Abstract Background Intraductal Papillary Mucinous Neoplasm (IPMN) of the pancreas is the precursor lesion from which pancreatic ductal adenocarcinoma (PDAC) arises in 10% of individuals. IPMNs may be associated with low-grade or high-grade dysplasia or an associated adenocarcinoma. Accurately determining low-risk from high-risk IPMN is crucial for early detection initiatives for PDAC, so treatment can be offered before invasive cancer in high-risk individuals but without causing harm to low-risk individuals. Currently, imaging forms the basis for stratification but this is costly, resource intense and is limited in accuracy. There is a need to develop biomarkers to improve the risk stratification of IPMN. Method A systematic review was conducted according to PRISMA-DTA guidelines by screening EMBASE, MEDLINE, CENTRAL and bibliographic reference lists for comparative studies. Studies were excluded if they were based on non-human subjects, not specific to IPMN, or determined IPMN from PDAC rather than low-grade from high-grade dysplasia in IPMN. Data extracted included study design, cohort demographics, specimen type, biomarker type, methodology for biomarker discovery, positive predictive value, negative predictive value, sensitivity, specificity or AUC value and were evaluated against the STARD checklist. Study quality was evaluated using the QUADAS-2 tool. Results We identified 1761 studies of which 88 were selected for analysis. Twenty-six studies identified biomarkers derived from serum/plasma, 25 from biopsy specimens, 18 from cystic fluid, 13 from radiological findings, 4 from pancreatic juice, 3 from clinical risk stratification and 1 urinary biomarker. Markers were based on proteins (43%), mRNA (1%), miRNA (14%), lncRNA (2%), DNA (16%), metabolites (1%), radiomics (19%), glycans (5%), inflammatory markers (5%) and clinical history (5%). We observed discriminatory values ranging from AUC 0.58-1, specificity 64-100% and sensitivity 56-90.9%. Conclusion This systematic review outlines the current evidence-base for potential biomarkers to determine low-risk from high-risk IPMNs of the pancreas. Current studies are limited by retrospective sample collection, limited cohort sizes and lack of external validation of candidate biomarkers. There is a need to develop and validate biomarkers in a longitudinal prospective cohort study of individuals undergoing IPMN screening with the ability to characterise low-risk to high-risk transformation which after external validation would be suitable for adoption into clinical practice.
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