Time trends in prevalence of p16 positivity and combined HPV/p16 positivity in a large cohort of Danish vulvar cancer patients.

Vulvar cancer is rare, but causes substantial morbidity in affected patients. A subset of vulvar cancers is caused by high-risk human papillomavirus (hrHPV), which primarily exerts its oncogenic effect through upregulation of tumor suppressor protein p16. Tumors positive for both hrHPV and p16 (double positive) are assumed to be HPV-driven, but only few large studies have investigated the combined prevalence of hrHPV and p16 positivity in vulvar cancer over time. In this Danish cross-sectional study, we assessed the prevalence of p16 positivity and double positivity for hrHPV and p16 in a large sample of vulvar squamous cell carcinomas (VSCCs) diagnosed during 1990 to 2017. In a nationwide register, we identified VSCCs from 13 hospitals across Denmark, and collected archival tumor tissue for hrHPV testing with INNO-LiPA and immunohistochemical p16 staining. We calculated the prevalence of hrHPV, p16 positivity and double positivity according to time, age and histological subtype and evaluated time trends through estimated annual percentage changes. We included 1278 VSCCs. Overall, 35.0% (95% confidence interval [CI]: 32.4-37.6) were positive for p16 and 31.0% (95% CI: 28.4-33.5) were positive for both hrHPV and p16. The prevalence of p16 positivity and double positivity increased over time, both in women aged ≤59 and ≥60 years. The double positive prevalence was higher in nonkeratinizing (60.7%) and warty/basaloid VSCCs (67.5%) than in keratinizing (16.1%) and verrucous VSCCs (5.0%). These results indicate that approximately one-third of vulvar cancers were caused by hrHPV infection, supporting a substantial preventive potential of the HPV vaccine.

Performance of HPV testing, Pap smear and VIA in women attending cervical cancer screening in Kilimanjaro region, Northern Tanzania: a cross-sectional study nested in a cohort.

OBJECTIVE: There is a concern about performance of the screening approaches, where information on the quality of novel and affordable screening approaches that will perform well in remote areas is warranted. This lack of information makes it difficult to prioritise resource use in efforts to improve cervical cancer outcomes. We aimed to compare the diagnostic value of human papillomavirus (HPV) testing on self-collected samples, Pap smear and visual inspection of the cervix with acetic acid (VIA) tests for detection of high-grade cervical intraepithelial neoplasia or worse (CIN2+). DESIGN: A combined cross-sectional and cohort study. SETTING: Three primary healthcare centres in Kilimanjaro region, Tanzania. PARTICIPANTS: 1620 women undergoing cervical cancer screening from December 2018 to September 2021. Inclusion criteria were being aged 25-60 years, and no history of premalignant or cervical cancer. Exclusion criteria were overt signs of cancer and previous hysterectomy. INTERVENTIONS: Participants underwent HPV self-sampling with Evalyn Brush and Care HPV kit assay was used to determine prevalence of high-risk HPV infection. Women with positive HPV test were together with a random sample of HPV negative women scheduled for follow-up where VIA was performed, and Pap smear and cervical biopsies obtained. RESULTS: Of 1620 women enrolled, 229 (14.1%) were HPV positive and 222 of these attended follow-up together with 290 (20.8%) women with negative HPV test. On VIA, 17.6% were positive. On Pap smear, 8.0% were classified as high-grade squamous intraepithelial lesion. The sensitivity and specificity, respectively, of the various tests, compared with histopathology for the detection of CIN2+ were: HPV test 62.5%, 59.3%; Pap smear 82.8%, 82.1% and; VIA 48.4%, 56.8%. When combined, the sensitivity and specificity for HPV and Pap smear were 90.6%, 70.6% while HPV and VIA were 65.6% and 75.5% for the detection of CIN2+. CONCLUSIONS: The performance of care HPV testing on self-collected samples opens the possibility of increasing coverage and early detection in resource-constrained settings.

HPV Test as Test of Cure After Conization for CIN2+: A Nationwide Register-Based Cohort Study.

OBJECTIVE: The purpose of this study was to assess if cytology can be omitted in the follow-up after treatment for cervical intraepithelial neoplasia grade 2 or worse (CIN2+) and if human papillomavirus (HPV) test can be used alone as test of cure (TOC) after stratifying for resection margins. MATERIAL AND METHODS: In this retrospective register-based study, women who had a conization performed in Denmark between January 1 and December 31, 2013, were included. Histology, cytology, and HPV test results were obtained from The Danish Pathology Data Bank for a 3-year follow-up. RESULTS: A total of 5,174 women were included, of whom 6.1% (318/5,174) had histological residual/recurrent disease in the follow-up period. In the group with free margins, 2.6% (73/2,780) had residual/recurrent disease in contrast to 10.2% (245/2,394) in the group with involved margins. In the group with free resection margins and negative HPV test results, residual/recurrent disease was found in 0.5% (13/2,780) compared with 0.3% (9/2,780) in the group with negative HPV test results and normal cytology at 6 months' follow-up. Based on margin status and HPV test result as follow-up, the sensitivity, specificity, and positive and negative predictive values were 95.9%, 43.2%, 10.0%, and 99.4% respectively, and for combined testing (margin status, HPV, and cytology), 97.2%, 41.2%, 9.8%, and 99.6%, respectively. CONCLUSIONS: Using the HPV test at the first post-treatment control as TOC for cervical intraepithelial neoplasia grade 2 or worse after stratifying for resection margins in cone resections yields an equally high sensitivity and negative predictive value as cotesting with cytology. We suggest that women with free resection margins return to the routine screening program after negative HPV test result as TOC at 6 months.

Endocervical sampling in women with suspected cervical neoplasia: a systematic review and meta-analysis of diagnostic test accuracy studies.

OBJECTIVE: Endocervical sampling in women with suspected cervical neoplasia can be performed by either endocervical brush or endocervical curettage. This study aimed to estimate the diagnostic accuracy, discomfort, and number of inadequate samples with either test. DATA SOURCES: Four bibliographic databases were searched on June 9, 2022, with no date or language restrictions. STUDY ELIGIBILITY CRITERIA: We included all diagnostic studies and randomized clinical trials that compared the endocervical brush with endocervical curettage in women with an indication for colposcopy. METHODS: The review protocol was registered on the International Prospective Register of Systematic Reviews (PROSPERO) (CRD42021222406). Two authors independently screened studies, extracted data, performed the risk-of-bias assessment (Quality Assessment of Diagnostic Accuracy Studies-2), and rated the certainty of the evidence using the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) methodology. A meta-analysis of diagnostic test accuracy was performed using a bivariate random-effects model. RESULTS: We included 7 studies: 4 diagnostic cohort studies and 3 randomized clinical trials. The reference standard was conization or hysterectomy. Risk of bias and concern about applicability were high for some of the studies in patient selection and flow and timing. Overall pooled sensitivity was 81% (95% confidence interval, 48-95; 799 women; 7 studies; low quality of evidence) for endocervical brush and 70% (95% confidence interval, 42-89; 761 women; 7 studies; low quality of evidence) for endocervical curettage. Overall pooled specificity was 73% (95% confidence interval, 36-93; 799 women; 7 studies; low quality of evidence) for endocervical brush and 81% (95% confidence interval, 56-94; 761 women; 7 studies; low quality of evidence) for endocervical curettage. The risk ratio for inadequate samples with endocervical curettage compared with endocervical brush was 2.53 (95% confidence interval, 0.58-11.0; P=.215; low-certainty evidence). Two studies reported on patient discomfort; one found less discomfort in the endocervical brush group, and the other found no difference. CONCLUSION: No difference was found between endocervical brush and endocervical curettage in diagnostic accuracy, inadequate sampling rate, and adverse effects based on low-quality of evidence. Variation in the characteristics of women and the resulting diagnostic pathways make the external validity limited.

Changes in HPV prevalence in Danish women with vulvar cancer during 28 years - A nationwide study of >1300 cancer cases.

OBJECTIVE: A substantial proportion of vulvar cancers are caused by high-risk human papillomavirus (hrHPV), but hrHPV prevalence in vulvar cancer has mainly been investigated in smaller studies which did not evaluate time trends. Our aim was to assess hrHPV prevalence in >1300 Danish vulvar cancers diagnosed during 1990-2017, including changes in hrHPV prevalence over time. METHODS: In a nationwide pathology register, we identified women diagnosed with vulvar cancer at thirteen hospitals from all Danish regions. Archival tumor tissue was collected from local repositories and, upon pathology review, sent to a central laboratory for HPV testing using INNO-LiPA. We calculated hrHPV prevalence according to time, age and histology, and evaluated the overall and age-specific estimated annual percentage change (EAPC). RESULTS: We included 1308 vulvar cancer cases, with a median age of 72 years at diagnosis. The overall hrHPV prevalence was 52.0% (95% CI: 49.3-54.7). HPV types 16/18 were found in 39.6% of cases, whereas nine-valent HPV (9vHPV) vaccine types 16, 18, 31, 33, 45, 52, and 58 were found in 50.8%. The hrHPV prevalence showed an increasing trend over time, with an EAPC of 0.35% (95% CI: 0.00-0.71). The hrHPV prevalence was higher in younger women throughout the study period, and increasing trends over time were seen in both older (age ≥ 60) and younger (age < 60) women. The hrHPV prevalence was higher in non-keratinizing (71.0%) and warty/basaloid (78.0%) carcinomas than in keratinizing (39.4%) and verrucous (36.4%) carcinomas. CONCLUSIONS: Our results indicate that the 9vHPV vaccine could potentially prevent a substantial proportion of vulvar cancers in Denmark.

The role of telepathology in diagnosis of pre-malignant and malignant cervical lesions: Implementation at a tertiary hospital in Northern Tanzania.

INTRODUCTION: Adequate and timely access to pathology services is a key to scale up cancer control, however, there is an extremely shortage of pathologists in Tanzania. Telepathology (scanned images microscopy) has the potential to increase access to pathology services and it is increasingly being employed for primary diagnosis and consultation services. However, the experience with the use of telepathology in Tanzania is limited. We aimed to investigate the feasibility of using scanned images for primary diagnosis of pre-malignant and malignant cervical lesions by assessing its equivalency to conventional (glass slide) microscopy in Tanzania. METHODS: In this laboratory-based study, assessment of hematoxylin and eosin stained glass slides of 175 cervical biopsies were initially performed conventionally by three pathologists independently. The slides were scanned at x 40 and one to three months later, the scanned images were reviewed by the pathologists in blinded fashion. The agreement between initial and review diagnoses across participating pathologists was described and measured using Cohen's kappa coefficient (κ). RESULTS: The overall concordance of diagnoses established on conventional microscopy compared to scanned images across three pathologists was 87.7%; κ = 0.54; CI (0.49-0.57).The overall agreement of diagnoses established by local pathologist on conventional microscopy compared to scanned images was 87.4%; κ = 0.73; CI (0.65-0.79). The concordance of diagnoses established by senior pathologist compared to local pathologist on conventional microscopy and scanned images was 96% and 97.7% respectively. The inter-observer agreement (κ) value were 0.93, CI (0.87-1.00) and 0.94, CI (0.88-1.00) for conventional microscopy and scanned images respectively. CONCLUSIONS: All κ coefficients expressed good intra- and inter-observer agreement, suggesting that telepathology is sufficiently accurate for primary diagnosis in surgical pathology. The discrepancies in interpretation of pre-malignant lesions highlights the importance of p16 immunohistochemistry in definitive diagnosis in these lesions. Sustainability factors including hardware and internet connectivity are essential components to be considered before telepathology may be deemed suitable for widely use in Tanzania.

SENTIREC - The sentinel node mapping in women with cervical cancer study - Patient-reported early lymphedema and its impact on quality of life.

OBJECTIVE: To evaluate patient-reported incidence and severity of early lymphedema and its impact on quality of life (QoL) after sentinel lymph node (SLN) mapping only and after SLN and pelvic lymphadenectomy (PL) in women undergoing surgery for early-stage cervical cancer. METHODS: In a national prospective multicenter study, we included women with early-stage cervical cancer from March 2017-January 2021 to undergo radical surgery including SLN mapping. Women with tumors >20 mm underwent completion PL. The incidence and severity of early lymphedema and its influence on QoL were evaluated using validated patient-reported outcome measures before surgery and three months postoperative. We investigated changes over time using linear regression. RESULTS: Two hundred of 245 (81.6%) included women completed questionnaires at baseline and three months postoperatively. The incidence of early lymphedema was 5.6% (95% CI 2.1-11.8%) and 32.3% (95% CI 22.9-42.7%) in women who underwent SLN mapping only and SLN + PL, respectively. Lymphedema symptoms in the legs, genitals, and groins increased in both groups postoperatively but three times more in women who underwent PL. Lymphedema symptoms after SLN + PL significantly impaired physical performance (p = 0.001) and appearance (p = 0.007). Reporting lymphedema was significantly associated with impaired body image, physical-, role-, and social functioning, and a high level of fatigue. CONCLUSIONS: SLN mapping alone carries a low risk of lymphedema in women undergoing surgery for early-stage cervical cancer. In contrast, completion PL is associated with a high incidence of early lymphedema. Reporting lymphedema is associated with significant impairment of several physical, psychological, and social aspects of QoL.

From FIGO-2009 to FIGO-2018 in women with early-stage cervical cancer; Does the revised staging reflect risk groups?

OBJECTIVES: We aimed to evaluate if the revised staging according to FIGO-2018 in early-stage cervical cancer correctly predicts the risk for nodal metastases. METHODS: We reallocated 245 women with early-stage cervical cancer from FIGO-2009 to FIGO-2018 stages using data from a national, prospective cohort study on sentinel lymph node (SLN) mapping. We used univariate and multivariate binary regression models to investigate the association between FIGO-2018 stages, tumor characteristics, and nodal metastases. RESULTS: Stage migration occurred in 54.7% (134/245) (95% CI 48.2-61.0), due to tumor size or depth of invasion (71.6%, 96/134) and nodal metastases (28.4%, 38/134). Imaging preoperatively upstaged 7.3% (18/245); seven had nodal metastatic disease on final pathology. Upstaging occurred in 49.8% (122/245) (95% CI 43.4-56.2%) and downstaging to FIGO-2018 IA stages in 4.9% (12/245) (95% CI 2.6-8.4). The tumor size ranged from 3.0-19.0 mm in women with FIGO-2018 IA tumor characteristics, and none of the 14 women had nodal metastases. In multivariate analysis, risk factors significantly associated with nodal metastases were FIGO-2018 ≥ IB2 (RR 5.01, 95% CI 2.30-10.93, p < 0.001), proportionate depth of invasion >2/3 (RR 1.88, 95% CI 1.05-3.35, p = 0.033), and lymphovascular space invasion (RR 5.56, 95% CI 2.92-10.62, p < 0.001). CONCLUSIONS: The FIGO-2018 revised staging system causes stage migration for a large proportion of women with early-stage cervical cancer. Women who were downstaged to FIGO-2018 IA stages did not have nodal metastatic disease. The attention on depth of invasion rather than horizontal dimension seems to correctly reflect the risk of nodal metastases.

Sentinel lymph node mapping in early-stage cervical cancer - A national prospective multicenter study (SENTIREC trial).

OBJECTIVES: Sentinel lymph node (SLN) mapping may replace staging radical pelvic lymphadenectomy in women with early-stage cervical cancer. In a national multicenter setting, we evaluated SLN mapping in women with early-stage cervical cancer and investigated the accuracy of SLN mapping and FDG-PET/CT in tumors >20 mm. METHODS: We prospectively included women with early-stage cervical cancer from March 2017-January 2021 to undergo SLN mapping. Women with tumors >20 mm underwent completion pelvic lymphadenectomy and removal of FDG-PET/CT positive nodes. We determined SLN detection rates, incidence of nodal disease, sensitivity and negative predictive value (NPV) of SLN mapping, and the sensitivity, specificity, NPV, and positive predictive value (PPV) of FDG-PET/CT. RESULTS: We included 245 women, and 38 (15.5%) had nodal metastasis. The SLN detection rate was 96.3% (236/245), with 82.0% (201/245) bilateral detection. In a stratified analysis of 103 women with tumors >20 mm, 27 (26.2%) had nodal metastases. The sensitivity of SLN mapping adhering to the algorithm was 96.3% (95% CI 81.0-99.9%) and the NPV 98.7% (95% CI 93.0-100%). For FDG-PET/CT imaging the sensitivity was 14.8% (95% CI 4.2-33.7%), the specificity 85.5% (95% CI 75.6-92.5%), the NPV 73.9% (95% CI 63.4-82.7%), and the PPV 26.7% (95% CI 7.8-55.1%). CONCLUSIONS: SLN mapping seems to be an adequate staging procedure in early-stage cervical cancer tumors ≤20 mm. In tumors >20 mm, SLN mapping is highly sensitive but demands full adherence to the SLN algorithm. We recommend completion pelvic lymphadenectomy in tumors >20 mm until the oncological safety is established. FDG-PET/CT for nodal staging of women with early-stage cervical cancer seems limited.

Sentinel lymph node mapping for endometrial and cervical cancer in Denmark.

INTRODUCTION: This was a surgical pilot study to systematically introduce the technique of sentinel lymph node (SLN) mapping in women with early-stage stage cervical cancer (CC) and endometrial cancer (EC) in Denmark. The study aimed to facilitate structured surgical training to ensure surgeon proficiency in SLN mapping. The study precedes two national prospective studies on the oncological safety and correct patient selection for SLN mapping in CC and EC. METHODS: The study was conducted at four gynaecological cancer centres at Odense and Aarhus University Hospital, Rigshospitalet and Herlev Hospital, between September 2016 and August 2019. All centres went through a protocolled introduction to the surgical technique, pelvic lymphatic drainage, pathological ultra-staging and data entry. A criterion of a total (uni- and bilateral) SLN detection of > 80%, based on 30 SLN mappings was set. RESULTS: The four centres performed 140 (range: 30-46) procedures. The total SLN detection rate was 91.3% with bilateral SLN detection in 68.8% and unilateral SLN detection in 22.5% of cases. The cumulated total SLN detection rate at three centres was above the pre-set 80% criterion from the beginning of inclusion, whereas one centre reached the criterion after 20 procedures. CONCLUSIONS: In this study, all centres demonstrated international-level SLN detection rates within 30 procedures. Hence, all centres met the study criterion regarding surgeon proficiency and were eligible for the national studies. FUNDING: Eva and Henry Frænkels Fond, Frimodt-Heineke Fonden, Kong Christian X Fond. TRIAL REGISTRATION: The study was approved by the Danish Data Protection Agency (R. no.15/52037). The SENTIREC studies including this pilot study are registered with clinicaltrials.gov (NCT02825355 and NCT02820506).

Acceptability and feasibility of self-sampling and follow-up attendance after text message delivery of human papillomavirus results: A cross-sectional study nested in a cohort in rural Tanzania.

INTRODUCTION: The objective was to determine if self-collection of vaginal samples for human papillomavirus (HPV) testing was acceptable and feasible in rural Tanzania and to assess the extent of attendance at a follow-up appointment among women who tested HPV-positive after delivery of HPV results via text messages. MATERIAL AND METHODS: A combined cross-sectional and cohort study was conducted among women aged 25-60 years from rural Kilimanjaro, Tanzania. Women were offered HPV self-sampling or traditional visual inspection of the cervix with acetic acid. If HPV self-sampling was preferred, participants received instructions on self-collection with an Evalyn Brush. A questionnaire was used to assess the acceptability and feasibility of the self-sampling procedure for the participants and delivery of HPV results via text messages. A mobile text message platform was used to send private text messages with the screening results to the participants. RESULTS: A total of 1108 women were enrolled and self-collected an HPV sample; 11.8% tested positive for high-risk HPV. The majority (98.9%) agreed that they had no trouble in understanding the instructions on how to perform the self-collection and that they would recommend it to a friend (94.5%) or as a standard screening method in Tanzania (95.5%). A minority of women experienced bleeding (2.4%) or pain (6%) while collecting the sample, while some were worried that they would get hurt (12.7%) or felt embarrassed (3.5%). The majority (98.4%) of women would like to receive the screening test results via text messages. Eighty-two per cent of those who tested positive for high-risk HPV attended the follow-up appointment after receiving a text message reminder and an additional 16% attended after receiving both a text message and a phone call reminder whereas 2% did not attend follow up at all. Attendance was not influenced by age, marital status, education level, parity, or HIV status. CONCLUSIONS: Human papillomavirus self-sampling and text-message feedback delivery are generally well-perceived and accepted among rural Tanzanian women, and the majority of HPV-positive women attended a follow-up appointment after receiving their HPV results and follow-up appointment via text messages. This screening method may have potential to be transferrable to other low-income countries with a high incidence of cervical cancer and so improve cervical cancer screening attendances.

ARAP1 is an independent prognostic biomarker in older women with ovarian high-grade serous adenocarcinoma receiving first-line platinum-based antineoplastic therapy.

Background: Little is known about the biological factors influencing ovarian cancer (OC) patient outcome, especially in older patients who are often underrepresented in clinical trials. We examined alterations in the transcriptomic profile of primary high-grade serous carcinoma (HGSC) samples from older OC patients (>70 years) receiving first-line platinum-based treatment to identify potential biomarkers for prediction of response to this therapy.Material and methods: Tumor samples from 50 HGSC patients were identified from a retrospective cohort, analyzed by gene expression array. The protein expression of selected biomarkers was examined using immunohistochemistry (IHC).Results: Gene expression profiling revealed 81 genes with significantly altered expression in patients experiencing progression after first-line platinum-based treatment within 6 months versus those who progressed later than 12 months. Expression of ankyrin repeat and PH domain 1 (ARAP1) was significantly lower in the group with early versus late progression (p ≤ .01). Correlation between ARAP1 expression and outcome was further confirmed by IHC staining in the discovery cohort (χ2-test, p = .004) and in independent validation cohorts. The sensitivity of ARAP1 allowed identification of 64.7% of patients with early progression in the discovery population, with a specificity of 78.6% and a negative predictive value of 78.6%. Multivariate regression analysis identified ARAP1 as an independent prognostic factor.Conclusions: This hypothesis generating study suggests that low expression of ARAP1 is an independent prognostic biomarker of shorter RFS in older patients with HGSC receiving first-line platinum-based antineoplastic therapy, which could be used to identify patients who should receive more intensive treatment and closer surveillance.

[Endometrioid adenocarcinoma with a co-existing non-gestational choriocarcinoma in uterus].

This is a case report of a 56-year-old woman with a history of postmenopausal bleeding, who presented with an endometrioid adenocarcinoma and a co-existing non-gestational choriocarcinoma. We performed robotic assisted hysterectomy, bilateral oophorectomy and pelvic lymphadectomy, and histopathologic examination revealed a malignant tumour showing an endometrioid adenocarcinoma grade 2 with a minor component of choriocarcinoma incorporated into the adenocarcinoma. We compared data from exome sequencing of DNA from tumour and blood to show, that the choriocarcinoma component was most likely non-gestational.

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.

Human papillomavirus mRNA and DNA testing in women with atypical squamous cells of undetermined significance: A prospective cohort study.

In this prospective cohort study, we compared the performance of human papillomavirus (HPV) mRNA and DNA testing of women with atypical squamous cells of undetermined significance (ASC-US) during cervical cancer screening. Using a nationwide Danish pathology register, we identified women aged 30-65 years with ASC-US during 2005-2011 who were tested for HPV16/18/31/33/45 mRNA using PreTect HPV-Proofer (n = 3,226) or for high-risk HPV (hrHPV) DNA using Hybrid Capture 2 (HC2) (n = 9,405) or Linear Array HPV-Genotyping test (LA) (n = 1,533). Women with ≥1 subsequent examination in the register (n = 13,729) were followed for up to 9.5 years for high-grade cervical intraepithelial neoplasia (CIN) or cancer. After 3 years' follow-up, mRNA testing had higher specificity for CIN3 or worse (CIN3+) than HC2 testing (88.1% [95% confidence interval (CI): 86.8-89.6%] versus 59.3% [95% CI: 58.1-60.4%]) and higher positive predictive value (PPV) (38.2% [95% CI: 33.8%-43.1%] versus 19.5% [95% CI: 17.8-20.9%]). However, the sensitivity of mRNA testing was lower than that of HC2 testing (66.7% [95% CI: 59.3-74.5%] versus 97.0% [95% CI: 95.5-98.4%]), and women testing mRNA negative had higher 3-year risk for CIN3+ than those testing HC2 negative (3.2% [95% CI: 2.2-4.2%] versus 0.5% [95% CI: 0.3-0.7%]). Patterns were similar after 18 months and 5 years'; follow-up; for CIN2+ and cancer as outcomes; across all age groups; and when comparing mRNA testing to hrHPV DNA testing using LA. In conclusion, the HPV16/18/31/33/45 mRNA test is not optimal for ASC-US triage due to its low sensitivity and the substantial risk for precancer following a negative test.

Trends in gynecologic cancer among elderly women in Denmark, 1980-2012.

BACKGROUND: The aim of this analysis was to describe trends in incidence, mortality, prevalence, and survival in Danish women with gynecologic cancer from 1980-2012 comparing women aged 70 years or more with younger women. MATERIAL AND METHODS: Gynecologic cancers included were ICD-10 codes C53 (cancer of the cervix uteri), C54 (corpus uteri cancer), C56 (ovarian cancer) and C57 (Fallopian tube cancer). Data derived from the NORDCAN database with comparable data on cancer incidence, mortality, prevalence and relative survival in the Nordic countries, where the Danish data are delivered from the Danish Cancer Registry and the Danish Cause of Death Registry with follow-up for death or emigration until the end of 2013. RESULTS: For cervical cancer the incidence decreased among women aged less than 70 years and remained stable among the elderly. The mortality rates were clearly separated by age groups with a 2-3 fold higher mortality rate among 70 + years-old than younger women. The mortality rates, however, decreased in all age groups from 1980-2012. For ovarian and Fallopian tube cancers the incidence was almost constant, whereas the average annual number of deaths decreased over time from 466 in 1980 to 396 in 2012. The mortality rates were clearly separated by age groups with mortality rates 3-4 times higher among the elderly. The mortality rate decreased among women less than 70 years during the entire period. The average annual number of newly diagnosed corpus uteri cancer increased from 631 in 1980 to 773 in 2012. The mortality rates were clearly separated by age groups with much higher mortality rates among the 70+ years-old as compared with younger women. Overall the mortality rates decreased from 1980 to 2012. CONCLUSION: In gynecologic cancer both mortality rates and survival are age-dependent with a significantly shorter survival in the group of elderly.

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.

HPV genotypes in invasive cervical cancer in Danish women.

OBJECTIVE: Human papillomavirus (HPV) genotype distribution in invasive cervical cancers may differ by geographic region. The primary objective of this study was to estimate HPV-genotype distribution in Danish women with a diagnosis of invasive cervical cancer. DESIGN: Observational, cross-sectional. POPULATION: Danish data from a multi-center study undertaken in 12 European countries. METHODS: A total of 342 archived fixed tissue samples with diagnosis of invasive cervical cancer from the Departments of Pathology in the University Hospitals in Hvidovre and Odense, Denmark, were anonymized and shipped to a central laboratory for histopathology review and PCR testing for HPV DNA. A standardized HPV-test methodology was used to enable comparison of HPV-type distribution. MAIN OUTCOME MEASURES: Occurrence of HPV genotypes in Danish women with cervical cancer. RESULTS: There were 261 samples evaluated as histologically adequate and 251 (96%) of these were HPV-positive (HPV+). The most frequent diagnosis was squamous cell carcinoma (78.9% of histological adequate and 79.3% of HPV+). Adenocarcinoma, adenosquamous carcinoma and other types were found in 14.9, 3.4 and 2.7% of the histologically adequate group and 14.7, 3.6 and 2.4% of the HPV+ group, respectively. In 92.8% of HPV+ women only a single HPV type was diagnosed. HPV-type distribution in the latter population was as follows: HPV-16: 62.2%; HPV-18: 14.6%; HPV-33: 6.9%; HPV-45: 6.4% and HPV-31: 3.4%. Of the HPV+ women, 6.4% were diagnosed with multiple HPV types and 0.8% had unknown HPV types. CONCLUSION: HPV-16 and -18 are detected in 74.3% of Danish women with diagnosis of invasive cervical cancer, while HPV-16, -18, -31, -33, -45 and 58 are detected in 90.0% of women with invasive cervical disease.

HPV-genotypes in high-grade intraepithelial cervical lesions in Danish women.

OBJECTIVE: A study was undertaken to assess the distribution of high-risk HPV-genotypes in high-grade cervical intraepithelial neoplastic lesions in Danish women. DESIGN: Observational, cross-sectional. SETTING: Danish data from a multi-centre study undertaken in 13 European countries. POPULATION: 290 archived fixed biopsies with high-grade cervical lesions from the Departments of Pathology at the University Hospitals in Hvidovre and Odense, Denmark. METHODS: Relevant histological samples were anonymized and shipped to a central laboratory for histopathology review and PCR-testing for HPV-DNA. A standardised HPV-test methodology was utilised to enable comparison of HPV-genotype distribution. RESULTS: Of 290 Danish cervical samples, 276 were evaluated as histologically adequate and all of these were HPV-positive (HPV⁺). Of the HPV⁺ samples 77.9% were diagnosed with a single HPV-type, with cervical intraepithelial neoplasia (CIN)3 diagnosed in 82.3% and CIN2, CIN2/3, adenocarcinoma in situ (AIS) and AIS⁺ other high-grade lesion diagnosed in the remaining 17.7%. The most prevalent HPV-types were: HPV16 (54.0%), HPV33 (13.5%), HPV31 (10.7%), HPV18 (7.9%) and HPV52 (4.7%). Of the HPV⁺ samples, 21.4% were diagnosed with multiple HPV-types, with CIN3 diagnosed in 79.6% and CIN2, CIN2/3, AIS and AIS⁺ other high-grade lesion diagnosed in the remaining 20.4%. The most prevalent HPV-types were: HPV16 (49.2%), HPV31 (30.5%), HPV52 (27.1%), HPV51 (20.3%), HPV18 (16.9%), HPV33 (13.6%), HPV45 (11.9%), with 0.7% unknown types. CONCLUSIONS: HPV16 and HPV18 were detected in approximately 75% of high-grade intraepithelial cervical lesions in a Danish population (single or multiple infections); these two genotypes are considered causative in at least 61.9% of the high-grade intraepithelial lesions (single infection).

Differences in human papillomavirus type distribution in high-grade cervical intraepithelial neoplasia and invasive cervical cancer in Europe.

Knowledge of differences in human papillomavirus (HPV)-type prevalence between high-grade cervical intraepithelial neoplasia (HG-CIN) and invasive cervical cancer (ICC) is crucial for understanding the natural history of HPV-infected cervical lesions and the potential impact of HPV vaccination on cervical cancer prevention. More than 6,000 women diagnosed with HG-CIN or ICC from 17 European countries were enrolled in two parallel cross-sectional studies (108288/108290). Centralised histopathology review and standardised HPV-DNA typing were applied to formalin-fixed paraffin-embedded cervical specimens dated 2001-2008. The pooled prevalence of individual HPV types was estimated using meta-analytic methods. A total of 3,103 women were diagnosed with HG-CIN and a total of 3,162 with ICC (median ages: 34 and 49 years, respectively), of which 98.5 and 91.8% were HPV-positive, respectively. The most common HPV types in women with HG-CIN were HPV16/33/31 (59.9/10.5/9.0%) and in ICC were HPV16/18/45 (63.3/15.2/5.3%). In squamous cell carcinomas, HPV16/18/33 were most frequent (66.2/10.8/5.3%), and in adenocarcinomas, HPV16/18/45 (54.2/40.4/8.3%). The prevalence of HPV16/18/45 was 1.1/3.5/2.5 times higher in ICC than in HG-CIN. The difference in age at diagnosis between CIN3 and squamous cervical cancer for HPV18 (9 years) was significantly less compared to HPV31/33/'other' (23/20/17 years), and for HPV45 (1 year) than HPV16/31/33/'other' (15/23/20/17 years). In Europe, HPV16 predominates in both HG-CIN and ICC, whereas HPV18/45 are associated with a low median age of ICC. HPV18/45 are more frequent in ICC than HG-CIN and associated with a high median age of HG-CIN, with a narrow age interval between HG-CIN and ICC detection. These findings support the need for primary prevention of HPV16/18/45-related cervical lesions.