Eurogin 2016 Roadmap: how HPV knowledge is changing screening practice.

Human papillomaviruses (HPVs) are the necessary cause of most cervical cancers, a large proportion of other anogenital cancers, and a subset of oropharyngeal cancers. The knowledge about HPV has led to development of novel HPV-based prevention strategies with important impact on clinical and public health practice. Two complementary reviews have been prepared following the 2015 Eurogin Conference to evaluate how knowledge about HPV is changing practice in HPV infection and disease control through vaccination and screening. This review focuses on screening for cervical and anal cancers in increasingly vaccinated populations. The introduction of HPV vaccines a decade ago has led to reductions in HPV infections and early cancer precursors in countries with wide vaccination coverage. Despite the high efficacy of HPV vaccines, cervical cancer screening will remain important for many decades. Many healthcare systems are considering switching to primary HPV screening, which has higher sensitivity for cervical precancers and allows extending screening intervals. We describe different approaches to implementing HPV-based screening efforts in different healthcare systems with a focus in high-income countries. While the population prevalence for other anogenital cancers is too low for population-based screening, anal cancer incidence is very high in HIV-infected men who have sex with men, warranting consideration of early detection approaches. We summarize the current evidence on HPV-based prevention of anal cancers and highlight important evidence gaps.

Eurogin Roadmap 2015: How has HPV knowledge changed our practice: Vaccines.

This review is one of two complementary reviews that have been prepared in the framework of the Eurogin Roadmap 2015 to evaluate how knowledge about HPV is changing practices in HPV infection and disease control through vaccination and screening. In this review of HPV vaccine knowledge, we present the most significant findings of the past year which have contributed to our knowledge of the two HPV prophylactic vaccines currently in widespread use and about the recently licensed nonavalent HPV vaccine. Whereas anal cancer is dealt with in the companion mini-review on screening, we also review here the rapidly evolving evidence regarding HPV-associated head and neck cancer and priority research areas.

EUROGIN 2014 roadmap: differences in human papillomavirus infection natural history, transmission and human papillomavirus-related cancer incidence by gender and anatomic site of infection.

Human papillomaviruses (HPVs) cause cancer at multiple anatomic sites in men and women, including cervical, oropharyngeal, anal, vulvar and vaginal cancers in women and oropharyngeal, anal and penile cancers in men. In this EUROGIN 2014 roadmap, differences in HPV-related cancer and infection burden by gender and anatomic site are reviewed. The proportion of cancers attributable to HPV varies by anatomic site, with nearly 100% of cervical, 88% of anal and <50% of lower genital tract and oropharyngeal cancers attributable to HPV, depending on world region and prevalence of tobacco use. Often, mirroring cancer incidence rates, HPV prevalence and infection natural history varies by gender and anatomic site of infection. Oral HPV infection is rare and significantly differs by gender; yet, HPV-related cancer incidence at this site is several-fold higher than at either the anal canal or the penile epithelium. HPV seroprevalence is significantly higher among women compared to men, likely explaining the differences in age-specific HPV prevalence and incidence patterns observed by gender. Correspondingly, among heterosexual partners, HPV transmission appears higher from women to men. More research is needed to characterize HPV natural history at each anatomic site where HPV causes cancer in men and women, information that is critical to inform the basic science of HPV natural history and the development of future infection and cancer prevention efforts.

Prevalence of high-risk human papilloma virus genotypes and associated risk of cervical precancerous lesions in a large U.S. screening population: data from the ATHENA trial.

OBJECTIVE: We assessed the age-related prevalence of high risk human papillomavirus (HR-HPV) genotypes and the genotype-associated risk for high-grade cervical intraepithelial neoplasia (CIN) in a large U.S. screening population. METHODS: A total of 40,901 women aged ≥25 years were screened with liquid-based cytology and HPV testing in the ATHENA (Addressing the Need for Advanced HPV Diagnostics) trial. Genotyping was performed using the LINEAR ARRAY HPV Genotyping Test. RESULTS: HPV16 was the most prevalent genotype in all age groups, ranging from 3.5% to 0.8% in women aged 25-29 and ≥50 years, respectively. The next most prevalent genotypes were HPV52, HPV31 and HPV18. In the overall population, HPV16 conferred the greatest absolute risk of ≥CIN3 both in women aged 25-29 and ≥30 years (14.2% and 15.1%, respectively) followed by HPV31 (8.0% and 7.9%), HPV52 (6.7% and 4.4%) and HPV18 (2.7% and 9.0%). Similar trends were seen in women with negative cytology. The percent positivity increased markedly with disease progression for HPV16 and HPV18 which were responsible for 45.6% and 8.4% of ≥CIN3, respectively. Of note, HPV 18 was responsible for 50% of adenocarcinoma in situ (AIS) and 50% of invasive cancer cases. CONCLUSIONS: HPV16 played a major role in the development of ≥CIN3 irrespective of age, supporting the identification of HPV16 in primary screening for all women. Identification of HPV18 is also warranted, given its significant contribution to AIS and cancer. Identification of non-16/18 genotypes as a pool should provide sufficient information for screening.

The APTIMA HPV assay versus the Hybrid Capture 2 test in triage of women with ASC-US or LSIL cervical cytology: a meta-analysis of the diagnostic accuracy.

Testing for DNA of 13 high-risk HPV types with the Hybrid Capture 2 (HC2) test has consistently been shown to perform better in triage of women with cervical cytology results showing atypical squamous cells of undetermined significance (ASC-US) but often not in triage of low-grade squamous intraepithelial lesions (LSIL) detected in cervical cancer screening. In a meta-analysis, we compared the accuracy of the APTIMA HPV test, which identifies RNA of 14 high-risk HPV types, to HC2 for the triage of women with ASC-US or LSIL. Literature search-targeted studies where the accuracy of APTIMA HPV and HC2 for detection of underlying CIN2/3+ was assessed concomitantly including verification of all cases of ASC-US and LSIL. HSROC (Hierarchical Summary ROC) curve regression was used to compute the pooled absolute and relative sensitivity and specificity. Eight studies, comprising 1,839 ASC-US and 1,887 LSIL cases, were retrieved. The pooled sensitivity and specificity of APTIMA to triage ASC-US to detect underlying CIN3 or worse was 96.2% (95% CI = 91.7-98.3%) and 54.9% (95% CI = 43.5-65.9%), respectively. APTIMA and HC2 showed similar pooled sensitivity; however, the specificity of the former was significantly higher (ratio: 1.19; 95% CI = 1.08-1.31 for CIN2+). The pooled sensitivity and specificity of APTIMA to triage LSIL were 96.7% (95% CI = 91.4-98.9%) and 38.7% (95% CI = 30.5-47.6%) for CIN3+. APTIMA was as sensitive as HC2 but more specific (ratio: 1.35; 95% CI = 1.11-1.66). Results were similar for detection of CIN2 or worse. In both triage of ASC-US and LSIL, APTIMA is as sensitive but more specific than HC2 for detecting cervical precancer.

EUROGIN 2011 roadmap on prevention and treatment of HPV-related disease.

The EUROGIN 2011 roadmap reviews the current burden of human papillomavirus (HPV)-related morbidity, as well as the evidence and potential practice recommendations regarding primary and secondary prevention and treatment of cancers and other disease associated with HPV infection. HPV infection causes ~600,000 cases of cancer of the cervix, vulva, vagina, anus and oropharynx annually, as well as benign diseases such as genital warts and recurrent respiratory papillomatosis. Whereas the incidence of cervical cancer has been decreasing over recent decades, the incidence of anal and oropharyngeal carcinoma, for which there are no effective screening programs, has been rising over the last couple of decades. Randomized trials have demonstrated improved efficacy of HPV-based compared to cytology-based cervical cancer screening. Defining the best algorithms to triage HPV-positive women, age ranges and screening intervals are priorities for pooled analyses and further research, whereas feasibility questions can be addressed through screening programs. HPV vaccination will reduce the burden of cervical precancer and probably also of invasive cervical and other HPV-related disease in women. Recent trials demonstrated that prophylactic vaccination also protects against anogenital HPV infection, anogenital intraepithelial lesions and warts associated with vaccine types, in males; and anal HPV infection and anal intraepithelial neoplasia in MSM. HPV-related oropharyngeal cancer could be treated less aggressively because of better survival compared to cancers of the oropharynx unrelated to HPV. Key findings in the field of cervical cancer prevention should now be translated in cost-effective strategies, following an organized approach integrating primary and secondary prevention, according to scientific evidence but adapted to the local situation with particular attention to regions with the highest burden of disease.

Risk assessment and clinical impact of liquid-based cytology, oncogenic human papillomavirus (HPV) DNA and mRNA testing in primary cervical cancer screening (the FASE study).

OBJECTIVE: New commercial HPV RNA assays require further validation studies in population-based cervical cancer screening settings. To assess the performance of (FDA-approved) APTIMA® HPV Assay (AHPV), Hybrid Capture 2 (HC2), in-house PCR genotyping, and ThinPrep LBC in population-based screening, stratified by three histological gold standards. STUDY DESIGN: A multi-center trial in 5006 women undergoing routine screening in France was designed to compare the absolute and relative risks of diagnosing CIN3+ and CIN2+ lesions by different diagnostic tests. RESULTS: Reproducibility between the primary and second pathology reading was excellent for CIN3+ and CIN2+ endpoints (Cohen's kappa 0.948 and 0.854). Absolute risks (PPV) of different tests (AHPV, HC2, PCR genotyping, LBC) in diagnosing CIN2+ (15-20%) and CIN3+ (4-6%) were similar for the first, second, and consensus pathology readings. The relative risks of diagnosing these lesions by the four tests were also similar when the first, second or third pathology readings were employed. AHPV had the highest absolute risk of both histological endpoints, and detects 5% to 15% more CIN3+ and CIN2+ lesions, respectively, than LBC. Compared with HC2 assay, the relative risk of AHPV is 24% to 29% higher, with a significant difference in CIN2+ detection. With LBC as reference, AHPV had the best sensitivity/specificity balance measured by AUC (area under ROC curve) comparison test (significant for CIN2+), and the colposcopy referral rate (9.2%) comparable to that of LBC (8.7%). CONCLUSIONS: These data corroborate the suitability of AHPV for the primary cervical cancer screening.

Evaluation of oncogenic human papillomavirus RNA and DNA tests with liquid-based cytology in primary cervical cancer screening: the FASE study.

The APTIMA HPV Assay (AHPV) allows detection of 14 high-risk human papillomavirus (HPV) RNA types in cervical specimens. Until present, the assay has been compared to HPV DNA tests only in triage settings. Herein, we compare AHPV with a DNA assay (Hybrid Capture 2; HC2) and liquid-based cytology (LBC; using PreservCyt ThinPrep liquid Pap) in a screening setting (French APTIMA screening evaluation [FASE] study). Women (N = 5,006) aged 20-65 were screened by gynecologists in 17 private practices in Paris, France. One cervical specimen was collected and tested with LBC, AHPV and HC2 assays. Women were referred to colposcopy if they were ASC-US+ in LBC or HPV positive in either HPV assay. To control for verification bias, a random group (14%) with normal LBC and dually HPV negative tests underwent colposcopy. Data from 4,429 women were analyzed. Sensitivity, specificity and predictive values were calculated for the three tests. AHPV and HC2 were highly sensitive for CIN2+ (92.0% and 96.7%) and CIN3+ (95.7% and 95.3%) detection and much more sensitive than LBC (69.1% for CIN2+ and 73.3% for CIN3+). Specificity of AHPV was higher than that of HC2, but similar to that of LBC (p < 0.001). Combining LBC with either HPV test slightly increased sensitivity but compromised specificity. AHPV assay is both specific and sensitive for the detection of high-grade precancerous lesions and may be considered as an option for routine cervical cancer screening for women over 20 years of age.

Eurogin 2010 roadmap on cervical cancer prevention.

The EUROGIN 2010 roadmap represents a continuing effort to provide and interpret updated information on cervical cancer screening and vaccination against the cause of the disease, high-risk human papillomavirus (HPV). Contrary to the two previous reports in 2008 and 2009, the present roadmap gives equal room to HPV-based screening and HPV vaccination, as a result of the recent strengthening of the evidence on the efficacy and feasibility of both approaches. The superiority of HPV testing in primary screening compared to cytology (in more developed countries) and to cytology or visual inspection methods (in less developed countries) has been demonstrated in several randomised trials. High vaccine efficacy has been confirmed up to 7 years after vaccination; school-based programmes in some countries have been able to reach over 70% coverage among adolescent girls. Demonstration projects have indicated that the delivery of HPV vaccines in less developed countries is feasible and favourably received by populations where cervical cancer is very common. HPV-based screening can diminish cervical cancer incidence more quickly than HPV vaccination, but vaccination can eventually facilitate screening efforts, especially if new vaccines against a greater number of HPV types are introduced. The availability of two highly complementary prevention tools such as HPV testing and HPV vaccination makes it possible to conceive integrated strategies for the elimination of cervical cancer that have no precedent in the cancer field. HPV tests and HPV vaccines remain, however, too expensive, and large-scale financing of screening and vaccination in less developed countries is sorely lacking.

Psychological impact, support and information needs for women with an abnormal Pap smear: comparative results of a questionnaire in three European countries.

BACKGROUND: Extensive information on cervical cancer is currently available. Its effectiveness in reducing anxiety in women receiving abnormal Pap tests is not clear. We investigated current practices of communicating abnormal Pap results to evaluate women's reactions and determine the sources of information they use subsequently. METHODS: A self-administered questionnaire-based study was performed in 1475 women in France, Spain and Portugal who had received an abnormal Pap smear result in the 12 months prior to completing the questionnaire. Questions covered methods of communication of the result, emotional reactions, support received (from the physician and entourage), and information sources, using pre-specified check box options and rating scales. Data were analyzed by country. RESULTS: Pap test results were mostly communicated by phone to Spanish women (76%), while physician letters were common in France (59%) and Portugal (36%). Frequent reactions were anxiety, panic and stress, which were less common in Spanish women than their French and Portuguese counterparts. After discussing with their physician, half of the participants were worried, despite rating highly the psychological support received. Over 90% of women in each country discussed their results with family or friends. Partners provided a high level of support. Overall, the abnormal diagnosis and consequences had a low to medium impact on daily, professional and family life and their relationships with their partner. Impact was higher in Spanish women than the French or Portuguese. Information on the diagnosis and its treatment was rated average, and nearly 80% of participants wanted more information, notably French women. Preferred sources were the physician and the Internet. CONCLUSIONS: Women expressed a strong wish for more information about cervical cancer and other HPV-related diseases, and that their physician play a major role in its provision and in support. There was a heavy reliance on the close entourage and the Internet for information, highlighting the need for dissemination of accurate material. Differences between countries suggest information management strategies may need to be tailored to different geographical regions.

Safety, immunogenicity, and efficacy of quadrivalent human papillomavirus (types 6, 11, 16, 18) recombinant vaccine in women aged 24-45 years: a randomised, double-blind trial.

BACKGROUND: Although the peak incidence of human papillomavirus (HPV) infection occurs in most populations within 5-10 years of first sexual experience, all women remain at risk for acquisition of HPV infections. We tested the safety, immunogenicity, and efficacy of the quadrivalent HPV (types 6, 11, 16, 18) L1 virus-like-particle vaccine in women aged 24-45 years. METHODS: Women aged 24-45 years with no history of genital warts or cervical disease were enrolled from community health centres, academic health centres, and primary health-care providers into an ongoing multicentre, parallel, randomised, placebo-controlled, double-blind study. Participants were allocated by computer-generated schedule to receive quadrivalent HPV vaccine (n=1911) or placebo (n=1908) at day 1, and months 2 and 6. All study site investigators and personnel, study participants, monitors, and central laboratory personnel were blinded to treatment allocation. Coprimary efficacy endpoints were 6 months' or more duration of infection and cervical and external genital disease due to HPV 6, 11, 16, 18; and due to HPV 16 and 18 alone. Primary efficacy analyses were done in a per-protocol population, but intention-to-treat analyses were also undertaken. This study is registered with ClinicalTrials.gov, number NCT00090220. FINDINGS: 1910 women received at least one dose of vaccine and 1907 at least one dose of placebo. In the per-protocol population, efficacy against the first coprimary endpoint (disease or infection related to HPV 6, 11, 16, and 18) was 90.5% (95% CI 73.7-97.5, four of 1615 cases in the vaccine group vs 41/1607 in the placebo group) and 83.1% (50.6-95.8, four of 1601 cases vs 23/1579 cases) against the second coprimary endpoint (disease or infection related to HPV 16 and 18 alone). In the intention-to-treat population, efficacy against the first coprimary endpoint was 30.9% (95% CI 11.1-46.5, 108/1886 cases vs 154/1883 cases) and against the second coprimary endpoint was 22.6% (-2.9 to 41.9, 90/1886 cases vs 115/1883 cases), since infection and disease were present at baseline. We recorded no vaccine-related serious adverse events. INTERPRETATION: The quadrivalent HPV vaccine is efficacious in women aged 24-45 years not infected with the relevant HPV types at enrolment. FUNDING: Merck (USA).

A Pooled Analysis to Compare the Clinical Characteristics of Human Papillomavirus-positive and -Negative Cervical Precancers.

Given that high-risk human papillomavirus (HPV) is the necessary cause of virtually all cervical cancer, the clinical meaning of HPV-negative cervical precancer is unknown. We, therefore, conducted a literature search in Ovid MEDLINE, PubMed Central, and Google Scholar to identify English-language studies in which (i) HPV-negative and -positive, histologically confirmed cervical intraepithelial neoplasia grade 2 or more severe diagnoses (CIN2+) were detected and (ii) summarized statistics or deidentified individual data were available to summarize proportions of biomarkers indicating risk of cancer. Nineteen studies including 3,089 (91.0%) HPV-positive and 307 (9.0%) HPV-negative CIN2+ were analyzed. HPV-positive CIN2+ (vs. HPV-negative CIN2+) was more likely to test positive for biomarkers linked to cancer risk: a study diagnosis of CIN3+ (vs. CIN2; 18 studies; 0.56 vs. 0.24; P < 0.001) preceding high-grade squamous intraepithelial lesion cytology (15 studies; 0.54 vs. 0.10; P < 0.001); and high-grade colposcopic impression (13 studies; 0.30 vs. 0.18; P = 0.03). HPV-negative CIN2+ was more likely to test positive for low-risk HPV genotypes than HPV-positive CIN2+ (P < 0.001). HPV-negative CIN2+ appears to have lower cancer risk than HPV-positive CIN2+. Clinical studies of human high-risk HPV testing for screening to prevent cervical cancer may refer samples of HPV test-negative women for disease ascertainment to correct verification bias in the estimates of clinical performance. However, verification bias adjustment of the clinical performance of HPV testing may overcorrect/underestimate its clinical performance to detect truly precancerous abnormalities.

Linear array genotyping and hybrid capture II assay in detecting human papillomavirus genotypes in women referred for colposcopy due to abnormal Papanicolaou smear.

The main objective of this study was to assess the feasibility of human papillomavirus (HPV) genotyping in women referred for colposcopy due to abnormal Papanicolaou (Pap) smear. A series of 248 women referred for colposcopy due to an abnormal Pap smear were analysed with the Roche Linear Array HPV genotyping test detecting 37 most frequent HPV types, and compared with hybrid capture II (HCII) assay for oncogenic (high-risk [HR] HPV) types as well as for p16INK4a expression using immunocytochemistry. All tests were performed in cervical samples collected in PreservCyt liquid media for liquid-based cytology (ThinPrep), and colposcopic biopsy and/or loop electro excision procedure cone biopsy was used as the gold standard. HPV16 was the single most frequent genotype (29/258; 11.7%), followed by HPV51 (4.4%), HPV66 (3.6%), HPV42, 52 and 56 (3.2% for all). Linear array genotyping test significantly predicts both abnormal colposcopy (odds ratio [OR] = 9.0; 3.12-25.93), high-grade squamous intraepithelial lesions (OR = 9.6; 1.26-74.17) and cervical intraepithelial neoplasia (CIN) 3+ (OR = 29.3; 3.95-218.06). In detecting CIN3, linear array was equivalent (97.6%) to colposcopy in sensitivity (SE), both being superior to HCII (92.7%). Concordance between linear array and HCII was moderate (Cohen's kappa kappa = 0.547; 95% confidence interval [CI]: 0.435-659). Specificity (SP) and positive predictive value (PPV) of linear array were significantly improved, if only HPV16 genotype was considered. Performance in the best balance is obtained, when linear array and colposcopy are combined, giving 82.9% SE, 93.9% SP, 73.9% PPV and 96.3% negative predictive value (NPV) as predictor of CIN3+ (OR 74.5; 95% CI: 27.36-202.72). In conclusion, linear array for HR-HPV is a highly sensitive test (97.6%) with high NPV (98.9%) in detecting CIN3+ lesions. HPV16 genotyping alone significantly improves SP and PPV of this test in management of women with abnormal cytology.

Human Papillomavirus Genotypes From Vaginal and Vulvar Intraepithelial Neoplasia in Females 15-26 Years of Age.

OBJECTIVE: To estimate the proportion of vulvar and vaginal low-grade and high-grade squamous intraepithelial lesions (LSILs and HSILs) in females 15-26 years of age attributable to 14 human papillomavirus (HPV) genotypes (6, 11, 16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59). METHODS: A post hoc analysis of prospectively diagnosed vulvar and vaginal LSILs and HSILs among females 15-26 years of age enrolled in the placebo arms of two phase 3, randomized HPV vaccine trials assessed 14 prespecified HPV genotypes associated with cervical cancers or anogenital warts using a type-specific multiplex polymerase chain reaction assay. The frequency of lesions associated with specific HPV genotypes was estimated by proportional and other attribution methods. RESULTS: During approximately 4 years of follow-up in 8,798 females, 40 vulvar LSILs and 46 vulvar HSILs were diagnosed in 68 females, and 118 vaginal LSILs and 33 vaginal HSILs were diagnosed in 107 females. Females developing vulvar (41.2%) or vaginal (49.5%) lesions also had cervical lesions, whereas 6.5% of females with cervical lesions had vaginal or vulvar lesions. At least 1 of the 14 HPV genotypes was detected in females with vulvar LSIL (72.5%), vulvar HSIL (91.3%), vaginal LSIL (61.9%), and vaginal HSIL (72.7%). Considering only HPV-positive lesions, the nine most common genotypes causing cervical cancer and anogenital warts (6, 11, 16, 18, 31, 33, 45, 52, and 58) were found in 89.4% of vulvar LSILs, 100% of vulvar HSILs, 56.0% of vaginal LSILs, and 78.3% of vaginal HSILs. CONCLUSION: Most vulvar and vaginal lesions were attributable to at least 1 of the 14 HPV genotypes analyzed. Effective immunization programs could potentially prevent substantial numbers of HPV-related vulvar and vaginal LSILs and HSILs. CLINICAL TRIAL REGISTRATION: CLINICALTRIALS.GOV,: NCT00092521 and NCT00092534.

P16(INK4a) immunocytochemistry in liquid-based cytology samples in equivocal Pap smears: added value in management of women with equivocal Pap smear.

OBJECTIVE: To test whether p1l6(INK4a) immunocytochemistry (ICC) in liquid-based cytology (LBC) is useful with colposcopy in abnormal Pap smears. STUDY DESIGN: A series of 248 women with abnormal Pap smear were analyzed for oncogenic (HR) human papillomavirus (HPV) types using the Hybrid Capture II assay and for p16(INK4a) expression using ICC on cervical samples in PreservCyt liquid media. Colposcopic and loop electrosurgical excision procedure (LEEP) cone biopsy were the gold standard. RESULTS: p16(INK4a) ICC did best as predictor of high-grade squamous intraepithelial lesion, with OR 12.18 (2.72-54.57) (p = 0.0001), showing 88.2% sensitivity (SE), 61.9% specificity (SP), 14.6% positive predictive value (PPV) and 98.6% negative predictive value (NPV). In sorting discrepant cases, p16(INK4a) ICC results in 100% SE and 100% NPV in detecting cervical intraepithelial neoplasia (CIN) 2 lesions among Pap+/biopsy- women. In atypical squamous cells undetermined significance (ASCUS) cytology, adding p16(INK4a) ICC improves specificity of colposcopy from 27.3% to 81.8% and PPV from 42.8% to 71.4%. Best performance is obtained with p16(INK4a) ICC and colposcopy: 83.3% SE, 81.8% SP, 71.4% PPV and 90.0% NPV. CONCLUSION p16(INK4a) is useful in sorting clinically relevant discrepant cases, and p16(INK4a) ICC significantly improves SP and PPV of colposcopy in management of ASCUS cytology.

[Prevention of cervical cancer: screening, progress and perspectives]. / Prévention du cancer du col utérin (I): apport du dépistage, récents progrès et perspectives.

Worldwide, cervical cancer is diagnosed annually in more than 500,000 women and accounts for 270,000 deaths, making it the second leading cause of cancer in women. In Europe, where many countries have set up screening program, cervical cancer ranks third among cancers in women. In France, cervical cancer is diagnosed in 3400-4500 women each year and kills 1000-1600. Since its introduction, Pap smear screening has transformed cervical cancer from a fatal disease into a rare condition. Despite the considerable success of this cytologic screening, Pap smears have not, as was first hoped, reduced incidence on a large scale. The principal reasons are related to the difficulties in ensuring optimum coverage of the population to be screened and in maximizing women's adherence: the success of screening depends on strict compliance with the calendar from 25 to 65 years of age. In 1/3 of cases, invasive cancers are found in women who undergo regular screening, because Pap smears are insufficiently sensitive. In 5% of cases, cancers are observed in women who were inappropriately managed after an abnormal Pap smear finding. The contribution of the HPV test to primary screening opens up promising perspectives of optimum protection. The test's sensitivity for high-grade lesions exceeds 95% and its negative predictive value exceeds 99%. The HPV test is the only test available for which a negative result provides instantaneous assurance that there is no risk of cervical cancer. The Pap smear alone, with its sensitivity of less than 70%, cannot provide this certainty. European and American guidelines recommend screening strategies based on a combined test using the Pap smear and HPV test after the age of 30 years. The impending availability of prophylactic HPV vaccines, which are expected to provide 70% protection against cervical cancer, will not affect the practice of screening, which must continue.

[Prevention of cervical cancer (II): prophylactic HPV vaccination, current knowledge, practical procedures and new issues]. / Prévention du cancer du col utérin (II): vaccination HPV prophylactique, connaissances actuelles, modalités pratiques et nouveaux enjeux.

Despite the considerable success of early screening for prevention of cervical cancer, Pap smears have not fulfilled the hopes that it would lead to a large-scale reduction of this cancer's incidence. Screening appears to be useful for a tiny portion of the world population, although a relatively large portion must put up with its limitations and disadvantages. Human papilloma viruses (HPV) 16 and 18 are responsible for two thirds of all cervical cancers worldwide. The condylomata (condyloma acuminatum), or genital warts, induced by HPV 6 and 11 are frequent among the young and difficult to manage. The extent and burden of HPV infection are considerable, as is the psychological and emotional impact of the diseases associated with it. Because cancer of the cervix is the final consequence of chronic HPV infection, it can be prevented by vaccination. A prophylactic vaccine to protect against the precancerous and cancerous lesions associated with HPV should save lives, reduce expensive diagnostic and therapeutic interventions, and have substantial individual and collective benefits. Clinical trials of anti-HPV vaccines for the prevention of cervical cancer and condyloma have shown remarkable results and an efficacy unequaled in the history of vaccination against infectious diseases. Vaccine efficacy has been shown only in young girls never exposed to the virus and only for the lesions associated with the specific viral types in the vaccine. Preliminary data indicate that the vaccination is effective in women who have previously eliminated naturally the virus. It has no therapeutic effects on existing lesions or in healthy virus carriers. Practical questions remain to be resolved. If the vaccination is left to individual initiative and vaccination coverage is insufficient, there will be no perceptible reduction in the frequency of cervical cancer. Vaccination policies will not be identical in poor countries, where the disease represents one of the leading causes of mortality among women, and in the rich countries, where screening programs have considerably reduced the frequency of this cancer. Current planning calls for the introduction of systematic vaccination of young girls aged 9-15 years, with progressive "catch-up" vaccination of the cohorts of young women aged 16-26 years. Nonetheless mathematical models and immunogenicity results indicate a possible benefit for individual vaccination of adults. This approach must still be assessed in the clinical trials underway. Because the vaccine does not protect against all types of HPV associated with cervical cancer, screening must be continued according to the conditions currently set. Vaccination and screening, which are complementary and synergistic, now constitute the new standards for prevention of this disease.

Is there an increased risk of cancer among spouses of patients with an HPV-related cancer: A systematic review.

BACKGROUND: High-risk human papillomaviruses (HR-HPV) are the cause of most ano-genital cancers and a fast growing subset of oropharyngeal cancer. As these malignancies occur as a result of an HPV- infection transmitted through intimate contact, many patients with HPV- induced cancer and their partners are concerned about HPV-transmission and the potential partners' cancer risk. Few studies have addressed this issue and whether the HPV-related cancer risk of partners of patients with HPV-related cancers is comparable to or greater than that of the general population. METHODS: We performed a systematic review of the published literature addressing this issue. Out of 1055 references screened, 53 articles were found eligible for inclusion. RESULTS: Regarding the issue of coincidence of HPV-induced oropharyngeal and/or anogenital cancers in couples, 13 case-reports or case-series were reported and 9 larger studies based on population-registries. Four of these registry studies showed an increased risk of cervical cancer in the partner while four did not. Among the four positive studies, odds ratios for the development of HPV-related cancer among spouses were between 2.6 and 6.7. One study showed an increased risk of tongue or tonsil cancer among husbands of women with cervical dysplasia or cancer. Overall the absolute risk increase in all these studies was small, on the order of 1-3%, although potentially underestimated. Indeed, all these studies have assessed partner's cancer risk at only one anatomical site whereas HPV- related malignancies can affect different locations. CONCLUSION: This systematic review suggests a small trend of increase risk in HPV-associated cancers among spouses of patients with HPV-related cancer.