BACKGROUND:Prior research on the association between thyroid disease, ovarian cancer, and borderline ovarian tumors has been inconsistent. This nationwide cohort study investigated the risk of epithelial ovarian cancer and borderline ovarian tumors among 1,058,745 Danish women born between January 1, 1960, and December 31, 1997, and were followed until December 31, 2022, in relation to hypothyroidism and hyperthyroidism. METHODS:Data on thyroid diagnoses, ovarian tumors, covariates, migration, and vital status were retrieved from Danish national registers. Hazard ratios (HR) and 95% confidence intervals (CI) for ovarian cancer and borderline ovarian tumors overall and for histologic subtypes were estimated using adjusted Cox proportional hazard models. A landmark analysis assessed ovarian tumor risk at age 60 years by thyroid disease status before age 40 years. RESULTS:Over a median of 18.4 years of follow-up, 49,015 women developed hypothyroidism, 26,950 hyperthyroidism, 905 ovarian cancer, and 1,111 borderline ovarian tumors. No association was found between hypothyroidism and ovarian cancer (HR, 1.10; CI, 0.78-1.55) or borderline tumors (HR, 0.88; CI, 0.60-1.29). Hyperthyroidism was associated with increased rates of serous ovarian cancer (HR, 1.62; CI, 1-2.63) and borderline ovarian tumors (HR, 1.78; CI, 1.26-2.52), especially in postmenopausal and premenopausal women, respectively. However, absolute risk differences at age 60 years were small and not statistically significant. CONCLUSIONS:Hyperthyroidism may increase the rate of epithelial ovarian tumors, though clinical significance remains unclear, warranting further research. IMPACT:These findings indicate that hyperthyroidism may modestly influence epithelial ovarian tumor risk, underscoring the need to clarify shared biological mechanisms between thyroid and ovarian function.

Codes used for ovarian cancer diagnoses in The Danish Cancer Register, 1960–2022.

Characteristics of the 621,494 women included in the study cohort used to assess the association between hypo- and hyperthyroidism and epithelial ovarian cancer using a landmark analytic approach. Age 40 was designated as the landmark and only individuals alive and cancer-free at that age were included. Highest obtained level of education was fixed at age 25, while all other characteristics were fixed at age 40.

Codes used for diagnoses from the Danish National Patient Register, 1977–2022.

Codes used for borderline ovarian tumor diagnoses in The Danish National Pathology Register, 1995-2022.

Codes used for drugs in the Danish National Prescription Register, 1995–2022.

Data on cancer risk in offspring of men with testicular germ cell cancer (TC) remain limited. We assessed the risk of childhood and adolescent and young adult (AYA) cancer in offspring of men with TC. Men diagnosed with TC in the Danish Cancer Registry (1943-2017) were identified (TC probands). For each TC proband, 10 men matched on birth year, alive, and cancer-free at the proband's date of diagnosis were selected from the National Civil Registration System (non-TC probands). Offspring were identified in the Danish Birth Registry, with cancer diagnoses obtained from national registries. Cumulative incidences, hazard ratios (HRs), with 95% confidence intervals (CIs) were calculated for childhood cancer (0-14 years) and AYA cancer (15-39 years), including TC specifically versus other cancers. Offspring were included regardless of whether they were born before or after their father's diagnosis (for TC probands) or the corresponding index date (for non-TC probands). Childhood cancer rates were similar between sons of TC probands and non-TC probands (HR 1.0, 95% CI 0.6-1.7) and daughters (HR 1.1, 95% CI 0.6-1.9). For AYA cancer, rates in daughters were comparable, while sons of TC probands had an increased rate (HR 1.9, 95% CI 1.6-2.4). This increase was driven by TC (HR 3.6, 95% CI 2.7-4.8), with no significant difference in rates of other cancers. The rate of childhood cancer in offspring of men with TC is comparable to the rate of the general population, while the elevated AYA cancer rate in sons is attributable to a higher rate of TC.

Characteristics of the 1,058,548 women included in the study cohort used to assess the association between hypo- and hyperthyroidism and borderline ovarian tumors. Women were included in the study cohort at 25 years of age or in 1996, whichever came last. Except birth year, all characteristics were determined at age 25 for all study participants.

Detailed descriptions of all registers used in the study.

Characteristics of the 621,101 women included in the study cohort used to assess the association between hypo- and hyperthyroidism and borderline ovarian tumors using a landmark analytic approach. Age 40 was designated as the landmark and only individuals alive and cancer-free at that age were included. Highest obtained level of education was fixed at age 25, while all other characteristics were fixed at age 40.

This meta-analysis aimed to explore penile cancer survival based on p53 and Ki-67 status.A systematic literature search identified studies assessing overall and cancer-specific survival after penile cancer with p53 or Ki-67 expression. Pooled hazard ratios (HRs) and restricted mean survival time differences (RMSTD) were calculated using a random-effects model. The analysis included 930 and 391 men for p53 expression in overall survival (OS) and cancer-specific survival (CSS), respectively. Those with the p53 mutant pattern exhibited significantly worse OS and CSS compared to the p53 wild-type pattern (HROS=2.42, 95%CI: 1.75-3.34. HRCSS=4.18, 95%CI: 1.87-9.35). The 5-year RMSTD for OS, according to p53 status, was -10.62 months (95%CI: -16.20– -5.03). We included 202 men with penile cancer tested for Ki-67 expression and found a HR of CSS of 1.96 (95%CI: 1.15–3.32).In conclusion, men with the p53 mutant pattern penile cancer have worse OS and CSS than men with p53 wild-type pattern penile cancer. Evidence regarding Ki-67 status was sparse, but the pooled estimate indicated that penile cancers with high Ki-67 expression may have a slightly worse CSS than those with low Ki-67 expression. These findings may inform clinicians when planning the best management and follow-up strategy for penile cancer patients.

Experimental evidence links thyroid hormones to breast cancer cell proliferation, but the association between thyroid disorders and breast cancer remains unclear, with previous research yielding conflicting results. This large cohort study investigated the association between hypo‐ and hyperthyroidism and breast cancer among all women born in Denmark between January 1, 1960, and December 31, 1997 ( n = 1,058,939). Data on hypo‐ and hyperthyroidism diagnoses, cancer diagnoses, covariates, migration, and vital status were obtained from Danish national registers. Hazard ratios (HRs) and 95% confidence intervals (CIs) for breast cancer overall and for histological subtypes were calculated based on adjusted Cox proportional hazard regression models. A total of 49,015 women developed hypothyroidism, 26,950 developed hyperthyroidism, and 15,703 were diagnosed with breast cancer during a median follow‐up of 18.8 years. Hypothyroidism was associated with a decreased rate of breast cancer (HR: 0.85, 95% CI 0.78–0.93), with a possible stronger association among postmenopausal women (HR: 0.78, 95% CI 0.68–0.90). In contrast, hyperthyroidism showed no association with breast cancer (HR: 1.00, 95% CI 0.89–1.11), and menopausal status did not affect this association. All findings were consistent across time since first thyroid disease diagnosis and histological subtypes. In conclusion, our study suggests that hypothyroidism is associated with a reduced risk of breast cancer, potentially most pronounced among postmenopausal women, while no association was observed between hyperthyroidism and breast cancer risk. These findings highlight the need for further research to understand the biological mechanisms linking thyroid dysfunction and breast cancer, especially in the context of menopausal status.

BACKGROUND:More evidence is needed to substantiate current recommendations about removing ovaries during hysterectomy for benign conditions.OBJECTIVE:To compare long-term outcomes in women with and without bilateral salpingo-oophorectomy (BSO) during hysterectomy for benign conditions.DESIGN:Emulated target trial using data from a population-based cohort.SETTING:Women in Denmark aged 20 years or older during 1977 to 2017.PARTICIPANTS:142 985 women with hysterectomy for a benign condition, 22 974 with BSO and 120 011 without.INTERVENTION:Benign hysterectomy with or without BSO.MEASUREMENTS:The primary outcomes were overall hospitalization for cardiovascular disease (CVD), overall cancer incidence, and all-cause mortality through December 2018.RESULTS:Compared with women without BSO, women with BSO who were younger than 45 years at surgery had a higher 10-year cumulative risk for hospitalization for CVD (risk difference [RD], 1.19 percentage points [95% CI, 0.09 to 2.43 percentage points]). Women with BSO had a higher 10-year cumulative risk for cancer for ages 45 to 54 years (RD, 0.73 percentage point [CI, 0.05 to 1.38 percentage points]), 55 to 64 years (RD, 1.92 percentage points [CI, 0.69 to 3.25 percentage points]), and 65 years or older (RD, 2.54 percentage points [CI, 0.91 to 4.25 percentage points]). Women with BSO had higher 10-year mortality in all age groups, although the differences were statistically significant only for ages 45 to 54 years (RD, 0.79 percentage point [CI, 0.27 to 1.30 percentage points]). The mortality at 20 years was inconsistent with that at 10 years in women aged 65 years or older.LIMITATION:Age was a proxy for menopausal status.CONCLUSION:The authors find that these results support current recommendations for conserving ovaries in premenopausal women without a high risk for ovarian cancer and suggest a cautious approach in postmenopausal women.PRIMARY FUNDING SOURCE:The Danish Cancer Society's Scientific Committee and the Mermaid Project.

Programmed cell death ligand‐1 (PD‐L1) expression in cancer may predict clinical response to immunotherapeutic treatment with PD‐1/PD‐L1 inhibitors. Within the vulvar cancer field, PD‐L1 expression has only been assessed by a few studies. We conducted a meta‐analysis to examine the prevalence of PD‐L1 positivity in vulvar cancer. PubMed, Embase, and Cochrane were searched for articles reporting on PD‐L1 expression in vulvar cancer. Study selection and data extraction were performed independently by two authors. We extracted data on PD‐L1 prevalence in vulvar cancer according to combined positive score (CPS) and tumour proportion score (TPS). Cutoff values for positivity were ≥1 or ≥10 for CPS and ≥1% and ≥5% for TPS. Random‐effects models were used to estimate pooled PD‐L1 prevalence, with 95% confidence intervals (CIs). Tests of between‐study heterogeneity were evaluated by the I 2 statistics. Sources of heterogeneity were explored by subgroup analyses and meta‐regression. In total, 19 studies were included. Pooled PD‐L1 prevalence in vulvar cancer was 83.4% (95% CI: 70.8–91.3; I 2 = 80.0) and 53.9% (95% CI: 37.4–69.6; I 2 = 93.0) according to CPS and TPS, respectively. Based on TPS, human papillomavirus (HPV)‐associated vulvar squamous cell carcinomas (SCC) showed a lower PD‐L1 prevalence (39.9%; 95% CI: 13.3–74.2) compared with HPV‐independent SCC (62.6%; 95% CI: 33.7–84.6), but meta‐regression showed no significant variation in PD‐L1 prevalence by HPV status. PD‐L1 prevalence was similar in advanced (44.9%; 95% CI: 29.8–61.1) and localized vulvar cancer (56.7%; 95% CI: 18.9–76.7). In conclusion, PD‐L1 expression in vulvar cancer is frequent but between‐study heterogeneity was high. Based on a subgroup of heterogenous studies, we found no strong variation in PD‐L1 prevalence according to HPV status and stage.

BACKGROUND:Preclinical studies have suggested that antidepressant drugs may possess antineoplastic properties. In a nationwide case-control study, we examined the association between use of antidepressants and endometrial-cancer risk with a particular focus on selective serotonin reuptake inhibitors (SSRIs).METHODS:From the Danish Cancer Registry, we identified all women with a histologically verified diagnosis of endometrial cancer between 2000 and 2016, and, for each woman, 15 age-matched controls. We obtained information on use of SSRIs, tricyclic antidepressants (TCAs) and other antidepressants based on records of filled prescriptions from the National Prescription Register. Using conditional logistic regression, we calculated adjusted odds ratios (ORs) and 95% confidence intervals (CIs) for associations between use of antidepressants and endometrial-cancer risk compared with non-use. In active comparator analyses, SSRI use was compared with TCA use.RESULTS:The study population comprised 8164 cases and 122 432 controls. Compared with non-use, SSRI use was associated with an OR of 0.88 (95% CI 0.82-0.96) for endometrial cancer, whereas the association with TCA use was close to unity (OR 1.05, 95% CI 0.90-1.22). Use of other antidepressants yielded an OR of 0.86 (95% CI 0.71-1.03). We observed no apparent trends in associations according to cumulative amount. The inverse association with SSRI use persisted when compared with TCA use (OR 0.81, 95% CI 0.66-0.99).CONCLUSIONS:Use of SSRIs was associated with a decreased risk of endometrial cancer, whereas no inverse association appeared with use of TCAs. The antineoplastic potential of SSRIs should be investigated in future studies.

Objectives: Base-of-tongue (BOT)/tonsillar cancer incidence is rising, primarily due to human papillomavirus; meanwhile, rates of the mainly smoking-associated laryngeal cancer is declining. Little is known about whether these trends are seen in all socioeconomic levels and age-groups. We describe incidence trends of BOT/tonsillar and laryngeal cancer in Denmark 1994-2018 by educational level and age. Methods: BOT/tonsillar and laryngeal cancer cases diagnosed 1994-2018 were identified from the Danish Cancer Registry. We obtained individual-level educational information from nationwide registries. We estimated agestandardized incidence rates of BOT/tonsillar and laryngeal cancer according to sex, education and age. Temporal incidence trends were evaluated by the average annual percentage change (AAPC) with corresponding 95% confidence intervals (CIs) using linear and Poisson regression models for age-standardized incidence rates. Results: We identified 4245 individuals with BOT/tonsillar cancer and 6123 with laryngeal cancer. BOT/tonsillar cancer incidence increased among men with short (AAPC:3.4, 95% CI 2.1;4.6) and long (AAPC:5.1, 95% CI 3.2;7.1) education, and all age-groups, while decreased from 2012 among men with medium education (AAPC:4.3, 95 %CI -7.6;-1.0). Laryngeal cancer incidence decreased from 2007 in men with medium (AAPC:-4.7, 95% CI -6.7;-2.7) and long (AAPC:-2.4, 95% CI -3.4;-1.4) education, and all age-groups, whereas increased in men with short education (AAPC:1.0, 95% CI 0.2;1.8). Similar trends were seen among women. Conclusions: Over the last 25 years, BOT/tonsillar cancer incidence in Denmark has generally increased in all agegroups and educational levels. In contrast, social inequality was seen in laryngeal cancer trends as incidence decreased in individuals with medium and long education, while incidence increased in individuals with short education.

Beta-blockers have shown antineoplastic effects in laboratory studies but epidemiologic evidence in relation to contralateral breast cancer (CBC) is sparse. We investigated postdiagnosis beta-blocker use and risk of CBC in a cohort of 52 723 women with breast cancer by using nationwide Danish health registers and the Danish Breast Cancer Group database. We defined postdiagnosis beta-blocker use as a time-varying covariate starting 1 year after a second prescription was redeemed. Cox proportional hazards regression was used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) for CBC associated with beta-blocker use compared to nonuse. We identified 1444 women with CBC of whom 209 women were beta-blocker users. We found an overall HR of 1.08 (95% CI: 0.93-1.27) for beta-blocker use and risk of CBC with no substantial variation according to cumulative amount, intensity or selectivity of beta-blocker use. Hence, our cohort study of women with breast cancer did not sustain a protective effect of beta-blocker use on risk of CBC, irrespective of beta-blocker type.

Squamous cell carcinoma (SCC) of the penis is rare. Some studies have suggested that the incidence is increasing but the available literature is equivocal. We examined the incidence of high-grade penile intraepithelial neoplasia (PeIN), the incidence and 5-year relative survival as well as mortality of penile SCC in Denmark over the latest 20 years. New cases of high-grade PeIN and penile cancer were identified from high-quality nationwide registries. Age-standardized (World) incidence rates per 100,000 person-years and average annual percentage change (AAPC) were estimated. For penile SCC, 5-year relative survival was calculated, and Cox regression was used to examine the effect of selected characteristics on mortality. Altogether, 1,070 new cases of high-grade PeIN were diagnosed (1997–2018) and the incidence increased from 0.87 to 1.84 per 100,000 person-years from 1997–1998 to 2017–2018 (AAPC = 4.73; 95% CI: 3.54–5.94). We identified 1,216 penile cancer cases (1997–2018) (95.7% SCC). The incidence of penile SCC increased slightly from 0.85 per 100,000 person-years in 1997–1998 to 1.13 per 100,000 person-years in 2017–2018 (AAPC = 1.01; 95% CI: 0.24–1.79). The 5-year relative survival of penile SCC did not change substantially, whereas the mortality tended to decrease. Penile SCC is increasing slightly in Denmark, while a pronounced increase in the incidence of high-grade PeIN is seen. The 5-year relative survival from penile cancer was relatively stable over time. Increasing exposure to HPV infection at the population level may have contributed to the observed increase in PeIN and penile SCC. Awareness of HPV may also have contributed to the increased detection of PeIN.

After some decades with an increasing incidence of borderline ovarian tumors, more recent studies have observed that the incidence rate seems to be leveling off or declining. In this study, we describe the incidence of borderline ovarian tumors in Denmark 1997‐2018 by histology, age at diagnosis and educational level.

Laboratory studies have shown anti-neoplastic properties of non-aspirin NSAID; however, no studies have examined the influence of non-aspirin NSAIDs as potential adjuvant cancer therapy in women with endometrial cancer. We therefore examined the association between post-diagnostic use of non-aspirin NSAIDs and endometrial cancer mortality in Denmark. We identified all women with a primary endometrial cancer diagnosis between 2000 and 2012, who were alive one year after the diagnosis. Information on drug use, cause-specific mortality and potential confounders was obtained from nationwide health- and demographic registries. Cox regression models were used to estimate adjusted hazard ratios (HRs) and 95% confidence intervals (CIs) for the association between post-diagnostic non-aspirin NSAID use and endometrial cancer mortality. Among 6 694 endometrial cancer patients with a maximum follow-up of 13 years, 753 women died from endometrial cancer. Post-diagnostic non-aspirin NSAID use (≥ 1 filled prescription) was associated with an overall HR of 1.15 (95% CI; 0.97–1.36) for endometrial cancer mortality, with higher HRs for the highest intensity of use (HR; 1.40, 95% CI; 1.11–1.77) and largest cumulative amount (HR; 1.56, 95% CI; 1.14–2.14). Our findings yielded no evidence that use of non-aspirin NSAIDs was associated with reduced endometrial cancer. Rather, we observed that high-intensity and large cumulative amount of non-aspirin NSAID use may be associated with increased endometrial cancer mortality.