Novel biomarkers and endoscopic techniques for diagnosing pancreaticobiliary malignancy

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The incidence of both cancers is increasing annually and these tumours continue to be diagnosed late and at an advanced stage, limiting options for curative treatment. Population-based screening programmes do not exist for these cancers, and diagnosis currently is dependent on symptom recognition, but often symptoms are not present until the disease is advanced. Recently, a number of promising blood and urine biomarkers have been described for pancreaticobiliary malignancy and are summarised in this review. Novel endoscopic techniques such as single-operator cholangioscopy and confocal endomicroscopy have been used in some centres to enhance standard endoscopic diagnostic techniques and are also evaluated in this review." } { "@context": "http://schema.org", "@type": "BreadcrumbList", "itemListElement": [ { "@type": "ListItem", "position": "1", "item": { "@id": "https://f1000research.com/", "name": "Home" } }, { "@type": "ListItem", "position": "2", "item": { "@id": "https://f1000research.com/browse/articles", "name": "Browse" } }, { "@type": "ListItem", "position": "3", "item": { "@id": "https://f1000research.com/articles/6-1643", "name": "Novel biomarkers and endoscopic techniques for diagnosing pancreaticobiliary..." } } ] } Home Browse Novel biomarkers and endoscopic techniques for diagnosing pancreaticobiliary... ALL Metrics - Views Downloads Get PDF Get XML Cite How to cite this article Keane MG, Shah A, Pereira SP and Joshi D. Novel biomarkers and endoscopic techniques for diagnosing pancreaticobiliary malignancy [version 1; peer review: 2 approved] . F1000Research 2017, 6 (F1000 Faculty Rev):1643 ( https://doi.org/10.12688/f1000research.11371.1 ) NOTE: If applicable, it is important to ensure the information in square brackets after the title is included in all citations of this article. Close Copy Citation Details Export Export Citation Sciwheel EndNote Ref. Manager Bibtex ProCite Sente EXPORT Select a format first Track Share ▬ ✚ Review Novel biomarkers and endoscopic techniques for diagnosing pancreaticobiliary malignancy [version 1; peer review: 2 approved] Margaret G Keane https://orcid.org/0000-0001-7477-4541 1 , Amar Shah 1 , Stephen P Pereira https://orcid.org/0000-0003-0821-1809 2 , Deepak Joshi 1 Margaret G Keane https://orcid.org/0000-0001-7477-4541 1 , Amar Shah 1 , Stephen P Pereira https://orcid.org/0000-0003-0821-1809 2 , Deepak Joshi 1 PUBLISHED 05 Sep 2017 Author details Author details 1 Institute of Liver Studies, King's College Hospital, London, UK 2 UCL Institute for Liver and Digestive Health, Royal Free Campus, London, UK OPEN PEER REVIEW DETAILS REVIEWER STATUS Abstract The UK incidence of pancreatic ductal adenocarcinoma is 9 per 100,000 population, and biliary tract cancer occurs at a rate of 1–2 per 100,000. The incidence of both cancers is increasing annually and these tumours continue to be diagnosed late and at an advanced stage, limiting options for curative treatment. Population-based screening programmes do not exist for these cancers, and diagnosis currently is dependent on symptom recognition, but often symptoms are not present until the disease is advanced. Recently, a number of promising blood and urine biomarkers have been described for pancreaticobiliary malignancy and are summarised in this review. Novel endoscopic techniques such as single-operator cholangioscopy and confocal endomicroscopy have been used in some centres to enhance standard endoscopic diagnostic techniques and are also evaluated in this review. READ ALL READ LESS Keywords Pancreaticobiliary malignancy, Endoscopic retrograde, cholangiopancreatography, CA 19-9, pancreatic, biliary Corresponding Author(s) Deepak Joshi ( [email protected] ) Close Corresponding author: Deepak Joshi Competing interests: The authors declare that they have no competing interests. Grant information: SPP is supported in part by National Institutes of Health grant P01CA8420. Part of the work was undertaken at University College London Hospitals/University College London, which received a portion of funding from the Department of Health’s National Institute for Health Research Biomedical Research Centres funding scheme. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Copyright: © 2017 Keane MG et al . This is an open access article distributed under the terms of the Creative Commons Attribution License , which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. How to cite: Keane MG, Shah A, Pereira SP and Joshi D. Novel biomarkers and endoscopic techniques for diagnosing pancreaticobiliary malignancy [version 1; peer review: 2 approved] . F1000Research 2017, 6 (F1000 Faculty Rev):1643 ( https://doi.org/10.12688/f1000research.11371.1 ) First published: 05 Sep 2017, 6 (F1000 Faculty Rev):1643 ( https://doi.org/10.12688/f1000research.11371.1 ) Latest published: 05 Sep 2017, 6 (F1000 Faculty Rev):1643 ( https://doi.org/10.12688/f1000research.11371.1 ) Introduction In the UK, pancreatic ductal adenocarcinoma (PDAC) is the 10 th commonest cancer and has an incidence of 9 per 100,000 population 1 , and biliary tract cancer (BTC) (including intra- and extra-hepatic cholangiocarcinoma and gallbladder cancer) has an incidence of 1–2 cases per 100,000 population 2 . Long-term survival is poor; 5-year survival is less than 4% for both tumours 3 , 4 . Often these tumours are diagnosed late, when patients have advanced disease and curative surgical resection is no longer possible. Globally the highest incidence of PDAC is seen in Northern Europe and North America 5 , where the rates are 3 to 4 times higher than in tropical countries 6 . Overall incidence is increasing 5 , and as most tumours are sporadic, this rising incidence is attributed to differences in lifestyles and exposure to environmental risk factors 7 , such as smoking 8 – 15 , diabetes mellitus, chronic pancreatitis 1 , 15 , 16 and obesity 17 . In BTC, the variations in incidence seen globally are even more pronounced; and the highest incidence is in northeastern Thailand (96 per 100,000 men) 18 , which has a population with high levels of chronic typhoid and infestation of liver fluke ( Clonorchis sinensis and Opisthorchis viverinni ) 18 . Other BTC risk factors seen in all populations include older age 18 , primary sclerosing cholangitis 19 , intraductal stones and rare biliary cystic diseases 20 . Inflammatory bowel disease, chronic viral hepatitis, cirrhosis, smoking, diabetes, obesity and excess alcohol consumption may also increase the risk of BTC 20 – 22 . Despite improved diagnostic techniques, detecting pancreaticobiliary malignancy remains a significant clinical challenge. A common presentation of these tumours is a biliary stricture with or without a mass lesion. The differential of an indeterminate biliary stricture is broad, and often the associated symptoms and radiological findings overlap between benign and malignant conditions, often making differentiation—particularly between cancer, primary sclerosing cholangitis and IgG4-related disease—impossible without further investigations, typically by endoscopic retrograde cholangiopancreatography (ERCP) or endoscopic ultrasound (EUS) 23 – 25 . However, biliary brush cytology is also an imperfect test, although specificity is high (96–100%), sensitivity for malignancy remains low (9–57%) and in early disease when tumours are small, sensitivities are even lower 26 , 27 . Therefore, patients frequently require multiple procedures to obtain a final diagnosis 28 – 30 . So there has been growing interest in the development of simple tests to streamline the diagnosis to pancreaticobiliary malignancy and guide appropriate and timely therapy for patients. Identifying better diagnostic tools for PDAC and BTC would also make screening and surveillance possible, particularly in high-risk populations 4 , 8 , 31 . This would enable the detection of tumours at an earlier stage when curative resection is possible, leading to substantial improvements in survival 32 . This review provides an overview of the latest innovations in diagnostic biomarkers and endoscopic techniques for pancreaticobiliary malignancy. Methods We performed a systematic review of the literature by using PubMed, EMBASE and the Cochrane Library. The search was limited to studies published in the English language between January 2013 and March 2017. Medical Subject Headings (MeSH) terms were decided by a consensus of the authors and included “pancreatic cancer” or “cholangiocarcinoma” and “biomarker”. The search was restricted to title, abstract and keywords. Articles that described outcomes for fewer than five patients were excluded. Case reports, abstracts and reviews were excluded. All references were screened for potentially relevant studies not identified in the initial literature search. The following variables were extracted for each report when available: number of malignant and benign cases, sensitivity, specificity and area under the curve (AUC). One hundred ten articles were included in the final review. Biomarkers 1. Serum biomarkers and blood tests Carbohydrate antigen (CA) 19-9 is the most widely used tumour marker in pancreaticobiliary malignancy. Overall sensitivity (78–89%) and specificity (67–87%) are low, and in around 7% of the population who lack the Lewis (a) antigen, CA19-9 will remain negative 33 . In small tumours, sensitivity decreases further. The marker can also be elevated in a number of other malignant diseases (for example, gastric adenocarcinoma) and benign diseases, particularly those causing jaundice (for example, primary biliary cirrhosis, cholestasis and cholangitis), and in smokers 34 . In addition, variation has been reported among commercially available assays, which may impact on interpretation 35 . Therefore, to improve the sensitivity of the marker in current clinical practice, it is always interpreted in the context of cross-sectional imaging findings 33 . Other commercially available tumour markers that have a role in diagnosing pancreaticobiliary cancer include carcinoembryonic antigen (CEA) and CA125. CEA is a glycosyl phosphatidyl inositol cell surface-anchored glycoprotein that is involved in cell adhesion. When elevated, it is highly suggestive of colorectal cancer, but it is also increased in about a third of patients with BTC 36 – 38 . CA125 is a protein encoded by the MUC16 gene and is a large membrane-associated glycoprotein with a single transmembrane domain. When elevated, it is suggestive of ovarian cancer, but it is also increased in about 40–50% of patients with pancreaticobiliary malignancy, particularly when there is peritoneal involvement 38 . Owing to the limitations of existing biomarkers, over the last few years several studies have evaluated various combinations of biomarkers to supplement or ultimately replace existing biomarkers. Biomarker panels using combinations of markers, often including CA19-9, have been particularly successful in detecting small tumours and early disease. Validation studies have also shown that these markers can differentiate PDAC from relevant benign conditions and in some cases detect tumours up to 1 year prior to diagnosis with a specificity of 95% and a sensitivity of 68% 7 ( Table 1 and Table 2 ). Table 1. Serum protein biomarkers for biliary tract cancer, 2013–2017. Author (year) Biomarker/ Combination (serum) Biliary tract cancer, number Benign lesion/ cholangitis, number Healthy volunteers, number Sensitivity Specificity Area under the curve Single biomarkers Han et al . (2013) 84 HDGF 83 - 51 66% 88% 0.81 Ruzzenente et al . (2014) 85 MUC5AC 49 23 16 - - 0.91 Voigtlander et al . (2014) 86 Angpt-2 56 111 - 74% 94% 0.85 Lumachi et al . (2014) 87 CA 19-9 24 25 - 74% 82% - Wang et al . (2014) 88 CA 19-9 78 78 78 72% 96% - Lumachi et al . (2014) 87 CEA 24 25 - 52% 55% - Wang et al . (2014) 88 CEA 78 78 78 11% 97% - Wang et al . (2014) 88 CA 125 78 78 78 45% 96% - Lumachi et al . (2014) 87 CYFRA 21-1 24 25 - 76% 79% - Liu et al . (2015) 89 VEGF-C 31 10 10 71% 80% 0.79 Liu et al . (2015) 89 VEGF-D 31 10 10 74% 85% 0.84 Huang et al . (2015) 90 CYFRA 21-1 134 52 - 75% 85% - Lumachi et al . (2014) 87 MMP7 24 25 - 78% 77% - Nigam et al . (2014) 91 Survivin 39 (gallbladder cancer) 30 25 81% 80% - Rucksaken et al . (2014) 92 HSP70 31 12 23 94% 74% 0.92 Rucksaken et al . (2014) 92 ENO1 31 - 23 81% 78% 0.86 Rucksaken et al . (2014) 92 RNH1 31 - 23 94% 67% 0.84 Wang et al . (2014) 88 CA242 78 78 78 64% 99% - Ince et al . (2014) 93 VEGFR3 96 129 - 48% 82% 0.62 Ince et al . (2014) 93 TAC 96 129 - 61% 60% 0.60 Rucksaken et al . (2017) 94 ORM2 70 46 20 92% 74% - Rose et al . (2016) 95 CEACAM6 41 42 - 87.5% 69% 0.74 Jiao et al . (2014) 96 Nucleosides 202 (gallbladder cancer) 203 205 91% 96% - Biomarker combinations Lumachi et al . (2014) 87 CEA + CA19-9 + CYFRA 21-1 + MMP7 24 25 - 92% 96% Table 2. Serum protein biomarkers for pancreatic cancer, 2012–2017. Author (year) Biomarker/ Combination (serum) PDAC, number Benign controls, number Healthy volunteers, number Sensitivity Specificity Area under the curve Single biomarkers Sogawa et al . (2016) 97 C4BPA 52 20 40 67% 95% 0.860 Rychlikova et al . (2016) 98 Osteopontin 64 71 48 - - - Lin et al . (2016) 99 APOA-I 78 - 36 96% 72.2% 0.880 Lin et al . (2016) 99 TF 78 - 36 75% 72.8% 0.760 Guo et al . (2016) 100 Dysbindin 250 80 150 81.9% 84.7% 0.849 Han et al . (2015) 101 Dickkopf-1 140 - 92 89.3% 79.3% 0.919 Qu et al . (2015) 102 DCLK1 74 74 - - - 0.740 Dong et al . (2015) 103 Survivin 80 - 80 - - - Gebauer et al . (2014) 104 EpCAM 66 43 104 66.7% 77.5% - Wang et al . (2014) 105 MIC-1 807 165 500 65.8% 96.4% 0.935 Kendrick et al . (2014) 106 IGFBP2 84 40 84 22% 95% 0.655 Kendrick et al . (2014) 106 MSLN 84 40 84 17% 95% 0.668 Kang et al . (2014) 107 COL6A3 44 46 30 - - 0.975 Willumsen et al . (2013) 108 C1M 15 - 33 - - 0.830 Willumsen et al . (2013) 108 C3M 15 - 33 - - 0.880 Willumsen et al . (2013) 108 C4M 15 - 33 - - 0.940 Willumsen et al . (2013) 108 C4M12a1 15 - 33 - - 0.890 Falco et al . (2013) 109 BAG3 52 - 44 75% 75% 0.770 Falco et al . (2013) 109 BAG3 52 17 (chronic pancreatitis) - 81% 77% 0.810 Chen et al . (2013) 110 TTR 40 - 40 91% 47% 0.730 Gold et al . (2013) 111 PAM4 298 - 79 76% 96% - Gold et al . (2013) 111 PAM4 298 120 - - - 0.890 Poruk et al . (2013) 112 OPN 86 48 86 - - 0.720 Poruk et al . (2013) 112 TIMP-1 86 48 86 - - 0.770 Lee et al. (2014) 113 CA 19-9 41 12 44 80.4% 70% 0.833 Lee et al. (2014) 113 Human complement factor B (CFB) 41 12 44 73.1% 97.9% 0.958 Mixed cohorts Ince et al . (2014) 93 CEA 96 (41 PDAC +25 BTC) 129 - 42.7% 89.9% 0.713 Ince et al . (2014) 93 CA19-9 96 (41 PDAC +25 BTC) 129 - 49% 84.5% 0.701 Ince et al . (2014) 93 VEGFR3 96 (41 PDAC +25 BTC) 129 - 48.4% 82.9% 0.622 Ince et al . (2014) 93 Total antioxidant capacity 96 (41 PDAC +25 BTC) 129 - 61.1% 60.5% 0.602 Abdel-Razik et al . (2016) 114 IGF-1 47 (25 PDAC + 18 BTC) 62 - 62% 51% 0.605 Abdel-Razik et al . (2016) 114 VEGF 47 (25 PDAC + 18 BTC) 62 - 58.3% 57.3% 0.544 Biomarker combinations Chen et al . (2013) 110 TTR + CA19-9 40 - 40 81% 85% 0.910 Lee et al . (2014) 113 CA19-9 + CFB 41 12 44 90.1% 97.2% 0.986 Sogawa et al . (2016) 97 C4BPA + CA19-9 52 20 40 86% 80% 0.930 Makawita et al . (2013) 115 CA19-9 + REG1B 100 - 92 - - 0.880 Makawita et al . (2013) 115 CA19-9 + SYCN + REG1B 100 - 92 - - 0.870 Willumsen et al . (2013) 108 C1M + C3M + C4M + C4M12a1 15 - 33 - - 0.990 Shaw et al . (2014) 116 IL10 + IL6 + PDGF + Ca19-9 84 45 (benign) - 93% 58% 0.840 Shaw et al . (2014) 116 IL8 + IL6 + IL-10 + Ca19-9 84 32 (chronic pancreatitis) - 75% 91% 0.880 Shaw et al . (2014) 116 IL8 + IL1b + Ca 19-9 127 - 45 94% 100% 0.857 Brand et al . (2011) 117 Ca-19 + CEA + TIMP-1 173 70 120 71% 89% - Capello et al . (2017) 118 TIMP1 + LRG1 + Ca19-9 73 - 60 0.849% 0.633% 0.949 Capello et al . (2017) 118 TIMP1 + LRG1 + Ca19-9 73 74 - 0.452% 0.541% 0.890 Chan et al . (2014) 119 Ca19-9 + Ca125 + LAMC2 139 65 10 82% 74%% 0.870 Makawita et al . (2013) 115 CA19-9 + REG1B 82 41 92 - - 0.875 Makawita et al . (2013) 115 CA19-9 + SYNC + REG1B 82 41 92 - - 0.873 Makawita et al . (2013) 115 CA19-9 + AGR2 + REG1B 82 41 92 - - 0.869 BTC, biliary tract cancer; PDAC, pancreatic ductal adenocarcinoma. In pancreaticobiliary malignancy and PDAC in particular, metastatic disease occurs at a very early stage in tumour development. This is demonstrated by the fact that patients who underwent resection of small primary tumours (<2 cm) with no clinical evidence of metastatic disease had a 5-year survival after pancreatectomy of less than 18% owing to recurrent metastatic disease 39 . Tumour development is driven by a series of cumulative genetic abnormalities; therefore, genetic and epigenetic changes have been explored as diagnostic targets in circulating tumour cells, cell-free DNA (cfDNA) and non-coding RNA ( Table 3 – Table 5 ). Owing to the position and composition of pancreaticobiliary tumours, tissue samples are frequently acellular, making diagnostics challenging. Recently, the utility of next-generation sequencing was explored as a technique that allows the detection of low-abundance mutations and abnormalities in small amounts of material 40 . Changes in the metabalome are also being explored as a potential diagnostic tool in pancreaticobiliary malignancy 41 . Table 3. Genetic and epigenetic alterations in circulating tumour cells in pancreatic ductal adenocarcinoma and biliary tract cancer, 2013–2017. Author (year) Target Biliary tract cancer, number Pancreatic ductal adenocarcinoma, number Benign lesions, number Healthy volunteers, number Detected Sensitivity Specificity Area under the curve Ankeny et al . (2016) 120 K-ras - 72 28 - - 75% 96.4% 0.867 Kulemann et al . (2016) 121 K-ras - 21 - 10 80% (stage IIA/IIB) 91% (stage III/IV) - - - Singh et al . (2015) 122 ctDNA, K-ras - - - - - 65.3% 61.5% 0.6681 Kinugasa et al . (2015) 123 K-ras - 141 20 20 - 62.6% - - Takai et al . (2015) 124 K-ras - 259 - - - 29.2% - - Sausen et al . (2015) 125 ctDNA - 77 - - - 43% - - Kulemann et al . (2015) 126 CTC K-ras - 11 - 9 75% (stage IIb) 71% (stage III) - - - Zhang et al . (2015) 127 DAPI + , CD45-, CK + , CEP8 > 2 + - 22 Validation cohort: 11 6 8 30 10 68.2% 63.6% 94.4% 0.84 Wu et al . (2014) 128 K-ras - 36 - 25 - 0 0 - Bidard et al . (2013) 129 CK, CD45 - 79 - - 11% - - - Bobek et al . (2014) 130 DAPI, CK, CEA, Vimentin - 24 - - 66.7% - - - Rhim et al . (2014) 131 DAPI, CD45, CK, PDX-1 - 11 21 19 78% - - - Iwanicki-Caron et al . (2013) 132 CTC - 40 - - - 55.5% 100% - Sheng et al . (2014) 133 CTC - 18 - - 94.4% - - - Catebacci et al . (2015) 134 CTC (in portal venous blood at EUS) 2 14 - - 100% (pulmonary vein blood) 22.2% (peripheral blood) - - - Earl et al . (2015) 135 CTC - 35 - - 20% - - - Cauley et al . (2015) 136 Circulating epithelial cells - 105 34 9 49% - - - Kamande et al . (2013) 137 DAPI, CD45, CK - 12 - - 100% - - - Table 4. Genetic and epigenetic alterations in circulating cell-free DNA pancreatic ductal adenocarcinoma and biliary tract cancer, 2013–2017. Author (year) Target PDAC or BTC Cancer, number Benign lesions, number Healthy volunteers, number Detected Sensitivity Specificity Takai et al . (2016) 138 K-ras PDAC 107 (non- operable) - - 59% - - Takai et al . (2015) 124 cfDNA PDAC 48 29% Hadano et al . (2016) 139 K-ras PDAC 105 - 20 31% - - Zill et al . (2015) 140 K-ras, TP53, APC, FBXW7, SMAD4 PDAC 26 - - - 92.3% 100% Earl et al . (2015) 135 K-ras PDAC 31 - - 26% - - Kinusaga et al . (2015) 123 G12V, G12D, and G12R in codon 12 of K-ras gene PDAC 141 20 20 62% - - Sausen et al . (2015) 125 cfDNA PDAC 77 - - 43% - - Wu et al . (2014) 128 K-ras PDAC 24 - 25 72% - - BTC, biliary tract cancer; PDAC, pancreatic ductal adenocarcinoma. Table 5. Epigenetics: circulating non-coding RNA and DNA methylation markers in pancreatic ductal adenocarcinoma/biliary tract cancer, 2013–2017. Author (year) MicroRNA Biliary tract cancer, number Pancreatic ductal adenocarcinoma, number Benign lesions, number Healthy volunteers, number Sensitivity Specificity Area under the curve Circulating non-coding RNA Kishimoto et al . (2013) 141 MiR-21 (↑) 94 94 - - - 23 50 - 85% 72.3% 100% 91.3% 0.93 0.83 Wang et al . (2013) 142 miR-27a-3p + CA19-9(↑) - 129 103 60 85.3% 81.6% 0.886 Kawaguchi et al . (2013) 143 miR-221 (↑), miR-375 (↓) - 47 - 30 - - 0.762 Zhao et al . (2013) 144 miR-192 (↑) - 70 - 40 76% 55% 0.63 Carleson et al . (2013) 145 MiR-375 (↑) - 48 47 - - - 0.72 Que et al . (2013) 146 miR-17-5p (↑) miR-21 (↑), - 22 12 8 - - 0.887 0.897 Schultz et al . (2014) 147 Index I + CA19-9 Index II + CA19-9 - 409 25 312 85% 85% 88% 86% 0.93 0.92 Silakit et al . (2014) 148 MiR-192 (↑) 11 - - 9 74% 72% 0.803 Lin et al . (2015) 149 MiR-492 (↑) MiR-663a (↑) - 49 - 27 75% 85% 70% 80% 0.787 0.870 Chen et al . (2014) 150 miR-182 (↑) - 109 38 50 64.1% 82.6% 0.775 Wang et al . (2015) 151 MiR-150 (↑) 15 - - 15 80% 58% 0.764 Ganepola et al . (2015) 152 miR-22 (↑), miR-642b (↑) miR-885-5p (↑) - 11 - 11 91% 91% 0.970 Voigtlander et al . (2015) 153 (serum) MiR-1281 (↑) MiR-126 (↑) MiR-26a (↑) MiR-30b (↑) MiR-122 (↑) 31 - 40 - 55% 68% 52% 52% 32% 90% 93% 93% 88% 90% 0.83 0.87 0.78 0.78 0.65 Voigtlander et al . (2015) 153 (bile) miR-412 (↑) miR-640 (↑) miR-1537 (↑) miR-3189 (↑) 31 - 53 - 50% 50% 67% 67% 89% 92% 90% 89% 0.81 0.81 0.78 0.80 Abue et al . (2015) 154 miR-21 (↑), miR-483-3p (↑) - 32 12 30 - - 0.790 0.754 Salter et al . (2015) 155 miR-196a (↑), miR-196b (↑) - 19 10 10 100% 90% 0.99 Kojima et al . (2015) 156 miR-6075, miR-4294, miR-6880-5p, miR-6799-5p, miR-125a-3p, miR-4530, miR-6836-3p, miR-4476 98 100 21 150 80.3% 97.6% 0.953 Xu et al . (2015) 157 miR-486-5p (↑) miR-938 (↑) - 156 142 65 - - 0.861 0.693 Madhaven et al . (2015) 158 PaCIC + miRNA serum-exosome marker panel - - - - 100% 80% - Komatsu et al . (2015) 159 miR-223 (↑) - 71 - 67 62% 94.1% 0.834 Alemar et al . (2016) 160 MiR-21 (↑) MiR-34a (↑) - 24 - 10 - - 0.889 0.865 Wu et al . (2016) 161 MiR-150 (↓) 30 30 28 50 - - - Bernuzzi et al . (2016) 162 MiR-483-5p(↑) MiR-194(↑) 40 40 70 40 - - 0.77 0.74 Kim et al . (2016) 163 mRNA – CDH3 (↑) mRNA –IGF2BP3(↑) mRNA – HOXB7 (↑) mRNA – BIRC5 (↑) - 21 14 - 57.1% 76.2% 71.4% 76.2% 64.3% 100% 57.1% 64.3% 0.776 0.476 0.898 0.818 Duell et al . (2017) 164 MiR-10a (↑) MiR-10b (↑) MiR-21-5p (↑) MiR-30c (↑) MiR-155 (↑) MiR-212 (↑) - 225 - 225 - - 0.66 0.68 0.64 0.71 0.64 0.64 DNA hypermethylation Branchi et al . (2016) 165 SHOX2 / SEPT9 20 - - 100 0.45% 0.99% 0.752 2. Bile and biliary brush biomarkers Patients with an indeterminate stricture on cross-sectional imaging are typically referred for an ERCP and biliary brushing with or without endobilary biopsy to obtain tissue for diagnosis, with or without therapeutic stenting 28 . Although these techniques do not compromise resection margins in potentially resectable cases, sensitivity remains low (9–57%) and patients frequently have to undergo multiple procedures to obtain a diagnosis 28 – 30 . Bile can be easily obtained at the time of ERCP and, owing to its proximity to the tumour, is a potentially important source of diagnostic biomarkers in these cancers ( Table 6 ). Unfortunately, owing to the invasiveness of ERCP, the role of these biomarkers is limited to diagnosis rather than screening or surveillance in these tumours. Table 6. Bile and biliary brush biomarkers for pancreatic and biliary tract cancer. Author (year) Biomarker Pancreatic ductal adenocarcinoma, number Biliary tract cancer, number Benign lesions, number Healthy controls, number Bile or biliary brush Sensitivity Specificity Area under the curve Single biomarkers Dhar et al . (2013) 166 M2-PK - 88 79 17 Bile 90.3% 84.3% - Navaneethan et al . (2015) 167 M2-PK - - - - Bile 52.9% 94.1% 0.77 Keane (2017) 168 MCM5 24 17 47 Biliary brush 55.6% 77.8% 0.79 Danese et al . (2014) 169 MUC5AC - 20 20 - Serum Bile - - 0.94 0.99 Farina et al . (2014) 170 CEAM6 23 6 12 - Bile 93% 83% 0.92 Budzynska et al . (2013) 171 NGAL 6 16 18 - Bile 77% 72% 0.74 Jiao et al . (2014) 96 Nucleosides 202 (gallbladder cancer) 203 205 Bile 95.3% 96.4% - Ince et al . (2014) 93 CE 41 25 129 - Bile 57.3% 68.2% 0.516 Ince et al . (2014) 93 CA 19-9 41 25 129 - Bile 74.0% 34.1% 0.616 Ince et al . (2014) 93 VEGFR3 41 25 129 - Bile 56.2% 79.1% 0.663 Ince et al . (2014) 93 Total antioxidant capacity 41 25 129 - Bile 65.6% 50.4% 0.581 Abdel-Razik et al . (2016) 114 IGF-1 25 18 62 - Bile 91.4% 89.5% 0.943 Abdel-Razik et al . (2016) 114 VEGF 25 18 62 - Bile 90.3% 84.9% 0.915 Kim et al . (2016) 163 mRNA – CDH3 (↑) mRNA –IGF2BP3(↑) mRNA – HOXB7 (↑) mRNA – BIRC5 (↑) - 21 14 - Biliary brush 57.1% 76.2% 71.4% 76.2% 64.3% 100% 57.1% 64.3% 0.776 0.476 0.898 0.818 3. Urinary biomarkers Urine provides a very easy and acceptable source for biomarker analysis. In BTC, a 42-peptide panel (consisting mostly of fragments of interstitial collagens) correctly identified 35 of 42 BTC patients with a sensitivity of 83% and a specificity of 79% 42 . In PDAC, the three-biomarker panel (LYVE-1, REG1A and TFF1) has been validated in a multi-centre cohort of 371 samples. When comparing PDAC stage I–IIA (resectable disease) with healthy urines, the panel achieved AUCs of 0.97 (95% confidence interval of 0.93–1.00). The performance of the urine biomarker panel in discriminating PDAC stage I–IIA was superior to the performance of serum CA19-9 ( P =0.006) 43 ( Table 7 ). Table 7. Summary of urine protein biomarkers for pancreatic and biliary tract cancer, 2013–2017. Author (year) Biomarker/ Combination (urine) Pancreatic ductal adenocarcinoma, number Biliary tract cancer, number Benign cancer/ Chronic pancreatitis, number Healthy volunteers, number Sensitivity Specificity Area under the curve Single biomarker Roy et al . (2014) 172 MMP2 51 - - 60 70% 85% - Roy et al . (2014) 172 TIMP-1 51 - - 60 90% 70% - Jiao et al . (2014) 96 Nucleosides - 202 (gallbladder cancer) 203 205 89.4% 97.1% - Metzger et al . (2013) 42 Urine Proteomic analysis - 42 81 - 83% 79% 0.87 Biomarker combinations Radon et al . (2015) 43 LYVE-1 + REG1A + TFF1 192 - - 87 - - 0.89 4. Symptoms and cancer decision support tools Recently, pre-diagnostic symptom profiles have been investigated as an alternative way of detecting hepato-pancreato-biliary (HPB) cancers at an early stage 8 , 9 , 16 , 44 . It is now recognised that the onset of PDAC and BTC is heralded by a collection of gastrointestinal and constitutional symptoms 45 . Although overlap occurs with other benign and malignant conditions, certain symptoms such as back pain, lethargy and new-onset diabetes have been identified as particularly suggestive of PDAC. Commonly performed blood tests such as liver function tests, glucose and haemoglobin also typically become abnormal in the months preceding diagnosis 46 . Therefore, cancer decision support tools have been produced from combinations of symptoms and risk factors. In the UK, they have been introduced into general practices in 15 cancer networks to date 8 , and their utility is currently being audited 47 . Modification to existing tools to enhance their diagnostic accuracy can be expected in the future. Endoscopy 1. Endoscopic ultrasonography If there is a mass lesion on cross-sectional imaging, endoscopic ultrasonography with fine-needle aspiration (EUS-FNA) provides an alternative method for visualising and sampling the extra-hepatic biliary tree, pancreas, gallbladder or peri-hilar lymph nodes. EUS-FNA has a diagnostic accuracy for PDAC of between 65% and 96% 48 , 49 . In BTC, a single-centre study reported a sensitivity of 73%, which was significantly better in distal compared with proximal tumours (81% versus 59% respectively, P =0.04) 50 . Recently, developed fine core biopsy needles appear to have improved diagnostic accuracy over traditional FNA needles, but randomised trials are awaited 49 , 51 , 52 . Rapid onsite examination by a cytopathologist is used in some centres, particularly in North America, and has been shown to improve the yield of EUS-FNA in individual centres 53 , 54 but this trend has not been borne out in recent randomised controlled trials 55 . To improve the diagnostic accuracy of EUS, it can also be combined with novel adjuncts such as contrast agents (SonoVue ® ), transient elastography (TE) or confocal laser endomicroscopy (CLE). TE allows the measurement of the tissue firmness, which tends to be increased in malignant tissue. In a recent single-centre study from the UK, quantitative strain measurements were found to have high sensitivity but low specificity for the detection of PDAC 56 . The technology to perform the techniques is available on most modern EUS machines and adds little time to the overall procedure time. The technique can be performed equally well by endosonographers with limited experience 57 , 58 and is particularly advantageous in cases where the diagnosis remains uncertain after standard EUS has been performed 59 . Contrast-enhanced EUS is performed with agents such as SonoVue ® and allows visualisation of the early arterial phase and late parenchymal phase enhancement of the pancreas. Pancreatic tumours are generally hypovascular compared with the surrounding parenchyma 60 , 61 . Dynamic contrast EUS is a relatively novel method that allows the non-invasive quantification of the tumour perfusion compared with the pancreatic parenchyma by using software that is now built into a number of EUS scanners. The use of this technology is evolving but is expected to be most applicable when predicting tumour response to chemotherapeutic agents, particularly new drugs against vascular angioneogenesis 62 , 63 . Recently, a needle-based confocal endomicroscope has also been developed which can be passed through a 19G FNA needle to assess indeterminate masses, cysts or lymph nodes. Malignancy in the hepatobilary tract is identified by the presence of irregular vessels, vascular leakage and large dark clumps ( Figure 1 ) 64 . In a recent study of 25 patients with indeterminate pancreatic masses referred for EUS-FNA, needle-based CLE was shown to be a safe and feasible technique 65 . Figure 1. Novel diagnostic adjuncts to ERCP and EUS. ( a ) Cholangioscopic view of a malignant hilar stricture with visualisation of the ulcerated, friable biliary mucosa via the Spyglass cholangioscope system (Boston Scientific Corp, Massachusetts, USA). ( b ) Confocal endomicroscopic image of pancreatic cancer, showing characteristic black clumps. Image was obtained using the Cellvizio AQ-Flex® probe which was introduced to the tumour via 19G FNA needle at the time of EUS. 2. Endoscopic retrograde cholangiopancreatography ERCP is typically undertaken when imaging demonstrates an indeterminate biliary stricture and tissue acquisition is required for cytological or histological assessment. Biliary brush cytology and endobiliary biopsy have a sensitivity for malignancy of 9–57% 29 , 30 , 66 , 67 . Most HPB tumours exhibit chromosomal aneuploidy 68 ; therefore, in some centres, fluorescence in situ hybridisation and digital image analysis are used to assess for the presence of DNA abnormalities in brush cytology 30 , 69 . Although these techniques have been adopted by only a few centres, the presence of polysomy is highly suggestive of BTC 30 , 69 . Poor diagnostic accuracy in biliary brush and endobiliary samples has been attributed to their being non-targeted samples obtained with only fluoroscopic guidance 70 . The single-operator cholangioscopy system (SpyGlass, Boston Scientific Corporation, Natick, MA, USA) introduced in 2006 and now superseded by the SpyGlass DS system enables intrabiliary biopsies under direct vision via small disposable forceps ( Figure 1 ). In a recent systematic review, the sensitivity and specificity of cholangioscopy-guided biopsies in the diagnosis of malignant biliary strictures were 60.1% and 98.0%, respectively 71 . Higher sensitivities are observed for intrinsic biliary malignancy compared with extrinsic compressing tumours 72 . Several techniques have been employed to augment the visualised mucosa during cholangioscopy, including chromendoscopy with methylene blue 73 – 75 , narrow-band imaging 76 , 77 and autofluorescence 78 . During ERCP, a “CholangioFlex” confocal probe (Mauna Kea Technologies, Paris, France) can be placed down the working channel of a cholangioscope or duodenoscope to obtain real-time CLE images, which are akin to standard histology ( Figure 1 ). If the images obtained from a point on the biliary mucosa contain dark areas, this is highly suggestive of malignancy 79 , 80 . The diagnostic accuracy of probe-based CLE was recently validated in a prospective multi-centre international study with 112 patients (71 with malignant lesions). Tissue sampling alone had a sensitivity, specificity and diagnostic accuracy of 56%, 100% and 72%, respectively. In comparison, ERCP with probe-based CLE had a sensitivity, specificity and diagnostic accuracy of 89%, 71% and 82%, respectively. Diagnostic accuracy increased to 88% when probe-based CLE and tissue sampling results were combined 81 . CLE is also feasible in the pancreatic duct during pancreaticoscopy but, owing to concerns over pancreatitis, is rarely used. In a case report by Meining et al ., the presence of a main duct-intraductal papillary mucinous neoplasia was confirmed by clear views of typical finger-like projections 82 . Intraductal ultrasound in small studies has also been shown to have a diagnostic accuracy of up to 90% 83 . Conclusions Currently, the most widely used tumour marker in pancreaticobiliary malignancy is CA19-9. However, its use is limited by its elevation in a number of other benign and malignant conditions. Furthermore, it is not produced in approximately 7% of the population who are Lewis antigen–negative and is often undetectable when tumours are small. Over the last few years, a number of very promising biomarker panels have been identified which can detect tumours at an early stage when curative intervention could be possible. These markers are subject to ongoing validation studies but appear likely to be implemented into screening programmes, particularly for high-risk groups, in the near future. Novel endoscopic techniques such as per-oral cholangioscopy and confocal endomicroscopy can enhance the diagnostic accuracy of standard techniques and are increasingly available in large-volume centres worldwide. Abbreviations AUC, area under the curve; BTC, biliary tract cancer; CA, carbohydrate antigen; CEA, carcinoembryonic antigen; CLE, confocal laser endomicroscopy; ERCP, endoscopic retrograde cholangiopancreatography; EUS, endoscopic ultrasound; FNA, fine-needle aspiration; HPB, hepato-pancreato-biliary; PDAC, pancreatic ductal adenocarcinoma; TE, transient elastography. Competing interests The authors declare that they have no competing interests. Grant information SPP is supported in part by National Institutes of Health grant P01CA8420. Part of the work was undertaken at University College London Hospitals/University College London, which received a portion of funding from the Department of Health’s National Institute for Health Research Biomedical Research Centres funding scheme. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript . Faculty Opinions recommended References 1. CRUK: Pancreatic cancer statistics. 2013. Reference Source 2. Khan SA, Toledano MB, Taylor-Robinson SD: Epidemiology, risk factors, and pathogenesis of cholangiocarcinoma. HPB (Oxford). 2008; 10 (2): 77–82. PubMed Abstract | Publisher Full Text | Free Full Text 3. CRUK: Cancer Research UK Cancer Stats Incidence 2008. 2011. Reference Source 4. Coupland VH, Kocher HM, Berry DP, et al. : Incidence and survival for hepatic, pancreatic and biliary cancers in England between 1998 and 2007. Cancer Epidemiol. 2012; 36 (4): e207–14. PubMed Abstract | Publisher Full Text 5. 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Roy R, Zurakowski D, Wischhusen J, et al. : Urinary TIMP-1 and MMP-2 levels detect the presence of pancreatic malignancies. Br J Cancer. 2014; 111 (9): 1772–9. PubMed Abstract | Publisher Full Text | Free Full Text Comments on this article Comments (0) Version 1 VERSION 1 PUBLISHED 05 Sep 2017 ADD YOUR COMMENT Comment Author details Author details 1 Institute of Liver Studies, King's College Hospital, London, UK 2 UCL Institute for Liver and Digestive Health, Royal Free Campus, London, UK Competing interests The authors declare that they have no competing interests. Grant information SPP is supported in part by National Institutes of Health grant P01CA8420. Part of the work was undertaken at University College London Hospitals/University College London, which received a portion of funding from the Department of Health’s National Institute for Health Research Biomedical Research Centres funding scheme. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Article Versions (1) version 1 Published: 05 Sep 2017, 6:1643 https://doi.org/10.12688/f1000research.11371.1 Copyright © 2017 Keane MG et al . This is an open access article distributed under the terms of the Creative Commons Attribution License , which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Download Export To Sciwheel Bibtex EndNote ProCite Ref. Manager (RIS) Sente metrics Views Downloads F1000Research - - PubMed Central info_outline Data from PMC are received and updated monthly. - - Citations open_in_new 0 open_in_new 0 open_in_new SEE MORE DETAILS CITE how to cite this article Keane MG, Shah A, Pereira SP and Joshi D. Novel biomarkers and endoscopic techniques for diagnosing pancreaticobiliary malignancy [version 1; peer review: 2 approved] . F1000Research 2017, 6 (F1000 Faculty Rev):1643 ( https://doi.org/10.12688/f1000research.11371.1 ) NOTE: If applicable, it is important to ensure the information in square brackets after the title is included in all citations of this article. COPY CITATION DETAILS track receive updates on this article Track an article to receive email alerts on any updates to this article. TRACK THIS ARTICLE Share Open Peer Review Current Reviewer Status: Key to Reviewer Statuses VIEW HIDE Approved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested Approved with reservations A number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit. Not approved Fundamental flaws in the paper seriously undermine the findings and conclusions Editorial Note on the Review Process Faculty Reviews are review articles written by the prestigious Members of Faculty Opinions . The articles are commissioned and peer reviewed before publication to ensure that the final, published version is comprehensive and accessible. The reviewers who approved the final version are listed with their names and affiliations. Reviewers who approved this article Pietro Fusaroli , Gastroenterology Unit, Department of Medical and Surgical Science, Hospital of Imola, University of Bologna, Italy Competing interests: No competing interests were declared. (for version 1) Peter Vilmann , Gastro Unit, Department of Surgery, Herlev Hospital, University of Copenhagen, Denmark Competing interests: No competing interests were declared. (for version 1) Pia Helene Klausen , Gastro Unit, Department of Surgery, Herlev Hospital, University of Copenhagen, Denmark Competing interests: No competing interests were declared. (for version 1) Vangelis Kalaitzakis , Gastro Unit, Department of Surgery, Herlev Hospital, University of Copenhagen, Denmark Competing interests: No competing interests were declared. (for version 1) Comments on this article Comments (0) Version 1 VERSION 1 PUBLISHED 05 Sep 2017 ADD YOUR COMMENT Comment keyboard_arrow_left keyboard_arrow_right Open Peer Review Reviewer Status info_outline Alongside their report, reviewers assign a status to the article: Approved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested Approved with reservations A number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit. Not approved Fundamental flaws in the paper seriously undermine the findings and conclusions Reviewer Reports Invited Reviewers 1 2 Version 1 05 Sep 17 Faculty Reviews are review articles written by the prestigious Members of Faculty Opinions . The articles are commissioned and peer reviewed before publication to ensure that the final, published version is comprehensive and accessible. The reviewers who approved the final version are listed with their names and affiliations. Pietro Fusaroli , Gastroenterology Unit, Department of Medical and Surgical Science, Hospital of Imola, University of Bologna, Italy Competing interests: No competing interests were declared. View more View less Peter Vilmann , Gastro Unit, Department of Surgery, Herlev Hospital, University of Copenhagen, Denmark Competing interests: No competing interests were declared. View more View less Pia Helene Klausen , Gastro Unit, Department of Surgery, Herlev Hospital, University of Copenhagen, Denmark Competing interests: No competing interests were declared. View more View less Vangelis Kalaitzakis , Gastro Unit, Department of Surgery, Herlev Hospital, University of Copenhagen, Denmark Competing interests: No competing interests were declared. 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