Cellular Proliferative Fraction Measured With Topoisomerase IIα Predicts Malignancy in Endocrine Pancreatic Tumors

Abstract

Abstract Context.—Endocrine pancreatic tumors (EPTs) are rare lesions with varying biological behavior. Establishing malignancy is a challenge for clinicians and pathologists. Objective.—To establish the role of proliferative, apoptotic, angiogenic, and hormonal markers as predictors of malignancy in EPTs. Design.—Paraffin-embedded EPT samples were studied for prognostic markers. Patients.—Twenty-one consecutive patients with a diagnosis of EPT. Main Outcome Measures.—The proliferative fraction (topoisomerase IIα), microvascular density (CD34), vascular endothelial growth factor expression, and estrogen receptor-beta (ERβ) expression were studied by immunohistochemistry on all EPTs. Apoptosis was also assessed with terminal deoxynucleotidyl transferase nick-end labeling. Results.—We identified 13 benign and 8 malignant tumors. Topoisomerase IIα was significantly increased in malignant tumors (P = .001), while there were no differences in apoptosis, microvascular density, or vascular endothelial growth factor expression in association with malignancy. No correlation could be identified between microvascular density and vascular endothelial growth factor expression, and ERβ was not detected. A receiver operating characteristic curve for topoisomerase IIα disclosed that above a labeling index of 13, the test had 88% sensitivity and 100% specificity for predicting malignancy. Conclusion.—Cellular proliferation measured with topoisomerase IIα is a simple prognostic marker for malignancy in EPTs, unlike apoptosis, angiogenesis, or the presence of ERβ, which were not associated with malignant behavior. These findings designate a defined field for future research on endocrine pancreatic carcinogenesis and a possible target for chemotherapeutic agents.