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The Significance and Treatment of Menopausal Bleeding
Medical Clinics of North America March, 1939. Baltimore Number
CLINIC OF DR. EMIL NOVAK FROM THE DEPARTMENT OF GYNECOLOGY, JOHNS HOPKINS MEDICAL SCHOOL THE SIGNIFICANCE AND TREATMENT OF MENOPAUSAL BLEEDING
WHEN one hears the title of "menopausal hemorrhage" announced, one prepares to hear a discussion of uterine cancer, with the usual emphasis upon the importance of early diagnosis. So many thousands of papers have been written upon this subject that, in spite of its obvious importance, it gives evidence at times of being just a bit hackneyed. But the menopausal years have other clinical connotations besides that of cancer, as I hope to show in this clinic. In the first place, when one speaks of menopausal hemorrhage~ one does not necessarily refer to hemorrhage. occurring precisely at the time of the climacterium. The customary interpretation of the "menopausal years" is much broader than this, referring roughly to the middle period of life, that corresponding to about the fifth decade. Before considering the various types of hemorrhage, one should remember the normal variations as to menstrual bleeding in the closing years of menstrual life. The average age at the menopause is about forty-seven years, with much individual variation. There are some women in whom the function ceases very abruptly, but more frequently its disappearance is much more gradual. The woman, for example, misses a period or two, often being concerned as to the possibility of pregnancy. When menstruation occurs, it may be regular for perhaps several months, with then amenorrhea for a good many more, again followed by the sporadic appearance of the flow for a variable period, perhaps stretching over a year or two. While the menstrual amount 295
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is usually normal or increasingly scanty, there are not a few essentially normal women in whom the flow may be much freer than normal, as I shall have occasion to discuss later. The irregularities of tempo and amount of the flow even in normal women may be confusing from the standpoint of diagnosis. I have already mentioned the fact that women are often kept in hot water during this dodging period of the menopause, because of uncertainty as to whether pregnancy may not be the cause, of the amenorrhea. Not infrequently it is, chiefly because of the fact that women who have previously been very cautious in the matter of contraception, become careless in this respect, because of the mistaken idea that they are reasonably safe at this time. Another thing which should be borne in mind is that while menstruation continues up to the menopause, ovulation may cease a considerable time before the cessation of the menstrual function. To put it another way, the mere fact that a woman continues to menstruate up to the age of forty-seven does not necessarily mean that she can conceive up to this age. Let me illustrate the practical importance of this fact by the first case I should like to present. Case I.-This patient, a woman of forty-two, has come for examination because of secondary sterility. Her general health has always been excellent, and menstruation has been normal in character and amount, with intervals of from twentysix to thirty days. There was a normal childbirth fourteen years ago, and following this the patient practiced contraception, not desiring any more children. Two years ago the one child was killed in an automobile accident, and the woman then became anxious for another child, but no pregnancy has occurred. Both husband and wife are in the best of general health, and the basal metabolic rate in each is within normal limits. The husband's semen shows a normal spermatozoon count, with' only a few abnormal forms. The pelvic examination of the patient reveals essentially normal organs, and tubal insuf-
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flation shows the tubes to be patent. There would seem to be no reason for the sterility except the possibility that the patient is not ovulating. An endometrial biopsy was therefore done on about the twenty-sixth day of the cycle, revealing a purely proliferative type of endometrium, with no secretory activity. It may therefore be assumed that there is no corpus luteum in the ovaries; that is, that the patient has not ovulated with this cycle, and probably with others during the past two years, apparently an adequate explanation of her sterility. While in this case the menstrual function was quantitatively normal, its' mention seems within the limits of the present discussion because essentially the same mechanism is concerned in the very frequent cases of functional bleeding of the menopause. In women with this type of bleeding, the ripe follicle not only fails to rupture but continues actively functional beyond the normal time, producing increasing amounts of estrogen, and thereby an excessive proliferative activity of the endometrium. In its frankest form this constitutes the so-called "hyperplasia" of the endometrium, though many women show lesser degrees of endometrial proliferation. The common histologic characteristic in this form of bleeding is an absence of the secretory activity which only the corpus luteum hormone can evoke, and here there are no corpora lutea because ovulation has not occurred. When the follicle hormone has reached a certain level, a reverse inhibition of the pituitary function takes place and thereby the further maturation of follicles is checked. The ensuing drop in the follicle hormone knocks the endocrine props, as it were, from beneath the built-up endometrium, and .a bleeding phase sets in, which may be moderate or profuse, short or prolonged, depending upon quantitative hormone reactions. It is this hormonal interplay between the ovaries and the pituitary which is responsible for the most common variety of menopausal functional bleeding. There are of course other types of functional bleeding, some probably due to insufficiency of the uterine musculature, some probably to quantitative imbalance between the ovarian and corpus luteum hormones,
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and some no doubt to vascular and vasomotor factors. But we know very little as to these theoretical possibilities, and the type of bleeding which I have described is certainly much the most common . • Functional bleeding of this type is far more common in the fifth decade than at any other, though it occurs not infrequently in the initial years of menstrual life (juvenile functional bleeding, functional bleeding of puberty or adolescence), and may be encountered at any age between puberty and the menopause. Perhaps most characteristically it is menorrhagic in character, but intermenstrual bleeding is frequently associated. At times each menstrual flow is so prolonged that it merges into the next, so that bleeding may be continuous for many months. When such bleeding is seen in a woman of middle life, you can see how important it becomes from the standpoint of differential diagnosis, for it at once comes into diagnostic conflict with cancer, the most dangerous of all causes of menopausal hemorrhage. I should like now to present several cases to illustrate the diagnostic and therapeutic problems which arise in the management of this general group. Case H.-The patient is forty-three years of age, and for four years has suffered with profuse menorrhagia, the bleeding phases lasting from ten to twelve days. She has had three children, the youngest nine years ago. There are no noteworthy palpable abnormalities of the pelvic organs, though there is a moderate relaxation of the vaginal outlet. Three years ago the patient was curetted, with only very temporary improvement in the bleeding. Following this she is said to have been treated with pregnancy urine preparations (antuitrin Sand follutein) and more recently with preparations of progesterone, the corpus luteum hormone (proluton and lipolutin) . There was some improvement, but the bleeding has again become very profuse, and the patient has become rather disgusted with the long-continued hypodermic medication and the persistence of the bleeding. Her blood count shows 3,600,000 red blood corpuscles with a hemoglobin of 60 per cent,
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299
in spite of the fact that she has been receiving hematinics for a long time. The proper procedure in this case seems quite clear. The history suggests the reasonable certainty that the bleeding is of .functional nature, but this should never be taken for granted in women of cancer age. A diagnostic curettage, how'ever, reveals a benign hyperplasia of the endometrium, with the characteristic picture to which many years ago I applied the descriptive term "swiss-cheese pattern," a designation which seems to have been generally adopted in the literature of all countries. Here, then, is a woman who has lived her reproductive life, who has had all the children she wants, and whose one desire is to be rid of the troublesome bleeding which has made her a semi-invalid for years. Why submit her further to the uncertainties of organotherapy when the bleeding can be surely apd permanently stopped by the simple abolition of ovarian function by, means of either radium or x-ray? If she were only twenty-four instead of forty-three years of age, the problem would be very different and much more difficult, and we would have to do the best possible with organotherapy (pregnancy urine preI?arations, progesterone, testosterone propionate, etc.) with perhaps an occasional curettage if the bleeding were persistent and profuse in spite of treatment. In young patients, in other words, we must have constantly in mind the preservation of reproductive function, using conservative measures, always with the hope, usually fulfilled, that after a variable and unpredictable period the wished-for endocrine readjustment will occur and menstrual normality be restored. Case IlL-This patient is forty-seven years of age, and is the mother of 4 children, the youngest eight years old. Menstruation had always been quite normal until one year ago, when moderate menorrhagia appeared. Six months ago the patient began to have intermenstrual staining, which more recently has been rather persistent. Usually it is rather scant, most frequently consisting of a rather watery brownish or
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rusty-colored discharge. The pelvic organs show no noteworthy abnormality on pelvic examination, and the cervix shows no suspicion of malignancy. Several months ago the patient, without preliminary diagnostic curettage, was sent by her family physician to a roentgenologist, who very unwisely gave her a course of x-ray treatments with the object of abolishing ovarian function. Following the treatments the patient had a rather prolonged and moderately free bleeding lasting twelve days, and since then there has been a persistence of slight uterine bleeding and discharge. A diagnostic curettage was done several days ago, yielding a considerable amount of friable fungoid tissue, and the microscopic examination shows a very frank adenocarcinoma of grade 3. This case points an important moral in the management of menopausal hemorrhage of intra-uterine origin. It emphasizes the importance of establishing the functional nature of the bleeding by microscopic examination before resorting to radiotherapy, and the ever-present danger of overlooking cancer if this is not done. No intelligent radiologist will be guilty of this error, but I have encountered a number of instances in which such a mistake occurred, with resulting delay in the proper treatment of the cancer. Not only cancer but other intra-uterine lesions, such as submucous myomata or even retained gestational products, may thus be erroneously treated if diagnostic curettage is not done. There are of course some cases in which a long-standing history of menorrhagia, with no intermenstrual bleeding or discharge, makes the diagnosis of functional bleeding reasonably certain, but the safe procedure is to perform diagnostic curettage, with microscopic examination, in all cases of this age group. While corporeal adenocarcinoma is most frequently' a postmenopausal disease, at least one fourth of all cases occur in women who are still in the menstruating epoch.
Case IV.-The next patient is a woman of forty-five, who has had 6 children. Menstruation had been regular and of
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normal amount until two months ago, when the last normal period occurred. One week ago, three weeks after an expected but missed period, profuse bleeding, with the passage of many clots, began, and continued up to her admission. A diagnosis of early incomplete abortion was made by her physician, and this seemed a justifiable suspicion in view of the history. The -uterus was not appreciably enlarged, however, nor was there any softening of the cervix. The curettage yesterday yielded a large amount of polypoid tissue, which grossly might be mistaken. for carcinoma, and which did not at all suggest retained gestational tissues. Placental tissue is most apt to come away in dark chunky particles, with frequently blackish-blue thrombi and considerable bleeding. Carcinoma, except in very early stages, yields a tissue which, while it may be polypoid, is characterized by friability and necrosis, as compared with the smooth and fairly firm polypi of polypoid hyperplasia (the "polypoid endometritis" of earlier writers). In this case the microscope shows a beautiful Swiss-cheese pattern, that of frank benign hyperplasia, with not the slightest trace of chorionic tissue or decidua. This case is presented because it exemplifies a not uncommon diagnostic error. It should be remembered that the functional bleeding of the menopause may at times have a rather abrupt and profuse onset, and that this may occur after the skipping of one or more menstrual periods. As a matter of fact, a prolongation of the intermenstrual intervals is quite common. With a history such as that exhibited by this patient, a diagnosis of early abortion is often made, and this error may prove very embarrassing, especially in the case of unmarried women. Only the microscope will settle the diagnosis decisively. It need scarcely be added that the opposite error is equally possible if one depends on the history and pelvic examination alone; that is, a functional cause of bleeding may be assumed, and the microscope may reveal indubitable evidence of an unsuspected early abortion.
Case V.-One other case is presented, because it illustrates
an important group in which troublesome difflculties of diag-
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nosis arise. This patient is fifty-one years old. For the past three years menstruation has been increasingly irregular and at times very free. Frequent periods of amenorrhea of from two to six months have occurred. The patient has been bleeding scantily but rather persistently for the past three weeks, the preceding bleeding phase having been four months ago. The possibility of malignancy in such cases is always a real one, but the curettage yields only a moderate amount of benignlooking tissue. The confusion comes, however, when the microscopic examination is made. Certainly the appearance is quite different from that of the Swiss-cheese hyperplasia of which we have spoken in the preceding cases. Here, on the other hand, there are areas showing a markedly adenomatous picture, with thick, heavily stained gland epithelium and a bizarre gland pattern which strongly resembles adenocarcinoma. Indeed, a diagnosis of malignancy would undoubtedly be made by many pathologists, and yet we are convinced that the lesion is a benign one, representing merely a highly proliferative variety of hyperplasia. We have followed up cases of this sort for a matter of years, and found no subsequent evidence of malignancy, and similar studies have been made by others, as was discussed in a paper by Novak and Yui in 1936. A number of authors have called attention to the apparent menace of a very late menopause as regards the subsequent development of adenocarcinoma. Our own studies indicate that this may be explained by the fact that postmenopausal hyperplasia is not rare, and that long after the menopause the endometrium may, from some unknown source, still receive estrogenic stimulation capable of producing even such proliferative lesions as hyperplasia. Furthermore, the not infrequent finding of postmenopausal hyperplasia in uteri which are the seat of genuine adenocarcinoma makes us think that such postmenopausal proliferative activity is an important predisposing cause of cancer. On the other hand, hyperplasia during the menstrual years, when the endometrium is better able, as it were, to cope with this hormonal stimulation, is a
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frankly benign lesion, with no tendency, so far as we know, to predispose to cancer. Certainly it would be unthinkable to discuss menopausal bleeding without mention of the most important cause of such bleeding, cancer. Cancer of the uterine body, as I have already mentioned, is characteristically a postmenopausal dis-ease, though at "least one fourth of the cases occur during menstrual life. Not a few cases are encountered in the thirties, and it may occur even in the twenties. I have already discussed the importance of diagnostic curettage and microscopic examination by one well versed in gynecological pathology. Many mistakes are made, for a good many hospital pathologists, especially in the smaller institutions, have not had the opportunity of familiarizing themselves very thoroughly with the microscopic differentiation of endometrial lesions. In the case of postmenopausal bleeding diagnostic curettage is doubly important, for in approximately one half of all cases carcinoma is revealed. Some years ago a well-known gynecologist expressed the view that when bleeding occurs well beyond the menopause panhysterectomy should be done without the necessity of resorting to preliminary diagnostic curettage. This, I am convinced, is a very unwise generalization, especially when the bleeding is of short duration and scanty in amount. In such cases the bleeding will often be found to be due to such perfectly benign causes as senile endometritis or polypi. It may even be of functional nature. When the bleeding has been present a long time and is quite free, there can be no criticism of the policy of radical operation, for almost always the cause is cancer. The ideal plan in most cases is to do the diagnostic curettage, establish the diagnosis by immediate frozen section, and to proceed at once with the hysterectomy if cancer is found. This plan presupposes that the pathologist is qualified to make good frozen sections, and that the surgeon or the pathologist is qualified to make an immediate diagnosis. There are some pathologists who object that it is difficult to make frozen sec-
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tions of curettings. This, in my experience, can apply only to those cases in which the scrapings are scant or fragmentary, which is not the case in most cases of cancer. In the latter, except when the ,disease is very early, one practically always finds larger, definitely suspicious chunks of tissue which lend themselves readily to frozen section. When there is any doubt as to diagnosis, as there must be in a minority of cases on the basis of frozen sections alone, it is better to wait for permanent sections, which by the acetone method which we employ can be secured within a few hours. The importance of competent pathologic examination in the very frequent cases of menopausal bleeding in which diagnostic curettage is necessary can scarcely be overestimated. I have already mentioned the fact that proliferative types of benign hyperplasia may readily be mistaken for adenocarcinoma, and thus be subjected to unnecessary radical operations. After all, however, the type of cancer which is most common, and which must always be thought of in cases of menopausal bleeding, is carcinoma of the cervix. It is, at this age epoch, many times as frequent as carcinoma of the corpus. It should especially be thought of when the patient's bleeding is of the "contact" type, with staining after coitus, or after defecation or any other straining effort. In all cases of this type the cervix should be meticulously examined, and this means not only palpation, but also minute inspection under the best possible light. It is only in this way that one can expect to find the suspicious areas on the cervix, whereas the more advanced lesions can be readily enough detected by palpation. But diagnosis in the latter group means comparatively little to the patient, for her chances of cure are very slim. The cases in which the patient has a really good chance, at least fiftyfifty, and for which we should therefore be constantly on the watch, are those in which both the doctor and the patient must go to some trouble to make the diagnosis. We must therefore cease thinking of "cauliflower growths" or "crater ulcers" as the characteristic lesions, for the early favorable stage of the
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disease doesn't resemble these at all. patient with such an early lesion.
Let me show you a
Case VI.-This patient, aged forty-three, is the mother of 5 children, and menstruation has been normal until very recently. Even now, as a matter of fact, the periods them- selves are normal in amount and rhythm, but during the past six weeks she has on several occasions, especially after coitus, noticed slight intermenstrual bleeding. No noteworthy abnormalities are revealed on bimanual palpation. On inserting a bivalve speculum, however, and brightly illuminating the cervix, we see on the posterior lip a slightly raised boss extending posteriorly from the os. Its surface is granular-looking, and on gentle rubbing with a cotton-wound applicator a trickle of blood is started. As in this patient the cervix is readily accessible, we take a thin slice of tissue directly from this area with a scalpel, touching up the resulting wound with an electrocautery knife. If the cervix were high and inaccessible we would employ a cervical biopsy punch instead of the scalpel, which would be awkward under these circumstances. Now that we have our tissue, we shall have a frozen section available in a few minutes. While waiting for this, I may remind you that even earlier stages than this are discoverable by proper examination. Even the most expert gynecologist cannot tell from mere inspection whether or not they are cancerous. He can, however, be suspicious, and settle the diagnosis almost always by biopsy and microscopic examination. In our case we are making a frozen section for demonstration purposes, but in these days of non-operative treatment of cervical carcinoma there is no particular need for immediate diagnosis, and permanent sections are perhaps more often employed. They will of course be made in this case also. In such a lesion as the one before us, there is no need for such methods of diagnosis as the colposcope or the Schiller test. The former has never achieved much popularity in this country, while the Schiller test likewise seems to have been evaluated as of very little service. In itself it cannot be conVOL. 23-20
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sidered to possess any diagnostic value, its chief usefulness. being to reveal suspicious areas, which must then be submitted to biopsy and microscopic examination. It will not, for example, distinguish between benign leukoplakia and very early cancer. As regards the latter, there is still much difference of opinion as to whether the noninvasive intra-epithelial lesion which Schiller speaks of as "early cancer" is really so to be considered. Many of us believe that a lesion showing no tendency to penetrate the basement membrane lacks the very essence of cancer. Only when it begins to break through the basement membrane, which may not be for many years and perhaps never, can we begin to speak of the lesion as a cancer. This, at any rate, is our viewpoint, though there would seem to be no doubt that an important relation of some sort exists between the so-called "noninvasive" cancer and genuine cancer itself. This subject, however, I have discussed at greater length in two recent papers. This patient I have just shown you incidentally illustrates the pos~ibly predisposing influence of chronic irritation in the development of carcinoma. She has a very obvious chronic endocervicitis in addition to the cancer-suspicious area. Most of us accept this viewpoint and practice and preach accordingly. On the other hand, most of the very early cancers I have seen, including chiefly the "accidental finds" on routine laboratory examinations in patients in whom cancer has not even been suspected, have been in cervices which grossly were quite normal, or which presented only a smallleukoplakic area, with little or no evidence of chronic inflammation. And yet we know that in other parts of the body, such as the mouth or lips, chronic irritation plays an undoubtedly important predisposing role. Two factors are apparently concerned in the development of cancer, viz: (1) an unknown constitutional factor present in some individuals and not in others, and (2) chronic irritation. In some patients the constitutional factor may be so strong that cancer develops even in the absence of irritation, but in
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others the chronic irritation may play an important role. We can do nothing about the constitutional factor, for we know nothing about its nature, and hence it would seem wise to continue our present methods of cancer prophylaxis, in the hope that we can confer at least some measure of protection , upon the patient. And now we have our section under the microscope. I think you will agree that, having been prepared by an expert technician, it is just as good as any permanent section. A glance at the slide shows unquestioned epidermoid carcinoma, on the basis of not only the individual cell changes, but also .of the characteristic invasive pattern. The patient should have at least a 50 per cent chance for cure. She will receive radiotherapy, especially since she is very obese, so that pan. hysterectomy would be associated with somewhat more risk than the average case. Finally, a word as to the value and the limitations of education of the public concerning the early warning signals of uterine cancer. I believe it to be of great value, for how can the doctor give the patient the proper treatment with any hope of success unless the patient presents herself for the treatment before the disease becomes hopelessly advanced? But popular education, important as it is, can bring about only a measure of improvement. Some patients really do not have a chance, no matter how well-informed they may be, for they may be doomed before the appearance of any symptoms at all. Furthermore, no sensible doctor can maintain that the skirts of our own profession are altogether clean, for there are still many doctors prone to dangerous delay and carelessness in the management of cases when the symptoms indicate a definite suspicion of cancer. In addition to our campaign of popular education, we must keep up a parallel educational campaign within our own ranks. Until we have available more effective methods of treatment than we now possess, our best hope in improving results is to make full use of existing knowledge, rather than to bemoan the fact that we know so little as to the nature of cancer and its effective treatment.
CLINIC OF DR. EMIL NOVAK FROM THE DEPARTMENT OF GYNECOLOGY, JOHNS HOPKINS MEDICAL SCHOOL THE SIGNIFICANCE AND TREATMENT OF MENOPAUSAL BLEEDING
WHEN one hears the title of "menopausal hemorrhage" announced, one prepares to hear a discussion of uterine cancer, with the usual emphasis upon the importance of early diagnosis. So many thousands of papers have been written upon this subject that, in spite of its obvious importance, it gives evidence at times of being just a bit hackneyed. But the menopausal years have other clinical connotations besides that of cancer, as I hope to show in this clinic. In the first place, when one speaks of menopausal hemorrhage~ one does not necessarily refer to hemorrhage. occurring precisely at the time of the climacterium. The customary interpretation of the "menopausal years" is much broader than this, referring roughly to the middle period of life, that corresponding to about the fifth decade. Before considering the various types of hemorrhage, one should remember the normal variations as to menstrual bleeding in the closing years of menstrual life. The average age at the menopause is about forty-seven years, with much individual variation. There are some women in whom the function ceases very abruptly, but more frequently its disappearance is much more gradual. The woman, for example, misses a period or two, often being concerned as to the possibility of pregnancy. When menstruation occurs, it may be regular for perhaps several months, with then amenorrhea for a good many more, again followed by the sporadic appearance of the flow for a variable period, perhaps stretching over a year or two. While the menstrual amount 295
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is usually normal or increasingly scanty, there are not a few essentially normal women in whom the flow may be much freer than normal, as I shall have occasion to discuss later. The irregularities of tempo and amount of the flow even in normal women may be confusing from the standpoint of diagnosis. I have already mentioned the fact that women are often kept in hot water during this dodging period of the menopause, because of uncertainty as to whether pregnancy may not be the cause, of the amenorrhea. Not infrequently it is, chiefly because of the fact that women who have previously been very cautious in the matter of contraception, become careless in this respect, because of the mistaken idea that they are reasonably safe at this time. Another thing which should be borne in mind is that while menstruation continues up to the menopause, ovulation may cease a considerable time before the cessation of the menstrual function. To put it another way, the mere fact that a woman continues to menstruate up to the age of forty-seven does not necessarily mean that she can conceive up to this age. Let me illustrate the practical importance of this fact by the first case I should like to present. Case I.-This patient, a woman of forty-two, has come for examination because of secondary sterility. Her general health has always been excellent, and menstruation has been normal in character and amount, with intervals of from twentysix to thirty days. There was a normal childbirth fourteen years ago, and following this the patient practiced contraception, not desiring any more children. Two years ago the one child was killed in an automobile accident, and the woman then became anxious for another child, but no pregnancy has occurred. Both husband and wife are in the best of general health, and the basal metabolic rate in each is within normal limits. The husband's semen shows a normal spermatozoon count, with' only a few abnormal forms. The pelvic examination of the patient reveals essentially normal organs, and tubal insuf-
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297
flation shows the tubes to be patent. There would seem to be no reason for the sterility except the possibility that the patient is not ovulating. An endometrial biopsy was therefore done on about the twenty-sixth day of the cycle, revealing a purely proliferative type of endometrium, with no secretory activity. It may therefore be assumed that there is no corpus luteum in the ovaries; that is, that the patient has not ovulated with this cycle, and probably with others during the past two years, apparently an adequate explanation of her sterility. While in this case the menstrual function was quantitatively normal, its' mention seems within the limits of the present discussion because essentially the same mechanism is concerned in the very frequent cases of functional bleeding of the menopause. In women with this type of bleeding, the ripe follicle not only fails to rupture but continues actively functional beyond the normal time, producing increasing amounts of estrogen, and thereby an excessive proliferative activity of the endometrium. In its frankest form this constitutes the so-called "hyperplasia" of the endometrium, though many women show lesser degrees of endometrial proliferation. The common histologic characteristic in this form of bleeding is an absence of the secretory activity which only the corpus luteum hormone can evoke, and here there are no corpora lutea because ovulation has not occurred. When the follicle hormone has reached a certain level, a reverse inhibition of the pituitary function takes place and thereby the further maturation of follicles is checked. The ensuing drop in the follicle hormone knocks the endocrine props, as it were, from beneath the built-up endometrium, and .a bleeding phase sets in, which may be moderate or profuse, short or prolonged, depending upon quantitative hormone reactions. It is this hormonal interplay between the ovaries and the pituitary which is responsible for the most common variety of menopausal functional bleeding. There are of course other types of functional bleeding, some probably due to insufficiency of the uterine musculature, some probably to quantitative imbalance between the ovarian and corpus luteum hormones,
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and some no doubt to vascular and vasomotor factors. But we know very little as to these theoretical possibilities, and the type of bleeding which I have described is certainly much the most common . • Functional bleeding of this type is far more common in the fifth decade than at any other, though it occurs not infrequently in the initial years of menstrual life (juvenile functional bleeding, functional bleeding of puberty or adolescence), and may be encountered at any age between puberty and the menopause. Perhaps most characteristically it is menorrhagic in character, but intermenstrual bleeding is frequently associated. At times each menstrual flow is so prolonged that it merges into the next, so that bleeding may be continuous for many months. When such bleeding is seen in a woman of middle life, you can see how important it becomes from the standpoint of differential diagnosis, for it at once comes into diagnostic conflict with cancer, the most dangerous of all causes of menopausal hemorrhage. I should like now to present several cases to illustrate the diagnostic and therapeutic problems which arise in the management of this general group. Case H.-The patient is forty-three years of age, and for four years has suffered with profuse menorrhagia, the bleeding phases lasting from ten to twelve days. She has had three children, the youngest nine years ago. There are no noteworthy palpable abnormalities of the pelvic organs, though there is a moderate relaxation of the vaginal outlet. Three years ago the patient was curetted, with only very temporary improvement in the bleeding. Following this she is said to have been treated with pregnancy urine preparations (antuitrin Sand follutein) and more recently with preparations of progesterone, the corpus luteum hormone (proluton and lipolutin) . There was some improvement, but the bleeding has again become very profuse, and the patient has become rather disgusted with the long-continued hypodermic medication and the persistence of the bleeding. Her blood count shows 3,600,000 red blood corpuscles with a hemoglobin of 60 per cent,
MENOPAUSAL BLEEDLNG
299
in spite of the fact that she has been receiving hematinics for a long time. The proper procedure in this case seems quite clear. The history suggests the reasonable certainty that the bleeding is of .functional nature, but this should never be taken for granted in women of cancer age. A diagnostic curettage, how'ever, reveals a benign hyperplasia of the endometrium, with the characteristic picture to which many years ago I applied the descriptive term "swiss-cheese pattern," a designation which seems to have been generally adopted in the literature of all countries. Here, then, is a woman who has lived her reproductive life, who has had all the children she wants, and whose one desire is to be rid of the troublesome bleeding which has made her a semi-invalid for years. Why submit her further to the uncertainties of organotherapy when the bleeding can be surely apd permanently stopped by the simple abolition of ovarian function by, means of either radium or x-ray? If she were only twenty-four instead of forty-three years of age, the problem would be very different and much more difficult, and we would have to do the best possible with organotherapy (pregnancy urine preI?arations, progesterone, testosterone propionate, etc.) with perhaps an occasional curettage if the bleeding were persistent and profuse in spite of treatment. In young patients, in other words, we must have constantly in mind the preservation of reproductive function, using conservative measures, always with the hope, usually fulfilled, that after a variable and unpredictable period the wished-for endocrine readjustment will occur and menstrual normality be restored. Case IlL-This patient is forty-seven years of age, and is the mother of 4 children, the youngest eight years old. Menstruation had always been quite normal until one year ago, when moderate menorrhagia appeared. Six months ago the patient began to have intermenstrual staining, which more recently has been rather persistent. Usually it is rather scant, most frequently consisting of a rather watery brownish or
300
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rusty-colored discharge. The pelvic organs show no noteworthy abnormality on pelvic examination, and the cervix shows no suspicion of malignancy. Several months ago the patient, without preliminary diagnostic curettage, was sent by her family physician to a roentgenologist, who very unwisely gave her a course of x-ray treatments with the object of abolishing ovarian function. Following the treatments the patient had a rather prolonged and moderately free bleeding lasting twelve days, and since then there has been a persistence of slight uterine bleeding and discharge. A diagnostic curettage was done several days ago, yielding a considerable amount of friable fungoid tissue, and the microscopic examination shows a very frank adenocarcinoma of grade 3. This case points an important moral in the management of menopausal hemorrhage of intra-uterine origin. It emphasizes the importance of establishing the functional nature of the bleeding by microscopic examination before resorting to radiotherapy, and the ever-present danger of overlooking cancer if this is not done. No intelligent radiologist will be guilty of this error, but I have encountered a number of instances in which such a mistake occurred, with resulting delay in the proper treatment of the cancer. Not only cancer but other intra-uterine lesions, such as submucous myomata or even retained gestational products, may thus be erroneously treated if diagnostic curettage is not done. There are of course some cases in which a long-standing history of menorrhagia, with no intermenstrual bleeding or discharge, makes the diagnosis of functional bleeding reasonably certain, but the safe procedure is to perform diagnostic curettage, with microscopic examination, in all cases of this age group. While corporeal adenocarcinoma is most frequently' a postmenopausal disease, at least one fourth of all cases occur in women who are still in the menstruating epoch.
Case IV.-The next patient is a woman of forty-five, who has had 6 children. Menstruation had been regular and of
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normal amount until two months ago, when the last normal period occurred. One week ago, three weeks after an expected but missed period, profuse bleeding, with the passage of many clots, began, and continued up to her admission. A diagnosis of early incomplete abortion was made by her physician, and this seemed a justifiable suspicion in view of the history. The -uterus was not appreciably enlarged, however, nor was there any softening of the cervix. The curettage yesterday yielded a large amount of polypoid tissue, which grossly might be mistaken. for carcinoma, and which did not at all suggest retained gestational tissues. Placental tissue is most apt to come away in dark chunky particles, with frequently blackish-blue thrombi and considerable bleeding. Carcinoma, except in very early stages, yields a tissue which, while it may be polypoid, is characterized by friability and necrosis, as compared with the smooth and fairly firm polypi of polypoid hyperplasia (the "polypoid endometritis" of earlier writers). In this case the microscope shows a beautiful Swiss-cheese pattern, that of frank benign hyperplasia, with not the slightest trace of chorionic tissue or decidua. This case is presented because it exemplifies a not uncommon diagnostic error. It should be remembered that the functional bleeding of the menopause may at times have a rather abrupt and profuse onset, and that this may occur after the skipping of one or more menstrual periods. As a matter of fact, a prolongation of the intermenstrual intervals is quite common. With a history such as that exhibited by this patient, a diagnosis of early abortion is often made, and this error may prove very embarrassing, especially in the case of unmarried women. Only the microscope will settle the diagnosis decisively. It need scarcely be added that the opposite error is equally possible if one depends on the history and pelvic examination alone; that is, a functional cause of bleeding may be assumed, and the microscope may reveal indubitable evidence of an unsuspected early abortion.
Case V.-One other case is presented, because it illustrates
an important group in which troublesome difflculties of diag-
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nosis arise. This patient is fifty-one years old. For the past three years menstruation has been increasingly irregular and at times very free. Frequent periods of amenorrhea of from two to six months have occurred. The patient has been bleeding scantily but rather persistently for the past three weeks, the preceding bleeding phase having been four months ago. The possibility of malignancy in such cases is always a real one, but the curettage yields only a moderate amount of benignlooking tissue. The confusion comes, however, when the microscopic examination is made. Certainly the appearance is quite different from that of the Swiss-cheese hyperplasia of which we have spoken in the preceding cases. Here, on the other hand, there are areas showing a markedly adenomatous picture, with thick, heavily stained gland epithelium and a bizarre gland pattern which strongly resembles adenocarcinoma. Indeed, a diagnosis of malignancy would undoubtedly be made by many pathologists, and yet we are convinced that the lesion is a benign one, representing merely a highly proliferative variety of hyperplasia. We have followed up cases of this sort for a matter of years, and found no subsequent evidence of malignancy, and similar studies have been made by others, as was discussed in a paper by Novak and Yui in 1936. A number of authors have called attention to the apparent menace of a very late menopause as regards the subsequent development of adenocarcinoma. Our own studies indicate that this may be explained by the fact that postmenopausal hyperplasia is not rare, and that long after the menopause the endometrium may, from some unknown source, still receive estrogenic stimulation capable of producing even such proliferative lesions as hyperplasia. Furthermore, the not infrequent finding of postmenopausal hyperplasia in uteri which are the seat of genuine adenocarcinoma makes us think that such postmenopausal proliferative activity is an important predisposing cause of cancer. On the other hand, hyperplasia during the menstrual years, when the endometrium is better able, as it were, to cope with this hormonal stimulation, is a
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frankly benign lesion, with no tendency, so far as we know, to predispose to cancer. Certainly it would be unthinkable to discuss menopausal bleeding without mention of the most important cause of such bleeding, cancer. Cancer of the uterine body, as I have already mentioned, is characteristically a postmenopausal dis-ease, though at "least one fourth of the cases occur during menstrual life. Not a few cases are encountered in the thirties, and it may occur even in the twenties. I have already discussed the importance of diagnostic curettage and microscopic examination by one well versed in gynecological pathology. Many mistakes are made, for a good many hospital pathologists, especially in the smaller institutions, have not had the opportunity of familiarizing themselves very thoroughly with the microscopic differentiation of endometrial lesions. In the case of postmenopausal bleeding diagnostic curettage is doubly important, for in approximately one half of all cases carcinoma is revealed. Some years ago a well-known gynecologist expressed the view that when bleeding occurs well beyond the menopause panhysterectomy should be done without the necessity of resorting to preliminary diagnostic curettage. This, I am convinced, is a very unwise generalization, especially when the bleeding is of short duration and scanty in amount. In such cases the bleeding will often be found to be due to such perfectly benign causes as senile endometritis or polypi. It may even be of functional nature. When the bleeding has been present a long time and is quite free, there can be no criticism of the policy of radical operation, for almost always the cause is cancer. The ideal plan in most cases is to do the diagnostic curettage, establish the diagnosis by immediate frozen section, and to proceed at once with the hysterectomy if cancer is found. This plan presupposes that the pathologist is qualified to make good frozen sections, and that the surgeon or the pathologist is qualified to make an immediate diagnosis. There are some pathologists who object that it is difficult to make frozen sec-
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tions of curettings. This, in my experience, can apply only to those cases in which the scrapings are scant or fragmentary, which is not the case in most cases of cancer. In the latter, except when the ,disease is very early, one practically always finds larger, definitely suspicious chunks of tissue which lend themselves readily to frozen section. When there is any doubt as to diagnosis, as there must be in a minority of cases on the basis of frozen sections alone, it is better to wait for permanent sections, which by the acetone method which we employ can be secured within a few hours. The importance of competent pathologic examination in the very frequent cases of menopausal bleeding in which diagnostic curettage is necessary can scarcely be overestimated. I have already mentioned the fact that proliferative types of benign hyperplasia may readily be mistaken for adenocarcinoma, and thus be subjected to unnecessary radical operations. After all, however, the type of cancer which is most common, and which must always be thought of in cases of menopausal bleeding, is carcinoma of the cervix. It is, at this age epoch, many times as frequent as carcinoma of the corpus. It should especially be thought of when the patient's bleeding is of the "contact" type, with staining after coitus, or after defecation or any other straining effort. In all cases of this type the cervix should be meticulously examined, and this means not only palpation, but also minute inspection under the best possible light. It is only in this way that one can expect to find the suspicious areas on the cervix, whereas the more advanced lesions can be readily enough detected by palpation. But diagnosis in the latter group means comparatively little to the patient, for her chances of cure are very slim. The cases in which the patient has a really good chance, at least fiftyfifty, and for which we should therefore be constantly on the watch, are those in which both the doctor and the patient must go to some trouble to make the diagnosis. We must therefore cease thinking of "cauliflower growths" or "crater ulcers" as the characteristic lesions, for the early favorable stage of the
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disease doesn't resemble these at all. patient with such an early lesion.
Let me show you a
Case VI.-This patient, aged forty-three, is the mother of 5 children, and menstruation has been normal until very recently. Even now, as a matter of fact, the periods them- selves are normal in amount and rhythm, but during the past six weeks she has on several occasions, especially after coitus, noticed slight intermenstrual bleeding. No noteworthy abnormalities are revealed on bimanual palpation. On inserting a bivalve speculum, however, and brightly illuminating the cervix, we see on the posterior lip a slightly raised boss extending posteriorly from the os. Its surface is granular-looking, and on gentle rubbing with a cotton-wound applicator a trickle of blood is started. As in this patient the cervix is readily accessible, we take a thin slice of tissue directly from this area with a scalpel, touching up the resulting wound with an electrocautery knife. If the cervix were high and inaccessible we would employ a cervical biopsy punch instead of the scalpel, which would be awkward under these circumstances. Now that we have our tissue, we shall have a frozen section available in a few minutes. While waiting for this, I may remind you that even earlier stages than this are discoverable by proper examination. Even the most expert gynecologist cannot tell from mere inspection whether or not they are cancerous. He can, however, be suspicious, and settle the diagnosis almost always by biopsy and microscopic examination. In our case we are making a frozen section for demonstration purposes, but in these days of non-operative treatment of cervical carcinoma there is no particular need for immediate diagnosis, and permanent sections are perhaps more often employed. They will of course be made in this case also. In such a lesion as the one before us, there is no need for such methods of diagnosis as the colposcope or the Schiller test. The former has never achieved much popularity in this country, while the Schiller test likewise seems to have been evaluated as of very little service. In itself it cannot be conVOL. 23-20
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sidered to possess any diagnostic value, its chief usefulness. being to reveal suspicious areas, which must then be submitted to biopsy and microscopic examination. It will not, for example, distinguish between benign leukoplakia and very early cancer. As regards the latter, there is still much difference of opinion as to whether the noninvasive intra-epithelial lesion which Schiller speaks of as "early cancer" is really so to be considered. Many of us believe that a lesion showing no tendency to penetrate the basement membrane lacks the very essence of cancer. Only when it begins to break through the basement membrane, which may not be for many years and perhaps never, can we begin to speak of the lesion as a cancer. This, at any rate, is our viewpoint, though there would seem to be no doubt that an important relation of some sort exists between the so-called "noninvasive" cancer and genuine cancer itself. This subject, however, I have discussed at greater length in two recent papers. This patient I have just shown you incidentally illustrates the pos~ibly predisposing influence of chronic irritation in the development of carcinoma. She has a very obvious chronic endocervicitis in addition to the cancer-suspicious area. Most of us accept this viewpoint and practice and preach accordingly. On the other hand, most of the very early cancers I have seen, including chiefly the "accidental finds" on routine laboratory examinations in patients in whom cancer has not even been suspected, have been in cervices which grossly were quite normal, or which presented only a smallleukoplakic area, with little or no evidence of chronic inflammation. And yet we know that in other parts of the body, such as the mouth or lips, chronic irritation plays an undoubtedly important predisposing role. Two factors are apparently concerned in the development of cancer, viz: (1) an unknown constitutional factor present in some individuals and not in others, and (2) chronic irritation. In some patients the constitutional factor may be so strong that cancer develops even in the absence of irritation, but in
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others the chronic irritation may play an important role. We can do nothing about the constitutional factor, for we know nothing about its nature, and hence it would seem wise to continue our present methods of cancer prophylaxis, in the hope that we can confer at least some measure of protection , upon the patient. And now we have our section under the microscope. I think you will agree that, having been prepared by an expert technician, it is just as good as any permanent section. A glance at the slide shows unquestioned epidermoid carcinoma, on the basis of not only the individual cell changes, but also .of the characteristic invasive pattern. The patient should have at least a 50 per cent chance for cure. She will receive radiotherapy, especially since she is very obese, so that pan. hysterectomy would be associated with somewhat more risk than the average case. Finally, a word as to the value and the limitations of education of the public concerning the early warning signals of uterine cancer. I believe it to be of great value, for how can the doctor give the patient the proper treatment with any hope of success unless the patient presents herself for the treatment before the disease becomes hopelessly advanced? But popular education, important as it is, can bring about only a measure of improvement. Some patients really do not have a chance, no matter how well-informed they may be, for they may be doomed before the appearance of any symptoms at all. Furthermore, no sensible doctor can maintain that the skirts of our own profession are altogether clean, for there are still many doctors prone to dangerous delay and carelessness in the management of cases when the symptoms indicate a definite suspicion of cancer. In addition to our campaign of popular education, we must keep up a parallel educational campaign within our own ranks. Until we have available more effective methods of treatment than we now possess, our best hope in improving results is to make full use of existing knowledge, rather than to bemoan the fact that we know so little as to the nature of cancer and its effective treatment.