Pancreas| Volume 169, ISSUE 2, P411-418, February 2021

Diabetes mellitus in intraductal papillary mucinous neoplasms: A systematic review and meta-analysis

Published:August 21, 2020DOI:



      Our current knowledge of diabetes mellitus in intraductal papillary mucinous neoplasm is very limited and its prevalence and predictive value for malignant transformation are not clear. This study sought to systematically review the literature to define the prevalence of diabetes mellitus in intraductal papillary mucinous neoplasm and to evaluate the association of diabetes mellitus with the progression to high-grade dysplasia or invasive cancer.


      A PubMed/Medline systematic search was performed to identify studies reporting data on preoperative diabetes mellitus in intraductal papillary mucinous neoplasm. Articles meeting the predefined inclusion criteria were analyzed and a meta-analysis was performed. The study was preregistered (PROSPERO ID: CRD42020153581).


      From the initially detected 827 studies, 27 studies including resected patients with histologically confirmed intraductal papillary mucinous neoplasm were included. The global prevalence of preoperative diabetes mellitus was 25% (1,112 of 4,412); whereas new-onset/worsening diabetes mellitus was reported in 6% of patients (68 of 1,202). The meta-analysis revealed that patients with pre-existing diabetes mellitus had an increased risk of harboring a main pancreatic duct involvement (risk ratio 1.43, 95% confidence interval: 1.21–1.69, P < .001), high-grade dysplasia (risk ratio 1.27, 95% confidence interval: 1.01–1.59, P = .04), and invasive cancer (risk ratio 1.61, 95% confidence interval: 1.33–1.95, P < .001).


      The prevalence of diabetes mellitus in intraductal papillary mucinous neoplasm is high, and diabetic patients demonstrate an increased risk of a more aggressive disease. Therefore, diabetes mellitus should be increasingly considered in the stratification of patients with intraductal papillary mucinous neoplasm. Further investigations to determine the mechanisms behind the association with progression should be carried out.
      To read this article in full you will need to make a payment

      Purchase one-time access:

      Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
      One-time access price info
      • For academic or personal research use, select 'Academic and Personal'
      • For corporate R&D use, select 'Corporate R&D Professionals'


      Subscribe to Surgery
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect


        • Del Chiaro M.
        • Verbeke C.S.
        • Kartalis N.
        • et al.
        Short-term results of a magnetic resonance imaging-based Swedish screening program for individuals at risk for pancreatic cancer.
        JAMA Surg. 2015; 150: 512-518
        • Laffan T.A.
        • Horton K.M.
        • Klein A.P.
        • et al.
        Prevalence of unsuspected pancreatic cysts on MDCT.
        Am J Roentgenol. 2008; 191: 802-807
        • Kromrey M.L.
        • Bülow R.
        • Hübner J.
        • et al.
        Prospective study on the incidence, prevalence and 5-year pancreatic-related mortality of pancreatic cysts in a population-based study.
        Gut. 2018; 67: 138-145
        • Adsay V.
        • Mino-Kenudson M.
        • Furukawa T.
        • et al.
        Pathologic evaluation and reporting of intraductal papillary mucinous neoplasms (IPMNs) of the pancreas and other tumoral intraepithelial neoplasms of pancreatobiliary tract: Recommendations of verona consensus meeting.
        Ann Surg. 2016; 263: 162-177
        • Furukawa T.
        • Hatori T.
        • Fujita I.
        • et al.
        Prognostic relevance of morphological types of intraductal papillary mucinous neoplasms of the pancreas.
        Gut. 2011; 60: 509-516
        • Omori Y.
        • Ono Y.
        • Tanino M.
        • et al.
        Pathways of progression from intraductal papillary mucinous neoplasm to pancreatic ductal adenocarcinoma based on molecular features.
        Gastroenterology. 2019; 156: 647-661.e2
        • Hruban R.H.
        • Goggins M.
        • Parsons J.
        • Kern S.E.
        Progression model for pancreatic cancer.
        Clin Cancer Res. 2000; 6: 2969-2972
        • Tanaka M.
        • Fernández-del Castillo C.
        • Kamisawa T.
        • et al.
        Revisions of international consensus Fukuoka guidelines for the management of IPMN of the pancreas.
        Pancreatology. 2017; 17: 738-753
        • The European Study Group on Cystic Tumours of the Pancreas
        European evidence-based guidelines on pancreatic cystic neoplasms.
        Gut. 2018; 67: 789-804
        • Falconi M.
        • Mantovani W.
        • Crippa S.
        • Mascetta G.
        • Salvia R.
        • Pederzoli P.
        Pancreatic insufficiency after different resections for benign tumours.
        Br J Surg. 2008; 95: 85-91
        • You D.D.
        • Choi S.H.
        • Choi D.W.
        • Heo J.S.
        • Ho C.Y.
        • Kim W.S.
        Long-term effects of pancreaticoduodenectomy on glucose metabolism.
        ANZ J Surg. 2012; 82: 447-451
        • Pannala R.
        • Leirness J.B.
        • Bamlet W.R.
        • Basu A.
        • Petersen G.M.
        • Chari S.T.
        Prevalence and clinical profile of pancreatic cancer-associated diabetes mellitus.
        Gastroenterology. 2008; 134: 981-987
        • Sharma A.
        • Kandlakunta H.
        • Nagpal S.J.S.
        • et al.
        Model to determine risk of pancreatic cancer in patients with new-onset diabetes.
        Gastroenterology. 2018; 155: 730-739.e3
        • Tamura K.
        • Ohtsuka T.
        • Date K.
        • et al.
        Distinction of invasive carcinoma derived from intraductal papillary mucinous neoplasms from concomitant ductal adenocarcinoma of the pancreas using molecular biomarkers.
        Pancreas. 2016; 45: 826-835
        • Wu J.
        • Matthaei H.
        • Maitra A.
        • et al.
        Recurrent GNAS mutations define an unexe.
        Sci Transl Med. 2011; 3: 1-19
        • Furukawa T.
        • Kuboki Y.
        • Tanji E.
        • et al.
        Whole-exome sequencing uncovers frequent GNAS mutations in intraductal papillary mucinous neoplasms of the pancreas.
        Sci Rep. 2011; 1: 161
        • Moher D.
        • Liberati A.
        • Tetzlaff J.
        • Altman D.G.
        • PRISMA Group
        Preferred reporting items for systematic reviews and meta-analyses: The PRISMA statement.
        Open Med. 2009; 3 (e123-e30)
        • Hjalgrim H.
        • Frisch M.
        • Ekbom A.
        • Kyvik K.
        • Melbye M.
        • Green A.
        Cancer and diabetes—A follow-up study of two population-based cohorts of diabetic patients.
        J Intern Med. 1997; 241: 471-475
        • Chow W.
        • Gridley G.
        • Nyren O.
        • et al.
        Risk of pancreatic cancer following diabetes mellitus: A nationwide cohort study in Sweden.
        J Natl Cancer Inst. 1995; 87: 930-931
      1. Higgins J, Green S (eds). Cochrane Handbook for Systematic Reviews of Interventions Version 5.1.0 [updated March 2011]. The Cochrane Collaboration, 2011 Web site. Accessed March 22, 2019.

        • Higgins J.P.
        • Thompson S.G.
        • Deeks J.J.
        • Altman D.G.
        Measuring inconsistency in meta-analyses testing for heterogeneity.
        BMJ. 2003; 327: 557-560
        • Taouli B.
        • Vilgrain V.
        • Vullierme M.-P.
        • et al.
        Intraductal papillary mucinous tumors of the pancreas: Helical CT with histopathologic correlation.
        Radiology. 2000; 217: 757-764
        • Wiesenauer C.A.
        • Schmidt C.M.
        • Cummings O.W.
        • et al.
        Preoperative predictors of malignancy in pancreatic intraductal papillary mucinous neoplasms.
        Arch Surg. 2003; 138: 610-617
        • Winner M.
        • Epelboym I.
        • Remotti H.
        • et al.
        Predictors of recurrence in intraductal papillary mucinous neoplasm: Experience with 183 pancreatic resections.
        J Gastrointest Surg. 2013; 17: 1618-1626
        • Kawakubo K.
        • Tada M.
        • Isayama H.
        • et al.
        Disease-specific mortality among patients with intraductal papillary mucinous neoplasm of the pancreas.
        Clin Gastroenterol Hepatol. 2014; 12: 486-491
        • Chang Y.T.
        • Tien Y.W.
        • Jeng Y.M.
        • et al.
        Overweight increases the risk of malignancy in patients with pancreatic mucinous cystic neoplasms.
        Medicine (Baltimore). 2015; 94: e797
        • Leal J.N.
        • Kingham T.P.
        • D’Angelica M.I.
        • et al.
        Intraductal papillary mucinous neoplasms and the risk of diabetes mellitus in patients undergoing resection versus observation.
        J Gastrointest Surg. 2015; 19: 1974-1981
        • Hirono S.
        • Kawai M.
        • Okada K.
        • et al.
        Factors associated with invasive intraductal papillary mucinous carcinoma of the pancreas.
        JAMA Surg. 2017; 152e165054
        • Morales-Oyarvide V.
        • Mino-Kenudson M.
        • Ferrone C.R.
        • et al.
        Diabetes mellitus in intraductal papillary mucinous neoplasm of the pancreas is associated with high-grade dysplasia and invasive carcinoma.
        Pancreatology. 2017; 17: 920-926
        • El Khoury R.
        • Kabir C.
        • Maker V.K.
        • Banulescu M.
        • Wasserman M.
        • Maker A.V.
        What is the incidence of malignancy in resected intraductal papillary mucinous neoplasms? An analysis of over 100 US institutions in a single year.
        Ann Surg Oncol. 2018; 25: 1746-1751
        • Marchegiani G.
        • Andrianello S.
        • Morbin G.
        • Secchettin E.
        • Onofrio M.D.
        • De Robertis R.
        Importance of main pancreatic duct dilatation in IPMN.
        Br J Surg. 2018; 105: 1825-1834
        • Aronsson L.
        • Ansari D.
        • Andersson B.
        • Persson U.
        • Fridhammar A.
        • Andersson R.
        Intraductal papillary mucinous neoplasms of the pancreas—A cost-effectiveness analysis of management strategies for the branch-duct subtype.
        HPB (Oxford). 2018; 20: 1206-1214
        • Del Chiaro M.
        • Beckman ÃR Ateeb Z.
        • et al.
        Main duct dilatation is the best predictor of high-grade dysplasia or invasion in intraductal papillary mucinous neoplasms of the pancreas [E-pub ahead of print].
        Ann Surg. 2019; (Accessed January 18, 2019)
        • Nagai K.
        • Doi R.
        • Kida A.
        • et al.
        Intraductal papillary mucinous neoplasms of the pancreas: Clinicopathologic characteristics and long-term follow-up after resection.
        World J Surg. 2008; 32: 271-278
        • Daudé M.
        • Muscari F.
        • Buscail C.
        • et al.
        Outcomes of nonresected main-duct intraductal papillary mucinous neoplasms of the pancreas.
        World J Gastroenterol. 2015; 21: 2658-2667
        • Sugimoto M.
        • Elliott I.A.
        • Nguyen A.H.
        • et al.
        Assessment of a revised management strategy for patients with intraductal papillary mucinous neoplasms involving the main pancreatic duct.
        JAMA Surg. 2017; 152e163349
        • Jang D.K.
        • Ryu J.K.
        • Chung K.H.
        • et al.
        Risk factors for progression or malignancy in main-duct and mixed-type intraductal papillary mucinous neoplasm of the pancreas.
        Pancreas. 2016; 45: 1027-1031
        • Woo S.M.
        • Ryu J.K.
        • Lee S.H.
        • Yoon W.J.
        • Kim Y.T.
        • Yoon Y.B.
        Branch duct intraductal papillary mucinous neoplasms in a retrospective series of 190 patients.
        Br J Surg. 2009; 96: 405-411
        • Nguyen A.H.
        • Toste P.A.
        • Farrell J.J.
        • et al.
        Current recommendations for surveillance and surgery of intraductal papillary mucinous neoplasms may overlook some patients with cancer.
        J Gastrointest Surg. 2015; 19: 258-265
        • Ridtitid W.
        • DeWitt J.M.
        • Schmidt C.M.
        • et al.
        Management of branch-duct intraductal papillary mucinous neoplasms: A large single-center study to assess predictors of malignancy and long-term outcomes.
        Gastrointest Endosc. 2016; 84: 436-445
        • Pérez-Cuadrado-Robles E.
        • Uribarri-González L.
        • Borbath I.
        • Vila J.J.
        • López-López S.
        • Deprez P.H.
        Risk of advanced lesions in patients with branch-duct IPMN and relative indications for surgery according to European evidence-based guidelines.
        Dig Liver Dis. 2019; 51: 882-886
        • Niedergethmann M.
        • Grützmann R.
        • Hildenbrand R.
        • et al.
        Outcome of invasive and noninvasive intraductal papillary-mucinous neoplasms of the pancreas (IPMN): A 10-year experience.
        World J Surg. 2008; 32: 2253-2260
        • Lubezky N.
        • Ben-Haim M.
        • Nakache R.
        • et al.
        Clinical presentation can predict disease course in patients with intraductal papillary mucinous neoplasm of the pancreas.
        World J Surg. 2010; 34: 126-132
        • Mimura T.
        • Masuda A.
        • Matsumoto I.
        • et al.
        Predictors of malignant intraductal papillary mucinous neoplasm of the pancreas.
        J Clin Gastroenterol. 2010; 44: e224-e229
        • Park J.
        • Lee K.T.
        • Jang T.H.
        • et al.
        Risk factors associated with the postoperative recurrence of intraductal papillary mucinous neoplasms of the pancreas.
        Pancreas. 2011; 40: 46-51
        • Hwang D.W.
        • Jang J.
        • Lee S.E.
        Clinicopathologic analysis of surgically proven intraductal papillary mucinous neoplasms of the pancreas in SNUH : A 15-year experience at a single academic institution.
        Langenbecks Arch Surg. 2012; 397: 93-102
        • Okabayashi T.
        • Shima Y.
        • Kosaki Takuhiro
        • et al.
        Invasive carcinoma derived from branch duct-type IPMN may be a more aggressive neoplasm than that derived from main duct-type IPMN.
        Oncol Lett. 2013; 5: 1819-1825
        • Sturm E.C.
        • Roch A.M.
        • Shaffer K.M.
        Obesity increases malignant risk in patients with branch-duct intraductal papillary mucinous neoplasm.
        Surgery. 2012; 154: 803-809
        • Centers for Disease Control and Prevention
        National diabetes statistics report, 2017.
        Centers for Disease Control and Prevention, US Dept of Health and Human Services, Atlanta, GA2017
        • Muniraj T.
        • Chari S.T.
        Diabetes and pancreatic cancer.
        Minerva Gastroenterol Dietol. 2012; 58: 331-345
        • Koh Y.X.
        • Zheng H.L.
        • Chok A.Y.
        • et al.
        Systematic review and meta-analysis of the spectrum and outcomes of different histologic subtypes of noninvasive and invasive intraductal papillary mucinous neoplasms.
        Surgery. 2015; 157: 496-509
        • Crippa S.
        • Fernandez-Del Castillo C.
        • Salvia R.
        • et al.
        Mucin-producing neoplasms of the pancreas: An analysis of distinguishing clinical and epidemiologic characteristics.
        Clin Gastroenterol Hepatol. 2010; 8: 213-219
        • Poultsides G.A.
        • Reddy S.
        • Cameron J.L.
        • et al.
        Histopathologic basis for the favorable survival after resection of intraductal papillary mucinous neoplasm-associated invasive adenocarcinoma of the pancreas.
        Ann Surg. 2010; 251: 470-476
        • Kalaitzakis E.
        • Braden B.
        • Trivedi P.
        • Sharifi Y.
        • Chapman R.
        Intraductal papillary mucinous neoplasm in chronic calcifying pancreatitis : Egg or hen ?.
        World J Gastroenterol. 2009; 15: 1273-1275
        • Capurso G.
        • Boccia S.
        • Salvia R.
        • et al.
        Risk factors for intraductal papillary mucinous neoplasm (IPMN) of the pancreas: A multicentre case-control study.
        Am J Gastroenterol. 2013; 108: 1003-1009