Does Pancreatic Cyst Stability Justify Stopping Intraductal Papillary Mucinous Neoplasm Surveillance?

Abstract

See “Long-term risk of malignancy in branch-duct intraductal papillary mucinous neoplasms,” by Oyama H, Tada M, Takagi K, et al, on page 226. See “Long-term risk of malignancy in branch-duct intraductal papillary mucinous neoplasms,” by Oyama H, Tada M, Takagi K, et al, on page 226. Pancreatic cyst surveillance of presumed branch duct-intraductal papillary mucinous neoplasms (BD-IPMN) represents an opportunity for early detection in pancreatic cancer.1Farrell J.J. Prevalence, diagnosis and management of pancreatic cystic neoplasms: current status and future directions.Gut Liver. 2015; 9: 571-589Crossref PubMed Scopus (105) Google Scholar Owing to the large numbers of asymptomatic pancreatic cysts and their overall very low risk of malignancy in the general population (relative to the numbers of actual pancreatic cancer), several tailored guidelines for surveillance based on these cysts’ calculated risk of malignancy and patients’ ability to undergo surgery have been proposed.2Tanaka M. Fernandez-Del Castillo C. Kamisawa T. et al.Revisions of international consensus Fukuoka guidelines for the management of IPMN of the pancreas.Pancreatology. 2017; 17: 738-753Crossref PubMed Scopus (841) Google Scholar,3Vege S.S. Ziring B. Jain R. et al.Gastroenterological Association institute guideline on the diagnosis and management of asymptomatic neoplastic pancreatic cysts.Gastroenterology. 2015; 148 (quiz: e12–3): 819-922Abstract Full Text Full Text PDF PubMed Scopus (599) Google Scholar Although the decision to stop surveillance is multifactorial, including patient’s life expectancy, preference, and tolerance for surgery, perhaps the most controversial item from the recent American Gastroenterological Association (AGA) clinical guidelines is the recommendation to stop surveillance if a pancreatic cyst has remained stable morphologically for >5 years.4Farrell J.J. Editorial: stopping pancreatic cyst surveillance?.Am J Gastroenterol. 2017; 112: 1162-1164Crossref PubMed Scopus (10) Google Scholar The rationale for the AGA recommendation stems from the overall very low risk of malignant progression and the assumption that the majority of pancreatic malignancy and mortality related to neoplastic cysts occur within the first 5 years of cyst discovery.3Vege S.S. Ziring B. Jain R. et al.Gastroenterological Association institute guideline on the diagnosis and management of asymptomatic neoplastic pancreatic cysts.Gastroenterology. 2015; 148 (quiz: e12–3): 819-922Abstract Full Text Full Text PDF PubMed Scopus (599) Google Scholar Since the publication of the AGA guidelines, multiple large surveillance studies of presumed BD-IPMN, with follow-up of >5 years have been published. Overall, these studies support a very high disease-specific-5 year survival for patients with low risk BD-IPMNs (without worrisome features [WF]) in the realm of 96%–98%, the persistent and often late (after 5 years) risk of developing WFs and even high-risk stigmata in otherwise low-risk IPMNs (about 5%), the late persistence of the risk of cancer (0%–4%) after 5 and 10 years of surveillance, and the potential value of using baseline cyst size or cyst rate of growth to predict progression of morphology and cancer in the setting of IPMN.5Pergolini I. Sahora K. Ferrone C.R. et al.Long-term risk of pancreatic malignancy in patients with branch duct intraductal papillary mucinous neoplasm in a referral center.Gastroenterology. 2017; 153: 1284-1294 e1Abstract Full Text Full Text PDF PubMed Scopus (136) Google Scholar, 6Mukewar S. de Pretis N. Aryal-Khanal A. et al.Fukuoka criteria accurately predict risk for adverse outcomes during follow-up of pancreatic cysts presumed to be intraductal papillary mucinous neoplasms.Gut. 2016; 66: 1811-1817Crossref PubMed Scopus (61) Google Scholar, 7Lawson R.D. Hunt G.C. Giap A.Q. et al.Pancreatic cysts suspected to be branch duct intraductal papillary mucinous neoplasm without concerning features have low risk for development of pancreatic cancer.Ann Gastroenterol. 2015; 28: 487-494PubMed Google Scholar, 8Gausman V. Kandel P. Van Riet P.A. et al.Predictors of progression among low-risk intraductal papillary mucinous neoplasms in a multicenter surveillance cohort.Pancreas. 2018; 47: 471-476Crossref PubMed Scopus (13) Google Scholar, 9Crippa S. Bassi C. Salvia R. et al.Low progression of intraductal papillary mucinous neoplasms with worrisome features and high-risk stigmata undergoing non-operative management: a mid-term follow-up analysis.Gut. 2017; 66: 495-506Crossref PubMed Scopus (130) Google Scholar, 10Crippa S. Pezzilli R. Bissolati M. et al.Active surveillance beyond 5 years is required for presumed branch-duct intraductal papillary mucinous neoplasms undergoing non-operative management.Am J Gastroenterol. 2017; 112: 1153-1161Crossref PubMed Scopus (53) Google Scholar, 11Lawrence S.A. Attiyeh M.A. Seier K. et al.Should patients with cystic lesions of the pancreas undergo long-term radiographic surveillance? Results of 3024 patients evaluated at a single institution.Ann Surg. 2017; 266: 536-544Crossref PubMed Scopus (47) Google Scholar, 12Han Y. Lee H. Kang J.S. et al.Progression of pancreatic branch duct intraductal papillary mucinous neoplasm associates with cyst size.Gastroenterology. 2018; 154: 576-584Abstract Full Text Full Text PDF PubMed Scopus (71) Google Scholar, 13Kayal M. Luk L. Hecht E.M. et al.Long-term surveillance and timeline of progression of presumed low-risk intraductal papillary mucinous neoplasms.AJR Am J Roentgenol. 2017; 209: 320-326Crossref PubMed Scopus (16) Google Scholar, 14Marchegiani G. Andrianello S. Pollini T. et al."Trivial" cysts redefine the risk of cancer in presumed branch-duct intraductal papillary mucinous neoplasms of the pancreas: a potential target for follow-up discontinuation?.Am J Gastroenterol. 2019; 114: 1678-1684Crossref PubMed Scopus (41) Google Scholar However, the issue of stopping surveillance after pancreatic cyst stability during the initial 5 years has been more difficult to study. Even defining cyst stability is challenging, and varies from study to study. In addition to the lack of a uniform consensus about how cyst size is measured, definitions of cyst stability vary from a 20% increase in cyst size, to a rate of growth of >2 mm/yr, to the development of new WFs.13Kayal M. Luk L. Hecht E.M. et al.Long-term surveillance and timeline of progression of presumed low-risk intraductal papillary mucinous neoplasms.AJR Am J Roentgenol. 2017; 209: 320-326Crossref PubMed Scopus (16) Google Scholar Of 412 patients with presumed BD-IPMN radiographic stability over 5 years of surveillance, 19% still had evidence of future growth and 1% developed carcinoma, with the observed rate of cancer development of nearly 6 times greater than what would be expected in the general population.11Lawrence S.A. Attiyeh M.A. Seier K. et al.Should patients with cystic lesions of the pancreas undergo long-term radiographic surveillance? Results of 3024 patients evaluated at a single institution.Ann Surg. 2017; 266: 536-544Crossref PubMed Scopus (47) Google Scholar The term “trivial BD-IPMN” was recently used in a separate study, to define 378 patients without WFs or high risk stigmata (HRS) who did not develop any WFs or HRS during a surveillance period of >5 years. Of these patients, 1.6% developed pancreatic cancer after a median time of 103 months, including 2 patients developing pancreatic cancer after >10 years of surveillance.14Marchegiani G. Andrianello S. Pollini T. et al."Trivial" cysts redefine the risk of cancer in presumed branch-duct intraductal papillary mucinous neoplasms of the pancreas: a potential target for follow-up discontinuation?.Am J Gastroenterol. 2019; 114: 1678-1684Crossref PubMed Scopus (41) Google Scholar In this issue of Gastroenterology, Oyama et al15Oyama H. Tada M. Takagi K. et al.Long-term risk of malignancy in branch-duct intraductal papillary mucinous neoplasms.Gastroenterology. 2020; 158: 226-237Abstract Full Text Full Text PDF PubMed Scopus (90) Google Scholar report on a large prospective surveillance study of 1404 presumed BD-IPMN without WF (dilated main PD, cyst size >3 cm), followed closely for ≤15 years.15Oyama H. Tada M. Takagi K. et al.Long-term risk of malignancy in branch-duct intraductal papillary mucinous neoplasms.Gastroenterology. 2020; 158: 226-237Abstract Full Text Full Text PDF PubMed Scopus (90) Google Scholar Sixty-eight patients developed pancreatic malignancy, with the overall cumulative incidence of pancreatic cancer being 3.5% at 10 years and 12% at 15 years, from the initial diagnosis of IPMN. Interestingly, of the 737 patients who did not develop additional WFs for 5 years, 23 developed pancreatic carcinoma, with the cumulative incidence rates of pancreatic carcinoma being 3.2% and 9.5% at 10 and 15 years, respectively. When studying small cysts (<15 mm) in this cohort, 22 patients were diagnosed with pancreatic carcinoma, for an overall cumulative incidence rate of pancreatic carcinoma of 2.2%, 4.6%, and 7.4% at 5, 10, and 15 years, respectively, a 7-fold increase in cancer development even in small 1.5 cm lesions compared with the general population. This finding is at variance with prior data following 557 patients for a median of 82 months where only 1 cancer developed in the 108 patients whose cyst remained <1.5 cm for a period of ≥5 years, compared with 19 cancers in 255 patients (7.5%) where the cyst size was >1.5 cm during the same period.5Pergolini I. Sahora K. Ferrone C.R. et al.Long-term risk of pancreatic malignancy in patients with branch duct intraductal papillary mucinous neoplasm in a referral center.Gastroenterology. 2017; 153: 1284-1294 e1Abstract Full Text Full Text PDF PubMed Scopus (136) Google Scholar The preponderance of the available data, then, does not support the guideline of stopping surveillance after periods of “stability”; and it is unclear that there is truly a subgroup population based on morphology alone (eg, <1.5 cm) in whom surveillance can also be stopped safely. Yes, the risk of developing cancer in these stable cysts is low, but it is not zero. In fact, the clinical guidelines focusing primarily on cyst morphology and stability to titrate surveillance are further complicated by the increasingly recognized risk of concomitant pancreatic ductal adenocarcinoma (PDAC) arising elsewhere in the pancreatic gland in patients with IPMN.16Tanaka M. Intraductal papillary mucinous neoplasm of the pancreas as the main focus for early detection of pancreatic adenocarcinoma.Pancreas. 2018; : 544-550Crossref PubMed Scopus (30) Google Scholar,17Torisu Y.T. Kinoshita K. Tomita Y. et al.Pancreatic cancer screening in patients with presumed branch-duct intraductal papillary mucinous neoplasms.World J Clin Oncol. 2019; 10: 67-74Crossref PubMed Google Scholar Concomitant PDAC in the setting of IPMN malignancy was originally reported to have a low incidence of between 2% and 7% in most surgical series.16Tanaka M. Intraductal papillary mucinous neoplasm of the pancreas as the main focus for early detection of pancreatic adenocarcinoma.Pancreas. 2018; : 544-550Crossref PubMed Scopus (30) Google Scholar However, more recent data suggest that the rate could be as high as 18% (from molecular pathology series) and ≤28% (from surgical series).18Felsenstein M.N. Masica D.L. IPMNs with co-occurring invasive cancers: neighbours but not always relatives.Gut. 2018; 67: 1652-1662Crossref PubMed Scopus (77) Google Scholar,19Lafemina J.K. Klimstra D. Malignant progression in IPMN: a cohort analysis of patients initially selected for resection or observation.Ann Surg Oncol. 2013; 20: 440-447Crossref PubMed Scopus (85) Google Scholar Even in the current study by Oyama et al,15Oyama H. Tada M. Takagi K. et al.Long-term risk of malignancy in branch-duct intraductal papillary mucinous neoplasms.Gastroenterology. 2020; 158: 226-237Abstract Full Text Full Text PDF PubMed Scopus (90) Google Scholar through the use of sophisticated molecular fingerprinting techniques, 30 of 68 (44%) of all pancreatic malignancies in the setting of BD-IPMN were concomitant PDACs, molecularly and often geographically distinct.15Oyama H. Tada M. Takagi K. et al.Long-term risk of malignancy in branch-duct intraductal papillary mucinous neoplasms.Gastroenterology. 2020; 158: 226-237Abstract Full Text Full Text PDF PubMed Scopus (90) Google Scholar Whereas IPMN-derived carcinomas correlate with IPMN size and main pancreatic duct diameter, there are no radiologic IPMN cyst-related risk factors (eg, size, mural nodules, presence of cancer) for the development of these concomitant PDACs. Other studies suggest normal main PD, small cyst size, multifocal IPMN, gastric subtype GNAS wild IPMNs, advanced age (>70 years), female sex, a family history of pancreas cancer, elevated CA19-9, and worsening diabetes may possibly increase the risk of concomitant PDAC.20Ingkakul T. Sadakari Y. Ienaga J. et al.Predictors of the presence of concomitant invasive ductal carcinoma in intraductal papillary mucinous neoplasm of the pancreas.Ann Surg. 2010; 251: 70-75Crossref PubMed Scopus (146) Google Scholar Because a goal of pancreatic cyst surveillance is to detect early pancreas cancer, and guidelines currently used are predominantly focused on cyst morphology and stability, is it possible that we will continue to miss the additional opportunities for early detection in pancreas cancer in these scenarios? Clinically, the paper by Oyama et al15Oyama H. Tada M. Takagi K. et al.Long-term risk of malignancy in branch-duct intraductal papillary mucinous neoplasms.Gastroenterology. 2020; 158: 226-237Abstract Full Text Full Text PDF PubMed Scopus (90) Google Scholar in this issue of Gastroenterology is a reminder that we should continue to image the cyst for as long as it carries risk and the patient is amenable to surgical resection, but that we should also not forget to evaluate the remainder of the pancreatic parenchyma. These approaches require confirmation in prospective clinical trials. Long-term Risk of Malignancy in Branch-Duct Intraductal Papillary Mucinous NeoplasmsGastroenterologyVol. 158Issue 1PreviewLong-term outcomes of patients with branch-duct intraductal papillary mucinous neoplasms (IPMNs), particularly those after 5 years of surveillance, have not been fully evaluated in large studies. We analyzed incidences of IPMN-derived carcinoma and concomitant ductal adenocarcinoma (pancreatic ductal adenocarcinoma [PDAC]) over 20 years in a large population of patients. Full-Text PDF