Patient must be >= 50 years and =< 75 years of age

Patient must not have acute pancreatitis or a history of chronic pancreatitis

Patient must have received a CT, MRI, or EUS within 6 months prior to randomization that revealed one or more >= 1 cm pancreatic cyst (s)

Patients of childbearing potential must not be known to be pregnant

Patient must not have a prior diagnosis of pancreatic malignancy of any type

Patient must not have a history of pancreatic resection

Patients with only pancreatic lesions without malignant risk (pancreatic pseudocyst or classic serous cystic lesion) are not eligible

Patient must not have a family history of pancreatic adenocarcinoma in one or more first-degree relatives (biological parents, full siblings or children)

Patient must not have pancreatic cyst morphology that would prompt immediate surgical consideration (enhancing mural nodule, solid component in cyst, pancreatic duct >= 10 mm, cyst causing obstructive jaundice)

Patient must not have a comorbid illness that precludes EUS or pancreatic cyst resection

Patient must not be currently participating in pancreatic cyst surveillance defined as organized, periodic up-to-date imaging directed towards the pancreatic cyst of interest

PRIMARY OBJECTIVE:
I. To compare the rates of unfavorable clinical outcomes in the two arms.

SECONDARY OBJECTIVES:
I. To compare rates of major surgical morbidity and/or mortality between arms.
II. To compare pancreatic cancer incidence and all-cause mortality across arms.
III. Compare institutional (direct) costs.
IV. Compare healthcare utilization of imaging, invasive testing, surgical, and other procedures across the two surveillance arms.
V. Compare patient (out-of-pocket and other indirect) costs.
VI. Describe diagnostic test and treatment pathways by arm.
VII. Compare patient reports of quality of life (QOL), situational anxiety.
VIII. Compare patient report of financial distress.
IX. Compare rates of non-adherence by arm assignment.
X. To evaluate and compare the predictive performance of known and future biomarkers for dysplasia or cancer.

EXPLORATORY OBJECTIVE:
I. To evaluate and compare the predictive accuracy of known and future radiomic markers for dysplasia and pancreatic cancer.

OUTLINE: Patients are randomized to 1 of 2 arms.

ARM A (LOW INTENSITY SURVEILLANCE): Patients undergo magnetic resonance imaging (MRI), computed tomography (CT), or endoscopic ultrasound (EUS) at the beginning of the trial and MRI or CT again in 1 year. Following the first year, patients with no abnormalities repeat MRI or CT every 2 years. Patients with positive imaging features on MRI and CT at 1 or 2 years and with negative EUS, repeat MRI or CT in 1 year. Patients with negative imaging repeat MRI or CT in 2 years.

ARM B (HIGH INTENSITY SURVEILLANCE): Patients undergo MRI, CT, or EUS at the beginning of the trial. Patients with >= 1 and < 2 cm cyst undergo MRI or CT every 6 months for 1 year, then every 12 months for 2 years, and then every 24 months thereafter. Patients with >= 2 and < 3 cm cyst undergo EUS within 6 months, and if EUS is negative, patients repeat MRI or CT in 1 year. If second EUS is negative, patients undergo alternate MRI or CT and EUS every 12 months. Patients with cyst >= 3 cm undergo undergo alternate MRI or CT with EUS every 3-6 months.

All patients may also optionally undergo blood sample collection, biopsy and/or EUS-fine needle aspiration (FNA) on study.

After completion of imaging procedures, patients are followed up for 5 years from the date of registration.