Objective: We report the development and validation of a combined DNA/RNA next-generation sequencing (NGS) platform to improve the evaluation of pancreatic cysts. Background and Aims: Despite a multidisciplinary approach, pancreatic cyst classification, such as a cystic precursor neoplasm, and the detection of high-grade dysplasia and early adenocarcinoma (advanced neoplasia) can be challenging. NGS of preoperative pancreatic cyst fluid improves the clinical evaluation of pancreatic cysts, but the recent identification of novel genomic alterations necessitates the creation of a comprehensive panel and the development of a genomic classifier to integrate the complex molecular results. Methods: An updated and unique 74-gene DNA/RNA-targeted NGS panel (PancreaSeq Genomic Classifier) was created to evaluate 5 classes of genomic alterations to include gene mutations (e.g., KRAS, GNAS, etc.), gene fusions and gene expression. Further, CEA mRNA (CEACAM5) was integrated into the assay using RT-qPCR. Separate multi-institutional cohorts for training (n=108) and validation (n=77) were tested, and diagnostic performance was compared to clinical, imaging, cytopathologic, and guideline data. Results: Upon creation of a genomic classifier system, PancreaSeq GC yielded a 95% sensitivity and 100% specificity for a cystic precursor neoplasm, and the sensitivity and specificity for advanced neoplasia were 82% and 100%, respectively. Associated symptoms, cyst size, duct dilatation, a mural nodule, increasing cyst size, and malignant cytopathology had lower sensitivities (41–59%) and lower specificities (56–96%) for advanced neoplasia. This test also increased the sensitivity of current pancreatic cyst guidelines (IAP/Fukuoka and AGA) by >10% and maintained their inherent specificity. Conclusions: PancreaSeq GC was not only accurate in predicting pancreatic cyst type and advanced neoplasia but also improved the sensitivity of current pancreatic cyst guidelines.

Pancreatic cystic lesions are an increasingly common clinical finding. They represent a heterogeneous group of lesions that include two of the three known precursors of pancreatic cancer, intraductal papillary mucinous neoplasms (IPMN) and mucinous cystic neoplasms (MCN). Given that approximately 8% of pancreatic cancers arise from these lesions, careful surveillance and timely surgery offers an opportunity for early curative resection in a disease with a dismal prognosis. This review summarizes the current evidence and guidelines for the diagnosis and management of IPMN/MCN. Current pre-operative diagnostic tests in pancreatic cysts are imperfect and a proportion of patients continue to undergo unnecessary surgical resection annually. Balancing cancer prevention while preventing surgical overtreatment, continues to be challenging when managing pancreatic cysts. Cyst fluid molecular markers, such as KRAS, GNAS, VHL, PIK3CA, SMAD4 and TP53, as well as emerging endoscopic technologies such as needle-based confocal laser endomicroscopy and through the needle microbiopsy forceps demonstrate improved diagnostic accuracy. Differences in management and areas of uncertainty between the guidelines are also discussed, including indications for surgery, surveillance protocols and if and when surveillance can be discontinued.

Incidental pancreatic cysts are highly prevalent, with management dependent on the risk of malignant progression. Serous cystadenomas (SCAs) are the most common benign pancreatic cysts seen on imaging. They have typical morphological patterns but may also show atypical features that mimic precancerous and cancerous cysts. If a confident diagnosis of SCA is made, no further follow-up is warranted. Therefore, a preoperative distinction between SCA and precancerous or cancerous lesions is critically essential. Distinguishing an SCA from other types of pancreatic cysts on imaging remains a challenge, thus leading to misdiagnosis and ramifications. This review summarizes the current evidence on diagnosing and managing SCA.

The aim of the present study is to assess the impact of smoking dose and duration on the distribution of risk factor(s) in patients with RAP and CP, and the impact of genetic testing on the distribution of risk factor(s) in patients with idiopathic RAP and CP. All adult patients with RAP and CP referred to a multidisciplinary pancreatitis clinic between 2010 and 2017 were evaluated. Risk factors included alcohol and smoking, hypertriglyceridemia, biliary, and other etiologies. Genetic testing was only pursued in patients with idiopathic RAP or CP. Among the 1770 patients evaluated, 167 had RAP and 303 had CP. After genetic testing and smoking, the most common risk factors for RAP and CP were pathogenic variant(s) (23%) and the combination of alcohol and smoking (23%), respectively. Genetic testing and smoking assessment decreased the proportion of patients with alcoholic RAP from 17% to 5%, alcoholic CP from 33% to 10%, idiopathic RAP from 49% to 12%, and idiopathic CP from 54% to 14%. Pathogenic CFTR variants were the most common variant in patients with RAP (51%) and CP (43%). Among the 68 patients with pancreas divisum, other risk factor(s) were identified in 72%. Genetic testing and a detailed assessment of smoking dose and duration reduce the proportion of patients with alcoholic and idiopathic pancreatitis. Other risk factor(s) for pancreatitis are found in the majority of patients with pancreas divisum further questioning its role as an independent risk factor.