Human papillomavirus (HPV) is a widespread sexually transmitted infection. In both men and women, HPV infection can result in a spectrum of genitourinary manifestations ranging from genital warts to cancer. Cervical cancer is nearly always associated with high-risk HPV infection. For men, penile cancer can develop following or independently of HPV infection. Basaloid and warty subtypes of penile squamous cell carcinoma are most frequently associated with HPV infection. Further research into the molecular alterations caused by HPV infection may provide prognostic markers and future treatment targets. Until an effective treatment for HPV infection is developed, prevention will remain the focus of disease control. For women, vaccination is increasingly utilized to prevent HPV infection and subsequent cervical cancer development. New recommendations for routine male vaccination may further reduce cancers for both men and women.
Introduction
Penile cancer is a relatively rare malignancy in the United States. Delay in presentation and misdiagnosis can result in both poor functional outcomes following treatment and reduced survival. Several risk factors have been identified for the development of penile cancer, demonstrating two pathways to malignant transformation, with the presence or absence of human papillomavirus (HPV) infection a central distinction between them. In addition to penile cancer, HPV infection is associated with several other malignancies, including cervical cancer, anal cancer, and oropharyngeal cancer. The nearly ubiquitous association between HPV infection and cervical cancer has resulted in widespread efforts to better understand and prevent HPV infection. In men, HPV infection results in a wide range of genitourinary pathology, ranging from genital warts to penile and anal carcinoma. HPV has been detected in one-third to one-half of penile cancers. This article provides a comprehensive and up-to-date review of the role of HPV infections in men and in the development of penile cancer.
Genital HPV Infection in Men
TO PUT THAT INTO CONTEXT
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Anna R. Giuliano, PhD
Gregory J. Diorio, DO
Center for Infection Research in Cancer (CIRC), Moffitt Cancer Center, Tampa, FloridaWhat Do We-and Don’t We-Know About Penile Cancers? Penile cancer is a rare cancer in the United States and other high-resource countries; however, incidence rates are significantly higher among US Hispanics and in men residing in low-resource countries. Due to its rarity, penile cancer is an understudied cancer; therefore, robust level 1 evidence that can drive treatment guidelines is lacking. More research focused on improving treatment options and maximizing survivorship is needed.What Is the Role of HPV in Penile Cancer?Infection with high-risk human papillomavirus (HPV) types 16 and 18 causes a subset of penile cancers, specifically those with warty and basaloid histologies. In contrast to cervical cancer and other HPV-associated malignancies, it remains unclear where HPV status stands as a prognostic factor in patients with penile cancer, and whether positivity for high-risk HPV is associated with a difference in the response to treatment.How Can the Burden of HPV-Associated Penile Cancer Be Most Effectively Reduced? While factors such as neonatal circumcision have been associated with a reduced incidence of penile cancer, vaccination against HPV types 16 and 18 will likely be the most effective method for reducing penile cancer and other HPV-related diseases in the future. Unfortunately, few countries currently have national recommendations for male HPV vaccination (the United States, Australia, and Austria are the only three to date), and uptake of the vaccine in both males and females in the United States has been relatively low. Broad dissemination of the cancer-preventing HPV vaccine and further research investigating HPV-specific targeted therapies are needed to reduce the burden of penile cancers and other HPV-related disease worldwide.Financial Disclosure:Dr. Giuliano has received grants from and consults for Merck.
HPV infection is the most common sexually transmitted infection in the United States.[1] Infection with oncogenic HPV appears to be required for the development of cervical cancer. From this observation, association studies of cervical cancer development have identified high-risk and low-risk HPV genotypes, classified by their oncogenicity.[2] High-risk genotypes include 16, 18, 33, and 35, while low-risk genotypes include 6 and 11. Although HPV infection appears to cause all cervical cancer, it causes only a fraction of penile cancers. This may be due to increased resistance to malignant transformation in penile tissue compared with cervical tissue.
To improve our understanding of the relationship between HPV infection and genital disease in men, studies have been conducted evaluating the prevalence of HPV infection and carriage in men. In studies attempting to detect HPV DNA from male anogenital sampling, the prevalence is often 20% or higher.[3,4] The prevalence of HPV infection in adult men appears to be constant across age groups, without showing a decline in older men, as is seen in older women.[4]
HPV infection can result in a spectrum of genitourinary manifestations. In men, infection can cause genital warts, penile intraepithelial neoplasia (PeIN), and penile carcinomas. Most HPV infections remain asymptomatic, and up to 70% are cleared within 1 year.[3] In a multinational, prospective, longitudinal study (HPV Infection in Men [HIM]), the median time to clearance of infection was 7.5 months.[5] For HPV 16-a high-risk oncogenic HPV-median clearance was longer, at 12.2 months. When the infections are not cleared, they most commonly manifest as genital warts. Although warts are benign and typically asymptomatic, the lesions can become problematic, with pain, itching, and bleeding. The presence of warts is cosmetically disfiguring and can cause patient distress. Warts can also become larger and spread to new locations. Genital warts are highly infectious, and up to 64% of sexual partners will eventually develop warts as well.[6] However, it is unlikely that treating genital warts would prevent transmission, as partners typically have already become infected before lesions appear.
PeIN is a clinical entity associated with HPV infection, with several differing classification systems. Similar to squamous cell carcinoma (SCC) in situ, PeIN represents a dysplastic premalignant lesion. To classify PeIN, doctors use a system similar to that used for cervical intraepithelial neoplasia, with the categories PeIN I, II, and III.[4] Clinically, PeIN is often subdivided into erythroplasia of Queyrat (EQ), Bowen disease (BD), and bowenoid papulosis. EQ arises from the mucosal surfaces of the glans and foreskin, while BD is found on the keratinized skin of the penile shaft.[7] EQ lesions typically have the highest risk of progressing to SCC.[8] Studies evaluating the prevalence of HPV DNA in PeIN lesions have found that 60% to 100% of lesions test positive.[4] In one of the larger studies, which also evaluated for HPV subtypes, 90% of PeIN lesions tested positive for HPV, with HPV 16 being the most common type (40.7%).[9] The lower frequency of HPV-associated invasive penile carcinoma relative to the more widespread correlation of HPV with PeIN has led to the proposal of a new classification system consisting of four categories based on immunohistochemical profiles: differentiated, basaloid, warty, and warty-basaloid PeIN.[7] The classification system identifies differentiated PeIN based on a lack of HPV association, while the undifferentiated or basaloid/warty/warty-basaloid lesions are typically HPV-positive. This system provides a basis for the bimodal pathogenesis of PeIN based on the presence or absence of HPV.[7] Differentiated PeIN appears more commonly in countries with a higher incidence of penile cancer, while undifferentiated PeIN is more common in areas with a lower incidence of penile cancer.[10] The College of American Pathologists has adopted the differentiated/undifferentiated classification system for PeIN.[11]
The progression of precursor lesions to invasive penile carcinoma is not completely understood. In a study of 288 invasive penile cancers and associated lesions, squamous hyperplasia was present in 83% of cases, low-grade PeIN in 59%, and high-grade PeIN in 44%.[12] This would suggest a progression from hyperplasia to low-grade PeIN to high-grade PeIN. It was noted that hyperplasia was more frequent in the usual and verrucous SCC, while high-grade PeIN was more common in warty/basaloid tumors.[12]
Penile Cancer Incidence
Penile SCC is uncommon in the developed world. In 2015, an estimated 1,820 men were diagnosed in the United States, and it was estimated that 310 would die from the disease.[13] The incidence in the United States is around 0.8 per 100,000 men.[14] However, in the developing world, an incidence of up to 4.4 per 100,000 men is reported but is declining.[15,16] Penile cancer most often occurs in older men, with a peak incidence in the seventh decade.[17] Two pathways have been proposed for penile cancer development-one related to HPV infection and the other related to phimosis and/or chronic inflammation. Several risk factors have been identified for the development of penile cancer, including poor hygiene, phimosis, smoking, and lack of circumcision. Other risk factors include increased number of sexual partners, lack of condom use, and presence of balanitis or lichen sclerosus.[4] Penile cancer is rare in men who are circumcised at birth. Even in the developing countries with high rates of penile cancer, subgroups within the population who conduct neonatal circumcision have lower rates of penile cancer.[17]
HPV Presence in Penile Carcinomas
In women, nearly all invasive cervical cancers are associated with detectable oncogenic HPV when using sensitive polymerase chain reaction.[18] However, HPV detection in men is more variable, and it has thus been proposed that some penile cancers are associated with HPV while others are not.[9] A systematic review of studies evaluating HPV prevalence in penile cancers found that 48% of evaluated tumors tested positive for HPV.[19] Another study confirmed these findings, identifying HPV in 46.9% of tumors, with HPV 16 and 18 representing the most common types (Table 1).[20]
Similar to the variation in HPV infection between differentiated and undifferentiated PeIN, variation in HPV rates among the differing SCC histologic subtypes has been observed. The more keratinized subtypes, such as usual and verrucous SCC, have lower HPV detection compared with warty and basaloid SCC. In a systematic review of HPV infection in penile cancer, HPV prevalence varied significantly among SCC histologic subtypes.[19] In this study, HPV was detected in only 22.4% of verrucous SCC but in 66.3% in the basaloid/warty subtypes. The most common HPV type identified was HPV 16, seen in 30.8%, while HPV 6 and HPV 18 represented 6.7% and 6.6%, respectively. Other studies have confirmed the highest rate of HPV detection in basaloid SCC, an intermediate rate in warty SCC, and low rates in usual and papillary carcinomas (Table 2).[21]
The heterogeneity of HPV-associated tumors has increased consideration of HPV presence as a prognostic marker for survival. In other HPV-related malignancies, studies have found that HPV association may result in improved survival. Among patients undergoing chemoradiation therapy for oropharyngeal SCC, those with HPV-positive tumors had improved 3-year overall survival.[22] Similarly, in anal cancer, HPV positivity was associated with improved overall and disease-specific survival.[23] In a multivariate model using p16 status as a surrogate for HPV, an independent and significant relationship between p16 and improved survival for anal cancer was reported. In penile carcinoma, an early study evaluated HPV prevalence with respect to survival in 176 patients treated between 1963 and 2001.[24] High-risk HPV was detected in 29% of tumors and was associated with better 5-year disease-specific survival-92%, compared with 78% for HPV-negative tumors. In a multivariate analysis, tumor HPV status was an independent predictor of survival. The same group recently conducted an updated study in contemporary penile cancer patients treated between 2001 and 2009.[25] High-risk HPV was detected in 25% of patients and was associated with improved 5-year disease-specific survival-96% compared with 82% (P = .016). This survival benefit remained significant on multivariate analysis (hazard ratio [HR], 0.2; P = .03). However, other studies have failed to show a survival benefit for HPV positivity. In a study of 82 men treated with penectomy and bilateral lymphadenectomy, HPV-positive tumors were associated with less lymphatic embolization by neoplastic cells, but this did not result in differences in lymph node metastases or 10-year overall survival.[26] Moreover, a study evaluating p53 status as a prognostic factor found that patients positive for p53 and HPV DNA had worse overall survival.[27] These conflicting results may be related to geographic variations in the frequency and pathogenesis of HPV-related penile cancer. A better understanding of the genetic pathways involved in malignant transformation may improve our understanding of HPV infection as a prognostic marker.
HPV-Induced Genetic and Epigenetic Alterations
Several studies have investigated the different oncogenic pathways of HPV-induced penile cancer and noninfectious penile cancer by evaluating the genomic and epigenetic alterations in penile cancer. The oncogenic properties of HPV infection are related to viral proteins E6 (which acts on the p53 pathway) and E7 (which acts on the retinoblastoma (Rb) tumor suppressor).[28] In particular, E7 activity on Rb blocks the feedback inhibition on p16Ink4a, resulting in increased expression of p16Ink4a .[29] In a study of 53 penile cancer specimens, 20 tested positive for HPV DNA, with high-risk HPV 16 being the most common HPV type identified (15/20).[29] Of these 15 samples, HPV 16 E6/E7 transcripts were identified in 13. Immunostaining for p16Ink4a found 12 of the 13 had strong nuclear and cytoplasmic staining, which confirmed the association of increased expression of p16Ink4a with high-risk HPV infection, consistent with findings in cervical lesions. The strong relationship between HPV infection and increased p16Ink4a expression has resulted in the use of p16Ink4a immunostaining as a means of HPV testing.[21]
Although interference with the tumor suppressors p53 and Rb are felt to be the most critical oncogenic effects of HPV infection, other genetic alterations may also be important. Altered micro RNA (miRNA) expression has been evaluated in other SCCs resulting from HPV infection and could be important for disruption of gene regulation that results in oncogenic effects. In a study evaluating miRNA expression in penile cancer specimens, miR-218 expression was reduced in specimens positive for high-risk HPV infection.[30] Along with p53 and Rb downregulation, reduction in miR-218 may be an important event in HPV-induced carcinogenesis.
To further characterize genomic alterations resulting from HPV infection, array comparative genomic hybridization has been used to compare tumors by HPV positivity. In one study, 19 regions of genomic alteration were identified that correlated with HPV-positive tumors.[31] Of these regions, nine sites exhibited alterations similar to previously described alterations in studies of cervical cancer. This finding may improve the understanding of cellular alterations caused by integration of the viral genome following HPV infection.
In addition to genomic alterations, HPV infection may result in epigenetic alterations that induce oncogenesis and may be predictive of survival. In a study using genome-wide methylation arrays to evaluate HPV-positive penile tumor samples, an HPV-specific epigenetic signature that was primarily hypomethylated was created.[32] This epigenetic signature was able to identify HPV-associated tumors in an independent cohort of head and neck SCC tumors. Further, a set of 30 HPV-specific methylation positions was able to predict disease-free survival in a group of head and neck and cervical cancer specimens. Identification of these epigenetic signatures may improve our understanding of HPV-related oncogenesis, predict survival in groups with HPV-induced cancers, and identify potential therapeutic targets.
Prevention of HPV Infection and Penile Cancer
Because there currently is no treatment for HPV infection, preventing infection is the only way to reduce disease burden. Although limiting lifetime sexual partners has been explored as a means of reducing HPV infection risk, even those with a single lifetime sexual partner may develop an infection.[16] Condom use has also been proposed as a means of reducing HPV transmission. A study of newly sexually active women demonstrated a 70% reduction in HPV infection when partners used condoms for all instances of sexual activity.[33]
Lack of circumcision is a known risk factor for penile cancer. However, it is unclear whether circumcision is protective against HPV infection. A report of three men who underwent neonatal circumcision and later developed penile cancer found that all three men had a remote history of penile condyloma, and one patient had oncogenic HPV detected in the tumor.[34] These three cases suggest that the oncogenic potential of HPV remains despite neonatal circumcision. Several studies have evaluated HPV prevalence based on circumcision status. In a study of college-aged men presenting to a sexually transmitted disease clinic, prior circumcision did not protect them from HPV infection.[35] In the longitudinal, multinational HIM study, HPV incidence and clearance were not significantly different in circumcised men.[36] However, studies of adult men undergoing circumcision have shown a protective effect compared with control groups.[37,38] In one study from Uganda, men undergoing circumcision had a 35% reduction in the risk of HPV infection.[38] The protective effect was similar against low-risk and high-risk HPV infections. The same group also showed reduced time to clearance of high-risk HPV infections in men who had undergone adult circumcision.[39]
One of the best methods of reducing HPV infection is vaccination. A large vaccination study in men showed a significant reduction in HPV infection and genital lesions with the vaccine.[40] No cases of PeIN developed in the vaccination arm, suggesting that over time vaccine use may reduce both precancerous and malignant lesions. In 2009, the quadrivalent HPV vaccine was approved for males aged 9 to 26 years. The Centers for Disease Control and Prevention (CDC) Advisory Committee on Immunization Practices (ACIP) initially considered HPV vaccination of males as an option in 2009 but did not recommend routine vaccination until 2011.[16] The most recent ACIP update recommends routine male vaccination beginning at age 11 or 12 with either the quadrivalent or 9-valent vaccine, and also recommends vaccination for males aged 13 to 21 who have not completed a three-dose cycle. Males aged 22 to 26 may be vaccinated, particularly men who have sex with men and those who are immunocompromised.[41] Currently, neither the National Comprehensive Cancer Network nor the European Association of Urology guidelines address vaccination as a method for reducing development of penile cancer. Future studies confirming vaccine benefit and cost-effectiveness may improve utilization.
Conclusion
HPV infection is the most common sexually transmitted infection and a known risk factor for the development of penile cancer. High-risk HPV infections are present in about 40% of penile cancer cases in the developed world. An improved understanding of the relationship between HPV infection and malignant transformation holds the potential for future prognostic markers and treatment targets. Currently, there is no treatment for HPV infection except for management of cutaneous lesions. An effective and safe vaccine has been developed that could reduce the frequency of genital lesions, with the expectation that cancer would also be prevented. Increasing vaccine use as recommended by the CDC may provide longstanding health benefits for both men and women.
Financial Disclosure:The authors have no significant financial interest in or other relationship with the manufacturer of any product or provider of any service mentioned in this article.
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