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INCORPORATING NEXT-GENERATION SEQUENCING IN THE MANAGEMENT ALGORITHM OF PANCREATIC CYSTS
Management of pancreatic cysts (PCs) is extremely complex due to the uncertainty about malignant potential. Next-generation sequencing (NGS) PancreaSeq is an adjunctive test performed on the PCs fluid. However, relying on NGS to predict high risk behavior and guide surveillance and surgical decisions has not been addressed. Our aim is to evaluate NGS performance in predicting high-risk PCs and incorporate it in the management algorithm.
Methods
This single-center retrospective study included adult patients with PCs who were seen at our high-risk pancreas clinic between 2016-2022 and had NGS data available. NGS performance in detecting high-grade dysplasia (HGD) and cancer was calculated. Reference gold standard was determined using positive surgical pathology or progression during follow-up. The risk of progression was compared between those with and without high-risk mutations using a logistic regression model. Two-sided P value <0.05 was considered statistically significant.
Results
We included a total of 440 patients with PCs and NGS. The mean age was 68.4 +13.1 with 234 women (53.2%). The mean cyst size was 25.8 + 14.4 mm. Worrisome features, defined as size >3 cm, pancreatic duct diameter 5-9 mm or mural nodule were present in 183 patients (41.6%). Patients were followed for 373 + 402 days. During follow-up, 12 patients (2.7%) were found to have HGD/cancer. PancreaSeq sensitivity in predicting HGD/cancer was 75% (95% CI: 42.8% - 94.5%) and specificity 95.6% (95% CI: 93.2% -97.3%). The area under receiving operator curve (ROC) was 0.85 (95% CI: 0.72 - 0.98). Among patients with worrisome features (n=183), high-risk mutations were detected in 17 (9.3%). Patients with worrisome features and high-risk mutations had significantly higher risk for developing HGD/cancer (35.3%) compared to those without high-risk mutations (1.2%), OR:44.7 (95% CI: 8 - 248, P<0.001). Among patients without worrisome features (n=238), high risk mutations were detected in 7 (2.9%) and these patients had significantly higher risk for developing HGD/cancer (14.3%) compared to those without high-risk mutations (0%), P<0.001 (Figure 1). Based on these findings, PCs without worrisome feature and negative for high-risk mutations could be followed less frequently. On the contrary, those with worrisome features and positive for high-risk mutations should consider surgery. Patients without worrisome features but with high-risk mutations should be followed more intensely than currently recommended, whereas those with worrisome features but without high-risk mutations could continue surveillance at the current recommended interval (Figure 2).
Conclusion
NGS has high performance in predicting the likelihood of developing advanced neoplasia. Incorporating NGS in the management algorithm of PCs further enhances our ability to guide surveillance and determine need for surgery.

Figure 1. Summary of 440 patients with pancreatic cysts and next-generation sequencing results including presence or absence of high-risk stigmata, worrisome features, and high-risk mutations with described risk of progression to high-grade dysplasia or cancer among each cohort. Abbreviations: high grade dysplasia (HGD)

Figure 2. Recommended surveillance intervals based upon risk of progression incorporating the presence of worrisome features and high-risk mutations for patients with pancreatic cysts without high-risk stigmata. Abbreviations: high grade dysplasia (HGD)