Using different data sources and extrapolation methods, this review showed that the overall estimated epidemiological burden of HPV-related cancers and non-malignant diseases is high among men in Europe. In addition to malignant diseases, which include a subset of head and neck cancers and anal and penile cancers, non-malignant diseases such as genital warts and recurrent respiratory papillomatosis are also associated with HPV. Moreover, the majority of HPV-positive cancers in men are attributable to oncogenic HPV16/18, while the great majority of genital warts and virtually all cases of recurrent respiratory papillomatosis are caused by HPV6/11.
In this report, a total of 72,694 new HPV-related cancer cases were estimated to occur each year in men in Europe. Moreover, we estimated that 17,403 of these cancers could be attributable to HPV, of which 15,497 were estimated to be specifically attributable to HPV16/18.
In addition, between 335,301 and 380,961 new cases of genital warts were estimated to occur annually in men in Europe, with 286,682-325,722 of them attributable to HPV6/11.
Recurrent respiratory papillomatosis is a very rare disease and incidence data in Europe are scarce. It was not possible to estimate the number of new annual cases in men in Europe. Nevertheless, the association with HPV is particularly strong for this disease, and virtually all cases are attributable to HPV6/11 [70
Head and neck cancers
There was high variability in the incidence of head and neck cancers, irrespective of HPV status, with age-standardised incidence rates in Europe ranging from 5.6 to 33.0 per 100,000 man-years. The distribution of the subset of head and neck cancers included herein also varied throughout Europe. This may be partially due to regional differences in HPV prevalence, which are in turn related to differences in the distribution of risk factors for HPV infection, such as sexual behaviour. It may also be due to differences in the distribution of non-HPV-related risk factors like alcohol consumption and tobacco use, which explain some 80% of these cancers.
Large cohort studies from Sweden show increasing evidence of a steady rise in the incidence of a subset of cancers of the oral cavity (especially lateral border of the tongue) [71
] and oropharynx (notably tonsillar and base of the tongue [22
]). In these studies oropharyngeal cancer was most strongly associated with HPV. The overall HPV detection rate in tonsillar carcinoma reached up to 51%, with HPV16 being the most common type (84%) [71
]. The increasing trend may be due to an increase of HPV infections in the head and neck, possibly related to changes in sexual behaviour.
An overall number of 2,162 annual cases were estimated to occur in men in Europe, irrespective of HPV status and the association of anal cancer with HPV is extremely strong (84.2% HPV-related) [19
An increasing trend in the incidence of anal cancer has been reported for a number of countries, including Denmark [25
], Sweden [27
], the Netherlands [28
] and the United Kingdom [24
]. Regional differences in incidence could be explained by regional differences in anal HPV prevalence, the key causal precursor for anal cancer [75
], and its associated causes and consequences, such as history of condyloma [76
], history of anoreceptive intercourse [76
] and increased lifetime number of sexual partners [78
Three thousand one hundred seventy-eight new penile cancer cases, irrespective of HPV status, were estimated to occur yearly in Europe with almost half of these cases (1,484) attributable to HPV.
In addition to regional differences in penile HPV prevalence, differences in the incidence of penile cancer may be due to differences in the regional distribution of risk factors that are not related to HPV infection, such as smoking, phimosis and absence of circumcision [79
HPV-related non-malignant diseases
The burden of genital warts in men in Europe is substantial. Extrapolated from the most robust European incidence data collected in Germany and in the United Kingdom, new cases were estimated to range between 335,301 and 380,961 in men in Europe every year. The vast majority are estimated to be attributable to HPV6/11. As for HPV-related malignant diseases, the incidence of genital warts varies highly by geographical region. This may be due partially due to differences in the distribution of risk factors for HPV infection. Furthermore, there is some evidence of a steady rise of genital warts in men in the United Kingdom [81
Genital warts are not life-threatening, but they are associated with high morbidity: psychosocial stigma, psychosexual dysfunction, depression and lower quality of life [82
]. Treatment is painful, and there is a high risk of recurrence.
Recurrent respiratory papillomatosis
In Europe, only two studies provided data on the incidence of recurrent respiratory papillomatosis in both sexes: 0.35-0.38 per 100,000 person-years. There was no specific information about incidence in men but the sex ratio for juvenile onset recurrent respiratory papillomatosis was reported to be 1:1, while there was a pronounced male preponderance in onset in adulthood [42
Virtually 100% of cases are caused by HPV, the most common types being HPV6/11 [11
]. Maternal condyloma or genital HPV infection during pregnancy is the overwhelming risk factor for juvenile onset recurrent respiratory papillomatosis (more than 200-fold increased risk) [43
]. Although non-malignant, the disease is associated with very high morbidity. It has the potential to be life-threatening and the number of lifetime surgeries may exceed 100 in children with severe disease [70
Head and neck
Overall HPV prevalence in the head and neck ranged from 0 to 18% among men in Europe, and specific prevalence of all high-risk HPV types from 0 to 14.5%. Due to the small number of European studies and the relatively small sample sizes, these results must be considered with caution. More robust data are available when worldwide studies are considered. Indeed, a systematic review of all published studies worldwide (n = 18) that detected HPV DNA in the oral cavity of 4,070 cancer-free subjects found a pooled HPV prevalence (any type) of 4.5% (95%CI: 3.9%-5.1%); the prevalence of high-risk types was 3.5% (95%CI: 3.0%-4.1%) [84
]. In a recent study of 1,680 healthy men from the United States, Mexico, and Brazil, HPV DNA was detected in the oral cavity of 4.0% (95%CI: 3.1%-5.0%), and carcinogenic HPV DNA in 1.3% (95%CI: 0.8%-2.0%) of subjects [85
The prevalence of anal HPV infection in men in European studies ranged between 15.3% [49
] and 94.1% [50
], but all these studies included presumably high-risk populations and there were no data on the prevalence of anal HPV infection in the general male population in Europe.
The prevalence of penile HPV infection in men in Europe ranged from 2.2% (95%CI: 0.0%-6.4%) [53
] to 72.9% (95%CI: 65.8%-79.3%) [54
]. The heterogeneity of the published data is partly due to the use of different sample techniques, detection methods, anatomical sites or specimens sampled, as well as study populations with different risk factors. The penis is made up of different types of body tissue, which differ in their susceptibility to HPV infection. Data from literature have indicated that the prepuce has the highest proportion of HPV-positive samples, though reports have also shown an increase in HPV DNA detection when multiple anatomical sites were sampled [86
Most of the studies that evaluated the prevalence of HPV infection in anogenital sites included high-risk populations. Nevertheless, data from the United States have shown a very high prevalence of anogenital HPV infection (65%) in population-based studies [87
]. The incidence of new genital HPV infections in this population was 38.4 per 1,000 person months (95%CI: 34.3-43.0) in a recent study including men aged 18-70 years with a median duration of HPV infection of 7.52 months (95%CI: 6.80-8.61) for any HPV infection and 12.19 months (95%CI: 7.16-18.17) for infection with HPV16 [89
In addition, a recent global review of the age-specific prevalence of HPV infection in men [86
] identified 64 abstracts with data on genital HPV infection in men worldwide, including 38 from populations at high risk of HPV infection. The authors of the study concluded that the risk of HPV infection is generally high for most men in many geographical areas, with comparable prevalence in both low-risk (1-84%) and high-risk populations (2-93%).
Little is known about the natural history of HPV infection in men. Few studies have prospectively assessed HPV infection, and therefore few data are available on the incidence, acquisition and persistence of HPV infection in men. A recent review on HPV prevalence in men concluded that, in contrast to results for women, age-specific prevalence curves remained relatively flat with age, or declined only slightly with post-peak prevalence. Thus, men may potentially have more long-term persistent HPV infections, or a higher rate of re-infection [86
Comparison to the burden in women
For comparison purposes, the methods described above were also used to estimate the epidemiological burden of HPV-related cancers and genital warts in women in Europe. Using our methods of estimation, a total of 32,562 cancer cases specifically due to HPV16/18 were expected to occur in women in Europe every year. The new annual number of cases of genital warts attributable to HPV6/11 in women in Europe was estimated to range between 288,959 and 388,873.
A total of 48,059 HPV16/18-positive cancer cases were estimated to occur annually in Europe in both sexes, of which more than 30% occur in men (Table ). Other than cervical cancer, 23,254 annual cases of which are estimated to be HPV16/18-positive, the estimated burden of cancer cases attributable to HPV is higher in men than in women, and is mainly driven by head and neck cancers.
The burden of new yearly human papillomavirus (HPV)16/18-related cancers in men vs. women in Europea
The incidence of head and neck cancers attributable to HPV16/18 is five-fold higher in men (12,707 new cases yearly) than women (2,531 new cases yearly). In addition, new cases of genital warts attributable to HPV6/11 in both genders were estimated to range between 614,681 and 675,555 yearly in Europe, half of them affecting men.
Impact of HPV vaccination
The preliminary effects of HPV vaccination on genital warts and precancerous lesions have been reported from Australia, where a vaccination programme using the quadrivalent HPV vaccine was implemented. The data showed that in addition to a significant decline in the number of cases of genital warts and in the incidence of high-grade cervical abnormalities among young women in Australia, the number of cases of genital warts among heterosexual men also declined markedly [90
Our report has several limitations. A short-term prediction method was used to estimate the expected number of incident cancer cases in 2008 from the most recent data collected from 1998 to 2002. Therefore these predictions were accurate only if the disease rates remained stable over time. In the case of an increasing trend, they would slightly underestimate the expected number of cases, and the opposite would be true in the case of a decreasing trend.
As mentioned above, the CI5 database contains national cancer incidence rates for 17 European countries. For the remaining nine countries included in this report only regional incidence rates were available in the CI5 database. Although we assessed the geographical coverage and distribution of these regional registries, other non-controllable factors, like differences in alcohol and tobacco consumption, could vary and influence regional incidence rates. The results should thus be interpreted with particular caution.
The presence of HPV DNA is used to calculate the prevalence of HPV in a given population. However the mere presence of HPV is insufficient to prove causation, as the infection may be transient and not related to the carcinogenic process. Therefore our application of previously published HPV prevalence to an estimated number of new cancer cases may have yielded an overestimation of cases attributable to HPV infection. Finally, the prevalence of HPV16/18 co-infections has not been evaluated, thus summarising HPV16/18 prevalence may have led to an overestimation of the cancer burden attributable to these types.
Another limitation is the absence of sex-specific HPV prevalence data in anal and head and neck cancers. Consequently, our report assumed that HPV prevalence is the same in both sexes. Currently, we have no reliable data that would confirm this hypothesis, and it seems to be inconsistent with the worldwide data from the meta-analysis by De Vuyst et al. [19
], which showed a higher HPV prevalence in anal carcinoma among women (90.8%) than men (74.9%). To our knowledge, sex-specific data on HPV prevalence in head and neck cancers are lacking, and future research is needed.
We applied the same HPV prevalence to all European countries in this report. However, regional differences in HPV prevalence could exist, notably due to the fact that in some countries other non-HPV-related risk factors, i.e., tobacco or alcohol consumption may predominate. Furthermore, when type-specific HPV data for Europe was lacking, we used worldwide data, thus assuming that there is no difference in the HPV16/18 distribution between Europe and other parts of the world.
The method used to estimate the expected annual number of new genital wart cases attributable to HPV6/11 has also some limitations. We based our estimations on incidence data extracted from only two studies and only one of them was population-based [17
]. In addition, due to the lack of data, it was not possible to extrapolate incidence data per age, but only by sex. However, there may be important differences in the age structure of European countries. Also, the incidence of genital warts throughout Europe may vary, due to regional differences in the prevalence of HPV infection and its underlying risk factors.