Michele T Yip-Schneider1, Huangbing Wu2, Ryan P Dumas2, Brad A Hancock2, Narasimhan Agaram3, Milan Radovich2, C Max Schmidt4. 1. Department of Surgery, Indiana University School of Medicine, Indianapolis, IN. Electronic address: maxschmi@iupui.edu. 2. Department of Surgery, Indiana University School of Medicine, Indianapolis, IN. 3. Department of Pathology, Indiana University School of Medicine, Indianapolis, IN. 4. Department of Surgery, Indiana University School of Medicine, Indianapolis, IN; Department of Biochemistry/Molecular Biology, Indiana University School of Medicine, Indianapolis, IN; Walther Oncology Center, Indiana University School of Medicine, Indianapolis, IN; Indiana University Cancer Center, Indianapolis, IN; Richard L Roudebush VA Medical Center, Indianapolis, IN.
Abstract
BACKGROUND: Mucinous pancreatic cysts (intraductal papillary mucinous neoplasm and mucinous cystic neoplasm) have the potential to progress to invasive pancreatic adenocarcinoma, presenting an opportunity for early detection, prevention, and cure. Serous cystic neoplasms (SCN) have no malignant potential, but can mimic mucinous pancreatic cysts on imaging. Therefore, identification of biomarkers that can distinguish between cystic lesions is critically important. We hypothesize that vascular endothelial growth factor (VEGF)-A levels in pancreatic fluid correlate with pathologic diagnosis. STUDY DESIGN: Pancreatic cyst/duct fluid samples were prospectively collected from patients undergoing pancreatic resection and correlated with surgical pathology. VEGF levels were detected by ELISA. VEGF-A and VEGF receptor 2 expression in pancreatic tissue was localized by immunohistochemistry. Genetic alterations of the von Hippel-Lindau gene were determined by targeted next-generation sequencing. RESULTS: Eighty-seven patients met inclusion criteria for enrollment. Final pathologic diagnoses included pseudocyst (n = 9), SCN (n = 17), mucinous cystic neoplasm (n = 24), low/moderate grade intraductal papillary mucinous neoplasm (n = 16), high-grade/invasive intraductal papillary mucinous neoplasm (n = 10), and pancreatic ductal adenocarcinoma (n = 11). VEGF-A was significantly upregulated in SCN cyst fluid compared with all other diagnoses (p < 0.0001). With a cut-off of 8,500 pg/mL, VEGF-A has 100% sensitivity and 97% specificity as an SCN biomarker. VEGF-A and VEGF receptor 2 are overexpressed in SCN cyst tissue. VEGF-C was also significantly elevated in SCN cyst fluid (p < 0.0001). With a cut-off set at 200 pg/mL, VEGF-C identifies SCN with 100% sensitivity and 90% specificity. The presence of a von Hippel-Lindau mutation in SCN cyst tissue correlates with elevated cyst fluid VEGF levels. CONCLUSIONS: This is the first report of a cyst fluid protein biomarker that can positively identify SCN. The ability to distinguish SCN from premalignant/malignant pancreatic cysts can spare the cost and risk of surveillance and surgical intervention in select patients.
BACKGROUND:Mucinous pancreatic cysts (intraductal papillary mucinous neoplasm and mucinous cystic neoplasm) have the potential to progress to invasive pancreatic adenocarcinoma, presenting an opportunity for early detection, prevention, and cure. Serous cystic neoplasms (SCN) have no malignant potential, but can mimic mucinous pancreatic cysts on imaging. Therefore, identification of biomarkers that can distinguish between cystic lesions is critically important. We hypothesize that vascular endothelial growth factor (VEGF)-A levels in pancreatic fluid correlate with pathologic diagnosis. STUDY DESIGN:Pancreatic cyst/duct fluid samples were prospectively collected from patients undergoing pancreatic resection and correlated with surgical pathology. VEGF levels were detected by ELISA. VEGF-A and VEGF receptor 2 expression in pancreatic tissue was localized by immunohistochemistry. Genetic alterations of the von Hippel-Lindau gene were determined by targeted next-generation sequencing. RESULTS: Eighty-seven patients met inclusion criteria for enrollment. Final pathologic diagnoses included pseudocyst (n = 9), SCN (n = 17), mucinous cystic neoplasm (n = 24), low/moderate grade intraductal papillary mucinous neoplasm (n = 16), high-grade/invasive intraductal papillary mucinous neoplasm (n = 10), and pancreatic ductal adenocarcinoma (n = 11). VEGF-A was significantly upregulated in SCN cyst fluid compared with all other diagnoses (p < 0.0001). With a cut-off of 8,500 pg/mL, VEGF-A has 100% sensitivity and 97% specificity as an SCN biomarker. VEGF-A and VEGF receptor 2 are overexpressed in SCN cyst tissue. VEGF-C was also significantly elevated in SCN cyst fluid (p < 0.0001). With a cut-off set at 200 pg/mL, VEGF-C identifies SCN with 100% sensitivity and 90% specificity. The presence of a von Hippel-Lindau mutation in SCN cyst tissue correlates with elevated cyst fluid VEGF levels. CONCLUSIONS: This is the first report of a cyst fluid protein biomarker that can positively identify SCN. The ability to distinguish SCN from premalignant/malignant pancreatic cysts can spare the cost and risk of surveillance and surgical intervention in select patients.
Authors: Rosalie A Carr; Michele T Yip-Schneider; Scott Dolejs; Bradley A Hancock; Huangbing Wu; Milan Radovich; C Max Schmidt Journal: J Am Coll Surg Date: 2017-05-18 Impact factor: 6.113
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Authors: Simeon Springer; David L Masica; Marco Dal Molin; Christopher Douville; Christopher J Thoburn; Bahman Afsari; Lu Li; Joshua D Cohen; Elizabeth Thompson; Peter J Allen; David S Klimstra; Mark A Schattner; C Max Schmidt; Michele Yip-Schneider; Rachel E Simpson; Carlos Fernandez-Del Castillo; Mari Mino-Kenudson; William Brugge; Randall E Brand; Aatur D Singhi; Aldo Scarpa; Rita Lawlor; Roberto Salvia; Giuseppe Zamboni; Seung-Mo Hong; Dae Wook Hwang; Jin-Young Jang; Wooil Kwon; Niall Swan; Justin Geoghegan; Massimo Falconi; Stefano Crippa; Claudio Doglioni; Jorge Paulino; Richard D Schulick; Barish H Edil; Walter Park; Shinichi Yachida; Susumu Hijioka; Jeanin van Hooft; Jin He; Matthew J Weiss; Richard Burkhart; Martin Makary; Marcia I Canto; Michael G Goggins; Janine Ptak; Lisa Dobbyn; Joy Schaefer; Natalie Sillman; Maria Popoli; Alison P Klein; Cristian Tomasetti; Rachel Karchin; Nickolas Papadopoulos; Kenneth W Kinzler; Bert Vogelstein; Christopher L Wolfgang; Ralph H Hruban; Anne Marie Lennon Journal: Sci Transl Med Date: 2019-07-17 Impact factor: 17.956