Benign Epithelial Ovarian Tumors Research Articles

Overexpression of follicle-stimulating hormone receptor facilitates the development of ovarian epithelial cancer

We previously showed that the expressing level of FSH receptor (FSHR) increased from ovarian epithelial inclusions (OEIs) to benign ovarian epithelial tumors (OETs) and to borderline OETs, whereas FSHR levels decreased with an increase in carcinoma grade. The aim of this study was to investigate the role of FSHR in OET development. MCV152 cells with FSHR overexpression showed an increased cellular proliferation and invasive capacity, which was associated with reduced levels of prohibitin and RII-β expression and increased levels of HER-2/neu, c-Myc, and EGFR expression. Overexpression of FSHR may be associated with an elevated level of OET cell proliferation via an enhanced activity of potential oncogenic pathways. Therefore, the findings in this study suggest that overexpression of FSHR may play a role in OET development.

Levels of Circulating Cell-Free Nuclear and Mitochondrial DNA in Benign and Malignant Ovarian Tumors

To analyze the levels of circulating cell-free nuclear DNA and circulating cell-free mitochondrial DNA in patients with benign and malignant ovarian tumors using a gold-standard assay and to investigate whether quantitative alterations of the circulating cell-free species have values in the management of the patients. One hundred four patients were recruited for this study. We developed a quantitative, multiplex polymerase chain reaction to measure the levels of circulating cell-free nuclear DNA and circulating cell-free mitochondrial DNA in serum and plasma of patients with epithelial ovarian cancer, benign epithelial ovarian tumors, or endometriosis. The levels of the circulating cell-free DNA were compared with those of a healthy, age-matched control group. The patients with epithelial ovarian cancer had significantly higher amounts of circulating cell-free nuclear DNA and circulating cell-free mitochondrial DNA in plasma compared with the healthy control group (mean of nuclear DNA 10,723/2,591 and mean of mitochondrial DNA 4,918,978/2,294,264, P=.009 and 0.022, respectively) and with the other group with benign ovarian diseases (mean of nuclear DNA 10,723/2,965 and mean of mitochondrial DNA 4,918,978/1,597,551, P=.027 and 0.002, respectively). However, no relationship between levels of the circulating cell-free DNA and the pathological parameters as well as CA 125 measurement in patients with epithelial ovarian cancer was found. A significant difference between the epithelial ovarian cancer and endometriosis group was found in circulating cell-free mitochondrial DNA but not in circulating cell-free nuclear DNA (mean of mitochondrial DNA 4,918,978/2,273,988 and mean of nuclear DNA 10,723/3,291, P=.013 and 0.105, respectively). Elevated levels of circulating cell-free nuclear DNA and circulating cell-free mitochondrial DNA in epithelial ovarian cancer may have diagnostic value. Our finding suggests that the circulating molecules might be potential biomarkers in the disease.

Dynamic contrast‐enhanced magnetic resonance imaging: A useful tool for characterizing ovarian epithelial tumors

To evaluate the utility of dynamic contrast enhancement (DCE) MRI for distinguishing among benign, borderline and invasive epithelial ovarian tumors. We analyzed preoperative MRI studies of 37 patients with ovarian epithelial tumors (10 benign, 11 borderline, and 16 invasive). A DCE-MRI sequence was acquired and regions of interest (ROIs) were drawn in the ovarian tumors and adjacent myometrium. A total of three patterns of enhancement were defined. Dynamic data were parameterized using mathematical models that included the enhancement amplitude (EA), the time of half rising (THR), and the maximal slope (MS). Using myometrium as the internal reference, ratios of EA (EAr), THR (THRr), MS (MSr), and initial area under the curve for 60 seconds after injection (IAUC(60) ratio) were determined. Morphological criteria such as septa, papillary projection, solid portion, and T2-weighted MR signal intensity of solid tissue were useful for discriminating invasive from noninvasive ovarian tumors (P = 0.01, P = 0.02, P = 0.002, and P < 0.0001 respectively) but not for discriminating benign from borderline tumors. Curve type 3 was specific for invasive ovarian tumors. EAr, MSr, and IAUC(60) ratio were higher for invasive than for benign (P < 0.0001) and borderline tumors (P = 0.005, P = 0.002, and P = 0.001, respectively). The IAU(60) ratio was the most relevant factor for discriminating benign from borderline and invasive tumors. MSr and IAU(60) ratio could be combined to generate a decision tree with 81% accuracy. DCE-MRI is a useful tool for characterizing epithelial ovarian tumors.

Serum insulin-like growth factor (IGF)-I, IGF binding protein (IGFBP)-3, leptin concentrations and insulin resistance in benign and malignant epithelial ovarian tumors in postmenopausal women

Aims. The aims of the present study were to determine the serum concentrations of insulin-like growth factor-I (IGF-I), insulin-like growth factor binding protein-3 (IGFBP-3) and leptin and insulin resistance in benign and malignant epithelial ovarian tumors, and to discuss the use of these markers in benign–malignant tumor differentiation.Methods. Forty-seven postmenopausal women with ovarian tumor and 31 age-matched, postmenopausal, healthy controls were included in this study. Insulin resistance index by homeostasis model assessment (HOMA score) and fasting blood glucose (FBG), serum IGF-I, IGFBP-3, leptin and CA-125 concentrations were determined in all patients preoperatively. The results were evaluated according to postoperative histopathology results.Results. According to postoperative histopathology results, the patients were divided into malignant (n = 23), benign (n = 24) and control (n = 31) groups. There were no differences among the groups in relation to age, body mass index, FBG and HOMA score (p > 0.05). Serum concentrations of CA-125 were elevated in the malignant group compared with the benign ovarian tumor and control groups (p < 0.05). In contrast, serum IGF-I concentrations were significantly decreased in patients with malignant and benign ovarian tumors compared with controls (p < 0.05). Serum IGFBP-3 concentrations were also found to be lower in women with malignant ovarian tumors than in women with benign tumors (p < 0.05). Serum leptin did not differ among patients with malignant–benign tumors and controls (p > 0.05).Conclusion. Serum leptin and HOMA score have not been found to be valid indicators in ovarian tumors. However, the present data suggest that low concentrations of IGF-I and IGFBP-3 could be a reliable marker to differentiate benign from malignant ovarian tumors. Further experimental studies are warranted to understand the impact of the IGF-I system in ovarian carcinogenesis.

Total Inhibin is a Potential Serum Marker for Epithelial Ovarian Cancer

Inhibins A and B are glycoproteins released by the human ovary. Levels of both forms become nondetectable, or nearly so, following menopause, but some ovarian tumors produce inhibin even in postmenopausal women. This controlled cross-sectional study evaluated a new immunoenzymatic assay for total inhibin, which detects both free inhibin α-subunit and inhibin dimers, as a tumor marker in women with epithelial ovarian cancers. Serum samples were taken from 4 groups of postmenopausal women: 89 with stage II–III epithelial ovarian cancers; 25 with benign epithelial ovarian tumors; 10 with cancer of the breast, colon, or stomach; and 95 normal control subjects. The epithelial ovarian cancers included 40 serous, 17 mucinous, 10 endometrioid, and 22 clear-cell adenocarcinomatous tumors. In addition to total inhibin, the samples were analyzed by enzyme-immunoassay for cancer antigen 125 (CA-125). The median serum total inhibin in women with epithelial ovarian cancer was 189 pg/mL, significantly higher than in all other groups. Levels were highest in patients having serous or mucinous tumors. Levels of CA-125 were significantly higher in women with epithelial ovarian cancers than in control subjects. Assay results were consistently improved by combining total inhibin and CA-125 levels. Compared to using a single marker, the rate of detection of clear-cell adenocarcinomas increased from 59%–68% to 96%. At 95% specificity, the total inhibin assay detected 93% of serous tumors and 94% of mucinous tumors. Combining both assays, again at 95% specificity, all serous and mucinous tumors were detected, and the overall sensitivity for epithelial ovarian cancers was 99%. Total inhibin levels declined significantly after serous or mucinous cancers were treated surgically. In 4 women with mucinous epithelial ovarian cancers who were followed up, total inhibin levels increased when disease recurred and decreased significantly after surgical treatment. The immunoenzymatic assay for total serum inhibin is a sensitive and specific marker of epithelial ovarian cancers in postmenopausal women. Optimal results are obtained by combining inhibin levels with those of CA-125. In addition to its diagnostic role, monitoring serum inhibin levels may be a useful means of detecting recurrent disease in treated patients.

Peritoneal Fluid Cytokines and the Differential Diagnosis of Benign and Malignant Ovarian Tumors and Residual/Recurrent Disease Examination

This study aimed to assess the potential value of peritoneal fluid cytokine examination for the differential diagnosis of ovarian tumors and for evaluating residual or recurrent disease after treatment. The cytokines that are commonly elevated in ovarian cancer, VEGF, IL-6, bFGF, IL-8 and M-CSF, and a reference ovarian tumor marker, CA 125, were measured in peritoneal fluids of 53 previously untreated patients with epithelial ovarian cancer, 18 ovarian cancer patients after surgical treatment and chemotherapy, and 17 patients with benign epithelial ovarian tumors. Non-parametric statistical analysis of data was performed. Ovarian cancer peritoneal fluids, as compared to peritoneal fluids of patients with benign ovarian tumors, contained significantly higher concentrations of IL-6, VEGF and CA 125, and significantly lower concentrations of bFGF and M-CSF, but only the levels of IL-6 and VEGF were significantly higher in peritoneal fluids of stage I and II ovarian cancer patients than of patients with benign ovarian conditions. IL-6 at the cutoff level of 400 pg/mL discriminated benign and malignant ovarian tumors with 92% sensitivity and 60% specificity, while VEGF at the cutoff of 400 pg/mL had 90% sensitivity and 80% specificity. At the cutoff level of 1200 pg/mL, IL-6 had 84% sensitivity and 87% specificity. A radical decrease in local cytokine and CA 125 levels in patients after treatment was independent of therapy outcome. IL-6 and VEGF measurements in peritoneal fluids might be useful for the differential diagnosis of malignant and benign ovarian conditions, but not for residual or recurrent disease examination.

Risk Factors for Benign Serous and Mucinous Epithelial Ovarian Tumors

To investigate the risk factors for benign serous and mucinous epithelial ovarian tumors. Cases were women newly diagnosed with benign serous ovarian tumors (n=230) or benign mucinous tumors (n=133) between 2002 and 2005. Control women were selected at random from the general population (n=752). All participants completed a comprehensive reproductive and lifestyle questionnaire. Multivariable logistic regression was used to calculate odds ratios (ORs) and 95% confidence intervals (CIs) and to simultaneously adjust for potential confounding factors. Current smoking was associated with a three-fold increase in risk of benign mucinous tumors (OR 3.25, 95% CI 1.97-5.34), and there was a trend of increasing risk with increasing amount smoked (P<.001). Both recent obesity (OR 1.93, 95% CI 1.30-2.88) and obesity at age 20 (OR 4.38, 95% CI 1.88-10.20) were associated with increased risk of benign serous ovarian tumors, and having had a hysterectomy was also related to increased risk of serous (OR 2.75, 95% CI 1.90-3.96), but not mucinous tumors. Ever having had a term pregnancy was inversely associated with both tumor types (combined OR 0.65, 95% CI 0.43-0.97), although greater numbers of pregnancies did not decrease risk further. Use of hormonal contraceptives was unrelated to risk. Our results suggest some differences in risk factors between benign serous and mucinous epithelial ovarian tumors and that risk factors for benign serous tumors differ from those well established for ovarian cancer. The results also suggest that there is potential for prevention of these common conditions through avoidance of smoking and obesity. II.

Peritoneal fluid cytokines and the differential diagnosis of benign and malignant ovarian tumors and residual/recurrent disease examination

This study aimed to assess the potential value of peritoneal fluid cytokine examination for the differential diagnosis of ovarian tumors and for evaluating residual or recurrent disease after treatment. The cytokines that are commonly elevated in ovarian cancer, VEGF, IL-6, bFGF, IL-8 and M-CSF, and a reference ovarian tumor marker, CA 125, were measured in peritoneal fluids of 53 previously untreated patients with epithelial ovarian cancer, 18 ovarian cancer patients after surgical treatment and chemotherapy, and 17 patients with benign epithelial ovarian tumors. Non-parametric statistical analysis of data was performed. Ovarian cancer peritoneal fluids, as compared to peritoneal fluids of patients with benign ovarian tumors, contained significantly higher concentrations of IL-6, VEGF and CA 125, and significantly lower concentrations of bFGF and M-CSF, but only the levels of IL-6 and VEGF were significantly higher in peritoneal fluids of stage I and II ovarian cancer patients than of patients with benign ovarian conditions. IL-6 at the cutoff level of 400 pg/mL discriminated benign and malignant ovarian tumors with 92% sensitivity and 60% specificity, while VEGF at the cutoff of 400 pg/mL had 90% sensitivity and 80% specificity. At the cutoff level of 1200 pg/mL, IL-6 had 84% sensitivity and 87% specificity. A radical decrease in local cytokine and CA 125 levels in patients after treatment was independent of therapy outcome. IL-6 and VEGF measurements in peritoneal fluids might be useful for the differential diagnosis of malignant and benign ovarian conditions, but not for residual or recurrent disease examination.

Clinical Significance of Expression of CD44v6 and LYVE-1 in Epithelial Ovarian Tumor

Objective To determine the expression of CD44v6 and LYVE-1 in epithelial ovarian tumor and its clinical significance.Methods The expression of CD44v6 and LYVE-1 was examined by immunohistochemical streptravidin-biothin peroxidase(SP) assay.The correlation between their expression and the clinicopathological features was analyzed.Results The expression of CD44v6 and LYVE-1 increased significantly in ovarian epithelial cancer compared to that in benign ovarian epithelial tumors and normal ovarian tissues.The expression of CD44v6 was positively associated with the FIGO stages and WHO grades of the patients with ovarian epithelial cancer.The expression of LYVE-1 was significantly related to the stages.The expression of CD44v6 and LYVE-1 was significantly associated with lymph node status.There was statistically significant correlation between CD44v6 and LYVE-1.Conclusion CD44v6 and LYVE-1 played certain roles in oncogenesis,progression and lymphatic metastasis of ovarian cancer.

Expression of Claudins 1, 4, 5, and 7 in Ovarian Tumors of Diverse Types

In this study, 60 different types of ovarian lesions, mainly consisting of ovarian neoplasms, were studied for the expression of claudins 1, 4, 5, and 7. Strong expression of claudins 1, 4, and 7 was seen in benign and malignant epithelial ovarian tumors. Expression of claudin 5, reported to be mainly present in endothelial cells, was seen in ovarian epithelial tumors, but with a significantly lower frequency than claudins 1, 4, and 7. On the contrary, sex-cord stromal tumors and cysts, such as fibromas/thecomas, Sertoli-Leydig cell tumors, granulosa cell tumors, and follicular and luteinized cysts were mainly negative for claudins 1, 4, 5, and 7. Interestingly, adenomatoid tumors did not express claudin 5, which is in agreement with their non-endothelial nature. They were also negative for claudin 4, but expressed claudins 1 and 7, but to a lesser degree than epithelial lesions. In immature teratomas, the epithelial component was usually positive whereas other components were negative for these claudins. Dysgerminomas did not express any of the claudins studied. The results show that claudins 1, 4, and 7 are mainly expressed in ovarian epithelial tumors and can thus be used to indicate epithelial differentiation in them. Eventhough considered an endothelial marker, claudin 5 was also present in a subset of epithelial lesions. However, this claudin can be used to differentiate adenomatoid tumors from vascular lesions. No significant difference was seen between epithelial benign and malignant lesions, except for claudin 5, which seemed stronger in malignant epithelial tumors.

Benign Epithelial Ovarian Tumours—cancer Precursors or Markers for Ovarian Cancer Risk?

The natural history of the development of epithelial ovarian cancer remains obscure and no effective screening test exists. In several human malignancies progression from benign to invasive tumour occurs, but this sequence has not been established for epithelial ovarian cancer. We have reviewed epidemiological, histopathological and molecular studies of benign epithelial ovarian tumours to assess the evidence for and against such a progression in ovarian cancer. These data suggest that a diagnosis of a benign ovarian cyst or tumour is associated with an increased risk of ovarian cancer later in life. Current evidence also suggests that benign serous tumours can progress to low-grade serous cancer and that benign mucinous tumours can progress to mucinous cancer. The more common high-grade serous ovarian cancers are likely to arise de novo.

Ephrin B expression in epithelial ovarian neoplasms correlates with tumor differentiation and angiogenesis

Differential gene expression studies are identifying new sets of genes with a role in the classification, differential diagnosis, and prognosis of some human tumors. Ephrin B1, a factor involved in angiogenesis, has been shown to be up-regulated in ovarian carcinomas, making it a potential target for cancer treatment. This study investigates ephrin B expression in ovarian tumors to validate results from gene expression studies and evaluates its significance with a clinical-pathological correlation. Specimens from 112 benign, borderline, and malignant epithelial ovarian tumors were examined. Tissue microarrays were constructed, and ephrin B expression was studied by immunohistochemistry. To correlate ephrin B expression with angiogenesis, CD31 immunostaining was performed to assess microvessel density. Ephrin B was detected in 50% of ovarian tumors: clear cell carcinomas (93%), serous carcinomas (74%), mucinous carcinomas (29%), and endometrioid carcinomas (27%). High-grade carcinomas showed greatest ephrin B expression, whereas benign tumors and low-grade carcinomas were rarely positive. A correlation was found between ephrin B expression and microvessel density, supporting the angiogenic role of this factor in ovarian carcinomas. Ephrin B expression was associated with higher rates of disease recurrence and a decrease in overall survival. A distinctive pattern of ephrin B expression was observed in ovarian tumors: high-grade tumors and clear cell and serous carcinomas show higher expression, correlating with the aggressiveness. On the other hand, ephrin B expression correlated with microvessel density of the tumors. Because Eph receptors and ephrins are targets for new therapeutic inhibitors, this pattern of ephrin B expression should be considered in future clinical studies.

Clinicopathological study of metallothionein immunohistochemical expression, in benign, borderline and malignant ovarian epithelial tumors.

Metallothioneins (MTs) are a family of cystein-rich metal-binding proteins, which are expressed in normal cells during fetal and postnatal life but also in a variety of human neoplasms. MT expression in human tumors has been linked to resistance to anticancer drugs and differentiation and progression in some types of tumors. This study examined the immunohistochemical expression of MTs in benign, borderline and malignant tumors of ovarian surface epithelium and the possible correlations with clinicopathological parameters and survival. A total of 87 cases with diagnosis of ovarian surface epithelial tumors were included. Specifically, 21 cases of benign cystadenomas (11 serous and 10 mucinous), 14 borderline (low malignant potential tumors, 8 mucinous and 6 serous) and 52 cases of ovarian cancer were analysed. Immunohistochemical expression of MT (cut-off level > 10% of tumor cells) was clearly associated with malignancy. A statistically significant correlation was found between the expression of MT in cancer cases and benign tumors (p < 0.0001) and cancer cases and borderline tumors p = 0.003. In cancer cases a difference was observed between grade I and III (p = 0.002). There was no correlation of MT overexpression with survival in the small number of ovarian carcinoma patients where it was analysed. MT constitutes a marker that characterizes aggressiveness and a high malignant potential in ovarian epithelial tumors. In diagnostic problems MT may help distinguish between benign, borderline and malignant tumors.

P63 expression in epithelial ovarian tumors

Ovarian cancer is a highly lethal disease and its underlying biology is poorly understood. The p63 is a homologue gene of the tumor suppressor p53. p63 appears to be important for the development and differentiation of reproductive epithelium and interacts with p53 in human tumorigenesis. This study presents the immunoexpression of the p63 in benign and malignant epithelial ovarian tumors. We evaluated the p63 immunoexpression in 91 ovarian benign cystadenomas (29 mucinous and 62 serous) and in 29 ovarian malignant tumors (3 mucinous borderline, 3 serous borderline, 17 serous carcinomas, 2 endometrioid, 2 undifferentiated, 1 mucinous, and 1 clear-cell carcinoma) using a monoclonal antibody clone 4A4 (1:200), which recognizes all p63 variants. The tumors were considered p63 positive if 5% or more cells presented nuclear immunostaining. We observed 85.7% of positivity in benign tumors, 50% in borderline tumors, and 8.7% in invasive ovarian cancer (P < .0001). The benign serous cystadenomas were positive in 91.9% of cases and benign mucinous cystadenomas in 72.4% (P= .02). These data suggests an important role of p63 in the control of ovarian epithelium behavior. The p63 may be involved in the development of benign and malignant epithelial ovarian tumors.

Diagnostic approach using the expression profiling of the P53 tumor suppressor gene and its related proteins in ovarian epithelial tumors

The initial aim of this study was to examine the expression profiles of P53 and its upstream genes, downstream genes, and cell cycle regulators to determine whether these markers are useful for making a differential diagnosis among the benign, borderline, and malignant ovarian epithelial tumors. Between borderline and malignant tumors, the increased expression levels of P53, Bax, Cyclin E, and cyclin-dependent kinase-2 as well as the decreased expression levels of growth arrest and DNA damage (GADD45) and murine double minute-2 (MDM2) were significantly associated with malignancy (P < 0.01, each). Using the receiver operating curve (ROC), the most reliable cutoff value of the added-up staining scores of those markers was 4.5 with 79% sensitivity and 89% specificity for malignancy. Between benign and borderline tumors, the P21 and Bax expression levels were significantly higher in borderline tumors, whereas the Bcl-2 expression level was much higher in benign tumors (P < 0.01, each). Using the ROC, the cutoff value of the added-up staining scores used to discriminate between the two groups was 2.5 with 70% sensitivity and 74% specificity for borderline tumors. Thus, for the differential diagnosis between borderline and malignant tumors, the cutoff value 4.5 of the cumulative staining scores can be used. However, the cutoff value 2.5 for discrimination between benign and borderline tumors may not be useful because of its relatively low sensitivity and specificity. In addition, the P53, GADD45, Cyclin E, and MDM2 expression levels in malignant ovarian tumors might be useful for determining the histologic grade and type.

Diagnostic approach using the expression profiling of the P53 tumor suppressor gene and its related proteins in ovarian epithelial tumors

The initial aim of this study was to examine the expression profiles of P53 and its upstream genes, downstream genes, and cell cycle regulators to determine whether these markers are useful for making a differential diagnosis among the benign, borderline, and malignant ovarian epithelial tumors. Between borderline and malignant tumors, the increased expression levels of P53, Bax, Cyclin E, and cyclin-dependent kinase-2 as well as the decreased expression levels of growth arrest and DNA damage (GADD45) and murine double minute-2 (MDM2) were significantly associated with malignancy (P&lt; 0.01, each). Using the receiver operating curve (ROC), the most reliable cutoff value of the added-up staining scores of those markers was 4.5 with 79% sensitivity and 89% specificity for malignancy. Between benign and borderline tumors, the P21 and Bax expression levels were significantly higher in borderline tumors, whereas the Bcl-2 expression level was much higher in benign tumors (P&lt; 0.01, each). Using the ROC, the cutoff value of the added-up staining scores used to discriminate between the two groups was 2.5 with 70% sensitivity and 74% specificity for borderline tumors. Thus, for the differential diagnosis between borderline and malignant tumors, the cutoff value 4.5 of the cumulative staining scores can be used. However, the cutoff value 2.5 for discrimination between benign and borderline tumors may not be useful because of its relatively low sensitivity and specificity. In addition, the P53, GADD45, Cyclin E, and MDM2 expression levels in malignant ovarian tumors might be useful for determining the histologic grade and type.

Papillary serous carcinoma of the ovary: an ultrastructural and immunohistochemical study.

Twenty-four patients with ovarian serous papillary carcinoma were enrolled in the present ultrastructural and immunohistochemical study. Immunohistochemistry was used to examine the status of proliferation activity with antibodies against Ki67 and BM28, and the status of EGFR family members with antibodies against EGFR, c-erbB-2, and c-erbB-4. Ultrastructurally, poorly differentiated tumors often revealed solid sheets of tumor cells with variable desmosomes, cell connection complexies, and microvilli. No mature cilia, which are often present in benign and borderline ovarian epithelial tumors, were seen in these 24 carcinomas. However, two poorly differentiated tumors demonstrated oligocilia. In addition, numerous secondary lysosomes and bizzare intracytoplasmic pseudocavities were more often present in the poorly differentiated tumors. Immunohistochemically, strong expressions of BM28 and Ki67 in more than 50% of the tumor cells were found in 12/15 (80%) and 11/15 (73%) of the poorly differentiated tumors, respectively, compared with 3/9 (33%) and 1/9 (11%) of the moderately differentiated tumors, respectively. Higher levels of EGFR and c-erbB-2 expressions were more often observed in the poorly differentiated tumors, compared with that in the moderately differentiated tumors. In conclusion, oligocilium, numerous secondary lysosomes, and bizarre intracytoplasmic inclusions are more often seen in poorly differentiated ovarian serous carcinomas. Poorly differentiated ovarian serous carcinomas express higher levels of Ki67, BM28, EGFR, and c-erbB-2 proteins.

CA 125 and Vascular Endothelial Growth Factor in the Differential Diagnosis of Epithelial Ovarian Tumors

Tumor markers have been investigated in differentiation of benign and malignant tumors. We analyzed CA 125 and vascular endothelial growth factor (VEGF) levels in serum and cyst fluid in patients with epithelial ovarian tumors. Serum and tumor cyst fluid of 50 patients with ovarian epithelial tumors (7 malignant, 3 bordeline and 40 benign) were assayed for VEGF by ELISA and CA 125 levels by chemoluminescence. CA 125 serum levels were significantly higher in patients with malignant and borderline tumors than in patients with benign cysts (p = 0.0005). CA 125 cyst fluid contents were comparable for malignant, borderline and benign ovarian tumors (p = 0.39). Significantly higher levels of VEGF were present in cyst fluid for malignant and borderline tumors compared with benign cysts (p < 0.0001); however, serum levels of VEGF were similar among all patients (p = 0.25). The CA 125 serum levels correlated with matched VEGF cyst fluid levels (r = 0.44, p = 0.0015). Serum CA 125 and cystic VEGF were good methods to differentiate benign and malignant epithelial ovarian tumors. Patients with elevated intracystic VEGF levels presented significantly higher CA 125 serum levels, although the CA 125 intracystic content overlapped. The angiogenesis and enhancement of vascular permeability induced by VEGF represents a new hypothesis for the release of the CA 125 antigen into the circulation in patients with ovarian epithelial neoplasm.

Different imprinting status of IGF-2 in epithelial ovarian tumors.

To explore whether the imprinting status of IGF-2 in the malignant epithelial ovarian tumors is different from that in benign tumors, the target sequences (DNA and RNA) which contain a polymorphism site for ApaI restriction endonuclease digestion were amplified with PCR and RT-PCR methods. Then the PCR/RT-PCR products were digested by ApaI. The IGF-2 transcriptional pattern came out from the results of endonucleases digestion. Among the 36 cases of benign epithelial ovarian tumors, 20 were heterozygous for ApaI locus and all showed genomic imprinting. While in the malignant group, 22 were heterozygous for ApaI locus but six were found to lose imprinting. Significant differences existed between the two groups (P < 0.05). Loss of imprinting of IGF-2 may serve as a marker for differentiating the malignant ovarian cancers from the benign ones. In a new field of molecular genetics, our research provides an experimental basis for genetic diagnosis and treatment of the ovarian cancers.

Effect of Reproductive Hormones on Ovarian Epithelial Tumors: I. Effect

We examined the effects of the 4 major female reproductive hormones, estradiol (E2), progesterone (P4), follicle stimulating hormone (FSH), and luteinizing hormone (LH) on thymidine incorporation in benign and malignant ovarian epithelial tumors cultured in vitro. Treatment of these tumors with E2, FSH and LH resulted in increased thymidine incorporation while treatment with P4 inhibited growth as well as thymidine incorporation. The inhibitory effect of progesterone could not be reproduced by treating the cells with ligands for other steroid hormone receptors known to interact with P4 such as the mineralocorticoid and glucocorticoid receptors. All cells lines expressed at least the PR-A isoform of the progesterone receptor. ORG2058, R5020, RU486, and ZK98299 acted as progesterone receptor agonists with regard to their effect on thymidine incorporation. P4 down-regulated cyclin B1 expression and cdk1 activity and up-regulated the p21 and p27 proteins. Expression of a reporter gene downstream to an AP-1 responsive element in a plasmid construct transfected into ovarian epithelial tumor cells was induced by P4 and inhibited by RU486. We conclude that P4 inhibits cell cycle activity in ovarian epithelial tumors, in part via down-regulation of the cdk1/cyclin B complex. This inhibitory effect may have therapeutic utility against ovarian epithelial tumors.