Influence of cytoplasmic steroid receptor content on prognosis of early stage endometrial carcinoma

The clinicopathologic associations and effect on prognosis of cytoplasmic steroid receptor content were studied in 168 patients with clinical Stage I and II endometrial carcinoma. Cytoplasmic estrogen receptor status was associated (p less than 0.01) with histologic differentiation, nuclear differentiation, and histologic documentation of extrauterine metastases. Progesterone receptor status was related (p less than 0.05) to histologic differentiation and histologic cell type, and combined estrogen receptor/progesterone receptor status was associated (p less than 0.05) with histologic differentiation, peritoneal cytology, extrauterine metastases, and histologic cell type among the 105 patients who had determination of both estrogen and progesterone receptors. Single-factor analysis revealed significant (p less than 0.05) effects of estrogen receptor status, progesterone receptor status, and estrogen receptor/progesterone receptor status on disease-free survival. All other clinicopathologic features significantly (p less than 0.05) affected prognosis, except for peritoneal cytology. With use of stepwise regression analysis of proportional hazards, estrogen receptor, progesterone receptor, and combined estrogen receptor/progesterone receptor status were significant independent prognostic factors, replacing histologic assessment of glandular or nuclear differentiation in the models. These data suggest that receptor status of primary endometrial carcinomas provides important information relevant to tumor behavior which complements the information provided by conventional clinicopathologic analysis.     

Heterogeneity in hormone receptor status in primary and metastatic endometrial cancer

The rationale for endocrine therapy in patients with advanced endometrial carcinoma may be based on the presence of estrogen or progesterone receptors in the primary tumor. A study was designed to evaluate tumor cell heterogeneity of steroid hormone receptors in the primary and metastatic sites in endometrial cancer. Primary endometrial cancer tissue samples from 10 patients and 16 metastatic tumor sites were simultaneously analyzed for estrogen and progesterone receptors, using a radioligand biochemical assay. The primary tumor was estrogen receptor (ER) and progesterone receptor (PR) positive in 70 and 60% of the patients, respectively. The metastatic sites were ER positive in 63% and PR positive in 25%. The primary tumor tissue and the metastatic disease showed an identical ER and PR status in only 25 and 19%, respectively. Four patients had multiple metastatic sites analyzed. In two of four patients the PR values, and in three of four patients the ER values, in these metastatic sites were discordant. These data support the concept of tumor cell heterogeneity for steroid hormone receptors in endometrial cancer. To optimize treatment planning, it may be important to biopsy primary, metastatic, and recurrent tumor sites for individual analysis of receptor activity.     

Endometrial carcinoma in tamoxifen-treated breast cancer patient: clinicopathological, immunohistochemical, and genetic analysis.

Endometrial polyps and endometrial neoplasms are a recognized complication of chronic tamoxifen treatment. This study describes an endometrial carcinoma that developed in a woman receiving low-dose tamoxifen treatment for breast cancer. Little is known about steroid receptor status, somatic alterations in oncogenes and tumor suppressor genes, and inherited susceptibility in endometrial carcinomas associated with tamoxifen use. In the present case, the endometrial carcinoma was negative for estrogen receptors and weakly positive for progesterone receptors. In addition, analysis of K-ras, c-erbB2/neu, cyclin D1, and p53 status revealed a codon 12 point mutation in the K-ras oncogene. The patient was determined not to be a carrier of germ-line mutations in cytochrome P-450 1A1 (CYP1A1), an estrogen-metabolizing gene previously associated with enhanced endometrial cancer risk, but she was a carrier of a methylenetetrahydrofolate reductase gene variant related with putative alterations in DNA methylation.     

An immunohistochemical study of estrogen and progesterone receptors in adenocarcinoma of the endometrium and in the adjacent mucosa

The immunoperoxidase stain for estrogen and progesterone receptor content in endometrial adenocarcinoma was correlated with the grade and stage, level of myometrial invasion, age and survival of the patients. Anti-estrogen and anti-progesteone receptor monoclonal antibodies were applied to paraffin-embedded tissue from hysterectomy specimens of 100 patients with adenocarcinoma of the endometrium. In 34 of the cases the receptors were studied in the endometrium adjacent to the tumor and compared to the nuclear receptor content in the carcinoma. There was a high inverse correlation between the estrogen receptor status and the grade of tumor ( R = − 0.45, P = 0.006). The estrogen receptor measured in the endometrium near the tumor showed a negative correlation with the grade of the tumor ( R = −0.42, P = 0.013). The estrogen, but not the progesterone, receptor content, was positively related to the age of the patient ( P < 0.05). No significant correlation of the receptor status with the depth of myometrial invasion was found, despite the obvious interdependence between the grade and myometrial invasion. The progesterone receptor staining index appeared to be a distinct independent prognostic factor in endometrial cancer. The immunohistochemical analysis of the steroid hormone status in endometrial cancer therefore offers an alternative to the quantitative ligand-binding assay.     

Steroid Hormone Receptor Content and Lymph Node Status in Endometrial Cancer

The purpose of this study was to correlate the steroid hormone receptor status in endometrial adenocarcinoma with tumor metastasis to the pelvic and para-aortic lymph nodes, and with other known prognostic variables which influence survival. Tumor samples from 85 patients with endometrioid adenocarcinoma, or adenocarcinoma with squamous differentiation of the endometrium who underwent complete surgical staging, were assayed for cytoplasmic steroid hormone receptors using a dextran-coated charcoal technique. Steroid hormone receptor content was correlated to lymph node status, along with other prognostic variables, such as patient's age, depth of myometrial invasion, tumor grade, and pelvic cytology. By univariate analysis, the likelihood of nodal involvement was associated with younger age and poorly differentiated tumors. Multivariate analysis revealed that age, tumor grade, and myometrial involvement added significant independent prognostic information. Estrogen or progesterone receptor content did not add independent prognostic information concerning lymph node status once other factors were controlled. Knowledge of estrogen and progesterone receptor binding status in adenocarcinoma of the uterus does not replace the prognostic information imparted by careful sampling of lymph nodes.     

Cytoplasmic estrogen and progesterone receptors as prognostic parameters in primary endometrial carcinoma

Eighty-six cases of primary endometrial carcinoma were assayed for the presence or absence of cytoplasmic estrogen and progesterone receptors by the saturation point dextran-coated charcoal assay. The levels of cytoplasmic progesterone receptors and estrogen receptors were analyzed according to clinical stage, histologic type and grade of the tumor, presence or absence of lymph node metastases, myometrial invasion, and survival. The cases were divided into positive and negative receptor groups with levels chosen of greater than 10 fmol/mg of cytosol protein for progesterone receptor and 5 fmol/mg of cytosol protein for estrogen receptor as discrimination points. Statistically significant survival differences were found between estrogen receptor positive versus estrogen receptor negative patients, progesterone receptor positive versus progesterone receptor negative patients, and estrogen positive-progesterone receptor positive versus estrogen negative-progesterone receptor negative patients. Mean cytoplasmic estrogen and progesterone receptor levels were inversely proportional to grade. This report suggests that treatment protocols should be devised to reflect the prognostic significance of receptor status.     

Estrogen and progesterone receptors in uterine sarcomas

Estrogen and progesterone receptors were measured in tissues from 43 patients with various uterine sarcomas using the dextran-coated charcoal assay. Estrogen receptor was present in 55.5% and progesterone receptor in 55.8% of samples, at median estrogen and progesterone receptor concentrations of 10.7 and 15.8 fmol/mg cytosol protein, respectively. These median values are much lower than those in 30 consecutive endometrial adenocarcinomas and 50 breast carcinomas assayed in our laboratory. Progesterone receptor status correlated strongly with estrogen receptor status in uterine sarcomas (P = .001). Estrogen and progesterone receptor levels were not influenced by stage, grade, or mitotic count. Patients 50 years of age or less had significantly higher progesterone receptor than those over 50. No such age effect was seen for estrogen receptor. Endometrial stromal sarcoma had higher estrogen and progesterone receptor levels than other histologic types. Low-grade endometrial stromal sarcomas had higher median estrogen receptors (238.9 fmol/mg) and better survival (all patients alive at 6-12 months) than did high grade (N = 7) endometrial stromal sarcomas (median ER = 6.6 fmol/mg, all dead of disease at 8-27 months). For all histologic types, evaluable patients with stage I or II disease (N = 16) were more likely to survive longer than one year than those with stage III or IV disease (N = 13, P = .003). Evaluable patients with estrogen receptor-positive sarcomas were more likely to survive longer than one year than those with estrogen receptor-negative tumors (P = .006). With one exception, an endometrial stromal sarcoma, hormonal therapy exerted no beneficial effect.(ABSTRACT TRUNCATED AT 250 WORDS)     

Effects of tamoxifen on steroid hormone receptors and hormone concentration and the results of DNA analysis by flow cytometry in endometrial carcinoma

OBJECTIVES: Tamoxifen is a nonsteroidal triphenylethylene derivate with a predominant antiestrogen activity, used in the endocrine treatment of breast and endometrial cancer. It is not known which endometrial carcinomas will respond favorably to tamoxifen and which ones will not. The aim of this study was to find out whether tamoxifen has an effect on hormone steroid receptors, hormone concentration, DNA content, and proliferative activity in endometrial cancer and to correlate the tamoxifen-induced changes with pathologic parameters such as clinical stage, tumor differentiation, depth of invasion, and histologic type. METHODS: Thirty postmenopausal women with endometrial carcinoma were treated with 30 mg of tamoxifen daily for 7-10 days after curettage. Steroid hormone receptors (estrogen and progesterone receptors), levels of follicle-stimulating hormone, luteinizing hormone, prolactin, estradiol, progesterone, testosterone, dehydroepiandrosterone sulfate, sex hormone binding globulin, and DNA ploidy and proliferative activity were determined before and after therapy. The patients were also divided into favorable and unfavorable prognosis groups according to classical histological parameters. The patients in the favorable group consisted of patients with stage I disease, well and moderately differentiated tumors, favorable histologic type, and a depth of myometrial invasion of less than (1/3). The patients with only one of the unfavorable parameters (clinical stage II or III, poorly differentiated tumors, unfavorable histologic types, and deeper invasion of myometrium) were included in the unfavorable prognosis group. RESULTS: After the treatment, there was a net increase in the progesterone receptors and sex hormone binding globulin and a significant decrease in the estrogen receptors. The increase in progesterone receptors and decrease in estrogen receptors occurred in the patient group with favorable prognosis regarding histologic type, degree of differentiation, and clinical stage, but also in the unfavorable prognosis group regarding the depth of myometrial invasion. Statistically significant decrease in the follicle-stimulating hormone concentration was observed in the groups with favorable prognosis regarding histologic type, depth of myometrial invasion, and grade of differentiation. Concentration of sex hormone binding globulin was significantly increased in groups with favorable prognosis if histologic type and grade of differentiation were taken into account. On the other hand, there was a significant decrease in the concentration of luteinizing hormone in the group with unfavorable histologic type and also a decrease in progesterone concentration in patients with unfavorable prognosis regarding the grade of differentiation. There was no statistical significance either in the concentrations of other hormones measured or in the DNA analysis by flow cytometry. CONCLUSIONS: Our results revealed that tamoxifen can increase progesterone receptors and decrease estrogen receptors in endometrial cancer. The effect was most pronounced in tumors with favorable clinicopathologic parameters. We conclude that tamoxifen therapy can induce progesterone receptor synthesis even in tumors with low initial progesterone receptor levels, making such tumors potentially responsive to additional hormonal therapy with progesterone.     

Steroid receptors and endometrial cancer

Like breast carcinomas, endometrial carcinomas are derived from sex steroid target tissue. Progress and research directed into the clinicopathologic relationship of steroid receptors and endometrial carcinomas have been hampered by many factors, including: limited numbers of patients with advanced-stage disease compared to the number with breast carcinoma; contamination of specimens with surrounding benign endometrial components which may contribute to total steroid binding; and amount of tissue required for standard biochemical assays. Nevertheless, several clinicopathological associations have been made for steroid receptor content of endometrial carcinomas. Receptor content appears to correlate with histological differentiation in that well-differentiated lesions have higher mean levels of receptor and more receptor 'positive' lesions than do poorly differentiated lesions. Furthermore, receptor levels and status appear to correlate with prognosis of primary endometrial carcinomas and response to hormonal therapy of advanced endometrial carcinoma. Newer techniques utilizing monoclonal antibodies to directly localize receptor in tissue specimens may lead to a greater understanding of the dynamics of receptor physiology in endometrial carcinomas, and may make possible more accurate predictions of clinical behavior by allowing the direct analysis of the receptor content of the malignant component within a tissue specimen.     

The prognostic value and clinical utility of estrogen and progesterone receptors in endometrial carcinoma

In the United States, endometrial carcinoma is the most common gynecologic malignancy, and accounts for 4,900 deaths per year in the United States. While this disease has relatively good cure rates, there is motivation to describe other determinants, which may help in the treatment of this disease. Attempts have been made to correlate hormone receptor status with disease-free intervals and survival in patients with endometrial carcinoma. The weight of evidence seems to support that of the two hormone receptors, progesterone is the more significant predictor of patient outcome. If hormone receptors are to be used in the management of endometrial carcinoma, they should be determined by immunohistochemistry. In the adjuvant setting, patients with progesterone positive tumors are more amenable to treatment with progestational agents than are patients with receptor negative tumors. Future areas of research include the use of tamoxifen and selective estrogen receptor modulators in the chemoprevention and treatment of endometrial carcinoma.     

Cytosol Oestradiol and Progesterone Receptors in Endometrial Hyperplasia and Adenocarcinoma: Determination by Single Saturating Dose Exchange Assays

Summary: Available oestradiol and progesterone binding site concentrations in endometrial cytosols were determined by a simplified single saturating dose assay in 16 normal women with proliferative endometrium, in 10 patients with endometrial hyperplasia, and in 20 patients with endometrial adenocarcinoma. The mean oestrogen receptor level tended to be higher in endometrial hyperplasia than in either proliferative or carcinomatous endometria. Mean progesterone receptor levels were comparable in proliferative and hyperplastic endometria, but were sequentially lower in highly differentiated carcinoma, moderately differentiated carcinoma, and undifferentiated carcinoma.
Correlation between results obtained by single saturating dose assays and by conventional Scatchard analysis in those endometria subjected to both procedures was high for both oestrogen (r = 0.998) and progesterone (r = 0.949) and indicates that with the simplified assays, large scale clinical studies on hormone sensitivity of endometrial adenocarcinomas are feasible.     

The influence of estrogen and progesterone receptors on survival in patients with carcinoma of the uterine cervix

The prognostic value of estrogen receptors (ER) and progesterone receptors (PR) was studied in 246 women with primary carcinoma of the uterine cervix. In addition to the receptor status information on tumor stage, histological type, age at operation, and menopausal status was recorded and analyzed. If the patient died the cause of death was ascertained. The median survival time for the 97 patients who died was 15 months and the survivors were followed for an average of 34 months. The survival curve was compared with an age, sex, and year of death matched West-Australian population. The survival curves for patients with ER+ or ER- and PR+ or PR- tumors were virtually indistinguishable. Overall survival in patients with cervical carcinoma is not influenced by the receptor status or the receptor concentration of the carcinoma.     

Histologic control of biochemical steroid receptor analysis in endometrial carcinomas

Histologic review of 422 specimens from endometrial carcinoma submitted for biochemical cytosol estrogen and progesterone receptor analysis revealed that 16 (4.0%) contained no evidence of carcinoma on permanent histologic sections. An additional 11 (2.5%) contained focal carcinomas on permanent sections but had no evidence of malignancy in frozen sections of the tissue submitted for receptor analyses. Despite the paucity or even absence of malignancy, many of these specimens had significant cytoplasmic estrogen and progesterone receptors derived from endometrial and myometrial tissues. Rigorous histologic control of specimens from endometrial carcinomas submitted for biochemical steroid receptor analyses is necessary to establish valid clinical and histologic associations of steroid receptor content.     

The prognostic importance of proliferative activity and oestrogen receptor expression in stage I endometrial carcinomas.

The purpose of this study was to evaluate the prognostic significance of steroid hormone receptor proliferation index in endometrial adenocarcinoma. In this study, the correlation between oestrogen receptor expression, proliferation index and FIGO grade, age, myometrial invasion, tumour size and menopause status was evaluated in 40 patients with endometrial carcinoma. For this purpose, all tumours were stained immunohistochemically with oestrogen receptor and Ki-67 monoclonal antibodies. Oestrogen receptor expression and proliferation indices were found to be statistically associated with grade, age, menopausal status, vascular invasion and tumour size ( p < 0.001). Quantitative assessment of tumour proliferation and expression of oestrogen receptor were found to be important prognostic indicators in endometrial adenocarcinoma.     

Estrogen and progestin receptor levels as prognosticators for survival in endometrial cancer

The survival of 213 postmenopausal patients with primary endometrial cancer was analyzed as a function of clinicopathologic features and cytosol steroid receptor levels. Estrogen receptor (ER) levels (P = 0.008) and progestin receptor (PR) levels (P = 0.0001) were negatively correlated with grade. ER and PR levels were positively correlated with each other (P = 0.0001), but neither was correlated with age. In 187 patients with stages I and II, ER positivity (greater than or equal to 20 fmole/mg cytosol protein (cp] was statistically associated with grade (P = 0.007); and PR (greater than or equal to 7 fmole/mg cp) was statistically associated with grade (P = 0.001). Univariant analysis revealed that survival for the early endometrial cancer patients was significantly dependent upon ER status (P = 0.0003), PR status (P = 0.0016), and grade (P = 0.0002). Multivariant analysis of ER status, PR status, age, and grade showed that the ER status was a significant prognostic factor for survival (P = 0.0168), even if the positivity of the PR status was defined at greater than or equal to 50 fmole/mg cp. If ER status was divided at 0-19, 20-100, and greater than 100 fmole/mg cp, survival was significantly different between the low range group and the other two groups. If PR status was divided at 0-6, 7-50, and greater than 50 fmole/mg cp survival was significantly different between the first two groups and the high range group. Thus, survival in these endometrial cancer patients was better predicted by ER status than grade.     

Primary peritoneal papillary serous adenocarcinoma: clinical and management aspects

From January 1, 1984 to April 30, 1990, 38 patients were surgically found to have an intraabdominal disease resembling epithelial ovarian cancer. This diagnosis was confirmed in 31 patients; the remaining 7 met the criteria of primary peritoneal papillary serous carcinoma. Five of these were diagnosed retrospectively and two during surgery. The mean age at diagnosis was 61.2 years. Tumor histology revealed papillary serous carcinoma in six and mixed (papillary serous and papillary clear cell carcinoma) in one patient. Optimal debulking was achieved in three of seven cases (42.8%). Cisplatin-based combination chemotherapy was administered to all in the study group. Complete response was obtained in four patients, with one surviving for 76 months. The median survival in these patients was 34.5 months (range 6-76 months). Currently, three patients with complete response are alive with clinically undetectable disease. CA-125 assays were available in three cases and blood levels corroborated the clinically determined status of the disease. Tumor steroid hormone receptor status was determined in one case and revealed low levels of estrogen and progesterone receptors. To the best of our knowledge, the usefulness of CA-125 in the diagnosis, management, follow-up, and determination of tumor steroid hormone receptor status, mixed papillary serous and clear cell subtype histological patterns for primary peritoneal papillary serous carcinoma are first described in this report. It seems that this neoplasm may be treated and followed up as in epithelial ovarian cancer, obtaining long-term survival; however, the biologic behavior and management problems of this relatively new entity deserve further clinical experience.     

Prognostic significance of steroid receptors measured in primary metastatic and recurrent endometrial carcinoma

Forty-two cases of recurrent and 14 cases of advanced clinical stage (III and IV) endometrial carcinoma are presented, in which progesterone and estrogen receptors from the metastatic sites were measured. Mean survival time (time from recurrence or, in advanced stages, from the time of diagnosis to death or last follow-up), mean total survival time (time from diagnosis to death or last follow-up), and mean time to recurrence (time from diagnosis of primary tumor to the time of recurrence) were positively correlated with positive progesterone and estrogen receptor status and with histologic grade of tumor. No correlation was found with age, clinical stage, depth of myometrial invasion, or site of metastasis. However, when multiple variables were considered with the Cox regression model, the combination most highly correlated with survival included progesterone receptor, grade of tumor, and site of metastasis (pelvis vs. other sites). All differences were statistically significant (p less than 0.05). We conclude that measurement of progesterone and estrogen receptors in metastatic or recurrent endometrial tumors may be used as an additional prognostic variable.     

Valence of immunohistochemical analysis of endometrial carcinoma biopsy specimen

OBJECTIVE: We compared immunohistological examination of endometrium biopsy specimen with the results of the immunohistological examination of tumor specimen to analyse the valence of this preoperative examination according to the clinico-pathological findings and overall-survival. MATERIAL AND METHOD: Between 1985 and 1995 193 women were treated of an endometrial carcinoma at the University hospital Mainz. In this group we evaluated 41 patients with enough preoperative endometrial biopsy material for a retrospective immunohistochemical analysis and complete follow-up data. The materials from diagnostic curettage were stained and analysed for oestrogen and progesterone receptor status and for MiB-1. The results were statistically analysed using Logrank-test for overall survival. RESULTS: The mean follow-up time was 49 months. We found a significant correlation between staining results of oestrogen (p-value = 0.0005) and progesterone (p-value=0.0003) receptor status with overall survival as well as for MiB-1 (p-value=0.05). The correlation of staining results between biopsy specimen results and tumor material from hysterectomy was 84-85 %. CONCLUSION: These well known prognostic factors are measurable on biopsy specimen material in same quality and high valence as on hysterectomy material.     

Prognostic significance of progesterone receptor immunohistochemistry for lymph node metastases in endometrial carcinoma

OBJECTIVE: The aim of this study was to determine whether progesterone receptor (PR), estrogen receptor (ER), p53 protein, and proliferating cell nuclear antigen (PCNA) expression constitute independent prognostic factors for lymph node metastases in endometrial carcinoma using immunohistochemical techniques on hysterectomy and biopsy specimens. METHODS: We evaluated the correlation between lymph node metastases and PR/ER immunohistochemistry, p53/PCNA expression, age, tumor grade, myometrial tumor invasion, cervical involvement, and ovarian metastases in a series of 99 cases of primary endometrial carcinoma surgically staged with systemic pelvic lymphadenectomy and para-aortic lymph node biopsy. RESULTS: Lymph node metastases from endometrial carcinoma were statistically correlated with negative PR immunohistochemistry (P = 0.001), intense p53 expression (66% or more of the tumor cells stained, P = 0.003), deep myometrial tumor invasion (greater than one-half, P = 0.001), and cervical involvement (P = 0.001). Tumor grade showed borderline statistical significance for lymph node metastases (P = 0.058). On multivariate analysis, negative PR, intense p53 expression, and cervical involvement were significant prognostic variables for lymph node metastases (P = 0.0001, 0.0023, and 0.002, respectively). Immunohistochemical study indicated that the PR status on preoperative biopsy specimens and hysterectomy specimens was in good agreement, but p53 status was not. Age, ovarian metastases, ER immunohistochemistry, and PCNA expression were not significantly related to lymph node metastases. CONCLUSION: PR immunohistochemistry appeared to be the most powerful prognostic factor associated with lymph node metastases in endometrial carcinoma, independent of other clinicopathological parameters.     

Endometrial carcinoma: Steroid receptors and response to medroxyprogesterone acetate

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.