1 American Gastroenterological Association Institute Guidelines for

2 Management of Asymptomatic Neoplastic Pancreatic Cysts

3 Santhi Swaroop Vege,1 Barry Ziring,2 Rajeev Jain,3 Paul Moayyedi4
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4 Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester; US 2 Division of Internal Medicine,
5 Sydney Kimmel College of Medicine, Jefferson University, Philadelphia, US; 3, Texas Digestive Disease
6 Consultants, Dallas, Texas, US; 4 Division of Gastroenterology, McMaster University, Hamilton, Canada.

7 Acknowledgements: Clinical Guidelines Committee included: Steven L. Flamm, Northwestern Feinberg

8 School of Medicine, Chicago, IL; Lauren Gerson, California Pacific Medical Center, San Francisco, CA; Ikuo
9 Hirano, Northwestern University School of Medicine, Chicago, Il; Joseph K. Lim, Yale Liver Center, Yale
10 University School of Medicine, New Haven, Connecticut; Geoffrey Nguyen, Mount Sinai Hospital, New
11 York, NY; Joel H. Rubenstein, Veterans Affairs Center for Clinical Management Research, Ann Arbor,
12 Michigan and Division of Gastroenterology, University of Michigan Medical School, Ann Arbor, Michigan;
13 Siddharth Singh, Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN; Neil
14 Stollman, Northern California Gastroenterology Consultants, Oakland, CA; David S. Weinberg, Fox Chase
15 Cancer Center, Philadelphia, PA; Yu-Xiao Yang, Division of Gastroenterology, Perelman School of
16 Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania

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18 Conflict of interest disclosure: All members were required to complete disclosure statement. These
19 statements are maintained at the American Gastroenterological Association Institute (AGA)
20 headquarters in Bethesda, Maryland and pertinent disclosure are published with the report.

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29 This document presents the official recommendations of the American Gastroenterological Association

30 (AGA) on the management of pancreatic cystic neoplasms. The guideline was developed by the AGAs

31 Clinical Practice Guideline Committee and approved by the AGA Governing Board.

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33 The incidental identification of pancreatic cysts is common with the growing use of sophisticated

34 abdominal imaging techniques. Approximately 15% of patients undergoing abdominal magnetic

35 resonance imaging (MRI) for other indications harbor unsuspected pancreatic cysts. Once detected,

36 these cysts can trigger significant anxiety for patients and their physicians. Immediate, as well as

37 surveillance evaluations can be invasive and expensive.

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39 A key component of pancreatic cyst clinical management is a reliable strategy to identify the small

40 minority of cysts with early invasive cancer or high-grade dysplasia (HGD) and to predict those that will

41 develop them in future. Appropriately timed surgical resection can reduce mortality from pancreatic

42 cystadenocarcinoma. However, surgical resection for pancreatic cysts is associated with significant rates

43 of morbidity and mortality. Ideally, the clinician would have highly effective methods to identify

44 patients most likely to benefit from surgery. A major challenge is that commonly employed diagnostic

45 tools such as computerized tomography (CT), MRI and endoscopic ultrasound (EUS) with fine needle

46 aspiration (FNA) cytology have suboptimal sensitivities and specificities to identify the highest risk

47 patients. These guidelines pertain to asymptomatic pancreatic neoplastic cysts. We did not evaluate

48 the impact of symptoms on the management of cysts and this guideline also does not consider

49 neoplastic lesions such as solid papillary neoplasms, cystic degeneration of neuroendocrine tumors, and

50 main duct intraductal papillary mucinous neoplasms (IPMN) without side-branch involvement.

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53 Several previous guidelines have provided recommendations regarding management of pancreatic cysts.

54 However, none have pursued a systematic evaluation of the available evidence. This guideline employs

55 the GRADE criteria (1). This approach breaks down the management of patients with a specific disorder

56 into a series of statements phrased in the PICO format that defines the Population under study, the

57 Intervention or investigation under consideration, the Comparator against which that intervention or

58 investigation is assessed and the Outcome worthy of evaluation (1). It is important to emphasize that

59 the outcomes in these statements should be focused on what is relevant to patients. In the case of

60 pancreatic cysts all statements refer to adult patients that have asymptomatic pancreatic cysts

61 identified by radiology and if a comparator is not stated then it is implied that the management strategy

62 is being compared against do nothing.

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64 Both the quality of the available evidence and the strength of the recommendation are provided for

65 each PICO statement. The quality of the evidence supporting the PICO is described on a four-point scale

66 from high to very low. A very low quality of evidence indicates great uncertainty regarding the estimate

67 of effect. The evidence for the management of pancreatic cysts is summarized in the technical review

68 (2) that accompanies this guideline. All the evidence related to the management of pancreatic cysts is

69 graded as very low quality. Nearly all data are derived from case series. Often these reports were

70 retrospective, usually there was major unexplained heterogeneity between studies, with outcomes

71 assessment that was indirect assuming reduced mortality from pancreatic cystadenocarcinoma as the

72 key outcome. A reasonable argument can be advanced that no recommendations regarding the

73 management of pancreatic cysts can be made, as the evidence pertaining to the available approaches is

74 so weak. Further, as discussed below, it is unclear that the benefits of surveillance outweigh the risks for

75 most patients. However, given the serious outcome of some pancreatic cysts and the need for clinical

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76 guidance on how to manage this complex problem it is important to develop guidelines employing the

77 limited evidence that is available.

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79 In addition to reviewing evidence quality, a strength of recommendation for each statement is made

80 that considers, as a whole, the quality of the evidence, the risks and benefits of the strategy, the values

81 and preferences of patients and the cost (financial and otherwise) of the approach being recommended.

82 A strong recommendation supports a clinical decision that should apply to most patients most of the

83 time while a weak (also called conditional in some settings) recommendation implies that the

84 decision is more nuanced and a significant number of patients could have a different approach.

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86 Issues related to the conduct of surveillance

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88 1. The AGA recommends that patients, before starting any pancreatic cyst surveillance program,

89 should have a clear understanding of programmatic risks and benefits

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91 This is a motherhood statement that does not require the application of the GRADE system (3).

92 Discussing risks and benefits of a management strategy with the patient is good clinical practice for

93 nearly all diseases and interventions. In the context of this guideline it is important to emphasize that

94 surveillance may not be appropriate for, or desired by, some patients. Certain patients may have a

95 higher tolerance of risk. When the probability of a cyst becoming malignant is explained to them they

96 may elect not to have surveillance. Patients that have a limited life expectancy are unlikely to benefit,

97 and surveillance may also be inappropriate for patients who are not surgical candidates because of age

98 or severe comorbidities.

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100 2. The AGA suggests that pancreatic cysts <3 cm without a solid component or a dilated pancreatic

101 duct should be offered an MRI surveillance in one year and then every two years for a total of five

102 years if there is no change in size or characteristics. Weak recommendation, very low quality evidence

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104 The incidence of pancreatic cysts in the US population increases with age and may be as common as

105 25% in those over 70 years old. Pancreatic cystadenocarcinoma is rare. Using SEER database statistics,

106 we estimate that the risk that a cyst seen incidentally on MRI has a 17 in 100,000 chance to be an

107 invasive malignancy. The overall risk that an incidental pancreatic cyst is malignant is therefore very

108 low. Provided a radiologist experienced in the accurate assessment of pancreatic cystic lesions reports

109 no concerning features then it should be safe to follow the great majority of patients. MRI does not

110 expose the patient to radiation and therefore is the preferred surveillance modality over CT. Also, MRI is

111 less invasive than EUS. The follow up interval of one and then 2 years is not based on any evidence but

112 was felt to be reasonable given the small absolute risk of malignancy. The recommendation was weak

113 as some patients may need closer follow up if there are other issues such as a first degree relative with

114 pancreatic cancer or there were equivocal findings on MRI.

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116 3. The AGA recommends that pancreatic cysts 3 cm and/or cysts with higher risk features such as a

117 dilated main pancreatic duct or associated solid component should have EUS/FNA. Strong

118 recommendation, very low quality evidence

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120 A systematic review of the literature suggests that cyst size 3cm, dilated pancreatic duct and the

121 presence of a solid component are factors associated with increased risk of malignancy. Supporting

122 evidence is indirect, utilizing selected cases of surgically resected IPMN where cyst histology is more

123 fully characterized than pre-operative imaging alone would allow. We conducted a review of the

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124 literature for the accuracy of the features for unselected cysts (2) and found that size 3cm increased

125 the risk of malignancy approximately 3x and the presence of a solid nodule increased the risk of

126 malignancy approximately 8x (2). There was no statistically significant association of dilated pancreatic

127 duct with malignancy in our review, but we included this as a risk factor given the systematic review

128 findings with resected IPMNs. The quality of the evidence was graded as very low as there was

129 unexplained variation between studies and the population evaluated was highly selected involving

130 patients undergoing pancreatic resection. A relative increase in malignancy risk of 8x is substantial, but

131 given the very low baseline risk the absolute effect is modest. Nevertheless we felt these features

132 should trigger further investigations to characterize the risk of malignancy more accurately. Systematic

133 review data would suggest this is best achieved by EUS and FNA with a sensitivity of approximately 60%

134 and a specificity of 90%.

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136 4. The AGA suggests patients without concerning EUS/FNA results should be offered MRI

137 surveillance after one year and then every two years to ensure no change in risk of malignancy.

138 Weak recommendation, very low quality evidence

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140 The sensitivity of EUS and FNA is modest but this is more than counterbalanced by the low

141 prevalence of malignancy in pancreatic cystic lesions. The negative predictive value of

142 unremarkable EUS/FNA results, although not 100%, is high with a very low associated risk of

143 malignancy. An alternative strategy of pancreatic resection in lieu of surveillance is associated with

144 surgical morbidity and mortality that we felt to exceed any benefits. The recommendation is weak

145 as the group recognized that the quality of evidence is very low and there may be some patients

146 where surgery is appropriate even if all criteria are not met.

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148

149 5. The AGA suggests that significant change in cyst characteristics including the development of a

150 solid component and/or increasing pancreatic duct size are indications for EUS/FNA. Weak

151 recommendation, very low quality evidence

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153 Our review (2) suggested that increase in size of the cyst was not a statistically significant risk factor

154 for malignancy. There are insufficient data on increasing size of pancreatic duct or the development

155 of a nodule in a cyst that previously did not exhibit this feature so we cautiously recommend

156 reassessing patients that have these features during follow-up with EUS/FNA. This is a weak

157 recommendation given the very low quality of evidence underpinning supporting the statement.

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159 When can pancreatic cyst surveillance be discontinued?

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161 6. The AGA recommends discontinuation of pancreatic cyst surveillance if there has been no

162 significant change in cyst characteristics after five years of surveillance or if the patient is no

163 longer a surgical candidate. Strong recommendation, very low quality evidence

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165 Our review of the literature (2) suggested that the risk of malignant transformation of pancreatic

166 cysts is approximately 0.4% per year. This estimate considers all cysts, including those that change

167 over time. The cancer risk in cysts without significant change over a five year period is likely to be

168 lower, although there are no data that specifically compare cancer rates in stable versus unstable

169 cysts. The small risk of malignant progression in stable cysts is likely outweighed by the costs of

170 surveillance including the risks of surgery. We gave this a strong recommendation as available data

171 suggest this approach will apply to most patients. The clinician may elect to continue surveillance

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172 for longer in a minority of patients, if there are other factors such as those with a strong family

173 history of pancreatic cancer or equivocal changes in cysts that possess high risk features.

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175 When to offer surgery for pancreatic cysts

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177 7. The AGA suggests that patients with both solid nodule and a dilated pancreatic duct and/or

178 concerning features on EUS and FNA should be offered surgery to reduce the risk of mortality from

179 mucinous cyst-adenocarcinoma. Weak recommendation, very low quality evidence

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181 Positive cytology on EUS-guided FNA has the highest specificity for diagnosing malignancy and if there

182 are a combination of high-risk features on imaging then this is likely to increase the risk of malignancy

183 even further. Similarly if a 3cm cyst has both a solid nodule and a dilated pancreatic duct (confirmed

184 on both EUS and MRI) then the specificity for malignancy is likely to be high even in the absence of

185 positive cytology. It is important to emphasize that there are no data on the impact of multiple high-risk

186 features on the risk of malignancy but in many areas of medicine multiple risk factors have at least an

187 additive effect in increasing the risk of disease being present. The specificity of this approach is likely to

188 be high (> 95%). Despite the low overall risk of malignancy, such a high test specificity will best identify

189 patients who will have malignant disease at resection. In the technical review (2) accompanying these

190 guidelines, we evaluated all surgical case series of cystic pancreatic neoplasms. Overall 15% patients

191 harbored invasive malignancy.

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193 These data would suggest the benefits of surgery outweigh the risks in this selected population.

194 Normally we would have given this a strong recommendation. To do so assumes most patients will

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195 benefit from the surgery; our review (2) estimated the overall 5 year survival of patients with invasive

196 cancer was approximately 28%. In addition, this estimate may be prone to some lead and length time

197 bias that, if present, would further reduce any surgical benefit. Surgery is likely to be most beneficial in

198 cases of cyst resection for HGD thereby preventing malignancy. Our review of the literature would

199 suggest approximately 17% of patients with IPMNs undergoing pancreatic resection have cysts that

200 harbor HGD. The challenge in interpreting these data is that it is unclear how many of these would have

201 progressed to invasive malignancy. It is clear from other cancers that not all HGD progresses so the

202 proportion of patients that truly benefit from surgery is unclear even in this high-risk group. Any benefit

203 also has to be taken in context with an overall post-operative mortality of 2% and major morbidity of

204 30% from our review of the literature (2). It is for these reasons that we only gave a weak

205 recommendation for surgery even in high-risk patients.

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207 8. The AGA recommends that if surgery is considered for a pancreatic cyst, patients are referred to a

208 center with demonstrated expertise in pancreatic surgery. Strong recommendation, very low quality

209 evidence

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211 A systematic review on outcomes of all pancreatic surgery demonstrated the lower immediate post-

212 operative mortality as well as long term mortality for patients operated in high volume pancreatic

213 centers. There are no direct data for pancreatic cyst surgery specifically, so the quality of the evidence is

214 very low. The SEER database, which reflects all pancreatic surgeries in the US, reports a 6.6% post-

215 operative mortality. In comparison, the 2% post-operative mortality in our review is derived

216 predominantly from centers of excellence providing indirect evidence supporting this statement.

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219 Surveillance after surgery

220 9. The AGA suggests that patients with invasive cancer or dysplasia in a cyst that has been surgically

221 resected should have MRI surveillance of any remaining pancreas every 2 years. Weak

222 recommendation, very low quality evidence

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224 We did not identify any evidence to support this statement. However, these patients may have a field

225 defect in the pancreas that predisposes them to develop cancer. It therefore seems sensible to offer

226 screening even after the cyst has been resected provided they have not had a total pancreatectomy.

227 Surveillance should continue as long as the patient remains a good candidate for surgery. MRI every 2

228 years may be a reasonable approach for these patients in line with our recommendations for incidental

229 pancreatic cysts. The clinician may elect to offer more frequent surveillance in the case of invasive

230 cancer resection, particularly if there is concern that the lesion has not been fully resected.

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232 10. The AGA recommends that pancreatic cyst patients without high grade dysplasia or malignancy at

233 surgical resection should not be offered any further surveillance. Strong recommendation, very low

234 quality evidence.

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236 There are no case series that report outcomes in this group. However it seems very likely that if the

237 patient did not have HGD or invasive malignancy in any cyst that was resected then they are likely not

238 have any field defect that predisposes them to malignancy. Continued surveillance in this group is

239 extremely unlikely to be cost effective.

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243 Summary

244 Pancreatic cysts are common and increase with age but mucinous cyst-adenocarcinoma development in

245 these cysts is extremely rare. The management strategy for pancreatic cysts aims either to prevent the

246 development of invasive cancer and or to resect invasive malignancy early when present. Current clinical

247 practice is based on minimal evidence and relies almost exclusively on case series of frequent cross

248 sectional imaging with or without EUS and/or FNA cytology and surgery for concerning features. The

249 above guidelines for asymptomatic mucinous cysts are different from all previously published guidelines

250 in the following areas: 2 year interval for cyst of any size undergoing surveillance, stopping surveillance

251 after 5 years if no change, surgery only if more than one concerning feature on MRI confirmed on EUS

252 and only in centers with high volumes of pancreatic surgery, and no surveillance after surgery if no

253 invasive cancer or dysplasia. Although based on extensive literature review and synthesis, these

254 recommendations may result in significant controversy as they advocate less frequent follow up and a

255 higher threshold before offering surgery. However, consistent utilization should decrease inadvertent

256 harm to patients and reduce the costs of health care delivery.

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267 References

268 1. Guyatt GH, Oxman AD, Vist G, Kunz R, Falck-Ytter Y, Alonso-Coello P, Schnemann HJ, for the

269 GRADE Working Group. Rating quality of evidence and strength of recommendations GRADE: an

270 emerging consensus on rating quality of evidence and strength of recommendations. BMJ 2008;

271 336: 924-926.

272 2. Scheiman J, Hwang JH, Moayyedi P. American Gastroenterological Association Technical Review

273 on the Diagnosis and Management of Pancreatic Cysts. Gastroenterology 2014.

274 3. Guyatt G, Oxman AD, Akl E, Kunz R, Vist G, Brozek J, Norris S, Falck-Ytter Y, Glasziou P, Debeer H,

275 Jaeschke R, Rind D, Meerpohl J, Dahm P, Schnemann HJ. GRADE guidelines 1. Introduction-

276 GRADE evidence profiles and summary of findings tables. J Clin Epidemiol 2011; 64: 383-94.

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280 Figure: Algorithm summarizing the AGA guideline on the management of pancreatic cysts.

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 Cyst seen on imaging
+ve feature = dilated main
pancreatic duct or solid nodule
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282

> 3cm and/or +ve

features on MRI

No Yes

Repeat MRI in 1 year

and then biennially to EUS+FNA
year five

Yes

> 3cm and/or +ve

features on MRI at
any point during 5
year surveillance
Repeat MRI in 1 year
Concerning
and then biennially to No cytology and/or
year five
both features +ve

Yes

Interval change so that

one/or both features +ve
No at any point during 5 year Consider surgery
surveillance
No Yes

Repeat EUS+FNA

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