Human Papillomavirus and Related Diseases Report EUROPE

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1 Human Papillomavirus and Related Diseases Report EUROPE Version posted at on 27 July 217

2 - ii - Copyright and Permissions ICO Information Centre on HPV and Cancer (HPV Information Centre), 217. All rights reserved. HPV Information Centre publications can be obtained from the HPV Information Centre Secretariat, Institut Català d Oncologia, Avda. Gran Via de l Hospitalet, L Hospitalet del Llobregat (Barcelona) Spain. hpvcentre@iconcologia.net. Requests for permission to reproduce or translate HPV Information Centre publications - whether for sale or for noncommercial distribution- should be addressed to the HPV Information Centre Secretariat, at the above address. The designations employed and the presentation of the material in this publication do not imply the expression of any opinion whatsoever on the part the HPV Information Centre concerning the legal status of any country, territory, city or area or of its authorities, or concerning the delimitation of its frontiers or boundaries. Dotted lines on maps represent approximate border lines for which there may not yet be full agreement. The mention of specific companies or of certain manufacturers products does not imply that they are endorsed or recommended the HPV Information Centre in preference to others of a similar nature that are not mentioned. Errors and omissions excepted, the names of proprietary products are distinguished by initial capital letters. All reasonable precautions have been taken by the HPV Information Centre to verify the information contained in this publication. However, the published material is being distributed without warranty of any kind, either expressed or implied. The responsibility for the interpretation and use of the material lies with the reader. In no event shall the HPV Information Centre be liable for damages arising from its use. The development of this report has been supported by grants from the European Comission (7th Framework Programme grant HEALTH-F , HEALTH-F , HPV AHEAD). Recommended citation: Bruni L, Barrionuevo-Rosas L, Albero G, Serrano B, Mena M, Gómez D, Muñoz J, Bosch FX, de Sanjosé S. ICO Information Centre on HPV and Cancer (HPV Information Centre). Human Papillomavirus and Related Diseases in Europe. Summary Report 27 July 217. [Date Accessed]

3 - iii - Abbreviations Abbreviation HPV PREHDICT Project Table 1: Abbreviations Full term Human papillomavirus Health economic modelling of prevention strategies for HPV-related diseases in European countries ICO Information Centre on HPV and Cervical Cancer Genital warts Recurrent respiratory papillomatosis Squamous intraepithelial lesions Low-grade cervical lesions High-grade cervical lesions Invasive cervical cancer Carcinoma in situ Cervical intraepithelial neoplasia HPV Information Centre GW RRP SIL LSIL HSIL ICC CIS CIN AIN2/3 Anal intraepithelial neoplasia of grade 2 and/or 3 VIN 2/3 Vulvar intraepithelial neoplasia of grade 2 and/or 3 VaIN 2/3 Vaginal intraepithelial neoplasia of grade 2 and/or 3 PeIN 2/3 Penile intraepithelial neoplasia of grade 2 and/or 3 95% CI 95% confidence interval N Number of cases tested HPV Prev HPV prevalence ASR Age-standardised rate MSM Men who have sex with men Non MSM Heterosexual men SCC Squamous cell carcinomas STI Sexually transmitted infections HIV/AIDS Human immunodeficiency virus/acquired immunodeficiency syndrome TS Type specific EIA Enzyme immunoassay RLBM Reverse line blotting method RFLP Restriction fragment length polymorphism RHA Reverse hybridisation assay RLH Reverse line hybridisation LiPA Line probe assay SBH Southern blot hybridisation ISH In situ hybridisation MABA Micro array-based assay LBA Line blot assay HC2 Hybrid Capture 2 SAT Suspension array technology PCR Polymerase chain reaction SPF Short primer fragment q-pcr Quantitative polymerase chain reaction RLBH Reverse line blot hybridisation RT-PCR Real-time polymerase chain reaction DBH Dot blot hybridisation HR High risk DSA Direct sequence analysis MAA Microchip array assay

4 - iv - Executive summary Human papillomavirus (HPV) infection is now a well-established cause of cervical cancer and there is growing evidence of HPV being a relevant factor in other anogenital cancers (anus, vulva, vagina and penis) as well as head and neck cancers. HPV types 16 and 18 are responsible for about 7% of all cervical cancer cases worldwide. HPV vaccines that prevent HPV 16 and 18 infections are now available and have the potential to reduce the incidence of cervical and other anogenital cancers. This report provides key information for Europe on: cervical cancer; other anogenital cancers, and head and neck cancers; HPV-related statistics; factors contributing to cervical cancer; cervical cancer screening practises; HPV vaccine introduction, and other relevant immunization indicators. The report is intended to strengthen the guidance for health policy implementation of primary and secondary cervical cancer prevention strategies in the region. Europe has an estimated population of million women aged 15 years and older who are at risk of developing cervical cancer. Current estimates indicate that every year 58,373 women are diagnosed with cervical cancer and 24,44 die from the disease. Cervical cancer ranks as the sixth most frequent cancer among women in Europe. Ranking of cervical cancer incidence to other cancers among all women according to highest incidence rates (ranking 1st). Ranking is based on crude incidence rates (actual number of cervical cancer cases). Ranking using age-standardized rate (ASR) may differ. Population Table 2: Key statistics on Europe and its regions Women at risk for cervical cancer (Female population aged >=15 yrs) in millions Burden of cervical cancer Europe Eastern Europe Northern Europe Southern Europe Western Europe Annual number of new cervical cancer cases 58,373 33,882 5,382 9,285 9,824 Standardised incidence rates per 1, population Annual number of cervical cancer deaths 24,44 15,436 1,963 3,526 3,479 Standardised mortality rates per 1, population Burden of cervical HPV infection Prevalence (%) of HPV 16 and/or HPV 18 among women with: Normal cytology Low-grade cervical lesions (LSIL/CIN-1) High-grade cervical lesions (HSIL/ CIN-2 / CIN-3 / CIS) Cervical cancer LSIL, low-grade intraepithelial lesions; HSIL, high-grade intraepithelial lesions; CIN, cervical intraepithelial neoplasia; CIS, carcinoma in-situ. Please see the specific sections for more information.

5 LIST OF CONTENTS - v - Contents Abbreviations Executive summary iii iv 1 Introduction 1 2 Demographic and socioeconomic factors 3 3 Burden of HPV-related cancers Cervical cancer Incidence Mortality Comparison of incidence and mortality Anogenital cancers other than the cervix Anal cancer Vulvar cancer Vaginal cancer Penile cancer Head and neck cancers Pharyngeal cancer (excluding nasopharynx) HPV-related statistics HPV burden in women with normal cervical cytology, cervical precancerous lesions or invasive cervical cancer HPV prevalence in women with normal cervical cytology HPV type distribution among women with normal cervical cytology, precancerous cervical lesions and cervical cancer HPV type distribution among HIV+ women with normal cervical cytology Terminology HPV burden in anogenital cancers other than the cervix Anal cancer and precancerous anal lesions Vulvar cancer and precancerous vulvar lesions Vaginal cancer and precancerous vaginal lesions Penile cancer and precancerous penile lesions HPV burden in men HPV burden in the head and neck Burden of oral HPV infection in healthy population HPV burden in head and neck cancers Factors contributing to cervical cancer Sexual behaviour and reproductive health indicators HPV preventive strategies Cervical cancer screening practices HPV vaccination HPV vaccine licensure and introduction Protective factors for cervical cancer References Glossary 22

6 LIST OF FIGURES - vi - List of Figures 1 European regions Population pyramid of Europe Population trends in four selected age groups in Europe for Age-standardised incidence rates (ASR) of cervical cancer in regions of Europe (estimates for 212) Age-standardised incidence rates of cervical cancer in Europe (estimates for 212) Age-standardised incidence rate of cervical cancer cases attributable to HPV by country in Europe (estimates for 212) Ranking of cervical cancer versus other cancers among all women and women aged years, according to incidence rates in Europe (estimates for 212) Comparison of the ten most frequent cancers in all women in Europe and its regions (estimates for 212) Comparison of the ten most frequent cancers in women aged years by Europe and its regions (estimates for 212) Age-specific incidence of cervical cancer in Europe and its regions (estimates for 212) Annual number of new cases of cervical cancer by age group in European regions (estimates for 212) Annual number of cases and age-specific incidence rates of cervical cancer in Europe and its regions (estimates for 212) Annual number of cases and age-specific incidence rates of cervical cancer in Europe and its regions (estimates for 212) (Continued) Time trends in cervical cancer incidence type in Austria (cancer registry data) Time trends in cervical cancer incidence type in Switzerland (cancer registry data) Time trends in cervical cancer incidence type in Spain (cancer registry data) Time trends in cervical cancer incidence type in France (cancer registry data) Time trends in cervical cancer incidence type in the United Kingdom (cancer registry data) Time trends in cervical cancer incidence type in Italy (cancer registry data) Time trends in cervical cancer incidence type in Poland (cancer registry data) Time trends in cervical cancer incidence type in the Russian Federation (cancer registry data) Age-standardised mortality rates (ASR) of cervical cancer in European regions (estimates for 212) Age-standardised mortality rates of cervical cancer in Europe (estimates for 212) Ranking of cervical cancer versus other cancers among all women and women aged years, according to mortality rates in Europe (estimates for 212) Comparison of the ten most frequent cancer deaths in women aged years in Europe and its regions (estimates for 212) Comparison of the ten most frequent cancer deaths in women of all ages in Europe and its regions (estimates for 212) Age-specific mortality of cervical cancer in Europe and its regions (estimates for 212) Annual number of deaths of cervical cancer by age group in European regions (estimates for 212) Annual number of deaths and age-specific mortality rates of cervical cancer in Europe and its regions (estimates for 212) Annual number of deaths and age-specific mortality rates of cervical cancer in Europe and its regions (estimates for 212) (Continued) Age-specific incidence and mortality rates of cervical cancer in Europe and its regions (estimates for 212) Age-standardised incidence rates of anogenital cancers other than the cervix in Europe (estimates for 212) Age-standardised incidence rate of other anogenital cancer cases attributable to HPV by country in Europe (estimates for 212) Time trends in anal cancer incidence in Austria (cancer registry data) Time trends in anal cancer incidence in Croatia (cancer registry data) Time trends in anal cancer incidence in Denmark (cancer registry data) Time trends in anal cancer incidence in Estonia (cancer registry data) Time trends in anal cancer incidence in France (cancer registry data) Time trends in anal cancer incidence in Iceland (cancer registry data) Time trends in anal cancer incidence in Italy (cancer registry data) Time trends in anal cancer incidence in the Netherlands (cancer registry data) Time trends in anal cancer incidence in Poland (cancer registry data) Time trends in anal cancer incidence in the Russian Federation (cancer registry data) Time trends in anal cancer incidence in Slovakia (cancer registry data) Time trends in anal cancer incidence in Spain (cancer registry data) Time trends in anal cancer incidence in Switzerland (cancer registry data) Time trends in anal cancer incidence in the United Kingdom (cancer registry data) Time trends in vulvar cancer incidence in Austria (cancer registry data) Time trends in vulvar cancer incidence in Croatia (cancer registry data) Time trends in vulvar cancer incidence in Denmark (cancer registry data) Time trends in vulvar cancer incidence in Estonia (cancer registry data) Time trends in vulvar cancer incidence in France (cancer registry data)

7 LIST OF FIGURES - vii - 53 Time trends in vulvar cancer incidence in Iceland (cancer registry data) Time trends in vulvar cancer incidence in Italy (cancer registry data) Time trends in vulvar cancer incidence in Netherlands (cancer registry data) Time trends in vulvar cancer incidence in Poland (cancer registry data) Time trends in vulvar cancer incidence in Russian Federation (cancer registry data) Time trends in vulvar cancer incidence in Slovakia (cancer registry data) Time trends in vulvar cancer incidence in Spain (cancer registry data) Time trends in vulvar cancer incidence in Switzerland (cancer registry data) Time trends in vulvar cancer incidence in United Kingdom (cancer registry data) Time trends in vaginal cancer incidence in Austria (cancer registry data) Time trends in vaginal cancer incidence in Croatia (cancer registry data) Time trends in vaginal cancer incidence in Denmark (cancer registry data) Time trends in vaginal cancer incidence in Estonia (cancer registry data) Time trends in vaginal cancer incidence in France (cancer registry data) Time trends in vaginal cancer incidence in Iceland (cancer registry data) Time trends in vaginal cancer incidence in Italy (cancer registry data) Time trends in vaginal cancer incidence in Netherlands (cancer registry data) Time trends in vaginal cancer incidence in Poland (cancer registry data) Time trends in vaginal cancer incidence in Russian Federation (cancer registry data) Time trends in vaginal cancer incidence in Slovakia (cancer registry data) Time trends in vaginal cancer incidence in Spain (cancer registry data) Time trends in vaginal cancer incidence in Switzerland (cancer registry data) Time trends in vaginal cancer incidence in United Kingdom (cancer registry data) Time trends in penile cancer incidence in Austria (cancer registry data) Time trends in penile cancer incidence in Croatia (cancer registry data) Time trends in penile cancer incidence in Denmark (cancer registry data) Time trends in penile cancer incidence in Estonia (cancer registry data) Time trends in penile cancer incidence in France (cancer registry data) Time trends in penile cancer incidence in Iceland (cancer registry data) Time trends in penile cancer incidence in Italy (cancer registry data) Time trends in penile cancer incidence in Netherlands (cancer registry data) Time trends in penile cancer incidence in Poland (cancer registry data) Time trends in penile cancer incidence in Russian Federation (cancer registry data) Time trends in penile cancer incidence in Slovakia (cancer registry data) Time trends in penile cancer incidence in Spain (cancer registry data) Time trends in penile cancer incidence in Switzerland (cancer registry data) Time trends in penile cancer incidence in United Kingdom (cancer registry data) Age-standardised incidence rates of head and neck cancer in Europe (estimates for 212) Age-standardised incidence rate of head and neck cancer cases attributable to HPV by country in Europe (estimates for 212) Comparison of cancer incidence and mortality of pharynx (excluding nasopharynx) in males by age group in Europe and its regions. Includes ICD-1 codes: C9-1,C12-14 (estimates for 212) Comparison of cancer incidence and mortality of pharynx (excluding nasopharynx) in females by age group in Europe and its regions. Includes ICD-1 codes: C9-1,C12-14 (estimates for 212) Prevalence of HPV among women with normal cervical cytology in Europe Crude age-specific HPV prevalence (%) and 95% confidence interval in women with normal cervical cytology in Europe and its regions Prevalence of HPV among women with normal cervical cytology in Europe by country and study Prevalence of HPV among women with normal cervical cytology in Europe by country and study (continued) Prevalence of HPV among women with normal cervical cytology in Europe by country and study (continued) Prevalence of HPV among women with normal cervical cytology in Europe by country and study (continued) Prevalence of HPV 16 among women with normal cervical cytology in Europe by country and study Prevalence of HPV 16 among women with normal cervical cytology in Europe by country and study (continued) Prevalence of HPV 16 among women with low-grade cervical lesions in Europe by country and study Prevalence of HPV 16 among women with low-grade cervical lesions in Europe by country and study (continued) Prevalence of HPV 16 among women with low-grade cervical lesions in Europe by country and study (continued) Prevalence of HPV 16 among women with high-grade cervical lesions in Europe by country and study Prevalence of HPV 16 among women with high-grade cervical lesions in Europe by country and study (continued) Prevalence of HPV 16 among women with high-grade cervical lesions in Europe by country and study (continued) Prevalence of HPV 16 among women with invasive cervical cancer in Europe by country and study Prevalence of HPV 16 among women with invasive cervical cancer in Europe by country and study (continued) Prevalence of HPV 16 among women with invasive cervical cancer in Europe by country and study (continued) Comparison of the ten most frequent HPV oncogenic types among women with and without cervical lesions in Europe and its regions

8 LIST OF FIGURES - viii Comparison of the ten most frequent HPV oncogenic types among women with and without cervical lesions in Europe and its regions (continued) Comparison of the ten most frequent HPV oncogenic types among women with invasive cervical cancer by histology in Europe and its regions Comparison of the ten most frequent HPV oncogenic types among women with invasive cervical cancer by histology in Europe and its regions (continued) Comparison of the ten most frequent HPV types in anal cancer cases in Europe and the World Comparison of the ten most frequent HPV types in AIN 2/3 cases in Europe and the World Comparison of the ten most frequent HPV types in cases of vulvar cancer in Europe and the World Comparison of the ten most frequent HPV types in VIN 2/3 cases in Europe and the World Comparison of the ten most frequent HPV types in vaginal cancer cases in Europe and the World Comparison of the ten most frequent HPV types in VaIN 2/3 cases in Europe and the World Comparison of the ten most frequent HPV types in penile cancer cases in Europe and the World Comparison of the ten most frequent HPV types in PeIN 2/3 cases in Europe and the World Prevalence of female tobacco smoking in Europe Total fertility rates in Europe Prevalence of hormonal contraceptive use in Europe Prevalence of HIV in Europe Percentage of 15-year-old girls who report sexual intercourse in Europe Percentage of 15-year-old boys who report sexual intercourse in Europe Status of HPV vaccination programmes in Europe Prevalence of male circumcision in Europe Prevalence of condom use in Europe

9 LIST OF TABLES - ix - List of Tables 1 Abbreviations iii 2 Key statistics on Europe and its regions iv 3 Population (in millions) estimates in Europe for Sociodemographic indicators in Europe Incidence of cervical cancer in Europe (estimates for 212) Cervical cancer mortality in Europe (estimates for 212) Incidence of anal cancer in Europe by cancer registry and sex Incidence of vulvar cancer in Europe by cancer registry Incidence of vaginal cancer in Europe by cancer registry Incidence of penile cancer in Europe by cancer registry Cancer incidence of pharynx (excluding nasopharynx) in Europe and its regions by sex. Includes ICD-1 codes: C9-1, C12-14 (estimates for 212) Cancer mortality of pharynx (excluding nasopharynx) in Europe and its regions by sex. Includes ICD-1 codes: C9-1, C12-14 (estimates for 212) Prevalence of HPV 16/18 in women with normal cytology, precancerous cervical lesions and invasive cervical cancer in Europe Type-specific HPV prevalence in women with normal cervical cytology, precancerous cervical lesions and invasive cervical cancer in Europe Type-specific HPV prevalence among invasive cervical cancer cases in Europe by histology European studies on HPV prevalence among HIV women with normal cytology European studies on HPV prevalence among anal cancer cases (male and female) European studies on HPV prevalence among AIN 2/3 cases (male and female) European studies on HPV prevalence among vulvar cancer cases European studies on HPV prevalence among VIN 2/3 cases European studies on HPV prevalence among vaginal cancer cases European studies on HPV prevalence among VaIN 2/3 cases European studies on HPV prevalence among penile cancer cases European studies on HPV prevalence among PeIN 2/3 cases European studies on anogenital HPV prevalence among men European studies on anogenital HPV prevalence among men from special subgroups European studies on oral HPV prevalence among healthy population European studies on HPV prevalence among cases of oral cavity cancer European studies on HPV prevalence in cases of oropharyngeal cancer European studies on HPV prevalence in cases of hypopharyngeal or laryngeal cancer Median age at first sex in Europe Average number of sexual partners in Europe Lifetime prevalence of anal intercourse among women in Europe Cervical cancer screening policies in Europe HPV vaccination policies for the female population in Europe References of studies included Glossary

10 1 INTRODUCTION Introduction Figure 1: European regions The HPV Information Centre aims to compile and centralise updated data and statistics on human papillomavirus (HPV) and HPV-related cancers. This report aims to summarise the data available to fully evaluate the burden of disease in Europe and to facilitate stakeholders and relevant bodies of decision makers to formulate recommendations on the prevention of cervical cancer and other HPV-related cancers. Data include relevant cancer statistic estimates, epidemiological determinants of cervical cancer such as demographics, socioeconomic factors, risk factors, burden of HPV infection in women and men, and cervical screening and immunisation practises. The report is structured into the following sections: Section 2, Demographic and socioeconomic factors. This section summarises the sociodemographic profile of Europe. For analytical purposes, Europe is divided into four regions: Eastern Europe, Northern Europe, Southern Europe, Western Europe (Figure 1). Section 3, Burden of HPV-related cancers. This section describes the current burden of invasive cervical cancer and other HPV-related cancers in Europe with estimates of prevalence, incidence and mortality rates. Section 4, HPV-related statistics. This section summarises reports on prevalence of HPV and HPV type-specific distribution in women with normal cytology, women with precancerous lesions and invasive cervical cancer. In addition, the burden of HPV in other anogenital cancers (anus, vulva, vagina, and penis) is presented. Section 5, Factors contributing to cervical cancer. This section describes factors that can modify the natural history of HPV and cervical carcinogenesis such as the use of smoking, parity, oral contraceptive use and co-infection with HIV. Section 6, Sexual behaviour and reproductive health indicators. This section presents sexual

11 1 INTRODUCTION and reproductive behaviour indicators that may be used as proxy measures of risk for HPV infection and anogenital cancers. Section 7, HPV preventive strategies. This section presents preventive strategies that include basic characteristics and performance of cervical cancer screening status, status of HPV vaccine licensure introduction, and recommendations in national immunisation programmes. Section 8, Protective factors for cervical cancer. This section presents the prevalence of male circumcision and condom use.

12 2 DEMOGRAPHIC AND SOCIOECONOMIC FACTORS Demographic and socioeconomic factors Table 3: Population (in millions) estimates in Europe for 217 Region / Country Male Female 1-14 years 15+ years Total 1-14 years 15+ years Total Europe 1,± Eastern Europe 1,± Belarus 1,± Bulgaria 1,± Czech Rep. 1,± Hungary 1,± Moldova 1,a,± Poland 1,± Romania 1,± Russia 1,± Slovakia 1,± Ukraine 1,b,± Northern Europe 1,c,± Denmark 1,± Estonia 1,± Finland 1,d,± Iceland 1,± Ireland 1,± Latvia 1,± Lithuania 1,± Norway 1,e,± Sweden 1,± UK 1,± Southern Europe 1,f,± Albania Andorra 2,± Bosnia & H. 1,± Croatia 1,± Cyprus 1,g,h,± Greece 1,± Italy 1,± Macedonia 1,i,± Malta 1,± Montenegro 1,± Portugal 1,± San Marino 2,± Serbia 1, j,± Slovenia 1,± Spain 1,k,± Western Europe 1,l,± Austria 1,± Belgium 1,± France 1,± Germany 1,± Liechtenstein 2,± Luxembourg 1,± Monaco 2,± Netherlands 1,± Switzerland 1,± Data accessed on 27 Mar 217. Please refer to original source for methods of estimation. a Including Transnistria. b Including Crimea c Including Faeroe Islands, and Isle of Man. d Including Åland Islands. e Including Svalbard and Jan Mayen Islands. f Including Andorra, Gibraltar, Holy See, and San Marino. g Including Northern-Cyprus. h Refers to the whole country i The former Yugoslav Republic of Macedonia. j Including Kosovo. k Including Canary Islands, Ceuta and Melilla. l Including Liechtenstein, and Monaco. Year of estimate: ± 217; Data sources: 1 United Nations, Department of Economic and Social Affairs, Population Division (215). World Population Prospects: The 215 Revision, DVD Edition. Available at: org/unpd/wpp/download/standard/population/. [Accessed on March 21, 217]. (Continued on next page)

13 2 DEMOGRAPHIC AND SOCIOECONOMIC FACTORS ( Table 3 continued from previous page) 2 International Programs Center for Demographic and Economic Studies, Population Division, U.S. Census Bureau. International Database. Available at population/international/data/idb/informationgateway.php. [Accessed on March 21, 217]. Figure 2: Population pyramid of Europe Males Females Under 5 12,889,798 24,231,287 1,62,55 15,671,83 13,496,265 17,22,632 18,44,73 22,28,14 22,77,975 25,657,11 24,99,128 27,25,652 26,42,45 27,3,161 25,487,419 26,81,991 25,656,41 25,985,629 25,864,557 25,816,18 26,41,886 25,9,782 24,774,54 24,18,695 2,92,742 2,28,642 18,874,728 17,966,348 19,424,445 18,479,13 2,575,143 19,537,521 2,272,989 19,178,526 Population (in thousands) in Europe by sex and age group Data accessed on 27 Mar 217. Please refer to original source for methods of estimation. Year of estimate: 217; Data sources: United Nations, Department of Economic and Social Affairs, Population Division (215). World Population Prospects: The 215 Revision, DVD Edition. Available at: unpd/wpp/download/standard/population/. [Accessed on March 21, 217]. Number of women (in millions) Figure 3: Population trends in four selected age groups in Europe for 217 Projections Women yrs Girls 1 14 yrs Number of women (in millions) Projections 4 All Women Women yrs Female population trends in Europe Number of women by year and age group Data accessed on 27 Mar 217. Please refer to original source for methods of estimation. Year of estimate: 217; Data sources: United Nations, Department of Economic and Social Affairs, Population Division (215). World Population Prospects: The 215 Revision, DVD Edition. Available at: unpd/wpp/download/standard/population/. [Accessed on March 21, 217].

14 2 DEMOGRAPHIC AND SOCIOECONOMIC FACTORS Table 4: Sociodemographic indicators in Europe Indicator Male Female Total Population in thousands 1,± 356, , ,27.7 Population growth rate (%) 1, Median age of the population (in years) 1, Population living in urban areas (%) 2, Crude birth rate (births per 1,) 1, Crude death rate (deaths per 1,) 1, Life expectancy at birth (in years) 3,a,b Adult mortality rate (probability of dying between 15 and 6 years old per 1,) 4 Under age five mortality rate (per 1, live births) 3,c Density of physicians (per 1, population) 5,d Gross national income per capita (PPP current international $) 6,e Adult literacy rate (%) (aged 15 and older) 7, Youth literacy rate (%) (aged years) 7, Net primary school enrollment ratio 7, Net secondary school enrollment ratio 7,f, Data accessed on 27 Mar 217. Please refer to original source for methods of estimation. a World Population Prospects, the 215 revision (WPP215). New York (NY): United Nations DESA, Population Division. b WHO annual life tables for based on the WPP215, on the data held in the WHO Mortality Database and on HIV mortality estimates prepared by UNAIDS. WHO Member States with a population of less than 9 in 215 were not included in the analysis. c Levels & Trends in Child Mortality. Report 215. Estimates Developed by the UN Inter-agency Group for Child Mortality Estimation. New York (NY), Geneva and Washington (DC): United Nations Children s Fund, World Health Organization, World Bank and United Nations; 215 ( Web_9_Sept_15.pdf, accessed 26 March 216). d Number of medical doctors (physicians), including generalist and specialist medical practitioners, per 1 population. e GNI per capita based on purchasing power parity (PPP). PPP GNI is gross national income (GNI) converted to international dollars using purchasing power parity rates. An international dollar has the same purchasing power over GNI as a U.S. dollar has in the United States. GNI is the sum of value added by all resident producers plus any product taxes (less subsidies) not included in the valuation of output plus net receipts of primary income (compensation of employees and property income) from abroad. Data are in current international dollars based on the 211 ICP round. f UIS Estimation Year of estimate: ± 217; ; 215; 214; Data sources: 1 United Nations, Department of Economic and Social Affairs, Population Division (215). World Population Prospects: The 215 Revision, DVD Edition. Available at: org/unpd/wpp/download/standard/population/. [Accessed on March 21, 217]. 2 United Nations, Department of Economic and Social Affairs, Population Division (214). World Urbanization Prospects: The 214 Revision, CD-ROM Edition. Available at: https: //esa.un.org/unpd/wup/cd-rom/. [Accessed on March 21, 217]. 3 World Health Statistics 216. Geneva, World Health Organization, 216. Available at: html. [Accessed on March 21, 217]. 4 World Health Organization. Global Health Observatory data repository. Available at: [Accessed on March 21, 217]. 5 The 216 update, Global Health Workforce Statistics, World Health Organization, Geneva ( [Accessed on March 21, 217]. 6 World Bank, World Development Indicators Database. Washington, DC. International Comparison Program database. Available at: aspx?source=world-development-indicators#. [Accessed on March 21, 217]. 7 UNESCO Institute for Statistics Data Centre [online database]. Montreal, UNESCO Institute for Statistics. Available at: [Accessed on March 21, 217].

15 3 BURDEN OF HPV-RELATED CANCERS Burden of HPV-related cancers 3.1 Cervical cancer Cancer of the cervix uteri is the 4th most common cancer among women worldwide, with an estimated 527,624 new cases and 265,672 deaths in 212 (GLOBOCAN). The majority of cases are squamous cell carcinoma followed by adenocarcinomas. (Vaccine 26, Vol. 24, Suppl 3; Vaccine 28, Vol. 26, Suppl 1; Vaccine 212, Vol. 3, Suppl 5; IARC Monographs 27, Vol. 9) This section describes the current burden of invasive cervical cancer in Europe and its regions with estimates of the annual number of new cases, deaths, incidence and mortality Incidence KEY STATS. About 58,373 new cervical cancer cases are diagnosed annually in Europe (estimates for 212). Cervical cancer ranks as the 6 th leading cause of female cancer in Europe. Cervical cancer is the 2 nd most common female cancer in women aged 15 to 44 years in Europe. Ranking of cervical cancer incidence to other cancers among all women according to highest incidence rates (ranking 1st). Ranking is based on crude incidence rates (actual number of cervical cancer cases). Ranking using age-standardized rate (ASR) may differ. Figure 4: Age-standardised incidence rates (ASR) of cervical cancer in regions of Europe (estimates for 212) Eastern Europe 16.3 Northern Europe 8.7 Southern Europe 8.5 Data accessed on 15 Nov 215. Western Europe Cervical cancer: Age standardised mortality rate per 1, women World Standard. Female (All ages) (Continued on next page)

16 3 BURDEN OF HPV-RELATED CANCERS ( Figure 4 continued from previous page) Rates per 1, women per year. Data sources: Ferlay J, Soerjomataram I, Ervik M, Dikshit R, Eser S, Mathers C, Rebelo M, Parkin DM, Forman D, Bray F. GLOBOCAN 212 v1.2, Cancer Incidence and Mortality Worldwide: IARC CancerBase No. 11 [Internet]. Lyon, France: International Agency for Research on Cancer; 213. Available from: Figure 5: Age-standardised incidence rates of cervical cancer in Europe (estimates for 212) Data accessed on 15 Nov 215. Rates per 1, women per year. Data sources: Ferlay J, Soerjomataram I, Ervik M, Dikshit R, Eser S, Mathers C, Rebelo M, Parkin DM, Forman D, Bray F. GLOBOCAN 212 v1.2, Cancer Incidence and Mortality Worldwide: IARC CancerBase No. 11 [Internet]. Lyon, France: International Agency for Research on Cancer; 213. Available from:

17 3 BURDEN OF HPV-RELATED CANCERS Figure 6: Age-standardised incidence rate of cervical cancer cases attributable to HPV by country in Europe (estimates for 212) Romania Lithuania Bulgaria Serbia Montenegro Estonia Moldova Hungary Latvia Ukraine Slovakia Russia Czech Rep. Bosnia & H. Ireland Belarus Macedonia Poland Denmark Slovenia Croatia Norway Portugal Belgium Germany Iceland Spain Sweden UK Netherlands France Italy Austria Greece Albania Luxembourg Finland Cyprus Malta Switzerland San Marino Monaco Liechtenstein Andorra Cervical cancer: Age standardised incidence rate per 1, women World Standard. Female (All ages) No rates are available. Data accessed on 15 Nov 215. Rates per 1, women per year. Data sources: Ferlay J, Soerjomataram I, Ervik M, Dikshit R, Eser S, Mathers C, Rebelo M, Parkin DM, Forman D, Bray F. GLOBOCAN 212 v1.2, Cancer Incidence and Mortality Worldwide: IARC CancerBase No. 11 [Internet]. Lyon, France: International Agency for Research on Cancer; 213. Available from:

18 3 BURDEN OF HPV-RELATED CANCERS Table 5: Incidence of cervical cancer in Europe (estimates for 212) Cumulative risk (%) Ranking of CC Area N cases Crude rate a ASR a ages -74 years b All women Women years Europe 58, Eastern Europe 33, Belarus Bulgaria 1, Czech Republic 1, Hungary 1, Poland 3, Republic of Moldova Romania 4, Russian Federation 15, Slovakia Ukraine 5, Northern Europe 5, Denmark Estonia Finland Iceland Ireland Latvia Lithuania Norway Sweden United Kingdom 2, Southern Europe 9, Albania Andorra Bosnia & Herzegovina Croatia Cyprus Greece Italy 2, Macedonia Malta Montenegro Portugal San Marino Serbia 1, Slovenia Spain 2, Western Europe 9, Austria Belgium France 2, Germany 4, Luxembourg Monaco Netherlands Switzerland Data accessed on 15 Nov 215. ASR: Age-standardized rate, Standardized rates have been estimated using the direct method and the World population as the reference; Standardised rates have ben estimated using the direct method and the World population as the reference. Ranking of cervical cancer incidence to other cancers among all women ages years according to highest incidence rates (ranking 1st). Ranking is based on crude incidence rates (actual number of cervical cancer cases). Ranking using ASR may differ. a Rates per 1, women per year. b Cumulative risk (incidence) is the probability or risk of individuals getting from the disease during ages -74 years. For cancer, it is expressed as the % of new born children who would be expected to develop from a particular cancer before the age of 75 if they had the rates of cancer observed in the period in the absence of competing causes. Data sources: Ferlay J, Soerjomataram I, Ervik M, Dikshit R, Eser S, Mathers C, Rebelo M, Parkin DM, Forman D, Bray F. GLOBOCAN 212 v1.2, Cancer Incidence and Mortality Worldwide: IARC CancerBase No. 11 [Internet]. Lyon, France: International Agency for Research on Cancer; 213. Available from:

19 3 BURDEN OF HPV-RELATED CANCERS Figure 7: Ranking of cervical cancer versus other cancers among all women and women aged years, according to incidence rates in Europe (estimates for 212) Data accessed on 15 Nov 215. Data sources: Ferlay J, Soerjomataram I, Ervik M, Dikshit R, Eser S, Mathers C, Rebelo M, Parkin DM, Forman D, Bray F. GLOBOCAN 212 v1.2, Cancer Incidence and Mortality Worldwide: IARC CancerBase No. 11 [Internet]. Lyon, France: International Agency for Research on Cancer; 213. Available from:

20 3 BURDEN OF HPV-RELATED CANCERS Figure 8: Comparison of the ten most frequent cancers in all women in Europe and its regions (estimates for 212) Europe Southern Europe Breast 69.9 Breast 74.5 Colorectum(a) 23.6 Colorectum(a) 24.1 Lung 15.1 Corpus uteri 12.9 Corpus uteri 13.9 Lung 12.8 Cervix uteri 11.4 Ovary 9.1 Ovary 9.9 Thyroid 8.6 Melanoma of skin 8.9 Cervix uteri 8.5 Thyroid 7.8 Melanoma of skin 8.3 Stomach 6.4 Non Hodgkin lymphoma(b) 6.6 Non Hodgkin lymphoma(b) 5.9 Stomach Eastern Europe Western Europe Breast 47.7 Breast 91.1 Colorectum(a) 21.7 Colorectum(a) 24.9 Cervix uteri 16.3 Lung 2. Corpus uteri 15.6 Melanoma of skin 12.8 Ovary 11.4 Corpus uteri 11.6 Lung 1.4 Thyroid 8.8 Stomach 8.9 Non Hodgkin lymphoma(b) 7.7 Thyroid 7.4 Ovary 7.5 Kidney 6.1 Cervix uteri 7.3 Leukaemia 5.1 Kidney Northern Europe Breast 89.4 Colorectum(a) Lung Melanoma of skin Corpus uteri Ovary Cervix uteri Non Hodgkin lymphoma(b) Leukaemia Pancreas Age standardised incidence rate per 1, women in Europe Data accessed on 15 Nov 215. a Includes anal cancer (C21). b Includes HIV disease resulting in malignant neoplasms (B21). Data sources: (Continued on next page)

21 3 BURDEN OF HPV-RELATED CANCERS ( Figure 8 continued from previous page) Ferlay J, Soerjomataram I, Ervik M, Dikshit R, Eser S, Mathers C, Rebelo M, Parkin DM, Forman D, Bray F. GLOBOCAN 212 v1.2, Cancer Incidence and Mortality Worldwide: IARC CancerBase No. 11 [Internet]. Lyon, France: International Agency for Research on Cancer; 213. Available from:

22 3 BURDEN OF HPV-RELATED CANCERS Figure 9: Comparison of the ten most frequent cancers in women aged years by Europe and its regions (estimates for 212) Europe Southern Europe Breast 35. Breast 47.1 Cervix uteri 13.2 Cervix uteri 9.3 Melanoma of skin 8. Melanoma of skin 8.7 Thyroid 7.3 Ovary 5.1 Ovary 5.1 Thyroid 5.1 Colorectum(a) 3.8 Colorectum(a) 4.5 Hodgkin lymphoma 3.2 Non Hodgkin lymphoma(b) 3.4 Brain, nervous system 2.8 Hodgkin lymphoma 3.1 Corpus uteri 2.5 Brain, nervous system 2.6 Non Hodgkin lymphoma(b) 2.5 Lung Eastern Europe Western Europe Breast 21.6 Breast 46.6 Cervix uteri 17.6 Melanoma of skin 12.9 Thyroid 6.8 Thyroid 1.4 Ovary 6.5 Cervix uteri 9. Corpus uteri 3.4 Colorectum(a) 4.5 Hodgkin lymphoma 3.1 Lung 4.3 Melanoma of skin 3.1 Hodgkin lymphoma 3.5 Colorectum(a) 3. Non Hodgkin lymphoma(b) 2.8 Brain, nervous system 2.9 Ovary 2.8 Non Hodgkin lymphoma(b) 1.9 Brain, nervous system Northern Europe Breast 38.8 Melanoma of skin Cervix uteri Thyroid Ovary Colorectum(a) Brain, nervous system Hodgkin lymphoma Non Hodgkin lymphoma(b) Leukaemia Age standardised incidence rate per 1, women in Europe Data accessed on 15 Nov 215. a Includes anal cancer (C21). b Includes HIV disease resulting in malignant neoplasms (B21). Data sources: (Continued on next page)

23 3 BURDEN OF HPV-RELATED CANCERS ( Figure 9 continued from previous page) Ferlay J, Soerjomataram I, Ervik M, Dikshit R, Eser S, Mathers C, Rebelo M, Parkin DM, Forman D, Bray F. GLOBOCAN 212 v1.2, Cancer Incidence and Mortality Worldwide: IARC CancerBase No. 11 [Internet]. Lyon, France: International Agency for Research on Cancer; 213. Available from: Figure 1: Age-specific incidence of cervical cancer in Europe and its regions (estimates for 212) Age specific incidence rates of cervical cancer per 1, Europe Eastern Europe Northern Europe Southern Europe Western Europe >=75 Data accessed on 15 Nov 215. Rates per 1, women per year. Data sources: Ferlay J, Soerjomataram I, Ervik M, Dikshit R, Eser S, Mathers C, Rebelo M, Parkin DM, Forman D, Bray F. GLOBOCAN 212 v1.2, Cancer Incidence and Mortality Worldwide: IARC CancerBase No. 11 [Internet]. Lyon, France: International Agency for Research on Cancer; 213. Available from:

24 3 BURDEN OF HPV-RELATED CANCERS Figure 11: Annual number of new cases of cervical cancer by age group in European regions (estimates for 212) Eastern Europe Southern Europe Western Europe Northern Europe Annual number of new cases of cervical cancer 35, 31,5 28, 24,5 21, 17,5 14, 1,5 7, 3,5 32,345 13,249 12, Eastern Europe years: 7,668 cases years: 19,618 cases. 65+ years: 6,595 cases. Southern Europe years: 1,765 cases years: 5,243 cases. 65+ years: 2,274 cases. Western Europe years: 2, cases years: 5,4 cases. 65+ years: 2,82 cases. Northern Europe years: 1,816 cases years: 2,48 cases. 65+ years: 1,86 cases. Data accessed on 15 Nov 215. Data sources: Ferlay J, Soerjomataram I, Ervik M, Dikshit R, Eser S, Mathers C, Rebelo M, Parkin DM, Forman D, Bray F. GLOBOCAN 212 v1.2, Cancer Incidence and Mortality Worldwide: IARC CancerBase No. 11 [Internet]. Lyon, France: International Agency for Research on Cancer; 213. Available from:

25 3 BURDEN OF HPV-RELATED CANCERS Figure 12: Annual number of cases and age-specific incidence rates of cervical cancer in Europe and its regions (estimates for 212) Europe 4 Age specific rates of cervical cancer(a) ,5 32,345 3, 27,5 25, Annual number of cases of cervical cancer 22,5 2, 17,5 15, 12,5 13,242 12,775 1, 7,5 5, 2, Europe yrs: 22 cases yrs: 798 cases yrs: 2,639 cases yrs: 4,235 cases yrs: 5,548 cases yrs: 6,449 cases yrs: 7,2 cases yrs: 7,137 cases yrs: 6,518 cases yrs: 5,221 cases. Data accessed on 15 Nov 215. a Rates per 1, women per year. Data sources: Ferlay J, Soerjomataram I, Ervik M, Dikshit R, Eser S, Mathers C, Rebelo M, Parkin DM, Forman D, Bray F. GLOBOCAN 212 v1.2, Cancer Incidence and Mortality Worldwide: IARC CancerBase No. 11 [Internet]. Lyon, France: International Agency for Research on Cancer; 213. Available from:

26 3 BURDEN OF HPV-RELATED CANCERS Figure 13: Annual number of cases and age-specific incidence rates of cervical cancer in Europe and its regions (estimates for 212) (Continued) Eastern Europe Southern Europe Age specific rates of cervical cancer(a) , 19,618 Annual number of cases of cervical cancer 17,5 15, 12,5 1, 7,5 5, 2,5 7,668 6, Northern Europe Age specific rates of cervical cancer(a) , 17,5 15, 12,5 1, 7,5 5, 2,5 1,765 5,243 2, Western Europe , 2, Annual number of cases of cervical cancer 17,5 15, 12,5 1, 7,5 5, 2,5 1,816 2,48 1, ,5 15, 12,5 1, 7,5 5, 2,5 5,4 2, 2, Eastern Europe yrs: 1 cases yrs: 493 cases yrs: 1,58 cases yrs: 2,44 cases yrs: 3,145 cases yrs: 3,525 cases yrs: 3,959 cases yrs: 4,483 cases yrs: 4,317 cases yrs: 3,334 cases. Northern Europe yrs: 2 cases yrs: 213 cases yrs: 427 cases yrs: 546 cases yrs: 628 cases yrs: 675 cases yrs: 64 cases yrs: 472 cases yrs: 384 cases yrs: 345 cases. Southern Europe yrs: 4 cases yrs: 38 cases yrs: 251 cases yrs: 584 cases yrs: 888 cases yrs: 1,15 cases yrs: 1,23 cases yrs: 1,141 cases yrs: 968 cases yrs: 826 cases. Western Europe yrs: 6 cases yrs: 55 cases yrs: 382 cases yrs: 667 cases yrs: 89 cases yrs: 1,144 cases yrs: 1,254 cases yrs: 1,41 cases yrs: 849 cases yrs: 716 cases. Data accessed on 15 Nov 215. (Continued on next page)

27 3 BURDEN OF HPV-RELATED CANCERS ( Figure 13 continued from previous page) a Rates per 1, women per year. Data sources: Ferlay J, Soerjomataram I, Ervik M, Dikshit R, Eser S, Mathers C, Rebelo M, Parkin DM, Forman D, Bray F. GLOBOCAN 212 v1.2, Cancer Incidence and Mortality Worldwide: IARC CancerBase No. 11 [Internet]. Lyon, France: International Agency for Research on Cancer; 213. Available from:

28 3 BURDEN OF HPV-RELATED CANCERS Annual crude incidence rate (per 1,) Figure 14: Time trends in cervical cancer incidence type in Austria (cancer registry data) Recent trend : 4.6 ( 5.9 to 3.4) (1, b) Overall trend : 3.7 ( 4.1 to 3.4) (1, a) All ages (2, c) yrs (2, c) yrs (2, c) Data accessed on 27 Apr 215. a Estimated annual percentage change based on the trend variable from the net drift for the most recent two 5-year periods. b Estimated annual percentage change based on the trend variable from the net drift for 2 years, from c The following regional cancer registries provided data and contributed to their national estimate: Tyrol, Vorarlberg. Data sources: 1 Vaccarella S, Lortet-Tieulent J, Plummer M, Franceschi S, Bray F. Worldwide trends in cervical cancer incidence: Impact of screening against changes in disease risk factors. eur J Cancer 213;49: Ferlay J, Bray F, Steliarova-Foucher E and Forman D. Cancer Incidence in Five Continents, CI5plus: IARC CancerBase No. 9 [Internet]. Lyon, France: International Agency for Research on Cancer; 214. Available from: Figure 15: Time trends in cervical cancer incidence type in Switzerland (cancer registry data) Annual crude incidence rate (per 1,) All ages (2, b) yrs (2, b) yrs (2, b) Data accessed on 27 Apr 215. a Estimated annual percentage change based on the trend variable from the net drift for the most recent two 5-year periods. b The following regional cancer registries provided data and contributed to their national estimate: Geneva, Graubunden and Glarus, Neuchatel, St Gall-Appenzell, Valais, Vaud. Data sources: 1 Vaccarella S, Lortet-Tieulent J, Plummer M, Franceschi S, Bray F. Worldwide trends in cervical cancer incidence: Impact of screening against changes in disease risk factors. eur J Cancer 213;49: Ferlay J, Bray F, Steliarova-Foucher E and Forman D. Cancer Incidence in Five Continents, CI5plus: IARC CancerBase No. 9 [Internet]. Lyon, France: International Agency for Research on Cancer; 214. Available from:

29 3 BURDEN OF HPV-RELATED CANCERS Annual crude incidence rate (per 1,) Figure 16: Time trends in cervical cancer incidence type in Spain (cancer registry data) Recent trend : 1.3 ( 3.1 to.5) (1, b) Overall trend :.6 ( 1.5 to.3) (1, a) All ages (2, c) yrs (2, c) yrs (2, c) Data accessed on 27 Apr 215. a Estimated annual percentage change based on the trend variable from the net drift for the most recent two 5-year periods. b Estimated annual percentage change based on the trend variable from the net drift for 15 years, from c The following regional cancer registries provided data and contributed to their national estimate: Albacete, Cuenca, Girona, Granada, Murcia, Navarra, Tarragona. Data sources: 1 Vaccarella S, Lortet-Tieulent J, Plummer M, Franceschi S, Bray F. Worldwide trends in cervical cancer incidence: Impact of screening against changes in disease risk factors. eur J Cancer 213;49: Ferlay J, Bray F, Steliarova-Foucher E and Forman D. Cancer Incidence in Five Continents, CI5plus: IARC CancerBase No. 9 [Internet]. Lyon, France: International Agency for Research on Cancer; 214. Available from: Annual crude incidence rate (per 1,) Figure 17: Time trends in cervical cancer incidence type in France (cancer registry data) Recent trend : 2.5 ( 4.2 to.7) (1, b) Overall trend : 3.5 ( 4.1 to 3.) (1, a) All ages (2, c) yrs (2, c) yrs (2, c) Data accessed on 27 Apr 215. a Estimated annual percentage change based on the trend variable from the net drift for the most recent two 5-year periods. b Estimated annual percentage change based on the trend variable from the net drift for 2 years, from c The following regional cancer registries provided data and contributed to their national estimate: Bas-Rhin, Calvados, Doubs, Haut-Rhin, Herault, Isere, Somme, Tarn. Data sources: 1 Vaccarella S, Lortet-Tieulent J, Plummer M, Franceschi S, Bray F. Worldwide trends in cervical cancer incidence: Impact of screening against changes in disease risk factors. eur J Cancer 213;49: Ferlay J, Bray F, Steliarova-Foucher E and Forman D. Cancer Incidence in Five Continents, CI5plus: IARC CancerBase No. 9 [Internet]. Lyon, France: International Agency for Research on Cancer; 214. Available from:

30 3 BURDEN OF HPV-RELATED CANCERS Figure 18: Time trends in cervical cancer incidence type in the United Kingdom (cancer registry data) Annual crude incidence rate (per 1,) Recent trend : 2.3 ( 2.8 to 1.7) (1, b) Overall trend : 4.1 ( 4.2 to 3.9) (1, a) All ages (2, c) yrs (2, c) yrs (2, c) Data accessed on 27 Apr 215. a Estimated annual percentage change based on the trend variable from the net drift for the most recent two 5-year periods. b Estimated annual percentage change based on the trend variable from the net drift for 25 years, from c The following regional cancer registries provided data and contributed to their national estimate: Birmingham and West Midlands Region, East of England Region, Merseyside and Cheshire, North Western, Northern Ireland, Oxford, Scotland, South and Western Regions, Yorkshire. Data sources: 1 Vaccarella S, Lortet-Tieulent J, Plummer M, Franceschi S, Bray F. Worldwide trends in cervical cancer incidence: Impact of screening against changes in disease risk factors. eur J Cancer 213;49: Ferlay J, Bray F, Steliarova-Foucher E and Forman D. Cancer Incidence in Five Continents, CI5plus: IARC CancerBase No. 9 [Internet]. Lyon, France: International Agency for Research on Cancer; 214. Available from: Annual crude incidence rate (per 1,) Figure 19: Time trends in cervical cancer incidence type in Italy (cancer registry data) Recent trend : 3.1 ( 4.7 to 1.5) (1, b) Overall trend : 2. ( 2.8 to 1.2) (1, a) All ages (2, c) yrs (2, c) yrs (2, c) Data accessed on 27 Apr 215. a Estimated annual percentage change based on the trend variable from the net drift for the most recent two 5-year periods. b Estimated annual percentage change based on the trend variable from the net drift for 15 years, from c The following regional cancer registries provided data and contributed to their national estimate: Ferrara Province, Florence, Lombardy, Varese province, Modena, Parma, Ragusa Province, Romagna, Sassari Province, Torino. Data sources: 1 Vaccarella S, Lortet-Tieulent J, Plummer M, Franceschi S, Bray F. Worldwide trends in cervical cancer incidence: Impact of screening against changes in disease risk factors. eur J Cancer 213;49: Ferlay J, Bray F, Steliarova-Foucher E and Forman D. Cancer Incidence in Five Continents, CI5plus: IARC CancerBase No. 9 [Internet]. Lyon, France: International Agency for Research on Cancer; 214. Available from:

31 3 BURDEN OF HPV-RELATED CANCERS Annual crude incidence rate (per 1,) Figure 2: Time trends in cervical cancer incidence type in Poland (cancer registry data) Recent trend :.8 ( 2.1 to.5) (1, b) Overall trend : 1.1 ( 1.7 to.4) (1, a) All ages (2) yrs (2) yrs (2) Data accessed on 27 Apr 215. a Estimated annual percentage change based on the trend variable from the net drift for the most recent two 5-year periods. b Estimated annual percentage change based on the trend variable from the net drift for 15 years, from Data sources: 1 Vaccarella S, Lortet-Tieulent J, Plummer M, Franceschi S, Bray F. Worldwide trends in cervical cancer incidence: Impact of screening against changes in disease risk factors. eur J Cancer 213;49: Ferlay J, Bray F, Steliarova-Foucher E and Forman D. Cancer Incidence in Five Continents, CI5plus: IARC CancerBase No. 9 [Internet]. Lyon, France: International Agency for Research on Cancer; 214. Available from: Figure 21: Time trends in cervical cancer incidence type in the Russian Federation (cancer registry data) Annual crude incidence rate (per 1,) Recent trend :1.7 (1.4 to 1.9) (1, b) Overall trend :.9 (.8 to 1.1) (1, a) All ages (2) yrs (2) yrs (2) Data accessed on 27 Apr 215. a Estimated annual percentage change based on the trend variable from the net drift for the most recent two 5-year periods. b Estimated annual percentage change based on the trend variable from the net drift for 15 years, from Data sources: 1 Vaccarella S, Lortet-Tieulent J, Plummer M, Franceschi S, Bray F. Worldwide trends in cervical cancer incidence: Impact of screening against changes in disease risk factors. eur J Cancer 213;49: Ferlay J, Bray F, Steliarova-Foucher E and Forman D. Cancer Incidence in Five Continents, CI5plus: IARC CancerBase No. 9 [Internet]. Lyon, France: International Agency for Research on Cancer; 214. Available from:

32 3 BURDEN OF HPV-RELATED CANCERS Mortality KEY STATS. About 24,44 new cervical cancer deaths occur annually in Europe (estimates for 212). Cervical cancer ranks as the 7 th leading cause of female cancer deaths in Europe. Cervical cancer is the 2 nd most common female cancer deaths in women aged 15 to 44 years in Europe. Ranking of cervical cancer incidence to other cancers among all women according to highest incidence rates (ranking 1st). Ranking is based on crude incidence rates (actual number of cervical cancer cases). Ranking using age-standardized rate (ASR) may differ. Figure 22: Age-standardised mortality rates (ASR) of cervical cancer in European regions (estimates for 212) Eastern Europe 6.2 Southern Europe 2.4 Northern Europe 2.2 Western Europe Cervical cancer: Age standardised mortality rate per 1, women World Standard. Female (All ages) Data accessed on 15 Nov 215. Rates per 1, women per year. Data sources: Ferlay J, Soerjomataram I, Ervik M, Dikshit R, Eser S, Mathers C, Rebelo M, Parkin DM, Forman D, Bray F. GLOBOCAN 212 v1.2, Cancer Incidence and Mortality Worldwide: IARC CancerBase No. 11 [Internet]. Lyon, France: International Agency for Research on Cancer; 213. Available from:

33 3 BURDEN OF HPV-RELATED CANCERS Figure 23: Age-standardised mortality rates of cervical cancer in Europe (estimates for 212) Data accessed on 15 Nov 215. ASR: Age-standardized rate, Standardized rates have been estimated using the direct method and the World population as the reference; Rates per 1, women per year. Data sources: Ferlay J, Soerjomataram I, Ervik M, Dikshit R, Eser S, Mathers C, Rebelo M, Parkin DM, Forman D, Bray F. GLOBOCAN 212 v1.2, Cancer Incidence and Mortality Worldwide: IARC CancerBase No. 11 [Internet]. Lyon, France: International Agency for Research on Cancer; 213. Available from: Table 6: Cervical cancer mortality in Europe (estimates for 212) Cumulative risk (%) Ranking of CC Area N cases Crude rate a ASR a ages -74 years b All women Women years Europe 24, Eastern Europe 15, Belarus Bulgaria Czech Republic Hungary Poland 1, Republic of Moldova Romania 1, Russian Federation 7, Slovakia Ukraine 2, Northern Europe 1, Denmark Estonia Finland Iceland Ireland Latvia Lithuania Norway Sweden United Kingdom Southern Europe 3, (Continued on next page)

34 3 BURDEN OF HPV-RELATED CANCERS ( Table 6 continued from previous page) Cumulative risk (%) Ranking of CC Area N cases Crude rate a ASR a ages -74 years b All women Women years Albania Andorra Bosnia & Herzegovina Croatia Cyprus Greece Italy 1, Macedonia Malta Montenegro Portugal San Marino Serbia Slovenia Spain Western Europe 3, Austria Belgium France 1, Germany 1, Luxembourg Monaco Netherlands Switzerland Data accessed on 15 Nov 215. ASR: Age-standardized rate, Standardized rates have been estimated using the direct method and the World population as the reference; Standardised rates have ben estimated using the direct method and the World population as the reference. Ranking of cervical cancer mortality to other cancers among all women ages years according to highest mortality rates (ranking 1st). Ranking is based on crude mortality rates(actual number of cervical cancer deaths). Ranking using AST may differ. a Rates per 1, women per year. b Cumulative risk (mortality) is the probability or risk of individuals dying from the disease during ages -74 years. For cancer, it is expressed as the % of new born children who would be expected to die from a particular cancer before the age of 75 if they had the rates of cancer observed in the period in the absence of competing causes. Data sources: Ferlay J, Soerjomataram I, Ervik M, Dikshit R, Eser S, Mathers C, Rebelo M, Parkin DM, Forman D, Bray F. GLOBOCAN 212 v1.2, Cancer Incidence and Mortality Worldwide: IARC CancerBase No. 11 [Internet]. Lyon, France: International Agency for Research on Cancer; 213. Available from:

35 3 BURDEN OF HPV-RELATED CANCERS Figure 24: Ranking of cervical cancer versus other cancers among all women and women aged years, according to mortality rates in Europe (estimates for 212) Data accessed on 15 Nov 215. Data sources: Ferlay J, Soerjomataram I, Ervik M, Dikshit R, Eser S, Mathers C, Rebelo M, Parkin DM, Forman D, Bray F. GLOBOCAN 212 v1.2, Cancer Incidence and Mortality Worldwide: IARC CancerBase No. 11 [Internet]. Lyon, France: International Agency for Research on Cancer; 213. Available from:

36 3 BURDEN OF HPV-RELATED CANCERS Figure 25: Comparison of the ten most frequent cancer deaths in women aged years in Europe and its regions (estimates for 212) Europe Southern Europe Breast 4.4 Breast 4.7 Cervix uteri 2.5 Lung 1.8 Lung 1.4 Cervix uteri 1.4 Brain, nervous system 1.3 Brain, nervous system 1.1 Ovary 1.2 Ovary 1. Stomach 1. Colorectum(a).9 Colorectum(a).9 Leukaemia.9 Leukaemia.9 Stomach.8 Melanoma of skin.7 Melanoma of skin.6 Non Hodgkin lymphoma(b).5 Non Hodgkin lymphoma(b) Eastern Europe Western Europe Cervix uteri 4.3 Breast 4.2 Breast 4.2 Lung 2.1 Ovary 1.8 Brain, nervous system 1.1 Brain, nervous system 1.5 Cervix uteri.9 Stomach 1.4 Colorectum(a).7 Colorectum(a) 1. Leukaemia.7 Leukaemia 1. Melanoma of skin.6 Lung 1. Ovary.6 Melanoma of skin.7 Stomach.5 Hodgkin lymphoma.6 Pancreas Northern Europe Breast 4.8 Cervix uteri Brain, nervous system Colorectum(a) Leukaemia Melanoma of skin Ovary Lung Stomach Non Hodgkin lymphoma(b) Age standardised mortality rate per 1, women in Europe Data accessed on 15 Nov 215. a Includes anal cancer (C21). b Includes HIV disease resulting in malignant neoplasms (B21). Data sources: (Continued on next page)

37 3 BURDEN OF HPV-RELATED CANCERS ( Figure 25 continued from previous page) Ferlay J, Soerjomataram I, Ervik M, Dikshit R, Eser S, Mathers C, Rebelo M, Parkin DM, Forman D, Bray F. GLOBOCAN 212 v1.2, Cancer Incidence and Mortality Worldwide: IARC CancerBase No. 11 [Internet]. Lyon, France: International Agency for Research on Cancer; 213. Available from:

38 3 BURDEN OF HPV-RELATED CANCERS Figure 26: Comparison of the ten most frequent cancer deaths in women of all ages in Europe and its regions (estimates for 212) Europe Southern Europe Breast 16.1 Breast 14.9 Lung 11.8 Lung 1. Colorectum(a) 9.9 Colorectum(a) 8.7 Ovary 5.4 Pancreas 4.9 Pancreas 5.3 Ovary 4.4 Stomach 4.6 Stomach 4. Cervix uteri 3.8 Brain, nervous system 3.1 Brain, nervous system 3. Leukaemia 2.8 Leukaemia 2.8 Liver 2.5 Corpus uteri 2.6 Cervix uteri Eastern Europe Western Europe Breast 16.5 Breast 16.2 Colorectum(a) 11.7 Lung 14.8 Lung 8.3 Colorectum(a) 8.3 Stomach 7.1 Pancreas 5.8 Cervix uteri 6.2 Ovary 4.7 Ovary 6. Brain, nervous system 2.7 Pancreas 4.9 Leukaemia 2.7 Corpus uteri 3.4 Stomach 2.5 Brain, nervous system 3.2 Liver 2.1 Leukaemia 2.8 Non Hodgkin lymphoma(b) Northern Europe Lung Breast Colorectum(a) 9.2 Ovary Pancreas Brain, nervous system Leukaemia Stomach Corpus uteri Oesophagus Age standardised mortality rate per 1, women in Europe Data accessed on 15 Nov 215. a Includes anal cancer (C21). b Includes HIV disease resulting in malignant neoplasms (B21). Data sources: (Continued on next page)

39 3 BURDEN OF HPV-RELATED CANCERS ( Figure 26 continued from previous page) Ferlay J, Soerjomataram I, Ervik M, Dikshit R, Eser S, Mathers C, Rebelo M, Parkin DM, Forman D, Bray F. GLOBOCAN 212 v1.2, Cancer Incidence and Mortality Worldwide: IARC CancerBase No. 11 [Internet]. Lyon, France: International Agency for Research on Cancer; 213. Available from: Figure 27: Age-specific mortality of cervical cancer in Europe and its regions (estimates for 212) Age specific mortality rates of cervical cancer per 1, Europe Eastern Europe Northern Europe Southern Europe Western Europe >=75 Data accessed on 15 Nov 215. Rates per 1, women per year. Data sources: Ferlay J, Soerjomataram I, Ervik M, Dikshit R, Eser S, Mathers C, Rebelo M, Parkin DM, Forman D, Bray F. GLOBOCAN 212 v1.2, Cancer Incidence and Mortality Worldwide: IARC CancerBase No. 11 [Internet]. Lyon, France: International Agency for Research on Cancer; 213. Available from:

40 3 BURDEN OF HPV-RELATED CANCERS Figure 28: Annual number of deaths of cervical cancer by age group in European regions (estimates for 212) Eastern Europe Southern Europe Western Europe Northern Europe Annual number of cervical cancer deaths 15, 13,5 12, 1,5 9, 7,5 6, 4,5 3, 1,5 11,779 1,413 2, Eastern Europe years: 1,7 cases years: 7,989 cases. 65+ years: 5,747 cases. Southern Europe years: 195 cases years: 1,575 cases. 65+ years: 1,756 cases. Western Europe years: 139 cases years: 1,421 cases. 65+ years: 1,919 cases. Northern Europe years: 178 cases years: 794 cases. 65+ years: 991 cases. Data accessed on 15 Nov 215. Data sources: Ferlay J, Soerjomataram I, Ervik M, Dikshit R, Eser S, Mathers C, Rebelo M, Parkin DM, Forman D, Bray F. GLOBOCAN 212 v1.2, Cancer Incidence and Mortality Worldwide: IARC CancerBase No. 11 [Internet]. Lyon, France: International Agency for Research on Cancer; 213. Available from:

41 3 BURDEN OF HPV-RELATED CANCERS Figure 29: Annual number of deaths and age-specific mortality rates of cervical cancer in Europe and its regions (estimates for 212) Europe 25 2 Age specific rates of cervical cancer(a) ,5 11,779 Annual number of deaths of cervical cancer 1, 7,5 5, 1,413 2,5 2, Europe yrs: 2 cases yrs: 32 cases yrs: 332 cases yrs: 715 cases yrs: 1,131 cases yrs: 1,565 cases yrs: 2,88 cases yrs: 2,647 cases yrs: 2,85 cases yrs: 2,629 cases. Data accessed on 15 Nov 215. a Rates per 1, women per year. Data sources: Ferlay J, Soerjomataram I, Ervik M, Dikshit R, Eser S, Mathers C, Rebelo M, Parkin DM, Forman D, Bray F. GLOBOCAN 212 v1.2, Cancer Incidence and Mortality Worldwide: IARC CancerBase No. 11 [Internet]. Lyon, France: International Agency for Research on Cancer; 213. Available from:

42 3 BURDEN OF HPV-RELATED CANCERS Figure 3: Annual number of deaths and age-specific mortality rates of cervical cancer in Europe and its regions (estimates for 212) (Continued) Eastern Europe Southern Europe Age specific rates of cervical cancer(a) Annual number of deaths of cervical cancer 8, 6, 4, 2, 1,7 7,989 5,747 8, 6, 4, 2, 1,575 1, Northern Europe Western Europe Age specific rates of cervical cancer(a) Annual number of deaths of cervical cancer 8, 6, 4, 2, , 6, 4, 2, 1,919 1, Eastern Europe yrs: 1 cases yrs: 25 cases yrs: 281 cases yrs: 564 cases yrs: 829 cases yrs: 1,44 cases yrs: 1,375 cases yrs: 1,86 cases yrs: 1,988 cases yrs: 1,776 cases. Northern Europe yrs: 1 cases yrs: 4 cases yrs: 29 cases yrs: 6 cases yrs: 84 cases yrs: 117 cases yrs: 145 cases yrs: 168 cases yrs: 174 cases yrs: 19 cases. Southern Europe yrs: cases yrs: 2 cases yrs: 1 cases yrs: 53 cases yrs: 13 cases yrs: 227 cases yrs: 31 cases yrs: 351 cases yrs: 352 cases yrs: 344 cases. Western Europe yrs: cases yrs: 1 cases yrs: 12 cases yrs: 38 cases yrs: 88 cases yrs: 177 cases yrs: 267 cases yrs: 322 cases yrs: 336 cases yrs: 319 cases. Data accessed on 15 Nov 215. (Continued on next page)

43 3 BURDEN OF HPV-RELATED CANCERS ( Figure 3 continued from previous page) a Rates per 1, women per year. Data sources: Ferlay J, Soerjomataram I, Ervik M, Dikshit R, Eser S, Mathers C, Rebelo M, Parkin DM, Forman D, Bray F. GLOBOCAN 212 v1.2, Cancer Incidence and Mortality Worldwide: IARC CancerBase No. 11 [Internet]. Lyon, France: International Agency for Research on Cancer; 213. Available from:

44 3 BURDEN OF HPV-RELATED CANCERS Comparison of incidence and mortality Figure 31: Age-specific incidence and mortality rates of cervical cancer in Europe and its regions (estimates for 212) Europe Southern Europe Age specific rates of cervical cancer per 1, Eastern Europe >= Western Europe >= >= >= >=75 4 Northern Europe Incidence Mortality Data accessed on 15 Nov 215. Rates per 1, women per year. Data sources: Ferlay J, Soerjomataram I, Ervik M, Dikshit R, Eser S, Mathers C, Rebelo M, Parkin DM, Forman D, Bray F. GLOBOCAN 212 v1.2, Cancer Incidence and Mortality Worldwide: IARC CancerBase No. 11 [Internet]. Lyon, France: International Agency for Research on Cancer; 213. Available from:

45 3 BURDEN OF HPV-RELATED CANCERS Anogenital cancers other than the cervix Data on the role of HPV in anogenital cancers other than the cervix are limited, but there is an increasing body of evidence strongly linking HPV DNA with cancers of the anus, vulva, vagina, and penis. Although these cancers are much less frequent compared to cancer of the cervix, their association with HPV make them potentially preventable and subject to similar preventative strategies as those for cervical cancer. (Vaccine 26, Vol. 24, Suppl 3; Vaccine 28, Vol. 26, Suppl 1; Vaccine 212, Vol. 3, Suppl 5; IARC Monographs 27, Vol. 9) Figure 32: Age-standardised incidence rates of anogenital cancers other than the cervix in Europe (estimates for 212) Data accessed on 8 May 217. ASR: Age-standardized rate, rates per 1, per year. Please refer to original source for methods. Other anogenital cancer cases (vulvar, vaginal, anal, and penile). GLOBOCAN quality index for availability of incidence data: - For Albania, Greece, Hungary, Republic of Moldova, Macedonia, Montenegro: No data. - For Austria, Belgium, Bulgaria, Belarus, Cyprus, Czech Republic, Denmark, Estonia, Finland, United Kingdom, Croatia, Ireland, Iceland, Lithuania, Latvia, Malta, Netherlands, Norway, Slovakia, Slovenia, Sweden, Ukraine: High quality national data or high quality regional (coverage greater than 5%). - For Bosnia & Herzegovina, Luxembourg, Russian Federation: National data (rates). - For Switzerland, Germany, Spain, France, Italy, Serbia: High quality regional (coverage between 1% and 5%). - For Poland, Portugal: High quality regional (coverage lower than 1%). - For Romania: Regional data (rates). GLOBOCAN quality index of methods for calculating incidence: Methods to estimate the sex- and age-specific incidence rates of cancer for a specific country: - For Albania, Greece, Hungary, Luxembourg, Republic of Moldova, Macedonia, Portugal, Romania, Serbia: Estimated from national mortality estimates by modelling using incidence mortality ratios derived from recorded data in local cancer registries in neighbouring countries - For Austria, Bulgaria, Belarus, Czech Republic, Germany, Denmark, Estonia, Finland, United Kingdom, Croatia, Ireland, Iceland, Lithuania, Latvia, Malta, Netherlands, Norway, Russian Federation, Slovakia, Slovenia, Sweden: Rates projected to For Belgium, Bosnia & Herzegovina, Cyprus, Ukraine: Most recent rates applied to 212 population - For Switzerland, Spain, France, Italy, Poland: Estimated from national mortality by modelling using incidence mortality ratios derived from recorded data in country-specific cancer registries - For Montenegro: The rates are those of neighbouring countries or registries in the same area Data sources: Worldwide burden of cancer attributable to HPV by site, country and HPV type. de Martel C, Plummer M, Vignat J, Franceschi S. Int J Cancer. 217 Apr 1. doi: 1.12/ijc [Epub ahead of print]. PMID:

46 3 BURDEN OF HPV-RELATED CANCERS Figure 33: Age-standardised incidence rate of other anogenital cancer cases attributable to HPV by country in Europe (estimates for 212) Denmark France Norway Netherlands Iceland Belgium Ireland UK Sweden Luxembourg Germany Slovenia Austria Serbia Montenegro Lithuania Italy Croatia Switzerland Malta Latvia Finland Estonia Spain Czech Rep. Bulgaria Slovakia Portugal Macedonia Hungary Cyprus Albania Ukraine Russia Romania Moldova Greece Poland Bosnia & H. Belarus San Marino Monaco Liechtenstein Andorra Age standardised incidence rate per 1, women World Standard No rates are available. Data accessed on 8 May 217. ASR: Age-standardized rate, rates per 1, per year. Please refer to original source for methods. (Continued on next page)

47 3 BURDEN OF HPV-RELATED CANCERS Other anogenital cancer cases (vulvar, vaginal, anal, and penile). ( Figure 33 continued from previous page) GLOBOCAN quality index for availability of incidence data: - For Belarus, Ukraine, Cyprus, Slovakia, Bulgaria, Czech Republic, Estonia, Finland, Latvia, Malta, Croatia, Lithuania, Austria, Slovenia, Sweden, United Kingdom, Ireland, Belgium, Iceland, Netherlands, Norway, Denmark: High quality national data or high quality regional (coverage greater than 5%). - For Bosnia & Herzegovina, Russian Federation, Luxembourg: National data (rates). - For Poland, Portugal: High quality regional (coverage lower than 1%). - For Greece, Republic of Moldova, Albania, Hungary, Macedonia, Montenegro: No data. - For Romania: Regional data (rates). - For Spain, Switzerland, Italy, Serbia, Germany, France: High quality regional (coverage between 1% and 5%). GLOBOCAN quality index of methods for calculating incidence: Methods to estimate the sex- and age-specific incidence rates of cancer for a specific country: - For Belarus, Russian Federation, Slovakia, Bulgaria, Czech Republic, Estonia, Finland, Latvia, Malta, Croatia, Lithuania, Austria, Slovenia, Germany, Sweden, United Kingdom, Ireland, Iceland, Netherlands, Norway, Denmark: Rates projected to For Bosnia & Herzegovina, Ukraine, Cyprus, Belgium: Most recent rates applied to 212 population - For Poland, Spain, Switzerland, Italy, France: Estimated from national mortality by modelling using incidence mortality ratios derived from recorded data in country-specific cancer registries - For Greece, Republic of Moldova, Romania, Albania, Hungary, Macedonia, Portugal, Serbia, Luxembourg: Estimated from national mortality estimates by modelling using incidence mortality ratios derived from recorded data in local cancer registries in neighbouring countries - For Montenegro: The rates are those of neighbouring countries or registries in the same area Data sources: de Martel C, Plummer M, Vignat J, Franceschi S. Worldwide burden of cancer attributable to HPV by site, country and HPV type. Int J Cancer Anal cancer Anal cancer is rare in the general population with an average worldwide incidence of 1 per 1,, but is reported to be increasing in more developed regions. Globally, there are an estimated 27, new cases every year (de Martel C et al. Lancet Oncol 212;13(6):67-15). Women have higher incidences of anal cancer than men. Incidence is particularly high among populations of men who have sex with men (MSM), women with history of cervical or vulvar cancer, and immunosuppressed populations, including those who are HIV-infected and patients with a history of organ transplantation. These cancers are predominantly squamous cell carcinoma, adenocarcinomas, or basaloid and cloacogenic carcinomas. Table 7: Incidence of anal cancer in Europe by cancer registry and sex Male Female Country / Registry Period N cases a Crude rate b ASR b N cases a Crude rate c ASR c Eastern Europe Belarus 1 National Bulgaria 1 National Czech Rep. 1 National Hungary Moldova Poland 1 Cracow Kielce Lower Silesia Podkarpackie Romania Russia 1 Saint Petersburg Slovakia 1 National Ukraine 1 National Northern Europe Denmark 1 National Estonia 1 National (Continued on next page)

48 3 BURDEN OF HPV-RELATED CANCERS ( Table 7 continued from previous page) Male Female Country / Registry Period N cases a Crude rate b ASR b N cases a Crude rate c ASR c Finland 1 National Iceland 1 National Ireland 1 National Latvia 1 National Lithuania 1 National Norway 1 National Sweden 1 National UK 1 England England, East of England Region England, North Western England, Northern and Yorkshire England, Oxford Region England, South and Western Regions England, Thames England, Trent England, West Midlands Northern Ireland Scotland Wales Southern Europe Albania Andorra Bosnia & H Croatia 1 National Cyprus 1 National Greece Italy 1 Biella Brescia Catania and Messina Catanzaro Como Ferrara Florence and Prato Friuli-Venezia Giulia Genoa (Continued on next page)

49 3 BURDEN OF HPV-RELATED CANCERS ( Table 7 continued from previous page) Male Female Country / Registry Period N cases a Crude rate b ASR b N cases a Crude rate c ASR c Latina Lecco Lombardy, South Mantua Milan Modena Naples Nuoro Palermo Parma Ragusa Reggio Emilia Romagna Salerno Sassari Sondrio South Tyrol Syracuse Trapani Trento Turin Umbria Varese Veneto Macedonia Malta 1 National Montenegro Portugal 1 Azores San Marino Serbia 1 Central Slovenia 1 National Spain 1 Albacete Asturias Basque Country Canary Islands Ciudad Real Cuenca Girona Granada La Rioja Mallorca Murcia (Continued on next page)

50 3 BURDEN OF HPV-RELATED CANCERS ( Table 7 continued from previous page) Male Female Country / Registry Period N cases a Crude rate b ASR b N cases a Crude rate c ASR c Navarra Tarragona Western Europe Austria 1 National Tyrol Vorarlberg Belgium 1 National France 1 Bas-Rhin Calvados Doubs Haut-Rhin Herault Isere Loire Atlantique Manche Martinique Somme Tarn Vendee Germany 1 Brandenburg Bremen Free State Of Saxony Hamburg Mecklenburg-Western Pomerania Munich North Rhine-Westphalia Saarland Schleswig-Holstein Luxembourg Monaco Netherlands 1 Eindhoven National Switzerland 1 Basel Geneva Graubunden and Glarus Neuchatel St Gall-Appenzell Ticino Valais Vaud Zurich Data accessed on 5 May 215. a Accumulated number of cases during the period in the population covered by the corresponding registry. (Continued on next page)

51 3 BURDEN OF HPV-RELATED CANCERS ( Table 7 continued from previous page) b Rates per 1, men per year. c Rates per 1, women per year. Data sources: 1 Forman D, Bray F, Brewster DH, Gombe Mbalawa C, Kohler B, Piñeros M, Steliarova-Foucher E, Swaminathan R and Ferlay J eds (213). Cancer Incidence in Five Continents, Vol. X (electronic version) Lyon, IARC. 1 Figure 34: Time trends in anal cancer incidence in Austria (cancer registry data) Anal cancer in men Annual crude incidence rate (per 1,) All ages yrs yrs Anal cancer in women 1 Annual crude incidence rate (per 1,) All ages yrs yrs No cases were registered for this age group. Data accessed on 27 Apr 215. The following regional cancer registries provided data and contributed to their national estimate: Tyrol, Vorarlberg. Data sources: Ferlay J, Bray F, Steliarova-Foucher E and Forman D. Cancer Incidence in Five Continents, CI5plus: IARC CancerBase No. 9 [Internet]. Lyon, France: International Agency for Research on Cancer; 214. Available from:

52 3 BURDEN OF HPV-RELATED CANCERS Figure 35: Time trends in anal cancer incidence in Croatia (cancer registry data) Anal cancer in men Annual crude incidence rate (per 1,) 1 All ages yrs yrs Anal cancer in women 2 Annual crude incidence rate (per 1,) 1 All ages yrs yrs No cases were registered for this age group. Data accessed on 27 Apr 215. Data was provided by the national registry. Data sources: Ferlay J, Bray F, Steliarova-Foucher E and Forman D. Cancer Incidence in Five Continents, CI5plus: IARC CancerBase No. 9 [Internet]. Lyon, France: International Agency for Research on Cancer; 214. Available from:

53 3 BURDEN OF HPV-RELATED CANCERS Figure 36: Time trends in anal cancer incidence in Denmark (cancer registry data) Anal cancer in men Annual crude incidence rate (per 1,) All ages yrs yrs Anal cancer in women 1 Annual crude incidence rate (per 1,) All ages yrs yrs No cases were registered for this age group. Data accessed on 27 Apr 215. Data was provided by the national registry. Data sources: Ferlay J, Bray F, Steliarova-Foucher E and Forman D. Cancer Incidence in Five Continents, CI5plus: IARC CancerBase No. 9 [Internet]. Lyon, France: International Agency for Research on Cancer; 214. Available from:

54 3 BURDEN OF HPV-RELATED CANCERS Figure 37: Time trends in anal cancer incidence in Estonia (cancer registry data) Anal cancer in men Annual crude incidence rate (per 1,) All ages yrs yrs Anal cancer in women 5 Annual crude incidence rate (per 1,) All ages yrs yrs No cases were registered for this age group. Data accessed on 27 Apr 215. Data was provided by the national registry. Data sources: Ferlay J, Bray F, Steliarova-Foucher E and Forman D. Cancer Incidence in Five Continents, CI5plus: IARC CancerBase No. 9 [Internet]. Lyon, France: International Agency for Research on Cancer; 214. Available from:

55 3 BURDEN OF HPV-RELATED CANCERS Figure 38: Time trends in anal cancer incidence in France (cancer registry data) Anal cancer in men Annual crude incidence rate (per 1,) All ages yrs yrs Anal cancer in women 1 Annual crude incidence rate (per 1,) All ages yrs yrs No cases were registered for this age group. Data accessed on 27 Apr 215. The following regional cancer registries provided data and contributed to their national estimate: Bas-Rhin, Calvados, Doubs, Haut-Rhin, Herault, Isere, Somme, Tarn. Data sources: Ferlay J, Bray F, Steliarova-Foucher E and Forman D. Cancer Incidence in Five Continents, CI5plus: IARC CancerBase No. 9 [Internet]. Lyon, France: International Agency for Research on Cancer; 214. Available from:

56 3 BURDEN OF HPV-RELATED CANCERS Figure 39: Time trends in anal cancer incidence in Iceland (cancer registry data) Anal cancer in men Annual crude incidence rate (per 1,) All ages yrs yrs Anal cancer in women 1 Annual crude incidence rate (per 1,) All ages yrs yrs No cases were registered for this age group. Data accessed on 27 Apr 215. Data was provided by the national registry. Data sources: Ferlay J, Bray F, Steliarova-Foucher E and Forman D. Cancer Incidence in Five Continents, CI5plus: IARC CancerBase No. 9 [Internet]. Lyon, France: International Agency for Research on Cancer; 214. Available from:

57 3 BURDEN OF HPV-RELATED CANCERS Figure 4: Time trends in anal cancer incidence in Italy (cancer registry data) Anal cancer in men Annual crude incidence rate (per 1,) All ages yrs yrs Anal cancer in women 5 Annual crude incidence rate (per 1,) All ages yrs yrs No cases were registered for this age group. Data accessed on 27 Apr 215. The following regional cancer registries provided data and contributed to their national estimate: Ferrara Province, Florence, Lombardy, Varese province, Modena, Parma, Ragusa Province, Romagna, Sassari Province, Torino. Data sources: Ferlay J, Bray F, Steliarova-Foucher E and Forman D. Cancer Incidence in Five Continents, CI5plus: IARC CancerBase No. 9 [Internet]. Lyon, France: International Agency for Research on Cancer; 214. Available from:

58 3 BURDEN OF HPV-RELATED CANCERS Figure 41: Time trends in anal cancer incidence in the Netherlands (cancer registry data) 5 Anal cancer in men Annual crude incidence rate (per 1,) All ages yrs yrs Anal cancer in women 5 Annual crude incidence rate (per 1,) All ages yrs yrs No cases were registered for this age group. Data accessed on 27 Apr 215. Data was provided by the national registry. Data sources: Ferlay J, Bray F, Steliarova-Foucher E and Forman D. Cancer Incidence in Five Continents, CI5plus: IARC CancerBase No. 9 [Internet]. Lyon, France: International Agency for Research on Cancer; 214. Available from:

59 3 BURDEN OF HPV-RELATED CANCERS Figure 42: Time trends in anal cancer incidence in Poland (cancer registry data) Anal cancer in men 14 Annual crude incidence rate (per 1,) All ages yrs yrs Anal cancer in women 14 Annual crude incidence rate (per 1,) All ages yrs yrs No cases were registered for this age group. Data accessed on 27 Apr 215. Data was provided by the Cracow City registry. Data sources: Ferlay J, Bray F, Steliarova-Foucher E and Forman D. Cancer Incidence in Five Continents, CI5plus: IARC CancerBase No. 9 [Internet]. Lyon, France: International Agency for Research on Cancer; 214. Available from:

60 3 BURDEN OF HPV-RELATED CANCERS Figure 43: Time trends in anal cancer incidence in the Russian Federation (cancer registry data) 5 Anal cancer in men Annual crude incidence rate (per 1,) All ages yrs yrs Anal cancer in women 5 Annual crude incidence rate (per 1,) All ages yrs yrs No cases were registered for this age group. Data accessed on 27 Apr 215. Data was provided by the St Petersburg registry. Data sources: Ferlay J, Bray F, Steliarova-Foucher E and Forman D. Cancer Incidence in Five Continents, CI5plus: IARC CancerBase No. 9 [Internet]. Lyon, France: International Agency for Research on Cancer; 214. Available from:

61 3 BURDEN OF HPV-RELATED CANCERS Figure 44: Time trends in anal cancer incidence in Slovakia (cancer registry data) Anal cancer in men Annual crude incidence rate (per 1,) All ages yrs yrs Anal cancer in women 5 Annual crude incidence rate (per 1,) All ages yrs yrs No cases were registered for this age group. Data accessed on 27 Apr 215. Data was provided by the national registry. Data sources: Ferlay J, Bray F, Steliarova-Foucher E and Forman D. Cancer Incidence in Five Continents, CI5plus: IARC CancerBase No. 9 [Internet]. Lyon, France: International Agency for Research on Cancer; 214. Available from:

62 3 BURDEN OF HPV-RELATED CANCERS Figure 45: Time trends in anal cancer incidence in Spain (cancer registry data) Anal cancer in men Annual crude incidence rate (per 1,) All ages yrs yrs Anal cancer in women 5 Annual crude incidence rate (per 1,) All ages yrs yrs No cases were registered for this age group. Data accessed on 27 Apr 215. The following regional cancer registries provided data and contributed to their national estimate: Albacete, Cuenca, Girona, Granada, Murcia, Navarra, Tarragona. Data sources: Ferlay J, Bray F, Steliarova-Foucher E and Forman D. Cancer Incidence in Five Continents, CI5plus: IARC CancerBase No. 9 [Internet]. Lyon, France: International Agency for Research on Cancer; 214. Available from:

63 3 BURDEN OF HPV-RELATED CANCERS Figure 46: Time trends in anal cancer incidence in Switzerland (cancer registry data) Anal cancer in men Annual crude incidence rate (per 1,) All ages yrs yrs Anal cancer in women 1 Annual crude incidence rate (per 1,) All ages yrs yrs No cases were registered for this age group. Data accessed on 27 Apr 215. The following regional cancer registries provided data and contributed to their national estimate: Geneva, Graubunden and Glarus, Neuchatel, St Gall-Appenzell, Valais, Vaud. Data sources: Ferlay J, Bray F, Steliarova-Foucher E and Forman D. Cancer Incidence in Five Continents, CI5plus: IARC CancerBase No. 9 [Internet]. Lyon, France: International Agency for Research on Cancer; 214. Available from:

64 3 BURDEN OF HPV-RELATED CANCERS Figure 47: Time trends in anal cancer incidence in the United Kingdom (cancer registry data) 5 Anal cancer in men Annual crude incidence rate (per 1,) All ages yrs yrs Anal cancer in women 5 Annual crude incidence rate (per 1,) All ages yrs yrs Data accessed on 27 Apr 215. The following regional cancer registries provided data and contributed to their national estimate: Birmingham and West Midlands Region, East of England Region, Merseyside and Cheshire, North Western, Northern Ireland, Oxford, Scotland, South and Western Regions, Yorkshire. Data sources: Ferlay J, Bray F, Steliarova-Foucher E and Forman D. Cancer Incidence in Five Continents, CI5plus: IARC CancerBase No. 9 [Internet]. Lyon, France: International Agency for Research on Cancer; 214. Available from: NOTE. Time trends in cancer incidence are shown only in countries with available data.

65 3 BURDEN OF HPV-RELATED CANCERS Vulvar cancer Cancer of the vulva is rare among women worldwide, with an estimated 27, new cases in 28, representing 4% of all gynaecologic cancers (de Martel C et al. Lancet Oncol 212;13(6):67-15). Worldwide, about 6% of all vulvar cancer cases occur in more developed countries. Vulvar cancer has two distinct histological patterns with two different risk factor profiles: (1) basaloid/warty types (2) keratinising types. Basaloid/warty lesions are more common in young women, are very often associated with HPV DNA detection (75-1%), and have a similar risk factor profile as cervical cancer. Keratinising vulvar carcinomas represent the majority of the vulvar lesions (>6%), they occur more often in older women and are more rarely associated with HPV (IARC Monograph Vol 1B) Table 8: Incidence of vulvar cancer in Europe by cancer registry Female Country Cancer registry Period N cases a Crude rate b ASR b Eastern Europe Belarus 1 National Bulgaria 1 National Czech Republic 1 National Hungary Poland 1 Cracow Kielce Lower Silesia Podkarpackie Republic of Moldova Romania Russian Federation 1 Saint Petersburg Slovakia 1 National Ukraine 1 National Northern Europe Denmark 1 National Estonia 1 National Finland 1 National Iceland 1 National Ireland 1 National Latvia 1 National Lithuania 1 National Norway 1 National Sweden 1 National United Kingdom 1 England England, East of England Region England, North Western England, Northern and Yorkshire England, Oxford Region England, South and Western Regions England, Thames England, Trent England, West Midlands Northern Ireland Scotland Wales Southern Europe Albania Andorra Bosnia & Herzegovina Croatia 1 National Cyprus 1 National (Continued on next page)

66 3 BURDEN OF HPV-RELATED CANCERS ( Table 8 continued from previous page) Female Country Cancer registry Period N cases a Crude rate b ASR b Greece Italy 1 Biella Brescia Catania and Messina Catanzaro Como Ferrara Florence and Prato Friuli-Venezia Giulia Genoa Latina Lecco Lombardy, South Mantua Milan Modena Naples Nuoro Palermo Parma Ragusa Reggio Emilia Romagna Salerno Sassari Sondrio South Tyrol Syracuse Trapani Trento Turin Umbria Varese Veneto Macedonia Malta 1 National Montenegro Portugal 1 Azores San Marino Serbia 1 Central Slovenia 1 National Spain 1 Albacete Asturias Basque Country Canary Islands Ciudad Real Cuenca Girona Granada La Rioja Mallorca Murcia Navarra (Continued on next page)

67 3 BURDEN OF HPV-RELATED CANCERS ( Table 8 continued from previous page) Female Country Cancer registry Period N cases a Crude rate b ASR b Tarragona Western Europe Austria 1 National Tyrol Vorarlberg Belgium 1 National France 1 Bas-Rhin Calvados Doubs Haut-Rhin Herault Isere Loire Atlantique Manche Martinique Somme Tarn Vendee Germany 1 Brandenburg Bremen Free State Of Saxony Hamburg Mecklenburg-Western Pomerania Munich North Rhine-Westphalia Saarland Schleswig-Holstein Luxembourg Monaco Netherlands 1 Eindhoven National Switzerland 1 Basel Geneva Graubunden and Glarus Neuchatel St Gall-Appenzell Ticino Valais Vaud Zurich Data accessed on 5 May 215. a Accumulated number of cases during the period in the population covered by the corresponding registry. b Rates per 1, women per year. Data sources: 1 Forman D, Bray F, Brewster DH, Gombe Mbalawa C, Kohler B, Piñeros M, Steliarova-Foucher E, Swaminathan R and Ferlay J eds (213). Cancer Incidence in Five Continents, Vol. X (electronic version) Lyon, IARC.

68 3 BURDEN OF HPV-RELATED CANCERS Figure 48: Time trends in vulvar cancer incidence in Austria (cancer registry data) Annual crude incidence rate (per 1,) All ages yrs yrs No cases were registered for this age group. Data accessed on 27 Apr 215. The following regional cancer registries provided data and contributed to their national estimate: Tyrol, Vorarlberg. Data sources: Ferlay J, Bray F, Steliarova-Foucher E and Forman D. Cancer Incidence in Five Continents, CI5plus: IARC CancerBase No. 9 [Internet]. Lyon, France: International Agency for Research on Cancer; 214. Available from: Figure 49: Time trends in vulvar cancer incidence in Croatia (cancer registry data) Annual crude incidence rate (per 1,) All ages yrs yrs Data accessed on 27 Apr 215. Data was provided by the national registry. Data sources: Ferlay J, Bray F, Steliarova-Foucher E and Forman D. Cancer Incidence in Five Continents, CI5plus: IARC CancerBase No. 9 [Internet]. Lyon, France: International Agency for Research on Cancer; 214. Available from: Figure 5: Time trends in vulvar cancer incidence in Denmark (cancer registry data) Annual crude incidence rate (per 1,) All ages yrs yrs Data accessed on 27 Apr 215. Data was provided by the national registry. Data sources: Ferlay J, Bray F, Steliarova-Foucher E and Forman D. Cancer Incidence in Five Continents, CI5plus: IARC CancerBase No. 9 [Internet]. Lyon, France: International Agency for Research on Cancer; 214. Available from:

69 3 BURDEN OF HPV-RELATED CANCERS Figure 51: Time trends in vulvar cancer incidence in Estonia (cancer registry data) Annual crude incidence rate (per 1,) All ages yrs yrs No cases were registered for this age group. Data accessed on 27 Apr 215. Data was provided by the national registry. Data sources: Ferlay J, Bray F, Steliarova-Foucher E and Forman D. Cancer Incidence in Five Continents, CI5plus: IARC CancerBase No. 9 [Internet]. Lyon, France: International Agency for Research on Cancer; 214. Available from: Figure 52: Time trends in vulvar cancer incidence in France (cancer registry data) Annual crude incidence rate (per 1,) All ages yrs yrs No cases were registered for this age group. Data accessed on 27 Apr 215. The following regional cancer registries provided data and contributed to their national estimate: Bas-Rhin, Calvados, Doubs, Haut-Rhin, Herault, Isere, Somme, Tarn. Data sources: Ferlay J, Bray F, Steliarova-Foucher E and Forman D. Cancer Incidence in Five Continents, CI5plus: IARC CancerBase No. 9 [Internet]. Lyon, France: International Agency for Research on Cancer; 214. Available from: Figure 53: Time trends in vulvar cancer incidence in Iceland (cancer registry data) Annual crude incidence rate (per 1,) All ages yrs yrs No cases were registered for this age group. Data accessed on 27 Apr 215. Data was provided by the national registry. Data sources: Ferlay J, Bray F, Steliarova-Foucher E and Forman D. Cancer Incidence in Five Continents, CI5plus: IARC CancerBase No. 9 [Internet]. Lyon, France: International Agency for Research on Cancer; 214. Available from:

70 3 BURDEN OF HPV-RELATED CANCERS Figure 54: Time trends in vulvar cancer incidence in Italy (cancer registry data) Annual crude incidence rate (per 1,) All ages yrs yrs Data accessed on 27 Apr 215. The following regional cancer registries provided data and contributed to their national estimate: Ferrara Province, Florence, Lombardy, Varese province, Modena, Parma, Ragusa Province, Romagna, Sassari Province, Torino. Data sources: Ferlay J, Bray F, Steliarova-Foucher E and Forman D. Cancer Incidence in Five Continents, CI5plus: IARC CancerBase No. 9 [Internet]. Lyon, France: International Agency for Research on Cancer; 214. Available from: Figure 55: Time trends in vulvar cancer incidence in Netherlands (cancer registry data) Annual crude incidence rate (per 1,) All ages yrs yrs Data accessed on 27 Apr 215. Data was provided by the national registry. Data sources: Ferlay J, Bray F, Steliarova-Foucher E and Forman D. Cancer Incidence in Five Continents, CI5plus: IARC CancerBase No. 9 [Internet]. Lyon, France: International Agency for Research on Cancer; 214. Available from: Figure 56: Time trends in vulvar cancer incidence in Poland (cancer registry data) Annual crude incidence rate (per 1,) All ages yrs yrs No cases were registered for this age group. Data accessed on 27 Apr 215. Data was provided by the Cracow City registry. Data sources: Ferlay J, Bray F, Steliarova-Foucher E and Forman D. Cancer Incidence in Five Continents, CI5plus: IARC CancerBase No. 9 [Internet]. Lyon, France: International Agency for Research on Cancer; 214. Available from:

71 3 BURDEN OF HPV-RELATED CANCERS Figure 57: Time trends in vulvar cancer incidence in Russian Federation (cancer registry data) Annual crude incidence rate (per 1,) All ages yrs yrs Data accessed on 27 Apr 215. Data was provided by the St Petersburg registry. Data sources: Ferlay J, Bray F, Steliarova-Foucher E and Forman D. Cancer Incidence in Five Continents, CI5plus: IARC CancerBase No. 9 [Internet]. Lyon, France: International Agency for Research on Cancer; 214. Available from: Figure 58: Time trends in vulvar cancer incidence in Slovakia (cancer registry data) Annual crude incidence rate (per 1,) All ages yrs yrs No cases were registered for this age group. Data accessed on 27 Apr 215. Data was provided by the national registry. Data sources: Ferlay J, Bray F, Steliarova-Foucher E and Forman D. Cancer Incidence in Five Continents, CI5plus: IARC CancerBase No. 9 [Internet]. Lyon, France: International Agency for Research on Cancer; 214. Available from: Figure 59: Time trends in vulvar cancer incidence in Spain (cancer registry data) Annual crude incidence rate (per 1,) All ages yrs yrs No cases were registered for this age group. Data accessed on 27 Apr 215. The following regional cancer registries provided data and contributed to their national estimate: Albacete, Cuenca, Girona, Granada, Murcia, Navarra, Tarragona. Data sources: Ferlay J, Bray F, Steliarova-Foucher E and Forman D. Cancer Incidence in Five Continents, CI5plus: IARC CancerBase No. 9 [Internet]. Lyon, France: International Agency for Research on Cancer; 214. Available from:

72 3 BURDEN OF HPV-RELATED CANCERS Figure 6: Time trends in vulvar cancer incidence in Switzerland (cancer registry data) Annual crude incidence rate (per 1,) All ages yrs yrs No cases were registered for this age group. Data accessed on 27 Apr 215. The following regional cancer registries provided data and contributed to their national estimate: Geneva, Graubunden and Glarus, Neuchatel, St Gall-Appenzell, Valais, Vaud. Data sources: Ferlay J, Bray F, Steliarova-Foucher E and Forman D. Cancer Incidence in Five Continents, CI5plus: IARC CancerBase No. 9 [Internet]. Lyon, France: International Agency for Research on Cancer; 214. Available from: Figure 61: Time trends in vulvar cancer incidence in United Kingdom (cancer registry data) Annual crude incidence rate (per 1,) All ages yrs yrs Data accessed on 27 Apr 215. The following regional cancer registries provided data and contributed to their national estimate: Birmingham and West Midlands Region, East of England Region, Merseyside and Cheshire, North Western, Northern Ireland, Oxford, Scotland, South and Western Regions, Yorkshire. Data sources: Ferlay J, Bray F, Steliarova-Foucher E and Forman D. Cancer Incidence in Five Continents, CI5plus: IARC CancerBase No. 9 [Internet]. Lyon, France: International Agency for Research on Cancer; 214. Available from: NOTE. Time trends in cancer incidence are shown only in countries with available data.

73 3 BURDEN OF HPV-RELATED CANCERS Vaginal cancer Cancer of the vagina is a rare cancer, with an estimated 13, new cases in 28, representing 2% of all gynaecologic cancers (de Martel C et al. Lancet Oncol 212;13(6):67-15). Although unreported and similar to cervical cancer, the majority of vaginal cancer cases (68%) occur in less developed countries. Most vaginal cancers are squamous cell carcinoma (9%) generally attributable to HPV, followed by clear cell adenocarcinomas and melanoma. Metastatic cervical cancer can be misclassified as cancer of the vagina. Invasive vaginal cancer is diagnosed primarily in old women (>=65 years) and the diagnosis is rare in women under 45 years whereas the peak incidence of carcinoma in situ is observed between ages 55 and 7 (Vaccine 28, Vol. 26, Suppl 1) Table 9: Incidence of vaginal cancer in Europe by cancer registry Female Country name Cancer registry Period N cases a Crude rate b ASR b Eastern Europe Belarus 1 National Bulgaria 1 National Czech Republic 1 National Hungary Poland 1 Cracow Kielce Lower Silesia Podkarpackie Republic of Moldova Romania Russian Federation 1 Saint Petersburg Slovakia 1 National Ukraine 1 National Northern Europe Denmark 1 National Estonia 1 National Finland 1 National Iceland 1 National Ireland 1 National Latvia 1 National Lithuania 1 National Norway 1 National Sweden 1 National United Kingdom 1 England England, East of England Region England, North Western England, Northern and Yorkshire England, Oxford Region England, South and Western Regions England, Thames England, Trent England, West Midlands Northern Ireland Scotland Wales Southern Europe Albania Andorra Bosnia & Herzegovina Croatia 1 National Cyprus 1 National (Continued on next page)

74 3 BURDEN OF HPV-RELATED CANCERS ( Table 9 continued from previous page) Female Country name Cancer registry Period N cases a Crude rate b ASR b Greece Italy 1 Biella Brescia Catania and Messina Catanzaro Como Ferrara Florence and Prato Friuli-Venezia Giulia Genoa Latina Lecco Lombardy, South Mantua Milan Modena Naples Nuoro Palermo Parma Ragusa Reggio Emilia Romagna Salerno Sassari Sondrio South Tyrol Syracuse Trapani Trento Turin Umbria Varese Veneto Macedonia Malta 1 National Montenegro Portugal 1 Azores San Marino Serbia 1 Central Slovenia 1 National Spain 1 Albacete Asturias Basque Country Canary Islands Ciudad Real Cuenca Girona Granada La Rioja Mallorca Murcia Navarra (Continued on next page)

75 3 BURDEN OF HPV-RELATED CANCERS ( Table 9 continued from previous page) Female Country name Cancer registry Period N cases a Crude rate b ASR b Tarragona Western Europe Austria 1 National Tyrol Vorarlberg Belgium 1 National France 1 Bas-Rhin Calvados Doubs Haut-Rhin Herault Isere Loire Atlantique Manche Martinique Somme Tarn Vendee Germany 1 Brandenburg Bremen Free State Of Saxony Hamburg Mecklenburg-Western Pomerania Munich North Rhine-Westphalia Saarland Schleswig-Holstein Luxembourg Monaco Netherlands 1 Eindhoven National Switzerland 1 Basel Geneva Graubunden and Glarus Neuchatel St Gall-Appenzell Ticino Valais Vaud Zurich Data accessed on 5 May 215. Please refer to original source (available at a Accumulated number of cases during the period in the population covered by the corresponding registry. b Rates per 1, women per year. Data sources: 1 Forman D, Bray F, Brewster DH, Gombe Mbalawa C, Kohler B, Piñeros M, Steliarova-Foucher E, Swaminathan R and Ferlay J eds (213). Cancer Incidence in Five Continents, Vol. X (electronic version) Lyon, IARC.

76 3 BURDEN OF HPV-RELATED CANCERS Figure 62: Time trends in vaginal cancer incidence in Austria (cancer registry data) Annual crude incidence rate (per 1,) All ages yrs yrs No cases were registered for this age group. Data accessed on 27 Apr 215. The following regional cancer registries provided data and contributed to their national estimate: Tyrol, Vorarlberg. Data sources: Ferlay J, Bray F, Steliarova-Foucher E and Forman D. Cancer Incidence in Five Continents, CI5plus: IARC CancerBase No. 9 [Internet]. Lyon, France: International Agency for Research on Cancer; 214. Available from: Figure 63: Time trends in vaginal cancer incidence in Croatia (cancer registry data) Annual crude incidence rate (per 1,) All ages yrs yrs No cases were registered for this age group. Data accessed on 27 Apr 215. Data was provided by the national registry. Data sources: Ferlay J, Bray F, Steliarova-Foucher E and Forman D. Cancer Incidence in Five Continents, CI5plus: IARC CancerBase No. 9 [Internet]. Lyon, France: International Agency for Research on Cancer; 214. Available from: Figure 64: Time trends in vaginal cancer incidence in Denmark (cancer registry data) Annual crude incidence rate (per 1,) All ages yrs yrs No cases were registered for this age group. Data accessed on 27 Apr 215. Data was provided by the national registry. Data sources: Ferlay J, Bray F, Steliarova-Foucher E and Forman D. Cancer Incidence in Five Continents, CI5plus: IARC CancerBase No. 9 [Internet]. Lyon, France: International Agency for Research on Cancer; 214. Available from:

77 3 BURDEN OF HPV-RELATED CANCERS Figure 65: Time trends in vaginal cancer incidence in Estonia (cancer registry data) Annual crude incidence rate (per 1,) All ages yrs yrs No cases were registered for this age group. Data accessed on 27 Apr 215. Data was provided by the national registry. Data sources: Ferlay J, Bray F, Steliarova-Foucher E and Forman D. Cancer Incidence in Five Continents, CI5plus: IARC CancerBase No. 9 [Internet]. Lyon, France: International Agency for Research on Cancer; 214. Available from: Figure 66: Time trends in vaginal cancer incidence in France (cancer registry data) Annual crude incidence rate (per 1,) All ages yrs yrs No cases were registered for this age group. Data accessed on 27 Apr 215. The following regional cancer registries provided data and contributed to their national estimate: Bas-Rhin, Calvados, Doubs, Haut-Rhin, Herault, Isere, Somme, Tarn. Data sources: Ferlay J, Bray F, Steliarova-Foucher E and Forman D. Cancer Incidence in Five Continents, CI5plus: IARC CancerBase No. 9 [Internet]. Lyon, France: International Agency for Research on Cancer; 214. Available from: Figure 67: Time trends in vaginal cancer incidence in Iceland (cancer registry data) Annual crude incidence rate (per 1,) All ages yrs yrs No cases were registered for this age group. Data accessed on 27 Apr 215. Data was provided by the national registry. Data sources: Ferlay J, Bray F, Steliarova-Foucher E and Forman D. Cancer Incidence in Five Continents, CI5plus: IARC CancerBase No. 9 [Internet]. Lyon, France: International Agency for Research on Cancer; 214. Available from:

78 3 BURDEN OF HPV-RELATED CANCERS Figure 68: Time trends in vaginal cancer incidence in Italy (cancer registry data) Annual crude incidence rate (per 1,) All ages yrs yrs No cases were registered for this age group. Data accessed on 27 Apr 215. The following regional cancer registries provided data and contributed to their national estimate: Ferrara Province, Florence, Lombardy, Varese province, Modena, Parma, Ragusa Province, Romagna, Sassari Province, Torino. Data sources: Ferlay J, Bray F, Steliarova-Foucher E and Forman D. Cancer Incidence in Five Continents, CI5plus: IARC CancerBase No. 9 [Internet]. Lyon, France: International Agency for Research on Cancer; 214. Available from: Figure 69: Time trends in vaginal cancer incidence in Netherlands (cancer registry data) Annual crude incidence rate (per 1,) All ages yrs yrs No cases were registered for this age group. Data accessed on 27 Apr 215. Data was provided by the national registry. Data sources: Ferlay J, Bray F, Steliarova-Foucher E and Forman D. Cancer Incidence in Five Continents, CI5plus: IARC CancerBase No. 9 [Internet]. Lyon, France: International Agency for Research on Cancer; 214. Available from: Figure 7: Time trends in vaginal cancer incidence in Poland (cancer registry data) Annual crude incidence rate (per 1,) All ages yrs yrs No cases were registered for this age group. Data accessed on 27 Apr 215. Data was provided by the Cracow City registry. Data sources: Ferlay J, Bray F, Steliarova-Foucher E and Forman D. Cancer Incidence in Five Continents, CI5plus: IARC CancerBase No. 9 [Internet]. Lyon, France: International Agency for Research on Cancer; 214. Available from:

79 3 BURDEN OF HPV-RELATED CANCERS Figure 71: Time trends in vaginal cancer incidence in Russian Federation (cancer registry data) Annual crude incidence rate (per 1,) All ages yrs yrs No cases were registered for this age group. Data accessed on 27 Apr 215. Data was provided by the St Petersburg registry. Data sources: Ferlay J, Bray F, Steliarova-Foucher E and Forman D. Cancer Incidence in Five Continents, CI5plus: IARC CancerBase No. 9 [Internet]. Lyon, France: International Agency for Research on Cancer; 214. Available from: Figure 72: Time trends in vaginal cancer incidence in Slovakia (cancer registry data) Annual crude incidence rate (per 1,) All ages yrs yrs No cases were registered for this age group. Data accessed on 27 Apr 215. Data was provided by the national registry. Data sources: Ferlay J, Bray F, Steliarova-Foucher E and Forman D. Cancer Incidence in Five Continents, CI5plus: IARC CancerBase No. 9 [Internet]. Lyon, France: International Agency for Research on Cancer; 214. Available from: Figure 73: Time trends in vaginal cancer incidence in Spain (cancer registry data) Annual crude incidence rate (per 1,) All ages yrs yrs No cases were registered for this age group. Data accessed on 27 Apr 215. The following regional cancer registries provided data and contributed to their national estimate: Albacete, Cuenca, Girona, Granada, Murcia, Navarra, Tarragona. Data sources: Ferlay J, Bray F, Steliarova-Foucher E and Forman D. Cancer Incidence in Five Continents, CI5plus: IARC CancerBase No. 9 [Internet]. Lyon, France: International Agency for Research on Cancer; 214. Available from:

80 3 BURDEN OF HPV-RELATED CANCERS Figure 74: Time trends in vaginal cancer incidence in Switzerland (cancer registry data) Annual crude incidence rate (per 1,) All ages yrs yrs No cases were registered for this age group. Data accessed on 27 Apr 215. The following regional cancer registries provided data and contributed to their national estimate: Geneva, Graubunden and Glarus, Neuchatel, St Gall-Appenzell, Valais, Vaud. Data sources: Ferlay J, Bray F, Steliarova-Foucher E and Forman D. Cancer Incidence in Five Continents, CI5plus: IARC CancerBase No. 9 [Internet]. Lyon, France: International Agency for Research on Cancer; 214. Available from: Figure 75: Time trends in vaginal cancer incidence in United Kingdom (cancer registry data) Annual crude incidence rate (per 1,) All ages yrs yrs Data accessed on 27 Apr 215. The following regional cancer registries provided data and contributed to their national estimate: Birmingham and West Midlands Region, East of England Region, Merseyside and Cheshire, North Western, Northern Ireland, Oxford, Scotland, South and Western Regions, Yorkshire. Data sources: Ferlay J, Bray F, Steliarova-Foucher E and Forman D. Cancer Incidence in Five Continents, CI5plus: IARC CancerBase No. 9 [Internet]. Lyon, France: International Agency for Research on Cancer; 214. Available from: NOTE. Time trends in cancer incidence are shown only in countries with available data.

81 3 BURDEN OF HPV-RELATED CANCERS Penile cancer The annual burden of penile cancer has been estimated to be 22, cases worldwide with incidence rates strongly correlating with those of cervical cancer (de Martel C et al. Lancet Oncol 212;13(6):67-15). Penile cancer is rare and most commonly affects men aged 5-7 years. Incidence rates are higher in less developed countries than in more developed countries, accounting for up to 1% of male cancers in some parts of Africa, South America and Asia. Precursor cancerous penile lesions (PeIN) are rare. Cancers of the penis are primarily of squamous cell carcinomas (SCC) (95%) and the most common penile SCC histologic sub-types are keratinising (49%), mixed warty-basaloid (17%), verrucous (8%) warty (6%), and basaloid (4%). HPV is most commonly detected in basaloid and warty tumours but is less common in keratinising and verrucous tumours. Approximately 6-1% of PeIN lesions are HPV DNA positive. Table 1: Incidence of penile cancer in Europe by cancer registry Male Country name Cancer registry Period N cases a Crude rate b ASR b Eastern Europe Belarus 1 National Bulgaria 1 National Czech Republic 1 National Hungary 2 County Szabolcs-Szatmar County Vas Poland 1 Cracow Kielce Lower Silesia Podkarpackie Republic of Moldova Romania 2 County Cluj Russian Federation 1 Saint Petersburg Slovakia 1 National Ukraine 1 National Northern Europe Denmark 1 National Estonia 1 National Finland 1 National Iceland 1 National Ireland 1 National Latvia 1 National Lithuania 1 National Norway 1 National Sweden 1 National United Kingdom 1 England England, East of England Region England, North Western England, Northern and Yorkshire England, Oxford Region England, South and Western Regions England, Thames England, Trent England, West Midlands Northern Ireland Scotland Wales Southern Europe Albania Andorra (Continued on next page)

82 3 BURDEN OF HPV-RELATED CANCERS ( Table 1 continued from previous page) Male Country name Cancer registry Period N cases a Crude rate b ASR b Bosnia & Herzegovina Croatia 1 National Cyprus 1 National Greece Italy 1 Biella Brescia Catania and Messina Catanzaro Como Ferrara Florence and Prato Friuli-Venezia Giulia Genoa Latina Lecco Lombardy, South Mantua Milan Modena Naples Nuoro Palermo Parma Ragusa Reggio Emilia Romagna Salerno Sassari Sondrio South Tyrol Syracuse Trapani Trento Turin Umbria Varese Veneto Macedonia Malta 1 National Montenegro Portugal 1 Azores San Marino Serbia 1 Central Slovenia 1 National Spain 1 Albacete Asturias Basque Country Canary Islands Ciudad Real Cuenca Girona Granada (Continued on next page)

83 3 BURDEN OF HPV-RELATED CANCERS ( Table 1 continued from previous page) Male Country name Cancer registry Period N cases a Crude rate b ASR b La Rioja Mallorca Murcia Navarra Tarragona Western Europe Austria 1 National Tyrol Vorarlberg Belgium 1 National France 1 Bas-Rhin Calvados Doubs Haut-Rhin Herault Isere Loire Atlantique Manche Martinique Somme Tarn Vendee Germany 1 Brandenburg Bremen Free State Of Saxony Hamburg Mecklenburg-Western Pomerania Munich North Rhine-Westphalia Saarland Schleswig-Holstein Luxembourg Monaco Netherlands 1 Eindhoven National Switzerland 1 Basel Geneva Graubunden and Glarus Neuchatel St Gall-Appenzell Ticino Valais Vaud Zurich Data accessed on 5 May 215. Please refer to original source (available at a Accumulated number of cases during the period in the population covered by the corresponding registry. b Rates per 1, men per year. Data sources: 1 Forman D, Bray F, Brewster DH, Gombe Mbalawa C, Kohler B, Piñeros M, Steliarova-Foucher E, Swaminathan R and Ferlay J eds (213). Cancer Incidence in Five Continents, Vol. X (electronic version) Lyon, IARC. 2 Parkin, D.M.,Muir, C.S.,Whelan, S.L.,Gao, Y.-T.,Ferlay, J.,Powell, J., eds (1992). Cancer Incidence in Five Continents, Vol. VI. IARC Scientific Publications No. 12, Lyon, IARC.

84 3 BURDEN OF HPV-RELATED CANCERS Figure 76: Time trends in penile cancer incidence in Austria (cancer registry data) Annual crude incidence rate (per 1,) All ages yrs yrs No cases were registered for this age group. Data accessed on 27 Apr 215. The following regional cancer registries provided data and contributed to their national estimate: Tyrol, Vorarlberg. Data sources: Ferlay J, Bray F, Steliarova-Foucher E and Forman D. Cancer Incidence in Five Continents, CI5plus: IARC CancerBase No. 9 [Internet]. Lyon, France: International Agency for Research on Cancer; 214. Available from: Figure 77: Time trends in penile cancer incidence in Croatia (cancer registry data) Annual crude incidence rate (per 1,) All ages yrs yrs No cases were registered for this age group. Data accessed on 27 Apr 215. Data was provided by the national registry. Data sources: Ferlay J, Bray F, Steliarova-Foucher E and Forman D. Cancer Incidence in Five Continents, CI5plus: IARC CancerBase No. 9 [Internet]. Lyon, France: International Agency for Research on Cancer; 214. Available from: Figure 78: Time trends in penile cancer incidence in Denmark (cancer registry data) Annual crude incidence rate (per 1,) All ages yrs yrs No cases were registered for this age group. Data accessed on 27 Apr 215. Data was provided by the national registry. Data sources: Ferlay J, Bray F, Steliarova-Foucher E and Forman D. Cancer Incidence in Five Continents, CI5plus: IARC CancerBase No. 9 [Internet]. Lyon, France: International Agency for Research on Cancer; 214. Available from:

85 3 BURDEN OF HPV-RELATED CANCERS Figure 79: Time trends in penile cancer incidence in Estonia (cancer registry data) Annual crude incidence rate (per 1,) All ages yrs yrs No cases were registered for this age group. Data accessed on 27 Apr 215. Data was provided by the national registry. Data sources: Ferlay J, Bray F, Steliarova-Foucher E and Forman D. Cancer Incidence in Five Continents, CI5plus: IARC CancerBase No. 9 [Internet]. Lyon, France: International Agency for Research on Cancer; 214. Available from: Figure 8: Time trends in penile cancer incidence in France (cancer registry data) Annual crude incidence rate (per 1,) All ages yrs yrs No cases were registered for this age group. Data accessed on 27 Apr 215. The following regional cancer registries provided data and contributed to their national estimate: Bas-Rhin, Calvados, Doubs, Haut-Rhin, Herault, Isere, Somme, Tarn. Data sources: Ferlay J, Bray F, Steliarova-Foucher E and Forman D. Cancer Incidence in Five Continents, CI5plus: IARC CancerBase No. 9 [Internet]. Lyon, France: International Agency for Research on Cancer; 214. Available from: Figure 81: Time trends in penile cancer incidence in Iceland (cancer registry data) Annual crude incidence rate (per 1,) All ages yrs yrs No cases were registered for this age group. Data accessed on 27 Apr 215. Data was provided by the national registry. Data sources: Ferlay J, Bray F, Steliarova-Foucher E and Forman D. Cancer Incidence in Five Continents, CI5plus: IARC CancerBase No. 9 [Internet]. Lyon, France: International Agency for Research on Cancer; 214. Available from:

86 3 BURDEN OF HPV-RELATED CANCERS Figure 82: Time trends in penile cancer incidence in Italy (cancer registry data) Annual crude incidence rate (per 1,) All ages yrs yrs No cases were registered for this age group. Data accessed on 27 Apr 215. The following regional cancer registries provided data and contributed to their national estimate: Ferrara Province, Florence, Lombardy, Varese province, Modena, Parma, Ragusa Province, Romagna, Sassari Province, Torino. Data sources: Ferlay J, Bray F, Steliarova-Foucher E and Forman D. Cancer Incidence in Five Continents, CI5plus: IARC CancerBase No. 9 [Internet]. Lyon, France: International Agency for Research on Cancer; 214. Available from: Figure 83: Time trends in penile cancer incidence in Netherlands (cancer registry data) Annual crude incidence rate (per 1,) All ages yrs yrs Data accessed on 27 Apr 215. Data was provided by the national registry. Data sources: Ferlay J, Bray F, Steliarova-Foucher E and Forman D. Cancer Incidence in Five Continents, CI5plus: IARC CancerBase No. 9 [Internet]. Lyon, France: International Agency for Research on Cancer; 214. Available from: Figure 84: Time trends in penile cancer incidence in Poland (cancer registry data) Annual crude incidence rate (per 1,) All ages yrs yrs No cases were registered for this age group. Data accessed on 27 Apr 215. Data was provided by the Cracow City registry. Data sources: Ferlay J, Bray F, Steliarova-Foucher E and Forman D. Cancer Incidence in Five Continents, CI5plus: IARC CancerBase No. 9 [Internet]. Lyon, France: International Agency for Research on Cancer; 214. Available from:

87 3 BURDEN OF HPV-RELATED CANCERS Figure 85: Time trends in penile cancer incidence in Russian Federation (cancer registry data) Annual crude incidence rate (per 1,) All ages yrs yrs No cases were registered for this age group. Data accessed on 27 Apr 215. Data was provided by the St Petersburg registry. Data sources: Ferlay J, Bray F, Steliarova-Foucher E and Forman D. Cancer Incidence in Five Continents, CI5plus: IARC CancerBase No. 9 [Internet]. Lyon, France: International Agency for Research on Cancer; 214. Available from: Figure 86: Time trends in penile cancer incidence in Slovakia (cancer registry data) Annual crude incidence rate (per 1,) All ages yrs yrs No cases were registered for this age group. Data accessed on 27 Apr 215. Data was provided by the national registry. Data sources: Ferlay J, Bray F, Steliarova-Foucher E and Forman D. Cancer Incidence in Five Continents, CI5plus: IARC CancerBase No. 9 [Internet]. Lyon, France: International Agency for Research on Cancer; 214. Available from: Figure 87: Time trends in penile cancer incidence in Spain (cancer registry data) Annual crude incidence rate (per 1,) All ages yrs yrs No cases were registered for this age group. Data accessed on 27 Apr 215. The following regional cancer registries provided data and contributed to their national estimate: Albacete, Cuenca, Girona, Granada, Murcia, Navarra, Tarragona. Data sources: Ferlay J, Bray F, Steliarova-Foucher E and Forman D. Cancer Incidence in Five Continents, CI5plus: IARC CancerBase No. 9 [Internet]. Lyon, France: International Agency for Research on Cancer; 214. Available from:

88 3 BURDEN OF HPV-RELATED CANCERS Figure 88: Time trends in penile cancer incidence in Switzerland (cancer registry data) Annual crude incidence rate (per 1,) All ages yrs yrs No cases were registered for this age group. Data accessed on 27 Apr 215. The following regional cancer registries provided data and contributed to their national estimate: Geneva, Graubunden and Glarus, Neuchatel, St Gall-Appenzell, Valais, Vaud. Data sources: Ferlay J, Bray F, Steliarova-Foucher E and Forman D. Cancer Incidence in Five Continents, CI5plus: IARC CancerBase No. 9 [Internet]. Lyon, France: International Agency for Research on Cancer; 214. Available from: Figure 89: Time trends in penile cancer incidence in United Kingdom (cancer registry data) Annual crude incidence rate (per 1,) All ages yrs yrs Data accessed on 27 Apr 215. The following regional cancer registries provided data and contributed to their national estimate: Birmingham and West Midlands Region, East of England Region, Merseyside and Cheshire, North Western, Northern Ireland, Oxford, Scotland, South and Western Regions, Yorkshire. Data sources: Ferlay J, Bray F, Steliarova-Foucher E and Forman D. Cancer Incidence in Five Continents, CI5plus: IARC CancerBase No. 9 [Internet]. Lyon, France: International Agency for Research on Cancer; 214. Available from: NOTE. Time trends in cancer incidence are shown only in countries with available data.

89 3 BURDEN OF HPV-RELATED CANCERS Head and neck cancers The majority of head and neck cancers are associated with high tobacco and alcohol consumption. However, increasing trends in the incidence at specific sites suggest that other aetiological factors are involved, and infection by certain high-risk types of HPV (i.e. HPV16) have been reported to be associated with head and neck cancers, in particular with oropharyngeal cancer. Current evidence suggests that HPV16 is associated with tonsil cancer (including Waldeyer ring cancer), base of tongue cancer and other oropharyngeal cancer sites. Associations with other head and neck cancer sites such as oral cancer are neither strong nor consistent when compared to molecular-epidemiological data on HPV and oropharyngeal cancer. Association with laryngeal cancer is still unclear (IARC Monograph Vol 1B). Figure 9: Age-standardised incidence rates of head and neck cancer in Europe (estimates for 212) Data accessed on 8 May 217. ASR: Age-standardized rate, rates per 1, per year. Please refer to original source for methods. Head and neck cancer cases (oropharynx, oral cavity and larynx). GLOBOCAN quality index for availability of incidence data: - For Albania, Greece, Hungary, Republic of Moldova, Macedonia, Montenegro: No data. - For Austria, Belgium, Bulgaria, Belarus, Cyprus, Czech Republic, Denmark, Estonia, Finland, United Kingdom, Croatia, Ireland, Iceland, Lithuania, Latvia, Malta, Netherlands, Norway, Slovakia, Slovenia, Sweden, Ukraine: High quality national data or high quality regional (coverage greater than 5%). - For Bosnia & Herzegovina, Luxembourg, Russian Federation: National data (rates). - For Switzerland, Germany, Spain, France, Italy, Serbia: High quality regional (coverage between 1% and 5%). - For Poland, Portugal: High quality regional (coverage lower than 1%). - For Romania: Regional data (rates). GLOBOCAN quality index of methods for calculating incidence: Methods to estimate the sex- and age-specific incidence rates of cancer for a specific country: - For Albania, Greece, Hungary, Luxembourg, Republic of Moldova, Macedonia, Portugal, Romania, Serbia: Estimated from national mortality estimates by modelling using incidence mortality ratios derived from recorded data in local cancer registries in neighbouring countries - For Austria, Bulgaria, Belarus, Czech Republic, Germany, Denmark, Estonia, Finland, United Kingdom, Croatia, Ireland, Iceland, Lithuania, Latvia, Malta, Netherlands, Norway, Russian Federation, Slovakia, Slovenia, Sweden: Rates projected to For Belgium, Bosnia & Herzegovina, Cyprus, Ukraine: Most recent rates applied to 212 population - For Switzerland, Spain, France, Italy, Poland: Estimated from national mortality by modelling using incidence mortality ratios derived from recorded data in country-specific cancer registries - For Montenegro: The rates are those of neighbouring countries or registries in the same area Data sources: Worldwide burden of cancer attributable to HPV by site, country and HPV type. de Martel C, Plummer M, Vignat J, Franceschi S. Int J Cancer. 217 Apr 1. doi: 1.12/ijc [Epub ahead of print]. PMID:

90 3 BURDEN OF HPV-RELATED CANCERS Figure 91: Age-standardised incidence rate of head and neck cancer cases attributable to HPV by country in Europe (estimates for 212) Hungary Slovakia Romania France Germany Belgium Moldova Denmark Czech Rep. Belarus Poland Luxembourg Switzerland Austria Ukraine Lithuania Russia Portugal UK Bulgaria Netherlands Latvia Ireland Estonia Slovenia Serbia Norway Croatia Sweden Montenegro Finland Spain Malta Italy Iceland Bosnia & H. Macedonia Albania Greece Cyprus San Marino Monaco Liechtenstein Andorra Age standardised incidence rate per 1, women World Standard No rates are available. Data accessed on 8 May 217. ASR: Age-standardized rate, rates per 1, per year. Please refer to original source for methods. (Continued on next page)

91 3 BURDEN OF HPV-RELATED CANCERS Head and neck cancer cases (oropharynx, oral cavity and larynx). ( Figure 91 continued from previous page) GLOBOCAN quality index for availability of incidence data: - For Cyprus, Iceland, Malta, Finland, Sweden, Croatia, Norway, Slovenia, Estonia, Ireland, Latvia, Netherlands, Bulgaria, United Kingdom, Lithuania, Ukraine, Austria, Belarus, Czech Republic, Denmark, Belgium, Slovakia: High quality national data or high quality regional (coverage greater than 5%). - For Greece, Albania, Macedonia, Montenegro, Republic of Moldova, Hungary: No data. - For Bosnia & Herzegovina, Russian Federation, Luxembourg: National data (rates). - For Italy, Spain, Serbia, Switzerland, Germany, France: High quality regional (coverage between 1% and 5%). - For Portugal, Poland: High quality regional (coverage lower than 1%). - For Romania: Regional data (rates). GLOBOCAN quality index of methods for calculating incidence: Methods to estimate the sex- and age-specific incidence rates of cancer for a specific country: - For Cyprus, Bosnia & Herzegovina, Ukraine, Belgium: Most recent rates applied to 212 population - For Greece, Albania, Macedonia, Serbia, Portugal, Luxembourg, Republic of Moldova, Romania, Hungary: Estimated from national mortality estimates by modelling using incidence mortality ratios derived from recorded data in local cancer registries in neighbouring countries - For Iceland, Malta, Finland, Sweden, Croatia, Norway, Slovenia, Estonia, Ireland, Latvia, Netherlands, Bulgaria, United Kingdom, Russian Federation, Lithuania, Austria, Belarus, Czech Republic, Denmark, Germany, Slovakia: Rates projected to For Italy, Spain, Switzerland, Poland, France: Estimated from national mortality by modelling using incidence mortality ratios derived from recorded data in country-specific cancer registries - For Montenegro: The rates are those of neighbouring countries or registries in the same area Data sources: de Martel C, Plummer M, Vignat J, Franceschi S. Worldwide burden of cancer attributable to HPV by site, country and HPV type. Int J Cancer Pharyngeal cancer (excluding nasopharynx) Table 11: Cancer incidence of pharynx (excluding nasopharynx) in Europe and its regions by sex. Includes ICD-1 codes: C9-1, C12-14 (estimates for 212). MALE FEMALE Area N cases Crude a ASR a Cum risk b N cases Crude a ASR a Cum risk b rate (%) ages rate (%) ages Europe Eastern Europe Belarus Bulgaria Czech Rep Hungary Moldova Poland Romania Russia Slovakia Ukraine Northern Europe Denmark Estonia Finland Iceland Ireland Latvia Lithuania Norway Sweden UK Southern Europe Albania Andorra - - Bosnia & H Croatia Cyprus Greece Italy Macedonia Malta Montenegro Portugal San Marino - - Serbia Slovenia Spain Western Europe Austria Belgium France (Continued on next page)

92 3 BURDEN OF HPV-RELATED CANCERS ( Table 11 continued from previous page) MALE FEMALE Area N cases Crude a ASR a Cum risk b N cases Crude a ASR a Cum risk b rate (%) ages rate (%) ages Germany Liechtenstein - - Luxembourg Monaco - - Netherlands Switzerland Data accessed on 15 Nov 215. a Male: Rates per 1, men per year. Female: Rates per 1, women per year. b Cumulative risk (incidence) is the probability or risk of individuals getting from the disease during ages -74 years. For cancer, it is expressed as the % of new born children who would be expected to develop from a particular cancer before the age of 75 if they had the rates of cancer observed in the period in the absence of competing causes. Data sources: Ferlay J, Soerjomataram I, Ervik M, Dikshit R, Eser S, Mathers C, Rebelo M, Parkin DM, Forman D, Bray F. GLOBOCAN 212 v1.2, Cancer Incidence and Mortality Worldwide: IARC CancerBase No. 11 [Internet]. Lyon, France: International Agency for Research on Cancer; 213. Available from: Table 12: Cancer mortality of pharynx (excluding nasopharynx) in Europe and its regions by sex. Includes ICD-1 codes: C9-1, C12-14 (estimates for 212). MALE FEMALE Area N cases Crude a ASR a Cum risk b N cases Crude a ASR a Cum risk b rate (%) ages rate (%) ages Europe Eastern Europe Belarus Bulgaria Czech Rep Hungary Moldova Poland Romania Russia Slovakia Ukraine Northern Europe Denmark Estonia Finland Iceland Ireland Latvia Lithuania Norway Sweden UK Southern Europe Albania Andorra - - Bosnia & H Croatia Cyprus Greece Italy Macedonia Malta Montenegro Portugal San Marino - - Serbia Slovenia Spain Western Europe Austria Belgium France Germany Liechtenstein - - (Continued on next page)

93 3 BURDEN OF HPV-RELATED CANCERS ( Table 12 continued from previous page) MALE FEMALE Area N cases Crude a ASR a Cum risk b N cases Crude a ASR a Cum risk b rate (%) ages rate (%) ages Luxembourg Monaco - - Netherlands Switzerland Data accessed on 15 Nov 215. a Male: Rates per 1, men per year. Female: Rates per 1, women per year. b Cumulative risk (mortality) is the probability or risk of individuals dying from the disease during ages -74 years. For cancer, it is expressed as the % of new born children who would be expected to die from a particular cancer before the age of 75 if they had the rates of cancer observed in the period in the absence of competing causes. Data sources: Ferlay J, Soerjomataram I, Ervik M, Dikshit R, Eser S, Mathers C, Rebelo M, Parkin DM, Forman D, Bray F. GLOBOCAN 212 v1.2, Cancer Incidence and Mortality Worldwide: IARC CancerBase No. 11 [Internet]. Lyon, France: International Agency for Research on Cancer; 213. Available from:

94 3 BURDEN OF HPV-RELATED CANCERS Figure 92: Comparison of cancer incidence and mortality of pharynx (excluding nasopharynx) in males by age group in Europe and its regions. Includes ICD-1 codes: C9-1,C12-14 (estimates for 212). Europe Southern Europe Age specific rates of pharyngeal cancer (excluding nasopharynx) per 1, >=75 Eastern Europe >=75 Northern Europe >=75 Western Europe >=75 Age group (years) >=75 Incidence Mortality Data accessed on 15 Nov 215. For specific estimation methodology refer to European countries included in the Seven framework programme PREHDICT project (43 countries). Please refer to Introduction (link) to see PREHDICT project aim and coverage. Male: Rates per 1, men per year. Female: Rates per 1, women per year. (Continued on next page)

95 3 BURDEN OF HPV-RELATED CANCERS ( Figure 93 continued from previous page) Data sources: Ferlay J, Soerjomataram I, Ervik M, Dikshit R, Eser S, Mathers C, Rebelo M, Parkin DM, Forman D, Bray F. GLOBOCAN 212 v1.2, Cancer Incidence and Mortality Worldwide: IARC CancerBase No. 11 [Internet]. Lyon, France: International Agency for Research on Cancer; 213. Available from:

96 3 BURDEN OF HPV-RELATED CANCERS Figure 93: Comparison of cancer incidence and mortality of pharynx (excluding nasopharynx) in females by age group in Europe and its regions. Includes ICD-1 codes: C9-1,C12-14 (estimates for 212). 1 Europe 1 Southern Europe 5 5 Age specific rates of pharyngeal cancer (excluding nasopharynx) per 1, >=75 1 Eastern Europe >=75 1 Northern Europe >=75 1 Western Europe >=75 Age group (years) >=75 Incidence Mortality Data accessed on 15 Nov 215. For specific estimation methodology refer to (Continued on next page)

97 3 BURDEN OF HPV-RELATED CANCERS ( Figure 93 continued from previous page) Male: Rates per 1, men per year. Female: Rates per 1, women per year. Data sources: Ferlay J, Soerjomataram I, Ervik M, Dikshit R, Eser S, Mathers C, Rebelo M, Parkin DM, Forman D, Bray F. GLOBOCAN 212 v1.2, Cancer Incidence and Mortality Worldwide: IARC CancerBase No. 11 [Internet]. Lyon, France: International Agency for Research on Cancer; 213. Available from:

98 4 HPV-RELATED STATISTICS HPV-related statistics HPV infection is commonly found in the anogenital tract of men and women with and without clinical lesions. The aetiological role of HPV infection among women with cervical cancer is well-established, and there is growing evidence of its central role in other anogenital sites. This section presents the HPV burden at each of the anogenital tract sites. The methodologies used to compile the information on HPV burden are derived from systematic reviews and meta-analyses of the literature. Due to the limitations of HPV DNA detection methods and study designs used, these data should be interpreted with caution and used only as a guide to assess the burden of HPV infection within the population (Vaccine 26, Vol. 24, Suppl 3; Vaccine 28, Vol. 26, Suppl 1; Vaccine 212,Vol. 3, Suppl 5; IARC Monographs 27, Vol. 9) 4.1 HPV burden in women with normal cervical cytology, cervical precancerous lesions or invasive cervical cancer The statistics shown in this section focus on HPV infection in the cervix uteri. HPV cervical infection results in cervical morphological lesions ranging from normalcy (cytologically normal women) to different stages of precancerous lesions (CIN-1, CIN-2, CIN-3/CIS) and invasive cervical cancer. HPV infection is measured by HPV DNA detection in cervical cells (fresh tissue, paraffin embedded or exfoliated cells). The prevalence of HPV increases with lesion severity. HPV causes virtually 1% of cervical cancer cases, and an underestimation of HPV prevalence in cervical cancer is most likely due to the limitations of study methodologies. Worldwide, HPV16 and 18 (the two vaccine-preventable types) contribute to over 7% of all cervical cancer cases, between 41% and 67% of high-grade cervical lesions and 16-32% of low-grade cervical lesions. After HPV16/18, the six most common HPV types are the same in all world regions, namely 31, 33, 35, 45, 52 and 58; these account for an additional 2% of cervical cancers worldwide (Clifford G, Vaccine 26;24(S3):26). Methods: Prevalence and type distribution of human papillomavirus in cervical carcinoma, low-grade cervical lesions, high-grade cervical lesions and normal cytology: systematic review and meta-analysis A systematic review of the literature was conducted regarding the worldwide HPV-prevalence and type distribution for cervical carcinoma, low-grade cervical lesions, high-grade cervical lesions and normal cytology from 199 to data as of indicated in each section. The search terms for the review were HPV AND cerv using Pubmed. There were no limits in publication language. References cited in selected articles were also investigated. Inclusion criteria were: HPV DNA detection by means of PCR or HC2, a minimum of 2 cases for cervical carcinoma, 2 cases for low-grade cervical lesions, 2 cases for highgrade cervical lesions and 1 cases for normal cytology and a detailed description of HPV DNA detection and genotyping techniques used. The number of cases tested and HPV positive extracted for each study were pooled to estimate the prevalence of HPV DNA and the HPV type distribution globally and by geographical region. Binomial 95% confidence intervals were calculated for each HPV prevalence. For more details refer to the methods document.

99 4 HPV-RELATED STATISTICS HPV prevalence in women with normal cervical cytology Figure 94: Prevalence of HPV among women with normal cervical cytology in Europe Data updated on 15 Dec 216 (data as of 3 Jun 215). The samples for HPV testing come from cervical specimens (fresh / fixed biopsies or exfoliated cells). Data sources: See references in Section 9.

100 4 HPV-RELATED STATISTICS Figure 95: Crude age-specific HPV prevalence (%) and 95% confidence interval in women with normal cervical cytology in Europe and its regions Europe Southern Europe < < Eastern Europe Western Europe < < Northern Europe < Data updated on 15 Dec 216 (data as of 3 Jun 215). Data sources: See references in Section 9.

101 4 HPV-RELATED STATISTICS Figure 96: Prevalence of HPV among women with normal cervical cytology in Europe by country and study Country Study Age N % (95% CI) Belarus Rogovskaya 213 (Minsk) ( ) Belgium Depuydt 21 (Flanders) a , ( ) Arbyn 29 (Antwerp) , ( ) Merckx 214 a,b , ( ) Baay 25 (Antwerp) 2 5 2, (5.9 8.) Depuydt , ( ) Schmitt 213 (Flanders) ( ) Weyn 213 (Brussels) >= (9. 13.) Depuydt 23 (Flanders) ( ) Baay 21 (Antwerp) ( ) Bulgaria Kovachev 213 a,c , ( ) Croatia Kaliterna 213 (Dalmatia County) a , ( ) Kaliterna 27 a,d ( ) Grahovac 27 (Zagreb,Rijeka) ( ) Czech Rep. Tachezy , ( ) Denmark Kjær 214 (Copenhagen) e , (2. 2.8) Nielsen 28 (Copenhagen) , ( ) Bonde 214 f , ( ) Nielsen 28 (Copenhagen) 4 5 1, ( ) Svare ( ) Estonia Uusküla 21 (Tartu) a ( ) Europe Joura , ( ) Paavonen 28 g , ( ) Finland Malila 213 a , ( ) Auvinen 25 (Helsinki) a , ( ) France Clavel 21 (Reims) , ( ) Monsonego 211 (Paris) , ( ) Boulanger 24 (Amiens) , ( ) Heard 213 h , ( ) Vaucel 211 (Nantes) ( ) Baudu 214 (Franche Comté) ( ) Dalstein 23 (Besançon) ( ) Haguenoer ( ) Beby Defaux 24 (Poitiers) ( ) Riethmuller 1999 i ( ) Casalegno 211 (Lyon) ( ) Pannier Stockman 28 (Amiens) ( ) Monsonego 25 (Paris) ( ) Germany Luyten 214 (Wolfsburg) 23, ( ) Petry 23 j , ( ) % 1% 2% 3% 4% 5% 6% (Continued on next page) Data updated on 15 Dec 216 (data as of 3 Jun 215). 95% CI: 95% Confidence Interval; N: number of women tested; The samples for HPV testing come from cervical specimens (fresh/fixed biopsies or exfoliated cells). The line represents the 95% confidence interval and the shadowed square is proportional to the sample size. a Women from the general population, including some with cytological cervical abnormalities (Continued on next page)

102 4 HPV-RELATED STATISTICS ( Figure 96 continued from previous page) b Flanders and Brussels c Sofia, Plovdiv, Varna, Burgas, Pleven and Vidin d Split and Dalmatian County e HPV prevalence for high-risk HPV types f Copenhagen and Frederiksberg g Czech Republic, Denmark, England, Finland, France, Germany, Greece, Iceland, Ireland, Italy, Netherlands, Norway, Poland, Portugal, Spain, and Sweden h Alsace, Auvergne, Centre - Pays de Loire, Ile-de-France and Vaucluse i Besançon, Belfort j Hannover and Tuebingen Data sources: See references in Section 9.

103 4 HPV-RELATED STATISTICS Figure 97: Prevalence of HPV among women with normal cervical cytology in Europe by country and study (continued) Country Study Age N % (95% CI) Germany Schneider 2 (East Thuringia) , ( ) Iftner , ( ) de Jonge 213 a >=2 1, ( ) Petry 213 (Wolfsburg) ( ) Petry 213 (Wolfsburg) b ( ) Greece Agorastos 214 b 5, ( ) Agorastos 215 c , ( ) Argyri 213 (Athens) , ( ) Tsiodras 211 1, ( ) Agorastos 24 d , (1.4 3.) Tsiodras 21 (Athens) , ( ) Paraskevaidis 21 (Ioannina) ( ) Panotopoulou 27 (Athens) ( ) Hungary Nyári ( ) Ireland Anderson 213 (Northern Ireland) , ( ) Keegan 27 (Dublin) ( ) Italy Del Mistro 214 (Veneto) b , ( ) Carozzi 214 e , ( ) Agarossi , ( ) Giorgi Rossi 211 f , ( ) Tenti 1997 (Pavia) , ( ) Ronco 25 (Turin) ( ) Giambi 213 g ( ) Ammatuna 28 (Sicily) ( ) Del Prete 28 (Apulia) b >= ( ) Verteramo 29 (Rome) ( ) Panatto 213 h ( ) Centurioni 25 (Genova) ( ) Salfa 211 (Asti) ( ) Sammarco 213 (Molise) ( ) Barzon 21 (Padova) ( ) Carozzi 2 (Florence) (3.2 8.) Masia 29 (Sardinia) ( ) Bellaminutti 214 b ( ) Piana 211 (North Sardinia) ( ) Zappacosta 29 (Molise) ( ) Astori 1997 (Udine) ( ) Tornesello 26 (Milan, Naples) ( ) Tornesello 28 (Naples) ( ) Latvia Silins 24 b ( ) % 1% 2% 3% 4% 5% (Continued on next page) Data updated on 15 Dec 216 (data as of 3 Jun 215). 95% CI: 95% Confidence Interval; N: number of women tested; The samples for HPV testing come from cervical specimens (fresh/fixed biopsies or exfoliated cells). The line represents the 95% confidence interval and the shadowed square is proportional to the sample size. a Nordrhein-Westfalen, Niedersachsen, Schleswig-Holstein, Bremen and Hamburg (Continued on next page)

104 4 HPV-RELATED STATISTICS ( Figure 97 continued from previous page) b Women from the general population, including some with cytological cervical abnormalities c Athens, Thessaloniki, Larissa, Patrasand Alexandroupolis d Thessaloniki, Thermi, Mihaniona, Corfu, Veria and Serres e Turin, Padua, Trento and Florence f Abruzzo, Campania, Lazio, Sardinia and Sicily g Abruzzo, Campania, Lazio, Tuscany, Emilia-Romagna and Piedmont h Turin, Milan and Genoa Data sources: See references in Section 9.

105 4 HPV-RELATED STATISTICS Figure 98: Prevalence of HPV among women with normal cervical cytology in Europe by country and study (continued) Country Study Age N % (95% CI) Lithuania Kliucinskas 26 a , ( ) Gudleviciene 25 (Vilnius) ( ) Simanaviciene 214 (Vilnius) ( ) Bumbuliene 212 (Vilnius) a ( ) Montenegro Vujosevic 212 (Podgorica) a ( ) Netherlands Rijkaart 212 (Utrecht) , ( ) Bulkmans 24 (Amsterdam) , ( ) Rijkaart , ( ) Jacobs 2 (Amsterdam) , ( ) Rozendaal 2 (Amsterdam) , ( ) Lenselink 28 a,b , ( ) Boers ( ) Hesselink 213 (Utrecht region) ( ) Zielinski 21 (Zeeland) ( ) Norway Molden 25 (Oslo) , ( ) Skjeldestad 28 a,c ( ) Molden 26 (Oslo) <= ( ) Gjøoen 1996 (Oslo) ( ) Poland Bardin 28 (Warsaw) ( ) Portugal Pista , ( ) Vieira ( ) Pista 211 d ( ) Dutra 28 (Açores) a ( ) Romania Moga 214 (Brasov County) ( ) Ursu 211 (Northeast) ( ) Russia Bdaizieva 21 (Moscow) a , ( ) Kubanov 25 (Moscow) 8, ( ) Goncharevskaya 211 (Moscow) , ( ) Rogovskaya 213 e ( ) Shipitsyna 211 (St Petersburg) ( ) Komarova 21 (Moscow) ( ) Alexandrova 1999 f ( ) Shargorodskaya 211 (Moscow) ( ) Shipulina 211 (Moscow) ( ) Slovenia Ucakar , ( ) Ucakar ( ) Spain Castellsagué , ( ) Martorell 21 (Valencia) a , ( ) Bernal 28 (Zaragoza) 1, ( ) Dillner 28 (Maresme) ( ) % 1% 2% 3% 4% 5% 6% (Continued on next page) Data updated on 15 Dec 216 (data as of 3 Jun 215). 95% CI: 95% Confidence Interval; N: number of women tested; The samples for HPV testing come from cervical specimens (fresh/fixed biopsies or exfoliated cells). The line represents the 95% confidence interval and the shadowed square is proportional to the sample size. a Women from the general population, including some with cytological cervical abnormalities (Continued on next page)

106 4 HPV-RELATED STATISTICS b Arnhem, Nijmegen, and Den Bosch c Oslo, Trondheim, and Levanger d Lisbon area and southern region e Moscow and Novgorod f St. Petersburg Data sources: See references in Section 9. ( Figure 98 continued from previous page)

107 4 HPV-RELATED STATISTICS Figure 99: Prevalence of HPV among women with normal cervical cytology in Europe by country and study (continued) Country Study Age N % (95% CI) Spain Lloveras 213 (Barcelona) ( ) de Sanjose 23 (Barcelona) (.7 2.3) Ortiz 26 (Madrid and Alicante) a ( ) González 26 (Alicante) (6.1 1.) Muñoz 1996 b ( ) Sweden Naucler 27 c , ( ) Elfström 214 c , ( ) Gyllensten 212 (Uppsala County) a , ( ) Ylitalo 2 (Uppsala) (4.2 8.) Kjellberg 1998 d (2.3 7.) Stenvall 27 (Uppsala) a ( ) Switzerland Bigras 25 e , ( ) UK Kitchener 26 (Manchester) , (1. 1.8) Hibbitts 214 (Wales) , ( ) Cuzick 23 f 3 6 9, (5.1 6.) Hibbitts 28 (South Wales) , ( ) Peto 24 (Manchester) , ( ) Kavanagh 214 (Scotland) a , ( ) Cuschieri 24 (Edinburgh) , ( ) Cuzick 1999 (London) , (2.7 4.) Howell Jones 21 g , ( ) Cuzick 1995 (London) , ( ) Geraets 214 (Scotland) a ( ) Herbert 27 (London) ( ) Grainge 25 (Nottingham) ( ) % 1% 2% 3% 4% 5% 6% Data updated on 15 Dec 216 (data as of 3 Jun 215). 95% CI: 95% Confidence Interval; N: number of women tested; The samples for HPV testing come from cervical specimens (fresh/fixed biopsies or exfoliated cells). The line represents the 95% confidence interval and the shadowed square is proportional to the sample size. a Women from the general population, including some with cytological cervical abnormalities b Alava, Girona, Guipuzcoa, Murcia, Navarra, Salamanca, Sevilla, Vizcaya, Zaragoza c Gothenburg, Malmö, Uppsala, Umeå, and Stockholm d Västerbotten County e Geneve, Vaud, Neuchatel, Fribourg, Valais and Tessin f Birmingham, Edinburg, London, Manchester and Mansfield g Gateshead, Birmingham, London, Gloucestershire and Norfolk Data sources: See references in Section 9.

108 4 HPV-RELATED STATISTICS HPV type distribution among women with normal cervical cytology, precancerous cervical lesions and cervical cancer Table 13: Prevalence of HPV 16/18 in women with normal cytology, precancerous cervical lesions and invasive cervical cancer in Europe Normal cytology Low-grade lesions High-grade lesions Cervical cancer Country /Region No. HPV Prev No. HPV Prev No. HPV Prev No. HPV Prev tested (95% CI) tested (95% CI) tested (95% CI) tested (95% CI) Europe 232, ( ) 19, ( ) 21, ( ) 18, ( ) Eastern Europe 7, ( ) 1, ( ) ( ) 1, ( ) Belarus ( ) ( ) ( ) ( ) Bulgaria ( ) Czech Rep. 1, ( ) ( ) ( ) ( ) Hungary ( ) ( ) Moldova Poland ( ) , (86.-9.) Romania ( ) ( ) ( ) Russia 2, ( ) ( ) ( ) ( ) Slovakia Ukraine Northern Europe 119, ( ) 4, ( ) 8, ( ) 5, ( ) Denmark 54, (6.-6.4) ( ) 2, ( ) ( ) Estonia Finland ( ) Iceland ( ) ( ) Ireland 5, ( ) ( ) ( ) ( ) Latvia ( ) ( ) ( ) Lithuania ( ) ( ) ( ) ( ) Norway 4, (2.-2.9) ( ) 1, ( ) ( ) Sweden 12, ( ) 1, ( ) ( ) ( ) UK 42, (3.-3.4) 2, ( ) 2, ( ) 3, ( ) Southern Europe 5, (3.-3.4) 1, ( ) 5, ( ) 4, ( ) Albania Andorra Bosnia & H ( ) Croatia ( ) 1, ( ) ( ) ( ) Cyprus Greece 1, ( ) 1, ( ) ( ) ( ) Italy 29, ( ) 4, ( ) 2, ( ) 1, ( ) Macedonia Malta Montenegro Portugal ( ) ( ) ( ) ( ) San Marino Serbia Slovenia 4, (2.9-4.) ( ) ( ) Spain 5, ( ) 2, ( ) ( ) 1, ( ) Western Europe 57, ( ) 2, ( ) 3, ( ) 3, ( ) Austria ( ) ( ) Belgium 14, ( ) 1, ( ) ( ) ( ) France 4, ( ) ( ) ( ) 1, ( ) Germany 1, ( ) ( ) ( ) ( ) Liechtenstein Luxembourg ( ) Monaco Netherlands 26, ( ) ( ) ( ) 1, ( ) Switzerland ( ) ( ) Data updated on 19 May 217 (data as of 3 Jun 215 / 3 Jun 215). 95% CI: 95% Confidence Interval; High-grade lesions: CIN-2, CIN-3, CIS or HSIL; Low-grade lesions: LSIL or CIN-1; Data sources: See references in Section 9.

109 4 HPV-RELATED STATISTICS Figure 1: Prevalence of HPV 16 among women with normal cervical cytology in Europe by country and study Country Study N % (95% CI) Belarus Rogovskaya ( ) Belgium Arbyn 29 8, ( ) Baay 25 2, ( ) Depuydt 212 1, (.9 2.3) Schmitt ( ) Weyn ( ) Depuydt ( ) Baay ( ) Croatia Grahovac ( ) Czech Rep. Tachezy 213 1, ( ) Denmark Kjær , (4. 4.4) Nielsen 28 11, ( ) Bonde 214 4, ( ) Svare ( ) France Heard 213 3,23 3. ( ) Vaucel ( ) Casalegno ( ) Pannier Stockman ( ) Beby Defaux (.6 5.1) Germany Klug 27 7, (.9 1.4) Iftner 21 1, ( ) de Jonge 213 1, ( ) Greece Agorastos 215 3, ( ) Argyri 213 2, (2. 3.4) Tsiodras 211 1, ( ) Agorastos 24 1,272.4 (.2.9) Tsiodras 21 1,29. (..4) Panotopoulou (.2 1.4) Ireland Anderson 213 5, ( ) Keegan (.9 3.1) Italy Carozzi , ( ) Agarossi 29 9, ( ) Giorgi Rossi 211 3, ( ) Ronco ( ) Panatto ( ) Centurioni ( ) Salfa (.3 2.3) Barzon ( ) Sammarco ( ) Astori ( ) % 1% 2% 3% (Continued on next page) Data updated on 15 Dec 216 (data as of 3 Jun 215). 95% CI: 95% Confidence Interval; N: number of women tested; The samples for HPV testing come from cervical specimens (fresh/fixed biopsies or exfoliated cells). The line represents the 95% confidence interval and the shadowed square is proportional to the sample size. Data sources: See references in Section 9.

110 4 HPV-RELATED STATISTICS Figure 11: Prevalence of HPV 16 among women with normal cervical cytology in Europe by country and study (continued) Country Study N % (95% CI) Italy Tornesello ( ) Tornesello (1. 7.9) Lithuania Gudleviciene ( ) Simanaviciene ( ) Netherlands Bulkmans 27 21, (.9 1.1) Jacobs 2 3,299.9 (.7 1.3) Rozendaal 2 2, ( ) Zielinski (.5 6.2) Norway Molden 25 3, (1. 1.7) Gjøoen ( ) Poland Bardin ( ) Portugal Pista ( ) Romania Moga ( ) Russia Rogovskaya (5.5 9.) Shipitsyna ( ) Alexandrova (5. 1.9) Komarova ( ) Slovenia Ucakar 212 4, (2.1 3.) Spain Castellsagué 212 3, (2. 3.1) de Sanjose (.1 1.) Dillner (2. 4.6) González (.6 2.9) Muñoz (.8 3.9) Sweden Naucler 27 5, (1.4 2.) Elfström 214 5, ( ) Ylitalo (4.2 8.) Kjellberg (.3 2.9) UK Sargent 28 21, ( ) Hibbitts 214 1, ( ) Cuschieri 24 3, ( ) Cuzick ,855.1 (..3) Cuzick , (.9 2.) Hibbitts 26 1, (.9 2.) Grainge (.7 2.6) % 1% 2% 3% Data updated on 15 Dec 216 (data as of 3 Jun 215). 95% CI: 95% Confidence Interval; N: number of women tested; The samples for HPV testing come from cervical specimens (fresh/fixed biopsies or exfoliated cells). The line represents the 95% confidence interval and the shadowed square is proportional to the sample size. Data sources: See references in Section 9.

111 4 HPV-RELATED STATISTICS Figure 12: Prevalence of HPV 16 among women with low-grade cervical lesions in Europe by country and study Country Study N % (95% CI) Belarus Kulmala ( ) Belgium Depuydt ( ) Beerens ( ) Arbyn ( ) Weyn ( ) Baay ( ) Croatia Grce 21 1, ( ) Grce ( ) Grce ( ) Czech Rep. Tachezy ( ) Denmark Kjær ( ) Kjaer ( ) Hording ( ) France Prétet ( ) Vaucel ( ) Bergeron ( ) Humbey ( ) Monsonego ( ) Germany de Jonge ( ) Meyer ( ) Klug ( ) Nindl ( ) Merkelbach Bruse ( ) Greece Argyri ( ) Panotopoulou ( ) Tsiodras ( ) Kroupis ( ) Labropoulou ( ) Mammas ( ) Ireland Keegan ( ) Murphy ( ) Butler (. 12.9) Italy Voglino 2 1, ( ) Spinillo 214 1, ( ) Chironna ( ) Agarossi ( ) Spinillo ( ) Capra ( ) Astori ( ) Tornesello ( ) % 1% 2% 3% 4% 5% 6% 7% 8% 9% (Continued on next page) Data updated on 28 Jun 217 (data as of 3 Jun 215). 95% CI: 95% Confidence Interval; Low-grade lesions: LSIL or CIN-1; N: number of women tested; The samples for HPV testing come from cervical specimens (fresh/fixed biopsies or exfoliated cells). The line represents the 95% confidence interval and the shadowed square is proportional to the sample size. Data sources: See references in Section 9.

112 4 HPV-RELATED STATISTICS Figure 13: Prevalence of HPV 16 among women with low-grade cervical lesions in Europe by country and study (continued) Country Study N % (95% CI) Italy Agodi ( ) Gargiulo ( ) Giorgi Rossi ( ) Sandri ( ) Zerbini ( ) Venturoli ( ) Laconi ( ) Menegazzi ( ) Venturoli ( ) Latvia Kulmala ( ) Lithuania Gudleviciene ( ) Netherlands Bollen ( ) Prinsen ( ) Reesink Peters ( ) Norway Roberts ( ) Molden ( ) Portugal Medeiros ( ) Nobre ( ) Romania Ursu ( ) Anton ( ) Russia Kulmala ( ) Spain de Oña 21 1, ( ) Martín ( ) Herraez Hernandez ( ) García Sierra ( ) Conesa Zamora ( ) Doménech Peris ( ) Sweden Söderlund Strand 211 1, ( ) Brismar Wendel ( ) Kalantari ( ) Andersson ( ) Zehbe ( ) Switzerland Dobec ( ) UK Sargent (15. 2.) Howell Jones ( ) Anderson ( ) Cuschieri ( ) Hibbitts ( ) Giannoudis ( ) Jamison ( ) % 1% 2% 3% 4% 5% 6% (Continued on next page) Data updated on 28 Jun 217 (data as of 3 Jun 215). 95% CI: 95% Confidence Interval; Low-grade lesions: LSIL or CIN-1; N: number of women tested; The samples for HPV testing come from cervical specimens (fresh/fixed biopsies or exfoliated cells). The line represents the 95% confidence interval and the shadowed square is proportional to the sample size. Data sources: See references in Section 9.

113 4 HPV-RELATED STATISTICS Figure 14: Prevalence of HPV 16 among women with low-grade cervical lesions in Europe by country and study (continued) Country Study N % (95% CI) UK Woo ( ) Cuzick ( ) Southern ( ) Arends ( ) Cuzick ( ) % 1% 2% 3% 4% 5% 6% Data updated on 28 Jun 217 (data as of 3 Jun 215). 95% CI: 95% Confidence Interval; Low-grade lesions: LSIL or CIN-1; N: number of women tested; The samples for HPV testing come from cervical specimens (fresh/fixed biopsies or exfoliated cells). The line represents the 95% confidence interval and the shadowed square is proportional to the sample size. Data sources: See references in Section 9.

114 4 HPV-RELATED STATISTICS Figure 15: Prevalence of HPV 16 among women with high-grade cervical lesions in Europe by country and study Country Study N % (95% CI) Austria Rössler ( ) Belarus Kulmala ( ) Belgium Depuydt ( ) Beerens ( ) Arbyn ( ) Baay ( ) Croatia Grce ( ) Grce ( ) Czech Rep. Tachezy ( ) Denmark Kjær 214 1, ( ) Thomsen ( ) Kirschner ( ) Kjaer ( ) Bonde ( ) Sebbelov ( ) Hording ( ) Europe Tjalma 213 3, ( ) France Prétet ( ) Vaucel ( ) Monsonego ( ) Germany Meyer ( ) de Jonge ( ) Merkelbach Bruse ( ) Nindl ( ) Nindl ( ) Klug ( ) Greece Argyri ( ) Panotopoulou ( ) Tsiodras ( ) Labropoulou ( ) Agorastos ( ) Daponte ( ) Paraskevaidis ( ) Kroupis ( ) Hungary Szoke ( ) Iceland Sigurdsson ( ) Ireland Keegan ( ) Murphy ( ) Butler ( ) O'Leary ( ) 1% 2% 3% 4% 5% 6% 7% 8% 9% 1% (Continued on next page) Data updated on 28 Jun 217 (data as of 3 Jun 215). 95% CI: 95% Confidence Interval; High-grade lesions: CIN-2, CIN-3, CIS or HSIL; N: number of women tested; The samples for HPV testing come from cervical specimens (fresh/fixed biopsies or exfoliated cells). The line represents the 95% confidence interval and the shadowed square is proportional to the sample size. Data sources: See references in Section 9.

115 4 HPV-RELATED STATISTICS Figure 16: Prevalence of HPV 16 among women with high-grade cervical lesions in Europe by country and study (continued) Country Study N % (95% CI) Italy Spinillo 214 1, ( ) Carozzi ( ) Carozzi ( ) Zerbini ( ) Sandri ( ) Agarossi ( ) Gargiulo ( ) Tornesello ( ) Venturoli ( ) Laconi ( ) Capra ( ) Latvia Kulmala ( ) Lithuania Simanaviciene ( ) Gudleviciene ( ) Netherlands Tang ( ) Bulkmans ( ) Reesink Peters ( ) Cornelissen ( ) Prinsen ( ) van Duin ( ) Norway Roberts ( ) Sjoeborg ( ) Kraus ( ) Molden ( ) Portugal Pista ( ) Pista ( ) Medeiros ( ) Nobre ( ) Romania Anton ( ) Ursu ( ) Russia Kulmala ( ) Slovenia Kovanda ( ) Spain de Oña ( ) Bosch ( ) Muñoz ( ) Martín ( ) Herraez Hernandez ( ) Conesa Zamora ( ) Darwich ( ) García Sierra ( ) 1% 2% 3% 4% 5% 6% 7% 8% 9% (Continued on next page) Data updated on 28 Jun 217 (data as of 3 Jun 215). 95% CI: 95% Confidence Interval; High-grade lesions: CIN-2, CIN-3, CIS or HSIL; N: number of women tested; The samples for HPV testing come from cervical specimens (fresh/fixed biopsies or exfoliated cells). The line represents the 95% confidence interval and the shadowed square is proportional to the sample size. Data sources: See references in Section 9.

116 4 HPV-RELATED STATISTICS Figure 17: Prevalence of HPV 16 among women with high-grade cervical lesions in Europe by country and study (continued) Country Study N % (95% CI) Sweden Kalantari ( ) Andersson ( ) Zehbe ( ) Switzerland Dobec ( ) UK Howell Jones 21 1, ( ) Sargent ( ) Cuzick ( ) Geraets ( ) Cuschieri ( ) Hibbitts ( ) Cuzick ( ) Anderson ( ) Jamison ( ) Arends ( ) Herrington ( ) Southern ( ) 2% 3% 4% 5% 6% 7% 8% Data updated on 28 Jun 217 (data as of 3 Jun 215). 95% CI: 95% Confidence Interval; High-grade lesions: CIN-2, CIN-3, CIS or HSIL; N: number of women tested; The samples for HPV testing come from cervical specimens (fresh/fixed biopsies or exfoliated cells). The line represents the 95% confidence interval and the shadowed square is proportional to the sample size. Data sources: See references in Section 9.

117 4 HPV-RELATED STATISTICS Figure 18: Prevalence of HPV 16 among women with invasive cervical cancer in Europe by country and study Country Study N % (95% CI) Austria Bachtiary ( ) Widschwendter ( ) Belarus Kulmala ( ) Belgium Baay ( ) Bulgaria Todorova ( ) Croatia Hadzisejdic ( ) Dabic ( ) Czech Rep. Tachezy ( ) Slama ( ) Tachezy ( ) Denmark Kirschner ( ) Hording ( ) Sebbelov ( ) Kjær ( ) Europe Tjalma 213 2, ( ) de Sanjose 21(a) 2, ( ) Finland Iwasawa ( ) France Prétet ( ) de Cremoux ( ) Lombard ( ) Riou ( ) Germany Milde Langosch ( ) Bosch ( ) Greece Panotopoulou ( ) Dokianakis (.7 9.2) Koffa ( ) Labropoulou ( ) Adamopoulou ( ) Hungary Kónya ( ) Iceland Sigurdsson ( ) Ireland Skyldberg ( ) Butler ( ) O'Leary ( ) Fay ( ) Italy Sideri ( ) Carozzi ( ) Spinillo ( ) Tornesello ( ) Voglino ( ) Ciotti ( ) (Continued on next page) Data updated on 28 Jun 217 (data as of 3 Jun 215). 95% CI: 95% Confidence Interval; N: number of women tested; The samples for HPV testing come from cervical specimens (fresh/fixed biopsies or exfoliated cells). The line represents the 95% confidence interval and the shadowed square is proportional to the sample size. a Includes cases from Bosnia-Herzegovina, Croatia, Czech Republic, France, Greece, Italy, Netherlands, Poland, Portugal, and Spain Data sources: See references in Section 9.

118 4 HPV-RELATED STATISTICS Figure 19: Prevalence of HPV 16 among women with invasive cervical cancer in Europe by country and study (continued) Country Study N % (95% CI) Italy Tornesello ( ) Del Mistro ( ) Garzetti ( ) Gargiulo ( ) Rolla ( ) Latvia Silins ( ) Kulmala ( ) Lithuania Gudleviciene ( ) Simanaviciene ( ) Luxembourg Ressler ( ) Netherlands Tang ( ) Baay ( ) Bulk ( ) Krul ( ) Baalbergen ( ) De Boer ( ) Zielinski ( ) Van Den Brule ( ) Resnick ( ) Norway Karlsen ( ) Bertelsen ( ) Poland Kwasniewska ( ) Baay ( ) Biesaga ( ) Bardin ( ) Pirog ( ) Dybikowska ( ) Bosch ( ) Portugal Pista ( ) Medeiros ( ) Nobre ( ) Russia Kleter ( ) Kulmala ( ) Slovenia Jancar ( ) Spain Muñoz ( ) Martró ( ) Darwich ( ) Rodriguez ( ) Bosch ( ) Mazarico ( ) (Continued on next page) Data updated on 28 Jun 217 (data as of 3 Jun 215). 95% CI: 95% Confidence Interval; N: number of women tested; The samples for HPV testing come from cervical specimens (fresh/fixed biopsies or exfoliated cells). The line represents the 95% confidence interval and the shadowed square is proportional to the sample size. Data sources: See references in Section 9.

119 4 HPV-RELATED STATISTICS Figure 11: Prevalence of HPV 16 among women with invasive cervical cancer in Europe by country and study (continued) Country Study N % (95% CI) Spain González Bosquet ( ) Herraez Hernandez ( ) Sweden Du ( ) Andersson ( ) Graflund ( ) Wallin ( ) Andersson ( ) Hagmar ( ) Andersson ( ) Skyldberg ( ) Zehbe ( ) UK Mesher 215 1, ( ) Howell Jones ( ) Cuschieri ( ) Cuschieri ( ) Powell ( ) Tawfik El Mansi ( ) Cuzick ( ) Arends ( ) Giannoudis ( ) Crook ( ) Data updated on 28 Jun 217 (data as of 3 Jun 215). 95% CI: 95% Confidence Interval; N: number of women tested; The samples for HPV testing come from cervical specimens (fresh/fixed biopsies or exfoliated cells). The line represents the 95% confidence interval and the shadowed square is proportional to the sample size. Data sources: See references in Section 9.

120 4 HPV-RELATED STATISTICS Figure 111: Comparison of the ten most frequent HPV oncogenic types among women with and without cervical lesions in Europe and its regions Europe Eastern Europe Northern Europe Normal cytology HPV type Low grade lesions HPV type High grade lesions HPV type Cervical Cancer HPV type Prevalence (%) Prevalence (%) Prevalence (%) Data updated on 19 May 217 (data as of 3 Jun 215). High-grade lesions: CIN-2, CIN-3, CIS or HSIL; Low-grade lesions: LSIL or CIN-1; The samples for HPV testing come from cervical specimens (fresh / fixed biopsies or exfoliated cells). Data sources: See references in Section 9.

121 4 HPV-RELATED STATISTICS Figure 112: Comparison of the ten most frequent HPV oncogenic types among women with and without cervical lesions in Europe and its regions (continued) Southern Europe Western Europe Normal cytology Low grade lesions High grade lesions Cervical Cancer Prevalence (%) Prevalence (%) Data updated on 19 May 217 (data as of 3 Jun 215). High-grade lesions: CIN-2, CIN-3, CIS or HSIL; Low-grade lesions: LSIL or CIN-1; The samples for HPV testing come from cervical specimens (fresh / fixed biopsies or exfoliated cells). Data sources: See references in Section 9.

122 4 HPV-RELATED STATISTICS Figure 113: Comparison of the ten most frequent HPV oncogenic types among women with invasive cervical cancer by histology in Europe and its regions Europe Eastern Europe Northern Europe Any Histology HPV type Squamous cell carcinoma HPV type Adenocarcinoma HPV type th 9th 1th Unespecified HPV type Prevalence (%) Prevalence (%) Prevalence (%) No data available. No more types than shown were tested or were positive. Data updated on 19 May 217 (data as of 3 Jun 215). The samples for HPV testing come from cervical specimens (fresh / fixed biopsies or exfoliated cells). Data sources: See references in Section 9.

123 4 HPV-RELATED STATISTICS Figure 114: Comparison of the ten most frequent HPV oncogenic types among women with invasive cervical cancer by histology in Europe and its regions (continued) Southern Europe Western Europe Any Histology Squamous cell carcinoma Adenocarcinoma Unespecified Prevalence (%) Prevalence (%) No data available. No more types than shown were tested or were positive. Data updated on 19 May 217 (data as of 3 Jun 215). The samples for HPV testing come from cervical specimens (fresh / fixed biopsies or exfoliated cells). Data sources: See references in Section 9.

124 4 HPV-RELATED STATISTICS Table 14: Type-specific HPV prevalence in women with normal cervical cytology, precancerous cervical lesions and invasive cervical cancer in Europe Normal cytology Low-grade lesions High-grade lesions Cervical cancer HPV Type No. HPV Prev No. HPV Prev No. HPV Prev No. HPV Prev tested % (95% CI) tested % (95% CI) tested % (95% CI) tested % (95% CI) ONCOGENIC HPV TYPES High-risk HPV types , ( ) 19, ( ) 21, ( ) 18, ( ) 18 23, (1.-1.1) 18, (6.-6.7) 2, ( ) 18, ( ) , ( ) 18, ( ) 2, ( ) 16, ( ) ,41.7 (.7-.8) 18, ( ) 2, ( ) 16, ( ) 35 22,237.4 (.4-.4) 14, (3.-3.5) 17, ( ) 15, ( ) 39 2,452.9 (.9-1.) 12, ( ) 17, ( ) 13, (1.-1.3) 45 23,777.8 (.8-.9) 14, ( ) 17, ( ) 14, (4.-4.6) 51 22, ( ) 11, ( ) 17, ( ) 13,589.9 (.8-1.1) 52 22, ( ) 12, ( ) 17, ( ) 14, ( ) 56 22,33.9 (.8-.9) 12, (6.2-7.) 17, ( ) 13,31.9 (.8-1.1) 58 23,642.6 (.6-.7) 13, ( ) 17, ( ) 14, (1.-1.4) ,931.6 (.6-.6) 11, ( ) 15, ( ) 13,153.7 (.6-.8) Probable/possible carcinogen 26 24,48.1 (.-.1) 4,439.3 (.2-.5) 5,18.3 (.2-.5) 5,751.1 (.-.2) 3 3,517.3 (.2-.5) 1,242.4 (.2-.9) 1,77. (.-.4) 2,986.2 (.1-.4) 34 11,28.1 (.1-.2) 2,45.1 (.-.4) 1,767.2 (.1-.5) 3,993.1 (.-.2) 53 95, ( ) 9, ( ) 1, ( ) 8,175.7 (.6-1.) ,3 1.1 (1.-1.2) 11, ( ) 15, ( ) 11,552.4 (.3-.5) 67 9,357.3 (.2-.4) 3, ( ) 3,79.5 (.3-.8) 4,72.2 (.1-.3) 68 2,131.7 (.7-.7) 1, ( ) 14, ( ) 12,165.8 (.7-1.) 69 5,342. (.-.1) 3,812.3 (.1-.5) 3,73.2 (.1-.4) 4,472. (.-.1) 7 68, ( ) 7, ( ) 7, ( ) 7,295.2 (.1-.3) 73 32,38.3 (.3-.4) 6, ( ) 6, ( ) 6,345.9 (.7-1.1) 82 33,125.5 (.4-.5) 6, ( ) 6, (.8-1.3) 6,538.1 (.1-.3) 85 7,647. (.-.1) 1,56.1 (.-.5) 1,165.2 (.-.6) , ( ) (.-1.5) NON-ONCOGENIC HPV TYPES 6 134, ( ) 12,72 7. ( ) 1, ( ) 8,735.7 (.6-.9) ,29.4 (.3-.4) 12, ( ) 9, ( ) 8,579.5 (.4-.7) 32 5,128.2 (.1-.3) 549. (.-.7) (.-.6) 4 72,726.2 (.2-.3) 2, ( ) 2,841.5 (.3-.8) 4,728. (.-.1) 42 72,818.8 (.8-.9) 2, ( ) 2, ( ) 4,797.2 (.1-.4) 43 7,263.3 (.2-.3) 2, ( ) 2,464.6 (.4-1.) 4,2. (.-.1) 44 75,996.9 (.8-1.) 3, ( ) 3, (3.6-5.) 4,63.3 (.2-.5) 54 66,578.8 (.7-.8) 1, ( ) 2,382.8 (.5-1.2) 5,136.4 (.3-.6) ,231. (.-.1) 549. (.-.7) 829. (.-.5) 928. (.-.4) 61 19, ( ) (.7-2.1) 1, (.8-2.2) 3,96.1 (.-.3) 62 13, (1.-1.4) (.7-2.1) 1, ( ) 1,128.3 (.1-.8) ,187.1 (.-.1) (.4-1.7) 1,18. (.-.3) 1,541. (.-.2) 72 17,393.2 (.1-.2) (.1-1.1) 1,18.3 (.1-.9) 1,356. (.-.3) 74 48,27 1. (.9-1.1) (.7-2.3) 2,31.9 (.6-1.5) 3,522.1 (.-.2) 81 17,818.7 (.6-.9) (.8-2.5) 1, (.6-1.9) 1,44.1 (.-.5) 83 2,877.7 (.6-.8) (.1-1.2) 1,112.3 (.1-.8) 1,273. (.-.3) 84 21,454.5 (.5-.6) (.8-2.3) 1,18.3 (.1-.7) 1,128.4 (.1-.9) 86 2,611.1 (.-.3) ,812.4 (.2-.9) 549. (.-.7) ,997.2 (.1-.3) (1.-2.8) (.1-1.) 1,287.1 (.-.4) 9 3,347.9 (.6-1.2) 549. (.-.7) (.-.9) 91 1,246.5 (.2-1.) 549. (.-.7) - - 2,722. (.-.2) Data updated on 19 May 217 (data as of 3 Jun 215 / 3 Jun 215). 95% CI: 95% Confidence Interval; High-grade lesions: CIN-2, CIN-3, CIS or HSIL; Low-grade lesions: LSIL or CIN-1; The samples for HPV testing come from cervical specimens (fresh / fixed biopsies or exfoliated cells). Data sources: See references in Section 9.

125 4 HPV-RELATED STATISTICS Table 15: Type-specific HPV prevalence among invasive cervical cancer cases in Europe by histology Any Histology Squamous cell carcinoma Adenocarcinoma Unespecified HPV Type No. HPV Prev No. HPV Prev No. HPV Prev No. HPV Prev tested % (95% CI) tested % (95% CI) tested % (95% CI) tested % (95% CI) ONCOGENIC HPV TYPES High-risk HPV types 16 18, ( ) 13, ( ) 2, ( ) 2, ( ) 18 18, ( ) 13, ( ) 2, ( ) 2, ( ) 31 16, ( ) 11, ( ) 2, (1.7-3.) 2, (4.-5.7) 33 16, ( ) 12, (4.3-5.) 2, ( ) 2, ( ) 35 15, ( ) 11, ( ) 1,882.5 (.3-.9) 1, ( ) 39 13, (1.-1.3) 1, (1.-1.4) 1, (.6-1.6) 1, (.8-2.2) 45 14, (4.-4.6) 11, ( ) 2,47 6. (5.-7.1) 1, ( ) 51 13,589.9 (.8-1.1) 1,731.8 (.7-1.) 1, (.9-2.) 1,166.7 (.3-1.3) 52 14, ( ) 11, ( ) 1, (.7-1.6) 1, (1.-2.3) 56 13,31.9 (.8-1.1) 1, (.9-1.3) 1,721.1 (.-.4) 1,294.8 (.4-1.4) 58 14, (1.-1.4) 11, ( ) 1,754.2 (.1-.6) 1, (.9-2.2) 59 13,153.7 (.6-.8) 1,398.8 (.6-.9) 1,779.2 (.1-.5) 1,116.9 (.5-1.6) Probable/possible carcinogen 26 5,751.1 (.-.2) ,986.2 (.1-.4) 2,494.2 (.1-.5) 26. (.-1.5) 232. (.-1.6) 34 3,993.1 (.-.2) 3,212.1 (.-.3) 41. (.-.9) 38. (.-1.) 53 8,175.7 (.6-1.) ,552.4 (.3-.5) 9,141.4 (.3-.6) 1,563.1 (.-.5) (.2-1.2) 67 4,72.2 (.1-.3) 3,893.2 (.1-.3) 52. (.-.8) 37.7 (.2-2.3) 68 12,165.8 (.7-1.) 9, (.8-1.2) 1,488.1 (.-.4) (.2-1.3) 69 4,472. (.-.1) ,295.2 (.1-.3) ,345.9 (.7-1.1) ,538.1 (.1-.3) 5,128.1 (.-.2) (.-.9) (.1-1.1) (.-1.5) 37.3 (.-1.5) NON-ONCOGENIC HPV TYPES 6 8,735.7 (.6-.9) ,579.5 (.4-.7) (.-.6) ,728. (.-.1) ,797.2 (.1-.4) 4,61.1 (.1-.3) 377. (.-1.) (.4-2.8) 43 4,2. (.-.1) ,63.3 (.2-.5) 3,858.3 (.2-.5) (.1-1.7) (.2-2.2) 54 5,136.4 (.3-.6) (.-.4) ,96.1 (.-.3) ,128.3 (.1-.8) ,541. (.-.2) ,356. (.-.3) ,522.1 (.-.2) ,44.1 (.-.5) ,273. (.-.3) ,128.4 (.1-.9) ,287.1 (.-.4) (.-.9) ,722. (.-.2) Data updated on 19 May 217 (data as of 3 Jun 215). 95% CI: 95% Confidence Interval; The samples for HPV testing come from cervical specimens (fresh / fixed biopsies or exfoliated cells). Data sources: See references in Section 9.

126 4 HPV-RELATED STATISTICS HPV type distribution among HIV+ women with normal cervical cytology Table 16: European studies on HPV prevalence among HIV women with normal cytology HPV detection method and targeted HPV prevalence Country Study HPV types No. Tested % (95% CI) Denmark Melbye 1996 PCR-L1, TS (HPV 6, 11, 16, 18, 31, 33, 35, 39, 45, 51, 52) ( ) Germany Kuhler-Obbarius 1994 PCR-MY11/MY9, No genotyping ( ) Germany Weissenborn 23 PCR-GP5+/GP6+, TS (HPV 16, 18, 31, 33, 45, 56) Italy Ammatuna 2 PCR- (MY9/MY11, GP5/GP6), No genotyping Italy Cappiello 1997 PCR-MY9/MY11, RFLP, (HPV 6, 11,16, 18, 26, 3-35, 39, 4, 42, 44, 45, 51-59, 61, 62, 64, 66-73, 77, 81-84) Italy Del mistro 21 PCR-MY9/MY11, RFLP, (HPV 6, 11, 16, 18, 26, 3-35, 39, 4, 42, 44, 45, 51-59, 61, 62, 64, 66-73, 77, 81-84) Italy Tanzi 29 PCR-MY9/MY11, RFLP, (HPV 6, 11, 16, 18, 26, 3-35, 39, 4, 42, 44, 45, 51-59, 61, 62, 64, 66-73, 77, 81-84) Italy Branca 2 PCR-MY9/MY11, RFLP,(HPV 6, 11, 16, 18, 26, 3-35, 39, 4, 42, 44, 45, 51-59, 61, 62, 64, 66-73, 77, 81-84) Italy Uberti-Foppa 1998 HC2 (HPV 6, 11, 16, 18, 31, 33, 35, 39, 42, 43, 44, 45, 51, 52, 56, 58, 59, 68), No genotyping Italy Tornesello 28 PCR-(GP5+/GP6+, MY9/MY11), sequencing (DSA) Netherlands Jong 28 PCR-SPF1, RHA, (HPV 6, 11, 16, 18, 31, 33-35, 39, 4, 42-45, 51-54, 56, 58, 59, 66, 68, 7, 71, 74) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) Netherlands Van Doornum 1993 PCR-,TS (HPV 6/11, 16, 18, 33), DBH ( ) Spain Cañadas 21 PCR (E6/E7), TS, (HPV 6, 11, 16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, 68) Spain Gonzalez 28 PCR (E6/E7), HC2, TS, (HPV 6, 11, 16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, 68) Spain De Sanjose 2 PCR (MY9/11),EIA, DBH, (HPV6, 11, 16, 18, 31, 33, 35, 39, 4, 41, 45, 51, 52, 53, 54, 56, 58, 59, 66, 73, 81) United Kingdom Cubie 2 HC2 (HPV 6, 11, 16, 18, 31, 33, 35, 39, 42, 43, 44, 45, 51, 52, 56, 58, 59, 68), No genotyping ( ) ( ) ( ) ( ) Data updated on 31 Jul 213 (data as of 31 Dec 211). Only for European countries. 95% CI: 95% Confidence Interval; DBH: Dot Blot Hybridization; EIA: Enzyme ImmunoAssay; HC2: Hybrid Capture 2; PCR: Polymerase Chain Reaction; RFLP: Restriction Fragment Length Polymorphism; RHA: Reverse Hybridization Assay; SPF: Short Primer Fragment; TS: Type Specific; Data sources: See references in Section 9.

127 4 HPV-RELATED STATISTICS Terminology Cytologically normal women No abnormal cells are observed on the surface of their cervix upon cytology. Cervical Intraepithelial Neoplasia (CIN) / Squamous Intraepithelial Lesions (SIL) SIL and CIN are two commonly used terms to describe precancerous lesions or the abnormal growth of squamous cells observed in the cervix. SIL is an abnormal result derived from cervical cytological screening or Pap smear testing. CIN is a histological diagnosis made upon analysis of cervical tissue obtained by biopsy or surgical excision. The condition is graded as CIN 1, 2 or 3, according to the thickness of the abnormal epithelium (1/3, 2/3 or the entire thickness). Low-grade cervical lesions (LSIL/CIN-1) Low-grade cervical lesions are defined by early changes in size, shape, and number of abnormal cells formed on the surface of the cervix and may be referred to as mild dysplasia, LSIL, or CIN-1. High-grade cervical lesions (HSIL/ CIN-2 / CIN-3 / CIS) High-grade cervical lesions are defined by a large number of precancerous cells on the surface of the cervix that are distinctly different from normal cells. They have the potential to become cancerous cells and invade deeper tissues of the cervix. These lesions may be referred to as moderate or severe dysplasia, HSIL, CIN-2, CIN-3 or cervical carcinoma in situ (CIS). Carcinoma in situ (CIS) Preinvasive malignancy limited to the epithelium without invasion of the basement membrane. CIN 3 encompasses the squamous carcinoma in situ. Invasive cervical cancer (ICC) / Cervical cancer If the high-grade precancerous cells invade the basement membrane is called ICC. ICC stages range from stage I (cancer is in the cervix or uterus only) to stage IV (the cancer has spread to distant organs, such as the liver). Invasive squamous cell carcinoma Invasive carcinoma composed of cells resembling those of squamous epithelium. Adenocarcinoma Invasive tumour with glandular and squamous elements intermingled.

128 4 HPV-RELATED STATISTICS HPV burden in anogenital cancers other than the cervix Methods: Prevalence and type distribution of human papillomavirus in carcinoma of the vulva, vagina, anus and penis: systematic review and meta-analysis A systematic review of the literature was conducted on the worldwide HPV-prevalence and type distribution for anogenital carcinomas other than cervix from January 1986 to data as of indicated in each section. The search terms for the review were HPV AND (anus OR anal) OR (penile) OR vagin OR vulv using Pubmed. There were no limits in publication language. References cited in selected articles were also investigated. Inclusion criteria were: HPV DNA detection by means of PCR, a minimum of 1 cases by lesion and a detailed description of HPV DNA detection and genotyping techniques used. The number of cases tested and HPV positive cases were extracted for each study to estimate the prevalence of HPV DNA and the HPV type distribution. Binomial 95% confidence intervals were calculated for each HPV prevalence Anal cancer and precancerous anal lesions Anal cancer is similar to cervical cancer with respect to overall HPV DNA positivity, with approximately 88% of cases associated with HPV infection worldwide (de Martel C et al. Lancet Oncol 212;13(6):67-15). HPV16 is the most common type detected, representing 73% of all HPV-positive tumours. HPV18 is the second most common type detected and is found in approximately 5% of cases. HPV DNA is also detected in the majority of precancerous anal lesions (AIN) (91.5% in AIN1 and 93.9% in AIN2/3) (De Vuyst H et al. Int J Cancer 29; 124: ). In this section, the HPV prevalence among anal cancer cases and precancerous anal lesions in Europe are presented. Table 17: European studies on HPV prevalence among anal cancer cases (male and female) HPV detection Prevalence of 5 most method and targeted HPV prevalence frequent HPVs Study HPV types No. Tested % (95% CI) HPV type (%) Tachezy 211 (Czech Rep.) Serup-Hansen 214 (Denmark) Alemany (Europe) 215 a Abramowitz 211 (France) PCR L1-Consensus primer,, Sequencing (HPV 6, 11, 16, 18, 2, 21, 22, 23, 26, 3, 31, 32, 33, 34, 35, 38, 39, 4, 42, 43, 44, 45, 51, 52, 53, 54, 56, 57, 58, 59, 6, 61, 62, 66, 67, 68, 69, 7, 71, 72, 73, 74, 8, 81, 82, 83, 84, 85, 86, 87, 89, 9, 91) PCR-E6, PCR-E7, PCR- MULTIPLEX (HPV 16, 18, 31, 33, 45, 52, 58) PCR-SPF1, EIA, (HPV 6, 11, 16, 18, 26, 3, 31, 33, 34, 35, 39, 4, 42, 43, 44, 45, 51, 52, 53, 54, 56, 58, 59, 61, 66, 67, 68, 69, 7, 73, 74, 82, 83, 87, 89, 91) PCR-SPF1, (HPV 6, 11, 16, 18, 26, 31, 33, 35, 39, 4, 43, 44, 45, 51, 52, 53, 54, 56, 58, 59, 66, 68, 69, 7, 71, 73, 82) ( ) HPV 16 (73.1%) ( ) HPV 16 (81.%) HPV 33 (5.1%) HPV 18 (2.2%) HPV 58 (.7%) ( ) HPV 16 (73.4%) HPV 6 (3.6%) HPV 18 (3.6%) HPV 11 (3.%) HPV 33 (2.4%) ( ) HPV 16 (75.5%) HPV 18 (5.9%) HPV 11 (3.7%) HPV 6 (3.%) HPV 52 (2.6%) (Continued on next page)

129 4 HPV-RELATED STATISTICS HPV detection ( Table 17 continued from previous page) Prevalence of 5 most method and targeted HPV prevalence frequent HPVs Study HPV types No. Tested % (95% CI) HPV type (%) Valmary-Degano 213 (France) Vincent-Salomon 1996 (France) Rödel 215 (Germany) Varnai 26 (Germany) Indinnimeo 1999 (Italy) Laytragoon-Lewin 27 (Sweden) Baricevic 215 (UK) PCR-E6, (HPV 6, 11, 16, 18, 26, 31, 33, 35, 39, 4, 43, 44, 45, 51, 52, 53, 54, 56, 58, 59, 66, 68, 69, 7, 71, 73, 74, 82) PCR L1-Consensus primer, PCR-E6, TS (HPV 6, 11, 16, 18, 33) PCR-SPF1, PCR- MULTIPLEX, (HPV 6, 11, 16, 18, 26, 31, 33, 35, 39, 4, 42, 43, 44, 45, 51, 52, 53, 54, 56, 58, 59, 66, 68, 69, 7, 71, 73, 74, 81, 82) PCR-MY9/11, TS, Sequencing (HPV 6, 11, 16, 18, 31, 33, 45, 58) ( ) HPV 16 (89.%) HPV 39 (4.1%) HPV 33 (2.7%) HPV 6 (1.4%) HPV 11 (1.4%) ( ) HPV 16 (63.%) HPV 18 (7.4%) ( ) HPV 16 (94.5%) HPV 11 (2.2%) HPV 31 (2.2%) HPV 35 (2.2%) HPV 18 (1.1%) ( ) HPV 16 (74.5%) HPV 33 (6.4%) HPV 18 (2.1%) HPV 31 (2.1%) HPV 45 (2.1%) PCR, TS (HPV 6, 11, 16, 18) ( ) HPV 16 (42.9%) PCR-MY9/11, Sequencing (HPV 16, 18, 33) PCR-L1C1/C2, PCR L1-Consensus primer, PCR-E6, PCR-E7, PCR- MULTIPLEX (HPV 6, 11, 16, 18, 31, 33, 45, 52, 58) Data updated on 28 Jun 217 (data as of 3 Jun 215). 95% CI: 95% Confidence Interval; EIA: Enzyme ImmunoAssay; PCR: Polymerase Chain Reaction; SPF: Short Primer Fragment; TS: Type Specific; a Includes cases from Bosnia-Herzegovina, Czech Republic, France, Germany, Poland, Portugal, Slovenia, Spain and United Kingdom Data sources: See references in Section ( ) HPV 16 (69.4%) HPV 18 (34.7%) HPV 33 (2.8%) ( ) HPV 16 (88.7%) HPV 6 (11.9%) HPV 33 (6.6%) HPV 18 (4.6%) HPV 58 (4.6%) Alemany (Europe) Table 18: European studies on HPV prevalence among AIN 2/3 cases (male and female) HPV detection Prevalence of 5 most method and targeted HPV prevalence frequent HPVs Study HPV types No. Tested % (95% CI) HPV type (%) 215 a Hampl 26 (Germany) Silling 212 b (Germany) Varnai 26 (Germany) PCR-SPF1, EIA, (HPV 6, 11, 16, 18, 26, 3, 31, 33, 34, 35, 39, 4, 42, 43, 44, 45, 51, 52, 53, 54, 56, 58, 59, 61, 66, 67, 68, 69, 7, 73, 74, 82, 83, 87, 89, 91), PCR-MY9/11, Sequencing (HPV 6, 11, 2, 21, 22, 23, 26, 3, 32) PCR- MULTIPLEX (HPV 6, 11, 16, 18, 26, 3, 31, 33, 34, 35, 39, 4, 42, 43, 44, 45, 51, 52, 53, 54, 56, 57, 58, 59, 61, 66, 67, 68, 7, 71, 72, 73, 81, 82, 83, 84, 89), PCR-MY9/11, TS, Sequencing (HPV 6, 11, 16, 18, 31, 33, 45, 58) ( ) HPV 16 (65.2%) HPV 6 (8.7%) HPV 18 (8.7%) HPV 51 (8.7%) HPV 74 (8.7%) ( ) ( ) HPV 16 (69.%) HPV 11 (23.8%) HPV 18 (23.8%) HPV 6 (19.%) HPV 67 (19.%) ( ) HPV 16 (7.8%) HPV 11 (12.5%) HPV 6 (8.3%) HPV 58 (4.2%) (Continued on next page)

130 4 HPV-RELATED STATISTICS HPV detection ( Table 18 continued from previous page) Prevalence of 5 most method and targeted HPV prevalence frequent HPVs Study HPV types No. Tested % (95% CI) HPV type (%) Wieland 26 b PCR, EIA (HPV 6, 11, 16, 18, 31, ( ) HPV 16 (88.9%) (Germany) 33, 34, 35, 42, 44, 45, 52, 53, 54, 56, 58, 59, 66, 68, 7, 72, 73, 81, 82, 83, 84, 89) HPV 18 (44.4%) HPV 83 (38.9%) HPV 52 (33.3%) HPV 58 (27.8%) Tanzi (Italy) 29 b Richel 214 b (Netherlands) García-Espinosa 213 b (Spain) Sirera (Spain) Torres (Spain) 213 b 213 b PCR-MY9/11, PCR L1-Consensus primer, RFLP (HPV 6, 11, 16, 18, 2, 21, 22, 23, 26, 3, 31, 32, 33, 34, 35, 38, 39, 4, 42, 43, 44, 45, 51, 52, 53, 54, 56, 57, 58, 59, 6, 61, 62, 66, 67, 68, 69, 7, 71, 72, 81, 83, 84) PCR L1-Consensus primer, PCR-SPF1, EIA, (HPV 6, 11, 16, 18, 26, 31, 33, 34, 35, 39, 4, 42, 43, 44, 45, 51, 52, 53, 54, 56, 58, 59, 66, 67, 68, 69, 7, 73, 74) PCR-GP5/6, PCR L1-Consensus primer, DBH (HPV 6, 11, 16, 18, 26, 31, 33, 35, 39, 4, 42, 43, 44, 45, 51, 52, 53, 54, 56, 57, 58, 59, 61, 66, 68, 7, 71, 72, 73, 81, 82, 84) PCR- MULTIPLEX (HPV 6, 11, 16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, 68) LBA (HPV 6, 11, 16, 18, 26, 31, 33, 34, 35, 39, 4, 42, 44, 45, 51, 52, 53, 54, 56, 58, 59, 61, 62, 66, 67, 68, 69, 7, 71, 72, 73, 81, 82, 83, 84) Fox 25 b (UK), PCR-MY9/11, (HPV 16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59) ( ) HPV 6 (38.7%) HPV 16 (37.1%) HPV 11 (27.4%) HPV 58 (8.1%) HPV 18 (4.8%) ( ) HPV 16 (58.8%) HPV 31 (17.6%) HPV 18 (11.8%) HPV 53 (11.8%) HPV 58 (11.8%) 2 1. ( ) HPV 16 (5.%) HPV 44 (35.%) HPV 58 (35.%) HPV 6 (3.%) HPV 31 (3.%) ( ) HPV 16 (55.1%) HPV 58 (34.8%) HPV 33 (29.%) HPV 51 (23.2%) HPV 18 (21.7%) ( ) HPV 16 (59.1%) HPV 6 (34.1%) HPV 66 (31.8%) HPV 52 (29.5%) HPV 53 (29.5%) ( ) HPV 16 (64.9%) HPV 18 (25.7%) HPV 33 (24.3%) HPV 58 (21.6%) HPV 31 (18.9%) Data updated on 28 Jun 217 (data as of 3 Jun 215). 95% CI: 95% Confidence Interval; AIN 2/3: Anal intraepithelial neoplasia of grade 2/3; DBH: Dot Blot Hybridization; EIA: Enzyme ImmunoAssay; LBA: Line-Blot Assay; PCR: Polymerase Chain Reaction; RFLP: Restriction Fragment Length Polymorphism; SPF: Short Primer Fragment; TS: Type Specific; a Includes cases from Bosnia-Herzegovina, Czech Republic, France, Germany, Poland, Portugal, Slovenia, Spain and United Kingdom b HIV positive cases Data sources: See references in Section 9.

131 4 HPV-RELATED STATISTICS Figure 115: Comparison of the ten most frequent HPV types in anal cancer cases in Europe and the World Europe (a) World (b) Type specific HPV prevalence (%) of anal cancer cases Data updated on 9 Feb 217 (data as of 3 Jun 214). a Includes cases from Bosnia-Herzegovina, Czech Republic, France, Germany, Poland, Portugal, Slovenia, Spain and United Kingdom. b Includes cases from Europe (Bosnia-Herzegovina, Czech Republic, France, Germany, Poland, Portugal, Slovenia, Spain and United Kingdom); America (Chile, Colombia, Ecuador, Guatemala, Honduras, Mexico, Paraguay and United States); Africa (Mali, Nigeria and Senegal); Asia (Bangladesh,India and South Korea) Data sources: See references in Section 9. Figure 116: Comparison of the ten most frequent HPV types in AIN 2/3 cases in Europe and the World Europe (a) World (b) Type specific HPV prevalence (%) of AIN 2/3 cases Data updated on 9 Feb 217 (data as of 3 Jun 214). AIN 2/3: Anal intraepithelial neoplasia of grade 2/3; a Includes cases from Bosnia-Herzegovina, Czech Republic, France, Germany, Poland, Portugal, Slovenia, Spain and United Kingdom b Includes cases from Europe (Bosnia-Herzegovina, Czech Republic, France, Germany, Poland, Portugal, Slovenia, Spain and United Kingdom); America (Chile, Colombia, Ecuador, Guatemala, Honduras, Mexico, Paraguay) Data sources: See references in Section 9.

132 4 HPV-RELATED STATISTICS Vulvar cancer and precancerous vulvar lesions HPV attribution for vulvar cancer is 43% worldwide (de Martel C et al. Lancet Oncol 212;13(6):67-15). Vulvar cancer has two distinct histological patterns with two different risk factor profiles: (1) basaloid/warty types (2) keratinising types. Basaloid/warty lesions are more common in young women, are frequently found adjacent to VIN, are very often associated with HPV DNA detection (86%), and have a similar risk factor profile as cervical cancer. Keratinising vulvar carcinomas represent the majority of the vulvar lesions (>6%). These lesions develop from non HPV-related chronic vulvar dermatoses, especially lichen sclerosus and/or squamous hyperplasia, their immediate cancer precursor lesion is differentiated VIN, they occur more often in older women, and are rarely associated with HPV (6%) or with any of the other risk factors typical of cervical cancer. HPV prevalence is frequently detected among cases of high-grade VIN (VIN2/3) (85.3%). HPV 16 is the most common type detected followed by HPV 33 (De Vuyst H et al. Int J Cancer 29; 124: ). In this section, the HPV prevalence among vulvar cancer cases and precancerous vulvar lesions in Europe are presented. Table 19: European studies on HPV prevalence among vulvar cancer cases HPV detection Prevalence of 5 most method and targeted HPV prevalence frequent HPVs Study HPV types No. Tested % (95% CI) HPV type (%) Tachezy 211 (Czech Rep.) Bryndorf 24 (Denmark) Hørding 1993 (Denmark) Hørding 1994 (Denmark) Madsen 28 (Denmark) de Sanjosé 213 a (Europe) Iwasawa 1997 (Finland) Choschzick 211 (Germany) Hampl 26 (Germany) Milde-Langosch 1995 (Germany) PCR L1-Consensus primer,, Sequencing (HPV 6, 11, 16, 18, 2, 21, 22, 23, 26, 3, 31, 32, 33, 34, 35, 38, 39, 4, 42, 43, 44, 45, 51, 52, 53, 54, 56, 57, 58, 59, 6, 61, 62, 66, 67, 68, 69, 7, 71, 72, 73, 74, 8, 81, 82, 83, 84, 85, 86, 87, 89, 9, 91) PCR-SPF1, (HPV 6, 11, 16, 18, 31, 33, 35, 42, 44, 45, 51, 52, 56, 58) PCR-E6, PCR-E7, TS (HPV 6, 11, 16, 18, 33) PCR-E6, PCR-E7, TS (HPV 6, 11, 16, 18, 33) EIA, (HPV 6, 11, 16, 18, 31, 33, 35, 42, 44, 45, 51, 52, 56, 58, 61, 67, 73) PCR-SPF1, EIA, (HPV 6, 11, 16, 18, 26, 3, 31, 33, 34, 35, 39, 4, 42, 43, 44, 45, 51, 52, 53, 54, 56, 58, 59, 61, 66, 67, 68, 69, 7, 73, 74, 82, 83, 87, 89, 91) PCR-MY9/11, PCR L1-Consensus primer, PCR-E6, TS (HPV 6, 11, 16, 18, 33) PCR-MY9/11, Sequencing (HPV 6, 11, 16, 18, 33) PCR-MY9/11, Sequencing (HPV 16, 18, 2, 21, 22, 23, 26, 3, 31, 32, 33, 35, 42, 44, 45, 51, 52, 56, 58, 61, 67, 73, 91) PCR-MY9/11, TS (HPV 6, 11, 16, 18, 31, 33, 35) ( ) HPV 16 (23.9%) HPV 33 (8.7%) HPV 6 (2.2%) HPV 42 (2.2%) HPV 45 (2.2%) 1 6. ( ) HPV 16 (4.%) HPV 33 (2.%) HPV 56 (1.%) ( ) HPV 16 (21.%) HPV 18 (4.8%) HPV 33 (4.8%) ( ) HPV 16 (28.2%) HPV 33 (3.8%) ( ) HPV 16 (36.7%) HPV 33 (11.7%) HPV 73 (3.3%) HPV 6 (1.7%) HPV 51 (1.7%) ( ) HPV 16 (13.8%) HPV 33 (1.2%) HPV 18 (.6%) HPV 31 (.6%) HPV 44 (.4%) ( ) HPV 16 (25.7%) HPV 18 (12.2%) HPV 33 (1.4%) ( ) HPV 16 (43.6%) HPV 33 (2.6%) ( ) HPV 16 (39.6%) HPV 33 (8.3%) HPV 31 (4.2%) HPV 18 (2.1%) ( ) HPV 16 (25.%) (Continued on next page)

133 4 HPV-RELATED STATISTICS HPV detection ( Table 19 continued from previous page) Prevalence of 5 most method and targeted HPV prevalence frequent HPVs Study HPV types No. Tested % (95% CI) HPV type (%) Reuschenbach 213 (Germany) Bonvicini 25 (Italy) Kagie 1997 (Netherlands) Trietsch 213 (Netherlands) van de Nieuwenhof 29 (Netherlands) van der Avoort 26 (Netherlands) Bujko 212 (Poland) Liss 1998 (Poland) Alonso 211 (Spain) Guerrero 211 (Spain) Lerma 1999 (Spain) Larsson 212 (Sweden) Lindell 21 (Sweden) Abdel-Hady 21 (UK) PCR- MULTIPLEX (HPV 6, 11, 16, 18, 31, 33, 35, 39, 42, 43, 44, 45, 51, 52, 56, 58, 59, 68, 7, 71, 73, 82) PCR-MY9/11 (HPV 16, 18, 31, 33, 35, 45, 52, 58) PCR-CPI/CPIIG, Sequencing (HPV 6, 11, 16, 31, 33, 45) PCR, (HPV 6, 11, 16, 18, 26, 31, 33, 35, 39, 4, 43, 44, 45, 51, 52, 53, 54, 56, 58, 59, 66, 68, 69, 7, 71, 73, 74, 82) PCR L1-Consensus primer, (HPV 6, 11, 16, 18, 31, 33, 35, 42, 45, 51, 52, 53, 54, 56, 58, 66, 73) PCR L1-Consensus primer, PCR-SPF1, (HPV 6, 11, 16, 18, 31, 33, 35, 42, 44, 45, 51, 52, 56, 58) PCR, LBA (HPV 6, 11, 16, 18, 26, 31, 33, 34, 35, 39, 4, 42, 43, 44, 45, 51, 52, 53, 54, 56, 57, 58, 59, 61, 66, 68, 7, 71, 72, 73, 81, 82, 83, 84) PCR-MY9/11, PCR L1-Consensus primer, PCR-E6, PCR-E7, RFLP (HPV 6, 11, 16, 18, 31, 33, 35, 45, 52, 58) PCR-SPF1, (HPV 6, 11, 16, 18, 31, 33, 35, 42, 45, 51, 52, 53, 54, 56, 58, 66) PCR L1-Consensus primer, (HPV 6, 11, 16, 18, 26, 31, 33, 34, 35, 39, 4, 42, 43, 44, 45, 51, 52, 53, 54, 56, 57, 58, 59, 61, 66, 68, 7, 71, 72, 73, 81, 82, 83, 84) PCR L1-Consensus primer, TS (HPV 16, 18) PCR-E6, (HPV 6, 11, 16, 18, 31, 33, 39, 45, 51, 52, 56, 58, 59) PCR-CPI/CPIIG, TS, Sequencing (HPV 6, 11, 16, 18, 33, 52) ( ) HPV 16 (36.1%) HPV 18 (2.7%) HPV 33 (1.1%) HPV 6 (.5%) HPV 11 (.5%) 16. (.-19.4) ( ) HPV 16 (16.7%) HPV 33 (1.5%) HPV 45 (1.5%) ( ) HPV 16 (1.2%) HPV 33 (5.6%) HPV 18 (1.9%) ( ) HPV 16 (15.4%) HPV 33 (5.4%) HPV 18 (2.3%) HPV 52 (1.5%) HPV 54 (1.5%) 16. (.-19.4) ( ) HPV 16 (2.5%) HPV 11 (11.4%) HPV 44 (4.5%) HPV 52 (4.5%) HPV 58 (4.5%) ( ) HPV 16 (16.7%) ( ) HPV 16 (14.3%) HPV 33 (2.%) HPV 31 (1.%) HPV 51 (1.%) HPV 52 (1.%) ( ) HPV 59 (1.%) HPV 6 (3.3%) HPV 16 (3.3%) HPV 18 (3.3%) ( ) HPV 16 (12.3%) ( ) HPV 16 (23.8%) HPV 33 (3.8%) HPV 18 (1.5%) HPV 56 (.8%) HPV 59 (.8%) ( ) HPV 16 (21.3%) HPV 18 (2.7%) HPV 33 (2.7%) HPV 52 (1.3%) TS (HPV 6, 11, 16, 18, 31, 33) ( ) HPV 16 (27.3%) HPV 33 (18.2%) HPV 18 (9.1%) (Continued on next page)

134 4 HPV-RELATED STATISTICS HPV detection ( Table 19 continued from previous page) Prevalence of 5 most method and targeted HPV prevalence frequent HPVs Study HPV types No. Tested % (95% CI) HPV type (%) Riethdorf 24 b PCR L1-Consensus primer, TS ( ) HPV 16 (87.3%) (World) (HPV 16) Data updated on 28 Jun 217 (data as of 3 Jun 215). 95% CI: 95% Confidence Interval; EIA: Enzyme ImmunoAssay; LBA: Line-Blot Assay; PCR: Polymerase Chain Reaction; RFLP: Restriction Fragment Length Polymorphism; SPF: Short Primer Fragment; TS: Type Specific; a Includes cases from Austria, Belarus, Bosnia-Herzegovina, Czech Republic, France, Germany, Greece, Italy, Poland, Portugal, Spain and United Kingdom b Includes cases from Germany and United States of America Data sources: See references in Section 9. Table 2: European studies on HPV prevalence among VIN 2/3 cases HPV detection Prevalence of 5 most method and targeted HPV prevalence frequent HPVs Study HPV types No. Tested % (95% CI) HPV type (%) Tachezy 211 (Czech Rep.) Junge 1995 (Denmark) de Sanjosé 213 a (Europe) Hampl 26 (Germany) Tsimplaki 212 (Greece) Bonvicini 25 (Italy) van Beurden 1995 (Netherlands) van der Avoort 26 (Netherlands) van Esch 214 (Netherlands) Lerma 1999 (Spain) Abdel-Hady 21 (UK) PCR L1-Consensus primer,, Sequencing (HPV 6, 11, 16, 18, 2, 21, 22, 23, 26, 3, 31, 32, 33, 34, 35, 38, 39, 4, 42, 43, 44, 45, 51, 52, 53, 54, 56, 57, 58, 59, 6, 61, 62, 66, 67, 68, 69, 7, 71, 72, 73, 74, 8, 81, 82, 83, 84, 85, 86, 87, 89, 9, 91) PCR-E6, PCR-E7, TS (HPV 6, 11, 16, 18, 31, 33) PCR-SPF1, EIA, (HPV 6, 11, 16, 18, 26, 3, 31, 33, 34, 35, 39, 4, 42, 43, 44, 45, 51, 52, 53, 54, 56, 58, 59, 61, 66, 67, 68, 69, 7, 73, 74, 82, 83, 87, 89, 91) PCR-MY9/11, Sequencing (HPV 6, 11, 16, 18, 2, 21, 22, 23, 26, 3, 31, 32, 33, 35, 42, 44, 45, 51, 52, 56, 58, 61, 67, 73, 74, 91) (HPV 6, 11, 16, 18, 31, 33, 35, 4, 42, 43, 44, 45, 51, 52, 53, 56, 58, 59, 66, 73) PCR-MY9/11 (HPV 16, 18, 31, 33, 35, 45, 52, 58) PCR-CPI/CPIIG, Sequencing (HPV 6, 11, 16, 18, 2, 21, 22, 23, 26, 3, 31, 32, 33, 45) PCR L1-Consensus primer, PCR-SPF1, (HPV 6, 11, 16, 18, 31, 33, 35, 42, 43, 44, 45, 51, 52, 56, 58, 59, 74) ( ) HPV 16 (71.3%) HPV 33 (8.5%) HPV 18 (5.3%) HPV 6 (4.3%) HPV 11 (2.1%) ( ) HPV 16 (77.6%) HPV 33 (1.3%) ( ) HPV 16 (69.6%) HPV 33 (11.2%) HPV 18 (2.2%) HPV 6 (1.6%) HPV 52 (1.3%) ( ) HPV 16 (79.8%) HPV 33 (1.7%) HPV 31 (4.2%) HPV 18 (3.%) ( ) HPV 16 (64.3%) HPV 18 (7.1%) HPV 51 (7.1%) HPV 52 (7.1%) HPV 53 (7.1%) ( ) HPV 16 (36.%) HPV 35 (8.%) HPV 33 (4.%) HPV 52 (4.%) ( ) HPV 16 (89.1%) HPV 33 (2.2%) HPV 45 (2.2%) ( ) HPV 16 (4.6%) HPV 6 (6.3%) HPV 31 (6.3%) HPV 33 (3.1%) TS (HPV 16, 18, 33, 73) ( ) HPV 16 (81.4%) HPV 33 (14.%) HPV 73 (2.3%) PCR L1-Consensus primer, TS ( ) HPV 16 (27.8%) (HPV 16, 18) TS (HPV 6/11, 16, 18, 31, 33) ( ) HPV 16 (62.5%) HPV 6/11 (18.8%) HPV 31 (3.1%) HPV 33 (3.1%) (Continued on next page)

135 4 HPV-RELATED STATISTICS HPV detection ( Table 2 continued from previous page) Prevalence of 5 most method and targeted HPV prevalence frequent HPVs Study HPV types No. Tested % (95% CI) HPV type (%) Baldwin 23 (UK) PCR L1-Consensus primer, Sequencing (HPV 6, 11, 16, 18, 31, 33) Bryant 211 (UK) PCR- MULTIPLEX (HPV 6, 11, 16, 18, 31, 33, 35, 4, 42, 43, 44, 45, 51, 52, 53, 56, 58, 59, 66, 73) Daayana 21 (UK) Winters 28 (UK) EIA, (HPV 6, 11, 16, 26, 31, 33, 34, 35, 39, 4, 42, 43, 44, 45, 51, 52, 53, 54, 56, 57, 58, 59, 61, 66, 68, 7, 71, 72, 73, 81, 82, 83, 84) EIA, (HPV 6, 11, 16, 18, 26, 31, 33, 34, 35, 39, 4, 42, 43, 44, 45, 51, 52, 53, 54, 56, 57, 58, 59, 61, 66, 68, 7, 71, 72, 73, 81, 82, 83, 84) PCR L1-Consensus primer, TS (HPV 16) ( ) HPV 16 (9.9%) HPV 33 (9.1%) ( ) HPV 16 (67.3%) HPV 33 (16.3%) HPV 6 (1.2%) HPV 18 (2.%) HPV 31 (2.%) ( ) HPV 16 (73.7%) HPV 33 (5.3%) HPV 42 (5.3%) HPV 84 (5.3%) ( ) HPV 16 (75.%) HPV 18 (5.%) HPV 33 (5.%) ( ) HPV 16 (68.3%) Riethdorf 24 b (World) Data updated on 28 Jun 217 (data as of 3 Jun 215). 95% CI: 95% Confidence Interval; VIN 2/3: Vulvar intraepithelial neoplasia of grade 2/3; EIA: Enzyme ImmunoAssay; PCR: Polymerase Chain Reaction; SPF: Short Primer Fragment; TS: Type Specific; a Includes cases from Austria, Belarus, Bosnia-Herzegovina, Czech Republic, France, Germany, Greece, Italy, Poland, Portugal, Spain and United Kingdom b Includes cases from Germany and United States of America Data sources: See references in Section 9. Figure 117: Comparison of the ten most frequent HPV types in cases of vulvar cancer in Europe and the World Europe (a) World (b) Type specific HPV prevalence (%) of vulvar cancer cases Data updated on 9 Feb 217 (data as of 3 Jun 214). VIN 2/3: Vulvar intraepithelial neoplasia of grade 2/3; a Includes cases from Austria, Belarus, Bosnia-Herzegovina, Czech Republic, France, Germany, Greece, Italy, Poland, Portugal, Spain and United Kingdom. b Includes cases from America (Argentina, Brazil, Chile, Colombia, Ecuador, Guatemala, Honduras, Mexico, Paraguay, Uruguay, United States of America and Venezuela); Africa (Mali, Mozambique, Nigeria, and Senegal); Oceania (Australia and New Zealand); Europe (Austria, Belarus, Bosnia-Herzegovina, Czech Republic, France, Germany, Greece, Italy, Poland, Portugal, Spain and United Kingdom); and in Asia (Bangladesh, India, Israel, South Korea, Kuwait, Lebanon, Philippines, Taiwan and Turkey) Data sources: See references in Section 9.

136 4 HPV-RELATED STATISTICS Figure 118: Comparison of the ten most frequent HPV types in VIN 2/3 cases in Europe and the World Europe (a) World (b) Type specific HPV prevalence (%) of VIN 2/3 cases Data updated on 9 Feb 217 (data as of 3 Jun 214). VIN 2/3: Vulvar intraepithelial neoplasia of grade 2/3; a Includes cases from Austria, Belarus, Bosnia-Herzegovina, Czech Republic, France, Germany, Greece, Italy, Poland, Portugal, Spain and United Kingdom. b Includes cases from America (Argentina, Brazil, Chile, Colombia, Ecuador, Guatemala, Honduras, Mexico, Paraguay, Uruguay and Venezuela); Oceania (Australia and New Zealand); Europe (Austria, Belarus, Bosnia-Herzegovina, Czech Republic, France, Germany, Greece, Italy, Poland, Portugal, Spain and United Kingdom); and in Asia (Bangladesh, India, Israel, South Korea, Kuwait, Lebanon, Philippines, Taiwan and Turkey) Data sources: See references in Section 9.

137 4 HPV-RELATED STATISTICS Vaginal cancer and precancerous vaginal lesions Vaginal and cervical cancers share similar risk factors and it is generally accepted that both carcinomas share the same aetiology of HPV infection although there is limited evidence available. Women with vaginal cancer are more likely to have a history of other anogenital cancers, particularly of the cervix, and these two carcinomas are frequently diagnosed simultaneously. HPV DNA is detected among 7% of invasive vaginal carcinomas and 91% of high-grade vaginal neoplasias (VaIN2/3). HPV16 is the most common type in high-grade vaginal neoplasias and it is detected in at least 7% of HPV-positive carcinomas (de Martel C et al. Lancet Oncol 212;13(6):67-15; De Vuyst H et al. Int J Cancer 29; 124: ). In this section, the HPV prevalence among vaginal cancer cases and precancerous vaginal lesions in Europe are presented. Table 21: European studies on HPV prevalence among vaginal cancer cases HPV detection Prevalence of 5 most method and targeted HPV prevalence frequent HPVs Study HPV types No. Tested % (95% CI) HPV type (%) Madsen 28 (Denmark) Alemany (Europe) 214 a Ferreira 28 (Portugal) Fuste 21 (Spain) Larsson 213 (Sweden) EIA, (HPV 6, 11, 16, 18, 31, 33, 35, 39, 4, 42, 44, 45, 51, 52, 56, 58) PCR-SPF1, EIA, (HPV 6, 11, 16, 18, 26, 3, 31, 33, 35, 39, 42, 45, 51, 52, 53, 56, 58, 59, 66, 67, 68, 69, 73, 82) PCR, (HPV 6, 11, 16, 18, 31, 33, 35, 4, 42, 44, 45, 51, 52, 56, 58) PCR-SPF1, (HPV 6, 11, 16, 18, 31, 33, 35, 39, 4, 42, 45, 51, 52, 56, 58, 59, 68) PCR-E6, (HPV 6, 11, 16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59) Data updated on 28 Jun 217 (data as of 3 Jun 215). 95% CI: 95% Confidence Interval; EIA: Enzyme ImmunoAssay; PCR: Polymerase Chain Reaction; SPF: Short Primer Fragment; a Includes cases from Austria, Belarus, Czech Republic, France, Germany, Greece, Poland, Spain and United Kingdom Data sources: See references in Section ( ) HPV 16 (77.8%) HPV 33 (7.4%) HPV 18 (3.7%) HPV 39 (3.7%) HPV 45 (3.7%) ( ) HPV 16 (47.4%) HPV 18 (3.3%) HPV 73 (3.3%) HPV 33 (2.6%) HPV 56 (2.6%) ( ) HPV 16 (33.3%) HPV 31 (28.6%) HPV 4 (14.3%) HPV 6 (9.5%) HPV 18 (9.5%) ( ) HPV 16 (56.3%) HPV 52 (6.3%) HPV 35 (3.1%) HPV 51 (3.1%) HPV 58 (3.1%) ( ) HPV 16 (37.7%) HPV 18 (2.9%) HPV 31 (2.9%) HPV 33 (2.9%) HPV 52 (2.9%) Table 22: European studies on HPV prevalence among VaIN 2/3 cases HPV detection Prevalence of 5 most method and targeted HPV prevalence frequent HPVs Study HPV types No. Tested % (95% CI) HPV type (%) Alemany 214 (Europe) PCR-SPF1, EIA, (HPV 6, 11, 16, 18, 26, 3, 31, 33, 35, 39, 42, 45, 51, 52, 53, 56, 58, 59, 66, 67, 68, 69, 73, 82) (Continued on next page) ( ) HPV 16 (65.6%) HPV 33 (7.3%) HPV 18 (5.2%) HPV 52 (3.1%) HPV 73 (3.1%)

138 4 HPV-RELATED STATISTICS HPV detection ( Table 22 continued from previous page) Prevalence of 5 most method and targeted HPV prevalence frequent HPVs Study HPV types No. Tested % (95% CI) HPV type (%) Hampl 26 (Germany) Tsimplaki 212 (Greece) PCR-MY9/11, Sequencing (HPV 6, 11, 16, 18, 2, 21, 22, 23, 26, 3, 31, 32, 33, 35, 4, 44, 52, 56, 58) (HPV 6, 11, 16, 18, 31, 33, 35, 39, 4, 42, 44, 45, 51, 52, 53, 56, 58, 66, 7) ( ) HPV 16 (63.6%) 1 4. ( ) HPV 16 (2.%) HPV 33 (2.%) Frega 27 (Italy) PCR, TS (HPV 16, 18) 3 1. ( ) HPV 16 (86.7%) HPV 18 (13.3%) Data updated on 28 Jun 217 (data as of 3 Jun 215). 95% CI: 95% Confidence Interval; VAIN 2/3: Vaginal intraepithelial neoplasia of grade 2/3; EIA: Enzyme ImmunoAssay; PCR: Polymerase Chain Reaction; SPF: Short Primer Fragment; TS: Type Specific; Based on systematic reviews (up to 28) performed by ICO for the IARC Monograph on the Evaluation of Carcinogenic Risks to Humans volume 1B and IARC s Infections and Cancer Epidemiology Group. The has updated data until June 215. Reference publications: 1) Bouvard V, Lancet Oncol 29;1:321 2) De Vuyst H, Int J Cancer 29;124:1626 Alemany L, Eur J Cancer 214; 5: 2846 Frega A, Cancer Lett 27; 249: 235 Hampl M, Obstet Gynecol 26; 18: 1361 Tsimplaki E, J Oncol 212; 212: Data sources: See references in Section 9. Figure 119: Comparison of the ten most frequent HPV types in vaginal cancer cases in Europe and the World Europe (a) World (b) Type specific HPV prevalence (%) of vaginal cancer cases Data updated on 9 Feb 217 (data as of 3 Jun 214). VAIN 2/3: Vaginal intraepithelial neoplasia of grade 2/3; a Includes cases from Austria, Belarus, Czech Republic, France, Germany, Greece, Poland, Spain and United Kingdom. b Includes cases from Europe (Austria, Belarus, Czech Republic, France, Germany, Greece, Poland, Spain and United Kingdom); America (Argentina, Brazil, Chile, Colombia, Ecuador, Guatemala, Mexico, Paraguay, Uruguay, United states of America and Venezuela); Africa (Mozambique, Nigeria); Asia (Bangladesh, India, Israel, South Korea, Kuwait, Philippines, Taiwan and Turkey); and Oceania (Australia) Data sources: See references in Section 9.

139 4 HPV-RELATED STATISTICS Figure 12: Comparison of the ten most frequent HPV types in VaIN 2/3 cases in Europe and the World Europe (a) World (b) Type specific HPV prevalence (%) of VaIN 2/3 cases Data updated on 9 Feb 217 (data as of 3 Jun 214). VAIN 2/3: Vaginal intraepithelial neoplasia of grade 2/3; a Includes cases from Austria, Belarus, Czech Republic, France, Germany, Greece, Poland, Spain and United Kingdom. b Includes cases from Europe (Austria, Belarus, Czech Republic, France, Germany, Greece, Poland, Spain and United Kingdom); America (Argentina, Brazil, Chile, Colombia, Ecuador, Guatemala, Mexico, Paraguay, Uruguay, United states of America and Venezuela); Asia (Bangladesh, India, Israel, South Korea, Kuwait, Philippines, Taiwan and Turkey); and Oceania (Australia) Data sources: See references in Section 9.

140 4 HPV-RELATED STATISTICS Penile cancer and precancerous penile lesions HPV DNA is detectable in approximately 5% of all penile cancers (de Martel C et al. Lancet Oncol 212;13(6):67-15). Among HPV-related penile tumours, HPV16 is the most common type detected, followed by HPV18 and HPV types 6/11 (Miralles C et al. J Clin Pathol 29;62:87-8). Over 95% of invasive penile cancers are SCC and the most common penile SCC histologic sub-types are keratinising (49%), mixed warty-basaloid (17%), verrucous (8%), warty (6%), and basaloid (4%). HPV is commonly detected in basaloid and warty tumours but is less common in keratinising and verrucous tumours. In this section, the HPV prevalence among penile cancer cases and precancerous penile lesions in Europe are presented. Table 23: European studies on HPV prevalence among penile cancer cases HPV detection Prevalence of 5 most method and targeted HPV prevalence frequent HPVs Study HPV types No. Tested % (95% CI) HPV type (%) Mannweiler 213 (Austria) D Hauwers 212 (Belgium) Alemany 216 (Europe) Humbey 23 (France) Perceau 23 (France) Poetsch 211 (Germany) Barzon 214 (Italy) Gentile 26 (Italy) Tornesello 28 (Italy) Heideman 27 (Netherlands) PCR L1-Consensus primer, PCR-SPF1, (HPV 6, 11, 16, 18, 26, 31, 33, 35, 39, 4, 43, 44, 45, 51, 52, 53, 54, 56, 58, 59, 66, 68, 69, 7, 71, 72, 73, 74, 82) PCR-E6, PCR-E7, qpcr (HPV 6, 11, 16, 18, 31, 33, 35, 39, 45, 51, 52, 53, 56, 58, 59, 66, 67, 68) PCR-SPF1, EIA, (HPV 6, 11, 16, 18, 26, 31, 32, 33, 34, 35, 39, 4, 42, 43, 44, 45, 51, 52, 53, 54, 56, 58, 59, 61, 66, 67, 68, 69, 7, 73, 74, 82, 83, 87, 89, 9, 91) PCR-MY9/11, PCR L1-Consensus primer, TS (HPV 6, 11, 16, 18, 31, 33, 35, 45, 51, 52, 58, 68) ( ) HPV 16 (45.5%) HPV 33 (4.9%) HPV 18 (4.1%) HPV 45 (3.3%) HPV 6 (.8%) ( ) HPV 16 (47.2%) HPV 59 (5.6%) HPV 6 (2.8%) HPV 11 (2.8%) HPV 33 (2.8%) ( ) HPV 16 (23.4%) HPV 52 (1.2%) HPV 6 (1.%) HPV 33 (1.%) HPV 45 (.7%) ( ) HPV 16 (25.%) TS (HPV 16, 18, 31, 33) ( ) HPV 16 (17.6%) PCR- MULTIPLEX, TS (HPV 6/11, 16, 18) qpcr,, TS (HPV 16, 18, 26, 31, 33, 35, 39, 43, 44, 45, 51, 52, 53, 54, 56, 58, 59, 66, 68, 69, 7, 71, 73, 74, 82) PCR-MY9/11, PCR L1-Consensus primer, Sequencing (HPV 16, 18, 53) PCR-MY9/11, PCR-L1C1/C2, PCR-E6, PCR-E7, Sequencing (HPV 6, 16, 18, 33, 35) PCR-E6, PCR-E7, EIA, (HPV 6, 11, 16, 18, 26, 31, 33, 34, 35, 39, 42, 43, 44, 45, 51, 52, 53, 54, 56, 57, 58, 59, 61, 66, 68, 7, 71, 72, 73, 81, 82, 83, 84) ( ) HPV 16 (32.7%) HPV 6/11 (3.8%) HPV 18 (1.9%) ( ) HPV 16 (25.9%) HPV 45 (1.9%) HPV 68 (1.9%) ( ) HPV 16 (45.5%) HPV 18 (18.2%) HPV 53 (9.1%) ( ) HPV 16 (42.6%) HPV 18 (3.3%) HPV 35 (1.6%) ( ) HPV 16 (22.8%) HPV 18 (2.3%) HPV 45 (1.8%) HPV 33 (1.2%) HPV 56 (.6%) (Continued on next page)

141 4 HPV-RELATED STATISTICS HPV detection ( Table 23 continued from previous page) Prevalence of 5 most method and targeted HPV prevalence frequent HPVs Study HPV types No. Tested % (95% CI) HPV type (%) Ferrándiz-Pulido 213 (Spain) Guerrero 28 (Spain) Pascual 27 (Spain) Stankiewicz 211 (UK) PCR-SPF1, EIA, (HPV 6, 11, 16, 18, 31, 33, 34, 35, 39, 4, 42, 43, 44, 45, 51, 52, 53, 54, 56, 58, 59, 66, 68, 7, 73, 74) (HPV 6, 11, 16, 18, 26, 31, 33, 34, 35, 39, 4, 42, 43, 44, 45, 51, 52, 53, 54, 56, 57, 58, 59, 61, 66, 68, 7, 71, 72, 73, 81, 82, 83, 84) PCR-MY9/11, PCR L1-Consensus primer, Sequencing (HPV 6, 11, 16, 18) PCR L1-Consensus primer, PCR-SPF1 (HPV 6, 11, 16, 18, 26, 31, 33, 35, 39, 4, 43, 44, 45, 51, 52, 53, 54, 56, 58, 59, 66, 68, 69, 7, 71, 73, 74, 82) Data updated on 28 Jun 217 (data as of 3 Jun 215). 95% CI: 95% Confidence Interval; EIA: Enzyme ImmunoAssay; PCR: Polymerase Chain Reaction; SPF: Short Primer Fragment; TS: Type Specific; Data sources: See references in Section ( ) HPV 16 (26.9%) HPV 58 (3.8%) HPV 6 (2.6%) HPV 33 (1.3%) HPV 45 (1.3%) ( ) HPV 16 (45.8%) HPV 39 (4.2%) ( ) HPV 16 (65.3%) HPV 18 (8.2%) ( ) HPV 16 (45.1%) HPV 11 (9.8%) HPV 6 (5.9%) HPV 45 (5.9%) HPV 31 (4.9%) Table 24: European studies on HPV prevalence among PeIN 2/3 cases HPV detection Prevalence of 5 most method and targeted HPV prevalence frequent HPVs Study Method No. Tested % (95% CI) HPV type (%) Mannweiler 213 (Austria) D Hauwers 212 (Belgium) Alemany 216 (Europe) Wikström 212 (Sweden) PCR L1-Consensus primer, PCR-SPF1, (HPV 6, 11, 16, 18, 26, 31, 33, 35, 39, 4, 43, 44, 45, 51, 52, 53, 54, 56, 58, 59, 66, 68, 69, 7, 71, 72, 73, 74, 82) PCR-E6, PCR-E7, qpcr (HPV 6, 11, 16, 18, 31, 33, 35, 39, 45, 51, 52, 53, 56, 58, 59, 66, 67, 68) PCR-SPF1, EIA, (HPV 6, 11, 16, 18, 26, 3, 31, 32, 33, 35, 39, 4, 42, 43, 44, 45, 51, 52, 53, 54, 56, 58, 59, 61, 66, 67, 68, 69, 7, 73, 74, 82, 83, 87, 89, 9, 91) PCR-MY9/11, PCR L1-Consensus primer (HPV 6, 11, 16, 18, 26, 31, 33, 35, 39, 42, 43, 44, 45, 51, 52, 53, 56, 58, 59, 66, 68, 7, 73, 82) Data updated on 28 Jun 217 (data as of 3 Jun 215). 95% CI: 95% Confidence Interval; PeIN 2/3: Penile intraepithelial neoplasia of grade 2/3; EIA: Enzyme ImmunoAssay; PCR: Polymerase Chain Reaction; SPF: Short Primer Fragment; Data sources: See references in Section ( ) HPV 16 (62.8%) HPV 18 (9.3%) HPV 33 (2.3%) HPV 73 (2.3%) ( ) HPV 16 (61.5%) HPV 18 (23.1%) HPV 11 (15.4%) HPV 53 (15.4%) HPV 56 (15.4%) ( ) HPV 16 (73.4%) HPV 33 (6.3%) HPV 6 (3.1%) HPV 18 (3.1%) HPV 31 (3.1%) ( ) HPV 16 (39.3%) HPV 6 (21.4%) HPV 31 (7.1%) HPV 33 (7.1%) HPV 45 (7.1%)

142 4 HPV-RELATED STATISTICS Figure 121: Comparison of the ten most frequent HPV types in penile cancer cases in Europe and the World Europe (a) World (b) Type specific HPV prevalence (%) of penile cancer cases Data updated on 9 Feb 217 (data as of 3 Jun 215). a Includes cases from Czech Republic, France, Greece, Poland, Portugal, Spain and United Kingdom b Includes cases from Australia, Bangladesh, India, South Korea, Lebanon, Philippines, Chile, Colombia, Ecuador, Guatemala, Honduras, Mexico, Paraguay, Venezuela and United States, Mozambique, Nigeria, Senegal, Czech Republic, France, Greece, Poland, Portugal, Spain and United Kingdom. Data sources: See references in Section 9. Figure 122: Comparison of the ten most frequent HPV types in PeIN 2/3 cases in Europe and the World Europe (a) World (b) Type specific HPV prevalence (%) of PeIN 2/3 cases Data updated on 9 Feb 217 (data as of 3 Jun 215). a Includes cases from Czech Republic, France, Greece, Poland, Portugal, Spain and United Kingdom b Includes cases from Australia, Bangladesh, India, South Korea, Lebanon, Philippines, Chile, Colombia, Ecuador, Guatemala, Honduras, Mexico, Paraguay, Venezuela, Mozambique, Nigeria, Senegal, Czech Republic, France, Greece, Poland, Portugal, Spain and United Kingdom. Data sources: See references in Section 9.

143 4 HPV-RELATED STATISTICS HPV burden in men The information to date regarding anogenital HPV infection is primarily derived from cross-sectional studies of selected populations such as general population, university students, military recruits, and studies that examined husbands of control women, as well as from prospective studies. Special subgroups include mainly studies that examined STD (sexually transmitted diseases) clinic attendees, MSM (men who have sex with men), HIV positive men, and partners of women with HPV lesions, CIN (cervical intraepithelial neoplasia), cervical cancer or cervical carcinoma in situ. Globally, prevalence of external genital HPV infection in men is higher than cervical HPV infection in women, but persistence is less likely. As with genital HPV prevalence, high numbers of sexual partners increase the acquisition of oncogenic HPV infections (Vaccine 212, Vol. 3, Suppl 5). In this section, the HPV burden among men in Europe is presented. Methods HPV burden in men was based on published systematic reviews and meta-analyses (Dunne EF, J Infect Dis 26; 194: 144, Smith JS, J Adolesc Health 211; 48: 54, Olesen TB, Sex Transm Infect 214; 9: 455, and Hebnes JB, J Sex Med 214; 11: 263) up to October 31, 215. The search terms for the review were human papillomavirus, men, polymerase chain reaction (PCR), hybrid capture (HC), and viral DNA. References cited in selected articles were also investigated. Inclusion criteria were: HPV DNA detection by means of PCR or HC (ISH if data are not available for the country), and a detailed description of HPV DNA detection and genotyping techniques used. The number of cases tested and HPV positive cases were extracted for each study to estimate the anogenital prevalence of HPV DNA. Binomial 95% confidence intervals were calculated for each anogenital HPV prevalence. Table 25: European studies on anogenital HPV prevalence among men Anatomic sites HPV detection Age HPV prevalence Country Study samples method Population (years) No % (95% CI) Croatia Grce 1996 Urethra Filter hybridization (slot-blot, TS 6,11,16,18) Denmark Finland Germany Vardas Penis RT-PCR-Multiplex 211 a or Biplex Hebnes 215 Kjaer 25 Hippeläinen 1993 Coronal sulcus, glans, preputial cavity, scrotum, shaft and perineum Glans and corona sulcus Glans, prepuce, corona sulcus, urethral meatus HC2 PCR-LIPAv2 PCR-GP5+/6+ TS oligoprobes PCR-MY9/11 TS 6,11,16,18,31,33 Kero 211 Urethra PCR-MY9/11 and GP5+/6+ Grussendorf- Conen 1987 Coronal sulcus and glans ISH Family planning clinic attendees Heterosexual men enrolled in a HPV vaccine trial Male employees and conscripts at military barracks Male employees and conscripts at military barracks ( ) Median 2 (15-24) Mean 23 (18-65) Mean 23 (18-65) ( ) ( ) ( ) Military conscripts ( ) Voluntary conscripts Sexual partners of pregnant women Blood donors or patients from department of dermatology Mean ( ) ( ) (4.-8.2) ( Table 25 continued from previous page)

144 4 HPV-RELATED STATISTICS ( Table 25 continued from previous page) Anatomic sites HPV detection Age HPV prevalence Country Study samples method Population (years) No % (95% CI) Italy Spain Sweden Vardas Penis RT-PCR-Multiplex 211 a or Biplex Lorenzon 214 Nasca 26 Franceschi 22 Coronal sulcus, shaft, prepuce, and urethral Penis Glans, corona, urethra PCR-Roche Linear Array HPV Genotyping test PCR-MY9/11 and GP5+/6+ PCR-GP5+/6+ Vardas Penis RT-PCR-Multiplex 211 a or Biplex Forslund 1993 Kataoka 1991 Urethra Urethra PCR-TS (6,11,16,18,31,33,35) and unespecified consensus primer PCR-TS 6,11,16,18,33 Heterosexual men enrolled in a HPV vaccine trial Heterosexual men for routine HPV testing Hospital based controls attending clinic for nongenital complaints Husbands of control women Heterosexual men enrolled in a HPV vaccine trial Median 2 (15-24) ( ) ( ) ( ) ( ) Median 2 (15-24) ( ) Military conscripts ( ) Army conscripts with normal epithelium Data updated on 28 Jun 217 (data as of 31 Oct 215). 95% CI: 95% Confidence Interval; HC2: Hybrid Capture 2; ISH: In Situ Hybridization; PCR: Polymerase Chain Reaction; RT-PCR: Real Time Polymerase Chain Reaction; TS: Type Specific; a Includes cases from Australia, Brazil, Canada, Croatia, Germany, Mexico, Spain, and USA. Data sources: See references in Section ( ) Table 26: European studies on anogenital HPV prevalence among men from special subgroups Anatomic sites HPV detection Age HPV prevalence Country Study samples method Population (years) No % (95% CI) Croatia Denmark France Goldstone 211 Svare 22 Aynaud 23 Anus Penis Coronal sulcus, glans, perianal area, scrotum, and shaft Meatal urethra RT-PCR-Multiplex or Biplex RT-PCR-Multiplex or Biplex PCR-GP5+/6+ and TS 6,11,16,18,31,33 PCR-TS 6,11,42,16,18,33 HIV- MSM HIV- MSM STD clinic attendees Men with normal peniscopy whose female partners have genital HPV lesions Median 22 (16-27) Median 22 (16-27) ( ) ( ) >= ( ) Mean ( ) ( Table 26 continued from previous page)

145 4 HPV-RELATED STATISTICS ( Table 26 continued from previous page) Anatomic sites HPV detection Age HPV prevalence Country Study samples method Population (years) No % (95% CI) Germany Greece Ireland Italy Damay 21 Philibert 214 Piketty 24 Goldstone 211 Schneider 1988 Wieland 215 Anal canal Anus PCR- PapilloCheck PCR-Cobas HR-HPV Men with penile and urethral lesions whose female partners have genital HPV lesions HIV+ MSM HIV- MSM HIV+ MSM Mean ( ) Median 45 ( ) Mean 46.4 (SD=9.4) Mean 46.4 (SD=9.4) ( ) ( ) ( ) Anal canal PCR-MY9/11 HIV+ MSM ( ) Anus Penis Glans, prepuce, fossa navicularis, shaft Anus RT-PCR-Multiplex or Biplex RT-PCR-Multiplex or Biplex Filter hybridization DNA/DNA PCR-Multiplex and hybridization HIV- MSM HIV- MSM Sexual partners of women with HPV associated lesions of the cervix HadjivassiliouUrethra HC2 HR, LR HIV- STD clinic 27 attendees without genital warts and sexual partners of women with genital warts Sadlier 214 Barzon 21 Benevolo 28 Median 22 (16-27) Median 22 (16-27) Mean ( ) ( ) ( ) HIV+ MSM ( ) Anus PCR-TS 16,18,31 HIV- MSM Mean 32 (SD=8) Glans, corona, shaft, perianal area, urethra, and semen Coronal sulcus, urethra, prepuce, shaft PCR-General primers for L1 (MY9/11, GP5 + /6+) PCR-L1 HIV+ MSM Mean 4 (SD=1) Men referred for HPV testing. Indications for testing: STD screening, HPV suspected lesions, HPV-positive partners Male partners of women with CIN and/or positive HPV ( ) ( ) ( ) ( ) ( ) ( Table 26 continued from previous page)

146 4 HPV-RELATED STATISTICS ( Table 26 continued from previous page) Anatomic sites HPV detection Age HPV prevalence Country Study samples method Population (years) No % (95% CI) Netherlands Chiarini 1998 Della Torre 1992 Urethra Urethra PCR-Generic primers in E1 PCR-TS 6,11,16,18 Men with symptoms of nongonococcal urethritis Partners of women with HPV Dona 215 Anus PCR-Linear Array HIV- MSM Median 32 (IQR=27-39) Garbuglia 215 Giovannelli 27 Orlando 28 Pierangeli 28 Sammarco 216 Bleeker 22 HIV+ MSM ( ) ( ) Median 41 (IQR=33-47) Anus PCR-MY9/11 HIV+ MSM Median 39 (IQR=33-44) Coronal sulcus, frenulum, glans, prepuce, shaft PCR-LiPA, GP5+/6+ and MY9/11 Partners of women with HPV Anus HC2 HIV+ Median 34 (IQR=3-42) ( ) ( ) ( ) ( ) ( ) Anal canal PCR-MY9/11 HIV- MSM ( ) Anus Coronal sulcus Urethra Glans, corona, frenulum, prepuce Bleeker Corona, 25 a frenulum, glans, inner prepuce Bleeker Corona, 25 b frenulum, glans, inner prepuce van der Snoek 23 Coronal sulcus Perianal area PCR-Multiplex and RFLP and sequencing PCR-Multiplex and RFLP and sequencing PCR-Multiplex and RFLP and sequencing PCR-GP5+/6+ PCR-GP5+/6+ PCR-GP5+/6+ PCR-TS primers and LiPA PCR-TS primers and LiPA HIV+ MSM ( ) HIV+ MSM Mean 38 (IQR=2-53) HIV+ MSM Mean 38 (IQR=2-53) HIV+ MSM Mean 38 (IQR=2-53) Partners of women with CIN Men visiting department of dermatology for non-sti complaints Partners of women with dyskaryosis and/or CIN 5 56 ( ) 5 22 ( ) 5 1 ( ) ( ) ( ) ( ) HIV- MSM ( ) HIV+ MSM ( ) HIV- MSM ( ) ( Table 26 continued from previous page)

147 4 HPV-RELATED STATISTICS ( Table 26 continued from previous page) Anatomic sites HPV detection Age HPV prevalence Country Study samples method Population (years) No % (95% CI) Van Doornum 1994 van 214 Vriend 213 Welling 215 Rijn Corona, urethra, anus, rectum Anal canal Penile shaft PCR-TS 6/11,16,18,33 PCR-LIPA TS 16,18,31,33,45,52,58 PCR-LIPA TS 16,18,31,33,45,52,58 HIV+ MSM ( ) STD clinic attendees HIV- MSM HIV+ MSM HIV- MSM HIV+ MSM Anal canal PCR-LIPA MSM STD clinic attendees MSW STD clinic attendees Penis PCR-LIPA MSM STD clinic attendees Anus Penis PCR-SPF DEIA LIPA PCR-SPF DEIA LIPA Russia Wirtz 215 Anus PCR-TS 6,11,16,18,31,33 MSW STD clinic attendees HIV- MSM HIV+ MSM HIV- MSM HIV+ MSM HIV- MSM HIV+ MSM Mean ( ) Median 37.6 (IQR= ) Median 45.6 (IQR= ) Median 37.6 (IQR= ) Median 45.6 (IQR= ) Median 22 (16-24) Median 22 (16-24) Median 22 (16-24) Median 22 (16-24) Median 38 (IQR=33-42) Median 46 (IQR=39-53) Median 38 (IQR=33-42) Median 46 (IQR=39-53) Median 29 (19-5) Median 29 (19-5) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) 58 5 ( ) ( Table 26 continued from previous page)

148 4 HPV-RELATED STATISTICS ( Table 26 continued from previous page) Anatomic sites HPV detection Age HPV prevalence Country Study samples method Population (years) No % (95% CI) Slovenia Golob 214 Penis PCR-Linear Array Men from infertile couples Spain Milosevic 21 Álvarez- Argüelles 213 Franceschi 22 Goldstone 211 Hidalgo- Tenorio 215 Sendagorta 214 Sendagorta 215 Torres 213 Videla 213 Mean ( ) Anal canal PCR-Linear Array HIV- MSM ( ) Anus Balanopreputial Glans, corona, urethra Anus Penis Anus Anus Anus Anus Anus PCR-General primers in L1 (MY9/11, GP5 + /6+), PCR with TS primers in E6/E7 for typing PCR-General primers in L1 (MY9/11, GP5 + /6+), PCR with TS primers in E6/E7 for typing PCR-GP5+/6+ RT-PCR-Multiplex or Biplex RT-PCR-Multiplex or Biplex PCR-GeneAmp HR-HPV PCR-Genomic amplification PCR-HR Clart HPV2 PCR-Roche Linear Array HPV Genotyping test PCR-TS primers in E6/E7 F-HPVTM typing (Molgentix SL, Spain) HIV+ MSM ( ) STD clinic attendees STD clinic attendees Husbands of women with cervical carcinoma in situ Husbands of women with invasive cervical cancer HIV- MSM HIV- MSM HIV+ MSM HIV+ MSM/bisexual men HIV+ MSM HIV+ MSM HIV+ Heterosexual men attending an outpatient HIV clinic HIV+ MSM attending an outpatient HIV clinic ( ) ( ) ( ) ( ) Median 22 (16-27) Median 22 (16-27) Mean 37.4 (SD=9.5) ( ) ( ) ( ) >= ( ) Median 42 (IQR=33-5) IQR= ( ) ( ) ( ) ( ) ( Table 26 continued from previous page)

149 4 HPV-RELATED STATISTICS ( Table 26 continued from previous page) Anatomic sites HPV detection Age HPV prevalence Country Study samples method Population (years) No % (95% CI) Sweden UK Kataoka 1991 Löwhagen 1999 Strand 1993 Voog 1997 Wikström 1991 Wikström 2 Bissett 211 Cuschieri 211 Hillman 1993 Coronal sulcus, glans, urethra, shaft Urethra PCR-TS primers in E6/E7 F-HPVTM typing (Molgentix SL, Spain) PCR-TS 6,11,16,18,33 HIV+ Heterosexual men attending an outpatient HIV clinic HIV+ MSM attending an outpatient HIV clinic Army conscripts with aceto-white epithelium ( ) ( ) ( ) Anus PCR-MY9/11 HIV- MSM ( ) Coronal sulcus, glans, preputium, and shaft Glans and prepuce Coronal sulcus, inner part of the prepuce, urethra Corona, glans, and prepuce Glans, prepuce, shaft, scrotum PCR-MY9/11 and GP5+/6+ PCR-MY9/11 and GP5+/6+ PCR-TS primers followed by dot blot PCR-GP5+/6+ PCR-General primers (GP5 + /6+), Bio-Plex array technology for typing HIV+ MSM ( ) STD clinic attendees STD clinic attendees STD clinic attendees STD clinic attendees Genitourinary clinic attendees with multiple sexual partners or diagnosis of genital warts within 6 months Shaft PCR-INNO-LiPA Drop-in sexual health service attendees Urethra PCR-GP5+/6+ Men infected with gonorrhea Jalal 27 Urethra PCR-General primers for L1 (MY9/11, GP5 + /6+) and RLH King 215 Anus PCR-Multiplex and Bio-Plex Any nonavalent vaccine HPV types Lacey 1999 Coronal sulcus, glans, penis shaft, scrotum and perianal area PCR-Multiplex and Bio-Plex Any nonavalent vaccine HPV types Genitourinary clinic attendees MSM MSM ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) Median 3 (IQR=25-35) Median 3 (IQR=25-35) ( ) ( ) Anal canal PCR-GP5+/6+ HIV+ MSM ( ) ( Table 26 continued from previous page)

150 4 HPV-RELATED STATISTICS ( Table 26 continued from previous page) Anatomic sites HPV detection Age HPV prevalence Country Study samples method Population (years) No % (95% CI) Data updated on 28 Jun 217 (data as of 31 Oct 215). 95% CI: 95% Confidence Interval; EIA: Enzyme ImmunoAssay; HC2: Hybrid Capture 2; LiPA: Line Probe Assay; PCR: Polymerase Chain Reaction; RFLP: Restriction Fragment Length Polymorphism; RLH: Reverse Line Hybridisation; RT-PCR: Real Time Polymerase Chain Reaction; SPF: Short Primer Fragment; TS: Type Specific; MSM: Men who have sex with men; MSW:Men who have sex with women; STD: sexually transmitted diseases; a Bleeker MC, Int J Cancer 25; 113: 36 b Bleeker MC, Clin Infect Dis 25; 41: 612 Data sources: See references in Section HPV burden in the head and neck The last evaluation of the International Agency for Research in Cancer (IARC) on the carcinogenicity of HPV in humans concluded that (a) there is enough evidence for the carcinogenicity of HPV type 16 in the oral cavity, oropharynx (including tonsil cancer, base of tongue cancer and other oropharyngeal cancer sites), and (b) limited evidence for laryngeal cancer (IARC Monograph Vol 1B). There is increasing evidence that HPV-related oropharyngeal cancers constitute an epidemiological, molecular and clinical distinct form as compared to non HPV-related ones. Some studies indicate that the most likely explanation for the origin of this distinct form of head and neck cancers associated with HPV is a sexually acquired oral HPV infection that is not cleared, persists and evolves into a neoplastic lesion. The most recent figures estimate that 25.6% of all oropharyngeal cancers are attributable to HPV infection with HPV16 being the most frequent type (de Martel C. Lancet Oncol. 212;13(6):67). In this section, the HPV burden in the head and neck in Europe is presented Burden of oral HPV infection in healthy population Table 27: European studies on oral HPV prevalence among healthy population Method HPV detection Prev. of 5 most specimen method frequent collection and and targeted Age No. HPV prevalence HPVs Study anatomic site HPV types Population (years) Tested % (95% CI) HPV type (%) MEN Eike 1995 (Denmark) Kero 212 (Finland) Montaldo 27 (Italy) Kujan 26 (UK) WOMEN Oral smear taken with a wooden stick, used on the right border of the tongue and right buccal mucosa Cytobrush from the buccal mucosa Saliva samples Two brushes: 1.-cervex brush into each side of buccal mucosa and 2.-cytobrush lateral border of the tongue PCR-MY9/11. Genotyping by amplification with TS primers (6, 11, 16, 18) and RFLP PCR-GP5+/GP6+ and MY9/MY11. Genotyping with Multimerix kit (6, 11, 16, 18, 31, 33, 39, 42, 43, 44, 45, 51, 52, 58, 59, 68, 7, 73, 82) PCR-MY9/MY11 and GP5+N. Genotyping by sequencing PCR-Roche master mix and HC2 digene (both able to detect the following HR types: 16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59 and 68). No further genotyping Patients with unrelated disease (otosclerosis, nasal complaints)and their accompanying relatives Fathers-to-be of cohort study Dental clinic visitors Healthy volunteers from university dental hospital (.-11.2) ( ) HPV 16 (9.2%) HPV 33 (2.3%) HPV 82 (2.3%) HPV 6 (.8%) HPV 11 (.8%) ( ) HPV 16 (13.%) HPV 31 (1.5%) ( ) - (Continued on next page)

151 4 HPV-RELATED STATISTICS ( Table 27 continued from previous page) Method HPV detection Prev. of 5 most specimen method frequent collection and and targeted Age No. HPV prevalence HPVs Study anatomic site HPV types Population (years) Tested % (95% CI) HPV type (%) Eike 1995 (Denmark) Kero 211 (Finland) Leimola- Virtanen 1996 (Finland) Montaldo 27 (Italy) Oral smear taken with a wooden stick, used on the right border of the tongue and right buccal mucosa Cytobrush from the buccal mucosa Oral smears collected from three sites of clinically healthy oral mucosa (i.e., buccal surface, palate, and tongue) with use of a sterile interdental brush Saliva samples Cañadas Toothbrush on the 24 (Spain) oral cavity Kujan 26 (UK) Two brushes: 1.-cervex brush into each side of buccal mucosa and 2.-cytobrush lateral border of the tongue BOTH OR UNSPECIFIED Eike 1995 (Denmark) Kero 211 (Finland) Kero 212 (Finland) Leimola- Virtanen 1996 (Finland) Lambropoulos 1997 (Greece) Oral smear taken with a wooden stick, used on the right border of the tongue and right buccal mucosa Cytobrush from the buccal mucosa Cytobrush from the buccal mucosa Oral smears collected from three sites of clinically healthy oral mucosa (i.e., buccal surface, palate, and tongue) with use of a sterile interdental brush Cytobrush from the buccal mucosa PCR-MY9/11. Genotyping by amplification with TS primers (6, 11, 16, 18) and RFLP PCR-GP5+/GP6+ and MY9/MY11. Genotyping with Multimerix kit (6, 11, 16, 18, 31, 33, 39, 42, 43, 44, 45, 51, 52, 58, 59, 68, 7, 73, 82) PCR-GP5/GP6. No genotyping PCR-MY9/MY11 and GP5+N. Genotyping by sequencing PCR-MY9/MY11. Genotyping by DBH with TS probes (6, 11, 16, 18, 26, 31-33, 35, 39, 4, 45, 51-56, 58, 59, 61, 66-68, 7, 71 (AE8), 72, 73, 81 (AE7), 83 (PAP291), 84 (PAP155), 85 (AE5), AE2 (IS39), and AE6) PCR-Roche master mix and HC2 digene (both able to detect the following HR types: 16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59 and 68). No further genotyping PCR-MY9/11. Genotyping by amplification with TS primers (6, 11, 16, 18) and RFLP PCR-GP5+/GP6+ and MY9/MY11. Genotyping with Multimerix kit (6, 11, 16, 18, 31, 33, 39, 42, 43, 44, 45, 51, 52, 58, 59, 68, 7, 73, 82) PCR-GP5+/GP6+ and MY9/MY11. Genotyping with Multimerix kit (6, 11, 16, 18, 31, 33, 39, 42, 43, 44, 45, 51, 52, 58, 59, 68, 7, 73, 82) PCR-GP5/GP6. No genotyping PCR-MY9/MY11. Genotyping by SBH with TS probes (6, 11, 16, 18, 33) Patients with unrelated disease (otosclerosis, nasal complaints)and their accompanying relatives Spouses in 3rd trimestres of pregnancy of the fathers-to-be of cohort study Post-menopausal women participating in annual mass-screening program for the detection of cervical precancerous lesions Dental clinic visitors Female sex workers who attended a dermatology or STD clinic. Healthy volunteers from university dental hospital. Patients with unrelated disease (otosclerosis, nasal complaints)and their accompanying relatives Spouses in 3rd trimestres of pregnancy of the fathers-to-be of cohort study Fathers-to-be of cohort study Post-menopausal women participating in annual mass-screening program for the detection of cervical precancerous lesions Healthy population receiving routine oral examination (Continued on next page) (.-11.6) ( ) HPV 16 (13.3%) HPV 6 (2.3%) HPV 58 (.8%) ( ) ( ) HPV 16 (14.7%) HPV 31 (6.3%) ( ) HPV 6 (2.7%) HPV 16 (2.1%) HPV 11 (.5%) ( ) (.-5.9) ( ) HPV 16 (13.3%) HPV 6 (2.3%) HPV 58 (.8%) ( ) HPV 16 (9.2%) HPV 33 (2.3%) HPV 82 (2.3%) HPV 6 (.8%) HPV 11 (.8%) ( ) ( ) HPV 6 (3.6%) HPV 16 (2.4%) HPV 11 (.6%)

152 4 HPV-RELATED STATISTICS ( Table 27 continued from previous page) Method HPV detection Prev. of 5 most specimen method frequent collection and and targeted Age No. HPV prevalence HPVs Study anatomic site HPV types Population (years) Tested % (95% CI) HPV type (%) Migaldi 212Cytobrush from the (Italy) buccal mucosa Montaldo 27 (Italy) Saliva samples Cañadas Toothbrush on the 24 (Spain) oral cavity Kujan 26 (UK) Two brushes: 1.-cervex brush into each side of buccal mucosa and 2.-cytobrush lateral border of the tongue PCR-GP5+/GP6+, MY9/11, LCRS/E7AS, pu-1m and pu-2r. Genotyping by sequencing PCR-MY9/MY11 and GP5+N. Genotyping by sequencing PCR-MY9/MY11. Genotyping by DBH with TS probes (6, 11, 16, 18, 26, 31-33, 35, 39, 4, 45, 51-56, 58, 59, 61, 66-68, 7, 71 (AE8), 72, 73, 81 (AE7), 83 (PAP291), 84 (PAP155), 85 (AE5), AE2 (IS39), and AE6) PCR-Roche master mix and HC2 digene (both able to detect the following HR types: 16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59 and 68). No further genotyping Patients undergoing to routine oral examination Dental clinic visitors Female sex workers who attended a dermatology or STD clinic. Healthy volunteers from university dental hospital (.-6.7) HPV 9 (1.2%) ( ) HPV 16 (14.%) HPV 31 (4.3%) ( ) HPV 6 (2.7%) HPV 16 (2.1%) HPV 11 (.5%) ( ) - Data updated on 15 Dec 214 (data as of 29 Feb 212). Only for European countries. 95% CI: 95% Confidence Interval; DBH: Dot Blot Hybridization; HC2: Hybrid Capture 2; PCR: Polymerase Chain Reaction; RFLP: Restriction Fragment Length Polymorphism; SBH: Southern Blot Hybridization; TS: Type Specific; Data sources: See references in Section HPV burden in head and neck cancers Table 28: European studies on HPV prevalence among cases of oral cavity cancer HPV detection Prevalence of 5 most method and targeted HPV prevalence frequent HPVs Study HPV types No. Tested % (95% CI) HPV type (%) MEN Nemes 26 (Hungary) Herrero 23 (Ireland) Herrero 23 (Italy) Cruz 1996 (Netherlands) MY9/MY11 (L1) Hybridization with TS probes ( ) GP5+/GP6+ (L1) Hybridization with EIA oligonucleotide probes ( ) GP5+/GP6+ (L1) Hybridization with EIA oligonucleotide probes ( ) GP5+/GP6+ (L1) and CPI/CPII (L1) Amplification with TS primers and hybridization with TS probes ( ) ( ) ( ) HPV 16 (4.5%) ( ) HPV 16 (54.5%) HPV 6 (4.5%) (Continued on next page)

153 4 HPV-RELATED STATISTICS HPV detection ( Table 28 continued from previous page) Prevalence of 5 most method and targeted HPV prevalence frequent HPVs Study HPV types No. Tested % (95% CI) HPV type (%) Herrero 23 (Poland) Kozomara 25 (Serbia) Kansky 23 (Slovenia) Herrero 23 (Spain) Llamas-Martínez 28 (Spain) Dahlgren 24 (Sweden) WOMEN Nemes 26 (Hungary) Herrero 23 (Ireland) Herrero 23 (Italy) Cruz 1996 (Netherlands) Herrero 23 (Poland) Kozomara 25 (Serbia) Kansky 23 (Slovenia) GP5+/GP6+ (L1) Hybridization with EIA oligonucleotide probes ( ) TS-PCR E6 for 16. L1 for 18. E4 for 31 and E1 for 33 Amplification with TS primers ( ) PGMY9/11 (L1). GP5+/GP6+ (L1) and WD72/76/66/67/154 (E6) RFLP GP5+/GP6+ (L1) Hybridization with EIA oligonucleotide probes ( ) WD-66/67/72/76/154 (E6) RFLP ( ) GP5+/GP6+ (L1) and CPI/CPII (L1) Amplification with TS primers ( ) and sequencing MY9/MY11 (L1) Hybridization with TS probes ( ) GP5+/GP6+ (L1) Hybridization with EIA oligonucleotide probes ( ) GP5+/GP6+ (L1) Hybridization with EIA oligonucleotide probes ( ) GP5+/GP6+ (L1) and CPI/CPII (L1) Amplification with TS primers and hybridization with TS probes ( ) GP5+/GP6+ (L1) Hybridization with EIA oligonucleotide probes ( ) TS-PCR E6 for 16. L1 for 18. E4 for 31 and E1 for 33 Amplification with TS primers ( ) PGMY9/11 (L1). GP5+/GP6+ (L1) and WD72/76/66/67/154 (E6) RFLP ( ) ( ) HPV 33 (2.1%) HPV 58 (2.1%) ( ) HPV 16 (5.7%) ( ) ( ) ( ) ( ) HPV 16 (25.%) ( ) HPV 16 (9.5%) ( ) HPV 16 (23.1%) ( ) ( ) HPV 16 (14.3%) (Continued on next page)

154 4 HPV-RELATED STATISTICS HPV detection ( Table 28 continued from previous page) Prevalence of 5 most method and targeted HPV prevalence frequent HPVs Study HPV types No. Tested % (95% CI) HPV type (%) Herrero 23 (Spain) Llamas-Martínez 28 (Spain) Dahlgren 24 (Sweden) BOTH OR UNSPECIFIED Koskinen 23 (Finland) Klussmann 21 (Germany) Ostwald 23 (Germany) Weiss 211 (Germany) Aggelopoulou 1999 (Greece) Romanitan 28 (Greece) Nemes 26 (Hungary) Szarka 29 (Hungary) Herrero 23 (Ireland) Badaracco 2 (Italy) Badaracco 27 (Italy) GP5+/GP6+ (L1) Hybridization with EIA oligonucleotide probes ( ) WD-66/67/72/76/154 (E6) RFLP ( ) GP5+/GP6+ (L1) and CPI/CPII (L1) Amplification with TS primers ( ) and sequencing ( ) HPV 16 (6.3%) ( ) SPF1 (L1) LiPA ( ) HPV 16 (46.4%) HPV 33 (21.4%) A1/A5-A6/A8 (L1) and ( ) HPV 16 (13.6%) CP62/7-CP65/69a (L1) HPV 19 (4.5%) Sequencing TS-PCR E6 for 6/11/16/18 Hybridization with TS probes (6/ ) RT-PCR E6/E7 for 16 Hybridization with TS probes (16) L1 consensus primers and TS-PCR E7 for 16/18 Amplification with TS primers (16. 18) GP5+/GP6+ (L1). CPI/CPIIG (E1) and TS-PCR E6/E7 for 16 Amplification with TS primers (16) MY9/MY11 (L1) Hybridization with TS probes ( ) MY9/MY11 (L1) and GP5+/GP6+ (L1) RFLP GP5+/GP6+ (L1) Hybridization with EIA oligonucleotide probes ( ) MY9/MY11 (L1) Amplification with TS primers (6. 16) and hybridization with TS probes ( ) MY9/MY11 (L1) and GP5+/GP6+ (L1) Sequencing ( ) HPV 16 (29.7%) HPV 18 (13.6%) ( ) HPV 16 (2.9%) ( ) HPV 18 (27.2%) HPV 16 (6.2%) (.2-7.2) ( ) HPV 16 (34.2%) HPV 18 (6.3%) HPV 31 (3.8%) HPV 33 (2.5%) ( ) HPV 16 (27.7%) HPV 11 (6.2%) HPV 18 (6.2%) HPV 33 (3.1%) HPV 31 (1.5%) 3 1. ( ) HPV 16 (1.%) ( ) HPV 18 (13.2%) HPV 6 (1.5%) HPV 16 (1.5%) HPV 11 (5.3%) HPV 56 (5.3%) ( ) HPV 16 (7.5%) HPV 33 (1.9%) HPV 58 (1.9%) (Continued on next page)

155 4 HPV-RELATED STATISTICS HPV detection ( Table 28 continued from previous page) Prevalence of 5 most method and targeted HPV prevalence frequent HPVs Study HPV types No. Tested % (95% CI) HPV type (%) Herrero 23 (Italy) Rittà 29 (Italy) Scapoli 29 (Italy) Braakhuis 24 (Netherlands) Cruz 1996 (Netherlands) Eu- Mork (Northern rope) 21 a Matzow 1998 (Norway) Herrero 23 (Poland) Snietura 21 (Poland) Kozomara 25 (Serbia) Kansky 23 (Slovenia) Herrero 23 (Spain) Llamas-Martínez 28 (Spain) GP5+/GP6+ (L1) Hybridization with EIA oligonucleotide probes ( ) MY9/MY11 (L1) and GP5+/GP6+ (L1) Sequencing RT-PCR for 16/18/31/45 Hybridization with TS probes ( ) GP5+/GP6+ (L1) and TS-PCR RLBH ( /MM /IS39. 71/CP /CP ) GP5+/GP6+ (L1) and CPI/CPII (L1) Amplification with TS primers and hybridization with TS probes ( ) GP5+/GP6+ (L1) and CPI/CPII (L1) Amplification with TS primers ( ) GP5+/GP6+ (L1). CPI/CPIIG (E1) and TS-PCR for 6/16/18/31/33 Amplification with TS primers ( ) GP5+/GP6+ (L1) Hybridization with EIA oligonucleotide probes ( ) Real-time High Risk HPV test (Abbott Molecular) using L1 consensus primers Amplification with TS primers ( and 68 - the technique only differentiates other) TS-PCR E6 for 16. L1 for 18. E4 for 31 and E1 for 33 Amplification with TS primers ( ) PGMY9/11 (L1). GP5+/GP6+ (L1) and WD72/76/66/67/154 (E6) RFLP GP5+/GP6+ (L1) Hybridization with EIA oligonucleotide probes ( ) WD-66/67/72/76/154 (E6) RFLP ( ) ( ) HPV 16 (3.8%) ( ) HPV 16 (36.%) (.4-3.5) HPV 16 (1.2%) ( ) HPV 16 (9.4%) ( ) HPV 16 (42.9%) HPV 6 (2.9%) ( ) HPV 16 (4.4%) HPV 6 (1.1%) HPV 11 (1.1%) HPV 33 (1.1%) ( ) HPV 16 (4.4%) ( ) HPV 31 (32.%) HPV 16 (26.%) HPV 18 (26.%) ( ) HPV 16 (1.8%) HPV 33 (1.8%) HPV 58 (1.8%) ( ) HPV 16 (5.8%) ( ) HPV 16 (33.3%) HPV 6 (3.3%) HPV 31 (9.1%) (Continued on next page)

156 4 HPV-RELATED STATISTICS HPV detection ( Table 28 continued from previous page) Prevalence of 5 most method and targeted HPV prevalence frequent HPVs Study HPV types No. Tested % (95% CI) HPV type (%) Dahlgren 24 (Sweden) Sand 2 (Sweden) Lopes 211 (UK) Snijders 1996 (UK) GP5+/GP6+ (L1) and CPI/CPII (L1) Amplification with TS primers ( ) and sequencing MY9/MY11 (L1) Amplification with TS primers (6b/ ) GP5+/GP6+ (L1) and qpcr for 16/18 Hybridization with TS probes (16. 18) GP5+/GP6+ (L1) Amplification with TS primers and SBH with TS probes ( ) Yeudall 1991 (UK) TS-PCR E6/E7 for 16. E6 for 18 and specific for 4 Hybridization with TS probes ( ) Ribeiro 211 b PGMY9/11 (L1) Amplification (World) with TS primers (16) (.6-8.2) HPV 16 (2.4%) ( ) HPV 16 (4.2%) HPV 18 (4.2%) (1.5-8.) HPV 16 (2.1%) HPV 18 (2.1%) ( ) HPV 16 (2.%) ( ) HPV 16 (25.6%) HPV 18 (2.5%) Data updated on 28 Jun 217 (data as of 31 Dec 215). 95% CI: 95% Confidence Interval; EIA: Enzyme ImmunoAssay; LiPA: Line Probe Assay; PCR: Polymerase Chain Reaction; RFLP: Restriction Fragment Length Polymorphism; RLBH: Reverse Line Blot Hybridization; RT-PCR: Real Time Polymerase Chain Reaction; SBH: Southern Blot Hybridization; SPF: Short Primer Fragment; TS: Type Specific; a Includes cases from Norway, Sweden and Finland b Includes cases from Argentina, Brazil, Cuba, Russia, Slovakia, Czech Republic, Romania and Poland Data sources: See references in Section 9. Table 29: European studies on HPV prevalence in cases of oropharyngeal cancer HPV detection Prevalence of 5 most method and targeted HPV prevalence frequent HPVs Study HPV types No. Tested % (95% CI) HPV type (%) MEN Rotnáglová 211 (Czech Rep.) Charfi 28 (France) Hoffmann 21 (Germany) Krupar 214 (Germany) Reimers 27 (Germany) Herrero 23 (Italy) Hannisdal 21 (Norway) GP5+/GP6+ (L1) RBLH ( ) GP5+/GP6+ (L1) and TS-PCR for 6/11/16/18/33 Amplification with TS primers ( ) GP5+/GP6+ (L1). MY9/MY11 (L1) and TS-PCR for 6/11/16/18 Hybridization with TS probes - Multiplex luminex PCR-E6, PCR-E7, PCR- MULTIPLEX (HPV 11, 16, 18, 31, 33, 35, 39, 42, 43, 44, 45, 51, 52, 56, 58, 59, 66, 68) A1/A5-A6/A8 (L1) and CP62/7-CP65/69a (L1) Sequencing GP5+/GP6+ (L1) Hybridization with EIA oligonucleotide probes ( ) ( ) ( ) ( ) HPV 16 (51.6%) HPV 35 (6.5%) ( ) HPV 16 (5.%) ( ) ( ) HPV 16 (2.%) HPV 33 (3.3%) HPV 35 (3.3%) GP5+/GP6+ (L1) Sequencing ( ) - (Continued on next page)

157 4 HPV-RELATED STATISTICS HPV detection ( Table 29 continued from previous page) Prevalence of 5 most method and targeted HPV prevalence frequent HPVs Study HPV types No. Tested % (95% CI) HPV type (%) Herrero 23 (Spain) Attner 21 (Sweden) Dahlgren 24 (Sweden) Hammarstedt 26 (Sweden) Näsman 29 (Sweden) Lindel 21 (Switzerland) WOMEN Rotnáglová 211 (Czech Rep.) Charfi 28 (France) Hoffmann 21 (Germany) Reimers 27 (Germany) Herrero 23 (Italy) Hannisdal 21 (Norway) Herrero 23 (Spain) Attner 21 (Sweden) GP5+/GP6+ (L1) Hybridization with EIA oligonucleotide probes ( ) 4 5. ( ) HPV 16 (5.%) GP5+/GP6+ (L1). CPI/IIG (E1) ( ) - and TS-PCR E6/7 for 16/33 Amplification with TS primers (16. 33) and sequencing GP5+/GP6+ (L1) and CPI/CPII ( ) - (L1) Amplification with TS primers ( ) and sequencing GP5+/GP6+ (L1). CPI/CPIIG ( ) - (E1) and TS-PCR E6 for 16 Sequencing GP5+/GP6+ (L1). CPI/CPIIG ( ) - (E1) and TS-PCR E6 for 16 Sequencing SPF1 (L1) Sequencing ( ) - GP5+/GP6+ (L1) RBLH ( ) ( ) - GP5+/GP6+ (L1) and TS-PCR for ( ) - 6/11/16/18/33 Amplification with TS primers ( ) GP5+/GP6+ (L1). MY9/MY ( ) HPV 16 (5.%) (L1) and TS-PCR for 6/11/16/18 Hybridization with TS probes - Multiplex luminex A1/A5-A6/A8 (L1) and ( ) - CP62/7-CP65/69a (L1) Sequencing GP5+/GP6+ (L1) Hybridization with EIA oligonucleotide probes ( ) GP5+/GP6+ (L1) Sequencing ( ) - GP5+/GP6+ (L1) Hybridization with EIA oligonucleotide probes ( ) GP5+/GP6+ (L1). CPI/IIG (E1) and TS-PCR E6/7 for 16/33 Amplification with TS primers (16. 33) and sequencing 4 5. ( ) HPV 16 (5.%) ( ) - (Continued on next page)

158 4 HPV-RELATED STATISTICS HPV detection ( Table 29 continued from previous page) Prevalence of 5 most method and targeted HPV prevalence frequent HPVs Study HPV types No. Tested % (95% CI) HPV type (%) Dahlgren 24 (Sweden) Hammarstedt 26 (Sweden) Näsman 29 (Sweden) Lindel 21 (Switzerland) BOTH OR UNSPECIFIED Klozar 28 (Czech Rep.) Rotnáglová 211 (Czech Rep.) Jouhi 215 (Finland) Charfi 28 (France) Fonmarty 215 (France) Fouret 1997 (France) Andl 1998 (Germany) Hoffmann 1998 (Germany) Hoffmann 21 (Germany) Holzinger 212 (Germany) GP5+/GP6+ (L1) and CPI/CPII (L1) Amplification with TS primers ( ) and sequencing ( ) - GP5+/GP6+ (L1). CPI/CPIIG ( ) - (E1) and TS-PCR E6 for 16 Sequencing GP5+/GP6+ (L1). CPI/CPIIG ( ) - (E1) and TS-PCR E6 for 16 Sequencing SPF1 (L1) Sequencing ( ) - GP5+/GP6+ (L1) RLBH ( ) GP5+/GP6+ (L1) RBLH ( ) PCR-E6, PCR-E7, PCR- MULTIPLEX (HPV 6, 11, 16, 18, 26, 31, 33, 35, 39, 42, 43, 44, 45, 51, 52, 53, 56, 58, 59, 66, 68, 7, 73, 82) GP5+/GP6+ (L1) and TS-PCR for 6/11/16/18/33 Amplification with TS primers ( ) PCR, LiPA (HPV 6, 11, 16, 18, 31, 33, 35, 39, 4, 43, 44, 45, 51, 52, 53, 54, 56, 58, 59, 66, 68, 69, 7, 71, 73, 74, 82) TS-PCR E6 for 16/18/31/33/45 Hybridization with TS probes ( ) TS-PCR for 6/11/16/18 Hybridization with TS probes ( ) and cycle sequencing system of BRL MY9/MY11 (L1) and TS-PCR for 6/11/16/18/33 SBH ( ) GP5+/GP6+ (L1). MY9/MY11 (L1) and TS-PCR for 6/11/16/18 Hybridization with TS probes - Multiplex luminex PCR-GP5+/6+, PCR L1-Consensus primer, PCR- MULTIPLEX (HPV 16, 18, 33, 35) ( ) HPV 16 (4.%) HPV 33 (5.%) ( ) HPV 16 (6.6%) HPV 33 (1.8%) HPV 18 (.9%) HPV 26 (.9%) HPV 52 (.9%) ( ) HPV 16 (45.7%) HPV 18 (2.9%) HPV 45 (2.9%) ( ) HPV 16 (51.9%) HPV 33 (1.9%) ( ) HPV 16 (28.2%) HPV 33 (2.8%) HPV 6 (1.4%) ( ) HPV 16 (15.5%) ( ) HPV 16 (38.1%) HPV 33 (4.8%) ( ) HPV 16 (8.7%) HPV 45 (8.7%) HPV 6 (4.3%) ( ) HPV 16 (51.3%) HPV 35 (5.1%) ( ) HPV 16 (48.7%) HPV 18 (.5%) HPV 33 (.5%) HPV 35 (.5%) (Continued on next page)

159 4 HPV-RELATED STATISTICS HPV detection ( Table 29 continued from previous page) Prevalence of 5 most method and targeted HPV prevalence frequent HPVs Study HPV types No. Tested % (95% CI) HPV type (%) Klussmann 21 (Germany) Krupar 214 (Germany) Reimers 27 (Germany) Weiss 211 (Germany) Wittekindt 25 (Germany) Romanitan 28 (Greece) Boscolo-Rizzo 29 (Italy) Herrero 23 (Italy) Licitra 26 (Italy) Rittà 29 (Italy) Braakhuis 24 (Netherlands) Henneman 215 (Netherlands) van Monsjou 212 (Netherlands) Hannisdal 21 (Norway) A1/A5-A6/A8 (L1) and CP62/7-CP65/69a (L1) Sequencing PCR-E6, PCR-E7, PCR- MULTIPLEX (HPV 11, 16, 18, 31, 33, 35, 39, 42, 43, 44, 45, 51, 52, 56, 58, 59, 66, 68) A1/A5-A6/A8 (L1) and CP62/7-CP65/69a (L1) Sequencing RT-PCR E6/E7 for 16 Hybridization with TS probes (16) A1/A5-A6/A8 (L1) and (L1) Sequencing GP5+/GP6+ (L1). CPI/CPIIG (E1) and TS-PCR E6/E7 for 16 Amplification with TS primers (16) MY9/MY11 (L1) RFLP and amplification with TS primers E6/E2 for 16 GP5+/GP6+ (L1) Hybridization with EIA oligonucleotide probes ( ) RT-PCR E1 for 16/18 Hybridization with TS probes (16. 18) MY9/MY11 (L1) and GP5+/GP6+ (L1) Sequencing GP5+/GP6+ (L1) and TS-PCR RLBH ( /MM /IS39. 71/CP /CP ) PCR-SPF1, LiPA (HPV 16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, 66, 68) PCR, LiPA (HPV 6, 11, 16, 18, 26, 31, 33, 35, 39, 4, 43, 44, 45, 51, 52, 53, 54, 56, 58, 59, 66, 68, 69, 7, 71, 72, 73, 82) ( ) HPV 16 (42.4%) HPV 5 (3.%) HPV 33 (3.%) HPV 96 (3.%) ( ) HPV 16 (5.%) ( ) HPV 16 (27.4%) HPV 33 (.9%) ( ) HPV 16 (38.4%) ( ) HPV 16 (5.%) HPV 33 (2.9%) ( ) HPV 16 (32.1%) ( ) HPV 16 (18.2%) ( ) HPV 16 (16.7%) HPV 33 (2.8%) HPV 35 (2.8%) ( ) HPV 16 (18.9%) ( ) HPV 16 (5.%) ( ) HPV 16 (37.8%) ( ) HPV 16 (32.2%) HPV 33 (2.1%) HPV 35 (.7%) ( ) HPV 16 (6.%) HPV 35 (5.%) GP5+/GP6+ (L1) Sequencing ( ) HPV 16 (48.9%) HPV 31 (2.9%) HPV 18 (2.2%) HPV 33 (.7%) HPV 67 (.7%) (Continued on next page)

160 4 HPV-RELATED STATISTICS HPV detection ( Table 29 continued from previous page) Prevalence of 5 most method and targeted HPV prevalence frequent HPVs Study HPV types No. Tested % (95% CI) HPV type (%) Snietura 21 (Poland) Szkaradkiewicz 22 (Poland) Herrero 23 (Spain) Attner 21 (Sweden) Dahlgren 24 (Sweden) Hammarstedt 26 (Sweden) Lindquist 212 (Sweden) Näsman 29 (Sweden) Lindel 21 (Switzerland) Anderson 27 (UK) Conway 212 (UK) Real-time High Risk HPV test (Abbott Molecular) using L1 consensus primers Amplification with TS primers ( and 68 - the technique only differentiates other) MY9/MY11 (L1) Amplification with TS primers (16. 18) GP5+/GP6+ (L1) Hybridization with EIA oligonucleotide probes ( ) GP5+/GP6+ (L1). CPI/IIG (E1) and TS-PCR E6/7 for 16/33 Amplification with TS primers (16. 33) and sequencing GP5+/GP6+ (L1) and CPI/CPII (L1) Amplification with TS primers ( ) and sequencing GP5+/GP6+ (L1). CPI/CPIIG (E1) and TS-PCR E6 for 16 Sequencing GP5+/GP6+ (L1) and CPI/CPIIG (E1) Amplification with TS primers (16) and Multiplex Luminex ( ) GP5+/GP6+ (L1). CPI/CPIIG (E1) and TS-PCR E6 for 16 Sequencing ( ) HPV 16 (5.%) ( ) ( ) HPV 16 (9.1%) ( ) HPV 16 (64.2%) HPV 33 (7.4%) HPV 35 (2.1%) HPV 58 (1.1%) ( ) HPV 16 (28.%) HPV 33 (4.%) HPV 35 (4.%) HPV 38 (4.%) ( ) HPV 16 (42.9%) HPV 33 (1.5%) HPV 35 (.5%) HPV 45 (.5%) ( ) HPV 16 (64.3%) ( ) HPV 16 (78.6%) HPV 33 (1.%) HPV 35 (1.%) HPV 59 (1.%) SPF1 (L1) Sequencing ( ) HPV 16 (11.1%) HPV 33 (1.%) HPV 35 (1.%) HPV 45 (1.%) GP5+/GP6+ (L1) Hybridization with Roche LBA ( ) PCR-GP5+/6+, TS, Sequencing (HPV 16, 18, 2, 21, 22, 23, 26, 3, 31, 32, 33, 34, 35, 38, 39, 4, 42, 43, 44, 45, 51, 52, 53, 54, 56, 57, 58, 59, 6, 61, 62, 66, 67, 68, 69, 7, 71, 72, 73, 74, 8, 81, 82, 83, 84, 85, 86, 87, 89, 9, 91) Evans 213 (UK) PCR-GP5+/6+, EIA (HPV 6, 11, 16, 18, 31, 33, 35, 39, 4, 42, 43, 44, 45, 51, 52, 56, 58, 59, 66, 68) (Continued on next page) ( ) HPV 16 (19.4%) HPV 11 (2.8%) 2 4. ( ) HPV 16 (4.%) ( ) HPV 16 (8.7%) HPV 18 (1.2%) HPV 33 (1.2%) HPV 56 (1.2%)

161 4 HPV-RELATED STATISTICS HPV detection ( Table 29 continued from previous page) Prevalence of 5 most method and targeted HPV prevalence frequent HPVs Study HPV types No. Tested % (95% CI) HPV type (%) Schache 211 (UK) Thavaraj 211 (UK) TS-PCR E6 for 16 Amplification with TS primers (16) GP5+/GP6+ (L1) Luminex 2 IS ( ) Wells 215 (UK) PCR- MULTIPLEX (HPV 16, 18, 35, 51, 82) Ribeiro (World) 211 a PGMY9/11 (L1) Amplification with TS primers (16) ( ) HPV 16 (4.8%) ( ) HPV 16 (64.1%) HPV 33 (2.1%) HPV 18 (.7%) HPV 35 (.7%) ( ) HPV 16 (45.6%) HPV 18 (5.3%) HPV 35 (1.8%) HPV 51 (1.8%) HPV 82 (1.8%) (.1-4.) HPV 16 (.7%) Data updated on 29 Jun 217 (data as of 31 Dec 215 / 31 Dec 215). 95% CI: 95% Confidence Interval; EIA: Enzyme ImmunoAssay; LBA: Line-Blot Assay; LiPA: Line Probe Assay; PCR: Polymerase Chain Reaction; RFLP: Restriction Fragment Length Polymorphism; RLBH: Reverse Line Blot Hybridization; RT-PCR: Real Time Polymerase Chain Reaction; SBH: Southern Blot Hybridization; SPF: Short Primer Fragment; TS: Type Specific; a Includes cases from Argentina, Brazil, Cuba, Russia, Slovakia, Czech Republic, Romania and Poland Data sources: See references in Section 9. Table 3: European studies on HPV prevalence in cases of hypopharyngeal or laryngeal cancer HPV detection Prevalence of 5 most method and targeted HPV prevalence frequent HPVs Study HPV types No. Tested % (95% CI) HPV type (%) MEN Hoffmann 26 (Germany) Hoffmann 29 (Germany) Azzimonti 24 (Italy) Cattani 1998 (Italy) Gallo 29 (Italy) Lie 1996 (Norway) Morshed 28 (Poland) MY9/MY11 (L1) and TS-PCR for 6/11/16/18/33 Hybridization with TS and consensus probes and further confirmation by SBH with TS and consensus probes ( ) ( ) HPV 16 (23.5%) MY9/MY11 (L1) and TS-PCR ( ) HPV 16 (19.%) for 6/11/16/18 Hybridization with TS and consensus probes and further confirmation by SBH with TS and consensus probes ( ) GP5+/GP6+ (L1) Sequencing ( ) HPV 16 (43.5%) HPV 18 (13.%) MY9/MY11 (L1) and TS-PCR 7 3. ( ) - for 33 Hybridization with TS probes ( ) and amplification with TS primer (33) MY9/MY11 (L1). LCRF LCRF2. LCRF3. LCRF4. E7R1. E7R2. E7R3. E7R4 (E6) and TS-PCR E1 for 6/11/16/18-31/33 Sequencing CP (E1). MY9/MY11 (L1) and ( ) HPV 16 (2.6%) GP5+/GP6+ (L1) Amplification with TS primers ( ) SPF1 (L1) LiPA ( ) - (Continued on next page)

162 4 HPV-RELATED STATISTICS WOMEN HPV detection ( Table 3 continued from previous page) Prevalence of 5 most method and targeted HPV prevalence frequent HPVs Study HPV types No. Tested % (95% CI) HPV type (%) Hoffmann 26 (Germany) Hoffmann 29 (Germany) Azzimonti 24 (Italy) Cattani 1998 (Italy) Gallo 29 (Italy) Lie 1996 (Norway) Morshed 28 (Poland) BOTH OR UNSPECIFIED Gudleviciene 214 (Belarus) Duray 211 (Belgium) Lindeberg 1999 (Denmark) Koskinen 23 (Finland) Fouret 1997 (France) MY9/MY11 (L1) and TS-PCR for 6/11/16/18/33 Hybridization with TS and consensus probes and further confirmation by SBH with TS and consensus probes ( ) ( ) HPV 16 (33.3%) MY9/MY11 (L1) and TS-PCR ( ) - for 6/11/16/18 Hybridization with TS and consensus probes and further confirmation by SBH with TS and consensus probes ( ) GP5+/GP6+ (L1) Sequencing 2 5. ( ) HPV 16 (5.%) MY9/MY11 (L1) and TS-PCR for 33 Hybridization with TS probes ( ) and amplification with TS primer (33) ( ) HPV 16 (21.4%) MY9/MY11 (L1). LCRF LCRF2. LCRF3. LCRF4. E7R1. E7R2. E7R3. E7R4 (E6) and TS-PCR E1 for 6/11/16/18-31/33 Sequencing CP (E1). MY9/MY11 (L1) and GP5+/GP6+ (L1) Amplification with TS primers ( ) SPF1 (L1) LiPA ( ) - PCR-GP5+/6+, PCR-PGMY9/11, PCR L1-Consensus primer, PCR-E6, PCR- MULTIPLEX (HPV 6, 11, 16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, 66, 68, 73, 82) GP5+/GP6+ (L1) and RT-PCR E6/E7 for L1. 68 TS real-time and consensus PCR E6/E7 ( L1. 68) MY9/MY11 (L1). GP5+/GP6+ (L1) and CPII/II (L1) Hybridization with TS probes ( ) ( ) HPV 6 (2.9%) HPV 16 (2.9%) ( ) HPV 16 (62.7%) HPV 18 (16.9%) HPV 51 (8.5%) HPV 33 (5.1%) HPV 66 (5.1%) ( ) - SPF1 (L1) LiPA ( ) HPV 16 (46.4%) HPV 33 (14.3%) HPV 6 (1.7%) HPV 11 (3.6%) HPV 51 (3.6%) TS-PCR E6 for 16/18/31/33/ ( ) HPV 16 (6.8%) Hybridization with TS probes ( ) (Continued on next page)

163 4 HPV-RELATED STATISTICS HPV detection ( Table 3 continued from previous page) Prevalence of 5 most method and targeted HPV prevalence frequent HPVs Study HPV types No. Tested % (95% CI) HPV type (%) Fischer 23 (Germany) Hoffmann 1998 (Germany) Hoffmann 26 (Germany) Hoffmann 29 (Germany) Kleist 2 (Germany) Klussmann 21 (Germany) Krupar 214 (Germany) Gorgoulis 1999 (Greece) Vlachtsis 25 (Greece) Major 25 (Hungary) Azzimonti 24 (Italy) Badaracco 2 (Italy) Badaracco 27 (Italy) Boscolo-Rizzo 29 (Italy) Cattani 1998 (Italy) L1-CP65F. 66F. 69F. 7F Sequencing MY9/MY11 (L1) and TS-PCR for 6/11/16/18/33 SBH ( ) MY9/MY11 (L1) and TS-PCR for 6/11/16/18/33 Hybridization with TS and consensus probes and further confirmation by SBH with TS and consensus probes ( ) MY9/MY11 (L1) and TS-PCR for 6/11/16/18 Hybridization with TS and consensus probes and further confirmation by SBH with TS and consensus probes ( ) MY9/MY11 (L1) Amplification with TS primers (16. 18) A1/A5-A6/A8 (L1) and CP62/7-CP65/69a (L1) Sequencing PCR-E6, PCR-E7, PCR- MULTIPLEX (HPV 11, 16, 18, 31, 33, 35, 39, 42, 43, 44, 45, 51, 52, 56, 58, 59, 66, 68) MY9/MY11 (L1) and GP5/GP6 (L1) Amplification with TS primers ( ) and confirmation by DBH with TS probes ( ). TS-PCR for 16/18 Amplification with TS primers (16. 18) MY9/MY11 (L1) and GP5+/GP6+ (L1) RFLP ( ) ( ) HPV 73 (4.3%) HPV 21 (2.1%) HPV 22 (2.1%) HPV 38 (2.1%) HPV 41 (2.1%) ( ) HPV 16 (3.9%) HPV 18 (2.%) HPV 45 (2.%) ( ) HPV 16 (25.%) ( ) HPV 16 (14.8%) ( ) HPV 16 (8.6%) HPV 18 (8.6%) ( ) HPV 16 (13.3%) HPV 19 (3.3%) ( ) HPV 16 (14.3%) HPV 6 (3.3%) HPV 18 (3.3%) HPV 33 (3.3%) 9 4. ( ) HPV 16 (34.4%) HPV 18 (6.7%) ( ) HPV 11 (18.2%) HPV 6 (13.6%) HPV 16 (13.6%) GP5+/GP6+ (L1) Sequencing ( ) HPV 16 (44.%) HPV 18 (12.%) MY9/MY11 (L1) Amplification with TS primers (6. 16) and hybridization with TS probes ( ) MY9/MY11 (L1) and GP5+/GP6+ (L1) Sequencing MY9/MY11 (L1) RFLP and amplification with TS primers E6/E2 for 16 MY9/MY11 (L1) and TS-PCR for 33 Hybridization with TS probes ( ) and amplification with TS primer (33) ( ) HPV 16 (27.3%) HPV 6 (18.2%) HPV 45 (4.5%) ( ) HPV 16 (1.%) HPV 6 (6.7%) ( ) HPV 16 (4.4%) ( ) HPV 16 (12.%) HPV 18 (1.7%) HPV 33 (1.3%) (Continued on next page)

164 4 HPV-RELATED STATISTICS HPV detection ( Table 3 continued from previous page) Prevalence of 5 most method and targeted HPV prevalence frequent HPVs Study HPV types No. Tested % (95% CI) HPV type (%) Gallo 29 (Italy) Gudleviciene 29 (Lithuania) Gudleviciene 214 (Lithuania) Koskinen 27 a (Northern Europe) Mork 21 a (Northern Europe) Lie 1996 (Norway) Morshed 28 (Poland) Snietura 211 (Poland) Poljak 1997 (Slovenia) Alvarez Alvarez 1997 (Spain) Pérez-Ayala 199 (Spain) Adams 1999 (Switzerland) Anderson 27 (UK) MY9/MY11 (L1). LCRF1. LCRF2. LCRF3. LCRF4. E7R1. E7R2. E7R3. E7R4 (E6) and TS-PCR E1 for 6/11/16/18-31/33 Sequencing Consensus primers from Master Mix Amplification with TS primers (16. 18) PCR-GP5+/6+, PCR-PGMY9/11, PCR L1-Consensus primer, PCR-E6, PCR- MULTIPLEX (HPV 6, 11, 16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, 66, 68, 73, 82) MY9/MY11 (L1). GP5+/GP6+ (L1) and SPF1 (L1) LiPA ( ) HPV 16 (12.%) ( ) HPV 6 (1.9%) HPV 16 (1.9%) HPV 31 (1.9%) HPV 39 (1.9%) HPV 58 (1.9%) ( ) HPV 16 (1.4%) GP5+/GP6+ (L1) and CPI/CPII (L1) Amplification with TS primers ( ) ( ) HPV 16 (2.5%) CP (E1). MY9/MY11 (L1) and ( ) HPV 16 (2.6%) GP5+/GP6+ (L1) Amplification with TS primers ( ) SPF1 (L1) LiPA ( ) HPV 16 (3.1%) HPV 18 (6.5%) HPV 33 (5.4%) Real-time High Risk HPV test (Abbott Molecular) using L1 consensus primers RT-PCR ( ) PGMY9/11 (L1). GP5+/GP ( ) HPV 16 (3.3%) (L1) and WD72/76/66/67/154 (E6) Amplification with TS primers ( ) TS-PCR E6 and L1 for 6b/16/18 Amplification with TS primers (6b ) TS-PCR E6 for 6/11 Hybridization with TS probes (11. 16) MY9/MY11 (L1) RFLP ( ) GP5+/GP6+ (L1) Hybridization with Roche LBA ( ) ( ) HPV 6 (22.9%) HPV 16 (5.7%) ( ) HPV 16 (56.9%) ( ) HPV 16 (16.7%) (Continued on next page)

165 4 HPV-RELATED STATISTICS HPV detection ( Table 3 continued from previous page) Prevalence of 5 most method and targeted HPV prevalence frequent HPVs Study HPV types No. Tested % (95% CI) HPV type (%) Conway 212 (UK) PCR-GP5+/6+, TS, Sequencing (HPV 16, 18, 2, 21, 22, 23, 26, 3, 31, 32, 33, 34, 35, 38, 39, 4, 42, 43, 44, 45, 51, 52, 53, 54, 56, 57, 58, 59, 6, 61, 62, 66, 67, 68, 69, 7, 71, 72, 73, 74, 8, 81, 82, 83, 84, 85, 86, 87, 89, 9, 91) Salam 1995 (UK) MY9/MY11 (L1) RFLP ( ) Snijders 1996 (UK) Ribeiro (World) 211 b GP5+/GP6+ (L1) Amplification with TS primers and SBH with TS probes ( ) PGMY9/11 (L1) Amplification with TS primers (16) ( ) HPV 6 (8.3%) HPV 16 (5.6%) HPV 11 (2.8%) ( ) HPV 16 (19.4%) (.2-3.) HPV 16 (.8%) Data updated on 28 Jun 217 (data as of 31 Dec 215). 95% CI: 95% Confidence Interval; DBH: Dot Blot Hybridization; LBA: Line-Blot Assay; LiPA: Line Probe Assay; PCR: Polymerase Chain Reaction; RFLP: Restriction Fragment Length Polymorphism; RT-PCR: Real Time Polymerase Chain Reaction; SBH: Southern Blot Hybridization; SPF: Short Primer Fragment; TS: Type Specific; a Includes cases from Norway, Sweden and Finland b Includes cases from Argentina, Brazil, Cuba, Russia, Slovakia, Czech Republic, Romania and Poland Data sources: See references in Section 9.

166 5 FACTORS CONTRIBUTING TO CERVICAL CANCER Factors contributing to cervical cancer HPV is a necessary cause of cervical cancer, but it is not a sufficient cause. Other cofactors are necessary for progression from cervical HPV infection to cancer. Tobacco smoking, high parity, long-term hormonal contraceptive use, and co-infection with HIV have been identified as established cofactors. Co-infection with Chlamydia trachomatis and herpes simplex virus type-2, immunosuppression, and certain dietary deficiencies are other probable cofactors. Genetic and immunological host factors and viral factors other than type, such as variants of type, viral load and viral integration, are likely to be important but have not been clearly identified. (Muñoz N, Vaccine 26; 24(S3): 1-1). In this section, the prevalence of smoking, parity (fertility), oral contraceptive use, and HIV in Europe are presented. Figure 123: Prevalence of female tobacco smoking in Europe Data accessed on 22 Mar 217. Adjusted and age-standardized prevalence estimates of tobacco use by country, for the year 213. These rates are constructed solely for the purpose of comparing tobacco use prevalence estimates across countries, and should not be used to estimate the number of smokers in the population. Data sources: WHO report on the global tobacco epidemic, 215: The MPOWER package. Geneva, World Health Organization, 215. Available at report/215/en/index.html

167 5 FACTORS CONTRIBUTING TO CERVICAL CANCER Figure 124: Total fertility rates in Europe Data accessed on 22 Mar 217. For Austria, Belgium, Bulgaria, Belarus, Germany, United Kingdom, Hungary, Netherlands, Romania, Sweden: The number of women by age is estimated by the United Nations Population Division and published in World Population Prospects: the 215 Revision. Data sources: For Channel Islands, Bosnia & Herzegovina, Republic of Moldova: United Nations, Department of Economic and Social Affairs, Population Division (215). World Fertility Data 215 (POP/DB/Fert/Rev215). Available at: [Accessed on March 22, 217]. Albania, Austria, Belgium, Bulgaria, Belarus, Switzerland, Cyprus, Czech Republic, Germany, Denmark, Spain, Estonia, Finland, France, United Kingdom, Greece, Croatia, Hungary, Ireland, Iceland, Italy, Liechtenstein, Lithuania, Luxembourg, Latvia, Macedonia, Malta, Montenegro, Netherlands, Norway, Poland, Portugal, Romania, Russian Federation, Serbia, Slovakia, Slovenia, Sweden, Ukraine: Eurostat - Statistical office of the European Comission [web site]. Luxembourg: European Commission; 215. Available at: eurostat/tgm/table.do?tab=table&init=1&language=en&pcode=tsdde22&plugin=1. [Accessed on March 22, 217].

168 5 FACTORS CONTRIBUTING TO CERVICAL CANCER Figure 125: Prevalence of hormonal contraceptive use in Europe Data accessed on 22 Mar 217. Proportion (%) of women using hormonal contraception (pill, injectable or implant), among those of reproductive age who are married or in union. For Belgium: Data pertain to sexually active women of reproductive age. For Bulgaria, Germany, Estonia, Lithuania, Romania: Data pertain to women with co-resident male partner. For Czech Republic, Russian Federation: Data pertain to women with a partner. For Denmark: Data pertain to women in a steady sexual relationship. For United Kingdom: Excluding Northern Ireland. For Greece, Poland: Data pertain to women who were sexually active during the month prior to the interview. For Croatia: Data pertain to all women of reproductive age, irrespective of marital status. For Malta: Data pertain to married women who visited a practitioner belonging to the Malta College of Family Doctors. For Norway: Data pertain to women who were sexually active during the three months prior to the interview. For Portugal: Data pertain to non-pregnant women. For Slovakia: Data pertain to women exposed to the risk of pregnancy. For Sweden: Data pertain to women who have ever had sex. Data sources: United Nations, Department of Economic and Social Affairs, Population Division (216). World Contraceptive Use 216 (POP/DB/CP/Rev216). development/desa/population/publications/dataset/contraception/wcu216.shtml. Available at: [Accessed on March 22, 217].

169 5 FACTORS CONTRIBUTING TO CERVICAL CANCER Figure 126: Prevalence of HIV in Europe Data accessed on 22 Mar 217. Estimates include all people with HIV infection, regardless of whether they have developed symptoms of AIDS. For Greece, Italy: Antiretroviral therapy data was not available at the time of publication Data sources: UNAIDS database [internet]. Available at: [Accessed on March 22, 217]

170 6 SEXUAL BEHAVIOUR AND REPRODUCTIVE HEALTH INDICATORS Sexual behaviour and reproductive health indicators Sexual intercourse is the primary route of transmission of genital HPV infection. Information about sexual and reproductive health behaviours is essential to the design of effective preventive strategies against anogenital cancers. In this section, we describe sexual and reproductive health indicators that may be used as proxy measures of risk for HPV infection and anogenital cancers. Several studies have reported that earlier sexual debut is a risk factor for HPV infection, although the reason for this relationship is still unclear. In this section, information on sexual and reproductive health behaviour in Europe is presented. Figure 127: Percentage of 15-year-old girls who report sexual intercourse in Europe Data accessed on 16 Mar 217. For Albania, Austria, Belgium, Bulgaria, Switzerland, Czech Republic, Germany, Denmark, Spain, Estonia, Finland, France, United Kingdom, Greece, Croatia, Hungary, Ireland, Iceland, Italy, Lithuania, Luxembourg, Latvia, Republic of Moldova, Macedonia, Malta, Netherlands, Poland, Portugal, Romania, Russian Federation, Slovakia, Slovenia, Sweden, Ukraine: Fifteenyear-olds teenagers only were asked whether they had ever had sexual intercourse. For Albania, Bulgaria, Switzerland, Spain, France, Greece, Croatia, Ireland, Lithuania, Latvia, Republic of Moldova, Macedonia, Portugal, Romania, Russian Federation, Slovenia, Ukraine: Indicates a significant gender difference (at p<.5). For Albania, Austria, Belgium, Bulgaria, Switzerland, Czech Republic, Germany, Denmark, Spain, Estonia, Finland, France, United Kingdom, Greece, Croatia, Hungary, Ireland, Iceland, Italy, Lithuania, Luxembourg, Latvia, Republic of Moldova, Macedonia, Malta, Netherlands, Poland, Portugal, Romania, Russian Federation, Slovakia, Slovenia, Sweden, Ukraine: Year of estimation: Data sources: For Albania, Austria, Belgium, Bulgaria, Switzerland, Czech Republic, Germany, Denmark, Spain, Estonia, Finland, France, United Kingdom, Greece, Croatia, Hungary, Ireland, Iceland, Italy, Lithuania, Luxembourg, Latvia, Republic of Moldova, Macedonia, Malta, Netherlands, Poland, Portugal, Romania, Russian Federation, Slovakia, Slovenia, Sweden, Ukraine: Growing up unequal: gender and socioeconomic differences in young people s health and well-being. Health Behaviour in School-aged Children (HBSC) study: international report from the 213/214 survey. Inchley J, Currie D, Young T, et al. Copenhagen, WHO Regional Office for Europe, 216 (Health Policy for Children and Adolescents, No. 7). Available at: http: // data/assets/pdf_file/3/33438/hsbc-no.7-growing-up-unequal-full-report.pdf?ua=1

171 6 SEXUAL BEHAVIOUR AND REPRODUCTIVE HEALTH INDICATORS Figure 128: Percentage of 15-year-old boys who report sexual intercourse in Europe Data accessed on 16 Mar 217. Please refer to original source for methods of estimation For Albania, Austria, Belgium, Bulgaria, Switzerland, Czech Republic, Germany, Denmark, Spain, Estonia, Finland, France, United Kingdom, Greece, Croatia, Hungary, Ireland, Iceland, Italy, Lithuania, Luxembourg, Latvia, Republic of Moldova, Macedonia, Malta, Netherlands, Poland, Portugal, Romania, Russian Federation, Slovakia, Slovenia, Sweden, Ukraine: Fifteenyear-olds teenagers only were asked whether they had ever had sexual intercourse. For Albania, Bulgaria, Switzerland, Spain, France, Greece, Croatia, Ireland, Lithuania, Latvia, Republic of Moldova, Macedonia, Portugal, Romania, Russian Federation, Slovenia, Ukraine: Indicates a significant gender difference (at p<.5). For Albania, Austria, Belgium, Bulgaria, Switzerland, Czech Republic, Germany, Denmark, Spain, Estonia, Finland, France, United Kingdom, Greece, Croatia, Hungary, Ireland, Iceland, Italy, Lithuania, Luxembourg, Latvia, Republic of Moldova, Macedonia, Malta, Netherlands, Poland, Portugal, Romania, Russian Federation, Slovakia, Slovenia, Sweden, Ukraine: Year of estimation: Data sources: For Albania, Austria, Belgium, Bulgaria, Switzerland, Czech Republic, Germany, Denmark, Spain, Estonia, Finland, France, United Kingdom, Greece, Croatia, Hungary, Ireland, Iceland, Italy, Lithuania, Luxembourg, Latvia, Republic of Moldova, Macedonia, Malta, Netherlands, Poland, Portugal, Romania, Russian Federation, Slovakia, Slovenia, Sweden, Ukraine: Growing up unequal: gender and socioeconomic differences in young people s health and well-being. Health Behaviour in School-aged Children (HBSC) study: international report from the 213/214 survey. Inchley J, Currie D, Young T, et al. Copenhagen, WHO Regional Office for Europe, 216 (Health Policy for Children and Adolescents, No. 7). Available at: http: // data/assets/pdf_file/3/33438/hsbc-no.7-growing-up-unequal-full-report.pdf?ua=1

172 6 SEXUAL BEHAVIOUR AND REPRODUCTIVE HEALTH INDICATORS Table 31: Median age at first sex in Europe MALE FEMALE TOTAL Median age Median age Median age Country Study Year/period Birth cohort N at first sex N at first sex N at first sex Albania Albania BBSS 25 a Albania DHS /29 Albania DHS /29 b Albania DHS /29 c Albania DHS /29 Albania DHS /29 Albania DHS /29 Albania DHS /29 Albania DHS /29 Albania DHS /29 d Albania DHS /29 d Albania DHS /29 d Austria Cibula 28 e,f,a Belarus Belgium Syrjanen g,h,f Syrjanen 23 i,h,f Syrjanen 23 h, j,f Fronteira k,f,a Hubert 1998 l Hubert 1998 l Hubert 1998 l Hubert 1998 l Hubert 1998 l Hubert 1998 l Bosnia & H. Arza 212 f,m Croatia Delva 27 n,f Croatia KABP (Landripet 211) Hirsl-Hecej k,o Hirsl-Hecej k,o Stulhofer Czech Rep. Crochard Czech Republic RHS 1993 Fronteira k,f,a Denmark Hubert 1998 l Estonia Hubert 1998 l Hubert 1998 l Hubert 1998 l Hubert 1998 l Hubert 1998 l Jensen Jensen Jensen Jensen Jensen Jensen Fronteira k,f,a Haldre Haldre / Haldre Haldre Haldre / Haldre Haldre Haldre Part (Continued on next page)

173 6 SEXUAL BEHAVIOUR AND REPRODUCTIVE HEALTH INDICATORS ( Table 31 continued from previous page) MALE FEMALE TOTAL Median age Median age Median age Country Study Year/period Birth cohort N at first sex N at first sex N at first sex Part Part Part Uusk la 28 f Finland Hubert 1998 l Hubert 1998 l Hubert 1998 l Hubert 1998 l Hubert 1998 l Hubert 1998 l Hubert 1998 l France Bajos Bajos Crochard France KABP France KABP France KABP France KABP France KABP p Hubert 1998 q,l Hubert 1998 q,l Hubert 1998 q,l Hubert 1998 q,l Hubert 1998 q,l Hubert 1998 q,l Hubert 1998 q,l Germany Griesinger 27 r,f Hubert 1998 s,l Hubert 1998 s,l Hubert 1998 s,l Hubert 1998 s,l Hubert 1998 s,l Hubert 1998 s,l Greece Hubert 1998 l Hubert 1998 l Hubert 1998 l Hubert 1998 l Hubert 1998 l Tsitsika 21 t,f Iceland Bender 1999 f,o Hubert 1998 l Hubert 1998 l Hubert 1998 l Hubert 1998 l Hubert 1998 l Hubert 1998 l Jensen Jensen Jensen Jensen Jensen Jensen Ireland Crochard ISSHR 26 a ISSHR 26 a ISSHR 26 a ISSHR 26 a ISSHR 26 a ISSHR 26 a ISSHR 26 a ISSHR 26 a ISSHR 26 a (Continued on next page)

174 6 SEXUAL BEHAVIOUR AND REPRODUCTIVE HEALTH INDICATORS ( Table 31 continued from previous page) MALE FEMALE TOTAL Median age Median age Median age Country Study Year/period Birth cohort N at first sex N at first sex N at first sex O Connell 29 u Israel Ben-Zur 2 v Italy Crochard 29 w Panatto 29 w Panatto 29 x Pannato 212 y Signorelli Signorelli Signorelli Signorelli Signorelli Signorelli Tafuri 21 z,f Latvia Syrjanen 23 h, j,f Syrjanen 23 i,h,f Syrjanen g,h,f Macedonia Delva 27 n,f Malta Malta HIS <= Montenegro Delva 27 n,f Labovic 211 f Netherlands Crochard degraaf 21 f degraaf 21 f degraaf 21 f degraaf 21 f Hubert 1998 l Hubert 1998 l Hubert 1998 l Hubert 1998 l Hubert 1998 l Lenselink 28 A,f Norway Bakken 27 B,f Hubert 1998 l Hubert 1998 l Hubert 1998 l Hubert 1998 l Hubert 1998 l Hubert 1998 l Jensen 211 a Jensen 211 a Jensen 211 a Jensen 211 a Jensen 211 a Jensen 211 a Pedersen 23 C,f Trfen Trfen Trfen Poland Crochard Olszewski D,f Portugal Aboim 212 f Romania Ferreira 211 x,f Fronteira k,f,a Hubert 1998 l Hubert 1998 l Hubert 1998 l Hubert 1998 l Hubert 1998 l Hubert 1998 l > Romania RHS a Romania RHS a Romania RHS 1993 a (Continued on next page)

175 6 SEXUAL BEHAVIOUR AND REPRODUCTIVE HEALTH INDICATORS ( Table 31 continued from previous page) MALE FEMALE TOTAL Median age Median age Median age Country Study Year/period Birth cohort N at first sex N at first sex N at first sex Romania RHS a Romania RHS a Romania RHS a Romania RHS Romania RHS Romania RHS Romania RHS Romania RHS Romania RHS Romania RHS d Russia Bobrova 25 f Crochard Syrjanen 23 h, j,f Syrjanen 23 i,h,f Syrjanen g,h,f Serbia Delva 27 n,f Slovenia Klavs 26 a Spain Sweden Castellsague E,f Castellsague E,f de Sanjose 28 f Gomez 27 F,f Spain ESHS Spain ESHS Spain ESHS Vaccarella 26 F,f Hdggstrvm Nordin 21 k Jensen Jensen Jensen Jensen Jensen Jensen Priebe 29 k,f Stenhammar f,g Switzerland Hubert 1998 l Hubert 1998 l Hubert 1998 l Hubert 1998 l Hubert 1998 l Turkey Turkey DHS 1998 H Turkey DHS H,c Turkey DHS H,b Turkey DHS H Turkey DHS H Turkey DHS H Turkey DHS H Turkey DHS H Turkey DHS H UK Hubert 1998 l Hubert 1998 l Hubert 1998 l (Continued on next page)

176 6 SEXUAL BEHAVIOUR AND REPRODUCTIVE HEALTH INDICATORS ( Table 31 continued from previous page) MALE FEMALE TOTAL Median age Median age Median age Country Study Year/period Birth cohort N at first sex N at first sex N at first sex Hubert 1998 l Hubert 1998 l Hubert 1998 l Wellings 21 a Wellings 21 a Wellings 21 a Wellings 21 a Wellings 21 a Wellings 21 a Wellings 21 a Wellings 213 a Wellings 213 a Wellings 213 a Wellings 213 a Wellings 213 a Wellings 213 a Wellings 213 a Ukraine Ukraine DHS 27 a Ukraine DHS c Ukraine DHS b Ukraine DHS Ukraine DHS a Ukraine DHS c Ukraine DHS b Ukraine DHS a Ukraine DHS a Ukraine DHS a Ukraine DHS a Ukraine DHS a Ukraine DHS Ukraine DHS d Data accessed on 16 Mar 217. a Number of subjects refers to the number of surveyed men/women (not all sexually active). b Rural. c Urban. d Data omitted because less than 5 percent of respondents had intercourse for the first time before reaching the beginning of the age group. e Data pertain to women randomly selected from a panel of more than three million women who had stated in a previous internet interview. f Mean age at first sex. g Data pertain to women attending a sexually transmitted disease clinic. h Data pertain to women attending six clinics in Belarus, Latvia and Russian Federation. i Data pertain to gynecological patients. j Data pertain to women participating in cervical cancer screening. k Data pertain to high school students. l Not especified if estimations are among sexually active or surveyed. m Sarajevo, Tuzla, Mostar, Banja Luka. n Data pertain to high school students in Bosnia (Sarajevo), the FYR of Macedonia (Skopje), and Serbia and Montenegro (Belgrade and Podgorica). o Not especified if estimations are among sexually active or surveyed (provided N among surveyed). p Ile-de-France. q Data from the Analysis on Sexual Behaviour in France (ACSF). r Data pertain to women attending a sample of gyneacologists in Berlin. s Data from the Survey performed in the Federal Republic of Germany (before reunification). t Data pertain to students attending 2 public junior high and high schools. u Data pertain to students attending student health units in three high education institutions (two universities and one institute of education). v Data pertain to Jewish adolescents. w Data pertain to workers. x Data pertain to secondary schools students. y Data pertain to secondary school students from Genova, Florence, Turin, Sassari and Cagliari. z Data pertain to school-leavers attending a pre-university study course. A Data pertain to unscreened women. B Data pertain to men recruited at student health services. C Data pertain to schools students. D Data pertain to high school and secondary schools students. E Data pertain to women attending routine cervical cancer screening. F Data pertain to population attending family planning centers or screening centers. G Swedish female university students from Uppsala undergoing contraceptive counseling at the students health center. H Data pertain to husbands. Data sources: See references in Section 9.

177 6 SEXUAL BEHAVIOUR AND REPRODUCTIVE HEALTH INDICATORS Table 32: Average number of sexual partners in Europe Period MALE FEMALE TOTAL Country Study of estimate Year/Period Birth cohort Mean(N) Mean(N) Mean(N) Albania Albania DHS 28-9 Lifetime ( ) 2.1 (123) 1. (2294) - (-) Albania DHS 28-9 Lifetime ( ) 3.1 (621) 1.1 (1887) - (-) Albania DHS 28-9 Lifetime ( ) 3.3 (242) 1.1 (71) - (-) Albania DHS 28-9 Lifetime ( ) 3.5 (266) 1.1 (516) - (-) Albania DHS 28-9 Lifetime ( ) 3. (395) 1.1 (698) - (-) Albania DHS 28-9 Lifetime ( ) 1.9 (129) 1. (181) - (-) Belarus Syrjanen 23 a,b Last 2 years (-) 2.2 (722) - (-) Syrjanen 23 c,b Last 2 years (-) 1.7 (761) - (-) Syrjanen 23 d,b Last 2 years (-) 1.6 (1692) - (-) Belgium Hubert 1998 e Last year 1993 ( ) 1.4 (1233) 1. (138) - (-) Czech Rep. Crochard 29 f Lifetime ( ) 4. (518) 3. (55) - (-) Denmark Buttmann 211 g Lifetime ( ) 8. (2241) - (-) - (-) Kjaer 27 g Lifetime ( ) - (-) 8.4 (22173) - (-) Estonia Lõhmus 23 Last year ( ) 2.1 (395) 1.4 (575) 1.7 (97) Lõhmus 23 Last year ( ) 3. (524) 1.9 (773) 2.3 (1272) Lõhmus 23 Last year ( ) 3.8 (251) 1.9 (392) 2.7 (643) Lõhmus 23 Last year ( ) 2.7 (94) 1.9 (112) 2.3 (25) Part 27 Lifetime ( ) - (-) 5.9 (68) - (-) Part 27 Last year ( ) - (-) 1.1 (68) - (-) Part 27 Lifetime ( ) - (-) 7.5 (77) - (-) Part 27 Last year ( ) - (-) 1.5 (77) - (-) Part 27 Lifetime ( ) - (-) 4.5 (98) - (-) Part 27 Last year ( ) - (-) 1.5 (98) - (-) Part 27 Lifetime ( ) - (-) 2.7 (9) - (-) Part 27 Last year ( ) - (-) 1.7 (9) - (-) France Bajos 21 g Lifetime 197 <= (125) 1.8 (1375) - (-) Bajos 21 g Lifetime 197 <= (125) 1.6 (1375) - (-) Bajos 21 g Lifetime 197 ( ) 12.8 (125) 1.9 (1375) - (-) Bajos 21 g Lifetime 197 ( ) 9.4 (125) 2. (1375) - (-) Bajos 21 g Lifetime 1992 ( ) 1.3 (8948) 2. (1198) - (-) Bajos 21 g Lifetime 1992 ( ) 11. (8948) 3.3 (1198) - (-) Bajos 21 g Lifetime 1992 ( ) 12.6 (8948) 4. (1198) - (-) Bajos 21 g Lifetime 1992 ( ) 1.4 (8948) 3.9 (1198) - (-) Bajos 21 g Lifetime 26 ( ) 12.9 (554) 3.9 (6824) - (-) Bajos 21 g Lifetime 26 ( ) 11.6 (554) 4.4 (6824) - (-) Bajos 21 g Lifetime 26 ( ) 12.9 (554) 5.1 (6824) - (-) Bajos 21 g Lifetime 26 ( ) 7.7 (554) 3.8 (6824) - (-) Crochard 29 f Lifetime ( ) 4. (419) 3. (46) - (-) Hubert 1998 g,h Lifetime ( ) 11.5 (6551) 3.8 (7777) - (-) Hubert 1998 e,h Last year ( ) 1.4 (6252) 1.1 (743) - (-) Germany Griesinger 27 i Lifetime 24 ( ) - (-) 3.5 (521) - (-) Hubert 1998 j,k Last year 199 ( ) 1.4 (927) 1.1 (156) - (-) Greece Hubert 1998 k Last year 199 ( ) 1.2 (743) 1. (839) - (-) Kordoutis 2 f Lifetime (179) 2. (279) - (-) Hungary Takacs 26 l Lifetime ( ) 19.1 (24) 1.8 (12) 16.5 (36) Takacs 26 l Last year ( ) 4.6 (24) 4.2 (12) 4.5 (36) Iceland Kjaer 27 g Lifetime ( ) - (-) 8.8 (1525) - (-) Ireland Crochard 29 f,m Lifetime ( ) 6. (371) 4. (377) - (-) ISSHR 26 n Lifetime ( ) 9.1 (3188) 3.1 (4253) - (-) ISSHR 26 n Last 5 years ( ) 9.1 (3188) 3.1 (4253) - (-) ISSHR 26 n Last year ( ) 9.1 (3188) 3.1 (4253) - (-) O Connell 29 o Lifetime ( ) - (-) 4.7 (215) - (-) Israel Ben-Zur 2 p Lifetime ( ) - (-) - (-) 3.6 (231) Chemtob 26 g Last 3 months 2 ( ) - (-) - (-) 1.1 (276) Chemtob 26 g Last 3 months 2 ( ) 1.9 (398) 1.5 (42) 1.3 (8) Chemtob 26 g Last 3 months 2 ( ) - (-) - (-) 1.3 (276) Chemtob 26 g Last 3 months 2 ( ) - (-) - (-) 1.6 (248) Italy Crochard 29 f Lifetime ( ) 5. (41) 3. (314) - (-) Panatto 212 q,r Lifetime ( ) 3. (277) 2. (733) - (-) Panatto 212 q,r Lifetime ( ) 3. (548) 2. (1288) - (-) Panatto 212 q,r Lifetime ( ) 2. (312) 1. (668) - (-) Latvia Syrjanen 23 a,b Last 2 years (-) 2.2 (722) - (-) Syrjanen 23 c,b Last 2 years (-) 1.7 (761) - (-) Syrjanen 23 d,b Last 2 years (-) 1.6 (1692) - (-) Moldova Moldova DHS 25 Lifetime 25 ( ) 6.3 (529) 1.5 (2142) - (-) Moldova DHS 25 Lifetime 25 ( ) 7.1 (425) 1.7 (1746) - (-) Moldova DHS 25 Lifetime 25 ( ) 8. (211) 1.8 (918) - (-) Moldova DHS 25 Lifetime 25 ( ) 6.6 (233) 1.8 (867) - (-) (Continued on next page)

178 6 SEXUAL BEHAVIOUR AND REPRODUCTIVE HEALTH INDICATORS ( Table 32 continued from previous page) Period MALE FEMALE TOTAL Country Study of estimate Year/Period Birth cohort Mean N Mean Moldova DHS 25 Lifetime 25 ( ) 5.7 (41) 1.7 (1175) - (-) Moldova DHS 25 Lifetime 25 ( ) 4.4 (167) 1.6 (38) - (-) Montenegro Labovic 211 Last year 29 ( ) 2.6 (398) 1.3 (194) - (-) Netherlands Crochard 29 f,m Lifetime ( ) 4. (476) 3. (463) - (-) degraaf 21 Lifetime 25 ( ) 4.9 (1273) 3.3 (136) - (-) degraaf 21 Lifetime 25 ( ) - (-) - (-) 4.7 (1214) degraaf 21 Lifetime 25 ( ) - (-) - (-) 3.4 (1124) degraaf 21 Lifetime 25 ( ) - (-) - (-) 3.8 (295) Hubert 1998 e Last year 1989 ( ) 1.2 (392) 1.1 (551) - (-) Kuyper 21 k Lifetime ( ) - (-) 4.1 (1965) - (-) Norway Bakken 27 f Last year 25 ( ) 2. (132) - (-) - (-) Bakken 27 f Last 6 months 25 ( ) 1. (973) - (-) - (-) Hubert 1998 g Lifetime 1992 ( ) 11.7 (1684) 5.5 (2116) - (-) Hubert 1998 e Last year 1992 ( ) 1.5 (1454) 1.2 (1944) - (-) Kjaer 27 g Lifetime ( ) - (-) 7.4 (16575) - (-) Træen 23 s Lifetime 1997 ( ) 7. (-) 6. (-) - (-) Træen 23 t Lifetime 1997 ( ) 6. (-) 6. (-) - (-) Træen 23 s Lifetime 22 ( ) 7. (-) 6. (-) - (-) Træen 23 t Lifetime 22 ( ) 6. (-) 7. (-) - (-) Poland Crochard 29 f Lifetime ( ) 3. (481) 2. (44) - (-) Portugal Hubert 1998 e Last year ( ) 1.8 (112) 1. (131) - (-) Russia Crochard 29 f,m Lifetime ( ) 5. (63) 3. (573) - (-) Syrjanen 23 a,b Last 2 years (-) 2.2 (722) - (-) Syrjanen 23 c,b Last 2 years (-) 1.7 (761) - (-) Syrjanen 23 d,b Last 2 years (-) 1.6 (1692) - (-) Takacs 26 l Lifetime ( ) 14.1 (14) 4.1 (16) 8.8 (3) Takacs 26 l Last year ( ) 3.6 (14) 1.8 (16) 2.7 (3) Slovenia Klavs 29 g Lifetime ( ) 9.5 (33) 3.1 (352) - (-) Klavs 29 g Last 5 years ( ) 2.1 (37) 1.1 (357) - (-) Klavs 29 g Last year ( ) 1.2 (36) 1. (357) - (-) Klavs 29 g Lifetime ( ) 8.3 (812) 3.2 (879) - (-) Klavs 29 g Last 5 years ( ) 3.2 (815) 1.5 (884) - (-) Klavs 29 g Last year ( ) 1.4 (812) 1. (889) - (-) Klavs 29 g Lifetime ( ) 7.9 (186) 3.4 (214) - (-) Klavs 29 g Last 5 years ( ) 3.1 (186) 1.4 (216) - (-) Klavs 29 g Last year ( ) 1.3 (185) 1. (217) - (-) Klavs 29 g Lifetime ( ) 6.5 (323) 2.9 (313) - (-) Klavs 29 g Last 5 years ( ) 5.5 (322) 2.5 (311) - (-) Klavs 29 g Last year ( ) 1.8 (321) 1.1 (315) - (-) Spain Castellsague 212 u Lifetime ( ) - (-) 1.4 (479) - (-) Castellsague 212 u Lifetime ( ) - (-) 2.8 (1617) - (-) Gomez 27 v Lifetime ( ) - (-) 1.9 (384) - (-) HSBS 23 Last year 23 ( ) 2.2 (-) 1. (-) 1.6 (-) HSBS 23 Last year 23 ( ) 2.6 (-) 1.2 (-) 1.9 (-) HSBS 23 Last year 23 ( ) 2.8 (-) 1.1 (-) 2. (-) HSBS 23 Last year 23 ( ) 2.8 (-) 1.4 (-) 2.1 (-) Vaccarella 26 v Lifetime ( ) - (-) 1.5 (98) - (-) Sweden Häggström-Nordin 21 w,f Lifetime 29 ( ) 3. (91) 2. (118) 2. (29) Kjaer 27 g Lifetime ( ) - (-) 8.6 (15713) - (-) Langstrom 26 g Lifetime 1996 ( ) 1.4 (1244) 1.2 (1142) - (-) Tyden 212 g,x Lifetime (-) 11. (35) - (-) Tyden 212 g,x Last year (-) 2.6 (35) - (-) Switzerland Jeannin 29 y,g,f Lifetime 27 ( ) 6. (-) 4. (-) - (-) Jeannin 29 y,g,f Last year 27 ( ) 1. (-) 1. (-) - (-) Jeannin 29 y,g,f Lifetime 27 ( ) 5. (-) 3. (-) - (-) Jeannin 29 y,g,f Last year 27 ( ) 1. (-) 1. (-) - (-) Jeannin 29 y,g,f Lifetime 27 ( ) 2. (-) 1. (-) - (-) Jeannin 29 y,g,f Last year 27 ( ) 1. (-) 1. (-) - (-) Jeannin 29 z Last year 27 ( ) 1. (-).6 (-).8 (3291) Jeannin 29 z Last year 27 ( ) 1.3 (-).9 (-) 1.1 (42) Jeannin 29 z Last year 27 ( ) 1.4 (-) 1.1 (-) 1.2 (489) Jeannin 29 z Last year 27 ( ) 2.2 (-) 1.3 (-) 1.7 (2262) UK Almonte 211 g,a Lifetime ( ) - (-) 5.6 (195) - (-) Almonte 211 g,a Lifetime ( ) - (-) 7.5 (436) - (-) Almonte 211 g,a Lifetime ( ) - (-) 7.7 (168) - (-) Almonte 211 g,a Lifetime ( ) - (-) 12. (73) - (-) Hubert 1998 g Lifetime ( ) 1.4 (6414) 3.7 (849) - (-) (Continued on next page)

179 6 SEXUAL BEHAVIOUR AND REPRODUCTIVE HEALTH INDICATORS ( Table 32 continued from previous page) Period MALE FEMALE TOTAL Country Study of estimate Year/Period Birth cohort Mean N Mean Hubert 1998 e Last year ( ) 1.3 (6134) 1.1 (779) - (-) Johnson 21 n Lifetime ( ) 16. (1691) 6.8 (2356) - (-) Johnson 21 n Last 5 years ( ) 2.2 (1669) 1.5 (2332) - (-) Johnson 21 n Lifetime ( ) 12.7 (4762) 6.5 (6399) - (-) Johnson 21 n Last 5 years ( ) 3.8 (4762) 2.4 (6399) - (-) Johnson 21 n Lifetime ( ) 13.6 (1759) 7.3 (2486) - (-) Johnson 21 n Last 5 years ( ) 4.2 (1751) 2.2 (2474) - (-) Johnson 21 n Lifetime ( ) 6.9 (1211) 5. (1433) - (-) Johnson 21 n Last 5 years ( ) 5.3 (12) 3.8 (1422) - (-) Mercer 29 n Last year ( ) 1.8 (4762) 1.3 (6399) - (-) Ukraine Ukraine DHS 27 Lifetime 27 ( ) 6.8 (747) 2.1 (1916) - (-) Ukraine DHS 27 Lifetime 27 ( ) 6. (743) 2.2 (1917) - (-) Ukraine DHS 27 Lifetime 27 ( ) 5.6 (367) 2.1 (97) - (-) Ukraine DHS 27 Lifetime 27 ( ) 5.3 (392) 2.2 (768) - (-) Ukraine DHS 27 Lifetime 27 ( ) 4.6 (527) 2.1 (94) - (-) Ukraine DHS 27 Lifetime 27 ( ) 2.9 (135) 1.6 (136) - (-) Data accessed on 8 Aug 213. N: number of subjects sexually active; a Data pertain to women attending a sexually transmitted disease clinic. b Data pertain to women attending six clinics in Belarus, Latvia and Russian Federation. c Data pertain to gynecological patients. d Data pertain to women participating in cervical cancer screening. e Data among responders who ever had a heterosexual partner. f Median number of sexual partners. g Number of surveyed people (not all sexually active). h Data from the Analysis on Sexual Behaviour in France (ACSF). i Data pertain to women attending a sample of gyneacologists in Berlin. j Data from the Survey performed in the Federal Republic of Germany (before reunification). k Data from "every man/woman who presents herself as heterosexual"; all partners are included. l Data pertain to heterosexual members from 12 social networks. m Weighted data based on national age distributions for Ireland, the Netherlands and Russia. n Number of heterosexual partners among surveyed (not all sexually active). o Data pertain to students attending student health units in three high education institutions (two universities and one institute of education) p Data pertain to Jewish adolescents. q Data pertain to secondary schools students. r Data pertain to students who reported regular sexual activity after their sexual debut. s Data pertain to heterosexuals not living with a partner. t Data pertain to heterosexuals married or living with a partner. u Data pertain to women attending routine cervical cancer screening. v Data pertain to population attending family planning centers or screening centers. w Data pertain to high school students. x Data pertain to university students. y Data from the EPSS (Enquête téléphonique périodique sur la Prévention du VIH/sida en Suisse). z Data from the ESS 27 (Enquête Suisse sur la Santé). Some of the questions that were only included in the EPSS survey were also integrated into the Swiss Health Survey (ESS) in 27. This allowes the documentation of these aspects also for people aged 46 to 74 years. A The authors used the following formula to estimate the Number of lifetime partners in year 2 in women aged years= Number of lifetime partners - Number of new partners in the last 5 years. Data sources: See references in Section 9. Table 33: Lifetime prevalence of anal intercourse among women in Europe FEMALE % among Country Study Year/Period Birth cohort N surveyed N sexual active sexually active Belgium Hubbert 1998 a,b 1993 ( ) Croatia Stulhofer ( ) Stulhofer ( ) Czech Rep. Brody 211 c 1993 <= Brody 211 c 1998 <= Brody 211 c 23 <= Brody 211 c 28 <= Estonia Part 27 d ( ) Part 27 d ( ) Part 27 d ( ) Part 27 d ( ) Finland Hubbert 1998 a ( ) France Bajos <= Bajos ( ) (Continued on next page)

180 6 SEXUAL BEHAVIOUR AND REPRODUCTIVE HEALTH INDICATORS ( Table 33 continued from previous page) FEMALE % among Country Study Year/Period Birth cohort N surveyed N sexual active sexually active Bajos ( ) Bajos ( ) Bajos ( ) Bajos ( ) Bajos ( ) Bajos ( ) Bajos ( ) Germany Hubbert 1998 e,a 199 ( ) Greece Hubbert 1998 a 199 ( ) Ireland ISSHR 26 c,f,g ( ) ISSHR 26 c,f,g ( ) ISSHR 26 c,f,g ( ) ISSHR 26 c,f,g ( ) ISSHR 26 c,f,g ( ) ISSHR 26 c,f,g ( ) Montenegro Labovic 211 d 29 ( ) Netherlands Bakker 26 h,f,g ( ) Hubbert 1998 a,i 1989 ( ) Slovenia Klavs ( ) Klavs ( ) Klavs ( ) Klavs ( ) ( ) Spain Faílde Garrido 28 j,g Sweden Häggström- Nordin 21 k,d Tyden 212 l,d Tyden 212 l,d Tyden 212 l,d UK Johnson 21 c,f ( ) Johnson 21 c,f ( ) Stone 26 c,m ( ) Data accessed on 8 Aug 213. N: number of subjects; a Data pertain to women in current steady heterosexual relationship. b Proportion among women who ever practice receptive anal intercourse with current partner. c Instead of number of women sexually active, this time was number of women who answered the question on anal intercourse. d Proportion among surveyed women (not all sexually active). e Data from the Survey performed in the Federal Republic of Germany (before reunification). f Data pertain to heterosexual women. g Proportion among women who ever practice receptive anal intercourse in the last 6 months. h Data on anal intercourse was not provided by the authors but calculated from percentage of those that have never practice anal intercourse. i Proportion among women who recently practice receptive anal intercourse with current partner. j Data pertain to adolescents and young adults. k Data pertain to high school students. l Data pertain to university students. m Data pertain to full and part time students. Data sources: See references in Section 9.

181 7 HPV PREVENTIVE STRATEGIES HPV preventive strategies It is established that well-organised cervical screening programmes or widespread good quality cytology can reduce cervical cancer incidence and mortality. The introduction of HPV vaccination could also effectively reduce the burden of cervical cancer in the coming decades. This section presents indicators on basic characteristics and performance of cervical cancer screening, status of HPV vaccine licensure, and introduction in Europe. 7.1 Cervical cancer screening practices Screening strategies differ between countries. Some countries have population-based programmes, where in each round of screening women in the target population are individually identified and invited to attend screening. This type of programme can be implemented nationwide or only in specific regions of the country. In opportunistic screening, invitations depend on the individual s decision or on encounters with health-care providers. The most frequent method for cervical cancer screening is cytology, and there are alternative methods such as HPV DNA tests and visual inspection with acetic acid (VIA). VIA is an alternative to cytology-based screening in low-resource settings (the see and treat approach). HPV DNA testing is being introduced into some countries as an adjunct to cytology screening ( co-testing ) or as the primary screening test to be followed by a secondary, more specific test, such as cytology. Table 34: Cervical cancer screening policies in Europe Country Availability of cervical cancer screening programme α Quality assurance structure and mandate to supervise and to monitor the screening process β Active invitation to screening γ Main screening test used for primary screening Demonstration projects Screening ages (years) Screening interval or frequency of screenings Albania Yes No No Cytology Above Years Andorra Yes No No Cytology - - Austria Yes No No Cytology Above 18 1 year Belarus Yes No No Cytology Above 18 1 year No Cytology years Belgium Yes No. Varies by region A Bosnia & H. Yes Yes B No Cytology year Bulgaria Yes No No Cytology years Croatia Yes Yes A,B No Cytology years Cyprus Yes No No Cytology Czech Rep. Yes Yes No Cytology year Denmark Yes Yes A Yes Cytology years (ages 23-49), 5 years (ages 5-65) Estonia Yes Yes A Yes Cytology years Finland Yes Yes A Yes Cytology years France Yes Yes A,B Yes Cytology years Germany Yes No No Cytology HPV test Above 2 1 year Greece Yes No No Cytology Above 2 1 year Hungary Yes Yes A Yes Cytology years Iceland Yes Yes Yes Cytology years (ages 2-39), 4 years (ages 4-69) Ireland Yes Yes Yes Cytology years (ages 25-44), 5 years (ages 45-6) (Continued on next page)

182 7 HPV PREVENTIVE STRATEGIES ( Table 34 continued from previous page) Country Availability of cervical cancer screening programme α Quality assurance structure and mandate to supervise and to monitor the screening process β Active invitation to screening γ Main screening test used for primary screening Demonstration projects Screening ages (years) Screening interval or frequency of screenings Italy Yes Yes A,B Yes Cytology/HPV test years (Cytology), 5 years (HPV test) Latvia Yes Yes A,B Yes Cytology years Lithuania Yes Yes A,B Yes Cytology years Luxembourg Yes No No Cytology Above 15 1 year Macedonia Yes No No Cytology years Malta Yes Yes Yes Cytology/HPV test Above 25 (cytology), Above 3 (HPV test) Cytology every 3 years (ages 25-5), VIA every 5 years (above 5 years old). HPV test every 5 years Moldova Yes No No Cytology Above 2 2 years Monaco Yes - No Cytology years after 2 consecutive annual negative tests Montenegro Yes Yes B No Cytology years Netherlands Yes Yes A Yes Cytology/HPV years test Norway Yes Yes Yes Cytology years Poland Yes Yes A Yes Cytology years Portugal Yes Yes A Yes Cytology years Romania Yes Yes A,B Yes Cytology years Russia Yes No No Cytology Above 18 1 year San Marino Yes - Yes Cytology/HPV test 25-3 (cytology), 3-65 (HPV test) 3 years (cytology), 5 years (HPV test) Serbia Yes Yes B Yes Cytology years Slovakia Yes No No Cytology years Slovenia Yes Yes Yes Cytology years Spain Yes No. Varies by region No. Varies by region Cytology/HPV test (cytology), 3-65 (HPV test) 3 years (cytology), 5 years (HPV test) Sweden Yes Yes A Yes Cytology years (ages 23-5), 5 years (ages 5-6) Switzerland Yes No No Cytology Above 2 3 years (Continued on next page)

183 7 HPV PREVENTIVE STRATEGIES ( Table 34 continued from previous page) Country Availability of cervical cancer screening programme α Quality assurance structure and mandate to supervise and to monitor the screening process β Active invitation to screening γ Main screening test used for primary screening Demonstration projects Screening ages (years) Screening interval or frequency of screenings UK Yes Yes A Yes Cytology/HPV test years (ages 25-49), 5 years (ages 5-64) Ukraine Yes No No Cytology year Data accessed on 31 Dec 216. A Information about performance indicators in organized and population-based cervical cancer screening programmes in European countries is found in the following document "Cancer Screening in the European Union (217). Report on the implementation of the Council: Recommendation on cancer screening. International Agency for Research on Cancer. European Commission. January 217. Available at: en.pdf." B Implementation is in progress. C To replace Pap-test by hrhpv DNA test as the primary screening instrument (starting in 216). D Screening program since α Public national cervical cancer screening program in place (Cytology/VIA/HPV testing). Countries may have clinical guidelines or protocols, and cervical cancer screening services in a private sector but without a public national program. Publicly mandated programmes have a law, official regulation, decision, directive or recommendation that provides the public mandate to implement the programme with an authorised screening test, examination interval, target group and funding and co-payment determined. β Self-reported quality assurance: Organised programmes provide for a national or regional team responsible for implementation and require providers to follow guidelines, rules, or standard operating procedures. They also define a quality assurance structure and mandate supervision and monitoring of the screening process. To evaluate impact, organised programmes also require ascertainment of the population disease burden. Quality assurance consists of the management and coordination of the programme throughout all levels of the screening process (invitation, testing, diagnosis and follow-up of screen-positives) to assure that the programme performs adequately and provides services that are effective and in-line with programme standards. The quality assurance structure is self-reported as part of the national cancer programs or plans. γ Self-reported active invitation or recruitment, as organised population-based programmes, identify and personally invite each eligible person in the target population to attend a given round of screening. Data sources: Data sources are detailed at the country-specific report

184 7 HPV PREVENTIVE STRATEGIES HPV vaccination HPV vaccine licensure and introduction Figure 129: Status of HPV vaccination programmes in Europe Data accessed on 31 Dec 216. Data sources: Adapted from Bruni L, Diaz M, Barrionuevo-Rosas L, Herrero R, Bray F, Bosch FX, de Sanjosé S, Castellsagué X. Global estimates of human papillomavirus vaccination coverage by region and income level: a pooled analysis. Lancet Glob Health. 216 Jul;4(7):e453-63