Clonal evolution, like the progression of preneoplasia to neoplasia, appears to involve a series of oncogene activations. Oncogene activation, by gene amplification or increased transcription, appears to correlate independently and adversely with prognosis. Histopathologic studies have revealed that in a breast cancer that is biochemically defined as estrogen receptor positive, there may be many estrogen receptor-negative cells as well as a broad quantitative range within the positive spectrum. Immunoperoxidase studies using monoclonal antibodies selective for specific human tumor antigens have shown that the antibodies are unevenly distributed within a particular tumor as well as among patients with the same type of tumor. Thus, there may be a range of tumor cells varying from those expressing no antigen to those expressing large amounts of antigen.
Tumor cells are cytogenetically heterogeneous.
Multiple evolving clones can be demonstrated cytogenetically in human solid tumors as well as in CML tumors entering blast crisis. Tumors are heterogeneous in their supply of blood, oxygen, and metabolites, and this variation influences the growth fraction as well as the response to radiotherapy and to some forms of chemotherapy. Further, such compromise in the supply of oxygen, metabolites, or both may increase mutation rates and thereby promote clonal evolution to greater diversity. It has long been evident that certain malignant tumors, such as neuroblastoma, may undergo differentiation. Pathologists have recognized morphological evidence of varying degrees of differentiation within a given tumor.