Ovarian Clear Cell Adenocarcinoma Patients Research Articles

Napsin A is a specific marker for ovarian clear cell adenocarcinoma

Ovarian clear cell adenocarcinoma has a relatively poor prognosis among the ovarian cancer subtypes because of its high chemoresistance. Differential diagnosis of clear cell adenocarcinoma from other ovarian surface epithelial tumors is important for its treatment. Napsin A is a known diagnostic marker for lung adenocarcinoma, and expression of napsin A is reported in a certain portion of thyroid and renal carcinomas. However, napsin A expression in ovarian surface epithelial tumors has not previously been examined. In this study, immunohistochemical analysis revealed that in 71 of 86 ovarian clear cell adenocarcinoma patients (83%) and all of the 13 patients with ovarian clear cell adenofibroma, positive napsin A staining was evident. No expression was observed in 30 serous adenocarcinomas, 11 serous adenomas or borderline tumors, 19 endometrioid adenocarcinomas, 22 mucinous adenomas or borderline tumors, 10 mucinous adenocarcinomas, or 3 yolk sac tumors of the ovary. Furthermore, expression of napsin A was not observed in the normal surface epithelium of the ovary, epithelia of the fallopian tubes, squamous epithelium, endocervical epithelium, or the endometrium of the uterus. Therefore, we propose that napsin A is another sensitive and specific marker for distinguishing ovarian clear cell tumors (especially adenocarcinomas) from other ovarian tumors.

Clinical features and drug resistance characteristics of ovarian clear cell adenocarcinoma and analysis of its prognostic factors

To investigate the clinical features and factors involved in the drug resistance and prognosis of ovarian clear cell adenocarcinoma (OCCA). Forty-seven OCCA patients and 53 ovarian serous cyst adenocarcinoma (OSCA) patients were included in this study. Their clinical characteristics, drug resistance, and prognostic factors were analyzed. The onset age of OCCA was (49.09 + 11.80) years old, and that of OSCA was (55.51 + 1.38) year old. There were 53.3% (24/45) of OCCA and 98.0% (50/51) of OSCA patients who had elevated CA125 levels. There were 46.8% (22/47) of OCCA patients and 7.5% (4/53) of OSCA patients who suffered from endometriosis (EMS). The percentage of early stage (stage I and stage II) OCCA was 80.9% (38/47), and that of OSCA was 11.3% (6/53). A statistically significant difference was observed on all these aspects (P < 0.05). The percentage of drug resistant OCCA was 26.1% (12/46), and that of OSCA was 24.0% (12/50), with a non-significant difference (P = 0.814).Among the patients with advanced stage disease, the percentage of drug resistance was 87.5% (7/8) for OCCA, while that of OSCA was 25.0% (11/44), showing a statistically significant difference (P = 0.003). Multiple logistic regression analysis revealed that OCCA (OR = 21.774, 95%CI: 2.438 to 194.431) and advanced stage (OR = 58.329, 95%CI: 5.750 to 591.703) were independent risk factors of drug resistance in ovarian epithelial cancers. For the advanced stage patients, the median overall survival time of OCCA and OSCA were 11 and 29 months, respectively, with a statistically significant difference (P = 0.000). Cox survival analysis showed that OCCA, advanced stage, suboptimal surgery, fewer than 6 cycles of chemotherapy and drug resistance were all risk factors of OS in ovarian cancer patients (P < 0.05). The age of onset in OCCA patients is younger than that of OSCA patients. The proportion of combination with endometriosis (EMS) is higher, and more early stage disease is observed in OCCA patients. The percentage of drug resistant in OCCA is higher, especially in advanced stage patients. The prognosis of advanced stage OCCA patients is poorer than that of OSCA patients in advanced stage.

Promoter Methylation status of HIN-1 associated with outcomes of ovarian clear cell adenocarcinoma

BackgroundThis study is to analyze promoter methylation of various tumor suppressor genes in different types of ovarian carcinoma and to identify potential therapeutic targets of ovarian clear cell adenocarcinoma (OCCA).Materials and methodsThe promoter methylation statuses of 40 genes in primary ovarian carcinomas including 47 clear- and 63 non-clear-cell type tissues, 6 OCCA cell lines, 29 benign ovarian endometriotic cysts, and 31 normal controls were analyzed by methylation-specific multiplex ligation-dependent probe amplification (MS-MLPA). The MS-MLPA results were correlated with clinicopathological features and outcomes of 47 OCCA patients. Functions of the target genes were further explored by Western Blot Analysis, apoptosis assay, and caspase-3/7 activity analysis.ResultsFrequencies of methylated RASSF1A, CDH13, CACNA1A, HIN-1, and sFRP5 genes in OCCA tissues were significantly higher than those in non-OCCA cancerous tissues and benign endometriotic cysts. The expected OS for patients with methylated promoters of HIN-1 was significantly worse than those for patients without methylated HIN-1 (30% vs. 62%, p = 0.002). The HIN-1 gene was over-expressed in ES2 cells, a significant reduction in cell growth and induction of apoptosis, and increasing paclitaxel sensitivity by reducing phosphorylation of Akt were observed.ConclusionsMethylation of HIN-1 promoter is a novel epigenetic biomarker associated with poor outcomes in OCCA patients. Ectopic expression of the HIN-1 gene increased paclitaxel sensitivity which is partly through Akt pathway.

IL6-STAT3-HIF Signaling and Therapeutic Response to the Angiogenesis Inhibitor Sunitinib in Ovarian Clear Cell Cancer

Ovarian clear cell adenocarcinoma (OCCA) is an uncommon histotype that is generally refractory to platinum-based chemotherapy. We analyze here the most comprehensive gene expression and copy number data sets, to date, to identify potential therapeutic targets of OCCA. Gene expression and DNA copy number were carried out using primary human OCCA tumor samples, and findings were confirmed by immunohistochemistry on tissue microarrays. Circulating interleukin (IL) 6 levels were measured in serum from patients with OCCA or high-grade serous cancers and related to progression-free and overall survival. Two patients were treated with sunitinib, and their therapeutic responses were measured clinically and by positron emission tomography. We find specific overexpression of the IL6-STAT3-HIF (interleukin 6-signal transducer and activator of transcription 3-hypoxia induced factor) pathway in OCCA tumors compared with high-grade serous cancers. Expression of PTHLH and high levels of circulating IL6 in OCCA patients may explain the frequent occurrence of hypercalcemia of malignancy and thromboembolic events in OCCA. We describe amplification of several receptor tyrosine kinases, most notably MET, suggesting other potential therapeutic targets. We report sustained clinical and functional imaging responses in two OCCA patients with chemotherapy-resistant disease who were treated with sunitinib, thus showing significant parallels with renal clear cell cancer. Our findings highlight important therapeutic targets in OCCA, suggest that more extensive clinical trials with sunitinib in OCCA are warranted, and provide significant impetus to the growing realization that OCCA is molecularly and clinically distinct to other forms of ovarian cancer.

Prognostic and predictive values of E-cadherin for patients of ovarian clear cell adenocarcinoma.

The purpose of the study was to analyze negative versus positive immunoexpression of epithelial cadherin (E-cadherin) and p53 in patients with primary advanced ovarian clear cell adenocarcinoma (OCCA) and its significance in relation to clinical features, progression-free survival and overall survival (OS). Protein expression of E-cadherin and p53 was immunohistochemically evaluated in 61 OCCA patients with stages IIC to IV. The clinical factors studied included stage, age, CA-125, residual tumors, and chemotherapy regimens. Positive p53 immunoexpression was 44.8% (26/58) of OCCAs; in contrast, E-cadherin immunoexpression was observed in 75.9% (44/58) of OCCAs. The expected 5-year OS rate of OCCA treated with paclitaxel-based chemotherapy was significantly better than non-paclitaxel-based chemotherapy (40% vs 0%, P = 0.001). The expected 5-year OS rate of OCCA patients with positive E-cadherin immunoexpression (>10%) was also significantly better than patients with negative E-cadherin immunoexpression (≤10%) (35% vs 0%, P = 0.02). The expected 5-year OS rate of those receiving paclitaxel-platinum chemotherapy was not significantly different from platinum-based chemotherapy for those with negative E-cadherin immunoexpression (P = 0.11). The expected 5-year OS rate of those receiving paclitaxel-based chemotherapy was better than non-paclitaxel-based chemotherapy for those with positive E-cadherin immunoexpression (43% vs 0%, P = 0.01). Paclitaxel-based chemotherapy and positive E-cadherin immunoexpression were 2 independent prognostic factors in OS of patients with OCCA (P = 0.01 and 0.04, respectively). E-cadherin is a useful prognostic marker for OCCA patients, and paclitaxel-based chemotherapy can improve survival among patients with positive E-cadherin immunoreactivity.

HOXA10 is Overexpressed in Human Ovarian Clear Cell Adenocarcinoma and Correlates With Poor Survival

Human homeobox gene (HOX) A10 is a homeobox allotype gene of the HOXA family in the HOX family. Human homeobox gene A10 may play an important role in cancer development. However, the role of HOXA10 in the carcinogenesis of ovarian clear cell adenocarcinoma (OCCA) has not been established. We have evaluated the prognostic significance of HOXA10 expression for human OCCA and the effects of HOXA10 on proliferation, motility, and invasion of OCCA cells. We found that HOXA10 was not expressed in normal ovarian epithelium, ovarian endometrial cysts, and ovarian serous carcinomas, but 20 (68.9%) of the 29 OCCAs were positive for the expression of HOXA10. Human homeobox gene A10 expression was negatively correlated to the 5-year survival of OCCA patients (R = -0.442, P = 0.043). When a HOXA10 expression vector was stably transfected into a human OCCA cell line, ES-2, the proliferation rate of ES-2-HOXA10 was much higher than the vector control, the motility of ES-2-HOXA10 cells was significantly increased compared with the control (P < 0.05), and the invasion of ES-2-HOXA10 cells was also much higher than the vector control (P < 0.01 at 5 hours and 12 hours after scratching). In conclusion, HOXA10 was overexpressed in OCCA and was correlated with poor survival. HOXA10 promotes proliferation, migration, and invasion of OCCA cells. Human homeobox gene A10 could be a promising prognostic marker for OCCA.

Expression of NEU3 (Plasma Membrane-Associated Sialidase) in Clear Cell Adenocarcinoma of the Ovary: Its Relationship With T Factor of pTNM Classification

Cell surface carbohydrate expression strongly influences the biological characteristics of cancer cells. Especially, it is known that the change of sialic acid expression could be related to the invasive and metastatic potentials of tumors. This study aimed to investigate sialidase expression of ovarian cancer cells and to evaluate the relationship between plasma membrane-associated sialidase (NEU3) expression and various clinicopathological factors in ovarian clear cell adenocarcinoma patients. In 18 cell lines derived from human ovarian cancers (including clear cell, mucinous, and serous adenocarcinoma), sialidase mRNA expression was evaluated by RT-PCR. NEU1 and NEU3 expression levels were found to be elevated in most cell lines while NEU2 and NEU4 expression was rarely elevated. Interestingly, NEU3 expression was detected in all clear cell adenocarcinoma cell lines. In 71 patients with ovarian clear cell adenocarcinoma, treated at Keio University Hospital from February 1983 to February 2002, NEU3 expression was examined by immunohistochemical staining of surgical specimens and clinicopathological factors were reviewed. NEU3 expression was found to be positive in 77.5% of all cases. Furthermore, a high level of NEU3 expression was significantly correlated with T3 factor of pTNM classification on univariate and multivariate analysis. This is the first report to show that NEU3 is expressed in most of ovarian clear cell adenocarcinoma. And our results show that NEU3 expression is correlated with T factor (pTNM classification) in ovarian clear cell adenocarcinoma.

Proliferative activity of early ovarian clear cell adenocarcinoma depends on association with endometriosis

Objective To investigate differences in the biological characteristics of ovarian clear cell adenocarcinoma based on the presence/absence of endometriosis and tumor proliferative activity. Methods Stage I ovarian clear cell adenocarcinoma patients were divided into groups with and without endometriosis, and immunohistochemical expression of proliferating cell nuclear antigen was determined in surgical specimens. Then xenograft models of human ovarian clear cell adenocarcinoma with or without human ectopic endometrium were created in severe combined immunodeficiency mice, and tumor growth was assessed from the wet weight and the bromodeoxyuridine uptake. Furthermore, a xenograft model of human endometriosis was made with or without ovarian clear cell adenocarcinoma and cytokine production was investigated. Results The proliferating cell nuclear antigen labeling index was significantly lower in the tumors of patients with endometriosis compared to the tumors of patients without endometriosis. In tumor-bearing mice, the tumor weight and bromodeoxyuridine uptake were both significantly lower when ovarian clear cell adenocarcinoma was associated with endometriosis than in its absence. Release of transforming growth factor-β1 and interleukin-6 from the ectopic human endometrium was greater in the presence of clear cell adenocarcinoma than without it, and transforming growth factor-β1 levels showed a significant difference. Conclusion The proliferative activity of early ovarian clear cell adenocarcinoma seems to depend on the association of this cancer with endometriosis. When endometriosis is associated with ovarian clear cell adenocarcinoma, there is a change of its cytokine production that may inhibit tumor growth.

P53 mutations and overexpression affect prognosis of ovarian endometrioid cancer but not clear cell cancer

Objectives Although ovarian clear cell adenocarcinoma (OCCA) and ovarian endometrioid adenocarcinoma (EC) are considered to be closely related to endometriosis, the mechanisms of carcinogenesis of these two malignancies and malignant transformation of endometriosis are unclear. In this study, we examined the biology of OCCA and EC by performing large-scale analysis of K- ras activation and p53 mutation and overexpression in these malignancies. The results were subsequently analyzed for correlation with the clinicopathologic data. Methods In the present study of OCCA and EC, we obtained clinicopathological data and analyzed frequency of mutations and overexpression of K- ras and p53. DNA was extracted from formalin-fixed, paraffin-embedded tissue, and target sequences were amplified in vitro by polymerase chain reaction. The DNA was analyzed for K- ras and p53 mutations by testing for single-strand conformation polymorphisms and by direct sequencing. Immunohistochemical staining was performed using p53 monoclonal antibody. Univariate analysis was performed using the Kaplan–Meier algorithm, and differences in survival were analyzed using the log rank test. The prognostic significance of the studied variables for survival was assessed using multivariate analysis with Cox regression analysis. Results K- ras mutation was detected in 16.2% (6/37) of OCCA patients and 3.7% (1/27) of EC patients. No evidence of p53 mutation was detected in OCCA patients, but p53 mutation was detected in 63.0% of EC patients; these findings are consistent with the results of p53 immunohistochemistry. No statistical significance was observed for K- ras mutation in OCCA or EC. In EC patients, the absence of endometriosis and p53 overexpression was associated with a poorer survival. In OCCA patients tubulocystic and papillary histotype as well as stage II correlated with a worse survival. Conclusion p53 mutation, which was found in 63% of EC tumors, is an independent prognostic factor for EC patients. However, no p53 mutation was found in OCCA tumors. K- ras mutations did not affect survival of OCCA or EC patients.

Steroid Sulfatase Expression in Ovarian Clear Cell Adenocarcinoma: Immunohistochemical Study

Objective. Steroid sulfatase (STS) is an important enzyme that converts biological inactive steroid sulfate to active free steroid. As estrogen is thought to play an important role in cell proliferation in gynecological cancer, the existence of STS may have particular significance in the prognosis of ovarian cancer. In the present study, we determined the STS expression of ovarian clear cell adenocarcinoma (OCCA), which has the poorest prognosis among various ovarian cancers, immunohistochemically to clarify the biological nature of OCCA and also to determine whether STS expression is one of the prognostic factors in OCCA.Methods. Forty-five archival, formalin-fixed, paraffin-embedded tissues from patients with OCCA and other epithelial ovarian cancers who were first operated on from 1987 to 1998 were subjected to analysis. Twenty-eight of forty-five (60.9%) OCCA cases coexisted with endometriosis. They were subclassified into papillary, solid, and tubulocystic types with respect to architectural pattern. Immunohistochemical staining of STS was performed using anti-human STS polyclonal rabbit antibody that had been immunized with purified STS from human placenta.Results. STS was immunohistochemically stained positively in 70% (32/45) of OCCA, 33.3% of serous adenocarcinoma (6/18), and 50.0% of mucinous adenocarcinoma (4/8) specimens and was localized in the cytoplasm of neoplastic epithelial cells. No significant relationship was found between STS staining and FIGO staging. However, patients diagnosed as papillary type had a significantly lower survival rate and showed significantly more positive staining of STS (P < 0.05) than those with solid type. Stage, STS expression, and architectural type yielded a significant association with survival rate.Conclusion. It was proven that STS is present in the cytoplasm of patients with OCCA by an immunohistochemical method. OCCA patients with papillary tumor with positive STS expression are considered to have a poor prognosis.

Survival Probability in Ovarian Clear Cell Adenocarcinoma

Objective. The aim of this study was to evaluate the 5-year survival probability (SP) of patients treated for ovarian clear cell adenocarcinoma (OCCA) at a single tertiary institution and to compare it to the 5-year SP of patients with other histologic subtypes of epithelial ovarian cancer.Methods. Sixty-four patients with pure OCCA treated at the Cleveland Clinic Foundation from 1981 to 1996 were retrospectively identified and clinical information was abstracted. All histologic materials were reviewed by a single gynecologic pathologist. SP was calculated by the Kaplan–Meier method. SPs for OCCA patients were compared to that of other high-grade epithelial ovarian cancer patients in the gynecologic tumor registry. Cox proportional hazards modeling was used to identify varibles associated with decreased SP.Results. The FIGO stages of OCCA study patients were Stage I, 31 (50%), Stage II, 6 (10%), Stage III, 17 (27%), and Stage IV, 8 (13%) (2 patients unstaged). Forty-four patients had no gross residual cancer at the completion of initial surgery while 9 patients had ≤1 cm diameter residual and 10 had >1 cm residual. Forty-five (73%) received postoperative chemotherapy. The median follow-up for surviving patients is 97 months (range 38 to 209 months). The overall 5-year SP of OCCA patients is 50% with limited disease (Stages I and II) patients having a 5-year SP of 72% versus 17% 5-year SP in patients with advanced disease (P < 0.001). FIGO stage was most predictive of outcome. The overall 5-year SP of OCCA patients (50%) differed significantly (P < 0.05) from that of other ovarian cancer registry patients (30%). OCCA patients with limited cancer survived similarly to registry patients (72 vs 72%) as did patients with advanced OCCA compared with registry patients (17 vs 22%).Conclusions. When controlled for grade and stage, the overall survival with OCCA is identical to that of other high-grade epithelial ovarian cancers. Factors that account for the better overall survival of OCCA patients are more favorable disease stage, younger age, and improved debulking status.

Ovarian clear cell adenocarcinoma

The clinical and pathologic features of 29 cases of ovarian clear cell adenocarcinoma (OCCA) were studied to evaluate outcome and potential predictors of survival. Patients' ages ranged from 30 to 89 years (median, 54 years). The study group, using the FIGO classification, consisted of 10 Stage I, 5 Stage II, 7 Stage III, 5 Stage IV, and 2 unstaged patients. Previous or concurrent endometriosis was noted in 45% of patients. Three patients (10.3%) had hypercalcemia. Only stage and the presence of macroscopic residual disease had a statistically significant association with survival. Stage I and II patients experienced a survival similar to a group of 305 patients with adenocarcinomas of non-clear cell type in our ovarian cancer registry with the exception of the very poor survival among Stage IC OCCA patients. Patients with Stage III and IV OCCA had a worse survival than non-OCCA registry patients of similar stage. Few objective responses to adjuvant chemotherapy could be demonstrated in these high-stage OCCA patients. Further study of postoperative adjuvant therapies is warranted.