Cystic lesions and their role in pancreatic cancer risk stratification

• PC is difficult to detect and to diagnose and is frequently diagnosed at advanced stages where treatment options and efficacy are limited. • A number of risk-factors are associated with the biological establishment of pancreatic cancer including pre-malignant pancreatic cystic lesions. • Certain pancreatic cystic lesions possess the ability to undergo malignant transformation and are regarded as precursor lesions for pancreatic cancer. • Risk-stratification guidelines for the diagnosis and management of pancreatic cystic lesions remains highly contended within the field. • Incorporation of an immunobiological component to current risk-stratification guidelines of pancreatic cystic lesions may permit more accurate identification of at-risk patients for pancreatic cancer. The prognosis for patients diagnosed with pancreatic cancer has changed little over the past 4 decades. Fewer than 20 % of patients are diagnosed at a stage amenable to potentially curative surgery and therapeutic resistance remains widespread, compounded by a lack of therapeutic targets. Early detection of pancreatic cancer is notoriously difficult, due to non-specific symptoms that delay early diagnosis in addition to limited sensitivity of current imaging modalities. However, pancreatic cystic lesions (PCLs), such as intraductal papillary mucinous neoplasms (IPMNs), provide a unique opportunity for earlier disease intervention. Indeed, PCLs can be stratified by risk of malignant transformation, but current stratification guidelines remain highly contended within the field. Importantly, accumulating evidence suggests that inflammatory and immunogenetic mechanisms may influence both cyst development and malignant progression, yet these immunobiological factors are not currently integrated into PCL risk-stratification and management frameworks. In this review, we focus on the immunobiological dimension of PCLs, highlighting the interplay between chronic inflammation, immune dysregulation, and genetic alterations that may drive cystogenesis and malignant transformation. Furthermore, we assess the evidence to support integrating an immunobiological aspect to existing risk stratification guidelines to enhance identification of high-risk pre-malignant PCLs. Such integration may ultimately identify high-risk patients more accurately and inform surveillance and therapeutic intervention strategies to prevent late-stage pancreatic cancer.