Chapter 1 Pathobiology of Neoplasia

We began our discussion of neoplasia with two unifying definitional concepts. First it was asserted that all forms of neoplasia can be seen as a failure of somatic tissues to differentiate appropriately. This failure was caused by arrested maturation of organ determined stem cell progeny which resulted in an immature or incompletely differentiated phenotype. From this fundamental concept it was possible to understand the histopathology of diverse forms of neoplasia, to derive an explanation for benign versus malignant phenotype, to theorize mechanisms which help explain invasion and metastasis, and even to account for the distinctive clinical features of neoplastic diseases. The second unifying concept was that the primary, and likely causal, structural lesions inherent to neoplastic diseases involve the genome, either in the germline, in the somatic tissues, or in both. This genetic pathology was heterogenous but, not unexpectedly, it induced abnormal expression of specific genes which control tissue growth and differentiation. Some of these genes mediate responses to environmental stimuli whereas others regulate critical aspects of cell proliferation. The net effect of the genetic alterations, at any rate, is to impose a proliferative—and thereby incompletely differentiated—phenotype. Further, the extent of genetic pathology is directly related to degree of differentiation abnormality, and hence clinical behavior. Thus, the inextricable connection between morphologic pathology and genetic pathology in neoplasia is made whole. Finally, with the discovery of gene products, such as p53, which function to maintain genomic structure, we can theorize that genetic instability accounts for the process of tumor progression, in which phenotypic evolution within a neoplasm occurs over time. The catalogue of genetic lesions involved in neoplasia is far from complete, as is the spectrum of consequences at the level of cell proliferation and differentiation. Moreover, we are a long way from understanding all of the mechanisms by which the genome becomes destabilized. Thus, our ability to predict whether neoplasia will arise, whether a neoplasm is likely to be lethal, or how it will respond to therapy, remains imperfect. Nevertheless, our understanding of the matrix of events that control the dynamics of normal differentiation and proliferation provides us with an organizational framework which can guide research efforts toward elucidating the detailed mechanisms which determine neoplastic development and behavior.