Introduction
Intraductal papillary mucinous neoplasms (IPMNs) of the pancreas are the most frequently identified precursor lesions of pancreatic cancer (PDAC). Only a minority progress towards malignancy, making their identification a critical point in cancer prevention. The available guidelines are imprecise, commonly resulting in over treatment of indolent lesions.
Aims & Methods
The aim of this study (EMI-IPMN, NCT06706700) is to discover novel biological and radiological biomarkers that can distinguish malignant from benign IPMNs. We focused on Endocrine, Metabolic and Inflammatory (EMI) factors, some pathways that are characterized in PDAC but poorly investigated in IPMN progression.
Patients with a presumed diagnosis of IPMN with indication for surgical resection who underwent high-quality magnetic resonance imaging (MRI) and/or computed tomography (CT), were prospectively enrolled. Peripheral blood (PB) and cyst fluid (CF) samples were collected during surgery, and lesions were histologically classified as IPMN with low-grade dysplasia (LGD), high-grade dysplasia (HGD), or invasive cancer (IC). Malignant IPMNs were defined as those with HGD and IC. Cytokine and hormone levels were measured in both fluids using multiplex assays and compared across the diagnostic groups. Continuous variables were converted into categorical variables based on optimal cut-off values, and both univariate and multivariate logistic regression analyses were conducted.
Results
Among the 205 patients enrolled, 133 (58 females, 75 males, median age 69.2) had a histological diagnosis of IPMN: 49 (36.8%) had LGD, 44 (33.1%) HGD and 40 (30.1%) had IC. Analysis of the EMI profile revealed higher concentrations of several markers (IL-8, VEGF, GLP-1, glucagon, and C-peptide) in CF compared to PB. Specific cytokines such as MCP-1 IP-10, TNFα, and IL-8 were significantly elevated in the CF of HGD/IC cases compared to LGD (p=0.05, 0.041, 0.001 and 0.025 respectively). Similarly, IP-10, IL-8, and MDC levels in PB were higher in HGD/IC patients (p=0.006, 0.008 and 0.004 respectively).
Pancreatic fat content, assessed with mDixon Quant Fat Fraction MRI sequences, was notably higher in HGD/IC patients (13.89%) compared to LGD patients (8.38%, p<0.05), and positively correlated with MCP-1 levels in CF.
Among these biological and radiological markers TNFα in the CF demonstrated a substantial diagnostic accuracy for identifying malignant IPMN, with an area under the ROC curve (AUC) of 0.72. In the final multivariable analysis we demonstrate that high TNFα levels in CF and HbA1c were the two independent risk factors for the identification of malignant IPMN (OR 10.8 and 1.11 respectively).
Conclusion
The progression of IPMN to PDAC is associated with a proinflammatory shift in the tumor microenvironment, reflected by local (CF) and systemic (PB) elevations in key cytokines (TNFα, MCP-1, and IL-8) whose involvement in PDAC progression is well established. Elevated hormone levels in CF, along with the strong association between malignant IPMN and HbA1c, underscore the critical role of endocrine alterations in the early stages of pancreatic tumorigenesis. These findings may be harnessed to enable earlier detection of malignant transformation in IPMN. Moreover, the correlation between imaging markers and biological profiles suggests that MRI could serve as non-invasive proxies for underlying pathological changes. Together, these results offer new insights into the pathophysiology of IPMN progression and may imporve diagnostic strategies