Immunohistochemical detection of a specific receptor for lipocalin2 (solute carrier family 22 member 17, SLC22A17) and its prognostic significance in endometrial carcinoma

Background: We previously reported the overexpression of lipocalin2 (LCN2), a 25 kDa secretory protein involved in iron-transportation, in endometrial carcinoma and its possible contribution to endometrial carcinogenesis. Recently, a specific receptor for LCN2, solute carrier family 22 member 17 (SLC22A17), was identified. The present study was undertaken to investigate the expression of SLC22A17 in endometrial carcinoma. Methods: The expression of the SLC22A17 and LCN2 proteins was examined immunohistochemically using 69 cases of endometrial carcinoma and adjacent normal endometrial tissues. Immunoreactivity was evaluated according to the percentage of positive cells and described as a positivity index (PI, full score 100). Results: The expression of SLC22A17 was negligible in normal endometria, but positive staining for SLC22A17 (PI 1) was observed in 35 cases of endometrial carcinoma. The PI for SLC22A17 was significantly higher in cases with histological grade 3 (P < 0.0005), advanced FIGO stage (P=0.002), deep myometrial invasion (P=0.029), positive lymph-vascular space invasion (P = 0.029), positive intraperitoneal cytology (P = 0.020) and adnexal metastasis (P= 0.029). The expression of SLC22A17 and LCN2 was positively correlated with a significant difference (P= 0.002), and the patients who overexpressed both SLC22A17 and LCN2 showed poorer survival than those without the expression of SLC22A17 or LCN2 (P= 0.002). Moreover, the overexpression of both SLC22A17 and LCN2 was indicated to be an independent prognostic factor by multivariable analysis. Conclusions: These results suggested that SLC22A17, in cooperation with LCN2, to be involved in the acquisition of aggressive behavior among endometrial carcinoma cells.ArticleEXPERIMENTAL AND MOLECULAR PATHOLOGY. 91(2):563-568 (2011)journal articl

Predicting the Route of Delivery in Women with Low-Lying Placenta Using Transvaginal Ultrasonography: Significance of Placental Migration and Marginal Sinus

Background/Aims: To examine the significance of placental migration and the presence of a placental marginal sinus to predict the eventual route of delivery in low-lying placenta. Methods: 49 women with a low-lying placenta after 30 weeks' gestation were studied. The distance between the internal os and leading edge of the placenta was measured weekly using transvaginal ultrasonography until 37 weeks' gestation. The relationship between the rate of placental migration, the presence of a placental marginal sinus and the eventual mode of delivery was investigated. Results: Although the cesarean section rate was 56.3% (9/16) in the 'slow' migration (0-2.0 mm/week) group, no patient (0/33) in the 'fast' (>2.0 mm/week) migration group underwent a cesarean section (p<0.01). The cesarean section rate was 71.4% (5/7) in patients with a placental marginal sinus, significantly greater than the rate of 9.5% (4/42) in patients without a marginal sinus (p<0.01). Conclusion:A decreased rate of placental migration until 37 weeks' gestation and the presence of a placental marginal sinus were associated with subsequent cesarean delivery because of antepartum vaginal bleeding. These parameters may be useful for predicting the route of delivery in women with a low-lying placenta.ArticleGYNECOLOGIC AND OBSTETRIC INVESTIGATION. 73(3):217-222 (2012)journal articl

Immunohistochemical expression of keratan sulfate: a possible diagnostic marker for carcinomas of the female genital tract

Aims The authors previously reported the expression of keratan sulfate (KS), a glycosaminoglycan, in the epithelium of normal and neoplastic endometria. The aim of this study was to evaluate its potential use as a diagnostic marker, and the expression of KS was investigated in other human epithelial tissues. Methods Expression was examined immunohistochemically using 102 samples of normal epithelia and 110 samples of carcinomas from the female genital tract (FGT; cervix, endometrium, ovary, fallopian tube), digestive organs (gastrointestinal tract, pancreas, liver), urinary tract, lung, mammary gland, thyroid and mesothelium. Results In normal tissues, KS was consistently detected in the FGT and ectopic endometrium (25/26), but was not found in the digestive organs (1/42) and urinary tract (0/6), and was only partly detected in the lung (7/10), mammary gland (3/9) and thyroid (4/4). In malignant tissues, KS was consistently observed in carcinomas of the endometrium, ovary and fallopian tube (29/32), and was partly detected in carcinomas of the lung, mammary gland, thyroid, pancreas and mesothelium, but was absent in carcinomas of the gastrointestinal tract (0/17), liver (0/5) and urinary tract (0/11). Among carcinomas of the FGT, digestive organs and urinary tract, KS positivity suggested the possibility of FGT carcinomas, with 79.5% (31/39) sensitivity and 92.9% (39/42) specificity. Conclusions KS is a potentially useful marker for the supportive diagnosis of the primary site of metastatic carcinomas or unknown primary carcinomas, especially in the abdominal cavity.ArticleJOURNAL OF CLINICAL PATHOLOGY. 64(12):1058-1063 (2011)journal articl

Laser-captured microdissection-microarray analysis of the genes involved in endometrial carcinogenesis: stepwise up-regulation of lipocalin2 expression in normal and neoplastic endometria and its functional relevance

Endometrial carcinoma often arises from normal endometrial glandular cells via a precursor, atypical endometrial hyperplasia. However, the genetic changes involved in this carcinogenetic process are not fully understood. Differentially expressed genes were selected from glandular cells of normal proliferative-phase endometria, atypical endometrial hyperplasia, and endometrial carcinoma using laser-captured microdissection and microarray. The microarray analysis revealed a total of 51 genes to be up-regulated and 23 genes to be down-regulated in neoplastic endometrial epithelia. We focused on lipocalin2 (LCN2), which showed the largest magnitude of up-regulation. Immunostaining for lipocalin2 confirmed a stepwise increase in its expression in endometrial hyperplasia and carcinoma. In addition, elevated expression of lipocalin2 was correlated with the poor outcome of endometrial carcinoma patients. The subcellular distribution of lipocalin2 was both cytoplasmic and nuclear, despite reports that lipocalin2 is a secretory protein. Treatment of endometrial carcinoma cells with 5-azacytidine increased the expression of lipocalin2, suggesting the expression to be controlled by methylation of the promoter. The forced expression of lipocalin2 resulted in the enhanced cell proliferation and invasion in vitro. The expression of lipocalin2 increased with the endometrial carcinogenesis, and accumulation of the protein conferred biological aggressiveness to endometrial carcinoma cells. These results suggest lipocalin2 to be a novel target in the treatment of endometrial carcinoma.ArticleHUMAN PATHOLOGY. 42(9):1265-1274 (2011)journal articl

Molecular Approach to Uterine Leiomyosarcoma: LMP2-Deficient Mice as an Animal Model of Spontaneous Uterine Leiomyosarcoma

Uterine leiomyosarcoma (LMS) develops more often in the muscle tissue layer of the uterine body than in the uterine cervix. The development of gynecologic tumors is often correlated with female hormone secretion; however, the development of uterine LMS is not substantially correlated with hormonal conditions, and the risk factors are not yet known. Importantly, a diagnostic-biomarker which distinguishes malignant LMS from benign tumor leiomyoma (LMA) is yet to be established. Accordingly, it is necessary to analyze risk factors associated with uterine LMS, in order to establish a treatment method. LMP2-deficient mice spontaneously develop uterine LMS, with a disease prevalence of ~40% by 14 months of age. We found LMP2 expression to be absent in human LMS, but present in human LMA. Therefore, defective LMP2 expression may be one of the risk factors for LMS. LMP2 is a potential diagnostic-biomarker for uterine LMS, and may be targeted-molecule for a new therapeutic approach

Inverse correlation between Skp2 and p27(Kip1) in normal endometrium and endometrial carcinoma

Copyright (c) 2010 Taylor & Francis. This is an electronic version of an article published in "GYNECOLOGICAL ENDOCRINOLOGY, Volume 26, Issue 3, pages 220-229 (2010)". GYNECOLOGICAL ENDOCRINOLOGY is available online at: https://doi.org/10.3109/09513590903215482Cyclin-dependent-kinase (cdk) inhibitor, p27<SUKip1</SU (p27), has been shown to participate in progestin-induced growth suppression of normal endometrial glands. To analyse the molecular mechanisms regulating p27 protein, we examined immunohistochemical expression of the SCF<SUSkp2</SU (Skp1-Cullin-F-box protein) complex factors, i.e. Skp1, Cul1 and Skp2, and compared them with that of p27, steroid receptors and Ki-67. In normal endometrial glands, the expression of Skp2 was observed in the proliferative phase, whereas that of p27 was observed in the secretory phase. Cultured normal endometrial glandular cells showed that progesterone induced the down-regulation of Skp2 along with up-regulation of p27. In endometrial carcinomas, the inverse topological correlation between Skp2 and p27 was evident in 39/66 (59%) cases, and the expression of Skp2 showed a strong correlation with Ki-67. These findings suggest that the expression of SCF<SUSkp2</SU complex changes during the menstrual cycle in normal endometrium and the SCF<SUSkp2</SU ubiquitin-proteasome pathway may also work in endometrial carcinomas.</.ArticleGYNECOLOGICAL ENDOCRINOLOGY. 26(3):220-229 (2010)journal articl

Placental Mesenchymal Dysplasia: Chronological Observation of Placental Images during Gestation and Review of the Literature

Placental mesenchymal dysplasia (PMD) is characterized by multiple hypoechoic vesicles which are similar to molar changes in the placenta; however, the process of such morphological changes of PMD during pregnancy has not been fully understood. We performed a review of all PMD cases published in English and identified 49 articles including 110 cases. With regard to the gestational age at which the multicystic pattern was seen, approximately 70% of cases were diagnosed at 13-20 weeks of gestation. Another characteristic feature of PMD is varicose dilation of fetal chorionic vessels. As many as 90% of cases were diagnosed as placenta with dilated fetal chorionic vessels in the third trimester. We also report a case of PMD which was found at 10 weeks of gestation according to ultrasonic molar patterns. Serial observations of the placenta using ultrasound and magnetic resonance imaging revealed that multicystic lesions became smaller after 23 weeks. In contrast, dilated placental vessels on the fetal side became apparent at 38 weeks. The present review highlights that placental vesicular lesions of PMD may precede dilation of fetal chorionic vessels during pregnancy. It also indicates the potential of a gradual reduction in size of PMD's placental vesicular lesions by serial study of placental images.ArticleGYNECOLOGIC AND OBSTETRIC INVESTIGATION. 75(4):217-223 (2013)journal articl

A Case of Vaginal Varices that Caused Massive Bleeding after Vaginal Delivery

Article信州医学雑誌 64(1):35-39 (2016)journal articl

Fetal Goitrous Hypothyroidism due to Maternal Thyroid Stimulation-Blocking Antibody: A Case Report

Most fetal goitrous hypothyroidisms are reportedly caused by the maternal use of an antithyroid drug or fetal dyshormonogenesis. However, fetal goitrous hypothyroidism due to the transplacental passage of maternal thyroid stimulation-blocking antibody (TSBAb) is extremely rare. A woman at 28 weeks of gestation was found to have a fetal goiter by ultrasonography. Because the maternal serum showed hypothyroidism with an elevated titer of TSBAb, levothyroxine sodium was administered. The patient delivered a male infant, 3,412 g, with a goiter at term. Umbilical blood revealed primary hypothyroidism with increased TSBAb, and the infant was given levothyroxine sodium. After a month, neonatal thyroid function and TSBAb levels became normal. Attention should be paid to possible fetal hypothyroidism when a fetal goiter is observed to avoid impaired mental development of the neonate.ArticleFETAL DIAGNOSIS AND THERAPY. 28(4):220-224 (2010)journal articl