
    Search in Google Scholar
  • 58 Ge X, Wang Y, Nie J. , et al. The diagnostic/prognostic potential and molecular functions of long non-coding RNAs in the exosomes derived from the bile of human cholangiocarcinoma. Oncotarget 2017; 8 (41) 69995-70005
    Search in Google Scholar
  • 59 Li L, Piontek K, Ishida M. , et al. Extracellular vesicles carry microRNA-195 to intrahepatic cholangiocarcinoma and improve survival in a rat model. Hepatology 2017; 65 (02) 501-514
    Search in Google Scholar
  • 60 Julich-Haertel H, Urban SK, Krawczyk M. , et al. Cancer-associated circulating large extracellular vesicles in cholangiocarcinoma and hepatocellular carcinoma. J Hepatol 2017; 67 (02) 282-292
    Search in Google Scholar
  • 61 Al-Nedawi K, Meehan B, Micallef J. , et al. Intercellular transfer of the oncogenic receptor EGFRvIII by microvesicles derived from tumour cells. Nat Cell Biol 2008; 10 (05) 619-624
    Search in Google Scholar
  • 62 Peinado H, Alečković M, Lavotshkin S. , et al. Melanoma exosomes educate bone marrow progenitor cells toward a pro-metastatic phenotype through MET. Nat Med 2012; 18 (06) 883-891
    Search in Google Scholar
  • 63 Arbelaiz A, Azkargorta M, Krawczyk M. , et al. Serum extracellular vesicles contain protein biomarkers for primary sclerosing cholangitis and cholangiocarcinoma. Hepatology 2017; 66 (04) 1125-1143
    Search in Google Scholar
  • 64 Severino V, Dumonceau JM, Delhaye M. , et al. Extracellular vesicles in bile as markers of malignant biliary stenoses. Gastroenterology 2017; 153 (02) 495-504.e8
    Search in Google Scholar
  • 65 Lankisch TO, Metzger J, Negm AA. , et al. Bile proteomic profiles differentiate cholangiocarcinoma from primary sclerosing cholangitis and choledocholithiasis. Hepatology 2011; 53 (03) 875-884
    Search in Google Scholar
  • 66 Metzger J, Negm AA, Plentz RR. , et al. Urine proteomic analysis differentiates cholangiocarcinoma from primary sclerosing cholangitis and other benign biliary disorders. Gut 2013; 62 (01) 122-130
    Search in Google Scholar
  • 67 Alix-Panabières C, Pantel K. Clinical applications of circulating tumor cells and circulating tumor DNA as liquid biopsy. Cancer Discov 2016; 6 (05) 479-491
    Search in Google Scholar
  • 68 Haber DA, Velculescu VE. Blood-based analyses of cancer: circulating tumor cells and circulating tumor DNA. Cancer Discov 2014; 4 (06) 650-661
    Search in Google Scholar
  • 69 Pantel K, Alix-Panabières C. Real-time liquid biopsy in cancer patients: fact or fiction?. Cancer Res 2013; 73 (21) 6384-6388
    Search in Google Scholar
  • 70 Gerlinger M, Rowan AJ, Horswell S. , et al. Intratumor heterogeneity and branched evolution revealed by multiregion sequencing. N Engl J Med 2012; 366 (10) 883-892
    Search in Google Scholar
  • 71 Murtaza M, Dawson SJ, Pogrebniak K. , et al. Multifocal clonal evolution characterized using circulating tumour DNA in a case of metastatic breast cancer. Nat Commun 2015; 6: 8760
    Search in Google Scholar
  • 72 Ilie M, Hofman V, Long-Mira E. , et al. “Sentinel” circulating tumor cells allow early diagnosis of lung cancer in patients with chronic obstructive pulmonary disease. PLoS One 2014; 9 (10) e111597
    Search in Google Scholar
  • 73 Rhim AD, Mirek ET, Aiello NM. , et al. EMT and dissemination precede pancreatic tumor formation. Cell 2012; 148 (1-2): 349-361
    Search in Google Scholar
  • 74 Hüsemann Y, Geigl JB, Schubert F. , et al. Systemic spread is an early step in breast cancer. Cancer Cell 2008; 13 (01) 58-68
    Search in Google Scholar
  • 75 Yang JD, Campion MB, Liu MC. , et al. Circulating tumor cells are associated with poor overall survival in patients with cholangiocarcinoma. Hepatology 2016; 63 (01) 148-158
    Search in Google Scholar
  • 76 Zill OA, Greene C, Sebisanovic D. , et al. Cell-free DNA next-generation sequencing in pancreatobiliary carcinomas. Cancer Discov 2015; 5 (10) 1040-1048
    Search in Google Scholar
  • 77 Andresen K, Boberg KM, Vedeld HM. , et al. Four DNA methylation biomarkers in biliary brush samples accurately identify the presence of cholangiocarcinoma. Hepatology 2015; 61 (05) 1651-1659
    Search in Google Scholar
  • 78 Yang J, Yab T, Taylor WR. , et al. Detection of cholangiocarcinoma by assay of methylated DNA markers in plasma. Gastroenterology 2017; 152: S1041-S1042
    Search in Google Scholar