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1.
Int J Cancer ; 144(8): 1975-1982, 2019 04 15.
Artículo en Inglés | MEDLINE | ID: mdl-30246864

RESUMEN

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.


Asunto(s)
Papillomaviridae/patogenicidad , Infecciones por Papillomavirus/epidemiología , Displasia del Cuello del Útero/epidemiología , Neoplasias del Cuello Uterino/epidemiología , Adulto , Carcinogénesis , Cuello del Útero/patología , Cuello del Útero/virología , ADN Viral/aislamiento & purificación , Dinamarca/epidemiología , Detección Precoz del Cáncer/métodos , Detección Precoz del Cáncer/estadística & datos numéricos , Femenino , Estudios de Seguimiento , Genotipo , Humanos , Tamizaje Masivo/métodos , Tamizaje Masivo/estadística & datos numéricos , Persona de Mediana Edad , Clasificación del Tumor , Papillomaviridae/genética , Papillomaviridae/aislamiento & purificación , Infecciones por Papillomavirus/diagnóstico , Infecciones por Papillomavirus/patología , Infecciones por Papillomavirus/virología , Estudios Prospectivos , Factores de Riesgo , Neoplasias del Cuello Uterino/patología , Neoplasias del Cuello Uterino/virología , Frotis Vaginal , Displasia del Cuello del Útero/patología , Displasia del Cuello del Útero/virología
2.
Am J Surg Pathol ; 41(6): 725-737, 2017 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-28248817

RESUMEN

Ovarian serous borderline tumors (SBTs) have been the subject of considerable controversy, particularly with regard to terminology and behavior. It has been proposed that they constitute a heterogenous group of tumors composed, for the most part, of typical SBTs that are benign and designated "atypical proliferative serous tumor (APST)" and a small subset of SBTs with micropapillary architecture that have a poor outcome and are designated "noninvasive low-grade serous carcinoma (niLGSC)". It also has been argued that the difference in behavior between the 2 groups is not due to the subtype of the primary tumor but rather the presence of extraovarian disease, specifically invasive implants. According to the terminology of the 2014 WHO Classification, typical SBTs are equivalent to APSTs and SBTs displaying micropapillary architecture are synonymous with niLGSC. In addition, "invasive implants" were renamed "low-grade serous carcinoma" (LGSC). The argument as to whether it is the appearance of the primary tumor or the presence of extraovarian LGSC that determines outcome remains unsettled. The current study was initiated in 2004 and was designed to determine what factors were predictive of outcome, with special attention to the appearance of the primary tumor (APST vs. niLGSC) and that of the extraovarian disease (noninvasive vs. invasive implants). Our study is population based, involving the entire female population of Denmark. None of the women in the study were lost to follow-up, which ranged up to 36 years (median, 15 y). All the microscopic slides from the contributing hospitals were rereviewed by a panel of 2 pathologists (R.V. and R.J.K.) who were blinded to the follow-up. After excluding those that were not SBTs by the pathology panel, as well as cases with a prior or concurrent cancer or undefined stage, 942 women remained, of which 867 were APSTs and 75 were niLGSCs. The median patient age was 50 years (range, 16 to 97 y). Eight hundred nine women (86%) presented with FIGO stage I disease, whereas 133 (14%) had advanced stage disease. Compared with APSTs, niLGSC exhibited a significantly greater frequency of bilaterality, residual gross disease after surgery, microinvasion/microinvasive carcinoma, advanced stage disease, and invasive implants at presentation (P-values <0.003). Because the cause of death is difficult to accurately ascertain from death certificates, we used development of invasive serous carcinoma as the primary endpoint as following development of carcinoma, the mortality is very high. In the entire cohort, subsequent development of carcinoma occurred in 4%, of which 93% were low grade and 7% high grade (median time, 10 y; range, up to 25 y). After adjusting for age at and time since diagnosis of APST or niLGSC, occurrence of subsequent carcinoma was significantly higher with niLGSC than APST among all stages combined (hazard ratio [HR]=3.8; 95% confidence interval [CI], 1.7-8.2). This difference was still significant for stage I but not advanced stage cases. Moreover, all-cause mortality was not statistically significantly different between APST and niLGSC. Of all women with advanced stage disease, 114 (86%) had noninvasive implants, whereas 19 (14%) were invasive. Noninvasive implants were significantly associated with subsequent development of carcinoma (HR=7.7; 95% CI, 3.9-15.0), but the risk with invasive implants was significantly higher (HR=42.3; 95% CI, 16.1-111.1). In conclusion, although invasive implants are the most important feature in predicting an adverse outcome, subclassification into APST and niLGSC is important as it stratifies women with respect to risk for advanced stage disease and invasive implants for all women and development of serous carcinoma for stage I cases.


Asunto(s)
Cistadenocarcinoma Seroso/patología , Cistadenoma Seroso/patología , Neoplasias Ováricas/patología , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Cistadenocarcinoma Seroso/mortalidad , Cistadenoma Seroso/mortalidad , Dinamarca , Femenino , Estudios de Seguimiento , Humanos , Persona de Mediana Edad , Clasificación del Tumor , Invasividad Neoplásica , Estadificación de Neoplasias , Neoplasias Ováricas/mortalidad , Pronóstico , Modelos de Riesgos Proporcionales , Adulto Joven
3.
Gynecol Oncol ; 144(3): 571-576, 2017 03.
Artículo en Inglés | MEDLINE | ID: mdl-28108026

RESUMEN

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.


Asunto(s)
Anticonceptivos Orales/administración & dosificación , Cistadenocarcinoma Seroso/epidemiología , Terapia de Reemplazo de Hormonas/estadística & datos numéricos , Infertilidad/epidemiología , Neoplasias Glandulares y Epiteliales/epidemiología , Neoplasias Ováricas/epidemiología , Adulto , Carcinoma Epitelial de Ovario , Estudios de Casos y Controles , Cistadenocarcinoma Seroso/diagnóstico , Dinamarca/epidemiología , Femenino , Humanos , Neoplasias Glandulares y Epiteliales/diagnóstico , Neoplasias Ováricas/diagnóstico , Paridad , Factores de Riesgo , Adulto Joven
4.
Gynecol Oncol ; 144(1): 174-180, 2017 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-27836204

RESUMEN

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.


Asunto(s)
Carcinoma/epidemiología , Carcinoma/patología , Recurrencia Local de Neoplasia/epidemiología , Neoplasias Quísticas, Mucinosas y Serosas/epidemiología , Neoplasias Quísticas, Mucinosas y Serosas/patología , Neoplasias Ováricas/epidemiología , Neoplasias Ováricas/patología , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Dinamarca/epidemiología , Femenino , Estudios de Seguimiento , Humanos , Persona de Mediana Edad , Invasividad Neoplásica , Estadificación de Neoplasias , Factores de Riesgo , Factores de Tiempo , Adulto Joven
5.
Int J Cancer ; 139(8): 1839-50, 2016 10 15.
Artículo en Inglés | MEDLINE | ID: mdl-27004595

RESUMEN

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.


Asunto(s)
Células Escamosas Atípicas del Cuello del Útero/virología , ADN Viral/análisis , Papillomaviridae/genética , Infecciones por Papillomavirus/virología , ARN Mensajero/análisis , ARN Viral/análisis , Adulto , Anciano , Células Escamosas Atípicas del Cuello del Útero/patología , Estudios de Cohortes , Femenino , Humanos , Persona de Mediana Edad , Clasificación del Tumor , Papillomaviridae/aislamiento & purificación , Infecciones por Papillomavirus/patología , Estudios Prospectivos , Neoplasias del Cuello Uterino/patología , Neoplasias del Cuello Uterino/virología , Displasia del Cuello del Útero/patología , Displasia del Cuello del Útero/virología
6.
Papillomavirus Res ; 2: 31-37, 2016 12.
Artículo en Inglés | MEDLINE | ID: mdl-29074183

RESUMEN

BACKGROUND: The novel BD OnclarityTM HPV assay (Onclarity) on the BD Viper™ LT system (BD Diagnostics, Sparks, MD), detects E6/E7 DNA from 13 high-risk HPV genotypes and HPV66. We compared the analytical and clinical performance of the Onclarity Assay to that of Hybrid Capture 2 and LINEAR ARRAY using adjudicated histological outcomes from Danish women referred for colposcopy. METHODS: 276 women from Copenhagen, Denmark were referred for colposcopy with abnormal cytology and/or a positive HPV test. Two samples for HPV analysis were taken in BD SurePath™ and in the BD cervical brush diluent (CBD) media. ClinicalTrial gov. identifier: NCT01671462, Ethical Approval: H-4-2012-070. RESULTS: Histology was normal in 84 (31%) women, 70 (26%) had CIN1, 47 (17%) CIN2, and 68 (25%) had CIN3. The Onclarity assay detected 67 out of 68 (99%) ≥CIN3 and 113/115 (98%) ≥CIN2. The specificities for

Asunto(s)
Técnicas de Diagnóstico Molecular/métodos , Infecciones por Papillomavirus/diagnóstico , Displasia del Cuello del Útero/diagnóstico , Adulto , Anciano , ADN Viral/genética , Dinamarca , Femenino , Humanos , Persona de Mediana Edad , Proteínas Oncogénicas Virales/genética , Sensibilidad y Especificidad , Adulto Joven
7.
Int J Cancer ; 138(2): 361-8, 2016 Jan 15.
Artículo en Inglés | MEDLINE | ID: mdl-26238558

RESUMEN

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.


Asunto(s)
Cuello del Útero/virología , Infecciones por Papillomavirus/virología , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Enfermedad Crónica , ADN Viral/análisis , Femenino , Humanos , Persona de Mediana Edad , Neoplasias del Cuello Uterino/virología , Adulto Joven
8.
Cancer Causes Control ; 26(8): 1105-16, 2015 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-26033777

RESUMEN

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.


Asunto(s)
Adenocarcinoma/epidemiología , Carcinoma de Células Escamosas/epidemiología , Displasia del Cuello del Útero/epidemiología , Neoplasias del Cuello Uterino/epidemiología , Adulto , Anciano , Anciano de 80 o más Años , Dinamarca/epidemiología , Femenino , Humanos , Incidencia , Persona de Mediana Edad , Vacunas contra Papillomavirus , Adulto Joven
9.
Int J Cancer ; 137(1): 193-203, 2015 Jul 01.
Artículo en Inglés | MEDLINE | ID: mdl-25471319

RESUMEN

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+.


Asunto(s)
Alphapapillomavirus/genética , Infecciones por Papillomavirus/diagnóstico , Displasia del Cuello del Útero/virología , Neoplasias del Cuello Uterino/virología , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Alphapapillomavirus/clasificación , Alphapapillomavirus/fisiología , ADN Viral/genética , Dinamarca , Detección Precoz del Cáncer , Femenino , Genotipo , Humanos , Persona de Mediana Edad , Infecciones por Papillomavirus/virología , Estudios Prospectivos , Factores de Riesgo , Neoplasias del Cuello Uterino/diagnóstico , Frotis Vaginal , Carga Viral , Adulto Joven , Displasia del Cuello del Útero/diagnóstico
10.
J Int AIDS Soc ; 17(4 Suppl 3): 19646, 2014.
Artículo en Inglés | MEDLINE | ID: mdl-25394150

RESUMEN

INTRODUCTION: Women living with HIV (WLWH) are reportedly at increased risk of invasive cervical cancer (ICC). WLWH in Denmark attend the National ICC screening program less often than women in the general population. We aimed to estimate the incidence of cervical dysplasia and ICC in WLWH in Denmark. METHODS: We studied a nationwide cohort of WLWH and a cohort of age-matched females from the general population in the period 1999-2010. Pathology samples were obtained from The Danish Pathology Data Bank containing nationwide records of all pathology specimens. The cumulative incidence and hazard ratios (HRs) for time from inclusion to first cervical intraepithelial neoplasia (CIN)/ICC and time from first normal cervical cytology to first CIN/ICC were estimated. Sensitivity analyses were performed to include prior screening outcome, screening intensity and treatment of CIN/ICC in the interpretation of results. RESULTS: We followed 1,143 WLWH and 17,145 controls with no prior history of ICC for 9,509 and 157,362 person-years. Compared to controls, the overall incidence of CIN1 or worse (CIN1+), CIN2+ and CIN3+ was higher in WLWH and predicted by young age and CD4 count <200 cells/µL. In women with normal baseline cytology, incidences of CIN1+ and CIN2+ were higher in WLWH. However, incidences were comparable between WLWH and controls adherent to the National ICC screening program. CONCLUSIONS: Overall, WLWH develop more cervical disease than controls. However, incidences of CIN are comparable amongst WLWH and controls adherent to the National ICC screening program and with a normal baseline cytology.

11.
Am J Surg Pathol ; 38(12): 1603-11, 2014 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-25188864

RESUMEN

Serous borderline tumor also known as atypical proliferative serous tumor (APST) is the precursor of ovarian low-grade serous carcinoma (LGSC). In this study, we correlated the morphologic and immunohistochemical phenotypes of 71 APSTs and 18 LGSCs with the mutational status of KRAS and BRAF, the most common molecular genetic changes in these neoplasms. A subset of cells characterized by abundant eosinophilic cytoplasm (EC), discrete cell borders, and bland nuclei was identified in all (100%) 25 BRAF-mutated APSTs but in only 5 (10%) of 46 APSTs without BRAF mutations (P<0.0001). Among the 18 LGSCs, EC cells were found in only 2, and both contained BRAF mutations. The EC cells were present admixed with cuboidal and columnar cells lining the papillae and appeared to be budding from the surface, resulting in individual cells and clusters of detached cells "floating" above the papillae. Immunohistochemistry showed that the EC cells always expressed p16, a senescence-associated marker, and had a significantly lower Ki-67 labeling index than adjacent cuboidal and columnar cells (P=0.02). In vitro studies supported the interpretation that these cells were undergoing senescence, as the same morphologic features could be reproduced in cultured epithelial cells by ectopic expression of BRAF(V600E). Senescence was further established by markers such as SA-ß-gal staining, expression of p16 and p21, and reduction in DNA synthesis. In conclusion, this study sheds light on the pathogenesis of this unique group of ovarian tumors by showing that BRAF mutation is associated with cellular senescence and the presence of a specific cell type characterized by abundant EC. This "oncogene-induced senescence" phenotype may represent a mechanism that impedes progression of APSTs to LGSC.


Asunto(s)
Senescencia Celular/genética , Cistadenocarcinoma Seroso/genética , Cistadenocarcinoma Seroso/patología , Mutación , Neoplasias Ováricas/genética , Neoplasias Ováricas/patología , Proteínas Proto-Oncogénicas B-raf/genética , Cistadenoma Seroso/genética , Cistadenoma Seroso/patología , Análisis Mutacional de ADN , Femenino , Humanos , Inmunohistoquímica , Proteínas Proto-Oncogénicas/genética , Proteínas Proto-Oncogénicas p21(ras) , Proteínas ras/genética
12.
Gynecol Oncol ; 134(2): 267-73, 2014 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-24924123

RESUMEN

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.


Asunto(s)
Neoplasias Ováricas/mortalidad , Neoplasias Ováricas/patología , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Dinamarca , Femenino , Humanos , Persona de Mediana Edad , Tasa de Supervivencia , Factores de Tiempo , Adulto Joven
13.
BMC Infect Dis ; 14: 256, 2014 May 13.
Artículo en Inglés | MEDLINE | ID: mdl-24885577

RESUMEN

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.


Asunto(s)
Infecciones por VIH , Tamizaje Masivo/estadística & datos numéricos , Cooperación del Paciente/estadística & datos numéricos , Neoplasias del Cuello Uterino/diagnóstico , Frotis Vaginal/estadística & datos numéricos , Adulto , Recuento de Linfocito CD4 , Estudios de Casos y Controles , Dinamarca , Detección Precoz del Cáncer , Femenino , Humanos , Persona de Mediana Edad , Oportunidad Relativa
14.
Cancer Causes Control ; 25(7): 915-22, 2014 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-24797870

RESUMEN

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.


Asunto(s)
Vacunas contra Papillomavirus/uso terapéutico , Displasia del Cuello del Útero/epidemiología , Neoplasias del Cuello Uterino/epidemiología , Adolescente , Adulto , Distribución por Edad , Anciano , Niño , Dinamarca/epidemiología , Femenino , Humanos , Incidencia , Persona de Mediana Edad , Neoplasias del Cuello Uterino/prevención & control , Adulto Joven , Displasia del Cuello del Útero/prevención & control
15.
Gynecol Oncol ; 134(1): 206-15, 2014 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-24607284

RESUMEN

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.


Asunto(s)
Neoplasias Endometriales/virología , Papillomaviridae/aislamiento & purificación , Infecciones por Papillomavirus/complicaciones , ADN Viral/aislamiento & purificación , Femenino , Humanos , Papillomaviridae/genética , Infecciones por Papillomavirus/virología
16.
Int J Cancer ; 135(4): 896-904, 2014 Aug 15.
Artículo en Inglés | MEDLINE | ID: mdl-24391021

RESUMEN

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.


Asunto(s)
Ácido Acético , Técnicas Citológicas , Infecciones por VIH/complicaciones , Papillomaviridae , Neoplasias del Cuello Uterino/diagnóstico , Neoplasias del Cuello Uterino/virología , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Cuello del Útero/patología , Estudios Transversales , ADN Viral/análisis , Detección Precoz del Cáncer , Femenino , Genotipo , Infecciones por VIH/virología , Seropositividad para VIH/complicaciones , Humanos , Tamizaje Masivo/métodos , Persona de Mediana Edad , Prevalencia , Análisis de Secuencia de ADN , Tanzanía , Frotis Vaginal , Adulto Joven
17.
Obstet Gynecol ; 123(1): 57-64, 2014 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-24463664

RESUMEN

OBJECTIVE: To determine the absolute risk of cervical intraepithelial neoplasia (CIN) grade 3 or cervical cancer (CIN 3 or worse) after detection of low-risk human papillomavirus (HPV) and after a negative high-risk HPV test. METHODS: In this prospective cohort study, consecutive liquid-based cervical cytology samples were collected from women screened for cervical cancer in Copenhagen, Denmark, during 2002-2005. Samples were tested with a clinical test for 13 high-risk and five low-risk HPV types. The cohort (N=35,539; aged 14-90 years) was monitored in a nationwide pathology register for up to 10.5 years for development of CIN 3 or worse. RESULTS: The 8-year absolute risk of CIN 3 or worse was 1.1% (95% confidence interval [CI] 1.0-1.3%) for HPV-negative women; 1.7% (0.8-2.6%) for low-risk HPV-positive women without concurrent high-risk HPV; 17.4% (16.4-18.5%) for high-risk HPV-positive women without concurrent low-risk HPV; and 15.9% (13.5-18.3%) for women with concurrent high-risk and low-risk HPV. The 8-year absolute risk of CIN 3 or worse after a negative high-risk HPV test (irrespective of low-risk HPV status) was lower than after a normal cytology result among women aged younger than 30 years (3.5% [95% CI, 2.9-4.0%] compared with 6.9% [6.2-7.5%], P<.001) and women aged 30 years or older (0.7% [95% CI, 0.6-0.9%] compared with 1.8% [95% CI, 1.6-2.0%], P<.001). CONCLUSION: A negative high-risk HPV test provides greater long-term reassurance against CIN 3 or worse than normal cytology. Detection of low-risk HPV does not predict CIN 3 or worse. Cervical cancer screening should not include testing for low-risk HPV types. LEVEL OF EVIDENCE: II.


Asunto(s)
Cuello del Útero/patología , Papillomaviridae/genética , Displasia del Cuello del Útero/virología , Neoplasias del Cuello Uterino/virología , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Dinamarca/epidemiología , Femenino , Humanos , Persona de Mediana Edad , Estudios Prospectivos , Medición de Riesgo , Neoplasias del Cuello Uterino/epidemiología , Adulto Joven , Displasia del Cuello del Útero/epidemiología
18.
Cancer Causes Control ; 25(2): 179-89, 2014 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-24242002

RESUMEN

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.


Asunto(s)
Cuello del Útero/citología , Papillomaviridae/aislamiento & purificación , Infecciones por Papillomavirus/epidemiología , Infecciones por Papillomavirus/prevención & control , Neoplasias del Cuello Uterino/epidemiología , Neoplasias del Cuello Uterino/prevención & control , Adolescente , Adulto , Factores de Edad , Anciano , Anciano de 80 o más Años , Cuello del Útero/patología , Cuello del Útero/virología , Dinamarca/epidemiología , Femenino , Genotipo , Humanos , Persona de Mediana Edad , Infecciones por Papillomavirus/virología , Prevalencia , Neoplasias del Cuello Uterino/virología , Adulto Joven
19.
J Pathol ; 232(1): 16-22, 2014 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-24307542

RESUMEN

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.


Asunto(s)
Cistadenocarcinoma Seroso/genética , Neoplasias Ováricas/genética , Neoplasias Peritoneales/genética , Proteínas Proto-Oncogénicas B-raf/genética , Proteínas Proto-Oncogénicas/genética , Proteínas ras/genética , Cistadenocarcinoma Seroso/patología , Análisis Mutacional de ADN , ADN de Neoplasias/química , ADN de Neoplasias/genética , Dinamarca , Femenino , Humanos , Inmunohistoquímica , Captura por Microdisección con Láser , Mutación , Neoplasias Ováricas/patología , Neoplasias Peritoneales/patología , Proteínas Proto-Oncogénicas/metabolismo , Proteínas Proto-Oncogénicas B-raf/metabolismo , Proteínas Proto-Oncogénicas p21(ras) , Sensibilidad y Especificidad , Análisis de Secuencia de ADN , Proteínas ras/metabolismo
20.
Acta Obstet Gynecol Scand ; 92(9): 1023-31, 2013 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-23763577

RESUMEN

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.


Asunto(s)
Adenocarcinoma/virología , Alphapapillomavirus/genética , Carcinoma de Células Escamosas/virología , ADN Viral/genética , Genotipo , Neoplasias del Cuello Uterino/virología , Adenocarcinoma/patología , Adulto , Anciano , Anciano de 80 o más Años , Carcinoma de Células Escamosas/patología , Estudios Transversales , Dinamarca , Femenino , Humanos , Persona de Mediana Edad , Neoplasias del Cuello Uterino/patología
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