Management of incidentally found pancreatic cysts

The use of advanced imaging technology has contributed to an increased incidence of incidentally found cysts detected in the pancreas (pancreas), ie cysts that are detected when, for example, an imaging is performed for another reason. There are several different types of pancreatic cysts, both benign and those that are or are at risk of developing cancer. Surgical treatment is both costly and risky and a common way to deal with discovered pancreatic cysts is to observe them over time.

Question

What systematic reviews are there on the management and follow-up of incidentally found cysts in the pancreas?

Identified literature

Table 1. Systematic reviews with low/medium risk of bias.

IPMN = Intraductal pancreatic mucinous neoplasm; BD-IPMN = Branch duct intraductal papillary mucinous neoplasm; NF-PNET = Non-functional pancreatic neuroendocrine tumours; MEN1 = Multiple endocrine neoplasia; FNA = Fine needle aspiration
Included studies Population/Intervention Outcome
Vanella et al, 2018 [1]
Search resulted in 1206 identified articles and 15 studies were included in qualitative synthesis and 8 studies in the quantitative synthesis.
The 8 studies selected for quantitative synthesis included 556 patients (323 with main-duct/mixed-type IPMNs and 233 with branch-duct IPMNs)
Included all study designs but excluded case series with ten or fewer patients.
Population: Individuals with IPMN with at least one worrisome feature or high-risk stigmata who had not undergone surgical resection.

Intervention: Surveillance
Overall mortality:
30.9% (95% CI, 19.6 to 45.1)
Disease-specific mortality:
11.6% (95% CI, 6.0 to 21.2).
Incidence rate of overall mortality per 1000 patient-years:
78 (95% CI, 44 to 111)
Incidence rate of disease-specific mortality per 1000 patient-years:
23 (95% CI, 9 to 37)
Incidence rate of disease-specific mortality per 1000 patient-years for IPMN in main-duct:
32 (95% CI, 12 to 52)
Incidence rate of disease-specific mortality per 1000 patient-years for IPMN in branch-duct:
5 (95% CI, 0 to 10)
Authors’ conclusion:
“The present results suggest that a specific subset of patients who have IPMNs with worrisome features or high-risk stigmata are more likely to die from co-morbidities rather than from an IPMN-related cancer. In this particular setting of elderly patients or those with co-morbidities, disease-specific mortality should be carefully balanced against the mortality and morbidity of pancreatic surgery.”
Sallinen et al, 2017 [2]
Search resulted in 5440 identified articles and 9 were included in the review.
The 9 studies included a total of 408 patients, whereof 344 with a sporadic neuroendocrine pancreatic tumour and 64 with MEN1-related tumours.
Included most study designs, but all included studies in the review were retrospective cohort studies.
Population: Patients with neuroendocrine pancreatic tumours without metastases at the time of diagnosis.

Intervention: Surveillance, median follow-up had to be at least 18 months.
Tumor growth (proportion):
NF-PNET: 0.22 (95% CI, 0.07 to 0.41)
MEN1: 0.52 (95% CI, 0.18 to 0.85)
Developed metastasis (proportion):
NF-PNET: 0%
MEN1: 9%
Tumor resection (proportion):
NF-PNET: 0.12 (95% CI, 0.04 to 0.23)
MEN1: 0.25 (95% CI, 0.04 to 0.54)
Authors’ conclusion:
“In conclusion, despite scarce literature with low level of evidence, expectant management of highly selected sporadic small asymptomatic NF-PNETs seems safe. These results should be interpreted with caution as the underlying studies are small retrospective series with only a short follow-up. How to best select patient for surveillance strategy (age, cut-off size, tumor location, imaging features) remains to be clearly determined, and studies with longer follow-up are needed.”
Lensing et al, 2017 [3]
Search resulted in 1357 identified articles and 31 were included in the review.
The review included experimental and observational studies, both prospective and retrospective. No RCT’s were found.
Population: Patients (n=8455) with untreated branch-duct intraductal papillary mucinous neoplasms.

Intervention: Surveillance, mean range of follow-up were between 7.9 to 120 months.
Increased cyst size (At least 20% increase)
Pooled incidence
20% (95% CI, 0.13 to 0,29)
Malignant BD-IPMN
3% (95% CI, 0.02 to 0.05)
Pancreatic malignancy
2.3% (95% CI, 0.01 to 0.04)
Death due to pancreatic malignancy:
0.5% (95% CI, 0.001 to 0.002)
Authors’ conclusion:
“The pooled incidences of increased cyst size, malignant BD-IPMN, pancreatic malignancy, and pancreatic malignancy-related death during follow-up were, respectively, 17.4%, 2.5%, 2.6%, and 0.5%.”, “In conclusion, a short-interval follow-up of maximum 6 months seems to be useful and necessary, in order to find these lesions at a resectable time. However, more research is needed to evaluate this in a prospective study.”
Guo et al, 2017 [4]
Search resulted in 1034 identified articles and 6 were included in the review.
Included both RCT’s and observational studies. No RCTs were found.
Population: Patients with small (<20 mm) non-functioning pancreatic neuroendocrine tumours.

Intervention: Surveillance or resection
Disease-specific survival
Three studies showed that both the resection (OP) and observation (OBS) group had 100% disease-specific survival.
Overall survival rate:
Two studies found that the OBS-group had 100% overall survival and the OP-group had 97% and 100% overall survival (No significant differences).
5-year overall survival
One study found that the OP group had a 72.3% to 86% 5-year overall survival while the OBS-group only had 27.6% (P>0.01).
Disease progression
Three studies presented data on disease progression (No significant differences).
OP: 0%; OBS: 3.5%
OP: 11%; OBS: 14%
OP: 0%; OBS: 0%
Surgical death
Four studies presented data on surgical death (0%,3%, 0%, 0%).
Surgical complications
Four studies presented data on surgical complications (46%, 44%, 33% and 35%).
Authors’ conclusion:
“After excluding distant metastasis, lymph node metastasis and local invasion on imaging studies, small NF-PNETs can adopt a wait-and-see policy without increase in death and disease progression. More evidences are needed to specify follow-up strategy and whether FNA is required for decision making.”
Choi et al, 2017 [5]
Search resulted in 804 identified articles and 17 were included in the review.
Included both observational and experimental studies.
Population: Patients with unresected intraductal papillary mucinous neoplasms (IPMN).
Patients were categorised as either low-risk (n=2411) or non-low-risk IPMN (n=825).
Low risk was defined as a lack of MPD dilatation (<5mm, or a claim of no MPD) plus a lack of mural nodules.
Intervention: Surveillance
Cumulative incidence of pancreatic cancer development. (% (95% CI))
Low-risk patients:
1 year: 0.02 (0.0 to 0.23)
3 year: 1.40 (0.58 to 2.48)
5 year: 3.12 (1.12 to 5.90)
10 year: 7.77 (4.09 to 12.39)
Non-low-risk patients
1 year: 1.95 (0.0 to 5.99)
3 year: 5.69 (1.10 to 12.77)
5 year: 9.77 (3.04 to 19.27)
10 year: 24.68 (14.87 to 35.9)
Authors’ conclusion:
“In conclusion, low-risk IPMNs had a notable cumulative incidence of pancreatic cancer at 10-year follow-up as the incidence steadily increased linearly with the follow-up duration at constant annual incidence rates of 0.65% to 0.8%/year. Hence, continued long-term surveillance is vital for low-risk IPMNs.”
Crippa et al, 2016 [6]
Search resulted in 2171 identified articles and 20 were include in the review.
Included both observational and experimental studies.
Population: Patients (n=2177) with low-risk branch-duct intraductal papillary mucinous neoplasms (BD-IPMN).
Low risk was defined as: no symptoms, <30mm, absence of nodules/thick walls, no atypical cells).
Intervention: Surveillance, mean follow-up were 29.3 to 76.7 months.
Development of overall pancreatic malignancy:
Events/patient-years (pyrs)
0.007/pyrs (95% CI, 0.005 to 0.008)
Development of malignant BD-IPMN
0.004/pyrs (95% CI, 0.002 to 0.006)
Development of distinct pancreatic ductal adenocarcinoma
0.002/pyrs (95% CI, 0.001 to 0.003)
Disease-specific mortality
0.002/pyrs (95% CI, 0.001 to 0.003)
Authors’ conclusion:
“In conclusion, in low-risk BD-IPMNs undergoing surveillance the rate of progression to pancreatic malignancies is low (7/1000 pyrs), and the rate of mortality due to pancreatic malignancies is even lower (2/1000 pyrs). These small risks of malignant degeneration and eventual mortality are comparable to the risk of postoperative mortality following pancreatic resection, and therefore prophylactic surgery likely represents an overtreatment. We affirm that nonoperative management of BD-IPMNs without worrisome or high-risk features, as has been suggested in the International Consensus Guidelines, is safe. Based on these data, aggressive management with surgical resection for all BD-IPMNs – including “low-risk” lesions – is not justified.”
Scheiman et al, 2015 [7]
Included both observational and experimental studies, but no RCT’s were found. Population: Patients with intraductal papillary mucinous neoplasms (IPMN) or mucinous cystic neoplasms (MCN).
Intervention: Surveillance or resection
Malignancy in patients undergoing resection
25% (95% CI, 23% to 27%)
Postoperative mortality
2.1% (95% CI, 1.5% to 2.7%)
Development of invasive neoplasi
2,8% (95% CI, 1,8% to 4%)
Postoperative morbidity
30% (95% CI, 25% to 35%)
Authors’ conclusion:
“For patients who have benign-appearing lesions with low-risk features on imaging, a decision regarding the patient’s willingness to undergo observation of the lesion should be developed in collaboration with a pancreatic surgeon. In many circumstances, surveillance with noninvasive imaging, typically MRI, and selected use of EUS with or without FNA with cytological analysis and measurement of fluid will allow watchful waiting of a presumed mucinous lesion, including both MCNs and branch duct IPMNs.”
“..given the high prevalence of patients with pancreatic cysts and the low rate of malignant transformation over time, this appears to be the most prudent approach to provide patients with the best overall survival”

 

Table 2. Health economic studies with at least medium quality regarding economic aspects and transferability of economic results.

Included studies Population/Intervention Outcome
Aronsson et al, 2018 [8]
Design: Markov model
Setting: Sweden Perspective: Healthcare
Discount rate: 3%
Duration: 35 annual cycles
Population: 65-year-old asymptomatic patient with suspected low-risk intraductal papillary mucinous neoplasms in branch duct (BD-IPMN).
Strategies:
(1) Upfront total pancreatectomy: BD-IPMN and other benign lesions had no postoperative surveillance.
(2) Upfront partial pancreatectomy: BD-IPMN on histopathology had postoperative surveillance with a risk of metachronous PDAC.
(3) Initial surveillance: partial pancreatectomy for progressive BD-IPMNs and for cancer found on follow-up (4) Watchful waiting: symptomatic lesions were investigated and underwent partial pancreatectomy if deemed operable.
Incremental cost effectiveness ratio (ICER):
Total pancreatectomy:
ICER: EUR 167731 per QALY
Partial pancreatectomy:
ICER: EUR 278696 per QALY
Initial surveillance:
ICER: EUR 31682 per QALY
Watchful waiting:
ICER: NA, Base case
Authors’ conclusion:
“Our data and other studies support initial surveillance. However, the extension of surveillance, the appropriate interval and type of investigations are not fully investigated. To date, no large comparative prospective studies exist. Future studies will hopefully elucidate this area, as it is apparent that tailored approaches based on more precise risk stratifications are necessary for a safe and cost-effective management of each patient.”
Huang et al, 2010 [10]
Design: Markov model
Setting: USA
Perspective: Healthcare
Discount rate: 3%
Duration: 6-month cycles until death.
Population: 60-year-old patient with BD-IPMN in the head of pancreas on either computed tomography (CT) or magnetic resonance imaging (MRI) with or without symptoms.
Strategies:
(1) Surveillance using consensus guidelines for surgical resection (surveillance strategy),
(2) Immediate surgery after initial diagnosis of branch-duct IPMN (surgery strategy) and
(3) Surgical resection only on development of symptoms (no surveillance strategy
Incremental cost effectiveness ratio (ICER):
Surveillance:
ICER: USD 20096 per QALY
Surgery:
ICER: USD 132436 per QALY
No surveillance:
ICER:
NA, Base case
Authors’ conclusion:
“In conclusion, our analysis demonstrates that surveillance with current guidelines is a cost-effective strategy in the management of branch duct IPMN in the head of pancreas when compared to no surveillance. These findings are dependent on the underlying age of the population, specificity and sensitivity of consensus guidelines, and progression from adenoma to dysplasia/CIS. Although surgery could be more effective, it may be prohibitively expensive from a policy perspective.”
Das et al, 2015 [9]
Design: Markov model
Setting: USA
Perspective: Third-party payer
Discount rate: 3%
Duration: Cycle length not known, until death.
Population: Asymptomatic patient with an incidentally found 3 cm solitary pancreatic cystic neoplasms.
Strategies:strong (1) Wait & watch. Follow all patients, refer for resection only if symptoms occur or worrisome features appear
(2) Resect if operable Refer all cysts for resection immediately, no follow-up if patient is inoperable
(3) Risk-stratify by EUS + FNA/CEA & cytology
▪ Mucinous: Refer for resection
▪ Non-Mucinous: Follow annually for first 3 years, every 3rd year thereafter
(4) Risk-stratify by EUS + FNA/CEA & cytology & IMP
▪ Non-Mucinous and Mucinous/Benign: Follow annually for first 3 years, every 3rd thereafter
▪ Mucinous/Indolent: Follow annually for first 5 years, every 3 years thereafter
▪ Mucinous/Aggressive: Refer for resection
Incremental cost effectiveness ratio (ICER):
4. IMP:
ICER: USD 62 (Preferred)
3. EUS-FNA+ Cytology +CEA:
ICER: USD 6590 (Dominated)
2. Resect if operable:
ICER: USD 32054 (Dominated)
1. Wait & watch
ICER: NA, base case
Authors’ conclusion:
“While current first-line diagnostic tests have lower cost and wider availability, they cannot provide consistent, meaningful prediction of malignant potential. Nevertheless, standard clinical management of patients with PCN relies on these first line tests, the results of which are reflected in Strategy III. Even with the model being heavily biased against IMP, we found that using IMP to predict malignant potential is superior to Strategy III and represents the most cost-effective strategy for managing PCN. These results demonstrate that a reasonably accurate risk stratification tool (e. g., IMP) provides a significant benefit in reducing cost and improving QALY for pancreatic cyst patients.”

References

  1. Vanella G, Crippa S, Archibugi L, Arcidiacono PG, Delle Fave G, Falconi M, et al. Meta-analysis of mortality in patients with high-risk intraductal papillary mucinous neoplasms under observation. British Journal of Surgery 2018;105:328-338.
  2. Sallinen V, Le Large TYS, Galeev S, Kovalenko Z, Tieftrunk E, Araujo R, et al. Surveillance strategy for small asymptomatic non-functional pancreatic neuroendocrine tumors - a systematic review and meta-analysis. HPB : the official journal of the International Hepato Pancreato Biliary Association 2017;19:310-320.
  3. Lensing RJ, Bipat S. Incidences of Pancreatic Malignancy and Mortality in Patients With Untreated Branch-Duct Intraductal Papillary Mucinous Neoplasms Undergoing Surveillance: A Systematic Review. Pancreas 2017;46:1098-1110.
  4. Guo J, Zhao J, Bi X, Li Z, Huang Z, Zhang Y, et al. Should surgery be conducted for small nonfunctioning pancreatic neuroendocrine tumors: a systemic review. Oncotarget 2017;8:35368-35375.
  5. Choi SH, Park SH, Kim KW, Lee JY, Lee SS. Progression of Unresected Intraductal Papillary Mucinous Neoplasms of the Pancreas to Cancer: A Systematic Review and Meta-analysis. Clinical Gastroenterology and Hepatology 2017;15:1509-1520.e4.
  6. Crippa S, Capurso G, Cammà C, Fave GD, Castillo CFD, Falconi M. Risk of pancreatic malignancy and mortality in branch-duct IPMNs undergoing surveillance: A systematic review and meta-analysis. Digestive and Liver Disease 2016;48:473-479.
  7. Scheiman JM, Hwang JH, Moayyedi P. American Gastroenterological Association Technical Review on the Diagnosis and Management of Asymptomatic Neoplastic Pancreatic Cysts. Gastroenterology 2015;148:824-848.e22.
  8. Aronsson L, Ansari D, Andersson B, Persson U, Fridhammar A, Andersson R. Intraductal papillary mucinous neoplasms of the pancreas - a cost-effectiveness analysis of management strategies for the branch-duct subtype. HPB 2018;20:1206-1214.
  9. Huang ES, Gazelle GS, Hur C. Consensus guidelines in the management of branch duct intraductal papillary mucinous neoplasm: a cost-effectiveness analysis. Digestive diseases and sciences 2010;55:852-60.
  10. Das A, Brugge W, Mishra G, Smith DM, Sachdev M, Ellsworth E. Managing incidental pancreatic cystic neoplasms with integrated molecular pathology is a cost-effective strategy. Endoscopy international open 2015;3:E479-86.

SBU Enquiry Service Consists of structured literature searches to highlight studies that can address questions received by the SBU Enquiry Service from Swedish healthcare or social service providers. We assess the risk of bias in systematic reviews and when needed also quality and transferability of results in health economic studies. Relevant references are compiled by an SBU staff member, in consultation with an external expert when needed.

Published: 1/15/2021
Report no: ut202101
Registration no: SBU 2020/147