Do molecular tests really differentiate malignant IPMNS from benign?

Bournet et al. have questioned the role of endoscopic ultrasound-guided fine needle aspiration (EUS-FNA) plus KRAS and GNAS mutations in malignant intraductal papillary mucinous neoplasms (IPMNs) of the pancreas in this issue of Endoscopy International Open [1]. Bournet et al. claimed that testing for KRAS mutations in cystic fluid improved the accuracy of results for cytopathologic diagnosis of malignancy whereas GNAS mutation testing did not improve the results. How should clinicians interpret these outcomes and do these results help to detect and treat an IPMN before it progresses to a pancreatic adenocarcinoma? IPMNs are the most frequently detected type of mucin-producing neoplasm and the exact rate of progression to malignancy has not yet been defined clearly (ranging from 38 to 68% for Main Duct-IPMNs [MD-IPMNs] and12 to47% forBranch Duct-IPMNs [BD-IPMNs] in surgical series of symptomatic patients) [2]. The goal of any diagnostic test for a pancreatic cystic neoplasm is accurate detection of its malignant potential. Recent guidelines on pancreatic cysts recommend a multimodal diagnostic approach including cross-sectional imaging, EUS-FNA and cyst fluid analysis (such as biochemistry, cytology and molecular analysis) to overcome this complex assessment. Although cross-sectional imaging provides detailed images of the high-risk lesions, use of EUS-FNA has increased the accuracy of diagnosis of advanced neoplasia. Cytology is highly specific but approximately 50% sensitive for diagnosis of a malignancy arising from IPMN, due to inadequate cellularity in most cases. On the other hand, elevated cyst fluid carcinoembryonic antigen (CEA) level is considered the most accurate test to distinguish a mucinous cyst from non-mucinous. However, CEA alone can be used neither to differentiate IPMN from a mucinous cystic neoplasm nor amalignant IPMN from a noninvasive IPMN. Several molecular techniques have been designed for further evaluation of pancreatic cystic neoplasms; however, DNA-based assays on aspirated cyst fluid have emerged as the most useful and reproducible tool. Recent studies on DNA sequencing have not only shown the genetic alterations specific for pancreatic cystic neoplasms, but also may help diagnose and differentiate these neoplasms. The most commonly found genetic alteration in IPMNs is KRAS mutation (found in over 80% of cases). It occurs predominantly in codon 12, but it may also occur in codons 13 and 61. KRAS mutations are associated with BD-IPMNs and more often present in pancreatobiliary and gastric type IPMNs. Moreover, GNAS mutation is a unique mutation for IPMNs with a frequency of 58% to 65%, occurring in codon 201 or 227. GNAS mutation is mostly found in MD-IPMNs rather than BD-IPMNs and mainly present in intestinal subtype. A mutation in KRAS and/or GNAS is found in over 90% of IPMNs. Bournet et al. enrolled 37 IPMNpatients with clinical and/or imaging predictors in a 4-year study [1]. The final diagnosis of IPMNs (n=10 were benign and n=27 were malignant) was obtained from pancreatic resections (n=18), biopsies during laparotomy, EUS-FNA analysis and follow-ups (n=19). Aspirated cyst fluid was evaluated for cytology. KRAS (codon 12) and GNAS (codon 201) mutation assays were performed using the TaqMan® allelic discrimination on EUS-FNA fluid. KRAS and GNAS assays were successful in all but one sample. The sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV) andaccuracyofcytologyalone todiagnose malignancy in IPMN were 55%, 100%, 100%, 45% and 66%, respectively. When KRAS mutation analysiswas combinedwith cytology, thesevalues were 92%, 50%, 83%, 71% and 81%, respectively. GNAS analysis improved performance of neither cytology alone, nor cytology combined with KRAS. The authors concluded that using the