Human Papillomavirus Infection and the Links to Penile and Cervical Cancer

Roberta Wattleworth, DO, MHA, MPH

Human papillomavirus (HPV) infection has been thoroughly demonstrated as a major factor in the pathogenesis of cer - vical 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.

J Am Osteopath Assoc . 2011;111(3 suppl 2):S3-S10

he role of human papillomavirus mosis), poor genital hygiene, smoking, cinomas of the penis are categorized as T(HPV) in the degradation of cer - and other social factors, such as sexual basal cell, verrucous, or squamous cell, vical epithelial cells toward malignancy orientation and lifetime number of sex with squamous cell carcinoma (SCC) has been thoroughly documented; infec - partners. 2-5 accounting for at least 95% of all penile tion with oncogenic HPV is a consistent Malignant tumors of the penis can malignant tumors. 9 finding in more than 95% of patients be primary or secondary, arising from It has been hypothesized that penile with cervical cancer worldwide. 1 How - metastases. Subcategories of primary SCC may develop by means of 2 distinct ever, past infection with high-risk HPV tumors include soft-tissue, urethral, and etiologic pathways: (1) an HPV-medi - has not been as well established as a epithelial tumors, and rare tumors ated etiology, which probably involves necessary prerequisite for penile cancer. include melanomas, lymphomas, and sexual contact and affects men in their In addition to HPV exposure, epidemi - schwannomas. Epithelial tumors, fifth decade, and (2) a nonviral pathway ologic research has implicated other risk including those caused by HPV, are fur - related to risk factors already mentioned, factors in the development of penile ther broken down into in situ and inva - which leads to the development of penile cancer, including lack of circumcision sive carcinomas. 6 Of the 4 types of in situ SCC decades after exposure. 10-12 The inci - (compounded by formation of phi - carcinoma—Bowen disease, erythro - dence of HPV DNA found in penile car - plasia of Queyrat, bowenoid papulosis, cinoma tissue ranges from 15% to 78%, and extramammary Paget disease—the varying according to the population first 3 have been linked to HPV infection studied, the method of specimen collec - Financial Disclosure: The author has no conflicts of and may become invasive carcinomas if tion, and the laboratory method used for interest or financial disclosure relevant to the patients are left untreated. 7,8 Invasive car - detection. 13 review topic. Address correspondence to Roberta Wattle - worth, DO, MHA, MPH, Department of Family Medicine, Des Moines University, 3200 Grand Ave, Des Moines, IA 50312-4104. This supplement is supported by an independent educational grant from Merck & Co, Inc. E-mail: [email protected]

Wattleworth • Human Papillomavirus and the Links to Penile and Cervical Cancer JAOA • Supplement 2 • Vol 111 • No 3 • March 2011 • S3 Worldwide, cancer of the penis sec - tion to detect epithelial abnormalities; smoking. 28 As a result, viral DNA is repli - ondary to oncogenic HPV accounts for this practice, however, may increase the cated, with virions assembled in infected less than 0.1% of cancers in men, varying number of unnecessary biopsies, because epithelial cells of the penis—cells that according to the developmental status both minor abrasions and areas of inflam - normally would have stopped prolifer - of the country. 14 In Western countries, mation tend to react by turning white. 19,20 ating and been sloughed off. Note that where circumcision is routinely per - One investigation comparing specimens this “immortalization” property does not formed, the incidence is one-third that obtained by clinicians with those col - take place in the low-risk HPV types 29 ; in developing nations, where circumci - lected by the patients themselves found however, low-risk types are still associ - sion is less common. 4 Results of various a greater yield of usable cells in self-col - ated with the formation of penile cancer, studies are contradictory as to whether lected specimens. 21 perhaps by other mechanisms. 30 the effects of circumcision are explained by lack of running water and poor gen - Pathophysiology Evolution of HPV Research ital hygiene, inflammatory effect of accu - Some investigators have attempted to Backes et al 28 performed a comprehen - mulated smegma, microtrauma to the correlate seropositivity to oncogenic HPV sive review of 30 studies from around foreskin during intercourse, formation with the presence of penile lesions. 22 the world on the prevalence of HPV in of phimosis, or the harboring of HPV However, this correlation is problematic cases of invasive penile carcinoma. The infection under the foreskin. 2,4,15,16 because antibodies do not develop in all studies encompassed 1266 cases of SCC men with HPV infection, and some men of the penis. The prevalence of HPV was Testing for HPV may be tested while an immune response broken down by SCC subtype and was The laboratory methods used to detect to HPV is still developing. By contrast, a 47.9% for all subtypes, 22.4% for verru - HPV seem to influence findings seropositive man may not be diagnosed cous SCC, and 66.3% for basaloid or regarding pathogenesis of penile carci - if lesions are no longer visible and he is warty SCC. HPV-16 was consistently noma. For example, Levi et al 17 found therefore not tested. 22 found to be the most common type that tissues that were frozen rather than Of more than 100 types of HPV that detected in North America, Europe, and paraffin embedded were more likely to have been discovered, nearly 40 affect most of South America, whereas HPV-6 yield positive results for the presence of the anogenital region and cause nearly 6 was most prevalent in Asia (but only HPV. 17 million new cases of infection annually. 23 0.6% more prevalent than HPV-16). 28 In Testing for HPV DNA can be done The oncogenic (high-risk) types, causing Argentina, unlike the rest of South by using in situ hybridization, hybrid the highest percentages of penile carci - America, HPV-18 was most prevalent. 31 capture (which identifies high- and low- noma, are HPV-16 and HPV-18, whereas These variations point to a possible inter - risk groups but not HPV type), and, most genital warts are caused by the low- action between genetic and geographic most commonly, polymerase chain reac - risk HPV-6 and HPV-11. 1 Most HPV contributions to HPV subtype prevalence tion (PCR). In one study, 18 in situ infections are asymptomatic and resolve in certain regions. hybridization failed to reveal the pres - within 2 years. 24,25 The theory that penile and cervical ence of HPV in 2 tissue samples, but The mechanisms by which HPV ini - cancer may have a common etiology was both were positive when tested with tiates neoplasia of penile epithelial cells proposed as early as 35 years ago. Some PCR, one for HPV-18 and the other for have become more clear with ongoing of the initial studies supported a causal HPV-16. Even when PCR is used, how - research. Human papillomaviruses are relationship between male sexual behav - ever, results may vary depending on double-stranded DNA viruses that can iors and the incidence of cervical carci - whether 1 or 2 sets of consensus primers cause persistent infection only if the virus noma before the role of HPV was even were used (a primer is a short piece of is successfully incorporated into the repli - recognized. For the present review, the genetic material that acts as the point cation structure of the host epithelial cells university librarian performed an initial from which replication proceeds). Pas - and if the host defenses are compromised electronic search for HPV , penile carci - cual et al 13 found that the HPV-positive in some way, preventing clearance of noma , and cervical carcinoma . A second rate was 60.9% for primer MY09/11 infected cells by apoptosis. 26 Healthy cells search was based on references from the alone, 37.5% for primer GP5+/GP6+ contain a tumor suppression protein, p53, initial set of articles. The following is a alone, and 71.9% for both sets of primers which serves to eliminate cells with aber - chronologic summary of major influen - in the same tissue samples. rant growth tendencies. High-risk HPVs tial studies since the mid-1970s that were Methods used to demonstrate penile stimulate E6 and E7 oncoproteins to com - identified in the searches. These studies lesions are also not standardized. Some bine with p53, allowing the virus to over - gradually confirmed the carcinogenic investigators use saline-soaked swabs to come this regulatory mechanism. 27 This impact of HPV infection transmission collect cells from various sites on male process alone has not proved sufficient to from men to their female sex partners. genitalia; others use sandpaper or emery cause neoplasia, but the degradation pro - boards to scrape cells. 19 In another cess may be augmented by other factors, Cervical cancer and social class (1976; method, acetic acid solution is applied such as altered host immune status, United Kingdom) —Singer et al 32 hypoth - to the genital area for 3 minutes, followed chronic infection or inflammation (eg, esized a correlation between the incidence by direct visualization with magnifica - caused by the presence of smegma), or of cervical cancer in wives and their hus -

S4 • JAOA • Supplement 2 • Vol 111 • No 3 • March 2011 Wattleworth • Human Papillomavirus and the Links to Penile and Cervical Cancer bands’ occupations, suggesting that age, had more sex partners, and were mata acuminata; 9 had abnormal Papan - “behavioral and sociological attributes ... more likely to be smokers than husbands icolaou test results, of whom 7 were pos - such as occupation, premature widow - of women in the control group (ie, itive for HPV (HPV-16 in 6, HPV-6 in 1). hood and perhaps sexual promiscuity” women with normal cervical cytologic The authors suggested that history of may influence sperm histones by con - findings). Despite their inability to iden - HPV infection in a male partner places a tributing to variation in basic proteins tify the infectious agent, the authors con - woman at greater risk for cervical dys - within the sperm head. Findings from cluded that “men can contract and plasia than does her sexual behavior. this study indicated that sperm proteins transmit to their wives a sexually trans - are probably associated with social class mitted infection which increases the risk Cervical SCC and spousal sexual his - similarly to the way that sexually trans - of premalignant and malignant change in tory (1986; United States) —In a study mitted disease and resultant cancer in their cervical epithelium.” by Zunzunegui et al 41 in the San Fran - situ are correlated with social class. cisco, California, Bay Area, 44 women Cervical cancer and male sexual with cervical SCC were matched with Increased cervical carcinoma in wives of behavior (1982; United Kingdom) — controls of similar age obtaining med - men with penile carcinoma (1979; Skegg et al 36 hypothesized about the ical care at the same institution. All par - United States) —This study by Graham impact of male sexual behavior on ticipants were low-income married His - et al 33 mirrored that by Singer et al 32 in women with increased prevalence of cer - panic women. Case patients were 5.3 the United Kingdom. Women in New vical cancer, such as number of sex part - times more likely than controls to be mar - York married to men with penile carci - ners, especially prostitutes, and whether ried to husbands who had had 20 or noma were followed up retrospectively men’s occupations involved extended more sex partners and had also been from 1958 to 1964. The authors’ findings travel with absence from the home. The younger than most controls at the time of revealed triple the expected number of suggestion that cancer of the cervix may their first sexual encounter. Case hus - cases of cervical carcinoma, whereas be caused by a virus was supported by bands were more likely than control hus - other forms of cancer were not more citations from Fraumeni et al, 37 which bands to be smokers and to have fre - prevalent than expected. Although race showed a much lower frequency of cer - quented prostitutes. If the husband had was a potential confounder, most people vical cancer among nuns, and from a had 20 or more sex partners, the wife’s living in New York were white. Because study of prostitutes by Keighley, 38 which risk for developing cervical SCC was 5 this was a retrospective study performed revealed greater numbers of cervical dys - times greater than that in women whose by examining tumor registries, informa - plasia in women who admitted to pros - husbands had had fewer than 20 sex tion regarding number of sex partners, titution. partners. socioeconomic status, and age at first intercourse could not be determined. Cervical neoplasia and male condylomas Determining “high-risk” HPV types (1984; United States and Canada) —In a (1986; United Kingdom and Brazil) — Cancer in spouses (1980; United study by Levine et al, 39 34 male sex part - McCance et al 42 tested for HPV in penile Kingdom) —Smith et al 34 studied 711 ners of women with cervical condylomas amputation specimens and cervical mate - widows of men who had died of penile or CIN were checked for visible lesions, rial obtained at hysterectomy from cancer, following them up for as long as with external lesions noted in 18 men women with cervical carcinoma. Of 53 11 years. During this period, 378 women (53%). In most pairs, the histologic grade penile tissue samples, 26 were positive for died, close to the expected number of of lesions in one partner did not corre - HPV-16 and 5 for HPV-18. Eight of 19 deaths (366.8). However, more women late well with that in the other partner. women with cervical carcinoma had died of cancer—specifically cervical Koilocytosis of cells, often seen in con - HPV-16, and none had HPV-18. At this cancer—than was expected (all cancer, junction with HPV infection, was seen in early phase of research into the sexually 89 compared with 76.5 expected; cervical urine sediment only in men whose transmitted nature of HPV, no attempt cancer, 11 compared with 3.9 expected). condylomas were visualized at the distal was made to test spouses of either the These findings supported the possibility urethra. men or the women from whom samples that wives of men with penile cancer were obtained. could be at increased risk of cervical Men with condylomas and cervical dys - cancer. plasia (1985; United Kingdom) —Cam - HPV typing among sex partners (1987; pion et al 40 studied 25 women who had United States and West Germany) — Cervical intraepithelial neoplasia due been sexually intimate for at least 12 Schneider et al 43 tested women with cer - to venereal infection (1981; United months with men known to have condy - vical dysplasia for the presence of HPV. Kingdom) —Buckley et al 35 studied hus - lomata acuminata. All of the men had Samples were positive for HPV DNA in bands of women who had confirmed lesions unresponsive to conservative 80 of 115 women (70%) from the United cervical dysplasia, cervical intraepithe - treatment, and cultures demonstrated States and 185 of 201 women (92%) from lial neoplasia (CIN), or SCC of the cervix. either single or mixed infection with West Germany. The study also investi - These women had had sex only with HPV-16, -11, or -6. Nineteen of the 25 gated the male partners of 40 of these their husbands, who had sex at an earlier women were found to have condylo - women, harvesting penile epithelial cells

Wattleworth • Human Papillomavirus and the Links to Penile and Cervical Cancer JAOA • Supplement 2 • Vol 111 • No 3 • March 2011 • S5 that were positive for HPV in 26 men. Nilsson, 46 the wives of men with penile because 47 of 80 men with genital HPV In 19 of these men, the HPV type was cancer were followed up from 1958 to lesions had subclinical disease or lesions identical to that found in the female 1980 and were matched with women of seen only with colposcopy. partner. The authors documented that similar age and marital status. The inci - 13 of the women with CIN grade I or II dence of genital cancer, including cer - Sexual activity of men and cervical dys - from HPV did eventually show regres - vical cancer, was within the expected plasia in wives (1993; India) —Agarwal sion of the lesions, supporting the theory range and was distributed equally et al 49 conducted a study from 1976 to that HPV infections can be self-elimi - among study and control groups. This 1987. The objective was to investigate the nated by individuals with healthy study did not support an association role of sexual activity of men married to immune statuses. between penile cancer in men and cer - monogamous women with persistent vical cancer in their partners. cervical dysplasia. The combined risk of Colposcopic findings in male sex part - persistent cervical disease for women in ners of women with CIN (1987; Condyloma in a male partner as pre - the study group was nearly 7 times that France) —In a study by Barrasso et al, 44 dictor of cervical cancer risk (1991; Den - in the control group, with an even greater colposcopic examination of the genitalia mark) —Of 645 women with carcinoma risk if the man had a history of sexually of male sex partners of 480 women with in situ or invasive cervical cancer studied transmitted disease before marriage or either cervical condyloma (n=294) or CIN by Kjaer et al, 47 26 had been sexually inti - if he was not circumcised. (n=186) was performed both before and mate with only 1 man; 22 of them, along after application of 5% acetic acid solu - with 59 controls, participated in the study HPV types in sex partners for HPV tion. Of 480 men studied, 309 (64.4%) with their partners. There was a 5-fold detection (1994; Finland) —Hippeläinen had lesions, of which 105 (22%) were relative risk of the woman having cer - et al 50 investigated the prevalence of iden - classified as condylomata acuminata by vical cancer if her partner had ever (vs tical HPV types in women with clinical appearance and 204 (42.5%) were never) visited a prostitute. A history of abnormal Papanicolaou test results and seen only after acetic acid exposure. Fur - genital warts in the male partner was the in their male sex partners. Of 270 men ther study of these lesions revealed penile most important predictor of risk of cer - enrolled, 193 (71%) were found to have intraepithelial neoplasia in 61 partners vical cancer in the female partner (relative HPV infection. Of 66 couples in which of the 186 women with CIN (32.8%). Two risk, 17.9). Tests showed HPV in none of both partners tested positive for HPV, types of HPV—16 and 33—were found the male controls and in only 2 of 22 men only 15 men (22.7%) were found to almost exclusively in dysplastic lesions in in the study group, with 1 man positive harbor the same HPV type as their both partners. for HPV-6/11 and the other for HPV- female partner. Of women with stage III 16/18. These findings do not support CIN, 24 of 25 (96%) were positive for Cervical cancer risk in monogamous those of other studies previously men - HPV, with HPV-16 and HPV-18 as the women (1989; Panama, Costa Rica, tioned that indicated HPV infection was most frequently occurring types. Colombia, and Mexico) —This large a cause of cervical cancer. This study also compared detection case-control study in 4 Latin American of HPV with in situ hybridization and countries, conducted by Brinton et al, 45 Use of acetic acid washes to study HPV with PCR and found PCR to have the focused on the husbands of monoga - lesions (1992; United States) —In a study highest yield of positive results. mous women who had cervical cancer by Bergman and Nalick, 48 men were and who had reportedly had 1 lifetime evaluated for the presence of HPV-asso - Prevalence of HPV-16 in sex partners sex partner, thus removing the risk of ciated lesions of the genitalia if they (1994; Japan) —Kyo et al 51 investigated any sexual transmission from prior sex reported a minimum of 6 months of the possible sexual transmission of HPV partners. For the women, 304 of 759 cases sexual contact with women who had within married couples. Cervical cells (40%) and 776 of 1467 controls (53%) met known HPV genital infection. They were and semen were collected and tested for the criterion of having had only 1 sex matched with men of similar age in HPV with PCR. Among 53 couples, 23 partner. The risk of cervical cancer in a sexual relationships with women having women and 12 men were positive for wife increased significantly with the no known HPV infection. In the former HPV-16. In 27 couples, both partners number of sex partners reported by her (high-risk) group, 78 of 113 (69%) were were negative for HPV. In 9 of the husband. Low educational status was found to have HPV lesions, vs 2 of 94 remaining 26 pairs (35%), both partners found to be an additional predictor of (2%) in the control group. The findings of were positive for HPV-16. The preva - risk. In this study, HPV was found in this study supported the use of acetic lence of HPV-16 DNA was 37% in approximately 20% of study participants acid washes in conjunction with col - women with normal cervical cytologic and was not statistically related to the poscopy to diagnose HPV lesions. Fewer findings, 60% in women with CIN, and risk of cervical cancer. than 1% (2 of 207) of all men in this study 100% in those with cervical cancer. had clinical appearance of HPV lesions at Lack of association of penile and colposcopy that were not proven to be Testing HPV subtypes in sex partners cervical cancer in partners (1989; positive at biopsy. The value of col - (1995; Sweden) —Strand et al 52 tested 25 Sweden) —In a study by Hellberg and poscopy was supported in this study women younger than 31 years with dis -

S6 • JAOA • Supplement 2 • Vol 111 • No 3 • March 2011 Wattleworth • Human Papillomavirus and the Links to Penile and Cervical Cancer tinct vaginal or cervical lesions for HPV. bands were omitted from analysis due to exclusion of those in whom HPV could For 18 of 25 HPV-positive women, their inability to type their HPV DNA). The not be typed, 7 couples were found to male sex partner also tested positive for use of prostitutes as sex partners and an be concordant for HPV-16. HPV. Eight couples (32%) harbored the increased number of lifetime sex part - same HPV type. Only 3 of the 25 men ners were male-related factors associated Potential for self-elimination of HPV (12%) were aware of any genital lesions, with an increased risk of cervical cancer (2001; United States and Thailand) — but peniscopy after acetic acid washes among women in the study group. In Thomas et al 57 investigated the presence revealed clinical lesions suggestive of men whose wives had CIN, seroposi - of oncogenic HPV among women with HPV lesions in 20 men (80%). These find - tivity to Chlamydia trachomatis (45 of 157 cervical cancer and interviewed their ings supported the theory that men [29%]) and lack of schooling after age 10 husbands and control husbands capable of transmitting high-risk HPV years (75 of 210 [36%]) were greater risk regarding past sexual history. The inter - were younger than 40 years and were factors for development of cervical cancer view was followed by analysis of cell unaware of harboring the viruses. The in their wives than the presence of HPV samples from all male participants study also theorized that discordant (28 of 109 [26%]). willing to undergo testing. Penile cells HPV types can be found in couples sec - were scraped from 57 husbands of ondary to transient viral shedding or Prostitutes as potential sources of high- women with in situ or invasive cervical from delayed reactivation of varying risk HPV (1996; Spain) —Bosch et al 55 cancer and from 68 husbands of women HPV types obtained from earlier rela - evaluated the relationship between the in the control group. Only 8 of 125 men tions hips. prevalence of cervical cancer in women tested positive for high-risk HPV, and and their husbands’ numbers of sexual prevalence was not significantly higher Comparing HPV prevalence with dot encounters outside the marriage. They for the study group than for the control filter hybridization and PCR (1995; concluded that men who had had mul - group. Because most women with cer - United States) —Baken et al 53 tested 50 tiple sex partners (especially if these part - vical cancer were monogamous yet har - couples for various sexually transmitted ners were prostitutes) or who were found boring oncogenic HPV, it was theorized diseases at a clinic in Washington state. to be carriers of high-risk HPV types may that men infected their wives early in the Out of 100 participants (50 of each place their wives at greater risk of cer - marriage and then were cleared of the gender), 10 were found to have gonor - vical cancer, with this risk escalating 6- to virus by self-elimination. rhea, 6 chlamydia, and 9 herpes simplex 9-fold if HPV-16 was isolated. Their In conjunction with this study, the virus. A history of genital warts was results also suggested that younger men authors also concluded that “commer - reported by 20 men, and 24 women had may be more likely to be HPV carriers; it cial sex workers in Bangkok were likely a history of condyloma. Samples were is uncertain whether that difference reservoirs of oncogenic HPV” and that collected for testing by both dot filter reflects decreased sexual activity or clear - monogamous Thai women may have hybridization and PCR. Only 9 women ance of the virus with age. obtained the virus as a result of their hus - (18%) and 2 men (4%) were HPV positive bands’ visits with prostitutes. by filter hybridization, compared with Geographic distribution of HPV (1997; 36 women (72%) and 30 of 48 men (63%) Spain and Colombia) —Castellsagué et Use of peniscopy to collect scrapings for PCR (2 male specimens were insuffi - al 56 chose Colombia and Spain for a com - for HPV testing (2002; The Nether - cient to test). Results showed that in cou - parative study, because women living lands) —Bleeker et al 58 investigated the ples with both male and female testing in Colombia have a high risk of cervical presence of penile lesions and HPV in positive for HPV, the same type was pre - cancer and those living in Spain have a penile epithelial cells in male sex part - sent in each partner in 13 of 20 couples low risk. The study included 816 hus - ners of women with CIN. Penile scrap - (65%). bands of women enrolled in 4 case-con - ings from 175 men were screened for trolled studies of cervical neoplasia con - HPV by means of acetic acid washes Male sexual activity and cervical cancer ducted during a 20-month period. The followed by peniscopy, with 14 men in sex partners (1996; Colombia) — prevalence of HPV DNA was found to excluded because of phimosis or his - Muñoz et al 54 attempted to link male be 5-fold higher in husbands of controls tory of prior surgery. Lesions were visu - sexual behaviors and history of HPV in Colombia than in husbands of con - ally identified in 110 of 161 men (68%) with cervical cancer in female partners. A trols in Spain. In Spain, results were pos - and included flat lesions (76 of 110 total of 210 husbands of women with itive in 32 of 183 husbands of case [69%]), papular lesions (15 of 110 [14%]), CIN III or invasive cervical SCC were patients (17.5%) vs 6 of 171 husbands of and condylomata acuminata (3 of 110 matched with 262 husbands of control controls (3.5%); the difference between [3%]), with mixed lesions in some men. women. Human papillomavirus was case and control groups was much less in In 59 men, HPV was detected in the found in scraped cells from the glans Colombia, with positive HPV results in penile scrapings, even in some men with penis in 28 of 109 case husbands (25.7%) 28 of 109 case husbands (25.7%) and 25 of no visible lesions at peniscopy. Among but was also found in 25 of 132 husbands 132 control husbands (18.9%). In 27 cou - men with lesions noted by peniscopy, 58 (18.9%) in the control group (note that ples (25 case and 2 control couples), both out of 70 scrapings (83%) were HPV 101 case husbands and 130 control hus - members tested positive for HPV. After positive.

Wattleworth • Human Papillomavirus and the Links to Penile and Cervical Cancer JAOA • Supplement 2 • Vol 111 • No 3 • March 2011 • S7 Bleeker et al 59 later studied regres - study was partially funded by the Digene lesions are left untreated, lymphatic sion of penile lesions in male sex part - Corporation, which produces hybrid cap - spread may occur to the superficial or ners of women with CIN. They found ture testing equipment.) deep inguinal nodes and then to pelvic that use of condoms promoted faster nodes. It is rare, however, for even locally regression of flat lesions but not of HPV type concordance in sexual part - advanced tumors to metastasize. Sur - papular lesions, and they concluded that ners (2005; The Netherlands) —Bleeker et vival rates are related to histologic type this finding was probably due to reduced al 62 studied HPV infection between 238 of penile cancer and degree of lymph viral transmission between sex partners. women with cervical dyskaryosis and node involvement; patients with verru - their male sex partners, testing them for cous carcinoma have excellent survival Husbands of women with cervical HPV type and HPV type concordance rates with surgery alone while SCC often cancer (2002; Spain, Colombia, Brazil, as couples. A total of 213 of 237 women necessitates radiotherapy in addition to Thailand, Philippines) —Franceschi et (89.9%) and 132 of 181 men (72.9%) were surgery. 66 Studies on the use of chemo- al 60 conducted a multinational study HPV positive; of the HPV-positive cou - therapy in conjunction with radiotherapy from 1985 to 1993 comparing husbands ples, 67 of 116 (57.8%) men had the same are ongoing. 67 of women with invasive cervical carci - HPV type as their partners. The viral noma or in situ cervical cancer and hus - loads found in penile scraped cells and Conclusion bands of control women. Women who cervical cells were increased in couples It has been estimated that the 2004 direct participated in the study were aged 19 to with HPV type concordance. medical costs associated with HPV infec - 82 years. Ninety-three of 717 (13%) hus - tion and treatment approached $4 bil - bands of controls, 80 of 445 (18%) hus - Urine sampling for HPV (2006; India) — lion in the United States. 68 To contain bands of women with invasive cervical Gupta et al 63 matched 30 women with costs, efforts must be aimed at reducing carcinoma, and 35 of 165 (21%) husbands invasive cervical cancer and their life - risk factors through education and, ide - of women with in situ cervical cancer long male sex partners with similar-age ally, vaccination. The most common fac - were positive for penile HPV, with HPV- controls. With PCR testing, HPV was tors associated with the presence of high- 16 the most prevalent type. The same found in 25 of 30 women (83%) in the risk HPV in men include lack of HPV type was seldom found in both study group and 8 of 30 women (27%) in circumcision, younger age, more lifetime husband and wife. The percentage of the control group. Of the 30 male part - sex partners, higher frequency of inter - HPV-positive men varied widely, ners in the study group, 20 (67%) were course (especially with prostitutes), and ranging from 3% in Spain to 39% in positive for HPV using urine sampling in history of intercourse without condoms. Brazil. addition to scraped penile cells. The degree of genital hygiene, level of An additional objective of this study education, and smoking status in both Sites of highest HPV content in affected was to investigate the accuracy of urine male and female partners may also have men (2005; Brazil) —The goals of this sampling for the presence of HPV; this a role in HPV transmission and survival. study by Nicolau et al 61 were to deter - method revealed HPV in 23 of 28 women The introductory studies of the mine the prevalence of HPV in male part - (82%) in the study group, compared with quadrivalent HPV vaccine indicate high ners of HPV-infected women, review the 25 of 30 (83%) for PCR (2 urine samples efficacy against infection with HPV-6, -11, identity of the virus in each member, were inadequate for testing). Although -16, and -18, but vaccination of boys does determine which sites are most often the prevalence of HPV was only 67% in not currently appear to be cost-effective. 69 infected in male partners, and compare the male study group, there was a 100% Unfortunately, there is a risk that non - methods of detection. Six different concordance of HPV results between mandatory vaccinations of adolescents anogenital areas on each man had cells PCR of scraped penile cells and urine would not result in enough protected brushed for cytologic study followed by sampling. individuals to promote herd immunity. 70 biopsy of lesions under peniscopy a week Costs could be contained somewhat by later. At least 1 sample brushing was Treatment and Prognosis vaccinating males in higher-risk groups HPV DNA positive in 35 of 50 men Treatment of patients with penile cancer only. One potential screening tool (70%), with high-risk HPV DNA in 16 caused by HPV can range from local exci - involves testing of oral cavity cells. of 50 (32%), low-risk HPV in 7 of 50 sion to radiotherapy to penectomy, Results indicate that if oral HPV anti - (14%), and coinfection with both in 12 of depending on the stage of cancer at the bodies are found, it is likely the partici - 50 (24%). By site, HPV detection rates time of presentation. The presence of pant has already become sexually active were as follows: inner prepuce, 44%; HPV infection at the time of diagnosis and will not derive as much benefit from distal urethra, 30%; glans, 24%; outer pre - does not appear to be correlated with the vaccine as those who test negative puce, 24%; scrotum, 12%; and anus, 8%. prognosis. 64 Unfortunately, because for oral HPV antibodies. 71 Ongoing Histologic examination of biopsy tissue patients are either not aware of lesions or research is needed to determine the most was compared to second-generation reluctant to see a healthcare provider, it appropriate subsets of males for even - hybrid capture testing, with the latter is estimated that at least 50% of them tual vaccination. method yielding a higher percentage of have lesions present for more than 6 HPV positivity. (Note, however, that this months before treatment is initiated. 65 If

S8 • JAOA • Supplement 2 • Vol 111 • No 3 • March 2011 Wattleworth • Human Papillomavirus and the Links to Penile and Cervical Cancer Acknowledgments tion-associated cancers in the year 2002. Int J nomas in Argentina: analysis of primary tumors Cancer . 2006;118(12):3030-3044. and lymph nodes. J Med Virol . 2000;61(1):65-69. I thank Ellen Bergerson, MLIS, at Des Moines University in Iowa for her expertise 15. Dillner J, von Krogh G, Horenblas S, Meijer 32. Singer A, Reid BL, Coppleson M. A hypothesis: CJLM. Etiology of squamous cell carcinoma of the the role of a high-risk male in the etiology of cer - in researching current and past published penis. Scand J Urol Nephrol Suppl . 2000;(205):189- vical carcinoma: a correlation of epidemiology and works in this area, and Sally Wallin for her 193. molecular biology. Am J Obstet Gynecol . 1976;126 (1):110-115. extreme efficiency in helping to prepare this 16. Tseng HF, Morgenstern H, Mack T, Peters RK. document. Risk factors for penile cancer: results of a popula - 33. Graham S, Priore R, Graham M, Browne R, Bur - tion-based case-control study in Los Angeles nett W, West D. Genital cancer in wives of penile County. Cancer Causes Control . 2001;12(3):267- cancer patients. Cancer . 1979;44(5):1870-1874. References 277. 1. Bosch FX, de Sanjosé S. Human papillomavirus 34. Smith PG, Kinlen LJ, White GC, Adelstein AM, and cervical cancer- burden and assessment of 17. Levi JE, Rahal P, Sarkis AS, Villa LL. Human Fox AJ. Mortality of wives of men dying with cancer causality. J Natl Cancer Inst . 2003;31:3-13. papillomavirus DNA and p53 status in penile car - of the penis. Br J Cancer . 1980;41(3):422-428. cinomas. Int J Cancer . 1998;76(6):779-783. 2. Daling JR, Madeleine MM, Johnson LG, et al. 35. Buckley JD, Harris RWC, Doll R, Vessey MP, 18. Poblet E, Pascual A, Godínez JM, Pariente- Penile cancer: importance of circumcision, human Williams PT. Case-control study of the husbands Martín M, Escario E, García-Olmo DC. Human papil - papillomavirus and smoking in in situ and inva - of women with dysplasia or carcinoma of the cervix lomavirus-associated penile sarcomatoid carcinoma. sive disease. Int J Cancer . 2005;116(4):606-616. uteri. Lancet . 1981;2(8254):1010-1014. J Cutan Pathol . 2008;35(6):559-65. 3. Castellsagué X, Bosch FX, Muñoz N, et al. Male 36. Skegg DCG, Corwin PA, Paul C, Doll R. Impor - 19. Palefsky JM. HPV infection in men. Dis Markers . tance of the male factor in cancer of the cervix. circumcision, penile human papillomavirus infec - 2007;23(4):261-272. tion, and cervical cancer in female partners. N Engl Lancet . 1982;2(8298):581-583. J Med . 2002;346(15):1105-1112. 20. Giraldo PC, Eleutério J, Cavalcante DIM, 37. Fraumeni JF, Lloyd JW, Smith EM, Wagoner Goncalves AK, Romão JAA, Eleutério RMN. The JK. Cancer mortality among nuns: role of marital 4. Maden C, Sherman KJ, Beckmann AM, et al. His - role of high-risk HPV-DNA testing in the male tory of circumcision, medical conditions, and sexual status in etiology of neoplastic disease in women. sexual partners of women with HPV-induced J Natl Cancer Inst . 1969;42(3):455-468. activity and risk of penile cancer. J Natl Cancer Inst . lesions. Eur J Obstet Gynaecol Reprod Biol . 1993;85(1):19-24. 2008;137(1):88-91. 38. Keighley E. Carcinoma of the cervix among 5. Holly EA, Palefsky JM. Factors related to risk of prostitutes in a women’s prison. Br J Vener Dis . 21. Hernandez BY, McDuffie K, Goodman MT, et 1968;44(3):254-255. penile cancer: new evidence from a study in the al. Comparison of physician- and self-collected gen - Pacific Northwest. J Natl Cancer Inst . 1993;85(1):2- ital specimens for detection of human papilloma - 39. Levine RU, Crum CP, Herman E, Silvers D, Fer - 4. virus in men. J Clin Microbiol . 2006;44(2):513-517. enczy A, Richart RM. Cervical papillomavirus infec - tion and intraepithelial neoplasia: a study of male 6. Micali G, Innocenzi D, Nasca MR, Musumeci ML, 22. Dunne EF, Nielson CM, Stone KM, Markowitz sexual partners. Obstet Gynecol . 1984;64(1):16-20. Ferraú F, Greco M. Squamous cell carcinoma of LE, Giuliano AR. Prevalence of HPV infection among the penis. J Am Acad Dermatol . 1996;35(3 pt 1): men: a systematic review of the literature. J Infect 40. Campion MJ, Singer A, Clarkson PK, McCance 432-451. Dis . 2006;194(8):1044-1057. DJ. Increased risk of cervical neoplasia in consorts of men with penile condylomata acuminata. 7. Ikenberg H, Gissmann L, Gross G, Grussendorf- 23. Weinstock H, Berman S, Cates W. Sexually trans - Lancet . 1985;1(8435):943-946. Conen EI, zur Hausen H. Human papillomavirus mitted diseases among American youth: incidence type 16-related DNA in genital Bowen’s disease and prevalence estimates, 2000. Perspect Sex 41. Zunzunegui MV, King MC, Coria CF, Charlet J. and in bowenoid papulosis. Int J Cancer . 1983;32(5): Reprod Health . 2004;36(1):6-10. Male influences on cervical cancer risk. Am J Epi - 563-565. 24. Hagensee ME. Infection with human papillo - demiol . 1986;123(2):302-307. 8. Callen JP. Possible precursors to epidermal malig - mavirus: update on epidemiology, diagnosis and 42. McCance DJ, Kalache A, Ashdown K, et al. nancies. In: Friedman RJ, Rigel DS, Kopf AW, et al, treatment. Curr Infect Dis Rep . 2000;2(1):18-24. Human papillomavirus types 16 and 18 in carci - eds. Cancer of the Skin . Philadelphia, PA: WB 25. Schiffman M, Kjaer SK. Natural history of nomas of the penis from Brazil. Int J Cancer . 1986; Saunder; 1991:27-34. anogenital human papillomavirus infection and 37(1):55-59. 9. Burgers JK, Badalament RA, Drago JR. Penile neoplasia. J Natl Cancer Inst Monogr . 2003;31:14- 43. Schneider A, Sawada E, Gissmann L, Shah K. cancer: clinical presentation, diagnosis, and staging. 19. Human papillomaviruses in women with a history Urol Clin North Am . 1992;19(2):247-256. 26. zur Hausen H. Immortalization of human cells of abnormal Papanicolaou smears and in their male partners. Obstet Gynecol . 1987;69(4):554-562. 10. Higgins GD, Uzelin DM, Phillips GE, Villa LL, and their malignant conversion by high risk human Burrell CJ. Differing prevalence of human papil - papillomavirus genotypes. Semin Cancer Biol . 44. Barrasso R, De Brux J, Croissant O, Orth G. High lomavirus RNA in penile dysplasias and carcinomas 1999;9(6):405-411. prevalence of papillomavirus-associated penile may reflect differing etiologies. Am J Clin Pathol . 27. Duensing S, Münger K. Mechanisms of genomic intraepithelial neoplasia in sexual partners of 1992;97(2):272-278. instability in human cancer: insights from studies women with cervical intraepithelial neoplasia. N Engl J Med . 1987;317(15):916-923. 11. Gross G, Pfister H. Role of human papillomavirus with human papillomavirus oncoproteins. Int J in penile cancer, penile intraepithelial squamous cell Cancer . 2004;109(2):157-162. 45. Brinton LA, Reeves WC, Brenes MM, et al. The neoplasias and in genital warts. Med Microbiol 28. Backes DM, Kurman RJ, Pimenta JM, Smith JS. male factor in the etiology of cervical cancer among Immunol . 2004;193(1):35-44. Systematic review of human papillomavirus preva - sexually monogamous women. Int J Cancer . 1989; 44(2):199-203. 12. Rubin MA, Kleter B, Zhou M, Ayala G, Cubilla lence in invasive penile cancer. Cancer Causes Con - AL, Quint WGV, et al. Detection and typing of trol . 2009;20(4):449-457. 46. Hellberg D, Nilsson S. Genital cancer among human papillomavirus DNA in penile carcinoma: 29. Münger K, Howley PM. Human papillomavirus wives of men with penile cancer: a study between evidence for multiple independent pathways of immortalization and transformation functions. 1958 and 1982. Br J Obstet Gynaecol . 1989;96(2): penile carcinogenesis. Am J Pathol . 2001;159(4): Virus Res . 2002;89(2):213-228. 221-225. 1211-1218. 30. Dorfman S, Cavazza M, Cardozo J. Penile cancer 47. Kjaer SK, de Villiers EM, Dahl C, et al. Case- 13. Pascual A, Pariente M, Godínez JM, Sánchez- associated with so-called low-risk human papilloma - control study of risk factors for cervical neoplasia Prieto R, Atienzar M, Segura M, et al. High preva - virus: report of five cases from rural Venezuela. in Denmark: role of the “male factor” in women lence of human papillomavirus 16 in penile carci - Trop Doct . 2006;36(4):232-233. with one lifetime sexual partner. Int J Cancer . noma. Histol Histopathol . 2007;22(2):177-183. 1991;48(1):39-44. 31. Picconi MA, Eiján AM, Distéfano AL, et al. 14. Parkin DM. The global health burden of infec - Human papillomavirus (HPV) DNA in penile carci - 48. Bergman A, Nalick R. Prevalence of human

Wattleworth • Human Papillomavirus and the Links to Penile and Cervical Cancer JAOA • Supplement 2 • Vol 111 • No 3 • March 2011 • S9 papillomavirus infection in men: comparison of 57. Thomas DB, Ray RM, Kuypers J, et al. Human as a prognostic factor in carcinoma of the penis: the partners of infected and uninfected women. J papillomaviruses and cervical cancer in Bangkok: analysis of 82 patients treated with amputation Reprod Med . 1992;37(8):710-712. the role of husbands and commercial sex workers. and bilateral lymphadenectomy. Cancer . 2001;91 Am J Epidemiol . 2001;153(8):740-748. (12):2315-2321. 49. Agarwal SS, Sehgal A, Sardana S, Kumar A, Luthra UK. Role of male behavior in cervical car - 58. Bleeker MCG, Hogewoning CJA, van den Brule 65. Buddington WT, Kickham CJE, Smith WE. An cinogenesis among women with one lifetime sexual AJC, et al. Penile lesions and human papillomavirus assessment of malignant disease of the penis. J partner. Cancer . 1993;72(5):1666-1669. in male sexual partners of women with cervical Urol . 1963;89:442-449. intraepithelial neoplasia. J Am Acad Dermatol . 50. Hippeläinen MI, Yliskoski M, Syrjänen S, et al. 2002;47(3):351-357. 66. Chen MF, Chen WC, Wu CT, Chuang CK, Ng KF, Low concordance of genital human papillomavirus Chang JTC. Contemporary management of penile (HPV) lesions and viral types in HPV-infected 59. Bleeker MCG, Hogewoning CJA, Voorhorst FJ, cancer including surgery and adjuvant radio - women and their male sexual partners. Sex Trans et al. Condom use promotes regression of human therapy: an experience in Taiwan. World J Urol . Dis . 1994;21(2):76-82. papillomavirus-associated penile lesions in male 2004;22(1):60-66. sexual partners of women with cervical intraep - 51. Kyo S, Inoue M, Koyama M, Fujita M, Tanizawa ithelial neoplasia. Int J Cancer . 2003;107(5):804- 67. Culkin DJ, Beer TM. Advanced penile carci - O, Hakura A. Detection of high-risk human papil - 810. noma. J Urol . 2003;170(2 pt 1):359-365. lomavirus in the cervix and semen of sex partners. 68. Insinga RP, Dasbach EJ, Elbasha EH. Assessing J Infect Dis . 1994;170(3):682-685. 60. Franceschi S, Castellsagué X, Dal Maso L, et al. Prevalence and determinants of human papilloma- the annual economic burden of preventing and 52. Strand A, Rylander E, Wilander E, Zehbe I. HPV virus genital infection in men. Br J Cancer . 2002;86 treating anogenital human papillomavirus-related infection in male partners of women with squa - (5):705-711. disease in the US: analytic framework and review mous intraepithelial neoplasia and/or high-risk of the literature. Pharmacoeconomics . 2005;23 HPV. Acta Derm Venereol . 1995;75(4):312-316. 61. Nicolau SM, Camargo CGC, Stávale JN, et al. (11):1107-1122. Human papillomavirus DNA detection in male 53. Baken LA, Koutsky LA, Kuypers J, et al. Genital sexual partners of women with genital human 69. Taira AV, Neukermans CP, Sanders GD. Evalu - ating human papillomavirus vaccination programs. human papillomavirus infection among male and papillomavirus infection. Urology . 2005;65(2):251- female sex partners: prevalence and type-specific 255. Emerg Infect Dis . 2004;10(11):1915-1923. concordance. J Infect Dis . 1995;171(2):429-432. 62. Bleeker MCG, Hogewoning CJA, Berkhof J, et 70. Gillison ML, Chaturvedi AK, Lowy DR. HPV pro - 54. Muñoz N, Castellsagué X, Bosch FX, et al. Dif - al. Concordance of specific human papillomavirus phylactic vaccines and the potential prevention of ficulty in elucidating the male role in cervical cancer types in sex partners is more prevalent than would noncervical cancers in both men and women. in Colombia, a high-risk area for the disease. J Natl be expected by chance and is associated with Cancer . 2008;113(10)(suppl):3036-3046. Cancer Inst . 1996;88(15):1068-1075. increased viral loads. Clin Infect Dis . 2005;41(5):612- 71. Marais DJ, Sampson C, Jeftha A, et al. More 620. 55. Bosch FX, Castellsagué X, Muñoz N, et al. Male men than women make mucosal IgA antibodies to sexual behavior and human papillomavirus DNA: 63. Gupta A, Arora R, Gupta S, et al. Human papil - human papillomavirus type 16 (HPV-16) and HPV- key risk factors for cervical cancer in Spain. J Natl lomavirus DNA in urine samples of women with or 18: a study of oral HPV and oral HPV antibodies in Cancer Inst . 1996;88(15):1060-1067. without cervical cancer and their male partners a normal healthy population. BMC Infect Dis . compared with simultaneously collected cer - 2006;6:95-104. 56. Castellsagué X, Ghaffari A, Daniel RW, Bosch FX, vical/penile smear or biopsy specimens. J Clin Virol . Muñoz N, Shah KV. Prevalence of penile human 2006;37(3):190-194. papillomavirus DNA in husbands of women with and without cervical neoplasia: a study in Spain 64. Bezerra ALR, Lopes A, Santiago GH, Ribeiro and Colombia. J Infect Dis . 1997;176(2):353-361. KC, Latorre MRDO, Villa LL. Human papillomavirus

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S10 • JAOA • Supplement 2 • Vol 111 • No 3 • March 2011 Wattleworth • Human Papillomavirus and the Links to Penile and Cervical Cancer