Spontaneous occurrence of atypical hyperplasia and adenocarcinoma of the uterus in androgen-sterilized SD rats.

In SD female rats sterilized by a single injection of testosterone propionate at 2 days after birth, the spontaneous occurrence of atypical hyperplasia and adenocarcinoma of the uterus was observed for a fairly long period (greater than 2 yr). Two atypical hyperplasias and 2 adenocarcinomas were detected in 25 androgen-sterilized rats (ASR) after 500 days of age; in contrast, in 111 normal control rats no abnormal uterine proliferation was detected during a 750-day observation period. These results indicate that a persistence of both hormone imbalances and dysfunctional uteri in ASR induces abnormal uterine proliferation at a late age.

In vivo and in vitro studies of experimental ovarian adenocarcinoma in rats.

When 7,12-dimethylbenz[a]anthracene-impregnated sutures were directly applied to the ovarian parenchyma of 8-week-old Sprague-Dawley rats (the clipping method), adenocarcinomas developed in 29 (39%) of the 75 rats during the 50-week observation period. When 20-methylcholanthrene was used, adenocarcinomas developed only in 1 (3%) of the 31 rats. Thus, the clipping method using 7,12-dimethylbenz[a]anthracene is satisfactory as an animal model of ovarian adenocarcinoma which comprises 85 to 90% of human malignant ovarian tumors. On the other hand, attempts were made to isolate cloned cell lines from these experimental ovarian adenocarcinomas in vitro, and two cloned cell lines were obtained. They were epithelioid and produced undifferentiated adenocarcinomas by back-transplantation into isologous newborn rats.

[Aspiration cytology of salivary gland lesions--analysis of 55 cases].

Aspiration cytology of 55 salivary gland lesions (10 cases of non-neoplastic lesions, 36 cases of benign tumors and 9 cases of malignant tumors) were reviewed with histologic examination. Accuracy of benign and malignancy was 91.8% (benign lesion 97.6%, malignant tumor 57.1%), accuracy rates was almost of satisfactory for benign lesions, but not for malignant tumors. Agreement rate with histological type was 73.5%. One case (1.8%) was false positive, basal cell adenoma with adenoid cystic like pattern was falsely taken for adenoid cystic carcinoma. Three false negative cases (5.5%) consist of 1 acinic cell carcinoma, 1 adenoid cystic carcinoma with minimum cellular atypia and 1 partial malignant change (minor area) in pleomorphic adenoma. Six cases (10.9%) belong to group of insufficient material. Technical improvement of cell sampling is expected.

[Immunocytohistochemical studies of AFP producing gastric cancer--cytomorphology and characteristics of AFP positive cells].

In 24 cases (5.5%) out of 438 cases of gastric cancer showing serum AFP over 20 ng/ml, 14 cases (3.2%) showed AFP positive reaction in cancer cells by immunostaining. AFP localization in cancer cells classified into marginal type, granular type, diffuse type and inclusion type. Mixed combination of these types increased in high serum AFP level. Cytomorphology of AFP positive cells was classified to clear cell type, hepatoid cell type and round cell type. Clear cell type showed endodermal sinus like pattern in histomorphology. Clear cell type and hepatoid cell type were mixed, and transient. These types showed eosinophilic hyaline like globules, poor mucin production, and rich glycogen in cytoplasm. By immunohistochemistry showed positive rate in HCG:21.4%, PLAL:50. 0%, SP1:50.0%, CK:14.3% and alpha 1-AT:92.9%, and recognized reaction of germ cell tumor (endodermal sinus tumor) marker. We thought AFP producing gastric cancer suggested differentiation to germ cell tumor (endodermal sinus tumor). The AFP-positively stained cases were found in a high age group with advanced cancer located pylorus to corpus, medullary growth pattern, and high rate in liver metastases.

[Diagnosis of precancerous lesions of the endometrium].

Cytodiagnosis of the precancerous lesions of the endometrium has remained unclear compared to that for cervical lesions. Endometrial cytology and biopsy have been performed for patients with atypical genital bleeding, who were over fifty, postmenopausal or nulliparous, We studied cytologic findings in cystic glandular, adenomatous and atypical hyperplasia, and compared to them in early cancer. Differential diagnosis was somewhat difficult between cystic glandular hyperplasia and benign lesions. Cytological diagnosis becomes gradually easier with progress of the lesions. A few cases with endometrial hyperplasia developed endometrial carcinoma for several years. Endometrial carcinoma has been detected even in the patients with suspicious endometrial cytology, so endometrial biopsy is still an important method. However, endometrial cytology is very easy, so we need to clarify the cytological cytological characteristics in precancerous lesions of the endometrium.

[Studies on the early diagnosis of endometrial carcinoma. Analysis of risk factors and cytological approach].

Clinical, cytological and hormonal studies were performed on 86 cases of endometrial carcinoma and 34 cases of endometrial hyperplasia for their early diagnosis. 68.6% of the endometrial carcinomas were in patients aged 50 to 64 and 3.5% in patients under 45 ages. The figures 17.4% infertility, 20.9% no delivery and 19.8% only one delivery indicate that endometrial carcinoma is associated with no birth or the birth of few child. Almost all cases of endometrial carcinoma had existed for more than ten years since the last pregnancy, when the lesions were detected. 20.9% of endometrial carcinomas belonged to premenopause and 24.4% to within the first 5 years following menopause. In total, 45.3% of them range around menopause and hormonal imbalance in climacteric periods. Clinical stages of endometrial carcinoma revealed no relation to enlargement of the uterus. 61.4% of endometrial carcinoma were found in obese patients. 63.1% of them showed abnormal glucose tolerance titers and preclinical lesions. Hypertension was found in 28.0% of them, but we did not consider it very significant, considering their advanced age. The serum steroid level indicated no hyperestrogenism in endometrial carcinoma. Diagnostic data showing positive and suspecious smears in endometrial carcinoma were 36.5% in vaginal, 67.5% in cervical and 84.3% in endometrial cytology. This means that direct sampling of cells from the uterine cavity is essential in the detection of endometrial carcinoma. The cytological features of endometrial carcinoma were nuclear enlargement, anisokaryosis, irregular distribution of chromatin and prominent nucleoli. Undifferentiated types of endometrial carcinoma were more characterized by these factors than differentiated types.

[Analytical diagnosis in colposcopy by subdivision of abnormal findings].

Abnormal findings of Colposcopy (Colp) were classified in contrast with histology. Varieties of colposcopic abnormal findings appear in more advanced changes in cervical diseases; single in squamous metaplasia, dysplasia and some Ca in situ, double in Ca in situ and microinvasive Ca, triple microinvasive and advanced carcinoma. Atypical vessels are frequently encountered in invasive carcinoma. Circular extension of abnormal figures around external os indicated the following correlation: Within 1/4-2/4 in dysplasia, 2/4-3/4 in Ca in situ and microinvasive Ca, 3/4-4/4 in microinvasive and invasive Ca. In squamous metaplasia and dysplasia, the white epithelia were flat on the surface, comparatively clear in the white part and less elevated. On the other hand, in carcinoma in situ, corresponding to the pathological area, they were rough on the surface, unclear in the white part and highly elevated. Compared with squamous metaplasia and dysplasia, carcinoma in situ in punctation revealed more surface elevation and unclear white part. Characteristic histological figures are dot types in the metaplasia and dysplasia, nest-like types in the carcinoma in situ and atypical vessel transition types in the microinvasive carcinoma. Complete types of mosaic were observed more in metaplasia, slight dysplasia and carcinoma in situ, while the incomplete types were common in moderate and severe dysplasia. Microinvasive carcinoma mosaic revealed more incomplete types and atypical vessel transition types. As for surface elevation and unclear white part, the same tendency was noticed as in punctation and white epithelium.(ABSTRACT TRUNCATED AT 250 WORDS)

Endometrial carcinoma following chronic anovulation in a premenopausal woman with systemic lupus erythematosus.

Endometrial carcinoma was diagnosed in a premenopausal woman suffering with systemic lupus erythematosus. She had received both prednisolone and an immunosuppressive agent for more than 10 years. Anovulatory cycles persisted during drug administration, along with dysfunctional uterine bleeding. The serum estrogen: progesterone ratio was high. Repeated endometrial biopsies revealed a progression of change from benign proliferation to cystic hyperplasia, adenomatous hyperplasia, atypical hyperplasia and invasive adenocarcinoma. These clinical data suggest that a result of long-term unopposed endogenous estrogen can have been the cause of the endometrial carcinoma.

[Pathological study of endometrial carcinogenesis in androgen-sterilized-rats].

As reported previously, squamous metaplasias, endometrial hyperplasias and cancers of the uterus occurred more frequently in androgen-sterilized-rats (ASR) than in normal rats (NR). This time we pathologically examined the endometrium of ASP in detail and obtained the following results: 1) In NR, aged from 70 to 750 days, no abnormal findings were found. In 61 ASR, aged more than 500 days, were found 8 simple endometrial hyperplasias, 2 atypical endometrial hyperplasias, 15 simple squamous metaplasias, 1 atypical squamous metaplasia, 2 adenocarcinomas, 1 adenosquamous carcinoma and 1 squamous carcinoma. 2) In ASR, proliferative and metaplastic changes coexisted in the endometrium. Two adenocarcinomas were accompanied by metaplasias and atypical hyperplasias, and one squamous carcinoma was accompanied by simple hyperplasias. 3) The endometrial carcinogenesis of ASR was thought to be as follows. In ASR, the endometrial epithelium loses its secretory function, becoming low columnar epithelium. A part of the non-secretory endometrium gains proliferative activity and progresses to metaplastic epithelium or to glandular hyperplasia. The former may develop to atypical metaplasia and squamous carcinoma, the latter to atypical hyperplasia and adenocarcinoma.

[Experimental studies on spontaneous occurrence of uterine adenocarcinoma (author's transl)].

Abnormal uterine proliferation was not detected in all 111 control normal rats (NR) during 750 days' observation period. In androgen sterile rats (ASR), 4 squamous metaplasias were detected in 25 ASR at 70-100 days of age. Thereafter, 9 squamous metaplasias and 2 non-atypical hyperplasias were detected in 20 ASR at 200-360 days of age. At 500-750 days of age, 12 squamous metaplasias, one non-atypical hyperplasia, 2 atypical hyperplasias and 2 adenocarcinomas were detected. Histological examination revealed that one of adenocarcinoma was composed of well differentiated type, poorly differentiated type and squamous metaplasia. Another case was composed of poorly differentiated adenocarcinoma, squamous cell carcinoma and squamous metaplasia. Hormonal environment of ASR with adenocarcinoma was characterized by an increase in estrogen/progesterone ratio, as compared to NR. After 500 days of age, 2 pituitary, 6 mammary and 3 adrenal tumors were detected in 33 NR, whereas 2 pituitary and 2 mammary tumors were detected in 25 ASR.

Effect of methotrexate on the growth and human chorionic gonadotropin secretion of human choriocarcinoma cell lines in vitro.

The effect of methotrexate (MTX) on the growth and human chorionic gonadotropin (hCG) secretion of five gestational and two nongestational human choriocarcinoma cell lines was studied in vitro. A striking heterogeneity in hCG secretion was noted among the cell lines. The growth of cells which secreted large quantities of hCG, such as HCCM-5, BeWo, and IMa, was inhibited by continuous exposure to 2 X 10(-8)M MTX. In contrast, cells which secreted little hCG, such as SCH, ENAMI-1, and GCH-1, showed no response to the growth inhibitory action of 2 X 10(-8)M MTX and the 3H-thymidine uptake was not reduced by treatment with MTX at doses of up to 10(-4)M for 48 hours. The common morphologic alterations observed in the cells which responded to MTX were an increase in the number of multinucleated giant cells, the appearance of vacuoles and granules in the cytoplasm, and enlargement of the nuclei. Increased hCG secretion was observed in accordance with the appearance of such morphologically altered cells. Part of the mechanisms of resistance to MTX appeared to involve both impairment of MTX uptake by the cells and an increase in the level of intracellular dihydrofolate reductase.

[Fundamental studies on high risk factor of endometrial carcinoma functional and histological abnormalities of ovaries and uteri in experimental anovulatory rats (author's transl)].

Anovulatory sterility is considered as one of high-risk factors of endometrial adenocarcinoma. We produced an animal model of anovulation in Sprague-Dawley rats and compared the changes of reproductive organs, such as ovary and uterus, of androgen sterilized rats (ASR) with normal rats (NR). The results obtained were as follow: 1) Vaginal opening was observed at 45 days of age in all of NR, however it was observed in 63% of ASR at 300 days of age. 2) Infertility rate of ASR was 98%, and all of ASR revealed persistent estrus. 3) The ovarian and uterine weights of ASR were smaller than those of NR. 4) Numerous vesicular follicles and absence of corpora lutes were characteristics in the ovary of ASR. 5) Severe hyperplasia of the endometrium was recognized in 5 of 49 ASR, including 2 atypical hyperplasia. 6) Serum progesterone levels of ASR was significantly lower than that of NR. Therefore E/P ratio increased in ASR. 7) The uterine sensitivity of ASR to gonadectomy and estradiol administration was reduced. These results indicate that uterus of ASR is tonically stimulated by estrogen and that androgenization also causes proliferative alterations in uterine morphology.