Robbins (1974) defined dysplasia as “an alteration in adult cells characterized by variation in their size, shape, and organization.” More recently Rubin and Farber (1988) have defined dys- plasia as being distinct from normal cell and tissue organization “by variations in the size and shape of the cells; by enlargement, irregularity, and hyperchromatism of the nuclei; and by dis- orderly arrangement of the cells within the epithelium.” Furthermore, Walter and Israel (1979), as well as Rubin and Farber (1988), have pointed out that the term dysplasia has been used by some pathologists to designate abnormalities in the development of tissues, although not always strictly with reference to developmental disorders. Because this variation in definition may be somewhat confusing, we have chosen to use the term anaplasia in a manner similar to that uti- lized by Ritchie (1970). Anaplasia is characterized at two different biological levels: (1) inter- cellular relations and associations, as described below, and (2) alterations in intracellular macromolecular syntheses.
Positional or organizational anaplasia refers to the interrelations of cells in a specific tis- sue. Normally, there are distinct histological patterns in tissues. When positional anaplasia occurs, these distinct patterns are altered in that either cell organelles are arranged randomly with respect to one another in adjacent cells or the cells themselves are disarranged with respect to one another.
Cytological anaplasia is largely a function of increased or altered nucleic acid synthesis in growing tissues. This term usually refers to the staining characteristics of cells, especially with respect to basophilia and the nuclear/cytoplasmic ratio. Cytologic anaplasia may also be a func- tion of the ploidy of the cell; it is seen normally in the placenta, in a callus, and occasionally in wound healing. Evidence by Therman et al. (1983) indicates that processes giving rise to differ- ent sizes and types of nuclei seen in the cytological anaplasia of neoplastic cells include en- doreduplication, true endomitosis, and a sort of polytenization. All of these latter processes result in nuclear enlargement from increased DNA content. Cytological anaplasia is extremely important in the cytological diagnosis of malignancy (Pap test). However, it should be empha- sized that, since normal tissues may exhibit cytological anaplasia as well as positional anaplasia, this phenomenon is not an absolute characteristic of malignancy.
Figure 2.3 is a conceptual drawing of both positional and cytological anaplasia. The art- ist’s conception demonstrates that in positional anaplasia there is an alteration in the distribution in space of cell organelles within a specific tissue or epithelium or in the spatial relation of one cell or group of cells to another within a tissue. Cytological anaplasia is shown as a distortion of cellular architecture compared with the normal cell type and is characterized by intensified staining (denoted by the darkened nuclei) of the nucleus and cytoplasm of the cell. The student should be aware, however, that in many neoplasms both positional and cytological anaplasia oc- cur simultaneously.
Another process, which histologically may be mistaken for cytological anaplasia, is a pro- cess of “controlled cell deletion” or programmed cell death occurring coincidentally with nor- mal physiological processes within a tissue. Kerr et al. (1972) employed the term apoptosis to refer to this process, which plays a complementary but opposite role to mitosis in the regulation of animal cell populations. Specific morphological changes occur in cells undergoing apoptosis (Wyllie, 1981, 1988). The first of these involves a rapid loss of the volume of the cell as well as a condensation of the chromatin with subsequent fragmentation and phagocytosis by macro- phages or a similar process by parenchymal cells. Figure 2.4A is an artist’s conception of the formation and fate of apoptic cells of an epithelial parenchyma such as that of liver. In the lower portion of the figure are shown simple morphological changes occurring during necrosis, which involves an initial generalized swelling and subsequent dissolution of organelles with final rup- ture of plasma membranes (Corcoran et al., 1994).
Figure 2.3 Artist’s representation of positional and cytological anaplasia. In positional anaplasia (cen- ter), in a single layer of epithelium, the altered position of nuclei in relation to one another in adjacent cells is depicted, as well as the altered position of ducts and glands in a specific representative structure. Cyto- logical anaplasia (right) is noted by the marked variation in nuclear size and staining characteristics, nucle- olar size, and nuclear/cytoplasmic ratio. Normal histology is shown at the left.
The apoptotic process in tissues is rapid, with complete disappearance of all phagocytosed cells within 4 hours (cf. Fesus et al., 1991). Apoptosis is to be distinguished both morphologi- cally and biochemically from cell necrosis, which is cell death resulting from unphysiological external environmental toxic factors. While there is some overlap both in occurrence and charac- teristics, certain general differences between the two processes can be noted (Table 2.1). Apop- tosis occurs spontaneously during embryological development and in a variety of normal tissues (cf. Wyllie, 1974). This process also occurs during involution of normal tissues, such as lactating breasts in rodents (Walker et al., 1989), as well as in hormone-induced cell death (Morris et al., 1984) and in the process of immunocyte-induced cell death (Wyllie, 1988). This process also occurs spontaneously in untreated malignant neoplasms but may be triggered in both normal and neoplastic cells by a variety of environmental agents including cytotoxic drugs (Schwartzman and Cidlowski, 1993) and promoting agents (Chapter 7). Apoptosis is a genetically directed pro- gram of cell death in contrast to necrosis, and there are distinctive morphological as well as mo- lecular differences between the two processes (Table 2.1 and Chapter 7).
As implied by the information in Table 2.1, the mechanism of apoptosis is significantly different from that of necrosis. A very important difference is the fact that gene expression is required for apoptosis, and the expression of a number of genes has now been implicated as a requirement for apoptosis in one or more tissue types (Schwartzman and Cidlowski, 1993; Hen- gartner, 2000). In neoplasms, apoptosis occurs spontaneously, although in a more haphazard and presumably autonomous manner than seen in normal tissues.
We have defined a neoplasm, and thus neoplasia, as a heritably altered, relatively autonomous growth of tissue. In the next sections, as we consider the classification of neoplasms, certain contradictions may become apparent. It should be emphasized that all neoplasms, regardless of their biological behavior, are components of the disease classification of neoplasia. In this sense the terms cancer and malignancy may occasionally be incorrectly used synonymously with neoplasm or neoplasia. This may be done without reference to the biological behavior of the
Figure 2.4 (A) Diagrammatic illustration of the morphological features of apoptosis of parenchymal cells of a glandular tissue. (Adapted from Kerr et al., 1972, with permission of authors and publisher.) (B) Diagram of parenchymal cell necrosis from a normal cell to the initial phase of generalized swelling progressing to a dissolution of organelles and final rupture of plasma membranes. (Adapted from Corcoran et al., 1994, with permission of authors and publisher.)
neoplasm, and for this reason the student must be on guard to ensure that the actual meanings of these terms are clear when they are used.