THE NATURAL HISTORY OF INTRADUCTAL PAPILLARY MUCINOUS NEOPLASM OF THE PANCREAS: REAPPRAISAL OF THE INDOLENT PRECURSOR OF PANCREATIC CANCER

INTRODUCTION Evidences from surgical series have been condensed into several guidelines for the management of Intraductal Papillary Mucinous Neoplasms of the pancreas (IPMNs). However, still a gap must be filled to better understand their biological behavior. Aim of the present study is to describe the natural history of IPMNs observed at a high-volume center for thirty years. METHODS All patients with a radiological or pathological diagnosis of IPMN referred to The Pancreas Institute, University of Verona Hospital Trust, from 1985 to 2016 were included. Growth rates were analyzed through a linear-mixed model. The development of worrisome features (WF), high-risk stigmata (HRS), and pancreatic cancer (PC), survival and risk for surgery were also analyzed. RESULTS Of 2189 observed patients, 1529 were included in the analysis. The overall median follow-up was 43 months. Three hundred and thirteen patients were sent to surgery upfront, while 181 after initial surveillance. The overall growth rate was 1mm/year. For about half of cases any dimensional change was documented. The presence of high risk stigmata (HRS), age 30mm at diagnosis were associated to a faster growth rate. During follow-up, trivial IPMNs developed WF in 6.5% of cases and HRS in 0.6%. Overall, 3.5% of patients developed PC after a median time of 28 months. Of these patients, 72% previously developed HRS/WF. Of 1043 initially observed trivial branch duct (BD) IPMNs, 16 eventually developed PC with 10% occurring after 15 years of follow-up. HRS and growth rate were independent predictors of PC. Growth rate was the only difference between IPMNs developing PC and those remaining stable after more than 5 years of follow-up (n=399). The mean estimated disease specific survival (DSS) for the overall population exceeded 19 years. Only 1.9% of BD-IPMNs developed PC, with a resulting 5-years DSS rate of 99.3%. Standardized incidence ratio of PC for patients with trivial BD-IPMN was 21 (95% CI 10 – 38), whereas was only 1.8 (95% CI 0.5 – 4.7) considering patients > 65 years. CONCLUSIONS IPMN of the pancreas is the indolent precursor of PDAC that will not show a detectable growth during follow-up in half of the cases. Those rapidly growing (>2.50 mm/year) will likely progress to pancreatic cancer through the development of WF and HRS during the first year of follow-up. In patients > 65 y/o, the presence of a BD-IPMN without WF or HRS at diagnosis might not increase the risk of developing PC than in the general populatio