Research Papers:

Identification of a serum biomarker panel for the differential diagnosis of cholangiocarcinoma and primary sclerosing cholangitis

Joy Cuenco _, Natascha Wehnert, Oleg Blyuss, Anna Kazarian, Harry J. Whitwell, Usha Menon, Anne Dawnay, Michael P. Manns, Stephen P. Pereira and John F. Timms

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Oncotarget. 2018; 9:17430-17442. https://doi.org/10.18632/oncotarget.24732

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Joy Cuenco1, Natascha Wehnert2, Oleg Blyuss1, Anna Kazarian1, Harry J. Whitwell1, Usha Menon1, Anne Dawnay3, Michael P. Manns2, Stephen P. Pereira4 and John F. Timms1

1Institute for Women's Health, University College London, London, WC1E 6BT, UK

2Hannover Medical School, Department of Gastroenterology, Hepatology and Endocrinology, Hannover, 30625, Germany

3Clinical Biochemistry, University College London Hospitals NHS Foundation Trust, London, W1T 4EU, UK

4Institute for Liver and Digestive Health, University College London, Royal Free Hospital, London, NW3 2PG, UK

Correspondence to:

John F. Timms, email: [email protected]

Keywords: cholangiocarcinoma; biliary tract cancer; serum biomarker; primary sclerosing cholangitis; differential diagnosis

Received: January 04, 2018     Accepted: March 06, 2018     Published: April 03, 2018


The non-invasive differentiation of malignant and benign biliary disease is a clinical challenge. Carbohydrate antigen 19-9 (CA19-9), leucine-rich α2-glycoprotein (LRG1), interleukin 6 (IL6), pyruvate kinase M2 (PKM2), cytokeratin 19 fragment (CYFRA21.1) and mucin 5AC (MUC5AC) have reported utility for differentiating cholangiocarcinoma (CCA) from benign biliary disease. Herein, serum levels of these markers were tested in 66 cases of CCA and 62 cases of primary sclerosing cholangitis (PSC) and compared with markers of liver function and inflammation. Markers panels were assessed for their ability to discriminate malignant and benign disease. Several of the markers were also assessed in pre-diagnosis biliary tract cancer (BTC) samples with performances evaluated at different times prior to diagnosis. We show that LRG1 and IL6 were unable to accurately distinguish CCA from PSC, whereas CA19-9, PKM2, CYFRA21.1 and MUC5AC were significantly elevated in malignancy. Area under the receiver operating characteristic curves for these individual markers ranged from 0.73–0.84, with the best single marker (PKM2) providing 61% sensitivity at 90% specificity. A panel combining PKM2, CYFRA21.1 and MUC5AC gave 76% sensitivity at 90% specificity, which increased to 82% sensitivity by adding gamma-glutamyltransferase (GGT). In the pre-diagnosis setting, LRG1, IL6 and PKM2 were poor predictors of BTC, whilst CA19-9 and C-reactive protein were elevated up to 2 years before diagnosis. In conclusion, LRG1, IL6 and PKM2 were not useful for early detection of BTC, whilst a model combining PKM2, CYFRA21.1, MUC5AC and GGT was beneficial in differentiating malignant from benign biliary disease, warranting validation in a prospective trial.

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