Paper - On the nature, occurrence, and identity of the plasma cells of Hofbauer (1918)
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Meyer AW. On the nature, occurrence, and identity of the plasma cells of Hofbauer. (1918) J Morphol. 32(1): 327-350.
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On the Nature, Occurrence, and Identity of the Plasma Cells of Hofbauer
Arthur William Meyer
Department of Embryology, Carnegie Institution of Washington, and Department of Anatomy, Stanford Medical School
The history of these cells illustrates very well how a re-discovery, when accompanied by a fuller description, succeeds in domiciling itself in anatomical literature as an original discovery. As we shall presently see, Hofbauer ('05) was impressed especially by a conspicuous phase in the life history of a particular cell. He noted its reaction in the fresh state, to certain stains, described it more fully, and speculated with some freedom on its functional role; but he did not discover this cell, as he supposed, in 1903. Although Hofbauer refers to his address given in 1903 in his book published in 1905, he does not refer to or list the paper based on this address, published in 1903, in the title of which he refers to these cells as ' hitherto unknown ' and as ' constantly occurring.' His failure, in 1905, to recognize earlier workers was, I presume, an oversight, which apparently led Essick ('15) and others to assume that "Hofbauer first called attention to specific round cells appearing in the human placenta toward the end of the fourth week of pregnancy. "
The type of cells which in recent years has been designated with Hofbauer's name was known previously especially as Wanderzelle and had been represented by various investigators. Minot ('12), in a footnote, refers to the latter fact and rightly adds: "It has long been known that strikingly large free cells appear in the mesenchyme of the chorion. They are pictured in my Human Embryology." Reference to the illustration in this work shows a large, rather granular cell, with a somewhat eccentrically placed, vesicular nucleus, but without vacuoles. Moreover, previous to the publication of the Embryology,
Minot ('89) not only spoke of large, granular, wandering cells in the stroma of the chorion, but also represented them. From Minot's familiarity with the work of Langhans ('77) and of Kastschenko ('85), it does not seem unlikely that, among others, he had these investigators particularly in mind when he referred to the earlier descriptions.
In the absence of a more discriminating term for these erratic and ephemeral elements, the original designation of wandering cell would seem far preferable to the designation lipoid interstitial cells, used by certain Italian writers. The former is a non-committal term, and, although too inclusive, is for this reason no more objectionable than the expression giant-cell. Although these cells may not — indeed, probably do not — wander in the sense of the amoeba or the leucocyte, they nevertheless may change their location decidedly. The qualification, intersititial, is objectionable for the very reason for which it was chosen — the alleged analogy to the interstitial cells of testis and ovary, and since they may contain lipoid substances merely because they are degenerate, the adjective lipoid is equally objectionable. For reasons to appear later, the designation plasma cell, used by certain Italian writers after Hofbauer, would not seem to be justified.
Virchow ('67) stated that isolated cells with clear vesicular spaces in their protoplasm are found in the stroma of the villi in cases of hydatiform degeneration, and identified them with certain other cells, physaliphores — previously described by him. He found these bubble-like cells, as he called them, also in the thymus of the new-born, in cancer, etc., and, according to Virchow, they were not merely vacuolated cells. He seems to have regarded these cells as identical also with the vacuolated syncytial masses, for he stated that Miiller described them as occurring in the chorionic epithelium. Since syncytial elements not rarely are found in the stroma, instances of confusion of these two cell types can be found in contemporary literature also.
Langhans ('77), in describing the stroma of the villi, said that it contained sharply delimited large cells with many granules in the protoplasm. Their form is variable — circular, spindle and star-shaped." These cells were said to lie mainly near the periphery. However, Langhans, who was interested mainly in other problems, did not represent them nor discuss their probable significance. But Kastschenko ('85) represented them and described them as being about 9/x large, and as corresponding exactly in form and size to the white blood cells of the same embryo. According to Kastschenko, the cytoplasm is reduced in quantity after the first month, so that the nucleus no longer is surrounded by it. The nuclei, also, are said to undergo a change and to appear later as solid structures. The latter observation cannot fail to remind one of pycnosis and of one of its well-known significances. Kastschenko found these cells mainly near the epithelium of the villi and stated that they vary greatly in size, number, and occurrence in the same placenta. The fact that Kastschenko identified the cells found in the mesenchyme of the embryonic villi as leucocytes might seem to indicate that what he saw and described were other than Hofbauer cells. However, his illustrations, especially when considered in connection with those of earlier investigators and those of Minot, leave little doubt that all these investigators saw the same type of cell. Moreover, it is not improbable that Kastschenko was influenced in his interpretation of these cells by the origin and current use of the term Wanderzelle. It will be recalled that von Recklinghausen ('63) showed that the leucocyte preeminently belonged in this class of cells, but even at the time that Kastschenko was writing and far later, all cells which were regarded as foreign to the tissue in which they lay still were included in the designation Wanderzelle. Reference to the literature of that period will make this fully evident.
The presence of these cells in pathologic 'ova' was noticed repeatedly by Mall ('08), who also designated them as wandering or migrating cells in his earlier protocols. Chaletzky ('91) also saw and described these cells, but perhaps the best description from an earlier date is that given by Kossman ('92), who also refered to the HofJDauer cells as Wanderzellen, and gave excellent representations of them. Indeed, from an inspection of the latter alone there can be no question as to the identity of these Wanderzellen and the Hofbauer cell. In speaking of them, Kossman said :
. . . . Auffallend sind zahlreiche grosse Zellen, die eine sehr wechselnde, oft amoboide, niemals sternformige Gestalt haben. Die Filarmasse ihres Protoplasma's ist durchaus fein netzartig angeordnet und farbt sich stark in Hamatoxylin. Die Zellen enthalten einen oder mehrere grosse blasenartige Hohlraume, von denen ich 'eider nicht sicher sagen kann, ob sie Fett fiihrten, da sie mir erst nach Behandlimg des Praparats mit Xylol auffielen. Der Kern dieser Zellen enthielt stets Nucleoli. Die Zellen sind also jedenfalls nicht in lebhafter Vermehrung; wahrscheinlich sind es Wanderzellen und da sie auf einem wenig alteren Stadium wieder fehlen, mag ihr Vorkommen in einigem Zusammenhange mit der um diese Zeit beginnenden Vascularisation des Stroma's stehen.
Merttens ('94) found the same cells in abortuses, and, in describing the stroma of the villi of his first case said :
An den Ernahrungszotten ist es kernreich, vielfach aufgelockert, mit stern- und spindelformigen Zellen, in den Maschen jene oben flir die normalen ersten Stadien beschriebenen grossen, runden oder polyedrischen Zellen mit kornigem oder auch vacuolarem Protoplasma mit grossem, blaschenformigem, rundem Kern.
Merttens seems also to have suggested that these cells are swollen stroma cells, but since he made this observation somewhat disconnectedly I am not quite certain of his meaning; yet the mere suggestion is particularly interesting in view of Minot's special emphasis upon the degenerate character of the Hofbauer cells. Marchand ('98) also wrote: Die durchsichtigen hellen Zellen im Stroma normaler oder pathologischer Zotten sind mir wohlbekannt, sie konnen denen der Zellschicht sehr ahnlich sein; ich halte sie jedoch fiir gequollene, rundlich gewordene Bindegewebszellen, da mann IJbergange zu solchen findet, ebenso wie in andern Schleimgeweben. "
Ulesco-Stranganowa ('96), who also saw these cells, says that if one compare the Langhans cells with round nuclei with these cells scattered about the stroma of the villi, and which have been named Wanderzellen by Kastschenko, one becomes convinced of the identity of these two types of cells. According to Ulesco-Stranganowa, then, the Hofbauer and Langhans cells are identical. Mall ('15) also called attention to this possibility, for, when speaking of the invasion of the mesoderm of the villi by trophoblast, he called attention to the presence of numerous Hofbauer cells, and added: "It would seem possible that these Hofbauer cells are free trophoblast cells within the mesoderm of the villus, an opinion already expressed in my paper on monsters." Neumann ('97) also noticed these cells and referred to Virchow's opinion regarding them, and von Lenhossek ('02) is credited in 1904 by the reviewer of his paper with having examined a large series of young human embryos, and having suggested that what Kastschenko regarded as Wanderzellen were mesenchyme cells. It should be noted, however, that von Lenhossek apparently came to this conclusion largely because of the absence of blood-forming organs or lymphatic centers in embryos the villi of the chorionic vesicles of which contained these cells. Strangely enough, Kworostansky ('03) also recorded the presence of these cells, and after describing the stroma of the villi wrote:
Zwischen den genannten Bindegwebszellen giebt es in der wolkigen Grundsubstanz Liicken, und am Rande oder im Winkel derselben sitzen freie andere Bindegewebszellen, die sehr gross sind, lappige, runde Form, wabenartiges Protoplasma und gleiche Kerne wie andere Bindegewebszellen haben; ihre Kerne werden auch, hie und da sternformig getheilt. Da sie stets nur in Gewebsliicken gefunden werden, so glaube ich, sie als Lymphgefassendothelien, oder vielleicht als Lymphocyten bezeichnen zu diirfen. Man findet sie in spateren Stadien der Placenta nur sind dann naturlich die zellen nicht mehr gross.
The illustration which accompanies Kworostansky's article, as well as his description, leaves no doubt that the cells seen by him are the same as those which we are considering, although his surmise that they are lymphocytes and that they arise from the endothelium of the lymphatics may, upon first thought, seem rather irreconcilable with such an interpretation.
From these references alone it is evident that Minot's statement, that the so-called Hofbauer cells were repeatedly mentioned in the earlier literature, is well founded. Muggia ('15) states that these cells were described also by Guicciardi ('99), Clivio ('03), Stoffel ('05), ^ Vecchi ('06), and Pazzi ('04). Indeed, many other names could be added, for surely any one of the many who studied even a small series of chorionic vesicles must have seen some of them in some villi, especially in unrecognized cases of hydatiform degeneration, but since they have been referred to as Hofbauer cells, it is his description that especially interests us. In describing the chorionic villi, Hofbauer ('05) spoke of certain gaps or spaces between the meshes of the mesenchyme of the villi which he thought might belong to the lymphatics or contain tissue fluid. In these spaces he found certain granular, round cells arranged longitudinally. He thought they often were spherical wdth a diamenter of 10.5 n to 12.5 fx but more commonly star-shaped or branched. By means of these branches they come into direct relation with other similar cells or wdth connective-tissue cells. However, Happe ('06) stated that he could not with certainty find cells united by their processes, as described by Hofbauer, in preparations stained after Hansen. According to Hofbauer, the cell processes are delicate, and the cells contain one or two nuclei from 4.7 ix to 5.7 ^ in diameter, oval or circular in form, eccentric in position, with a definite membrane and a dense chromatin network. Mitoses were common, and fragmentation of nuclei and indications of pluripolar mitoses also were seen. Hofbauer emphasized that the most characteristic thing in these cells which he regarded as being specific was the presence of vacuolation in the 'plasma' and the existence of a perinuclear clear zone, which was said to be the result of fusion of 'small light spots.' As the cytoplasm becomes vacuolated the nucleus is said to become pycnotic, which stage is followed by failure to stain and finally by complete disappearence. Hofbauer also noticed the presence of granules and fat droplets, and regarded the life history of the cell as a circumscribed one. He did not find them present in real young villi. They were said to appear at the end of the fourth week, and were more common in young than in old placentae. They reacted to vital stains like plasma cells, and Hofbauer regarded the vacuoles as having an assimilative and digestive function. A reference to the plates accompanying Hofbauer's monograph, however, shows that vacuolation was not always present, and that the largest of the cells were almost twice the size of the smallest.
- A rereading of Stoffel's article shows quite conclusively that he did not describe the plasma cell of Hofbauer.
In his earlier paper Hof bauer ('03) also said that his preparations taken from material from the fourth to the ninth week of pregnancy, and obtained at operation, showed these cells in all stages of mitotic division. Hofbauer further wondered whether the spaces surrounding these cells are lumina of capillaries, added that the cells discovered by him undoubtedly are found in capillaries, and made some rather unguarded surmises concerning them.
Berlin ('07), in writing on the changes in retained placentae, also spoke of large swollen, hydropic cells which lie in spaces. These cells she regarded as undoubted mesenchyme cells. However, Berlin did not believe that they are degeneration products, although her description certainly would lead one to suppose that they were such. Even when she states that they bear no sign of degeneration, emphasizing that the chromatin network is fine, she speaks of swollen nuclei which have gathered a larger amount of protoplasm about them, phenomena which she regarded as signs of luxurious nutrition. Moreover, Berlin never observed mitoses and never found the nuclei increased in villi containing many of these cells, an observation wholly in harmony with that of others and directly opposed to proliferation.
Grosser ('10), who was plainly aware of the fact that Hofbauer was not the discoverer of these cells, also represented a cell which, however, is non-vacuolated and binucleated, and added that their significance is still unknown.
I have given Hofbauer's description, partly to emphasize the vacuolation, for it was this which also impressed Minto, ('04), who rightfully stated:
We frequently find in the literature mention of wandering cells with vacuolated protoplasm, but they seem not to have been recognized as degenerating cells The disintegration by vacuolation has, so far as known to me, not been described heretofore, and consequently may be treated somewhat more fully. Renewed investigation has led me to the conclusion that we have to do with erythrocytes which have gotten into the mesenchyma and, remaining there, have swollen by imbibition and are undergoing degeneration by vacuolization of their protoplasm We can explain the appearance of these cells by the assumption of imbibition, in which the
nucleus has participated Since I have found similar cells
in a considerable number of placentas, I draw the conclusion that they are constant and normal. I regard the interpretation of the pictures unattackable as proof of progressive degeneration.
In association with these remarks, Minot represented a series of cells showing progressive degeneration, beginning with the nucleated red cells and ending with a highly degenerated, but nevertheless nucleated, Hofbauer cell which apparently is in process of disintegration. These cells were seen by Minot especially in a human embryo of 15-mm. length, from the Mall collection.
As shown in the references to the literature above, it is not quite correct to say that the degenerate character of vacuolation has not before been recognized, for the surmises that Hofbauer cells contain fat granules may, and that they are swollen mesenchyme cells must, carry this implication. Moreover, those familar with the effects of inanition know that investigators of this subject long ago called attention to vacuolation as one of the evidences of degeneration although, certainly, no one contends that it always is such.
Instead of regarding these cells as degeneration products, certain Italian writers (notably Acconci '14) regard cells which they found, especially in the first half of pregnancy, as morphologically and functionally comparable to the intersitital cells of the ovary and testis. Acconci believed that certain cells which he and other Italian writers after him designated lipoid-interstitial cells, probably produce a special internal secretion. He, like Hofbauer, found these cells to contain lipoid granules, and regarded them also as equivalent to certain cells described by Ciaccio in various parts of the organism, or by Brugnatelli in the interstitial tissue of the mammary gland." Acconci further emphasized certain similarities between the syncytium and the interstitial cells, both of which he conceived as exercising a protective role. Muggia ('15), too, instead of regarding the lipoid interstitial cells of Acconci as degenerate, emphasized his belief that they are particularly resistant to degeneration, being found perfectly preserved in the midst of detritus. Since the young connective-tissue cell loses, or rather retracts, its processes as it becomes converted into a Hofbauer cell, it need not surprise us that the latter survives the former. Retraction of the processes contributes to the apparent increase of cytoplasm of the rounded swollen cell and also is involved in the formation of the spaces in which these cells usually lie. Muggia, who considered the cells found by him in great numbers in a case of partial hydatiform degeneration, as identical with those described by Acconci, gave a fine detailed description absolutely typical of the cells described in greatest detail by Hofbauer. Moreover, the excellent illustrations which accompany Muggia's article leave no doubt as to the identity of the cells or of their degenerate character. Muggia stated that these cells in normal villi increase until the end of the fifth month, when, according to Savare, they are most numerous. Muggia further found numerous cells very similar to the interstitial cells of Acconci, or the plasma-like cells of Hofbauer," which he says are regarded by some as early stages of interstitial cells and by others as mast cells, although he regarded them as partially differentiated interstitial cells.
Until I had seen sections of the chorion of embryo no. 1531, I was largely at a loss to know why Hofbauer cells so frequently were described as lying in gaps or spaces in the mesenchyme. However, in this specimen cross-sections of a number of villi showed splendid examples of this condition, which alone made the cells very conspicuous. The cells often were very numerous, in fact more numerous than the mesenchyme cells which remained, although some well-preserved villi contained no Hofbauer cells whatever. Some of the younger specimens also contained none. This was true of a chorionic vesicle with an embryo 1 mm. in length. They were found most commonly in the villi, but not infrequently some of them lay in areas of the chorionic membrane which had undergone degeneration. They were not so common here, but sometimes were exceedingly numerous in small areas. They were found in the amnion also, in the umbilical cord, and in the tentorium cerebelli, and as isolated specimens in embryonic mesenchyme elsewhere. As emphasized by other investigators there seemed to be nothing particularly characteristic about their distribution except that they were more common in places where the mesenchyme was degenerating. Sometimes a considerable number were contained in one villus and none in an adjacent one. As many as twelve might lie in one field and none in the next. Very rarely was there a solid mass of them, but usually they were scattered about at random, although groups also were seen. The betterpreserved cells were small, the poorer-preserved larger, the size varying from 8.5 n to 30 ii. The smaller cells usually were quite circular in outline, stained evenly and possessed a nongranular cytoplasm with a nucleus quite centrally located. Binucleate cells, as described by Grosser, were not uncommon, and multinucleated cells — fusion products — also were found. The nuclei of the latter frequently were more unequal in size, and usually also more oval in outline, than the single nucleus of the typical Hofbauer cell. Measurements of the larger cells made with a micrometer caliper, gave the following results which are considerably above those given by Hofbauer, whose estimation of 10.5 IX to 12.5 yu applies to the average-sized cell.
of the larger Hofl
However, the size of the cells varied from specimen to specimen of chorionic vesicle, but not nearly so much as their state of preservation. This no doubt, partly is due to the varying state of preservation of the villi themselves.
In outline they varied from irregular to circular, as stated by Hofbauer, and as represented by Minot ('11) in his series showing progressive degeneration. Although it was easy to distinguish the vacuolated Hofbauer cell from the well-preserved mesenchyme cell with cylindrical nucleus and many processes, specimens which represent transition forms as stated by Marchand, were quite common. The latter generally were oval or slightly irregularly formed cells with a number of short processes, which latter, as well as the character of the nuclei and the form of the cell itself, certainly suggested a mesenchymal origin. They were also most numerous in villi the stroma of which had become vacuolated or fenestrated. Here the reciprocal numerical relationship betw^een the Hofbauer and the mesenchyme cells often was especially evident. In certain areas in which almost no mesenchyme cells remained intact, numerous Hofbauer cells occurred in all stages of degeneration. In other portions of the chorionic membrane or of the villi, mesenchyme cells with processes in all stages of retraction also were clearly outlined in the homogeneous ground substance. Such evidences naturally remind one of Hofbauer's statement that *Marchand called his attention to the fact that these cells were mesenchyme cells, a conclusion which Hofbauer accepted. My implication, however, is not that degeneration of the mesenchyme or of individual mesenchyme cells can proceed only through a Hofbauer stage, but that, especially in the chorionic villi, a form of degeneration of the mesenchyme seems to occur which gives rise to this peculiar cell form, the degenerate character of which rightly impressed Minot. This relationship also attracted the attention of Mall ('15), who represented degenerating villi and stated
The core of the villus gradully breaks down and disintegrates. While this process is taking place we often see scattered through the stroma of the villus large protoplasmic cells These cells, which I have repeatedly seen in the villi of pathological ova, may be a type of wandering cells; at any rate, when the villus is being invaded by the leucocytes and trophoblast it might be thought that they arise from the latter, but this is improbable.
It is of particular interest in this connection that Virchow ('63) stated that Schroeder van der Kolk ('51) had concluded that large clear cells in the stroma of the villi, later classed among the physaliphores by Virchow, occurred too frequently to be correlated with hydatiform degeneration. This suggests that the so-called Hofbauer cells were known since the early days of cytology, and that some one must have noticed, even at that early date, that they were very common in some hydatiform moles. Whether or not this was van der Kolk I am unable to say, but that Hofbauer cells are especially numerous in some cases of hydatiform degeneration is undoubted. But it does not therefore follow that they constantly are present in this condition. Large numbers of Hofbauer cells occurred in seventeen out of the sixty-one cases of normal and pathologic chorionic vesicles in which they were especially studied. Of these seventeen cases fourteen later were independently identified as showing hydatiform degeneration, and the other three were considered as possibly such. In other words, every case of this series of so-called normal and pathological chorions in which the Hofbauer cells were numerous, was one showing hydatiform degeneration of the villi. It also is true, however, that thirty-four cases containing a few or some Hofbauer cells were not identified as being hydatiform moles, although three cases containing smaller numbers of these cells were so recognized. Moreover, not a single case of this series of sixty-one specimens which contained no Hofbauer cells whatever was later identified as showing hydatiform degeneration.
Somewhat similar evidence was afforded by the study of the twenty-two cases in the protocols of which Mall had noted that Hofbauer cells were present. Of these twenty-two cases, thirteen later were identified as showing this degeneration. However, since a total of 112 cases of hydatiform degeneration were identified among the 313 classed as pathologic among the first thousand accessions in the Mall collection, it is evident that the presence of Hofbauer cells was especially noted in but a relatively small percentage of the series of embryos classed as pathologic. If we include certain other cases in which they came to attention later, the percentage becomes 26.7; that is, 30 out of 112 cases of hydatiform degeneration. Of these thirty cases containing Hofbauer cells in sufficient numbers to attract attention in the course of a routine examination made for other purposes, seventeen or 56.6 per cent, were later identified as instances of hydatiform degeneration. Since the sixty-one cases in the first series were examined especially for the purpose of study of Hofbauer cells, the higher percentage of correlation observed in this series may be due partly to this fact. At any rate, that such a correlation exists seems to be quite clear, although I do not conclude that the two conditions necessarily or invariably are associated.
It is interesting that Pazzi ('04) considered a distrophy of the connective tissue with the development of cellular elements not very well differentiated, but like the plasma cell of Hofbauer," as the initial and pathognomonic change in hydatiform degeneration. Pazzi further stated that the plasma cell of Hofbauer may be in a state of hyperactivity or of degeneration, and questioned the statements that Hofbauer cells appear only at the end of the fourth week and that they have a short life. Pazzi regarded the Hofbauer cell as fundamentally a constituent of the villi, as the decidual cell is of the decidua. He, like Essick, attributed their origin to the endothelium of the vessels, and Pazzi suggested that the Hofbauer cell may have a special internal secretion intended to preserve the stroma of the young villus against degeneration. Pazzi further considered the question whether a Hofbauer cell can transform itself into an epithelial cell and finally into a syncytial cell, adding that the invasion of the stroma of the villus by epithelial growth, is only a special development of Hofbauer cells!
As already stated, Muggia also found these cells very abundant in a case of partial hydatiform degeneration, and held that their appearance and condition was correlated with the proliferation and vacuolation of the syncytium, maintaining that, as the latter becomes vaculolated the lipoid interstitial cells of Acconci appear, the changes in the two being wholly parallel.
Since thirty-two of the fifty-one specimens in this series of sixty-one containing a few, some, or many Hofbauer cells had been classed among the pathologic, it follows that these cells were noticed more frequently in the pathological than in specimens classed as normal. This becomes especially evident if we exclude from this series of fifty-one cases all those containing some or many Hofbauer cells, for of twenty-seven of these, nineteen, or 70.4 per cent, had been classed among the pathologic. Moreover, since the great majority of the conceptuses classed as normal belong among abortuses, one would be entirely justified in questioning the strictly histologically normal nature of the chorionic vesicles which accompany some embryos classed as normal. At any rate, it is evident that the plasma cell of Hofbauer is associated with degenerative changes in the mesenchyme of the villi. Since such changes are more common in pathologic abortuses it is not surprising that Hofbauer cells are more common in the latter than in normal specimens, and, since degenerative changes in the stroma are especially pronounced in advanced cases of hydatiform degeneration, it is still less surprising that Hofbauer cells are particularly common in this condition. But they are not necessarily pathognomonic of hydatiform degeneration, although it is true that when at all numerous they are associated with hydatiform degeneration in about 75 per cent of the cases.
A ter a careful survey of a considerable number of specimens, both normal and pathologic, ectopic and uterine, of human conceptuses of widely different ages, I am led to concur entirely in the opinion of Minot that the typical vacuolated cell, as described by Hofbauer, is a degeneration product, though usually not a degenerate erythroblast, as Minot concluded. Rarely havg I seen a chorionic vesicle in which the rather small, clear, isolated Hofbauer cells scattered throughout the stroma of a villus undoubtedly were erythroblastic in origin. In these villi capillaries in various stages of disintegration were present, and the erythroblasts could be traced directly to these degenerate capillaries. In the earlier stages of this degeneration these degenerating erythroblasts are not surrounded by spaces, however, and this is true also of early stages in the degeneration of the fixed or already detached mesenchyme cell, which later forms the typical, degenerating, wandering cell. However, it represents but one stage in this degeneration.
It is significant that, although Hofbauer suggested that these cells might have a digestive or assimilative function, he, too, frequently found fragmentation of the nuclei and complete disappearance of the cytoplasm and even of the cell itself. All stages of degeneration, as manifested by crenation of both cytoplasm and nucleus, even to complete disappearance of the cell, can easily be found. Signet-ring forms are common, and the nuclei are found in all stages of extrusion and degeneration. The cell boundaries are often ragged, the nuclei crenated and pycnotic, the cytoplasm granular, vacuolated, webbed or fenestrated, until finally nothing but a faint ring or shadow form without a trace of a nucleus remains. However, in these transparent or shadow forms the nuclei, if not previously extruded or dissolved, are frequently represented by a mere outline or by a faint trace of one. Since all stages between the latter and the well-preserved cells, without vacuoles and well-preserved nucleus and cytoplasm, and also with processes, occur in good material, one can scarcely doubt their origin.
Undoubted instances of mitoses were never seen in any Hofbauer cells, no matter how well preserved. This no doubt can be accounted for by the fact that from the time the mesenchyme cells retract their processes and become isolated in the ground substance of the villus, they are in a stage of degeneration. Under such circumstances one would hardly expect to see instances of cell division, although these possibly may be simulated by necrobiotic phenomena.
Hofbauer ('05), and also in his first publication, stated that the cells described by him increase by mitoses which are frequent. He also found examples of what seemed to be instances of pluripolar mitoses, but also noted fragmentation of the nuclei. Acconci ('14) also found mitotic figures in cells designated lipoid interstitial cells by . him, but most investigators say nothing about this. On the contrary, a number of them specifically state that they could not find an actual increase in the number of nuclei present in the stroma of villi containing large numbers of these cells. Furthermore, every one except Muggia (and also he in his description and illustrations, as also Acconci) has noted characteristics, and described the cells in such a way as to suggest the presence of degenerative changes. When at all distinct they are of various shapes and sizes, and are surrounded by a relatively large clear zone. Their occurrence is erratic and they contain lipoid granules or vacuoles, and have nuclei varying considerably in size, position, and staining reaction, as does also the cytoplasm. They are most frequent in degenerate villi and not infrequently lie in detritus. The better preserved the stroma the fewer one finds, and in these observations on this rather large series of chorionic vesicles, some of which were obtained fresh — one living — in hysterectomly specimens, I have only found a few instances of what possibly could be regarded as mitotic figures. Since almost all are agreed that these cells are of mesenchymal or connective-tissue origin, it is easy to see that considerable difficulty must be encountered in deciding just when to regard a mesenchyme cell, which is the precursor, as a Hofbauer cell. However, since I have not made this aspect of the question a particular subject of investigation, I have no other evidence to offer.
Since some of these cells, during the early period of degeneration, after they have become quite circular in outline and the nucleus has taken an eccentric position, have a decidedly granular or even a lumped cytoplasm, the confusion with plasma cells, or their earlier designation as granular wandering cells, need not surprise us. Nevertheless, the term plasma cells is hardly applicable, as many of them are not granular. Moreover, no one has shown that in fixed preparations these cells take the stains specific for plasma cells. Indeed, although he stained material with borax methylene-blue after Jadassohn, Happe ('06) did not find any of the Hofbauer cells impregnated. It must be remembered, however, that failure to stain may be dependent very largely upon the degree o' degeneration which the particular cells have undergone, for, as already stated, Hofbauer found that in fresh material these cells reacted as plasma cells to vital stains.
The opinion of Minot that Hofbauer cells are degenerating ery throblasts probably can be accounted for by the fact that in the chorionic vesicle from which Minot's series, showing a progressive degeneration of the latter into the former, was obtained, it was impossible to distinguish between the two. This difficulty was due partly to the poor state of preservation of the particular specimen, a larger survey, especially of better material, would have revealed the fact that Hofbauer cells are found in villi, the blood-vessels of which contain no erythroblasts. Moreover, as will appear later, the distribution of these cells in the villi is not such as one rightfully would expect if they have their source in the vessels. However, since the final form of the typical Hofbauer cell is a mere shadow cell, it necessarily may be impossible to determine the kind of cell from which this shadow form arose, for, as is well known, the end forms in processess of degeneration of many different types of cells are indistinguishable. Consequently, a group of swollen, highly vacuolated cells also may contain among them degenerated, nucleated red blood cells, as Minot held. Indeed, degenerating erythroblasts which are indistinguishable from some Hofbauer cells, can be seen occasionally not only in the vessels, but in the heart and also within the cavity of the chorionic vesicle; but such occurrences do not prove that the Hofbauer cells of the villi arise from erythroblasts. That this usually is not the case follows also from the fact that well-preserved, nonvacuolated Hofbauer cells occur in villi which have not become vascularized or which, as stated above, no longer contain vessels. It is true that it often is impossible to distinguish between degenerate erythroblasts within the vessels and Hofbauer cells lying outside of, even if near to them, in the stroma of the villus. This difficulty is entirely avoided by examining the older specimens without nucleated reds, for, since Hofbauer cells always are nucleated except in their very last stages, confusion with nucleated cells thus is avoided.
Although the eUmination of the erythroblast as the source of the Hofbauer cell was thus very easy, some difficulty was encountered, strangely enough, with regard to polymorphonuclear leucocytes. This largely is due to the fact that the nucleus of the latter often ceases to be polymorphous as the cell degenerates. Instances of this kind are quite common, especially in the membranes of hemorrhagic or infected abortuses. They are, however, also met with in the decidua. Since the polymorphous character of the nuclei of these leucocytes usually can be recognized without difficulty in degenerated accumulations of pus, I was at first predisposed against regarding a circular nucleus as possibly polymorphous in origin, but careful scrutiny of numerous specimens in which these misleading degeneration forms occurred soon left no doubt as to the facts.
As stated above, Hofbauer cells were found in the cavity of the chorionic vesicle in abortuses which contained blood or had become infected. In these specimens the degenerated polymorphonuclear leucocytes usually lie in groups, or more commonly in rows along the inner borders of the chorionic membrane, or in long narrow clefts or folds of the same. Some also were scattered about among the degenerating erythrocytes, but an examination of the contained blood usually surprises one by the entire absence not only of well-preserved polymorphonuclear leucocytes, but of all leucocytes whatsoever. This, to be sure, is in marked contrast to what is found in the case of ordinary hemorrhages and is a fact full of significance for the question under discussion. Most of the degenerated polymorphonuclear leucocytes, many of which contain undoubted evidence of phagocytosis, possess a relatively small, circular, vesicular nucleus which often is eccentric in position. Others are filled with a granular cytoplasm, or even with very discrete golden granules, while still others are filled with dark, black pigment granules corresponding in size to the golden ones. Here and there the field of degenerating erythrocytes may also be studded with masses of pigment which clearly declare their origin by the presence of all manner of transition forms, between the well-preserved, easily recognizable polymorphonuclear leucocytes and the disintegrated pigmented detritus. The phagocytic nature of these cells is especially noticeable in the specimens of young chorionic vesicles with nucleated reds, stained with iron hematoxylin, for in these the leucocytes are often seen filled with a mass of nuclei only.
Similar appearances can also be seen occasionally in the decidua from cases of endometritis, as well as in portions of the decidua in which the glands have undergone considerable maceration and degeneration. In the former the polymorphonuclear leucocyte is the misleading form, while in the latter the degenerating, cast-off glandular epithelial cells simulate Hofbauer cells in almost every morphological detail. I have also seen similar specimens of degenerated polymorphonuclear leucocytes in ill-preserved hemorrhagic lymph nodes, especially from cases of septicemia, and, until the true nature of such degenerate leucocytes became evident, it was very puzzling to see why the Hofbauer cell, which never was found to contain evidences of phagocytosis when lying in the stroma of the villus, should become phagocytic when contained in a degenerated amniotic or chorionic membrane or when lying in a hemorrhagic area. Undoubted instances of phagocytic Hofbauer cells were never seen, although certain misleading forms other than those already mentioned were encountered also in pregnant tubes and in an ovarian pregnancy. Among these misleading forms were specimens of binucleate cells in which one nucleus had undergone almost complete chromatolysis, leaving only a nuclear membrane. These nuclear remnants or so-called nuclear shadows, can easily simulate a phagocytosed erythrocyte. The same is true of small areas of cytoplasm which stain but faintly, and hence look more translucent, and particularly of vacuoles themselves.
Essick ('15) found what he regarded as morphologically similar cells in transitory cavities in the corpus striatum, and believed them be macrophages. Consequently, he concluded that Hofbauer cells also are phagocytic and regarded them as having an endothelial origin. I have not been able to find any evidence for the latter origin, however, for in specimens in which the capillaries are plugged with degenerate endothelial cells or in which they are composed of a layer of greatly enlarged oedematous endothelial cells, so as to make the cross-section of the vessels look not unlike that of a duct, Hofbauer cells never were found in close proximity to capillaries or other vessels or in unusual numbers elsewhere in the stroma of such villi. Nor did I see any evidence for such an origin in villi from hemorrhagic or inflammatory cases, and although Hofbauer cells often lay near to, or even in extravasations in the villi, they never were found engorged with erythrocytes or pigmented. Nevertheless, if Hofbauer cells arise from mesenchyme cells, it stands to reason that they at least may be potentially phagocytic, and failure to find them so may be accounted for by the fact that they possess a lowered vitality in consequence of degenerative changes.
I am prompted to suggest, in connection with the question of phagocytosis, that, unless we regard the process as other than an actively vital movement on the part of the cell for the purpose of engulfing things, we have undoubtedly misused the term. That the mere possession of parts of cells, or even of whole cells within the cytoplasm, is not sufficient evidence for the possession of phagocytic activity on the part of a particular cell, seems to me to be beyond question. In some instances, for example, degenerating phagocytic leucocytes fuse with each other in groups of twos, threes or even in greater number, thus forming multinucleated and not infrequently vacuolated complexes. Similar phenomena can be seen also among degenerated erythroblasts and trophoblast cells. Although it would be incorrect to regard these degenerate fusion products as true, living giant-cells, they nevertheless simulate such very closely indeed. Moreover, when these larger fusion products fuse with an individual cell of the kind that gave rise to them, it would be quite natural to regard them as being phagocytic, while, as a matter of fact, the process is merely one of degeneration. Another example of what we may call pseudophagocytosis is that represented by the isolated erythroblasts rarely seen in the stroma of a villus. In some instances two or three cells, whose boundaries for the most part still are clearly outlined, can be seen to have partly fused, forming a so-called giant-cell. All transition forms and stages can be found, and were it not for this fact, the resultant large multinucleated fusion product, if seen to join with an isolated trophoblast cell, might be regarded as being phagocytic. Other instances of a similar nature were discussed briefly elsewhere (Meyer, '18), and I am inclined to believe that the non- vital character of this kind of cell formation, which occurs under conditions of cell degeneration, needs further emphasis. It certainly would seem to be a non-vital, rather than a vital phenomenon. It is indicative of degeneration and death, rather than of regeneration and life.
Cells which are morphologically identical with certain stages in the degeneration of the Hofbauer cell can also be found in entirely different locations than those mentioned. Such instances occur in the Graafian follicle. In some of these, germinal epithelial cells which have become detached and displaced in the liquor folliculi become swollen and transparent and the nucleus takes an eccentric position. In all details of structure and ordinary staining reaction, as shown by hematoxylin and eosin, by iron hematoxylin, by van Gieson, and by Mallory, these cells are identical with phases in the typical Hofbauer cells. This, however, does not justifj^ us in designating them as such, unless we wish to extend the use of this name to degenerating and disintegrating forms of cells of very many different types and origins.
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