Ovarian Cancer
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Cancer of the ovaries are the second most common group of gynaecologic cancers, and account for about 5% of all women's cancers. There are two main types; (i) epithelial tumours (carcinomas) which account for 90% of ovarian cancers, and (ii) non-epithelial tumours (eg. Stroma cell and germ cell tumours of the ovary). The epithelial ovarian cancers are usually found in women aged over 40, while the non-epithelial tumours are more common in girls and young women. Epithelial ovarian cancer has few early symptoms, a risk factor is having a family history of the disease. Taking the contraceptive pill is known to be protective against ovarian cancer.

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Latest Research Publications

Information Patients and the Public (20 links)


Information for Health Professionals / Researchers (11 links)

Latest Research Publications

This list of publications is regularly updated (Source: PubMed).

Aich RK, Dasgupta S, Chakraborty B, et al.
Primary fallopian tube carcinoma with metastasis in the contralateral ovary.
J Indian Med Assoc. 2012; 110(7):494-5, 498 [PubMed]
Primary malignant neoplasm of the fallopian tube is one of the rarest gynaecological malignancies and a pre-operative diagnosis is often missed due to its diagnostic confusion with the tubo-ovarian mass, hydrosalpinx, ectopic pregnancy and ovarian malignancy. Transcoelomic, lymphatic, transluminal and haematogenous spread may occur to the other abdominal and pelvic organs as well as to the distant sites. Though the body of the uterus, ovaries and the contralateral fallopian tube are frequently involved, in the present case the contralateral ovary was the only site of involvement which is very unusual.


Nezhat FR, Denoble SM, Cho JE, et al.
Safety and efficacy of video laparoscopic surgical debulking of recurrent ovarian, fallopian tube, and primary peritoneal cancers.
JSLS. 2012 Oct-Dec; 16(4):511-8 [PubMed] Free Access to Full Article
BACKGROUND AND OBJECTIVE: Studies on the role of laparoscopy in secondary or tertiary cytoreduction for recurrent ovarian cancer are limited. Our objective is to describe our preliminary experience with laparoscopic secondary/tertiary cytoreduction in patients with recurrent ovarian, fallopian, and primary peritoneal cancers.
METHODS: This is a retrospective analysis of a prospective case series. Women with recurrent ovarian, fallopian tube, or primary peritoneal cancers deemed appropriate candidates for laparoscopic debulking by the primary surgeon(s) were recruited. The patients underwent exploratory video laparoscopy, biopsy, and laparoscopic secondary/tertiary cytoreduction between June 1999 and October 2009. Variables analyzed include stage, site of disease, extent of cytoreduction, operative time, blood loss, length of hospital stay, complications, and survival time.
RESULTS: Twenty-three patients were recruited. Only one surgery involved conversion to laparotomy. Seventeen (77.3%) of the patients had stage IIIC disease at the time of their initial diagnosis, and 20 (90.9%) had laparotomy for primary debulking. Median blood loss was 75 mL, median operative time 200 min, and median hospital stay 2 d. No intraoperative complications occurred. One patient (4.5%) had postoperative ileus. Eighteen (81.8%) of the patients with recurrent disease were optimally cytoreduced to 1cm. Overall, 12 patients have no evidence of disease (NED), 6 are alive with disease (AWD), and 4 have died of disease (DOD), over a median follow-up of 14 mo. Median disease-free survival was 71.9 mo.
CONCLUSIONS: In a well-selected population, laparoscopy is technically feasible and can be utilized to optimally cytoreduce patients with recurrent ovarian, fallopian, or primary peritoneal cancers.


Tsubamoto H, Kawaguchi R, Ito K, et al.
Phase II study of carboplatin and weekly irinotecan combination chemotherapy in recurrent ovarian cancer: a Kansai clinical oncology group study (KCOG0330).
Anticancer Res. 2013; 33(3):1073-9 [PubMed]
BACKGROUND: A multicenter phase II trial was conducted to evaluate the efficacy and toxicity of irinotecan plus carboplatin chemotherapy in patients with epithelial ovarian cancer (EOC).
PATIENTS AND METHODS: Patients with either radiologically- or serologically-recurrent EOC were administered intravenous irinotecan (60 mg/m(2); days 1 and 8) and carboplatin area under the curve of 5 mg/ml/min (day 1), repeated every 21 days. The primary end-point was response rate (RR), while the secondary end-points were adverse events and progression-free survival (PFS).
RESULTS: Between 2005 and 2009, 40 patients (median age=59 years) with EOC were enrolled. Intention-to-treat analysis showed an RR of 43% [95% confidence interval (CI)=27-58%]. For patients with a platinum-free interval (PFI) of <6 months, overall RR based on RECIST was 21% (95% CI=0-43%) and median PFS was 3.7 months (95% CI=2.5-7.7 months), while those in patients with PFI ≥6 months were 52% (95% CI=31-74%) and 9.1 months (95% CI=7.9-11.2 months), respectively. Grade 3/4 toxicity encountered during the first cycle included G3/G4 neutropenia in 65% of patients (12/14), G3/G4 thrombocytopenia in 48% (18/1), G3 febrile neutropenia in 5% (2), G3 nausea in 5% (2), G3 diarrhea in 5% (2), and G3 fatigue in 5% of patients (2).
CONCLUSION: This carboplatin plus irinotecan combination demonstrated a modest activity in recurrent EOC. However, considering its hematological toxicities, the regimen should be further investigated to establish the feasibility of the modified dose for platinum-sensitive disease.


Jung PS, Kim DY, Kim MB, et al.
Progression-free survival is accurately predicted in patients treated with chemotherapy for epithelial ovarian cancer by the histoculture drug response assay in a prospective correlative clinical trial at a single institution.
Anticancer Res. 2013; 33(3):1029-34 [PubMed]
This study aimed to prospectively correlate clinical outcomes of advanced epithelial ovarian cancer (AEOC), with the results of in vitro chemosensitivity testing of taxol and carboplatin using the in vitro histoculture drug response assay (HDRA). A total of 104 patients with AEOC were treated with combination chemotherapy of taxol and carboplatin after primary cytoreductive surgery between 2007 and 2012 at the Asan Medical Center, Seoul, Korea. To compare chemosensitivity in the HDRA with clinical response, all patients were first categorized into two groups as either sensitive to both taxol and carboplatin (SS), or not sensitive to one or both drugs (R) based on HDRA results. The recurrence rate was much lower in the SS group compared to the R group; 29.2% vs 69.8%, respectively (p=0.02). The SS group had a significantly longer progression-free survival compared to the R group, 34.0 months vs 16.0 months, respectively (p=0.025). These results demonstrate that the HDRA prospectively correlates to clinical outcome from chemotherapy and that treatment regimens can be individualized based on the HDRA.


Paulsson G, Andersson S, Sorbe B
A population-based series of ovarian carcinosarcomas with long-term follow-up.
Anticancer Res. 2013; 33(3):1003-8 [PubMed]
AIM: The aim of the present study was to evaluate a consecutive series of ovarian carcinosarcomas with regard to prognosis, treatment and prognostic factors.
PATIENTS AND METHODS: A consecutive series of 81 ovarian carcinosarcomas from two well-defined geographic regions were studied with regard to survival, type of primary and adjuvant therapy and prognostic factors. All patients but one underwent primary surgery and some patients also received adjuvant chemotherapy (platinum-based) alone or in combination with radiotherapy. Univariate and multivariate Cox proportional regression analysis was used. Survival was analyzed by the Kaplan-Meier technique and differences were assessed by the log-rank test.
RESULTS: The mean age of the patients was 73 years. Fifty-one patients received adjuvant chemotherapy and nine patients pelvic irradiation. The 5-year overall survival rate was 10%. Adjuvant therapy (any type) and six completed cycles of chemotherapy were highly significant factors with regard to improved overall survival rate. The only significant tumor-associated prognostic factor was the International Federation of Gynecology and Obstetrics (FIGO) grade of the tumor. FIGO stage, site of metastatic spread, tumor size, histology, DNA ploidy, and tumor necrosis were non-significant factors. Therapy was rather well-tolerated and 29 patients (57%) completed at least six cycles of adjuvant chemotherapy.
CONCLUSION: Adjuvant and completed chemotherapy according to the treatment plan were the most important prognostic factors. FIGO grade (grade 3 vs. 1-2) of the epithelial component of the tumor was also a significant prognostic factor in multivariate Cox analysis.


Zou B, Li QQ, Zhao J, et al.
β-Elemene and taxanes synergistically induce cytotoxicity and inhibit proliferation in ovarian cancer and other tumor cells.
Anticancer Res. 2013; 33(3):929-40 [PubMed]
β-Elemene, originally derived from plants, has been recently investigated as a new anticancer agent. The purpose of this study was to explore the efficacy and mechanisms of action of the combined use of β-elemene plus a taxane as an antitumor therapeutic strategy for ovarian cancer and other carcinomas. The interaction of β-elemene with paclitaxel or docetaxel produced additive to moderately synergistic effects against the platinum-resistant ovarian cancer cell line A2780/CP70 and its parental cell line A2780, and showed moderately synergistic activity against PC-3 prostate cancer cells. In addition, the co-administration of β-elemene and a taxane at low-micromolar concentrations dramatically increased the rate of micronucleus formation and the percentage of mitotic arrest in both ovarian cancer cell lines, as compared with treatment with either agent alone. The highest synergy towards the ovarian cancer cells was observed with β-elemene plus docetaxel. Consistent with these data, treatment of A2780/CP70 cells with β-elemene plus a taxane strikingly reduced cell viability and increased cell apoptosis, as assessed by annexin V binding. Moreover, β-elemene plus docetaxel induced elevated levels of caspase-9 and p53 proteins in A2780/CP70 cells, and the combination of β-elemene plus a taxane caused marked cell-cycle arrest at the G2/M phase in these cells. One possible mechanism to account for the enhanced cytotoxic efficacy of this combination treatment is a β-elemene-induced increase in taxane influx into cancer cells. These observations indicate that combination therapy with β-elemene and taxanes has synergistic antitumor activity against ovarian and prostate carcinomas in vitro. This promising new therapeutic combination warrants further pre-clinical exploration for the treatment of chemoresistant ovarian cancer and other types of tumors.


Shah MM, Zerlin M, Li BY, et al.
The role of Notch and gamma-secretase inhibition in an ovarian cancer model.
Anticancer Res. 2013; 33(3):801-8 [PubMed]
BACKGROUND: The Notch pathway is dysregulated in ovarian cancer. We sought to examine the role of Notch and gamma-secretase (GS) inhibition in ovarian cancer.
MATERIALS AND METHODS: Established ovarian cancer cell lines were used. Quantitative polymerase chain reaction (qPCR) was used to determine the relative expression of Notch receptor and ligands. Effects of GS inhibition on proliferation, colony formation, and downstream effectors were examined via methylthiazole tetrazolium (MTT) and Matrigel assays, and qPCR, respectively. In vivo experiments with a GS inhibitor and cisplatin were conducted on nude mice. Tumors were examined for differences in microvessel density, proliferation, and apoptosis.
RESULTS: Notch3 was the most up-regulated receptor. The ligands JAGGED1 and DELTA-LIKE4 were both up-regulated. GS inhibition did not affect cellular proliferation or anchorage-independent cell growth over placebo. The GS inhibitor Compound-E reduced microvessel density in vivo.
CONCLUSION: GS inhibition does not directly affect cellular proliferation in ovarian carcinoma, but Notch pathway blockade may result in angiogenic alterations that may be therapeutically important.


Huang CY, Ho CM, Chen YL, et al.
Impact of lymphadenectomy in uterine endometrioid carcinoma.
Eur J Surg Oncol. 2013; 39(4):350-7 [PubMed]
AIMS: To investigate the role of lymphadenectomy in uterine endometrioid carcinoma based on the 2009 FIGO staging system.
METHODS: Using an institution-maintained cancer registry database, all patients who were treated surgically for endometrial cancer from 1991 to 2008 in two medical centers were analyzed. Kaplan-Meier and Cox proportional hazards methods were used to determine the role of lymphadenectomy.
RESULTS: From 961 women with uterine endometrioid carcinoma, 680 underwent lymphadenectomy and 281 did not. Young age, early-stage disease, low-grade tumor, and lymphadenectomy were favorable independent prognostic factors. The five-year disease-specific survival (DSS) of stages IA, IB, II, and III, and the two-year DSS of stage IV patients who underwent lymphadenectomy were 97.8%, 88.3%, 91.5%, 70.5%, and 32.1%, respectively, compared to 98.7%, 70.0%, 73.3%, 42.9%, and 16.6% in those without lymphadenectomy (p > 0.05 for stage IA; p < 0.01 for stages IB-IV, log-rank test). In high-risk patients (i.e., poorly-differentiated, outer-half myometrial invasion, and stages II-IV), more extensive lymph node resection was associated with an improved five-year DSS, from 71.3% (1-10 nodes removed) and 85.3% (11-20 nodes removed) to 86.8% (>20 nodes removed) (p = 0.02, log-rank test). For stage IIIC-IV patients with nodal metastasis, the extent of node resection also significantly improved the five-year DSS, from 34.4% (1-10 nodes removed) and 62.4% (11-20 nodes removed) to 79.6% (>20 nodes removed) (p = 0.04, log-rank test).
CONCLUSIONS: Lymphadenectomy improves the survival of patients with uterine endometrioid carcinoma stage IB to stage IV. The extent of lymphadenectomy also improves the survival of high-risk patients and those with nodal disease.


Al-Loh S, Al-Hussaini M
Undifferentiated endometrial carcinoma: a diagnosis frequently overlooked.
Arch Pathol Lab Med. 2013; 137(3):438-42 [PubMed]
Undifferentiated endometrial carcinoma (UEC) is a relatively uncommon neoplasm with only few studies published thus far. It has always been a diagnostic challenge because of the lack of proper definition cited in most of the standard textbooks. Recently however, a few studies have highlighted the clinicopathologic features of UEC. The distinctive morphology of UEC was noted by the group from MD Anderson Cancer Center, which enabled them to establish the defining criteria. It appears to be more aggressive than endometrial endometrioid adenocarcinoma, FIGO (International Federation of Gynecology and Obstetrics) grade 3, its main differential diagnosis. Proper recognition of this entity is important owing to its aggressive behavior.


Al Rawahi T, Lopes AD, Bristow RE, et al.
Surgical cytoreduction for recurrent epithelial ovarian cancer.
Cochrane Database Syst Rev. 2013; 2:CD008765 [PubMed]
BACKGROUND: The standard management of primary ovarian cancer is optimal cytoreductive surgery followed by platinum-based chemotherapy. Most women with primary ovarian cancer achieve remission on this combination therapy. For women achieving clinical remission after completion of initial treatment, most (60%) with advanced epithelial ovarian cancer will ultimately develop recurrent disease. However, the standard treatment of women with recurrent ovarian cancer remains poorly defined. Surgery for recurrent ovarian cancer has been suggested to be associated with increased overall survival.
OBJECTIVES: To evaluate the effectiveness and safety of optimal secondary cytoreductive surgery for women with recurrent epithelial ovarian cancer. To assess the impact of various residual tumour sizes, over a range between 0 cm and 2 cm, on overall survival.
SEARCH METHODS: We searched the Cochrane Gynaecological Cancer Group Trials Register, MEDLINE, EMBASE and the Cochrane Central Register of Controlled Trials (CENTRAL) up to December 2012. We also searched registers of clinical trials, abstracts of scientific meetings, reference lists of included studies and contacted experts in the field. For databases other than MEDLINE, the search strategy has been adapted accordingly.
SELECTION CRITERIA: Retrospective data on residual disease, or data from randomised controlled trials (RCTs) or prospective/retrospective observational studies that included a multivariate analysis of 50 or more adult women with recurrent epithelial ovarian cancer, who underwent secondary cytoreductive surgery with adjuvant chemotherapy. We only included studies that defined optimal cytoreduction as surgery leading to residual tumours with a maximum diameter of any threshold up to 2 cm.
DATA COLLECTION AND ANALYSIS: Two review authors (KG, TA) independently abstracted data and assessed risk of bias. Where possible the data were synthesised in a meta-analysis.
MAIN RESULTS: There were no RCTs; however, we found nine non-randomised studies that reported on 1194 women with comparison of residual disease after secondary cytoreduction using a multivariate analysis that met our inclusion criteria. These retrospective and prospective studies assessed survival after secondary cytoreductive surgery in women with recurrent epithelial ovarian cancer.Meta- and single-study analyses show the prognostic importance of complete cytoreduction to microscopic disease, since overall survival was significantly prolonged in these groups of women (most studies showed a large statistically significant greater risk of death in all residual disease groups compared to microscopic disease).Recurrence-free survival was not reported in any of the studies. All of the studies included at least 50 women and used statistical adjustment for important prognostic factors. One study compared sub-optimal (> 1 cm) versus optimal (< 1 cm) cytoreduction and demonstrated benefit to achieving cytoreduction to less than 1 cm, if microscopic disease could not be achieved (hazard ratio (HR) 3.51, 95% CI 1.84 to 6.70). Similarly, one study found that women whose tumour had been cytoreduced to less than 0.5 cm had less risk of death compared to those with residual disease greater than 0.5 cm after surgery (HR not reported; P value < 0.001).There is high risk of bias due to the non-randomised nature of these studies, where, despite statistical adjustment for important prognostic factors, selection is based on retrospective achievability of cytoreduction, not an intention to treat, and so a degree of bias is inevitable.Adverse events, quality of life and cost-effectiveness were not reported in any of the studies.
AUTHORS' CONCLUSIONS: In women with platinum-sensitive recurrent ovarian cancer, ability to achieve surgery with complete cytoreduction (no visible residual disease) is associated with significant improvement in overall survival. However, in the absence of RCT evidence, it is not clear whether this is solely due to surgical effect or due to tumour biology. Indirect evidence would support surgery to achieve complete cytoreduction in selected women. The risks of major surgery need to be carefully balanced against potential benefits on a case-by-case basis.


Shylasree TS, Bryant A, Athavale R
Chemotherapy and/or radiotherapy in combination with surgery for ovarian carcinosarcoma.
Cochrane Database Syst Rev. 2013; 2:CD006246 [PubMed]
BACKGROUND: Ovarian carcinosarcoma, also known as malignant mixed Mullerian tumour, is a rare malignant gynaecological tumour constituting about 1% or less of all ovarian cancers. In over 80% of cases, there is extra-ovarian intra-abdominal spread at diagnosis. The primary treatment has traditionally been surgical cytoreduction followed by radiotherapy and chemotherapy or chemotherapy alone. Regimes have included cisplatin alone; a combination of doxorubicin, ifosfamide, dacarbazine, cyclophosphamide, taxol; and various other combinations. The effectiveness of these various regimens appears to be mixed. Therefore, there is a need to clarify if there is an optimum neoadjuvant or adjuvant therapy after surgical cytoreduction for this rare tumour. Also, it is important to address quality of life (QoL) issues related to treatment, particularly toxicity, as the overall prognosis appears to be poor.
OBJECTIVES: To assess the effectiveness and safety of various adjuvant and neoadjuvant chemotherapy and radiotherapy options or chemotherapy alone in combination with surgery in the management of ovarian carcinosarcoma.
SEARCH METHODS: We searched the Cochrane Gynaecological Cancer Group Trials Register, the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE and EMBASE up to February 2012. We also searched registers of clinical trials, abstracts of scientific meetings, reference lists of review articles and contacted experts in the field.
SELECTION CRITERIA: We searched for randomised controlled trials (RCTs) that compared neoadjuvant or adjuvant chemotherapy and radiotherapy, or chemotherapy alone, in women with ovarian carcinosarcoma (malignant mixed Mullerian sarcoma of the ovary). We also reviewed non-randomised studies (NRS) for discussion in the absence of RCTs.
DATA COLLECTION AND ANALYSIS: Two review authors independently assessed whether potentially relevant studies met the inclusion criteria. No trials were found and therefore no data were analysed.
MAIN RESULTS: The search strategy identified 297 unique references of which all were excluded.
AUTHORS' CONCLUSIONS: We found no evidence to inform decisions about neoadjuvant and adjuvant chemotherapy and radiotherapy regimens, or chemotherapy alone, for women with ovarian carcinosarcoma. Ideally, an RCT that is multicentre or multinational, or well designed non-randomised studies that use multivariate analysis to adjust for baseline imbalances, are needed to compare treatment modalities and improve current knowledge. Further research in genetic and molecular signalling pathways might improve understanding of this tumour subtype.


Lawrie TA, Medeiros LR, Rosa DD, et al.
Laparoscopy versus laparotomy for FIGO stage I ovarian cancer.
Cochrane Database Syst Rev. 2013; 2:CD005344 [PubMed]
BACKGROUND: This is an updated version of the original review that was first published in the Cochrane Database of Systematic Reviews 2008, Issue 4. Laparoscopy has become an increasingly common approach to surgical staging of apparent early-stage ovarian tumours. This review was undertaken to assess the available evidence on the benefits and risks of laparoscopy compared with laparotomy for the management of International Federation of Gynaecology and Obstetrics (FIGO) stage I ovarian cancer.
OBJECTIVES: To evaluate the benefits and risks of laparoscopy compared with laparotomy for the surgical treatment of FIGO stage I ovarian cancer (stages Ia, Ib and Ic).
SEARCH METHODS: For the original review, we searched the Cochrane Gynaecological Cancer Group Trials (CGCRG) Register, Cochrane Central Register of Controlled Trials (CENTRAL 2007, Issue 2), MEDLINE, EMBASE, LILACS, Biological Abstracts and CancerLit from 1 January 1990 to 30 November 2007. We also handsearched relevant journals, reference lists of identified studies and conference abstracts. For this updated review, we extended the CGCRG Specialised Register, CENTRAL, MEDLINE, EMBASE and LILACS searches to 6 December 2011.
SELECTION CRITERIA: Randomised controlled trials (RCTs), quasi-RCTs and prospective case-control studies comparing laparoscopic staging with open surgery (laparotomy) in women with stage I ovarian cancer according to FIGO.
DATA COLLECTION AND ANALYSIS: There were no studies to include, therefore we tabulated data from non-randomised studies (NRS) for discussion.
MAIN RESULTS: We performed no meta-analyses.
AUTHORS' CONCLUSIONS: This review has found no good-quality evidence to help quantify the risks and benefits of laparoscopy for the management of early-stage ovarian cancer as routine clinical practice.


Bunyavejchevin S, Phupong V
Laparoscopic surgery for presumed benign ovarian tumor during pregnancy.
Cochrane Database Syst Rev. 2013; 1:CD005459 [PubMed]
BACKGROUND: The surgical management of ovarian tumors in pregnancy is similar to that of non-pregnant women. The procedures include resection of the tumor (enucleation), removal of an ovary or ovaries (oophorectomy), or surgical excision of the fallopian tube and ovary (salpingo-oophorectomy). The procedure can be done by open surgery (laparotomy) or keyhole surgery (laparoscopy) technique. The benefits of laparoscopic surgery include shorter hospital stay, earlier return to normal activity, and reduced postoperative pain. However, conventional laparoscopic surgery techniques required the infusion of gas carbon dioxide in the peritoneum to distend the abdomen and displace the bowel upward to create the room for surgical manipulation. Serious complications such as abnormally high levels of carbon dioxide in the circulating blood (hypercarbia) and perforation of internal organs have also been reported. These serious complication may be harmful to the fetus.
OBJECTIVES: To compare the effects of using laparoscopic surgery for benign ovarian tumor during pregnancy on maternal and fetal health and the use of healthcare resources.
SEARCH METHODS: We updated the search of the Cochrane Pregnancy and Childbirth Group's Trials Register on 11 November 2012.
SELECTION CRITERIA: Randomized controlled trials with reported data that compared outcomes of laparoscopic surgery for benign ovarian tumor in pregnancy to conventional laparotomy technique.
DATA COLLECTION AND ANALYSIS: Two review authors planned to independently assess trial quality and extract data.
MAIN RESULTS: The updated search did not identify any randomized controlled trials.
AUTHORS' CONCLUSIONS: The practice of laparoscopic surgery for benign ovarian tumour during pregnancy is associated with benefits and harms. However, the evidence for the magnitude of these benefits and harms is drawn from case series studies, associated with potential bias. The results and conclusions of these studies must therefore be interpreted with caution.The available case series studies of laparoscopic surgery for benign ovarian tumour during pregnancy provide limited insight into the potential benefits and harms associated with this new surgical technique in pregnancy. Randomized controlled trials are required to provide the most reliable evidence regarding the benefits and harms of laparoscopic surgery for benign ovarian tumour during pregnancy.


Ferraro S, Braga F, Lanzoni M, et al.
Serum human epididymis protein 4 vs carbohydrate antigen 125 for ovarian cancer diagnosis: a systematic review.
J Clin Pathol. 2013; 66(4):273-81 [PubMed]
BACKGROUND: Human epididymis protein 4 (HE4) measurements in serum have been proposed for improving the specificity of laboratory identification of ovarian cancer (OC).
OBJECTIVE: To critically revise the available literature on the comparison between the diagnostic accuracy of HE4 and carbohydrate antigen 125 (CA-125) to confirm the additional clinical value of HE4.
METHODS: A literature search was undertaken on electronic databases and references from retrieved articles; articles were analysed according to predefined criteria. Meta-analyses for HE4 and CA-125 biomarkers with OR, diagnostic sensitivity, specificity, positive (LR+) and negative (LR-) likelihood ratios as effect sizes were performed.
RESULTS: 16 articles were originally included in meta-analyses, but two for HE4 and one for CA-125 were eliminated as outliers. Furthermore, for HE4 a publication bias was detected. ORs for both HE4 (37.2, 95% CI 19.0 to 72.7, adjusted for publication bias) and CA-125 (15.4, 95% CI 10.4 to 22.8) were significant, although in a heterogeneous set of studies (p<0.0001). By combining sensitivity and specificity, the overall LR+ and LR- were 13.0 (95% CI 8.2 to 20.7) and 0.23 (95% CI 0.19 to 0.28) for HE4 and 4.2 (95% CI 3.1 to 5.6) and 0.27 (95% CI 0.23 to 0.31) for CA-125, respectively.
CONCLUSIONS: HE4 measurement seems to be superior to CA-125 in terms of diagnostic performance for identification of OC in women with suspected gynaecological disease. Due to the high prevalence of OC in post-menopausal women and the need for data focused on early tumour stages, more studies tailored on these specific subsets are needed.


Kipps E, Tan DS, Kaye SB
Meeting the challenge of ascites in ovarian cancer: new avenues for therapy and research.
Nat Rev Cancer. 2013; 13(4):273-82 [PubMed]
Malignant ascites presents a considerable clinical challenge to the management of ovarian cancer, but also provides a wealth of opportunities for translational research. The accessibility of ascitic fluid and its cellular components make it an excellent source of tumour tissue for the investigation of prognostic and predictive biomarkers, pharmacodynamic markers and for molecular profiling analysis. In this Opinion article, we discuss recent advances in our understanding of its pathophysiology, the development of new methods to characterize its molecular features and how these findings can be used to improve the treatment of malignant ascites, particularly in the context of ovarian cancer.


Karamurzin Y, Soslow RA, Garg K
Histologic evaluation of prophylactic hysterectomy and oophorectomy in Lynch syndrome.
Am J Surg Pathol. 2013; 37(4):579-85 [PubMed]
Women with Lynch syndrome (LS) are at increased risk for endometrial (EC) and ovarian carcinoma (OC). Current surveillance recommendations for detection of EC and OC in LS patients are not effective. Small studies have shown that prophylactic hysterectomy and bilateral salpingo-oophorectomy (P-TH-BSO) are the most effective and least expensive preventive measures in these patients. Data regarding histologic findings in prophylactic specimens in these patients are lacking. All LS patients who underwent P-TH-BSO at the Memorial Sloan-Kettering Cancer Center from 2000 to 2011 were identified. Slides were evaluated for the presence of endometrial hyperplasia (EH), EC, OC, or any other recurrent histologic findings. Twenty-five patients were identified, with an age range of 36 to 61 years. Fifteen patients had a synchronous or prior colorectal carcinoma, and 2 patients had a history of sebaceous carcinoma. Focal FIGO grade 1 endometrioid ECs were detected in 2 patients; 1 was 54 years of age (MSH2 mutation; superficially invasive), and the other was 56 years of age (MLH1 mutation; noninvasive). Focal complex atypical hyperplasia, unassociated with carcinoma, was seen in 3 patients, ages 35 and 45 (MLH1 mutations) and 53 years (MSH2 mutation). One patient (44 y, with MSH2 mutation) was found to have a mixed endometrioid/clear cell OC and simple EH without atypia. The OC was adherent to the colon but did not show distant metastasis. In our study, P-TH-BSOs performed because of the presence of LS revealed incidental EC and/or EH in 24% of cases and OC in 4%. The ECs were low grade, confined to the endometrium, and seen in patients older than 50 years. Prophylactic hysterectomy allows detection of early lesions in LS; these lesions appear to be small and focal. This small series of prophylactic hysterectomies may provide some clues about LS-associated endometrial carcinogenesis.


Park JY, Nam JH, Kim YT, et al.
Poor prognosis of uterine serous carcinoma compared with grade 3 endometrioid carcinoma in early stage patients.
Virchows Arch. 2013; 462(3):289-96 [PubMed]
Difference in prognosis between grade 3 endometrioid carcinoma (G3EC) of the endometrium and uterine serous carcinoma (USC) is controversial. In this study, we further evaluated the difference in prognosis, if any, between G3EC (n = 61) and USC (n = 47) on a total of 565 patients with endometrial cancer. In addition, meta-analysis was performed using data from seven previous publications (n = 8,637) and from the Asan Medical Center (n = 108). Regarding the cases from our institution, USC tended to occur in older patients (≥65 years) than G3EC (P = 0.011). Deep myometrial invasion (more than or equal to half) was more frequently identified in G3EC (36/61, 59.0 %) than in USC (17/47, 36.2 %) (P = 0.021). Between patients with early stage G3EC and USC (stages I and II), there were no significant differences in any clinicopathological parameter, but there was a significant difference in overall survival (P = 0.017) that was not found in advanced stage (P = 0.588). USC was an independent prognostic factor for poor overall survival (hazard ratio, 6.125; P = 0.030) in early stage patients. In the meta-analysis on 5-year survival in patients with early stage cancers, which also included our study results, a higher relative risk (1.92, 95 % CI 1.62-2.27) was demonstrated in USC than in G3EC (P < 0.001). In conclusion, our study reveals that USC is associated with a poorer prognosis compared with G3EC, only in patients with early stage carcinoma, suggesting that different treatment strategies should be considered according to the histologic type in order to improve treatment outcome.


Germano G, Frapolli R, Belgiovine C, et al.
Role of macrophage targeting in the antitumor activity of trabectedin.
Cancer Cell. 2013; 23(2):249-62 [PubMed]
There is widespread interest in macrophages as a therapeutic target in cancer. Here, we demonstrate that trabectedin, a recently approved chemotherapeutic agent, induces rapid apoptosis exclusively in mononuclear phagocytes. In four mouse tumor models, trabectedin caused selective depletion of monocytes/macrophages in blood, spleens, and tumors, with an associated reduction of angiogenesis. By using trabectedin-resistant tumor cells and myeloid cell transfer or depletion experiments, we demonstrate that cytotoxicity on mononuclear phagocytes is a key component of its antitumor activity. Monocyte depletion, including tumor-associated macrophages, was observed in treated tumor patients. Trabectedin activates caspase-8-dependent apoptosis; selectivity for monocytes versus neutrophils and lymphocytes is due to differential expression of signaling and decoy TRAIL receptors. This unexpected property may be exploited in different therapeutic strategies.


Yang D, Sun Y, Hu L, et al.
Integrated analyses identify a master microRNA regulatory network for the mesenchymal subtype in serous ovarian cancer.
Cancer Cell. 2013; 23(2):186-99 [PubMed] Article available free on PMC after 11/02/2014
Integrated genomic analyses revealed a miRNA-regulatory network that further defined a robust integrated mesenchymal subtype associated with poor overall survival in 459 cases of serous ovarian cancer (OvCa) from The Cancer Genome Atlas and 560 cases from independent cohorts. Eight key miRNAs, including miR-506, miR-141, and miR-200a, were predicted to regulate 89% of the targets in this network. Follow-up functional experiments illustrate that miR-506 augmented E-cadherin expression, inhibited cell migration and invasion, and prevented TGFβ-induced epithelial-mesenchymal transition by targeting SNAI2, a transcriptional repressor of E-cadherin. In human OvCa, miR-506 expression was correlated with decreased SNAI2 and VIM, elevated E-cadherin, and beneficial prognosis. Nanoparticle delivery of miR-506 in orthotopic OvCa mouse models led to E-cadherin induction and reduced tumor growth.


van der Gun BT, Huisman C, Stolzenburg S, et al.
Bidirectional modulation of endogenous EpCAM expression to unravel its function in ovarian cancer.
Br J Cancer. 2013; 108(4):881-6 [PubMed] Article available free on PMC after 05/03/2014
BACKGROUND: The epithelial cell adhesion molecule (EpCAM) is overexpressed on most carcinomas. Dependent on the tumour type, its overexpression is either associated with improved or worse patient survival. For ovarian cancer, however, the role of EpCAM remains unclear.
METHODS: Cell survival of ovarian cancer cell lines was studied after induction or repression of endogenous EpCAM expression using siRNA/cDNA or artificial transcription factors (ATF) consisting of engineered zinc-fingers fused to either a transcriptional activator or repressor domain.
RESULTS: Two ATFs were selected as the most potent down- and upregulator, showing at least a two-fold alteration of EpCAM protein expression compared with control. Downregulation of EpCAM expression resulted in growth inhibition in breast cancer, but showed no effect on cell growth in ovarian cancer. Induction or further upregulation of EpCAM expression decreased ovarian cancer cell survival.
CONCLUSION: The bidirectional ATF-based approach is uniquely suited to study cell-type-specific biological effects of EpCAM expression. Using this approach, the oncogenic function of EpCAM in breast cancer was confirmed. Despite its value as a diagnostic marker and for immunotherapy, EpCAM does not seem to represent a therapeutic target for gene expression silencing in ovarian cancer.


Siu MK, Cheng CY
The blood-follicle barrier (BFB) in disease and in ovarian function.
Adv Exp Med Biol. 2012; 763:186-92 [PubMed]
The blood-follicle barrier (BFB) is one of the blood-tissue barriers in mammalian body found in developing follicles in the ovary. The BFB, besides the tight junction (TJ)-permeability barrier of the endothelial cells in the microvessels that surround the developing follicle, is constituted and contributed significantly by the basement membrane of the developing follicle which alters its composition rapidly during follicle development. While the concept of the BFB and its ultrastructure were described more than six decades ago, fewer than 20 reports are found in the literature that were dedicated to investigate the biology, regulation, and function of the BFB either in health or in disease. Furthermore, detailed analysis of the adhesion protein complexes and the regulation of the junction dynamics at the BFB are still missing in the literature. The goal of this short chapter is to provide an update on this important blood-tissue barrier, it is obvious that future investigation is much needed in the field to understand this ultrastructure better in order to treat and better ovarian disorders including ovarian cancer.


Koch M, Krieger ML, Stölting D, et al.
Overcoming chemotherapy resistance of ovarian cancer cells by liposomal cisplatin: molecular mechanisms unveiled by gene expression profiling.
Biochem Pharmacol. 2013; 85(8):1077-90 [PubMed]
Previously we reported that liposomal cisplatin (CDDP) overcomes CDDP resistance of ovarian A2780cis cancer cells (Krieger et al., Int. J. Pharm. 389, 2010, 10-17). Here we find that the cytotoxic activity of liposomal CDDP is not associated with detectable DNA platination in resistant ovarian cancer cells. This suggests that the mode of action of liposomal CDDP is different from the free drug. To gain insight into mechanisms of liposomal CDDP activity, we performed a transcriptome analysis of untreated A2780cis cells, and A2780cis cells in response to exposure with IC50 values of free or liposomal CDDP. A process network analysis of upregulated genes showed that liposomal CDDP induced a highly different gene expression profile in comparison to the free drug. p53 was identified as a key player directing transcriptional responses to free or liposomal CDDP. The free drug induced expression of essential genes of the intrinsic (mitochondrial) apoptosis pathway (BAX, BID, CASP9) most likely through p38MAPK activation. In contrast, liposomal CDDP induced expression of genes from DNA damage pathways and several genes of the extrinsic pathway of apoptosis (TNFRSF10B-DR5, CD70-TNFSF7). It thus appears that liposomal CDDP overcomes CDDP resistance by inducing DNA damage and in consequence programmed cell death by the extrinsic pathway. Predictions from gene expression data with respect to apoptosis activation were confirmed at the protein level by an apoptosis antibody array. This sheds new light on liposomal drug carrier approaches in cancer and suggests liposomal CDDP as promising strategy for the treatment of CDDP resistant ovarian carcinomas.


Hanker LC, Karn T, Holtrich U, et al.
Prognostic impact of fascin-1 (FSCN1) in epithelial ovarian cancer.
Anticancer Res. 2013; 33(2):371-7 [PubMed]
BACKGROUND: Fascin-1 (FSCN1) plays an important role in cancer development and is associated with invasion and metastasis. Therefore, we explored the expression and localization of FSCN1 in epithelial ovarian cancer (EOC).
MATERIALS AND METHODS: Expression analysis was performed by immunohistochemistry of paraffin-embedded tumor samples from 89 patients with EOC. Staining intensity and the percentage of positively stained tumor cells were used to calculate an immunoreactive score of 0-12 (IRS). These results were correlated to clinical and pathological characteristics as well as to patient survival.
RESULTS: Negative (IRS=0), weak (IRS=0-2) and strong (IRS>2) expression of FSCN1 in EOC was found in 5 (5.6%), 30 (33.7%) and 54 (60.7%) tumor samples, respectively. There was a strong correlation of residual postoperative tumor of >1 cm with higher immunoexpression of FSCN1 (p=0.04). Lower FSCN1 expression was associated with significantly poorer overall survival (p=0.02).
CONCLUSION: FSCN1 is frequently expressed in primary EOC. Its prognostic impact and function remains inconclusive and should be further examined in larger trials.


Isacson R, Segal A, Alberton J, et al.
Abdominal cocoon: a potential pitfall in patients with ovarian carcinoma.
Tumori. 2012; 98(6):176e-8e [PubMed]
Background. Abdominal cocoon, or sclerosing encapsulating peritonitis, is a rare condition characterized by partial or total encasement of small bowel and mesentery by a thick fibrocollagenous sack that looks like a cocoon. Within the sack, bowel loops are drawn together causing intestinal obstruction.Case presentation. We report on a 57-year-old female patient who developed a very unusual complication of ovarian cancer: abdominal cocoon formation.Conclusions. This report highlights the need for a timely diagnosis of sclerosing encapsulating peritonitis in cancer patients.


Hazard FK, Longacre TA
Ovarian surface epithelial neoplasms in the pediatric population: incidence, histologic subtype, and natural history.
Am J Surg Pathol. 2013; 37(4):548-53 [PubMed]
Surface epithelial neoplasms account for a small but significant proportion of pediatric ovarian tumors. The overall incidence, prevalence of histologic subtypes, and natural history of these neoplasms has not been thoroughly evaluated. A retrospective review of the pathology archives of Stanford University School of Medicine yielded 69 surface epithelial ovarian tumors in 64 pediatric patients 18 years of age or younger from 1974 to 2010. Tumors comprised benign (57.8%), borderline/low malignant potential (LMP) (37.5%), and malignant (4.7%) subgroups and exhibited serous, mucinous, and mixed histology; there were no clear cell, pure endometrioid, or transitional (Brenner) tumors. In addition, no high-grade carcinomas were identified. Clinical follow-up data were available in a subset of patients (maximum follow-up, 22 y). Similar numbers of recurrences were found in each of the 3 subgroups. However, overall survival was 100% for benign and borderline/LMP tumors and 50% for carcinomas. The type of surgical management and the use of chemotherapy varied; 2 patients with borderline/LMP tumors were treated by sterilizing procedures and/or chemotherapy. These data suggest that surface epithelial neoplasms comprise a small but significant proportion of ovarian tumors in the pediatric population, and they exhibit a marked preponderance for benign, borderline, and low-grade malignant subgroups. In contrast to their adult counterpart, high-grade serous carcinoma in children is extraordinarily rare and not seen in this series. Given this difference, uniform treatment modalities with consideration for ovarian conservation and fertility preservation should be rigorously adopted in any pediatric patient with a suspected ovarian surface epithelial neoplasm.


Hall M, Gourley C, McNeish I, et al.
Targeted anti-vascular therapies for ovarian cancer: current evidence.
Br J Cancer. 2013; 108(2):250-8 [PubMed] Article available free on PMC after 05/03/2014
Ovarian cancer presents at advanced stage in around 75% of women, and despite improvements in treatments such as chemotherapy, the 5-year survival from the disease in women diagnosed between 1996 and 1999 in England and Wales was only 36%. Over 80% of patients with advanced ovarian cancer will relapse and despite a good chance of remission from further chemotherapy, they will usually die from their disease. Sequential treatment strategies are employed to maximise quality and length of life but patients eventually become resistant to cytotoxic agents. The expansion in understanding of the molecular biology that characterises cancer cells has led to the rapid development of new agents to target important pathways but the heterogeneity of ovarian cancer biology means that there is no predominant defect. This review attempts to discuss progress to date in tackling a more general target applicable to ovary cancer-angiogenesis.


Raspagliesi F, Ditto A, Martinelli F, et al.
Advanced ovarian cancer: omental bursa, lesser omentum, celiac, portal and triad nodes spread as cause of inaccurate evaluation of residual tumor.
Gynecol Oncol. 2013; 129(1):92-6 [PubMed]
OBJECTIVE: We evaluated the role of omental bursa (OB), surface of the pancreas, lesser omentum, caudate lobe, celiac nodes (CNs), portal nodes and triad nodes spread in advanced ovarian cancer (AOC). We investigated if the exploration and cleaning up of these areas can lead to a more complete cytoreduction and to a more realistic assessment of residual tumor in AOC.
METHODS: We prospectively recruited patients diagnosed with AOC, who underwent a complete cytoreduction. Demographics, surgical procedures, morbidities, pathologic findings and correlations with OB spread were assessed.
RESULTS: A total of 37 patients had an optimal debulking including OB evaluation and peritonectomy. The OB area procedure required in mean 65 min with an estimated blood loss of 250 ml. OB involvement was found in 67% (25/37) of cases. Peritoneal disease was found in 22 cases including 18 supragastric lesser sac and 4 porta hepatis peritoneum. CNs metastases were found in 5 cases, of which 3 cases are with bulky nodes, all presented also bulky nodes in the para-aortic area. Only in the case of a macroscopic involvement of the diaphragm OB was positive for disease. When adhesions occluding the Winslow foramen were present, no OB peritoneum involvement was found. OB resection related complications were low (2 out 25).
CONCLUSIONS: The data of this prospective study demonstrate the high rate of OB, surface of the pancreas, lesser omentum, caudate lobe, CNs, portal and triad nodes involvement and the value of investigating the dissemination and cytoreduction in these sites to obtain a real optimal debulking.


Sheu JJ, Choi JH, Guan B, et al.
Rsf-1, a chromatin remodelling protein, interacts with cyclin E1 and promotes tumour development.
J Pathol. 2013; 229(4):559-68 [PubMed]
Chromosome 11q13.5 containing RSF1 (HBXAP), a gene involved in chromatin remodelling, is amplified in several human cancers including ovarian carcinoma. Our previous studies demonstrated requirement of Rsf-1 for cell survival in cancer cells, which contributed to tumour progression; however, its role in tumourigenesis has not yet been elucidated. In this study, we co-immunoprecipitated proteins with Rsf-1 followed by nanoelectrospray mass spectrometry and identified cyclin E1, besides SNF2H, as one of the major Rsf-1 interacting proteins. Like RSF1, CCNE1 is frequently amplified in ovarian cancer, and both Rsf-1 and cyclin E1 were found co-up-regulated in ovarian cancer tissues. Ectopic expression of Rsf-1 and cyclin E1 in non-tumourigenic TP53(mut) RK3E cells led to an increase in cellular proliferation and tumour formation by activating cyclin E1-associated kinase (CDK2). Tumourigenesis was not detected if either cyclin E1 or Rsf-1 was expressed, or they were expressed in a TP53(wt) background. Domain mapping showed that cyclin E1 interacted with the first 441 amino acids of Rsf-1. Ectopic expression of this truncated domain significantly suppressed G1/S-phase transition, cellular proliferation, and tumour formation of RK3E-p53(R175H) /Rsf-1/cyclin E1 cells. The above findings suggest that Rsf-1 interacts and collaborates with cyclin E1 in neoplastic transformation and TP53 mutations are a prerequisite for tumour-promoting functions of the RSF/cyclin E1 complex.


Xu HT, Liu Y, Liu SL, et al.
TC-1 (C8orf4) expression is correlated with differentiation in ovarian carcinomas and might distinguish metastatic ovarian from metastatic colorectal carcinomas.
Virchows Arch. 2013; 462(3):281-7 [PubMed]
Thyroid cancer 1 (TC-1, C8orf4) is involved in the development of many cancers. In this study, we investigated the correlation between the expression of TC-1 and the clinicopathological characteristics of ovarian and colorectal adenocarcinomas. We also explored the possible use of TC-1 as a marker to distinguish between metastatic tumors of the ovary and colorectum. We used immunohistochemistry to examine the expression level of TC-1 in 100 ovarian and 100 colorectal adenocarcinomas and 25 metastatic carcinomas with the ovary or colorectum as primary site. TC-1 was expressed in all ovarian carcinoma samples. The high expression rate of TC-1 was 84 % in ovarian carcinomas, which was much higher than that observed in colorectal adenocarcinomas (35 %, P < 0.001). High expression of TC-1 significantly correlated with poor differentiation of ovarian carcinomas (P = 0.013). To explore the value of TC-1 in distinguishing metastatic ovarian cancers from colorectal cancers, we found the area under the receiver operator characteristic curve of TC-1 to be 0.819 (95 % confidence interval, 0.760-0.878; P < 0.001). Furthermore, TC-1 was highly expressed in 100 % of nine metastatic ovarian cancers, but only in 31 % of 16 metastatic colorectal cancers. The higher expression of TC-1 in ovarian compared to colorectal adenocarcinomas suggests its potential use as a marker, to distinguish between metastatic ovarian and colorectal adenocarcinomas.


Cao Z, Yu D, Fu S, et al.
Lycorine hydrochloride selectively inhibits human ovarian cancer cell proliferation and tumor neovascularization with very low toxicity.
Toxicol Lett. 2013; 218(2):174-85 [PubMed]
Uncontrolled tumor cell proliferation and robust neovascularization are prominent features of aggressive ovarian cancers. Although great efforts in anti-ovarian cancer therapy have been made in the past 4 decades, the 5-year survival rates for ovarian cancer patients are still poor, and effective drugs to cure ovarian cancer patients are absent. In this study, we evaluated the anti-cancer effects of lycorine hydrochloride (LH), a novel anti-ovarian cancer agent, using the highly-invasive ovarian cancer cell line, Hey1B, as a model. Our data showed that LH effectively inhibited mitotic proliferation of Hey1B cells (half maximal inhibitory concentration=1.2μM) with very low toxicity, resulting in cell cycle arrest at the G2/M transition through enhanced expression of the cell cycle inhibitor p21 and marked down-regulation of cyclin D3 expression. Moreover, LH suppressed both the formation of capillary-like tubes by Hey1B cells cultured in vitro and the ovarian cancer cell-dominant neovascularization in vivo when administered to Hey1B-xenotransplanted mice. LH also suppressed the expression of several key angiogenic genes, including VE-cadherin, vascular endothelial growth factor, and Sema4D, and reduced Akt phosphorylation in Hey1B cells. These results suggest that LH selectively inhibits ovarian cancer cell proliferation and neovascularization and is a potential drug candidate for anti-ovarian cancer therapy.


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