Pancreatic cyst guidelines: Which one to live by?

Abstract

In this issue of Gastrointestinal Endoscopy, Lekkerkerker et al1Lekkerkerker S.J. Besselink M.G. Busch O.R. et al.Comparing 3 guidelines on the management of surgically removed pancreatic cysts with regard to pathological outcome.Gastrointest Endosc. 2017; 85: 1025-1031Abstract Full Text Full Text PDF PubMed Scopus (54) Google Scholar compare the accuracy of 3 guidelines for treating intraductal papillary mucinous neoplasm (IPMN). The authors report in their retrospective study that the American Gastroenterology Association (AGA) guidelines2Vege 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 12-3): 819-822Abstract Full Text Full Text PDF PubMed Scopus (598) Google Scholar would have missed 12% of patients with high-grade dysplasia (HGD) or malignancy when the guideline was applied to their cohort of patients, compared with no misses with the European or 2012 International Consensus Guidelines (ICGs).3Tanaka 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: 183-197Abstract Full Text Full Text PDF PubMed Scopus (1691) Google Scholar The AGA guidelines would have avoided unnecessary resection in 28% of patients. These results may question the use of guidelines in the management of pancreatic cystic neoplasms and also question which guideline should be used in daily clinical practice. In 2005 the American Society for Gastrointestinal Endoscopy established preliminary practice guidelines for EUS-FNA, cyst fluid analysis, and risk analysis. The International Association of Pancreatology published its ICGs (widely known as the Sendai guidelines) in 2006, and in 2007, the American College of Gastroenterology developed practice guidelines for the diagnosis and management of neoplastic pancreatic cysts. Currently, there are 3 guidelines for the management of pancreatic cystic neoplasms. In 2012, the ICG was updated (widely known as the Fukuoka guidelines) for the management of mucinous cysts, including IPMNs and mucinous cystic neoplasms MCNs). The European consensus statement on cystic tumors of the pancreas (European guidelines)4Del Chiaro M. Verbeke C. Salvia R. et al.European experts consensus statement on cystic tumours of the pancreas.Dig Liver Dis. 2013; 45: 703-711Abstract Full Text Full Text PDF PubMed Scopus (344) Google Scholar was released in 2013, and in 2015 AGA reported its guidelines for neoplastic cysts of the pancreas. In all of the current 3 guidelines, one of the most important key points is predicting the high-risk features (HRFs) of malignancy in pancreatic cysts. Literature reports state no risk of malignancy in serous cystic neoplasms, simple cysts, lymphoepithelial cysts, and mucinous nonneoplastic cysts; however, several studies have reported a malignancy risk of 38% to 68% for main duct IPMNs (MD-IPMNs), 38% to 65% risk for mixed-IPMNs, 12% to 47% risk for branch duct IPMNs (BD-IPMNs), 10% to 17% risk for MCNs, 8% to 20% risk for solid pseudopapillary neoplasms (SPNs), and 6% to 31% risk for cystic pancreatic neuroendocrine tumors.5Stark A. Donahue T.R. Reber H.A. et al.Pancreatic cyst disease: a review.JAMA. 2016; 315: 1882-1893Crossref PubMed Scopus (149) Google Scholar Generally there is a consensus among the guidelines about the high risk of MD-IPMNs, mixed-IPMNs, MCNs, and SPNs; however, the high risk of malignancy features of BD-IPMNs is still controversial (Table 1).Table 1Selected features of BD-IPMNs for predicting high risk of malignancy by the guidelinesFukuoka 2012European 2013AGA 2015High-risk stigmata•Obstructive jaundice•Enhancing solid component•MPD ≥10 mmWorrisome features•Cyst >3 cm•Thickened/enhancing cyst wall•MPD 5-9 mm•Nonenhancing mural nodule•Abrupt change in PD caliber with distal pancreatic atrophy•Mural nodule•Dilatated MPD•Growth rate of cyst (cysts growing over 2 mm/year)•Presence of symptoms (abdominal pain, pancreatitis, new-onset diabetes, jaundice)•Increased serum levels of CA 19.9•Cyst size >4 cmHigh-risk features•Cyst >3 cm•Associated solid component•Dilatated MPDAGA, American Gastroenterological Association; BDIPMNs, branch-duct intraductal papillary mucinous neoplasms; MPD, main pancreatic duct; PD, pancreatic duct. Open table in a new tab AGA, American Gastroenterological Association; BDIPMNs, branch-duct intraductal papillary mucinous neoplasms; MPD, main pancreatic duct; PD, pancreatic duct. Given the high risk of malignancy, the Fukuoka, European, and AGA guidelines recommend surgery for MCNs, MD-mixed-IPMNs, and SPNs. However, for suspected BD-IPMNs, the Fukuoka guidelines recommend the use of high-risk stigmata (HRS) and worrisome features (WFs) (Table 1). Patients with HRS should be referred for surgical resection, and patients with WFs should be directed to EUS-FNA to enable a search for concerning features of malignancy (main duct feature suggestive of involvement, definite mural nodule, or cytologic features suggestive of or positive for adenocarcinoma). Patients with any worrisome EUS-FNA features should also be referred for resection, whereas the remaining should be treated according to the size of cyst. The European guidelines define symptoms, dilatated main pancreatic duct (MPD), mural nodule, rapidly increasing size, elevated levels of CA 19.9, and cyst size >4 cm as high-risk factors of malignancy and have recommended surgery. Patients with suspected BD-IPMNs <4 cm with risk factors and BD-IPMNs ≥4 cm are directed to surgery, and those with BD-IPMNs <4 cm without risk factors are recommended for surveillance imaging. The AGA guidelines define HRFs for malignancy (Table 1) and recommend magnetic resonance imaging (MRI) surveillance for patients without HRFs. EUS-FNA is recommended for patients having at least 2 of these HRFs. Surgical resection is recommended for patients with a solid component and MPD ≥5 mm on both MRI and EUS and those with malignant cytologic features. The clinical utility of these guidelines has been evaluated in many retrospective trials, which have usually compared preoperative cross-sectional imaging-based cyst classification results with definitive surgical pathologic features. Cysts from 317 patients who had undergone surgical resection and who had been classified according to the Fukuoka guidelines into low, worrisome, and high risk were compared with the use of final pathologic reports. The positive predictive value (PPV) and negative predictive value (NPV) for detecting potentially malignant/malignant cysts were 88% and 92.5%, respectively, according to the Fukuoka guidelines. Although many patients without high risk were operated on, the use of the Fukuoka guidelines avoided more unnecessary surgical resections in comparison with the old ICG guidelines.6Goh B.K. Tan D.M. Thng C.H. et al.Are the Sendai and Fukuoka consensus guidelines for cystic mucinous neoplasms of the pancreas useful in the initial triage of all suspected pancreatic cystic neoplasms? A single-institution experience with 317 surgically treated patients.Ann Surg Oncol. 2014; 21: 1919-1926Crossref PubMed Scopus (65) Google Scholar Moreover, a recent study including 194 patients with pancreatic cysts has reported that the Fukuoka guidelines accurately determine which patients with pancreatic cysts will have advanced neoplasia with 55.6% sensitivity, 73% specificity, 32% PPV, and 87.9% NPV.7Kaimakliotis P. Riff B. Pourmand K. et al.Sendai and Fukuoka consensus guidelines identify advanced neoplasia in patients with suspected mucinous cystic neoplasms of the pancreas.Clin Gastroenterol Hepatol. 2015; 13: 1808-1815Abstract Full Text Full Text PDF PubMed Scopus (40) Google Scholar By contrast, the AGA guidelines were evaluated in 225 patients by comparison with EUS-FNA findings and cyst fluid analysis, and advanced neoplasia were found with 62% sensitivity, 79% specificity, 57% PPV, and 82% NPV.8Singhi A.D. Zeh H.J. Brand R.E. 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: 1107-1117Abstract Full Text Full Text PDF PubMed Scopus (100) Google Scholar Lekkerkerker et al1Lekkerkerker S.J. Besselink M.G. Busch O.R. et al.Comparing 3 guidelines on the management of surgically removed pancreatic cysts with regard to pathological outcome.Gastrointest Endosc. 2017; 85: 1025-1031Abstract Full Text Full Text PDF PubMed Scopus (54) Google Scholar extracted 115 patients who underwent pancreatic resection from their prospective pancreatic cyst database from 2006 to the present. The histopathologic diagnoses in these patients were compared with the initial indications for surgery according to the Fukuoka, European, and AGA guidelines. In their series of patients, the preoperative diagnosis was correct in 72% of patients, and the discrimination of benign and (pre)malignant cysts was correct in 86%. Surgery was considered to be justified in 52 of 115 (45%) patients. In patients with IPMN, surgery was justified in 54%, 53%, and 59% of patients on the basis of the Fukuoka, European, and AGA guidelines, respectively. When the Fukuoka, European, and AGA guidelines were applied strictly, the unnecessary surgery would have been avoided in 11%, 9%, and 21% of patients. However, advanced neoplasia (HGD and adenocarcinoma) would have been missed in 12% of patients when the AGA guidelines were applied to their series of patients, in contrast to no misses with the Fukuoka or European guidelines. Although some current literature reports suggest that MCNs are less aggressive than was previously thought, the current guidelines recommend surgery for MCNs in patients who are fit for surgery. However, there is a controversy about potential surgical resection criteria of BD-IPMNs among the current 3 guidelines. The AGA guidelines prefer a more conservative approach to predicting high-risk patients and their surgical treatment. Patients with any HRS or any EUS feature are recommended for resection according to the Fukuoka guidelines. The European guidelines recommend surgery for patients who have characteristics similar to those of the Fukuoka guidelines (Table 2). However, the AGA guidelines recommend surgery in the presence of a solid component and MPD ≥5 mm, with or without the presence of EUS features. A recent systematic review to evaluate the clinical utility of the Fukuoka guidelines analyzed 1382 surgically resected IPMNs, and patients with high risk and worrisome risk had PPVs ranging from 27% to 62%. However, stratification of IPMN patients into high-risk and worrisome-risk groups resulted in an improved PPV of 66% in the high-risk group. Although the low-risk group had an NPV ranging from 82% to 100%, overall 11% malignancies were missed.9Goh B.K. Lin Z. Tan D.M. 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: 1192-1202Abstract Full Text Full Text PDF PubMed Scopus (58) Google Scholar Singhi et al8Singhi A.D. Zeh H.J. Brand R.E. 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: 1107-1117Abstract Full Text Full Text PDF PubMed Scopus (100) Google Scholar reported that the AGA guidelines were inaccurate in determining patients with pancreatic cysts who had advanced neoplasia because the guideline failed to recognize 38% of cases in their series. Furthermore, when applied to their series, the AGA guidelines missed 45% of IPMN patients with HGD or adenocarcinoma. By contrast, the current study reported that both the Fukuoka and the AGA guidelines missed 5% of patients with invasive cancer at surgery, which was defined as low-risk small cysts and without WFs.10Ridtitid W. DeWitt J.M. Schmidt C.M. et al.Management of branch-duct intraductal papillary mucinous neoplasms: a large single-center study to assess predictors of malignancy and long-term outcomes.Gastrointest Endosc. 2016; 84: 436-445Abstract Full Text Full Text PDF PubMed Scopus (44) Google Scholar Although each set of guidelines is not perfect in predicting the rate of malignancy and misses a proportion of patients at high risk for malignancy, the AGA guidelines seem to miss malignancy at a greater rate.Table 2Surgical resection recommendations for pancreatic cysts according to current guidelinesDiagnosisFukuoka 2012European 2013AGA 2015MCNResectionResectionResectionSPNNot mentionedResectionResectionMD-IPMNResectionResectionYes, however∗AGA does not recommend surgery for MPD alone, but also requires presence of a nodule or malignant cytologic features.Mixed-IPMNResectionResectionYes, however∗AGA does not recommend surgery for MPD alone, but also requires presence of a nodule or malignant cytologic features.BD-IPMN•Pancreatitis (for relief of symptoms)•Obstructive jaundice•Solid component•MPD ≥1 cm•+Cytologic features suggestive of adenocarcinoma•Definite mural nodule on EUS•MPD features suspicious for involvement§Presence of thickened walls, intraductal mucin, or mural nodules is suggestive of MPD involvement; in their absence, MPD involvement is inconclusive.•>3 cm cyst in young surgically fit patient•Acute pancreatitis jaundice, diabetes•Mural nodule•MPD>6 mm•Size ≥4cm•Rapidly increasing size‡Relative indication for surgery according to European Guideline.•Elevated serum CA19-9 level‡Relative indication for surgery according to European Guideline.•Solid component and MPD ≥5 mm (both on EUS and MRI)•and/or concerning features on EUS†Definite mural nodule, cytologic features positive for malignancy.AGA, American Gastroenterological Association; BD-IPMN, branch duct–intraductal papillary mucinous neoplasm; EUS, endoscopic ultrasonography; MCN, mucinous cystic neoplasm; MD-IPMN, main duct–intraductal papillary mucinous neoplasm; MPD, main pancreatic duct; SPN, solid-pseudopapillary neoplasm.∗ AGA does not recommend surgery for MPD alone, but also requires presence of a nodule or malignant cytologic features.† Definite mural nodule, cytologic features positive for malignancy.‡ Relative indication for surgery according to European Guideline.§ Presence of thickened walls, intraductal mucin, or mural nodules is suggestive of MPD involvement; in their absence, MPD involvement is inconclusive. Open table in a new tab AGA, American Gastroenterological Association; BD-IPMN, branch duct–intraductal papillary mucinous neoplasm; EUS, endoscopic ultrasonography; MCN, mucinous cystic neoplasm; MD-IPMN, main duct–intraductal papillary mucinous neoplasm; MPD, main pancreatic duct; SPN, solid-pseudopapillary neoplasm. In addition, the AGA guidelines do not recommend follow-up of low-risk small cysts. Furthermore, the AGA guidelines continue their more conservative strategy on surveillance of other pancreatic cysts. Compared with the more strict follow-up recommendations of both the Fukuoka and the European guidelines, the AGA guidelines recommended MRI surveillance up to 5 years for patients without concerning EUS features and were opposed to continued surveillance after 5 years in the absence of significant changes in cyst nature. Although fewer patients would have undergone unnecessary resection with the AGA guidelines, the combination of the recent findings of Lekkerkerker at al1Lekkerkerker S.J. Besselink M.G. Busch O.R. et al.Comparing 3 guidelines on the management of surgically removed pancreatic cysts with regard to pathological outcome.Gastrointest Endosc. 2017; 85: 1025-1031Abstract Full Text Full Text PDF PubMed Scopus (54) Google Scholar with AGA guidelines validation studies of Singhi et al8Singhi A.D. Zeh H.J. Brand R.E. 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: 1107-1117Abstract Full Text Full Text PDF PubMed Scopus (100) Google Scholar and Ridtitid et al10Ridtitid W. DeWitt J.M. Schmidt C.M. et al.Management of branch-duct intraductal papillary mucinous neoplasms: a large single-center study to assess predictors of malignancy and long-term outcomes.Gastrointest Endosc. 2016; 84: 436-445Abstract Full Text Full Text PDF PubMed Scopus (44) Google Scholar continues the concern that the AGA guidelines are at risk of missing some malignant cyst or cysts with HGD in the initial evaluation and surveillance. All authors disclosed no financial relationships relevant to this publication. Comparing 3 guidelines on the management of surgically removed pancreatic cysts with regard to pathological outcomeGastrointestinal EndoscopyVol. 85Issue 5PreviewCurrently, 3 guidelines are available for the management of pancreatic cysts. These guidelines vary in their indication for resection of high-risk cysts. We retrospectively compared the final pathologic outcome of surgically removed pancreatic cysts with the indications for resection according to 3 different guidelines. 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