涎腺肿瘤中雌,孕激素受体的表达及意义

用酶联亲合组化法在石蜡切片上对４４例涎腺肿瘤组织中的ＥＲ和ＰｇＲ进行检测。结果表明，多形性腺瘤ＥＲ（＋）率为３３．３３％，ＰｇＲ（＋）率为８．３３％；涎腺癌ＥＲ（＋）率为６８．７５％，ＰｇＲ（＋）率为５３．３３％，这些肿瘤尤其是涎腺癌可能是激素依赖性。阳性颗粒在多形性腺瘤多出现在细胞核中，在涎腺癌多出现在细胞浆内。另外，在粘液表皮样癌中ＥＲ和ＰｇＲ表达与肿瘤分化程度呈正相关，并且粘液样细胞对ＥＲ和ＰｇＲ均不表达，表皮样细胞和中间型细胞表达与否和表达强度基本一致。     

Results of two or five years of adjuvant tamoxifen correlated to steroid receptor and S-phase levels

A Swedish cooperative trial demonstrated that 5 years of adjuvant tamoxifen was more beneficial than 2 years of tamoxifen in the treatment of postmenopausal women with estrogen receptor (ER) positive, early stage, invasive breast cancer. The main aim of the present study was to investigate the importance of progesterone receptor (PgR) and ER concentration levels for patients participating in the trial and still distant recurrence free two years after the primary operation. Subgroup analyses revealed that only patients with ER positive and PgR positive breast cancer had improved distant recurrence free survival (DRFS) by prolonged tamoxifen therapy (p=0.0016). Patients with ER negative and PgR negative as well as ER positive and PgR negative tumors showed no significant effect of prolonged tamoxifen (p=0.53 and p=0.80, respectively). The percentage of ER negative and PgR positive breast cancers was too small (2.2%) for any meaningful subgroup analysis. There was a significant positive trend that the concentration level of PgR (high positive vs. low positive vs. negative) decreased the recurrence rate for those with prolonged therapy. No corresponding pattern was found for the ER content. S-phase fraction did not correlate to the recurrence rate of PgR positive breast cancers. Patients recurring during tamoxifen therapy had receptor negative tumors to a greater extent than those recurring after tamoxifen treatment.In conclusion, prolonged tamoxifen therapy for 5 years instead of 2 years was found to be beneficial for patients with ER positive and PgR positive breast cancer, whereas three extra years of tamoxifen had little or no effect for patients with ER positive but PgR negative tumors as well as for steroid receptor negative patients.     

Relationship of PS2 with response to tamoxifen therapy in patients with recurrent breast cancer.

PS2, an oestrogen-inducible protein, was measured in the cytosol of 230 primary tumours from patients who were subjected to first-line tamoxifen therapy for advanced disease without prior adjuvant therapy with tamoxifen. PS2 correlated positively with oestrogen receptor (ER, P < 0.01) and progesterone receptor content (PgR, P < 0.001), and with the length of progression-free survival (PFS, P = 0.05). Although not statistically significant, higher levels of PS2 (> or = 10 ng mg-1 protein) were also associated with increased probability of response to tamoxifen treatment and a longer total post-relapse survival (PRS). ER, PgR, menopausal status, site of disease and prior adjuvant chemotherapy were all associated with response to tamoxifen therapy and with PFS. In multivariate analysis for PFS, low levels of ER and PgR, visceral metastasis, a disease-free interval of less than 1 year and prior adjuvant chemotherapy were all significantly associated with an increased probability of a rapid disease progression after start of tamoxifen therapy. In the subset of 83 tumours with intermediate levels of ER and PgR (both > or = 10, but not both > or = 75 fmol mg-1 protein), PS2 was positively related with the length of PFS (P < 0.01) and PRS (P < 0.05). PS2 remained the strongest factor in multivariate analysis for PFS (P < 0.01) in this ER/PgR intermediate subgroup, but was not of predictive value in univariate or multivariate analysis for both PFS and PRS in tumours classified as ER/PgR low or high (> or = 75 fmol mg-1 protein). It is concluded that PS2 status may be used as a parameter, additional to ER and PgR, for better refinement of prediction of response to tamoxifen treatment in advanced breast cancer patients especially with intermediate ER/PgR levels in their primary tumour.     

Prolactin regulation of estrogen and progesterone receptors in normal and neoplastic mouse mammary tissue

The transplantable mouse mammary tumor, TPDMT-4, is pregnancy-dependent and requires prolactin (PRL), estradiol (E2) and progesterone (Pg) for growth. To examine the role of PRL in regulating tissue growth and the levels of estrogen receptor (ER) and progesterone receptor (PgR), tumor-bearing mice were ovariectomized, hysterectomized and then injected with ergocornine hydrogenmaleate (ERG), ERG + PRL, or ERG + PRL + E2 + Pg. Total (nuclear + cytoplasmic) ER and PgR in normal and neoplastic mammary tissues were measured. In addition, tumor size and tritium-labeled thymidine [( 3H]dThd) incorporation into nuclei of the tumor and mammary gland were determined. PRL alone caused a 2- to 3-fold increase in ER and PgR levels in normal mammary gland but not in the tumor. PRL alone caused a modest increase in the number of 3H-thymidine-labeled nuclei in both tissues. PRL combined with E2 and Pg increased the percent of labeled nuclei 5- to 10-fold in both tissues, and increased the PgR levels in normal but not in tumor tissue. Thus, PRL alone can increase ER in normal mammary tissue but this increase is not required for growth since ER levels are unchanged when PRL + E2 + Pg are injected and mammary cell growth is stimulated. The ability of PRL to up-regulate ER has been lost in the tumor. Since basal levels of ER and PgR are not altered in the tumor when PRL + E2 + Pg are given, an increase in ER and PgR levels is not required for the three hormones to stimulate tumor growth.     

Osteopontin expression in salivary gland tumours

Osteopontin (OPN) is expressed in numerous carcinomas and plays a role in tumour development, invasion and metastasis. This study examines by immunohistochemistry the expression of OPN in normal salivary gland tissue and three types of salivary gland tumour: pleomorphic adenoma (PA), adenoid cystic carcinoma (ACC) and polymorphous low grade adenocarcinoma (PLGA). PAs and PLGAs demonstrated higher levels of OPN than normal salivary gland tissue, while ACC, although showing a trend towards increased OPN, was not significantly different. The results of this study indicate that OPN expression is present in normal salivary gland tissue, and is increased in certain salivary gland tumours, but further investigation is necessary to clarify its role.     

酪氨酸激酶B在涎腺腺样囊性癌中的表达及与嗜神经侵袭的关系

目的检测酪氨酸激酶B(TrkB)在涎腺腺样囊性癌(ACC)的表达情况，探讨TrkB与ACC嗜神经侵袭的关系。方法研究对象为28例ACC，3例正常腮腺，3例正常颌下腺，3例正常舌下腺及5例涎腺腺泡细胞癌标本，采用免疫组织化学及图像分析法对组织切片中的TrkB进行检测。结果以病理学表现为标准，28例ACC中的嗜神经侵袭率为46．4％(13／28)，TrkB阳性率为92．8％(26／28)，存在嗜神经现象组中TrkB表达水平明显高于未见嗜神经现象组(P=0．001)。TrkB的表达在正常大涎腺的导管细胞为阳性，而在腺泡细胞癌胞浆内均为阴性。结论TrkB可能作为ACC嗜神经侵袭的生物学标志物。TrkB表达的增高可能是ACC嗜神经侵袭的机理之一。     

Hormone steroid receptor variation after tamoxifen administration in endometrial adenocarcinoma from postmenopausal patients

Cytoplasmic and nuclear variations of estrogen (ER) and progesterone receptors (PgR) induced by tamoxifen (TAM) treatment were investigated in 38 postmenopausal women with endometrial carcinoma. The treatment consisted of a daily oral administration of 40 mg for 7 days. Tumor samples from each patient were withdrawn before TAM administration under hysteroscopy and at the time of hysterectomy. Cytoplasmic and nuclear receptors were respectively determined by the dextran-coated charcoal assay and the hydroxylapatite technique. In the cytoplasmic fraction no significant change in mean ER value was observed, but a statistically significant increase in PgR was found (P less than 0.001). Conversely, in the nuclear fraction PgR did not vary, but a significant increase in ER content (P less than 0.001) was observed. PgR, analyzed by sucrose density gradient after TAM, showed the same sedimentation property (9 S) as the preexisting receptor, but with a single peak profile, indicating a lower heterogeneity. Our data support the hypothesis that the mechanism of PgR synthesis is induced by the ER-TAM complex and suggest the possibility of increasing the PgR content in these patients for sequential endocrine therapy.     

Changes of steroid hormone receptor content by chemotherapy and/or endocrine therapy in advanced breast cancer

In several sequences during the progression of cancer, the authors assayed estrogen receptors(ER) in 940 breast cancers and progesterone receptors(PgR) in 773 cancers. The percentages of ER+ and PgR+ cancers diminished according to the progression of malignancy. Sequential assays of ER and PgR were carried out in primary tumors and in the metastatic tumors at the first recurrence in 42 patients. During the disease-free interval, 10 (37%) of 27 ER+ tumors changed to ER- and all 15 ER- tumors remained negative. The hormone receptors were assayed before the treatments and after the tumor relapsed following regression or after the progression of cancer. The change of ER and PgR in 99 patients with advanced breast cancer were studied according to the type of systemic treatments. Through endocrine therapy, marked changes from ER+ to ER-, were noted (by antiestrogens, 47% [7/15]; by adreno-oophorectomy, 61% [11/18]). Almost no breast cancers changed from ER- to Er+ during the endocrine therapy (by antiestrogen, 1/6; by adreno-oophorectomy, 0/10). All of six PgR+ tumors changed to PgR- after therapy. By chemotherapy treatment, 44% (4/9) ER+ cancers became ER-, while 19% (3/16) ER- tumors changed to ER+. After the simultaneous combination of chemotherapy and endocrine therapy, 67% (10/15) of ER+ cancers changed to ER-, and 20% (2/10) of ER- tumors changed to ER+. Through the intervention of more than two kinds of chemotherapy and/or endocrine therapy between the first treatment and the last therapy, 79% (19/24) ER+ breast cancers changed to ER-. Thus, ER and PgR contents of breast cancer gradually became negative as the malignancy progressed, and with some kinds of treatments particularly including endocrine therapy. The significance of changes in hormone receptors after therapy was discussed.     

脑膜瘤的雌孕激素受体

本文对３３例脑膜瘤的ＥＲ，ＰＲ作了分析。脑膜瘤性激素受体的阳性率：ＥＲｃ为０，ＥＲｎ为６．１％，ＰＲｃ为１２．１％，ＰＲｎ为６３．３％。多数肿瘤中测不到ＥＲ，且测到者含量变极低。ＰＲ含量明显高于ＥＲ，认为脑膜瘤以ＰＲ占优势。ＰＲ与ＥＲ间无相关关系，ＥＲｎ（ｇ ），ＰＲｎ（＋）者明显多于ＥＲｎ（＋），ＰＲｎ（＋）者，提示脑瘤的ＰＲ可能是一个不依赖于ＥＲ调节的独立系统。本资料为脑膜瘤的激素治疗可能性提     

Prognostic significance of progesterone receptor levels in estrogen receptor-positive patients with metastatic breast cancer treated with tamoxifen: results of a prospective Southwest Oncology Group study.

PURPOSE: Southwest Oncology Group (SWOG) protocol 8228 is a prospective trial designed to investigate the prognostic significance of progesterone receptor (PgR) levels in estrogen receptor (ER)-positive breast cancer patients who were treated with tamoxifen. This study was undertaken because the value of PgR measurements in advanced breast cancer had been assessed previously only in studies that were small, retrospective, or included heterogeneously treated patients. METHODS: Receptor assays were performed only in the laboratories that met strict quality control guidelines. Of the 398 patients entered, 342 patients were eligible and assessable for the study end points of objective clinical response, time to treatment failure, and overall survival. RESULTS: Multivariate analysis shows that elevated PgR levels significantly and independently correlated with increased probability of response to tamoxifen, longer time to treatment failure, and longer overall survival. Overall response rate (defined as complete response [CR], partial response [PR], or stable disease [SD] for greater than 6 months) in this trial was 54%. Response rates to tamoxifen were 43%, 53%, and 61% in subsets of patients with less than 10, 10 to 99, and more than 100 fmol/mg PgR, respectively. Exploratory subset analysis using PgR and other prognostic variables identified ER-positive patient subsets with response rates to tamoxifen ranging from 24% (premenopausal patients) to 86% (postmenopausal patients with ER greater than 38 and PgR greater than 329 fmol/mg). No groups of ER-positive patients were identified who had such a low response rate as to absolutely preclude considering the use of tamoxifen. Multivariate analysis showed the independent, statistically significant predictors were: for response to tamoxifen, menopausal status, PgR, and ER; for time to treatment failure, menopausal status, disease-free interval (DFI), PgR, and ER; and for overall survival DFI, PgR, ER, site of disease, and history of adjuvant therapy. CONCLUSION: We conclude that knowledge of PgR levels together with other clinical information can improve the pretreatment assessment of ER-positive breast cancer patients with metastatic disease.     

Effects of high-dose medroxyprogesterone acetate in advanced breast cancer, with special reference to prior endocrine therapy and hormone receptors

Forty-six patients with advanced breast cancer were treated orally with high-dose medroxyprogesterone acetate (MPA), and a 28% (2 CRs, 11 PRs) response rate was obtained. The patient groups that showed a favorable response to MPA were as follows: patients in a postmenopausal state, with soft tissue or bone metastases, with slow-growing tumors, without prior therapy or with good response to prior endocrine therapy, and with positive estrogen (ER)- and/or progesterone (PgR) receptors. Six of 10 patients who had responded to prior endocrine therapy responded to MPA, while only 2 of 23 who had not responded to prior endocrine therapy showed a good response to MPA. There was a significant difference in response to MPA between patients with positive ER or PgR and those with negative ER or PgR tumors. The ER detected in primary or initially relapsed tumors correlated well with the effects of MPA given as a 2nd-line endocrine therapy for advanced breast cancer. The possible roles of MPA in the treatment of advanced breast cancer were discussed.     

Salivary gland adenoid cystic carcinoma: a review of chemotherapy and molecular therapies

Adenoid cystic carcinoma (ACC) accounts for about 1% of all head and neck malignancies. It has a tendency for a prolonged clinical course, with local recurrences and distant metastases sometimes occurring many years after presentation. Standard treatment for salivary gland ACC is surgery and post-operative radiotherapy. The aim of this review was to examine the reported efficacy of various chemotherapy regimens and molecular therapies on recurrent/metastatic salivary gland ACC. One hundred and fourteen publications were reviewed on chemotherapy as well as possible molecular targets of therapy, including KIT, epidermal growth factor receptor (EGFR), human epidermal growth receptor-2 (HER-2), oestrogen and progesterone receptors, proliferating cell nuclear antigen (PCNA), Ki-67 and the p53, bcl-2 and SOX-4 genes. Reported response rates to combination chemotherapy are low and response duration generally short lived. The response to molecular therapies is low also. More research into novel molecular targets is needed.     

Treatment relevant target immunophenotyping of 139 salivary gland carcinomas (SGCs)

Salivary gland carcinomas (SGCs) are rare tumors encompassing a wide spectrum of histologic/biologic entities. Standard non-surgical treatments are ineffective in case of advanced disease. Our aim was to analyze SGCs deregulation gene profiles that could become target for innovative treatment options.Samples from 139 patients with primary, recurrent and/or metastatic SGCs were investigated by immunohistochemistry for protein encoded by tyrosine kinases receptors (TKRs) i.e. c-kit, HER2, EGFR and hormonal receptors, i.e. androgen (AR), estrogen (ER) and progesterone receptors (PgR). In 26 cases, the HER2 immunohistochemical analysis was complemented by fluorescence in-situ hybridization analysis.EGFR was the most expressed TKRs (71%) and it was found across all histotypes.c-Kit expression was mainly restricted to adenoid cystic carcinoma (78%) while HER2 expression, mostly sustained by gene amplification, correlated with salivary duct carcinoma (SDC) in 44% of cases and adenocarcinoma, not otherwise specified (AD, NOS) in 21% of cases. With respect to histogenetic classification, TKRs expression occurred more often in tumors derived from intercalated duct rather than excretory ones with the only exception of HER2. AR was found in 13% of samples, restricted to SDC and AD, NOS and it was co-expressed with HER2 in more than half of the SDC cases. ER and PgR positivity was never detected.This TK-hormonal receptors analysis identify a histotype-specific profiles that could be exploited for better selecting patients for innovative treatment within prospective studies.     

Most cystosarcoma phyllodes and fibroadenomas have progesterone receptor but lack estrogen receptor: stromal localization of progesterone receptor

Biochemical study of fibroepithelial tumors of the female breast showed presence of progesterone receptor (PgR) in all five cystosarcoma phyllodes (two malignant, three benign), and in 11 of 13 fibroadenomas tested. Estrogen receptor (ER) was detected in only one of five cystosarcomas and 2 of 13 fibroadenomas. The relative volumes occupied by epithelium and stroma in each tumor were measured from histologic sections. The results were consistent with presence of PgR in the stroma and ER in the epithelium. Different types of cystosarcoma (benign and malignant) and different types of fibroadenomas (intracanalicular, pericanalicular, and mixed) did not differ significantly in content of PgR, and mean levels of PgR in cystosarcoma were comparable with those in fibroadenomas. The presence of PgR in cystosarcomas suggests that progestational therapy, and possibly other forms of hormonal therapy, should be tested in the treatment of advanced, malignant cystosarcoma phyllodes.     

A unifying gene signature for adenoid cystic cancer identifies parallel MYB-dependent and MYB-independent therapeutic targets

MYB activation is proposed to underlie development of adenoid cystic cancer (ACC), an aggressive salivary gland tumor with no effective systemic treatments. To discover druggable targets for ACC, we performed global mRNA/miRNA analyses of 12 ACC with matched normal tissues, and compared these data with 14 mucoepidermoid carcinomas (MEC) and 11 salivary adenocarcinomas (ADC). We detected a unique ACC gene signature of 1160 mRNAs and 22 miRNAs. MYB was the top-scoring gene (18-fold induction), however we observed the same signature in ACC without detectable MYB gene rearrangements. We also found 4 ACC tumors (1 among our 12 cases and 3 from public databases) with negligible MYB expression that retained the same ACC mRNA signature including over-expression of extracellular matrix (ECM) genes. Integration of this signature with somatic mutational analyses suggests that NOTCH1 and RUNX1 participate with MYB to activate ECM elements including the VCAN/HAPLN1 complex. We observed that forced MYB-NFIB expression in human salivary gland cells alters cell morphology and cell adhesion in vitro and depletion of VCAN blocked tumor cell growth of a short-term ACC tumor culture. In summary, we identified a unique ACC signature with parallel MYB-dependent and independent biomarkers and identified VCAN/HAPLN1 complexes as a potential target.     

Changing behavior of estrogen and progesterone receptors with metastasis or recurrence of breast cancer

Changes in level of estrogen receptor (ER) and progesterone receptor (PgR) and their affecting factors were studied with metastasis or recurrence of breast cancer. Since 1983, from 177 patients, 443 specimens were obtained and 244 simultaneous and 122 sequential pairs were compared. The consistency rate was 81% for both ER and PgR with simultaneous comparison,and 69% for ER and 71% for PgR with sequential comparison, mainly due to positive-to-negative change, and less than 10% of negative-to-positive change. Positive-to-negative change was prominent with intervening endocrine treatment, and it was significant (p=0.015) for ER by multiple regression analysis of age, interval of sampling and from prior surgery, intervening chemotherapy, endocrine therapy and human epidermal growth factor receptor 2 (HER 2). Based on recent data of ER and PgR, feasible treatment seems to be planned, because about 30% of them are different from that of primary lesion.     

Study of FHIT and WWOX expression in mucoepidermoid carcinoma and adenoid cystic carcinoma of salivary gland

Mucoepidermoid carcinoma (MEC) and adenoid cystic carcinoma (ACC) are salivary gland neoplasms with divergent morphological features and clinical behavior. ACC is a basaloid tumor whereas MEC is a glandular epithelial neoplasm. FHIT and WWOX are tumor suppressor genes that encompass the FRA3B and FRA16D fragile sites at chromosomes 3p14.2 and 16q23.3, respectively. In previous studies, we have shown concordant loss of Fhit and Wwox expression in breast cancer, with significantly more frequent loss in cancers of basal-like phenotype. To determine if there is a similar association in salivary gland neoplasms, we designed a study of MEC and ACC of salivary gland on tissue microarrays (TMA). TMAs were constructed from 25 MEC and 19 ACC of salivary gland. Fhit and Wwox protein expression was assessed by immunohistochemical staining of cores on TMAs. Correlations among immunohistochemical markers and histological type were determined by statistical analyses. Significantly reduced Fhit and Wwox expression was observed in ACC (p = 0.002 and p < 0.001, respectively). The results suggest that, as for breast cancer, loss of Fhit and Wwox expression might have a role in the pathogenesis of basaloid differentiation in salivary gland neoplasms; alternatively, differences in chromatin structure at chromosome fragile regions might make fragile genes more accessible to DNA damage and rearrangement early during preneoplastic stages of basaloid cancers. Studies of basaloid tumors of other organ systems may show similar results and these findings may have implications for treatment modalities designed for basal-like tumors.     

Molecular aspects of estrogen receptor variants in breast cancer

Summary Measurements of the estrogen receptor (ER) and the estrogen-induced progesterone receptor (PgR) are used by most clinicians as indicators of both overall prognosis and likelihood of response to endocrine therapy. Patients with ER+/PgR+ tumors have the highest likelihood of response; conversely, patients with ER-/PgR- tumors have the lowest likelihood of response. Unfortunately, most patients treated successfully with endocrine therapy eventually develop endocrine-resistant disease recurrence. In an effort to study potential mechanisms of endocrine resistance, we have studied discordant ER-/PgR+ tumors, in which the normally estrogen-regulated PgR gene is induced in the apparent absence of ER. Our laboratory has previously cloned, from ER-/PgR+ tumors, a variant ER mRNA precisely missing the sequence corresponding to ER exon 5, and has demonstrated that the truncated protein product translated from this variant RNA is capable of constitutively inducing the expression of an estrogen-responsive reporter gene in a yeast expression vector system (Fuqua et al, Cancer Res 51:105-109, 1991). In the present report we describe further experiments to characterize the activity and biological consequences of expression of this variant ER in human breast cancer cells. We have stably transfected MCF-7 human breast cancer cells with a mammalian expression vector for the exon 5 deletion variant ER. These transfected cells produce a truncated ER protein of the expected 40 kDa size. Cells expressing the exon 5 ER deletion variant constitutively express PgR, and manifest increased anchorage-independent colony formation in the absence of estrogen. Furthermore, the anchorage-dependent growth of these cells was not inhibited by the triphenylethylene antiestrogens tamoxifen or 4-hydroxytamoxifen, unlike MCF-7 cells transfected with a control plasmid, which were growth inhibited by both of these compounds. Interestingly, the pure antiestrogen ICI 164,384 did inhibit the growth of exon 5 ER deletion variant-expressing transfectants. The implications of these results with regard to the treatment of tamoxifen-resistant disease are discussed.