Characterizing Biological Behavior Beyond Morphologic Features: Next-Generation Sequencing Analysis of Large vs Small Pancreatic Cystic Lesions in a Large Multicenter Cohort of Patients

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BACKGROUND: Large pancreatic cystic lesions (PCLs) have a higher risk of malignant transformation compared with smaller PCLs, although the biological basis for this remains unclear. We aimed to study the high-risk mutation (HRM) patterns in large vs small PCLs using cyst fluid next-generation sequencing (NGS) analysis. STUDY DESIGN: This is a large multicenter study that included patients with PCLs who underwent pancreatic cyst fluid PancreaSeq NGS testing between January 2018 and February 2020. Patients without index cyst size data were excluded from this study. HRMs were defined as alterations in TP53 , SMAD4 , CTNNB1 , mTOR , and MEN1 genes. Patients were categorized into large PCLs (greater than or equal to 3 cm) and small PCLs (less than 3 cm) groups. Primary outcomes included rates of HRMs and the co-occurrence of multiple HRMs. Diagnostic performance of PancreaSeq NGS and guideline parameters for predicting advanced neoplasia was also assessed in patients with large intraductal papillary mucinous neoplasms (IPMNs). RESULTS: A total of 1,167 patients were included, with 404 having large PCLs. HRMs were identified in 175 patients (15%), with TP53 and SMAD4 mutations more frequently in large PCLs. Large PCLs showed significantly higher rates of any HRMs and co-occurrence of multiple HRMs. On multivariate analysis, cyst size greater than or equal to 3 cm was independently associated with HRMs (odds ratio 3.63, 95% CI 1.28 to 10.29). In large IPMNs, NGS detection of TP53 , SMAD4 , CTNNB1 , and/or mTOR alterations showed a sensitivity of 92.3% and specificity of 94.7% for predicting advanced neoplasia. CONCLUSIONS: The higher malignant potential of large PCLs may be explained by their greater propensity to harbor HRMs associated with advanced neoplasia. Given the superior diagnostic accuracy of NGS for predicting advanced neoplasia in large IPMNs, we recommend incorporating cyst fluid NGS into the management algorithm for patients with IPMNs greater than or equal to 3 cm.

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