{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,17]],"date-time":"2026-06-17T11:53:13Z","timestamp":1781697193216,"version":"3.54.5"},"reference-count":34,"publisher":"MDPI AG","issue":"12","license":[{"start":{"date-parts":[[2026,6,17]],"date-time":"2026-06-17T00:00:00Z","timestamp":1781654400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["JCM"],"abstract":"<jats:p>Background: Accurate preoperative risk stratification of intraductal papillary mucinous neoplasms (IPMNs) remains a major challenge in pancreatic surgery. Cytology obtained through endoscopic ultrasound-guided fine needle aspiration (EUS-FNA) demonstrates high specificity but limited sensitivity, whereas molecular analysis of cyst fluid\u2014particularly KRAS and GNAS mutations\u2014has emerged as a promising complementary diagnostic tool. Methods: We conducted a narrative review combined with a retrospective single-center observational study of patients evaluated for suspected IPMN between 2018 and 2025 who underwent EUS-FNA with cytology and KRAS\/GNAS testing followed by surgical resection. Histology was used as the reference standard. Given the limited number of resected cases (n = 25), results should be interpreted with caution. Results: A total of 105 patients were included, of whom 70 underwent EUS-FNA and 25 surgical resection. Final histology showed low-grade dysplasia in 12 cases (48%) and high-grade dysplasia in 13 cases (52%), with no invasive carcinoma detected, limiting the evaluation of diagnostic performance for invasive disease. Cytology demonstrated a sensitivity of 38.5% and specificity of 75% for advanced neoplasia. Molecular testing achieved 100% sensitivity but low specificity. A combined diagnostic strategy increased sensitivity to 92.3% compared with 38.5% for cytology alone, although with reduced specificity. Conclusions: A multimodal diagnostic approach integrating morphology, cytology, and molecular testing improves risk stratification of IPMNs and may supports surgical decision-making within multidisciplinary pancreatic teams, particularly in indeterminate cases, although its impact should be interpreted in the context of limited sample size.<\/jats:p>","DOI":"10.3390\/jcm15124701","type":"journal-article","created":{"date-parts":[[2026,6,17]],"date-time":"2026-06-17T10:19:53Z","timestamp":1781691593000},"page":"4701","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Cytology and KRAS\/GNAS Molecular Testing of Pancreatic Cyst Fluid for Risk Stratification of Intraductal Papillary Mucinous Neoplasms: A Single-Center Study with Histological Correlation"],"prefix":"10.3390","volume":"15","author":[{"given":"Laura","family":"Mastrangelo","sequence":"first","affiliation":[{"name":"Department of Surgery, IRCCS Azienda Ospedaliero-Universitaria di Bologna, 40133 Bologna, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elena","family":"Antelmi","sequence":"additional","affiliation":[{"name":"Department of Surgery, IRCCS Azienda Ospedaliero-Universitaria di Bologna, 40133 Bologna, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stefano","family":"Landi","sequence":"additional","affiliation":[{"name":"Gastroenterology and Interventional Endoscopy Unit, AUSL Bologna, 40133 Bologna, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4329-0859","authenticated-orcid":false,"given":"Adele","family":"Fornelli","sequence":"additional","affiliation":[{"name":"Department of Pathology, Ospedale Santa Maria della Scaletta, 40026 Imola, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1514-7772","authenticated-orcid":false,"given":"Elio","family":"Jovine","sequence":"additional","affiliation":[{"name":"Department of Surgery, IRCCS Azienda Ospedaliero-Universitaria di Bologna, 40133 Bologna, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,6,17]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"738","DOI":"10.1016\/j.pan.2017.07.007","article-title":"Revisions of international consensus Fukuoka guidelines for the management of IPMN of the pancreas","volume":"17","author":"Tanaka","year":"2017","journal-title":"Pancreatology"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"3381","DOI":"10.1158\/0008-5472.CAN-14-0734","article-title":"The early detection of pancreatic cancer: What will it take to diagnose and treat curable pancreatic neoplasia?","volume":"74","author":"Lennon","year":"2014","journal-title":"Cancer Res."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"789","DOI":"10.1136\/gutjnl-2018-316027","article-title":"European evidence-based guidelines on pancreatic cystic neoplasms","volume":"67","author":"Besselink","year":"2018","journal-title":"Gut"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"255","DOI":"10.1016\/j.pan.2023.12.009","article-title":"International evidence-based Kyoto guidelines for the management of IPMN of the pancreas","volume":"24","author":"Ohtsuka","year":"2024","journal-title":"Pancreatology"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"1270","DOI":"10.1053\/j.gastro.2013.01.073","article-title":"Prevalence, diagnosis and management of pancreatic cystic neoplasms","volume":"144","author":"Farrell","year":"2013","journal-title":"Gastroenterology"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"338","DOI":"10.1002\/cncy.21427","article-title":"The Papanicolaou Society of Cytopathology system for reporting pancreaticobiliary cytology","volume":"122","author":"Pitman","year":"2014","journal-title":"Cancer Cytopathol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"92ra66","DOI":"10.1126\/scitranslmed.3002543","article-title":"Recurrent GNAS mutations define an unexpected pathway for pancreatic cyst development","volume":"3","author":"Wu","year":"2011","journal-title":"Sci. Transl. Med."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"360","DOI":"10.1097\/PAS.0000000000000117","article-title":"GNAS sequencing identifies IPMN-specific mutations in a subgroup of diminutive pancreatic cysts referred to as \u201cincipient IPMNs\u201d","volume":"38","author":"Matthaei","year":"2014","journal-title":"Am. J. Surg. Pathol."},{"key":"ref_9","first-page":"303ra128","article-title":"A combination of molecular markers and clinical features improves classification of pancreatic cysts","volume":"7","author":"Springer","year":"2015","journal-title":"Sci. Transl. Med."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"967","DOI":"10.1016\/S1542-3565(05)00409-X","article-title":"Pancreatic cyst fluid DNA analysis in evaluating pancreatic cysts: A report of the PANDA study","volume":"3","author":"Khalid","year":"2005","journal-title":"Clin. Gastroenterol. Hepatol."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"819","DOI":"10.1053\/j.gastro.2015.01.015","article-title":"American Gastroenterological Association guidelines on the diagnosis and management of pancreatic cysts","volume":"148","author":"Vege","year":"2015","journal-title":"Gastroenterology"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"117","DOI":"10.1053\/j.gastro.2022.09.028","article-title":"Prospective, multi-institutional, real-time next-generation sequencing of pancreatic cyst fluid reveals diverse genomic alterations that improve the clinical management of pancreatic cysts","volume":"164","author":"Paniccia","year":"2023","journal-title":"Gastroenterology"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"217","DOI":"10.1002\/path.4344","article-title":"Targeted next-generation sequencing of cancer genes dissects the molecular profiles of intraductal papillary mucinous neoplasms","volume":"233","author":"Amato","year":"2014","journal-title":"J. Pathol."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"140","DOI":"10.1016\/j.gie.2015.06.047","article-title":"Impact of next-generation sequencing on the clinical diagnosis of pancreatic cysts","volume":"83","author":"Jones","year":"2016","journal-title":"Gastrointest. Endosc."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"41","DOI":"10.1002\/cncy.21775","article-title":"Next-generation sequencing adds value to the preoperative diagnosis of pancreatic cysts","volume":"125","author":"Rosenbaum","year":"2017","journal-title":"Cancer Cytopathol."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"2131","DOI":"10.1136\/gutjnl-2016-313586","article-title":"Preoperative next-generation sequencing of pancreatic cyst fluid is highly accurate in cyst classification and detection of advanced neoplasia","volume":"67","author":"Singhi","year":"2018","journal-title":"Gut"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"489","DOI":"10.1002\/gcc.22682","article-title":"Next generation sequencing of pancreatic cyst fluid supports discrimination of IPMN from pseudocysts","volume":"58","author":"Volckmar","year":"2019","journal-title":"Genes Chromosom. Cancer"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"1019","DOI":"10.1016\/j.gie.2020.12.014","article-title":"Molecular analysis of EUS-acquired pancreatic cyst fluid for KRAS and GNAS mutations: A systematic review and meta-analysis","volume":"93","author":"McCarty","year":"2021","journal-title":"Gastrointest. Endosc."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"1322","DOI":"10.1016\/j.pan.2024.11.006","article-title":"Next-generation sequencing improves diagnostic accuracy of imaging and carcinoembryonic antigen alone for pancreatic cystic neoplasms","volume":"24","author":"Belfrage","year":"2024","journal-title":"Pancreatology"},{"key":"ref_20","doi-asserted-by":"crossref","unstructured":"Gyimesi, G., Keczer, B., Rein, P., Horv\u00e1th, M., Gell\u00e9rt, B., Marjai, T., T\u00f3th, E., Sz\u0171cs, \u00c1., Szij\u00e1rt\u00f3, A., and Barbai, T. (2025). Clinical benefits of KRAS\/GNAS gene mutation analysis in addition to morphology and conventional cyst fluid testing in differentiating pancreatic cysts. J. Clin. Med., 14.","DOI":"10.3390\/jcm14248671"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"1218","DOI":"10.1056\/NEJMra031623","article-title":"Diagnosis of pancreatic cystic neoplasms: A report of the cooperative pancreatic cyst study","volume":"351","author":"Brugge","year":"2004","journal-title":"N. Engl. J. Med."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"984","DOI":"10.1097\/SLA.0000000000000884","article-title":"Salvia Observational study of the incidence of pancreatic malignancy in branch-duct IPMN undergoing surveillance","volume":"261","author":"Malleo","year":"2015","journal-title":"Ann. Surg."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"1097","DOI":"10.1093\/bjs\/znab131","article-title":"Actual malignancy risk of either operated or non-operated presumed mucinous cystic neoplasms of the pancreas under surveillance","volume":"108","author":"Marchegiani","year":"2021","journal-title":"Br. J. Surg."},{"key":"ref_24","first-page":"167","article-title":"Endoscopic ultrasound guided pancreatic cyst fluid analysis for the differential diagnosis of pancreatic cysts: A meta-analysis","volume":"62","author":"Thornton","year":"2013","journal-title":"Gut"},{"key":"ref_25","first-page":"961","article-title":"Incidental pancreatic cysts: Clinicopathologic characteristics and comparison with symptomatic patients","volume":"251","author":"Ferrone","year":"2010","journal-title":"Ann. Surg."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"144","DOI":"10.1159\/000243733","article-title":"Incidental pancreatic cysts: Do we really know what we are watching?","volume":"10","author":"Fritz","year":"2010","journal-title":"Pancreatology"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"1346","DOI":"10.1007\/s10620-017-4521-2","article-title":"Needle-based confocal laser endomicroscopy for evaluation of cystic neoplasms of the pancreas","volume":"62","author":"Kadayifci","year":"2017","journal-title":"Dig. Dis. Sci."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"794","DOI":"10.1007\/s00428-005-0039-7","article-title":"Classification of types of intraductal papillary-mucinous neoplasm of the pancreas: A consensus study","volume":"447","author":"Furukawa","year":"2005","journal-title":"Virchows Arch."},{"key":"ref_29","first-page":"819","article-title":"ACG clinical guideline: Diagnosis and management of pancreatic cysts","volume":"154","author":"Elta","year":"2018","journal-title":"Gastroenterology"},{"key":"ref_30","first-page":"1225","article-title":"Current roles of endoscopy in IPMN management","volume":"47","author":"Tanaka","year":"2018","journal-title":"Pancreas"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"eaav4772","DOI":"10.1126\/scitranslmed.aav4772","article-title":"A multimodality test to guide the management of patients with a pancreatic cyst","volume":"11","author":"Springer","year":"2019","journal-title":"Sci. Transl. Med."},{"key":"ref_32","first-page":"978","article-title":"Long-term risk of pancreatic malignancy in branch-duct IPMN undergoing surveillance","volume":"66","author":"Pergolini","year":"2017","journal-title":"Gut"},{"key":"ref_33","first-page":"349","article-title":"Pancreatic intraepithelial neoplasia and IPMN progression pathways","volume":"40","author":"Yamaguchi","year":"2011","journal-title":"Pancreas"},{"key":"ref_34","first-page":"35","article-title":"Intraductal papillary mucinous neoplasm of the pancreas: Progress and challenges","volume":"4","author":"Tanaka","year":"2020","journal-title":"Ann. Gastroenterol. Surg."}],"container-title":["Journal of Clinical Medicine"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2077-0383\/15\/12\/4701\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,6,17]],"date-time":"2026-06-17T11:07:12Z","timestamp":1781694432000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2077-0383\/15\/12\/4701"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,6,17]]},"references-count":34,"journal-issue":{"issue":"12","published-online":{"date-parts":[[2026,6]]}},"alternative-id":["jcm15124701"],"URL":"https:\/\/doi.org\/10.3390\/jcm15124701","relation":{},"ISSN":["2077-0383"],"issn-type":[{"value":"2077-0383","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,6,17]]}}}