Research Article: The Strong Protective Effect of Circumcision against Cancer of the Penis

Date Published: May 22, 2011

Publisher: Hindawi Publishing Corporation

Author(s): Brian J. Morris, Ronald H. Gray, Xavier Castellsague, F. Xavier Bosch, Daniel T. Halperin, Jake H. Waskett, Catherine A. Hankins.

http://doi.org/10.1155/2011/812368

Abstract

Male circumcision protects against cancer of the penis, the invasive form of which is a devastating disease confined almost exclusively to uncircumcised men. Major etiological factors are phimosis, balanitis, and high-risk types of human papillomavirus (HPV), which are more prevalent in the glans penis and coronal sulcus covered by the foreskin, as well as on the penile shaft, of uncircumcised men. Circumcised men clear HPV infections more quickly. Phimosis (a constricted foreskin opening impeding the passage of urine) is confined to uncircumcised men, in whom balanitis (affecting 10%) is more common than in circumcised men. Each is strongly associated with risk of penile cancer. These findings have led to calls for promotion of male circumcision, especially in infancy, to help reduce the global burden of penile cancer. Even more relevant globally is protection from cervical cancer, which is 10-times more common, being much higher in women with uncircumcised male partners. Male circumcision also provides indirect protection against various other infections in women, along with direct protection for men from a number of genital tract infections, including HIV. Given that adverse consequences of medical male circumcision, especially when performed in infancy, are rare, this simple prophylactic procedure should be promoted.

Partial Text

Penile cancer is a devastating disease, although uncommon in developed countries. It accounts for less than 1% of all malignancies in men in the USA and 0.1% of cancer deaths. The 5-year survival rate is approximately 50% [1], having decreased little over recent decades [2, 3]. The disease is confined almost exclusively to men who are uncircumcised, the lifetime risk of penile cancer in an uncircumcised man being 1 in 600 in the USA and 1 in 900 in Denmark [2]. These figures are not to be confused with the often quoted annual incidence figure of the order of 1 in 100,000 [1, 4]. In the USA the annual incidence of primary malignant penile cancer decreased from 0.84 per 100,000 men in 1973 to 0.58 per 100,000 in 2002 [5]. Squamous cell carcinoma is the most common type of penile cancer. In the USA it represents 93% of all penile malignancies [6]. From 1998 to 2003, 4,967 men were diagnosed with invasive squamous cell carcinoma, representing less than 1% of all new cancers in men and occurring at 0.81 cases per 100,000 US men over the five years [7]. In 2010 there were 1,250 new cases of penile cancer and 310 deaths [8].

An extensive review in 2006 concluded that penile cancer is an “emerging problem”, noting that “public health measures, such as prophylactic use of circumcision, have proven successful” [10]. Neonatal circumcision virtually abolishes the risk [11].

Phimosis is strongly associated with invasive penile carcinoma, the adjusted OR for this being 16 in one study [16] and 11 in another [36]. In fact 45–85% of men with penile cancer have a history of phimosis [16, 33, 96]. Phimosis causes dysplastic (pre-cancerous) changes in the skin of the preputial sac [97]. Although length of the foreskin has been suggested as a factor, the evidence for this is weak [98]. In this study, 52% of penile cancer cases with a long foreskin had phimosis. These findings have led to the conclusion that circumcision in early childhood, by eliminating phimosis, may help prevent penile cancer [36]. A meta-analysis yielded an overall OR of 12.1 (95% CI = 5.6–26.2) (Table 2) for the association of phimosis with penile cancer.

Smegma is a whitish film found under the foreskin of uncircumcised males. It contains bacteria, other microorganisms, dead skin cells, mucous, and other components. Evidence for a role of smegma in the etiology of penile cancer was obtained in an early study [102]. The carcinogenicity of smegma was subsequently confirmed by others [103–105]. It was not clear in these studies from the 1950s and 1960s what component was responsible, but in hindsight it could have been the presence of HPV. Smegma may cause chronic inflammation and recurrent infections that lead to preputial adhesions and phimosis [16, 97]. Male horses produce large amounts of smegma and 23% of cancers in these animals are of the penis. Geldings do not get erections that would normally help eliminate smegma, and in such horses penile cancer is 10 times higher than in stallions [106]. In a meta-analysis of the available data we found an OR of 3.04 (95% CI = 1.29–7.16) for the association between penile cancer and smegma (Table 3).

These conditions are all more prevalent in uncircumcised men. Chronic relapsing balanitis of bacterial, mycotic, or viral origin increases the risk of invasive penile cancer [107, 108]. A history of balanitis has been reported in 45% of penile cancer patients compared with 8% of controls [20, 96]. Penile lichen sclerosis (also termed balanitis xerotica obliterans (BXO)), an inflammatory disorder that can lead to meatal stenosis or phimosis, is associated with penile cancer (reviewed in [10]). BXO is well known in boys where it is more common than is generally assumed [109]. In penile carcinoma patients incidence of lichen sclerosis was initially estimated as 2.6–5.8%, but subsequent research found the rate to be very much higher. In one study it was 28%, with 77% of patients having squamous cell carcinoma and 23% carcinoma in situ [110]. Other studies found BXO in 33% [111], 44% [112], and 50% [113] of cases of squamous cell carcinoma. HPV infection was 2.6 times higher amongst patients with penile lichen sclerosis [114]. Lichen sclerosis is not always associated with presence of HPV and it could be that lichen sclerosis acts as a catalyst in the onset of penile cancer [115]. Although this and other evidence supports the view that oncogenic HPV is more prevalent in patients with genital lichen sclerosis (17% versus 9%), other data suggests that lichen sclerosis is a preneoplastic condition unrelated to HPV infection (reviewed in [10]). One review suggested that approximately half of penile squamous cell carcinomas (which represent 95% of penile neoplasms) are associated with lichen sclerosis and half with HPV [91]. A meta-analysis indicates an OR of 3.82 (95% CI = 1.61–9.06) for the association of balanitis with penile cancer (Table 4).

A cocarcinogenic role of recurrent HSV-2 in penile cancer has also been suggested [116, 117].

Risk of prostate cancer correlates with a history of STIs, most consistently syphilis, gonorrhoea, Chlamydia, and HPV [122–129]. In contrast to penile cancer, however, no consistent association has been seen between rate of prostate cancer and rate of cervical cancer in different geographic localities [130]. A study of 20,243 men in Finland found infection with HPV18 was associated with a 2.6-fold increase in risk of prostate cancer (P < .005) [131]. For HPV16 the increased risk was 2.4-fold. These figures are similar to the increased prevalence of penile HPV infection in uncircumcised men [45]. In contrast, a Swedish study found an association of HPV33, but not HPV16 or HPV18, with prostate cancer [132]. A study in Crete, however, found HPV in only 5% of samples, none of which had the common high-risk types 16 and 18, making a role for HPV unlikely [133]. Consistent with this, a study in Saudi Arabia was unable to detect HPV in any of the prostate biopsies of 56 patients with benign prostatic hyperplasia or prostate cancer [134]. 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 billion [158]. This figure does not portray the social cost of cervical cancer to individuals and families. There is now overwhelming evidence that male circumcision affords very strong protection against penile cancer. Unlike the many other conditions that affect up to half of uncircumcised males over their lifetime [178], penile cancer affects only about 0.1% of uncircumcised men. Although rare, its devastating effect and poor prognosis in those affected, and impact on their families, should not be downplayed, especially in the developing countries where penile cancer rates are highest and treatment options are limited. Very importantly, given its role in protecting against cervical cancer, HIV, other STIs and medical conditions, programs aimed at increasing infant male circumcision now would be an excellent investment of public monies for the long run. They would complement the enormously expensive vaccination programs targeting two of the over 15 high-risk HPV types that cause cervical cancer. This strategy would add the many other benefits of male circumcision to the equation [178, 179].   Source: http://doi.org/10.1155/2011/812368