Fractal Dimension of Tumor Microvasculature by DCE-US: Preliminary Study in Mice

Neoangiogenesis, which results in the formation of an irregular network of microvessels, plays a fundamental role in the growth of several types of cancer. Characterization of microvascular architecture has therefore gained increasing attention for cancer diagnosis, treatment monitoring and evaluation of new drugs. However, this characterization requires immunohistologic analysis of the resected tumors. Currently, dynamic contrast-enhanced ultrasound imaging (DCE-US) provides new options for minimally invasive investigation of the microvasculature by analysis of ultrasound contrast agent (UCA) transport kinetics. In this article, we propose a different method of analyzing UCA concentration that is based on the spatial distribution of blood flow. The well-known concept of Mandelbrot allows vascular networks to be interpreted as fractal objects related to the regional blood flow distribution and characterized by their fractal dimension (FD). To test this hypothesis, the fractal dimension of parametric maps reflecting blood flow, such as UCA wash-in rate and peak enhancement, was derived for areas representing different microvascular architectures. To this end, subcutaneous xenograft models of DU-145 and PC-3 prostate-cancer lines in mice, which show marked differences in microvessel density spatial distribution inside the tumor, were employed to test the ability of DCE-US FD analysis to differentiate between the two models. For validation purposes, the method was compared with immunohistologic results and UCA dispersion maps, which reflect the geometric properties of microvascular architecture. The results showed good agreement with the immunohistologic analysis, and the FD analysis of UCA wash-in rate and peak enhancement maps was able to differentiate between the two xenograft models (p < 0.05).