Talk:Book - Uterine and tubal gestation (1903) 3
PART III. OVARIAN AND PLACENTAL SECRETION
THE RELATION OF THE CHORIONIC EPITHELIUM TO CHORIO-EPITHELIOMA.
There have been observed and reported over 150 cases of a uterine growth of exceedingly malignant character occurring after abortion and labor, or even after tubal abortion. The clinical symptoms are: (1) Pronounced uterine hemorrhage, recurring even after repeated curettage; (2) very early metastases, especially in the lungs and vagina; and (3) early death through hemorrhage, cachexia, or septic infection.
Macroscopically, these tumors are more or less localized, ulcerating, degenerating, hemorrhagic growths, frequently passing deeply into the uterine wall, or through it with involvement of the peritoneum.
Microscopically, these tumors are characterized by hemorrhagic areas, areas of degeneration, the presence of fibrin, and the involvement and invasion of capillaries and large vessels. They are especially characterized by the presence of (1) pale round and polygonal cells with pale protoplasm and pale nucleus, and (2) of large round and spindle-shaped cells with large dark nuclei and also (3) of large, irregular branches composed of polynuclear protoplasmatic masses.
These atypical growths have been variously described as sarcoma, carcinoma, carcinoma after abortion and labor, and as sarcoma and carcinoma causing abortion.
Sanger, in reviewing these cases, found a decided resemblance in their characteristic elements, and came to the conclusion that the decidua cells were the cause of the growth, giving it then the name of deciduo-sarcom or deciduoma malignum.
As a result of the investigations of Frankel, and later of Marchand, attention was called to the fact that those cells which so closely resembled decidua cells were really of fetal origin and were, in fact, the cells of Langlians, while the spindle-shaped and grouped masses of polynuclear protoplasm were of syncytial origin.
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From all sides, especially in England and Germany, this viewwas attacked. It was pointed out how baseless was the viewthat fetal cells could produce a growth of this malignant character, differing from carcinoma only in the fact that metastases resulted through the blood channels instead of the lymph paths.
This controversy is to-day by no means settled, many holding the view that these tumors are sarcomatous, originating from the decidua cells. The giant cells and the protoplasmatic masses are referred, likewise, to changes in the decidua. Others hold that these growths result from the epithelial covering of the villi. That these cells, if they are of fetal origin, should be mistaken for decidua cells is a natural error, for we know that even in the normal processes a positive distinction is often very difficult. It is to be noted that many investigators have called the typical trophoblast cells in tubal placentation, too, decidua cells. Still others lean to the view that the stroma of the villi plays its part.
On the other hand, among those who hold that these growths originate from the chorionic covering a division of sentiment exists ; for those who consider the syncytium and cells of Langhans to be of uterine origin class these growths as carcinoma and sarcoma of a somewhat atypical character. Those who believe, as we have shown, that the epithelial covering of the villi is of fetal ectodermal origin, and who therefore also class these tumors under the category of carcinoma, are introducing into pathology a new element.
A factor which has served to clear our views on these various disputed points is the knowledge that fifty per cent of these malignant uterine growths, commonly known as deciduoma, follow the presence of hydatid mole.
In hydatid mole we find the same elements as in normal placentation, only that these elements are excessive in number and size. Hydatid mole represents a hypertrophic growth of the chorionic covering, accompanied by dropsical swelling of the chorionic stroma. As is well known, the covering of the villi consists of two layers, an outer syncytium, an inner, the cell layer of Langhans. The growth concerns both the syncytium and the cell layer of Langhans. The abnormal element is the occurrence of very large cells with immense nuclei in large number, and a decided growth of the syncytium, accompanied by the formation in the. latter of large vacuoles.
Leaving out of consideration those cases malignant because of the diffuse and deep infiltration of the uterine wall by the cystic
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villi, by no means are all hydatid moles of a malignant character. An attempt to distinguish between the benign and malignant cases was proposed by Neumann. He observed, in three cases subsequently resulting in the so-called deciduoma, large cell elements in the stroma of numerous villi which he considered to be infiltrating elements of the syncytium. He observed, further, an abnormal infiltration of cell groups through such syncytial elements. Investigation of subsequent cases shows that malignant forms are not always preceded by such changes in the hydatid mole, while others have found these changes and yet no malignant growth occurred.
Even the occurrence of metastases is no proof of malignancy, for Pick reported a case with a metastasis of villi in the vagina and yet the patient recovered. We know that fetal cells are given off from the normal placenta into the maternal circulation. Even the normal placenta, as Pick believes, may give metastases of villi, and these may (1) degenerate or (2) grow slightly or (3) produce the same syncytial growth as is observed in benign hydatid mole. (4) Primary malignant growths may originate, and have originated, from such metastases.
Malignancy, in the case of hydatid mole, is not then to be judged alone by the occurrence of metastases. Those cases which subsequently develop into the so-called deciduoma evidence their malignant character by the ability of their cells to grow in an unlimited manner, aided by the character of the tissue which permits or also aids this growth. Various theories have been propounded in explanation of this, phenomenon. 1. Through the syncytium there is a constant exchange of products, and after hydatid mole, or on the occurrence of abortion or labor or any process causing the removal or death of the fetus, this exchange ceases. The fetal cells then, if in a favorable surrounding, are supposed to use this nutrition for themselves and increase until an unlimited growth results (theory of Marchand). 2. Ribbert considers the unlimited ability of certain malignant tissues to grow to be due to the separation of their mother cells from their normal connections. 3. As is well known, Cohnheim considered displaced embryonal cells to be the future source of many Benign and malignant tumors.
An interesting power or potential retained by displaced cells is that of differentiation. We know that displaced cells, cells removed from their normal relations, are able, after an interval of many years, to grow and produce structures of varying form.
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This is best exemplified in the case of dermoid cysts, for their character distinguishes them from all other tumors. The later in the stage of embryonal development these cells are displaced the more simple is the structure of the resulting dermoid; the earlier in the period of embryonal development their displacement occurs the less differentiated are these cells. For that reason embryonal cells displaced in the early weeks produce tumors of complicated character, for their potential as regards differentiation is great. Cells displaced at a later period possess a lesser potential as regards differentiation, while those epithelial and connective-tissue cells displaced very late, as at points where the skin only remains, to be united, and at the branchial clefts, produce only the simplest form of dermoid growth. They produce only cells of the same character and structure as the parent cell if the stage of complete differentiation had been already reached. If the displacement occurs before this period, such elements are found in the subsequent growth as the parent cells would have produced had they remained in their normal situation. Such early cells, however, reproduce far greater growths and far more extensive tissues than would have resulted had they not been displaced. This is evidenced by the fact that no loss of any normal tissue or structure results. In dermoid cysts of the ovary, for instance, very large and complicated tumors are found, resulting from the displacement of ectodermal and mesodermal cells by the Wolffian body, and yet the maternal body is otherwise normally developed.
In the genital tract, especially, we find numerous evidences of another cell potential, that is, the ability to first display accelerated growth after a lapse of many years. We find in the uterine wall, under the peritoneum, in the broad ligament, and in the ovary, generally after puberty, epithelial and glandular growths, sometimes of considerable size, resulting from the displacement of cells of the Wolffian body. In the fetus and in the newly-born, hundreds of uteri and appendages have been examined and yet relatively few such displacements of Wolffianbody, cells can be found. This means that the displacement concerns simply embryonal cells of this organ, which even at a much later period possess the power to develop the same structures as the parent organ. This growth takes place, as a rule, at and after puberty, and the same is true in the case of dermoid cysts.
We find, then, that the general stimulation of tissue and cell
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growth occurring after puberty may influence some embryogically displaced cells in the same manner.
We find, on close investigation, that almost all ovarian and parovarian cysts result from the continued growth of structures which in the embryo were functionating organs', but which in the fetus and in the adult are supposed to undergo regressive changes, namely, the epoophoron and the paroophoron, constituting the two divisions of the Wolffian body. Papillomata of the ovary, in all probability, also develop from cells, of these supposedly regressive structures. Ovarian cysts also frequently show papillomatous changes. These are, strictly speaking, only huge increases of the characteristics of the primary embryonal organ.
Not infrequently these papillomatous growths are macroscopically of a malignant character, in that they break through the covering of the cyst or through the ovary, grow without restriction, invade the peritoneum, infiltrate the surrounding organs, and produce cachexia.
Such changes may also display the microscopic characteristics which we attribute to carcinoma— that is, a continued growth of the epithelium, a breaking through of the membrana propria, and an infiltration, microscopically, of the tissue surrounding the epithelial cells. In other words, we find a continued unlimited growth of cells, reproducing, even though in a changed relation, the character of the mother cell.
These smaller and larger reproductions of the Wolffian body, these cystic growths originating from the Wolffian-body cells, these papillary and malignant growths originating from the same source, as well as dermoid cysts, furnish us with evidence of the ability of regressive cells and organs, and cells removed from their normal relations, to undergo a more or less unlimited growth, even after lying dormant for many years. These cells, however, are cells of the patient and are open to the same influences as normally situated cells.
In the case of chorio-epithelioma, however, we find fetal cells, often only a few weeks old, possessing naturally no great potential as regards differentiation, but an exceedingly high potential as regards their ability to grow. The energy and potential of these cells may be appreciated from the fact that the earliest case occurred two weeks after the interruption of pregnancy, while the latest occurred nearly four years after hydatid mole.
150 RELATION OF THE CHORIONIC EPITHELIUM
The most prominent point of a ripening Graafian follicle is poor in blood supply and is called the stigma folliculi. It is here that the opening takes place which furnishes an outlet for the ovum. This opening is probably the result of the reaction or chemical effect produced by the ripe ovum, for, in the newly-born and in children, follicles, of the same size and even larger ones exist without bursting— the so-called atresic follicles.
After ovulation the ovum is thrown out into the abdominal cavity, and then, influenced by the wave movement of the ciliated epithelium of the tube, the fimbria? of the ampulla, and the fimbria; ovaricae, finds its way into the uterus. The wave movement of the ciliated epithelium causes a current in the peritoneal plasma which directs the ovum into one or other of the tubes.
A fecundated ovum embeds itself in the lining of the uterus through centrifugal descent. The ovum then causes a reaction in the surrounding tissue and a dilatation of the surrounding lymph spaces, so that a resulting localized edema takes place. In addition a dilatation of the capillaries is produced.
The outer layer of the ovum develops into what is known as the trophoblast, which is a product of the ectoderm, and from it develop the cells of Langhans and the syncytium.
Shortly after the ovum is embedded in the mucosa a connection between the trophoblast and the maternal blood takes place through a rupture of the capillaries. The maternal blood then bathes the ectodermal trophoblast. This, opening of the maternal vessels occurs, however, before the formation of villi; and the cells of the trophoblast may therefore enter the maternal veins at the very earliest period.
The compact layer of the decidua is the zone which envelops the ovum. The trophoblast at points may extend far into the compacta, for the cells have a decided poiver of wandering. The trophoblast, therefore, invades the maternal tissues even at the earliest period.
A gradual transition of trophoblast cells into syncytial cells, and a gradual change of trophoblast nuclei to syncytial nuclei, take place through the corrosive action of the maternal blood, and elements of the maternal blood aid in forming the syncytial protoplasm. The syncytium does not originate from the maternal endothelium, nor from the uterine epithelium, nor from the decidua cells.
Just as, in the early stages, the trophoblast invades the decidua, so, after the formation of villi, is the future course of the
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ectodermal trophoblast and of the syncytial cells of a destructive character so far as the decidua is concerned. The trophoblast and syncytium invade the maternal tissue and mingle with it. They infiltrate the decidua and bring it to destruction. The trophoblast and syncytial cells erode the capillaries and blood vessels, the blood in turn changing fetal cells to syncytium.
The invading trophoblast and syncytial cells have at all times a great power of wandering. They enter, between bundles of muscular and connective tissue, into the lymph spaces and into the blood vessels. At full term the uterine wall is infiltrated with fetal cells of a syncytial character.
From the very earliest moment fetal cells are continually entering the blood of the mother, not only in the primary intervillous space but in the fully formed intervillous space, as well as through the vessels of the uterine decidua and wall.
Under chorio-epithelioma we distinguish two forms, the typical and atypical. In the typical form (Fig. 60) we find large, round, polyhedral cells with strikingly large, very irregular, lobulated nuclei which stain very deeply and often degenerate, forming vacuoles. The protoplasm is relatively scanty. These cells are capable of great wandering and are found more or less isolated between the muscle and the connective-tissue bundles (Fig. 63), in the lymph spaces and in the vessels. They form the advance guard in the way of infiltration. There are, further, irregular bridges of protoplasm containing scattered or grouped nuclei of various sizes (Fig. 61). Many of these groups of nuclei are the same large, irregular, lobulated nuclei as were observed in the form just mentioned. In addition are found irregular masses of protoplasm containing many small nuclei. The character of the latter is identical with normal syncytium.
The irregular groups of protoplasm containing grouped nuclei of various sizes are undoubtedly of syncytial character, for they result through the blood surrounding and infiltrating the cells of Langhans, and it is very evident that these cells form the aforementioned grape-like nuclei (Fig. 63). The isolated large cells are likewise of syncytial character. They have generally been mistaken for decidua cells. They may be distinguished from the cells of Langhans, for the latter are pale, polyhedral groups of distinctly epithelial character. They are rich in glycogen and therefore often contain vacuoles. The nuclei are large but pale.
RELATION OP THE CHORIONIC EPITHELIUM
The cells of Langhans are better illustrated in the atypical form (Fig. 64) where the syncytial elements are relatively in the background. In fact, no more and no different syncytial cells are present here than in normal gestation. The trophoblast cells lie closely grouped and are surrounded by syncytial elements in
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Fig. 60. — Low-power drawing of the typical form of chorio-epithelioma, showing the uterine wall invaded by chorionic elements. X, X, X, three areas of dense connective tissue surrounded by chorionic epithelial elements and resembling chorionic villi. Y, connective tissue centre surrounded by polynuclear syncytial mass of considerable thickness, probably a villus.
quite the same manner as in normal gestation, or especially in tubal gestation. They are polygonal cells, concerning which different views have been held. They have been called decidua cells. No vessels of their own, however, are present in these epithelial-like groups, and their character, their structure, and their arrangement so closely resemble the trophoblast cells observed in normal gestation that any other view is not to be con
TO CHORIO-EPITHELIOM A .
sidered. These epithelial-like cells and the syncytial masses of various forms all originate from the trophoblast cells.
In these growths newly formed villi have not yet been found — a proof of the limited power of differentiation possessed by the
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Fig. 61. — Upper left-hand corner of Fig. 60 highly magnified, showing the character of the polynuclear syncytial masses. Along the right and lower borders are larger isolated mononuclear syncytial cells.
trophoblast cells alone. It may be said, therefore, that two forms of this tumor exist, the first typical, the second atypical. The former cases are so characteristic that they cannot be mistaken. The latter have been so frequently called carcinoma by eminent an
RELATION OF THE CHORIONIC EPITHELIUM
thorities that our belief that many of these are overlooked and incorrectly diagnosed is certainly true.
A study of the histology of so-called deciduomata, and a comparison of their structure with the structure of normal placental elements, prove these tumors to be of fetal origin. The cells from which they develop are the cells which cover the chorionic villi. Since these are epithelial in character, these tumors, belonging as they do to the most malignant forms, should be called chorio-epithelioma.
We have, then, in the chorio-epitheliomata a reproduction of
TrophoMast cells forming syncytial masses Blood and olood cells
Fig. 62. — Highly magnified area of Fig. 61, showing finer characteristics of syncytial masses. Change of trophoblast cells en masse into polynuclear, vacuolar structures.
the same constituent elements as are found in normal placenta tion and as are observed in benign and malignant cases of hydatid mole. These cells exert the same influence and effect on the maternal tissues as do the fetal cells in a normal uninterrupted pregnancy. They invade, as do the normal trophoblast cells, the maternal decidua and destroy it. They infiltrate and erode the walls of the vessels. They invade and infiltrate deeply, too, the uterine wall. They advance either as, distinct Langhans or trophoblast cells or
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as syncytial cells, or else they undergo in their advance a change from the former to the latter, especially when in contact with maternal blood, as in the case of placentation either uterine or tubal. Their invasion of the maternal vessels and capillaries gives them, from their earliest existence as malignant cells, the opportunity of invading the maternal circulation with a resulting early formation of metastases. Their ability to erode the vessels causes profuse and constant bleeding. Their ability to destroy the maternal tissue as they advance produces larger and smaller areas of degeneration and necrosis accompanied by the presence of much fibrin. These cells preserve their ability to grow when
Fig. 63. — Highly magnified area of Fig. 60, showing character of isolated mononuclear giant syncytial cells and the infiltration by them of the uterine tissue and lymph spaces.
they reach their new locations, with the result that they produce in the various organs, but most frequently in the vagina, malignant nodules of the same character as the parent growth. In fact, these secondary nodules have in some cases been observed before the character of the uterine symptoms called attention to the presence of malignant conditions, in the uterus.
The fetal cells producing a chorioma are situated in the most favorable surrounding. They have been performing practically malignant functions in that they have destroyed, even during normal placentation, maternal tissues, and have invaded maternal vessels, and have been carried off into the maternal circulation.
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When connected as part and parcel of an ovum, when feeding and nourishing the fetus with the products of the maternal blood which have passed through them, they are, so to speak, under control of the parent organism the ovum, yet when released from this connection they continue an independent growth of their own. It is quite probable that in hydatid mole the edematous swelling of the chorionic stroma is due to interference with the proper exchange between the fetus and the mother, due to a more or less increased and independent growth on the part of those cells whose function it is, normally, to aid and permit of this exchange. It is likewise probable that the growth of the chorionic
Island of cells
_ Syncytial veils
Pig. 64. — High-power drawing of atypical chorio-epithelioma greatly resernblins carcinoma.
cells in chorio-epithelioma takes place during the pregnancy and is rather the cause than the result of abortion.
We have observed in the development and change of trophoblast cells to syncytium that the closely grouped cells, when vascularized, change to plasmodial or syncytial cells. That the blood of the mother furnishes the greater portion of the protoplasm of these syncytial cells has been clearly shown. Therefore their production and growth, even in normal conditions, depends upon their taking up from the mother essential elements, while the trophoblast cells themselves furnish the nuclei. Therefore the growth of so pathological a tumor as a chorio-epithelioma is not absolutely a reproduction of fetal cells, but is in a more or less direct manner a maternal production also.
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The invasion and destruction of maternal tissues in normal gestation occurs within certain fixed limits, and the fetal cells entering the maternal circulation undergo no future growth. What preserves this balance? What limits and controls the potential of the parasitic fetal cells? In hydatid mole, and especially in chorio-epithelioma, the fetal cells, are no longer held in check and they possess the power of unlimited growth. What has upset the normal balance ?
When the fecundated ovum enters the uterus, it destroys the surface epithelium under it and descends actively into the decidua. It produces a decided reaction in its immediate circumference, so that even in its earliest stages it evidences a chemical power. When the maternal blood makes its exit from the capillaries it ought to coagulate, but does not. It circulates against the fetal cells which have the power to prevent coagulation. The trophoblast and syncytial cells are bathed by maternal blood and enter the circulation; therefore the ovum has a certain enzyme action and the fetal cells may be said to furnish or represent a placental secretion.
On the other hand, the blood contains elements which exert a corrosive action on the trophoblast cells, changing them to syncytium. The resulting syncytial cells then cover the villi; they play the part of endothelium (which they then greatly resemble) and protect the cells of Langhans and the stroma from the corrosive influence of the blood. That the individual cells in chorioepithelioma have the power to grow without limit, and that the cells entering the circulation have the energy to produce malignant metastases, shows that the decidua and the blood no longer have the power to limit and control their growth.
In reviewing the anatomical and physiological characteristics of the female sex before and during pregnancy, and bearing in mind the normal changes of pregnancy (such as the cessation of menstruation, the act of labor, etc.), but especially the pathological states occurring almost entirely or exclusively in connection with pregnancy (such as osteomalacia, eclampsia, and chorioepithelioma), we are forced to the conclusion which, while partly theoretical, is nevertheless logical.
Ovarian secretion has a great trophic influence upon the uterus. It stimulates the growth of the round cells of the stroma into decidua cells. The lining of the uterus is truly a lymphoid tissue, and it is the great development of the decidua and its secretion which prevents the involvement and macroscopical perforation of
158 RELATION OP THE CHORIONIC EPITHELIUM
the uterine wall by the placental villi. Although it may be said that ovarian secretion stimulates the growth of the fetal cells and that certain elements in the blood hold their growth in check, it is probably the ovarian secretion in the maternal blood which aids the decidua in holding the placental development within normal limits, and which renders the trophoblast cells and the syncytial cells entering the circulation innocuous.
In normal placentation the human organism furnishes us with a process parallel to that occurring in certain bacterial infections, that is, the production of two opposing toxins or ferments : (1) a blood element, probably the ovarian secretion, and (2) the placental secretion.
In the normal woman the ovary is responsible for the periodical loss of blood known as. menstruation. This process is due to a secretion furnished by the ovaries, for on their removal this process ceases and the reduction of oxygen exchange amounts to twenty per cent. This secretion stimulates various functions, of the body, and at regular periods an outlet for this secretion occurs. Every menstruation represents, in addition, the birth of a non-fecundated ovum, that is, a labor en miniature.
When, however, fecundation and development of the ovum take place, the ovum and its enzymes nullify the menstrual stimulation of the ovarian secretion. The trophoblast cells invade the maternal decidua which is stimulated by the ovarian secretion, and likewise enter the blood of the mother. A normal gestation is accompanied by the stimulating effects of the retained ovarian secretion and these two enzymes are then opposed in their action. No menstruation occurs, for the placental secretion has nullified the action of the usual forces.
At the end of nine months, when the ovarian secretion is sufficient in amount or character to overcome the neutralizing action of the enzymes of the ovum, labor occurs, that is, the same process as is observed in a minuter degree in menstruation, for menstruation, as said before, is a labor en miniature.
Remembering the constitutional action of ovarian secretion, itmay be said that if, shortly before, during, or after labor, there is an overwhelming superiority of the ovarian secretion over the placental or an opposite mal-relation between ovarian and placental secretion, the constitutional involvement known as eclampsia results.
Following the analogy further, it may be said that chorioepithelioma is due to the fact that the resistance to the fetal en
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zymes and fetal cells offered by the blood and the ovarian secretion is insufficient to hold the growth of the fetal cells in check. Chorio-epithelioma occurring generally after abortion or hydatid mole is certainly the cause rather than the result of the abortion. Chorio-epithelioma represents a more advanced stage than that of hydatid mole, but both of these conditions follow the normal processes in their course and growth. The only difference is the power of unlimited growth possessed by the chorionic cells in these pathological conditions. The difference in the resistance offered by the patient points to a constitutional element as an important factor in the etiology of chorio-epithelioma.