Serum macrophage inhibitory cytokine 1 as a marker of pancreatic and other periampullary cancers.
OBJECTIVE
Patients with pancreatic ductal adenocarcinoma usually present with advanced-stage disease and a dismal prognosis. One effective strategy likely to improve the morbidity and mortality from pancreatic cancer would be the identification of accurate, noninvasive diagnostic markers that would enable earlier diagnosis of symptomatic patients and earlier detection of cancer in asymptomatic individuals at high risk for developing pancreatic cancer. In this study, we evaluated serum macrophage inhibitory cytokine-1 (MIC-1) as a marker of pancreatic cancer.


METHODS
MIC-1 expression in primary pancreatic cancers, intraductal papillary mucinous neoplasms, and pancreatic cancer cell lines was determined using the National Center for Biotechnology Information serial analysis of gene expression database, oligonucleotide microarrays analysis, in situ hybridization, and immunohistochemistry. Serum MIC-1 levels were determined by ELISA in 80 patients with pancreatic adenocarcinomas, in 30 patients with ampullary and cholangiocellular carcinomas, in 42 patients with benign pancreatic tumors, in 76 patients with chronic pancreatitis, and in 97 healthy control subjects. The diagnostic performance of serum MIC-1 as a marker of pancreatic cancer was compared with that of serum CA19-9.


RESULTS
Oligonucleotide microarray and serial analysis of gene expression data demonstrated that MIC-1 RNA levels were higher in primary pancreatic cancers, intraductal papillary mucinous neoplasms, and pancreatic cancer cell lines than in nonneoplastic pancreatic ductal epithelium. MIC-1 expression was localized to the malignant epithelium in pancreatic adenocarcinomas by in situ hybridization. MIC-1 protein was expressed in 14 of 16 primary pancreatic adenocarcinomas (88%) by immunohistochemistry and was also expressed in some pancreata affected by pancreatitis but not in normal pancreas. Serum MIC-1 levels were significantly higher in patients with pancreatic ductal adenocarcinoma (mean +/- SD, 2428 +/- 2324 pg/ml) and in patients with ampullary and cholangiocellular carcinomas (2123 +/- 2387 pg/ml) than in those with benign pancreatic neoplasms (940 +/- 469 pg/ml), chronic pancreatitis (1364 +/- 1236 pg/ml), or in healthy controls (546 +/- 262 pg/ml). An elevated serum MIC-1 (defined as 2 SD above the mean for healthy controls) performed as well as CA19-9 (area under the receiver operating characteristic curve, 0.81 and 0.77, respectively), and the combination of MIC-1 and CA19-9 significantly improved diagnostic accuracy (P < 0.05; area under the receiver operating characteristic curve, 0.87; sensitivity, 70%; specificity, 85%).


CONCLUSIONS
Serum MIC-1 measurement can aid in the diagnosis of pancreatic adenocarcinoma.
Koopmann
Jens
J
Department of Pathology, Johns Hopkins Medical Institutions, Baltimore, Maryland 21205, USA.
Buckhaults
Phillip
P
Brown
David A
DA
Zahurak
Marianna L
ML
Sato
Norihiro
N
Fukushima
Noriyoshi
N
Sokoll
Lori J
LJ
Chan
Daniel W
DW
Yeo
Charles J
CJ
Hruban
Ralph H
RH
Breit
Samuel N
SN
Kinzler
Kenneth W
KW
Vogelstein
Bert
B
Goggins
Michael
M
D000230:Adenocarcinoma / Q000378:metabolism; D000328:Adult; D000368:Aged; D001650:Bile Duct Neoplasms / Q000378:metabolism*; D018395:CA-19-9 Antigen / Q000378:metabolism; D045744:Cell Line, Tumor; D018281:Cholangiocarcinoma / Q000378:metabolism; D016207:Cytokines / Q000096:biosynthesis* / Q000097:blood*; D019992:Databases as Topic; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D055436:Growth Differentiation Factor 15; D006801:Humans; D007150:Immunohistochemistry; D017403:In Situ Hybridization; D008297:Male; D008875:Middle Aged; D020411:Oligonucleotide Array Sequence Analysis; D009841:Oligonucleotides / Q000737:chemistry; D010179:Pancreas / Q000378:metabolism; D010190:Pancreatic Neoplasms / Q000378:metabolism*; D010195:Pancreatitis / Q000378:metabolism; D011230:Precancerous Conditions / Q000378:metabolism; D012680:Sensitivity and Specificity
D018395:CA-19-9 Antigen; D016207:Cytokines; C526140:GDF15 protein, human; D055436:Growth Differentiation Factor 15; D009841:Oligonucleotides