MR-derived cerebral blood volume maps: issues regarding histological validation and assessment of tumor angiogenesis

In an effort to develop MRI methods for the evaluation of tumor angiogenesis (new blood vessel formation), MRI-derived cerebral blood volume (CBV) information has been compared to histologic measures of microvessel density (MVD). Although MVD is a standard marker of angiogenesis, it is not a direct correlate of the volume measurements made with MRI, and therefore inappropriate for the development and validation of the MR techniques. Therefore, the goal of this study was to develop an approach by which MR measurements of CBV can be directly correlated. To this end, dynamic susceptibility contrast (DSC) MRI experiments were performed in six Fisher rats implanted with 9L gliosarcoma brain tumors. Subsequently, the circulation was perfused with a latex compound (Microfil), after which 50-microm tissue sections were analyzed for vessel count, diameter, and the fraction of area comprised of vessels. The results demonstrate that while fractional area (FA) does not provide a good measure of CBV, FA corrected for section thickness effects does. Whereas the FA in normal brain was found to be 13.03 +/- 1.83% the corrected FA, or fractional volume (FV), was 1.89 +/- 0.39%, a value in agreement with those reported in the literature for normal brain. Furthermore, while no significant difference was found between normal brain and tumor FA (P = 0.55), the difference was significant for FV (P = 0.036), as would be expected. And only with FV does a correlation with the MRI-derived CBV become apparent (r(S) = 0.74). There was strong correlation (r(s) = 0.886) between the tumor / normal blood volume ratios as estimated by each technique, although the MR-ratio (1.56 +/- 0.29) underestimated the histologic-ratio (2.35 +/- 0.75). Thus, the correlation of MRI CBV methods requires a measurement of fractional vessel area and correction of this area for section thickness effects. This new independent correlative measure should enable efficient and accurate progress in the development of MRI methods to evaluate tumor angiogenesis.