A cervical screening initiative for elderly women in Denmark.

INTRODUCTION: To assess outcome of a one-time human papillomavirus (HPV)-screening in 2017 of Danish women aged 70+. MATERIAL AND METHODS: Women born 1947 or before were personally invited to have a cell-sample collected by their general practitioner. Screening- and follow-up samples were analyzed in hospital laboratories in the five Danish regions and registered centrally. Follow-up procedures varied slightly across regions. Cervical intraepithelial neoplasia 2 (CIN2) was recommended treatment threshold. Data were retrieved from the Danish Quality Database for Cervical Cancer Screening. We calculated CIN2+ and CIN3+ detection rates per 1000 screened women, and number of biopsies and conizations per detected CIN2+ case. We tabulated annual number of incident cervical cancer cases in Denmark for the years 2009-2020. RESULTS: In total, 359 763 women were invited of whom 108 585 (30% of invited) were screened; 4479 (4.1% of screened, and 4.3% of screened 70-74 years) tested HPV-positive; of whom 2419 (54% of HPV-positive) were recommended follow-up with colposcopy, biopsy and cervical sampling, and 2060 with cell-sample follow-up. In total, 2888 women had histology; of whom 1237 cone specimen and 1651 biopsy only. Out of 1000 screened women 11 (95% confidence interval [CI]: 11-12) had conization. In total, 579 women had CIN2+; 209 CIN2, 314 CIN3, and 56 cancer. Out of 1000 screened women five (95% CI: 5-6) had CIN2+. Detection rate of CIN2+ was highest in regions where conization was used as part of first-line follow-up. In 2009-2016, number of incident cervical cancers in women aged 70+ in Denmark fluctuated around 64; in 2017 it reached 83 cases; and by 2021 the number had decreased to 50. CONCLUSIONS: The prevalence of high-risk HPV of 4.3% in women aged 70-74 is in agreement with data from Australia, and the detection of five CIN+2 cases per 1000 screened women is in agreement with data for 65-69 year old women in Norway. Data are thus starting to accumulate on primary HPV-screening of elderly women. The screening resulted in a prevalence peak in incident cervical cancers, and it will therefore take some years before the cancer preventive effect of the screening can be evaluated.

The SENTIREC-endo study - Risks and benefits of a national adoption of sentinel node mapping in low and intermediate risk endometrial cancer.

OBJECTIVE: The SENTIREC-endo study aims to investigate risks and benefits of a national protocolled adoption of sentinel lymph node (SLN) mapping in women with early-stage low-grade endometrial cancer (EC) with low- (LR) and intermediate-risk (IR) of lymph node metastases. METHODS: We performed a national multicenter prospective study of SLN-mapping in women with LR and IR EC from March 2017-February 2022. Postoperative complications were classified according to Clavien-Dindo. Lymphedema was assessed as a change score and as incidence of swelling and heaviness evaluated by validated patient-reported outcome measures at baseline and three months postoperatively. RESULTS: 627 women were included in the analyses; 458 with LR- and 169 with IR EC. The SLN detection rate was 94.3% (591/627). The overall incidence of lymph node metastases was 9.3% (58/627); 4.4% (20/458) in the LR- and 22.5% (38/169) in the IR group. Ultrastaging identified 62% (36/58) of metastases. The incidence of postoperative complications was 8% (50/627) but only 0.3% (2/627) experienced an intraoperative complication associated with the SLN procedure. The lymphedema change score was below the threshold for clinical importance 4.5/100 CI: (2.9-6.0), and the incidence of swelling and heaviness was low; 5.2% and 5.8%, respectively. CONCLUSION: SLN mapping in women with LR and IR EC carries a very low risk of early lymphedema and peri- and postoperative complications. The national change in clinical practice contributed to a more correct treatment allocation for both risk groups and thus supports further international implementation of the SLN technique in early stage, low grade EC.

Germline pathogenic variants associated with ovarian cancer: A historical overview.

The risk of ovarian, tubal, and peritoneal cancer is related to germline pathogenic variants, and over time, the number of known disease-associated genes has increased significantly. This study reviews the literature regarding the topic from a historical perspective. The aim is to present a timeline of the knowledge gained from the early 1900s until today. The findings are put into perspective by looking at the current gene panel used for screening for suspected hereditary ovarian cancer in Denmark compared to what is known internationally. In 1929, the first familial ovarian cancer incidents were registered, and in 1950, the involvement of a genetic component was suggested for the first time. During the 1970s, several studies reported an accumulation of ovarian cancer in certain families, and during this time, it was discovered that ovarian cancer was linked to both breast cancer and colorectal cancer. The inheritance of cancer disposition has been thoroughly investigated, leading to the discovery of the BRCA genes in the 1990s. Furthermore, new studies based on new genetic technologies have revealed several genes with germline pathogenic variants that increase the risk of ovarian cancer. The identification of these pathogenic variants has led to preventive measures and specific treatment of women with genetic disposition to ovarian cancer. In Denmark, consensus is to include at least ten genes in the screening panel for hereditary ovarian cancer, and in the future additional genes will probably be added.

Improved stratification of stage-specific survival for cervical uterine cancer by integrating FDG-PET/CT and MRI for lymph node staging in 2018 FIGO classification.

OBJECTIVE: Staging carcinoma of the uterine cervix (CCU) by FIGO-2018 suggests stage migration of FIGO-2009 stage I-III patients with lymph node metastasis into FIGO-2018 stage IIIC. We aimed to investigate the prognostic value of lymph node metastases identified by imaging. METHODS: We enrolled all patients with biopsy-verified CCU from 2007 to 2016 at Odense University Hospital, Denmark. FDG-PET/CT and MRI were performed before clinical examination in general anesthesia. Disease-specific mortality was compared between women with lymph node-positive and lymph node-negative imaging. RESULTS: In total, 488 patients underwent clinical staging according to FIGO-2009. Lymph node-positive imaging was identified in 146 (30%) patients: 0/36 (0%) in stage IA, 22/195 (11%) in IBI, 14/30 (47%) in IB2, 70/164 (43%) in II and 40/63 (63%) in III. The 5-year cumulative incidence of death due to CCU lymph node-negative vs. lymph node-positive patients was 0.8% vs. 7.1% (p = 0.034) in stage IBI, 0% vs. 34.5% (p = 0.003) in stage IB2, 15.1% vs. 41.4% (p < 0.0001) in stage II, and 33.3% vs. 46.6% (p = 0.28) in stage III by FIGO-2009. CONCLUSIONS: One of three women with FIGO-2009 stage I-III CCU had suspected lymph node metastasis on imaging and is upstaged to stage IIIC according to FIGO-2018. The cancer-specific mortality by CCU was significantly lower in the lymph node-negative women stages IBI-II, thus supporting stage migration due to suspected lymph node metastasis. However, the exact prognostic value within stage IIIC is challenged, and future revision of FIGO stages may include new sub-stages.

Epithelial ovarian cancer and the use of circulating tumor DNA: A systematic review.

OBJECTIVE: One way to improve the survival rate of epithelial Ovarian Cancer (EOC) is by identifying effective biomarkers useful at different stages and time points of the disease. A potential biomarker is circulating tumor DNA (ctDNA) in plasma or serum. In this systematic review, we provide an overview of applications of ctDNA in EOC to discuss the direction of future research in this field. METHODS: We performed a systematic search in Pubmed, Embase, and Scopus to identify relevant clinical studies eligible for inclusion. Furthermore, the references in the identified studies and relevant reviews were assessed to identify additional studies. The PRISMA guideline was employed to perform the systematic review, and data from the studies were extracted using piloted data extraction forms. RESULTS: A total of 36 observational studies were included. The concordance between tumor and ctDNA was assessed in 19 studies, early diagnosis in 1, diagnosis in 23, monitoring of treatment response in 7, detection of reversion mutations in 3, prognosis in 9, but no studies assessed early detection of recurrence. Data from the studies were reported descriptively. The studies had a large variation in the methods used for ctDNA analysis and limited sample sizes of 10-126 patients. Overall, the studies show that ctDNA is a potential biomarker for EOC useful in several settings during assessment and treatment of these patients. CONCLUSIONS: Although the identified studies are limited in number and their methods for ctDNA analysis vary, it is clear that ctDNA as a biomarker for EOC is promising for several applications in diagnostics, monitoring of treatment response, and prognostics. However, more studies are needed to establish the ideal methods and settings for the clinical use of ctDNA in EOC.

Histological outcomes in HPV-screened elderly women in Denmark.

INTRODUCTION: Danish women exit cervical cancer screening at age 65 years, but 23% of cervical cancer cases occur beyond this age. In addition, due to gradual implementation of cervical cancer screening, older women are underscreened by today´s standards. A one-time screening with HPV test was therefore offered to Danish women born before 1948. METHODS: Register based study reporting histology diagnoses and conizations in women found HPV positive in the one-time screening. Number and proportion of women with severe or non-severe histology results were calculated for screened and HPV-positive women by age group or region of residence. Number of women with biopsy and/or conization per case of cervical intraepithelial neoplasia (CIN) grade 2 or worse (CIN2+) or CIN3+ were also calculated by age groups and region. RESULTS: 4,479 (4.1% of screened women) had positive HPV test. 94% of these had one or more additional tests. 2,785 (62%) of HPV-positive women had histology results, and conization was performed in 1,076 (24% of HPV-positive and 1% of all screened women). HPV positivity and CIN3+ detection varied little between regions, but the proportions of HPV positive women undergoing histology varied between regions from 40% to 86% and the proportion with conization from 13% to 36%. Correspondingly, the number of histologies and conizations per CIN3+ detected varied from 5.9 to 11.2 and 1.8 to 4.7, respectively. In total, 514 CIN2+ (0.47% of screened women, 11% of HPV-positive) and 337 CIN3+ (0.31% of screened women, 7.5% of HPV-positive) were diagnosed, including 37 cervical cancer cases. DISCUSSION: HPV screening of insufficiently screened birth cohorts can potentially prevent morbidity and mortality from cervical cancer but longer follow-up is needed to see if cancer incidence declines in the screened women in the coming years. Management strategies differed among regions which influenced the proportions undergoing biopsy/conization.

HPV-prevalence in elderly women in Denmark.

AIM: In countries like Denmark, cervical cancer incidence is at present relatively high in elderly women, while routine screening stops at age 65 years. On this background, all women aged 69 and above were invited to human papillomavirus (HPV)-screening in Denmark in 2017. METHODS: Women were identified from the Central Population Register and personally invited by digital or ordinary mail to have a screening sample taken by their general practitioner. In four regions, samples were tested for high risk (HPV) with the cobas 4800® HPV-assay, and in the last region with the BD Onclarity® HPV-assay. Participation rate, prevalence of high risk HPV, and proportion of positive samples with HPV16, HPV18, and other high risk HPV-types were tabulated by 5-year age-groups. RESULTS: 455,612 women were invited, and 30.2% (95 confidence interval (CI) 30.0-30.3) participated. Average age of participants was 74.6 years. Overall, 4.3% (95% CI 4.1-4.4) of participants were HPV-positive, of whom 24% had HPV 16/18. HPV-prevalence decreased slightly from 4.5% in women aged 69-73 years to 3.1% in women aged 84-88 years, but was 5.2% in the very small group of participants aged 89+ years. CONCLUSION: Invitation to HPV-screening was well received by elderly women. The HPV-prevalence decreased slightly with increasing age. No rebound of HPV-prevalence after menopause was found when our data were combined with previously published Danish data from younger women. The presently relatively high cervical cancer incidence in elderly women was not reflected in the HPV-prevalence.

Screening history and FIGO-stages among Danish women with cervical cancer in 2012-2014: a register-based study.

The objective was to examine whether attendance in the mass cervical screening programme has implications for the prognosis when cervical cancer is diagnosed. We performed a retrospective analysis of all cases of cervical cancer between 1st of January 2012 and 31st of December 2014 in the Region of Southern Denmark. The cases were retrieved from the Danish National Pathology Registry, PatoBank. Odds ratios (OR) with confidence intervals (95% CI) were calculated for attendees versus non-attendees of the screening programme by using χ2-test. 216 patients were included in the study. 61.6% of the study population had not attended the screening programme. Patients who had attended the programme were characterised by disease in low stage (OR = 3.14, 95% CI; 1.66 to 5.92), treatment with surgery alone (OR = 2.63, 95% CI; 1.49 to 4.64) and a lower risk of death (OR = 0.36, 95% CI; 0.15 to 0.87). Adenocarcinomas were more often detected among attendees of the programme compared to squamous cell carcinomas (OR = 4.06, 95% CI; 2.03 to 8.14). Statistically significant results regarding relapse of cancer (OR = 0.62, 95% CI; 0.23 to 1.68, p = 0.47) and lymph node metastases (OR = 0.62, 95% CI; 0.32 to 1.21, p = 0.19) were not found. Cervical cancer detected in women who had attended the mass cervical screening programme prior to the diagnosis, was shown to have a statistically significant lower FIGO stage (p = 0.0004) and was therefore linked to less extensive treatment options. Continued focus on increasing the participation rate of the programme is of importance, as the nonattendance rate continues to be high.

[Septic abortion with massive coagulopathy and subsequent acute hysterectomy].

Septic abortion is a rare, but potentially life-threatening condition. Quick diagnosis and treatment is essential for the outcome. This case report describes a healthy 34-year-old woman who was admitted with abdominal pain, fever and an ongoing spontaneous abortion at gestational age week 13 + 6 days. During evacuation severe bleeding and coagulopathy was seen. She was treated with multiple coagulation products but due to a life-threatening situation an acute hysterectomy was performed. She was discharged after nine days.

Danish Gynecological Cancer Database.

AIM OF DATABASE: The Danish Gynecological Cancer Database (DGCD) is a nationwide clinical cancer database and its aim is to monitor the treatment quality of Danish gynecological cancer patients, and to generate data for scientific purposes. DGCD also records detailed data on the diagnostic measures for gynecological cancer. STUDY POPULATION: DGCD was initiated January 1, 2005, and includes all patients treated at Danish hospitals for cancer of the ovaries, peritoneum, fallopian tubes, cervix, vulva, vagina, and uterus, including rare histological types. MAIN VARIABLES: DGCD data are organized within separate data forms as follows: clinical data, surgery, pathology, pre- and postoperative care, complications, follow-up visits, and final quality check. DGCD is linked with additional data from the Danish "Pathology Registry", the "National Patient Registry", and the "Cause of Death Registry" using the unique Danish personal identification number (CPR number). DESCRIPTIVE DATA: Data from DGCD and registers are available online in the Statistical Analysis Software portal. The DGCD forms cover almost all possible clinical variables used to describe gynecological cancer courses. The only limitation is the registration of oncological treatment data, which is incomplete for a large number of patients. CONCLUSION: The very complete collection of available data from more registries form one of the unique strengths of DGCD compared to many other clinical databases, and provides unique possibilities for validation and completeness of data. The success of the DGCD is illustrated through annual reports, high coverage, and several peer-reviewed DGCD-based publications.

The value of random biopsies, omentectomy, and hysterectomy in operations for borderline ovarian tumors.

OBJECTIVE: Borderline ovarian tumors (BOTs) are treated surgically like malignant ovarian tumors with hysterectomy, salpingectomy, omentectomy, and multiple random peritoneal biopsies in addition to removal of the ovaries. It is, however, unknown how often removal of macroscopically normal-appearing tissues leads to the finding of microscopic disease. To evaluate the value of random biopsies, omentectomy, and hysterectomy in operations for BOT, the macroscopic and microscopic findings in a cohort of these patients were reviewed retrospectively. MATERIALS: Women treated for BOT at Odense University Hospital from 2007 to 2011 were eligible for this study. Data were extracted from electronic records. Intraoperative assessment of tumor spread (macroscopic disease) and the microscopic evaluation of removed tissues were the main outcome measures. RESULTS: The study included 75 patients, 59 (78.7%) in International Federation of Gynecology and Obstetrics stage I, 9 (12%) in stage II, and 7 (9.3%) in stage III. The histologic subtypes were serous (68%), mucinous (30.7%), and Brenner type (1.3%). Macroscopically radical surgery was performed in 62 patients (82.7%), and 46 (61.3%) received complete staging. The surgeon's identification of macroscopic tumor spread to the contralateral ovary and the peritoneum had a sensitivity of 88% and 69.2% and a specificity of 90.2% and 92.5%, respectively. The macroscopic assessment of the uterine surface, the omentum, and the pelvic and para-aortal lymph nodes was not a good predictor of microscopic disease. During follow-up, 4 patients (5.3%) relapsed with no relation to surgical radicality or the extent of staging procedures. CONCLUSIONS: Ovaries and peritoneal surfaces with a macroscopically normal appearance rarely contain a microscopic focus of BOT.

[Association between endometriosis and ovarian cancer]. / Relationen mellem endometriose og ovariecancer.

The objective of this study was to review the literature concerning the possible link between endometriosis and ovarian cancer, and to highlight common aetiological factors. The aetiology for both diseases seems to be multifactorial. Hormonal, genetic and immunologic factors seem to play a role. With a twofold increased risk of developing ovarian cancer in patients with endometriosis in general and a further fourfold increased risk for high risk endometriosis patients with infertility, the findings seem relevant and should be kept in mind when encountering and treating patients with endometriosis.

RNA quality and gene expression analysis of ovarian tumor tissue undergoing repeated thaw-freezing.

Gene expression profiles evaluated by microarray-based quantization of RNA are used in studies of differential diagnosis and prognosis in cancer. RNA of good quality is mandatory for this evaluation. The RNA most often comes from tumor banks with limited amount of tissue, and the tissue often undergoes repeated thawing and freezing. We evaluated the influence of repeated division of tumor samples at room temperature, on RNA quality and quantity, in addition to the gene expression profile. Sixteen ovarian tumor samples were divided in three aliquots each, undergoing respectively one, two, and three thaw-freeze cycles. RNA from each aliquot was extracted on the day of division, and quantity and quality were evaluated. RNA from all three aliquots of four tumor samples underwent microarray analysis on Affymetrix Human Genome U133A 2.0 arrays. Microarray data were evaluated using both unsupervised, and supervised multivariate statistical methods, reliability analysis, as well as verification using published gene lists in ovarian cancer studies. RNA quality and quantity did not change during the division procedure and microarray data showed insignificant difference in gene expression. Tumor samples from tumor banks can be frozen and thawed at least three times without compromising the RNA integrity and genetic expression profile.

Carcinoma in situ cervicis uteri and inheritance--a Danish twin study.

OBJECTIVE: To determine the relative environmental and genetic influence in the development of carcinoma in situ (CIS) cervicis uteri. METHODS: Retrospective follow-up study with record linkage between The Danish Twin Register and The Danish Cancer Register. The study base comprises 27,004 female twins from 13,502 same-sex twin pairs. 5,258 were monozygotic and 8,244 dizygotic twin pairs. The statistic measurements are the coincidence ratio and the probandwise concordance rate in the two groups of twins with different zygosity. RESULTS: 750 twins were diagnosed with CIS cervicis uteri. 291 monozygotic twins came from 275 pairs and 459 dizygotic twins came from 435 pairs. There were 16 concordant monozygotic twin pairs and 24 concordant dizygotic pairs. The probandwise concordance rate was 0.11 (0.06-0.16) in monozygotic twins and 0.10 (0.06-0.14) in dizygotic twins. CONCLUSION: A family clustering of CIS was demonstrated in both groups of zygosity. The probandwise concordance rate was equal in the monozygotic and the dizygotic groups, which means that genetic factors are not important in the development of the disease. However, a shared environment among twins plays a role in the development of CIS cervicis uteri.