Article Versions
Export Article
Cite this article
  • Normal Style
  • MLA Style
  • APA Style
  • Chicago Style
Research Article
Open Access Peer-reviewed

Serum Bilirubin Levels Can Predict Pancreatic and Biliary Malignancies in Patients with Obstructive Jaundice and Non-conclusive Cytology

Assad Khan, Snehal Lapsia, Mohammed Aslam, Vishal Kaushik, Yogi Reddy,
Daren Subar
Global Journal of Surgery. 2018, 6(1), 11-15. DOI: 10.12691/js-6-1-3
Received August 20, 2018; Revised October 10, 2018; Accepted November 05, 2018

Abstract

Background: Elevated serum bilirubin has been shown to be a reliable predictor of pancreatic and biliary malignancy but the relationship between serum bilirubin and inadequate (C1), benign (C2) and indeterminate (C3) cellular samples has not been explored. The aim of this study is to determine the relationship between serum bilirubin and pancreatic, biliary or ampullary malignancy in the context of non-confirmatory cytology. Methods: This is a retrospective analysis of patients with obstructive jaundice undergoing investigation for possible pancreatic, peri-ampullary or biliary malignancy between 2009 and 2013. Results: 135 patients were included; 84 had a malignant diagnosis and 51 benign. All patients with C4 or C5 cytology (n=49) had confirmed malignancy. 35 out of 86 C1 – C3 samples were falsely negative. ROC curve analysis demonstrated a strong association (AUC 0.912) between elevated serum bilirubin and malignancy; serum bilirubin ≥ 100 µmol/L had a sensitivity of 86% and a specificity of 88%. In the C1-C3 subgroup, this association was maintained (AUC 0.905). Serum bilirubin ≥ 100 µmol/L had a sensitivity of 80% and specificity of 88%. Using this cut-off highlighted 28 out of 35 of the malignancies missed by cytology (p = 0.003). Conclusion: Our study demonstrates that a serum bilirubin ≥ 100 µmol/L is associated with malignancy and this relationship is maintained in C1-C3 cytology. When faced with non-confirmatory cytology in the absence of a benign aetiology and an elevated serum bilirubin ≥ 100 µmol/L, we advocate more aggressive investigation to avoid missing an occult malignancy.

1. Introduction

In the absence of choledocholithiasis or a radiologically visible mass, the underlying pathology in obstructive jaundice can be a diagnostic challenge. Inflammatory or neoplastic changes involving the biliary tree, ampulla, pancreas or duodenum are often responsible. The diagnosis of malignancy can be difficult because of subtle differences in appearance between benign and neoplastic aetiologies and the focus of investigation is ensuring that an occult malignancy is not missed.

When there is high radiological suspicion for malignancy and the lesion is potentially resectable with curative intent, it is accepted that surgery can be undertaken without pre-operative histological confirmation 1. However, where there is diagnostic uncertainty about the aetiology of disease or the presence of an incurable malignancy, histological or cytological confirmation of the diagnosis is imperative prior to embarking on treatment 1.

Tissue or cellular samples can be obtained via endoscopic retrograde cholangiopancreatography (ERCP), endoscopic ultrasound and fine needle aspiration cytology (EUS-FNAC) or percutaneous biopsy. These techniques can have variable sensitivity for malignancy, with EUS tending to demonstrate a greater diagnostic ability over ERCP 2. More recently, the advent of peroral cholangioscopy has allowed for direct visualisation of the biliary tree and greater accuracy with tissue sampling.

However ERCP is more commonly used in patients in whom drainage of the biliary tree is deemed necessary prior to surgery and it allows for opportunistic cytological sampling at the same time as biliary stenting 3.

Because biliary brush cytology (BBC) has a low sensitivity for neoplasia, the potential of missed malignancies exists in patients whose cytology returns as either inadequate, benign or indeterminate 4. Garcea et al demonstrated that an elevated serum bilirubin > 100 µmol/L has been shown to be a reliable predictor of pancreatic/biliary malignancy, with a high sensitivity and specificity 5. This link between elevated bilirubin and pancreatic/biliary malignancy has been replicated in other studies 6, 7, 8, 9, 10, 11. However there is no published data on the sensitivity and specificity of serum bilirubin in inadequate (C1), benign (C2) and indeterminate (C3) cytology. The aim of the study was to assess if serum bilirubin is a reliable predictor of malignancy within the context of C1-C3 cytology.

2. Materials & Methods

This is a retrospective single institution study performed at a tertiary referral centre for hepatobiliary and pancreatic disease. Case records of patients presenting with obstructive jaundice between January 2009 to December 2013 were analysed. Biochemical blood tests including liver function tests with the serum bilirubin 24 hours prior to ERCP were recorded; computed tomography (CT) images were reviewed by a specialist hepatobiliary radiologist; ERCP reports were reviewed; BBC samples were obtained, analysed and graded based on the Royal College of Pathologists guidelines; endoscopic ultrasound (EUS) reports were analysed where available, as were histological samples (targeted biopsy or surgical specimen where available). Confirmation of malignancy was done directly (through positive tissue diagnosis) or indirectly (using surrogate markers like death certification or post-mortem reports). Patients were included in the study only if they had undergone all of the above investigations as part of their diagnostic workup, with the exception of EUS. All patients were discussed at the specialist HPB multidisciplinary team (MDT) meeting. The study was registered and ethical approval was granted locally (Reference 17883) Cases were excluded if they were undergoing surveillance of a suspected lesion or if the pancreaticobiliary lesion was metastatic in origin.

Statistics were analysed using SPSS version 20 (IBM Corp 2012). Mann Whitney-U tests were used to compare the distribution of continuous variables between groups. Chi-square analysis was used to compare dichotomised data. The level of serum bilirubin that demonstrated significant sensitivity and specificity for malignancy in C1-C3 cytology was ascertained using ROC curve analysis. Statistical significance was set at p 0.05

3. Results

The case notes of 145 patients were scrutinised for the study. No cases were excluded because of incomplete data. Ten patients were excluded because their disease was metastatic disease to the site of interest leaving 135 patients in the study. The male to female ratio was 1:1 with a median age of 67 (interquartile range 59-76). 84 (62%) patients had a malignant diagnosis and 51 benign (38%) (Table 1). The most common malignant diagnosis was pancreatic ductal adenocarcinoma (51%) and the most common benign diagnosis was a benign biliary stricture (59%). Nine (7%) patients had C1 cytology. C2 and C3 accounted for the majority of cytology reports from ERCP (57%). All patients with C4 or C5 cytology (36%) had a confirmed final diagnosis of malignancy. Twenty-two patients had EUS-FNAC and 38 had a percutaneous biopsy as part of their investigative work-up.

The mean serum bilirubin for benign and malignant disease was 48 µmol/L and 240 µmol/L (p < 0.001) respectively in the total cohort. ROC curve analysis illustrated a close association between serum bilirubin levels and malignancy with an area under the curve (AUC) of 0.912 (p <0.001). A serum bilirubin level ≥ 100 µmol/L demonstrated a sensitivity and specificity for malignancy of 86% and 88% respectively. A serum bilirubin of < 100 µmol/L was also associated with a high sensitivity and specificity for benign disease (Figure 1)

35 out of 86 C1 – C3 samples were falsely negative. In the C1-C3 subgroup, the mean serum bilirubin was 48 µmol/L and 239 µmol/L between the benign and malignant causes respectively (p <0.001).

ROC curve analysis for this subgroup demonstrated that serum bilirubin maintained a strong association with malignancy (AUC 0.905). A serum bilirubin of ≥ 100 µmol/L demonstrated a sensitivity and specificity of 80% and 88% (Figure 2). Univariate analysis using a serum bilirubin cut-off of 100 µmol/L was statistically significant for predicting malignancy in this group (p <0.001 95% CI 0.838 – 0.973) (Table 2) and would have identified 28 of the 35 malignancies.

4. Discussion

Serum bilirubin has previously been demonstrated to be a good marker of pancreaticobiliary malignancy. Our study is, to our knowledge, the first that specifically explores the relationship between serum bilirubin and C1-C3 cytology.

Garcea et al have demonstrated that serum bilirubin >100 µmol/L is closely correlated with a diagnosis of malignancy irrespective of the initial reason for investigation and independently of any other investigation 5. Patients were significantly less likely to harbour a malignancy if the serum bilirubin was < 100 µmol/L, a finding replicated in many other studies 6, 7, 8, 9. This is possibly due to progressive and irreversible extra-luminal compression of the biliary tree that is associated with a malignancy.

Patients with obstructive jaundice in whom pancreatic or biliary malignancy is suspected and tissue biopsies prove elusive present a management challenge to clinicians11. The poor sensitivity associated with BBC is well documented, and can make the confident exclusion of malignancy difficult. Furthermore, although CT has a high sensitivity and specificity for malignancy it can sometimes be radiologically difficult to distinguish between benign and malignant aetiologies, particularly smaller lesions and on a background of pancreatitis 12, 13, 14, 15, 16, 17. In our study, the sensitivity and specificity of CT at diagnosing benign lesions was 40% and 73% respectively. This contrasts with a 97% sensitivity and 88% specificity for malignancy. Just as certain radiological features may raise suspicion of a possible malignancy 15, we propose that an elevated serum bilirubin >100 µmol/L may help identify patients who would also benefit from closer scrutiny in order to exclude malignancy, especially in those patients where radiology is indeterminate.

Despite the mean serum bilirubin for all malignant disease being > 200 µmol/L, we chose a cut-off of 100 µmol/L. This is because the ROC Curve at 200 µmol/L demonstrates a specificity of 95% but a sensitivity of 61%. Whilst this is comparable to the sensitivity and specificity of BBC in some published studies 18, the sensitivity is still too low, as over a third of malignancies would be missed at this level. Indeed, the specificity of BBC is 100% in our series. Therefore, applying a cut-off at > 200 µmol/L with a specificity lower than BBC would fail to add anything useful to the diagnostic work-up.

We acknowledge that there are limitations to the study. The small sample size may introduce a type 2 error and limits the ability to generalise to all patients with obstructive jaundice and a potential malignancy. In addition we did not investigate the ability of serum bilirubin to determine the difference in sensitivities between biliary, ampullary and pancreatic pathology. However, the statistical analyses conducted still demonstrate a strong, significant correlation. Also, we acknowledge that EUS-FNAC is more sensitive at detecting pancreatic and biliary malignancy in comparison to ERCP and BBC 4, 19, 20. However, there is evidence to suggest that patients with obstructive jaundice that need stenting and without a clear tissue diagnosis should have ERCP performed as it allows for cytological sampling at the same time as stenting 1, 12, 21, 22, 23. Peroral cholangioscopy has been shown to demonstrate a high visual and tissue diagnostic rate for biliary tract lesions, but there is less evidence for its superiority over other modalities in the diagnosis of pancreatic pathologies 24, which comprise a substantial number of the patients in this series.

We conclude that in the face of non-confirmatory investigations and an elevated serum bilirubin; we advocate more aggressive investigation to avoid missing a malignancy.

Fund

No external funding sources were used.

Conflicts of Interest

We have no conflicts of interest to declare.

Excerpts of this manuscript were presented in poster format at the 2014 Annual Scientific Meeting of the Association of Upper Gastrointestinal Surgeons on 18th – 19th September 2014 (Khan et al. Bilirubin level as a predictor of pancreatic and biliary malignancy. BJS 2014; 101(S6) p30.).

References

[1]  Asbun, HJ, Conlon, K, Fernandez-Cruz, L, et al 2014. When to perform a pancreatoduodenectomy in the absence of positive histology? A consensus statement by the International Study Group of Pancreatic Surgery. Surgery, 155(5), pp. 887-892.
In article      View Article  PubMed
 
[2]  Fusaroli, P, Kypraios, D, Caletti, G et al., 2012. Pancreatico-biliary endoscopic ultrasound: a systematic review of the levels of evidence, performance and outcomes. World Journal of Gastroenterology: WJG, 18(32), p.4243.
In article      View Article  PubMed
 
[3]  Berberat, P.O., Ingold, H., Goblins, A., et al 2007. Fast track-different implications in pancreatic surgery. Journal of gastrointestinal surgery, 11(7), pp.880-887.
In article      View Article  PubMed
 
[4]  Oppong, K., Raine, D., Near, M., Wadehra, V., Ramakrishnan, S. and Charnley, R.M., 2010. EUS-FNA versus biliary brushings and assessment of simultaneous performance in jaundiced patients with suspected malignant obstruction. JOP. Journal of the Pancreas, 11(6), pp. 560-567.
In article      PubMed
 
[5]  Garcea, G., Ngu, W., Neal, C.P., Dennison, A.R. and Berry, D.P., 2011. Bilirubin levels predict malignancy in patients with obstructive jaundice. HPB, 13(6), pp. 426-430.
In article      View Article  PubMed
 
[6]  Vasilieva, L., Alexopoulou, A., Papadhimitriou, S.I., Romanos, A., Xynopoulos, D. and Dourakis, S.P., 2012. Total bilirubin is a good discriminator between benign and malignant biliary strictures. HPB, 14(1), p. 71.
In article      View Article  PubMed
 
[7]  Liu, C.L., Fan, S.T., Lo, C.M., Tso, W.K., Wong, Y., Poon, R.T.P., Lam, C.M., Wong, B.C. and Wong, J., 2005. Clinico‐biochemical prediction of biliary cause of acute pancreatitis in the era of endoscopic ultrasonography. Alimentary pharmacology & therapeutics, 22(5), pp. 423-431.
In article      View Article  PubMed
 
[8]  Thomasset, S.C., Saunders, D., Holland, A., Dennison, A.R. and Garcea, G., 2015. Malignant biliary strictures in patients with a normal bilirubin and/or normal liver enzymes. HPB, 17(11), pp. 969-974.
In article      View Article  PubMed
 
[9]  Kasapidis, P., Mironidis, L., Giannakopoulos, A., Delis, V., Balatsos, V., Konstantinidis, A. and Skandalis, N., 2008. Clinical discrimination between choledocholithiasis and biliopancreatic malignancy based on a new biochemical model. Annals of Gastroenterology, 21(2), pp.119-126.
In article      
 
[10]  Al-Mofleh, I. A., Aljebreen, A. M., Al-Amri, S. M., Al-Rashed, R. S., Al-Faleh, F. Z., Al-Freihi, H. M., ... & Isnani, A. C. (2004). Biochemical and radiological predictors of malignant biliary strictures. World journal of gastroenterology, 10(10), 1504.
In article      View Article  PubMed
 
[11]  Bain, V. G., Abraham, N., Jhangri, G. S., Alexander, T. W., Henning, R. C., Hoskinson, M. E., ... & Sadowski, D. C. (2000). Prospective study of biliary strictures to determine the predictors of malignancy. Canadian Journal of Gastroenterology and Hematology, 14(5), 397-402.
In article      View Article
 
[12]  Bowlus, C.L., Olson, K.A. and Gershwin, M.E., 2016. Evaluation of indeterminate biliary strictures. Nature reviews. Gastroenterology & hepatology, 13(1), p. 28.
In article      View Article  PubMed
 
[13]  de Jong, K., Nio, C.Y., Mearadji, B., Phoa, S.S., Engelbrecht, M.R., Dijkgraaf, M.G., Bruno, M.J. and Fockens, P., 2012. Disappointing interobserver agreement among radiologists for a classifying diagnosis of pancreatic cysts using magnetic resonance imaging. Pancreas, 41(2), pp. 278-282.
In article      View Article  PubMed
 
[14]  Singh, A., Gelrud, A. and Agarwal, B., 2015. Biliary strictures: diagnostic considerations and approach. Gastroenterology report, 3(1), pp. 22-31.
In article      View Article  PubMed
 
[15]  Sultana, A., Jackson, R., Tim, G., Bostock, E., Psarelli, E. E., Cox, T. F., ... & Halloran, C. M. (2015). What is the best way to identify malignant transformation within pancreatic IPMN: a systematic review and meta-analyses. Clinical and translational gastroenterology, 6(12), e130.
In article      View Article  PubMed
 
[16]  Khashab, M. A., Kim, K., Lennon, A. M., Shin, E. J., Tignor, A. S., Amateau, S. K., ... & Canto, M. I. (2013). Should we do EUS/FNA on patients with pancreatic cysts? The incremental diagnostic yield of EUS over CT/MRI for prediction of cystic neoplasms. Pancreas, 42(4), 717-721.
In article      View Article  PubMed
 
[17]  Schema, W., Ba-Ssalamah, A., Kölblinger, C., Kulinna-Cosentini, C., Puespoek, A., & Götzinger, P. (2007). Pancreatic adenocarcinoma. European radiology, 17(3), 638-649.
In article      View Article  PubMed
 
[18]  Govil, H., Reddy, V., Kluskens, L., Treaba, D., Massarani-Wafai, R., Selvaggi, S., & Gattuso, P. (2002). Brush cytology of the biliary tract: retrospective study of 278 cases with histopathologic correlation. Diagnostic cytopathology, 26(5), 273-277.
In article      View Article  PubMed
 
[19]  Scheiman, J.M., Hwang, J.H. and Moayyedi, P., 2015. American gastroenterological association technical review on the diagnosis and management of asymptomatic neoplastic pancreatic cysts. Gastroenterology, 148(4), pp. 824-848.
In article      View Article  PubMed
 
[20]  Weilert, F., Bhat, Y.M., Binmoeller, K.F., Kane, S., Jaffee, I.M., Shaw, R.E., Cameron, R., Hashimoto, Y. and Shah, J.N., 2014. EUS-FNA is superior to ERCP-based tissue sampling in suspected malignant biliary obstruction: results of a prospective, single-blind, comparative study. Gastrointestinal endoscopy, 80(1), pp. 97-104.
In article      View Article  PubMed
 
[21]  National Institute for Clinical Excellence (2018). Pancreatic cancer in adults; diagnosis and management [NG85]. Retrieved from: https://www.nice.org.uk/guidance/ng85.
In article      
 
[22]  Singh Saluja, S., Sharma, R., Pal, S., Sahni, P. and Kanti Chattopadhyay T, 2007. Differentiation between benign and malignant hilar obstructions using laboratory and radiological investigations: a prospective study. HPB, 9(5), pp. 373-382.
In article      View Article  PubMed
 
[23]  Ferreira, R., Loureiro, R., Nunes, N., Santos, A.A., Maio, R., Crave, M. and Duarte, M.A., 2016. Role of endoscopic retrograde cholangiopancreatography in the management of benign biliary strictures: What’s new?. World journal of gastrointestinal endoscopy, 8(4), p. 220.
In article      View Article  PubMed
 
[24]  Navaneethan, U., Hasan, M. K., Lourdusamy, V., Njei, B., Varadarajulu, S., & Hawes, R. H. (2015). Single-operator cholangioscopy and targeted biopsies in the diagnosis of indeterminate biliary strictures: a systematic review. Gastrointestinal endoscopy, 82(4), 608-614.
In article      View Article  PubMed
 

Published with license by Science and Education Publishing, Copyright © 2018 Assad Khan, Snehal Lapsia, Mohammed Aslam, Vishal Kaushik, Yogi Reddy and Daren Subar

Creative CommonsThis work is licensed under a Creative Commons Attribution 4.0 International License. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/

Cite this article:

Normal Style
Assad Khan, Snehal Lapsia, Mohammed Aslam, Vishal Kaushik, Yogi Reddy, Daren Subar. Serum Bilirubin Levels Can Predict Pancreatic and Biliary Malignancies in Patients with Obstructive Jaundice and Non-conclusive Cytology. Global Journal of Surgery. Vol. 6, No. 1, 2018, pp 11-15. http://pubs.sciepub.com/js/6/1/3
MLA Style
Khan, Assad, et al. "Serum Bilirubin Levels Can Predict Pancreatic and Biliary Malignancies in Patients with Obstructive Jaundice and Non-conclusive Cytology." Global Journal of Surgery 6.1 (2018): 11-15.
APA Style
Khan, A. , Lapsia, S. , Aslam, M. , Kaushik, V. , Reddy, Y. , & Subar, D. (2018). Serum Bilirubin Levels Can Predict Pancreatic and Biliary Malignancies in Patients with Obstructive Jaundice and Non-conclusive Cytology. Global Journal of Surgery, 6(1), 11-15.
Chicago Style
Khan, Assad, Snehal Lapsia, Mohammed Aslam, Vishal Kaushik, Yogi Reddy, and Daren Subar. "Serum Bilirubin Levels Can Predict Pancreatic and Biliary Malignancies in Patients with Obstructive Jaundice and Non-conclusive Cytology." Global Journal of Surgery 6, no. 1 (2018): 11-15.
Share
  • Figure 2. ROC curve analysis looking at the correlation between serum bilirubin > 100 µmol/L and malignant disease in patients with C1-C3 cytology
  • Table 2. Serum bilirubin > 100 µmol/L can help distinguish between benign and malignant aetiologies in those with C1-C3 cytology
[1]  Asbun, HJ, Conlon, K, Fernandez-Cruz, L, et al 2014. When to perform a pancreatoduodenectomy in the absence of positive histology? A consensus statement by the International Study Group of Pancreatic Surgery. Surgery, 155(5), pp. 887-892.
In article      View Article  PubMed
 
[2]  Fusaroli, P, Kypraios, D, Caletti, G et al., 2012. Pancreatico-biliary endoscopic ultrasound: a systematic review of the levels of evidence, performance and outcomes. World Journal of Gastroenterology: WJG, 18(32), p.4243.
In article      View Article  PubMed
 
[3]  Berberat, P.O., Ingold, H., Goblins, A., et al 2007. Fast track-different implications in pancreatic surgery. Journal of gastrointestinal surgery, 11(7), pp.880-887.
In article      View Article  PubMed
 
[4]  Oppong, K., Raine, D., Near, M., Wadehra, V., Ramakrishnan, S. and Charnley, R.M., 2010. EUS-FNA versus biliary brushings and assessment of simultaneous performance in jaundiced patients with suspected malignant obstruction. JOP. Journal of the Pancreas, 11(6), pp. 560-567.
In article      PubMed
 
[5]  Garcea, G., Ngu, W., Neal, C.P., Dennison, A.R. and Berry, D.P., 2011. Bilirubin levels predict malignancy in patients with obstructive jaundice. HPB, 13(6), pp. 426-430.
In article      View Article  PubMed
 
[6]  Vasilieva, L., Alexopoulou, A., Papadhimitriou, S.I., Romanos, A., Xynopoulos, D. and Dourakis, S.P., 2012. Total bilirubin is a good discriminator between benign and malignant biliary strictures. HPB, 14(1), p. 71.
In article      View Article  PubMed
 
[7]  Liu, C.L., Fan, S.T., Lo, C.M., Tso, W.K., Wong, Y., Poon, R.T.P., Lam, C.M., Wong, B.C. and Wong, J., 2005. Clinico‐biochemical prediction of biliary cause of acute pancreatitis in the era of endoscopic ultrasonography. Alimentary pharmacology & therapeutics, 22(5), pp. 423-431.
In article      View Article  PubMed
 
[8]  Thomasset, S.C., Saunders, D., Holland, A., Dennison, A.R. and Garcea, G., 2015. Malignant biliary strictures in patients with a normal bilirubin and/or normal liver enzymes. HPB, 17(11), pp. 969-974.
In article      View Article  PubMed
 
[9]  Kasapidis, P., Mironidis, L., Giannakopoulos, A., Delis, V., Balatsos, V., Konstantinidis, A. and Skandalis, N., 2008. Clinical discrimination between choledocholithiasis and biliopancreatic malignancy based on a new biochemical model. Annals of Gastroenterology, 21(2), pp.119-126.
In article      
 
[10]  Al-Mofleh, I. A., Aljebreen, A. M., Al-Amri, S. M., Al-Rashed, R. S., Al-Faleh, F. Z., Al-Freihi, H. M., ... & Isnani, A. C. (2004). Biochemical and radiological predictors of malignant biliary strictures. World journal of gastroenterology, 10(10), 1504.
In article      View Article  PubMed
 
[11]  Bain, V. G., Abraham, N., Jhangri, G. S., Alexander, T. W., Henning, R. C., Hoskinson, M. E., ... & Sadowski, D. C. (2000). Prospective study of biliary strictures to determine the predictors of malignancy. Canadian Journal of Gastroenterology and Hematology, 14(5), 397-402.
In article      View Article
 
[12]  Bowlus, C.L., Olson, K.A. and Gershwin, M.E., 2016. Evaluation of indeterminate biliary strictures. Nature reviews. Gastroenterology & hepatology, 13(1), p. 28.
In article      View Article  PubMed
 
[13]  de Jong, K., Nio, C.Y., Mearadji, B., Phoa, S.S., Engelbrecht, M.R., Dijkgraaf, M.G., Bruno, M.J. and Fockens, P., 2012. Disappointing interobserver agreement among radiologists for a classifying diagnosis of pancreatic cysts using magnetic resonance imaging. Pancreas, 41(2), pp. 278-282.
In article      View Article  PubMed
 
[14]  Singh, A., Gelrud, A. and Agarwal, B., 2015. Biliary strictures: diagnostic considerations and approach. Gastroenterology report, 3(1), pp. 22-31.
In article      View Article  PubMed
 
[15]  Sultana, A., Jackson, R., Tim, G., Bostock, E., Psarelli, E. E., Cox, T. F., ... & Halloran, C. M. (2015). What is the best way to identify malignant transformation within pancreatic IPMN: a systematic review and meta-analyses. Clinical and translational gastroenterology, 6(12), e130.
In article      View Article  PubMed
 
[16]  Khashab, M. A., Kim, K., Lennon, A. M., Shin, E. J., Tignor, A. S., Amateau, S. K., ... & Canto, M. I. (2013). Should we do EUS/FNA on patients with pancreatic cysts? The incremental diagnostic yield of EUS over CT/MRI for prediction of cystic neoplasms. Pancreas, 42(4), 717-721.
In article      View Article  PubMed
 
[17]  Schema, W., Ba-Ssalamah, A., Kölblinger, C., Kulinna-Cosentini, C., Puespoek, A., & Götzinger, P. (2007). Pancreatic adenocarcinoma. European radiology, 17(3), 638-649.
In article      View Article  PubMed
 
[18]  Govil, H., Reddy, V., Kluskens, L., Treaba, D., Massarani-Wafai, R., Selvaggi, S., & Gattuso, P. (2002). Brush cytology of the biliary tract: retrospective study of 278 cases with histopathologic correlation. Diagnostic cytopathology, 26(5), 273-277.
In article      View Article  PubMed
 
[19]  Scheiman, J.M., Hwang, J.H. and Moayyedi, P., 2015. American gastroenterological association technical review on the diagnosis and management of asymptomatic neoplastic pancreatic cysts. Gastroenterology, 148(4), pp. 824-848.
In article      View Article  PubMed
 
[20]  Weilert, F., Bhat, Y.M., Binmoeller, K.F., Kane, S., Jaffee, I.M., Shaw, R.E., Cameron, R., Hashimoto, Y. and Shah, J.N., 2014. EUS-FNA is superior to ERCP-based tissue sampling in suspected malignant biliary obstruction: results of a prospective, single-blind, comparative study. Gastrointestinal endoscopy, 80(1), pp. 97-104.
In article      View Article  PubMed
 
[21]  National Institute for Clinical Excellence (2018). Pancreatic cancer in adults; diagnosis and management [NG85]. Retrieved from: https://www.nice.org.uk/guidance/ng85.
In article      
 
[22]  Singh Saluja, S., Sharma, R., Pal, S., Sahni, P. and Kanti Chattopadhyay T, 2007. Differentiation between benign and malignant hilar obstructions using laboratory and radiological investigations: a prospective study. HPB, 9(5), pp. 373-382.
In article      View Article  PubMed
 
[23]  Ferreira, R., Loureiro, R., Nunes, N., Santos, A.A., Maio, R., Crave, M. and Duarte, M.A., 2016. Role of endoscopic retrograde cholangiopancreatography in the management of benign biliary strictures: What’s new?. World journal of gastrointestinal endoscopy, 8(4), p. 220.
In article      View Article  PubMed
 
[24]  Navaneethan, U., Hasan, M. K., Lourdusamy, V., Njei, B., Varadarajulu, S., & Hawes, R. H. (2015). Single-operator cholangioscopy and targeted biopsies in the diagnosis of indeterminate biliary strictures: a systematic review. Gastrointestinal endoscopy, 82(4), 608-614.
In article      View Article  PubMed