Interstitial fluid flow along white matter tracts: a potentially important mechanism for the dissemination of primary brain tumors.

Abstract

High grade astrocytomas remain incurable even though these tumors often appear localized on modern imaging studies, rarely metastasize to systemic sites, and can be aggressively treated with surgery and radiation therapy. Recent data suggest that the dissemination of astrocytoma cells along white matter tracts to distant regions of the brain may be responsible for the poor survival of these patients and the limited impact of local therapies. Movement of astrocytoma cells along these white matter tracts can be active or passive in nature. To study the potential for tumor dissemination by bulk flow of interstitial fluid resulting from peritumoral edema. 20 microL of tritiated inulin, Evans Blue, and rat albumin were injected stereotactically into the right frontal lobe and the left temporal lobe at the gray-white matter junction in Sprague-Dawley rats. Six hours later, the rats were sacrificed and the brains were removed, frozen and prepared for quantitative autoradiography and histologic analysis. Interstitial flow rates were calculated from the autoradiographs, and flow pathways were determined from the movement of Evans Blue, inulin and histologic data. In each animal injected in the frontal lobe, Evans Blue and inulin were primarily confined to large ipsilateral white matter tracts and extended from the frontal injection site to the occipital lobe. The average interstitial fluid flow rate in the association fibers of the external capsule was 0.86 mm/hr. In contrast, the animals receiving temporal lobe injections had Evans Blue and inulin confined to the temporal lobe. The average interstitial fluid flow rate in the white matter tracts of the temporal lobe was 0.61 mm/hr. The rapid and preferential flow of interstitial fluid along white matter tracts and the differences in the clearance of extracellular fluid observed between the frontal and temporal lobes may have important clinical implications. These data suggest that aggressive treatment of peritumoral edema, expansion of radiotherapy ports, and consideration of the location of the tumor in treatment planning may improve therapeutic outcomes for some patients. An improved understanding of the mechanisms of tumor dissemination is crucial to designing more effective therapeutic approaches for patients with this devastating malignancy.