DNA-mutation Analysis by Next Generation Sequencing in Cyst Fluid of Suspected Intraductal Papillary Mucinous Neoplasia of the Pancreas Obtained by Endoscopic Ultrasound-guided Fine Needle Aspiration (ZYSTEUS-Study)

Intraductal papillary mucinous neoplasm (IPMN) with low grade dysplasia (LGD) can progress to high grade dysplasia (HGD) or invasive cancer. Main duct IPMN, mixed type IPMN or branch duct IPMN with high risk stigmata are highly predictive for malignancy. Therefore, patients in good general state should be considered for surgical resection. Guidelines like the International Fukuoka Consensus Guidelines from 2017 or the European evidence-based Guidelines on Pancreatic cyst neoplasms from 2018 provide detailed recommendations on the management of IPMNs by focusing on clinical characteristics, image morphology, cytology and laboratory parameters. However, these applied guidelines still lead to surgical overtreatment of pancreas cysts based on the pathologic outcomes as neither HGD nor carcinoma is found in up to 82.1 % of the resected cysts. Cyst fluid sent for cytology usually provides adequate cellular material for analysis in only 31% of the cases and Endoscopic Ultrasound-guided forceps biopsy has not yet shown to be better than fine needle aspiration. Hence, further diagnostic tools are needed to identify mucinous cysts for further evaluation or follow-up respectively to identify cysts with HGD or invasive cancer at an early stage for surgical resection. Molecular genetic analysis of pancreatic cyst fluid is possibly able to identify KRAS/GNAS oncogenic driver mutations in mucinous cysts and to identify tumour suppressor gene mutations which are involved in advanced cysts with HGD or carcinoma. This workgroup described a high sensitive method of targeted Next Generation Sequencing in pancreas cyst fluid with a limit of detection of allele frequency down to 0.01 %. Further investigations of the ongoing ZYSTEUS-study are focused on the implementation of DNA mutation analysis by NGS in the diagnostic algorithm of pancreas cyst evaluation. The first aim is to reliably distinguish mucinous from non-mucinous cysts respectively main duct IPMN from chronic pancreatitis with main duct dilatation as the absence of KRAS/GNAS-mutations is highly predictive for non-mucinous diseases. The second aim is to define relevant tumour suppressor gene mutations which are relevant to differentiate LGD from HGD/carcinoma in mucinous cysts. DNA mutation analysis will be compared with already established peroperative diagnostic tests of pancreas cyst fluid: Measurement of CEA and lipase as well as cytology.