While cancer is a clonal process, cumulative evidence suggest that tumors are rather heterogenous and are composed of multiple genetically-distinct subclones that arise at different times and either persist and co-exist, expand and evolve, or are eliminated. A paradigm of tumor heterogeneity is renal cell carcinoma (RCC). By exploiting morphological traits and building upon a framework around three axes (architecture, cytology and the microenvironment), we review recent advances in our understanding of RCC evolution leading to an integrated molecular genetic and morphologic evolutionary model with both prognostic and therapeutic implications. The ability to predict cancer evolution may have profound implications for clinical care and is central to oncology.
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