Managing branch-duct intraductal papillary mucinous neoplasms (BD-IPMNs) remains challenging, as guideline criteria (worrisome features/high-risk stigmata) and nomograms often leave uncertainty. Next-generation sequencing (NGS) on Endoscopic Ultrasound guided fine needle aspiration (EUS-FNA) of cyst fluid may provide actionable molecular information to refine decisions.

We conducted a national, vignette-based decision-impact study involving 132 clinicians (gastroenterologists and surgeons). Four complex BD-IPMN vignettes (each with 2–4 worrisome features) were evaluated twice: pre-NGS and post-NGS after disclosure of either a high-risk mutation (positive) or its absence (negative). The primary endpoint was the within-physician change in management in the NGS-concordant direction (NGS+ surveillance to surgery; NGS− surgery to surveillance) assessed McNemar’s test and mixed-effects logistic regression. Secondary endpoints included change in decision confidence, inter-physician agreement (Fleiss’κappa), practitioner factors.

NGS on EUS-FNA cyst fluid significantly changed management in all vignettes (all p<0.001): with NGS−, surgical plans shifted to surveillance (43% in distal pancreatectomy; 61% in pancreatoduodenectomy scenarios); with NGS+, surveillance shifted to surgery (90% and 72%, respectively; both p<0.001). In mixed-model, post-NGS reduced surgery in NGS− cases (OR 0.30, 95%CI[0.16–0.57]) and the post-NGS effect was strongly amplified in NGS+ cases (interaction OR 76.51, 95%CI[26.47–221.13]). Population-averaged probabilities of choosing surgery shifted from 20% to 7% (NGS−) and 42% to 94% (NGS+). Decision confidence increased (proportional-odds OR 4.66, 95%CI[3.62–6.02], p<0.0001). Inter-physician agreement rose from κ=0.044 (95%CI[0.033–0.055]) pre-NGS to κ=0.590 (95%CI[0.580–0.601]) post-NGS (p<2×10⁻¹⁶). After NGS, practitioner characteristics no longer explained decision patterns.

In complex BD-IPMN scenarios, NGS refines management, promotes surgical decisions when high-risk mutations are present, reinforces surveillance when absent, and homogenizes clinician choices.