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Human Papillomavirus Infection and the Links to Penile and Cervical Cancer

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Human Papillomavirus Infection and the Links to Penile and Cervical Cancer 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 ..
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