Circumcision - Cancer of the Penis

Incidence:

The predicted lifetime risk of penile cancer for an uncircumcised man has been estimated as 1 in 600 in the USA and 1 in 900 in Denmark [304]. Penile cancer accounts for approx. 0.2% of all malignancies in men in the USA and 0.1% of cancer deaths, the 5-year survival rate being approx. 50% [19]. Mortality rate is 25-33% [304, 344].

The annual incidence of cancer of the penis in the USA is approx. 1 per 100,000 men per year [19, 133]. (In comparison, cervical cancer incidence is 10 times higher [see below], breast cancer is 60 times higher, prostate cancer is 100 times higher, and fatal heart attack is 200 times higher.) Statistics on the American Cancer Society web page point to 1,280 new cases of penile cancer in 2007, with 290 deaths [21]. Squamous cell carcinoma is the most common type of penile cancer in the USA, representing 93% of all malignancies [207].

In the USA, Hispanic men have the highest incidence (6.6 per million), then Black men (4.0 per million), White (3.9), American Indians (2.8) and Asian-Pacific Islanders (2.4) [207]. For ages >85 y incidence was 47 and 36 per million in Hispanic and Black men, respectively [207]. Owing to earlier diagnosis, incidence has been decreasing by 1.9% per year in Blacks and 1.2% in Whites [207]. The majority (61%) were diagnoses at the localized stage. Regional differences were apparent.    

Penile cancer is regarded as an ‘emerging problem’ [366]. This large review also noted that ‘public health measures, such as prophylactic use of circumcision, have proven successful’ [366]. Neonatal circumcision virtually abolishes the risk [499]. 

The rate data in the USA has to be viewed in the context of the high proportion of circumcised men in the USA, especially in older age groups, and the age group affected (mean age at presentation = 60 years [468]), where older men represent only a portion of the total male population.

Thus the incidence of 1 in 100,000 men per year of life translates to 75 in 100,000 during each man's lifetime (assuming an average life expectancy of 75 years). However, penile cancer occurs almost entirely in uncircumcised men. If we assume that these represent 30% of males in the USA, the chance an uncircumcised man will get it would be (very approximately) 75 per 30,000 = 1 in 400. Perhaps not surprisingly this accords with the incidence that is actually seen (as stated at the beginning of this paragraph).

In 5 major series in the USA, starting in 1932 [642], not one man with invasive penile cancer had been circumcised neonatally [344], i.e., this disease is almost completely confined to uncircumcised men. In fact penile cancer is so rare in a man who had been circumcised in infancy, that when it does occur it can even be the subject of a published case report [283]. The finite residual risk appears to be greater in those circumcised after the newborn period, but still less than the uncircumcised. In this regard penile cancer in circumcised men (av. age 62) in Saudi Arabia (where circumcision is performed in older children) was associated with ritual, nonclassical vigorous circumcision [522].

Lifetime risk in the total population of circumcised men is only 1 in 50,000 to 1 in 12,000,000 [638, 639]. In a study of 213 cases in California only 2 of 89 men with of invasive penile cancer was circumcised in infancy, so that uncircumcised men were stated to have a 22 times higher risk [501, 502]. Of 118 with the localized, and thus more easily curable, variety of penile cancer, namely carcinoma in situ (which is not lethal), only 16 had been circumcised as newborns, i.e., incidence was 3-fold higher in the uncircumcised [344, 501, 502]. A study in Louisiana found that only 2 of 45 penile cancer patients had been circumcised in infancy [98]. Circumcision later in life is much less effective [577].

Overall there were 50,000 cases of penile cancer in the USA from 1930 to 1990 and these resulted in 10,000 deaths. Only 10 of these cases were in circumcised men [497], and these had been circumcised later in life. In Denmark (circumcision rate = 2%), penile cancer has been decreasing steadily [189] in parallel with an increase in indoor bathrooms. Urban unmarried men were more likely to get it.

Since the rate of penile cancer in Denmark is lower than in the USA other factors besides circumcision are also at work in these climatically, genetically, dietary and culturally different countries. The statistics for Denmark have been used by anti-circ advocates to draw a sweeping and fallacious conclusion about lack of circumcision per se in penile cancer. The Danish themselves have concluded that although their uncircumcised men are at lower risk, this is only 1 in 900 as opposed to 1 in 600 in the USA, as stated above [304]. A study in Spain concluded that "circumcision should be performed in childhood [as a] prophylactic [to penile cancer] [487].

As a historical point of interest, Diego Rivera, the famous Mexican muralist, who had multiple sexual partners over many years in a country where most men are uncircumcised, developed penile cancer [514]. He refused penectomy (surgical removal of the penis) and instead (as a Communist) went to the Soviet Union for radiation therapy. He died a painful death from the disease and the side effects of his therapy.

In underdeveloped countries the incidence is higher: approx. 3-10 cases per 100,000 per year [304]. In those underdeveloped countries where circumcision is not routinely practiced, such as South America and parts of Africa, it can be ten times more common than in developed countries, representing 10–22% of all male cancers [19, 223, 386]. In Uganda and some other African countries it is the most common malignancy in males, leading to calls for greater circumcision [152]. Enormous differences are, moreover, seen in third world nations such as Nigeria (circumcised: low rate) when compared with Uganda, Puerto Rico [647] and Brazil [593], where most males are uncircumcised and penile cancer is very much more common.

In Australia there were 67 cases in 2003, and over the decade to that year cases averaged 66 per year [39]. Typical age distribution of cases is approx. 4% aged in their 30s, 14% in their 40s, 15% in their 50s, 22% in their 60s, 31% in their 70s, and was 12% in those aged over 80 [40]. One in four died as a result, the rate being higher in older men. The annual incidence of penile cancer is 0.8 per 100,000 population [40], i.e., was similar to the USA, and was also similar in each state of Australia. Life-time (age 0–74) risk was estimated as 1 in 1,574 males [40]. As in the USA, over two-thirds of older men in Australia are circumcised, so any future decline in proportion of uncircumcised males in the Australian population will, by itself, be expected to be accompanied by an escalation in the rate of penile cancer.

As mentioned earlier, the rate of cervical cancer is 10 times higher, with 725 cases in Australia in 2003 (incidence 9.1 per 100,000) and 212 deaths [41].

In Israel, where almost all males are circumcised, the rate of penile cancer is extremely low: 0.1 per 100,000, i.e., is 1/10th that of Denmark [647].

Cause:

Cancer of the penis presents as carcinoma in situ or invasive penile cancer. The proportion of each of these is roughly equal (45% vs 55% in the USA). Invasive penile cancer is lethal, whereas carcinoma in situ is comparatively benign. Moreover, the former is not necessarily a continuum of the latter [137].

Human papillomavirus (HPV) is present in most basaloid and warty carcinomas which comprise 50% of cases [223]. Similarly, in women, half of all vulvar carcinomas are HPV-positive (cf. the close to 100% positivity for high-risk HPVs in cervical cancer). High-risk HPV is found more frequently in verrucous carcinomas than giant condylomas (which are caused by low-risk HPV). Although relatively harmless, such benign condylomas are readily apparent and, as shown in the picture below of a promiscuous man who was still having sex at the time can be quite shocking to look at.

Keratinizing and verrucous carcinomas are HPV positive in one-third of cases [223]. A Spanish study found HPV in 78% of penile carcinoma specimens and of these 84% had HPV16 and 11% had HPV18 [429]. But in Thailand HPV was found in 82% of penile cancers, of which 55% were HPV18, followed by HPV6 (43%), with a large proportion having each [519]. 

Thus high risk HPV (types 16, 18 and a large number of rarer types) are found in a large proportion of cases and there is good reason to suspect that they are involved in the causation of penile cancer [359], i.e, the same virus is responsible as is the case for virtually all cases of cervical cancer in women (see below). The distribution of HPV on the penis has been reported as 28% foreskin, 24% shaft, 17% scrotum, 16% glans and 6% urine [605]. HPVs, notably high-risk types, are more common in uncircumcised males [60, 101, 305, 319, 396]. In Copenhagen, Denmark, being uncircumcised was associated with a 5-fold higher likelihood of being infected with HPV [555].

In a large study published in the New England Journal of Medicine in 2002 HPV was detected in 19.6% of 847 uncircumcised men, but only 5.5% of 292 circumcised men (overall odds ratio after adjusting for potential confounding factors = 0.37) [101]. In a study of healthy military men in Mexico the odds ratio for persistent HPV infection was 10 times higher in uncircumcised compared with circumcised [319]. The high-risk types of HPV produce flat warts that are normally only visible by application of dilute acetic acid (vinegar) to the penis. The majority of infections are subclinical, being more prevalent in uncircumcised men with balanoposthitis [305]. The data on high-risk HPVs should not be confused with the incidence figures for genital warts, which are large and readily visible, and are caused by the relatively benign HPV types 6 and 11 [290].

A meta-analysis of 8 studies published in 2007 showed that circumcision is associated with a statistically significant reduced risk of penile HPV and related lesions (odds ratio 0.56; 95% CI = 0.39-0.82) [103]. This was prompted by the publication of a biased, inaccurate and misleading meta-analysis by the notorious anti-circ activist, Robert Van Howe, who is well known for using statistical games to discredit good peer-reviewed studies that disagree with his biases.

Interestingly, 93% of men whose female partner was positive for early signs of cervical cancer (cervical intra-epithelial neoplasia, CIN) had the male equivalent, penile intra-epithelial neoplasia (PIN) [46]. This reflects the fact that the disease, via HPV, is sexually transmitted. Oncogenic HPV was present in 75% of patients with PIN grade I, 93% with PIN grade II and 100% of PIN grade III, which is one step before penile cancer itself [46]. Moreover, the rate of PIN was 10% in uncircumcised men cf. only 6% in circumcised men [46]. HPV DNA was found in 80% of tumor specimens, with 69% being the high-risk type 16 [137]. That condom use may lower HPV infection was reported in a study of 393 men [60].

Phimosis is strongly associated with invasive penile carcinoma (adjusted odds ratio = 16 in one study [577] and 11 in another [137]). In fact 45-85% of men with penile cancer have a history of phimosis [149, 577]. It causes dysplastic (cancerous) changes in the skin of the preputial sac [459]. Although length of the foreskin has been suggested as a factor, the evidence for this is weak [590]. In this study 52% of penile cancer cases with a long foreskin had phimosis.

Smegma (found only under the foreskin) was implicated in an early study [447]. The carcinogenicity of smegma was subsequently confirmed by others [141, 241, 460]. It is not clear, however, what component was responsible, and could have been HPV present in the smegma. Smegma may cause chronic inflammation and recurrent infections that lead to preputial adhesions and phimosis [459, 577]. Male horses produce large amounts of smegma and 23% of cancers in these animals involve 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 [495].

Chronic relapsing balanitis of bacterial, mycotic or viral origin may also increase risk of invasive penile cancer [234, 491]. A history of balanitis has been reported in 45% of penile cancer patients compared with 8% of controls [149, 501]. Penile lichen sclerosis (balanitis xerotica obliterans (BXO)), an inflammatory disorder that can lead to meatal stenosis or phimosis is associated with penile cancer (reviewed in [366]). Incidence in penile carcinoma patients was estimated as 2.6-5.8%, but subsequent research found the rate of BXO to be 28% [441]. Of these, 77% had squamous cell carcinoma and 23% carcinoma in situ. The rate of HPV infection is 2.6 times higher amongst patients with penile lichen sclerosis [387].

Although this and other evidence that found oncogenic HPV is higher in patients with genital lichen sclerosis (17% vs 9%), other data suggest that lichen sclerosis is a preneoplastic condition unrelated to HPV infection (reviewed in [366]).

A co-carcinogenic role of recurrent herpes simplex type 2 (HSV-2) in penile cancer has also been suggested [176, 660].

The widely used vaginal spermicide, nonoxynol-9, greatly increases susceptibility of the genital epithelium to HPV16 infection [471]. In this study, carrageenan, a polysaccharide present in some vaginal lubricants, prevented infection.   

In addition, other factors, such as smoking (4.5-fold increase in risk [137]), poor hygiene (even in the absence of phimosis) and other STIs have been suspected as contributing to penile cancer as well [58, 344], but it would seem that lack of circumcision is the primary prerequisite, with such other factors adding to the risk in the uncircumcised man. Indeed, there is no scientific evidence that improved penile hygiene is effective in reducing the risk in an uncircumcised man [380]. A study in California showed there was no correlation between penile cancer and frequency of bathing or method of cleaning the anogenital area before or after sexual intercourse [577]. It has been concluded that circumcision in early childhood, by eliminating phimosis, may help prevent penile cancer [137].

There may be two routes to penile cancer: one via sexual transmission of oncogenic HPV in young men and the other unrelated to HPV that mostly affects older men (reviewed in [366]).

Treatment:

Complete or partial surgical amputation is the traditional treatment. Radiation is an alternative (or additional) therapy and in early-stage disease can preserve function of the organ. In a retrospective study in Switzerland of 41 consecutive patients with non-metastatic invasive carcinoma of the penis 44% underwent surgery (to remove all or part of the penis, as well as lymph nodes in one third), followed by radiation therapy (in three-quarters) and the rest (56%) had just radiation therapy [659]. Over the median 70 months of follow-up 63% relapsed. For all patients 5-year survival rate was 57% and 10-year survival was 38%. Local relapse rate was lower in those who underwent surgery. However, there was no difference in survival when compared with radiation therapy, either alone, or in conjunction with salvage surgery. In a Swiss study, local control was better with surgery (87%) than radiation therapy alone (44%), but 5 year survival was similar: 53% vs. 56% [421]. After 5 years 43% of those with an intact penis were alive, and by 10 years this was 26%.  A recent review has emphasized the role of lack of circumcision and poor prognosis, as well as providing an update on treatment options [87].

The psychosexual implications to a man are, understandably, not inconsequential [411]. The fact that, as is the case for breast cancer, the sex-related organ is often surgically removed adds to the devastating physical and emotional impact of penile cancer. But the 5-year survival rate is lower [461]. It would be cold comfort to a man so afflicted to know that his disease could almost certainly have been prevented had he been circumcised in infancy.

Cost:

Financial considerations are, moreover, not inconsiderable. In the USA it was estimated that the cost for treatment and lost earnings in a man of 50 with cancer, even back in 1980, was $103,000 [239]. The amount today is very much higher.

Deaths from penile cancer vs. circumcision:

In Australia between 1960 and 1966 there were 78 deaths from cancer of the penis and 2 from circumcision. (Circumcision fatalities today are virtually unknown in hospital settings.) At the Peter McCallum Cancer Institute 102 cases of penile cancer were seen between 1954 and 1984, with twice as many in the latter decade compared with the first [489]. Moreover, several authors have linked the rising incidence of penile cancer to a decrease in the number of neonatal circumcisions [136, 489]. It would thus seem that "prevention by circumcision in infancy is the best policy". Indeed it would be an unusual parent who did not want to ensure their child was completely protected by this simple procedure. Indeed, the protective effect of circumcision against invasive penile cancer is equivalent to the protective effect that not smoking has against lung cancer and heart disease [512].

Thus, to quote, “Despite overwhelming evidence from urological surgeons that neoplasm of the penis is a lethal disease that can be prevented by removal of the foreskin, some physicians continue to argue against routine newborn circumcision in a highly emotional and aggressive fashion” [136]. In the interests of public health, such ignorance must change.