Diagnostic utility of p53, SMAD4, and the novel biomarker PON2 in FNA of pancreatic ductal adenocarcinoma

Abstract Background Accurate cytologic diagnosis of pancreatic ductal adenocarcinoma (PDAC) remains challenging. In this retrospective study, the authors assessed the utility of p53, SMAD4, and paraoxonase‐2 (PON2) expression in fine‐needle aspiration (FNA) diagnosis of PDAC. Methods Cytologic cases with sufficient cell block material were retrieved from pathology archives. p53 and SMAD4 immunostains were performed in two separate cohorts, primary cohort (10 benign and 23 PDAC cases) and indeterminate cohort (3 atypical and 17 suspicious cases). PON2 immunostain was performed in the primary cohort (10 benign and 23 PDAC cases). p53 and SMAD4 immunostains were qualitatively assessed and PON2 test was evaluated by semiquantitative H‐score. Results In the primary cohort, p53 aberrant expression and SMAD4 loss were identified in 74% and 48% of PDAC cases compared to none in benign lesions. The combination of p53 and SMAD4 achieved a superior performance with an area under the curve (AUC) value of 0.96, compared to either marker alone (AUC = 0.87 and 0.74, respectively). In the indeterminate cohort, p53 aberrant expression or SMAD4 loss was seen in 13 of 17 (76%) malignant follow‐up cases. PON2 was variably expressed in PDAC cases with H‐scores ranging from 110 to 290, significantly higher in PDACs compared to benign cases ( p < .001). Furthermore, strong PON2 expression was seen in two PDAC cases with wild‐type p53 and intact SMAD4 expression. Conclusions Combined p53 and SMAD4 immunostaining could help improve FNA diagnosis of PDACs, particularly in challenging cases. PON2 is differentially expressed in PDAC cases and may serve as a potential biomarker, warranting further investigation.