Risk of CIN3 or worse with persistence of 13 individual oncogenic HPV types.

Human papillomavirus (HPV) is essential in cervical carcinogenesis, however, less is known about the carcinogenic potential of individual HPV types. Our aim was to examine the risk of cervical intraepithelial neoplasia grade 3 or worse (CIN3+) after persistence of 13 individual oncogenic HPV types. Liquid-based cervical samples (n = 40,399) collected in 2002-2005 were tested for HPV by hybrid capture 2 and genotyped with INNO-LiPAv2. Persistence was defined as having the same genotype twice 1-4.5 years apart. The absolute risk of CIN3+ was estimated by the Aalen-Johansen estimator and Cox proportional hazard regression was used to compare the rates of CIN3+ according to HPV type adjusting for age and time between HPV tests. Of 2,875 oncogenic HPV-positive women, 874 had persistence of one or more types and 761 persisted for one oncogenic HPV type only. Persistent HPV16 infection was associated with the highest risk of CIN3+, with an 8-year absolute risk of 55% (95% CI: 45%-66%), followed by HPV33 (33% (95% CI: 20%-50%)), HPV18 (32% (95% CI: 20%-48%)) and HPV31 (31% (95% CI: 21%-46%)). Other HPV types, including HPV52 and HPV45, were also associated with high risks. Persistent HPV56 had the lowest 8-year absolute risk of CIN3+ (3% (95% CI: 0.4%-20%)). In Cox analyses, a similar pattern remained after adjustment for age and time between tests. Our results add knowledge about the varying carcinogenic potential of individual persistent oncogenic HPV types, which may have implications for the clinical use of HPV testing.

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

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

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

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

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.

Factors associated with type-specific persistence of high-risk human papillomavirus infection: A population-based study.

Persistent genital infection with high-risk (HR) human papillomavirus (HPV) is a prerequisite for cervical cancer development. The aim of this study was to identify factors associated with type-specific persistence of HR HPV infections. From a population-based cohort of 40,399 women participating in cervical cancer screening established during 2002-2005, we selected all HR HPV-positive women (N = 7,778). During follow-up (2005-2008), we collected cervical samples from these women and tested them for HPV DNA to determine type-specific HR HPV persistence in the interval 1-4.5 years after enrolment. Data on hospitalisations, prescriptions and socioeconomic factors were obtained from nationwide registers. Women with abnormal cytology at baseline or who had undergone conisation during follow-up were excluded. Factors associated with persistence were identified by logistic regression analysis. The overall rate of HR HPV persistence was 31.4%. The risk for persistence was significantly increased among women with a previous episode of genital warts (OR, 1.35; 95% CI, 1.04-1.74), current use of oral contraceptives (OR, 1.35; 95% CI, 1.13-1.63) or use of systemic glucocorticoids (OR, 2.04; 95% CI, 1.16-3.56). The number of pregnancies or births or use of a hormonal intrauterine device, hormonal therapy or nonsteroidal anti-inflammatory drugs was not associated with risk for HR HPV persistence. A history of genital warts and current use of oral contraceptives or systemic glucocorticoids increased the risk, potentially indicating a decreased immune response to HPV infection. These findings suggest that host immune response characteristics are important in HR HPV persistence and consequently in cervical cancer development.

Long-term risk of cervical intraepithelial neoplasia grade 3 or worse according to high-risk human papillomavirus genotype and semi-quantitative viral load among 33,288 women with normal cervical cytology.

In this prospective cohort study, we estimated the long-term risk of cervical intraepithelial neoplasia grade 3 or cancer (CIN3+) by high-risk human papillomavirus (hrHPV) genotype and semi-quantitative viral load at baseline among 33,288 women aged 14-90 years with normal baseline cytology. During 2002-2005, residual liquid-based cervical cytology samples were collected from women screened for cervical cancer in Copenhagen, Denmark. Samples were HPV-tested with Hybrid Capture 2 (HC2) and genotyped with INNO-LiPA. Semi-quantitative viral load was measured by HC2 relative light units in women with single hrHPV infections. The cohort was followed in a nationwide pathology register for up to 11.5 years. In women aged ≥30 years at baseline, the 8-year absolute risk for CIN3+ following baseline detection of HPV16 was 21.8% (95% confidence interval [CI]: 18.0-25.6%). The corresponding risks for HPV18, HPV31, HPV33, and other hrHPV types, respectively, were 12.8% (95% CI: 7.6-18.0%), 11.3% (95% CI: 7.7-14.9%), 12.9% (95% CI: 7.0-18.8%) and 3.9% (95% CI: 2.7-5.2%). Similar absolute risk estimates were observed in women aged <30 years. Higher HPV16-viral load was associated with increased risk of CIN3+ (hazard ratio = 1.34, 95% CI: 1.10-1.64, per 10-fold increase in viral load). A similar trend, although statistically nonsignificant, was found for viral load of HPV18. The 8-year absolute risk of CIN3+ in women with HPV16-viral load ≥100.0 pg/ml was 30.2% (95% CI: 21.9-38.6%). Our results support that hrHPV genotyping during cervical cancer screening may help identify women at highest risk of CIN3+.

Trends in the incidence of cervical cancer and severe precancerous lesions in Denmark, 1997-2012.

PURPOSE: The incidence of cervical cancer, including squamous cell carcinoma (SCC), has been decreasing in several developed countries since the onset of organized screening programs; in some countries, however, the incidence of adenocarcinoma has increased among young women. We investigated the Danish incidence trends during 1997-2011 when cervical screening coverage was high. Incidences of cervical intraepithelial neoplasia grade 3 (CIN3) and adenocarcinoma in situ (AIS) were also assessed, with the latest part of the study period coinciding with introduction of free-of-charge human papillomavirus (HPV) vaccination. METHODS: Using nationwide registries, we estimated age-specific and age-standardized incidence rates and estimated annual percentage change (EAPC). RESULTS: The incidence of SCC decreased significantly, especially in women aged ≥45 years [EAPC: -3.1 % (95 % CI -4.3 to -2.5)], whereas the incidence of adenocarcinoma increased significantly, from 2.4 to 3.1/100,000 primarily due to increases in women aged ≤44 years [EAPC: 4.3 % (95 % CI 1.8-6.7)]. The incidences of CIN3 and AIS increased significantly from 94.7 to 156.5/100,000 and 3.3 to 11.3/100,000, respectively, but, importantly, they decreased significantly during 2009-2012 in women aged ≤20 years. CONCLUSIONS: The Danish screening program has successfully reduced the incidence of cervical cancer, especially of SCC in older women; however, the program has not significantly reduced the incidence in young women or the incidence of adenocarcinoma, which is increasing. Decreases in the incidences of CIN3 and AIS in age groups with high HPV vaccine coverage may herald a future decrease in cervical cancer incidence in young Danish women.

Mutational analysis of BRAF and KRAS in ovarian serous borderline (atypical proliferative) tumours and associated peritoneal implants.

There is debate as to whether peritoneal implants associated with serous borderline tumours/atypical proliferative serous tumours (SBT/APSTs) of the ovary are derived from the primary ovarian tumour or arise independently in the peritoneum. We analysed 57 SBT/APSTs from 45 patients with advanced-stage disease identified from a nation-wide tumour registry in Denmark. Mutational analysis for hotspots in KRAS and BRAF was successful in 55 APSTs and demonstrated KRAS mutations in 34 (61.8%) and BRAF mutations in eight (14.5%). Mutational analysis was successful in 56 peritoneal implants and revealed KRAS mutations in 34 (60.7%) and BRAF mutations in seven (12.5%). Mutational analysis could not be performed in two primary tumours and in nine implants, either because DNA amplification failed or because there was insufficient tissue for mutational analysis. For these specimens we performed VE1 immunohistochemistry, which was shown to be a specific and sensitive surrogate marker for a V600E BRAF mutation. VE1 staining was positive in one of two APSTs and seven of nine implants. Thus, among 63 implants for which mutation status was known (either by direct mutational analysis or by VE1 immunohistochemistry), 34 (53.9%) had KRAS mutations and 14 (22%) had BRAF mutations, of which identical KRAS mutations were found in 34 (91%) of 37 SBT/APST-implant pairs and identical BRAF mutations in 14 (100%) of 14 SBT/APST-implant pairs. Wild-type KRAS and BRAF (at the loci investigated) were found in 11 (100%) of 11 SBT/APST-implant pairs. Overall concordance of KRAS and BRAF mutations was 95% in 59 of 62 SBT/APST-implant (non-invasive and invasive) pairs (p < 0.00001). This study provides cogent evidence that the vast majority of peritoneal implants, non-invasive and invasive, harbour the identical KRAS or BRAF mutations that are present in the associated SBT/APST, supporting the view that peritoneal implants are derived from the primary ovarian tumour.

Performance of visual inspection with acetic acid and human papillomavirus testing for detection of high-grade cervical lesions in HIV positive and HIV negative Tanzanian women.

The aim of this cross sectional study was to assess type distribution of human papillomavirus (HPV) among HIV positive and HIV negative women who underwent cervical cancer screening, and to examine the ability of visual inspection with acetic acid (VIA), the standard detection method in Tanzania, and HPV-testing to detect cytologically diagnosed high grade lesions or cancer (HSIL+). Women from different areas in Tanzania were invited by public announcement to cervical cancer screening organized by Ocean Road Cancer Institute (Dar-es-Salaam). A total of 3,767 women were enrolled. Women underwent gynecological examination with collection of cervical cells for conventional cytological examination, and swab for HPV-DNA detection (Hybrid-Capture2) and genotyping (LiPAv2 test). Subsequently VIA was performed. The participants were also tested for HIV. HPV16, HPV52 and HPV18 were the three most common HR HPV types among women with HSIL+ cytology with prevalences of 42.9, 35.7 and 28.6%, respectively, in HIV positive women which was higher than among HIV negative women (30.2, 21.9 and 16.7%). A total of 4.5% of the women were VIA positive, and VIA showed a low sensitivity compared to HPV-testing for detection of HSIL+. The sensitivity of VIA varied with staff VIA experience, HIV status and age. Vaccines including HPV16, HPV52 and HPV18 will likely reduce the number of HSIL+ cases independently of HIV status. The frequency of HSIL+ was high among HIV positive women, emphasizing the importance of establishing a screening program which also reaches HIV positive women. Our results highlight the importance of continuous training of staff performing VIA, and also point to the need for other screening methods such as HPV-testing at low cost.

Carcinogenic HPV prevalence and age-specific type distribution in 40,382 women with normal cervical cytology, ASCUS/LSIL, HSIL, or cervical cancer: what is the potential for prevention?

BACKGROUND: Assessment of the prevaccination type-specific prevalence of human papillomavirus (HPV) in the general population is important for the prediction of the impact of HPV vaccination. METHODS: We collected consecutively residual specimens from liquid-based cytology samples from 40,382 women from the general population in Copenhagen, Denmark, during 2002-2005. All samples were tested for high-risk HPV using the Hybrid Capture 2 technique, and genotyping was done using LiPa (Innogenetics). Through linkage with the Pathology Data Bank, we obtained information on the cytology result, and histology if any, on all women. RESULTS: The participants were 14-95 years of age (median age 37 years) at enrollment. The overall prevalence of HR HPV was 20.6 % ranging from 46.0 % in 20-23-year-old women to 5.7 % in women 65 years or older. Independently of cytology/histology, HPV16 was the most prevalent type. For virtually all HPV types, the occurrence of CIN3+ was higher when the specific HPV type was present together with HPV16 than it was together with other high-risk HPV types than HPV16 or if the HPV type occurred as a single infection. The prevalence of HPV16 and/or HPV18 was 74 % in cervical cancer and the corresponding prevalence of HPV16/18/31/33/45/52/58 was 89 %. CONCLUSION: This study forms a valuable starting point for monitoring the effect of HPV vaccination in Denmark. In addition, the particular carcinogenic role of HPV16 and 18 is confirmed and may support a role of genotyping for HPV16 and 18 in cervical cancer screening.

Incidence of cervical lesions in Danish women before and after implementation of a national HPV vaccination program.

PURPOSE: Approximately 70% of cervical cancers and about 50% of high-grade cervical precursor lesions are caused by human papillomavirus (HPV) types 16 and 18. Denmark introduced the quadrivalent HPV vaccine into the vaccination program for 12-year-old girls in 2009 supplemented by a first catch-up program for 13-15-year-old girls in 2008, and a second program for women up to the age of 27 years in 2012; all with high vaccination coverage. The aim of this study was to evaluate the effectiveness of the vaccine by comparing the incidence trends of cervical lesions before and after its introduction. METHODS: Incident cases of cervical lesions were identified from the nationwide Pathology Data Bank. Age-specific incidence rates were estimated for six age groups, and Poisson regression was used to calculate estimated annual percentage change (EAPC). RESULTS: The incidence of atypia or worse (atypia+) and cervical intraepithelial neoplasia grade 2 or worse (CIN2+) increased in all age groups in 2000-2010. After introduction of the quadrivalent HPV vaccine into the vaccination program, the incidence of atypia+ decreased significantly in women younger than 18 years (EAPC -33.4%; 95% CI -49.6; -12.0) and in 18-20-year-old women (EAPC -12.6%; 95% CI -19.3; -5.3). The incidence of CIN2+ also decreased significantly in 18-20-year-old women (EAPC -14.8%; 95% CI -21.6; -7.5) in 2010-2013, but no significant decrease was seen in older age groups. CONCLUSION: The incidence of cervical lesions decreased significantly in age groups with high HPV vaccine coverage, indicating an early effect of HPV vaccination.

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

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

Prevalence of Human Papillomavirus in endometrial cancer: a systematic review and meta-analysis.

OBJECTIVE: HPV is a common sexually transmitted infection and is considered to be a necessary cause of cervical cancer. The anatomical proximity to the cervix has led researchers to investigate whether Human Papillomavirus (HPV) has a role in the etiology of endometrial cancer. METHODS: We conducted a systematic review and meta-analysis to investigate the pooled prevalence of HPV DNA in endometrial cancer. Using meta-regression, we further analyzed whether factors such as geographical region, HPV DNA detection method, publication year and tissue type were associated with HPV prevalence. Pooled odds ratios (ORs) and 95% confidence intervals (CIs) were calculated for studies providing data on HPV prevalence in cases with endometrial cancer and in controls with normal or hyperplastic endometrial tissue. RESULTS: We identified 28 papers (29 studies) examining the prevalence of HPV DNA in tumor tissue from endometrial cancer comprising altogether 1026 cases of endometrial cancer. The HPV prevalence varied considerably from 0% to 61.1%. From the random effects meta-analysis, the pooled prevalence of HPV DNA in endometrial cancer was 10.0% (95% CI: 5.2-16.2) with large between-study heterogeneity (I(2)=88.2%, p<0.0001). The meta-regression showed that HPV DNA detection method was statistically significantly associated with HPV prevalence (p=0.0016): the pooled HPV prevalence was 6.0% (95% CI: 1.5-13.0) using general primers, 18.9% (95% CI: 8.6-32.1) using type-specific primers and 1.0% (95% CI: 0.0-3.6) using non-PCR based methods. None of the other a priori defined variables were statistically significantly associated with HPV prevalence. The pooled OR was 1.43 (95% CI: 0.68-3.00) indicating that the odds of HPV was not increased in cases versus controls. CONCLUSIONS: HPV appears to have a limited or no role in the etiology of endometrial cancer.

Adherence to the cervical cancer screening program in women living with HIV in Denmark: comparison with the general population.

BACKGROUND: Women living with HIV (WLWH) are at increased risk of invasive cervical cancer (ICC). International HIV guidelines suggest cervical screening twice the first year after HIV diagnosis and thereafter annually. Adherence to the HIV cervical screening program in Denmark is unknown. METHODS: We studied women from a population-based, nationwide HIV cohort in Denmark and a cohort of age-matched females from the general population. Screening behaviour was assessed from 1999-2010. Adjusted odds ratios (OR's) for screening attendance in the two cohorts and potential predictors of attendance to guidelines were estimated. Pathology specimens were identified from The Danish Pathology Data Bank. RESULTS: We followed 1143 WLWH and 17,145 controls with no prior history of ICC for 9,509 and 157,362 person-years. The first year after HIV diagnosis 2.6% of WLWH obtained the recommended two cervical cytologies. During the different calendar intervals throughout the study period between 29-46% of WLWH followed the HIV cervical screening guidelines. Adjusted OR's of attendance to the general population screening program for WLWH aged 30, 40 and 50 years, compared to controls, were 0.69 (95% CI: 0.56-0.87), 0.67 (0.55-0.80) and 0.84 (0.61-1.15). Predictors of attendance to the HIV cervical screening program were a CD4 count > 350 cells/µL and HIV RNA < 500 copies/mL. Calendar period after 2002 and HIV RNA < 500 copies/mL predicted attendance to the general population cervical screening program. CONCLUSIONS: The majority of WLWH do not follow the HIV guidelines for cervical screening. We support the idea of cytology as part of an annual review and integration of HIV care and cervical screening in a single clinic setting.

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).

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.

The importance of low-risk HPV infection for the risk of abnormal cervical cytology/histology in more than 40 000 Danish women.

OBJECTIVES: To estimate the age and type-specific distribution of low-risk (LR) human papillomavirus (HPV) types in cervical samples from women in the general population and to assess the distribution of LR-HPV without the coexistence of high-risk HPV types in different cytology and histology categories. METHODS: In a cross-sectional study, liquid-based cytology samples (SurePath) were collected over a 3-year period. The samples were HPV tested by Hybrid Capture II (HC2; Digene) and genotyped using a PCR-based assay (INNO-LiPAv2; Innogenetics Inc.). A total of 40 382 women (14-95 years of age) were included in the study. By linkage with the nationwide Pathology Data Bank, the HPV test results were directly linked to cytological diagnoses made from the same samples and to subsequent histology results. RESULTS: Overall, 2790 women (6.9%) tested positive for LR-HPV types, with HPV6 and HPV70 being the most frequent types detected, whereas HPV11 was uncommon. The highest prevalence was observed in the youngest age group (≤19 years). The LR-HPV prevalence was 6.3% in women with normal cytology, 33.1% in atypical squamous cells of undetermined significance (ASCUS), 19.6% in low-grade squamous intraepithelial lesion and 12.7% in those with high-grade squamous intraepithelial lesion. When considering women with LR-HPV alone, the prevalence was 2.0% (normal cytology), 11.3% (ASCUS), 2.6% (low-grade squamous intraepithelial lesion) and 0.7% in women with high-grade squamous intraepithelial lesion, respectively. A similar pattern was observed in relation to the histological diagnoses with the majority of LR-HPV infections detected in CIN1 lesions (24.7%). CONCLUSIONS: LR-HPV types alone are relatively common in ASCUS, whereas LR-HPV types without coexisting high-risk HPV types are virtually never detected in severe cervical lesions.

Human papillomavirus prevalence and type distribution in 3603 HIV-positive and HIV-negative women in the general population of Tanzania: the PROTECT study.

OBJECTIVE: The aim of the Prevention of Cervical Cancer in Tanzania (PROTECT) study is to assess the prevalence of oncogenic human papillomavirus (HPV) and to determine the type distribution among women in the general population according to human immunodeficiency virus (HIV) status, in preparation for a potential HPV immunization program. METHODS: We included 3603 women from the general population in urban and rural areas of Tanzania. All women underwent a gynecological examination where a Pap smear was obtained and cervical cells were collected to assess the presence of high-risk (HR) HPV DNA by hybrid capture 2 test. Genotyping was performed by the LiPaExtra method. These women were also tested for HIV. RESULTS: The prevalence of HR HPV types was 20.1%, ranging from 14.8% in women with normal cytology to 94.2% in women with high grade squamous intraepithelial lesion (HSIL) or worse (100% in 5 cancers). In women with normal cytology or low-grade lesions, the most common type was HPV52 (3.2%), followed by HPV16 (2.1%). In contrast, HPV16 was the dominating type in HSIL or worse (32.8%). No cancers contained HPV52. The HR HPV prevalence was higher in HIV-positive women (46.7%) than in HIV-negative women (17.2%). No specific HR HPV types were significantly more common in HIV-positive women. CONCLUSION: The HPV type distribution is similar in HIV-positive and HIV-negative women. These results suggest that the HPV vaccines that are currently available could protect women from HPV infection independently of their HIV status.

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

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

Screening history in women with cervical cancer in a Danish population-based screening program.

OBJECTIVE: The aim of this study was to explore the screening histories of all cervical cancers in a Danish screening population. The intention was to decide suboptimal sides of the screening program and to evaluate the significance of routine screening in the development of cervical cancer. METHODS: The study describes the results of a quality control audit, performed on all new cervical cancer cases diagnosed in the years 2008-2009 at two major Danish screening-centers. All relevant cytological and histological cervical samples were reviewed. RESULTS: 202.534 cytological samples were evaluated in the study period, while 112 women were diagnosed with cervical cancer. The histological diagnoses comprised: 62 (55.4%) squamous cell carcinomas, 20 (17.9%) microinvasive squamous cell carcinomas, 25 (22.3%) adenocarcinomas and 5 cancers of different histology. The mean age of study subjects was 46.6 years. 51 (45.5%) women had deficient screening histories, while 45 (40.2%) women had followed the screening recommendations and had normal cervical samples in review. 11 (9.8%) women were diagnosed with false negative cytology, 2 women had false negative histological tests, while pathological review was not feasible for 3 subjects. CONCLUSIONS: More than 45% of the cervical cancer cases in our study were due to deficient cervical screening, stressing the importance of increasing the screening-uptake and coverage. 40% interval cancers emphasize the relevance of further cervical testing of women with relevant symptoms, despite of prior normal cervical samples. Finally, 9.8% false negative cytological samples are consistent with previous reports, but still a part of the screening program that should be improved.