Cervical carcinoma: standard and pharmacokinetic analysis of time–intensity curves for assessment of tumor angiogenesis and patient survival

Abstract

Since detailed knowledge regarding the pathophysiological properties—which in turn are responsible for differences in contrast enhancement—remain fairly undetermined, it was the aim of this study (i) to examine the association of standard and pharmacokinetic analysis of time–intensity curves in dynamic MRI with histomorphological markers of tumor angiogenesis (microvessel density [MVD]; vascular endothelial growth factor [VEGF]); and (ii) to determine the ultimate value of a histomorphological and a dynamic MRI approach by correlation of those data with disease outcome in patients with primary cancer of the uterine cervix. Pharmacokinetic parameters (amplitude A, exchange rate constant k21) and standard parameters (maximum signal intensity (SI)-increase [SI–I] over baseline and steepest SI-upslope per second [SI-U/s]) were calculated from contrast-enhanced dynamic MR imaging series in 37 patients with biopsy-proven primary cervical cancer. On the surgical whole mount specimens, histomorphological markers of tumor angiogenesis (MVD, VEGF) were compared with similar sized and positioned regions-of-interest (ROIs) on the MRI-derived parameters. For MRI and histomorphological data, Kaplan–Meier survival curves were calculated and compared using log-rank statistics. A significant association was found between MVD and amplitude A (P<0.01) and SI-I (P<0.05). No significant relationships were observed between the VEGF expression and all dynamic MRI parameters. Kaplan–Meier curves based on k21and SI-U/s showed that tumors with high k21 and SI-U/s values had a significantly (P<0.05, 0.001, respectively) worse disease outcome than tumors with low k21 and SI-U/s values. None of the histomorphological gold standard markers for assessing tumor angiogenesis (MVD, VEGF) had any significant power to predict patient survival. It is concluded that (1) the pathophysiological basis for differences in dynamic MRI is MVD but not VEGF-expression; (2) a functional, dynamic MRI approach (both standard and a pharmacokinetic analysis) may be better suited to assess angiogenic activity in terms of patient survival than current histomorphological-based markers of tumor angiogenesis; and [3] compared with standard analysis, a simple pharmacokinetic analysis of time–intensity curves is not superior to assess MVD or patient survival.