title: Diagnostic and prognostic role of the insulin growth factor pathway members insulin-like growth factor-II and insulin-like growth factor binding protein-3 in serous effusions.
abstract: We recently reported on higher expression of the insulin-like growth factor pathway genes IGF-II and IGFBP3 in serous ovarian/peritoneal carcinoma compared to malignant peritoneal mesothelioma. The present study analyzed the diagnostic and clinical role of these proteins in serous effusions. Effusions (n = 327), including 294 carcinomas (205 ovarian, 48 breast, 17 cervical/endometrial, 12 lung, 12 gastrointestinal/genitourinary) and 33 malignant mesotheliomas, were immunostained for insulin-like growth factor-II and insulin-like growth factor binding protein-3. Surgical ovarian carcinoma (n = 124) and peritoneal mesothelioma (n = 18) specimens were additionally studied. Insulin-like growth factor binding protein-3 levels were measured in 148 effusion supernatants (114 ovarian carcinomas, 18 breast carcinomas, 16 mesotheliomas) using enzyme-linked immunosorbent assay. Insulin-like growth factor binding protein-3 promoter methylation was analyzed in 11 ovarian carcinoma effusions. Insulin-like growth factor binding protein-3 (P = .002) and insulin-like growth factor-II (P < .001) expression by immunohistochemistry was significantly higher in carcinomas compared to mesotheliomas, with diagnostic sensitivity of 77% and 70% and specificity of 55% and 70%, respectively. In surgical specimens, insulin-like growth factor binding protein-3 expression was higher in ovarian carcinomas compared to peritoneal mesotheliomas (P = .007), whereas insulin-like growth factor-II expression was comparable (P = .505). Insulin-like growth factor binding protein-3 levels by enzyme-linked immunosorbent assay were comparable in the 3 analyzed cancer types. Insulin-like growth factor binding protein-3 promoter methylation was found in 6 of 11 effusions. High insulin-like growth factor binding protein-3 expression in prechemotherapy and high insulin-like growth factor-II expression in postchemotherapy ovarian carcinoma effusions correlated with poor overall survival (P = .031 and P = .024, respectively). Insulin-like growth factor-II expression in postchemotherapy effusions was an independent prognostic factor in Cox multivariate analysis (P = .04). In conclusion, insulin-like growth factor-II and insulin-like growth factor binding protein-3 are more frequently expressed in metastatic carcinomas compared to mesothelioma in effusions but are less specific than currently used markers. Insulin-like growth factor-II and insulin-like growth factor binding protein-3 may be novel prognostic markers in metastatic ovarian carcinoma.
authors.affiliation: Division of Pathology, Norwegian Radium Hospital, Rikshospitalet Medical Center, N-0310 Oslo, Norway.
authors.forename: Ana
authors.initials: A
authors.lastname: Slipicevic
authors.forename: Geir Frode
authors.initials: GF
authors.lastname: Øy
authors.forename: Inger Cecilie
authors.initials: IC
authors.lastname: Askildt
authors.forename: Arild
authors.initials: A
authors.lastname: Holth
authors.forename: Ellen
authors.initials: E
authors.lastname: Hellesylt
authors.forename: Vivi Ann
authors.initials: VA
authors.lastname: Flørenes
authors.forename: Ben
authors.initials: B
authors.lastname: Davidson
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001202:Ascitic Fluid / Q000378:metabolism*; D014408:Biomarkers, Tumor / Q000032:analysis*; D002277:Carcinoma / Q000150:complications / Q000378:metabolism* / Q000401:mortality; D003937:Diagnosis, Differential; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D018972:Insulin-Like Growth Factor Binding Protein 3; D018969:Insulin-Like Growth Factor Binding Proteins / Q000096:biosynthesis*; D007335:Insulin-Like Growth Factor II / Q000096:biosynthesis*; D053208:Kaplan-Meier Estimate; D008654:Mesothelioma / Q000378:metabolism* / Q000401:mortality; D008875:Middle Aged; D010051:Ovarian Neoplasms / Q000378:metabolism / Q000401:mortality; D016133:Polymerase Chain Reaction; D011379:Prognosis; D012680:Sensitivity and Specificity; D046888:Tissue Array Analysis
chemical_list: D014408:Biomarkers, Tumor; C515497:IGFBP3 protein, human; D018972:Insulin-Like Growth Factor Binding Protein 3; D018969:Insulin-Like Growth Factor Binding Proteins; D007335:Insulin-Like Growth Factor II