Definition of Radiological and Endocrine/metabolic/inflammatory Biomarker(s) to Identify Highgrade Dysplasia/invasive Carcinoma in Patients with Intraductal Papillary Mucinous Neoplasms of the Pancreas

Up to 40% of patients (pts) undergoing abdominal imaging harbor unsuspected pancreatic cysts, the majority of which intraductal papillary mucinous neoplasms (IPMN). IPMNs are well-known precursors of pancreatic ductal adenocarcinoma (PDAC) without an established temporal window of progression. Current guidelines identify high-risk stigmata (HRS)/absolute criteria(AC) and worrisome features(WF)/relative criteria(RC) as indications for surgical resection of IPMN. Previous guideline criteria were found to be associated with high sensitivity but low specificity for malignancy, resulting in an overtreatment of benign IPMNs, a clinical relevant issue considering the high morbidity/mortality of pancreatectomy. Currently, there are no available hematic biomarkers in peripheral blood, be they DNA, RNA or protein-based, which can identify High Grade Dysplasia(HGD)/Invasive Carcinoma (IC). DNA-based molecular testing of pancreatic cyst fluid obtained during endoscopic ultrasound (EUS)/surgery have been developed and are used to identify advanced neoplasia, with good sensitivity/specificity, and therefore hypothetically, an IPMN HGD/IC-based biomarker could be more readily detected in cyst fluid or in portal blood. This strategy, however has a number of limitations: i) it is highly invasive and costly ii) poor quantity and quality of cyst fluid may lead to incorrect detection (false negatives in molecular testing) ; and iii) a lack of predictive potential of progression over time. New diagnostic tools based on samples of portal blood obtained during EUS or potentially peripheral samples (of new biomarkers) may overcome these limitations.

PDAC has been associated with altered inflammatory and endocrine/metabolic profiles but limited data are available on IPMN and other precursors. Inflammation and malignant progression have become cardinal in cancer research. Tumor-associated neutrophils and cytokines, including TNFalpha and IL-1ß, have been associated with malignant progression also in IPMN. About 40-70% of patients with PDAC experience diabetes or alterations of glucose homeostasis. Diabetes-induced hyperglycemia, hyperinsulinemia, altered insulin-like growth factors production, chronic inflammation and metabolic syndrome have been associated with cancer . In a large cohort of resected IPMNs, preoperative diabetes was significantly associated with HGD/IC, and the risk of IC was highest in patients with recent-onset diabetes.

Obesity is also a well-known risk factor for PDAC; proinflammatory cytokines, known as adipokines are released mainly from visceral adipose tissue stimulating aberrant angiogenesis. An association between visceral obesity and pancreatic fatty infiltration with poor survival was found in PDAC patients. In the setting of IPMN, in a very small cohort of resected patients, significantly higher BMI was associated to an increased rate of malignant IPMN.

EUS, Computed tomography(CT) and magnetic resonance imaging(MRI) are of use in current clinical practice to study and monitor pancreatic diseases. They are all imaging techniques that allow to characterize pancreatic alterations and simultaneously detect endocrino-metabolic alterations (i.e.visceral obesity, liver steatosis, pancreatic fatty infiltration) that may be associated to pancreatic diseases.

Current literature is still debating the superiority of radiological imaging (specifically MRI) or endoscopic ultrasound in identifying worrisome features/high risk stigmata and in correctly distinguishing benign/malignant IPMNs. Preliminary analysis performed in the context of this study, specifically in retrospective Cohort A, aimed at validating International and European guidelines, supports an important role for EUS in identifying risk of malignancy in IPMNs. In fact, 31/116 patients (26.7%) with WF at MRI were "upstaged" by EUS and the majority of these (77.4%) had malignancy at final pathology. Furthermore, EUS confirmed MRI findings in 87.5% of cases, including 72.4% of radiological WF.