Incorporating pathologists' criteria of malignancy into the evolutionary model for cancer development.

A wide variety of alterations in cell and tissue structure still form the basis for cancer diagnosis by pathologists. Cancer development is recognized to be an evolutionary process [Foulds, 1954; Cairns, 1975; Nowell, 1976; Sager, 1982; Tomlinson et al., 1996; Cahill et al., 1999; Tomlinson and Bodmer, 1999], but the phenotypic changes diagnostic of cancer (pathologists' "criteria of malignancy") have not been integrated into the existing evolutionary framework. Since phenotypic changes bear an important relationship to the genetic and physiologic changes underlying Darwinian evolution, we propose that diagnostic structural alterations also bear an important and predictable relation to both the cancer genes and the functional alterations active at any particular step in the development of a cancer. Cancer genes are predicted to mediate the acquisition of cellular-level diagnostic criteria and the diagnostic cellular-level structural changes should reflect in a useful manner the altered cell physiology required for the cell to achieve increased "cellular fitness" at any particular step of colonal evolution. Tissue-level criteria of malignancy should relate less directly to specific cancer genes, but tissue-level criteria should still provide essential insight into the interplay of the altered cellular fitness with the constraints imposed by the cells' microenvironment. The evolutionary framework allows tissue-level criteria of malignancy to be expressed in terms of viable hypotheses for the mechanism of clonal expansion at any particular step in cancer development. This approach to conveying the tissue-level criteria of malignancy complements pattern recognition approaches to diagnosis, and establishes common ground between pathology and cell biology. When viewed from this perspective, the functions of cancer genes appear quite different from those predicted by the "Gatekeeper, Caretaker" or "Hallmarks of Cancer" models. Finally, a full evolutionary framework incorporating the criteria of malignancy restores congruity between the histogenetic classification and the emerging molecular classification of cancer.