Antidepressant use and ovarian cancer risk: Evidence from nationwide studies with >14,000 cases from Denmark and Sweden.

OBJECTIVE: Given that the evidence regarding the link between antidepressant use and ovarian cancer risk is equivocal, we investigated this research question by conducting two nationwide nested case-control studies among the Danish and Swedish populations. METHODS: Altogether, 14,121 women with epithelial ovarian cancer (30-84 years old) (Denmark: 8976 diagnosed 2000-2019, Sweden: 5145 diagnosed 2010-2018) were randomly age-matched with 564,840 female controls (359,040 from Denmark, and 205,800 from Sweden) using risk set sampling. We used conditional logistic regression to estimate odds ratios (OR) with 95 % confidence intervals (CI) and combined the estimates based on the fixed-effect assumption. We also investigated potential effect modification by well-established risk factors for ovarian cancer. RESULTS: Antidepressant use was associated with an overall reduced risk of ovarian cancer (OR = 0.92, 95%CI: 0.88-0.96), and that reduction was more pronounced in postmenopausal women and long-term users. The effect was most pronounced for serous ovarian tumors (OR = 0.90, 95%CI: 0.86-0.95) but was also observed in other subtypes, although not statistically significant. Among different types of antidepressants, selective serotonin reuptake inhibitors in general and citalopram in particular exhibited a noteworthy reduction in ovarian cancer risk (OR = 0.89, 95%CI: 0.82-0.96). Additionally, use of oral contraceptives and hormone replacement therapy individually modified the association between antidepressant use and ovarian cancer risk. CONCLUSIONS: Use of an antidepressant was associated with a slight, but statistically significant, decrease in ovarian cancer risk. Given the morbidity and mortality associated with ovarian cancer, and increasing use of antidepressants, these findings may be of significance to cancer prevention and should be studied in more detail mechanistically.

Prediagnostic use of menopausal hormone therapy and long-term survival of localized epithelial ovarian cancer: The Extreme study.

Use of menopausal hormone therapy (MHT) prior to an epithelial ovarian cancer (EOC) diagnosis has been suggested to be associated with improved survival. In a recent nationwide cohort study, we found that prediagnostic long-term MHT use, especially estrogen therapy (ET), was associated with improved long-term survival in women with nonlocalized EOC. Our aim was to investigate the influence of prediagnostic MHT use on long-term survival among women with localized EOC in the same nationwide study. Our study cohort comprised all women aged 50 years or older with an EOC diagnosis in Denmark 2000-2014 (n = 2097) identified from the Extreme study. We collected information on usage of systemic ET and estrogen plus progestin therapy (EPT) from the Danish National Prescription Registry. By using pseudo-values, 5- and 10-year absolute and relative survival probabilities were estimated with 95% confidence intervals (CIs) while adjusting for histology, comorbidity, and income. Relative survival probabilities >1 indicate better survival. The 5-year absolute survival probabilities were 61% and 56%, respectively, among women who were nonusers and users of prediagnostic MHT, whereas these numbers were 46% and 41%, respectively, regarding 10-year survival. Use of MHT was not significantly associated with an improved 5- or 10-year survival in women with localized EOC (5-year relative survival probability = 0.95, 95% CI: 0.89-1.02; 10-year relative survival probability = 0.92, 95% CI: 0.84-1.02). Similar findings were seen for systemic ET or EPT use. Our findings do not suggest a positive benefit from prediagnostic MHT use on long-term survival of localized EOC.

History of autoimmune disease and long-term survival of epithelial ovarian cancer: The extreme study.

OBJECTIVE: Patients with autoimmune disease may have impaired cancer survival. The aim was to investigate the association between autoimmune disease and ovarian cancer survival. METHODS: From the Extreme study, we included women diagnosed with epithelial ovarian cancer (EOC) in Denmark during 1990-2014 (n = 11,870). Information on exposure and covariates was retrieved from nationwide registries. Using pseudo-values, we estimated absolute and relative 5- and 10-year survival probabilities with 95% confidence intervals (CIs) for autoimmune diseases combined and for the four most common individual disorders in our study population, namely type 1 diabetes, rheumatoid arthritis, Graves' disease, and inflammatory bowel disease. RESULTS: The overall 5- and 10-year absolute survival probabilities were 35% and 24%, respectively, in women with EOC without autoimmune disease. Autoimmune diseases combined was not significantly associated with survival among women with EOC (5-year adjusted relative survival probability = 1.01, 95% CI: 0.94-1.09; 10-year adjusted relative survival probability = 0.90, 95% CI: 0.81-1.00). However, stratification by disease stage showed an impaired 10-year survival in women with autoimmune disease and a localized EOC (relative survival probability = 0.86, 95% CI: 0.76-0.97). None of the individual autoimmune diseases were statistically significantly associated with EOC survival. CONCLUSIONS: Only among women with localized EOC, there seemed to be a long-term survival loss associated with a history of autoimmune disease. In contrast, no significant association between a history of autoimmune disease and survival was observed in women with nonlocalized EOC where the survival is already low.

Prognostic impact of socioeconomic status on long-term survival of non-localized epithelial ovarian cancer ꟷ The Extreme study.

OBJECTIVE: To examine the influence of socioeconomic status (SES) on long-term survival of non-localized ovarian cancer. METHODS: All women in Denmark with a first diagnosis of non-localized epithelial ovarian cancer 1982-2007 were identified in the Cancer Registry and/or the Pathology Registry and followed up until December 2017. The survival probability was estimated after respectively 5 and 10 years, using so-called pseudo observations, and analyzed according to education, income, and marital status defined from nationwide registries. RESULTS: The study cohort included 6486 women, and the estimated 5- and 10-year survival probabilities were 21.4% and 12.7%, respectively. Compared to women with short education, the 5-year survival probability was 7% higher for women with medium (relative survival probability = 1.07, 95% CI: 0.97, 1.19) and long education (relative survival probability = 1.07, 95% CI: 0.93, 1.24). Compared with married women, the 5-year survival probability for divorced women/widower was slightly lower (0.85, 95% CI: 0.69, 1.04) and for unmarried women slightly higher (1.08, 95% CI: 0.94, 1.23). Finally, the probability of being alive 5 years after diagnosis was 1.09 times higher (95% CI: 0.95, 1.24) for medium-income women and 1.23 times higher (95% CI: 1.08, 1.41) for high-income women compared with low-income women. Similar patterns were observed for 10-year survival. CONCLUSIONS: Non-localized ovarian cancer patients have a poor prognosis. Our data suggest that among Danish women with advanced ovarian cancer, higher personal income is associated with slightly higher probability of long-term survival, whereas education and marital status did not affect the probability of long-term survival.

Use of paracetamol, low-dose aspirin, or non-aspirin non-steroidal anti-inflammatory drugs and risk of ovarian borderline tumors in Denmark.

OBJECTIVE: Few studies have examined ovarian borderline tumor (BOT) risk associated with analgesics, and with inconclusive findings. The aim was to examine serous borderline tumor (SBT) or mucinous borderline tumor (MBT) risk associated with use of paracetamol, low-dose aspirin, or non-aspirin non-steroidal anti-inflammatory drugs (NSAIDs). METHODS: We identified all women with SBTs or MBTs in the Danish Pathology Data Bank, 1997-2015. Using risk-set sampling, we randomly selected 15 controls per case. We excluded women with previous cancer (except non-melanoma skin cancer) and controls with bilateral oophorectomy/salpingo-oophorectomy. Information on redeemed prescriptions of medications/confounders was identified from nationwide registries. We used conditional logistic regression to estimate adjusted odds ratios (ORs) and 95% confidence intervals (CIs). RESULTS: We observed a decreased MBT risk among recent paracetamol users (OR = 0.77; 95% CI: 0.60-0.98), but no association with SBTs. Regarding non-aspirin NSAIDs, we found an increased SBT risk with recent (OR = 1.29; 95% CI: 1.11-1.51) and former use (OR = 1.19; 95% CI: 1.04-1.37), and an elevated MBT risk with recent use (OR = 1.14; 95% CI: 0.97-1.33). Low-dose aspirin use did not seem related with SBT risk, and the association with MBTs was unclear. CONCLUSIONS: No strong associations between the examined medications and BOTs were observed. However, our nationwide case-control study may suggest that recent paracetamol use could have a chemopreventive effect on MBTs, whereas neither low-dose aspirin nor non-aspirin NSAIDs use seem to protect against SBTs or MBTs. Larger studies are needed to firmly establish a potential association between these medications and BOT risk.

Parity, infertility, oral contraceptives, and hormone replacement therapy and the risk of ovarian serous borderline tumors: A nationwide case-control study.

OBJECTIVE: Few studies have examined the risk of an ovarian serous borderline tumor (SBT) associated with parity, infertility, oral contraceptives (OCs), or hormone replacement therapy (HRT), which was the study aim. METHODS: This nationwide case-control study included all women with an SBT diagnosis in Denmark, 1978-2002. SBTs were confirmed by centralized expert pathology review. For each case, 15 age-matched female controls were randomly selected using risk-set sampling. Cases and controls with previous cancer (except for non-melanoma skin cancer) and controls with bilateral oophorectomy or salpingo-oophorectomy were excluded. Conditional logistic regression was used to estimate adjusted odds ratios (ORs) and 95% confidence intervals (CIs). RESULTS: We found a strongly decreased risk of SBTs among parous women which decreased with increasing number of children (p<0.01). Older age at first birth also decreased the SBT risk (p=0.03). An increased SBT risk was associated with infertility (OR=3.31; 95% CI: 2.44-4.49), which was present both among parous and nulliparous women. HRT use increased the SBT risk (OR=1.32; 95% CI: 1.02-1.72), whereas OC use decreased the risk (OR=0.40; 95% CI: 0.26-0.62). CONCLUSIONS: Our nationwide study with expert histopathologic review of all SBTs showed that parity, infertility, use of HRT, and use of OCs, respectively, were strongly associated with the risk of SBTs. This is the first study to report a strong and significantly decreased SBT risk associated with OC use and a significantly increased risk with infertility, and HRT use. This supports that SBTs and serous ovarian cancer share similar risk factors.

A nationwide study of ovarian serous borderline tumors in Denmark 1978-2002. Risk of recurrence, and development of ovarian serous carcinoma.

OBJECTIVE: Absolute risk and risk factors for recurrence and ovarian serous carcinoma following ovarian serous borderline tumors (SBTs) is not well-established. METHODS: We included all women with SBTs in Denmark, 1978-2002. Diagnoses were confirmed by centralized pathology review and classified as atypical proliferative serous tumor (APST) or noninvasive low-grade serous carcinoma (LGSC). Implants were classified as noninvasive or invasive. Medical records were collected and reviewed, and follow-up was obtained. Subsequent diagnoses were also confirmed by centralized pathology review. We examined absolute risk and risk factors for recurrent APST and serous carcinoma using Cox regression. RESULTS: The absolute serous carcinoma risk after, respectively, 5 and 20years was 5.0% and 13.9% for noninvasive LGSC, and 0.9% and 3.7% for APST. Serous carcinoma risk was significantly higher following noninvasive LGSC compared with APST among stage I patients/patients without implants (HR=5.3; 95% CI: 1.7-16.3), whereas no significant association with tumor type was found in advanced stage patients/patients with implants. Advanced stage - notably invasive implants - bilaterality, surface involvement, and residual disease increased serous carcinoma risk. However, women with stage I APST also had a higher risk than the general population. CONCLUSIONS: This largest population-based cohort of verified SBTs revealed that women with noninvasive LGSC are significantly more likely to develop serous carcinoma than women with APST, which could not entirely be explained by invasive implants. Although invasive implants was a strong risk factor for serous carcinoma, even women with stage I APST were at increased risk compared with the general population.

A nationwide study of serous "borderline" ovarian tumors in Denmark 1978-2002: centralized pathology review and overall survival compared with the general population.

OBJECTIVE: To describe the study population and estimate overall survival of women with a serous "borderline" ovarian tumor (SBT) in Denmark over 25 years relative to the general population. METHODS: The Danish Pathology Data Bank and the Danish Cancer Registry were used to identify 1487 women diagnosed with SBTs from 1978 to 2002. The histologic slides were collected from Danish pathology departments and reviewed by expert pathologists and classified as SBT/atypical proliferative serous tumor (APST) or noninvasive low-grade serous carcinoma (LGSC). Associated implants were classified as noninvasive or invasive. Medical records were collected from hospital departments and reviewed. Data were analyzed using Kaplan-Meier and relative survival was estimated with follow-up through September 2, 2013. RESULTS: A cohort of 1042 women with a confirmed SBT diagnosis was identified. Women with stage I had an overall survival similar to the overall survival expected from the general population (p=0.3), whereas women with advanced stage disease had a poorer one (p<0.0001). This was evident both in women with noninvasive (p<0.0001) and invasive implants (p<0.0001). Only among women with advanced stage, overall survival of women with SBT/APST (p<0.0001) and noninvasive LGSC (p<0.0001) was poorer than expected from the general population. CONCLUSIONS: To date this is the largest nationwide cohort of SBTs where all tumors have been verified by expert pathologists. Only in women with advanced stage SBT, overall survival is poorer than in the general population which applies both to women with noninvasive and invasive implants as well as to women with SBT/APST and noninvasive LGSC.

A binary histologic grading system for ovarian serous carcinoma is an independent prognostic factor: a population-based study of 4317 women diagnosed in Denmark 1978-2006.

OBJECTIVE: To evaluate the prognostic significance of histologic grade on survival of ovarian serous cancer in Denmark during nearly 30 years. METHODS: Using the nationwide Danish Pathology Data Bank, we evaluated 4317 women with ovarian serous carcinoma in 1978-2006. All pathology reports were scrutinized and tumors classified as either low-grade serous carcinomas (LGSC) or high-grade serous carcinomas (HGSC). Tumors in which the original pathology reports were described as well-differentiated were classified as LGSC, and those that were described as moderately or poorly differentiated were classified as HGSC. We obtained histologic slides from the pathology departments for women with a diagnosis of well-differentiated serous carcinoma during 1997-2006, which were then reviewed by expert gynecologic pathologists. Data were analyzed using Kaplan-Meier methods and Cox proportional hazards regression analysis with follow-up through June 2009. RESULTS: Women with HGSC had a significantly increased risk of dying (HR=1.9; 95% CI: 1.6-2.3) compared with women with LGSC while adjusting for age and stage. Expert review of 171 women originally classified as well-differentiated in 1997-2006 were interpreted as LGSC in 30% of cases, whereas 12% were interpreted as HGSC and 50% as serous borderline ovarian tumors (SBT). Compared with women with confirmed LGSC, women with SBT at review had a significantly lower risk of dying (HR=0.5; 95% CI: 0.22-0.99), and women with HGSC at review had a non-significantly increased risk of dying (HR=1.6; 95% CI: 0.7-3.4). CONCLUSIONS: A binary grading system is a significant predictor of survival for ovarian serous carcinoma.

Increased incidence of penile cancer and high-grade penile intraepithelial neoplasia in Denmark 1978-2008: a nationwide population-based study.

OBJECTIVE: To assess the trends in incidence of penile cancer during 1978-2008 and high-grade penile intraepithelial neoplasia (PIN2/3) during 1998-2008 in Denmark. METHODS: Using two nationwide registries, we estimated age- and period-specific incidence rates. Log-linear Poisson regression analysis was used to estimate average annual percentage change (AAPC) and 95% confidence intervals (CI). RESULTS: We identified 1,488 men with penile cancer and 285 men with PIN2/3. The incidence of penile cancer increased from 1.0 to 1.3 per 100,000 men-years in 1978-1979 to 2006-2008; this represented an AAPC of 0.8% (95% CI: 0.17-1.37). Squamous cell carcinoma (SCC) was the most common histological type (91.7%). The median age at diagnosis was 67 years, and the age-specific incidence rate of penile SCC increased with increasing age. The incidence rate of PIN2/3 increased significantly (0.5 to 0.9 per 100,000 men-years) in 1998-1999 to 2006-2008, and this represented an AAPC of 7.1% (95% CI: 3.30-11.05). CONCLUSIONS: The incidence of penile cancer increased in 1978-2008 in Denmark, and the same applied to PIN2/3 in 1998-2008. A high prevalence of human papillomavirus (HPV) and a low circumcision rate in Denmark may partly explain our results.

Papillary tubal hyperplasia: the putative precursor of ovarian atypical proliferative (borderline) serous tumors, noninvasive implants, and endosalpingiosis.

In contrast to the controversy regarding the terminology and behavior of ovarian noninvasive low-grade serous tumors [atypical proliferative serous tumor (APST) and serous borderline tumor], little attention has been directed to their origin. Similarly, until recently, proliferative lesions in the fallopian tube had not been extensively studied. The recent proposal that ovarian high-grade serous carcinomas are derived from intraepithelial carcinoma in the fallopian tube prompted us to evaluate the possible role of fallopian tube in the genesis of low-grade serous tumors. We have identified a lesion, designated "papillary tubal hyperplasia (PTH)," characterized by small rounded clusters of tubal epithelial cells and small papillae, with or without associated psammoma bodies, that are present within the tubal lumen and which are frequently associated with APSTs. Twenty-two cases in this study were selected from a population-based study in Denmark of approximately 1000 patients with low-grade ovarian serous tumors in whom implants were identified on the fallopian tube. Seven additional cases were seen recently in consultation at The Johns Hopkins Hospital (JHH). These 7 cases were not associated with an ovarian tumor. PTH was found in 20 (91%) of the 22 cases in the Danish study. On the basis of this association of PTH with APSTs with implants and the close morphologic resemblance of PTH, not only to primary ovarian APSTs but also to noninvasive epithelial implants and endosalpingiosis, we speculate that the small papillae and clusters of cells from the fallopian tube implant on ovarian and peritoneal surfaces to produce these lesions. The 7 JHH cases of PTH that were not associated with an ovarian tumor support the view that PTH is the likely precursor lesion. We propose a model for the development of ovarian and extraovarian low-grade serous proliferations (APST, noninvasive epithelial implants, and endosalpingiosis) that postulates that all of these lesions are derived from PTH, which appears to be induced by chronic inflammation. If this hypothesis is confirmed, it can be concluded that low-grade and high-grade ovarian tumors develop from tubal epithelium and involve the ovary secondarily.

Trends in incidence of borderline ovarian tumors in Denmark 1978-2006.

OBJECTIVE: To examine period-, age- and histology-specific trends in the incidence rate of borderline ovarian tumors in Denmark in 1978-2006. DESIGN: Register-based cohort study. SETTING: Denmark 1978-2006. POPULATION: 5079 women diagnosed with a borderline ovarian tumor in at least one of two nationwide registries (4312 epithelial tumors and 767 non-epithelial/unspecified tumors). METHODS: Estimation of overall incidence rates and period-, age- and histology-specific incidence rates. Age-adjustment was done using the World Standard POPULATION. To evaluate incidence trends over time, we estimated average annual percentage change and 95% confidence intervals (CI) using log-linear Poisson models. MAIN OUTCOME MEASURES: Age-standardized and age-specific incidence rates and average annual percentage change. RESULTS: The incidence of epithelial borderline ovarian tumors increased from 2.6 to 5.5 per 100,000 women-years between 1978 and 2006, with an average annual percentage change of 2.6% (95% CI: 2.2-3.0). The median age at diagnosis was 52 years. Women 40 years or older had a higher average annual percentage change than women younger than 40 years. Most tumors were mucinous (49.9%) and serous tumors (44.4%). Women with mucinous tumors were younger at diagnosis (50 years) compared with women with serous tumors (53 years). Women with serous tumors had a higher average annual percentage incidence change than women with mucinous tumors. CONCLUSIONS: The incidence rate of borderline ovarian tumors increased significantly in Denmark in 1978-2006. In line with results for ovarian cancer, Denmark had a higher incidence rate of borderline ovarian tumors compared with the other Nordic countries in 1978-2006.

Survival of ovarian cancer patients in Denmark: excess mortality risk analysis of five-year relative survival in the period 1978-2002.

OBJECTIVE: To explore the variation in ovarian cancer survival in Denmark in the period 1978-2002 in relation to time since diagnosis, age at diagnosis, period of diagnosis, stage and histology. DESIGN: Register-based cohort study. SETTING: Denmark in the period 1978-2002. POPULATION: Using the nationwide Danish Cancer Registry, we included a total of 13,035 women diagnosed with invasive ovarian cancer in Denmark in the period 1978-2002. METHODS: Excess mortality risk analyses of five-year relative survival of ovarian cancer patients diagnosed in the period 1978-2002 with follow-up through 2006 were made based on data from the NORDCAN database. MAIN OUTCOME MEASURES: Five-year relative survival, excess mortality rate (ER) and relative excess mortality risk (RER) after an ovarian cancer diagnosis. RESULTS: The relative survival of Danish ovarian cancer patients slightly increased in the period 1978-2002. The ERs were highest in the first year following diagnosis, in particular in the first three months, and among older patients, even for localized and regional tumors. The pattern remained the same when stratified by histological subgroup. Older age at diagnosis, earlier period of diagnosis, more advanced stage at diagnosis and being diagnosed with undifferentiated carcinoma predicted poorer survival among Danish ovarian cancer patients diagnosed in the period 1978-2002. CONCLUSIONS: The survival of Danish ovarian cancer patients has slightly increased from 1978 through 2002. Despite this, the mortality rate of ovarian cancer in Denmark is still higher than in the other Nordic countries. Explanations for these differences are still to be identified.

Social inequality and incidence of and survival from cancer of the female genital organs in a population-based study in Denmark, 1994-2003.

We investigated the effects of socioeconomic, demographic and health-related indicators on the incidence of and survival from cancers of the cervix, endometrium and ovary diagnosed in 1994-2003 with follow-up through 2006 in Denmark using information from nationwide registers. The analyses were based on the data on 3007 patients with cervical cancer, 3826 with endometrial cancer and 3855 with ovarian cancer in a cohort of 3.22 million persons born between 1925 and 1973 and aged >or=30 years. The incidence of cervical cancer increased with decreasing socioeconomic position; the incidences of endometrial and ovarian cancer were mostly associated with higher disposable income. Relative survival from cervical cancer was the highest among women of high socioeconomic position; increased excess mortality rates from endometrial and ovarian cancer were associated with low educational level, mainly during the first year after diagnosis. Socioeconomic position seemed to affect both the incidence of and the survival from cancers of the female genital organs.

Malignant melanoma risk after exposure to fertility drugs: results from a large Danish cohort study.

OBJECTIVE: The aim was to examine the effects of fertility drugs on malignant melanoma risk using data from the largest cohort of infertile women to date. METHODS: A cohort of 54,362 women with infertility problems referred to Danish fertility clinics in the period 1963-1998 was established. A detailed data collection including information about type and amount of treatment was conducted. Using case-cohort techniques, we calculated rate ratios (RRs) of malignant melanoma associated with different fertility drugs after adjustment for parity status. RESULTS: 112 malignant melanomas were identified during follow-up through 2000. Use of clomiphene, gonadotrophins, hCG or GnRH did not affect risk of malignant melanoma significantly. When stratifying for parity, however, use of gonadotrophins (RR = 2.29; CI: 1.16-4.52) or GnRH (RR = 3.26; 95% CI: 1.50-7.09) among parous women was associated with a significant increased risk. For all groups of fertility drugs, we found no association with number of cycles of use or years since first use (latency). CONCLUSIONS: Our findings showed no strong association between malignant melanoma risk and use of fertility drugs, although the results indicated that use of gonadotrophins or GnRH might increase risk in parous women. Longer follow-up is needed to confirm our findings.

Maternal smoking predicts the risk of spontaneous abortion.

BACKGROUND: Few studies have examined smoking prior to pregnancy and the occurrence of spontaneous abortion, as most studies have addressed the risk of spontaneous abortion in relation to smoking during pregnancy. However, results are not entirely consistent. The aim of the present study was to assess the risk of spontaneous abortion considering smoking prior to pregnancy. METHODS: We performed a nested case-control study using prospective data from a population-based cohort comprising 11,088 women aged 20-29 years. From this cohort, women who experienced either a spontaneous abortion (n=343) or who gave birth (n=1,578) during follow-up were selected. Associations between self-reported smoking at enrollment and subsequent spontaneous abortion were analyzed by means of multiple logistic regression. RESULTS: The risk of spontaneous abortion in relation to pre-pregnancy smoking showed a clear dose-response effect. The adjusted odds ratio (95% confidence interval) for spontaneous abortion among current smokers prior to conception was 1.20 (1.04-1.39) per every extra five cigarettes smoked per day. The increased risk was only present for current smokers. The duration of smoking prior to pregnancy was not a significant predictor for subsequent spontaneous abortion. CONCLUSIONS: The amount of daily smoking prior to pregnancy seems to be associated with an increased risk of spontaneous abortion, whereas the duration of smoking does not seem to be related to an increased risk of spontaneous abortion.