Subtypes Of Epithelial Ovarian Cancer Research Articles

Hyaluronidase-1 (Hyal-1) Is Differentially Expressed in Epithelial Ovarian Cancer of Distinct Histopathological Subtypes.

Epithelial ovarian cancer (EOC) is the leading cause of death from gynecologic cancer in most Western countries. Because of its asymptomatic growth and the lack of effective screening methods, about 70% of all cases are diagnosed in an advanced stage. Although most of the patients respond to chemotherapy initially, recurrence rate is very high resulting in poor prognosis. Furthermore, EOCs are morphologically heterogeneous, and different histopathological subtypes have distinct molecular characteristics and diverse response to treatment. In the present work we investigated the expression pattern of hyaluronidase-1 (Hyal-1) in different histopathological EOC subtypes as well as in EOC cell lines. The HYAL1 gene (together with those of HYAL2 and HYAL3) is located on the short arm of chromosome 3 (3p), a region described to contain tumour suppressor genes implicated in lung and ovarian cancer pathogenesis. However, levels of both Hyal-1 and its substrate, hyaluronic acid (hyaluronan), have also been reported to be increased in bladder, prostate and head and neck cancers, and to be implicated in tumor progression and metastasis. However, up to date, no studies have been conducted to analyze the transcriptional status of this enzyme and its role in EOC. Herein, quantitative RT-PCR was performed in ovarian tumor samples classified as borderline, serous, endometrioid, mucinous or clear cell. Distinct grade and stage were also attributed according to the International Federation of Gynecology and Obstetrics (FIGO) criteria. Cell lines derived from different EOC subtypes or from normal ovarian epithelial cells (NOSE) were also included in these analyses. Our results show that Hyal-1 expression was significantly increased in clear cell and mucinous EOC samples when compared to borderline tumors. In contrast, lower levels of Hyal-1 expression were observed in serous samples, and no difference was observed between endometrioid and borderline tumors. Accordingly, higher mRNA expression levels and higher enzymatic activity were observed in EOC cell lines derived from clear cell tumors. Cell lines derived from serous tumors had no detectable enzymatic activity and low levels of mRNA expression. However, treatment of one of these cell lines with 5-Azacytidine (DNA methyltransferase inhibitor) restored its Hyal-1 expression and activity, indicating that transcription repression through epigenetic regulation is occurring in serous EOCs. No correlation could be made between Hyal-1 expression and ovarian tumor grade or stage. In conclusion, our results show that Hyal-1 is differentially expressed in distinct EOC subtypes, with high expression levels in mucinous and clear cell carcinomas and low in serous adenocarcinoma. It is important to mention that specificity and sensitivity of the CA-125 antigen is particularly not good for these two former EOC subtypes. Therefore, Hyal-1 could be a potential marker for these tumors; however, further validation using a bigger tissue/serum sample cohort is needed. Supported by NSERC, RRCancer and FRSQ. (poster)

Development and Preliminary Evaluation of a Multivariate Index Assay for Ovarian Cancer

BackgroundMost women with a clinical presentation consistent with ovarian cancer have benign conditions. Therefore methods to distinguish women with ovarian cancer from those with benign conditions would be beneficial. We describe the development and preliminary evaluation of a serum-based multivariate assay for ovarian cancer. This hypothesis-driven study examined whether an informative pattern could be detected in stage I disease that persists through later stages.Methodology/Principal FindingsSera, collected under uniform protocols from multiple institutions, representing 176 cases and 187 controls from women presenting for surgery were examined using high-throughput, multiplexed immunoassays. All stages and common subtypes of epithelial ovarian cancer, and the most common benign ovarian conditions were represented. A panel of 104 antigens, 44 autoimmune and 56 infectious disease markers were assayed and informative combinations identified. Using a training set of 91 stage I data sets, representing 61 individual samples, and an equivalent number of controls, an 11-analyte profile, composed of CA-125, CA 19-9, EGF-R, C-reactive protein, myoglobin, apolipoprotein A1, apolipoprotein CIII, MIP-1α, IL-6, IL-18 and tenascin C was identified and appears informative for all stages and common subtypes of ovarian cancer. Using a testing set of 245 samples, approximately twice the size of the model building set, the classifier had 91.3% sensitivity and 88.5% specificity. While these preliminary results are promising, further refinement and extensive validation of the classifier in a clinical trial is necessary to determine if the test has clinical value.Conclusions/SignificanceWe describe a blood-based assay using 11 analytes that can distinguish women with ovarian cancer from those with benign conditions. Preliminary evaluation of the classifier suggests it has the potential to offer approximately 90% sensitivity and 90% specificity. While promising, the performance needs to be assessed in a blinded clinical validation study.

CA-125 change after chemotherapy in prediction of treatment outcome among advanced mucinous and clear cell epithelial ovarian cancers: a Gynecologic Oncology Group study.

There are limited data regarding unique clinical or laboratory features associated with advanced clear cell (CC) and mucinous (MU) epithelial ovarian cancers (EOC), particularly the relationship between CA-125 antigen levels and prognosis. A retrospective review of 7 previously reported Gynecologic Oncology Group phase 3 trials in patients with stage III/IV EOC was conducted. A variety of clinical parameters were examined, including the impact of baseline and changes in the CA-125 level after treatment of CC and MU EOC on progression-free (PFS) and overall survival (OS). Clinical outcomes among patients with advanced CC and MU EOC were significantly worse when compared with other cell types (median PFS, 9.7 vs 7.0 vs 16.7 months, respectively, P < .001; median OS, 19.4 vs 11.3 vs 40.5 months, respectively, P < .001). Suboptimal debulking was associated with significantly decreased PFS and OS among both. Although baseline CA-125 values were lower in CC (median, 154 micron/mL) and MU (100 micron/mL), compared with other cell types (275 micron/mL), this level did not appear to influence outcome among these 2 specific subtypes of EOC. However, an elevated level of CA-125 at the end of chemotherapy was significantly associated with decreased PFS and OS (P < .01 for all). Surgical debulking status is the most important variable at prechemotherapy predictive of prognosis among advanced CC and MU EOC patients. Changes in the CA-125 levels at the end treatment as compared with baseline can serve as valid indicators of PFS and OS, and likely the degree of inherent chemosensitivity.

Endometriosis may be the pre-malignant lesion for certain histologic subtypes of ovarian cancers

16504 Background: The association of ovarian carcinoma and endometriosis has been suggested but there has been limited analysis of this relationship. Recent studies have shown only a 20–40% correlation of ovarian cancer with endometriosis. The objective of this study was to demonstrate the concurrent findings of endometriosis and ovarian cancer in our diverse population and to investigate if endometriosis is the pre-malignant lesion for certain ovarian cancer subtypes. Methods: Microscopic slides of primary epithelial ovarian cancers resected at the time of hysterectomy and salpingo-oopherectomy from 2000–2005 were reviewed for the presence of endometriosis. Their counterpart paraffin-embedded tissue samples were obtained and used for immunohistochemical staining of several candidate genes and their differential protein expression profiles were recorded. Results: While the overall incidence of epithelial ovarian cancers in Hawaii was comparable to other populations, the incidence of cancer subtypes differed. Serous, endometrioid, and clear cell cancers had similar incidence rates (28%, 29%, and 21% respectively) in our population compared to the general population where serous subtypes predominate (40–50%) and clear cell is found less often (10%). Unlike the general population, clear cell and endometrioid subtypes in our population were associated with endometriosis to a much greater extent (92% and 94%) - the highest correlation seen to date. Mucinous cancers were less commonly associated (67%), while serous carcinomas were rarely associated (6%). There also appeared to be a predilection for age <50 yo with the endometriosis-associated cancers. Finally, examination of different candidate genes revealed discrete expression patterns among the cancer subtypes, mimicked to a lesser extent in their coexisting endometriosis sites. Conclusions: This data represents the first time that endometriosis has been associated with clear cell and endometrioid subtypes to such a profound degree suggesting that endometriosis may indeed be the pre-malignant lesion of certain epithelial ovarian cancer subtypes. Further studies will be needed to elucidate this association fully and examine, if perhaps, ethnicity plays a larger role than previously thought. No significant financial relationships to disclose.

Body size and risk of epithelial ovarian and related cancers: A population‐based case‐control study

Different subtypes of ovarian cancer appear to have different causes; however, the association between body mass index (BMI) and the different subtypes is unclear. We examined the associations between body-mass index (BMI) and weight gain and risk of the different histological subtypes of epithelial ovarian cancer in a case-control study in Australia. Cases aged 18-79 with a new diagnosis of invasive epithelial ovarian cancer (n = 1,269) or borderline tumor (n = 311) were identified through a network of clinics and cancer registries throughout Australia. Controls (n = 1,509) were selected from the Electoral Roll. Height and weight (1 year previously, at age 20 and maximum weight) and other risk factor information were ascertained via a self-administered questionnaire. Obesity was positively associated with clear cell tumors (Odds Ratio 2.3; 95% confidence interval 1.2-4.2) but not invasive endometrioid or mucinous tumors. Although there was no association with invasive serous tumors overall (0.9; 0.7-1.2), we did see an increased risk of serous peritoneal tumors (2.9; 1.7-4.9), but not of serous tumors of the ovary and fallopian tube. Of the borderline subtypes, obesity was positively associated with serous (1.8; 1.1-2.8) but not mucinous tumors (1.1; 0.7-1.7). Overweight was not associated with any subtype overall. There was no association with BMI at age 20, or weight gain for any of the histological subtypes. These results add to the current evidence that obesity increases a woman's risk of developing distinct histological subtypes of ovarian cancer.

Association of SNPs in the promoter of&lt;I&gt;MMP-2&lt;/I&gt;and&lt;I&gt;TIMP-2&lt;/I&gt;genes with epithelial ovarian cancer

The association between single nucleotide polymorphisms (SNPs) in the promoter region of MMP-2 and TIMP-2 genes and the risk of epithelial ovarian cancer was investigated. MMP-2 C-1306T, C-735T and TIMP-2 G-418C SNPs were genotyped by polymerase chain reaction-restrictive fragment length polymorphism (PCR-RFLP) analysis in 246 patients with epithelial ovarian cancer and 324 healthy women as control. Results showed no significant difference between the patient and control groups in allele or genotype distributions of MMP-2 C-1306T (P=0.55 and P=0.42). However, the frequencies of the C allele and the C/C genotype of the MMP-2 C-735T were significantly higher in ovarian cancer patients (80.7% and 66.7%) than those in healthy controls (75.5% and 55.9%). Compared with the T/T+C/T genotypes, the C/C genotype significantly increased the risk of ovarian cancer (OR=1.58, 95%CI=1.12-2.23). Stratification analysis showed that subjects carrying C/C genotype were significantly associated with the risk of endometrioid ovarian cancer and with ovarian cancer in subjects that were 50 or older, with odds ratio at 1.69 (95%CI=1.03-2.79) and 1.71 (95%CI=1.14-2.57), respectively. Haplotype analysis showed that the frequencies of four haplotypes (T(-1306)-T(-735), T(-1306)-C(-735), C(-1306)-T(-735) and C(-1306)-C(-735)) of MMP-2 C-1306T and C-735T were not significantly different between the patient and control groups (P=0.24). The allele and genotype frequencies of TIMP-2 G-418C were not significantly different between the patient and control groups (P=0.33 and P=0.47). But TIMP-2 -418G/G genotype was associated with a trend for endometrioid ovarian cancer by stratification analysis according to histological subtypes (OR=1.62, 95%CI=0.94-2.78). Thus, the study suggested that the C/C genotype of the C-735T SNP in the promoter region of MMP-2 gene may be a potential risk factor for epithelial ovarian cancer, but the C-1306T SNP may have no association with the risk of epithelial ovarian cancer. The TIMP-2 G-418C SNP may be associated with the risk of different histological subtypes of epithelial ovarian cancer.

MtDNA sequence variants in subtypes of epithelial ovarian cancer stages in relation to ethnic and age difference

Epithelial ovarian cancer is the fifth leading cause of cancer mortality among women in the United States. For this disease, differences in age-adjusted incidence and survival rates between African American and Caucasian women are substantial. The objective of this study was to examine mtDNA sequence variants in 118 frozen tissues of three subtypes of epithelial ovarian cancer (serous, n = 48 endometrioid, n = 47 and mucinous, n = 23) and matched paracancerous normal tissues (n = 18) in relation to racial/ethnic and age differences. Restriction fragment length polymorphism (RFLP) and polymerase chain reaction (PCR)-based sequencing were used to evaluate two regions of mtDNA spanning 5317 to 7608 and 8282 to 10110 bp and including ND subunits 2, 3, MT-COI, II, and III, ATPase 8, a part of ATPase 6, and tRNA genes in frozen ovarian tissues obtained from the southern regional Cooperative Human Tissue Network (CHTN) and University of Alabama-Birmingham (UAB) Ovarian Spore Center. Thirty-nine mtDNA variants were detected of which 28 were previously unreported. One somatic variant of C9500T was observed. A variant, C7028T in the MT-CO1 gene, had an ascending frequency from borderline (8%) to stages III/IV (75%) among the three ovarian cancer subtypes and stages. It was found in 86% (42/49) of African-American and 43% (37/87) of the Caucasian women. A variant, T8548G in the ATPase 6 gene was detected at a frequency of 72% (18/25) in ovarian serous subtype tissues in stages III/IV. Of the African American patients under age 40, 95% (20/21) harbored the T8548G variant; this was in contrast to only 22% (8/35) of Caucasian patients in same age group. Variants C7256T and G7520A had a frequency of 54% (6/11) in endometrioid stage III; no corresponding variants were observed in mucinous subtype stage III. Furthermore, variants C7256T and G7520A were absent in serous ovarian cancer subtype. Interestingly, the C7520T variant in tRNA gene was present in 74% (36/49) of African American and 26% (23/87) of Caucasian patients. Taken together, our results suggest that, with respect to ethnic and age difference, these mtDNA variants may be involved in epithelial ovarian carcinogenesis.

Wnt signaling in ovarian tumorigenesis

Data are emerging implicating Wnt signaling in ovarian tumorigenesis. We sought to review the current literature on the subject and discuss the pathway's potential role as a prognostic marker and therapeutic target. We conducted a systematic literature review of studies investigating the association between Wnt signaling and ovarian cancer. Search strategies included online searching of the MEDLINE database and hand searching of relevant publications and reviews. Additional reports were collected by systematically reviewing all references from retrieved papers. Twenty-nine papers were identified that directly investigate Wnt signaling and ovarian cancer. Mutations in the CTNNB1 gene that codes for beta-catenin, the key effector in the pathway, are directly linked to carcinogenic transformation but are mostly found in ovarian endometrioid adenocarcinomas, a histologic subtype of epithelial ovarian cancer. These mutations, along with others, lead to deregulation of the pathway and transcription of target genes. Differences in various intra- and extracellular components of the Wnt pathway have been demonstrated between normal ovarian and cancer cell lines and between benign tissue and ovarian cancer. These differences implicate Wnt signaling in the molecular events that lead to ovarian cancer development despite the fact that gene mutations are uncommon. The data suggest that Wnt signaling plays a role in ovarian tumorigenesis. The exact mechanisms by which this occurs need to be further elucidated. Wnt signaling is probably involved via multiple, diverse mechanisms. Further research in this area is warranted.

Survival in ovarian cancer patients by histology and family history

Introduction. Earlier studies suggest that histology has no prognostic significance in patients with invasive ovarian tumors. Studies about the effect of family history on survival have given conflicting results, which we try to clarify in this study. As an additional question, we examined whether family members share survival experience. Methods. We used the nation-wide Swedish Family-Cancer Database to estimate hazard ratios (HRs) for cause-specific and overall survival in ovarian cancer patients by histology and family history. HRs show the probability of death in the study group compared to the reference group. Results. A total of 6 049 ovarian cancer patients with specific histologies were retrieved from our Database from years 1993 to 1999. Compared to women with epithelial ovarian cancer, women with borderline epithelial tumors had the best survival (HR 0.02 and 0.14 for cause-specific and overall survival). Good survival was also noted for patients with sex cord-stromal tumors and germ cell tumors. Among specific subtypes of epithelial ovarian cancers, good survival was noted for women with clear cell and endometrioid carcinomas and mucinous cystadenocarcinoma. The study covered 80 mother-daughter pairs with a family history. Patients with a family history had a poorer survival than sporadic cases in both maternal and offspring generations. When the survival was analyzed according to the probands’ length of survival, there was a non-significant concordance of prognosis. Conclusion. Our data showed that histology and family history are prognostic factors for ovarian tumors. Patients with a family history had a more aggressive course than the sporadic cases.

Potential benefit of Sunitinib in recurrent and refractory ovarian clear cell adenocarcinoma

Ovarian clear cell adenocarcinoma (OCCA) is a unique biological subtype of epithelial ovarian cancer, with a similar gene profile to renal cell carcinoma (RCC). Sunitinib is a vascular endothelial growth factor receptor tyrosine kinase inhibitor with proven antitumor activity in RCC and a rational biological option for treatment of OCCA. A 60-year-old woman presented with recurrent and refractory stage IA OCCA, after 9 years of remission. Sunitinib was initiated as fifth-line chemotherapy, associated with cystic degeneration of liver metastasis and a short downward trend in her CA125 level. Recurrent and refractory OCCA may respond to Sunitinib. Clinical trials are needed to objectively confirm these findings, as benefit may be limited in patients with extensively pretreated tumors.

Talcum powder, chronic pelvic inflammation and NSAIDs in relation to risk of epithelial ovarian cancer

Chronic inflammation has been proposed as the possible causal mechanism that explains the observed association between certain risk factors, such as the use of talcum powder (talc) in the pelvic region and epithelial ovarian cancer. To address this issue we evaluated the potential role of chronic local ovarian inflammation in the development of the major subtypes of epithelial ovarian cancer. Factors potentially linked to ovarian inflammation were examined in an Australia-wide case-control study comprising 1,576 women with invasive and low malignant potential (LMP) ovarian tumours and 1,509 population-based controls. We confirmed a statistically significant increase in ovarian cancer risk associated with use of talc in the pelvic region (adjusted odds ratio 1.17, 95% CI: 1.01-1.36) that was strongest for the serous and endometrioid subtypes although the latter was not statistically significant (adjusted odds ratios 1.21, 95% CI 1.03-1.44 and 1.18, 95% CI 0.81-1.70, respectively). Other factors potentially associated with ovarian inflammation (pelvic inflammatory disease, human papilloma virus infection and mumps) were not associated with risk but, like others, we found an increased risk of endometrioid and clear cell ovarian cancer only among women with a history of endometriosis. Regular use of aspirin and other nonsteroidal anti-inflammatory drugs was inversely associated with risk of LMP mucinous ovarian tumours only. We conclude that on balance chronic inflammation does not play a major role in the development of ovarian cancer.

P16(CDKN2) gene polymorphism: association with histologic subtypes of epithelial ovarian cancer in China

p16 is an important tumor suppressor gene, which is inactivated in many kinds of tumors. The common variants of p16 may be associated with the risk of certain tumors development. We analyzed the frequency of two adjacent polymorphisms in p16 exon 3 (540C-->G and 580C-->T) and their haplotype in blood samples from epithelial ovarian cancer (EOC) patients and healthy controls using polymerase chain reaction-restriction fragment length polymorphism. The results showed that the genotype frequency of p16 580C-->T polymorphism was significantly different among histologic subtypes of EOC (P= 0.02). T allele carriers significantly reduced the risk of serous EOC; the adjusted odds ratio was 0.40 (95% CI = 0.19-0.84). There are neither association between p16 540C-->G polymorphism and EOC development, progression, nor association between the haplotypes of two single nucleotide polymorphisms and the tumor development. Our results suggested that the p16 580C-->T polymorphism might affect the individual susceptibility to specific subtypes of EOC. Different types of ovarian cancer might adopt distinct carcinogenetic pathways. However, this result may be further validated in a larger sample of patients.

Treatment Issues in Clear Cell Carcinoma of the Ovary: A Different Entity?

Ovarian clear cell carcinoma (OCCC) is a distinct histopathologic subtype of epithelial ovarian cancer (EOC) with an incidence of <5% of all ovarian malignancies. Our goal was to review the clinical features and management of patients with OCCC. We performed a PubMed search using the phrase "clear cell ovarian cancer." We reviewed 54 articles referring to OCCC. OCCC patients have a high incidence of stage I disease and frequently present with a large pelvic mass. Recurrences are more frequent with this entity than with other types of EOC. The clinical management of advanced EOC includes maximal cytoreduction and platinum plus paclitaxel-based chemotherapy. The survival rates of patients with advanced OCCC are lower than those of patients with advanced serous EOC (serous subtype). The poor response rate to platinum-based regimens may be related to the intrinsic chemoresistance of these tumors. Despite their aggressive clinical course, OCCCs are still treated similarly to the other EOCs at the present time, because the rarity of these tumors prevents the conduction of randomized studies. Novel treatment approaches should be adopted in OCCC. Molecular-targeted therapies and effective new agents without cross-resistance to platinum compounds should be evaluated in a prospective clinical trial in OCCC.

Emerging roles for PAX8 in ovarian cancer and endosalpingeal development

Epithelial ovarian carcinomas develop from ovarian surface epithelia that undergo complex differentiation to form distinguishable phenotypes resembling those of the epithelia of the female urogenital regions. While previous studies have implicated regulatory developmental homeobox (HOX) genes in this process, other factors responsible for this differentiation are largely unknown. Aberrant transcriptional expression of PAX8 has been reported in epithelial ovarian cancer, prompting us to initiate the molecular characterization of this master regulatory gene in ovarian cancer development. Immunohistochemistry, immunoblotting and RT-PCR were used to investigate the presence of PAX8 and its protein products in epithelial ovarian cancer subtypes, normal ovarian surface epithelia, ovarian inclusion cysts and normal endosalpingeal epithelia. In this report, we confirm microarray results indicating that the transcription factor, PAX8, is highly expressed in epithelial ovarian cancer but absent from the precursor ovarian surface epithelia of healthy individuals. Furthermore, we report that PAX8 is localized to the nucleus of non-ciliated epithelia in simple ovarian epithelial inclusion cysts and in three epithelial ovarian cancer subtypes (serous, endometrioid and clear cell). We also determined that PAX8 is expressed in the non-ciliated, secretory cells of healthy fallopian tube mucosal linings but not in the adjacent ciliated epithelia. These findings support the hypothesis that PAX8 plays parallel roles in the development of epithelial ovarian cancer and in the developmental differentiation of coelomic epithelia into endosalpingeal epithelia.

Does smoking increase risk of ovarian cancer? A systematic review

Although early reports suggested that smoking was not associated with ovarian cancer risk, recent studies have reported positive associations for cancers of the mucinous subtype. We sought to clarify the relationship between smoking and ovarian cancer by histological subtype. We conducted a systematic literature review and meta-analysis of studies investigating the association between smoking and risk of the different histological subtypes of epithelial ovarian cancer. Eight population-based case-control studies, one pooled analysis of case-control studies, and one cohort study met the inclusion criteria. Summary relative risks (RR), 95% confidence intervals (CI), and tests for heterogeneity were generated from random effects models. Combined, these studies included a total of 910 women with mucinous and 5564 with non-mucinous ovarian cancers. There was a significant doubling of risk of mucinous ovarian cancer in current smokers compared to never smokers (summary RR 2.1, 95% CI 1.7-2.7), but no increased risk of serous (1.0, 95% CI 0.8-1.2) or endometrioid (0.8, 95% CI 0.6-1.1) cancers and a significant risk reduction for clear cell cancers (0.6, 95% CI 0.3-0.9). The risk of mucinous cancer increased with increasing amount smoked but returned to that of never smokers within 20-30 years of stopping smoking. Meta-analysis suggests that current smoking doubles a woman's risk of developing mucinous ovarian cancer. Stopping smoking returns the risk to normal in the long term. Smoking may thus be one of the few modifiable factors offering potential for primary prevention of mucinous ovarian cancer.

18F-FDG PET/CT in a Patient with Lymph Node Metastasis from Ovarian Adenocarcinoma

18F-FDG PET/CT in a Patient with Lymph Node Metastasis from Ovarian AdenocarcinomaEric Gontier1, Myriam Wartski1, Jean-Marc Guinebretiere2 and Jean-Louis Alberini1Audio Available | Share

Transitional Cell Carcinoma of the Ovary

Transitional cell carcinoma (TCC) of the ovary is a rare, recently recognized, subtype of ovarian surface epithelial cancer. We present a case of TCC of the ovary, managed by staging operation and followed by postoperative chemotherapy with carboplatin and cyclophosphamide. A 67-year-old postmenopausal woman presented with a 2-year history of progressive enlargement of an abdominal mass. Pelvic sonography and abdominal computed tomography showed a pelvic mass measuring 210 x 165 x 203 mm. The serum CA-125 titer was also elevated (65.01 U/mL). A staging operation with total abdominal hysterectomy, bilateral salpingo-oophorectomy, infracolic omentectomy and pelvic lymph node dissection was performed. After surgery, the pathologic report of the left ovarian tumor was TCC, grade 2-3, stage IA. The patient then underwent four cycles of postoperative chemotherapy with carboplatin and cyclophosphamide. CA-125 levels declined to within the normal range after the first cycle of chemotherapy. TCC of the ovary is a rare subtype of epithelial ovarian cancer. It differs from malignant Brenner tumor by the absence of a benign or borderline Brenner component. Surgical resection is the primary therapeutic approach, and patient outcomes after chemotherapy are better than for other types of common epithelial ovarian cancers.

Antisense Suppression of Pygopus2 Results in Growth Arrest of Epithelial Ovarian Cancer

The Pygopus proteins are critical elements of the canonical Wnt/beta-catenin transcriptional complex. In epithelial ovarian cancer, constitutively active Wnt signaling is restricted to one (endometrioid) tumor subtype. The purpose of this study was to determine the level of expression and growth requirements of human Pygopus2 (hPygo2) protein in epithelial ovarian cancer. Expression and subcellular localization of hPygo2 was determined in epithelial ovarian cancer cell lines and tumors using Northern blot, immunoblot, and immunofluorescence. Immunohistochemistry was done on 125 archived patient epithelial ovarian cancer tumors representing all epithelial ovarian cancer subtypes. T-cell factor-dependent transcription levels were determined in epithelial ovarian cancer cells using TOPflash/FOPflash in vivo assays. Phosphorothioated antisense oligonucleotides were transfected into cell lines and growth assayed by cell counting, anchorage-independent colony formation on soft agar, and xenografting into severe combined immunodeficient mice. All six epithelial ovarian cancer cell lines and 82% of the patient samples overexpressed nuclear hPygo2 compared with control cells and benign disease. Depletion of hPygo2 by antisense oligonucleotides in both Wnt-active (TOV-112D) and Wnt-inactive serous (OVCAR-3, SKOV-3) and clear cell (TOV-21G) carcinoma cell lines halted growth, assessed using tissue culture, anchorage-independent, and xenograft assays. hPygo2 is unexpectedly widely expressed in, and required in the absence of, Wnt signaling for malignant growth of epithelial ovarian cancer, the deadliest gynecologic malignancy. These findings strongly suggest that inhibition of hPygo2 may be of therapeutic benefit for treating this disease.

Advanced stage clear-cell epithelial ovarian cancer: The Hellenic cooperative oncology group experience

Purpose. Ovarian clear-cell carcinomas (OCCC) are known to be possibly resistant to platinum-based chemotherapy and to have a poorer prognosis with respect to other subtypes of epithelial ovarian cancer (EOC). This study was undertaken to compare response and survival to platinum-based chemotherapy between patients with advanced stage III and IV OCCC and serous EOC (sEOC). Patients and methods. A retrospective analysis was performed in patients with advanced stage of OCCC treated with first-line platinum-based chemotherapy in the context of several study protocols of the Hellenic Cooperative Oncology Group (HeCOG) between 1/2/1987 and 31/10/2003. The outcome was compared to that of patients with sEOC treated according to the same protocols during the same study period. Results. One hundred and five patients (35 stage III and IV OCCC, 70 stage III and IV sEOC) treated with platinum-based chemotherapy were analyzed. The overall response rate for OCCC was 45% (complete response 25%) (95% CI, 23.1% to 68.5%) and 81% (complete response 46%) (95% CI, 67.4% to 91.1%) for sEOC. The overall response rate was significantly higher for sEOC ( P = 0.008). In the subgroup of stage III patients, the rate of complete responders was higher among sEOC patients ( P = 0.023). After a median follow-up of 61.1 months, median survival and time to tumor progression were not significantly different between the two groups (25.1 months [95% CI 11.7 to 38.5 months] versus 49.1 months [95% CI 36.5 to 61.6 months], P = 0.141, 12.0 months [95% CI 6.5 to 17.3 months] versus 18.0 months [95% CI 14.7 to 21.6 months], P = 0.384, respectively). Conclusion. Patients with OCCC have significantly lower response to platinum-based first-line chemotherapy compared to patients with sEOC. This low response to platinum-based chemotherapy was not translated in significantly shorter survival. The current study outcomes are provocative and suggest that a new strategy for chemotherapy in OCCC should be adopted, possibly one that focuses on new agents without cross-resistance to platinum agents.

A distinct molecular profile associated with mucinous epithelial ovarian cancer

Mucinous epithelial ovarian cancers (MOC) are clinically and morphologically distinct from the other histological subtypes of ovarian cancer. To determine the genetic basis of MOC and to identify potential tumour markers, gene expression profiling of 49 primary ovarian cancers of different histological subtypes was performed using a customised oligonucleotide microarray containing >59 000 probesets. The results show that MOC express a genetic profile that both differs and overlaps with other subtypes of epithelial ovarian cancer. Concordant with its histological phenotype, MOC express genes characteristic of mucinous carcinomas of varying epithelial origin, including intestinal carcinomas. Differences in gene expression between MOC and other histological subtypes of ovarian cancer were confirmed by RT–PCR and/or immunohistochemistry. In particular, galectin 4 (LGALS4) was highly and specifically expressed in MOC, but expressed at lower levels in benign mucinous cysts and borderline (atypical proliferative) tumours, supporting a malignant progression model of MOC. Hence LGALS4 may have application as an early and differential diagnostic marker of MOC.