Intrinsic susceptibility MR imaging of chemically induced rat mammary tumors: relationship to histologic assessment of hypoxia and fibrosis.

Abstract

To investigate relationships between magnetic resonance (MR) imaging measurements of R2* and carbogen-induced DeltaR2* in vivo with subsequent histologic assessment of grade, hypoxia, fibrosis, and necrosis in a chemically induced rat mammary tumor model. All experiments were performed in accordance with the local ethics review panel, the UK Home Office Animals Scientific Procedures Act of 1986, and the UK Co-ordinating Committee on Cancer Research guidelines. Of 30 rats injected with N-methyl-N-nitrosourea, 17 developed mammary tumors. Prior to MR imaging, rats were administered pimonidazole. Tumor R2* was then quantified while the host first breathed air and then carbogen (95% O(2), 5% CO(2); n = 16). Tumor sections were subsequently stained for pimonidazole, sirius red, cytokeratin 14, and hematoxylin-eosin for quantitative assessment of hypoxia, fibrosis, malignancy, and necrosis, respectively, and graded according to the Scarff-Bloom-Richardson scale. Linear regression analysis was used to identify any correlates of the MR imaging data with histologic data. Tumors exhibited wide heterogeneity in the magnitude of carbogen-induced reduction in R2*, an emerging imaging biomarker of fractional blood volume. Significant correlations were found between pimonidazole adduct formation and both baseline tumor R2* (r = -0.54, P = .03) and carbogen-induced DeltaR2* (r = 0.56, P = .02), demonstrating that tumors with a larger fractional blood volume were less hypoxic. There was also a significant correlation between pimonidazole and sirius red staining (r = 0.76, P < .01), indicating that more fibrotic tumors were also more hypoxic. There were no correlations of R2* with grade. In this model of breast cancer, baseline tumor R2* and carbogen-induced DeltaR2* are predictive imaging biomarkers for hypoxia and primarily determined by blood volume.