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.
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
Anna R. Giuliano, PhD
Gregory J. Diorio, DO
Center for Infection Research in Cancer (CIRC), Moffitt Cancer Center, Tampa, Florida
What 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. 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. 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.
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. In a multinational, prospective, longitudinal study (HPV Infection in Men [HIM]), the median time to clearance of infection was 7.5 months. 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. 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. 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. EQ lesions typically have the highest risk of progressing to SCC. Studies evaluating the prevalence of HPV DNA in PeIN lesions have found that 60% to 100% of lesions test positive. 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%). 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. 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. 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. The College of American Pathologists has adopted the differentiated/undifferentiated classification system for PeIN.
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%. 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.
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. The incidence in the United States is around 0.8 per 100,000 men. 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. 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. 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.
HPV Presence in Penile Carcinomas
In women, nearly all invasive cervical cancers are associated with detectable oncogenic HPV when using sensitive polymerase chain reaction. 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. A systematic review of studies evaluating HPV prevalence in penile cancers found that 48% of evaluated tumors tested positive for HPV. Another study confirmed these findings, identifying HPV in 46.9% of tumors, with HPV 16 and 18 representing the most common types (Table 1).
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. 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).
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. Similarly, in anal cancer, HPV positivity was associated with improved overall and disease-specific survival. 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. 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. 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. Moreover, a study evaluating p53 status as a prognostic factor found that patients positive for p53 and HPV DNA had worse overall survival. 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.
1. Cates W Jr. Estimates of the incidence and prevalence of sexually transmitted diseases in the United States. American Social Health Association Panel. Sex Transm Dis. 1999;26:S2-S7.
2. Muñoz N, Bosch FX, de Sanjose S, et al. Epidemiologic classification of human papillomavirus types associated with cervical cancer. N Engl J Med. 2003;348:518-27.
3. Dunne EF, Nielson CM, Stone KM, et al. Prevalence of HPV infection among men: a systematic review of the literature. J Infect Dis. 2006;194:1044-57.
4. Anic GM, Giuliano AR. Genital HPV infection and related lesions in men. Prev Med. 2011;53(suppl 1):S36-S41.
5. Giuliano AR, Lee J-H, Fulp W, et al. Incidence and clearance of genital human papillomavirus infection in men (HIM): a cohort study. Lancet. 2011;377:932-40.
6. Oriel JD. Natural history of genital warts. Br J Vener Dis. 1971;47:1-13.
7. Chaux A, Pfannl R, Rodríguez IM, et al. Distinctive immunohistochemical profile of penile intraepithelial lesions: a study of 74 cases. Am J Surg Pathol. 2011;35:553-62.
8. Wieland U, Jurk S, Weissenborn S, et al. Erythroplasia of Queyrat: coinfection with cutaneous carcinogenic human papillomavirus type 8 and genital papillomaviruses in a carcinoma in situ. J Invest Dermatol. 2000;115:396-401.
9. Rubin MA, Kleter B, Zhou M, et al. Detection and typing of human papillomavirus DNA in penile carcinoma: evidence for multiple independent pathways of penile carcinogenesis. Am J Pathol. 2001;159:1211-8.
10. Soskin A, Vieillefond A, Carlotti A, et al. Warty/basaloid penile intraepithelial neoplasia is more prevalent than differentiated penile intraepithelial neoplasia in nonendemic regions for penile cancer when compared with endemic areas: a comparative study between pathologic series from Paris and Paraguay. Hum Pathol. 2012;43:190-6.
11. Velazquez EF, Amin MB, Epstein JI, et al. Protocol for the examination of specimens from patients with carcinoma of the penis. Arch Pathol Lab Med. 2010;134:923-9.
12. Cubilla AL, Velazquez EF, Young RH. Epithelial lesions associated with invasive penile squamous cell carcinoma: a pathologic study of 288 cases. Int J Surg Pathol. 2004;12:351-64.
13. Siegel RL, Miller KD, Jemal A. Cancer statistics, 2015. CA Cancer J Clin. 2015;65:5-29.
14. Hernandez BY, Barnholtz-Sloan J, German RR, et al. Burden of invasive squamous cell carcinoma of the penis in the United States, 1998-2003. Cancer. 2008;113:2883-91.
15. Wabinga HR, Parkin DM, Wabwire-Mangen F, et al. Trends in cancer incidence in Kyadondo County, Uganda, 1960-1997. Br J Cancer. 2000;82:1585-92.
16. Markowitz LE, Dunne EF, Saraiya M, et al. Human papillomavirus vaccination: recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR Recomm Rep. 2014;63:1-30.
17. Bleeker MC, Heideman DA, Snijders PJ, et al. Penile cancer: epidemiology, pathogenesis and prevention. World J Urol. 2008;27:141-50.
18. Walboomers JM, Jacobs MV, Manos MM, et al. Human papillomavirus is a necessary cause of invasive cervical cancer worldwide. J Pathol. 1999;189:12-9.
19. Backes DM, Kurman RJ, Pimenta JM, et al. Systematic review of human papillomavirus prevalence in invasive penile cancer. Cancer Causes Control. 2009;20:449-57.
20. Miralles-Guri C, Bruni L, Cubilla AL, et al. Human papillomavirus prevalence and type distribution in penile carcinoma. J Clin Pathol. 2009;62:870-8.
21. Cubilla AL, Lloveras B, Alejo M, et al. Value of p16(INK4a) in the pathology of invasive penile squamous cell carcinomas: a report of 202 cases. Am J Surg Pathol. 2011;35:253-61.
22. Ang KK, Harris J, Wheeler R, et al. Human papillomavirus and survival of patients with oropharyngeal cancer. N Engl J Med. 2010;363:24-35.
23. Serup-Hansen E, Linnemann D, Skovrider-Ruminski W, et al. Human papillomavirus genotyping and p16 expression as prognostic factors for patients with American Joint Committee on Cancer stages I to III carcinoma of the anal canal. J Clin Oncol. 2014;32:1812-7.
24. Lont AP, Kroon BK, Horenblas S, et al. Presence of high-risk human papillomavirus DNA in penile carcinoma predicts favorable outcome in survival. Int J Cancer. 2006;119:1078-81.
25. Djajadiningrat RS, Jordanova ES, Kroon BK, et al. Human papillomavirus prevalence in invasive penile cancer and association with clinical outcome. J Urol. 2015;193:526-31.
26. Bezerra ALR, Lopes A, Santiago GH, et al. Human papillomavirus as a prognostic factor in carcinoma of the penis. Cancer. 2001;91:2315-21.
27. Lopes A, Bezerra ALR, Pinto CAL, et al. p53 as a new prognostic factor for lymph node metastasis in penile carcinoma: analysis of 82 patients treated with amputation and bilateral lymphadenectomy. J Urol. 2002;168:81-6.
28. Heidegger I, Borena W, Pichler R. The role of human papilloma virus in urological malignancies. Anticancer Res. 2015;35:2513-9.
29. Ferreux E, Lont AP, Horenblas S, et al. Evidence for at least three alternative mechanisms targeting the p16INK4A/cyclin D/Rb pathway in penile carcinoma, one of which is mediated by high-risk human papillomavirus. J Pathol. 2003;201:109-18.
30. Barzon L, Cappellesso R, Peta E, et al. Profiling of expression of human papillomavirus-related cancer miRNAs in penile squamous cell carcinomas. Am J Pathol. 2014;184:3376-83.
31. Busso-Lopes AF, Marchi FA, Kuasne H, et al. Genomic profiling of human penile carcinoma predicts worse prognosis and survival. Cancer Prev Res (Phila). 2015;8:149-56.
32. Feber A, Arya M, de Winter P, et al. Epigenetics markers of metastasis and HPV-induced tumorigenesis in penile cancer. Clin Cancer Res. 2015;21:1196-206.
33. Winer RL, Hughes JP, Feng Q, et al. Condom use and the risk of genital human papillomavirus infection in young women. N Engl J Med. 2006;354:2645-54.
34. Saibishkumar EP, Crook J, Sweet J. Neonatal circumcision and invasive squamous cell carcinoma of the penis: a report of 3 cases and a review of the literature. Can Urol Assoc J. 2008;2:39-42.
35. Weaver BA, Feng Q, Holmes KK, et al. Evaluation of genital sites and sampling techniques for detection of human papillomavirus DNA in men. J Infect Dis. 2004;189:677-85.
36. Albero G, Castellsagué X, Lin H-Y, et al. Male circumcision and the incidence and clearance of genital human papillomavirus (HPV) infection in men: the HPV Infection in Men (HIM) cohort study. BMC Infect Dis. 2014;14:75.
37. Auvert B, Sobngwi-Tambekou J, Cutler E, et al. Effect of male circumcision on the prevalence of high-risk human papillomavirus in young men: results of a randomized controlled trial conducted in Orange Farm, South Africa. J Infect Dis. 2009;199:14-9.
38. Tobian AAR, Serwadda D, Quinn TC, et al. Male circumcision for the prevention of HSV-2 and HPV infections and syphilis. N Engl J Med. 2009;360:1298-309.
39. Gray RH, Serwadda D, Kong X, et al. Male circumcision decreases acquisition and increases clearance of high-risk human papillomavirus in HIV-negative men: a randomized trial in Rakai, Uganda. J Infect Dis. 2010;201:1455-62.
40. Giuliano AR, Palefsky JM, Goldstone S, et al. Efficacy of quadrivalent HPV vaccine against HPV infection and disease in males. N Engl J Med. 2011;364:401-11.
41. Petrosky E, Bocchini JA, Hariri S, et al. Use of 9-valent human papillomavirus (HPV) vaccine: updated HPV vaccination recommendations of the Advisory Committee on Immunization Practices. MMWR Morb Mortal Wkly Rep. 2015;64:300-4.