Incidence of Male Neonatal Circumcision in New Zealand

The New England Journal of Medicine, Volume 346, Issue 15: Pages 1160-1161, 11 April 2002.

Editorial

Cervical Cancer and the Elusive Male Factor

Male circumcision is probably one of the oldest surgical procedures and is still the most common. Globally, about one man in four is likely to undergo circumcision for various reasons.¹ In the United States, an estimated 80 percent of all newborn boys were circumcised in the 1970s. These rates have subsequently decreased, however, as a result of several policy statements issued by the American Academy of Pediatrics. According to the most recent of these documents, the medical benefits are not sufficient to recommend routine neonatal circumcision.²

Notwithstanding this balanced statement, it is generally accepted that circumcision may reduce the prevalence and thereby the sexual transmission of several infectious diseases. Of the various infectious agents involved,¹ certain oncogenic subtypes of human papillomavirus (HPV) are directly linked to some genital cancers and are considered to be the main cause of both premalignant and malignant lesions of the uterine cervix.

The article by Castellsagué and colleagues³ in this issue of the Journal represents the culmination of a major research effort undertaken by the International Agency for Research on Cancer to evaluate the role of HPV and various modifying factors in the development of cervical cancer. In the context of this large project, seven case­control studies were undertaken in five countries on three continents. Using results from all seven studies, Castellsagué et al. report two main findings that are ostensibly interrelated: male circumcision is associated with a reduced risk both of penile HPV infection and of cervical cancer in the female partners of men who had six or more lifetime sexual partners.

That circumcision may reduce the risk of cervical cancer in the female partner has long been suspected.⁴ However, until certain types of HPV were conclusively implicated in the etiologic process of this cancer, the reason underlying the reduced risk remained poorly understood. The convincing evidence provided by Castellsagué and colleagues that the prevalence of HPV infection is reduced among circumcised men clarifies the nature of the elusive male factor⁵ in the causation of cancer of the cervix and provides a biologically plausible explanation for the overall excess risk of cervical cancer among female partners of uncircumcised men.

The study has several strengths: it was large, used state-of-the-art laboratory procedures for the detection of HPV infection, and included several different populations, a factor that enhances the generalizability of the results. The integration of molecular techniques and epidemiologic methods produced a powerful composite tool for the study of the etiologic process of cervical cancer.

However, the shortcomings of the study should also be recognized. Because many factors associated with HPV infection are also more common among uncircumcised than circumcised men, such as a history of multiple sexual partners and poor genital hygiene, these factors may help to explain the results of the study. That confounding was important is demonstrated by the finding that strong associations in the crude data between circumcision and penile HPV infection and between circumcision and cervical cancer in a man's female partner were attenuated after adjustment for these and other factors. Appropriate statistical techniques were used to adjust for confounding. Nonetheless, when variables are difficult to define and measure accurately (such as the frequency of genital washing after intercourse or the general adequacy of a subject's genital hygiene judged on the basis of a single assessment), they are also difficult to control for.

Another, probably unavoidable, limitation was the way in which the factor of main interest ‹ circumcision ‹ was ascertained. Progression from infection with an oncogenic HPV to the development of carcinoma in situ and, ultimately, to invasive cervical cancer may take several decades.⁶ Because of this long latency, the possibility that the female partner may have become infected with HPV many years earlier by a different male partner cannot be ruled out. Castellsagué et al. appropriately limited their analyses to the husbands or stable partners of the women, but misclassification would tend to attenuate the true association between circumcision and the risk of cervical cancer, and the reduction in risk among the female partners of circumcised as compared with uncircumcised men may well be more substantial than reported.

With respect to the public health implications of this study, it is important to emphasize that circumcision itself does not protect against cervical cancer. Rather, circumcision should be considered as a modifying factor, in that it protects against cervical cancer by reducing the prevalence of the principal cause, HPV infection. In other words, in the absence of penile infection with an oncogenic HPV strain, circumcision should have no effect on the female partner's risk of cervical cancer. In this regard, the lower incidence of cervical cancer was limited to the female partners of circumcised, as compared with uncircumcised, men who also had six or more lifetime sexual partners.

As Castellsagué et al. indicate, circumcision of men at high risk for penile HPV infection may reduce the overall risk of cervical cancer among their female partners by 50 percent or more. If we assume that 25 percent of men around the world are circumcised,¹ then the general adoption of circumcision might lead to a further reduction in the incidence of cancer of the cervix of 23 to 43 percent. Because circumcision also tends to reduce the risk of penile cancer,⁷ human immunodeficiency virus infection,⁸ and perhaps other urogenital infections,⁸ this practice should have considerable public health benefits.

These implications need, however, to be considered in the broader context of costs and feasibility. Although carcinoma of the cervix remains one of the leading causes of death from cancer among relatively young women, notably in developing countries,⁹ numerous approaches could change this gloomy picture. In Sweden, for example, earlier clinical detection of invasive cancer, achieved through increased public and professional awareness, combined with ready access to basic treatment, reduced the five-year case fatality rates from about 80 percent to 40 percent between 1920 and 1960. Indeed, before this intervention, the situation in Sweden was similar to that in many poor countries, where most cervical cancers are diagnosed in advanced, incurable stages.⁶ With more resources and a sophisticated infrastructure, the incidence of cervical cancer and the associated mortality can be further reduced by detecting and eliminating precursor lesions, chiefly carcinoma in situ. Since the mid-20th century, cytologic screening with use of the Papanicolaou test has achieved this aim in many developed countries,⁶ and HPV testing may soon become a complementary tool.

Regular use of condoms may also inhibit sexual transmission of HPV and thereby prevent cervical cancer. The use of condoms can, at least in theory, be targeted to men involved in high-risk sexual behavior. Prophylactic vaccination against HPV infection¹⁰ is now being evaluated in clinical trials and could substantially reduce the rates of HPV infection and associated cervical cancers. Whether interventions intended to increase the rates of circumcision are a realistic and quantitatively important addition to other strategies to combat cancer of the cervix remains to be documented.

Hans-Olov Adami, M.D., Ph.D.
Karolinska Institutet, SE-171 77 Stockholm, Sweden

Dimitrios Trichopoulos, M.D., Ph.D.
Harvard School of Public Health, Boston, MA 02115

• Adami H, Trichopoulos D. Cervical Cancer and the Elusive Male Factor. New Engl J Med 2002;346(15):1160-61.

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