Title page
Title of the article
Risk Factors for the Development of High-risk Stigmata in Branch-duct Intraductal Papillary
Mucinous Neoplasms

Authors' names
Tatsuhiro Yamazaki, MD*, Takeshi Tomoda, PhD*, Hironari Kato, PhD*, Kazuya Miyamoto,
MD*, Akihiro Matsumi, MD*, Eijiro Ueta, MD*, Yuki Fujii, MD*, Yosuke Saragai, MD*,
Daisuke Uchida, PhD*, Kazuyuki Matsumoto, PhD*, Shigeru Horiguchi, PhD*, Koichiro
Tsutsumi, PhD*, and Hiroyuki Okada, Prof*

Authors' institutions*Department of Gastroenterology and Hepatology, Okayama University Hospital, Okayama,Japane-mail and postal address
Tatsuhiro Yamazaki, MD
E-mail: ty1114db@gmail.com

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2-5-1 Shikata-cho, Kita-ku, Okayama-city, Okayama 700-8558, Japan13

Abstract
Objective: Strict follow-up is recommended for branch-duct intraductal papillary mucinous
neoplasms (BD-IPMNs) to avoid missing the development of high-risk stigmata (HRS) at apremalignant stage. This study explored the risk factors associated with the development of
HRS during follow-up.
Methods: We performed a retrospective analysis of 283 patients with BD-IPMN, treated at
Okayama University Hospital in Japan between January 2009 and December 2016. Only
patients with imaging studies indicative of classical features of BD-IPMN without HRS andfollowed for over one year were included in the study. We performed radiological follow-up
every six months and collected patients’ demographic data, cyst characteristics, and clinicaloutcomes and used univariate logistic regression models to determine the odds of developing
HRS.
Results: Ten patients (3.5%) developed HRS after a median surveillance period of 55.8 months.
The main pancreatic duct (MPD) size (5-9 mm) and cyst growth rate (>2.5 mm/year) were bothsuggested to be possible risk factors for the development of HRS (odds ratio, 14.2; 95%
confidence interval [CI], 3.1-65.2, P=0.0006, and odds ratio, 6.1; 95% CI 1.5-25.5, P=0.014).
Regarding the number of worrisome features (WFs), the rate of HRS development was 2.0%
(4/199) in cases with no WF, 1.6% (1/62) in cases with single WF and 22.7% (5/22) in cases

13with multiple WFs, respectively. The rate of HRS development was significantly higher incases with multiple WFs than in the other cases (P<0.0001).
Conclusion: MPD dilation, rapid cyst growth, and multiple WFs were significant risk factors
for the development of HRS. In the presence of such features, it is necessary to closely follow
the development of HRS and avoid missing the best opportunity to perform surgicalintervention.

Key words
Surveillance; Prognosis factor; Intraductal papillary mucinous neoplasm; Pancreatic Cancer

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Main text
Introduction
The detection of intraductal papillary mucinous neoplasms (IPMNs) of the pancreas has
increased due to the use of cross-sectional imaging, such as computed tomography (CT),magnetic resonance imaging (MRI), magnetic resonance cholangiopancreatography (MRCP),and endoscopic ultrasound (EUS).(1,2) However, the type of case determines whether or not
resection is required and how follow-up should be performed.
The 2017 International Association of Pancreatology guideline (Fukuoka guideline)
classifies clinical and radiological findings predicting malignancy into "high-risk stigmata(HRS)" and "worrisome features (WFs)".(3) HRS include ⅰ) obstructive jaundice, ⅱ) enhancing
mural nodule ≥5 mm, and iii) main pancreatic duct (MPD) ≥10 mm, with surgical resection
recommended for patients with any findings due to the high prevalence of cancer. WFs includeⅰ) a history of pancreatitis, ⅱ) cyst ≥3 cm, ⅲ) enhancing mural nodule <5 mm, ⅳ)
thickened/enhancing cyst walls, ⅴ) MPD size 5-9 mm, ⅳ) abrupt change in caliber of thepancreatic duct with distal pancreatic atrophy, ⅶ) lymphadenopathy, ⅷ) increased serum
level of CA19-9, and ⅰx) a cyst growth rate ≥5 mm/2 years. Features viii and ix were recently
added as new WFs in the IPMN International Guidelines for 2017 (Fukuoka Guideline). In

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cases of branch-duct IPMN (BD-IPMN), it is also necessary to be aware of the tumor markers
and the rate cyst growth.
Strict follow-up is recommended for cases without HRS, and it seems important to not
miss the development of HRS at a premalignant stage.(4) However, which factors areassociated with the development of HRS during follow-up is unclear.
The present study explored which WFs of BD-IPMN were risk factors for thedevelopment of HRS during follow-up.

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Materials and Methods
Study design
This single-center retrospective study examined the predictive factors for the development of
HRS from BD-IPMN during follow-up. Informed consent was obtained from all participants.
The study protocol was approved by the ethical guidelines of the World Medical Association
Declaration of Helsinki and was approved by the Okayama University Ethics Committee.

Patients and the diagnosis of BD-IPMN
Patients were identified from our EUS database, and consecutive patients with a clinicaldiagnosis of BD-IPMN at the Okayama University Hospital with a minimum of 12 months
follow-up between January 2009 and December 2016 were included in this study. Patients were
those with at least one cross-sectional imaging study (CT, MRI/MRCP, and EUS) performed
three months or longer after the initial diagnosis. If there were no contraindications, EUS,
contrast-enhanced CT (CE-CT), and MRCP were performed in all cases at the initial diagnosis.
BD-IPMN was defined as the presence of unilocular or multicystic lesions ≥5 mm in sizecommunicating with the MPD, as clearly demonstrated by CT, MRCP, or EUS. When EUS
revealed a suspected nodule in the cystic lesions, contrast-enhanced EUS (CE-EUS) using an
ultrasound contrast agent (SonazoidTM; Daiichi-Sankyo, Tokyo, Japan) was performed. If there13was an absence of blood flow signals in the intracystic structures, we diagnosed it as a protein
plaque.
All patients with HRS at the initial diagnosis or with cysts suggestive of anotherdiagnosis besides BD-IPMN (e.g. serous cystadenoma, mucinous cystic neoplasm, cystic
neuroendocrine tumor, solid pseudopapillary tumor, or pseudocyst) were excluded from thestudy.

Follow-up and data collection
Patients diagnosed with BD-IPMN underwent radiological follow-up by CE-CT or MRCP
alternately every six months, and cyst characteristics, including the location, maximum cyst
size, solid component with or without enhancement, thickened cyst walls, MPD size,
lymphadenopathy, and abrupt change in MPD caliber with distal pancreatic atrophy, were
examined. The CA19-9 serum levels were routinely measured. The diameter of the cyst and
MPD size were defined as the maximum diameter measured by MRCP, as recommended by
the Fukuoka guidelines for evaluating pancreatic cysts.(3,5,6) In multifocal cases, the largest
cyst was used. Thickened cyst walls were defined in cases with cyst walls thicker than 2 mm.
Increased serum levels of CA19-9 were defined in cases with levels >40 U/mL. If findings suchas an increased cyst diameter or appearance of nodules were suspected on CE-CT or MRCP,

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EUS was performed. The follow-up period was set as the time between the initial cyst diagnosis(the first cross-sectional imaging on which the cyst was detected) and one of the following
endpoints: the date of the last visit or death for patients without development of HRS; date of
HRS development; or the date of the first discovery of malignancy on imaging for patients withan unresectable tumor.
We recommended surgical resection for cases in which HRS developed during followup. For other patients with a solid mass suspected of being pancreatic cancer or rapid growthin the cyst size, we considered surgical resection. Some patients who met the criteria forresection did not undergo surgery due to severe comorbidities or patient preference.

Assessments
The primary outcome was to evaluate the risk factors for the development of HRS in patientswith BD-IPMN without HRS at the initial diagnosis. The evaluated risk factors were as follows:a history of pancreatitis, cyst ≥3 cm, enhancing mural nodule <5 mm, thickened/enhancing cyst
walls, MPD size 5-9 mm, abrupt change in caliber of the pancreatic duct with distal pancreatic
atrophy, lymphadenopathy, increased serum level of CA19-9 (>40 U/mL), and cyst growth rate
≥5 mm/2 years, which is defined as a WF by the Fukuoka guidelines. The cyst growth rate wascalculated as the cyst size at last follow-up –13

cyst size at the initial diagnosis / follow-up

period ; an increase of ≥2.5 mm/year was defined as a WF. Furthermore, the initial cyst sizeand cyst growth rate were compared, and cases were assigned to four different groups
according to the cyst size.

Statistical analyses
Continuous variables were presented as the mean with standard deviation (SD) or the medianwith range when appropriate, and categorical variables were expressed as frequencies withpercentages. Wilcoxon’s rank sum test was performed to compare the continuous variables,
and Fisher’s exact test was performed to evaluate the categorical variables. A P-value <0.05
was considered statistically significant. Univariate analyses were performed to predict the odds
ratio (OR) of developing HRS. A multivariate model was not feasible because of the small
sample size of the HRS group. All statistical analyses were performed using the JMP® software
program, version 14 (SAS Institute Inc., Cary, NC, USA).

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Results
Patient characteristics
A total of 476 patients who underwent EUS for suspicious IPMN on CT/MRCP were identified
during the study period. Among these patients, 48 were excluded for the following reasons: nocommunication with MPD (n=8), cyst size <5 mm (n=6), possibility of another pancreatic cyst
disease (n=11), and main duct IPMN (n=23). A total of 428 patients were diagnosed with BDIPMN. However, those who underwent surgical resection within 6 months or who had been
diagnosed with advanced pancreatic ductal adenocarcinoma (PDAC) or HRS at the initialdiagnosis (n=76) and with follow-up periods of <1 year (n=69) were excluded from the study.
Ultimately, 283 patients were included in this analysis (Fig. 1).
The baseline characteristics are summarized in Table 1. In this study, 139 men and 144
women with a mean age of 66.3 years were included. The median follow-up duration was 53.3
months (13.7-121.6). The WF excluding cyst growth rate >2.5 mm, which could not be
identified at the initial diagnosis, was detected in 89 WFs of 76 patients at the initial diagnosis.

Morphological data at the initial diagnosis and during follow-up
The mean initial cyst size was 18.0 mm, and the MPD was 2.5 mm. At the final follow-up
examination, the mean cyst size was 20.4 mm, and the MPD was 2.8 mm. The mean annual

13rate of cyst growth was 0.57 mm, and the size in 21 cases (7.4%) increased by more than 2.5mm/year, which is a WF (Table 2). Among these cases, eight had no WFs at the initial diagnosis.
A total of 110 WFs in 84 patients were ultimately detected at the initial diagnosis, including acyst growth rate >2.5 mm/year.

Development of HRS and risk factors
Of the 283 patients, 10 (3.5%) developed HRS after a median surveillance period of 55.8
months (range, 30.4-112.3) before HRS development, including an enhancing mural nodule ≥5mm (n=7), MPD size ≥10 mm (n=2), and enhancing solid component ≥5 mm with an MPD
size ≥10 mm (n=1). No patients developed obstructive jaundice. Among these patients, fivepatients developed HRS after a five-year surveillance period.
We evaluated which WF was a potential risk factor for the development of HRS in thisstudy (Table 3). The MPD size (5-9 mm) and cyst growth rate (>2.5 mm/year) were bothsuggested as possible risk factors for the development of HRS (OR 14.2, 95% CI 3.1-65.2,
P=0.0006 and OR 6.1, 95% CI 1.5-25.5, P=0.014). An increased serum level of CA19-9 (>40
U/mL) at the diagnosis was not a feature of HRS development (P=0.20).
Subsequently, we examined whether or not the simultaneous presence of WF at theinitial diagnosis could be used as a predictive marker of HRS development during follow-up.

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For each patient, the number of WFs was counted, and the rate of HRS development wascompared (Fig. 2). When the patients were classified into groups with no WFs, a single WF,
and multiple WFs, HRS development was seen in 4 of 199 (2.0%) patients with no WFs, 1 of
62 (1.6%) patients with a single WF, and 5 of 22 (22.7%) patients with multiple WFs. The
multiple WF group showed a significantly higher incidence rate of HRS than the other groups,
and its OR was 15.1 (95% confidence interval [CI]: 4.0–57.1; P=0.0003).

Morphological changes in cysts in terms of initial size
The participants were categorized into 4 groups according to their initial cyst size: group 1,<10 mm (n=51); group 2, 10 mm to <20 mm (n=125); group 3, 20 mm to <30 mm (n=69); andgroup 4, ≥30 mm (n=38). The respective median annual growth rates for groups 1, 2, 3, and 4
were 0 mm, 0.20 mm, 0.40 mm, and 0.98 mm (Fig. 3). The annual growth rates weresignificantly different among the 4 groups (P <.001). However, the incidence of newly
developed HRS was not related to the initial cyst size (0% [0/51], 2.4% [3/125], 5.8% [4/69],
and 7.9% [3/38] in groups 1, 2, 3, and 4, respectively; P=0.11).

Surgery and progress
Of the 10 patients who developed HRS, 3 underwent surgery (diagnosed with IPMN-derived

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invasive carcinoma in 2 and IPMN with low-grade dysplasia in 1), and 1 was found to havepancreatic cancer with bone metastases. The other six patients continued to receive follow-up
because of severe comorbidities or the patient’s preference. In addition, regarding the patients
who developed HRS, 5 (1.8%) underwent surgery, including 2 for suspected concomitant
PDAC and 3 due to the patient’s wish in response to cyst size enlargement after a mean
surveillance period of 62.4 months. The two with suspected concomitant PDAC were
pathologically diagnosed PDAC, while the other three were diagnosed with IPMN with lowgrade dysplasia.

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Discussion
Previous reports have shown that the presence of HRS is associated with a 40% risk of IPMNrelated death, reinforcing the notion that surgical resection should be offered to fit patients.(7)In cases of IPMN with HRS, the 3-year pancreatic carcinoma risks of obstructive jaundice, anenhancing solid component, and MPD >10 mm were 79.8%, 37.3%, and 39.4%,
respectively.(4) Thus, in the follow-up of BD-IPMN, HRS is considered the most importantfactor for predicting the appearance of IPMN-derived carcinoma. In the present study, we
explored the risk factors associated with the development of HRS during follow-up.
Reports have evaluated the risk factors of malignancy associated with individual cyst
features of BD-IPMN, and a cyst size >3 cm, presence of a mural nodule, and MPD dilatation>5 mm proved to be the strongest predictors of pancreatic malignancy.(8,9)
In our study, in addition to dilation of the MPD, rapid cyst growth and multiple WFs
were found to be factors potentially associated with the development of HRS. Kang et al.
reported that cysts growing faster than 2 mm/year presented a significantly higher risk ofmalignancy in all 201 subjects with an initial cyst size of <30 mm without MPD dilation andno mural nodule than more slowly growing cysts.(10) Kolb et al. studied a group of 188 patientswith low-risk IPMN, and 12 developed WF. Among them, the rate of BD-IPMN growth was
greater in patients who developed WF than in those who did not (2.84 mm/year vs. 0.2313

mm/year; P<0.001).(11) In a recent study, a rapid cyst growth rate (≥2.5 mm/year) was themain predictor of malignancy development in presumed BD-IPMN without WFs or HRS.(12)In the present study, of the 21 patients with a cyst growth rate ≥2.5 mm/year, 3 (14.3%)
developed HRS. Although most BD-IPMNs are indolent and dormant, some cysts rapidly growwith the development of HRS. During surveillance of BD-IPMN, particular focus should beplaced on the cyst growth rate.
In a recently published multi-institutional study by Wilson et al., high-grade
dysplasia and invasive carcinoma were found in 57.4% of patients with multiple WFs, 31.1%
with a single WF, and 24.6% with no WFs, among surgical cases of IPMN. This study indicatedthat the number of WFs was associated with malignancy of BD-IPMN.(13) Other studies havescored the morphology of IPMN and created risk models for malignancy, arguing that the larger
the nodule diameter, cyst size, and MPD diameter, the higher the risk of malignancy.(14)Consistent with these studies, the group with multiple WFs in the present study developed HRS
more frequently than other groups. However, another study found that the WF counts were notrelated to the risk of malignant IPMN. In surgical cases, the mean WF counts were 1.52, 2.11,
2.14, and 2.20 for low-, intermediate-, and high-grade dysplasia and invasive carcinoma,
respectively.(15) Therefore, additional confirmatory studies are necessary to validate ourresults.

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Cyst size >3 cm was not a significant factor in the development of HRS, but larger cysts
had a greater cyst growth rate than smaller ones in this study. Han et al. reported that larger
cysts, particularly those larger than 2 cm, showed significantly faster annual growth rates, andpatients with initially larger cysts developed more WFs during surveillance than others.(16)Thus, the initial cyst size is an important factor for the follow-up of BD-IPMN as it is related
to the rate of cyst growth. Although a mural nodule, which has been reported to be associatedwith cancer in many reports, was not extracted as a risk factor, our study had too little power
to detect differences due to the small number of cases with a mural nodule at the initialdiagnosis.(16,17)
The American Gastroenterological Association guidelines recommend discontinuingsurveillance of non-progressive IPMNs within five years.(18) Conversely, accumulating
evidence suggests that patients with BD-IPMN may remain at high risk of developing
pancreatic carcinoma even after five-year surveillance.(19-21) In a Japanese study involving
804 patients with BD-IPMNs followed for >5 years, the overall cumulative incidence ofpancreatic cancer was 3.5% at 10 years from the initial diagnosis.(21) In a study at a US referral
center, high-grade dysplasia and invasive carcinoma were observed in 20 (5.5%) and 16 (4.4%)
patients, respectively, among 363 patients included after 5 years of follow-up.(22) Consistent
with these studies, 5 out of the 10 patients who developed HRS in our study showed HRS after13

5 years of follow-up, supporting the prolonged surveillance of patients with BD-IPMN. Further
investigations are warranted to create surveillance programs based on these results.
Several limitations associated with the present study warrant mention. First, this was a
retrospective single-center study with a small sample size. Therefore, the possibility ofunintentional selection bias in the selection of patients could not be fully excluded. Second,
there were only 10 patients among the 285 included who met the primary outcome(development of HRS). Due to the small outcome number, a multivariate analysis was not
performed. A further study in a large patient cohort with a long follow-up period is required tovalidate our results.
In conclusion, this study shows that among BD-IPMN patients without HRS at theinitial diagnosis, 3.5% ultimately developed HRS during surveillance, and the dilation of the
MPD, rapid cyst growth, and multiple WFs were suggested to be possible risk factors for thedevelopment of HRS. In cases with such features, it is necessary to closely follow thedevelopment of HRS and be careful not to miss the timing of surgery.

Ethics approval and consent to participate
This study was conducted in accordance with the Declaration of Helsinki and approved by the
Okayama University Hospital review board. Informed consent was omitted, and information13

on this study was disclosed in the form of opt-out on our hospital website. Information
regarding the conduct of the research, including the objectives, was disclosed, and the researchsubjects were provided an opportunity to refuse inclusion in the research.

Acknowledgements
We would like to thank Dr. Toshiharu Mitsuhashi for his statistical advice.

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Figure legends
Fig. 1: Flow diagram of the study population
Fig. 2: Relationship between the number of WFs at the initial diagnosis and the rate of HRS
development
Fig. 3: Depiction of cyst growth rate according to initial cyst size. The median annual cyst
growth rate was 0.57 mm. The larger the cyst size at the diagnosis, the faster the cyst growthrate increased.

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References
1.

Klibansky DA, Reid-Lombardo KM, Gordon SR, Gardner TB. The clinical relevanceof the increasing incidence of intraductal papillary mucinous neoplasm. Clin
Gastroenterol Hepatol 10(5):555-558, 2012.

2.

Bassi C, Sarr MG, Lillemoe KD, Reber HA. Natural history of intraductal papillary
mucinous neoplasms (IPMN): current evidence and implications for management. J
Gastrointest Surg 12(4):645-650, 2008.

3.

Tanaka M, Fernandez-Del Castillo C, Kamisawa T, et al. Revisions of international
consensus Fukuoka guidelines for the management of IPMN of the pancreas.
Pancreatology 17(5):738-753, 2017.

4.

Mukewar 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 66(10):1811-1817, 2017.

5.

Zhang XM, Mitchell DG, Dohke M, Holland GA, Parker L. Pancreatic cysts: depiction
on single-shot fast spin-echo MR images. Radiology 223(2):547-553, 2002.

6.

Berland LL, Silverman SG, Gore RM, et al. Managing incidental findings on abdominal
CT: white paper of the ACR incidental findings committee. J Am Coll Radiol
7(10):754-773, 2010.

13

7.

Crippa 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 66(3):495-506, 2017.

8.

Anand N, Sampath K, Wu BU. Cyst features and risk of malignancy in intraductal
papillary mucinous neoplasms of the pancreas: a meta-analysis. Clin Gastroenterol
Hepatol 11(8):913-921; quiz e959-960, 2013.

9.

Petrone MC, Magnoni P, Pergolini I, et al. Long-term follow-up of low-risk branchduct IPMNs of the pancreas: is main pancreatic duct dilatation the most worrisomefeature? Clin Transl Gastroenterol 9(6):158, 2018.

10.

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
9(1):87-93, 2011.

11.

Kolb JM, Argiriadi P, Lee K, et al. Higher Growth Rate of Branch Duct Intraductal
Papillary Mucinous Neoplasms Associates With Worrisome Features. Clin
Gastroenterol Hepatol 16(9):1481-1487, 2018.

12.

Marchegiani G, Andrianello S, Pollini T, et al. "Trivial" Cysts Redefine the Risk ofCancer in Presumed Branch-Duct Intraductal Papillary Mucinous Neoplasms of the13Pancreas: A Potential Target for Follow-Up Discontinuation? Am J Gastroenterol
114(10):1678-1684, 2019.
13.

Wilson GC, Maithel SK, Bentrem D, et al. Are the Current Guidelines for the SurgicalManagement of Intraductal Papillary Mucinous Neoplasms of the Pancreas Adequate?
A Multi-Institutional Study. J Am Coll Surg 224(4):461-469, 2017.

14.

Shimizu Y, Hijioka S, Hirono S, et al. New Model for Predicting Malignancy in Patients
With Intraductal Papillary Mucinous Neoplasm. Ann Surg, 2018.

15.

Aso T, Ohtsuka T, Matsunaga T, et al. "High-risk stigmata" of the 2012 international
consensus guidelines correlate with the malignant grade of branch duct intraductal
papillary mucinous neoplasms of the pancreas. Pancreas 43(8):1239-1243, 2014.

16.

Han Y, Lee H, Kang JS, et al. Progression of Pancreatic Branch Duct Intraductal
Papillary Mucinous Neoplasm Associates With Cyst Size. Gastroenterology
154(3):576-584, 2018.

17.

Seo N, Byun JH, Kim JH, et al. Validation of the 2012 International Consensus
Guidelines Using Computed Tomography and Magnetic Resonance Imaging: Branch
Duct and Main Duct Intraductal Papillary Mucinous Neoplasms of the Pancreas. Ann
Surg 263(3):557-564, 2016.

13

18.

Vege SS, Ziring B, Jain R, Moayyedi P, Clinical Guidelines C, American
Gastroenterology A. American gastroenterological association institute guideline on the
diagnosis

andmanagementof

asymptomatic

neoplastic

pancreatic

cysts.

Gastroenterology 148(4):819-822; quize812-813, 2015.
19.

Imbe K, Nagata N, Hisada Y, et al. Validation of the American Gastroenterological
Association guidelines on management of intraductal papillary mucinous neoplasms:
more than 5 years of follow-up. Eur Radiol 28(1):170-178, 2018.

20.

Oyama H, Tada M, Takagi K, et al. Long-term Risk of Malignancy in Branch-Duct
Intraductal Papillary Mucinous Neoplasms. Gastroenterology 158(1):226-237 e225,
2020.

21.

Khannoussi W, Vullierme MP, Rebours V, et al. The long term risk of malignancy inpatients with branch duct intraductal papillary mucinous neoplasms of the pancreas.
Pancreatology 12(3):198-202, 2012.

22.

Pergolini I, Sahora K, Ferrone CR, et al. Long-term Risk of Pancreatic Malignancy inPatients With Branch Duct Intraductal Papillary Mucinous Neoplasm in a Referral
Center. Gastroenterology 153(5):1284-1294 e1281, 2017.

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