Arthur T. Hertig

Dating the Endometrial Biopsy

It is asserted that examination of the endometrium during the secretory phase yields more information about the time of ovulation degree of progestational change and normality of the endometrium than any other test used in sterility studies. Attention to qualitative changes in 8 morphological factors is most useful in dating the endometrial biopsy. During the 1st week of luteal activity attention should be focused on changes occurring in gland epithelium: gland mitosis pseudostratification of nuclei basal vacuolation and secretion. During the 2nd week stromal changes (including edema) predecidual reaction stromal mitosis and leukocytic infiltration are the key criteria. Tissue from the fundus of the uterus gives the most reliable information. These critera were used in 300 sterility biopsies taken from normally menstruating women over a 3-year period. Absence of organic endometrial disease and availability of accurate menstrual history were the only selection criteria. 12 observers dated the biopsies. 42 of the 300 patients (14%) menstruated on the day predicted 36 (12%) menstruated later and 222 (74%) menstruated earlier. When a +or- 1 day error was allowed 112 patients (38%) were found to menstruate at the time predicted. When these same slides were reviewed by a single observer and the date for the most advanced area of the biopsy was used 179 patients (60%) menstruated within 1 day of prediction. To test the validity of the dating criteria change in basal body temperature was used to correlate endometrial dating with ovulation rather than onset of menstruation. Of the 40 patients who had adequate temperature records 31 (78%) ovulated as predicted allowing a +or- 1 day error indicating that dating is a better gauge of duration of progesterone effect than predictor of onset of menses. To determine whether biopsy caused early menstruation the secretory phases of the 25 patients who had recorded temperatures in at least 2 cycles in addition to that in which the biopsy was taken were examined. The secretory phase was definitely shorter in the biopsied than control cycle suggesting that biopsy does accelerate the onset of flow. However further analysis showed that biopsy does not interfere with length of flow or succeeding menstrual rhythm.

The pathologic anatomy of eclampsia, bilateral renal cortical necrosis, pituitary necrosis, and other acute fatal complications of pregnancy, and its possible relationship to the generalized Shwartzman phenomenon.

Abstract Intravascular fibrin deposition in arterioles and capillaries throughout the body is responsible for the necrosis and hemorrhage seen in eclampsia, bilateral renal cortical necrosis, and pituitary necrosis associated with pregnancy. These cases are often accompanied by severe shock, hemorrhage, and anuria. Fibrinogenopenia and fibrinolysins develop in this group of patients. It is suggested that the mechanism behind the fibrin deposition is similar to that in the generalized Shwartzman reaction. In some cases the source of “toxin” may be a bacterial infection. In some cases, particularly those associated with toxemia of pregnancy, the “toxin” may be similar to the “menstrual toxin” described by the Smiths.

The ovary in endometrial carcinoma with notes on the morphological history of the aging ovary.

Abstract Routine sections of the ovary from 331 cases of carcinoma of the endometrium were studied, and the findings compared with a control group of approximately the same number and age distribution obtained from selected autopsy material. Sections of the ovary from early infancy to old age obtained at autopsy were also studied with the aid of connective tissue, reticulum and nuclear stains, to determine the changes in the stroma throughout life.

The Overall Problem in Man

Reproductive failure occurs in all forms of life, plant and animal. I have been asked to make a few introductory or general remarks about the problem in man. Whatever I have to say is based upon 35 years’ experience in obstetric and gynecologic pathology, seasoned by interest in the early embryology of the human and interspersed with a nine-year interval as clinical obstetrician. These remarks are in no sense an exhaustive review of reproductive anatomy, physiology and pathology, even as applied to the human, let alone to mammals in general. Comments will be confined to my observations on the early or potentially abortive phases of human development and a pathologic evaluation of a thousand consecutive human abortions, most of them spontaneous.

Carcinoma in situ of the endometrium

Abstract Carcinoma in situ of the endometrium is the name applied to a complex hyperplastic glandular pattern in the endometrium also labeled atypical hyperplasia or adenomatous hyperplasia. When these latter names are applied they are usually modified by “severe” or “marked.” This lesion is often followed by or accompanies definite adenocarcinoma. Indeed, the terms are sometimes applied to lesions already carcinoma! There is an accumulation of evidence to suggest that endometrial carcinoma is preceded by changes atypical for the normal menstrual cycle. Such changes may be general or focal. There is no proof that carcinoma may appear suddenly in an absolutely normal endometrium. Indeed, we have never observed carcinoma to arise from normal endometrium. There is evidence to suggest there has been some prior abnormality and so, the carcinoma may well have arisen in such a focus. Only rarely is cystic hyperplasia followed by carcinoma. The more complex the hyperplastic pattern the greater is the likelihood of subsequent adenocarcinoma. The role of estrogen in the development of endometrial carcinoma is obscure. That hyperplasia of sequential patterns, carcinoma in situ and adenocarcinoma may be produced in rabbits by estrogen has been shown: methylcholanthrene may produce similar results. Only on rare occasions does estrogen seem definitely at fault in the human. Many patients take estrogens for a considerable time without ill effect. Management of the patient with carcinoma in situ has been modified with knowledge of the synthetic progestins and clomiphene citrate. It is known that hysterectomy will cure carcinoma in situ but many of the pateints present as infertility problems so a less final form of therapy should be attempted. In general, the interpretation of the many changes within the spectrum bridging the obviously normal and obviously malignant requires human judgment based upon experience. It is logical to expect that the interpretation of preinvasive changes will show great variation from pathologist to pathologist. Even the same pathologist may not always be consistent in viewing the same specimen at different times. Hence, it is small wonder that there is so much confusion over nomenclature, criteria and even validity itself of carcinoma in situ as an entity.

Epidemiologic evidence for the spectrum of change from dysplasia through carcinoma in situ to invasive cancer.

From a prospective study of precancerous lesions at the Boston Hospital for Women and from studies in the literature, evidence is examined for a relationship between dysplasia and carcinoma in situ. Epidemiologic observations indicate that dysplasia is the precursor of carcinoma in situ. The discovery rate of cervical epithelial abnormality (consisting of the combined rates of dysplasia, carcinoma in situ and invasive cancer) is constant throughout the decades from 20 to 70 years of age; the incidence of carcinoma in situ is 22 times greater in populations with dysplasia than in populations with negative cytology; in all age groups, entrance‐into the population with cervical epithelial abnormality is by way of dysplasia. The course of dysplasia in patients studied for periods up to 9 years is one of regression and recurrence. There is suggestive evidence that carcinoma in situ evolves from dysplasia during a period of recurrence.

On the development of the early human ovum, with special reference to the trophoblast of the previllous stage: A desoription of 7 normal and 5 pathologic human ova

Abstract A series of 5 previllous and 2 villous normal human ova, ranging from 7.5 to 16.5 days in developmental age, shows that the human blastocyst implants on the posterior wall, probably during the late sixth or nearly seventh day of its development, on endometrium that may range from the eighteenth to the twenty-third day of its development. Actually there are no precise data on the time of implantation, since the youngest specimen, and therefore the most critical one with respect to this process, is already implanted. The figures given (late sixth or early seventh day) are deduced on the basis of this youngest specimen. Even younger ova must be secured in order to determine the actual time of implantation. Trophoblast proliferates at the site of implantation which, at first, consists of solid cyto- and syncytiotrophoblast. The latter becomes vacuolated on the eighth day to develop lacunae for the reception of maternal blood on about the eleventh day. The chorionic villi begin to form as cytotrophoblastic masses on the twelfth to thirteenth day and grow peripherally along the syncytiotrophoblastic framework, ultimately coalescing peripherally to displace the syncytiotrophoblast, except the portion lining the intervillous space. Remnants of the desquamated syncytiotrophoblast are encountered in the placental site as giant cells. A series of 5 abnormal previllous ova, the developmental ages of which range from approximately the eleventh to the fourteenth day, but which are difficult to interpret accurately because of their abnormality, shows a variety of conditions ranging from shallow implantation of an otherwise normal ovum, through extreme hypoplasia of the trophoblast, to complete absence of the embryonic mass. The pathologic ova were all found on the anterior wall of the uterus.

Some aspects of early human development

Abstract 1. 1. Seven very young normal human conceptuses and five abnormal ones have been recovered from twelve of 60 excised uteri. One of the normal specimens, Mu-8020, estimated to be seven to eight days old (mean: 7.5) is, as far as we know, the youngest human embryo yet reported. The others range in age up to sixteen to seventeen days (mean: 16.5). By comparison of the age of the embryo with the associated endometrial histology, it is apparent that ovulation in two well-controlled cases occurred about fourteen (fifteen to thirteen) days before the anticipated dates of menstruation. 2. 2. From a consideration of three ova estimated to be 7.5, 9.5, and 12.5 days old (mean values), we learn that nidation takes place at a variable age of the embryo, perhaps from the fifth to the eighth day of age, and on an endometrium which may vary in phase from the nineteenth to the twenty-second day of a twenty-seven-day cycle (catamenia on the twenty-eighth day). 3. 3. The seven normal conceptuses were found on the posterior wall of the uterus, and the five abnormal ones on the anterior wall, probably a correlation which will not hold when more specimens are collected. The locus of nidation is not affected by the side on which the egg enters the uterus. 4. 4. Five (42 per cent) of our twelve young embryos are so pathologic as to indicate probable early abortion. This figure (42 per cent) is of course higher than the percentage of abortions among diagnosed pregnancies. It is conceivable that more cases will show a lower proportion of defective ova. It seems likely from these findings, however, that either many pregnancies abort before recognition, during apparent normal menstruation, or that cytologic improvement takes place in some formerly abnormal conceptuses.

Treatment of trophoblastic disease: With rationale for the use of adjunctive chemotherapy at the time of indicated operation☆☆☆

Abstract The results of therapy in 16 patients with metastatic or nonmetastatic trophoblastic disease have been reported. Therapy consisted of chemotherapy alone or chemotherapy with indicated surgery carried out in the middle of a course of drug administration. Agents used were Methotrexate and actinomycin D. A complete remission rate of 75 per cent among 8 patients with metastatic trophoblastic disease and 100 per cent among 8 patients with nonmetastatic disease is recorded. The rationale and feasibility of operating during a course of “adjunctive” chemotherapy are discussed. In this series there was no evidence of delay in wound healing nor spread of disease following the 13 surgical procedures carried out under cover of chemotherapy in 11 of this group of 16 patients. No claim is made in regard to the relative efficacy of this type of combined therapy and chemotherapy alone.

Localization of homologous plasma proteins in the human placenta by fluorescent antibody

Abstract Normal and abnormal human placentas, as well as specimens of hydatidiform mole and choriocarcinoma, have been surveyed for homologous plasma albumin and globulin by the fluorescent antibody technique. Protein has been found broadly dispersed throughout the stromal ground substance of the villi, decidua, and cord, as well as in the intervillous spaces. Slight specific localization has been noted in the trophoblastic cytoplasm, but not within nuclei. Syncytial knots have shown somewhat higher levels of cytoplasmic protein accumulation. Albumin and gamma globulin exhibited similar distribution, and all placental material, including that from a case of erythroblastosis fetalis, presented similar topography. Syncytial masses in the choriocarcinoma revealed intracytoplasmic localization, while the mole showed a general diffusion through the vesicular stroma. The findings do not indicate synthesis of blood protein by the human placenta, but rather point to a transfer of maternal albumin and globulin across the syncytium, perhaps by pinocytosis and subsequent discharge into the villous stroma.