Pancreas cysts: More is not necessarily better!
BY SANTHI SWAROOP VEGE, MD
Pancreas cysts (PC) are very common, incidental findings on cross-sectional imaging, performed for non–pancreas-related symptoms. The important issues in management of patients with PC in my practice are the prevalence, natural history, frequency of occurrence of high-grade dysplasia (HGD) and/or pancreatic cancer (PDAC), concerning clinical symptoms and imaging findings, indications for EUS and fine-needle aspiration cytology, ideal method and frequency of surveillance, indications for surgery (up front and during follow-up), follow-up after surgery, stopping surveillance, costs, and unintentional harms of management. Good population-based evidence regarding many of the issues described above does not exist, and all information is from selected clinic, radiology, EUS, and surgical cohorts (very important when trying to assess the publications). Cohort studies should start with all PC undergoing surveillance and assess various outcomes, rather than looking backward from EUS or surgical cohorts.
The 2015 American Gastroenterological Association guidelines on asymptomatic neoplastic pancreas cysts, which I coauthored, recommend, consistent with principles of High Value Care (minimal unintentional harms and cost effectiveness), that two of three high-risk features (mural nodule, cyst size greater than 3 cm, and dilated pancreatic duct) be present for EUS-guided fine-needle aspiration (EUS-FNA). By the same token, they advise surgery for those with two of three high-risk features and or concerning features on EUS and cytology. Finally, they suggest stopping surveillance at 5 years if there are no significant changes. Rigorous GRADE methodology along with systematic review of all relevant questions (rather than cohorts of 500 or fewer patients) formed the basis of the guidelines. Those meta-analyses showed that risk of PDAC in mural nodules, cyst size >3 cm, and dilated pancreatic duct, while elevated, still is very low in absolute terms. Less than 20% of resections for highly selected, high-risk cysts showed PDAC. The guidelines were met with a lot of resistance from several societies and physician groups. The recommendations for stopping surveillance after 5 years and no surveillance for absent or low-grade dysplasia after surgery are hotly contested, and these areas need larger, long-term studies.
The whole area of cyst fluid molecular markers that would suggest mucinous type (KRAS and GNAS mutations) and, more importantly, the presence or imminent development of PDAC (next-generation sequencing or NGS) is an exciting field. One sincerely hopes that there will be a breakthrough in this area to achieve the holy grail. Cost effectiveness studies demonstrate the futility of existing guidelines and favor a less intensive approach. Guidelines are only a general framework, and management of individual patients in the clinic is entirely at the discretion of the treating physician. One should make every attempt to detect advanced lesions in PC, but such effort should not subject a large majority of patients to unintentional harms by overtreatment and add further to the burgeoning health care costs in the country.
Mayo Clinic
Dr. Santhi Swaroop Vege
PC are extremely common (10% of all abdominal imaging), increase with age, are seen in as many as 40%-50% of MRI examinations for nonpancreatic indications, and most (>50%) are IPMNs. Most of the debate centers around the concerns of PDAC and/or HGD associated with mucinous cysts (MCN, IPMN, side-branch, main duct, or mixed).
The various guidelines by multiple societies differ in some aspects, such as in selection of patients based on clinical, laboratory, and imaging findings for up-front surgery or surveillance, the frequency of surveillance based on the size of the cyst and the presence of other concerning cyst features (usually with MRCP), the indications for EUS (both initial and subsequent), importance of the magnitude of growth (most IPMNs slowly grow over a period of time), indications for surgery during surveillance and postsurgery surveillance, and the decision to stop surveillance at some point in time. The literature is replete with small case series reporting a proportion of cancers detected and often ignoring the harms of surgery. Incidence of and mortality caused by PDAC are very low (about 1% for both) in a large national cohort of VA pancreatic cyst patients with long-term follow-up and other studies.
Marcov modeling suggests that none of the guidelines would lead to cost-effective care with low mortality because of overtreatment of low-risk lesions, and a specificity of 67% or more for PDAC/HGB is required. AGA guidelines came close to it but with low sensitivity. Monte Carlo modeling suggests that less intensive strategies, compared with more intensive, result in a similar number of deaths at a much lower cost. While molecular markers in PC fluid are reported to increase the specificity of PDAC/HGD to greater than 70%, it should be observed that such validation was done in a small percentage of patients who had both those markers and resection.
The costs of expensive procedures like EUS, MRI, and surgery, the 3% complication rate with EUS-FNA (primarily acute pancreatitis), and the 1% mortality and approximately 20%-30% morbidity with surgery (bleeding, infection, fistula) and postpancreatectomy diabetes of approximately 30% in the long run need special attention.
In conclusion, one could say pancreas cysts are extremely frequent, most of the neoplastic cysts are mucinous (IPMN and MCN) and slowly growing over time without an associated cancer, and the greatest need at this time is to identify the small proportion of such cysts with PDAC and/or HGD. Until such time, judicious selection of patients for surveillance and reasonable intervals of such surveillance with selective use of EUS will help identify patients requiring resection. In our enthusiasm to detect every possible pancreatic cancer, we should not ignore the unintentional outcomes of surgery to a large majority of patients who would never develop PDAC and the astronomical costs associated with such practice.
Dr. Vege is professor of medicine at the Mayo Clinic. He reported having no conflicts of interest regarding this article.
References
Vege SS et al. Gastroenterology. 2015;148:819-22.
Lobo JM et al. Surgery. 2020;168:601-9.
Lennon AM and Vege SS. Clin Gastroenterol Hepatol. 2022;20:1663-7.
Harris RP. Ann Intern Med. 2015;162:787-9.
