miRNA biomarkers in cyst fluid augment the diagnosis and management of pancreatic cysts.
OBJECTIVE
The diagnosis of pancreatic cystic lesions has increased dramatically. Most are benign, whereas some, such as intraductal papillary mucinous neoplasms (IPMN), represent precursors of pancreatic adenocarcinoma. Therapeutic stratification of IPMNs is challenging without precise information on dysplasia grade and presence of invasion. We assessed the diagnostic benefit of using miRNAs as biomarkers in pancreatic cyst fluid, focusing on IPMNs because of their frequency and malignant potential.


METHODS
RNA was extracted from 55 microdissected formalin-fixed, paraffin-embedded (FFPE) IPMN specimens, and 65 cyst fluid specimens aspirated following surgical resection. Expression of 750 miRNAs was evaluated with TaqMan miRNA Arrays using 22 FFPE and 15 cyst fluid specimens. Differential expression of selected miRNA candidates was validated in 33 FFPE and 50 cyst fluid specimens using TaqMan miRNA Assays.


RESULTS
We identified 26 and 37 candidate miRNAs that distinguish low-grade from high-grade IPMNs using FFPE and cyst fluid specimens, respectively. A subset of 18 miRNAs, selected from FFPE and cyst fluid data, separated high-grade IPMNs from low-grade IPMNs, serous cystadenomas (SCA) and uncommon cysts, such as solid pseudopapillary neoplasms (SPN) and cystic pancreatic neuroendocrine tumors (PanNET). A logistic regression model using nine miRNAs allowed prediction of cyst pathology implying resection (high-grade IPMNs, PanNETs, and SPNs) versus conservative management (low-grade IPMNs, SCAs), with a sensitivity of 89%, a specificity of 100%, and area under the curve of 1.


CONCLUSIONS
We found candidate miRNAs that helped identify patients with high-grade IPMN and exclude nonmucinous cysts. These classifiers will require validation in a prospective setting to ultimately confirm their clinical usefulness.
Departments of Pathology, Oncology, and Surgery, The Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins University School of Medicine, Baltimore, MD 21231, USA.
Hanno
H
Matthaei
Dennis
D
Wylie
Maura B
MB
Lloyd
Marco
M
Dal Molin
Jon
J
Kemppainen
Skye C
SC
Mayo
Christopher L
CL
Wolfgang
Richard D
RD
Schulick
Laura
L
Langfield
Bernard F
BF
Andruss
Alex T
AT
Adai
Ralph H
RH
Hruban
Anna E
AE
Szafranska-Schwarzbach
Anirban
A
Maitra
D000230:Adenocarcinoma / Q000175:diagnosis / Q000378:metabolism / Q000473:pathology; D014408:Biomarkers, Tumor / Q000235:genetics / Q000378:metabolism; D020420:Cyst Fluid / Q000378:metabolism; D018293:Cystadenoma, Serous / Q000175:diagnosis / Q000378:metabolism / Q000473:pathology; D003937:Diagnosis, Differential; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism; D060787:Neoplasm Grading; D010181:Pancreatic Cyst / Q000378:metabolism / Q000473:pathology; D010190:Pancreatic Neoplasms / Q000175:diagnosis / Q000378:metabolism / Q000473:pathology; D011446:Prospective Studies
D014408:Biomarkers, Tumor; D035683:MicroRNAs