Risk Of Borderline Ovarian Tumors Research Articles

Pelvic inflammatory disease and risk of borderline ovarian tumors: A national population-based case-control study in Sweden.

The resemblance between fallopian tube cells and serous borderline ovarian tumors (BOTs) suggests a potential origin link, with salpingitis proposed as a contributing factor in the pathogenesis of BOT. This study aimed to explore the potential association between pelvic inflammatory disease (PID) and the risk of developing BOT. A national population-based case-control study in Sweden included women with BOT between 1999 and 2020 and 10 matched controls. Data from nationwide registers were analyzed using conditional logistic regression, adjusting for age, residential district, educational level and parity. Among 4782 cases and 45,167 controls, 2.0% of cases and 1.3% of controls had a history of PID. Previous PID was associated with an increased risk of BOT overall (aOR, 1.48; 95% CI, 1.19-1.85). Significant association was observed with serous tumors (aOR, 1.76; 95% CI, 1.36-2.29), while not with mucinous tumors (aOR, 0.95; 95% CI, 0.60-1.49). A dose-response relationship between number of PID episodes and serous BOT risk was noted (Ptrend < .001). This study demonstrates that PID is associated with increased risk of serous BOT, with a dose response relationship. The study highlights the potential serious implications of upper reproductive tract infections and inflammation. This underscores the need for further investigation of biological mechanisms and possible impact of PID on serous BOT development.

Effects of Infertility Drug Exposure on the Risk of Borderline Ovarian Tumors: A Systematic Review and Meta-Analysis.

Whether infertility drug exposure increases the risk of borderline ovarian tumors (BOTs) remains controversial. The present study was conducted with a comprehensive search for studies published from January 1990 to December 2021 in the online databases Cochrane Library, PubMed, Web of Science and EMBASE. We considered the first diagnosis of a BOT as the primary outcome. The odds ratio (OR) was calculated with corresponding 95% confidence intervals (CIs) for the risk of BOTs in patients who were treated with infertility drugs. Ten studies, a total of 2,779,511 women, qualified for inclusion in this meta-analysis. The pooled OR of 1.56 (95% CI: 1.09-2.22) revealed a significant positive association between infertility drugs and an increased risk for BOTs, but for specific drugs, only CC plus Gn had statistical significance. No publication bias was detected using the Egger and Begg tests (p > 0.05). A significant difference in BOT incidence was observed among infertile women and nulliparous women who were treated with or without infertility drugs. In conclusion, the use of infertility drugs may increase the risk of BOTs, but a dose-dependent relationship was not observed between the number of assisted reproduction technology cycles and the risk of BOTs, and infertile women who successfully became pregnant might have a reduced risk. Registration: PROSPERO, CRD42022330775.

Evidence of human cytomegalovirus infection and expression of 5-lipoxygenase in borderline ovarian tumors.

Borderline ovarian tumors (BOTs) belong to a group of tumors that are distinctly different from ovarian carcinomas. There is an increased risk of BOTs in patients with pelvic inflammatory disease. Human cytomegalovirus (HCMV) has been detected in ovarian cancer tissue specimens. This virus favors the inflammatory milieu by inducing expression of the potent inflammatory factor 5-lipoxygenase (5LO), which stimulates cellular viability, cellular proliferation and activates antiapoptotic signaling pathways. Here, we aimed to examine presence of HCMV and 5LO in BOTs. Expression levels of HCMV proteins (IE and pp65) and 5LO were examined in paraffin embedded BOT tissue sections by immunohistochemistry staining and HCMV immunoglobulin M and immunoglobulin G (IgG) levels were determined by serology in blood samples obtained from 15 patients with BOTs identified in a prospective study at Karolinska University Hospital. Extensive expression of HCMV-IE, pp65, and 5LO were detected in 87%, 40%, and 90% of examined BOT tissue sections, respectively. HCMV-IgG prevalence and antibody levels were significantly higher in patients with BOT compared to age matched healthy women (83.3% vs. 65,6%, respectively, p = .01). Whether HCMV can induce inflammation and affect the pathogenesis of BOTs should therefore be further investigated.

Long-Term Risk of Ovarian Cancer and Borderline Tumors After Assisted Reproductive Technology.

Long-term effects of assisted reproductive technology (ART) on ovarian tumor risk are unknown. This nationwide cohort study comprises 30625 women who received ovarian stimulation for ART in 1983-2000 and 9988 subfertile women not treated with ART. Incident invasive and borderline ovarian tumors were ascertained through linkage with the Netherlands Cancer Registry and the Dutch Pathology Registry until July 2018. Ovarian tumor risk in ART-treated women was compared with risks in the general population and the subfertile non-ART group. Statistical tests were 2-sided. After a median follow-up of 24 years, 158 invasive and 100 borderline ovarian tumors were observed. Ovarian cancer risk in the ART group was increased compared with the general population (standardized incidence ratio [SIR] = 1.43, 95% confidence interval [CI] = 1.18 to 1.71) but not when compared with the non-ART group (age- and parity-adjusted hazard ratio [HR] = 1.02, 95% CI = 0.70 to 1.50). Risk decreased with higher parity and with a larger number of successful ART cycles (resulting in childbirth, Ptrend = .001) but was not associated with the number of unsuccessful ART cycles. Borderline ovarian tumor risk was increased in ART-treated women compared with the general population (SIR = 2.20, 95% CI = 1.66 to 2.86) and with non-ART women (HR = 1.84, 95% CI = 1.08 to 3.14). Risk did not increase with more ART cycles or longer follow-up time. Increased ovarian cancer risk in ART-treated women compared with the general population is likely explained by nulliparity rather than ART treatment. The increased risk of borderline ovarian tumors after ART must be interpreted with caution because no dose-response relationship was observed.

Risk of ovarian cancer in women treated with ovarian stimulating drugs for infertility.

This is an updated version of the original Cochrane Review published in the Cochrane Library in 2013 (Issue 8) on the risk of ovarian cancer in women using infertility drugs when compared to the general population or to infertile women not treated. The link between fertility drugs and ovarian cancer remains controversial. To evaluate the risk of invasive ovarian cancer and borderline ovarian tumours in women treated with ovarian stimulating drugs for subfertility. The original review included published and unpublished observational studies from 1990 to February 2013. For this update, we extended the searches from February 2013 to November 2018; we evaluated the quality of the included studies and judged the certainty of evidence by using the GRADE approach. We have reported the results in a Summary of findings table to present effect sizes across all outcome types. In the original review and in this update, we searched for randomised controlled trials (RCTs) and non-randomised studies and case series including more than 30 participants. At least two review authors independently conducted eligibility and 'Risk of bias' assessments and extracted data. We grouped studies based on the fertility drug used for two outcomes: borderline ovarian tumours and invasive ovarian cancer. We conducted no meta-analyses due to expected methodological and clinical heterogeneity. We included 13 case-control and 24 cohort studies (an additional nine new cohort and two case-control studies), which included a total of 4,684,724 women.Two cohort studies reported an increased incidence of invasive ovarian cancer in exposed subfertile women compared with unexposed women. One reported a standardised incidence ratio (SIR) of 1.19 (95% confidence interval (CI) 0.54 to 2.25) based on 17 cancer cases. The other cohort study reported a hazard ratio (HR) of 1.93 (95% CI 1.18 to 3.18), and this risk was increased in women remaining nulligravid after using clomiphene citrate (HR 2.49, 95% CI 1.30 to 4.78) versus multiparous women (HR 1.52, 95% CI 0.67 to 3.42) (very low-certainty evidence). The slight increase in ovarian cancer risk among women having between one and three cycles of in vitro fertilisation (IVF) was reported, but this was not clinically significant (P = 0.18). There was no increase in risk of invasive ovarian cancer after use of infertility drugs in women with the BRCA mutation according to one cohort and one case-control study. The certainty of evidence as assessed using GRADE was very low.For borderline ovarian tumours, one cohort study reported increased risk in exposed women with an SIR of 3.61 (95% CI 1.45 to 7.44), and this risk was greater after treatment with clomiphene citrate (SIR 7.47, 95% CI 1.54 to 21.83) based on 12 cases. In another cohort study, the risk of a borderline ovarian tumour was increased, with an HR of 4.23 (95% CI 1.25 to 14.33), for subfertile women treated with IVF compared with a non-IVF-treated group with more than one year of follow-up. A large cohort reported increased risk of borderline ovarian tumours, with HR of 2.46 (95% CI 1.20 to 5.04), and this was based on 17 cases. A significant increase in serous borderline ovarian tumours was reported in one cohort study after the use of progesterone for more than four cycles (risk ratio (RR) 2.63, 95% CI 1.04 to 6.64). A case-control study reported increased risk after clomiphene citrate was taken, with an SIR of 2.5 (95% CI 1.3 to 4.5) based on 11 cases, and another reported an increase especially after human menopausal gonadotrophin was taken (odds ratio (OR) 9.38, 95% CI 1.66 to 52.08). Another study estimated an increased risk of borderline ovarian tumour, but this estimation was based on four cases with no control reporting use of fertility drugs. The certainty of evidence as assessed using GRADE was very low.However, although some studies suggested a slight increase in risks of ovarian cancer and borderline ovarian tumour, none provided moderate- or high-certainty evidence, as summarised in the GRADE tables. Since the last version of this review, only a few new relevant studies have provided additional findings with supporting evidence to suggest that infertility drugs may increase the risk of ovarian cancer slightly in subfertile women treated with infertility drugs when compared to the general population or to subfertile women not treated. The risk is slightly higher in nulliparous than in multiparous women treated with infertility drugs, and for borderline ovarian tumours. However, few studies have been conducted, the number of cancers is very small, and information on the dose or type of fertility drugs used is insufficient.

Risk of borderline ovarian tumors among women with benign ovarian tumors: A cohort study

ObjectiveA growing number of studies suggest that some ovarian cancers can arise from benign and borderline ovarian tumors. However, studies on the association between benign and borderline ovarian tumors are lacking. We studied the overall- and histotype-specific risk of borderline ovarian tumors among women with a benign ovarian tumor. MethodsThis nationwide cohort study included all Danish women diagnosed with a benign ovarian tumor (n=139,466) during 1978–2012. The cohort was linked to the Danish Pathology Data Bank and standardized incidence ratios (SIR) with 95% confidence intervals (CI) were calculated. ResultsWomen with benign ovarian tumors had increased risks for subsequent borderline ovarian tumors (SIR 1.62, 95% CI 1.43–1.82), and this applied to both serous (SIR 1.69, 95% CI 1.39–2.03) and mucinous (SIR 1.75, 95% CI 1.45–2.10) histotypes of borderline ovarian tumors. The risk for borderline ovarian tumors was primarily increased for women diagnosed with a benign ovarian tumor before 40years of age. The risk remained increased up to 9years after a benign ovarian tumor diagnosis. Finally, the associations did not change markedly when analyzed for the different histotypes of benign (solid and cystic tumors) and borderline (serous and mucinous tumors) ovarian tumors. ConclusionsWomen with benign ovarian tumors have a long-term increased risk for borderline ovarian tumors. However, as all associations in this study were only adjusted for age and calendar period of diagnosis, more studies that are able to adjust for additional potential confounding variables are required to further understand these associations.

Telomerase Expression Increased the Risk of Borderline Ovarian Tumors

Objective: To compare the expression of telomerase in benign ovarian tumors and borderline ovarian tumors.&#x0D; &#x0D; Methods: Thirteen samples of paraffin blocks of ovarian borderline tumors and benign ovarian tumors were taken from patients who underwent surgery from January 2006 to December 2011. In all samples, we performed immunohistochemical staining to the paraffin blocks. Semi quantitative determination of the expression of&#x0D; telomerase is done by an Anatomic Pathology specialist and Gynecologist, which already had the same perception about assessing the standardization sample. We used Fisher’s test to analyze the data.&#x0D; &#x0D; Results: There were significant relationship in the moderate expression of telomerase in the nucleus and cytoplasm between benign and borderline ovarian tumors, with an odds ratio of moderate telomerase expression in the cytoplasm and nucleus of 19.3 (95% CI: 1.4 - 943) and 26 (95% CI : 2.3 - 1211). This means that the risk&#x0D; of borderline ovarian tumors in the expression of moderate telomerase in the cytoplasm was 3.19 times compared to the negative expression, whereas in the nucleus it became 26-fold. There is no significant&#x0D; relationship among menopause, age, and telomerase expression in the nucleus and cytoplasm.&#x0D; &#x0D; Conclusion: There are significant differences in the expression of moderate strength telomerase in nucleus and cytoplasm between benign and borderline ovarian tumors.&#x0D; &#x0D; [Indones J Obstet Gynecol 2013; 37-1: 32-40]&#x0D; &#x0D; Keywords: benign ovarian tumor, borderline ovarian tumor, telomerase expression

Pelvic Inflammatory Disease and the Risk of Ovarian Cancer and Borderline Ovarian Tumors: A Pooled Analysis of 13 Case-Control Studies.

Inflammation has been implicated in ovarian carcinogenesis. However, studies investigating the association between pelvic inflammatory disease (PID) and ovarian cancer risk are few and inconsistent. We investigated the association between PID and the risk of epithelial ovarian cancer according to tumor behavior and histotype. We pooled data from 13 case-control studies, conducted between 1989 and 2009, from the Ovarian Cancer Association Consortium (OCAC), including 9,162 women with ovarian cancers, 2,354 women with borderline tumors, and 14,736 control participants. Study-specific odds ratios were estimated and subsequently combined into a pooled odds ratio using a random-effects model. A history of PID was associated with an increased risk of borderline tumors (pooled odds ratio (pOR) =1.32, 95% confidence interval (CI): 1.10, 1.58). Women with at least 2 episodes of PID had a 2-fold increased risk of borderline tumors (pOR=2.14, 95% CI: 1.08, 4.24). No association was observed between PID and ovarian cancer risk overall (pOR=0.99, 95% CI: 0.83, 1.19); however, a statistically nonsignificantly increased risk of low-grade serous tumors (pOR=1.48, 95% CI: 0.92, 2.38) was noted. In conclusion, PID was associated with an increased risk of borderline ovarian tumors, particularly among women who had had multiple episodes of PID. Although our results indicated a histotype-specific association with PID, the association of PID with ovarian cancer risk is still somewhat uncertain and requires further investigation.

Fertility drugs and cancer: a guideline.

Methodological limitations in studying the association between the use of fertility drugs and cancer include the inherent increased risk of cancer in women who never conceive, the low incidence of most of these cancers, and that the age of diagnosis of cancer typically is many years after fertility drug use. Based on available data, there does not appear to be a meaningful increased risk of invasive ovarian cancer, breast cancer, or endometrial cancer following the use of fertility drugs. Several studies have shown a small increased risk of borderline ovarian tumors; however, there is insufficient consistent evidence that a particular fertility drug increases the risk of borderline ovarian tumors, and any absolute risk is small. Given the available literature, patients should be counseled that infertile women may be at an increased risk of invasive ovarian, endometrial, and breast cancer; however, use of fertility drugs does not appear to increase this risk.

Increased risk of borderline ovarian tumors in women with a history of pelvic inflammatory disease: A nationwide population-based cohort study

ObjectiveSome studies suggest that pelvic inflammatory disease (PID) is a potential risk factor for ovarian cancer. However, only few studies have investigated the association between PID and risk of borderline ovarian tumors. We conducted a population-based cohort study to investigate the association between PID and risk of borderline ovarian tumors. MethodsUsing various nationwide Danish registries we identified all women in Denmark during 1978–2012, who were born during 1940–1970 (n=1,318,925). Of these, 81,263 women were diagnosed with PID in the study period, and 2736 women had a borderline ovarian tumor (1290 serous and 1344 mucinous). Hazard ratios (HRs) and 95% confidence intervals (CIs) for the association between PID and risk of borderline tumors were estimated using Cox regression models with adjustment for potential confounders. ResultsA history of PID was associated with an increased risk of borderline ovarian tumors (HR=1.39; 95% CI: 1.19–1.61). However, histotype-specific analyses revealed significant variation in risk as PID was only associated with an increased risk of serous borderline tumors (HR=1.85; 95% CI: 1.52–2.24), but not with mucinous borderline tumors (HR=1.06; 95% CI: 0.83–1.35). ConclusionsPID is associated with an increased risk of serous borderline tumors. Further research on the potential underlying biological mechanisms and on the identification of the subset of women with PID who are at increased risk of serous borderline tumors is warranted.

Management of borderline ovarian tumors

Borderline ovarian tumors (BOT) are epithelial tumors of the ovaries with both malignant and non-malignant aspects. On the one hand, they are characterized by cellular proliferation and nuclear atypia but, on the other hand, they usually do not show infiltrative growth pattern. Balancing radicality between oncologic safety and treatment burden has already led to remarkable changes in the management pattern over the last decades and is still a challenging task. This review is based on both a systematic review published by the authors and added with evidence gained from actually published literature. As they frequently affect younger patients, the clinical management of BOT is complicated by aspects as preserving fertility and reducing postoperative morbidity. Over the past decades, the surgical therapy shifted from a radical approach to more conservative treatment. Today, fertility-sparing surgery is first-choice treatment in younger patients. In addition, minimal-invasive surgery has become the preferred surgical approach in these patients. Even recurrences are curable in most patients because only a minority of relapses transform to invasive cancer. More studies on BOT are needed and longer follow-up and better characterization of high-risk subtypes are crucial to better understand long-term risk of BOT and avoid the rare but the fatal outcome in those few patients being undertreated by the current management strategies.

Abstract 881: Association of adult body mass index and height with risk of ovarian cancer in 39,000 women: Results of a Mendelian randomization study

Abstract INTRODUCTION: Observational studies have reported positive associations between higher body mass index (BMI) and risks of borderline ovarian tumors and non-high grade serous ovarian cancer (non-HGSC), but the lack of association observed for HGSC may be due to bias arising from weight loss before diagnosis. Observational studies also suggest a positive association between greater height and ovarian cancer risk, but confounding factors may be obscuring the true relationship. The Mendelian randomization (MR) technique uses genetic markers as proxies for environmental risk factors, and can overcome the limitations of bias and confounding which affect observational studies. AIM / METHODS: This study used MR to elucidate the relationship between body size (BMI and height) and risk of ovarian cancer. We pooled data from 16,395 cases and 23,003 controls, all genetically European, from 39 studies in the Ovarian Cancer Association Consortium. We constructed a weighted genetic risk score (GRS) for each trait, summing trait-increasing alleles at 31 single nucleotide polymorphisms (SNPs) associated with BMI and 609 SNPs associated with height in genome-wide association studies, weighting alleles by published β-coefficients for their effect on the trait. Each GRS was a strong instrument for the trait (F-statistics 33.8 [BMI] and 516 [height]). In a two-stage predictor substitution MR approach, we used multivariate logistic regression to model case-control status on body size predicted by each GRS. Study-specific estimates per 5-unit increase in predicted BMI or height were pooled to generate pooled odds ratios (OR) and 95% confidence intervals (CI) using random-effects meta-analysis. Our primary hypotheses were that genetic BMI would be associated with increased risk of non-HGSC but not HGSC and genetic height would be associated with increased risk of ovarian cancer overall. RESULTS: Higher genetically-predicted BMI was associated with increased risk of non-HGSC cancer (OR 1.37, 95% CI 1.02-1.83 per 5-unit increase) but not HGSC (OR 1.05, 95% CI 0.83-1.33). In secondary analyses stratified by behavior/subtype, the strongest association was seen for low grade/borderline serous cancers (OR 2.02, 95% CI 1.24-3.30). Women with greater genetically-predicted height had a modestly increased risk of all (invasive and borderline) ovarian tumors (OR 1.06, 95% CI 1.01-1.11 per 5 cm). In secondary analyses stratified by histologic subtype, the strongest association was seen for clear cell cancers (OR 1.20, 95% CI 1.04-1.38). CONCLUSION: This study is the first to apply MR to investigate ovarian cancer risk factors. These data confirm results from epidemiologic studies, suggesting that obesity is causally associated with non-HGSC, but does not increase risk of the most common HGSC subtype. They also support an association between height and ovarian cancer. Citation Format: Suzanne C. Dixon, Christina M. Nagle, Aaron P. Thrift, Paul D.P Pharoah, Ailith Pirie, Celeste Leigh Pearce, Wei Zheng, Penelope M. Webb, for the Ovarian Cancer Association Consortium. Association of adult body mass index and height with risk of ovarian cancer in 39,000 women: Results of a Mendelian randomization study. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 881. doi:10.1158/1538-7445.AM2015-881

Tubal Ligation and Salpingectomy and the Risk of Epithelial Ovarian Cancer and Borderline Ovarian Tumors

Objective According to the recent theories on the ovarian cancer origin, any protective effect of tubal ligation may vary with histologic subtype of ovarian cancer. Furthermore, bilateral salpingectomy may represent an opportunity for surgical prevention of serous ovarian cancer. Design Nationwide register-based case–control study. Setting Denmark during 1982–2011. Population Cases were all Danish women diagnosed with epithelial ovarian cancer (n = 13 241) or borderline ovarian tumor (n = 3605) in the study period. Age-matched female population controls were randomly selected by risk set sampling. We required that cases and controls have no previous cancer and that controls have no previous bilateral oophorectomy. Methods Conditional logistic regression was used to estimate odds ratios and 95% confidence intervals, adjusting for potential confounders. Main outcome measures Epithelial ovarian cancer and borderline ovarian tumors stratified according to histology. Results Tubal ligation reduced overall epithelial ovarian cancer risk (odds ratios 0.87; 95% confidence interval 0.78–0.98). We observed significant risk variation according to histology (p = 0.003) with the strongest risk reductions associated with endometrioid cancer (odds ratios 0.66; 95% confidence interval 0.47–0.93) and epithelial ovarian cancer of “other” histology (odds ratios 0.60; 95% confidence interval 0.43–0.83). Tubal ligation was not associated with risk of borderline ovarian tumors. Finally, bilateral salpingectomy reduced epithelial ovarian cancer risk by 42% (odds ratios 0.58; 95% confidence interval 0.36–0.95). Conclusions We confirmed that tubal ligation reduces the risk of epithelial ovarian cancer and particularly endometrioid cancer. To our knowledge, this is the first observational publication to report on salpingectomy and ovarian cancer risk and our promising findings warrant further investigation.

Tubal ligation and salpingectomy and the risk of epithelial ovarian cancer and borderline ovarian tumors: a nationwide case-control study.

According to the recent theories on the ovarian cancer origin, any protective effect of tubal ligation may vary with histologic subtype of ovarian cancer. Furthermore, bilateral salpingectomy may represent an opportunity for surgical prevention of serous ovarian cancer. Nationwide register-based case-control study. Denmark during 1982-2011. Cases were all Danish women diagnosed with epithelial ovarian cancer (n=13241) or borderline ovarian tumor (n=3605) in the study period. Age-matched female population controls were randomly selected by risk set sampling. We required that cases and controls have no previous cancer and that controls have no previous bilateral oophorectomy. Conditional logistic regression was used to estimate odds ratios and 95% confidence intervals, adjusting for potential confounders. Epithelial ovarian cancer and borderline ovarian tumors stratified according to histology. Tubal ligation reduced overall epithelial ovarian cancer risk (odds ratios 0.87; 95% confidence interval 0.78-0.98). We observed significant risk variation according to histology (p=0.003) with the strongest risk reductions associated with endometrioid cancer (odds ratios 0.66; 95% confidence interval 0.47-0.93) and epithelial ovarian cancer of "other" histology (odds ratios 0.60; 95% confidence interval 0.43-0.83). Tubal ligation was not associated with risk of borderline ovarian tumors. Finally, bilateral salpingectomy reduced epithelial ovarian cancer risk by 42% (odds ratios 0.58; 95% confidence interval 0.36-0.95). We confirmed that tubal ligation reduces the risk of epithelial ovarian cancer and particularly endometrioid cancer. To our knowledge, this is the first observational publication to report on salpingectomy and ovarian cancer risk and our promising findings warrant further investigation.

Risk of ovarian cancer in women treated with ovarian stimulating drugs for infertility

The use of assisted reproductive techniques is increasing, but the possible link between fertility drugs and ovarian cancer remains controversial. To evaluate the risk of ovarian cancer in women treated with ovulation stimulating drugs for subfertility. We searched for published and unpublished observational studies from 1990 to February 2013. The following databases were used: the Cochrane Gynaecological Cancer Collaborative Review Group's Trial Register, Cochrane Central Register of Controlled Trials (CENTRAL) 2013, Issue 1, MEDLINE (to February week 4 2013), EMBASE (to 2013 week 09) and databases of conference abstracts. We also scanned reference lists of retrieved articles. The search was not restricted by language of publication. We searched for randomised controlled trials (RCTs) and non-randomised studies, and case series including more than 30 participants, reporting on women with exposure to ovarian stimulating drugs for treatment of subfertility and histologically confirmed borderline or invasive ovarian cancer. At least two review authors independently conducted eligibility and 'Risk of bias' assessment, and extracted data. We grouped studies based on the fertility drug used for two outcomes: borderline ovarian tumours and invasive ovarian cancer. We expressed findings as adjusted odds ratio (OR), risk ratio (RR), hazard ratio (HR) or crude OR if adjusted values were not reported and standardised incidence ratio (SIR) where reported. We conducted no meta-analyses due to expected methodological and clinical heterogeneity. We included 11 case-control studies and 14 cohort studies, which included a total of 182,972 women.Seven cohort studies showed no evidence of an increased risk of invasive ovarian cancer in subfertile women treated with any drug compared with untreated subfertile women. Seven case-control studies showed no evidence of an increased risk, compared with control women of a similar age. Two cohort studies reported an increased incidence of invasive ovarian cancer in subfertile women treated with any fertility drug compared with the general population. One of these reported a SIR of 5.0 (95% confidence interval (CI) 1.0 to 15), based on three cancer cases, and a decreased risk when cancer cases diagnosed within one year of treatment were excluded from the analysis(SIR 1.67, 95% CI 0.02 to 9.27). The other cohort study reported an OR of 2.09 (95% CI 1.39 to 3.12), based on 26 cases.For borderline ovarian tumours, exposure to any fertility drug was associated with a two to three-fold increased risk in two case-control studies. One case-control study reported an OR of 28 (95% CI 1.5 to 516), which was based on only four cases. In one cohort study, there was more than a two-fold increase in the incidence of borderline tumours compared with the general population (SIR 2.6, 95% CI 1.4 to 4.6) and in another the risk of a borderline ovarian tumour was HR 4.23 (95% CI 1.25 to 14.33) for subfertile women treated with in vitro fertilisation (IVF) compared with a non-IVF treated group with more than one year of follow-up.There was no evidence of an increased risk in women exposed to clomiphene alone or clomiphene plus gonadotrophin, compared with unexposed women. One case-control study reported an increased risk in users of human menopausal gonadotrophin (HMG)(OR 9.4, 95% CI 1.7 to 52). However, this estimate is based on only six cases with a history of HMG use. We found no convincing evidence of an increase in the risk of invasive ovarian tumours with fertility drug treatment. There may be an increased risk of borderline ovarian tumours in subfertile women treated with IVF. Studies showing an increase in the risk of ovarian cancer had a high overall risk of bias, due to retrospective study design, lack of accounting for potential confounding and estimates based on a small number of cases. More studies at low risk of bias are needed.

In vitro fertilization is associated with an increased risk of borderline ovarian tumours

ObjectivesTo compare the risk of borderline ovarian tumours in women having in vitro fertilization (IVF) with women diagnosed with infertility but not having IVF. MethodsThis was a whole-population cohort study of women aged 20–44years seeking hospital infertility treatment or investigation in Western Australia in 1982–2002. Using Cox regression, we examined the effects of IVF treatment and potential confounders on the rate of borderline ovarian tumours. Potential confounders included parity, age, calendar year, socio-economic status, infertility diagnoses including pelvic inflammatory disorders and endometriosis and surgical procedures including hysterectomy and tubal ligation. ResultsWomen undergoing IVF had an increased rate of borderline ovarian tumours with a hazard ratio (HR) of 2.46 (95% confidence interval [CI] 1.20–5.04). Unlike invasive epithelial ovarian cancer, neither birth (HR 0.89; 95% CI 0.43–1.88) nor hysterectomy (1.02; 0.24–4.37) nor sterilization (1.48; 0.63–3.48) appeared protective and the rate was not increased in women with a diagnosis of endometriosis (HR 0.31; 95% CI 0.04–2.29). ConclusionsWomen undergoing IVF treatment are at increased risk of being diagnosed with borderline ovarian tumours. Risk factors for borderline ovarian tumours appear different from those for invasive ovarian cancer.

Risk of borderline and invasive ovarian tumours after ovarian stimulation for in vitro fertilization in a large Dutch cohort.

BACKGROUNDLong-term effects of ovarian stimulation for IVF on the risk of ovarian malignancies are unknown.METHODSWe identified a nationwide historic cohort of 19 146 women who received IVF treatment in the Netherlands between 1983 and 1995, and a comparison group of 6006 subfertile women not treated with IVF. In 1997–1999, data on reproductive risk factors were obtained from 65% of women and data on subfertility (treatment) were obtained from the medical records. The incidence of ovarian malignancies (including borderline ovarian tumours) through 2007 was assessed through linkage with disease registries. The risk of ovarian malignancies in the IVF group was compared with risks in the general population and the subfertile comparison group.RESULTSAfter a median follow-up of 14.7 years, the risk of borderline ovarian tumours was increased in the IVF group compared with the general population [standardized incidence ratio (SIR) = 1.76; 95% confidence interval (CI) = 1.16–2.56]. The overall SIR for invasive ovarian cancer was not significantly elevated, but increased with longer follow-up after first IVF (P = 0.02); the SIR was 3.54 (95% CI = 1.62–6.72) after 15 years. The risks of borderline ovarian tumours and of all ovarian malignancies combined in the IVF group were significantly increased compared with risks in the subfertile comparison group (hazard ratios = 4.23; 95% CI = 1.25–14.33 and 2.14; 95% CI = 1.07–4.25, respectively, adjusted for age, parity and subfertility cause).CONCLUSIONSOvarian stimulation for IVF may increase the risk of ovarian malignancies, especially borderline ovarian tumours. More large cohort studies are needed to confirm these findings and to examine the effect of IVF treatment characteristics.

IVF Ovarian Stimulation Increases Risk of Borderline Ovarian Tumors in 15-Year Follow-Up

IVF Ovarian Stimulation Increases Risk of Borderline Ovarian Tumors in 15-Year Follow-Up

Ovulation induction treatment and risk of borderline ovarian tumors

Aim. Research has suggested an association between the use of ovulation induction drugs and the risk of ovarian cancer. It has also been proposed that there may be pre-cancerous alterations in the ovary which themselves are the cause of infertility. The aim of the present study was to evaluate the relationship between the use of ovulation induction drugs and the appearance of borderline ovarian tumors.Material and methods. This was a case–control study in which the study group comprised 42 women with a borderline ovarian tumor and the control group comprised 257 women with benign ovarian pathology.Results. No differences were found between the borderline tumor and control groups (14.3% vs. 27.2%, respectively) in terms of infertility history. Nor were there any differences between the groups with respect to the type of drug used, whether clomiphene citrate (9.5% vs. 6.2%, respectively) or gonadotropins (7.1% vs. 10.1%, respectively). Analysis in terms of the number of cycles administered also failed to reveal any differences. The mean number of cycles with clomiphene citrate/gonadotropins was 2.50 ± 1.00 and 3.00 ± 2.64 in the borderline tumor group and 2.44 ± 1.75 and 3.27 ± 2.25 in the control group.Conclusions. Our series produced no evidence that ovulation induction treatment predisposes women to the development of borderline ovarian tumors.

Association between fertility drugs and gynecologic cancers, breast cancer, and childhood cancers

Ovulation-inducing drugs have been widely used for various types of infertility since the beginning of 1960s and their use increases day by day parallel to the success achieved in fertility treatment. However, the researches performed in the last two decades have begun to discuss about the safety of these drugs and the risks associated with their use. Especially, the potential neoplastic effects of these drugs are increasingly questioned. The studies have discussed whether there is an association between the exposure to ovulation-inducing drugs and the incidence of various cancers. Moreover, several studies have been performed to reveal whether there is an increased risk of childhood cancers in children conceived after fertility treatment. The point we reached through the available data is that the risk of breast, uterine and invasive ovarian cancers is not increased, but the risk of borderline ovarian tumors might increase after such a therapy. The risk of cancer has been found similar for children conceived after fertility treatment and those conceived naturally. It should also be kept in mind that cancers are overdiagnosed in infertile women population because of the close medical surveillance, which may also contribute to the early detection of cancers. Although it is still early to state the last words on this topic, the possible association should be addressed when obtaining an informed consent before starting treatment.