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.
The association among obesity, diabetes, inflammation, alterations of specific
endocrine/metabolic pathways and pancreatic cancer development from its precursors (IPMN)
are more complex, and needs further investigations.
The driving hypotheses of this study are that i) a more accurate patients selection could
limit the problem of overtreatment, ii) that benign/indolent IPMN have a distinguishable
Endocrine/Metabolic/Inflammatory (EMI) profile from those with HGD/IC, and therefore this
research has the following three specific aims.
Aim 1: To retrospectively evaluate and to validate the updated versions of International
and European guidelines for the management of IPMN (Cohort A) Aim 2: To identify
pre-operative biological and/or imaging biomarker(s) to distinguish low- versus high-risk
IPMN for cancer progression in a prospective study of surgically-resected patients
(Cohort B) Aim 2.1: To compare MRI and EUS in the pre-operative evaluation of IPMNs and
with respect to pathological findings. In particular, primary endpoint will be the
identification of main pancreatic duct involvement. Secondary endpoints will be
evaluation of the degree of main duct involvement (extension of IPMN involvement, MPD
diameter at predetermined points, maximum diameter of MPD), the presence of thickened
ductal walls, mural nodules and the characteristics of the surrounding parenchyma (fatty
infiltration/vanishing pancreas).
Aim 3: To prospectively validate biological and/or imaging biomarker(s) previously
identified (Aim 2) on patients with IPMN undergoing surgical resection (Cohort C)