Impact of trimodality sampling on detection of malignant biliary strictures compared with patients with primary sclerosing cholangitis

Published:December 02, 2021DOI:

      Background and Aims

      Malignant biliary strictures can be difficult to diagnose, with up to 20% considered indeterminate after initial tissue sampling. This study aimed to determine the performance characteristics of transpapillary biopsy sampling (TPB) and fluorescence in situ hybridization (FISH) in isolation or in combination with standard brush cytology (BC) in patients who received trimodality sampling for biliary strictures.


      This single-center retrospective cohort study included patients with biliary strictures undergoing ERCP with trimodality sampling between September 2014 and April 2019. Performance characteristics for each diagnostic test alone and in combination were calculated.


      Two hundred four patients underwent trimodality biliary sampling, including 104 (51.0%) with malignancy. The diagnostic sensitivity for malignancy with BC (17.3%) significantly improved with dual modality (BC+FISH, 58.7%; BC+TPB, 40.4%) or trimodality sampling (68.3%; P < .001 for all comparisons). Trimodality sampling improved diagnostic sensitivity for malignancy compared with BC+FISH (P = .002) and BC+TPB (P < .001). There was no statistically significant difference in the sensitivity of trimodality sampling in detecting cholangiocarcinoma (79.7%) compared with pancreatic cancer (62.5%; P = .1). Among 57 patients with primary sclerosing cholangitis (PSC), the sensitivity of detecting biliary malignancy (n = 20) was 20% for BC and significantly improved with the addition of FISH (80%; P < .001) but not with TPB (35.0%; P = .25). Trimodality sampling did not further improve diagnostic sensitivity (85%) over BC+FISH (80%) for malignancy in the setting of PSC (P = 1).


      Trimodality sampling improves the diagnostic sensitivity for the detection of malignant biliary strictures with no significant difference in sensitivity for cholangiocarcinoma compared with pancreatic cancer. However, in patients with PSC, trimodality sampling was not superior to BC+FISH.

      Graphical abstract


      BC (brush cytology), CCA (cholangiocarcinoma), FISH (fluorescence in situ hybridization), NPV (negative predictive value), PPV (positive predictive value), PSC (primary sclerosing cholangitis), SOC (single-operator cholangioscopy), TPB (transpapillary biopsy sampling)
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        • Rizvi S.
        • Khan S.A.
        • Hallemeier C.L.
        • et al.
        Cholangiocarcinoma—evolving concepts and therapeutic strategies.
        Nat Rev Clin Oncol. 2018; 15: 95-111
        • Jan Y.-Y.
        • Yeh C.-N.
        • Yeh T.-S.
        • et al.
        Clinicopathological factors predicting long-term overall survival after hepatectomy for peripheral cholangiocarcinoma.
        World J Surg. 2005; 29: 894-898
        • Valle J.
        • Wasan H.
        • Palmer D.H.
        • et al.
        Cisplatin plus gemcitabine versus gemcitabine for biliary tract cancer.
        N Engl J Med. 2010; 362: 1273-1281
        • Everhart J.E.
        • Ruhl C.E.
        Burden of digestive diseases in the United States part III: liver, biliary tract, and pancreas.
        Gastroenterology. 2009; 136: 1134-1144
        • Clayton R.A.
        • Clarke D.L.
        • Currie E.J.
        • et al.
        Incidence of benign pathology in patients undergoing hepatic resection for suspected malignancy.
        Surgeon. 2003; 1: 32-38
        • Gerhards M.F.
        • Vos P.
        • van Gulik T.M.
        • et al.
        Incidence of benign lesions in patients resected for suspicious hilar obstruction.
        Br J Surg. 2001; 88: 48-51
        • Corvera C.U.
        • Blumgart L.H.
        • Darvishian F.
        • et al.
        Clinical and pathologic features of proximal biliary strictures masquerading as hilar cholangiocarcinoma.
        J Am Coll Surg. 2005; 201: 862-869
        • Franken L.C.
        • Schreuder A.M.
        • Roos E.
        • et al.
        Morbidity and mortality after major liver resection in patients with perihilar cholangiocarcinoma: a systematic review and meta-analysis.
        Surgery. 2019; 165: 918-928
        • Barr Fritcher E.G.
        • Voss J.S.
        • Brankley S.M.
        • et al.
        An optimized set of fluorescence in situ hybridization probes for detection of pancreatobiliary tract cancer in cytology brush samples.
        Gastroenterology. 2015; 149: 1813-1824
        • Navaneethan U.
        • Njei B.
        • Lourdusamy V.
        • et al.
        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: 168-176
        • Kitajima Y.
        • Ohara H.
        • Nakazawa T.
        • et al.
        Usefulness of transpapillary bile duct brushing cytology and forceps biopsy for improved diagnosis in patients with biliary strictures.
        J Gastroenterol Hepatol. 2007; 22: 1615-1620
        • Chen W.M.
        • Wei K.L.
        • Chen Y.S.
        • et al.
        Transpapillary biliary biopsy for malignant biliary strictures: comparison between cholangiocarcinoma and pancreatic cancer.
        World J Surg Oncol. 2016; 14: 140
        • Higashizawa T.
        • Tamada K.
        • Tomiyama T.
        • et al.
        Biliary guidewire facilitates bile duct biopsy and endoscopic drainage.
        J Gastroenterol Hepatol. 2002; 17: 332-336
        • Blechacz B.
        • Komuta M.
        • Roskams T.
        • et al.
        Clinical diagnosis and staging of cholangiocarcinoma.
        Nat Rev Gastroenterol Hepatol. 2011; 8: 512-522
        • Rizvi S.
        • Eaton J.
        • Yang J.D.
        • et al.
        Emerging technologies for the diagnosis of perihilar cholangiocarcinoma.
        Semin Liver Dis. 2018; 38: 160-169
        • Nanda A.
        • Brown J.M.
        • Berger S.H.
        • et al.
        Triple modality testing by endoscopic retrograde cholangiopancreatography for the diagnosis of cholangiocarcinoma.
        Therap Adv Gastroenterol. 2015; 8: 56-65
        • Naitoh I.
        • Nakazawa T.
        • Kato A.
        • et al.
        Predictive factors for positive diagnosis of malignant biliary strictures by transpapillary brush cytology and forceps biopsy.
        J Dig Dis. 2016; 17: 44-51
        • Adler D.G.
        • Witt B.
        Cytologic diagnosis of biliary strictures: FISH or cut the sensitivity rate?.
        Dig Dis Sci. 2018; 63: 549-550
        • Vlajnic T.
        • Somaini G.
        • Savic S.
        • et al.
        Targeted multiprobe fluorescence in situ hybridization analysis for elucidation of inconclusive pancreatobiliary cytology.
        Cancer Cytopathol. 2014; 122: 627-634
        • Kipp B.R.
        • Stadheim L.M.
        • Halling S.A.
        • et al.
        A comparison of routine cytology and fluorescence in situ hybridization for the detection of malignant bile duct strictures.
        Am J Gastroenterol. 2004; 99: 1675-1681
        • Timmer M.R.
        • Lau C.T.
        • Meijer S.L.
        • et al.
        Genetic abnormalities in biliary brush samples for distinguishing cholangiocarcinoma from benign strictures in primary sclerosing cholangitis.
        Gastroenterol Res Pract. 2016; 2016: 4381513
        • Singhi A.D.
        • Nikiforova M.N.
        • Chennat J.
        • et al.
        Integrating next-generation sequencing to endoscopic retrograde cholangiopancreatography (ERCP)-obtained biliary specimens improves the detection and management of patients with malignant bile duct strictures.
        Gut. 2020; 69: 52-61
        • Tischendorf J.J.
        • Krüger M.
        • Trautwein C.
        • et al.
        Cholangioscopic characterization of dominant bile duct stenoses in patients with primary sclerosing cholangitis.
        Endoscopy. 2006; 38: 665-669
        • Kalaitzakis E.
        • Sturgess R.
        • Kaltsidis H.
        • et al.
        Diagnostic utility of single-user peroral cholangioscopy in sclerosing cholangitis.
        Scand J Gastroenterol. 2014; 49: 1237-1244
        • Arnelo U.
        • von Seth E.
        • Bergquist A.
        Prospective evaluation of the clinical utility of single-operator peroral cholangioscopy in patients with primary sclerosing cholangitis.
        Endoscopy. 2015; 47: 696-702
        • Njei B.
        • McCarty T.R.
        • Varadarajulu S.
        • et al.
        Cost utility of ERCP-based modalities for the diagnosis of cholangiocarcinoma in primary sclerosing cholangitis.
        Gastrointest Endosc. 2017; 85: 773-781
        • Kaura K.
        • Sawas T.
        • Bazerbachi F.
        • et al.
        Cholangioscopy biopsies improve detection of cholangiocarcinoma when combined with cytology and FISH, but not in patients with PSC.
        Dig Dis Sci. 2020; 65: 1471-1478
        • Chen Y.K.
        • Parsi M.A.
        • Binmoeller K.F.
        • et al.
        Single-operator cholangioscopy in patients requiring evaluation of bile duct disease or therapy of biliary stones (with videos).
        Gastrointest Endosc. 2011; 74: 805-814
        • Mohamadnejad M.
        • DeWitt J.M.
        • Sherman S.
        • et al.
        Role of EUS for preoperative evaluation of cholangiocarcinoma: a large single-center experience.
        Gastrointest Endosc. 2011; 73: 71-78
        • Navaneethan U.
        • Njei B.
        • Venkatesh P.G.
        • et al.
        Endoscopic ultrasound in the diagnosis of cholangiocarcinoma as the etiology of biliary strictures: a systematic review and meta-analysis.
        Gastroenterol Rep. 2015; 3: 209-215
        • Gleeson F.C.
        • Lee J.H.
        • Dewitt J.M.
        Tumor seeding associated with selected gastrointestinal endoscopic interventions.
        Clin Gastroenterol Hepatol. 2018; 16: 1385-1388
        • Rosen C.B.
        • Heimbach J.K.
        • Gores G.J.
        Liver transplantation for cholangiocarcinoma.
        Transpl Int. 2010; 23: 692-697
        • Malikowski T.
        • Levy M.J.
        • Gleeson F.C.
        • et al.
        Endoscopic ultrasound/fine needle aspiration is effective for lymph node staging in patients with cholangiocarcinoma.
        Hepatology. 2020; 72: 940-948
        • Levy M.J.
        • Heimbach J.K.
        • Gores G.J.
        Endoscopic ultrasound staging of cholangiocarcinoma.
        Curr Opin Gastroenterol. 2012; 28: 244-252
        • Weismüller T.J.
        • Wedemeyer J.
        • Kubicka S.
        • et al.
        The challenges in primary sclerosing cholangitis—aetiopathogenesis, autoimmunity, management and malignancy.
        J Hepatol. 2008; 48: S38-S57
        • Sawas T.
        • Kaura K.
        • Chandrasekhara V.
        Endoscopic diagnosis and therapy in primary sclerosing cholangitis.
        Curr Treat Opt Gastroenterol. 2020; 18: 353-368
        • Eaton J.E.
        • Barr Fritcher E.G.
        • Gores G.J.
        • et al.
        Biliary multifocal chromosomal polysomy and cholangiocarcinoma in primary sclerosing cholangitis.
        Am J Gastroenterol. 2015; 110: 299-309
        • Azeem N.
        • Gostout C.J.
        • Knipschield M.
        • et al.
        Cholangioscopy with narrow-band imaging in patients with primary sclerosing cholangitis undergoing ERCP.
        Gastrointest Endosc. 2014; 79: 773-779

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