Proteomic Profiling of EUS-FNA Samples Differentiates Pancreatic Adenocarcinoma from Mass-Forming Chronic Pancreatitis

<b>Background/Objectives:</b> Mass-forming chronic pancreatitis (MFP) and pancreatic ductal adenocarcinoma (PDAC) can present with overlapping radiological, clinical, and serological features in patients with underlying chronic pancreatitis (CP), making differential diagnosis particularly challenging. Current diagnostic tools, including CA19-9 and endoscopic ultrasound (EUS) imaging, often lack the specificity needed to reliably distinguish between these conditions. The objective of this study was to investigate whether the proteomic profiling of endoscopic ultrasound-guided fine-needle aspiration (EUS-FNA) samples could provide molecular-level discrimination between MFP and PDAC in patients with CP. <b>Methods</b>: Thirty CP patients with solid pancreatic lesions were prospectively enrolled: 15 with histologically confirmed PDAC and 15 with MFP. Traditional diagnostic parameters, including CA19-9 levels and EUS characteristics, were recorded but found insufficient for differentiation. EUS-FNA samples were analyzed using label-free mass spectrometry. A total of 928 proteins were identified in PDAC samples and 555 in MFP samples. Differential abundance analysis and pathway enrichment were performed. <b>Results</b>: Overall, 88 proteins showed significant differential abundance between PDAC and MFP samples, of which 26 met stringent statistical thresholds. Among these, Carboxylesterase 2 (CES2), Carcinoembryonic Antigen-Related Cell Adhesion Molecule 1 (CEACAM1), Lumican (LUM), Transmembrane Protein 205 (TMEM205), and NAD(P)H Quinone Dehydrogenase 1 (NQO1) emerged as key discriminatory proteins. Pathway enrichment analysis revealed distinct biological processes between the groups, including mitochondrial fatty acid β-oxidation, Rho GTPase signaling, and platelet degranulation. <b>Conclusions</b>: Proteomic signatures derived from EUS-FNA samples offer a promising molecular approach to distinguish inflammatory pseudotumoral lesions from malignant pancreatic tumors in CP patients. This minimally invasive strategy could enhance diagnostic accuracy where current methods fall short. Further validation in larger, multicenter cohorts is warranted to confirm these findings and evaluate their clinical applicability.