Cytology and KRAS/GNAS Molecular Testing of Pancreatic Cyst Fluid for Risk Stratification of Intraductal Papillary...

Background: Accurate preoperative risk stratification of intraductal papillary mucinous neoplasms (IPMNs) remains a major challenge in pancreatic surgery. Cytology obtained through endoscopic ultrasound-guided fine needle aspiration (EUS-FNA) demonstrates high specificity but limited sensitivity, whereas molecular analysis of cyst fluid-particularly KRAS and GNAS mutations-has emerged as a promising complementary diagnostic tool. Methods: We conducted a narrative review combined with a retrospective single-center observational study of patients evaluated for suspected IPMN between 2018 and 2025 who underwent EUS-FNA with cytology and KRAS/GNAS testing followed by surgical resection. Histology was used as the reference standard. Given the limited number of resected cases (n = 25), results should be interpreted with caution. Results: A total of 105 patients were included, of whom 70 underwent EUS-FNA and 25 surgical resection. Final histology showed low-grade dysplasia in 12 cases (48%) and high-grade dysplasia in 13 cases (52%), with no invasive carcinoma detected, limiting the evaluation of diagnostic performance for invasive disease. Cytology demonstrated a sensitivity of 38.5% and specificity of 75% for advanced neoplasia. Molecular testing achieved 100% sensitivity but low specificity. A combined diagnostic strategy increased sensitivity to 92.3% compared with 38.5% for cytology alone, although with reduced specificity. Conclusions: A multimodal diagnostic approach integrating morphology, cytology, and molecular testing improves risk stratification of IPMNs and may supports surgical decision-making within multidisciplinary pancreatic teams, particularly in indeterminate cases, although its impact should be interpreted in the context of limited sample size.