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The distribution of prekeratin, vimentin, epithelial membrane antigen (EMA), and secretory component (SC) was demonstrated immunohistochemically in 31 patients with adenomatous hyperplasia (AH), 12 patients with atypical adenomatous hyperplasia (AAH), and 39 patients with endometrial carcinoma. Prekeratin was presented in 94% of AHs, 92% of AAHs, and 87% of adenocarcinomas. Vimentin was detected in 68% of AHs, 50% of AAHs, and 37% of adenocarcinomas, showing decreased expression as the lesion progressed to malignancy (P less than 0.05). EMA was detected in 26% of AHs, 67% of AAHs, and 95% of adenocarcinomas (P less than 0.001). SC demonstrated focal and weak expression in 29% of AHs, but showed increased staining intensity in 67% of adenocarcinomas (P less than 0.01). Well-differentiated tumors expressed SC better than poorly differentiated tumors (P less than 0.01). All markers showed a heterogeneous staining pattern and, for a given histologic hyperplastic or neoplastic state, corresponded to several phenotypes. In conclusion, prekeratin seems to be a good marker for epithelial differentiation in hyperplastic endometrium, and EMA is a good marker in neoplastic endometrium. In hyperplastic lesions, the loss of vimentin expression in the absence of secretory changes gives rise to suspicions regarding their benign process. Also, EMA can help in distinguishing between hyperplastic and neoplastic states, while detection of SC may be of help in more precise grading of endometrial carcinoma.

Eighteen (18) previously untreated patients with grade I (9) and II (9) endometrial adenocarcinoma provided endometrial samples for biochemical analysis of estrogen and progesterone receptors. The same samples were evaluated by histology and ultrastructure. Progesterone receptor negative samples (PR less than 1000 fmole/g tissue) showed more ultrastructural characteristics of malignancy and a wider range of changes than the progesterone positive specimens (PR greater than 1000 fmole/g tissue). These findings appeared to be independent of estrogen receptor status. No significant ultrastructural changes were seen when grades I and II were compared.

The nuclear DNA contents of labeled and unlabeled nuclei of trophoblastic cells of 8 normal pregnancies, 2 missed abortions, and 14 cases of trophoblastic diseases were measured by Feulgen-DNA cytofluorometry combined with autoradiography. Syncytiotroblasts were rarely labeled and were considered to be inactive with regard to cell proliferation. Most of the labeled cells were cytotrophoblasts. The predominantly labeled cells ranged between 2 and 4C in cases of normal pregnancy and missed abortion, and a shift to a higher ploidy was seen in the more grave trophoblastic disease. From the point of cellular proliferation kinetics of trophoblastic cells, it is presumed that the cells in cases of normal pregnancy and type I hydatidiform mole are in the 2C cell cycle and in type II hydatidiform mole and in invasive mole there are heterogeneous cell populations, most of which are in the 2C cell cycle while the remaining are undergoing polyploidization or aneuploidization. In choriocarcinoma, the cells are not in the 2C cell cycle and also are probably undergoing polyploidization or aneuploidization in the hyper-4C area.

Estradiol receptors (ER) were measured in 71 and progesterone receptors (PR) in 62 primary endometrial carcinomas. ER were found in 62 (87%) and PR in 56 (90%) of the tumors. Fifty-six tumors were ER+/PR+ and 4 were ER-/PR-. The frequency of receptor positive tumors was not significantly correlated to histological grade. Highly differentiated tumors were, however, more often ER and PR rich (greater than or equal to 30 fmole/mg protein) as compared to poorly differentiated tumors. The median ER and PR values for grade I tumors were also significantly higher than for grade III tumors. No significant differences were found in the frequency of patients with ER or PR rich tumors in the different FIGO or surgical stages. The receptor status was not related to depth of myometrial infiltration. Recurrence rates and death rates were significantly higher in patients with PR poor as compared to those with PR rich tumors. This prognostic information could not be shown for ER.

Eleven cases of endometrial stromal sarcoma were obtained from the files of Yale New Haven Hospital from 1969 to 1981 for clinicopathologic correlation and determination of the outcome after hormonal therapy with progestational agents. Histologically, nine of the tumors were classified as low grade stromal sarcomas, and two were of a high grade. All of the patients underwent total abdominal hysterectomy and bilateral salpingo-oophorectomy as the main modality of treatment. Two patients received radiation, three adjuvant chemotherapy, two hormonal therapy (Megace 160 mg qd), three received no therapy at all, and the treatment is not known in one case. Two of the patients who received no therapy had recurrences and were placed on hormonal therapy. The remaining patient was a stage IV and died of disease 3 months after diagnosis. All four of the patients who were treated with hormonal therapy are alive, free of disease, or with stable tumor from 2 to 6 years after diagnosis. The presence of estrogen receptors (ER) and progestin receptors (PR) was demonstrated in the tumor in some of the cases; this may explain the sensitivity of this neoplasm to hormonal therapy.

Estrogen and progesterone receptors were measured in cystosols prepared from 32 normal ovaries and 25 benign and 49 malignant ovarian tumors. In normal ovarian tissue, estrogen and progesterone receptors were detected in 22 and 75% of specimens, respectively. Estrogen receptors were present in low concentrations ranging from 2 to 9 fmol/mg cytosol protein. The estrogen receptor content and distribution were similar in benign tumors (20%), but progesterone receptors were significantly decreased in 16% of specimens (P less than 0.001). In malignant ovarian tissues, estrogen receptors were present in 57% of specimens in concentration ranging from 1 to 132 fmol/mg cytosol protein. Of these, 72% of tissues had estrogen-receptor concentrations greater than 10 fmol/mg cytosol protein. The presence of estrogen receptors in ovarian cancer was significantly different from normal ovaries and benign tumor tissues (P less than 0.01). Progesterone receptors were detectable in 29% of ovarian cancer specimens. Estrogen and progesterone receptors were present alone or in combination, in 65% of ovarian cancers. The similarity in sex steroid content between ovarian and breast cancer warrants prospective studies of sex steroid receptor content in ovarian malignancies as a possible predictive index of survival and response to hormone therapy.

Cytoplasmic estrogen receptor levels (ER) were measured in ovarian epithelial malignancies from 44 patients using a dextran-coated charcoal assay with analysis of the data by Scatchard plots. In 31 cases, progesterone receptor levels (PR) were also determined. In untreated patients, 68.8% of malignancies were ER-positive (greater than or equal to 10 fmole receptor/mg protein) and 35.0% were PR-positive (greater than or equal to 50 fmole/mg protein). Receptor levels in ovarian epithelial malignancies were not dependent on patient age, menopausal status, tumor stage, or histologic grade. However, ovarian endometrioid carcinomas contained significantly more PR than other histologic variants (P less than 0.02). Excluding endometrioid carcinoma, tissues from patients treated with chemotherapy contained less ER and PR than tissues from untreated patients. ER-positive tumors from three patients assayed before cyclophosphamide or combination chemotherapy became ER-negative after therapy. In addition, tamoxifen increased cytoplasmic PR (124 to 333 fmol/mg) and decreased cytoplasmic ER (65 to 4 fmol/mg) in a single patient with endometrioid carcinoma.

The presence of estradiol and progesterone receptors in endometrial stromal sarcoma (ESS) has not been studied previously. Two cases of ESS are reported in which high concentrations of these receptors were found in the tumor tissue. One of these patients had retained the reactivity to hormone treatment for several years. It is suggested that the steroid receptors should be analyzed in all cases of ESS to find tumors with a high receptor content. Hormone treatment of these patients should be part of the primary adjuvant therapy. In cases of a good response the therapy should be prolonged and continued for the rest of the patient's life.

In a series of 173 consecutive patients with endometrial cancer treated by a fixed protocol 62 tumors (36%) appear "estrogen independent," i.e. there is no history of estrogen ingestion and no recognized risk factors such as obesity or diabetes mellitus. A high proportion of these tumors are of advanced stage and grade. Prognosis is poorer and mortality higher than for "estrogen-dependent" tumors. Twenty-two tumors were truly occult (no spontaneous vaginal bleeding). Factors which identify this high-risk group are described and the reasons for delay in diagnosis discussed. Spread by intraperitoneal dissemination is considered a major factor in the poorer prognosis. Cytology of peritoneal washings is a useful diagnostic and prognostic aid. An estrogen provocation test is suggested as a means of earlier recognition which could reduce mortality in this group.

Cytosol progesterone (PgR) and estradiol (E2R) receptors were quantified simultaneously in "normal" and tumoral endometrium samples, located symmetrically on the longitudinal axis of the uterine cavity. With this experimental model two different groups of patients were detected. In the first group (7 of 10 women), the endometrial carcinoma had a greater cytosolic concentration of PgR than the corresponding "normal" endometrium, both kinds of tissue being affected by the same circulating hormonal "environment," peculiar to each patient. The opposite occurs in the other group (3 of 10 women), since the "normal" endometrium was found to be "richer" in receptors than the tumoral endometrium. It is suggested that this difference in the capacity of the tumor for synthesizing PgR and even E2R as compared to the "normal" endometrium may be a marker which improves selection of patients who will be more likely to respond favorably to endocrine therapy.

The steroid receptor content of the primary endometrial cancer of 22 patients who were treated for recurrent or advanced disease has been measured and correlated with response to medroxyprogesterone acetate. No patient with a progesterone receptor (PR)-negative tumor responded and only 2 patients with PR-positive tumors responded, perhaps related to the low levels of PR in the tumors. It waits to be assessed whether receptor status is as good a guide to response to hormone therapy as tumor differentiation, site of recurrence, or disease-free interval.

Forty-six eligible women with metastatic endometrial cancer were randomly allocated to receive monthly cycles of either CAF (cyclophosphamide, adriamycin, 5-fluorouracil) or CAF plus Provera 200 mg daily for 3 weeks followed cyclically by Tamoxifen 20 mg daily for 3 weeks. Overall response rates of 15 and 43% were seen with CAF and CAF plus hormonal therapy. Using a multivariate analysis of the results, this difference is significant (P value 0.05). In 8 patients with operable endometrial cancer, negative estrogen receptor concentration (ER less than 15 fmole/mg protein) and Grade 3 disease, the clinical course was aggressive in 4 patients with systemic and local relapse. In 10 other similar patients (negative ER and Grade 3) who received adjuvant cyclical hormonal therapy only 1 relapsed and the other 9 are disease-free for an average of more than 31 months. Sequential cyclical hormonal therapy with ER and progesterone receptor analysis has a place in the management of endometrial carcinoma.

Pancreatic secretory trypsin inhibitor (PSTI) is a specific trypsin inhibitor secreted by the acinar cells of the pancreas. Serum levels of immunoreactive PSTI have been reported elevated in patients with various malignancies including gynecologic tumors. The immunohistochemical localization of PSTI is studied in the comparison with argyrophilia and amylase immunoreactivity on 100 ovarian tumors, 35 endometrial carcinomas, and 34 cervical carcinomas. PSTI was noted in 19 of 85 common epithelial tumors of the ovary, being most frequently in mucinous tumors and less in endometrioid, but only occurred in immature pancreatic tissue of 1 of 15 germ cell tumors tested. In the uterus, 5 of 19 adenocarcinomas of the endometrium and 3 of 10 adenocarcinomas of the cervix were positive for PSTI immunoreactivity. PSTI was found more frequently in the tumors with argyrophil cells, especially of type I, but was related to the intestinal metaplasia and exocrine secretion rather than argyrophilia itself, judging from the different localization of PSTI and argyrophilic granules. No relationship was observed between amylase and PSTI immunoreactivity.

This report describes a case of recurrent and metastatic endolymphatic stromal myosis (ESM), which showed good response to progestin therapy. Metastatic lung nodules regressed after medroxyprogesterone acetate (MPA) treatment, recurred while MPA was stopped, and disappeared again when MPA was restarted. The levels of estrogen and progesterone receptors measured in the resected tumor amounted to 79.5 and 310 fmole/mg protein, respectively. Sex steroid hormone dependency of ESM was reviewed in the literature.

The location of transferrin receptor (Tf.R) which is abundantly contained in proliferating cells and positional relationships of cells containing much Tf.R was observed on cervical and endometrial tissue sections by immunohistochemistry. In normal squamous epithelium, the parabasal cell layer was positive and the basal, intermediate, and superficial cell layers negative. This shows that the cells of the parabasal cell layer are proliferating most actively among those layers. Squamous carcinoma contained many positive cancer cells. But negative as well as positive cells were present, indicating that cancer cells proliferate under various conditions. Cancer cells infiltrating the stroma were made clear by Tf.R staining, and it became easier to identify them when only a few were present. Endometrial glandular cells in the basal layer stained only on the basal side of a cell regardless of the menstrual cycle, whereas in the functional layer glandular lumen side also stained positive in the secretory phase. Based on the present data, an immunohistochemical study of Tf.R seems useful to confirm the localization of proliferating cells and cancer cells and determine the conditions for cancer cell proliferation on the tissue sections.

The growth inhibitory effects of medroxyprogesterone acetate (MPA) and tamoxifen (TAM) were tested on three long-established endometrial carcinoma cell lines (HEC-1, KLE, and RL95-2) and on UM-EC-1, a new endometrial carcinoma cell line established in our laboratory. MPA and TAM were used in growth experiments either alone, simultaneously, or sequentially. The MCF-7 breast cancer cell line was used as a control. None of the endometrial carcinoma cell lines showed significant sensitivity to 0.1-10 microM MPA. In contrast, 10 days exposure to 5 microM TAM induced 83 and 70% growth inhibition in HEC-1 and KLE cultures, whereas the growth of UM-EC-1 was inhibited by 99.7% and RL95-2 cultures by 100%. TAM-induced growth inhibition was reversible since all cell lines resumed logarithmic growth when TAM was removed from the culture medium. Addition of 17 beta-estradiol (E2) to the culture medium did not accelerate recovery, and reversal of TAM-induced growth inhibition was not seen when TAM and E2 were added simultaneously. This is consistent with our finding that, except for MCF-7, these cell lines did not show detectable estrogen receptor (ER) activity in assays performed at the time of these experiments. When treated sequentially with TAM and MPA, all cell lines resumed logarithmic growth when medium containing TAM was replaced with medium containing MPA. Simultaneous exposure to 5 microM MPA and 5 microM TAM resulted in a slight additive growth inhibitory effects only in KLE cultures. Our results show that MPA does not have growth inhibitory effects in these endometrial carcinoma cell cultures, whereas TAM exerts a potent inhibitory effect that is not reversed by estrogen and may thus be mediated through a mechanism different from blockade of ER. In vitro results with the UM-EC-1 cell line correlated with the clinical response of the cell line donor. Her disease progressed during postoperative MPA therapy, but subsequently she responded to TAM therapy.

Immunocytochemical assay (ICAs) were performed on frozen sections from human endometrial samples (n = 89) including normal endometrium, decidua, hyperplasia with and without atypia, and carcinomas. Monoclonal antiestrogen receptor (ER), anti-laminin (Lam), anti-type IV collagen (Coll IV), and anti-Ki67 were applied with avidin-biotin-peroxidase complex or peroxidase-antiperoxidase complex. The results of the ICAs were evaluated through a computerized system of image analysis referred to as SAMBA. It was shown that this system provided for an accurate reliable and reproducible analysis of ICAs in tissue sections. It is concluded that this multiparametric and standardized method of analysis of ICAs can further be applied in correlations with clinical and biochemical data.

Plasminogen activator activity (PAA) has been proposed as an indicator of aggressiveness of tumors and has been shown to be hormonally modulated. To test this hypotheses in human endometrial carcinoma, tumor explants were assayed for PAA secretion and the results correlated with histopathologic criteria of aggressiveness. The effect of medroxyprogesterone acetate (MPA) on PAA secretion was also investigated. Lower levels of PAA were found to be associated with tumors displaying aggressive tendencies. MPA generally decreased PAA secretion. No apparent correlation was found between estrogen or progesterone receptor concentrations and PAA levels.