Types Of Ovarian Carcinoma Research Articles

A Case of Clear Cell carcinoma of the Ovary

Although Clear cell carcinoma of ovary is a rare epithelial ovarian tumor, prevalence in Asian is higher than other ethnicity. Recently, Clear cell carcinoma has increased in its incidence. Clear cell carcinoma of the ovary constitutes 5-6% all ovarian malignancies. Clear cell carcinoma is frequently present at early stage with unilateral large pelvic mass, deep vein thrombosis, hyper kalemia. Atypical endometriosis is a malignant precursor which associated with clear cell carcinoma 35.9%. Microscopic feature are multiple papillae, densely hyaline basement membrane and hyaline bodies. Mitosis are less frequent than in other types of ovarian carcinomas. Clear cell carcinoma of ovary was known poor prognosis compared to other epithelial ovarian carcinoma because of Platinum based chemotherapy resistance. We experienced a case of clear cell adenocarcinoma of the ovary in 40 years old woman. Clinicopathologic findings of one case with a brief review related literatures are presented.

Ovarian carcinoma associated with endometriosis

ObjectivesPrevious studies have suggested an association between endometriosis and development of ovarian cancer. A study was performed to evaluate the cases of ovarian carcinoma associated with endometriosis. Study designThe study includes patients with ovarian carcinoma associated with endometriosis diagnosed between 2000 and 2010 at Hacettepe University Hospital, Ankara, Turkey. A total of 1086 patients who underwent surgical staging for ovarian carcinoma were analyzed retrospectively for the presence of histologically documented endometriosis. The clinical and pathological characteristics of 45 ovarian carcinoma patients associated with endometriosis were evaluated including histologic subtype, stage and grade. ResultsOvarian carcinoma was found to be associated with endometriosis in 4.1% (45/1086) of the cases. Of them, 17 patients (37.8%) had clear cell, 15 (33.3%) had endometrioid, 6 (13.3%) had serous papillary, 4 (8.9%) had mucinous and the remaining 3 patients had an undifferentiated subtype of ovarian carcinoma. Twenty-three (51.1%) patients had stage I, 4 (8.9%) had stage II and 18 (40.0%) had stage III disease. The frequency of coexistence of endometriosis was 20.4% (17/83) for clear cell carcinoma and 9.3% (15/161) for endometrioid cell carcinoma. ConclusionsOnly a small proportion of ovarian cancer cases were found to be associated with endometriosis. Endometriosis was most frequently associated with clear cell and endometrioid types of ovarian carcinoma. Ovarian carcinoma associated with endometriosis seems to represent a distinct disease entity with different histological subtypes, early presentation and a relatively favorable outcome.

Targeting Signaling Pathways in Epithelial Ovarian Cancer

Ovarian carcinoma (OC) is the most lethal gynecological malignancy. Response to platinum-based chemotherapy is poor in some patients and, thus, current research is focusing on new therapy options. The various histological types of OC are characterized by distinctive molecular genetic alterations that are relevant for ovarian tumorigenesis. The understanding of these molecular pathways is essential for the development of novel therapeutic strategies.PurposeWe want to give an overview on the molecular genetic changes of the histopathological types of OC and their role as putative therapeutic targets.In Depth Review of Existing DataIn 2012, the vascular endothelial growth factor (VEGF) inhibitor, bevacizumab, was approved for OC treatment. Bevacizumab has shown promising results as single agent and in combination with conventional chemotherapy, but its target is not distinctive when analyzed before treatment. At present, mammalian target of rapamycin (mTOR) inhibitors, poly-ADP-ribose polymerase (PARP) inhibitors and components of the EGFR pathway are in the focus of clinical research. Interestingly, some phytochemical substances show good synergistic effects when used in combination with chemotherapy.ConclusionOngoing studies of targeted agents in conjunction with chemotherapy will show whether there are alternative options to bevacizumab available for OC patients. Novel targets which can be assessed before therapy to predict efficacy are needed. The assessment of therapeutic targets is continuously improved by molecular pathological analyses on tumor tissue. A careful selection of patients for personalized treatment will help to reduce putative side effects and toxicity.

Abstract 3166: Clinopathologic correlation with the LCM based instability profiles for the mitochondrial microsatellite regions in the benign to metastatic transitions of surface epithelium ovarian tumor subtypes.

Abstract Background: Up to date, genomic and microgenomic changes have been identified in nuclear genome whereas, there is no available data about the mitochondrial genome alterations in paired ovarian tumors. Additionally, genomic factors that involve in the progression to advanced stages of ovarian malignancy is still largely unknown. Current work suggest that the mitochondrial alterations have importance in the progress of carcinogenesis in spesific cell populations at clinical, pathological and molecular pathological levels. Methods and Findings: We analyzed subtypes of 41 ovarian carcinoma samples including normal and tumor (benign, borderline and malignant) using laser captured microdissection technology. Out of 41 ovarian cases, 19 serous papillary carcinoma, 6 mucinous adenomcarcinoma, 9 endometrioid adenocarcinoma, 5 mixed type ovarian carcinoma, 1 undifferentiated carcinoma and 1 clear cell adenocarcinoma were included in the study. All samples were screened for 5.5kb (MT-D-Loop, MT-CytB, MT-ATPaz6-8, MT-12SrRNA, MT-16SrRNA) of mitochondrial genome by PCR-based sequencing analysis. A total of 91 variations were found. Sixty six percent (60/91) of these variations is shown in MITOMAP and 34% (31/91) is observed as novel variations. Overall, we did not find any correlation in D-Loop variations between pathological prognostic and molecular pathological prognostic factors (CD34,ER,PR,c-erbB-2,p53,MDR1,MDR3). However, the expression of a key component of drug resistance, protein GST (gluthatione S transferase), was detected as 270 in samples with instability; and 165 (median 25-75 percentile) in samples with stability in D-Loop position at 309 for C7TC6 repeats, (p<0.05). Additionally, there was a significant difference in the mitotic index of Ki-67 expression in the samples whom had no changes in CA5 repeats as 37.2+20.00 and 54.3+17.0 in samples with CA5 repeat variations at position 514 (p<0.05). Conclusion: Our results suggest that our findings will add clinical value for the spesific/novel genetic variations detected in 34% of ovarian tumors. The results of microsatellite analysis in ovarian tumors showed changes of 26% for D310 (C)7-9, 37% for position 16184 (C)8-14. Our data supports the idea that, the variations spesifically in MT-D Loop and MT-CytB gene regions would reflect the preliminary transitional changes in progression of tumorigenesis. The functional use of LCM system and the microgenomic profiles will be definetely helpful for prognostic and therapeutic approaches in the field of mitochondrial oncology . Citation Format: Ozgul Alper, Gulgun Erdogan, Elif Pestereli, Tayup Simsek, Mualla O. Caliskan, Hakan Gulkesen, Durkadin Demir, Gökhan Görgişen, Seyda Karaveli, Güven Lüleci. Clinopathologic correlation with the LCM based instability profiles for the mitochondrial microsatellite regions in the benign to metastatic transitions of surface epithelium ovarian tumor subtypes. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 3166. doi:10.1158/1538-7445.AM2013-3166

Recent alcohol consumption and risk of incident ovarian carcinoma: a pooled analysis of 5,342 cases and 10,358 controls from the Ovarian Cancer Association Consortium

BackgroundStudies evaluating the association between alcohol intake and ovarian carcinoma (OC) are inconsistent. Because OC and ovarian borderline tumor histologic types differ genetically, molecularly and clinically, large numbers are needed to estimate risk associations.MethodsWe pooled data from 12 case-control studies in the Ovarian Cancer Association Consortium comprising 5,342 OC cases, 1,455 borderline tumors and 10,358 controls with quantitative information on recent alcohol intake to estimate odds ratios (OR) and 95% confidence intervals (CI) according to frequencies of average daily intakes of beer, wine, liquor and total alcohol.ResultsTotal alcohol intake was not associated with all OC: consumption of >3 drinks per day compared to none, OR=0.92, 95% CI=0.76-1.10, P trend=0.27. Among beverage types, a statistically non-significant decreased risk was observed among women who consumed >8 oz/d of wine compared to none (OR=0.83, 95% CI=0.68-1.01, P trend=0.08). This association was more apparent among women with clear cell OC (OR, 0.43; 95% CI, 0.22-0.83; P trend=0.02), although based on only 10 cases and not statistically different from the other histologic types (P value for statistical heterogeneity between histologic types = 0.09). Statistical heterogeneity of the alcohol- and wine-OC associations was seen among three European studies, but not among eight North American studies. No statistically significant associations were observed in separate analyses evaluating risk with borderline tumors of serous or mucinous histology. Smoking status did not significantly modify any of the associations.ConclusionsWe found no evidence that recent moderate alcohol drinking is associated with increased risk for overall OC, or that variation in risk is associated strongly with specific histologic types. Understanding modifiable causes of these elusive and deadly cancers remains a priority for the research community.

MAD2 Expression in Ovarian Carcinoma: Different Expression Patterns and Levels among Various Types of Ovarian Carcinoma and Its Prognostic Significance in High-Grade Serous Carcinoma

BackgroundMitotic arrest deficiency protein 2 (MAD2) is a key component of spindle assembly checkpoint function, which mediates cell apoptosis through microtubule kinetics. Aberrant expression of MAD2 is believed to be associated with the development of chromosome instability. MAD2 also has a signihicant role in cellular drug resistance to taxane chemotherapeutic agents.MethodsExpression of MAD2 and p53 was investigated using immunohistochemistry in 85 cases of ovarian carcinomas. Clinicopathological data including progression-free survival were analyzed.ResultsA significant (p=.035) association was observed between the grade of serous carcinoma and the expression level of MAD2. While low-grade serous carcinoma showed a low-level expression of MAD2, high-grade serous carcinoma showed a high-level expression of MAD2. We also determined that low-level expression of MAD2 was associated with reduced progression-free survival (PFS) (p=.016) in high-grade serous carcinoma.ConclusionsMAD2 expression in ovarian carcinoma is related to the grade of serous carcinoma and PFS of high-grade serous carcinoma. Expression level of MAD2 detected by immunohistochemistry may serve as an indicator in predicting the response of microtubule-interfering chemotherapeutic agents.

Prevalence of Loss of Expression of DNA Mismatch Repair Proteins in Primary Epithelial Ovarian Tumors

Although different histologic subtypes of epithelial ovarian tumors have long been recognized, their molecular abnormalities have not been fully defined. We examined the prevalence of DNA mismatch repair (MMR) protein loss in these tumors. Tissue microarrays (TMA) of suspected ovarian carcinomas were stained for hMLH1, hMSH2, hMSH6, and hPMS2 and scored separately by 2 groups of investigators. Loss of staining (negative) or discrepant staining results on TMA were verified on whole-section slides. Intact (positive) staining results were also verified for an additional 25 randomly selected cases. Clinical data for cases demonstrating MMR protein loss were collected. A second set of TMA composed purely of mucinous tumors was also stained for antibodies to MMR proteins and scored by 1 group of investigators. TMA was an effective method for screening a large number of ovarian tumors for MMR protein expression, with a sensitivity of 100% for all 4 MMR proteins, and a specificity of 22.2%-53.8% for different MMR proteins. Of the primary epithelial tumors of the ovary, loss of expression of MMR proteins was significantly more common in the endometriosis-associated carcinomas (7/69; 10.1%) than in high-grade serous carcinomas (2/182; 1.1%): P=0.0021. The former group also showed more frequent loss of MMR proteins compared with mucinous intestinal-type carcinomas (0/32; P=0.0940). Cases within the group of endometriosis-associated carcinomas were endometrioid (2/29 cases), clear cell (1/27 cases), undifferentiated (1/8 cases), and mixed carcinomas with an endometrioid, clear cell, and/or undifferentiated component (3/5 cases). No loss of MMR protein expression was identified in epithelial tumors of other histologic subtypes. Our study demonstrated the loss of MMR protein expression in 10.1% of endometriosis-associated ovarian carcinomas. These results raise the possibility of selective screening for Lynch syndrome in patients with these types of ovarian carcinoma.

Clinicopathologic and Immunohistochemical Features of Ovarian Clear Cell Carcinomas in Comparison With Type I and Type II Tumors

Two types of ovarian carcinomas are distinguished with respect to morphology, biology, and clinical course, and are designated as Type I and Type II tumors. However, placement of clear cell carcinomas into one of these 2 groups has been problematic as they exhibit morphologic, molecular, and clinical features that do not entirely resemble either Type I or Type II tumors. The present study aimed at better elucidating the clinicopathologic and immunohistochemical features of clear cell carcinomas, in comparison with the 2 main broad categories. To this end, a panel of classic clinicopathologic and immunohistochemical parameters, including estrogen receptor α (ERα), ERβ, progesterone receptor, Ki67, p53, and HER2/neu was evaluated in 71 Type I, 157 Type II, and 21 clear cell carcinomas. Overall, findings from the present study support the idea that ovarian clear cell carcinomas are neither Type I nor Type II carcinomas of the ovary; indeed, results obtained showed that similarities between clear cell carcinomas and Type I were limited to the patient's age, tumor dimension, incidence of lymph node and extranodal metastases, and p53 labeling index, whereas the patient's age and incidence of extranodal metastases were the only parameters comparable with the Type II group. The hormonal receptor profile of clear cell carcinomas was characterized by low expression of nuclear ERα and progesterone receptor, and by almost exclusively nuclear ERβ immunopositivity, features significantly different from both Type I and II tumors. Finally, the percentage of HER2/neu-positive samples in clear cell carcinomas was 10- and 2.5-fold higher than Type I and Type II ovarian tumors, respectively. In conclusion, our study provides insights into clear cell carcinoma that could help in explaining its unique prognostic features, and, eventually, in orienting toward new therapeutic options.

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.

Utility of hepatocyte nuclear factor‐1β as a diagnostic marker in ovarian carcinomas with clear cells

Overexpression of hepatocyte nuclear factor-1β (HNF-1β) has been found in ovarian clear cell carcinoma (OCCC) but not in other types of ovarian carcinoma. The aim of this study was to clarify whether the overexpression of HNF-1β is specific for OCCC, and does not occur in ovarian carcinoma with clear cell change. Immunohistochemistry was performed on 178 ovarian carcinomas with clear cells (80 OCCCs, 60 high-grade serous, 25 endometrioid, and 13 mixed endometrioid and clear cell), 22 ovarian high-grade serous carcinomas without clear cells, 41 renal cell carcinomas (RCCs) and 20 hepatocellular carcinomas (HCCs) with clear cytoplasm. Results were evaluated using an H-score (percentage × intensity). Most OCCCs were diffusely and strongly positive (mean H-score 15.1). High-grade serous carcinoma and endometrioid carcinoma with clear cells were usually negative or focally and weakly positive (mean H-scores 1.5 and 1.7, respectively). High-grade serous carcinoma without clear cells had a mean H-score of 0.77. The mean H-scores of the endometrioid and clear cell components in mixed endometrioid and clear cell carcinoma were 6.2 and 15.7, respectively. HNF-1β was expressed in 95.1% of RCCs and in 30% of HCCs. The diagnosis of ovarian carcinomas with clear cells can be made with greater accuracy by using the intensity and extent of immunoreactivity for HNF-1β.

Association of a Newly Identified Variant of DNA Polymerase Beta (polβΔ63-123, 208-304) with the Risk Factor of Ovarian Carcinoma in India

DNA polymerase is a single-copy gene that is considered to be part of the DNA repair machinery in mammalian cells. The encoded enzyme is a key to the base excision repair (BER) pathway. It is evident that pol beta has mutations in various cancer samples, but little is known about ovarian cancer. Identification of any variant form of polβ cDNA in ovarian carcinoma and determination of association between the polymorphism and ovarian cancer risk in Indian patients. We used 152 samples to isolate and perform RT-PCR and sequencing. A variant of polymerase beta (deletion of exon 4-6 and 11-13, comprising of amino acid 63-123, and 208-304) is detected in heterozygous condition. The product size of this variant is 532 bp while wild type pol beta is 1 kb. Our study of association between the variant and the endometrioid type shows that it is a statistically significant factor for ovarian cancer [OR=31.9 (4.12-246.25) with p<0.001]. The association between variant and stage IV patients further indicated risk (χ2 value of 29.7, and OR value 6.77 with 95% CI values 3.3-13.86). The correlation study also confirms the association data (Pearson correlation values for variant/stage IV and variant/endometrioid of 0.44 and 0.39). Individuals from this part of India with this type of variant may be at risk of stage IV, endometrioid type ovarian carcinoma.

Abstract 884: Basonuclin1 (BNC1): A novel therapeutic target in ovarian cancer identified through integrative TCGA-based functional genomic analysis

Abstract High-grade serous ovarian cancer (HGS-OvCa) is the most common and lethal type of ovarian carcinoma. While TCGA provides comprehensive genomic profiling of clinically annotated HGS-OvCa tumors, identification of novel therapeutic targets using this dataset is still needed. We coupled TCGA mRNA expression and clinical response data to systematically identify genes which could alter progression of HGS-OvCa and investigated associated alterations in DNA promoter methylation and microRNA expression. For selected targets, we also used siRNA functional studies to clarify gene-specific effects. We identified 102 genes as up-regulated in tumors from patients whose cancer had progressed within 7 months of diagnosis (chemo-resistant group: 53 cases) compared to tumors from patients who had no disease progression for more than 3 years (chemo-sensitive group: 57 cases). These genes had two-sample t-test p-values &amp;lt; 0.05 according to level 3 TCGA data from both Agilent and Affymetrix platforms. Basonuclin1 (BNC1), a transcription factor which regulates ribosomal biogenesis, cell proliferation, and epithelial differentiation, was one of the key targets identified. Its expression was found to be increased by more than two-fold (Agilent platform; p=0.001) in chemo-resistant tumors. While no significant associated changes in microRNA expression were evident in TCGA for the BNC1 gene, we found that the expression of BNC1 negatively correlated with the degree of methylation at the promoter region of transmembrane 4 superfamily member 1, TM4SF1 (-0.42, Agilent platform), a known up-regulated pro-angiogenic gene in ovarian cancer. Importantly, the siRNA functional study had revealed a 35% reduction in cell viability in cisplatin-resistant A2780-CP20 cells following BNC1 siRNA treatment, and a further 15% reduction was noted when the cells were treated with cisplatin at the IC30 concentration determined using the chemo-sensitive parental cell line. Overall, our results demonstrate (a) the feasibility of using TCGA data, coupled with functional siRNA studies, to identify novel targets for the treatment of ovarian cancer and (b) the potential of targeting BNC1 as a treatment strategy. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 884. doi:1538-7445.AM2012-884

In Silico Analysis and Immunohistochemical Characterization of NaPi2b Protein Expression in Ovarian Carcinoma With Monoclonal Antibody Mx35

Ovarian adenocarcinoma is frequently detected at the late stage, when therapy efficacy is limited and death occurs in up to 50% of the cases. A potential novel treatment for this disease is a monoclonal antibody that recognizes phosphate transporter sodium-dependent phosphate transporter protein 2b (NaPi2b). To better understand the expression of this protein in different histologic types of ovarian carcinomas, we immunostained 50 tumor samples with anti-NaPi2b monoclonal antibody MX35 and, in parallel, we assessed the expression of the gene encoding NaPi2b (SCL34A2) by in silico analysis of microarray data. Both approaches detected higher expression of NaPi2b (SCL34A2) in ovarian carcinoma than in normal tissue. Moreover, a comprehensive analysis indicates that SCL34A2 is the only gene of the several phosphate transporters genes whose expression differentiates normal from carcinoma samples, suggesting it might exert a major role in ovarian carcinomas. Immunohistochemical and mRNA expression data have also shown that 2 histologic subtypes of ovarian carcinoma express particularly high levels of NaPi2b: serous and clear cell adenocarcinomas. Serous adenocarcinomas are the most frequent, contrasting with clear cell carcinomas, rare, and with worse prognosis. This identification of subgroups of patients expressing NaPi2b may be important in selecting cohorts who most likely should be included in future clinical trials, as a recently generated humanized version of MX35 has been developed.

Ovarian Cancer is an Imported Disease: Fact or Fiction?

The cell of origin of ovarian cancer has been long debated. The current paradigm is that epithelial ovarian cancer (EOC) arises from the ovarian surface epithelium (OSE). OSE is composed of flat, nondescript cells more closely resembling the mesothelium lining the peritoneal cavity, with which it is continuous, rather than the various histologic types of ovarian carcinoma (serous, endometrioid, and clear cell carcinoma), which have a Müllerian phenotype. Accordingly, it has been argued that the OSE undergoes a process termed "metaplasia" to account for this profound morphologic transformation. Recent molecular and clinicopathologic studies not only have failed to support this hypothesis but also have provided evidence that EOC stems from Müllerian-derived extraovarian cells that involve the ovary secondarily, thereby calling into question the very existence of primary EOC. This new model of ovarian carcinogenesis proposes that fallopian tube epithelium (benign or malignant) implants on the ovary to give rise to both high-grade and low-grade serous carcinomas, and that endometrial tissue implants on the ovary and produces endometriosis, which can undergo malignant transformation into endometrioid and clear cell carcinoma. Thus, ultimately EOC is not ovarian in origin but rather is secondary, and it is logical to conclude that the only true primary ovarian neoplasms are germ cell and gonadal stromal tumors analogous to tumors in the testis. If this new model is confirmed, it has profound implications for the early detection and treatment of "ovarian cancer."

Transitional cell carcinoma of the ovary (Review)

Transitional cell carcinoma (TCC) of the ovary is a rare recently recognized subtype of ovarian epithelial cancer. Ovarian TCC has a modest response to chemotherapy, and metastatic TCC from the renal pelvis results in mortality. The clinical presentation is indistinguishable from other types of ovarian carcinoma. Histopathological examination remains the first tool used in the diagnosis of these heterogeneous tumors and in the separation of closely related tumors. Since it is generally accepted that surgical resection is the primary therapeutic approach, and patient outcomes following chemotherapy are better than for other types of ovarian cancers, it is a reasonable concept to detect tumors when they are still confined within the ovaries. Thus, the aim of this review was to describe typical cases of primary TCC, and to review the medical literature for information on TCC management in order to determine appropriate diagnostic methods and therapy.

Telomere length in different histologic types of ovarian carcinoma with emphasis on clear cell carcinoma

Ovarian carcinoma is composed of a heterogeneous group of tumors with distinct clinico-pathological and molecular features. Alteration of telomerase activity has been reported in ovarian tumors but the pattern of telomere length in their specific histological subtypes has not been reported. In this study, we performed quantitative telomere fluorescence in situ hybridization on a total of 219 ovarian carcinomas including 106 high-grade serous carcinomas, 26 low-grade serous carcinomas, 56 clear cell carcinomas and 31 low-grade endometrioid carcinomas. The mean relative telomere length of carcinoma to stromal cells was calculated as a telomere index. This index was significantly higher in clear cell carcinoma compared with the other histologic types (P=0.007). Overall there was no association between the telomere index and mortality, but when stratified by histologic types, the hazard ratio for death among women with clear cell carcinoma with a telomere index >1 was significantly increased at 4.93 (95% CI 1.64–14.86, P=0.005) when compared with those with a telomere index ≤1. In conclusion, our results provide new evidence that telomere length significantly differs by histologic type in ovarian carcinoma. Specifically, clear cell carcinomas have longer mean relative telomere lengths compared with the other histologic types and longer telomeres in clear cell carcinoma are associated with increased mortality suggesting that aberrations in telomere length may have an important role in the development and progression of this neoplasm.

Epithelial Ovarian Carcinoma Types and the Coexistence of Ovarian Tumor Conditions

Objective. Ovarian carcinomas are presumed to arise within ovarian inclusion cysts or from a coexisting epithelial lesion in the ovary. Insight may be gained by relating different subtypes of ovarian cancer with the presence of coexisting tumor-like conditions. Methods. The Dutch nation-wide pathology database PALGA (Pathologisch Anatomisch Landelijk Geautomatiseerd Archief) identified the various histopathological subtypes of ovarian cancer in 824 patients diagnosed in 1996–2003, and recorded the presence of epithelial tumor conditions around the ovarian tumors. In addition, a PALGA database of all 153 consecutive patients referred to the Nijmegen University Medical Centre in 2007 for histopathological work-up was analyzed. Results. The prevalence of coexisting ovarian tumor conditions was 16.4% (135 out of 824 patients, (95% CI: 8.4%–24.4%)). The coexistence was highest for endometrioid, mucinous, clear cell, and borderline malignancies. The referral group revealed 35% (54 out of 153 patients, (95% CI: 28%–42%)) of coexisting epithelial ovarian tumor conditions. Conclusion. One in six patients with a malignant ovarian tumor has a coexisting epithelial tumor condition in the ovary, which is also rather frequently observed in the diagnostic work-up practice.

Mucinous carcinomas of the ovary and colorectum: different organ, same dilemma

Mucinous carcinomas are uncommon histological types that affect several organ sites. Primary mucinous carcinomas of the ovary are distinct from other ovarian carcinoma types, but they can pose a particular challenge for correct diagnosis from metastases, which most usually originate from the colorectum. Correct diagnosis is the mainstay of treatment, because standard practice states that protocols are tailored to the primary organ site. Little is known of mutational alterations in primary and metastatic mucinous carcinomas of the ovary, and few markers exist that can discriminate between them. We reviewed commonalities between ovarian and colorectal mucinous carcinomas with respect to aetiology, molecular alterations, differential diagnosis, and implications for treatment. Although primary mucinous carcinomas of the ovary and colorectum share similar mutational patterns and unfavourable outcomes at advanced stage, compared with their non-mucinous counterparts, important differences exist with respect to mucin localisation and specific molecular alterations. Technologies--eg, next-generation sequencing--could aid identification of additional driver molecular changes that will help clarify the relation between mucinous carcinomas from different organ sites. Perhaps, then, we can consider moving towards testing and adoption of therapeutic approaches tailored to molecular characteristics of mucinous carcinomas, irrespective of organ site, so patients' survival can be optimised.

Significance of Cell Cycle Regulatory Proteins as Malignant and Prognostic Biomarkers in Ovarian Epithelial Tumors

The principal objective of this study was to comprehensively assess the clinicopathologic and prognostic impacts of the expression of various cell cycle regulatory proteins in patients with ovarian epithelial tumors. The tissue microarrays were constructed from formalin-fixed, paraffin-embedded tissues of 205 ovarian epithelial tumors. We investigated 55 benign (20 serous cystadenomas, 17 mucinous cystadenomas, and 18 endometriotic cysts), 72 borderline (26 serous borderline tumors and 46 mucinous borderline tumors), and 78 malignant tumors (45 serous carcinomas, 10 mucinous adenocarcinomas, 15 endometrioid adenocarcinomas, and 8 clear cell carcinomas). Immunohistochemical staining was performed using antibodies to p16(Ink4a), p53, p21(Waf1/Cip1), p27(Kip1), Cyclin D1, Cyclin E, Cyclin A, Cyclin B1, and Cyclin-dependent Kinase2. We noted significantly different levels of p53 and Cyclin B1 expressions between malignant and borderline tumors and between borderline and benign tumors excepting the mucinous type. The p21(Waf1/Cip1) and Cyclin A were significantly overexpressed in malignant tumors compared with borderline tumors. Cyclin A, Cyclin E, and p16(Ink4a) were more pronounced proteins, showing differential expression patterns among the histologic types of ovarian carcinomas. We determined that the overexpression of p16(Ink4a) (P=0.031), Cyclin E (P=0.009), and Cyclin-dependent Kinase2 (P=0.004) were significantly associated with higher tumor grades. Overexpression of p16(Ink4a) was correlated with both lymph node metastasis (P=0.030) and distant metastasis (P=0.034). Overexpression of Cyclin E was associated with advanced stage (P=0.004). Higher tumor grade (P=0.008), advanced stage (P=0.001), mucinous histologic type (P=0.012), low expression levels of p16(Ink4a) (P=0.032), and overexpression of p53 (P=0.032) were associated with poor overall survival on multivariate analysis in patients with ovarian cancer. In serous carcinomas, old age (P=0.005), distant metastasis (P=0.020), low expression of p16(Ink4a) (P=0.047), and overexpression of cytoplasmic p27(Kip1) (P=0.007) and Cyclin A (P=0.031) were all independent predictors of worse overall survival. Our data indicate that the overexpression of p16 and Cyclin E are valuable factors predicting disease progression and metastatic potential. Low p16(Ink4a) expression, overexpression of p53, cytoplasmic p27(Kip1), and Cyclin A are predictive markers for shorter overall survival in ovarian carcinomas.

Typing of ovarian carcinomas: an update

Classification of ovarian carcinomas into different subtypes is no longer only an exercise in pattern recognition that lacks clinical and biological significance. Biologically validated diagnostic criteria now separate ovarian carcinomas into specific disease types that have clinical relevance: high-grade serous carcinoma, low-grade serous carcinoma, endometrioid carcinoma, clear cell carcinoma and primary ovarian mucinous carcinoma. This review summarizes the clinical and pathologic features of these types of ovarian carcinoma and provides information about refined diagnostic criteria and the use of ancillary diagnostic techniques for diagnosis.