Paratubal borderline tumor incidentally found during cesarean section: case report and review of literature.

Diagnosis of a gynecologic malignancy during cesarean section is quite rare. We report a case of a 39-year-old, nulliparous woman who underwent elective cesarean section during which a paratubal cyst was noticed and removed. The pathology revealed serous borderline tumor. Subsequent staging laparotomy was done 23 days after cesarean section. She was diagnosed with stage IC paratubal serous borderline tumor and underwent no further therapy. For the time being 15 months have passed from the staging laparotomy and she is currently free of disease recurrence. This case presented the importance of the evaluation of adnexa during cesarean section together with a short review of the literature on the rare paratubal borderline tumors and the role of fertility-sparing, conservative surgery in their management.

Expression of cyclooxygenase-2 in endometrial adenocarcinoma.

Studies have shown that COX-2 is up-regulated in several epithelial carcinomas. In this study, we wish to elucidate if endometrial cyclooxygenase-2 (COX-2) expression in endometrial adenocarcinoma is increased relative to normal endometrium. Thirty-six deparaffinized tissue sections from patients with endometrial adenocarcinoma were analyzed by immunohistochemistry for the presence of COX-2. A control group consisted of 13 age-matched patients without malignancy, who underwent surgery for uterine prolapse. Statistical analysis was performed using the Kruskal-Wallis test; differences between groups were evaluated using the Fisher's Exact Test. We found that COX-2 expression was markedly increased in 13 of 36 patients (36.1%) with endometrial adenocarcinoma: in contrast only one of 13 (7.7%) control patients demonstrated increased COX-2 expression (p < or = 0.05). Eight of the 13 COX-2 positive patients in the study had well differentiated adenocarcinoma; the remaining five COX-2 positive patients had moderately and poorly differentiated adenocarcinoma (4 and 1, respectively). In conclusion, COX-2 expression in the endometrium is associated with endometrial adenocarcinoma, especially of the well differentiated type. This may provide an avenue for chemoprevention of endometrial adenocarcinoma. In addition, with new selective inhibitory drugs being developed, inhibition of COX-2 may play an adjunctive role approach to standard therapy, especially for well-differentiated endometrial carcinoma. Further studies are required to investigate the role of COX-2 expression in carcinogenesis.

Induction of cyclooxygenase-2 in human endometrial stromal cells by malignant endometrial epithelial cells: evidence for the involvement of extracellularly regulated kinases and CCAAT/enhancer binding proteins.

We previously reported that human malignant endometrial epithelial cell conditioned medium (MECM) up-regulated cyclooxygenase (COX)-2 mRNA and protein levels in human normal endometrial stromal cells (ESC). Here we showed that pretreatment with a selective inhibitor of the extracellularly regulated kinase (ERK)1/2 signaling pathway blocked the MECM-induced COX-2 expression in ESC. Transient transfection assays indicated critical roles of a cAMP response element (CRE,-59/-53 bp) and a nuclear factor for interleukin (IL)-6 expression (NF-IL6) site (-132/-124 bp) in the regulation of basal and MECM-induced activity of COX-2 gene promoter in ESC. Employing electrophoretic mobility shift assays, we demonstrated that increased functional binding of CCAAT/enhancer binding protein (C/EBP)alpha, C/EBPbeta and upstream stimulatory factor-2 to the CRE and C/EBPalpha and C/EBPbeta to the NF-IL6 site were, at least in part, responsible for MECM-induced COX-2 expression in ESC. Moreover, overexpression of C/EBPalpha and C/EBPbeta significantly induced COX-2 promoter activity in ESC. Collectively, these results suggest that the basal and MECM-induced transcription of the COX-2 gene in ESC is regulated through a combination of the CRE and the NF-IL6 site by functional interactions of C/EBPalpha and C/EBPbeta.

Stromal PRs mediate induction of 17beta-hydroxysteroid dehydrogenase type 2 expression in human endometrial epithelium: a paracrine mechanism for inactivation of E2.

Progesterone stimulates the expression of 17beta-hydroxysteroid dehydrogenase (HSD) type 2, which catalyzes the conversion of the potent estrogen, E2, to an inactive form, estrone, in epithelial cells of human endometrial tissue. Various effects of progesterone on uterine epithelium have recently been shown to be mediated by stromal PRs in mice. We describe herein a critical paracrine mechanism whereby progesterone induction of 17beta-HSD type 2 enzyme activity, transcript levels, and promoter activity in human endometrial epithelial cells are mediated primarily by PR in endometrial stromal cells. Medium conditioned with progestin-pretreated human endometrial stromal cells robustly increased 17beta-HSD type 2 enzyme activity (2-fold) and mRNA levels (13.2-fold) in Ishikawa malignant endometrial epithelial cells. In contrast, direct progestin treatment of Ishikawa epithelial cells gave rise to much smaller increases in enzyme activity (1.2-fold) and mRNA levels (4-fold). These results suggest that progesterone- dependent paracrine factors arising from stromal cells are primarily responsible for the induction of epithelial 17beta-HSD type 2 expression in the endometrium. We transfected serial deletion mutants of the -1,244 bp 5'-flanking region of the 17beta-HSD type 2 gene into Ishikawa cells. No progesterone response elements could be identified upstream of the 17beta-HSD type 2 promoter. Stromal PR-dependent induction of the 17beta-HSD type 2 promoter was mediated by a critical regulatory region mapped to the -200/-100 bp sequence. Direct treatment of Ishikawa cells with progestin gave rise to a maximal increase in the activity of -200 bp/Luciferase construct only by 1.2-fold, whereas medium conditioned by progestin-pretreated endometrial stromal cells increased promoter activity up to 2.4-fold in a time- and concentration-dependent manner. The stimulatory effect of medium conditioned by progestin-pretreated stromal cells was enhanced strikingly by increasing stromal cell PR levels with the addition of estrogen. This epithelial-stromal interaction was specific for endometrial epithelial cells, since 17beta-HSD type 2 could not be induced in malignant breast epithelial cells by media conditioned with progestin-treated breast or endometrial stromal cells. In conclusion, progesterone regulates the conversion of biologically active E2 to estrone by inducing the 17beta-HSD type 2 enzyme in human endometrial epithelium primarily via PR in stromal cells, which secrete factors that induce transcription mediated primarily by the -200/-100 bp 5'-regulatory region of the 17beta-HSD type 2 promoter.

Malignant breast epithelial cells stimulate aromatase expression via promoter II in human adipose fibroblasts: an epithelial-stromal interaction in breast tumors mediated by CCAAT/enhancer binding protein beta.

Expression of aromatase P450 (P450arom), which catalyzes the formation of estrogens, is aberrantly increased in adipose fibroblasts surrounding breast carcinomas, giving rise to proliferation of malignant cells. Aromatase in human adipose tissue is primarily expressed in undifferentiated fibroblasts under the control of several distinct and alternatively used P450arom promoters. In tumor-free breast adipose tissue, P450arom is usually expressed at low levels via a distal promoter (I.4), whereas in the breast adipose tissue bearing a tumor, P450arom is increased through the activation of two proximal promoters, II and I.3. Because the in vivo activation of P450arom promoter II is a key event responsible for aberrantly high P450arom expression in breast tumors, we studied the molecular basis for the enhancement of P450arom promoter II using human adipose fibroblasts (HAFs) in primary culture treated with T47D breast cancer cell-conditioned medium (TCM) as a model system. Upon treatment with TCM, HAFs displayed a striking induction of P450arom mRNA levels via promoter II usage. This effect appeared to be specific for malignant breast epithelial cells, because conditioned media from breast cancer cell lines T47D and MCF-7 induced promoter II activity, whereas normal breast epithelial cells or liver or prostate cancer cell lines did not produce such an effect. Although treatment with a cyclic AMP analogue also caused a switch in the promoter use from I.4 to II in cultured HAFs, TCM-induced promoter II use was found to be mediated via a cyclic AMP-independent pathway. Use of serial deletion mutants of the promoter II 5'-flanking sequence revealed the presence of critical cis-acting elements in the -517/-278 bp region, which regulate the baseline activity. TCM caused a 5.7-fold induction of the -517-bp promoter II construct, whereas site-directed mutagenesis of a CCAAT/enhancer binding protein (C/EBP) binding site (-317/-304 bp) abolished both baseline and TCM-induced activities. Ectopic expressions of C/EBPalpha and C/EBPbeta, but not C/EBPdelta, significantly induced promoter II activity. Moreover, we demonstrated the presence of both C/EBPbeta and C/EBPdelta but not C/EBPalpha in a DNA-protein complex formed by the nuclear extract from TCM-treated HAFs and a probe containing this critical C/EBP binding element (-317/-304 bp). Finally, treatment of HAFs with TCM strikingly induced C/EBPbeta expression, whereas this did not affect the levels of C/EBPalpha or C/EBPdelta transcripts. In conclusion, malignant breast epithelial cells secrete factors, which induce aromatase expression in adipose fibroblasts via promoter II. This is, at least in part, mediated by a TCM-induced up-regulation and enhanced binding of C/EBPbeta to a promoter II regulatory element.

Role of aromatase in endometrial disease.

Aromatase is the key enzyme for estrogen biosynthesis. It is normally expressed in the human ovary, skin, adipose tissue and brain. Aromatase activity is not detectable in normal endometrium. In contrast, aromatase is expressed aberrantly in endometriosis and is stimulated by PGE2. This results in local production of estrogen, which induces PGE2 formation and establishes a positive feedback cycle. Another abnormality in endometriosis, i.e. deficient 17beta-hydroxysteroid dehydrogenase (17beta-HSD) type 2 expression, impairs the inactivation of estradiol to estrone. These molecular aberrations collectively favor accumulation of increasing quantities of estradiol and PGE2 in endometriosis. The clinical relevance of these findings was exemplified by the successful treatment of an unusually aggressive case of post-menopausal endometriosis using an aromatase inhibitor.

Presacral solitary giant neurofibroma without neurofibromatosis type 1 presenting as pelvic mass--case report.

A 35-year-old woman presented with a solitary neurofibroma in an unusual presacral location without neurofibromatosis manifesting as bilateral chronic sciatica for 2 years. She was initially considered as having a giant right ovarian mass, but was referred with a prediagnosis of solitary giant sacral nerve sheath tumor. The initial differential diagnosis was based on neuroimaging. A right-sided J incision with the extraperitoneal approach provided good exposure and handling of the tumor bed. Almost total excision without neurological deficit was possible. The histological diagnosis was neurofibroma. Benign retroperitoneal neural sheath tumors in patients without von Recklinghausen's disease are quite rare. Intrapelvic tumors are often diagnosed at a later stage. Neuroimaging is very helpful to delineate this unusual site and the extent of tumor development, and to determine the appropriate surgical intervention. A clear understanding of retroperitoneal anatomy is essential for safe removal of such tumors. Complete resection is preferred to prevent local recurrence and malignant transformation. Although root section is inevitable, neurological deficit is unlikely.