Macromolecular Contrast Media- enhanced MRI Estimates of Microvascular Permeability Correlate with Histopathologic Tumor Grade Robert C. Brasch, MD, Heike Daldrup, MD, David Shames, MD, Michael Wendland, PhD Yoshitaka Okuhata, MD, Werner Rosenau, MD Use of contrast enhancement in conjunction with diagnos- tic imaging provides a means to evaluate tissue function as well as morphology. Physiologic properties derived from kinetic analysis of dynamic contrast-enhanced data can improve the specificity of our imaging examinations by supplementing the detailed anatomic information often available from unenhanced images. Tumors represent a clinically important disease category for which a combina- tion of improved sensitivity and specificity could favor- ably influence patient management and outcome. For ex- ample, MR mammography, recognized as a highly sensi- tive tumor detection method (up to 97%) (1-3), has been faulted for a limited specificity. Nonmalignant pathologies are reported in 18% of "strongly enhancing, positive" le- sions (1). Improved specificity could better guide the man- agement of patients, potentially decreasing the current high rate of negative biopsies as well as providing indi- vidualized tumor characteristics for the optimal selection of therapeutic options. Various schemes have been proposed for analysis of dynamic contrast-enhanced MRI data, with the supposition that such analysis will serve to characterize tumors and to improve specificity. In support of this assumption, studies have shown that measures derived from dynamic contrast- enhanced MRI data correlate with surrogates of tumor an- giogenesis (4). Reports from our group have shown that kinetic analyses based upon principles of solute diffusion across vascular endothelial barriers can be used to quanti- tatively estimate microvascular permeabilities (5-8). MATERIALS AND METHODS Acad Radio11998; 5(suppl 1):$2-$5 1 From fhe Contrasf Media Laborafory, Department of Radiology, Uni- versity of California San Francisco, 513 Parnassus Ave, San Francisco, CA 94143-0628. Address reprint requests to R.C, B, ©AUR, 1998 Endothelial permeability depends upon both vascular morphology and the physicochemical characteristics of the solute molecule. Based on the repeatedly demonstrated hyperpermeability of tumor microvessels to macromolecular solutes (9-11), we hypothesize that MRI permeability esti- mates based on MMCM-enhanced data should allow reliable differentiation of benign from malignant tumors. The purpose of this study was to define the correlation between histopathologic tumor grade and quantitative MR- derived estimates of tumor microvascular permeability in a spectrum of induced mammary tumors using a prototype MMCM, albumin-(Gd-DTPA)30. Tumor Induction and Animals N-ethyl-N-nitrosurea (ENU) is an alkylating agent and a potent carcinogen that induces tumors of varying grade and location in rats, depending on the site of injection, the dose, and the age and the sex of the animal (12-14). For our study ENU (ENU Isopack; Sigma Chemicals, St. Louis, Mo), pur- chased as a crystalline substance, was dissolved shortly be- fore administration in 0.9% sterile saline to a concentration of 10 mg/mL. Fifty 30-day-old female Sprague Dawley rats were randomly divided into two groups. Group one (n = 35) received a single i.p. ENU dose of 45 mg/kg, and group two (n = 15) received 180 mg/kg ENU intraperitoneally. The animals were treated according to the guidelines of the Na- tional Institutes of Health and with the approval of the insti- tutional committee on animal research. Tumors, when visu- ally apparent, were allowed to continue growing until they reached a diameter of 1-1.5 cm. Animals were eliminated from the study if no visible tumor was observed within 160 days or no tumor grew in the mammary fat pad. Before MRI, the animals were anesthetized by administration of pentobarbital, 50 mg/kg body weight i.p. $2