Metaplasia

METAPLASIA (from Greek metaplasso - transform), a term introduced into pathology by Virchow, who in 1871 in general terms, and more specifically and precisely at the medical congress in Copenhagen in 1884, defined the concept of metaplasia as the transformation or alteration of the character of a given tissue while preserving its cells ("Veränderung des Gewebscharakters unter Persistenz der Zellen"). In general, Virchow applied the term metaplasia to very diverse cases, and on the question of the limits of metaplasia, he set very broad boundaries for the change in tissue character; in particular, he even admitted the possibility of the transformation of connective tissue elements into epithelial ones. After Virchow, the question of metaplasia underwent thorough morphological and experimental development; however, it must be acknowledged that even to the present time, many disagreements and ambiguities remain in this matter, for example, in the sense of the exact definition of the concept of metaplasia, the recognition of the boundaries of this tissue change, terminology, and so on. It can only be noted that after Virchow, the term metaplasia began to be applied more cautiously, and at the same time it became possible to clarify this concept and isolate a whole series of other similar tissue changes not belonging to metaplasia. Lubarsch (1901), striving to classify all types of morphological tissue changes united by him under the term "alloplasia," divides them into the following three categories: 1) pseudometaplasia, by which is meant a change only in the shape of cells (now called histological accommodation); 2) metaplasia, representing a true transformation of specific tissue structures into specific structures of a completely different kind, although belonging to a homogenous tissue; 3) dedifferentiation (Entdifferenzierung) of tissue, based on the transformation of highly differentiated cells into less differentiated ones. An even greater clarity into the conception of metaplasia was attempted to be introduced by Schridde, who, working on the question of changes in the character of epithelium (ortsfremde Epithelbildung), came to the conclusion that from the concept of "formation of epithelium alien to the given site," the following are subject to exclusion: a) formal accommodation, manifested in a change only in cell shape, and b) prosoplasia, representing the maturation, further differentiation of epithelium (see below). The formation of epithelium alien to the given site, according to Schridde, manifests itself in only two forms: 1) heteroplasia, expressed in the formation of epithelium uncharacteristic of the given site in the order of abnormal development (formation of gastric mucosa islands in the esophagus, formation of intestinal mucosa islands in the stomach); 2) indirect metaplasia, manifested in the change of differentiated epithelium in the sense of its acquiring the properties of another type of epithelium during cell multiplication. Subsequently, researchers came to the conclusion that metaplasia is a change in tissue of such a kind when a mature, fully differentiated tissue acquires in morphological and functional respects the character of another tissue. In connection with this, it became clear that metaplasia has nothing in common with the change of tissue occurring in the order of embryonic differentiation. From the heteromorphosis of tissues, which takes place in lower animals, metaplasia differs in that it concerns mature, rather than embryonic tissues. Furthermore, metaplasia does not include the change in cell shape, now usually called histological accommodation (see Histological accommodation), and at one time called allomorphy or dysmorphy by Orth. Neither can embryonic tissue displacements, i.e., aberrations or heterotopias (see), called allotopias or dystopias by Orth, be confused with metaplasia, nor the appearance of tissue uncharacteristic of a given site in the order of its abnormal development, which Schridde called heteroplasia (see above). It must also be noted that metaplasia certainly does not include those cases where some tissue, proliferating, destroys and replaces another tissue, locating itself in place of the latter. Nor can the term metaplasia be applied to those changes in tissue character that occur in the order of physiological or pathological involution, as for example takes place in the thymus gland, bone marrow, and so on. Some exclude from the concept of metaplasia yet another example, extramedullary development of myeloid tissue (in the spleen, liver, lymph nodes, and other places) on the grounds that here it is not a question of changing the character of the entire tissue as such, but only of a local variation based on the multiplication and corresponding differentiation of only certain cells. As regards the limits of metaplasia in humans, it was established soon after Virchow that they are very limited. If in the heteromorphosis of lower animals the possibility of tissue character changes within very wide limits is proven, then in relation to metaplasia, the majority of pathologists and biologists have constantly put forward Waldeyer's rule of the specific productivity of tissues ("omnis cellula e cellula ejusdem generis"), according to which in a formed organism, tissue developed from a certain germ layer does not pass into tissue belonging to another germ layer; for example, epithelium does not pass into connective and muscular tissue, and conversely, connective and muscular tissues do not pass into epithelium. In general, metaplasia in higher animals, particularly in man, indeed usually takes place only within each of the two types of tissues: in epithelial tissue, in which metaplasia of one type of epithelium into another is possible, and in connective tissue, in which metaplasia can occur into tissues belonging to the middle germ layer, i.e., into myeloid, adipose, mucous, cartilaginous, osseous, and muscular tissues; in connective tissue, autochthonous formation of blood vessels is also possible. Very diverse types of metaplasia, however, still, as generally believed, within the limits of the aforementioned tissues, are observed in tumors. It must be recognized that in recent years observations have accumulated speaking in favor of the fact that in higher animals, particularly in humans, exceptions to the rule of the specific productivity of tissues do take place. For example, there is very weighty reason to think that during inflammatory, regenerative, and blastomatous proliferations of epithelium, its cells can metaplasticize into connective tissue elements; in other words, young epithelial cells turn into connective tissue elements similarly to how elements of mesenchyme are formed from the ectoderm of the embryo (desmoplasia of epithelium, according to Kromayer, mesenchymoplasia of epithelium, according to Koritsky). As Lubarsch asserts (1930), the possibility of metaplasia in the reverse direction is also theoretically admissible, i.e., the formation of epithelium from connective tissue elements, which Virchow admitted 50 years ago. Lubarsch, just like Virchow, believes that when discussing the question of the limits of metaplasia, there is no need to approach its solution with premises drawn from embryology and developmental mechanics; the conditions in which a cell finds itself during pathological tissue changes are so peculiar and unusual that they have no analogy in the course of normal development and life of cells. In general, pathological conditions reveal that the prospective potency of cells is much wider and more diverse than normal conditions of multiplication and existence of cells discover. Thus, the majority of modern pathologists define metaplasia as a change in the character of mature, fully differentiated tissue, and as a result of this change, a tissue of another type appears, with other structural and functional features, although in most cases belonging to the same type of tissue. From the point of view of formal genesis, two types of metaplasia are accepted: 1. Direct metaplasia, the basis of which lies the change in tissue character without cell multiplication (possibly by means of saltatory mutation of them). A typical example of this kind of metaplasia is the transformation of connective tissue into bone without any participation of bone-forming elements (in scars, intermuscular tissue, etc.). It is assumed that here the collagenous substance turns into osteoid, which subsequently petrifies; simultaneously, connective tissue cells acquire the character of bone corpuscles. 2. Indirect, or neoplastic metaplasia, associated with cell multiplication; in it, two phases are distinguished: a) cell multiplication (neoplastic phase) with the formation of young, poorly differentiated cellular elements; b) differentiation of these elements in a new direction with the formation of a tissue differing to one degree or another from the former tissue (metaplastic phase). The difference of the newly formed tissue from the former can be of a twofold nature, in connection with which two types of indirect metaplasia are distinguished: 1. In some cases, during the differentiation of the newly formed tissue, its development reaches a higher degree than was characteristic of the former tissue; this is designated as progressive, prosoplastic metaplasia. Examples of this can be considered: the formation of hepatic tissue during the multiplication of bile duct epithelium, the formation of stratified squamous keratinizing epithelium in place of cubic or polymorphic (transitional) epithelium; the formation of ciliated columnar epithelium from the squamous epithelium of serous membranes; the development of smooth muscle fibers from connective tissue; 2.

In other cases, the differentiation of the proliferated cells does not reach the degree of development of the preexisting tissue, and the newly formed tissue turns out to be at a lower stage of development; this is called regressive or anaplastic metaplasia. Examples of it are the formation of bile ducts from proliferating liver cells; the formation of a polymorphic or single-layer cubic epithelium in place of a stratified keratinizing epithelium; the development of a stratified squamous epithelium in place of a ciliated columnar epithelium, as well as the transformation of muscle tissue into fibrous connective tissue; the transformation of epithelial cells into connective tissue cells. Tumors provide numerous examples of anaplastic metaplasia. In general, cell proliferation, which lies at the basis of indirect metaplasia, has a regenerative character in the majority of cases; therefore, one can speak here of manifestations of atypical regeneration, regenerative dysplasia (Krompecher), or regeneration with tissue dedifferentiation. It must be added that the division of metaplasia into direct and indirect is not entirely established. Great doubt is raised by the existence of direct metaplasia; more and more facts are accumulating which suggest that any metaplasia proceeds with cell proliferation (Pozharisky and others). On the other hand, some investigators (Bostroem, Wilms) have spoken out in favor of the fact that indirect metaplasia specifically is unproven, and have advanced the assumption that in all cases relating hereto it is simply a matter of the development of germ cells present in almost every tissue that were not used during embryogenesis. It goes without saying that the latter assumption is completely incorrect; for the manifestation of metaplasia, not only are embryonic cells not needed, but there is even no basis to believe that metaplasia can originate only from elements that remain undifferentiated or poorly differentiated (for example, from the so-called germ layer of the epithelium); after all, any cell division results in the formation of young, undifferentiated elements capable of developing in a new direction. It should also be noted the disagreement existing among authors regarding the term "prosoplasia" proposed by Beneke to designate those cases where it is not a matter of a change in the character of the tissue, but of the maturation of a tissue that had previously stood at a lower stage of development. For example, according to Schridde, the so-called transitional epithelium of the urinary tract is an underdeveloped stratified squamous epithelium; therefore, if the epithelial lining of the urinary tract acquires the character of a stratified keratinizing epithelium, then this is not metaplasia, but merely maturation, prosoplasia of the tissue. Many investigators also use the term "prosoplasia" in this sense and thus, as it were, contrast prosoplasia with metaplasia; in contrast to this, other investigators do not find sufficient data to distinguish between the concepts of prosoplasia and prosoplastic metaplasia in relation to the mature organism. A similar ambiguity exists regarding the terms anaplasia and anaplastic metaplasia; some investigators identify these terms, others separate them. When separating the concepts of prosoplasia and anaplasia from metaplasia, one obtains a division of all types of changes in the morphological character of mature tissue into three groups: 1) prosoplasia—maturation of tissue; 2) anaplasia—dedifferentiation of tissue; 3) metaplasia—change in the type of tissue. However, such a subdivision can hardly be considered correct; insofar as it is difficult to admit that in the mature organism the processes of prosoplasia and anaplasia can proceed without cell proliferation, it is difficult to draw a boundary between them and metaplasia; upon this is based the identification of prosoplasia with progressive prosoplastic metaplasia, and of anaplasia with regressive anaplastic metaplasia. As for dedifferentiation, which some investigators (Lubarsch) categorically separate from metaplasia, here it must be borne in mind that various tissue changes can be understood under this term; some of them correspond to anaplasia, while others, essentially very close to atrophy, relate to those cases when there is no change in the character of the tissue, but only the loss by cells of structures relating to their differentiation, and their acquisition of a similarity with earlier stages of development of these same cells. The latter kind of cell change does not relate to metaplasia. Koritsky gives the concepts of metaplasia and anaplasia a different definition than is generally accepted; in his opinion, metaplasia is a change in the character of tissue within the limits of a species, and anaplasia is a change in the character of tissue within the limits of a genus. It can be said that some (Krompecher) find the term metaplasia generally superfluous. It should be noted that the above-mentioned disagreements are partly connected with the dissimilar attitude of investigators to the very concept of metaplasia and to what can be considered a change in the character of tissue in morphological and functional relations, and partly with the fact that there are not a few cases that are difficult to qualify and are attributed by some authors to one category, and by others to another. Borst points out that in relation to each case of a change in the character of tissue, very strict criticism is needed in order to recognize metaplasia or pseudometaplasia or something else entirely. The causes of metaplasia, or rather the environment in which tissue metaplasia occurs, reduce to changes in the environment and conditions of existence of a given tissue. Indirect metaplasia, in the majority of cases closely associated with regenerative cell proliferation, can be observed in all those cases when there has been a preceding death of a portion of the cells; most often this concerns chronic inflammatory processes and frequently repeating traumas. At the same time, a change in the function of the tissue is of extremely great importance for the metaplastic change in the character of the tissue. A change in the functional conditions of the existence of tissue is the main basis for direct metaplasia as well. The mechanism of metaplasia can be studied particularly well in cases of metaplasia of the covering epithelium. Thus, the metaplasia of the columnar epithelium of the bronchus into a stratified squamous epithelium, observed in certain bronchitises (in measles, influenza, inhalation of asphyxiating gases), proceeds in such a way that during the inflammatory process in the wall of the bronchus, a portion of the epithelial cells dies off; the latter is accompanied by regeneration, expressed in the proliferation of the preserved basal cells of the epithelial lining. However, the newly forming epithelial tissue finds itself in new functional conditions associated with a different pressure in the lumen of the bronchus and the presence in it, instead of air, of an exudate (usually in these cases thick, frequently fibrinous), acting on the epithelium mechanically and chemically; in connection with this, the differentiation of the growing epithelium proceeds in a different direction, revealing new structures with a different function, specifically—in the sense of the formation of a stratified squamous epithelium instead of a columnar one. In this process, it is easy to see the manifestation of the interaction of function and form. The metaplasia of the columnar epithelium of the trachea into a stratified squamous epithelium when wearing a tracheostomy tube, the metaplasia of the polymorphic epithelium of the renal pelvis into a keratinizing stratified squamous epithelium in kidney stones, pyelitis, tuberculosis of the pelvis (here the functional conditions of the existence of the epithelium change in connection with the mechanical and chemical influence of foreign material—a tube, a stone, an exudate), as well as the metaplasia of the epithelium of the mucosa of the urinary bladder and uterus during their prolapse and inversion, are explained in the same way. The same thing is present during processes of metaplasia in connective tissue: inflammatory and traumatic irritations in combination with changed functional conditions can explain many cases of the metaplasia of connective tissue into smooth muscles (for example, in frequently stretched adhesions of the abdominal cavity, in scars of lung tissue), as well as the transformation of connective tissue into bone—in scars, around foci of necrosis, in intermuscular cellular tissue (for example, the formation of cavalry bone in the adductor muscles of the thighs, riflemen's bone in the deltoid muscle of the right shoulder). In all these cases, the intimate essence of the process of metaplasia consists in the gradual differentiation of proliferating cells in a new direction depending on a change in function. In addition to a change in local conditions, a disruption of the general state of the organism can also be the cause of metaplasia. Thus, metaplasia of the conjunctiva of the eyes into a keratinizing stratified epithelium ("xerophthalmia") takes place in vitamin A deficiency; besides, some investigators experimentally obtained in rats the metaplasia of the columnar epithelium of the respiratory and urinary tracts into a keratinizing squamous epithelium when feeding animals a diet devoid of vitamins A and D. Whether saltationist mutational changes in the character of cells are of significance in metaplasia cannot yet be considered established. Regarding the anaplasia of tumor cells, see Tumors.