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Risk of Neoplastic Progression in Individuals at High Risk for Pancreatic Cancer Undergoing Long-term Surveillance

  • Author Footnotes
    ∗ Authors share co-first authorship.
    Marcia Irene Canto
    Correspondence
    Reprint requests Address requests for reprints to: Marcia Irene Canto, MD, MHS, Johns Hopkins Medical Institutions, Department of Medicine, Division of Gastroenterology, 1800 Orleans Street, Blalock 407, Baltimore, Maryland 21231. fax: (410) 614-2490.
    Footnotes
    ∗ Authors share co-first authorship.
    Affiliations
    Department of Medicine (Gastroenterology), The Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins Medical Institutions, Baltimore, Maryland

    Department of Oncology, The Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins Medical Institutions, Baltimore, Maryland
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  • Author Footnotes
    ∗ Authors share co-first authorship.
    Jose Alejandro Almario
    Footnotes
    ∗ Authors share co-first authorship.
    Affiliations
    Department of Medicine (Gastroenterology), The Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins Medical Institutions, Baltimore, Maryland

    Department of Pathology, The Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins Medical Institutions, Baltimore, Maryland
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  • Richard D. Schulick
    Affiliations
    Department of Surgery, University of Colorado School of Medicine, Denver, Colorado
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  • Charles J. Yeo
    Affiliations
    Department of Surgery, Thomas Jefferson University, Philadelphia, Pennsylvania
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  • Alison Klein
    Affiliations
    Department of Oncology, The Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins Medical Institutions, Baltimore, Maryland
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  • Amanda Blackford
    Affiliations
    Department of Oncology, The Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins Medical Institutions, Baltimore, Maryland
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  • Eun Ji Shin
    Affiliations
    Department of Medicine (Gastroenterology), The Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins Medical Institutions, Baltimore, Maryland
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  • Abanti Sanyal
    Affiliations
    The Johns Hopkins Biostatistics Center, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland
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  • Gayane Yenokyan
    Affiliations
    The Johns Hopkins Biostatistics Center, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland
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  • Anne Marie Lennon
    Affiliations
    Department of Medicine (Gastroenterology), The Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins Medical Institutions, Baltimore, Maryland
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  • Ihab R. Kamel
    Affiliations
    Department of Radiology, The Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins Medical Institutions, Baltimore, Maryland
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  • Elliot K. Fishman
    Affiliations
    Department of Radiology, The Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins Medical Institutions, Baltimore, Maryland
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  • Christopher Wolfgang
    Affiliations
    Department of Surgery, The Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins Medical Institutions, Baltimore, Maryland
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  • Matthew Weiss
    Affiliations
    Department of Surgery, The Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins Medical Institutions, Baltimore, Maryland
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  • Ralph H. Hruban
    Affiliations
    Department of Pathology, The Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins Medical Institutions, Baltimore, Maryland
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  • Michael Goggins
    Affiliations
    Department of Medicine (Gastroenterology), The Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins Medical Institutions, Baltimore, Maryland

    Department of Pathology, The Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins Medical Institutions, Baltimore, Maryland
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  • Author Footnotes
    ∗ Authors share co-first authorship.

      Background & Aims

      Screening of individuals who have a high risk of pancreatic ductal adenocarcinoma (PDAC), because of genetic factors, frequently leads to identification of pancreatic lesions. We investigated the incidence of PDAC and risk factors for neoplastic progression in individuals at high risk for PDAC enrolled in a long-term screening study.

      Methods

      We analyzed data from 354 individuals at high risk for PDAC (based on genetic factors of family history), enrolled in Cancer of the Pancreas Screening cohort studies at tertiary care academic centers from 1998 through 2014 (median follow-up time, 5.6 years). All subjects were evaluated at study entry (baseline) by endoscopic ultrasonography and underwent surveillance with endoscopic ultrasonography, magnetic resonance imaging, and/or computed tomography. The primary endpoint was the cumulative incidence of PDAC, pancreatic intraepithelial neoplasia grade 3, or intraductal papillary mucinous neoplasm with high-grade dysplasia (HGD) after baseline. We performed multivariate Cox regression and Kaplan-Meier analyses.

      Results

      During the follow-up period, pancreatic lesions with worrisome features (solid mass, multiple cysts, cyst size > 3 cm, thickened/enhancing walls, mural nodule, dilated main pancreatic duct > 5 mm, or abrupt change in duct caliber) or rapid cyst growth (>4 mm/year) were detected in 68 patients (19%). Overall, 24 of 354 patients (7%) had neoplastic progression (14 PDACs and 10 HGDs) over a 16-year period; the rate of progression was 1.6%/year, and 93% had detectable lesions with worrisome features before diagnosis of the PDAC or HGD. Nine of the 10 PDACs detected during routine surveillance were resectable; a significantly higher proportion of patients with resectable PDACs survived 3 years (85%) compared with the 4 subjects with symptomatic, unresectable PDACs (25%), which developed outside surveillance (log rank P < .0001). Neoplastic progression occurred at a median age of 67 years; the median time from baseline screening until PDAC diagnosis was 4.8 years (interquartile range, 1.6–6.9 years).

      Conclusions

      In a long-term (16-year) follow-up study of individuals at high-risk for PDAC, we found most PDACs detected during surveillance (9/10) to be resectable, and 85% of these patients survived for 3 years. We identified radiologic features associated with neoplastic progression.

      Graphical abstract

      Keywords

      Abbreviations used in this paper:

      CAPS (Cancer of the Pancreas Screening), CT (computed tomography), EUS (endoscopic ultrasonography), FPC (familial pancreatic cancer), HGD (high-grade dysplasia), HR (hazard ratio), HRI (high-risk individual), IPMN (intraductal papillary mucinous neoplasm), IQR (interquartile range), MPD (main pancreatic duct), MRI (magnetic resonance imaging), PanIN (pancreatic intraepithelial neoplasia), PDAC (pancreatic ductal adenocarcinoma), PanNET (pancreatic neuroendocrine tumor)
      See Covering the Cover synopsis on page 584.

       Background and Context

      Screening of high risk individuals (HRI) with a genetic predisposition can frequently detect pancreatic lesions. However, there is limited data on the incidence of pancreatic cancer and outcomes of screening and treatment.

       New Findings

      Pancreatic cancer and its high-grade precursor neoplasms develop in 7% of HRI, at a rate of 1.6% per year, after an average of 5 years from screening. Certain detectable radiologic abnormalities predict progression. Nearly all screen-detected tumors are resectable and survival is improved.

       Limitations

      This single-center cohort study has a relatively small number of progressors, and pancreatic cancer is a rare disease.

       Impact

      The study results support surveillance of HRI with EUS and MRI and continued research to improve biomarkers for early detection.
      Pancreatic ductal adenocarcinoma (PDAC) is the third—and is projected to soon become the second—leading cause of cancer deaths in the United States.
      • Siegel R.L.
      • Miller K.D.
      • Jemal A.
      Cancer statistics, 2016.
      The estimated incidence rate of developing PDAC is 1.5%, with 53,670 new cases and 43,090 deaths expected in 2017.
      National Cancer Institute. SEER cancer statistics review, 1975-2014.
      • Ibrahim I.S.
      • Bonsing B.A.
      • Swijnenburg R.J.
      • et al.
      Dilemmas in the management of screen-detected lesions in patients at high risk for pancreatic cancer.
      The 5-year survival rates of patients with PDAC remains low (8.2%).
      National Cancer Institute. SEER cancer statistics review, 1975-2014.
      Screening for pancreatic cancer is not recommended for the general population but is being evaluated for patients with a significantly elevated risk. Risk can be estimated by considering the number of affected blood relatives who have had pancreatic cancer (familial pancreatic cancer [FPC] kindred, defined as having at least 2 first-degree relatives with pancreatic cancer)
      • Canto M.I.
      • Harinck F.
      • Hruban R.H.
      • et al.
      International Cancer of the Pancreas Screening (CAPS) Consortium summit on the management of patients with increased risk for familial pancreatic cancer.
      • Klein A.P.
      • Brune K.A.
      • Petersen G.M.
      • et al.
      Prospective risk of pancreatic cancer in familial pancreatic cancer kindreds.
      and knowing whether an individual carries a deleterious germline mutation in a pancreatic cancer susceptibility gene.
      • Klein A.P.
      • Beaty T.H.
      • Bailey-Wilson J.E.
      • et al.
      Evidence for a major gene influencing risk of pancreatic cancer.
      The latter include germline mutations in BRCA1, BRCA2, ATM, PALB2, and CDKN2A (familial atypical multiple mole melanoma syndrome), mismatch repair genes MLH1, MSH2, MSH6, and PMS2 (Lynch syndrome), STK11 (Peutz-Jeghers syndrome), and PRSS1 (hereditary pancreatitis).
      • Jones S.
      • Hruban R.H.
      • Kamiyama M.
      • et al.
      Exomic sequencing identifies PALB2 as a pancreatic cancer susceptibility gene.
      • van Lier M.G.
      • Wagner A.
      • Mathus-Vliegen E.M.
      • et al.
      High cancer risk in Peutz-Jeghers syndrome: a systematic review and surveillance recommendations.
      • Zhen D.B.
      • Rabe K.G.
      • Gallinger S.
      • et al.
      BRCA1, BRCA2, PALB2, and CDKN2A mutations in familial pancreatic cancer: a PACGENE study.
      • Rebours V.
      • Boutron-Ruault M.C.
      • Schnee M.
      • et al.
      Risk of pancreatic adenocarcinoma in patients with hereditary pancreatitis: a national exhaustive series.
      • Al-Sukhni W.
      • Rothenmund H.
      • Borgida A.E.
      • et al.
      Germline BRCA1 mutations predispose to pancreatic adenocarcinoma.
      • Kastrinos F.
      • Mukherjee B.
      • Tayob N.
      • et al.
      Risk of pancreatic cancer in families with Lynch syndrome.
      • Roberts N.J.
      • Jiao Y.
      • Yu J.
      • et al.
      ATM mutations in patients with hereditary pancreatic cancer.
      Several large academic centers have conducted screening programs for these asymptomatic high-risk individuals (HRIs).
      • Al-Sukhni W.
      • Borgida A.
      • Rothenmund H.
      • et al.
      Screening for pancreatic cancer in a high-risk cohort: an eight-year experience.
      • Bartsch D.K.
      • Dietzel K.
      • Bargello M.
      • et al.
      Multiple small “imaging” branch-duct type intraductal papillary mucinous neoplasms (IPMNs) in familial pancreatic cancer: indicator for concomitant high grade pancreatic intraepithelial neoplasia?.
      • Canto M.I.
      • Goggins M.
      • Hruban R.H.
      • et al.
      Screening for early pancreatic neoplasia in high-risk individuals: a prospective controlled study.
      • Canto M.I.
      • Goggins M.
      • Yeo C.J.
      • et al.
      Screening for pancreatic neoplasia in high-risk individuals: an EUS-based approach.
      • Canto M.I.
      • Hruban R.H.
      • Fishman E.K.
      • et al.
      Frequent detection of pancreatic lesions in asymptomatic high-risk individuals.
      • Kimmey M.B.
      • Bronner M.P.
      • Byrd D.R.
      • et al.
      Screening and surveillance for hereditary pancreatic cancer.
      • Langer P.
      • Kann P.H.
      • Fendrich V.
      • et al.
      Five years of prospective screening of high-risk individuals from families with familial pancreatic cancer.
      • Ludwig E.
      • Olson S.H.
      • Bayuga S.
      • et al.
      Feasibility and yield of screening in relatives from familial pancreatic cancer families.
      • Schneider R.
      • Slater E.P.
      • Sina M.
      • et al.
      German national case collection for familial pancreatic cancer (FaPaCa): ten years experience.
      • Vasen H.F.
      • Wasser M.
      • van Mil A.
      • et al.
      Magnetic resonance imaging surveillance detects early-stage pancreatic cancer in carriers of a p16-Leiden mutation.
      • Poley J.W.
      • Kluijt I.
      • Gouma D.J.
      • et al.
      The yield of first-time endoscopic ultrasonography in screening individuals at a high risk of developing pancreatic cancer.
      An international consortium of experts recommended pancreatic screening and surveillance be evaluated for HRIs with an estimated lifetime risk of PDAC of > 5%.
      • Canto M.I.
      • Harinck F.
      • Hruban R.H.
      • et al.
      International Cancer of the Pancreas Screening (CAPS) Consortium summit on the management of patients with increased risk for familial pancreatic cancer.
      Pancreatic cancer surveillance programs using a combination of endoscopic ultrasonography, magnetic resonance imaging (MRI), and computed tomography (CT) scans have detected a high prevalence of asymptomatic pancreatic lesions, mostly cysts, that represent the major associated precursor lesions (pancreatic intraepithelial neoplasia [PanINs], intraductal papillary mucinous neoplasms [IPMNs]) in HRIs. Most of the pancreatic cysts identified in HRIs are small (<1 cm) and often multiple; their prevalence is much more common than in the general population and increases with patient age.
      • Canto M.I.
      • Hruban R.H.
      • Fishman E.K.
      • et al.
      Frequent detection of pancreatic lesions in asymptomatic high-risk individuals.
      Depending on the age and other characteristics of the study population and the imaging modalities, the prevalence of precursor lesions identified by screening has ranged from 6%–52%.
      • Canto M.I.
      • Goggins M.
      • Hruban R.H.
      • et al.
      Screening for early pancreatic neoplasia in high-risk individuals: a prospective controlled study.
      • Canto M.I.
      • Hruban R.H.
      • Fishman E.K.
      • et al.
      Frequent detection of pancreatic lesions in asymptomatic high-risk individuals.
      • Ludwig E.
      • Olson S.H.
      • Bayuga S.
      • et al.
      Feasibility and yield of screening in relatives from familial pancreatic cancer families.
      • Schneider R.
      • Slater E.P.
      • Sina M.
      • et al.
      German national case collection for familial pancreatic cancer (FaPaCa): ten years experience.
      • Poley J.W.
      • Kluijt I.
      • Gouma D.J.
      • et al.
      The yield of first-time endoscopic ultrasonography in screening individuals at a high risk of developing pancreatic cancer.
      • Vasen H.
      • Ibrahim I.
      • Ponce C.G.
      • et al.
      Benefit of surveillance for pancreatic cancer in high-risk individuals: outcome of long-term prospective follow-up studies from three European expert centers.
      • Harinck F.
      • Konings I.C.
      • Kluijt I.
      • et al.
      A multicentre comparative prospective blinded analysis of EUS and MRI for screening of pancreatic cancer in high-risk individuals.
      Pancreatic neuroendocrine tumors (PanNETs) have also been detected.
      • Canto M.I.
      • Goggins M.
      • Hruban R.H.
      • et al.
      Screening for early pancreatic neoplasia in high-risk individuals: a prospective controlled study.
      • Canto M.I.
      • Hruban R.H.
      • Fishman E.K.
      • et al.
      Frequent detection of pancreatic lesions in asymptomatic high-risk individuals.
      • Ludwig E.
      • Olson S.H.
      • Bayuga S.
      • et al.
      Feasibility and yield of screening in relatives from familial pancreatic cancer families.
      • Schneider R.
      • Slater E.P.
      • Sina M.
      • et al.
      German national case collection for familial pancreatic cancer (FaPaCa): ten years experience.
      • Poley J.W.
      • Kluijt I.
      • Gouma D.J.
      • et al.
      The yield of first-time endoscopic ultrasonography in screening individuals at a high risk of developing pancreatic cancer.
      • Vasen H.
      • Ibrahim I.
      • Ponce C.G.
      • et al.
      Benefit of surveillance for pancreatic cancer in high-risk individuals: outcome of long-term prospective follow-up studies from three European expert centers.
      • Harinck F.
      • Konings I.C.
      • Kluijt I.
      • et al.
      A multicentre comparative prospective blinded analysis of EUS and MRI for screening of pancreatic cancer in high-risk individuals.
      Most studies evaluating the diagnostic yield of pancreatic screening have reported lesions detected only at baseline screening.
      • Kastrinos F.
      • Mukherjee B.
      • Tayob N.
      • et al.
      Risk of pancreatic cancer in families with Lynch syndrome.
      • Al-Sukhni W.
      • Borgida A.
      • Rothenmund H.
      • et al.
      Screening for pancreatic cancer in a high-risk cohort: an eight-year experience.
      • Bartsch D.K.
      • Dietzel K.
      • Bargello M.
      • et al.
      Multiple small “imaging” branch-duct type intraductal papillary mucinous neoplasms (IPMNs) in familial pancreatic cancer: indicator for concomitant high grade pancreatic intraepithelial neoplasia?.
      • Canto M.I.
      • Goggins M.
      • Hruban R.H.
      • et al.
      Screening for early pancreatic neoplasia in high-risk individuals: a prospective controlled study.
      • Canto M.I.
      • Goggins M.
      • Yeo C.J.
      • et al.
      Screening for pancreatic neoplasia in high-risk individuals: an EUS-based approach.
      • Canto M.I.
      • Hruban R.H.
      • Fishman E.K.
      • et al.
      Frequent detection of pancreatic lesions in asymptomatic high-risk individuals.
      • Kimmey M.B.
      • Bronner M.P.
      • Byrd D.R.
      • et al.
      Screening and surveillance for hereditary pancreatic cancer.
      • Langer P.
      • Kann P.H.
      • Fendrich V.
      • et al.
      Five years of prospective screening of high-risk individuals from families with familial pancreatic cancer.
      • Ludwig E.
      • Olson S.H.
      • Bayuga S.
      • et al.
      Feasibility and yield of screening in relatives from familial pancreatic cancer families.
      • Poley J.W.
      • Kluijt I.
      • Gouma D.J.
      • et al.
      The yield of first-time endoscopic ultrasonography in screening individuals at a high risk of developing pancreatic cancer.
      • Harinck F.
      • Konings I.C.
      • Kluijt I.
      • et al.
      A multicentre comparative prospective blinded analysis of EUS and MRI for screening of pancreatic cancer in high-risk individuals.
      Identification of screening abnormalities and other risk factors that predict neoplastic progression to PDAC or high-grade precursor neoplasms might improve surveillance programs and guide management of detected lesions.
      The aims of this study were to determine the cumulative incidence of PDAC and high-grade dysplasia (HGD) precursor neoplasms (IPMN-HGD and PanIN-3) and identify risk factors that predict neoplastic progression in HRIs undergoing long-term surveillance after baseline screening. We also report the outcomes of HRIs with detected neoplasms.

      Methods

       Study Design and Patients

      From 1998 to 2014, 581 asymptomatic HRIs were prospectively enrolled into 1 of the Johns Hopkins Cancer of the Pancreas Screening (CAPS) studies (CAPS 1,
      • Canto M.I.
      • Goggins M.
      • Yeo C.J.
      • et al.
      Screening for pancreatic neoplasia in high-risk individuals: an EUS-based approach.
      CAPS 2,
      • Canto M.I.
      • Goggins M.
      • Hruban R.H.
      • et al.
      Screening for early pancreatic neoplasia in high-risk individuals: a prospective controlled study.
      CAPS 3,
      • Canto M.I.
      • Hruban R.H.
      • Fishman E.K.
      • et al.
      Frequent detection of pancreatic lesions in asymptomatic high-risk individuals.
      or CAPS 4) at participating tertiary referral American academic medical centers with comprehensive multidisciplinary pancreas screening programs. The institutional review boards of The Johns Hopkins Medical Institutions and all participating sites approved the CAPS studies. All subjects provided informed consent for baseline screening and follow-up.
      Inclusion criteria for HRIs in the CAPS studies were the following:
      • Patients who met clinical criteria for Peutz-Jeghers syndrome, or who had a mutation in the STK11 gene, and who were at least 30 years old;
      • Individuals from an FPC kindred who had at least 1 affected first-degree relationship to the HRI, and were at least 50 years old (CAPS studies 1–3, from 1998 to 2010) or at least 55 years (CAPS 4 study, from 2010), or 10 years younger than the youngest pancreatic cancer in the family; and
      • Individuals with confirmed germline mutations in the BRCA1, BRCA2, PALB2, PRSS1, CDKN2A, or MLH1, MSH2, MSH6, PMS2 (Lynch syndrome), with at least 1 affected first- or second-degree relative, and at least 50 years old, or 10 years younger than the youngest age at pancreatic cancer diagnosis in the family.
      Since this study evaluated predictors of progression during surveillance, we did not include HRIs enrolled in the CAPS studies who had (1) less than 6 months of follow-up after baseline screening, (2) surveillance at an outside institution without available medical records or clinical follow-up (lost to follow-up at John Hopkins Hospital), (3) prior surgery that prevented complete endoscopic ultrasonographic (EUS) examination of the pancreas. From 584 HRIs enrolled in the CAPS 1–4 studies from 1998 to 2014, 104 patients were excluded from the current study because they continued surveillance at an outside institution, and 123 patients were excluded for less than 6 months of follow-up after baseline screening.

       Surveillance Methods, Clinical Management, and Final Diagnosis

      HRIs were referred to the CAPS studies through the Johns Hopkins National Familial Pancreas Tumor Registry (www.nfptr.org), physicians, genetic counselors, or self-referral. After providing informed consent and completing a detailed questionnaire, all HRIs were screened at baseline with EUS. Individuals who participated in the CAPS 3 study also underwent baseline CT, individuals who enrolled in the CAPS 1 study (1998–2002, n = 38) underwent baseline EUS only,
      • Canto M.I.
      • Goggins M.
      • Yeo C.J.
      • et al.
      Screening for pancreatic neoplasia in high-risk individuals: an EUS-based approach.
      and those in the CAPS 2 study (2002–2004, n = 78) underwent both EUS and CT.
      • Canto M.I.
      • Goggins M.
      • Hruban R.H.
      • et al.
      Screening for early pancreatic neoplasia in high-risk individuals: a prospective controlled study.
      Since 2005, surveillance after baseline screening was performed on the CAPS 3 subjects (n = 216)
      • Canto M.I.
      • Hruban R.H.
      • Fishman E.K.
      • et al.
      Frequent detection of pancreatic lesions in asymptomatic high-risk individuals.
      continuing follow-up at Johns Hopkins and all CAPS 4 subjects enrolled at Johns Hopkins (n = 249) using a combination of EUS, MRI/magnetic resonance cholangiopancreatography, and/or computed tomography (CT) at intervals dependent on the presence or absence of neoplastic-type pancreatic lesions. HRIs with a normal pancreas or EUS features of chronic pancreatitis were followed annually. Those with pancreatic cysts or indeterminate radiologic lesions underwent more frequent imaging with EUS and/or MRI or CT, according to published international guidelines
      • Canto M.I.
      • Harinck F.
      • Hruban R.H.
      • et al.
      International Cancer of the Pancreas Screening (CAPS) Consortium summit on the management of patients with increased risk for familial pancreatic cancer.
      • Tanaka M.
      • Chari S.
      • Adsay V.
      • et al.
      International consensus guidelines for management of intraductal papillary mucinous neoplasms and mucinous cystic neoplasms of the pancreas.
      • Tanaka M.
      • Fernandez-del Castillo C.
      • Adsay V.
      • et al.
      International consensus guidelines 2012 for the management of IPMN and MCN of the pancreas.
      : every 6–12 months for those without a mural nodule or dilated pancreatic duct and every 3–6 months for larger cysts or cysts with worrisome features. Stable or improved appearance of pancreatic lesions resulted in decreased surveillance imaging frequency to every 12 months.
      EUS-guided fine needle aspiration was not routinely performed on small cystic lesions < 1 cm.
      Recommendations for pancreatic surveillance and surgical treatment were discussed at CAPS multidisciplinary clinical conferences, and decision-making was individualized. After Sendai
      • Tanaka M.
      • Chari S.
      • Adsay V.
      • et al.
      International consensus guidelines for management of intraductal papillary mucinous neoplasms and mucinous cystic neoplasms of the pancreas.
      and Fukuoka
      • Tanaka M.
      • Fernandez-del Castillo C.
      • Adsay V.
      • et al.
      International consensus guidelines 2012 for the management of IPMN and MCN of the pancreas.
      international consensus guidelines for management of sporadic IPMNs became available, these were used as a guides for data collection and patient management, recognizing that these guidelines were not developed primarily for HRIs. Worrisome features were defined in this study according to the Sendai and Fukuoka International Consensus Guidelines for management of a mucinous cysts
      • Tanaka M.
      • Chari S.
      • Adsay V.
      • et al.
      International consensus guidelines for management of intraductal papillary mucinous neoplasms and mucinous cystic neoplasms of the pancreas.
      • Tanaka M.
      • Fernandez-del Castillo C.
      • Adsay V.
      • et al.
      International consensus guidelines 2012 for the management of IPMN and MCN of the pancreas.
      and included cyst size ≥ 3 cm, thickened/enhancing cyst walls, main pancreatic duct (MPD) dilation > 5 mm, mural nodule in the cyst or MPD, abrupt change in MPD caliber, or rapid cyst growth rate > 2 mm in 6 months or > 4 mm in 1 year. The latter was defined based on studies reporting rapid cyst growth rate in sporadic IPMNs of > 2–5 mm per year associated with increased risk of malignancy.
      • Kang M.J.
      • Jang J.Y.
      • Kim S.J.
      • et al.
      Cyst growth rate predicts malignancy in patients with branch duct intraductal papillary mucinous neoplasms.
      • Kwong W.T.
      • Lawson R.D.
      • Hunt G.
      • et al.
      Rapid growth rates of suspected pancreatic cyst branch duct intraductal papillary mucinous neoplasms predict malignancy.
      Suspicious cytology for pancreatic malignancy, when available, was also considered a worrisome feature.
      • Tanaka M.
      • Chari S.
      • Adsay V.
      • et al.
      International consensus guidelines for management of intraductal papillary mucinous neoplasms and mucinous cystic neoplasms of the pancreas.
      • Tanaka M.
      • Fernandez-del Castillo C.
      • Adsay V.
      • et al.
      International consensus guidelines 2012 for the management of IPMN and MCN of the pancreas.
      • Vege S.S.
      • Ziring B.
      • Jain R.
      • et al.
      American gastroenterological association institute guideline on the diagnosis and management of asymptomatic neoplastic pancreatic cysts.
      For this study, any solid mass > 5 mm was considered a worrisome feature, if confirmed by repeated EUS, at least 2 imaging modalities, and/or increasing size.
      Surgical intervention was offered to those suspected of having pancreatic cancer or high-grade dysplasia, based on imaging or cytology. In some cases, surgical resection was undertaken because of concern that it might be difficult to detect an early-stage pancreatic cancer in HRIs with numerous pancreatic cysts. HRIs with pancreatic lesions with any worrisome features were discussed in a multidisciplinary clinical conference consisting of a team of surgeons, gastroenterologists, radiologists, and pathologists. Decision making was individualized, using clinical criteria and published guidelines for pancreatic cyst management. Most pancreatic resections were performed at the Johns Hopkins Hospital by very experienced surgeons specializing in pancreaticobiliary diseases (CJY, RDS, CW, MW).
      The final diagnoses were made by surgical pathology or cytology (percutaneous or EUS-guided fine needle aspirates). All pathological diagnoses were made by an expert pathologist (RHH) using standard and consensus international classification systems. Pathological reports and slides were reviewed for HRIs who had surgery outside of Johns Hopkins. If the pathological specimen had multiple pancreatic lesions, the lesion with the highest pathologic grade was considered for endpoint analysis. Clinical findings and imaging characteristics were tracked over time to the last follow-up by prospective recording of imaging test results at Johns Hopkins Hospital and retrospective review of outside medical records and images, when applicable, up to December 2016.

       Statistical Analysis

      “Neoplastic progression” was defined the development of pathologically proven PDAC and/or high-grade PDAC precursor neoplasms (PanIN-3, IPMN-HGD). “Radiologic progression” was defined as the development of a lesion with 1 or more worrisome features after baseline imaging. PanNETs were defined as well-differentiated neoplasms > 0.5 cm in size with predominantly neuroendocrine differentiation and low proliferation indices.
      World Health Organization
      WHO Classification of Tumours of the Digestive System.
      World Health Organization
      WHO Classification of Tumors of the Endocrine Organs.
      PanNETs were not included in the primary and secondary outcome variables but were listed separately as 1 of the final pathological diagnoses.
      Primary study outcome variables were (1) the demographic, clinical, and imaging factors associated with neoplastic progression (analyzed using chi-squared and Fisher exact test for categorical variables and t test and Mann-Whitney test for continuous variables), (2) the rate of neoplastic progression stratified by age and adjusted for varying rates of radiologic progression (analyzed by Kaplan-Meier and Cox regression analyses), and, (3) the hazard rates of neoplastic progression among all radiologic progressors and those with different types of lesions (solid mass, cyst, or pancreatic duct lesions), adjusted for clinical factors and baseline pancreatic abnormalities (analyzed by Cox proportional hazards regression modeling).
      Secondary study outcome variables were (1) the cumulative incidence of pathologically proven PDAC and high-grade PDAC precursors (PanIN-3, IPMN-HGD); (2) the resectability and tumor stage of clinically relevant pancreatic neoplasms detected by screening/surveillance; and (3) the median survival time, 3-year survival rate, and overall mortality of neoplastic progressors. All statistical analysis were performed using Stata, version 14.1 (Stata Corp., College Station, TX).

      Results

       Baseline Characteristics of Screened HRIs

      The baseline characteristics of the 354 HRIs are summarized in Table 1. Most HRIs (97%) were FPC relatives, and 16% of those screened had a known deleterious germline variant. About half the study population was male, predominantly white race, with the mean age at baseline of 56.4 years (range, 22–81 years).
      Table 1Baseline Patient Characteristics
      Progressor (n = 24)Non-progressor (n = 330)Total (N = 354)P value
      PDAC (n = 14)High-grade precursor neoplasm
      High-grade precursor neoplasm is an IPMN with high-grade dysplasia or pancreatic intraepithelial neoplasia (PanIN)-3.
      (n = 10)
      Mean age (range), y62.5 (45-75)64.4 (47-78)55.8 (29-81)56.4 (29-81)<.0001
      Age > 60 y, n (%)9 (70)7 (64)117 (35)133 (38).009
      Male, n (%)7 (50)1 (10)160 (48)168 (48).052
      Race and ethnicity, n (%)>.99
       Black008 (2.4)8 (2.2)
       White14 (100)10 (100)308 (93)332 (94)
       Asian004 (1)4 (1.1)
       More than 1 race009 (3)9 (2.5)
       Hispanic001 (0.3)1 (0.2)
      FPC, n (%)14 (100)8 (80)322 (94)344 (97).043
      3 or more FDR with PDAC3 (21)026 (8)29 (8).167
      3 or more relatives with PDAC11 (79)5 (50)179 (54)195 (55).178
      Mutation carrier, n (%)1 (7)3 (30)53 (16)57 (16).327
       Peutz-Jeghers syndrome02 (20)8 (2)10 (3).043
       CDKN2A004 (1)4 (1)>.99
       BRCA1/BRCA2/PALB21 (7)1 (10)39 (12)41 (12)>.99
       Lynch syndrome001 (0.3)1 (0.3)>.99
       PRSS1001 (0.3)1 (0.3)>.99
      Current smoking, n (%)1 (7)3 (30)25 (86)29 (8).07
      Ever smoked, n (%)5 (36)5 (50)119 (36)129 (36).702
      Personal history of other cancer, n (%)4 (29)3 (30)64 (19)71 (20).419
      Type II diabetes, n (%)1 (7)027 (8)28 (8)1.0
      BMI ≥ 30 kg/m22 (14)3 (30)82 (24)87 (25).694
      Dilated MPD at baseline
      Dilated MPD defined by Rosemont criteria (≥ 3.5 mm in the head, ≥ 2.5 mm in the body, and/or ≥ 1.5 mm in the tail), but < 5 mm in any area.
      9 (64)5 (50)62 (19)76 (21)<.0001
      Three or more cysts at baseline5 (36)8 (80)36 (11)49 (14)<.0001
      BMI, body mass index; FDR, first- degree relatives.
      a High-grade precursor neoplasm is an IPMN with high-grade dysplasia or pancreatic intraepithelial neoplasia (PanIN)-3.
      b Dilated MPD defined by Rosemont criteria (≥ 3.5 mm in the head, ≥ 2.5 mm in the body, and/or ≥ 1.5 mm in the tail), but < 5 mm in any area.
      One hundred eighty-five HRIs (52% of 354) had no lesions detected at baseline. Fourteen HRIs (4%) had solid hypoechoic masses > 1 cm or nodules < 1 cm at baseline, and 4 (1.1%) had both cysts and solid lesions. The remaining 151 (43% of 354) HRIs had no solid lesions and 1 or more cystic lesions detected at baseline, and 14% (49/354) had 3 or more cysts. The mean size of the largest cyst at baseline was 8 mm (range, 1.6–28 mm). At baseline, 76 (21.4%) HRIs had a mildly dilated MPD according to the Rosemont criteria
      • Catalano M.F.
      • Sahai A.
      • Levy M.
      • et al.
      EUS-based criteria for the diagnosis of chronic pancreatitis: the Rosemont classification.
      (≥3.5 mm in the head, ≥ 2.5 mm in the body, and/or ≥1.5 mm in the tail) but < 5 mm (Table 1).

       Cumulative Incidence of Neoplastic Progression and Types of Detected Neoplasms

      The median follow-up time for the entire cohort was 5.6 years (interquartile range, 3.9–8.9 years). Fifty-four (79%) of the 68 HRIs with pancreatic lesions with worrisome features detected by surveillance had diagnostic pathology either by surgical resection (n = 44) and/or percutaneous or EUS-guided fine needle aspiration (n = 6). Thirty of these 54 asymptomatic HRIs (8.5% of the entire cohort) were diagnosed with a clinically significant primary pancreatic neoplasm: 14 had PDAC (4% or the entire cohort), 10 had IPMN-HGD and/or PanIN-3 (3% of the cohort), and 6 had PanNET > 5 mm (1.7% of the entire cohort). The overall detection rate for PDAC or a high-grade dysplasia in 354 HRIs over the 16-year study period was 7%, including prevalent and incident neoplasms. Detailed information about the 24 patients with PDAC or high-grade dysplasia is summarized in Table 2. The cumulative incidence for PDAC or a high-grade precursor neoplasm during the study period (excluding 2 asymptomatic cancers detected at baseline) was 22 of 339 (6.5%).
      Table 2Description of 24 HRIs With Neoplastic Progression
      Patient numberAge at diagnosis, y/sexHRI categoryTime to detection of tumor, yTumor type/size, mmManagementTNM stageOutcome/survival time from diagnosis, yCause of death
      Patients with PDACs detected during surveillance who had surgery
       172/FFPC0.2PDAC/2Distal pancreatectomyT1N1M1Alive/10.9NA
       246/FFPC0.6PDAC/28WhippleT2N1M0Died/12.3Gastric cancer surgery complications
       366/MFPC2.2PDAC/28Distal pancreatectomyT2N1M0Died/1.1PDAC
       479/FFPC4.4PDAC/25WhippleT3N1M0Alive/1.8NA
       573/FFPC4.4PDAC/15WhippleT3N0M0Alive/3.9NA
       670/MFPC5.2PDAC/45No surgery; metachronous PDAC 5 years after Whipple for main duct IPMNT4N1M1Died/0.2PDAC
       751/FFPC6.8PDAC/35Distal pancreatectomyT2N1M0Alive/7.2NA
       855/MFPC9.7PDAC/27Distal pancreatectomy 8 years after Whipple for IPMN-adenomaT3N0M0Died/1.1PDAC
       970/MFPC9.1PDAC/7Total pancreatectomyT1NM0Alive/3.7NA
       1074/MFPC9.9PDAC/36Distal pancreatectomyT3N1M0Died/3.7PDAC
      Patients with high-grade precursor neoplasms detected and treated during surveillance
       1167/FFPC0.3PanIN3/—Total pancreatectomyNAAlive/10.2NA
       1256/FFPC0.3Combined IPMN-HGD/—Total pancreatectomyNAAlive/8.6NA
       1353/FFPC0.4PanIN3/—Total pancreatectomyNAAlive/4.4NA
       1467/FFPC2.0IPMN-HGD/10;

      IPMN-HGD/5
      Distal pancreatectomy followed by completion WhippleNAAlive/4.8NA
       1558/FFPC2.5IPMN-HGD/—; PanIN-3/—WhippleNAAlive/9.9NA
       1666/FPJS2.5IPMN-HGD/—Distal pancreatectomyNAAlive/4.1NA
       1776/FFPC2.0PanIN3/—WhippleNAAlive/7.2NA
       1856/FFPC1.5PanIN3 in MPD/—WhippleNAAlive/8.1NA
       1972/MFPC1.9IPMN-HGD/—Distal pancreatectomyNAAlive/7.2NA
       2047/MPJS0.3IPMN-HGD/—WhippleNAAlive/14.7NA
      Patients with tumors detected outside surveillance (late or stopped surveillance)
       2177/MFPC1.6PDAC/25No surgeryT2N1M1Dead/2.2PDAC
       2268/MFPC4.5PDAC/22No surgeryT2N1M1Dead/0.3PDAC
       2359/MFPC9.0PDAC/25Total pancreatectomyT2N1M0Dead/4.0PDAC
       2482/FFPC6.9PDAC/
      Patient reported diagnosis of an unresectable cancer, tumor size unknown.
      No surgeryTxNxM1Dead/0.5PDAC
      NOTE. First degree relatives of patients 2 and 7 diagnosed with PDAC at age < 55 years.
      F, female; M, male; NA, not applicable.
      a Patient reported diagnosis of an unresectable cancer, tumor size unknown.
      One patient with multiple pancreatic lesions and abdominal lymphadenopathy was diagnosed with a metastatic pancreatic B-cell lymphoma by EUS-guided fine needle aspiration. The remaining 23 of the 54 HRIs (43%) with pathologic diagnoses had lower-grade dysplasia or non-dysplastic lesions in their resection specimens (IPMN–low-grade dysplasia/moderate-grade dysplasia, PanIN-1/2, benign PanNET microadenomas < 0.5 cm, serous cyst adenoma). Most of these patients underwent resection in the early years of the CAPS program.

       Outcomes of HRIs With Worrisome Features Who Did Not Have Surgery

      Of the 68 HRIs who had lesions with worrisome radiologic features at any time during the study period, 24 (35%) did not undergo surgery and were followed up for an average of 5.8 years (range, 1–12 years). Five of these 24 HRIs had cyst growth during follow-up but otherwise no evidence of neoplastic progression. Fourteen HRIs with a dilated MPD had stable or improved duct diameter. Five HRIs who did not undergo surgery developed a solid mass diagnosed by EUS–fine-needle aspiration: 3 HRIs had advanced PDAC (stopped or late for surveillance, Table 2), 1 HRI had the lymphoma mentioned earlier, and 1 HRI had a PanNET confirmed by EUS–fine-needle aspiration but declined surgery.

       Factors Associated With Neoplastic Progression

      The mean age of HRIs who developed PDAC or high-grade dysplasia in this cohort was significantly greater than non-progressors (P < .0001) (Table 1). Age > 60 years at baseline was associated with radiologic progression (hazard ratio [HR], 3.1, adjusted model) (Supplementary Table 1). However, age was not a significant predictor of neoplastic progression in the multivariate analyses (HR, 1.64; 95% confidence interval [CI], 0.65–4.14) (Table 3). A greater proportion of HRIs who developed PDAC or a high-grade precursor neoplasm had a dilated MPD at baseline compared with non-progressors (64% and 50% vs 19%, respectively; P < .0001) (Table 1), but the HR for a dilated MPD was not significant in the multivariate analysis (HR, 1.68; 95% CI, 0.70–4.06) (Table 3).
      Table 3Cox Proportional Hazards Regression Model for Neoplastic Progression After Adjusting for Time, Varying Radiologic Progression, and Type of Radiologic Progression
      Adjusted Model
      HRP value95% CI
      Any radiologic progression23.96<.00019.43–60.87
      Type of radiologic progression
       Cyst or duct changes41.20<.000112.52–135.53
       Solid mass422.60<.0001102.42–1743.74
      Age at baseline > 60 years1.64.290.65–4.14
      Mutation positive0.66.530.18–2.41
      Total lesions at baseline ≥ 34.85<.00012.02–11.64
      Dilated MPD at baseline
      Dilated MPD defined by Rosemont criteria35 (≥3.5 mm in the head, ≥2.5 mm in the body, and/or ≥1.5 mm in the tail), but <5 mm in any area.
      1.68.250.70–4.06
      CI, confidence interval.
      a Dilated MPD defined by Rosemont criteria
      • Catalano M.F.
      • Sahai A.
      • Levy M.
      • et al.
      EUS-based criteria for the diagnosis of chronic pancreatitis: the Rosemont classification.
      (≥3.5 mm in the head, ≥2.5 mm in the body, and/or ≥1.5 mm in the tail), but <5 mm in any area.
      Neoplastic progressors were more likely to have multiple cysts (3 or more) at baseline compared with non-progressors (PDAC, 36% and high-grade precursor neoplasm, 80% vs others, 11%; P < .0001), even after adjusting for other factors (HR, 4.85; 95% CI, 2.02–11.64) (Table 3). Specific EUS and radiologic features (worrisome features) were associated with neoplastic progression (univariate and multivariate analysis) (Supplementary Tables 1 and 2). In particular, the presence of a solid mass, mural nodule, thickened cyst wall, rapid cyst growth rate, and MPD dilated to ≥ 5 mm at any time during surveillance were associated with the development of PDAC or high-grade precursor neoplasm.
      After adjusting for time-varying rates of radiologic progression, Cox-proportional multivariate regression analysis showed that any radiologic progression was the strongest predictor for developing PDAC or a high-grade precursor neoplasm (23-fold, P < .0001) (Table 3, Figure 1). Specifically, the adjusted risk for neoplastic progression was 41-fold higher (95% CI, 12.52–135.53) (Table 3) for HRIs with radiologic progression in a pancreatic cyst or in the MPD and 423-fold higher for HRIs with a solid mass (95% CI, 102.42–1743.74).
      Figure thumbnail gr1
      Figure 1Risk for neoplastic progression was significantly increased in (A) HRIs with worrisome features (radiologic progression) (P < .0001) (B) and those beginning screening at age > 60 years.

       Rates of Progression and Time to Radiologic and Neoplastic Progression

      The estimated rate of radiologic progression after baseline screening, after excluding the 17 HRIs who had a solid mass or cyst with worrisome features at baseline, was 4.3% per year (Supplementary Figure 1). Progression rates were higher among those HRIs > 60 years old at baseline screening (Supplementary Figure 2). The median time for any radiologic worrisome feature to occur in HRIs after baseline was 13.1 months (interquartile range [IQR], 0.2–52 months). The median time for radiologic progression in HRIs who developed PDAC was 4.3 years (IQR, 1.0–6.5 years).
      Neoplastic progression occurred at a rate of 1.6% per year (Figure 2) and at a much higher and faster rate in HRIs with a lesion with a worrisome feature (Figure 1A). Twelve of the 14 HRIs with PDACs and 8 of the 10 with high-grade precursor neoplasms (IPMN-HGD and PanIN-3) resected were incident lesions detected during follow-up (Table 2). The median time to neoplastic progression from baseline screening for the 14 HRIs who developed invasive PDAC after baseline screening was 4.8 years (IQR, 1.6–6.9 years) but was significantly shorter in those beginning screening at 60 years or older (median, 1.7 years; IQR, 0.5–4.4 years) compared with younger HRIs (median, 5.2 years; IQR, 0.4–8 years) (Figure 1B). The mean age for HRIs who developed PDAC was 67.6 years (IQR, 59–74 years). Twelve of the 14 PDAC patients and 7 of the 10 HRIs with HGD were > 60 years old at the time of diagnosis.
      Figure thumbnail gr2
      Figure 2Cumulative risk (hazard) for neoplastic progression (PDAC, IPMN-HGD, or PanIN-3) for HRIs after baseline screening. Overall neoplastic progression rate was 1.6% per year.

       Outcomes of Surveillance and Treatment

      Detailed information on the HRIs with pancreatic neoplasia is summarized in Table 2. The mean diameter of the screening-detected PDACs was 24.8 mm (range, 7–45 mm). The 2 stage I pancreatic cancers were detected by EUS and not visualized by preoperative MRI or CT. Two of the resected PDACs were TNM stage IA (size, 5 and 7 mm) (Figure 3), 2 were stage IIA (size, 15 and 27 mm), and 7 were stage IIB (size range, 13–36 mm). Nine of the 10 invasive PDACs detected in patients followed up according to the CAPS surveillance schedule were asymptomatic and resectable, whereas only 1 of the 4 patients presenting with symptoms had resectable disease. These latter patients had either stopped or were late for surveillance (patients 21–24 in Table 2) by a median of 37 months (IQR, 10.8–66 months). The other advanced metastatic PDAC developed in the remnant pancreas of patient 6 at 5 years after a Whipple operation for a main duct IPMN, despite annual CT surveillance.
      Figure thumbnail gr3
      Figure 3Incident asymptomatic 7-mm pancreatic cancer detected after 10 years of surveillance, shown by arrows in (A) EUS image and (B) gross pathology section of the pancreatic body. (C) Final pathologic diagnosis was stage T1N0 moderately differentiated adenocarcinoma with negative margins (cytology smear from EUS-guided fine-needle aspiration). (D) Hematoxylin and eosin stain. Venous and perineural invasion were not identified.
      As of last follow-up, the overall mortality for HRIs with PDAC was 64% (9/14). PDAC-specific mortality was 8/14 (57%), with 1 patient (patient 2) surviving 13 years before dying of complications related to a metachronous early gastric cancer surgery (Table 2). None of the 10 HRIs with IPMN-HGD/PanIN3 and 6 with PanNet have died as of last follow-up.
      The median survival time for the 20 HRIs with PDAC or high-grade precursor neoplasm (targets of screening) diagnosed during surveillance was significantly greater than that for the 4 HRIs who were late for or stopped surveillance: 5.3 years (IQR, 1.2–11.1 years) vs 1.4 years (IQR, 0.39–3.5 years) (P < .0001. The overall 3-year survival rate was 57% for the 14 PDAC patients, but the survival was significantly greater for the 10 asymptomatic HRIs diagnosed during surveillance, compared with that for 4 HRIs presenting with symptomatic advanced disease developing outside surveillance (85% vs 25%, respectively; log rank, P < .0001) (Figure 4).
      Figure thumbnail gr4
      Figure 4Kaplan-Meier curves for overall survival for HRIs diagnosed with pancreatic neoplasms diagnosed by surgery or EUS-guided fine-needle aspiration. The group “Others” includes pathologically proven lower-grade pancreatic neoplasms that were not PDAC, IPMN-HGD, or PanIN-3 (IPMN with low-grade dysplasia or moderate-grade dysplasia, PanIN-2, PanNET, serous cystadenoma, pseudocyst).

      Discussion

      Pancreatic lesions are frequently detected in HRIs by EUS and/or MRI in pancreatic cancer screening programs.
      • Al-Sukhni W.
      • Borgida A.
      • Rothenmund H.
      • et al.
      Screening for pancreatic cancer in a high-risk cohort: an eight-year experience.
      • Canto M.I.
      • Goggins M.
      • Hruban R.H.
      • et al.
      Screening for early pancreatic neoplasia in high-risk individuals: a prospective controlled study.
      • Canto M.I.
      • Hruban R.H.
      • Fishman E.K.
      • et al.
      Frequent detection of pancreatic lesions in asymptomatic high-risk individuals.
      • Langer P.
      • Kann P.H.
      • Fendrich V.
      • et al.
      Five years of prospective screening of high-risk individuals from families with familial pancreatic cancer.
      • Ludwig E.
      • Olson S.H.
      • Bayuga S.
      • et al.
      Feasibility and yield of screening in relatives from familial pancreatic cancer families.
      • Vasen H.F.
      • Wasser M.
      • van Mil A.
      • et al.
      Magnetic resonance imaging surveillance detects early-stage pancreatic cancer in carriers of a p16-Leiden mutation.
      • Poley J.W.
      • Kluijt I.
      • Gouma D.J.
      • et al.
      The yield of first-time endoscopic ultrasonography in screening individuals at a high risk of developing pancreatic cancer.
      • Vasen H.
      • Ibrahim I.
      • Ponce C.G.
      • et al.
      Benefit of surveillance for pancreatic cancer in high-risk individuals: outcome of long-term prospective follow-up studies from three European expert centers.
      The majority of detected lesions are small cysts.
      • Bartsch D.K.
      • Dietzel K.
      • Bargello M.
      • et al.
      Multiple small “imaging” branch-duct type intraductal papillary mucinous neoplasms (IPMNs) in familial pancreatic cancer: indicator for concomitant high grade pancreatic intraepithelial neoplasia?.
      • Canto M.I.
      • Hruban R.H.
      • Fishman E.K.
      • et al.
      Frequent detection of pancreatic lesions in asymptomatic high-risk individuals.
      • Langer P.
      • Kann P.H.
      • Fendrich V.
      • et al.
      Five years of prospective screening of high-risk individuals from families with familial pancreatic cancer.
      • Vasen H.
      • Ibrahim I.
      • Ponce C.G.
      • et al.
      Benefit of surveillance for pancreatic cancer in high-risk individuals: outcome of long-term prospective follow-up studies from three European expert centers.
      In this study, we found that neoplastic progression is more common in HRIs older than 60 years, those with multiple cysts, and/or those with a mildly dilated MPD at baseline. Although having multiple cysts (≥3) at baseline was a robust predictor of radiologic and neoplastic progression, it has not been identified as a significant predictor of progression in cohorts of sporadic IPMN.
      • Maguchi H.
      • Tanno S.
      • Mizuno N.
      • et al.
      Natural history of branch duct intraductal papillary mucinous neoplasms of the pancreas: a multicenter study in Japan.
      • Tada M.
      • Kawabe T.
      • Arizumi M.
      • et al.
      Pancreatic cancer in patients with pancreatic cystic lesions: a prospective study in 197 patients.
      Close to 19% of HRIs developed evidence of a worrisome radiologic feature while undergoing surveillance, corresponding to an average rate of radiologic progression of 4.3% per year. One important question for pancreatic cancer screening programs is the age at which to begin screening. There was no consensus among experts on this question in the 2012 CAPS Consensus Summit.
      • Canto M.I.
      • Harinck F.
      • Hruban R.H.
      • et al.
      International Cancer of the Pancreas Screening (CAPS) Consortium summit on the management of patients with increased risk for familial pancreatic cancer.
      In the CAPS 1–3 studies (1998–2010), age 50 years was selected as the age to initiate pancreatic screening for FPC relatives. After 2010, this age was raised to 55 years, but in all studies, screening would start at age 10 years younger than that of the PDAC relative with the youngest age at diagnosis. Two of the 14 PDAC patients and 3 of the 24 with PDAC or high-grade precursor neoplasms in our cohort were younger than age 55 years at the time of diagnosis, but both patients with young-onset PDAC had young-onset pancreatic cancers in their families that made them eligible for screening using the rule of age 55 years or 10 years younger. Determining the optimal age to begin PDAC screening requires additional studies.
      After initial screening, the cumulative incidence of invasive PDAC in our cohort was 3.4% (12/354 HRIs). Our overall PDAC detection rate is higher than reported in other screening programs of FPC relatives, most of which are closer to 1% or less.
      • Al-Sukhni W.
      • Borgida A.
      • Rothenmund H.
      • et al.
      Screening for pancreatic cancer in a high-risk cohort: an eight-year experience.
      • Bartsch D.K.
      • Dietzel K.
      • Bargello M.
      • et al.
      Multiple small “imaging” branch-duct type intraductal papillary mucinous neoplasms (IPMNs) in familial pancreatic cancer: indicator for concomitant high grade pancreatic intraepithelial neoplasia?.
      • Langer P.
      • Kann P.H.
      • Fendrich V.
      • et al.
      Five years of prospective screening of high-risk individuals from families with familial pancreatic cancer.
      • Vasen H.
      • Ibrahim I.
      • Ponce C.G.
      • et al.
      Benefit of surveillance for pancreatic cancer in high-risk individuals: outcome of long-term prospective follow-up studies from three European expert centers.
      • Harinck F.
      • Konings I.C.
      • Kluijt I.
      • et al.
      A multicentre comparative prospective blinded analysis of EUS and MRI for screening of pancreatic cancer in high-risk individuals.
      This probably reflects the longer period of surveillance and the older average age of our cohort. In our study consisting mostly of familial PDAC relatives, the number of individuals needed to undergo regular screening and surveillance (using EUS and MRI) to detect a PDAC or high-grade precursor neoplasm was 23. Recently, 3 European centers performing prospective screening with MRI and EUS in 411 HRIs reported a detection of incident PDAC in 13 (7.3%) of 178 CDKN2A mutation carriers and 3 (1.4%) of 214 FPC relatives.
      • Vasen H.
      • Ibrahim I.
      • Ponce C.G.
      • et al.
      Benefit of surveillance for pancreatic cancer in high-risk individuals: outcome of long-term prospective follow-up studies from three European expert centers.
      In patients with sporadic IPMNs, the cumulative incidence for PDAC over 5 years is generally lower but varies considerably depending on the cohort studied.
      • Maguchi H.
      • Tanno S.
      • Mizuno N.
      • et al.
      Natural history of branch duct intraductal papillary mucinous neoplasms of the pancreas: a multicenter study in Japan.
      • Hisada Y.
      • Nagata N.
      • Imbe K.
      • et al.
      Natural history of intraductal papillary mucinous neoplasm and non-neoplastic cyst: long-term imaging follow-up study.
      • Kamata K.
      • Kitano M.
      • Kudo M.
      • et al.
      Value of EUS in early detection of pancreatic ductal adenocarcinomas in patients with intraductal papillary mucinous neoplasms.
      The National Cancer Institute estimates the lifetime risk for PDAC is 1.6%, based on 2012–2014 data.
      National Cancer Institute. SEER cancer statistics review, 1975-2014.
      Most (71%) PDACs detected during surveillance in our high-risk cohort were asymptomatic resectable TNM stage I and II cancers, which compares favorably with the tumor stage and resectability rate (15%–20%) of symptomatic PDAC.
      National Cancer Institute. SEER cancer statistics review, 1975-2014.
      A similar down-staging was found in the European study that followed mostly CKDN2A/p16-Leiden mutation carriers; 75% of screening-detected PDACs were resectable.
      • Vasen H.
      • Ibrahim I.
      • Ponce C.G.
      • et al.
      Benefit of surveillance for pancreatic cancer in high-risk individuals: outcome of long-term prospective follow-up studies from three European expert centers.
      Furthermore, the overall 3-year survival rate of our HRIs with PDAC was substantially higher than that of PDAC patients in the United States (57% vs 8.9%.
      National Cancer Institute. SEER cancer statistics review, 1975-2014.
      The difference is even greater when considering only screening-detected PDAC in our cohort (3-year survival, 90%). Similarly, the 5-year survival rate for 13 CDKN2A/p16 Leiden mutation carriers with screening-detected PDAC (24%) was higher than that for symptomatic mutation carriers (15%)
      • Vasen H.
      • Ibrahim I.
      • Ponce C.G.
      • et al.
      Benefit of surveillance for pancreatic cancer in high-risk individuals: outcome of long-term prospective follow-up studies from three European expert centers.
      or sporadic PDAC (4%–7%).
      National Cancer Institute. SEER cancer statistics review, 1975-2014.
      Even with the limited number of progressors in large high-risk cohorts, these accumulated data of increased resectability and improved survival rates suggest a potential benefit of surveillance for HRIs.
      Our screening program using EUS and MRI also identified IPMN-HGD and PanIN-3 in resection specimens of 3.1% of the cohort (10/354). Other high-risk surveillance programs have detected and treated a low number of patients with high-grade precursor neoplasms, ranging from none to 1.9%; this lower rate may result from the demographic profile of patients undergoing screening.
      • Langer P.
      • Kann P.H.
      • Fendrich V.
      • et al.
      Five years of prospective screening of high-risk individuals from families with familial pancreatic cancer.
      • Vasen H.
      • Ibrahim I.
      • Ponce C.G.
      • et al.
      Benefit of surveillance for pancreatic cancer in high-risk individuals: outcome of long-term prospective follow-up studies from three European expert centers.
      • Harinck F.
      • Konings I.C.
      • Kluijt I.
      • et al.
      A multicentre comparative prospective blinded analysis of EUS and MRI for screening of pancreatic cancer in high-risk individuals.
      Precursor neoplasms with high-grade dysplasia have been recommended by the International Cancer of the Pancreas Screening Consortium as ideal targets for detection and treatment.
      • Canto M.I.
      • Harinck F.
      • Hruban R.H.
      • et al.
      International Cancer of the Pancreas Screening (CAPS) Consortium summit on the management of patients with increased risk for familial pancreatic cancer.
      The selection of asymptomatic HRIs for pancreatic resection to treat PDAC or to remove concerning pancreatic lesions is challenging. Currently, selection of patients for surgery relies on the detection of specific concerning radiologic and EUS features that are predictive of high-grade pancreatic neoplasia or PDAC. The criteria for surgical resection have evolved over the 16-year study period, with improved understanding of the natural history of pancreatic cysts and other lesions identified in both HRIs and those with incidentally detected pancreatic abnormalities. The selection of patients for surgery is still far from perfect and reflects the limitations of pancreatic imaging to detect high-grade precursor neoplasms, particularly PanIN-3. Better biomarkers that can detect high-grade pancreatic neoplasia in secretin-stimulated pancreatic juice, pancreatic cyst fluid, and blood are needed to improve the selection of patients for surgery.
      • Eshleman J.R.
      • Norris A.L.
      • Sadakari Y.
      • et al.
      KRAS and guanine nucleotide-binding protein mutations in pancreatic juice collected from the duodenum of patients at high risk for neoplasia undergoing endoscopic ultrasound.
      • Kanda M.
      • Knight S.
      • Topazian M.
      • et al.
      Mutant GNAS detected in duodenal collections of secretin-stimulated pancreatic juice indicates the presence or emergence of pancreatic cysts.
      • Kanda M.
      • Sadakari Y.
      • Borges M.
      • et al.
      Mutant TP53 in duodenal samples of pancreatic juice from patients with pancreatic cancer or high-grade dysplasia.
      • Yu J.
      • Sadakari Y.
      • Shindo K.
      • et al.
      Digital next-generation sequencing identifies low-abundance mutations in pancreatic juice samples collected from the duodenum of patients with pancreatic cancer and intraductal papillary mucinous neoplasms.
      • Cohen J.D.
      • Javed A.A.
      • Thoburn C.
      • et al.
      Combined circulating tumor DNA and protein biomarker-based liquid biopsy for the earlier detection of pancreatic cancers.

      Suenega M, Yu J, Shindo K, et al. Pancreatic juice mutation concentrations can help predict the grade of dysplasia in patients undergoing pancreatic surveillance [published online ahead of print May 25, 2018]. Clin Cancer Res https://doi.org/10.1158/1078-0432.CCR-17-2463.

      The current study has several limitations. First, the methods for surveillance and management of pancreatic precursor lesions evolved thanks to improvements in imaging and better understanding of the natural history of these lesions. Second, we were unable to track the outcomes of HRIs who chose to continue surveillance at other centers. In addition, the gene mutation status for the pancreatic cancer risk in most HRIs in our cohort was not known. Furthermore, the estimation of the prevalence of high-grade precursor neoplasms in our cohort is limited by the inability of standard pancreatic imaging tests to detect PanIN-3. Our results are derived from a predominantly FPC cohort followed up at a single institution, which may limit generalizability. Finally, we do not have a concurrent control group.
      In conclusion, the results of our long-term pancreatic cancer screening program show that continued follow-up of HRIs can successfully detect resectable PDAC and high-grade precursor neoplasms. Among individuals undergoing pancreatic surveillance, specific detectable lesions with worrisome features predicted neoplastic progression. The short-term outcomes of patients with screening-detected PDAC are improved. Large prospective multicenter studies are needed to further evaluate the potential benefits of PDAC screening.
      Author contributions: conceived and designed the study: Marcia Irene F. Canto and Michael Goggins; acquisition of data: Jose Alejandro Almario, Marcia Irene F. Canto, Anne Marie Lennon, Eun J. Shin, Elliot K. Fishman, Ihab Kamel, Richard D. Schulick, Charles J. Yeo, Christopher Wolfgang, and Matthew Weiss; analysis and interpretation of data: Jose Alejandro Almario, Marcia Irene F. Canto, Michael Goggins, Ralph H. Hruban, and Alison Klein; drafted the manuscript: Jose Alejandro Almario, and Marcia Irene F. Canto; statistical analysis: Marcia Irene F. Canto, Amanda Blackford, Abanti Sanyal, and Gayane Yenokyan; revised the manuscript and agreed with the manuscript’s results and conclusions: all authors; study support: Marcia Irene F. Canto and Michael Goggins; obtained funding: Marcia Irene F. Canto, Ralph H. Hruban, and Michael Goggins; study supervision: Marcia Irene F. Canto and Michael Goggins.

      Supplementary Material

      Figure thumbnail fx2
      Supplementary Figure 1Cumulative risk (hazard) for radiologic progression over the 16-year study period for HRIs after baseline screening.
      Figure thumbnail fx3
      Supplementary Figure 2Cumulative risk (hazard) for radiologic progression stratified by baseline age > 60 years (red upper curve) and ≤ 60 years (blue lower curve) (P = .0001).
      Supplementary Table 1Association of Neoplastic Progression With Type of Radiologic Worrisome Feature
      Radiologic Worrisome Featuren (%) of all 354 HRIs with featureFrequency (%) associated with PDAC and/or high-grade precursor neoplasmP value
      Solid mass28 (7.9)12/28 (43)<.0001
      Cyst or MPD with mural nodule6 (1.7)5/6 (83)<.0001
      Multiple cysts, ≥ 3 at baseline20 (5.7)12/20 (60)<.0001
      Cyst > 3 cm2 (0.6)1 (50)>.99
      Cyst wall thick or enhancing5 (1.4)3/5 (60).003
      Cyst growth rate > 4 mm in 1 year11 (3.1)3/11 (27).032
      Dilated MPD at baseline
      Dilated MPD defined by Rosemont criteria1 (≥3.5 mm in the head, ≥2.5 mm in the body, and/or ≥1.5 mm in the tail), but <5 mm in any area.
      76 (21.5)14/76 (18)<.0001
      Dilated MPD ≥ 5 mm anytime21 (5.9)3/21 (14).162
      NOTE. n = 354 HRIs (univariate analysis). Pathological diagnoses made by surgery in 48 HRIs and percutaneous or EUS-guided fine-needle aspiration in 5 HRIs.
      1. Catalano MF, Sahai A, Levy M, et al. EUS-based criteria for the diagnosis of chronic pancreatitis: the Rosemont classification. Gastrointest Endosc 2009;69:1251–1261.
      aHigh-grade precursor neoplasm is IPMN with high-grade dysplasia or PanIN-3.
      b Dilated MPD defined by Rosemont criteria1 (≥3.5 mm in the head, ≥2.5 mm in the body, and/or ≥1.5 mm in the tail), but <5 mm in any area.
      Supplementary Table 2Cox Proportional Hazards Regression Model Showing Estimated Hazard Ratios for Radiological Progression
      CharacteristicUnadjusted modelAdjusted model
      HRP value95% CIHRP value95% CI
      Age at baseline > 60 y3.0<.00011.72–5.363.1<.00011.69–5.70
      Mutation carrier1.4.3620.69–2.772.7.0171.20–6.25
      Total number of lesions at baseline ≥ 34.9<.00012.70–8.704.3<.00012.32–7.92
      Total number of relatives with PDAC (for each additional relative)1.0.9250.79–1.231.1.6400.81–1.40
      Dilated MPD at baseline
      Dilated MPD defined by Rosemont criteria1 (≥3.5 mm in the head, ≥2.5 mm in the body, and/or ≥1.5 mm in the tail), up to 5 mm.
      3.5<.00011.98–6.044.2<.00012.40–7.49
      a Dilated MPD defined by Rosemont criteria1 (≥3.5 mm in the head, ≥2.5 mm in the body, and/or ≥1.5 mm in the tail), up to 5 mm.

      References

        • Siegel R.L.
        • Miller K.D.
        • Jemal A.
        Cancer statistics, 2016.
        CA Cancer J Clin. 2016; 66: 7-30
      1. National Cancer Institute. SEER cancer statistics review, 1975-2014.
        (Updated April 2, 2018. Accessed June 15, 2018)
        • Ibrahim I.S.
        • Bonsing B.A.
        • Swijnenburg R.J.
        • et al.
        Dilemmas in the management of screen-detected lesions in patients at high risk for pancreatic cancer.
        Fam Cancer. 2017; 16: 111-115
      2. US Preventive Services Task Force.
        (Available from) (Accessed August 5, 2018)
        • Canto M.I.
        • Harinck F.
        • Hruban R.H.
        • et al.
        International Cancer of the Pancreas Screening (CAPS) Consortium summit on the management of patients with increased risk for familial pancreatic cancer.
        Gut. 2013; 62: 339-347
        • Klein A.P.
        • Brune K.A.
        • Petersen G.M.
        • et al.
        Prospective risk of pancreatic cancer in familial pancreatic cancer kindreds.
        Cancer Res. 2004; 64: 2634-2638
        • Klein A.P.
        • Beaty T.H.
        • Bailey-Wilson J.E.
        • et al.
        Evidence for a major gene influencing risk of pancreatic cancer.
        Genet Epidemiol. 2002; 23: 133-149
        • Jones S.
        • Hruban R.H.
        • Kamiyama M.
        • et al.
        Exomic sequencing identifies PALB2 as a pancreatic cancer susceptibility gene.
        Science. 2009; 324: 217
        • van Lier M.G.
        • Wagner A.
        • Mathus-Vliegen E.M.
        • et al.
        High cancer risk in Peutz-Jeghers syndrome: a systematic review and surveillance recommendations.
        Am J Gastroenterol. 2010; 105 (author reply 1265): 1258-1264
        • Zhen D.B.
        • Rabe K.G.
        • Gallinger S.
        • et al.
        BRCA1, BRCA2, PALB2, and CDKN2A mutations in familial pancreatic cancer: a PACGENE study.
        Genet Med. 2015; 17: 569-577
        • Rebours V.
        • Boutron-Ruault M.C.
        • Schnee M.
        • et al.
        Risk of pancreatic adenocarcinoma in patients with hereditary pancreatitis: a national exhaustive series.
        Am J Gastroenterol. 2008; 103: 111-119
        • Al-Sukhni W.
        • Rothenmund H.
        • Borgida A.E.
        • et al.
        Germline BRCA1 mutations predispose to pancreatic adenocarcinoma.
        Hum Genet. 2008; 124: 271-278
        • Kastrinos F.
        • Mukherjee B.
        • Tayob N.
        • et al.
        Risk of pancreatic cancer in families with Lynch syndrome.
        JAMA. 2009; 302: 1790-1795
        • Roberts N.J.
        • Jiao Y.
        • Yu J.
        • et al.
        ATM mutations in patients with hereditary pancreatic cancer.
        Cancer Discov. 2012; 2: 41-46
        • Al-Sukhni W.
        • Borgida A.
        • Rothenmund H.
        • et al.
        Screening for pancreatic cancer in a high-risk cohort: an eight-year experience.
        J Gastrointest Surg. 2012; 16: 771-783
        • Bartsch D.K.
        • Dietzel K.
        • Bargello M.
        • et al.
        Multiple small “imaging” branch-duct type intraductal papillary mucinous neoplasms (IPMNs) in familial pancreatic cancer: indicator for concomitant high grade pancreatic intraepithelial neoplasia?.
        Fam Cancer. 2013; 12: 89-96
        • Canto M.I.
        • Goggins M.
        • Hruban R.H.
        • et al.
        Screening for early pancreatic neoplasia in high-risk individuals: a prospective controlled study.
        Clin Gastroenterol Hepatol. 2006; 4 (quiz 665): 766-781
        • Canto M.I.
        • Goggins M.
        • Yeo C.J.
        • et al.
        Screening for pancreatic neoplasia in high-risk individuals: an EUS-based approach.
        Clin Gastroenterol Hepatol. 2004; 2: 606-621
        • Canto M.I.
        • Hruban R.H.
        • Fishman E.K.
        • et al.
        Frequent detection of pancreatic lesions in asymptomatic high-risk individuals.
        Gastroenterology. 2012; 142 (quiz e14–15): 796-804
        • Kimmey M.B.
        • Bronner M.P.
        • Byrd D.R.
        • et al.
        Screening and surveillance for hereditary pancreatic cancer.
        Gastrointest Endosc. 2002; 56: S82-S86
        • Langer P.
        • Kann P.H.
        • Fendrich V.
        • et al.
        Five years of prospective screening of high-risk individuals from families with familial pancreatic cancer.
        Gut. 2009; 58: 1410-1418
        • Ludwig E.
        • Olson S.H.
        • Bayuga S.
        • et al.
        Feasibility and yield of screening in relatives from familial pancreatic cancer families.
        Am J Gastroenterol. 2011; 106: 946-954
        • Schneider R.
        • Slater E.P.
        • Sina M.
        • et al.
        German national case collection for familial pancreatic cancer (FaPaCa): ten years experience.
        Fam Cancer. 2011; 10: 323-330
        • Vasen H.F.
        • Wasser M.
        • van Mil A.
        • et al.
        Magnetic resonance imaging surveillance detects early-stage pancreatic cancer in carriers of a p16-Leiden mutation.
        Gastroenterology. 2010; 140: 850-856
        • Poley J.W.
        • Kluijt I.
        • Gouma D.J.
        • et al.
        The yield of first-time endoscopic ultrasonography in screening individuals at a high risk of developing pancreatic cancer.
        Am J Gastroenterol. 2009; 104: 2175-2181
        • Vasen H.
        • Ibrahim I.
        • Ponce C.G.
        • et al.
        Benefit of surveillance for pancreatic cancer in high-risk individuals: outcome of long-term prospective follow-up studies from three European expert centers.
        J Clin Oncol. 2016; 34: 2010-2019
        • Harinck F.
        • Konings I.C.
        • Kluijt I.
        • et al.
        A multicentre comparative prospective blinded analysis of EUS and MRI for screening of pancreatic cancer in high-risk individuals.
        Gut. 2016; 65: 1505-1513
        • Tanaka M.
        • Chari S.
        • Adsay V.
        • et al.
        International consensus guidelines for management of intraductal papillary mucinous neoplasms and mucinous cystic neoplasms of the pancreas.
        Pancreatology. 2006; 6: 17-32
        • Tanaka M.
        • Fernandez-del Castillo C.
        • Adsay V.
        • et al.
        International consensus guidelines 2012 for the management of IPMN and MCN of the pancreas.
        Pancreatology. 2012; 12: 183-197
        • Kang M.J.
        • Jang J.Y.
        • Kim S.J.
        • et al.
        Cyst growth rate predicts malignancy in patients with branch duct intraductal papillary mucinous neoplasms.
        Clin Gastroenterol Hepatol. 2011; 9: 87-93
        • Kwong W.T.
        • Lawson R.D.
        • Hunt G.
        • et al.
        Rapid growth rates of suspected pancreatic cyst branch duct intraductal papillary mucinous neoplasms predict malignancy.
        Dig Dis Sci. 2015; 60: 2800-2806
        • Vege S.S.
        • Ziring B.
        • Jain R.
        • et al.
        American gastroenterological association institute guideline on the diagnosis and management of asymptomatic neoplastic pancreatic cysts.
        Gastroenterology. 2015; 148 (quiz 12–13): 819-822
        • World Health Organization
        WHO Classification of Tumours of the Digestive System.
        WHO Press, Geneva2010
        • World Health Organization
        WHO Classification of Tumors of the Endocrine Organs.
        4th edition. WHO Press, Geneva2017
        • Catalano M.F.
        • Sahai A.
        • Levy M.
        • et al.
        EUS-based criteria for the diagnosis of chronic pancreatitis: the Rosemont classification.
        Gastrointest Endosc. 2009; 69: 1251-1261
        • Maguchi H.
        • Tanno S.
        • Mizuno N.
        • et al.
        Natural history of branch duct intraductal papillary mucinous neoplasms of the pancreas: a multicenter study in Japan.
        Pancreas. 2011; 40: 364-370
        • Tada M.
        • Kawabe T.
        • Arizumi M.
        • et al.
        Pancreatic cancer in patients with pancreatic cystic lesions: a prospective study in 197 patients.
        Clin Gastroenterol Hepatol. 2006; 4: 1265-1270
        • Hisada Y.
        • Nagata N.
        • Imbe K.
        • et al.
        Natural history of intraductal papillary mucinous neoplasm and non-neoplastic cyst: long-term imaging follow-up study.
        J Hepatobiliary Pancreat Sci. 2017; 12: 645-650
        • Kamata K.
        • Kitano M.
        • Kudo M.
        • et al.
        Value of EUS in early detection of pancreatic ductal adenocarcinomas in patients with intraductal papillary mucinous neoplasms.
        Endoscopy. 2014; 46: 22-29
        • Eshleman J.R.
        • Norris A.L.
        • Sadakari Y.
        • et al.
        KRAS and guanine nucleotide-binding protein mutations in pancreatic juice collected from the duodenum of patients at high risk for neoplasia undergoing endoscopic ultrasound.
        Clin Gastroenterol Hepatol. 2015; 13 (e4): 963-969
        • Kanda M.
        • Knight S.
        • Topazian M.
        • et al.
        Mutant GNAS detected in duodenal collections of secretin-stimulated pancreatic juice indicates the presence or emergence of pancreatic cysts.
        Gut. 2013; 62: 1024-1033
        • Kanda M.
        • Sadakari Y.
        • Borges M.
        • et al.
        Mutant TP53 in duodenal samples of pancreatic juice from patients with pancreatic cancer or high-grade dysplasia.
        Clin Gastroenterol Hepatol. 2013; 11 (e5): 719-730
        • Yu J.
        • Sadakari Y.
        • Shindo K.
        • et al.
        Digital next-generation sequencing identifies low-abundance mutations in pancreatic juice samples collected from the duodenum of patients with pancreatic cancer and intraductal papillary mucinous neoplasms.
        Gut. 2017; 66: 1677-1687
        • Cohen J.D.
        • Javed A.A.
        • Thoburn C.
        • et al.
        Combined circulating tumor DNA and protein biomarker-based liquid biopsy for the earlier detection of pancreatic cancers.
        Proc Natl Acad Sci U S A. 2017; 114: 10202-10207
      3. Suenega M, Yu J, Shindo K, et al. Pancreatic juice mutation concentrations can help predict the grade of dysplasia in patients undergoing pancreatic surveillance [published online ahead of print May 25, 2018]. Clin Cancer Res https://doi.org/10.1158/1078-0432.CCR-17-2463.