The term hyperplasia has been used to denote an increase in cell number. Hypertrophy indicates an increase in cell size but not in cell number. Although many neoplasms are characterized by hyperplasia, many normal tissues are also characterized by a dramatic increase in cell number. Embryonic tissue has perhaps the fastest rate of hyperplasia, but some adult tissues, especially those involved in certain metabolic functions—such as the crypt cells of the small intestine, cells of the bone marrow, and, to a lesser extent, the cells of the basal layer of the skin—are normally hyperplastic. In reactions such as wound healing and callus formation, hyperplasia is a normal process. Thus, hyperplasia may occur in cancer but is not a unique characteristic or even an ab- solute requirement of neoplasia.
Metaplasia is a process in which one adult, differentiated cell type in a specific organ or organ structure is replaced by another differentiated cell type. In most instances the secondary or re-placing cell type is not normally seen in the particular region in which the metaplasia occurs. Metaplasia may be either epithelial or mesenchymal and has been observed in a wide variety of reactive and neoplastic human tissues (Willis, 1962; Leube and Rustad, 1991). In recent years developmental biologists have referred to this process as “transdifferentiation,” which refers to changes occurring not only in the adult but also in the developing fetus and newborn (Okada,
1986). Thus, as might be expected, the potential pathways of transdifferentiation are somewhat more complex, since the cells involved usually have a greater potential for differentiation. Okada points out that transdifferentiation is “principally an irreversible process.” However, in the adult, the “operational reversibility” of metaplasia does occur (see below).
There are several known and presumed mechanisms of metaplasia. Lugo and Putong (1984) have proposed that the abnormal differentiation of metaplasia could occur by several pathways. These can be seen in Figure 2.1. Stem cell metaplasia results from the differentiation of immature, undifferentiated stem cells, which are present in tissues for the purpose of repairing and replacing mature cellular loss, along a new pathway leading to abnormal differentiation. This has generally been considered to be the mechanism most often involved in metaplasia, es- pecially in epithelial metaplasia. A second possible pathway has been termed direct metaplasia, which was originally proposed by Virchow (1853) and is the result of normal, mature, differentiated cells being converted in the absence of cell division directly into another mature differentiated cell type. Finally, indirect metaplasia involves the formation of intermediate cells, which are still capable of proliferation and differentiation, differentiating into a new or abnormal cell type. Lugo and Putong (1984) have described several examples of these various types of metaplasia.
The most common example of epithelial metaplasia is in the change of columnar or pseu- dostratified columnar epithelium of the respiratory tract to squamous epithelium. This phenome- non is known as squamous metaplasia and may result from numerous stimuli, among which are chronic irritation and inflammation. In this particular example, the mechanism of metaplasia of respiratory epithelial cells is most commonly the result of stem cell metaplasia. However, stud- ies by McDowell et al. (1979) suggested that metaplasia may arise from fully mature cells, such as mucus-secreting cells, which are still capable of cell division. But more recent findings have indicated that an indirect mechanism of metaplasia (Figure 2.1) may play a role in this process (Leube and Rustad, 1991).
In the respiratory epithelium, the stem cell normally gives rise to pseudostratified colum- nar epithelium, but in the presence of certain stimuli it may differentiate into squamous epithe- lium. The lack of vitamin A may be associated with such squamous metaplasia, since animals deficient in this vitamin show extensive squamous metaplasia of mucous columnar epithelium; treatment with vitamin A may reverse the squamous metaplasia. The appearance of mucous co-
Figure 2.1 Scheme of potential pathways of metaplasia in a tissue composed of A cells to a tissue com- position of B cells. (1) proliferation and differentiation; (2) the path of direct metaplasia; (3) indirect meta- plasia; (4) stem cell metaplasia. (From Lugo and Putong, 1984, with permission.)
lumnar epithelium and its conversion to squamous epithelium by vitamin A deficiency, with its reversal to its original form when vitamin A is again added to the diet, is shown schematically in Figure 2.2. The mechanism of this metaplasia also appears to result from redifferentiation of certain stem cells (shown as small black nuclei along the basement membrane) of each of the epithelia. Because these epithelial cells are constantly being replaced by progeny of the stem cells, in the absence of vitamin A or in the presence of some chronic stimulus as yet undefined, the differentiation of the stem cell may be redirected to the more primitive squamous epithelium. In the presence of vitamin A or some other unknown environmental factor, normal differentia- tion of the stem cell may recur. It should be noted, however, that once a cell begins on the path- way of differentiation toward either a squamous cell or a columnar cell, the process appears to be irreversible, as predicted in the definition of transdifferentiation (see above). A further discus- sion of the effect of vitamin A on carcinogenesis may be found in Chapter 8.
Another interesting example of epithelial metaplasia induced by a specific experimental protocol is the differentiation of regenerating pancreatic cells into hepatocytes identical with those present in normal liver (Scarpelli and Rao, 1981). Rao and associates (1988) have demon- strated that adult rats maintained on a copper-deficient diet for several months and then returned to a normal diet exhibit an almost complete loss of pancreatic acinar cells and the development of multiple foci of hepatocytes during the recovery phase. Cossel (1984) has suggested that this metaplasia is the result of the redifferentiation of “intermediate” cells seen in the adult pancreas of mammals, including the human. By Cossel’s thesis, this epithelial differentiation would be classified as indirect metaplasia (Figure 2.1).
Mesenchymal metaplasia, like epithelial metaplasia, may result from any of the mecha- nisms seen in Figure 2.1. Examples of the conversion of epithelial cells to mesenchymal cells, mesenchymal cells to epithelial cells, and mesenchymal cells of one differentiated form to that of another have been described (cf. Lugo and Putong, 1984). In fact, these authors have sug- gested that, under appropriate environmental circumstances, a given cell, by the process of meta- plasia, may exhibit epithelial or mesenchymal characteristics regardless of the tissue of origin. Metaplasia may also occur in cell culture, since it is possible to alter the differentiated state ex- perimentally by a variety of methods of cell biology (Blau, 1989). It is not surprising that meta- plasia occurs in adult tissues under a variety of different circumstances.
Figure 2.2 Artist’s representation of the morphological changes occurring in the metaplasia of ciliated columnar epithelium to squamous epithelium in vitamin A–deficient animals and the subsequent rediffer- entiation of the squamous epithelium to columnar epithelium in the presence of vitamin A.