Clinical aspects of steroid hormone receptors in human renal cell carcinoma

A review of the role of steroid hormone receptors and hormonal dependence of renal cell carcinoma in certain patients is presented. The results of a cumulative series of estrogen, progesterone, and androgen receptor assays performed on 48 normal and malignant human renal tumor specimens are given. The detectable presence of receptor proteins in certain patients could obviate the empirical use of hormonal therapy, an issue that may be resolved through a randomized multiinstitutional trial.     

滤泡上皮源性甲状腺癌的性类固醇激素受体的临床病理研究

应用ABC免疫组化法于石蜡切片检测70例甲状腺癌三种性类固醇激素受体(SSHR)的表达。结果表明:雌激素、孕激素和雄激素三种受体在不同的组织类型表达率不同,以甲状腺乳头状腺癌阳性率最高,并见于转移的淋巴结,滤泡状腺癌的阳性率次之,未分化癌三种受体的表达均阴性。提示肿瘤细胞分化程度的越差,SSHR的表达越弱。并且三种受体的表达具有相关一致性。淋巴结的转移状态与SSHR的表达对预后的判断无相关性。32例随访病例表明:5年内无癌复发者SSHR阳性率高于有癌复发者。预后指数的高低同SSHR阳性率的表达呈正相关。     

CORRELATION OF STEROID HORMONE RECEPTORS AND CLINICAL PATHOLOGICAL FEATURES WITH PROGNOSIS OF HUMAN BREAST CANCER

Clinical, pathological features and steroid hormone receptors (SR) including receptors of estrogen (ER), progesterone (PR) and androgen (AR) were observed in 58 cases of breast carcinoma, and related to patient 5- year survival rate through stratification and multivariatc analysis. The results showed that histologic tumor type and grading, lymphnode status, ER value and patient age took more important role in patient survival, and SR, especially, conferred survival advantage in advanced cases with tumor size larger than 2 cm, node involved, or TNM Stage Ⅱ-Ⅲ.     

Cytochemistry of sex steroid receptors: A critique

Summary A number of histochemical methods for sex steroid receptors, especially estrogen receptors, have been proposed to replace standard biochemical receptor methods used to predict hormone responsiveness in breast cancer. This discussion addresses a number of serious concerns as to whether these histochemical procedures do in fact adequately detect receptors in situ, and concludes that most of the observed results can be explained by Type II and Type III non-receptor binding. Until further studies are performed, it is not valid to consider the histochemical localization of binding in cancer specimens as indicating the presence of steroid receptor proteins. Address for reprints: Dr. K.S. McCarty, Jr., Departments of Pathology and Medicine, Duke University Medical Center, Durham, NC 27710, USA.     

Electrocautery: Effects on steroid receptors in human breast cancer

The determination of steroid receptors in human breast cancers has assumed increasing importance over the past several decades. Improper handling of the specimens could affect results obtained. This study details the effects excessive levels of heat that occur with the use of electrocautery can have on steroid receptor quantities and localization. Twelve resected primary and metastatic human breast cancers were analyzed for cytoplasmic and nuclear receptors by biochemical analysis. In addition, steroid binding was determined by direct fluorescent histochemical techniques. To a portion of each resected specimen a Bovie^c was applied to simulate electrocautery resection. Analysis of the different portions of the same tumor revealed that there was a decrease in measurable cytoplasmic receptor in all cauterized specimens and a concomitant increase in the nuclear receptor. A similar shift in steroid binding was noted in all the specimens analyzed by fluorescent histochemical techniques. The results of this study show that the application of excessive heat to human breast cancers will lead to false negative biochemical steroid receptor determination by shifting the receptors intranuclear.     

Steroid hormone receptors and prognosis in breast cancer

Summary The importance of steroid receptors for the prognosis of mammary carcinoma has been evaluated by investigating the course of disease in 163 patients for a median follow up time of 66 months after mastectomy. Multivariate analysis including estrogen receptor (ER), progesterone receptor (PgR), the presence of 8S and 4S ER together or 4S ER only, and the lymph node status revealed only the latter to have significant (p<0.001) predictive potency. Lymph node positive (N-pos) patients had a 3.3 (1.7–6.2) fold risk of death and 2.8 (1.7–4.7) fold risk of recurrence relative to node negative (N-neg) patients.When we compared overall survival (OAS) and disease-free survival (DFS) in the various receptorpositive groups with the groups that displayed neither ER nor PgR, significant differences in prognosis were only seen in N-neg patients. PgR did not turn out to be a better prognostic factor than ER, nor was the 8S ER a sing of increased OAS and DFS compared to total ER. However, the number of patients in this group was too small to allow a definite statement.     

Tumour steroid hormone synthesis and estrogen receptor status in breast cancer patients

Summary The capacity of breast cancer to synthesise active androgens and estrogens has been related to estrogen receptor (ER) status in 79 postmenopausal patients with breast cancer. Although there was no quantitative relationship between levels of ER and steroid metabolism in ER positive tumours, there was (a) a positive correlation between estrogen synthesis and ER positivity and (b) increased androgen synthesis and ER negativity. This may imply an inherent difference in the handling of hormones in ER positive and negative tumours. Address for reprints: R.C. Mason, University Department of Clinical Surgery, Royal Infirmary, Edinburgh EH39YW, United Kingdom.     

Better prognosis of many cancers in female: A phenomenon not explained by study of steroid receptors

Experimental evidence indicates that specific sex hormonal imbalance, deficiency, and excess may be causes of tumors or at least contribute in some way to their development. Clinical observations show that the prognoses of patients with various malignancies differ among males and females, and some cancers can be alleviated and partially controlled by altering the accustomed hormonal environment. Although beneficial effects usually are only temporary, there is no doubt that some cancers are hormone-dependent to a degree. A significant number of prostatic carcinoma in males and breast carcinoma in both sexes have been treated with various additive or ablative endocrine manipulations. The detection and quantitation of specific steroid binding proteins in hormone-sensitive tumors have enhanced our understanding of the mechanism of endocrinal therapy. Excluding carcinoma of the breast and of the sex organs (ovary and uterus in females, testis and prostate in males), many other solid tumors have been tested for the presence of estrogen and other steroid receptors. A fair number of solid cancers contains estrogen and progesterone receptors (ER, PR), even those from male patients. Thus, the better prognosis of females with sarcoma, melanoma, liver, colorectal and other cancers cannot simply be explained by the presence or absence of estrogen or progesterone receptors. This review attempts to summarize clinical reports of this interesting phenomenon, including therapeutic results with estrogenic, antiestrogenic, and other hormonal approaches.     

Receptors for epidermal growth factor and steroid hormones in primary colorectal tumors

The presence of epidermal growth factor, estrogen, and progesterone receptors (EGFR, ER, and PR) was investigated by a competitive binding assay in 43 colorectal adenocarcinomas and 32 normal colorectal mucosa specimens. EGFR were expressed in most of the tumor specimens analyzed at levels comparable with normal mucosa. There was no correlation between EGFR and tumor localization, tumor size, tumor stage, and grading. Among tumor specimens, 13.9% and 6.9% expressed very low but detectable ER and PR levels, respectively. No statistically significant difference was found between steroid hormone receptor levels in the tumor and normal mucosa specimens, and neither was there any correlation of ER and PR with the pathological findings. Our results suggest that the EGFR system may play a role in regulating the growth of colorectal tissues. Further studies should demonstrate whether, despite the lack of correlation with histopathological parameters, EGFR expression may have a biological significance in human colorectal cancer.     

In vitro studies of steroid hormones in neurofibromatosis 1 tumors and Schwann cells

The most common NF1 feature is the benign neurofibroma, which consists predominantly of Schwann cells. Dermal neurofibromas usually arise during puberty and increase in number throughout adulthood. Plexiform neurofibromas, associated with larger nerves, are often congenital and can be life threatening. Malignant peripheral nerve sheath tumors (MPNST) in NF1 are believed to arise from plexiforms in 5%-10% of patients. There are reports of increased potential for malignant transformation of plexiform tumors and increase in dermal neurofibromas, during pregnancy. These observations suggest that steroid hormones influence neurofibroma growth, and our work is the first to examine steroid hormone receptor expression and ligand-mediated cell growth and survival in normal human Schwann cells and neurofibroma-derived Schwann cell cultures. Immunohistochemistry and real-time PCR showed that estrogen receptors (ERs), progesterone receptor (PR), and androgen receptor are differentially expressed in primary neurofibromas and in NF1 tumor-derived Schwann cell cultures compared to normal Schwann cells. However, there is substantial heterogeneity, with no clear divisions based on tumor type or gender. The in vitro effects of steroid hormone receptor ligands on proliferation and apoptosis of early passage NF1 tumor-derived Schwann cell cultures were compared to normal Schwann cell cultures. Some statistically significant changes in proliferation and apoptosis were found, also showing heterogeneity across groups and ligands. Overall, the changes are consistent with increased cell accumulation. Our data suggest that steroid hormones can directly influence neurofibroma initiation or progression by acting through their cognate receptor, but that these effects may only apply to a subset of tumors, in either gender.     

Breast cancer prognosis in three different racial groups in relation to steroid hormone receptor status

Summary Follow-up studies on 466 patients over a 5-year period showed Whites to have an overall significantly longer disease-free interval and survival than Blacks and Asians. No racial differences in prognosis were seen in patients with Stage II disease (p>0.2) but in Stage III, White patients had significantly longer disease-free periods than Blacks or Asians; the same was not true of survival. Whites had a 67% incidence of cytoplasmic estrogen receptor (CER) positive tumors compared with only 49% in Blacks and 41% in Asians. When tumors were assayed for CER, nuclear estrogen receptor (NER), and cytoplasmic progesterone receptor (CPR), there were no racial differences in the proportions of tumors containing all 3 receptors, but significant variations were found in neoplasms with no receptors and in those with apparently defective receptors. In White patients receptor status had no influence on prognosis (p>0.3). Black patients whose tumors contained both CER and NER had a significantly better time to recurrence than those whose tumors lacked these receptors, while in Asian women the presence of CER alone, or CER together with NER, or CER, NER, and CPR, was indicative of a significantly longer disease-free period.     

Epidermal growth factor receptor in breast cancer: Storage conditions affecting measurement,and relationship to steroid receptors

Summary This study investigates the effect of freezing and storage of tissue and subcellular fractions on the measurement of epidermal growth factor receptors (EGF-r); compares competition binding and single saturating dose assays (SSD) for quantitating EGF-r levels; investigates several tissues as potential quality control; and examines the relationship between EGF-r and hormone receptor expression in human breast cancers.Mouse and calf uterine cell membranes were preferred sources of quality control tissue with similar levels of high affinity EGF-r to human breast cancer tissue (<150–200 fmol/mg membrane protein). Studies using pooled mouse uterine tissues indicated a loss of 40% in EGF-r activity following a single –20°C freeze/thaw cycle, while a breast cancer tissue showed a 75% loss, independent of storage temperature (liquid nitrogen, –70°C, –20°C). A single freeze/thaw cycle of mouse uterine broken cell pellets (nuclei plus membrane fraction) again indicated a loss of EGF-r irrespective of storage temperature (43% loss at –70°C, 52% loss at –20°C). In most cases irrespective of the tissue type or tissue fraction being stored, the length of storage had little impact on the extent of the loss in activity. A second freeze/thaw cycle of intact tissue, or freezing of broken cell pellets from a previously-frozen tissue, led to a further major or total loss of the remaining EGF-r. Overall these results are commensurate with the published effects of freezing and storage on estrogen receptor measurement. In addition, our studies suggest that the most suitable procedure for assaying frozen breast cancer specimens for EGF-r levels in conjunction with steroid receptor quantitation is to prepare and assay both cytosol and membrane fractions for their respective receptor content without further storage. A concordance of 86% was found in 44 breast cancers assayed for EGF-r by saturation analysis and SSD. Statistically significant inverse relationships were found between EGF-r and estrogen and progesterone receptor levels in a study of approximately 350 breast cancer patients. No association was found with tumor stage or diameter, axillary node involvement, or patient age.     

Steroid receptors in sarcomatous lesions.

Clinical observations showed that the natural history of sarcomatous lesions may be different among males and females, and it may be influenced by hormonal factors. Estrogen receptors (ER) were measured on biopsy specimens of melanoma (two patients), soft-tissue sarcoma (four patients), cystosarcoma phylloides (five patients), benign breast tissues (27 patients), and breast carcinoma (109 patients). Thirty-four specimens also had progesterone receptors (PR) analyzed. One of the five cystosarcoma phylloides and five of the six nonmammary sarcoma tissues contained ER (mainly of the 4 Svedburg (S) variety) of more than 7 femtomoles (fmoles)/mg cytosol proteins (6/11 = 54%). For comparison three of the 14 fibroadenoma specimens and two of the 13 patients with other benign lesions had positive ERs (5/27 = 19%), whereas 56% of the breast carcinomas were ER positive. Since the amount of 8S ER found in sarcomatous tissues is relatively low, hormonal treatment would not be effective.     

Sex steroid hormone levels in breast adipose tissue and serum in postmenopausal women

Elevated levels of circulating estrogens and androgens are linked to higher breast cancer risk among postmenopausal women; however, little is known about hormone levels within the breast. Hormone concentrations within the breast may not be reflected in the blood and are likely important contributors to breast carcinogenesis. We used a previously validated method to measure levels of estrone, estradiol, androstenedione, and testosterone in adipose tissue removed as part of breast excisions performed for cancer in 100 postmenopausal women (69 ER/PR +/+ and 31 ER/PR −/−) participating in a breast cancer case–control study. We also measured the same steroid hormones, as well as estrone sulfate, and sex hormone-binding globulin (SHBG) in serum from these patients and 100 controls matched on ages at blood collection and on menopause. Overall, concentrations of serum hormones did not vary significantly between controls and cases. However, women with ER−/PR− breast cancers had lower circulating levels of all measured sex steroid hormones and higher SHBG levels than women with ER+/PR+ breast cancers and controls. Similarly, hormone concentrations in breast adipose tissue were higher among women with ER+/PR+ compared to ER−/PR− breast cancer, although differences were only significant for testosterone. These data demonstrate that high sex steroid concentrations in both serum and adipose tissues are more strongly related to ER+/PR+ than ER−/PR− breast cancers. Measurement of sex hormones in serum and in the microenvironment may help in understanding the hormonal etiology of breast cancer, suggest methods for prevention, and have value in gauging treatment response and prognosis.     

Comparison of immunohistochemical and biochemical measurement of steroid receptors in primary breast cancer: Evaluation of discordant findings

Tumor samples of 240 patients with primary breast cancer were biochemically and immunohistochemically investigated for estrogen receptors (ER) and, in 130 of the samples, for progesterone-receptors (PgR) in order to examine reasons for discordant findings. The biochemical (DCCA) and immunohistochemical assays (ICA) yielded positivity in 71% for ER, and in 44% for PgR. Concordant ER-DCCA and ER-ICA results were obtained in 84%; two thirds of the discordant ER-findings manifested as DCCA-neg/ICA-pos. Concordance in the case of PgR amounted to 72%, and of the discordances 60% were DCCA-neg/ICA-pos. Significant association with postmenopausal status existed only for ER positivity in ICA (p=0.01), whereas ER-DCCA, PgR-DCCA and PgR-ICA were all more or less independent of the menopausal status. The frequency of discordances was independent of menopausal status. Discordance for ER-assays increased significantly near the respective cut-off point; this was not unequivocally true for PgR-assays. The correlation of tumor types of sparse cellularity, as well as prominent stroma content (scirrhous carcinoma) with increased frequency of the constellation DCCA-neg/ICA-pos was of borderline significance for PgR (p=0.06), but not for ER. The percentage of discordant ER-findings, figuring as DCCA-neg/ICA-pos, was statistically significantly increased in locally advanced breast cancer (p=0.03). Fibrocystic disease in peritumoral breast tissue had no impact on receptor-assay discordance. In any case, the models derived from theoretical thought, laboratory data and singular observations can only in part explain the discordance in steroid receptor values measured with different methods.     

恶性冬眠瘤的临床病理和免疫组化及超微结构观察

目的：了解恶性冬眠瘤独特的临床病理和免疫组化及超微结构变化。方法：收集2例恶性冬眠瘤和4例粘液性脂肪肉瘤的临床资料,所有标本光镜常规切片观察,免疫组化染色检测CKp,SMA,RMA,MyOD1,S100,PCNA,p53。冬眠瘤和粘液性脂肪肉瘤各1例取新鲜组织做透射电镜观察。结果：恶性冬眠瘤与粘液性脂肪肉瘤有显著的组织学、免疫组化和超微结构的不同;例1与腺泡状软组织肉瘤的组织学和免疫组化改变相似,唯有超微结构不同。例2免疫组化与有腺泡样结构的肉瘤不同。结论：恶性冬眠瘤的诊断主要靠超微结构的观察和免疫组化染色。     

Proliferation, steroid receptors and clinical/pathological response in breast cancer treated with letrozole

Sixty-three postmenopausal women with large primary breast cancers were treated with neoadjuvant letrozole (2.5 mg daily) for 3 months. Tumour samples were taken at diagnosis and after 10-14 days and 3 months treatment. Immunohistochemical staining for Ki67, oestrogen receptor (ER) and progesterone receptor (PgR) was performed and related to clinical (ClinR) and pathological responses (PathR) after 3 months treatment. ClinR was observed in 48 of 63 cases (76.2%) and PathR in 47 of 62 (75.8%). Pretreatment Ki67 scores were similar in responders (R) and non-responders (NR). Highly significant Ki67 decreases occurred in all tumour subgroups at 10-14 days (P<0.005). A significant difference in Ki67 scores at 10-14 days (P<0.007) was found between PathR and PathNR but not between ClinR and ClinNR. At 3 months, decreases from pretreatment Ki67 scores were highly significant in all tumour subgroups irrespective of response status. However, whereas Ki67 scores were significantly different between pathological R and NR (P = 0.009), the corresponding comparison of ClinR status was not. Significant decreases between 10-14 days and 3 months were found only in ClinR and PathR (P = 0.02 and 0.045, respectively). Treatment significantly reduced PgR expression at 14 days and 3 months (both P<0.0001), but the level of changes was not different between response status groups. In summary, letrozole produces rapid and profound decreases in expression of Ki67 and PgR but changes do not always correlate with clinical and pathological responses.     

Sex steroid receptors in intracranial tumors

Estrogen (ER), progestin (PGR), and androgen (AR) receptors were assayed in cytosols prepared from 38 various intracranial tumors. The receptors were in the following proportions (number of receptor-positive/number of tumors examined): meningiomas were positive for PGR (4/6) and AR (2/5); glioblastomas were also positive for PGR (3/21) and AR (7/21); astrocytomas were positive only for PGR (4/5); and oligodendrogliomas only for AR. In two hamartomas AR was present, while in one chordoma both PGR and AR were present. In this latter tumor ER were not assayed due to insufficient material. The receptors were present in concentrations between 10 and 20 fmol/mg protein. Exceptions were two meningiomas and a chordoma with a high concentration of PGR and AR. Our results support the notion that a proportion of intracranial tumors contains sex steroid receptors, and some of these tumors might be hormonally dependent.