Any discussion of penile cancer in men cannot fail to mention cervical cancer in women. Sexual transmission of high-risk HPV infection is responsible for virtually all cervical cancer. The incidence of cervical cancer is 10 times higher than that of penile cancer, with 12,000 new cases and 4,000 deaths from cervical cancer each year in the USA [155
]. Australian data indicate 725 cases in 2003 (incidence 9.1 per 100,000) and 212 deaths [156
]. In the USA, high-risk HPVs account for the loss of 3.3
million DALYs through cervical cancer [157
]. The cost of treating cervical disease in the USA each year is approximately $3.5
]. This figure does not portray the social cost of cervical cancer to individuals and families.
The study in Denmark referred to earlier that found 5-fold lower HPV in circumcised men concluded that “the female partners of circumcised men are less exposed to cervical cancer because these men are less likely to be infected with HPV” [54
High-risk HPV types 16, 18 and over a dozen other less common types are responsible for virtually every case of cervical cancer [159
] and are the same high-risk HPVs that cause PIN, which is the precursor to penile cancer and is the male equivalent of CIN, more often referred to these days as “squamous intra-epithelial lesion” (SIL), the precursor to cervical cancer. Women with cervical cancer are more likely to have partners with PIN [162
]. In women with CIN, PIN was present in the male partner in 93% of cases [94
]. This is consistent with the known sexual transmission of oncogenic HPV. CIN/SIL may progress to cancer or, more often, it will resolve. Thus cofactors are suspected. Smegma, obtained from under the foreskin of human and horse, was shown to be capable of producing cervical cancer in mice in one study [163
], but not in another [105
]. Differences in exposure time in each study could have contributed to this difference, and followup is needed to confirm whether or not these old studies have any validity.
The large, well-designed, multinational study by the International Agency for Research on Cancer published in the New England Journal of Medicine
mentioned earlier irrefutably implicated lack of male circumcision in cervical cancer [45
]. It involved 1,913 couples in 5 global locations in Europe, Asia, and South America. As stated earlier, penile HPV was found in 19.6% of uncircumcised, but only 5.5% of circumcised men (adjusted OR = 0.37; 95% CI = 0.16–0.85; P
< .001). Monogamous women whose male partner had had 6 or more sexual partners were over 5.6 times more likely to have cervical cancer if their partner was uncircumcised (OR = 0.18; 95% CI = 0.04–0.89). Male circumcision was also protective in women whose partner had an intermediate sexual behavior risk index (OR = 0.50; 95% CI = 0.27–0.94). In this study, penile HPV infection was associated with a 4-fold increase in the risk of cervical HPV infection in the female partner, and cervical HPV infection was associated with a 77-fold increase in the risk of cervical cancer. In an accompanying editorial it was suggested that “reduction in risk among female partners of circumcised as compared with uncircumcised men may well be more substantial than reported" [164
Genital HPV types are highly infectious and can infect skin throughout the genital region. Skin-to-skin contact that does not extend to actual sexual penetration by an uncircumcised penis could infect women. In the NEJM
study condom use provided only a slight protective effect—the odds ratio between condom users and nonusers (0.83) was not statistically significant [45
]. A study in Seattle of university undergraduates, however, found that HPV incidence in women whose partners always used condoms was 70% less than those whose partners used condoms less than 5% of the time [165
]. Squamous intraepithelial lesions were absent in the group with 100% condom use, compared with an incidence of 15 per 100 patient-years in non-users. Interestingly, the uncircumcised men washed their genitals more often after intercourse, but the circumcised men had better penile hygiene when examined by a physician. So why are uncircumcised men more likely to get infected? One suggested reason is that the more delicate, mucosal lining of the foreskin is pulled back fully or partially during intercourse, exposing it to the vaginal secretions of an infected woman. The higher incidence of HPV in uncircumcised men translates into an increased risk of infection to future sexual partners.
An ecological analysis of data from 117 developing countries revealed a cervical cancer incidence of 35 per 100,000 women per year in 51 countries with a low (<20%) circumcision prevalence compared with 20 per 100,000 in 52 countries with a high (>80%) circumcision prevalence (P
< .001) [166
]. Of all factors examined, male circumcision had the strongest association with cervical cancer incidence.
A meta-analysis of 14 studies up until September 2007 (5 in the USA, 2 in Mexico, 2 in Australia, and one each in South Korea, Denmark, England, Kenya, and the multinational study involving Brazil, Spain, Thailand, and The Philippines referred to above) found an OR of 0.75 (95% CI 0.49–1.14) for the association between male circumcision and cervical cancer in monogamous women [67
A RCT in Rakai, Uganda, studied the female partners of men who underwent circumcision and those of men who remained uncircumcised [167
]. Of these women, 84% were monogamous and 97% had had only one sex partner in the previous year. At the 2-year point an as-treated analysis showed that the 544 whose male partner had been circumcised had a lower prevalence of high-risk HPV infection (28%) than the 488 whose male partner was uncircumcised (38%): PRR = 0.75. For low-risk HPV these figures were 35% and 41%, respectively (PRR = 0.83). The prevalence of multiple high-risk HPV was 8.9% and 12.6%, respectively, giving an IRR of 0.71, while that of multiple low-risk HPV was 9.2% and 14.2% (IRR = 0.65). Between enrolment and year 2 the prevalence of high-risk HPV decreased by 7.4%
= .006) in the women whose male partner had been circumcised, but did not change significantly (+1.6%) in the women whose male partner had remained uncircumcised. The study also found that by 2 years women with circumcised partners had cleared 82% of high-risk HPV acquired during the first year of the trial, compared with 70% for women with uncircumcised partners (P
= .14). The authors pointed out that the estimated efficacy of male circumcision in prevention of high-risk HPV (28%) could, for a number of reasons, have been an underestimate.
Thus the epidemic of cervical cancer worldwide in women would appear to be facilitated, at least in part, by the lack of circumcision in men. We speculate that in countries that have experienced a downturn in the uptake of neonatal circumcision, as occurred in the USA and to a greater extent in Australia in the late 1970s and 1980s, the incidence of cervical cancer can be expected to increase. This is because these males would now have reached sexual maturity. The higher proportion of uncircumcised men in the male population increases the overall risk to women today, more than would otherwise have been the case if male circumcision prevalence had remained high.
Prophylactic vaccines against HPV 16 and 18 became available for administration to girls prior to sexual activity in 2007. These two HPVs represent 70% of the HPV types found in cervical cancers. They were also the two genotypes that had the highest population prevalence in the past. In 2007, however, the CDC reported that HPV 16 and 18 are now less prevalent, type 16 becoming only the 6th most common and HPV18 now being even less prevalent [168
]. Moreover, replacement of types 16 and 18 by other HPV types not included in current vaccines could occur. Other concerns include the very high ongoing costs of vaccination programs, levels of uptake, the possibility of the need for booster doses if efficacy wanes over time, weak cross-genotype immunity, poor efficacy in women with prior HPV 16 and 18 infections, and the false belief that the vaccines protect against all cervical cancer, which may result in fewer women continuing to participate in screening programs or practicing safe sex.
Various studies have demonstrated increasing infection with genital HPV types at a younger age. In the UK, 5% of girls under 14 had HPV antibodies, indicating current or prior infection [169
]. By age 16 this was 12%, by 18 it was 20%, and by age 24 the proportion infected was 45%, with a subsequent decrease thereafter. Oncogenic HPV16 was the most common type. In the USA, 7% of teenagers (ages 12–19) had HPV16 antibodies, rising to 25% for 20–29-year olds [170
]. Chlamydia and genital herpes cases are also rising in teenagers in developed countries.
HPV can be transmitted to the mouth during oral sex and is an independent risk factor for some oropharyngeal cancers [171
It should be noted that there might be as many as 200 types of HPV, up to 50 of which have been described in the anogenital region. Most of these range from uncommon to extremely rare. The number of HPV types relevant to screening for cervical cancer risk in the population is approximately 20. Ideally, many expect that vaccination against the most common types (HPV 16 and 18) could prevent two-thirds of cervical cancers. A randomized, placebo-controlled, double-blind trial involving 5,455 women aged 16–24 years found that vaccination reduced the rate of cervical lesions by only 20% [172
]. The study lasted only 3 years however. One study found HPV vaccination to not be cost-effective, even under favourable assumptions for vaccination programs [173
]. Yet a subsequent review of cost-effectiveness studies concluded that vaccination of girls against HPV will be cost-effective [174
]. At an uptake of 80% in 12 year-old girls, HPV vaccines could reduce cervical cancer by 38–82% over 60 years of an ongoing vaccination programme, should vaccine protection last 20 years [175
]. Vaccination of boys has, however, been found to not be cost-effective [174
Complete elimination of HPV 16 and 18 from the population by vaccination might, under optimal conditions of uptake and efficacy, take 20–30 years or more. In the meantime at the population level, other oncogenic HPV types not included in vaccines might take over and replace these two types of HPV [176
]. Participation in vaccination programs has been impeded by the “religious right” who have expressed concerns that vaccination will increase promiscuity. Moreover, like the anticircumcision movement, vigorous anti-immunization lobby groups also exist. Most of the adverse events that have received publicity in the news media were not related to the vaccine in the first place and would be seen in any large-scale vaccination program by pure coincidence. One exception might be Guillain-Barre syndrome, which is known to be an uncommon adverse consequence of vaccination in a minority of individuals. The two HPV vaccines currently on the market appear to be at least as safe as any other vaccine, although HPV vaccines can increase tumour invasiveness if a tumour is present [177
Given the high cost of vaccinating all girls compared with the lesser cost and proven protective effect of universal male circumcision against a raft of other conditions and diseases in men [178
], the latter would appear to be a better investment. In women it would help reduce the burden of cervical cancer, and, more recently, the possiblity of a small proportion of breast cancers [180
], but also herpes simplex virus type 2 [55
], less assuredly Chlamydia trachomatis
], then Trichomonas vaginalis
, bacterial vaginosis, genital ulceration [179
], and bacterial vaginosis associated with CIN/SIL [194