Infections of the Genital Tract: Human Papillomavirus–Related Infections

EURSUP-724; No. of Pages 14 EUROPEAN UROLOGY SUPPLEMENTS XXX (2016) XXX–XXX

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Infections of the Genital Tract: Human Papillomavirus–Related Infections Tet Yap a,*, Nicholas Watkin a, Suks Minhas b a

Andrology Research Unit, Department of Urology, St. George’s Hospital NHS Foundation Trust, London, UK;

b

Department of Urology, University College

Hospital NHS Foundation Trust, London, UK

Article info

Abstract

Keywords: Infection Human papillomavirus Penile cancer HPV vaccination Genital warts

Context: The human papillomaviruses (HPVs) are a major global health burden, playing a part in diseases ranging from genital warts to malignancies such as penile cancer in men and cervical cancer in women. Objective: To explore the molecular biology and epidemiology of HPV infection; the diseases linked to it; and current prevention strategies, including the potential role of vaccination. Evidence acquisition: The relevant papers, reviews, and guidelines pertaining to the topics were collected for the purpose of this review from PubMed and online guidelines resources including the European Association of Urology and the Centers for Disease Control and Prevention. Evidence synthesis: The current knowledge on genital HPV in men is explained and summarised. Conclusions: There is an urgent need for more data on the incidence and persistence of HPV at the different anatomic sites, the incidence of external genital lesions, and the types of HPV in these lesions. This will allow a more comprehensive understanding of the natural history of HPV infection and its progression to both benign and malignant disease in men and will help formulate the development and implementation of vaccination programs. Patient summary: This review explores the molecular biology and epidemiology of human papillomavirus (HPV) infection; the diseases linked to it; and current prevention strategies, including the potential role of vaccination. There is an urgent need for more data on the incidence and persistence of HPV at the different anatomic sites, the incidence of external genital lesions, and the types of HPV in these lesions. # 2016 Published by Elsevier B.V. on behalf of European Association of Urology.

* Corresponding author. St. George’s Hospital NHS Foundation Trust, Blackshaw Road, London SW170QT, UK. E-mail address: [email protected] (T. Yap).

1.

What is human papillomavirus?

Human papillomaviruses (HPVs) are small nonenveloped viruses containing double-stranded DNA genomes of approximately 8000 base pairs within 55-nm-diameter

icosahedral capsids [1]. More than 200 HPVs exist. These members of the papovaviruses infect various epithelial tissues, including the epidermis (cutaneous types) and the epithelial linings of the upper respiratory system and anogenital tract (mucosotropic types) (Fig. 1). They are

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Please cite this article in press as: Yap T, et al. Infections of the Genital Tract: Human Papillomavirus–Related Infections. Eur Urol Suppl (2016), http://dx.doi.org/10.1016/j.eursup.2016.08.005

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genetic alterations are needed for malignant progression, though [4]. The HPV oncoproteins E5, E6, and E7 are the primary viral factors responsible for development and growth of cancer, primarily via altering growth regulation by host proteins and by inducing genomic instability. 1.1.

The human papillomavirus life cycle

Most viruses infect and produce progeny virus within a target cell. In HPV infections, though, new virion synthesis happens only after the infected cell has undergone mitosis and one of the infected daughter cells has differentiated [5]. HPVs infect cells in the basal layer of stratified squamous epithelium that becomes exposed as a result of microtrauma. These are the only proliferating cells in normal epithelia. Following infection, HPV genomes are established as extrachromosomal elements or episomes. These genomes do not encode enzymes necessary for viral replication and so rely on host cell replication proteins to mediate viral DNA synthesis. The suprabasal cells remain active in the cell cycle as they undergo differentiation, and a subset of cells re-enter S phase in the top epithelial layers to replicate HPV genomes in a process called amplification. This is followed by capsid protein synthesis, virion assembly, and release. 1.2.

The molecular biology behind human papillomavirus–

induced tumours Fig. 1 – Transmission electron micrograph of the human papillomavirus structure. Reproduced from the Laboratory of Tumor Virus Biology with permission from the National Cancer Institute [125].

classified into low- and high-risk types based on their ability to promote malignant transformation (Table 1) [2]. Most HPVs are low risk in oncogenic potential and produce localised benign warts that do not undergo malignant progression even if left untreated. Low-risk mucosal HPVs such as HPV-6 and HPV-11 cause genital warts (condyloma acuminata), whereas the high-risk HPVs cause squamous intraepithelial lesions that can progress to invasive squamous cell carcinoma (SCC). HPV-16 is by far the most prevalent mucosal high-risk HPV type, followed by HPV-18 and HPV-31 [3]. The 2008 Nobel Prize in Physiology or Medicine was awarded to Harald zur Hausen for his discovery that highrisk HPV types are the causative agents of cervical cancer. Infection with high-risk HPVs is not enough and additional

Table 1 – Human papillomavirus types and oncogenic potential Classification High risk Probably oncogenic Low risk

HPV types 16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59 26, 53, 66, 68, 73, 82 6, 11, 40, 42, 43, 44, 54, 61, 70, 72, 81

HPV = human papillomavirus. ˜ oz et al [2]. Adapted from Mun

Chronic HPV infection can ultimately lead to cancer development [3]. In precancerous lesions, most HPV genomes persist in an episomal state, whereas in many high-grade lesions, genomes are integrated into host chromosomes [6]. The proapoptotic viral E2 protein represses transcription of early viral genes like the E6/E7 oncogenes [7]. Integration of viral DNA disrupts E2 expression and increases proliferative capacity, a crucial step in progression to cancer [8]. Integrated copies of E6/E7 messenger RNA are also more stable than episomal copies, and coexistence of HPV episomes with integrated copies may be crucial in HPV carcinogenesis [9]. E1 and E2 viral proteins from episomes can initiate DNA replication from integrated copies, resulting in their amplification, induction of chromosomal abnormalities, and activation of DNA repair systems, which can result in further genomic anomalies and ultimately malignant progression [6]. 1.3.

Role of E6/E7 viral proteins

The E6 and E7 oncoproteins act synergistically and are central to the development of HPV-induced cancers [10]. Both E6 and E7 are approximately 18- and 13-kDa nuclear proteins and have also been found in the cytoplasm [11,12]. E7 but not E6 protein expression can immortalise human keratinocytes. The combination of E6 and E7, however, can immortalise most types of primary cells [13,14]. Still, HPV-immortalised cells are not tumourigenic in nude mouse models and require extensive passaging in

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tissue culture or the expression of other oncogenes, such as FBJ/R v-fos or ras, to form tumours [15–17]. This is borne out in clinical practice: most people infected with genital HPVs do not develop genital cancers [6]. E6/E7 proteins are necessary but not sufficient for malignant progression. For this to happen, accumulation of DNA damage and mutations from the E6/E7-mediated proliferation of suprabasal cells and inhibition of apoptosis are important. This is consistent with the long latency period between initial HPV infection and the development of cancer [18]. Multiple pathways are targeted by E6/E7 oncoproteins, which can ultimately lead to carcinogenesis (summarised in Table 2 and 3) [19–39].

The HPV protein-activated DNA damage pathways are required for viral replication, but this also contributes to malignant progression. E5 viral proteins have also been found to augment the function of E6/E7 and contribute to tumour progression [21]. Importantly, high-level expression of HPV-16 E5 in the skin of mouse models induces epithelial hyperproliferation, which results in spontaneous tumour formation [40]. It is likely there are multiple pathways to HPV-induced carcinogenesis. One pathway is through high-level expression of E6 and E7 because of viral integration into host DNA and consequent E2 protein suppression. A second pathway could occur in cells that still maintain viral episomes, in

Table 2 – Key pathways to carcinogenesis involving E6/E7 proteins Action Degradation of Rb protein and activation of E2F-dependent promoters

Modulation of cyclins and CDK inhibitors

Targeting of p53 for degradation, inhibition of p53 acetylation, and suppression of p53 gene expression

Activation of telomerase

Cell immortalisation Early induction of genomic instability

Induction of centrosome abnormalities

Activation of the ATM-ATR pathway and DNA damage

Antiapoptosis pathways: anoikis, growth inhibitory cytokines, and IFN response

FA pathway

Effect Proliferation of HPV-infected cells is uncoupled from differentiation and is controlled by cellular factors, the most prominent of which are members of the Rb family, consisting of p105-RB, p107, and p130. E7 binds to Rb targets and marks them for degradation, resulting in activation of E2F transcription factors that drive expression of Sphase genes. High-risk E7 proteins bind Rb proteins with much higher affinity. These cell cycle checkpoint regulators are targeted by E6/E7, resulting in accumulation of cellular mutations over time and progression to cancer. Cyclins E and A are activated and numerous CDK inhibitors suppressed by E7 protein. E7 binding to Rb can lead to inhibited cell growth and apoptosis through the tumor suppressor p53-dependent pathway. In response, high-risk E6 proteins have evolved to target p53 for degradation. This and other strategies counteract the various stimuli that can induce programmed cell death and are also used to promote replication. High-risk E6 proteins activate transcription of telomerase reverse transcriptase, which (with RB inactivation by E7) is essential for immortalisation of HPV-infected cells. HPV-immortalised cells still require the expression of more oncogenes for carcinogenesis to progress. High-risk E6 and E7 independently induce genome instability via mechanisms such as whole chromosome loss/gain (aneuploidy) and chromosomal rearrangements (see Table 3). This is thought to be an early event before integration of the virus into host DNA. These activities are limited to high-risk E6 and E7 proteins as no such activities are seen in cells expressing their low-risk counterparts. High-risk E6 and E7 induce numerous mitotic defects, including multipolar mitoses, which are characteristic of most high-risk HPV lesions and associated with abnormal centrosome numbers. E6 and E7 activate the ATM-ATR DNA damage repair pathway. E6 and E7 have been shown to independently induce DNA damage and increase the frequency of foreign DNA integration into the host genome. Anoikis, which is associated with anchorage-independent growth, is a major apoptotic pathway targeted by E6/E7. In addition, high-risk E6 proteins block apoptosis induced by TNFa following infection by directly binding to TNFR1, which inhibits the formation of the deathinducing signaling molecule. IFN is activated following viral infection and HPV proteins act at several levels to interfere with this response, including inhibiting the transcription of many of the hundreds of IFN-inducible genes such as STAT1. This pathway, which promotes DNA repair in response to replication stress, is normally activated by HPV-16 E7. In cells deficient for an intact FA response, E7 expression leads to increased chromosomal instability.

References Dyson et al [19]; Gage et al [20]

DiMaio and Mattoon [21]; Zerfass et al [22]

–Boyer et al [23]; Evan and Vousden [24]; Moody et al [25]

Howie et al [12]; Nguyen and Mu¨nger [26] Hawley-Nelson et al [13]; Mu¨nger et al [14] DeGregori et al [27]; Stevaux and Dyson [28]; Brehm et al [29]

Longworth et al [30]; Boyer et al [23]; Jones et al [31] Duensing and Mu¨nger [32]; Kessis et al [33]

Chiarugi and Giannoni [34]; Filippova et al [35]; Beglin et al [36]; Chang and Laimins [37]

Kutler et al [38]; Spardy et al [39]

ATM = ataxia telangiectasia mutated; ATR = ataxia telangiectasia and Rad3 related; CDK = cyclin-dependent kinase; FA = Fanconi anaemia; HPV = human papillomavirus; IFN = interferon; Rb = retinoblastoma; STAT1 = signal transducer and activator of transcription 1 gene; TNFa = tumor necrosis factor alpha; TNFR1 = tumor necrosis factor receptor 1.

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Table 3 – Key effects of E6/E7 proteins promoting genome instability in human papillomavirus–infected cells Molecular alterations Copy number gains 19q13 and 5p15 Deletions Aneuploidy Gene overexpression Gene hypoexpression Gene mutations Imbalance of protein expression DNA hypermethylation in the promoter region of gene

Gene/chromosome 8q24, 16p11-12, 20q11-13, 22q 13q21-22, 4q21-32, along the X chromosome p53 p53, p21, RB, NF-kB p16INK4a p53, c-rasHa, PIK3CA, H-RAS, K-RAS bcl-2/Bax DAPK, FHIT, MGMT, p16 INK4a, p14ARF

5.9 mo (95% confidence interval [CI], 5.7–6.1 mo), with 75% of infections clearing within 12 mo [46]. Circumcision in men seems to reduce the risk of persistent infection [49]. Only a small number of HPV studies of heterosexual couples have been performed [41]. Kyo et al [50] demonstrated that 75% of women whose male partners were HPV positive had HPV DNA in their cervix, whereas only 39% of the men whose partners were HPV positive carried HPV DNA in their semen. Campion et al [51] examined HPV disease in women whose sexual partners had penile warts, and they found that 76% of the women had genital HPV infections. 2.1.

which the expression of E1 and E2 promotes genome instability via aberrations in integrated HPV DNA replication. In addition, E5 may promote the activity of E6 and E7, resulting in tumour progression. 2. Epidemiology of genital human papillomavirus infection in men The prevalence of genital HPV infection in men ranges from 1.3–72.9%, which may be higher than the prevalence in women [41]. The wide variation in prevalence is likely due to differences in populations studied, sites sampled, and HPV DNA detection methods. The geographical prevalence of HPV by DNA detection shows ranges for different regions of 7.1–50% (Scandinavia), 15.8–72.9% (Europe), 10–63% (United States), 1.3–8.7% (East Asia), and 15.3–70% (South America) from studies sampling multiple genital sites and specimens [41]. A further multinational prospective cohort study reported that 50.5% of men were positive for at least one known HPV type, and an additional 14.7% were positive for an unclassified HPV infection (tested positive for HPV but negative for 37 mucosal HPV types by polymerase chain reaction [PCR]) [42]. HPV-16 was the most common type detected (6.5%). Similar results were observed in a crosssectional study of US men [43]. Among asymptomatic heterosexual men, the penile shaft, corona/glans penis (including prepuce in uncircumcised men), and scrotum are the sites contributing to >95% of genital HPV infection detected [44]. HPV infections may be less likely to persist in men than in women. In a Dutch study, persistent infection (defined as detection of HPV DNA of a specific type at two consecutive visits over 1 yr) was observed more frequently in women than in men (20% vs 6%, respectively; p < 0.05) [45]. The cumulative risk of acquiring a new HPV infection among a cohort of US men was estimated to be 29.2% in 12 mo [46], with similar estimates reported for young males [47] and females [48]. There does not seem to be an agerelated trend in rates of HPV infection in men, unlike in women [46]. This suggests that the relatively constant HPV prevalence observed in cross-sectional studies may be due to lifetime acquisition of new infections. The time to clearance of an infection has been reported at a median of

Condom use

Approximately 50% of penile cancer cases may be due to HPV infection. The avoidance of HPV transmission between sexual partners may lead to a reduction of penile cancer incidence. Few studies are available evaluating the effect of condom use as a preventive strategy or therapy for HPV infection. In a retrospective case-control study of nearly 1000 patients, Wen et al [52] demonstrated a protective effect of condom use in patients with genital warts. In both sexes, failure to use condoms was independently associated with an increased risk of acquisition of genital warts, and consistent condom use was associated with a decreased risk of acquisition of genital warts (Table 4). In a study of 82 female university students, Winer et al [53] showed that in newly sexually active women, consistent condom use by their partners appeared to reduce the risk of cervical and vulvovaginal HPV infection. In addition, in couples who reported no condom use, no cervical squamous intraepithelial lesions could be observed, in contrast to couples without condom use. Bleeker et al [54] performed a randomised trial with couples in whom women had cervical intraepithelial neoplasia and their male partner had HPV-associated flat lesions of the penis. Couples were randomised for the use of a condom. In this study, men in the condom use group experienced a significantly reduced time to regression of the flat lesion of the penis. The effect of the described phenomenon is probably due to the blocking of viral transmission between the sexual partners. The same group showed in another study that in couples infected by the same HPV type, the use of condoms led to the regression of flat penile lesions, whereas in couples with HPV nonconcordance, a significant effect of condom use could not be observed [55]. 2.2.

Risk factors

Positive associations between HPV detection and measures of sexual history, including lifetime and recent numbers of sexual partners and sexual frequency, have been observed despite the lack of specific correlative studies in men with genital HPV infection [41,56]. Four recent studies have reported circumcision being associated with reduced detection of HPV infection in men [41,57–59]. HPV prevalence was significantly lower among circumcised men [42]. Less consistently, condom use has been associated

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Table 4 – Risk of genital warts in relation to condom use Condom use

Cases, no. (%)

Controls, no. (%)

Adjusted OR (95% CI)

Men (x24 ¼ 62:3, p < 0.001) Not applicable, no sex Never Sometimes, <50% Usually, >50% Always, 100%, excluding breakages

78 195 89 81 159

(13.0) (32.4) (14.8) (13.5) (26.4)

52 80 41 52 222

(11.6) (17.9) (9.2) (11.6) (49.4)

1 1.9 (1.3–2.9) 3.0 (2.2–4.3) 0.9 (0.7–2.0) 0.7 (0.3–0.9) p < 0.0001

Women (x24 ¼ 15:2, p = 0.004) Not applicable, no sex Never Sometimes, <50% Usually, >50% Always, 100%, excluding breakages

34 91 59 54 77

(10.8) (28.9) (18.7) (17.1) (24.4)

23 63 22 38 87

(9.9) (27.0) (9.4) (16.3) (37.3)

1 1.8 (0.9–3.6) 1.7 (1.0–2.9) 0.8 (0.7–1.7) 0.7 (0.4–1.0) p = 0.013

CI = confidence interval; OR = odds ratio. Adapted from Wen et al [54].

with reduced risk of HPV detection in men [41,56]. Most studies have found no association between male age and genital HPV prevalence [50]. Diagnostic tests for human papillomavirus 3. detection Clinical examination is not sensitive for detecting either latent or subclinical genital HPV infection. Diagnosis of genital warts and penile tumours is usually clinical, made by visual inspection and examination. More information on penile cancer diagnosis and staging is available in the current EAU guidelines for penile cancer [60]. Genital warts can be confirmed by biopsy, which might be indicated if (1) the diagnosis is uncertain or the lesion atypical; (2) the lesions do not respond to standard therapy; (3) the disease worsens during therapy; (4) the patient is immunocompromised; or (5) the warts are pigmented, indurated, fixed, bleeding, or ulcerated. Genital warts are usually asymptomatic, but they might be painful or pruritic. The use of HPV DNA testing for genital wart diagnosis is not recommended because test results would not alter clinical management of the condition. The application of 3–5% acetic acid, which causes the skin to turn white, has been used by some clinicians to detect HPV-infected genital mucosa. However, acetic acid application is not a specific test for HPV infection [61]. Immunohistochemistry and HPV testing are not routinely used in diagnostic practice for primary penile tumours or preinvasive lesions. Immunohistochemical analysis of p16 expression has been used in attempts to stratify high- and low-risk tumours, but there is as yet insufficient evidence for use in diagnostic practice [62]. The p16 protein is a cyclin-dependent kinase (CDK) inhibitor that decelerates the cell cycle by inactivating the CDKs that phosphorylate retinoblastoma protein—in other words, it is a tumour suppressor protein. Strong immunostaining for p16 correlates with HPV-16/ HPV-18 infection in both penile lichen sclerosus (LS) and penile SCC [63]. In contrast, condylomata acuminata and low-grade squamous intraepithelial lesions infected by

low-risk HPV such as HPV-6/HPV-11 showed focal and weak immunohistochemical staining for p16 [64]. In the research setting, because it is not possible to culture HPV in vitro, other laboratory methods have to be used. Early studies were performed using immunohistochemistry. Subsequently, microbiological techniques such as Southern blot hybridisation, dot blot, and in situ hybridisation were developed, which could differentiate between various HPV types. These techniques have been replaced by PCR, by which the HPV detection rate is usually >90% [65]. After HPV amplification, PCR products can be HPV genotyped with hybridisation to fluorescence-labelled polystyrene bead microarrays, such as the Luminex suspension array technology (using the Multimetrix kit; Progen Biotechnik GmbH, Heidelberg, Germany). This assay can detect the following 24 HPV types: low-risk HPV: 6, 11, 42, 43, 44, 70; high-risk HPV: 16, 18, 26, 31, 33, 35, 39, 45, 51, 52, 53, 56, 58, 59, 66, 68, 73, and 82 [66]. Human papillomavirus and urogenital tumours 4. in men The urogenital tumours affecting men are benign genital warts in low-risk HPV infection and penile cancer in highrisk HPV infection. High-risk HPV infection is also causally related to cancer of the cervix, vagina, vulva, anal canal, and oropharynx [67]. Table 5 summarises the cancers associated with high-risk HPV infection and their effect globally in numbers [68]. 4.1.

Genital warts (condyloma acuminatum)

Around 1 million new cases each year of genital warts are reported in the United States, making it one of the most common sexually transmitted diseases [69]. Its prevalence is highest among men aged 25–29 yr and decreases with age [70]. In the 1999–2004 National Health and Nutrition Examination Survey, 4.0% of sexually active men aged 18–59 yr reported having been diagnosed with genital warts at some point [71]. Although genital warts are benign and not associated with mortality, they are a source of

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Table 5 – Cancers associated with high-risk human papillomavirus infection and with human papillomavirus type 16 or 18 infection Site

Attributable to hrHPV, %

Attributable to HPV-16 or HPV-18, %

Cases, no. Total

Penis Cervix Vulva Vagina Anus (male) Anus (female) Oropharynx (female) Oropharynx (male) All sites (male) All sites (female) All sites (both sexes)

47 100 40 70 84 84 19 19 0.5 9.4 4.8

74 71 93 93 94 94 89.3 89.3 0.4 6.8 3.5

26 529 30 15 14 15 12 48 6 617 6 044 12 662

Attributable to hrHPV

Attributable to HPV-16 or HPV-18

12 361 529 500 12 000 10 500 12 180 13 356 2394 9291 33 832 567 750 601 582

9098 375 945 11 100 9750 11 455 12 561 2138 8299 28 852 411 494 440 346

300 500 000 000 500 900 600 900 844 710 554

HPV = human papillomavirus; hrHPV = high-risk human papillomavirus. Adapted from Arbyn et al [70].

psychosocial distress such as shame and embarrassment [72] and are a major global health burden. The incubation period is 3 wk to 8 mo, with most warts developing 23 mo after infection with HPV [73] (Fig. 2). Genital warts are highly infectious, and approximately 65% of people who have sex with an infected partner will develop warts themselves [68]. About 20–30% of genital warts will spontaneously regress; however, recurrence of warts is common [74]. More than 90% of genital warts are caused by nononcogenic HPV types 6 and 11 [75], but approximately one-third of genital warts have multiple HPV types including coinfection with oncogenic types [76]. Data available for

the HPV type distribution of genital warts in men are sparse. One case series of 135 men from Hong Kong detected HPV DNA in 96% of genital warts [75]. Among warts that tested positive for HPV, 75.4% had nononcogenic types only, 3.8% had oncogenic types only, and 20.8% had both oncogenic and nononcogenic types. There was a high rate of multiple infections (33.8%), often including coinfection with oncogenic types. HPV-6 was the most common type detected (54.6%), followed by HPV-11 (40.8%) and HPV-16 (6.2%). It has been observed that genital warts are more common in men with penile cancer. A history of warts on or around the genital or rectal area that occurred 2 yr before the reference date increased the rates of both penile carcinoma in situ (odds ratio [OR]:1.7; 95% CI, 0.41–7.2) and invasive penile carcinoma (OR: 3.7; 95% CI, 0.81–15) [77]. Maden et al [78] reported that the risk of penile cancer in men with a history of genital warts was 5.9 times that of men with no such history (95% CI, 2.1–17.6). In a case-control study of men with penile cancer, 25.7% reported a history of genital warts compared with 4.8% of controls (OR: 7.6; 95% CI, 4.3–13) [79]. 4.2.

Fig. 2 – Genital warts. Photograph courtesy of Cathy Corbishley, St George’s Hospital, London, UK.

Premalignant lesions

HPV-related premalignant lesions include malignant giant condylomata acuminata, Bowenoid papulosis, Bowen’s disease, and erythroplasia of Queyrat (EQ). HPV-related precancerous lesions are associated with persistent HPV-16 and HPV-18 infection. Giant condyloma is associated with HPV-6 and HPV-11 [80]. Studies have estimated that approximately 60–100% of in situ (penile intraepithelial neoplasia [PeIN]) lesions are positive for HPV DNA [81–85]. In a large multicentre study of HPV DNA prevalence in penile cancer, HPV DNA was detected in 100% of condylomas, 90% of dysplasia cases, and 42% of penile carcinomas [83]. There were significant differences in HPV prevalence among the different histologic tumour subtypes. Keratinising and verrucous carcinoma were positive for HPV DNA in 34.9% and 33.3% of the cases, respectively. Basaloid and warty penile cancers were positive for HPV DNA in 80% and 100% of the cases, respectively. The results suggest that PeIN

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is a precursor lesion to only a subset of tumours, including basaloid and warty carcinomas [83]. In another series, 117 formalin-fixed specimens of penile cancer were analysed with PCR for HPV DNA and the findings revealed no significant association with typical keratinising verrucous SCC of the penis, whereas the association with basaloid SCC was 75% [86]. From these findings, it is now believed that giant condyloma differs from verrucous carcinoma [87], as papillary and verrucous SCCs are not strongly HPV related, whereas the basaloid warty variants and giant condyloma are. Foci of infiltrating carcinoma may be found in 23% of cases of giant condyloma, and there are reports of progression to carcinoma [83]. Bowen’s disease and EQ are the same disease entity with a different clinical presentation; Bowen’s disease involves the penile shaft, whereas EQ involves the inner aspect of the prepuce or the glans penis. Both diseases are related to HPV16 and HPV-18, with HPV-16 being more common (80%). Bowen’s disease and EQ are both penile carcinoma in situ (PeIN) histologically. A study of 12 biopsies from eight patients with EQ demonstrated 100% positivity for HPV DNA [82]. Invasive SCC may arise in 5% of long-standing Bowen’s disease cases and 10–30% of EQ cases [88– 90]. Bowenoid papulosis may rarely evolve to invasive cancer, especially in immune-suppressed individuals [91].

Table 6 – Overall prevalence of human papillomavirus DNA in penile carcinomas Reference McCance et al [93] Iwasawa et al [94] Maden et al [78] Chan et al [95] Cupp et al [81] Gregoire et al [87] Picconi et al [96] Rubin et al [83] Guerrero et al [97] Tornesello et al [98] Scheiner et al [99] Bezerra et al [100] Pascual et al [101] Giuliano et al [44] Nielson et al [43] Rombaldi et al [102] Ding et al [103] Suzuki et al [104] Senba et al [105] Salazar et al [106]

Penile cancer

In penile cancer, the role of high-risk HPV infection seems to be variable and is not as clear as for cervical cancer, for which HPV infection is considered responsible for nearly all cases. The International Consultation on Penile Cancer reviewed the overall prevalence of HPV DNA in penile cancer and quoted a range from 15–81%, with high-risk HPV in 24–65% of penile cancer cases, compared with 12% of controls (Table 6) [43,44,78,81,83,86,92–106]. Specifically, penile carcinoma was associated with HPV-16 in 25–94.7% of cases and with HPV-18 in 10.5–55.4% (Table 7) [78,83,92,97–101,105,107,108]. Scheiner et al [99] determined the prevalence of HPV in Rio de Janeiro, Brazil, in 80 consecutive cases and found HPV DNA in 75% of patients with invasive carcinoma and 50% with verrucous carcinoma. Rubin et al [83] reported that keratinising SCC and verrucous carcinoma were positive for HPV DNA in only 34.9% and 33.3% of cases, respectively, and HPV DNA was detected in 80% of basaloid tumour subtypes and 100% of warty tumour subtypes (Fig. 3). Cubilla et al [109] reported detection of HPV-16 in nine of 11 basaloid cases (81%) and 3 of 5 warty SCC cases (60%) of the penis. Miralles-Guri et al [110] calculated a weighted estimate of overall HPV prevalence of 38.9% from a systematic review of 31 cases (n = 1466), in which HPV-16 was detected in 60%, HPV-18 in 13.3%, and HPV-6/HPV-11 in 8.1%. A summary from this report of HPV distribution according to specific histologic subtypes is detailed in Table 8 [110]. The seropositivity to HPV-16, HPV-18, or HPV-45, the most common oncogenic types of HPV, was 46% among penile cancer cases and 12% among controls (OR: 5.0; 95% CI, 1.4–17.2) in a case-control study in Uganda [111]. In a

HPV DNA positive, %

53 111 67 41 42 117 38 142 10 41 80 82 49 303 463 99 28 13 65 54

51 63 49 15 55 22 71 42 40 46 72 30 77 65 65 54 61 54 81 65

HPV = human papillomavirus. Adapted from Pow-Sang et al [92].

Table 7 – Prevalence of high-risk human papillomavirus in penile carcinoma Reference

4.2.1.

Cases, no.

Guerrero et al [97] Varma et al [107] Bezerra et al [100] Maden et al [78] Rubin et al [83] Pascual et al [101] Lont et al [108] Scheiner et al [99] Tornesello et al [98] Senba et al [105]

HPV-16 prevalence, %

HPV-18 prevalence, %

25 65 52 63 60 84.2 76 52 94.7 –

75 – – – – 10.5 – – – 55.4

HPV = human papillomavirus. Adapted from Pow-Sang et al [92].

North American case-control study, positive HPV-16 serology was found among 24% of cases and 12% of controls (OR: 1.9; 95% CI, 1.2–3.2), and 80% of penile cancer tissue specimens were positive for HPV DNA [79]. HPV-related tumours such as warty and basaloid cancers affect younger patients (aged 45–55 yr) and verrucous and pseudohyperplastic carcinomas occur at older ages (70–80 yr). Although there is some evidence for the role of HPV in the aetiology of penile cancer, there is not yet a consensus on its significance in penile cancer prognosis. Gregoire et al [86] described a more aggressive vertical tumour growth and increase in poorly differentiated cancers in HPV DNA–associated tumours. Daling et al [79] also found an increased risk for invasive cancers with positive HPV-16 serology. Cubilla et al [112] reported HPV in 6% of grade 1 tumours compared with 53% of grade 3 tumours (p < 0.0001). Lont et al [108] found that HPV status was an independent predictor for disease-specific mortality in penile cancer in a multivariate analysis

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explanation why HPV-negative patients should have lower cancer-specific survivals. No correlation between HPV presence and survival could be found in two further studies [100–113]. 4.3.

Fig. 3 – Warty penile carcinoma. Photograph courtesy of Cathy Corbishley, St George’s Hospital, London, UK.

(p = 0.01), with the presence of high-risk HPV conferring a survival advantage in patients with penile carcinoma (disease-specific 5-year survival in high-risk HPV-negative group vs high-risk HPV-positive group: 78% vs 93%, respectively; p = 0.03). There is presently no scientific

Human papillomavirus infection prevention: vaccination

The economic burden of HPV disease in individuals aged 15–24 yr has been estimated at nearly US $3 billion in America alone, with an estimated $200 million spent annually in direct medical costs just for genital wart treatment [114,115]. HPV infection leads to cervical cancer with a latency period of 8–10 yr. This highlights the major health burden of HPV and has led to the search for effective prevention strategies. Two vaccines against the most frequent high-risk HPV types (HPV-16 and HPV-18, the most commonly associated with cervical cancer) have been developed: Gardasil (Merck and Co., Inc., Kenilworth, NJ, USA), a quadrivalent vaccine targeting HPV-6, HPV-11, HPV16, and HPV-18; and Cervarix (GlaxoSmithKline, London, UK), a bivalent vaccine that targets HPV-16 and HPV-18. Vaccination could prevent nearly 70% of all cervical cancers. The preventive effect is restricted to countries with predominantly HPV-16 and HPV-18 infections. Although HPV types 16, 18, 31, and 45 are the main high-risk HPV types in Europe and the United States, HPV types 13, 33, 39, and 59 are the most common in South America [114]. The approval studies for HPV vaccines included some boys aged 9–15 yr. The rate of seroconversion after vaccination was comparable to that in girls and as high as 99.1–100%. The anti-HPV immunoreaction after vaccination was higher in boys and girls than in women. The protection from HPV infection is secure up to 5 yr after vaccination. Further long-term data are currently not available [116]. Furthermore, the efficacy of the vaccine at preventing penile cancer or premalignant penile lesions could not be assessed given the low incidence of the disease in the study population (only four cases of PeIN and no cases of penile cancer in the entire study group of 4065 patients) [116]. In the absence of data, one can only assume that vaccination in males can prevent HPV-associated penile

Table 8 – Human papillomavirus prevalence by penile squamous cell carcinoma histologic subtypes Histology

SCC (unspecified) Basaloid SCC Warty SCC Nonkeratinising (typical) Mixed warty-basaloid Keratinising SCC Other SCC mixed Verrucous Papillary

Cases, no.

Overall HPV prevalence, % (95% CI)

HPV-16 relative contribution, % (95% CI)

HPV-18 relative contribution, % (95% CI)

HPV-5/HPV-11 relative contribution, % (95% CI)

671 46 56 117 19 448 42 57 10

49.62 (45.7–53.4) 76.00 (61.2–87.4) 58.9 (44.9–71.9) 47.8 (38.5–57.2) 47.3 (38.8–48.2) 43.5 (38.8–48.2) 33.33 (19.5–49.5) 24.5 (14.1–37.7) 0.0 (0.0–30.8)

75.37 (70.4–79.9) 65.71 (47.8–80.8) 75.75 (57.7–88.9) 67.85 (54.0–79.7) 0.0 (0.0–33.6) 31.79 (25.3–38.8) 62.5 (24.4–91.4) 35.71 (12.7–64.8) 0.0 (0.0–30.8)

12.01 (8.7–15.9) 0.0 (0.0–10.0) 3.03 (0.0–15.7) 14.28 (6.3–26.2) 0.0 (0.0–33.6) 21.02 (15.5–27.4) 12.5 (0.3–52.6) 7.14 (0.1–33.8) 0.0 (0.0–30.8)

5.10 (3.0–8) 2.85 (0.0–14.9) 9.09 (1.9–24.3) 16.07 (7.6–28.3) 0.0 (0.0–33.6) 12.30 (8.0–17.7) 0.0 (0.0–36.9) 14.28 (1.7–42.8) 0.0 (0.0–30.8)

CI = confidence interval; HPV = human papillomavirus; SCC = squamous cell carcinoma. Adapted from Miralles-Guri et al [110].

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cancer development by herd immunity. If one takes into account the wider-ranging benefits of HPV vaccination to men in terms of reducing the burden of other HPV-related conditions and malignancies, such as genital warts, anal cancer (90% HPV related), and oropharyngeal cancers (10% HPV related), the argument for extending vaccination programs to cover both sexes is considerably strengthened in terms of public health benefits and cost-effectiveness [117]. The Advisory Committee on Immunization Practices from the Centers for Disease Control and Prevention in the United States recently changed its guidelines on male HPV immunisation in the United States based on the wider health benefits, recommending use of the quadrivalent vaccine in males aged 13–22 yr [118]. As such, any beneficial effect of vaccination in males on the prevention of penile cancer would be an added bonus rather than the main indication for extending the vaccination program to both sexes. As in the United States, a program of vaccination using the quadrivalent vaccine prior to first sexual contact would provide the most cost-effective approach. If there is a decision for HPV vaccination, for example, by parental choice, male vaccination should be performed as in girls before the first sexual contact. Penile cancer is not exclusively restricted to HPV infection but is also associated with chronic inflammatory processes like phimosis, balanoposthitis, or LS; therefore, HPV vaccination cannot be an absolute guarantee for prevention of penile cancer. So, is vaccination a realistic health strategy in prevention of penile carcinoma in men? In the absence of preventive strategies, it is projected that the relative increase in the older male population worldwide will result in an increase in penile cancer incidence of approximately 23%. Despite presuming that vaccination reduces the risk by 90%, it is calculated that the incidence of penile cancer by 2050 would only be reduced by 27%. As yet, there is no evidence supporting the use of mass vaccination of the male population as a preventive measure in penile cancer [119]. Many of the arguments for male vaccination are related to the direct benefits men can receive from vaccination as well as the indirect benefits women can receive from male vaccination. The potential for herd immunity after only one sex is vaccinated is suggested by recent results from Australia that demonstrate a protective effect for males when a majority of females, but no males, are vaccinated [120]. In 2007, the quadrivalent HPV vaccine was administered to females aged 12–26 yr, with coverage rates of 65–75%. Both heterosexual men and women younger than 28 yr showed a significant decrease in the incidence of genital warts in 2008 compared with 2004 to 2007, with prevalence ratios of 0.83 (95% CI, 0.74–0.92) and 0.52 (95% CI, 0.44–0.63), respectively. The decrease in incidence of genital warts was not observed among men who have sex with men or among women older than 28 yr. Especially in countries such as the United States, where only 18% of ageeligible females have received all three doses of vaccine, male vaccination may provide a viable approach to increase protection against HPV in both males and females.

9

The effectiveness of any vaccination program that incorporates males will rely on awareness of HPV infection and disease within the general male population. Population-based data among Danish men (n = 23 000) aged 18–45 yr suggest there is lower awareness of HPV in men (10%) compared with women (25%) [121,122]; thus, low awareness of HPV in males may be a barrier to the prevention of HPV infection. More data are needed regarding the transmission dynamics of the different HPV types and the effectiveness of male vaccination to reduce HPV-related disease in men and women. Further open areas to explore are the following: (1) vaccination of special risk groups (men with multiple partners); (2) vaccination in countries with high prevalence of penile cancer and predominant HPV-16 or HPV-18 infections; (3) partners of patients with genital warts or other sexually transmitted diseases; and (4) boys from high-risk groups. 4.4.

Human papillomavirus infection prevention: circumcision

Circumcision at a young age is associated with a decreased risk of penile cancer [119]. Recent randomised clinical trials have shown that adult male circumcision resulted in approximately 50% decreased incidence of human immunodeficiency virus (HIV) infection as well as a significantly lower incidence of penile high-risk HPV infection in both HIV-negative and HIV-positive men and in female partners of HIV-negative men but not in the female partners of HIVpositive men [123]. Circumcision of neonatal boys and men contributes directly to HPV control and potentially to control of other sexually transmitted diseases acting as an HPV transmission cofactor. 4.5.

Human papillomavirus treatment

The primary reason for treating genital warts is symptom control (including cosmesis) and ultimately their removal. In most patients, treatment can induce wart-free periods. If left untreated, visible genital warts can resolve, remain unchanged, or increase in size or number. Available therapies for genital warts likely reduce but probably do not eradicate HPV infectivity. Whether the reduction in HPV

Table 9 – Treatment regimens for external genital warts Recommended regimens for external genital warts treatment Patient applied: Podofilox 0.5% solution/gel Imiquimod 5% cream Sinecatechins 15% ointment Clinician-administered: Cryotherapy (liquid nitrogen/cryoprobe) with repeated applications every 1–2 wk Podophyllin resin 10–25% (in a compound tincture of benzoin) Trichloroacetic acid/bichloroacetic acid 80–90% Surgical removal Adapted from the Centers for Disease Control and Prevention 2010 sexually transmitted disease treatment guidelines [61].

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Fig. 4 – European Urological Association of Urology recommendations for stage-dependent local treatment of penile carcinoma [74]. CO2 = carbon dioxide; GR = grade of recommendation; LE = level of evidence; Nd:YAG = neodymium:yttrium-aluminium-garnet.

viral DNA resulting from treatment reduces future transmission remains unclear [61]. Factors that influence selection of treatment include wart size and number, anatomic site and morphology of the wart, patient preference, cost of treatment, convenience, adverse effects, and clinician experience. Factors that might affect response to therapy include the presence of immunosuppression and compliance with therapy, which can consist of either a single treatment or a complete course of treatment (Table 9). Most genital warts respond within 3 mo of therapy. A summary of the EAU recommendations for stagedependent local treatment of penile cancer is shown in Figure 4. More detailed management recommendations, including treatment of nodal disease, can be found in the latest EAU guidelines [60]. 5.

Future areas for research

There is an urgent need for more data on the incidence and persistence of HPV at the different anatomic sites, the incidence of external genital lesions, and the types of HPV in these lesions. This will allow a more comprehensive understanding of the natural history of HPV infection and its progression to both benign and malignant disease in men

and will help formulate the development and implementation of vaccination programs. Further areas of research include progression rates of HPV lesions and the role of the immune response in protection against infection, persistence, and disease progression [51,58]. In addition to the available modelling studies, there is still a need for more research into the efficacy of vaccination in males and its effect on female protection. A number of ongoing studies taking place in the United States, Mexico, Brazil, the Netherlands, and Denmark are currently addressing issues surrounding both the natural history and transmission of HPV infection in men [124]. Conflicts of interest The authors have nothing to disclose. Funding support None. References [1] Mu¨nger K, Baldwin A, Edwards K, et al. Mechanisms of human papillomavirus-induced oncogenesis. J Virol 2004;78:11451–60.

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