Cyst Fluid Biomarkers for Intraductal Papillary Mucinous Neoplasms of the Pancreas: A Critical Review from the International Expert Meeting on Pancreatic Branch-Duct-Intraductal Papillary Mucinous Neoplasms

The recognition of pancreatic cysts and intraductal papillary mucinous neoplasms of the pancreas (IPMN) has increased largely secondary to greater utilization of high-quality cross-sectional abdominal imaging.1, 2 Although the general characteristics of IPMNs, radiographic diagnosis, cyst fluid composition, and their delineation from other pancreatic tumors have been well established, several issues regarding their growth and progression into malignancy remain poorly described. The degree of neoplastic transformation within IPMN is highly variable, from those with an entirely innocuous cell population typically resembling gastric epithelium and lacking any cytologic atypia, to those that have progressively increasing degrees of cytoarchitectural atypia. Though some patients with highly dysplastic and invasive IPMN may present with clinical symptoms or characteristic radiographic findings, including jaundice, an associated pancreatic mass, or main pancreatic duct dilation; increasingly IPMN are incidentally discovered. Once IPMN are radiographically diagnosed, there is currently no reliable way to determine the level of epithelial dysplasia or to predict the time frame of progression to high-grade dysplasia or cancer.3–6 A biologic marker of IPMNs is urgently needed – one that can be easily obtained and tested without significant morbidity for the patient. An evidence-based expert meeting on pancreatic branch-duct IPMNs (BD-IMPN) was held in Verona, Italy and the authors reviewed the current role of existing technologies and molecular markers for predicting the biological behavior of IPMNs. The status of endoscopic ultrasound (EUS) and EUS-guided fine needle aspiration (FNA) cytology, cyst fluid biochemistry, mucins, cytokines, DNA, and microRNA profiles were critically reviewed by the group in order to identify the most promising clinically relevant biomarkers, and to target analyses for further development. Endoscopic ultrasound Endoscopic ultrasound (EUS) is a highly sensitive imaging modality for the evaluation of pancreatic cystic lesions that was developed as a diagnostic modality, but rapidly gained a role in IPMN for morphologic assessment and for its interventional capabilities, namely aspiration of cyst fluid and fine-needle aspiration (FNA). Diagnosis of IPMN based solely on EUS findings requires attention to cyst size, characteristics of the cyst wall, internal characteristics of the cyst, communication with the MPD, and the existence of any background lesions. Using EUS morphologic parameters, the sensitivity, specificity and accuracy to differentiate between benign and malignant, or potentially malignant, cystic lesions has been reported to be between 56%–91%, 45%–60% and 51%–72%, respectively7, 8 Although evaluation and the differential diagnosis of cystic lesions based solely on EUS morphology is feasible; inter-observer variability, operator dependency, and moderate diagnostic performance limit its accuracy without the addition of cyst fluid aspiration and FNA cytology, especially for determination of high-risk IPMN without overt malignant features.