THE DEFINITION OF NEOPLASIA
As an illustration of the enigma that cancer has presented to physicians and scientists over the years, it was not until the 1920s that meaningful attempts were made to define cancer. In the ensuing half-century, a number of definitions of this biological phenomenon were proposed, mostly by physicians and scientists but more recently also by lay persons writing for the scien- tific press. Some definitions have been rather extensive and detailed, usually reflecting the au- thor’s basic experience and research interests; others have been of a more general character. To confuse the field further, clinicians, scientists, and lay persons have used such terms as cancer, neoplasm, tumor, and malignancy as if they were synonymous in every way (cf. Maugh and Marx, 1975). In this text we use the terms neoplasm and neoplasia for the basic disease process defined below. Cancer has come to be used almost exclusively to indicate a process that has the biological characteristics of a malignant neoplasm (see below). The term malignancy should also be limited to references to malignant neoplasms. Perhaps the greatest confusion is caused by the use of the word tumor. Since the Greco-Roman era, tumor has been used to denote a readily defined mass of tissue distinct from normal physiological growth. Thus, a scar, a healing bone fracture or callus, “proud flesh,” a granuloma, a chronic abscess, or a parasitic mass are all tumors, but they are not neoplasms. Part of this confusion arises because several English pathol- ogists employed the term tumour synonymously with neoplasia (cf. Walter and Israel, 1979; Willis, 1967). In this text, however, we do not use this last terminology.
Most of the definitions of neoplasia that have been proposed have common themes, but we use the definition modified from that originally proposed by the pathologist James Ewing (1940):
A neoplasm is a heritably altered, relatively autonomous growth of tissue.
This definition encompasses several concepts. The changes from normal exhibited by a neoplastic cell are heritable in that such characteristics are passed on from the neoplastic cell to its progeny. Heritably altered indicates alterations that are transmitted to all progeny in a herita- ble and irreversible manner. This characteristic does not necessarily imply that the heritable change is dependent on structural genomic alteration(s), since phenotypic characteristics are transmitted to the progeny of cells of a specific differentiated lineage without known qualitative genomic alterations—e.g., hepatocytes, intestinal crypt cells, neurons, etc. Autonomy indicates that a cancer is not subject to the “rules and regulations” that govern the individual cells and the overall cell interactions of the functional organism. The adverb relatively modifies autonomous to indicate that neoplasms are not completely autonomous. In many instances the autonomy that a neoplasm possesses may be quite subtle and relative only to the tissue from which it arose.
However, it should be emphasized that this phrase, relatively autonomous, is, together with the heritable nature of neoplasia, the most important aspect of the definition and characterizes a par- ticular cell type as being neoplastic in the general sense. Relative autonomy is used here in the biological sense, but it is anticipated that one day we will understand it in the molecular sense; when we do, we will probably understand the mechanisms of the malignant process itself.
The next essential component of the definition is the term growth. Here this term may indicate the rate of cell division as modified by the rate of cell death (apoptosis, see below) or the rate of intracellular processes involved in the synthesis of macromolecules for use within the cell or for excretion by the cell. The actual rate of growth may be extremely low, differing little from that in the normal counterpart of the neoplasm; or, in the most serious cases, the rate may be extremely rapid, approaching that of the growth rate of embryonic tissue. In some instances, as with neoplasms of the small intestine or certain chronic leukemias (see below), the rate of growth of the neoplastic cell may even be less than that of its normal counterpart. Obviously, if the cells of a neoplasm do not proliferate to a point where the tumor is grossly or histologically recognizable, it is practically impossible to designate the cellular population as neoplastic. Thus, enhanced cell replication and/or decreased cell death becomes a part of the operational defini- tion of neoplasia. Furthermore—from the results of a number of experiments and clinical obser- vations—we recognize that neoplastic cells may exist for a lifetime in the host without ever undergoing demonstrable cell division (Chapter 10).
The final component of the definition is the term tissue, which stems from the fact that, at our present state of knowledge, cancer or neoplasia can be defined only in a multicellular organ- ism. By this definition, unicellular organisms are free of the disease. In this sense cancer may be called “the curse of evolution.”
The definition of neoplasia proposed by Ewing in the mid-1930s was that of a pathologist knowledgeable in the biology of cancer as expressed in vivo. Today, the in vivo system is still the basic reference for our definition of the neoplastic cell. On the other hand, with the recent advances of carcinogenesis in vitro, characteristics of the cancer cell as it grows in tissue culture have been described (Chapter 14). Although it is not yet possible to define the malignant cell in vitro without reference to its behavior in vivo, an ultimate goal of experimental oncology is to elucidate the molecular definition of the cancer cell regardless of its environment.