Differentiating IgG4-related pancreatitis (IgG4-RP) from pancreatic malignancy remains a diagnostic challenge due to overlapping clinical and imaging features. This study aimed to identify key clinical and radiological factors that can reliably distinguish between these two conditions through a comparative analysis.

This retrospective cohort study included 31 patients with IgG4-RP and 42 patients with pancreatic malignancy who met predefined inclusion and exclusion criteria. All patients underwent contrast-enhanced computed tomography (CT). Clinical symptoms, serum biomarkers, and CT imaging features were retrospectively collected from hospital databases between January 2017 and June 2025 and were comparatively analyzed between the two groups. Statistical analysis included univariate logistic regression with Firth’s penalized maximum likelihood correction to account for small-sample bias.

A total of 73 patients (mean age, 62±8 years; 57 men) were evaluated. IgG4-RP was predominantly characterized by diffuse pancreatic enlargement (80.6%), gradual enhancement (69.6%), lower CT attenuation values (1.74 ± 9.05 HU), and frequent extra-pancreatic involvement, including peripancreatic fascia thickening (65.5%), common bile duct or gallbladder wall thickening (32.3% and 35.7%, respectively), and pleural thickening (28.0%). In contrast, pancreatic malignancies typically presented as focal masses (97.6%) with uneven enhancement (100%), higher CT attenuation values (34.59 ± 8.07 HU), and aggressive local features such as vascular invasion (42.9%) and peripancreatic or porta hepatis lymphadenopathy (63.4%). Univariate analysis identified male sex (OR 0.1), elevated serum IgG4 (OR 0.003), diffuse pancreatic enlargement (OR 0.009), gradual enhancement (OR 0.2), and various fibroinflammatory features as significantly associated with IgG4-RP. Conversely, factors associated with malignancy included anorexia (OR 5.2), elevated CA19-9 (OR 1.1), higher mass CT attenuation (OR 1.2 per HU), peripancreatic or porta hepatis lymphadenopathy (OR 6.6), and vascular invasion (OR 16.7). No significant differences were observed in pancreatic duct dilation, bile duct dilation, or retroperitoneal lymphadenopathy between groups.

This study demonstrates distinct clinical and radiological profiles for IgG4-RP and pancreatic malignancy. Key distinguishing features—particularly diffuse pancreatic involvement, gradual enhancement, and fibroinflammatory changes in IgG4-RP versus focal masses, vascular invasion, and regional lymphadenopathy in malignancy—can aid in reducing misdiagnosis and guiding appropriate therapeutic strategies.