Vascular endothelial growth factor A (VEGF-A) levels in pancreatic fluid may distinguish serous cystic neoplasms (SCN) from premalignant or malignant pancreatic cysts, according to a prospective study published online February 12 in the Journal of the American College of Surgeons. If the findings are confirmed, use of this biomarker could potentially reduce the costs and risks associated with monitoring and surgical intervention.
“With the increased use of body imaging, small asymptomatic cystic lesions of the pancreas are being found more frequently,” Henry A. Pitt, MD, professor of surgery and associate vice dean for clinical affairs at the Temple University School of Medicine and chief quality officer of the Temple University Health System, Philadelphia, Pennsylvania, toldMedscape Medical News when asked for independent comment. “However, several varieties of pancreatic cysts exist, and differentiation among them by imaging alone is not very accurate. In addition, while some of these cysts are premalignant or malignant, others have very little or no malignant potential.”
Mucinous pancreatic cysts, including intraductal papillary mucinous neoplasm and mucinous cystic neoplasm, may progress to invasive pancreatic adenocarcinoma, whereas SCN have no malignant potential but can resemble mucinous pancreatic cysts on imaging. Identifying biomarkers that could differentiate cystic lesions is therefore important to allow early detection, prevention, and cure of pancreatic cancer without unnecessary intervention for SCN. The hypothesis tested by this study was that VEGF-A levels in pancreatic fluid would correlate with pathologic diagnosis.
The investigators prospectively collected pancreatic cyst and duct fluid samples from patients who underwent pancreatic resection and who had final pathologic diagnoses. They used enzyme-linked immunosorbent assay testing to measure VEGF levels, immunohistochemistry to detect VEGF-A and VEGF receptor 2 expression in pancreatic tissue, and targeted next-generation sequencing to uncover genetic alterations of the von Hippel-Lindau gene.
Of 87 patients meeting inclusion criteria, 9 had pseudocyst, 17 had SCN, 24 had mucinous cystic neoplasm, 16 had low/moderate grade intraductal papillary mucinous neoplasm, 10 had high-grade or invasive intraductal papillary mucinous neoplasm, and 11 had pancreatic ductal adenocarcinoma.
VEGF Levels Highest in SCN Cyst Fluid
Compared with cyst fluid from all other diagnoses, cyst fluid from SCN had significant upregulation of VEGF-A (P < .0001). With a cut-off of 8500 pg/mL, VEGF-A was 100% sensitive and 97% specific as an SCN biomarker. Both VEGF-A and VEGF receptor 2 were overexpressed in SCN cyst tissue.
Furthermore, VEGF-C was also significantly elevated in SCN cyst fluid (P < .0001) and was 100% sensitive and 90% specific for SCN, using a cut-off of 200 pg/mL. Having a von Hippel-Lindau mutation in SCN cyst tissue correlated with elevated VEGF levels in cyst fluid.
“The clinical implications of this study are significant,” Dr. Pitt said. “[H]aving a test which can differentiate benign cysts from potentially malignant ones may avoid surgery, endoscopic procedures, and/or multiple expensive imaging studies. [These data] suggest that pancreatic fluid VEGF-A can differentiate benign SCNs from other premalignant or malignant pancreatic lesions.”
Potential Utility and Limitations of This Biomarker
Dr. Pitt noted that a major strength of this study was the inclusion of a large variety of patients with various pancreatic cysts as well as pancreatic cancer. However, limitations were that the number of patients in each of the six subgroups was relatively small, only 17 patients had SCNs, and none had rare cystic neuroendocrine tumors.
“Unfortunately, serum levels of VEGF-A did not differentiate SCNs from the other lesions, so relatively invasive methods to obtain cyst fluid will still be required,” Dr. Pitt said. “Future research that will be required includes…validation of this work by other groups,… further studies comparing VEGF-A with VEGF-C, and…identification of the exact isoform of VEGF-A that is elevated in SCNs.”
Standard testing during endoscopy for evaluation of pancreatic cysts often includes obtaining pancreatic cyst fluid. Early diagnosis of pancreatic cancer, ideally in premalignant stages, might improve the poor prognosis associated with late diagnosis, when surgical resection may not be an option. The National Cancer Institute estimates that in 2014, about 45,220 people will be diagnosed with pancreatic cancer, and about 38,460 will die from it.
“Only 15 percent of pancreatic cancer patients will benefit from surgery, and of those, only about 20 percent will survive five years,” senior author C. Max Schmidt, MD, PhD, MBA, professor of surgery, biochemistry, and molecular biology and director of the Indiana University Pancreatic Cyst and Cancer Early Detection Center in Indianapolis, said in an Indiana University news release.
In addition, Dr. Schmidt noted the importance of sparing a patient unnecessary pancreatic surgery, as complications are common and may be life-threatening. US prevalence of pancreatic cysts is above 2%, but many patients are asymptomatic and are not diagnosed during their lifetime. Patients in whom these cysts are detected have often undergone extensive follow-up medical visits and invasive biopsies.
“Many of my patients, when initially told they have pancreatic cysts, are very fearful and ask for surgical removal of the cyst or the entire pancreas before they even learn their options,” Dr. Schmidt said. “Now, physicians will have an outpatient procedure to offer that can take some of the guesswork out of the equation.”
The Indiana Genomics Initiative of Indiana University, supported in part by Lilly Endowment Inc, provided financial support for this study. Dr. Schmidt is a paid advisor for Redpath Integrated Pathology Inc and Asurgen Inc. He is founder of B9 Inc and has a VEGF-A use patent pending. The other study authors and Dr. Pitt have disclosed no relevant financial relationships.