Practical Applications of Molecular Testing in the Cytologic Diagnosis of Pancreatic Cysts

Mucinous pancreatic cysts are precursor lesions of ductal adenocarcinoma. Discoveries of the molecular alterations detectable in pancreatic cyst fluid (PCF) that help to define a mucinous cyst and its risk for malignancy have led to more routine molecular testing in the preoperative evaluation of these cysts. The differential diagnosis of pancreatic cysts is broad and ranges from non-neoplastic to premalignant to malignant cysts. Not all pancreatic cysts—including mucinous cysts—require surgical intervention, and it is the preoperative evaluation with imaging and PCF analysis that determines patient management. PCF analysis includes biochemical and molecular analysis, both of which are ancillary studies that add significant value to the final cytological diagnosis. While testing PCF for carcinoembryonic antigen (CEA) is a very specific test for a mucinous etiology, many mucinous cysts do not have an elevated CEA. In these cases, detection of a KRAS and/or GNAS mutation is highly specific for a mucinous etiology, with GNAS mutations supporting an intraductal papillary mucinous neoplasm. Late mutations in the progression to malignancy such as those found in TP53, p16/CDKN2A, and/or SMAD4 support a high-risk lesion. This review highlights PCF triage and analysis of pancreatic cysts for optimal cytological diagnosis.