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 thesetumors often appear localized on modern imaging studies, rarely metastasize to systemic sites, and can be aggressivelytreated with surgery and radiation therapy. Recent data suggestthat 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 μL 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 ratswere sacrificed and the brains were removed, frozen and prepared for quantitative autoradiography and histologic analysis. Interstitial flow rates were calculated from the autoradiographs, andflow 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 confinedto large ipsilateral white matter tracts and extended from the frontal injection site to the occipital lobe. The averageinterstitial fluid flow rate in the association fibers ofthe external capsule was 0.86 mm/hr. In contrast, the animalsreceiving temporal lobe injections had Evans Blue and inulin confined to the temporal lobe. The average interstitial fluid flow rate inthe 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, expansionof 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.