Pancreatic Cysts - Part 2

Transcription

1 REVIEW Pancreatic Cysts - Part 2 Should We Be Less Cyst Centric? Anne Marie Lennon, MD, PhD and Marcia Irene Canto, MD, MHS Abstract: The management of pancreatic cysts is a common problem faced by physicians and surgeons. Pancreatic cysts are important because some of them are mucin-producing cysts (MPCs), which may harbor or develop pancreatic ductal adenocarcinoma. Thus, accurate classification of pancreatic cysts and diagnosis of MPCs offer a potential for the prevention or early detection of pancreatic cancer. However, the diagnosis and management of asymptomatic pancreatic cysts are complicated by 2 factors. First, incidentally detected pancreatic cysts are often misdiagnosed as branch duct intraductal papillary mucinous neoplasms. Although most are MPCs, there are other types of cysts, such as serous cystadenomas, which are managed differently. Second, only a minority of MPCs will ultimately develop into invasive pancreatic ductal adenocarcinoma. Thus, on the one hand, pancreatic cysts offer a unique opportunity to identify precursors to pancreatic cancer and improve outcomes. On the other hand, misdiagnosis and overzealous testing or unnecessary surgery may lead to high cost and harm to patients. Several guidelines have been developed by various groups for the management of pancreatic cysts. In this article, we review the strengths and weaknesses of the American Gastroenterology Association guidelines, highlight key recommendations requiring further validation, and provide our balanced approach to diagnosing and managing pancreatic cysts. Key Words: pancreatic cysts, IPMN, guidelines, AGA Abbreviations: AGA - American Gastroenterology Association, EUS - endoscopic ultrasound, GNAS - guanine nucleotide-binding protein, IPMN - intraductal papillary mucinous neoplasm, KRAS - v-ki-ras2 Kirsten rat sarcoma viral oncogene homolog, MRI - magnetic resonance imaging, MCN - mucinous cystic neoplasm, VHL - Von Hippel Lindau (Pancreas 2017;46: ) WHY DO WE CARE ABOUT PANCREATIC CYSTS? The management of pancreatic cysts is a common problem faced by physicians and surgeons, with pancreatic cysts incidentally identified in up to 13% to 15% of individuals. 1 We care about pancreatic cysts because some of these are intraductal papillary mucinous neoplasms (IPMNs) and mucinous cystic neoplasms (MCNs), which may harbor or develop invasive malignancy. 2 Pancreatic ductal adenocarcinoma (PDAC) is a deadly cancer, with an overall survival of less than 8%. 3 Intraductal papillary mucinous neoplasms may also be associated with concomitant From the Department of Medicine, Division of Gastroenterology, The Johns Hopkins Medical Institutions, Baltimore, MD. Received for publication February 5, 2017; accepted March 15, Address correspondence to: Anne Marie Lennon, MD, PhD, Sheikh Zayed Tower, 7125J, The Johns Hopkins Hospital, 1800 Orleans St, Baltimore, MD (e mail: amlennon@jhmi.edu). This study was supported by the Lustgarten Foundation for Pancreatic Cancer Research, the Sol Goldman Center for Pancreatic Cancer Research, the Virginia and D.K. Ludwig Fund for Cancer Research, Susan Wojcicki and Dennis Troper, the Michael Rolfe Foundation, and the National Institutes of Health grants P50 CA62924, R01CA176828, and U01 CA Dr Lennon was supported by the Benjamin Baker Scholarship. Dr Lennon and Dr Canto have no disclosures. DOI: /MPA PDAC. 2 Thus, accurate classification of pancreatic cysts and diagnosis of mucin-producing precursor cystic neoplasms offer a potential for the prevention or early detection of pancreatic cancer. 4 The increasing attention paid to pancreatic cysts in the last decade stems from the complexities related to the diagnosis and management of asymptomatic patients. The latter is complicated by 2 factors. First of all, incidentally detected pancreatic cysts are often misdiagnosed by routine imaging to be possible branch duct (BD) IPMNs. Although most of these incidentalomas are mucin-producing cysts, there are other types of cysts that are managed differently (Fig. 1). Some are also serous cystadenomas (SCAs), which have a very low malignant potential. These do not typically need surgical treatment, unless very large and symptomatic. On the other hand, other cysts such as solid-pseudopapillary neoplasms (SPNs) harbor a significant risk of developing invasive cancer. 5,6 Second, only a minority of MCNs and IPMNs will ultimately develop into invasive PDAC. Thus, on the one hand, pancreatic cysts offer a unique opportunity to identify precursors to pancreatic cancer and improve outcomes. On the other hand, misdiagnosis and overzealous testing or unnecessary surgery may lead to high cost and harm to patients. PANCREATIC CYST GUIDELINES With the increasingly common detection of asymptomatic pancreatic cysts, several guidelines have been developed by various groups for the management of pancreatic cysts. Guidelines are typically developed to potentially minimize practice variability when there is limited scientific evidence but high-impact consequences on patients and the cost of health care on a population level. Hence, guideline recommendations might provide suggestions when high-quality evidence is lacking. The cyst guidelines include the revised International Consensus Guidelines ( ICGs, also known as the Sendai 2006 guidelines 7 and, subsequently, the Fukuoka 2012 guidelines 8 ) and the European Expert Consensus Guidelines 9 (Table 1). The most extensively studied are the ICGs, which were developed by a multidisciplinary panel of 14 experts in pancreatic disease. These guidelines provide recommendations for the management of pancreatic cysts specifically, suspected IPMNs and MCNs. Importantly, they do not provide us with a practical diagnostic approach to all pancreatic cysts, only presumed mucin-producing cysts. These guidelines proposed a 2-phase set of criteria for investigation of malignancy, which provided a practical approach to risk stratification high-risk cysts with high-risk stigmata should undergo surgical resection, further diagnostic testing for those with worrisome features, and surveillance with imaging tests for low-risk cysts. 8 The Sendai and Fukuoka ICGs have undergone clinical validation and were found to have a high negative predictive value (100%) but only moderate positive predictive value (Sendai ICG, 46%) for identifying IPMNs with high-grade dysplasia or PDAC. 10,11 Specifically, many cysts greater than 3 cm with other stigmata were being resected with the Sendai guidelines, and only 13% to 22% harbored high-grade dysplasia or PDAC. The updated 2012 Fukuoka guidelines lowered the Pancreas Volume 46, Number 6, July

2 Lennon and Canto Pancreas Volume 46, Number 6, July 2017 FIGURE 1. Pancreatic cyst classification: low versus high risk. threshold ( 5 mm) of the pancreatic duct and removed the size criterion of greater than 3 cm from high-risk stigmata to increase the sensitivity for diagnosis of main duct IPMN. With this change, the positive predictive value increased to 62.5%, 10 but this is likely to still result in many unnecessary operations. In 2013, the European consensus statements formulated by a multidisciplinary panel of experts after a literature review and grading process included recommendations for diagnosis and surveillance of all types of neoplastic cysts, including IPMN, MCN, SPN, and SCA. 9 These guidelines also do not support routine evaluation of cysts with endoscopic ultrasound-guided fine needle aspiration (EUS-FNA) (Table 1). In 2015, the American Gastroenterology Association (AGA) published its own guidelines authored by the Clinical Guidelines Committee, which did not apply the multidisciplinary team approach used by other published cyst guidelines. 12 The aim of the AGA guidelines was to provide evidence-based recommendations on managing pancreatic cysts based on a technical review of the scientific literature using the Grading of Recommendations Assessment, Development and Evaluation framework to evaluate the quality of the evidence. 13 The AGA guidelines consist of 10 recommendations (Table 1). Although the AGA guidelines provide the most comprehensive and systematic review of the scientific evidence of pancreatic cysts, they have raised considerable controversy. Importantly, physicians, patients, and insurance companies should understand that 8 of the 10 recommendations are conditional (weak) due to low-quality evidence. Hence, decision making can still be nuanced, leading to different approaches in similar situations. How can these AGA guidelines be practice changing? In this article, we review the strengths and weaknesses of the AGA guidelines, highlight key recommendations requiring further validation, and provide our balanced approach to diagnosing and managing pancreatic cysts. AGA PANCREATIC CYST GUIDELINES: RISK ESTIMATION We fully support that the recommendation that patients should understand what surveillance entails before entering a surveillance program is important. We also suggest a discussion with the patient of what risk for pancreatic cancer really means. Part of the problem with managing pancreatic cysts and suspected BD-IPMNs is that studies involving risk estimation are retrospective, combine imaging and surgical cases, and involve mostly tertiary referral centers (selection bias). Patients and physicians facing decisions of cyst surveillance or surgery should understand the difference between the prevalent TABLE 1. Comparison of Pancreatic Cyst Guidelines 2012 Fukuoka Guidelines 2013 European Guidelines 2015 AGA Guidelines Process Multidisciplinary experts Multidisciplinary experts AGA committee Cyst type Mucin-producing cysts (IPMNs, MCNs) Neoplastic cysts (IPMNs, MCNs, Asymptomatic neoplastic cysts SPNs, SCNs) Target High-grade dysplasia and PDAC High-grade dysplasia and PDAC PDAC Methods Scientific review Scientific review, grading Technical review, GRADE Key decisions Surgery Surgery Surgery EUS-FNA No routine EUS-FNA EUS-FNA Surveillance schedule Surveillance schedule Surveillance schedule Stopping surveillance GRADE indicates Grading of Recommendations Assessment, Development and Evaluation Wolters Kluwer Health, Inc. All rights reserved.

3 Pancreas Volume 46, Number 6, July 2017 Pancreatic Cysts: Non Cyst Centric and incident risk of cancer in a cyst. The estimated risk of cancer in a cyst is dependent on the type. It is very low in SCAs (0.1%), variable in a BD-IPMN (0% 31%, mostly 15% 25% in surgical series) and MCN (10% 36%), and very high in main or mixedduct IPMN (35% 75%). When imaging tests show a cyst communicating with the pancreatic duct, a BD-IPMN may be a likely clinical diagnosis. However, which ones deserve attention? Certain BD-IPMN characteristics (also known as high-risk or worrisome features in the ICG guidelines) increase the likelihood of a prevalent malignancy: those that are larger (>3 cm), with a dilated main pancreatic duct, or a solid mass component. In contrast, there is accumulating evidence that the risk for developing PDAC from a low-risk pancreatic cyst (suspected BD-IPMN) is low, approximately 0.72% per year or 2% to 4% (average, 2.8%; 95% confidence interval, 1.8% 4%) for a period of 10 years. 1 Hence, most patients found to have a low-risk cyst using standard imaging criteria need not worry about cancer or having surgery. We only need to do a better job of distinguishing high risk that have or will develop cancer from low-risk cysts. AGA GUIDELINES RELY ONLY ON MAGNETIC RESONANCE IMAGING The vast majority of asymptomatic pancreatic cysts are diagnosed by magnetic resonance imaging (MRI) or computed tomography (CT), which have a suboptimal accuracy for distinguishing types of cysts and detecting high-risk stigmata. Magnetic resonance imaging is the proposed sole method of diagnosing and surveying pancreatic cysts because it can demonstrate duct communication with high accuracy, 14 it does not result in radiation exposure like CT, and it provides better parenchymal and ductal imaging compared with transabdominal ultrasound. The ICGs include high-quality CT scan for investigation of high-risk stigmata and surveillance. 7,8 Although the recommendation for relying on MRI as the main noninvasive diagnostic and surveillance technique may seem reasonable, the cost- and comparativeeffectiveness of MRI have not been formally studied. WHAT IS THE ROLE OF EUS AND CYST FLUID ASPIRATION? The ICG and AGA guidelines (but not the European guidelines) recommend EUS for further evaluation of cysts with highrisk features. Endoscopic ultrasound is a more invasive test than MRI and is reserved for confirmation of high-risk cyst features on MRI, which are more generally defined in the AGA guidelines as either a solid component, dilated main pancreatic duct (no specific duct cutoff suggested, such as ICG), or size greater than 3 cm. When at least 2 high-risk features are present, EUS with cyst aspiration for cytologic examination is recommended by the AGA. This conditional recommendation is problematic for several reasons. First, many patients with 2 or more high-risk features may not need an EUS. For example, if a patient has a 1-cm dilated main pancreatic duct and a solid enhancing mass on high-quality MRI, it is unlikely that performing EUS or aspirating the mass will alter the plan for surgery. Second, small neoplastic mural nodules may not be visible on MRI, and these are best detected by EUS. After EUS-FNA, PDAC or high-grade dysplasia can be found in 23% of resected cysts with mural nodules versus 3% without nodules (P = 0.02). 15 Endoscopic ultrasound guided cyst aspiration by itself can distinguish mucus from neoplastic soft tissue by physically displacing the echogenic material in real time. Confirmation of neoplastic-type mural nodules in cysts lowers the bar for consideration of surgical resection. Assessment of high-risk features and fluid aspiration can provide incremental diagnostic value to MRI/CT. In a study of 154 patients, EUS plus FNA can correctly identify an additional 54% neoplastic cysts after MRI, 16 and the combination of EUS and MRI increases the sensitivity for identifying pancreatic cysts with high-grade dysplasia or PDAC by 25%. 17 However, it is well recognized that cytologic examination of cyst fluid has limited sensitivity (only >50%). 18,19 Malignant cells are uncommonly found in cyst aspirates, and atypical cells may not be sufficiently diagnostic. 20 Only 34% of cytology samples are deemed adequate for cytologic analysis. 21 Second, other diagnostic tests, specifically biomarkers, which improve cyst classification, are not considered in AGA guidelines, even if high-quality studies suggest that these might be helpful. Specifically, cyst fluid carcinoembryonic antigen (CEA) has been incorporated into routine practice by many gastroenterologists. A large multicenter prospective study demonstrated that an elevated cyst fluid CEA greater than 192 ng/ml has a 79.2% accuracy for distinguishing mucin-producing from non mucin-producing cysts, which is superior to cytology alone (58.7%). 19 Furthermore, very high (>800 ng/ml) and low (<5 mg/ml) CEA levels can be helpful for distinguishing mucin-producing cysts and SCAs, respectively. 22,23 Finally, the 2015 AGA guidelines did not include consideration of recent advances in EUS imaging. Prospective studies in Japan and Europe suggest that contrast enhancement with or without harmonic EUS imaging may demonstrate vascularity in mural nodules and significantly improve the diagnosis of malignant cysts (hyperenhanced) Unfortunately, the contrast agents used are not approved by the Food and Drug Administration for this indication, and off-label use and cost limit its broader application in the United States. CAN BIOMARKERS HELP WITH RISK STRATIFICATION OF PANCREATIC CYSTS? With the development of next-generation sequencing and Safe-Seq sequencing techniques, our ability to identify DNA mutations at very low levels in small amounts of fluid has greatly improved. Three of the most promising molecular markers for differentiating IPMNs and MCNs from other cysts are mutations in guanine nucleotide-binding protein (GNAS), 28,29 v-ki-ras2 Kirsten rat sarcoma viral oncogene homolog (KRAS) mutation, and the Von Hippel Lindau (VHL) genes. The presence of a mutation in either GNAS or KRAS has been shown to identify 85% of IPMNs and MCNs. 30 Mutations in the VHL gene are primarily found in SCAs, with 67% of SCAs harboring either a mutation in VHL or loss of heterozygosity in chromosome 3 where the VHL gene is located. 30 These 3 genetic markers could potentially improve the differentiation of mucin-producing over non mucin-producing and nonneoplastic cysts (Table 2). 31 TABLE 2. Genetic Profiling of Pancreatic Cysts From Cyst Fluid Sequencing: Somatic Gene Mutations Cyst Type Nonneoplastic SCA SPN MCN IPMN PDAC KRAS RNF GNAS + (+) CTNNB VHL + The plus sign (+) denotes cyst types in which that mutation is found. Some PDACs harbor a GNAS mutation (+) suggesting that they arose from an IPMN Wolters Kluwer Health, Inc. All rights reserved

4 Lennon and Canto Pancreas Volume 46, Number 6, July 2017 How might we use these molecular markers in clinical practice? One of the most important aims of the AGA guidelines is to avoid unnecessary surgery and surveillance. In a multicenter study of pathologically classified pancreatic cysts, a combination panel of clinical features and molecular markers (mutations in BRAF, CDKN2A, CTNNB1, GNAS, KRAS, NRAS, PIK3CA, RNF43, SMAD4, TP53, and VHL; loss of heterozygosity at CDKN2A, RNF43, SMAD4, TP53, and VHL tumor suppressor loci; and aneuploidy) correctly classified pancreatic cyst type with 76% to 100% sensitivity and 75% to 100% specificity. 30 Furthermore, the molecular marker panel correctly identified 67 of the 74 patients with SCAs or IPMNs without high-grade dysplasia or PDAC who did not require surgery and could therefore reduce the number of unnecessary operations by 91%. Another recent study from Pittsburgh combining clinical features with EUS, cytology, and multiple molecular markers (hotspot mutations and deletions for KRAS, GNAS, VHL, TP53, PIK3CA, and PTEN) found improved patient selection for surgery or MRI surveillance compared with the AGA guidelines. 32 These alternative approaches to the diagnosis of pancreatic cysts need further rigorous validation but could potentially prevent unnecessary surveillance and surgery in a significant number of patients. WHEN AND WHERE SHOULD SURGERY BE PERFORMED? Surgery should be performed at a high-volume center. 12 Several studies have shown that the number of procedures performed by a surgeon affects patient outcomes, including a recent study of patient outcome in the Netherlands, which found that mortality from a pancreaticoduodenectomy (Whipple operation) varied from 4% to 15% depending on the volume of cases performed by the surgeon. 33 The AGA guidelines set a high bar before surgical resection is performed, with surgery only recommended in the presence of a solid component and a dilated pancreatic duct and/or concerning features on EUS. We agree that highly selective surgery approach can be recommended for asymptomatic patients because pancreatic resection carries a significant morbidity and a small mortality, even in the best hands. However, the requirement for multiple worrisome cyst features has not been validated and may at times not be appropriate. For example, a 2.8-cm cyst with a solid enhancing component and cytology showing high-grade dysplasia but not invasive adenocarcinoma does not meet the AGA criteria for surgery, but many experts in the field would agree that this patient should have an operation, if surgically fit. A recent large study assessed the accuracy of AGA guidelines in detecting advanced neoplastic cysts and found that the AGA guidelines missed 45% of IPMNs with PDAC or high-grade dysplasia. 32 A more appropriate clinical guideline with regard to the need for surgery may be that patients with any of these high-risk features should be evaluated by a multidisciplinary group, similar to a tumor board, ideally at an expert center. Multidisciplinary care has been shown to alter the diagnosis of 30% of patients and actually change the recommendation in 50% of patients referred for surgery from surgery to surveillance. 32 SHOULD WE STOP SURVEILLANCE AFTER 5 YEARS? One of the most controversial aspects of the AGA guidelines is the recommendation that surveillance should cease if pancreatic cysts show no change in size or appearance after 5 years. Even more concerning is that this unproven recommendation is likely impacting the surveillance of individuals because of the wide dissemination of the AGA guidelines to primary care providers and patients. It is certainly possible that at-risk individuals not properly classified by MRI would discontinue surveillance. Molecular and pathological studies suggest that PDAC develops from noninvasive precursors, which progress from low- to high-grade dysplasia and eventually to invasive carcinoma. Genetic models suggest that this progression takes between 15 and 20 years. 32 These data are supported by results from multicenter cohort studies, which report that IPMNs with no concerning features at baseline can progress up to 16 years after diagnosis. 32 Should cyst surveillance be discontinued in a healthy 50-year-old asymptomatic patient based on our limited understanding of the natural history of IPMN? We agree that there should be a discussion about when surveillance should be ceased. However, we believe that considering factors other than MRI findings, such as the age and medical comorbidities, may be appropriate. 34 Cyst growth rate and the number of negative stable examinations could also be considered, rather than fixed time frame. One prospective study reporting pathologically confirmed IPMNs (mostly small, with an average size of 14.7 mm) reported a rapid cyst growth rate of more than 4.1 mm per year that was associated with a high incidence of PDAC of 46%. 35 There is no evidence to support the arbitrary AGA recommendation for stopping cyst surveillance after 5 years of negative MRI evaluation. We have grave concerns about this particular recommendation because the AGA guidelines have been extensively promoted in print and online media to internal medicine physicians and patients. A more sensible approach would be to modify the guidelines similar to the US Multi- Society Task Force for Colon Cancer guidelines for colorectal cancer screening, which specify an age to stop surveillance (after the age of 85 years) and consideration of age, comorbidities, and negative surveillance tests. 36 We believe that the recommendation for stopping surveillance of pancreatic cysts should stress the importance of individualized decision making based on an assessment of risk, benefit, age, and comorbidities. In the future, cyst aspirates from any cyst, regardless of size or morphologic features, might accurately be combined with clinical and imaging features to allow us to lengthen or discontinue surveillance with a higher degree of confidence. For example, cysts with no high-risk imaging features and negative molecular marker panel could be classified as very low risk with a high negative predictive value (Table 2). WHAT NEXT? A LESS CYST-CENTRIC APPROACH Although we have focused research and clinical resources to finding PDAC in patients with cysts, it is critical to realize that PDAC can arise without previous detected cysts or in patients with low-risk IPMNs (Fig. 2). Furthermore, incident PDAC can be diagnosed in a different location from the BD-IPMN. 37,38 It is important to understand that the origin of most PDACs is likely from invisible pancreatic intraepithelial neoplasms, which escape detection and surveillance by routine imaging, not detectable IPMNs and MCNs. A less cyst-centric approach to lowering PDAC mortality is needed. Almost 90% of the AGA guideline recommendations have a very low quality of evidence and are conditional recommendations, meaning that a significant number of patients could have a different management approach. Thus, the AGA guidelines are similar to the other guidelines and ultimately represent expert opinion and/or individual case management associated with high practice variability. The most important achievement of the AGA guidelines is to highlight the lack of high-quality data to guide the management of pancreatic cysts. This gap in knowledge needs to be filled. We look forward to large collaborative, prospective, multicenter Wolters Kluwer Health, Inc. All rights reserved.

5 Pancreas Volume 46, Number 6, July 2017 Pancreatic Cysts: Non Cyst Centric FIGURE 2. Pancreatic cancer developing remotely from a low-risk BD-IPMN EUS image of an incident 6-mm invasive PDAC (arrow) detected in the tail of the pancreas of a healthy woman without risk factors (smoking, family history) after 6 years of MRI surveillance of low-risk subcentimeter cysts in the body. studies that provide validation of various approaches to cyst diagnosis and management, which might provide high-quality evidence to revise future guidelines. Translational research studies including patient factors, imaging findings, and blood and tissue markers will only help us develop a more cyst-ematic approach to the diagnosis and prediction of PDAC. The diagnosis and management of pancreatic cysts continue to be challenging. However, scientific advances will continue to provide us with an optimism for better and clearer pathways for our patients. REFERENCES 1. Scheiman JM, Hwang JH, Moayyedi P. American gastroenterological association technical review on the diagnosis and management of asymptomatic neoplastic pancreatic cysts. Gastroenterology. 2015;148: e Adsay NV, Merati K, Basturk O, et al. Pathologically and biologically distinct types of epithelium in intraductal papillary mucinous neoplasms: delineation of an intestinal pathway of carcinogenesis in the pancreas. Am J Surg Pathol. 2004;28: National Cancer Institute. Surveillance, Epidemiology, and End Results Program Available at: Accessed September 7, Lennon AM, Wolfgang CL, Canto MI, et al. The early detection of pancreatic cancer: what will it take to diagnose and treat curable pancreatic neoplasia? Cancer Res. 2014;74: Lennon AM, Wolfgang C. Cystic neoplasms of the pancreas. J Gastrointest Surg. 2013;17: Law JK, Ahmed A, Singh VK, et al. A systematic review of solid-pseudopapillary neoplasms: are these rare lesions? Pancreas.2014; 43: 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: Tanaka M, Fernández-del Castillo C, Adsay V, et al. International consensus guidelines 2012 for the management of IPMN and MCN of the pancreas. Pancreatology. 2012;12: Del Chiaro M, Verbeke C, Salvia R, et al. European experts consensus statement on cystic tumours of the pancreas. Dig Liver Dis. 2013;45: Goh BK, Lin Z, Tan DM, et al. Evaluation of the Fukuoka Consensus Guidelines for intraductal papillary mucinous neoplasms of the pancreas: results from a systematic review of 1,382 surgically resected patients. Surgery. 2015;158: Goh BK, Thng CH, Tan DM, et al. Evaluation of the Sendai and 2012 International Consensus Guidelines based on cross-sectional imaging findings performed for the initial triage of mucinous cystic lesions of the pancreas: a single institution experience with 114 surgically treated patients. Am J Surg. 2014;208: Vege SS, Ziring B, Jain R, et al. American gastroenterological association institute guideline on the diagnosis and management of asymptomatic neoplastic pancreatic cysts. Gastroenterology. 2015;148: Guyatt G, Oxman AD, Akl EA, et al. GRADE guidelines: 1. Introduction-GRADE evidence profiles and summary of findings tables. JClinEpidemiol. 2011;64: Jones MJ, Buchanan AS, Neal CP, et al. Imaging of indeterminate pancreatic cystic lesions: a systematic review. Pancreatology.2013;13: Zhong N, Zhang L, Takahashi N, et al. Histologic and imaging features of mural nodules in mucinous pancreatic cysts. Clin Gastroenterol Hepatol. 2012;10: , 198.e1 e Khashab MA, Kim K, Lennon AM, et al. Should we do EUS/FNA on patients with pancreatic cysts? The incremental diagnostic yield of EUS over CT/MRI for prediction of cystic neoplasms. Pancreas.2013;42: de Jong K, van Hooft JE, Nio CY, et al. Accuracy of preoperative workup in a prospective series of surgically resected cystic pancreatic lesions. Scand J Gastroenterol. 2012;47: Thornton GD, McPhail MJ, Nayagam S, et al. Endoscopic ultrasound guided fine needle aspiration for the diagnosis of pancreatic cystic neoplasms: a meta-analysis. Pancreatology. 2013;13: Brugge WR, Lewandrowski K, Lee-Lewandrowski E, et al. Diagnosis of pancreatic cystic neoplasms: a report of the cooperative pancreatic cyst study. Gastroenterology. 2004;126: Pitman MB, Genevay M, Yaeger K, et al. High-grade atypical epithelial cells in pancreatic mucinous cysts are a more accurate predictor of malignancy than positive cytology. Cancer Cytopathol. 2010;118: de Jong K, Poley JW, van Hooft JE, et al. Endoscopic ultrasound-guided fine-needle aspiration of pancreatic cystic lesions provides inadequate material for cytology and laboratory analysis: initial results from a prospective study. Endoscopy. 2011;43: van der Waaij LA, van Dullemen HM, Porte RJ. Cyst fluid analysis in the differential diagnosis of pancreatic cystic lesions: a pooled analysis. Gastrointest Endosc. 2005;62: Al-Haddad M, Dewitt J, Sherman S, et al. Performance characteristics of molecular (DNA) analysis for the diagnosis of mucinous pancreatic cysts. Gastrointest Endosc. 2014;79: Fusaroli P, Napoleon B, Gincul R, et al. The clinical impact of ultrasound contrast agents in EUS: a systematic review according to the levels of evidence. Gastrointest Endosc. 2016;84: e Fusaroli P, Serrani M, De Giorgio R, et al. Contrast harmonic-endoscopic ultrasound is useful to identify neoplastic features of pancreatic cysts (with videos). Pancreas. 2016;45: Seicean A, Badea R, Stan-Iuga R, et al. The added value of real-time harmonics contrast-enhanced endoscopic ultrasonography for the characterisation of pancreatic diseases in routine practice. J Gastrointestin Liver Dis. 2010;19: Kamata K, Kitano M, Omoto S, et al. Contrast-enhanced harmonic endoscopic ultrasonography for differential diagnosis of pancreatic cysts. Endoscopy. 2016;48: Wolters Kluwer Health, Inc. All rights reserved

6 Lennon and Canto Pancreas Volume 46, Number 6, July Wu J, Matthaei H, Maitra A, et al. Recurrent GNAS mutations define an unexpected pathway for pancreatic cyst development. Sci Transl Med. 2011;3:92ra Wu J, Jiao Y, Dal Molin M, et al. Whole-exome sequencing of neoplastic cysts of the pancreas reveals recurrent mutations in components of ubiquitin-dependent pathways. Proc Natl Acad Sci U S A. 2011;108: Springer S, Wang Y, Dal Molin M, et al. A combination of molecular markers and clinical features improve the classification of pancreatic cysts. Gastroenterology. 2015;149: Kadayifci A, Atar M, Wang JL, et al. Value of adding GNAS testing to pancreatic cyst fluid KRAS and carcinoembryonic antigen analysis for the diagnosis of intraductal papillary mucinous neoplasms. Dig Endosc. 2017; 29: Singhi AD, Zeh HJ, Brand RE, et al. American Gastroenterological Association guidelines are inaccurate in detecting pancreatic cysts with advanced neoplasia: a clinicopathologic study of 225 patients with supporting molecular data. Gastrointest Endosc. 2016;83: e de Wilde RF, Besselink MG, van der Tweel I, et al. Impact of nationwide centralization of pancreaticoduodenectomy on hospital mortality. Br J Surg. 2012;99: Sahora K, Ferrone CR, Brugge WR, et al. Effects of comorbidities on outcomes of patients with intraductal papillary mucinous neoplasms. Clin Gastroenterol Hepatol. 2015;13: Kang MJ, Jang JY, Kim SJ, et al. Cyst growth rate predicts malignancy in patients with branch duct intraductal papillary mucinous neoplasms. Clin Gastroenterol Hepatol. 2011;9: Lieberman DA, Rex DK, Winawer SJ, et al. Guidelines for colonoscopy surveillance after screening and polypectomy: a consensus update by the US multi-society task force on colorectal cancer. Gastroenterology. 2012; 143: Tanno S, Nakano Y, Sugiyama Y, et al. Incidence of synchronous and metachronous pancreatic carcinoma in 168 patients with branch duct intraductal papillary mucinous neoplasm. Pancreatology. 2010;10: 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: Wolters Kluwer Health, Inc. All rights reserved.