EUROGIN 2008 roadmap on cervical cancer prevention

The EUROGIN 2008 Roadmap represents a continuing effort to provide updated information on primary and secondary prevention of cervical cancer. The report addresses several areas including the progress made toward global implementation of currently licensed human papillomavirus (HPV) vaccines, the possibilities and value of future‐generation HPV vaccines, endpoints under consideration for evaluation of candidate HPV vaccines, and monitoring impact of HPV vaccination programmes that can be implemented within developed and less‐developed countries. For the sake of completeness, a short update on the evolution of HPV testing in primary screening programmes at present and after HPV vaccine introduction has also been included. The report is available on the EUROGIN website ( www.eurogin.com ). © 2009 UICC     

Cervical cancer prevention in Australia: Planning for the future

The high rate of coverage that has been achieved to date by the Australian government's Human Papillomavirus (HPV) Vaccination Program has already led to profound reductions in the prevalence of biopsy‐confirmed, high‐grade abnormalities and of vaccine‐preventable HPV types in Australia. Declines in the prevalence of vaccine preventable HPV have occurred not only in vaccinated women but also in unvaccinated women, suggesting a herd‐immunity affect. These declines were anticipated on the basis of modelling and were the major drivers for the changes proposed to the Australian National Cervical Screening Program. The federal and state‐based Australian governments established a “Renewal Steering Committee,” which conducted a literature search and a review of the available evidence to assess its applicability and quality. Together with this information the committee also used modeling to determine the optimal screening pathway for cervical cancer screening and constructed a plan for implementing the changes that will be required to transition from the currently successful screening program to the renewed program. The committee recommended that Australia move to a screening program based on testing every 5 years using an HPV test with partial genotyping with reflex liquid‐based cytology (LBC) triage for HPV‐vaccinated and unvaccinated women ages 25 to 69 years, and an additional exit test for women up to age 74 years. Primary HPV testing and reflex LBC will be funded by government. Symptomatic women outside the screening program will also be able to access government funded testing. The new screening program, to be rolled out in 2017, will also provide a cost‐effective framework for an evaluation of the national HPV vaccination program, enabling ongoing monitoring of HPV genotypes and cervical lesions in screened women. Cancer Cytopathol 2016;124:235–40 . © 2015 American Cancer Society.     

Impact of HPV vaccination on outcome of cervical cytology screening in Denmark—A register‐based cohort study

4vHPV vaccination has been tested in randomized controlled trials under almost ideal conditions, and studies of real‐life use have compared outcome between vaccinated and unvaccinated women from the same birth cohort and mostly before screening age. Here we present the first—to our knowledge—evaluation of the impact of the 4vHPV vaccination in real life without selection bias in the reported data. The study has been carried out by comparing the results after first cervical screening between an HPV‐vaccinated and an unvaccinated birth cohort, consisting of women born in Denmark in 1993 and 1983, respectively. Cytology data covering an 8‐year period, from the age of 15 (age of HPV‐vaccination) to age 23 (age of invitation to first cervical screening), were retrieved from the Danish National Pathology Register. Abnormal cytology, defined as atypical squamous cell of undetermined significance and worse (ASCUS+) was detected in 9.4% of women born in 1993 as compared with 9.0% of women born in 1983; RR = 1.04 (95% CI 0.96–1.12), p = .29. Detection of high‐grade squamous intraepithelial lesion (HSIL) was statistically significantly lower in the 1993 than in the 1983 cohort, RR = 0.6 (95% CI 0.5–0.7), p < .0001, while the opposite pattern was seen for ASCUS RR = 1.4 (95% CI 1.2–1.6), p < .0001. The decrease in HSIL means that more women can be spared referral for colposcopy and biopsy. The increase of ASCUS could be explained by transition from conventional to liquid‐based cytology, but this observation requires further monitoring.     

世界范围内9~26岁女性对HPV的认知现状及预防性HPV疫苗的应用现况

持续感染人乳头状瘤病毒(human papilloma virus,HPV)是宫颈癌发生的必要病因.目前HPV疫苗作为宫颈癌的一级预防措施正在全球范围内很多国家和地区实施.世界卫生组织(WHO)推荐9岁以上女性接种HPV疫苗,而9～26岁被认为是最佳接种年龄,很多国家也对接种年龄界定在9～26岁之间.2016年7月18日,HPV二价疫苗(HPV 16和18型)希瑞适(R)(Cervarix(R))获得中国食品药品监督管理局(CFDA)的上市许可,它适用于9～25岁女性,采用3剂免疫接种程序.而该人群对于HPV的认知以及疫苗接种的组织形式是影响HPV疫苗计划成功实施的重要因素.全文综述了国内外9～26岁女性关于HPV认知的现状及HPV疫苗应用现况,为将来在我国适龄人群中成功推广和接种预防性HPV疫苗提供参考依据.     

Cervical cancer in Africa,Latin America and the Caribbean and Asia: Regional inequalities and changing trends

The vast majority (86% or 453,000 cases) of the global burden of cervical cancer occurs in Africa, Latin America and the Caribbean and Asia, where one in nine new cancer cases are of the cervix. Although the disease has become rare in high‐resource settings (e.g., in North America, parts of Europe, Japan) that have historically invested in effective screening programs, the patterns and trends are variable elsewhere. While favourable incidence trends have been recorded in many populations in Asia and Latin America and the Caribbean in the past decades, rising rates have been observed in sub‐Saharan African countries, where high quality incidence series are available. The challenge for countries heavily affected by the disease in these regions is to ensure resource‐dependent programmes of screening and vaccination are implemented to transform the situation, so that accelerated declines in cervical cancer are not the preserve of high‐income countries, but become the norm in all populations worldwide.     

Eurogin Roadmap: Comparative epidemiology of HPV infection and associated cancers of the head and neck and cervix

The EUROGIN 2012 roadmap is focused on the comparative epidemiology of human papillomavirus (HPV) associated head and neck squamous cell cancers (HNSCC) and cervical cancers. Discussed are the similarities and differences between the two cancers with regard to global disease burden, HPV prevalence and type distribution, disease cofactors, molecular pathogenesis, treatment approaches, prognostic factors and primary and secondary prevention. The global incidence of HNSCC and cervical cancer is similar; however, a minority of HNSCC in comparison to virtually all cervical cancers is caused by HPV. HPV infection prevalence is considerably lower in the oral than genital regions for reasons that are as yet unclear. Infection at both sites is strongly associated with sexual behavior, but this association does not appear to explain the male predominance of oral HPV infection. Studies of the molecular pathogenesis of HPV‐associated HNSCC (predominantly oropharyngeal cancers) are hampered by the lack of a readily detectable intermediate clinical endpoint analogous to cervix intraepithelial neoplasia. Nevertheless, similarities in chromosomal aberrations, gene expression, methylation and microRNA profiles between HPV‐positive HNSCC and cervical cancer argue for shared carcinogenic pathways. Treatment approaches to oropharyngeal and cervical cancers are remarkably similar, with the development of HPV‐targeted therapies as the ultimate treatment goal. Key research challenges include understanding oral HPV transmission and male predominance, clarifying the role of cofactors, and developing new screening and treatment methods for HPV‐associated HNSCC.     

Cervical cancer control in Latin America: A call to action

Cervical cancer (CC) is second most common cause of cancer in Latin America and is a leading cause of cancer mortality among women. In 2015, an estimated 74,488 women will be diagnosed with CC in Latin America and 31,303 will die of the disease. CC mortality is projected to increase by 45% by 2030 despite human papillomavirus (HPV) vaccination and screening efforts. In this setting, the goal was of the current study was to examine CC control efforts in Latin America and identify deficiencies in these efforts that could be addressed to reduce CC incidence and mortality. The authors found that HPV vaccination has been introduced in the majority of Latin American countries, and there is now a need to monitor the success (or shortcomings) of these programs and to ensure that these programs are sustainable. This topic was also reviewed in light of emerging data demonstrating that visual inspection with acetic acid and HPV DNA testing without Papanicolaou tests have efficacy from a screening perspective and are good alternatives to cytology‐based screening programs. Overall, there is a need to build capacity for CC control in Latin America and the best strategy will depend on the country/region and must be tailored to meet the needs of the population as well as available resources. Cancer 2016;122:502–514. © 2015 American Cancer Society.     

Testing for human papillomavirus in cervical cancer screening: a review of indications and methodology

High‐risk human papillomavirus (hrHPV) testing has become an integral component of cervical cancer screening, given that persistent infection with hrHPV was recognized as a significant risk factor for most precancers and cancers of the cervix. Particularly, testing for hrHPV types (in conjunction with cervical cytology) has been approved for primary screening in women over 30 years of age and for cost‐effective triaging of equivocal cervical cytology results. HPV was a small double‐stranded DNA virus that cannot be cultured in vitro; so, different types of tests have been developed to detect its presence. Various molecular techniques were available for detecting the presence and/or quantity of hrHPV. In this review, the testing options for hrHPV and its surrogates, with an emphasis on those approved by the US Food and Drug Administration (FDA), were detailed. Cancer (Cancer Cytopathol) 2011;. © 2011 American Cancer Society.     

The predicted impact of vaccination on human papillomavirus infections in Australia

Vaccines based on human papillomavirus (HPV) 16 and 18 virus-like particles have the potential to prevent approximately 70% of cervical cancers. In Australia, public vaccination against HPV commenced in April 2007, and includes routine vaccination of females aged 12-13 years, and a 2-year school and GP-based catch-up in females aged 12-26 years. The objectives of this study were to estimate initial vaccination coverage rates, to describe current patterns of sexual behavior in young females, and to predict the impact of vaccination on HPV16 infections. We reviewed early coverage data, estimating that coverage in 2007/2008 will reach 86% (feasible range 67-90%) for 12- to 13-year-old girls, with lower rates attained in older females. A review of survey data found that the median age of first intercourse in Australian females is 16 years, with approximately 90% of women sexually active at 22 years. Using these data, we performed an analysis of HPV transmission to predict the impact of vaccination on HPV infection rates. The public program is predicted to result in a reduction in the age-standardized incidence of HPV16 infections of 56% by 2010 (feasible range 48-61%), and 92% by 2050 (feasible range 76-95%). Elective vaccination of older women and vaccination of males may provide some incremental gains, but the benefits to women of vaccinating males will be less if coverage of females remains high. In conclusion, the current vaccination program is expected to result in a substantial and rapid reduction in the incidence of HPV16 in Australia.     

Vulvar cancer in high‐income countries: Increasing burden of disease

The aim of this study was to assess trends in the age‐specific incidence of vulvar cancer in 13 high‐income countries satisfying a priori conditions regarding the availability of cancer registry data over a 20‐year period; these were Canada, the United States, nine European countries, Australia and Japan. Five‐yearly incidence and population at risk were obtained from the International Agency for Research on Cancer's Cancer Incidence in Five Continents for the years 1988–1992 (Volume 7) to 2003–2007 (Volume 10). The 5‐yearly average percent change (AvPC) over the period and standardised rate ratios (SRRs) for 2003–2007 versus 1988–1992 were used to assess changes in the age‐standardised incidence rates of vulvar cancer for all ages, and for <60 years and 60+ years. During the study period, the 5‐yearly AvPC across the 13 countries increased by 4.6% (p = 0.005) in women of all ages, and 11.6% (p = 0.02) in those <60 years. No change was observed in women aged 60+ years (5‐yearly AvPC = 0.1%, p = 0.94). The SRR for 2003–2007 versus 1988–1992 was significantly elevated in women <60 years of age (SRR = 1.38, 95% CI: 1.30–1.46), but not in women of 60+ years (SRR = 1.01, 95% CI: 0.97–1.05). The increase in incidence in women <60 years of age drove a significant increase in the overall SRR in women of all ages (SRR = 1.14, 95% CI: 1.11–1.18). Some differences in the specific findings at the individual country level were observed. The findings are consistent with changing sexual behaviours and increasing levels of exposure to human papillomavirus (HPV) in cohorts born around/after about 1950, but younger cohorts offered HPV vaccination are likely to receive some protection against developing vulvar cancer in the future.     

The road ahead for cervical cancer prevention and control

Since the early 1950s, Papanicolaou (“Pap”) cytology screening has dramatically reduced cervical cancer mortality in most high-income settings. Currently, human papillomavirus (hpv) vaccination has the greatest potential to reduce the global burden of cervical cancer and precancerous lesions. However, as the prevalence of precancerous lesions declines, maintaining cytology as the primary screening test in settings with established programs might become less efficient. A reduction in test performance (sensitivity, specificity, and positive predictive value) would lead to an increase in unnecessary colposcopy referrals. Fortunately, hpv dna testing has emerged as a suitable candidate to replace cytology. Compared with the Pap test, hpv testing is less specific but much more sensitive in detecting high-grade precancerous lesions, less prone to human error, and more reproducible across settings. Linkage of hpv vaccination and screening registries could serve the added role of monitoring vaccine efficacy. As a triage test, cytology is expected to perform with sufficient accuracy because most hpv-positive smears would contain relevant abnormalities. This approach and others—for example, hpv testing followed by genotyping—are being evaluated in large population studies and have already been recommended in some settings. Other specific biomarkers that might perform well for screening and triage include hpv E6/E7 messenger rna testing, methylation of host or viral genes, and p16^INK4a staining. Considering the rapid pace of major discoveries and the anticipated arrival of a nonavalent hpv vaccine (currently in phase iii trials), the evidence base in this field has become an elusive target and will continue to be an obstacle for policymakers.     

Multi-site study of HPV type-specific prevalence in women with cervical cancer, intraepithelial neoplasia and normal cytology, in England

Background:

Knowledge of the prevalence of type-specific human papillomavirus (HPV) infections is necessary to predict the expected, and to monitor the actual, impact of HPV immunisation and to design effective screening strategies for vaccinated populations.

Methods:

Residual specimens of cervical cytology (N=4719), CIN3/CGIN and cervical cancer biopsies (N=1515) were obtained from sites throughout England, anonymised and tested for HPV DNA using the Linear Array typing system (Roche).

Results:

The prevalence of HPV 16 and/or 18 (with or without another high-risk (HR) type) was 76% in squamous cell carcinomas, 82% in adeno/adenosquamous carcinomas and 63% and 91% in CIN3 and CGIN, respectively. Of all HR HPV-infected women undergoing cytology, non-vaccine HPV types only were found in over 60% of those with mild dyskaryosis or below, and in <20% of those with cancer. In women of all ages undergoing screening, HR HPV prevalence was 16% and HPV 16 and/or 18 prevalence was 5%.

Conclusion:

Pre-immunisation, high-grade cervical disease in England was predominantly associated with HPV 16 and/or 18, which promises a high impact from HPV immunisation in due course. Second-generation vaccines and screening strategies need to consider the best ways to detect and prevent disease due to the remaining HR HPV types.     

A novel mucosal orthotopic murine model of human papillomavirus‐associated genital cancers

Cervical cancer results from infection with high‐risk type human papillomaviruses (HPV). Therapeutic vaccines aiming at controlling existing genital HPV infections and associated lesions are usually tested in mice with HPV‐expressing tumor cells subcutaneously implanted into their flank. However, effective vaccine‐induced regression of these ectopic tumors strongly contrasts with the poor clinical results of these vaccines produced in patients with HPV‐associated genital neoplasia. To assess HPV therapeutic vaccines in a more relevant setting, we have, here, established an orthotopic mouse model where tumors in the genital mucosa (GM) develop after an intravaginal instillation of HPV16 E6/E7‐expressing tumor cells transduced with a luciferase‐encoding lentiviral vector for in vivo imaging of tumor growth. Tumor take was 80–90% after nonoxynol‐9 induced damage of the epithelium. Tumors remained localized in the genital tract, and histological analysis showed that most tumors grew within the squamous epithelium of the vaginal wall. Those tumors induced (i) E7‐specific CD8 T cells restricted to the GM and draining lymph nodes, in agreement with their mucosal location and (ii) high Foxp3+ CD4+ infiltrates, similarly to those found in natural non‐regressing HPV lesions. This novel genital HPV‐tumor model by requiring GM homing of vaccine‐induced immune responses able to overcome local immuno‐suppression may be more representative of the situation occurring in patients upon therapeutic vaccination.     

The role of miRNAs in human papilloma virus (HPV)-associated cancers: bridging between HPV-related head and neck cancer and cervical cancer

Background:

Although the role of human papilloma virus (HPV) in cervical squamous cell carcinoma (CSCC) is well established, the role in head and neck SCC (HNSCC) is less clear. MicroRNAs (miRNAs) have a role in the cancer development, and HPV status may affect the miRNA expression pattern in HNSCC. To explore the influence of HPV in HNSCC, we made a comparative miRNA profile of HPV-positive (HPV+) and HPV-negative (HPV−) HNSCC against CSCC.

Methods:

Fresh frozen and laser microdissected-paraffin-embedded samples obtained from patients with HPV+/HPV− HNSCC, CSCC and controls were used for microarray analysis. Differentially expressed miRNAs in the HPV+ and HPV− HNSCC samples were compared with the differentially expressed miRNAs in the CSCC samples.

Results:

Human papilloma virus positive (+) HNSCC had a distinct miRNA profile compared with HPV− HNSCC. Significantly more similarity was seen between HPV+ HNSCC and CSCC than HPV− and CSCC. A set of HPV core miRNAs were identified. Of these especially the miR-15a/miR-16/miR195/miR-497 family, miR-143/miR-145 and the miR-106-363 cluster appear to be important within the known HPV pathogenesis.

Conclusion:

This study adds new knowledge to the known pathogenic pathways of HPV and substantiates the oncogenic role of HPV in subsets of HNSCCs.