Relation of endometrial hyperplasia to adenocarcinoma of the uterus

Abstract The evidence presented in this paper points to a relationship of some sort between hyperplasia of the endometrium and corporeal adenocar-cinoma. The material studied includes 804 cases of hyperplasia and 104 of adenocarcinoma, encountered in a review of 12,813 cases passing through our laboratory during an eleven-year period (Jan. 1, 1925, to Jan. 1, 1936). While in the overwhelming majority of cases hyperplasia is a very frankly benign lesion, a small minority (14 of our 804) reveals evidences of marked proliferative tendencies which may even simulate cancer. The histologic characteristics of benign hyperplasia present degrees and variations which are discussed in the paper, as are the proliferative and pseudomalignant pictures at times encountered (stratification, adenomatous proliferation, marked atypicalness of glands, syncytium-like epithelial proliferation, squamous metaplasia of gland or surface epithelium, etc.). Atypical gland proliferations, simulating adenocar-cinoma, are especially frequent in the polyps so often seen with hyperplasia. An interesting finding in this study was that hyperplasia is not rare in women long after the menopause (40 of 804 cases); and the etiology and significance of this are discussed. The occasional occurrence of hyperplasia with bleeding in elderly women lessens the significance of these findings as pointing to the probability of granulosa-cell carcinoma of the ovary, unless an ovarian tumor can actually be palpated. In the study of the 104 cases of adenocarcinoma, the most impressive result was the demonstration of a coexisting hyperplasia and adenocar-cinoma in fully 25 of the cases in which some of the noncancerous endometrium was available for study. Since the great majority of the adenocarcinoma cases (78 of 92 in which we have accurate age data) were beyond the menopausal age, this at once suggests that a postmenopausal hyperplasia, or, perhaps more accurately, the endocrine dysfunction responsible for it, must strongly predispose to the development of adenocarcinoma. Since a persistence and relative excess of estrin is accepted as the cause of hyperplasia, it would seem that it is this endocrine factor which must be suspected as the one predisposing to cancer genesis. It should be emphasized that the ordinary hyperplasia of the reproductive epoch is not only frankly benign from the histologic standpoint, but also that it has no apparent predisposing influence in the causation of adenocarcinoma during menstrual life. It would seem from our studies that it is the postmenopausal persistence of hyperplasia which is in some way bound up with the occurrence of the common postmeno-pausal type of adenocarcinoma. The question of the relation between estrogenic and carcinogenic substances, and the carcinogenic properties of estrogenic substances, is discussed in our paper. Whether the persisting estrin stimulation in cases of postmenopausal hyperplasia serves merely to keep up a form of chronic irritation, or whether its carcinogenic effects are more direct and fundamental, cannot be answered as yet, though the latter seems, in the light of recent experimental work, to be the more likely explanation. In our own cases of coexisting hyperplasia and adenocarcinoma, we have in some been able to show a definite transition of the benign to a border-line and then to an undoubtedly malignant pattern: so that, in the endometrium at least, it would seem that we are dealing with histologic intergrades between benign and malignant lesions. When such pictures are encountered in the endometrium obtained by diagnostic curettage, there is often a justification for the dictum, “Nicht Karzinom, aber besser heraus.” Since, on the basis of these observations, hyperplasia is to be classed as a precancerous lesion, in the sense of one predisposing to later adenocarcinoma, it would at first thought seem that we should all the more generally recommend abolition of ovarian function by x-ray or radium in the treatment of functional bleeding of the menopause. Whether or not this would be of any practical value, however, is questionable since it seems quite certain that other sources of estrogenic substance than the ovary must be reckoned with. One must be struck with the analogy of this problem to that of the breast, in which likewise the ovarian hormones can produce either very benign forms of cystic mastitis, or more markedly proliferative pictures which are scarcely or not at all distinguishable from cancer. In still an-other field, the cervix, we are now finding similarly puzzling borderline pictures, though we know almost nothing about their possible endocrine relationships. We refer particularly to leucoplakia and, even more, to the intraepithelial carcinoma or Bowen's disease, in which the epithelial layer presents all the characteristics of cancer except for invasiveness, and which are quite similar in appearance to the growing margin of an actual cancer. Are such lesions in themselves benign, as would seem to be indicated by the fact that they have often been cured by the most conservative procedures? Or are they inevitable precursors or very early stages of cancer, which, as in Bowen's disease of the skin, may not develop invasiveness and other malignant characteristics until the lapse of perhaps many years? Finally, may such lesions represent the response of the cervical epithelium to abnormal endocrine stimulation? In all three of these fields, cervix uteri, corpus uteri, and breasts, we have to deal with the possible roˆle of ovarian hormones. This seems significant in view of the growing opinion that the carcinogenic possibilities of estrogenic substances are most to be reckoned with in those organs in whose growth and activities estrin normally plays an important part.