Pancreatic cystic lesions (PCLs) are increasing in prevalence, largely owing to aging of the general population and widespread use of advanced cross-sectional imaging modalities [1]. A recent systematic review and meta-analysis estimated the global prevalence of PCLs to be between 13 and 18 %, with incidence rising with age [2]. PCLs are broadly divided into mucinous and non-mucinous subtypes which range from benign to premalignant lesions. Approximately 15–20 % of pancreatic ductal adenocarcinomas (PDAC) arise from mucinous cysts, most commonly intraductal papillary mucinous neoplasms (IPMN) [3,4]. Given varying malignant potential, accurate risk stratification of PCLs is critical for guiding appropriate clinical management [5]. Current guidelines rely on clinical history, imaging, endoscopic ultrasound (EUS) features, and cyst fluid analysis for risk stratification of PCLs [6,7]. However, current guidelines remain suboptimal. Over the past decade, there has been a sharp rise in the surgical treatment of incidentally found cystic lesions. In 2014, 31 % of pancreatic resections in the US were performed to remove cysts (approximately 5000 operations), compared to just over 10 % in 2001. However, this increase in surgical resections has not been accompanied by a reduction in the number of invasive cancers diagnosed, suggesting that a substantial proportion of these procedures represent overtreatment [8]. Greater than 50 % of resected branch duct (BD)- intraductal papillary mucinous neoplasm (IPMNs) show only low-grade dysplasia [9,10] highlighting a significant rate of unnecessary surgeries [6]. A 2023 study found a 19 % subtype misdiagnosis and a 34 % grade of dysplasia mismatch for malignant PCLs, even when following current guidelines [11]. These errors highlight significant limits in risk assessment strategies for high-grade dysplasia-invasive carcinoma (HGD-IC) [11]. Additionally, long-term surveillance of PCLs including presumed IPMNs has been associated with increased psychological distress among patients [12]. These challenges emphasize the urgent need for improved diagnostic accuracy in the evaluation and management of PCLs.

Standard of care cyst fluid analysis with carcinoembryonic antigen (CEA) and cytology offer high specificity but only moderate sensitivity for identifying mucinous PCLs, while glucose testing shows promise but lacks uniform protocols and validated cutoff values [3,[13], [14], [15], [16], [17]]. Additionally, next-generation sequencing (NGS) of cyst fluid, which can detect mutations specific to cyst type, has become less accessible following the cessation of Medicare reimbursement, further limiting diagnostic options for many patients [3,16]. This withdrawal of coverage by Centers for Medicare & Medicaid Services (CMS) underscores the need for accurate, cost-effective, evidence-based diagnostic strategies. Among EUS-based innovations, through-the-needle biopsy (EUS-TTNB) allows acquisition of true histological samples, enabling definitive cyst subtyping and more precise risk stratification. However, this technique is associated with a higher risk of adverse events, including pancreatitis and bleeding, and therefore should be performed primarily in high-volume, expert centers with experience in advanced pancreatic interventions [18]. EUS-guided needle-based confocal laser endomicroscopy (EUS-nCLE) is a novel imaging technique that allows for high-resolution, real-time, microscopic visualization of PCL epithelium. Here, we will review its diagnostic performance, clinical applications, limitations, and future directions.