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Articles  |   March 2011
Human Papillomavirus Infection and the Links to Penile and Cervical Cancer
Author Notes
  • Address correspondence to Roberta Wattleworth, DO, MHA, MPH, Department of Family Medicine, Des Moines University, 3200 Grand Ave, Des Moines, IA 50312-4104. E-mail: roberta.wattleworth@dmu.edu 
Article Information
Obstetrics and Gynecology / Urological Disorders
Articles   |   March 2011
Human Papillomavirus Infection and the Links to Penile and Cervical Cancer
The Journal of the American Osteopathic Association, March 2011, Vol. 111, S3-S10. doi:
The Journal of the American Osteopathic Association, March 2011, Vol. 111, S3-S10. doi:
Abstract

Human papillomavirus (HPV) infection has been thoroughly demonstrated as a major factor in the pathogenesis of cervical cancer, but HPV's role in penile cancer has not been demonstrated as convincingly. The author reviews several major investigations from the past 35 years and finds that men with certain risk factors (eg, intact foreskin, history of sexual encounters outside marriage, and history of first intercourse at a younger age) place their current female sex partners at greater risk for cervical carcinoma caused by transmission of HPV infection. A brief description of HPV prevention and treatment options is also provided.

The role of human papillomavirus (HPV) in the degradation of cervical epithelial cells toward malignancy has been thoroughly documented; infection with oncogenic HPV is a consistent finding in more than 95% of patients with cervical cancer worldwide.1 However, past infection with high-risk HPV has not been as well established as a necessary prerequisite for penile cancer. In addition to HPV exposure, epidemiologic research has implicated other risk factors in the development of penile cancer, including lack of circumcision (compounded by formation of phimosis), poor genital hygiene, smoking, and other social factors, such as sexual orientation and lifetime number of sex partners.2-5 
Malignant tumors of the penis can be primary or secondary, arising from metastases. Subcategories of primary tumors include soft-tissue, urethral, and epithelial tumors, and rare tumors include melanomas, lymphomas, and schwannomas. Epithelial tumors, including those caused by HPV, are further broken down into in situ and invasive carcinomas.6 Of the 4 types of in situ carcinoma—Bowen disease, erythroplasia of Queyrat, bowenoid papulosis, and extramammary Paget disease—the first 3 have been linked to HPV infection and may become invasive carcinomas if patients are left untreated.7,8 Invasive carcinomas of the penis are categorized as basal cell, verrucous, or squamous cell, with squamous cell carcinoma (SCC) accounting for at least 95% of all penile malignant tumors.9 
It has been hypothesized that penile SCC may develop by means of 2 distinct etiologic pathways: (1) an HPV-mediated etiology, which probably involves sexual contact and affects men in their fifth decade, and (2) a nonviral pathway related to risk factors already mentioned, which leads to the development of penile SCC decades after exposure.10-12 The incidence of HPV DNA found in penile carcinoma tissue ranges from 15% to 78%, varying according to the population studied, the method of specimen collection, and the laboratory method used for detection.13 
Worldwide, cancer of the penis secondary to oncogenic HPV accounts for less than 0.1% of cancers in men, varying according to the developmental status of the country.14 In Western countries, where circumcision is routinely performed, the incidence is one-third that in developing nations, where circumcision is less common.4 Results of various studies are contradictory as to whether the effects of circumcision are explained by lack of running water and poor genital hygiene, inflammatory effect of accumulated smegma, microtrauma to the foreskin during intercourse, formation of phimosis, or the harboring of HPV infection under the foreskin.2,4,15,16 
Testing for HPV
The laboratory methods used to detect HPV seem to influence findings regarding pathogenesis of penile carcinoma. For example, Levi et al17 found that tissues that were frozen rather than paraffin embedded were more likely to yield positive results for the presence of HPV.17 
Testing for HPV DNA can be done by using in situ hybridization, hybrid capture (which identifies high- and low-risk groups but not HPV type), and, most commonly, polymerase chain reaction (PCR). In one study,18 in situ hybridization failed to reveal the presence of HPV in 2 tissue samples, but both were positive when tested with PCR, one for HPV-18 and the other for HPV-16. Even when PCR is used, however, results may vary depending on whether 1 or 2 sets of consensus primers were used (a primer is a short piece of genetic material that acts as the point from which replication proceeds). Pascual et al13 found that the HPV-positive rate was 60.9% for primer MY09/11 alone, 37.5% for primer GP5+/GP6+ alone, and 71.9% for both sets of primers in the same tissue samples. 
Methods used to demonstrate penile lesions are also not standardized. Some investigators use saline-soaked swabs to collect cells from various sites on male genitalia; others use sandpaper or emery boards to scrape cells.19 In another method, acetic acid solution is applied to the genital area for 3 minutes, followed by direct visualization with magnification to detect epithelial abnormalities; this practice, however, may increase the number of unnecessary biopsies, because both minor abrasions and areas of inflammation tend to react by turning white.19,20 One investigation comparing specimens obtained by clinicians with those collected by the patients themselves found a greater yield of usable cells in self-collected specimens.21 
Pathophysiology
Some investigators have attempted to correlate seropositivity to oncogenic HPV with the presence of penile lesions.22 However, this correlation is problematic because antibodies do not develop in all men with HPV infection, and some men may be tested while an immune response to HPV is still developing. By contrast, a seropositive man may not be diagnosed if lesions are no longer visible and he is therefore not tested.22 
Of more than 100 types of HPV that have been discovered, nearly 40 affect the anogenital region and cause nearly 6 million new cases of infection annually.23 The oncogenic (high-risk) types, causing the highest percentages of penile carcinoma, are HPV-16 and HPV-18, whereas most genital warts are caused by the low-risk HPV-6 and HPV-11.1 Most HPV infections are asymptomatic and resolve within 2 years.24,25 
The mechanisms by which HPV initiates neoplasia of penile epithelial cells have become more clear with ongoing research. Human papillomaviruses are double-stranded DNA viruses that can cause persistent infection only if the virus is successfully incorporated into the replication structure of the host epithelial cells and if the host defenses are compromised in some way, preventing clearance of infected cells by apoptosis.26 Healthy cells contain a tumor suppression protein, p53, which serves to eliminate cells with aberrant growth tendencies. High-risk HPVs stimulate E6 and E7 oncoproteins to combine with p53, allowing the virus to overcome this regulatory mechanism.27 This process alone has not proved sufficient to cause neoplasia, but the degradation process may be augmented by other factors, such as altered host immune status, chronic infection or inflammation (eg, caused by the presence of smegma), or smoking.28 As a result, viral DNA is replicated, with virions assembled in infected epithelial cells of the penis—cells that normally would have stopped proliferating and been sloughed off. Note that this “immortalization” property does not take place in the low-risk HPV types29; however, low-risk types are still associated with the formation of penile cancer, perhaps by other mechanisms.30 
Evolution of HPV Research
Backes et al28 performed a comprehensive review of 30 studies from around the world on the prevalence of HPV in cases of invasive penile carcinoma. The studies encompassed 1266 cases of SCC of the penis. The prevalence of HPV was broken down by SCC subtype and was 47.9% for all subtypes, 22.4% for verrucous SCC, and 66.3% for basaloid or warty SCC. HPV-16 was consistently found to be the most common type detected in North America, Europe, and most of South America, whereas HPV-6 was most prevalent in Asia (but only 0.6% more prevalent than HPV-16).28 In Argentina, unlike the rest of South America, HPV-18 was most prevalent.31 These variations point to a possible interaction between genetic and geographic contributions to HPV subtype prevalence in certain regions. 
The theory that penile and cervical cancer may have a common etiology was proposed as early as 35 years ago. Some of the initial studies supported a causal relationship between male sexual behaviors and the incidence of cervical carcinoma before the role of HPV was even recognized. For the present review, the university librarian performed an initial electronic search for HPV, penile carcinoma, and cervical carcinoma. A second search was based on references from the initial set of articles. The following is a chronologic summary of major influential studies since the mid-1970s that were identified in the searches. These studies gradually confirmed the carcinogenic impact of HPV infection transmission from men to their female sex partners. 
Cervical cancer and social class (1976; United Kingdom)—Singer et al32 hypothesized a correlation between the incidence of cervical cancer in wives and their husbands' occupations, suggesting that “behavioral and sociological attributes... such as occupation, premature widowhood and perhaps sexual promiscuity” may influence sperm histones by contributing to variation in basic proteins within the sperm head. Findings from this study indicated that sperm proteins are probably associated with social class similarly to the way that sexually transmitted disease and resultant cancer in situ are correlated with social class. 
Increased cervical carcinoma in wives of men with penile carcinoma (1979; United States)—This study by Graham et al33 mirrored that by Singer et al32 in the United Kingdom. Women in New York married to men with penile carcinoma were followed up retrospectively from 1958 to 1964. The authors' findings revealed triple the expected number of cases of cervical carcinoma, whereas other forms of cancer were not more prevalent than expected. Although race was a potential confounder, most people living in New York were white. Because this was a retrospective study performed by examining tumor registries, information regarding number of sex partners, socioeconomic status, and age at first intercourse could not be determined. 
Cancer in spouses (1980; United Kingdom)—Smith et al34 studied 711 widows of men who had died of penile cancer, following them up for as long as 11 years. During this period, 378 women died, close to the expected number of deaths (366.8). However, more women died of cancer—specifically cervical cancer—than was expected (all cancer, 89 compared with 76.5 expected; cervical cancer, 11 compared with 3.9 expected). These findings supported the possibility that wives of men with penile cancer could be at increased risk of cervical cancer. 
Cervical intraepithelial neoplasia due to venereal infection (1981; United Kingdom)—Buckley et al35 studied husbands of women who had confirmed cervical dysplasia, cervical intraepithelial neoplasia (CIN), or SCC of the cervix. These women had had sex only with their husbands, who had sex at an earlier age, had more sex partners, and were more likely to be smokers than husbands of women in the control group (ie, women with normal cervical cytologic findings). Despite their inability to identify the infectious agent, the authors concluded that “men can contract and transmit to their wives a sexually transmitted infection which increases the risk of premalignant and malignant change in their cervical epithelium.” 
Cervical cancer and male sexual behavior (1982; United Kingdom)—Skegg et al36 hypothesized about the impact of male sexual behavior on women with increased prevalence of cervical cancer, such as number of sex partners, especially prostitutes, and whether men's occupations involved extended travel with absence from the home. The suggestion that cancer of the cervix may be caused by a virus was supported by citations from Fraumeni et al,37 which showed a much lower frequency of cervical cancer among nuns, and from a study of prostitutes by Keighley,38 which revealed greater numbers of cervical dysplasia in women who admitted to prostitution. 
Cervical neoplasia and male condylomas (1984; United States and Canada)—In a study by Levine et al,39 34 male sex partners of women with cervical condylomas or CIN were checked for visible lesions, with external lesions noted in 18 men (53%). In most pairs, the histologic grade of lesions in one partner did not correlate well with that in the other partner. Koilocytosis of cells, often seen in conjunction with HPV infection, was seen in urine sediment only in men whose condylomas were visualized at the distal urethra. 
Men with condylomas and cervical dysplasia (1985; United Kingdom)—Campion et al40 studied 25 women who had been sexually intimate for at least 12 months with men known to have condylomata acuminata. All of the men had lesions unresponsive to conservative treatment, and cultures demonstrated either single or mixed infection with HPV-16, -11, or -6. Nineteen of the 25 women were found to have condylomata acuminata; 9 had abnormal Papanicolaou test results, of whom 7 were positive for HPV (HPV-16 in 6, HPV-6 in 1). The authors suggested that history of HPV infection in a male partner places a woman at greater risk for cervical dysplasia than does her sexual behavior. 
Cervical SCC and spousal sexual history (1986; United States)—In a study by Zunzunegui et al41 in the San Francisco, California, Bay Area, 44 women with cervical SCC were matched with controls of similar age obtaining medical care at the same institution. All participants were low-income married Hispanic women. Case patients were 5.3 times more likely than controls to be married to husbands who had had 20 or more sex partners and had also been younger than most controls at the time of their first sexual encounter. Case husbands were more likely than control husbands to be smokers and to have frequented prostitutes. If the husband had had 20 or more sex partners, the wife's risk for developing cervical SCC was 5 times greater than that in women whose husbands had had fewer than 20 sex partners. 
Determining “high-risk” HPV types (1986; United Kingdom and Brazil)—McCance et al42 tested for HPV in penile amputation specimens and cervical material obtained at hysterectomy from women with cervical carcinoma. Of 53 penile tissue samples, 26 were positive for HPV-16 and 5 for HPV-18. Eight of 19 women with cervical carcinoma had HPV-16, and none had HPV-18. At this early phase of research into the sexually transmitted nature of HPV, no attempt was made to test spouses of either the men or the women from whom samples were obtained. 
HPV typing among sex partners (1987; United States and West Germany)—Schneider et al43 tested women with cervical dysplasia for the presence of HPV. Samples were positive for HPV DNA in 80 of 115 women (70%) from the United States and 185 of 201 women (92%) from West Germany. The study also investigated the male partners of 40 of these women, harvesting penile epithelial cells that were positive for HPV in 26 men. In 19 of these men, the HPV type was identical to that found in the female partner. The authors documented that 13 of the women with CIN grade I or II from HPV did eventually show regression of the lesions, supporting the theory that HPV infections can be self-eliminated by individuals with healthy immune statuses. 
Colposcopic findings in male sex partners of women with CIN (1987; France)—In a study by Barrasso et al,44 colposcopic examination of the genitalia of male sex partners of 480 women with either cervical condyloma (n=294) or CIN (n=186) was performed both before and after application of 5% acetic acid solution. Of 480 men studied, 309 (64.4%) had lesions, of which 105 (22%) were classified as condylomata acuminata by clinical appearance and 204 (42.5%) were seen only after acetic acid exposure. Further study of these lesions revealed penile intraepithelial neoplasia in 61 partners of the 186 women with CIN (32.8%). Two types of HPV—16 and 33—were found almost exclusively in dysplastic lesions in both partners. 
Cervical cancer risk in monogamous women (1989; Panama, Costa Rica, Colombia, and Mexico)—This large case-control study in 4 Latin American countries, conducted by Brinton et al,45 focused on the husbands of monogamous women who had cervical cancer and who had reportedly had 1 lifetime sex partner, thus removing the risk of any sexual transmission from prior sex partners. For the women, 304 of 759 cases (40%) and 776 of 1467 controls (53%) met the criterion of having had only 1 sex partner. The risk of cervical cancer in a wife increased significantly with the number of sex partners reported by her husband. Low educational status was found to be an additional predictor of risk. In this study, HPV was found in approximately 20% of study participants and was not statistically related to the risk of cervical cancer. 
Lack of association of penile and cervical cancer in partners (1989; Sweden)—In a study by Hellberg and Nilsson,46 the wives of men with penile cancer were followed up from 1958 to 1980 and were matched with women of similar age and marital status. The incidence of genital cancer, including cervical cancer, was within the expected range and was distributed equally among study and control groups. This study did not support an association between penile cancer in men and cervical cancer in their partners. 
Condyloma in a male partner as predictor of cervical cancer risk (1991; Denmark)—Of 645 women with carcinoma in situ or invasive cervical cancer studied by Kjaer et al,47 26 had been sexually intimate with only 1 man; 22 of them, along with 59 controls, participated in the study with their partners. There was a 5-fold relative risk of the woman having cervical cancer if her partner had ever (vs never) visited a prostitute. A history of genital warts in the male partner was the most important predictor of risk of cervical cancer in the female partner (relative risk, 17.9). Tests showed HPV in none of the male controls and in only 2 of 22 men in the study group, with 1 man positive for HPV-6/11 and the other for HPV-16/18. These findings do not support those of other studies previously mentioned that indicated HPV infection was a cause of cervical cancer. 
Use of acetic acid washes to study HPV lesions (1992; United States)—In a study by Bergman and Nalick,48 men were evaluated for the presence of HPV-associated lesions of the genitalia if they reported a minimum of 6 months of sexual contact with women who had known HPV genital infection. They were matched with men of similar age in sexual relationships with women having no known HPV infection. In the former (high-risk) group, 78 of 113 (69%) were found to have HPV lesions, vs 2 of 94 (2%) in the control group. The findings of this study supported the use of acetic acid washes in conjunction with colposcopy to diagnose HPV lesions. Fewer than 1% (2 of 207) of all men in this study had clinical appearance of HPV lesions at colposcopy that were not proven to be positive at biopsy. The value of colposcopy was supported in this study because 47 of 80 men with genital HPV lesions had subclinical disease or lesions seen only with colposcopy. 
Sexual activity of men and cervical dysplasia in wives (1993; India)—Agarwal et al49 conducted a study from 1976 to 1987. The objective was to investigate the role of sexual activity of men married to monogamous women with persistent cervical dysplasia. The combined risk of persistent cervical disease for women in the study group was nearly 7 times that in the control group, with an even greater risk if the man had a history of sexually transmitted disease before marriage or if he was not circumcised. 
HPV types in sex partners for HPV detection (1994; Finland)—Hippeläinen et al50 investigated the prevalence of identical HPV types in women with abnormal Papanicolaou test results and in their male sex partners. Of 270 men enrolled, 193 (71%) were found to have HPV infection. Of 66 couples in which both partners tested positive for HPV, only 15 men (22.7%) were found to harbor the same HPV type as their female partner. Of women with stage III CIN, 24 of 25 (96%) were positive for HPV, with HPV-16 and HPV-18 as the most frequently occurring types. 
This study also compared detection of HPV with in situ hybridization and with PCR and found PCR to have the highest yield of positive results. 
Prevalence of HPV-16 in sex partners (1994; Japan)—Kyo et al51 investigated the possible sexual transmission of HPV within married couples. Cervical cells and semen were collected and tested for HPV with PCR. Among 53 couples, 23 women and 12 men were positive for HPV-16. In 27 couples, both partners were negative for HPV. In 9 of the remaining 26 pairs (35%), both partners were positive for HPV-16. The prevalence of HPV-16 DNA was 37% in women with normal cervical cytologic findings, 60% in women with CIN, and 100% in those with cervical cancer. 
Testing HPV subtypes in sex partners (1995; Sweden)—Strand et al52 tested 25 women younger than 31 years with distinct vaginal or cervical lesions for HPV. For 18 of 25 HPV-positive women, their male sex partner also tested positive for HPV. Eight couples (32%) harbored the same HPV type. Only 3 of the 25 men (12%) were aware of any genital lesions, but peniscopy after acetic acid washes revealed clinical lesions suggestive of HPV lesions in 20 men (80%). These findings supported the theory that men capable of transmitting high-risk HPV were younger than 40 years and were unaware of harboring the viruses. The study also theorized that discordant HPV types can be found in couples secondary to transient viral shedding or from delayed reactivation of varying HPV types obtained from earlier relationships. 
Comparing HPV prevalence with dot filter hybridization and PCR (1995; United States)—Baken et al53 tested 50 couples for various sexually transmitted diseases at a clinic in Washington state. Out of 100 participants (50 of each gender), 10 were found to have gonorrhea, 6 chlamydia, and 9 herpes simplex virus. A history of genital warts was reported by 20 men, and 24 women had a history of condyloma. Samples were collected for testing by both dot filter hybridization and PCR. Only 9 women (18%) and 2 men (4%) were HPV positive by filter hybridization, compared with 36 women (72%) and 30 of 48 men (63%) for PCR (2 male specimens were insufficient to test). Results showed that in couples with both male and female testing positive for HPV, the same type was present in each partner in 13 of 20 couples (65%). 
Male sexual activity and cervical cancer in sex partners (1996; Colombia)—Muñoz et al54 attempted to link male sexual behaviors and history of HPV with cervical cancer in female partners. A total of 210 husbands of women with CIN III or invasive cervical SCC were matched with 262 husbands of control women. Human papillomavirus was found in scraped cells from the glans penis in 28 of 109 case husbands (25.7%) but was also found in 25 of 132 husbands (18.9%) in the control group (note that 101 case husbands and 130 control husbands were omitted from analysis due to inability to type their HPV DNA). The use of prostitutes as sex partners and an increased number of lifetime sex partners were male-related factors associated with an increased risk of cervical cancer among women in the study group. In men whose wives had CIN, seropositivity to Chlamydia trachomatis (45 of 157 [29%]) and lack of schooling after age 10 years (75 of 210 [36%]) were greater risk factors for development of cervical cancer in their wives than the presence of HPV (28 of 109 [26%]). 
Prostitutes as potential sources of high-risk HPV (1996; Spain)—Bosch et al55 evaluated the relationship between the prevalence of cervical cancer in women and their husbands' numbers of sexual encounters outside the marriage. They concluded that men who had had multiple sex partners (especially if these partners were prostitutes) or who were found to be carriers of high-risk HPV types may place their wives at greater risk of cervical cancer, with this risk escalating 6- to 9-fold if HPV-16 was isolated. Their results also suggested that younger men may be more likely to be HPV carriers; it is uncertain whether that difference reflects decreased sexual activity or clearance of the virus with age. 
Geographic distribution of HPV (1997; Spain and Colombia)—Castellsagué et al56 chose Colombia and Spain for a comparative study, because women living in Colombia have a high risk of cervical cancer and those living in Spain have a low risk. The study included 816 husbands of women enrolled in 4 case-controlled studies of cervical neoplasia conducted during a 20-month period. The prevalence of HPV DNA was found to be 5-fold higher in husbands of controls in Colombia than in husbands of controls in Spain. In Spain, results were positive in 32 of 183 husbands of case patients (17.5%) vs 6 of 171 husbands of controls (3.5%); the difference between case and control groups was much less in Colombia, with positive HPV results in 28 of 109 case husbands (25.7%) and 25 of 132 control husbands (18.9%). In 27 couples (25 case and 2 control couples), both members tested positive for HPV. After exclusion of those in whom HPV could not be typed, 7 couples were found to be concordant for HPV-16. 
Potential for self-elimination of HPV (2001; United States and Thailand)—Thomas et al57 investigated the presence of oncogenic HPV among women with cervical cancer and interviewed their husbands and control husbands regarding past sexual history. The interview was followed by analysis of cell samples from all male participants willing to undergo testing. Penile cells were scraped from 57 husbands of women with in situ or invasive cervical cancer and from 68 husbands of women in the control group. Only 8 of 125 men tested positive for high-risk HPV, and prevalence was not significantly higher for the study group than for the control group. Because most women with cervical cancer were monogamous yet harboring oncogenic HPV, it was theorized that men infected their wives early in the marriage and then were cleared of the virus by self-elimination. 
In conjunction with this study, the authors also concluded that “commercial sex workers in Bangkok were likely reservoirs of oncogenic HPV” and that monogamous Thai women may have obtained the virus as a result of their husbands' visits with prostitutes. 
Use of peniscopy to collect scrapings for HPV testing (2002; The Netherlands)—Bleeker et al58 investigated the presence of penile lesions and HPV in penile epithelial cells in male sex partners of women with CIN. Penile scrapings from 175 men were screened for HPV by means of acetic acid washes followed by peniscopy, with 14 men excluded because of phimosis or history of prior surgery. Lesions were visually identified in 110 of 161 men (68%) and included flat lesions (76 of 110 [69%]), papular lesions (15 of 110 [14%]), and condylomata acuminata (3 of 110 [3%]), with mixed lesions in some men. In 59 men, HPV was detected in the penile scrapings, even in some men with no visible lesions at peniscopy. Among men with lesions noted by peniscopy, 58 out of 70 scrapings (83%) were HPV positive. 
Bleeker et al59 later studied regression of penile lesions in male sex partners of women with CIN. They found that use of condoms promoted faster regression of flat lesions but not of papular lesions, and they concluded that this finding was probably due to reduced viral transmission between sex partners. 
Husbands of women with cervical cancer (2002; Spain, Colombia, Brazil, Thailand, Philippines)—Franceschi et al60 conducted a multinational study from 1985 to 1993 comparing husbands of women with invasive cervical carcinoma or in situ cervical cancer and husbands of control women. Women who participated in the study were aged 19 to 82 years. Ninety-three of 717 (13%) husbands of controls, 80 of 445 (18%) husbands of women with invasive cervical carcinoma, and 35 of 165 (21%) husbands of women with in situ cervical cancer were positive for penile HPV, with HPV-16 the most prevalent type. The same HPV type was seldom found in both husband and wife. The percentage of HPV-positive men varied widely, ranging from 3% in Spain to 39% in Brazil. 
Sites of highest HPV content in affected men (2005; Brazil)—The goals of this study by Nicolau et al61 were to determine the prevalence of HPV in male partners of HPV-infected women, review the identity of the virus in each member, determine which sites are most often infected in male partners, and compare methods of detection. Six different anogenital areas on each man had cells brushed for cytologic study followed by biopsy of lesions under peniscopy a week later. At least 1 sample brushing was HPV DNA positive in 35 of 50 men (70%), with high-risk HPV DNA in 16 of 50 (32%), low-risk HPV in 7 of 50 (14%), and coinfection with both in 12 of 50 (24%). By site, HPV detection rates were as follows: inner prepuce, 44%; distal urethra, 30%; glans, 24%; outer prepuce, 24%; scrotum, 12%; and anus, 8%. Histologic examination of biopsy tissue was compared to second-generation hybrid capture testing, with the latter method yielding a higher percentage of HPV positivity. (Note, however, that this study was partially funded by the Digene Corporation, which produces hybrid capture testing equipment.) 
HPV type concordance in sexual partners (2005; The Netherlands)—Bleeker et al62 studied HPV infection between 238 women with cervical dyskaryosis and their male sex partners, testing them for HPV type and HPV type concordance as couples. A total of 213 of 237 women (89.9%) and 132 of 181 men (72.9%) were HPV positive; of the HPV-positive couples, 67 of 116 (57.8%) men had the same HPV type as their partners. The viral loads found in penile scraped cells and cervical cells were increased in couples with HPV type concordance. 
Urine sampling for HPV (2006; India)—Gupta et al63 matched 30 women with invasive cervical cancer and their lifelong male sex partners with similar-age controls. With PCR testing, HPV was found in 25 of 30 women (83%) in the study group and 8 of 30 women (27%) in the control group. Of the 30 male partners in the study group, 20 (67%) were positive for HPV using urine sampling in addition to scraped penile cells. 
An additional objective of this study was to investigate the accuracy of urine sampling for the presence of HPV; this method revealed HPV in 23 of 28 women (82%) in the study group, compared with 25 of 30 (83%) for PCR (2 urine samples were inadequate for testing). Although the prevalence of HPV was only 67% in the male study group, there was a 100% concordance of HPV results between PCR of scraped penile cells and urine sampling. 
Treatment and Prognosis
Treatment of patients with penile cancer caused by HPV can range from local excision to radiotherapy to penectomy, depending on the stage of cancer at the time of presentation. The presence of HPV infection at the time of diagnosis does not appear to be correlated with prognosis.64 Unfortunately, because patients are either not aware of lesions or reluctant to see a healthcare provider, it is estimated that at least 50% of them have lesions present for more than 6 months before treatment is initiated.65 If lesions are left untreated, lymphatic spread may occur to the superficial or deep inguinal nodes and then to pelvic nodes. It is rare, however, for even locally advanced tumors to metastasize. Survival rates are related to histologic type of penile cancer and degree of lymph node involvement; patients with verrucous carcinoma have excellent survival rates with surgery alone while SCC often necessitates radiotherapy in addition to surgery.66 Studies on the use of chemotherapy in conjunction with radiotherapy are ongoing.67 
Conclusion
It has been estimated that the 2004 direct medical costs associated with HPV infection and treatment approached $4 billion in the United States.68 To contain costs, efforts must be aimed at reducing risk factors through education and, ideally, vaccination. The most common factors associated with the presence of high-risk HPV in men include lack of circumcision, younger age, more lifetime sex partners, higher frequency of intercourse (especially with prostitutes), and history of intercourse without condoms. The degree of genital hygiene, level of education, and smoking status in both male and female partners may also have a role in HPV transmission and survival. 
The introductory studies of the quadrivalent HPV vaccine indicate high efficacy against infection with HPV-6, -11, -16, and -18, but vaccination of boys does not currently appear to be cost-effective.69 Unfortunately, there is a risk that nonmandatory vaccinations of adolescents would not result in enough protected individuals to promote herd immunity.70 Costs could be contained somewhat by vaccinating males in higher-risk groups only. One potential screening tool involves testing of oral cavity cells. Results indicate that if oral HPV antibodies are found, it is likely the participant has already become sexually active and will not derive as much benefit from the vaccine as those who test negative for oral HPV antibodies.71 Ongoing research is needed to determine the most appropriate subsets of males for eventual vaccination. 
 Financial Disclosure: The author has no conflicts of interest or financial disclosure relevant to the review topic.
 
 This supplement is supported by an independent educational grant from Merck & Co, Inc.
 
I thank Ellen Bergerson, MLIS, at Des Moines University in Iowa for her expertise in researching current and past published works in this area, and Sally Wallin for her extreme efficiency in helping to prepare this document. 
Bosch FX, de Sanjosé S. Human papillomavirus and cervical cancer-burden and assessment of causality. J Natl Cancer Inst. 2003;31:3-13.
Daling JR, Madeleine MM, Johnson LG, et al. Penile cancer: importance of circumcision, human papillomavirus and smoking in in situ and invasive disease. Int J Cancer. 2005;116(4):606-616.
Castellsagué X, Bosch FX, Muñoz N, et al. Male circumcision, penile human papillomavirus infection, and cervical cancer in female partners. N Engl J Med. 2002;346(15):1105-1112.
Maden C, Sherman KJ, Beckmann AM, et al. History of circumcision, medical conditions, and sexual activity and risk of penile cancer. J Natl Cancer Inst. 1993;85(1):19-24.
Holly EA, Palefsky JM. Factors related to risk of penile cancer: new evidence from a study in the Pacific Northwest. J Natl Cancer Inst. 1993;85(1):2-4.
Micali G, Innocenzi D, Nasca MR, Musumeci ML, Ferraú F, Greco M. Squamous cell carcinoma of the penis. J Am Acad Dermatol. 1996;35(3 pt 1): 432-451.
Ikenberg H, Gissmann L, Gross G, Grussendorf-Conen EI, zur Hausen H. Human papillomavirus type 16-related DNA in genital Bowen's disease and in bowenoid papulosis. Int J Cancer. 1983;32(5):563-565.
Callen JP. Possible precursors to epidermal malignancies. In: Friedman RJ, Rigel DS, Kopf AW, et al, eds. Cancer of the Skin. Philadelphia, PA: WB Saunder; 1991:27-34.
Burgers JK, Badalament RA, Drago JR. Penile cancer: clinical presentation, diagnosis, and staging. Urol Clin North Am. 1992;19(2):247-256.
Higgins GD, Uzelin DM, Phillips GE, Villa LL, Burrell CJ. Differing prevalence of human papillomavirus RNA in penile dysplasias and carcinomas may reflect differing etiologies. Am J Clin Pathol. 1992;97(2):272-278.
Gross G, Pfister H. Role of human papillomavirus in penile cancer, penile intraepithelial squamous cell neoplasias and in genital warts. Med Microbiol Immunol. 2004;193(1):35-44.
Rubin MA, Kleter B, Zhou M, Ayala G, Cubilla AL, Quint WGV, et al. Detection and typing of human papillomavirus DNA in penile carcinoma: evidence for multiple independent pathways of penile carcinogenesis. Am J Pathol. 2001;159(4):1211-1218.
Pascual A, Pariente M, Godínez JM, Sánchez-Prieto R, Atienzar M, Segura M, et al. High prevalence of human papillomavirus 16 in penile carcinoma. Histol Histopathol. 2007;22(2):177-183.
Parkin DM. The global health burden of infection-associated cancers in the year 2002. Int J Cancer. 2006;118(12):3030-3044.
Dillner J, von Krogh G, Horenblas S, Meijer CJLM. Etiology of squamous cell carcinoma of the penis. Scand J Urol Nephrol Suppl. 2000;(205):189-193.
Tseng HF, Morgenstern H, Mack T, Peters RK. Risk factors for penile cancer: results of a population-based case-control study in Los Angeles County. Cancer Causes Control. 2001;12(3):267-277.
Levi JE, Rahal P, Sarkis AS, Villa LL. Human papillomavirus DNA and p53 status in penile carcinomas. Int J Cancer. 1998;76(6):779-783.
Poblet E, Pascual A, Godínez JM, Pariente-Martín M, Escario E, García-Olmo DC. Human papillomavirus-associated penile sarcomatoid carcinoma. J Cutan Pathol. 2008;35(6):559-65.
Palefsky JM. HPV infection in men. Dis Markers. 2007;23(4):261-272.
Giraldo PC, Eleutério J, Cavalcante DIM, Goncalves AK, Romão JAA, Eleutério RMN. The role of high-risk HPV-DNA testing in the male sexual partners of women with HPV-induced lesions. Eur J Obstet Gynaecol Reprod Biol. 2008;137(1):88-91.
Hernandez BY, McDuffie K, Goodman MT, et al. Comparison of physician- and self-collected genital specimens for detection of human papillomavirus in men. J Clin Microbiol. 2006;44(2):513-517.
Dunne EF, Nielson CM, Stone KM, Markowitz LE, Giuliano AR. Prevalence of HPV infection among men: a systematic review of the literature. J Infect Dis. 2006;194(8):1044-1057.
Weinstock H, Berman S, Cates W. Sexually transmitted diseases among American youth: incidence and prevalence estimates, 2000. Perspect Sex Reprod Health. 2004;36(1):6-10.
Hagensee ME. Infection with human papillomavirus: update on epidemiology, diagnosis and treatment. Curr Infect Dis Rep. 2000;2(1):18-24.
Schiffman M, Kjaer SK. Natural history of anogenital human papillomavirus infection and neoplasia. J Natl Cancer Inst Monogr. 2003;31:14-19.
zur Hausen H. Immortalization of human cells and their malignant conversion by high risk human papillomavirus genotypes. Semin Cancer Biol. 1999;9(6):405-411.
Duensing S, Münger K. Mechanisms of genomic instability in human cancer: insights from studies with human papillomavirus oncoproteins. Int J Cancer. 2004;109(2):157-162.
Backes DM, Kurman RJ, Pimenta JM, Smith JS. Systematic review of human papillomavirus prevalence in invasive penile cancer. Cancer Causes Control. 2009;20(4):449-457.
Münger K, Howley PM. Human papillomavirus immortalization and transformation functions. Virus Res. 2002;89(2):213-228.
Dorfman S, Cavazza M, Cardozo J. Penile cancer associated with so-called low-risk human papillomavirus: report of five cases from rural Venezuela. Trop Doct. 2006;36(4):232-233.
Picconi MA, Eiján AM, Distéfano AL, et al. Human papillomavirus (HPV) DNA in penile carcinomas in Argentina: analysis of primary tumors and lymph nodes. J Med Virol. 2000;61(1):65-69.
Singer A, Reid BL, Coppleson M. A hypothesis: the role of a high-risk male in the etiology of cervical carcinoma: a correlation of epidemiology and molecular biology. Am J Obstet Gynecol. 1976;126 (1): 110-115.
Graham S, Priore R, Graham M, Browne R, Burnett W, West D. Genital cancer in wives of penile cancer patients. Cancer. 1979;44(5):1870-1874.
Smith PG, Kinlen LJ, White GC, Adelstein AM, Fox AJ. Mortality of wives of men dying with cancer of the penis. Br J Cancer. 1980;41(3):422-428.
Buckley JD, Harris RWC, Doll R, Vessey MP, Williams PT. Case-control study of the husbands of women with dysplasia or carcinoma of the cervix uteri. Lancet. 1981;2(8254):1010-1014.
Skegg DCG, Corwin PA, Paul C, Doll R. Importance of the male factor in cancer of the cervix. Lancet. 1982;2(8298):581-583.
Fraumeni JF, Lloyd JW, Smith EM, Wagoner JK. Cancer mortality among nuns: role of marital status in etiology of neoplastic disease in women. J Natl Cancer Inst. 1969;42(3):455-468.
Keighley E. Carcinoma of the cervix among prostitutes in a women's prison. Br J Vener Dis. 1968;44(3):254-255.
Levine RU, Crum CP, Herman E, Silvers D, Ferenczy A, Richart RM. Cervical papillomavirus infection and intraepithelial neoplasia: a study of male sexual partners. Obstet Gynecol. 1984;64(1):16-20.
Campion MJ, Singer A, Clarkson PK, McCance DJ. Increased risk of cervical neoplasia in consorts of men with penile condylomata acuminata. Lancet. 1985;1(8435):943-946.
Zunzunegui MV, King MC, Coria CF, Charlet J. Male influences on cervical cancer risk. Am J Epidemiol. 1986;123(2):302-307.
McCance DJ, Kalache A, Ashdown K, et al. Human papillomavirus types 16 and 18 in carcinomas of the penis from Brazil. Int J Cancer. 1986;37 (1):55-59.
Schneider A, Sawada E, Gissmann L, Shah K. Human papillomaviruses in women with a history of abnormal Papanicolaou smears and in their male partners. Obstet Gynecol. 1987;69(4):554-562.
Barrasso R, De Brux J, Croissant O, Orth G. High prevalence of papillomavirus-associated penile intraepithelial neoplasia in sexual partners of women with cervical intraepithelial neoplasia. N Engl J Med. 1987;317(15):916-923.
Brinton LA, Reeves WC, Brenes MM, et al. The male factor in the etiology of cervical cancer among sexually monogamous women. Int J Cancer. 1989;44 (2):199-203.
Hellberg D, Nilsson S. Genital cancer among wives of men with penile cancer: a study between 1958 and 1982. Br J Obstet Gynaecol. 1989;96(2):221-225.
Kjaer SK, de Villiers EM, Dahl C, et al. Case-control study of risk factors for cervical neoplasia in Denmark: role of the “male factor” in women with one lifetime sexual partner. Int J Cancer. 1991;48(1):39-44.
Bergman A, Nalick R. Prevalence of human papillomavirus infection in men: comparison of the partners of infected and uninfected women. J Reprod Med. 1992;37(8):710-712.
Agarwal SS, Sehgal A, Sardana S, Kumar A, Luthra UK. Role of male behavior in cervical carcinogenesis among women with one lifetime sexual partner. Cancer. 1993;72(5):1666-1669.
Hippeläinen MI, Yliskoski M, Syrjänen S, et al. Low concordance of genital human papillomavirus (HPV) lesions and viral types in HPV-infected women and their male sexual partners. Sex Trans Dis. 1994;21(2):76-82.
Kyo S, Inoue M, Koyama M, Fujita M, Tanizawa O, Hakura A. Detection of high-risk human papillomavirus in the cervix and semen of sex partners. J Infect Dis. 1994;170(3):682-685.
Strand A, Rylander E, Wilander E, Zehbe I. HPV infection in male partners of women with squamous intraepithelial neoplasia and/or high-risk HPV. Acta Derm Venereol. 1995;75(4):312-316.
Baken LA, Koutsky LA, Kuypers J, et al. Genital human papillomavirus infection among male and female sex partners: prevalence and type-specific concordance. J Infect Dis. 1995;171(2):429-432.
Muñoz N, Castellsagué X, Bosch FX, et al. Difficulty in elucidating the male role in cervical cancer in Colombia, a high-risk area for the disease. J Natl Cancer Inst. 1996;88(15):1068-1075.
Bosch FX, Castellsagué X, Muñoz N, et al. Male sexual behavior and human papillomavirus DNA: key risk factors for cervical cancer in Spain. J Natl Cancer Inst. 1996;88(15):1060-1067.
Castellsagué X, Ghaffari A, Daniel RW, Bosch FX, Muñoz N, Shah KV. Prevalence of penile human papillomavirus DNA in husbands of women with and without cervical neoplasia: a study in Spain and Colombia. J Infect Dis. 1997;176(2):353-361.
Thomas DB, Ray RM, Kuypers J, et al. Human papillomaviruses and cervical cancer in Bangkok: the role of husbands and commercial sex workers. Am J Epidemiol. 2001;153(8):740-748.
Bleeker MCG, Hogewoning CJA, van den Brule AJC, et al. Penile lesions and human papillomavirus in male sexual partners of women with cervical intraepithelial neoplasia. J Am Acad Dermatol. 2002;47(3):351-357.
Bleeker MCG, Hogewoning CJA, Voorhorst FJ, et al. Condom use promotes regression of human papillomavirus-associated penile lesions in male sexual partners of women with cervical intraepithelial neoplasia. Int J Cancer. 2003;107(5):804-810.
Franceschi S, Castellsagué X, Dal Maso L, et al. Prevalence and determinants of human papillomavirus genital infection in men. Br J Cancer. 2002;86 (5):705-711.
Nicolau SM, Camargo CGC, Stávale JN, et al. Human papillomavirus DNA detection in male sexual partners of women with genital human papillomavirus infection. Urology. 2005;65(2):251-255.
Bleeker MCG, Hogewoning CJA, Berkhof J, et al. Concordance of specific human papillomavirus types in sex partners is more prevalent than would be expected by chance and is associated with increased viral loads. Clin Infect Dis. 2005;41(5):612-620.
Gupta A, Arora R, Gupta S, et al. Human papillomavirus DNA in urine samples of women with or without cervical cancer and their male partners compared with simultaneously collected cervical/penile smear or biopsy specimens. J Clin Virol. 2006;37(3):190-194.
Bezerra ALR, Lopes A, Santiago GH, Ribeiro KC, Latorre MRDO, Villa LL. Human papillomavirus as a prognostic factor in carcinoma of the penis: analysis of 82 patients treated with amputation and bilateral lymphadenectomy. Cancer. 2001;91 (12): 2315-2321.
Buddington WT, Kickham CJE, Smith WE. An assessment of malignant disease of the penis. J Urol. 1963;89:442-449.
Chen MF, Chen WC, Wu CT, Chuang CK, Ng KF, Chang JTC. Contemporary management of penile cancer including surgery and adjuvant radiotherapy: an experience in Taiwan. World J Urol. 2004;22(1):60-66.
Culkin DJ, Beer TM. Advanced penile carcinoma. J Urol. 2003;170(2 pt 1): 359-365.
Insinga RP, Dasbach EJ, Elbasha EH. Assessing the annual economic burden of preventing and treating anogenital human papillomavirus-related disease in the US: analytic framework and review of the literature. Pharmacoeconomics. 2005;23 (11):1107-1122.
Taira AV, Neukermans CP, Sanders GD. Evaluating human papillomavirus vaccination programs. Emerg Infect Dis. 2004;10(11):1915-1923.
Gillison ML, Chaturvedi AK, Lowy DR. HPV prophylactic vaccines and the potential prevention of noncervical cancers in both men and women. Cancer. 2008;113(10)(suppl):3036-3046.
Marais DJ, Sampson C, Jeftha A, et al. More men than women make mucosal IgA antibodies to human papillomavirus type 16 (HPV-16) and HPV-18: a study of oral HPV and oral HPV antibodies in a normal healthy population. BMC Infect Dis. 2006;6:95-104.