Kirsten Frederiksen

Fertility treatment and risk of ovarian cancer in a large nationwide cohort of infertile Danish women

AbstractWhether fertility treatment increases the risk of ovarian cancer has been a concern for many decades, but previous research has yielded conflicting findings. We therefore investigated this association within a large population‐based cohort study of infertile women aged 20–45 years and living in Denmark between 1995 and 2017, as identified in the Danish Infertility Cohort (n = 146,110). The study cohort was linked to nationwide registers to obtain information on fertility drug use, cancer diagnoses, covariates, emigration, and vital status was. Hazard ratios (HR) and 95% confidence intervals (CI) with adjustment for potential confounders for ovarian cancer overall and for serous ovarian cancer were estimated using Cox proportional hazard models. During a median 10.3 years of follow‐up, 114 women were diagnosed with ovarian cancer of which 65 had serous ovarian cancer. Our results showed that the rate of serous ovarian cancer (HR 1.92; 95% CI 1.16–3.17) was increased after every use of progesterone but the association was not affected by increased follow‐up time since first use or with increased cumulative dose. We performed a secondary analysis adding less extensive data from 1971 through 1994 from the Danish Infertility Cohort. In this study cohort, 332 women developed ovarian cancer of which 192 had serous ovarian cancer. The overall results were similar, including the association between every use of progesterone and serous ovarian cancer (HR 2.05: 95% CI: 1.31–3.21). In conclusion, the novel finding that use of progesterone is associated with an increased rate of serous ovarian cancer warrants further investigation.

The risk of vaginal, vulvar and anal precancer and cancer according to high‐risk HPV status in cervical cytology samples

AbstractHigh‐risk human papillomavirus (hrHPV) is the cause of virtually all cervical cancers, most vaginal and anal cancers, and some vulvar cancer cases. With HPV testing becoming the primary screening method for cervical cancer, understanding the link between cervical hrHPV infection and the risk of other anogenital cancers is crucial. We assessed the risk of vulvar, vaginal and anal cancer and precancer (VIN2+, VaIN2+ and AIN2+) in a prospective cohort study including 455,349 women who underwent cervical hrHPV testing in Denmark from 2005 to 2020. We employed Cox proportional hazard models, adjusting for age, calendar year and HPV vaccination status, and estimated hazard ratios (HRs) and 95% confidence intervals (CI). We used the Aalen Johansen estimator to calculate the absolute risks of VIN2+, VaIN2+ and AIN2+. In total, 15% of the women were hrHPV positive at baseline. A positive cervical hrHPV test was associated with increased incidence of vulvar, vaginal and anal squamous cell carcinoma (SCC). Five‐year risk estimates of VIN2+, VaIN2+ and AIN2+ among hrHPV‐positive women (0.45%, 0.14% and 0.12%) were higher than among hrHPV‐negative women (0.14%, 0.01% and 0.05%). Particularly high risk was observed among the hrHPV‐positive women of the oldest age, with a history of anogenital precancer and those not HPV vaccinated. In conclusion, our study confirms the association between cervical hrHPV infection and non‐cervical anogenital precancers and cancers. Currently, no established risk threshold or guidelines for follow‐up. As HPV testing becomes the primary method for cervical cancer screening, future data will help define high‐risk groups and acceptable risk thresholds.

Risk of specific types of ovarian cancer after borderline ovarian tumors in Denmark: A nationwide study

Population‐based evidence regarding risk of ovarian cancer after a borderline ovarian tumor (BOT) is sparse. We aimed to examine the incidence of specific types of ovarian cancer in women with serous or mucinous BOTs in a nationwide cohort study with up to 36 years of follow‐up. Using the nationwide Danish Pathology Data Bank, we identified 4,281 women with a BOT (2,058 serous BOTs and 2,223 mucinous BOTs) in Denmark during 1978–2012. We computed standardized incidence ratios (SIRs) to compare the incidence of ovarian cancer among women with BOTs compared to general population rates. We found that a serous BOT was especially and strongly associated with subsequent serous ovarian cancer (SIR = 9.2; 95% CI: 6.8–12.2), and that a mucinous BOT was strongly related to mucinous ovarian cancer (SIR = 18.6; 95% CI: 10.8–29.8). The SIRs remained elevated ≥10 years after a serous BOT and up to 5–9 years after a mucinous BOT. The increased incidence of serous ovarian cancer in women with a serous BOT was mostly pronounced in women <50 years at the serous BOT diagnosis. In conclusion, women with a serous BOT experience long‐term increased incidence of serous ovarian cancer, and women with a mucinous BOT have long‐term elevated incidence of mucinous ovarian cancer compared to the general population. This is the first population‐based study to show compelling evidence of the histo‐specific increased risk of ovarian cancer following specific types of BOTs. Thus, these results are supportive of the hypothesis that BOTs may be precursor lesions to carcinomas of the corresponding histologic type.

Risk of nonovarian cancer in a nationwide‐based study of nearly 5000 women with borderline ovarian tumors in Denmark

AbstractEvidence regarding cancer risk after borderline ovarian tumors (BOTs) is limited. We conducted a nationwide cohort study examining the incidence of nonovarian cancers in women with serous or mucinous BOTs compared with the general female population with up to 41 years of follow‐up. Through the nationwide Pathology Registry, we identified nearly 5000 women with BOTs (2506 serous and 2493 mucinous) in Denmark, 1978 to 2018. We computed standardized incidence ratios (SIRs) with 95% confidence intervals (CIs) as relative risk estimates of specific nonovarian cancers. Compared with general female population rates, women with serous BOTs had increased rates of particularly malignant melanoma (SIR = 1.9; 95% CI: 1.3‐2.6), thyroid cancer (SIR = 3.0; 95% CI: 1.4‐5.4) and myeloid leukemia (SIR = 3.2; 95% CI: 1.5‐5.8), and women with mucinous BOTs had elevated rates of lung cancer (SIR = 1.7; 95% CI: 1.3‐2.1), pancreatic cancer (SIR = 1.9; 95% CI: 1.2‐2.9) and myeloid leukemia (SIR = 2.3; 95% CI: 0.9‐4.7). We found no convincing association with neither breast nor colorectal cancer in women with BOTs. This is the first large nationwide study showing that women with specific types of BOTs have increased risks of several nonovarian cancers, likely due to some shared risk factors or genetic characteristics.

Six‐pattern p53 interpretation in 1293 vulvar squamous cell carcinomas: inter‐pathologist variation and pattern distribution according to p16 status

Aims Vulvar squamous cell carcinoma (VSCC) is classified into human papillomavirus (HPV)‐associated and HPV‐independent types, primarily using p16 immunohistochemistry, with p53 staining playing a complementary role since a subset of HPV‐independent VSCC is driven by TP53 mutations. We aimed to assess the robustness of the six‐pattern p53 classification by evaluating interobserver agreement and mapping pattern distribution in relation to p16 status. Methods We performed p53 immunohistochemistry on 1293 VSCC cases, comprising 832 p16‐negative and 461 p16‐positive cases. Eight pathologists independently evaluated p53, with each case assessed by two pathologists. Expression was classified as wild‐type (scattered or mid‐epithelial) or mutated (basal overexpression, parabasal/diffuse overexpression, absent or cytoplasmic). Interobserver agreement was measured using kappa statistics. Results Overall concordance across the six p53 patterns was 66.7%, increasing to 86.9% when dichotomized as wild‐type versus mutated. In the p16‐negative cases, concordance was 68.8% across all six patterns and 82.6% when dichotomized. Corresponding rates in the p16‐positive cases were 62.9% and 94.6%. Kappa values for pairwise assessments ranged from 0.44 to 0.73 (six‐pattern) and from 0.60 to 0.88 (dichotomized). After resolving discordant cases, 79.9% of p16‐negative cases showed a mutated pattern, and 20.1% were wild type (scattered). Among the p16‐positive cases, 93.1% exhibited a wild‐type pattern. Conclusions Findings support the clinical robustness of the six‐pattern p53 framework, as interobserver agreement was high and most discrepancies were unlikely to impact tumour classification. While p16 proved helpful in p53 interpretation, certain cases remained challenging due to p53 heterogeneity or ambiguous p16/p53 combinations indicating a need for additional molecular testing in such instances.

Prognostic impact of p16 and high‐risk HPV DNA in ~1300 patients with vulvar cancer

AbstractThe study aimed to investigate whether vulvar squamous cell carcinoma (VSCC) survival varies by human papillomavirus (HPV) status measured by p16 expression and to determine whether high‐risk HPV (hrHPV) DNA detection adds further prognostic information. Our cohort included 1277 women with histologically verified VSCC (1990–2017) categorized according to p16 and hrHPV DNA. Crude survival was estimated using Kaplan–Meier, and differences in restricted mean survival time were estimated in linear regression models. Analyses were stratified by p16 and p16/hrHPV status and stage, and adjustment included age, calendar year, and comorbidity. Overall analysis showed that 5‐year survival was 67% (95% CI: 63–71%) and 45% (95% CI: 42–48%) in p16‐positive and p16‐negative VSCC, respectively. Overall, detection of hrHPV was associated with a 23% (95% CI: 6–40%) improvement in 5‐year survival in p16‐positive VSCC, whereas hrHPV status did not impact 5‐year survival in p16‐negative VSCC. In adjusted analysis, the survival difference by p16 status increased with increasing stage with a 26% (95% CI: 4–46%) higher 5‐year survival in FIGO IV disease if the tumor was p16‐positive compared to p16‐negative, corresponding to a restricted mean survival time difference of 18 months in favor of p16 positivity. The largest VSCC cohort to date confirms the beneficial prognostic impact of p16 expression regardless of age and comorbidity and with the greatest impact in women with advanced disease. Classification according to p16 was adequate for p16‐negative VSCC, whereas the survival of p16‐positive VSCC was higher if hrHPV testing was also positive.