Phytoestrogens and carcinogenesis-differential effects of genistein in experimental models of normal and malignant rat endometrium

The phytoestrogen genistein was studied in normal and malignant experimental uterine models in vivo. The action of genistein on the uterus and vagina of ovariectomized DA/Han rats after 3 day oral administration (25, 50 or 100 mg/kg/BW/d) was compared to ethinyl oestradiol (0.1 mg/kg/BW/d). Effects on uterine and vaginal morphology, uterine growth and uterine gene expression were studied. A dose dependent increase of the uterine wet weight and the uterine and vaginal epithelial height, a dose dependent up-regulation of complement C3, down-regulation of clusterin mRNA expression and a stimulation of the vaginal cornification was observed after administration of genistein. Uterine gene expression and vaginal epithelium respond to genistein at doses where no significant effects on uterine wet weight were detectable. In general the vagina was more sensitive to genistein than the uterus. To analyse the action of genistein in malignant uterine tissue, the impact of a 28 d treatment with 50 mg/kg/d of genistein on the in-vivo tumour growth of RUCA I endometrial adenocarcinoma cells, following subcutaneous inoculation into syngeneic DA/Han rats, was assessed. In contrast to ethinyl oestradiol (0.1 mg/kg/BW/d), a dose of 50 mg/kg/BW/d of genistein did not affect tumour growth. Nevertheless C3 and TRPM2 mRNA expression in the tumour were both significantly stimulated by ethinyl oestradiol and genistein. In comparison to ovariectomized animals genistein up-regulated uterine wet weight and uterine dependent gene expression in tumour bearing animals. In conclusion, four independent uterine and vaginal parameters indicate genistein is a weak oestrogen receptor agonist in the uterus and vagina of female DA/Han rats, and evidence is provided for a selective oestrogen receptor modulator (SERM)-like action of genistein in normal and malignant uterine tissue.     

Diagnostic value of endometrium associated with papillary metaplastic changes in endometrial cytopathology

Papillary metaplastic changes especially occur in both non‐neoplastic and neoplastic endometrium. We tried to investigate to assess the relationship between endometrial cytologic diagnosis and papillary metaplasia. The material consists of 160 cases of cytologic smears obtained by direct sampling of the endometrial cavity comprising 54 cases of normal proliferative endometrium (NPE), 36 cases of glandular and stromal breakdown (EGBD), and 70 cases of endometrial hyperplasia without atypia (EH). As for the correlation between the appearance of papillary metaplasia and cytological diagnosis, a statistical significance test was performed. The material consists of 40 cases of cytologic smears examined by direct sampling of the endometrial cavity comprising 10 cases of EGBD with papillary metaplasia, 10 cases of G1 without pappilary metaplasia, 10 cases of NPE without papillary metaplasia, and 10 cases of EH without papillary metaplasia. Using the comparison between appearance of papillary metaplasia and cytological diagnosis, a significant difference was only seen in the rate of correct diagnoses in EGBD cases. The nuclear area of papillary metaplastic cells in EGBD was 888.8, G1 was 928.7, NPE was 682.0, and EH was 722.2. Significant difference was observed between ECC cells in EGBD to NPE, between papillary metaplastic cells in EGBD to EH, between G1 to NPE, or between G1 to EH. This study provides new and important information on the correlation between endometrial cytological diagnosis and papillary metaplastic changes. Diagn. Cytopathol. 2009. © 2009 Wiley‐Liss, Inc.     

Molecular genetic changes in epithelial, stromal and mixed neoplasms of the endometrium

Endometrial carcinoma, endometrial stromal tumours and mixed malignant mesodermal tumours (MMMT) develop along distinctive molecular genetic pathways. Two distinctive types of endometrial carcinoma are distinguished, type I and type II, which develop along distinctive pathways and show different clinical behaviour and histological features. Type I carcinomas show endometrioid histology, are oestrogen-related and develop from atypical endometrial hyperplasia. The molecular tumorigenesis is comparable to colorectal carcinoma with a step-like progression and an accumulation of genetic alterations. Alterations of PTEN, K-Ras mutations and microsatellite instability are frequent and early events in type I carcinoma, whereas p53 mutations occur during progression to grade 3 carcinoma. Serous and clear cell carcinomas are considered type II carcinomas which are mostly unrelated to oestrogen. p53 mutations occur in almost all serous carcinomas and seem to occur early, leading to massive chromosomal instability and rapid tumour progression. Gene expression profiling has supported this dualistic model of endometrial carcinoma. There is evidence of molecular differences between serous and clear cell carcinomas as well as between endometrioid carcinomas with and without microsatellite instability. A dualistic model of tumorigenesis may be also suggested for endometrial stromal tumours. Endometrial stromal sarcomas (ESS; type I endometrial sarcoma) are oestrogen-related and seem to develop from endometrial stromal nodules (ESN). They are histologically and genetically distinct from undifferentiated endometrial sarcoma (UES) which seem to be mostly unrelated to oestrogen (type II endometrial sarcoma). ESS and ESN share the fusion gene JAZF1/JJAZ1 caused by a t(7;17)(p15;q21) translocation, whereas UES lacks a distinctive molecular alteration so far. In MMMT, which is considered a metaplastic carcinoma, p53 alteration occurs early, before clonal expansion and acquisition of genetic diversity during progression.     

妊娠早期小鼠子宫内膜热休克蛋白70的免疫组化研究

目的 :研究妊娠早期小鼠子宫内膜热休克蛋白 70的表达。方法 :采用免疫组织化学方法。结果 :热休克蛋白 70主要存在于子宫内膜固有层的基质细胞及蜕膜细胞 ,内膜上皮、腺上皮中未见表达。与未孕小鼠相比 ,孕鼠热休克蛋白 70免疫反应阳性细胞显著增多 (P <0 .0 1 )且随妊娠日龄的增加而增加 (P <0 .0 1 )。结论 :热休克蛋白70可能参与了子宫内膜蜕膜反应中基质细胞的增殖 ,与蜕膜反应密切相关     

Plastic changes in nociceptive transmission of the rat spinal cord with advancing age

To understand characteristics of the pain system in the elderly, we investigated the electrophysiological properties of nociceptive neurons in the lumbar spinal dorsal horn of aged (29-34-mo old) and adult (7-13-mo old) rats. The responses of nociceptive neurons to noxious thermal stimulation, as well as the spontaneous firing rate, were significantly higher in the aged as compared with adult rats. Furthermore, the size of the high-threshold receptive field area of wide dynamic range neurons was larger (P < 0.01) and that of the low-threshold area was smaller (P < 0.05) in aged rats than in adult rats. The increased nociceptive neuronal activity in the aged rats correlated with the finding that the paw withdrawal latency was significantly shorter in the aged rats than those of the adult rats following heat stimulation of the hind paw (P < 0.05). Reversible local anesthetic block of descending pathways resulted in a dramatic increase in neuronal activity in adult rats but had little effect in aged rats. There was also a significant loss of serotoninergic and noradrenergic fibers in the spinal dorsal horn of the aged rats. These results demonstrate an age-related plasticity in spinal nociceptive processing that is related to impairment of descending modulatory pathways.     

Inflammatory myofibroblastic tumor of the uterus with prominent myxoid change

A surgical case of inflammatory myofibroblastic tumor arising in the uterine corpus and exhibiting prominent myxoid change of the stroma is reported. The patient was a 63-year-old woman with a large tumor mass that filled the uterine cavity and measured 11 cm in maximal dimension. The tumor had a gelatinous appearance and consisted of a loose proliferation of stellate or polygonal cells on a myxomatous background. Fascicular proliferation of spindle cells was also observed focally, and a chronic inflammatory cell infiltration was seen in many areas. Tumor cells had mild atypism and were immunoreactive for vimentin, alpha-smooth muscle actin, and anaplastic lymphoma kinase (ALK). Focal immunoreactivity for high-molecular-weight caldesmon (h-caldesmon) was also noted. The patient has been free from recurrence for 8 months. Inflammatory myofibroblastic tumor of the uterus occasionally shows prominent myxoid change of the stroma, and differentiation from myxoid leiomyosarcoma is problematic in these cases. Based on the immunoreactivity of tumor cells for ALK and h-caldesmon, the present tumor was considered inflammatory myofibroblastic tumor showing a focal phenotypic transition from myofibroblasts to smooth muscle cells.     

Uterus and endometrium: Transvaginal ultrasound studies of vascular and morphological changes in uteri exposed to diethylstilbestrol in utero

The aim of this prospective study was to establish complementarydata of uteri exposed to diethylstilbestrol (DES) in utero fortransvaginal analysis and vascularity changes during the menstrualcycle. A total of 28 women with DES-exposed uteri were comparedwith 60 non-exposed women. Transvaginal ultrasound and colourDoppler imaging were performed on days 5 and 22 of the menstrualcycle. Uteri were measured on sagittal and transverse scans.Uterine length, width, thickness and uterine cavity length andwidth were measured. Uterine volume and uterine cavity areawere calculated. DES-exposed uterine volume was equal to 31.84± 337 cm³. The cavity area of DES-exposed uterus wasequal to 35.85 ± 3.93 cm². Cervix length of DES-exposeduterus was significantly smaller than that of non-exposed uterus.The uterine artery pulsatility index (PI) of DES-exposed uteruswas significantly higher than that of normal uterus. Blood flowremained stable throughout the menstrual cycle. The PI of DES-exposeduterus remained stable during the menstrual cycle, as in non-exposeduterus, and it decreased during the luteal phase. This lackof modification in vascularity of DES-exposed uterus may explainmiscarriages and obstetric complications such as intrauterinegrowth retardation or pre-eclampsia. The data may have implicationsfor the assessment of reproductive status and the design offuture studies on disorders of implantation in DES-exposed uterus.     

Adenocarcinoma of the endometrium with glassy-cell features-immunohistochemical observations

A case of adenocarcinoma of the endometrium with glassy-cell features is reported and histochemical and immunohistochemical data are provided together with a review of the relevant literature. The microscopical features of glassy-cell carcinoma appear to be highly characteristic and diagnostic. The tumour is considered to be a distinctive and poorly differentiated type of adenosquamous carcinoma originating in the cervix or the endometrium. We studied the expression of several differentiating characteristics and detected the presence of secretory component and lysozyme in some tumour cells, whereas keratin and prekeratin were consistently absent. Since in normal uterine mucosa immunoreactivity for lysozyme is restricted to endocervical and isthmic epithelium, the presence of this antigen in the tumour would favour an endocervical or isthmic origin of the tumour cells. Furthermore our results suggest that this peculiar type of tumour is not poorly differentiated and that the assertion that glassy-cell carcinoma is a variant of adenosquamous carcinoma is open to doubt.     

Liquid-based endometrial cytology in the management of sonographically thickened endometrium

Liquid-based cytology represents an opportunity to re-evaluate endometrial cytology. We evaluated the accuracy of liquid-based endometrial cytology as compared to biopsy in 670 women scheduled for histeroscopy because of thickened endometrium (>4 mm), as evaluated by transvaginal sonography. Endometrial biopsy detected pathology in 41 (6%) of cases (21 of which were adenocarcinomas). Cytologic study found pathology in 62 (9%) cases (19 of which were adenocarcinomas). Two hundred ninety-one biopsies (43%) and 28 (4%) cytologies were inadequate. The sensitivity and the specificity were estimated, respectively, at 95% and 98%; the positive and negative predictive values were estimated, respectively, at 83% and 99%. Cytology provided sufficient material more often than biopsy (P < 0.01). We consider endometrial cytology an efficacious diagnostic opportunity. It could be usefully applied in association with transvaginal sonography. The combination of these procedures might reduce more invasive and expensive diagnostic procedures.     

Peri-partum changes in the intraepithelial lymphocyte population of sheep interplacentomal endometrium

PROBLEM: Previous studies have shown that the proportion of gammadeltaTCR+ large granulated lymphocytes (LGLs) increased markedly during pregnancy and declined dramatically by 2 days after parturition in sheep interplacentomal uterine epithelium. In the present study, the distribution, dynamics and fate of these cells, just before, during and immediately after parturition are described. METHODS OF STUDY: Interplacentomal tissues were collected at 140 days postcoitus (dpc), 148 dpc, during parturition, 1-2 hr postpartum, 1 day postpartum (dpp) and 3 dpp, and were studied using light and electron microscopy, and immuno histochemistry. Uterine washings were collected at 148 dpc and examined for the presence of LGLs. Semi-thin Araldite sections taken at different stages were used to quantify the intraepithelial LGLs, non-granulated lymphocytes (NGLs) and apoptotic cells, whereas frozen sections were used to quantify CD45R+, CD8+ and gammadeltaTCR+ intraepithelial lymphocytes (IELs). RESULTS: A dramatic decline in the proportion of IELs in the luminal epithelium during parturition was observed, mainly because of the decline in CD45R+, CD8+ and gammadeltaTCR+ IELs. There was also a significant decline in the number of granules/ LGL at parturition. This was accompanied by the presence of apoptotic cells of which some were LGLs. The proportions of IELs, LGLs and apoptotic cells markedly increased at 3 dpp. LGLs were found both in uterine washings at 148 dpc and in the uterine lumen at 3 dpp. Apoptosis of glandular epithelial cells was also evident at parturition and markedly increased at 1 dpp. CONCLUSIONS: Our results demonstrated that the dramatic decline in the proportion of gammadeltaTCR+ LGLs at parturition was because of de-granulation, apoptosis and migration of these cells into the uterine lumen.     

Complex papillary hyperplasia of the endometrium: An uncommon case report with cytopathological features and diagnostic implications

Papillary proliferations of the endometrium, without atypia have been uncommonly documented, including on cytology specimens. Herein, we present an uncommon case of a 55‐year‐old obese lady, on antihypertensive medications, who presented with history of irregular perimenopausal bleeding. A year ago, she was diagnosed with simple cystic hyperplasia on dilation and curettage specimen. Presently, she underwent endometrial aspiration. Cytology smears were prepared from the collected tissue specimen that was further submitted for histopathological analysis. Although the smears were initially diagnosed as negative for malignancy, the tissue sections were reported as a uterine papillary serous carcinoma (UPSC). Review of the smears revealed prominent overlapping clusters and papillary arrangements of relatively banal endometrial cells exhibiting focal metaplasia. Histopathology sections confirmed diagnosis of complex papillary hyperplasia (CPH). Immunohistochemical (IHC) stains reinforced this impression with diffuse estrogen receptor positivity, low Ki‐67/MIB1, and lack of diffuse p53 immunostaining. Subsequent hysterectomy, at the time of intraoperative consultation showed a small residual focus of CPH, restricted to endometrium with intramural leiomyomas and adenomyosis. This case is presented to highlight the fact that despite lack of significant atypia, cytological features like overlapping, clustering, and papillary formations are indicators of papillary lesions of the endometrium, including CPH, especially in postmenopausal women. On histopathology, in spite of conspicuous papillary formations, lack of significant nuclear pleomorphism, and tumor invasion are helpful features in avoiding an overdiagnosis of UPSC in such cases. IHC stains are supportive. Correct identification has significant therapeutic implications. Diagn. Cytopathol. 2015;43:163–168. © 2014 Wiley Periodicals, Inc.     

Relative binding activity of new antigestagens with progesterone receptors in human hyperplastic endometrium

We determined the content and binding capacity of progesterone receptors in the endometrium of patients with adenomatous and fibroid polyps, adenocystic hyperplasia, and atypical hyperplasia before and after gestagen therapy. Hyperplasia of the endometrium was accompanied by changes in affinity of cytosolic progesterone receptors for antigestagens, which provides the possibility of individual correction of hormone therapy.     

小鼠前脑线粒体蛋白的增龄性变化

目的　探讨小鼠前脑不同发育阶段线粒体蛋白的表达变化。 方法　分别取妊娠12.5 d（E12.5）及17.5 d（E17.5）的胎鼠、出生2 d的新生鼠、出生3周的幼鼠和2月龄成年鼠的前脑组织,利用QRT-PCR和Western blotting检测小鼠前脑发育不同阶段中COX IV、HSP60、OGDH、PDHE1α的mRNA和蛋白表达水平。 结果　在E12.5 ~2 d的前脑组织中COX IV mRNA呈低水平表达,3周时表达量明显升高并达到顶峰;HSP60和PDHE1α mRNA在E17.5表达明显增高,OGDH mRNA则在2 d显著上升,三者表达水平均于2月达到顶峰。COX IV、HSP60、OGDH的蛋白水平从E12.5 ~3周无明显差异,但在2月时表达显著上升;PDHE1α蛋白随前脑发育其表达水平不断提高,并于2月达到高峰。此外,COX IV、HSP60、OGDH、PDHE1α mRNA与蛋白表达水平呈正相关。 结论　COX IV、HSP60、OGDH和PDHE1α可能参与了小鼠前脑发育过程且与年龄密切相关。     

Uterine sarcomas in Norway. A histopathological and prognostic survey of a total population from 1970 to 2000 including 419 patients

Aims:  To determine the frequency and survival of the various types of uterine sarcoma in the total population of Norway and evaluate histopathological prognostic factors in order to identify risk groups.
Methods and results:  Histopathological review of all uterine sarcoma cases reported to the Norwegian Cancer Registry during 1970–2000 was undertaken. Survival dates were provided by The Cancer Registry. Kaplan–Meier survival curves were generated. The log rank test was used for univariate analysis and a Cox proportional hazards regression model for multivariate evaluation of survival. Stage of disease was the most important prognostic factor for all tumour types. Tumour size and the mitotic index (MI) were significant prognostic factors ( P  < 0.0001) in leiomyosarcomas confined to the uterus and allowed for separation into three risk groups with marked differences in prognosis. The prognosis of endometrial stromal sarcomas confined to the uterus was related to MI ( P  < 0.0001) and tumour cell necrosis ( P  < 0.004). Combining these parameters allowed for separation into three risk groups with marked difference in prognosis. In adenosarcomas, tumour cell necrosis was the only significant prognostic factor.
Conclusions:  There are marked differences in survival between uterine sarcoma types. Leiomyosarcomas and endometrial stromal sarcomas can be divided into different groups.     

Mucinous adenocarcinoma of the endometrium with intestinal differentiation: A case report

Mucinous differentiation of endocervical type has been well documented in endometrial carcinoma. However, we describe an unusual case of adenocarcinoma of the endometrium showing diffuse histological, immunohistochemical, and ultrastructural evidence of intestinal differentiation. Although intestinal differentiation has been described in mesodermally derived tissues including endocervix, ovary, and urinary tract, it has not been reported in normal endometrium. One previous case has been reported showing this pattern in endometrial carcinoma. Possible histogenetic mechanisms of this pattern are discussed.