SIU Penile Cancer Supplement Penile CancerPrevention and Premalignant Conditions

Suks Minhas, Andreas Manseck, Stephen Watya, and Paul K. Hegarty

OBJECTIVES Relatively little evidence is available in the published studies on the prevention of penile cancer and premalignant conditions of the penis. The present review examined the current evidence available in preventing penile cancer and pathologic subtypes of premalignant conditions and their treatment. The recommendations made in the present review formulate the basis of the recent 2009 International Consultation on Urologic Disease Consensus Publishing Group. The association of human papillomavirus subtypes and penile cancer is well-established, although the etiology, natural history, and treatment of premalignant lesions have mainly been reported in retrospective case series with short-term follow-up. The exact pathologic role of chronic inammatory conditions, such as balanitis xerotica obliterans in the etiology of penile cancer remains largely unknown. Some of the potential strategies for the prevention of penile cancer could include circumcision, reducing the risk of transmission of penile human papillomavirus infection with male vaccination, early treatment of phimosis, smoking cessation, and hygienic measures. Implementing some of these measures would require extensive cost/benet analysis, with signicant changes in the global health policy. Owing to the current levels of evidence from published studies, rm guidelines cannot be formulated for the treatment of premalignant conditions, although preventative measures, such as reducing human papillomavirus transmission, could become strategic health targets. UROLOGY 76 (Suppl 2A): S24 S35, 2010. 2010 Elsevier Inc.

METHODS

RESULTS

CONCLUSIONS

enile cancer is a rare male cancer. Although in Western countries the incidence of penile cancer is very low (0.1-0.9/100 000 men in Europe), in some countries, the incidence is signicantly greater, with penile cancer accounting for 10% of all male malignancies. For example, in Uganda and Paraguay, the incidence is as great as 4.4 or 4.2/100 000 men.1,2 The variations in prevalence are likely explained largely by the variance in risk factors, in particular, the practice of neonatal circumcision. Thus, as a health strategy, great scope and potential appears to be present for the prevention of penile cancer. The present review reports on the current levels of evidence available in the published reports on the prevention of penile cancer. Furthermore, the pathologic features and treatment of premalignant lesions of the penis have also been reviewed. The recommendations

made in the present review formulated the basis for the recent International Consultation on Urologic Disease 2009 consensus publication. A summary of the levels of evidence and recommendations from the consensus meeting are also discussed. Penile cancer has been associated with a number of established risk factors and associated diseases or conditions. Phimosis with chronic inammation, human papillomavirus (HPV) infection, poor hygiene, and smoking are the most commonly described risk factors. Thus, circumcision, HPV vaccination, and improved genital hygiene might prevent penile cancer (Table 1).3-5 Table 1 summarize these potential factors discussed in the following sections.

RISK AND PREVENTIVE FACTORS

CircumcisionRoutine Neonatal Current estimates have suggested a circumcision rate of 25% of all males worldwide.6 Interestingly, up to 1999, the American Academy of Pediatrics7 recommended routine neonatal circumcision for health-related reasons. Circumcision as a measure to prevent penile cancer has been repeatedly advocated by different investigators. Morris5 reported circumcision as a biomedical imperative for the 21st century, not only for the reduction of penile cancer, but also for a decrease in urinary tract
0090-4295/10/$34.00 doi:10.1016/j.urology.2010.04.007

Financial Disclosure: The authors have no conicts of interest to declare. From the Institute of Urology, Division of Surgical and Interventional Sciences, University College London, London, United Kindgom; Department of Urology, Klinikum Ingolstadt, Ingolstadt, Germany; Mulago Hospital, Kampala, Uganda; and Department of Urology, Guys and St. Thomas Hospital, London, United Kingdom Reprint requests: Suks Minhas, , Institute of Urology, Division of Surgical and Interventional Sciences, University College London, 2a Maple House, Ground Floor, Rosenheim Wing, 25 Grafton Way, London WC1E 6AU United Kingdom. E-mail: sminhas@btinternet.com Submitted: February 2, 2010; received (with revisions): April 9, 2010

S24

2010 Elsevier Inc. All Rights Reserved

Table 1. Risk factors for the development of penile cancer Risk Factor Phimosis Smegma retention Chronic balanoposthitis HPV infection Penile oral sex5 Lifetime number of female sex partners4 Lifetime intercourse4 Priapism5 Poor genital hygiene Smoking Urethral stricture PUVA therapy Preventive Factors Circumcision HPV vaccination Cessation of smoking Therapy of genital inammation Hygiene education Alcohol absence4 Shielding PUVA

risk was dose dependent and was not explained by the investigated confounding factors, such as phimosis and sexual history. HPV Infection Some studies have shown an association between HPV infection and penile cancer comparable to that of cervical cancer, for which high-risk HPV infection plays a very important role. In cervical cancer, HPV infection has been considered responsible for nearly all cases. In penile cancer, the role of high-risk HPV infection seems to vary and is not clear. Cupp et al11 detected HPV in 55% of their 46 penile cancer cases using the polymerase chain reaction technique. The rate of HPV infection reported by Sarkar et al12 was even greater at 81.8%. Senba et al13 studied 88 specimens of penile cancer in Thailand. They detected HPV DNA in 81.5% using polymerase chain reaction. The most prevalent HPV type was HPV 18 (55.4%), followed by HPV 6 (43.1%). Scheiner et al14 determined the prevalence of HPV in Rio de Janeiro, Brazil, in 80 consecutive penile cancer cases and found HPV DNA was expressed in 75% of patients with invasive carcinoma and 50% with verrucous carcinoma. In contrast, in healthy controls, the HPV infection rates differed markedly. The seropositivity to HPV 16, HPV 18, or HPV 45, the most common oncogenic HPV types, was 46% among those with penile cancer and 12% among controls (odds ratio 5.0, 95% condence interval 1.4-17.2) in a case-control study in Uganda.15 Positive HPV 16 serology was found in 24% of cases and 12% of controls in a North American case-control study (odds ratio 1.9, 95% condence interval 1.2-3.2), and 80% of penile cancer tissue specimens were positive for HPV DNA.8 It would, therefore, seem an attractive and logical assumption that measures reducing HPV transmission would be an important health strategy in the prevention of penile cancer. The prognostic signicance HPV expression and penile cancer has also been investigated by several investigators, with no correlation found by Wiener et al16 and Bezerra et al.17 In contrast, however, Gregoire et al18 described more aggressive vertical tumor growth and more poorly differentiated cancers. Daling et al8 also found an increased risk of invasive cancer with HPV 16 serology. Background Information to HPV Vaccination. HPV is an uncoated double chain DNA virus. It belongs to the family of the papova viruses and is composed of 2 socalled L1 and L2 capsides. There are 100 known variants of HPV. Muoz et al19 has classied HPV types according to their oncogenic potential (Table 3). In gynecologic oncology, it is well-established that persisting HPV infection leads to cervical cancer, with a latency period of 8-10 years. Recently, 2 vaccines against the most frequent high-risk HPV types (HPV 16 and 18) have been developedGardasil, a quadrivalent vaccine
S25

HPV, human papillomavirus; PUVA, psoralen plus ultraviolet light A.

infections, inammatory dermatoses, and sexually transmitted diseases. Recent studies have suggested that phimosis and balanoposthitis are responsible for the development of penile cancer; thus, the reduced rate of penile cancer is probably explained by the effective reduction of phimosis/balanoposthitis, smegma retention, and lichen sclerosus comparison with the incidence in noncircumcised men. Daling et al8 conducted a population-based case-control study in western Washington state that included 137 men diagnosed with in situ (n 75) or invasive (n 62) penile cancer from 1979 to 1998 and 671 control men (Table 2). The investigators found that men who had not been circumcised in childhood had a 1.5-fold increased risk of developing penile cancer. From their study, it was concluded that circumcision in early childhood could help prevent penile cancer by eliminating phimosis and preventing co-factors, such as HPV infection. The ndings from clinical observation studies would appear to support this in that the vast majority of men with penile cancer were uncircumcised. However, the question remains whether circumcising all males at birth would be a realistic health target for reducing the risk of penile cancer. In countries, such as the United Kingdom, with a low prevalence, this would be a difcult health strategy to justify. In less well-developed countries, it might be a more realistic option and would also reduce the risk of HPV and human immunodeciency virus infection transmission. Smoking Smoking has been shown to have a consistent association with penile cancer. Harish and Ravi9 found a signicant association between smoking or chewing tobacco and the development of penile carcinoma. In 503 men and agematched controls, a multivariate analysis demonstrated a signicant association and dose-dependent relationship. Dillner et al10 found a consistent association between penile cancer and smoking from scientic publications identied by a MEDLINE search from 1966 to 2000. The
UROLOGY 76 (Supplement 2A), August 2010

Table 2. Risk of penile cancer associated with selected characteristics, stratied to circumcision status Circumcision in Childhood Controls Cases OR (n 392) (n 64) (95% CI) Phimosis No Yes Genital warts No Yes Smegma Never/rarely Sometimes/ usually Smoking Never Former Current HPV 16 serology Negative Positive Never Circumcised Controls Cases OR (n 247) (n 60) (95% CI) Circumcised Later Controls Cases (n 31) (n 11)

237 (96.3) 41 (68.3) 1.0 17 (58.6) 4 (40.0) 9 (3.7) 19 (31.7) 15.7 (6.0-41.1) 12 (41.4) 6 (60.0)

367 (93.6) 43 (68.3) 1.0 241 (98.0) 47 (78.3) 1.0 30 (96.8) 9 (81.8) 25 (6.4) 20 (31.7) 6.7 (3.2-14.0) 5 (2.0) 13 (21.7) 13.3 (4.3-41.3) 1 (3.2) 2 (18.2) 239 (97.1) 54 (90.0) 7 (2.9) 6 (10.0) 79 (32.0) 9 (15.0) 113 (45.7) 34 (56.7) 55 (22.3) 17 (28.3) 189 (88.7) 46 (83.6) 24 (11,3) 9 (16.4) 1.0 24 (82.8) 9 (100.0) 4.0 (1.2-13.0) 5 (17.2) 0 (0.0) 1.0 2.8 (1.2-65) 3.1 (1.2-8.0) 1.0 1.5 (0.6-3.5) 10 (32.3) 2 (18.2) 7 (22.6) 2 (18.2) 14 (45.2) 7 (63.6) 24 (85.7) 8 (100.0) 4 (14.3) 0 (0.0)

135 (34.4) 16 (25.0) 1.0 174 (44.4) 20 (31.3) 0.8 (0.4-1.7) 83 (21.2) 28 (43.7) 2.2 (1.1-4.5) 295 (86.8) 37 (66.1) 1.0 45 (13.2) 19 (33.9) 2.6 (1.3-5.1)

OR, odds ratio; CI, condence interval; HPV, human papillomavirus. Data presented as numbers, with percentages in parentheses, unless otherwise noted. Main risk factors associated with development of penile cancer by decreasing odds ratio. Data from Daling et al.8

Table 3. HPV types and oncogenic potential Classication High risk Probably oncogenic Low risk HPV Type 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

Modied from Muoz et al.19

targeting HPV 6, 11, 16, and 18, and Cervarix, a bivalent vaccine that targets HPV 16 and 18. Both HPV 16 and 18 have been the most commonly associated with cervical cancer, and it has been estimated that the vaccination could prevent nearly 70% of all cases of cervical cancer. Because the distribution of HPV types is different worldwide, the preventive effect would be restricted to countries with predominantly HPV 16 and HPV 18 infections. HPV types 16, 18, 31, and 45 are most prevalent in Europe and the United States. In contrast, in South America, HPV types 13, 33, 39, and 59 are the most common high-risk HPV types. HPV Vaccination in Males. The approval studies for HPV vaccines included boys 9-15 years old. The rate of seroconversion after vaccination was comparable to that in girls and was as great as 99.1%-100%. The anti-HPV immunoreaction after vaccination was greater in boys and girls than in women. The protection from HPV infection is secure for 5 years after vaccination. Additional long-term data are not yet available.20 In the absence of data regarding male vaccination, one can only assume that male vaccination could prevent HPV-associated penile cancer development. If a decision has been
S26

made for HPV vaccination (eg, by parental choice), male vaccination should be performed, as in girls, before the rst sexual contact. However, 2 important arguments against vaccination have been presented. In countries with a low prevalence of penile cancer, such as in the United Kingdom and Europe, routine vaccination might not be justiable as a cost-effective preventative measure. Furthermore, given the variation and distribution of HPV subtypes worldwide, targeting dened geographic populations might be difcult. Furthermore, penile cancer is not exclusively restricted to HPV infection but has also been associated with chronic inammatory processes, such as phimosis, balanoposthitis, and lichen sclerosus. Therefore, HPV vaccination cannot be an absolute guarantee for the prevention of penile cancer. Another, and perhaps more cost-effective, approach would be to avoid HPV transmission between sexual partners by condom use. Condom Use. Few reports are available on the effect of condom use in the prevention of HPV infection transmission. In a retrospective case-control study of nearly 1000 patients, Wen et al21 were able to demonstrate 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 the acquisition of genital warts, and consistent condom use was associated with a decreased risk of the acquisition of genital warts. In a follow-up study of 82 female university students, Winer et al22 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
UROLOGY 76 (Supplement 2A), August 2010

Table 4. Incidence of phimosis Population British, aged 5-13 Danish, aged 8 British soldiers German youths German men Japanese, aged 11-15 Taiwanese, age 13
Data from Morris.
5

Incidence 20% 8% 14% 9% 9% 23% 16%

References Gairdner,24 1949 Oster,25 1968 Osmond,26 1953 Saitmacher,27 1960 Schberlein,28 1976 Ishikawa and Kawakita,29 2004 Ko et al.,30 2007

100% condom use, no cervical squamous intraepithelial lesions could be observed compared with couples without condom use. Bleeker et al23 performed a randomized trial with couples, of whom, the women had cervical intraepithelial neoplasia and their male partners had HPVassociated at lesions of the penis. The couples were randomized to the use of condoms. In their study, the men in the condom use group experienced a signicantly reduced interval to regression of the at lesion of the penis. This effect was probably due to the blocking of viral transmission between the sexual partners. Phimosis Phimosis is a condition in which the male foreskin cannot be retracted. The main causes of acquired phimosis include chronic inammation, balanoposthitis, forceful foreskin retraction, lichen sclerosus, and diabetes mellitus. The prevalence of phimosis differs regionally from 8% to 23% (Table 4).24-30 It should be remembered that the denitions of phimosis and the interval to diagnosis have differed from study to study. Tseng et al31 performed a population-based, case-control study in Los Angeles County with 100 matched case-control pairs. Phimosis was strongly associated with penile invasive cancer. An inverse correlation was found between penile cancer and neonatal circumcision; however, the correlation was appreciably weakened when the analysis was restricted to subjects with no history of phimosis. Thus, the investigators concluded that the protective effect of neonatal circumcision was largely mediated by the prevention of phimosis. Infection Balanitis and posthitis are an inammation of the glans and prepuce. The incidence differs between circumcised (11%-13%) and uncircumcised men (2%). Dillner et al10 reported a Swedish case-control study of 244 patients, 45% of whom had had 1 episode of balanitis compared with 8% among the controls. Those at increased risk of developing balanitis those with diabetes mellitus, in whom balanitis is seen in 35% of men. However, the exact relationship between inammation and infection and the development of penile cancer remains to be determined, although it might be related to the development of phimosis.
UROLOGY 76 (Supplement 2A), August 2010

Chronic Inammatory Conditions, Lichen Sclerosus Et Atrophicus Lichen sclerosus et atrophicus (LS) and balanitis xerotica obliterans (BXO) are synonymous. LS is a chronic inammatory skin disorder that is restricted to the glans and foreskin, with a prevalence of 1% in children. LS can occur in skin already scarred or damaged; however, both trauma and injury have also been suggested in its etiopathogenesis. An autoimmune pathogenesis after infection has also been suggested. In addition, phimosis has often been associated with LS. Kiss et al32 and Yardley et al33 found LS in their circumcision specimens in 40% and 34.5%, respectively. Nasca et al34 evaluated HPV prevalence in parafn-embedded penile specimens from 46 men with LS and in brush cytology of a randomly selected control group. They detected about twice as many HPV infections in the patients with LS (17.4%) than in the healthy controls (8.7%). They concluded that high-risk HPV infection in patients with LS might increase the risk of penile cancer arising in patients with LS. Prowse et al35 analyzed penile cancer and LS lesions in 46 men for HPV status. In 54% of the cancer cases and 33% of the LS cases, HPV 16 was detected. Barbagli et al36 performed an observational descriptive study. They reviewed the histologic ndings from 130 patients with LS to determine the presence of premalignant and malignant lesions and reported that 11 (8.4%) of the 130 patients had premalignant or malignant histopathologic changes. They concluded that patients with LS should be followed up closely. The incidence of LS has been reported to be 2.3%-5.8% in other studies.37,38 Some studies have suggested that patients with squamous cell carcinoma (SCC) have much greater rates of preexisting LS. Powell et al39 found preexisting LS in 10 of 20 patients with SCC. Pietrzak et al40 reviewed the data from 155 patients with penile carcinoma. They found LS in 28% of the men with penile cancer. Perceau et al41 demonstrated that 44% of penile SCC cases were associated with LS. They found that penile SCC not associated with LS tended to be associated with high-risk HPV infection. In contrast, LS-associated penile SCC was not, although their study was retrospective with a small number of patients.41 von Krogh and Horenblas42 stated that no consensus has been reached regarding an appropriate follow-up policy for LS. However, from the published data, patients presenting with LS should at least be instructed to perform regular self-examinations.

Hygiene Very little evidence is available to establish a link between penile hygiene and cancer. van Howe and Hodges43 have refuted any scientic basis for the carcinogenicity of smegma. One cross-sectional study44 postulated an association between circumcision and penile hygiene. Poor genital hygiene was more common in the
S27

uncircumcised (26%) than in the circumcised (4%). Of the circumcised men, 37% washed more than once a day compared with 19% of the uncircumcised. Frisch et al45 investigated the long-term trends (Denmark 1943-1990) in the incidence of penile cancer in an uncircumcised population. They concluded that the decreasing incidence of penile cancer in Denmark probably resulted from better penile hygiene owing to improvement in sanitary installations. Psorsalen Plus Ultraviolet Light A Treatment The rst description of SCC after psoralen plus ultraviolet light A (PUVA) therapy for psoriasis was reported by Tam et al46 in 1979. In 1990, Stern47 prospectively reported on 892 men during a 12-year follow-up period. In the patients treated with high levels of oral methoxsalen (8-methoxy psoralen) and ultraviolet A photochemotherapy (PUVA), the incidence was 286 times that in the general population. A strong dose-dependent increase was found in the risk of genital cancer development. The same group reported additional follow-up data in 2002. Although penile protection was administered during PUVA therapy, the risk of genital tumor development persisted. These studies would suggest that patients undergoing PUVA therapy should be advised to carefully shield their genitalia and closely observe any skin changes, especially after high levels of PUVA therapy.

PENILE PREMALIGNANT LESIONS

SCC of the penis is often seen to develop in a preexisting lesion. Such lesions have often been referred to generically as premalignant lesions. They might be better categorized as those that are either HPV related or due to chronic inammation. Paradoxically, not all penile premalignant lesions will develop into invasive SCC, although the evidence within the published data has not been extensive. The natural history and biologic behavior of these conditions varies considerably. The situation has been further complicated by the small numbers of reported case studies and the confusing pathologic nomenclature used to describe such conditions. HPV-related lesions include malignant giant condylamata acuminata, bowenoid papulosis, Bowens disease, and erythroplasia de Queyrat. Those due to chronic inammation include genital LS (also termed balanitis xerotica obliterans or BXO), penile horn, leukoplakia, and pseudoepitheliomatous, keratotic, and micaceous balanitis. When diagnosing such conditions, it is imperative that representative biopsies of the lesion be obtained to exclude the presence of invasive malignancy and to provide enough information for an accurate histopathologic diagnosis. Strict follow-up is mandatory because of the association of these conditions with penile SCC. HPV-related precancerous lesions are often associated with persistent HPV type 16 and 18 infection. Giant
S28

condylomas are associated with HPV 6 and 11 subtypes.48 In a large multicenter study of HPV DNA prevalence in penile cancer, HPV DNA was detected in 100% of condyloma cases, 90% of dysplasia cases, and 42% of penile carcinoma cases. However, signicant differences were found in HPV prevalence among the different histologic tumor subtypes. Keratinizing and verrucous carcinoma was positive for HPV DNA in 34.9% and 33.3% of cases, respectively. Basaloid and warty penile cancer was positive for HPV DNA in 80% and 100% of cases, respectively. The difference in HPV prevalence between these 2 groups was statistically signicant. These results suggest that penile intraepithelial neoplasia or penile dysplasia, as currently dened, is a precursor lesion only for a subset of tumors, including basaloid and warty carcinomas.2 In contrast, verrucous and keratinizing SCC might be the result of a chronic inammatory process. The natural history of many of these premalignant lesions is largely unknown, with differing degrees of malignant potential. The investigators have advocated that premalignant lesions should be classied into those representing true carcinoma in situ (CIS) histopathologically (ie, Bowens disease of the penis, erythroplasia de Queyrat) and such pathologic entities as penile horn and giant condylomata, which have a documented association with penile carcinoma. The etiopathogenesis and association of BXO with SCC of the penis is also unclear. The evidence base for the association of BXO and carcinoma is not robust,40 and, as such, no current recommendations can be made in terms of long-term follow-up or the treatment of patients diagnosed with this BXO. Long-term prospective studies are needed with the appropriate controls to evaluate this association. However, on reviewing the published data, the following lesions have been shown to have invasive potential or have been associated with penile SCC and have been outlined in more detail: Bowenoid papulosis Erythroplasia de Queyrat Bowens disease of the penis Genital lichen sclerosus (LS, also termed BXO) Penile horn Leukoplakia Pseudoepitheliomatous, keratotic, and micaceous balanitis Malignant giant condylomata acuminate

HPV-RELATED PENILE PREMALIGNANT CONDITIONS

Giant Condyloma (Buschke-Lwenstein Tumor) Other names for giant condyloma (Buschke-Lwenstein tumor) include giant malignant condyloma, verrucous carcinoma, and carcinoma-like condyloma. However, it is now believed that giant condyloma is different from
UROLOGY 76 (Supplement 2A), August 2010

verrucous carcinoma.49 This stems from the nding that, as mentioned, papillary and verrucous variants of SCC are not HPV related, but that the basaloid warty variants and giant condyloma are related to HPV infection. In 1 series, 117 formalin-xed specimens of penile cancer were analyzed using polymerase chain reaction for HPV DNA. The ndings revealed no signicant association with typical keratinizing verrucous SCC of the penis. In contrast, the association with basaloid SCC was 75%.18 The disease usually affects uncircumcised males of any age. Patients usually notice a slow-growing cauliower lesion that can reach 5 cm within the preputial sac. The disease can affect other anogenital structures, such as the groin, urethra, and the anal canal, with the development of stulas of the urethra and rectum and ulceration of the underlying subcutaneous tissues because of downgrowth of the lesion into the underlying structures. Infection is a usual feature in this condition.50 On the penis, this can lead to destruction of the glans and thus can mimic aggressive basaloid carcinoma.18 The histologic type is mixed with benign condyloma, with areas of atypical cells or well-differentiated squamous cell CIS. Reports of tumors with a mixture of benign condyloma, warty carcinoma, and either basaloid or atypical SCC have been published.51 Foci of inltrating carcinoma have been found in 23% of cases, and reports of progression to carcinoma have been published.51-54 Owing to the clinical similarity of some varieties of giant condyloma and benign condyloma, basaloid SCC, and the coexistence of giant condyloma and inltrative carcinoma, extensive biopsies are necessary whenever this lesion is suspected. A number of treatment modalities have been advocated. Gilbert and Beckert55 reported circumcision and neodymium-yttrium-aluminum-garnet laser as treatment of giant condylomata acuminata of the penis. Two cycles of interferon therapy were also administered postoperatively. The investigators concluded that this therapy provided excellent cosmetic and functional results.55 Others have reported combination treatment with 5-uorouracil (5-FU) cream and electrocautery plus surgical excision.56 Hatzichristou et al57 reported the outcomes in patients with exophytic, papillary lesions involving the glans penis and advocated glansectomy as the treatment of choice in patients with Buschke-Lwenstein tumors of the penis. Biopsy led to the diagnosis of verrucous carcinoma in 4 patients and giant condyloma acuminatum in 3 patients. Glansectomy was performed in all the patients. At 18-65 months of follow-up, all patients were disease free, with 1 patient requiring additional treatment of local tumor recurrence.

noposthitis.58,59 On examination, these lesions are usually multiple maculopapular lesions with a smooth velvety surface. They can at times be single or might coalesce into large plaques. It is rare that the lesions become erosive. The color depends on the pigmentation of the lesion. Those involving the inner prepuce are usually brownish, salmon red, or grayish white and leukoplakia-like. Lesions that affect the more pigmented areas of the penile shaft tend to be ash gray or brownish black.60 The differential diagnosis includes at condylomas, lichen planus, and psoriasis. Usually histopathologic features of Bowens disease are present.61 It usually runs a benign course with possible spontaneous regression. It can rarely evolve toward an invasive cancer, especially in immunosuppressed individuals.62-64 Treatment involves either observation or surgical/laser ablation, although few case series have been published. Bowen Disease and Erythroplasia de Queyrat Bowens disease and erythroplasia de Queyrat are the same disease with a different clinical presentation. If the lesion is on the penile shaft, Bowens disease is used, and when it involves the inner aspect of the prepuce or the glans penis, it is called erythroplasia de Queyrat. Both diseases are related to HPV 16 and 18 infection, with HPV 16 more common (80%). Bowens disease and erythroplasia de Queyrat are both histologically CIS. In 1 study, all 8 patients with penile erythroplasia de Queyrat were positive for HPV DNA compared with the controls.65 Bowens Disease (Squamous Cell Carcinoma In Situ) The patients with Bowens disease (squamous cell carcinoma in situ) are commonly elderly. Patients present with a lesion on the shaft of the penis that can be a single, scaly, sharply dened erythematous plaque. Other areas such as the inguinal or suprapubic area can be involved. The lesions can sometimes be heavily pigmented, resembling melanoma.17 They can also macroscopically appear in different forms, including crusted and ulcerated plaques, keratotic plaques, and elevated esh-colored plaques. The differential diagnosis includes bowenoid papulosis, psoriasis, and supercial basal cell carcinoma. A biopsy is mandatory to conrm the diagnosis and eliminate the possibility of invasive components. Invasive SCC has been suggested to develop in 5% of long-standing cases.66 Erythroplasia de Queyrat Erythroplasia de Queyrat is CIS histologically.67 It is a rare condition that affects men with an average age of 61 years.68 Most often, the men have no symptoms. However, patients might complain of a lesion that is painful or that bleeds, and they might have an inability to retract the prepuce owing to crusting and scaling. Most (about
S29

Bowenoid Papulosis Bowenoid papulosos usually affects men 28 years old, but it also occurs in older men. Patients might notice a lesion on the penis that itches periodically and occasionally results in localized dyspareunia with recurrent balaUROLOGY 76 (Supplement 2A), August 2010

80%-90%) cases develop in uncircumcised men.69 On examination, single or multiple lesions will be present, with a slightly raised, erythematous, sharply dened plaque on the glans penis or inner prepuce. The texture is smooth, velvety, scaly, or verrucous. It can co-exist with nontender polymorphic warty lesions. It can also be eroded and ooze occasionally.69,70 The lesions can appear at other sites such as the groin and scrotum.71 The differential diagnosis includes eczema and psoriasis.42 Approximately 10%-30% of erythroplasia de Queyrat cases have been reported to transform into SCC.72,73 The exact biologic behavior of CIS is unknown, although investigators have advocated that all CIS of the penis should be treated as having the potential to develop into an invasive malignancy. In this context, it is imperative that deep tissues biopsies be obtained to exclude invasive SCC; therefore, denitive treatment should be offered in all cases with strict follow-up protocols.

Treatment of CIS A number of surgical and medical therapies have been advocated for CIS of the penis, including topical 5-FU, topical imiquimod, topical interferon-2a, cryosurgery, laser therapy (photodynamic therapy), and surgical excision with skin grafting (glans resurfacing). It is mandatory to stage the primary lesion histologically. Multiple and deep biopsies should be included in the specimen, because foci of invasive elements will often be present. If in doubt, gadolinium-enhanced magnetic resonance imaging after the induction of an articial erection with prostaglandin E1 might be of use to exclude the presence of invasive components.74 Topical 5-FU is a structural analog of thymine that blocks DNA synthesis by inhibiting thymidylate synthetase. Topical 5-FU has been used as a topical agent for the treatment of CIS of the glans penis (erythroplasia de Queyrat) and cellular atypia.75,76 In 1 such study,75 7 men with histopathologic conrmation of erythroplasia de Queyrat were cured of the malignancy after application of 5-FU. The men remained recurrence free for 70 months. Several other studies have conrmed the clinical efcacy of 5-FU in the treatment of erythroplasia de Queyrat. 5-FU has also been used in the treatment of Bowens disease of the shaft of the penis.77 Imiquimod is an imidazoquinonin tetracyclic amine and exhibits both antiviral and antitumor properties. The immune response modication might, at least in part, be dependent on its ability to induce the production of interferon-. Imiquimod has been used in the treatment of a number of premalignant lesions, including erythroplasia de Queyrat.78-81 Laser therapy has been used in the treatment of both premalignant and malignant squamous cell lesions of the penis. In 1 such study,82 19 patients with penile intraepithelial neoplasia and CIS were treated with either carbon dioxide or neodymium:yttrium-aluminum-garnet laser therapy. One patient underwent treatment with a
S30

potassium titanyl phosphate laser. Follow-up after 2 years showed that the patients were free of malignancy. In an additional study by Tietjen and Malek,83 92 patients were treated with laser therapy. They reported excellent cosmetic results and preservation of sexual function, although long-term surveillance of the patients was not available. In other studies,84-86 photodynamic therapy has been used in the treatment of both Bowens disease of the penis and erythroplasia de Queyrat. Axcrona et al84 treated a group of 10 patients with cellular atypia/CIS with photodynamic therapy. The group consisted of 5 patients with primary lesions and 5 with cellular atypia after organ-preserving surgery for carcinoma of the penis. After a median follow-up period of 20 months, 3 of the 10 patients had histopathologically residual disease. The investigators concluded that photodynamic therapy for CIS appears to achieve oncologic control with organ preservation. Similarly, Stables et al86 reported the use of topical aminolevulinic acid and photodynamic therapy to treat premalignant and malignant skin diseases. The investigators reported on 4 patients with erythroplasia de Queyrat treated with topical aminolevulinic acid photodynamic therapy. Of the 2 patients with limited disease, 1 achieved a long-term complete response and another had a complete response for 18 months. The patients with more extensive disease saw an improvement. The neodymium:yttrium-aluminum-garnet laser87 has also been used in the treatment of bowenoid papulosis of the penis. Sonnex et al88 described the treatment of erythroplasia de Queyrat with liquid nitrogen cryosurgery in 2 cases. In addition, SCC of the penis has been treated with cryosurgery, as has the Buschke-Lwenstein lesion. In a study by van Bezooijen et al,89 18 patients with CIS of the penis were treated with neodymium:yttriumaluminum-garnet or carbon dioxide laser. No complications developed, and the cosmetic outcome was excellent. For the 3 patients who underwent repeat treatment, the lesion disappeared. At an average follow-up of 25 months, CIS had occurred in 5 patients, and 1 had developed inltrating carcinoma. Laser therapy appears to be an oncologically safe treatment for CIS of the penis, although with a high incidence of recurrence, suggesting that vigilant follow-up is required. However, the number of patients in each reported series has been small, with considerable variation in the follow-up periods. Surgical excision (excluding laser excision) has also been used in the treatment of CIS. Two studies reported on the role of resurfacing and glanular reconstruction using split-thickness skin grafting.90,91 In 1 study,91 the patients underwent total glans resurfacing involving removal of the skin of the glans penis down to its spongiosum. Six patients had developed recurrent erythroplasia de Queyrat after 5-FU therapy, 1 patient had had a severe allergic reaction to 5-FU, and 1 patient had had no
UROLOGY 76 (Supplement 2A), August 2010

response to 5-FU or imiquimod. Of these patients, 2 had extended glans hyperkeratosis and severe dysplasia. No postoperative complications developed, and in all cases, the pathologic resection margins were clear. At a median follow-up of 30 months, no evidence of recurrent disease was found. The investigators suggested that surgical excision with skin grafting might minimize the local recurrence rate by replacing the diseased epithelium with healthy skin. However, additional studies are needed to conrm these ndings. Pseudoepitheliomatous, Keratotic, and Micaceous Balanitis Pseudoepitheliomatous, keratotic, and micaceous balanitis is a rare condition of unknown etiology affecting older men.92 Patients complain of an inability to retract the prepuce. On examination, the lesion appears as a single, well-demarcated, elevated growth on the glans penis. It usually occurs on the glans of older uncircumcised men. Clinically, the skin is hyperkeratotic and inelastic. Histologically, it has hyperkeratosis with prominent rete ridges and a dense dermal polymorphonuclear inltrate and pseudoepitheliomatous hyperplasia.92,93 The lesion can transform into low-grade SCC.94,95 All reported cases have transformed into malignancy. Leukoplakia Leukoplakia occasionally occurs on the glans or prepuce as a whitish and slightly inltrated verrucous plaque. The histologic nding is that of hyperkeratosis, parakeratosis, and irregular acanthosis or atrophy of the malpighian layer, with an altered keratinocyte arrangement and possibly cellular atypia. Ulceration, erosion, or ssuring is usually a sign of malignancy.63,67 Penile Horn Penile horn is a rare form of cutaneous horn of unknown etiology.71 It occurs on the glans as a hard and conical keratotic mass with a bulging erythematous base. The histologic nding is that of a benign epidermoid outgrowth or various epithelial disorders, such as warts, keratoacanthoma, intraepithelial carcinoma, SCC, or verrucous carcinoma.94,96 Histologically, it appears similar to a wart, with excessive keratosis, acanthosis, dyskeratosis, papillomatosis, and chronic inammatory inltration in the adjacent dermis. Approximately 30% of penile horns transform into SCC, most of which are low grade.97 However, the number of cases described in published reports has been low; thus, the recommendations for treatment are not clear. Cruz Guerra et al98 reported on 1 case of malignant recurrence of a cutaneous horn of the glans penis. The biopsy of the lesion was reported as hyperkeratosis with pseudoepitheliomatous hyperplasia. Partial penectomy of the glans penis was performed after recurrence 3 months later and SCC was found in the base of the lesion. The investigators emphasized the capacity of penile cutaneous
UROLOGY 76 (Supplement 2A), August 2010

horn to become malignant and recommended close observation of these lesions after excision. Similarly, Fields et al99 reported on 1 case of a patient treated with surgical excision and external radiotherapy because of the invasive components of the lesion.

BXO or LS BXO, or LS, is a chronic inammatory skin condition of unknown cause. It occurs on the glans and prepuce at a mean age of 60 years.40 Histologically, hyperkeratosis of the epithelium is present, with atrophic thinning of the rete pegs, sometimes with cleft formation, a band-like inltrate of lymphocytes, and plasma cells in the dermis. Vacuolar degeneration of the basal layer could be present. The papillary and reticular dermis present a washed out appearance, and the dermal collagen forms a homogenous band at the dermal-epithelial junction, in conjunction with elastin bers, to produce an amorphous hybrid substance and hyalinization of collagen in the upper dermis.100 The association between vulvar LS and SCC is well documented.101 The precancerous nature of BXO (or LS) in the penis has not been as well studied as in the vulva, but the association with penile carcinoma at least suggests a common etiology.67 Published reports that have linked penile cancer to BXO as a cause included case reports.102-104 Two case series reported an incidence of 2.6%-5.8% of penile carcinomas in patients with BXO.34,104 In a study of 155 patients with penile malignancy, BXO was an associated nding in 28% of the patients.67 In that study, only patients with histologically conrmed BXO were included.67 Powell et al39 reported an incidence of 50%. Barbagli et al36 retrospectively reviewed the histologic ndings and clinical records of 130 patients with LS involving the male genitalia and reported premalignant or malignant histopathologic features in 11 (8.4%), including SCC in 7 (64%), verrucous carcinoma in 2 (18%), erythroplasia de Queyrat in 1 (9%), and SCC associated with verrucous carcinoma in 1 (9%). In 6 (55%) of 11 patients, the histologic study showed the presence of epithelial dysplasia. In summary, several treatment modalities have been used in the management of premalignant lesions of the penis (Table 5). However, the evaluation of these studies has been limited owing to the small number of patients and the varied treatment regimens used. Overall, from the evidence in the published data, a number of modalities (Table 5) have been shown to be effective in the treatment of these premalignant conditions. Future research should be targeted at further evaluating the various treatment modalities in the treatment of CIS. This will require multi-institutional collaboration because the numbers of patients seen by single institutions are small.
S31

Table 5. Penile lesions Lesion Erythroplasia de Queyrat Bowens disease of the penis Bowenoid papulosis Penile horn Malignant giant condylomata acuminata Leukoplakia Treatment Modality Imiquimod, 5-uorouracil, cryosurgery, laser, photodynamic therapy, surgical excision Imiquimod, 5-uorouracil, cryosurgery, laser, photodynamic therapy, surgical excision Laser, imiquimod Surgical excision Surgical excision, 5-uorouracil, immunotherapy Bleomycin

COMMENT
Because of the current levels of evidence in published reports, it is difcult to formulate guidelines on the prevention and treatment of premalignant conditions of the penis. Although preventative measures, such as a reduction in HPV transmission, might become future health targets, owing to the variation in incidence of this cancer, standard strategies, such as vaccination or circumcision, might not be applicable in certain countries. What is quite clear is that multi-institutional studies must be conducted to develop appropriate levels of evidence for the treatment and management of premalignant conditions. In the present review, we extensively researched the published data on the prevention of penile cancer and premalignant conditions. Most, if not all, the data or research has been level 3 or 4 evidence, and, as such, the recommendations outlined in the following section are not exhaustive and are also recommendations of best practice.

SUMMARY OF LEVELS OF EVIDENCE

1. Circumcision in early childhood might help prevent penile cancer by eliminating phimosis and preventing cofactors, such as HPV infection and improving hygiene (level of evidence, 3). With such small numbers of penile cancer cases (eg, in Europe and the United States), it would be difcult to justify routine circumcision for all boys. 2. Smoking has repeatedly been shown to have a consistent association with penile cancer. Smokers have a considerably increased risk of invasive cancer compared with nonsmokers. Therefore, smoking cessation should be strongly advocated through educational programs (level of evidence, 3). 3. The role of HPV infection in the induction of penile carcinoma appears to vary and is not clear, although an association with some subtypes of HPV does seem to exist. The inuence of HPV DNA expression on the prognosis of penile cancer is also not clear (level of evidence, 3). 4. Long-term data are not available that male vaccination could prevent HPV-associated penile cancer development (level of evidence, 4). At present, one can only assume that male vaccination could prevent
S32

HPV-associated penile cancer development, and it is possible that targeting high-risk groups might reduce the risk of developing HPV-associated penile cancer. However, a more plausible strategy might be to promote condom use between sexual partners to avoid transmission of HPV infection. 5. The pathologic nomenclature describing the various penile premalignant lesions is confusing and has not been consistently described in published reports (level of evidence, 3). This would require a consensus opinion from a pathology steering committee. 6. True CIS of the penis should be distinguished from those conditions associated with penile cancer, because the natural history and treatment of the 2 pathologic entities differ considerably (level of evidence, 3). 7. The precancerous nature of BXO or LS of the penis is not well-established, although there does appear to be an association (level of evidence, 3). The level of evidence suggesting a link between the 2 conditions is weak, without the appropriate control populations. From the available published data, routine lifelong follow-up of all men with BXO cannot be justied, but self-examination could be advocated (level of evidence, 4).

RECOMMENDATIONS FOR PENILE CANCERINTERNATIONAL CONSULTATION ON UROLOGIC DISEASE 2009-PREVENTION AND PREMALIGNANT CONDITIONS
A program of circumcising all males to prevent penile cancer is difcult to justify (grade of recommendation D). Smoking cessation should be strongly advocated through educational programs (grade C). Male vaccination to prevent HPV-associated penile cancer development cannot be recommended from the currently available data (grade of recommendation D). The pathologic nomenclature describing the various penile premalignant lesions is confusing and has not been consistently described in published reUROLOGY 76 (Supplement 2A), August 2010

ports; thus, a pathology steering committee should be established (grade of recommendation B). The precancerous nature of BXO or LS of the penis is not well established; thus, routine lifelong follow-up of all men with BXO cannot currently be justied (grade of recommendation C). Multinational prospective trials are needed to dene the best management of premalignant lesions of the penis (grade of recommendation C). References
1. Wabinga HR, Parkin DM, Wabwire-Mangen F, et al. Trends in cancer incidence in Kyadondo County, Uganda 1960-1997. Br J Cancer. 2000;82:1585-1592. 2. 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;159:1211-1218. 3. Madsen BS, van den Brule AJ, Jensen HL, et al. Risk factors for squamous cell carcinoma of the penispopulation-based casecontrol study in Denmark. Cancer Epidemiol Biomarkers Prev. 2008;17:2683-2691. 4. Bleeker MC, Heideman DA, Snijders PJ, et al. Penile cancer: epidemiology, pathogenesis and prevention. World J Urol. 2009; 27:141-150. 5. Morris BJ. Why circumcision is a biomedical imperative for the 21(st) century. Bioessays. 2007;29:1147-1158. 6. Moses S, Bailey RC, Ronald AR. Male circumcision: assessment of health benets and risks. Sex Transm Infect. 1998;74:368-373. 7. American Academy of Pediatrics Task Force on Circumcision. Circumcision policy statement. Pediatrics. 1999;103:686-693. 8. Daling JR, Madeleine MM, Johnson LG, et al. Penile cancer: importance of circumcision, human papillomavirus and smoking in in situ and invasive disease. Int J Cancer. 2005;116:606-616. 9. Harish K, Ravi R. The role of tobacco in penile carcinoma. Br J Urol. 1995;75:375-377. 10. Dillner J, von Krogh G, Horenblas S, et al. Etiology of squamous cell carcinoma of the penis. Scand J Urol Nephrol Suppl. 2000;205: 189-193. 11. Cupp MR, Malek RS, Goellner JR, et al. The detection of human papillomavirus deoxyribonucleic acid in intraepithelial, in situ, verrucous and invasive carcinoma of the penis. J Urol. 1995;154: 1024-1029. 12. Sarkar FH, Miles BJ, Plieth DH, et al. Detection of human papillomavirus in squamous neoplasm of the penis. J Urol. 1992; 147:389-392. 13. Senba M, Kumatori A, Fujita S, et al. The prevalence of human papillomavirus genotypes in penile cancers from northern Thailand. J Med Virol. 2006;78:1341-1346. 14. Scheiner MA, Campos MM, Ornellas AA, et al. Human papillomavirus and penile cancers in Rio de Janeiro, Brazil: HPV typing and clinical features. Int Braz J Urol. 2008;34:467-476. 15. Newton R, Bousarghin L, Ziegler J, for the Uganda Kaposis Sarcoma Study Group. Human papillomaviruses and cancer in Uganda. Eur J Cancer Prev. 2004;2:113-118. 16. Wiener JS, Effert PJ, Humphrey PA, et al. Prevalence of human papillomavirus types 16 and 18 in squamous-cell carcinoma of the penis: a retrospective analysis of primary and metastatic lesions by differential polymerase chain reaction. Int J Cancer. 1992;50:694701. 17. Bezerra AL, Lopes A, Santiago GH, et al. Human papillomavirus as a prognostic factor in carcinoma of the penis: analysis of 82 patients treated with amputation and bilateral lymphadenectomy. Cancer. 2001;91:2315-2321. 18. Gregoire L, Cubilla AL, Reuter VE, et al. Preferential association of human papillomavirus with high-grade histologic variants of

19.

20. 21.

22.

23.

24. 25.

26. 27. 28. 29. 30.

31.

32.

33.

34.

35.

36.

37.

38. 39.

40.

41.

penile-invasive squamous cell carcinoma. J Natl Cancer Inst. 1995;87:1705-1709. Muoz N, Bosch FX, de Sanjose S, et al, for the International Agency for Research on Cancer Multicenter Cervical Cancer Study Group. Epidemiologic classication of human papillomavirus types associated with cervical cancer. N Engl J Med. 2003;348: 518-527. Giuliano AR. Human papillomavirus vaccination in males. Gynecol Oncol. 2007;107(suppl 1):S24-S26. Wen LM, Estcourt CS, Simpson JM, et al. Risk factors for the acquisition of genital warts: are condoms protective? Sex Transm Infect. 1999;75:312-316. 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;354:2645-2654. Bleeker MC, Hogewoning CJ, Voorhorst FJ, et al. Condom use promotes regression of human papillomavirus-associated penile lesions in male sexual partners of women with cervical intraepithelial neoplasia. Int J Cancer. 2003;107:804-810. Gairdner D. The fate of the foreskin, a study of circumcision. BMJ. 1949;2:1433-1437. Oster J. Further fate of the foreskin: incidence of preputial adhesions, phimosis, and smegma among Danish schoolboys. Arch Dis Child. 1968;43:200-203. Osmond TE. Is routine circumcision advisable? J R Army Med Corps. 1953;99:254. Saitmacher F. Social hygiene studies on routine circumcision of male infants. Dtsch Gesundheitsw. 1960;15:1217-1220. Schberlein W. [Signicance and incidence of phimosis and smegma]. Mnch Med Wochenschr. 1967;108:373-377. Ishikawa E, Kawakita M. [Preputial development in Japanese boys]. Hinyokika Kiyo. 2004;50:305-308. Ko MC, Liu CK, Lee WK, et al. Age-specic prevalence rates of phimosis and circumcision in Taiwanese boys. J Formos Med Assoc. 2007;106:302-307. Tseng HF, Morgenstern H, Mack T, et al. Risk factors for penile cancer: results of a population-based case-control study in Los Angeles county (United States). Cancer Causes Control. 2001;12: 267-277. Kiss A, Kirly L, Kutasy B, et al. High incidence of balanitis xerotica obliterans in boys with phimosis: prospective 10-year study. Pediatr Dermatol. 2005;22:305-308. Yardley IE, Cosgrove C, Lambert AW. Paediatric preputial pathology: are we circumcising enough? Ann R Coll Surg Engl. 2007;89:62-65. Nasca MR, Innocenzi D, Micali G. Penile cancer among patients with genital lichen sclerosus. J Am Acad Dermatol. 1999;41:911914. Prowse DM, Ktori EN, Chandrasekaran D, et al. Human papillomavirus-associated increase in p16INK4A expression in penile lichen sclerosus and squamous cell carcinoma. Br J Dermatol. 2008;158:261-265. Barbagli G, Palminteri E, Mirri F, et al. Penile carcinoma in patients with genital lichen sclerosus: a multicenter survey. J Urol. 2006;175:1359-1363. Nasca MR, Innocenzi D, Micali G. Association of penile lichen sclerosus and oncogenic human papillomavirus infection. Int J Dermatol. 2006;45:681-683. Depasquale I, Park AJ, Bracka A. The treatment of balanitis xerotica obliterans. BJU Int. 2000;86:459-465. Powell J, Robson A, Cranston D, et al. High incidence of lichen sclerosus in patients with squamous cell carcinoma of the penis. Br J Dermatol. 2001;145:85-89. Pietrzak P, Hadway P, Corbishley CM, et al. Is the association between balanitis xerotica obliterans and penile carcinoma underestimated? BJU Int. 2006;98:74-76. Perceau G, Derancourt C, Clavel C, et al. Lichen sclerosus is frequently present in penile squamous cell carcinomas but is not

UROLOGY 76 (Supplement 2A), August 2010

S33

42.

43.

44.

45.

46.

47.

48.

49.

50.

51.

52.

53. 54.

55. 56. 57.

58. 59.

60.

61. 62. 63.

always associated with oncogenic human papillomavirus. Br J Dermatol. 2003;148:934-938. von Krogh G, Horenblas S. The management and prevention of premalignant penile lesions. Scand J Urol Nephrol Suppl. 2000;205: 220-229. van Howe RS, Hodges FM. The carcinogenicity of smegma: debunking a myth. J Eur Acad Dermatol Venereol. 2006;20:10461054. OFarrell N, Quigley M, Fox P. Association between the intact foreskin and inferior standards of male genital hygiene behaviour: a cross-sectional study. Int J STD AIDS. 2005;16:556-559. Frisch M, Biggar RJ, Goedert JJ. Human papillomavirus-associated cancers in patients with human immunodeciency virus infection and acquired immunodeciency syndrome. J Natl Cancer Inst. 2000;92:1500-1510. Tam DW, Van SEJ, Urbach F. Bowens disease and squamous cell carcinoma. Occurrence in a patient with psoriasis after topical, systemic, and PUVA therapy. Arch Dermatol. 1979;115:203-204. Stern RS. Genital tumors among men with psoriasis exposed to psoralens and ultraviolet A radiation (PUVA) and ultraviolet B radiation: the Photochemotherapy Follow-up Study. N Engl J Med. 1990;322:1093-1097. Dianzani C, Bucci M, Pierangeli A, et al. Association of human papillomavirus type 11 with carcinoma of the penis. Urology. 1998;51:1046-1048. Cubilla AL, Velazques EF, Reuter VE, et al. Warty (condylomatous) squamous cell carcinoma of the penis: a report of 11 cases and proposed classication of verruciform penile tumors. Am J Surg Pathol. 2000;24:505-512. Knoblich R, Failing JF Jr. Giant condyloma acuminatum (Buschke-Lwenstein tumor) of the rectum. Am J Clin Pathol. 1967; 48:389-395. Schmauz R, Findlay M, Lalwak A, et al. Variation in the appearance of giant condyloma in an Ugandan series of cases of carcinoma of the penis. Cancer. 1977;40:1686-1696. Sanders CJG. Condylomata acuminata of the penis progressing rapidly to invasive squamous cell carcinoma. Genitourin Med. 1997;73:402-403. Johnson DE, Lo RK, Srigley J, et al. Verrucous carcinoma of the penis. J Urol. 1985;133:216-218. Youngberg GA, Thornthwaite JT, Inoshita T, et al. Cytologically malignant squamous-cell carcinoma arising in a verrucous carcinoma of the penis. J Dermatol Surg Oncol. 1983;9:474-479. Gilbert P, Beckert R. Combination therapy for penile giant Buschke-Lwenstein condyloma. Urol Int. 1990;45:122-124. Harvey JM, Glen E, Watson GS. Buschke-Lewenstein tumor of the penis: a case report. Br J Vener Dis. 1983;59:273-276. Hatzichristou DG, Apostolidis A, Tzortzis V, et al. Glansectomy: an alternative surgical treatment for Buschke-Lwenstein tumors of the penis. Urology. 2001;57:966-969. Wikstrom A, von Krogh G, Hedblad M-A, et al. Papillomavirusassociated balanoposthitis. Genitourin Med. 1994;70:175-181. Wikstrom A, Hedblad M-A, Johansson B, et al. The acetic acid test in evaluation of sub clinical genital papillomavirus infection: a comparative study on penoscopy, histopathology, virology and scanning electron microscopy ndings. Genitourin Med. 1992;68: 90-96. Gimeno E, Vilata JJ, Sanchez JL, et al. Bowenoid papulosis: clinical and histological study of eight cases. Genitourin Med. 1987;63:109-113. Wade TR, Kopf AW, Ackerman AB. Bowenoid papulosis of the genitalia. Arch Dermatol. 1979;115:306-308. Schwartz RA, Janniger CK. Bowenoid papulosis. J Am Acad Dermatol. 1991;24(2 Pt. 1):261-264. De Villez RL, Stevens CS. Bowenoid papules of the genitalia: a case progressing to Bowens disease. J Am Acad Dermatol. 1980;3: 149-152.

64. Bonnekoh B, Mahrle G, Steigleder GK. [Transition to cutaneous squamous cell carcinoma in 2 patients with bowenoid papulomatosis]. Z Hautkr. 1987;62:773-784. 65. 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. 66. Lucia MS, Miller GJ. Histopathology of malignant lesions of the penis. Urol Clin North Am. 1992;19:227-246. 67. Mikhail GR. Cancers, precancers and pseudocancers of the male genitalia: a review of clinical appearances, histopathology, and management. J Dermatol Surg Oncol. 1980;6:1027-1035. 68. Jaeger AB, Gramkow A, Hjalgrim H, et al. Bowen disease and risk of subsequent malignant neoplasms: a population-based cohort study of 1147 patients. Arch Dermatol. 1999;135:790-793. 69. Graham JH, Helwig EB. Erythroplasia of Queyrat: a clinicopathologic and histochemical study. Cancer. 1973;32:1396-1414. 70. Raghavaiah NV, Soloway MS, Murphy WM. Malignant penile horn. J Urol. 1997;118:1068-1069. 71. Park KC, Kim KH, Youn S-W, et al. Heterogeneity of human papillomavirus DNA in a patient with bowenoid papulosis that progressed to squamous cell carcinoma. Br J Dermatol. 1998;139: 1087-1091. 72. Micali G, Innocenzi D, Nasca M, et al. Squamous cell carcinoma of the penis. J Am Acad Dermatol. 1996;35(3 Pt. 1):432-451. 73. Kaye V, Zhang G, Dehner LP. Carcinoma in situ of penis: is distinction between erythroplasia de Queyrat and Bowens disease relevant? Urology. 1990;36:479-482. 74. Kayes O, Minhas S, Allen C, et al. The role of magnetic resonance imaging in the local staging of penile cancer. Eur Urol. 2007;51: 1313-1319. 75. Goette DK, Carson TE. Erythroplasia of Queyrat: treatment with topical 5-uorouracil. Cancer. 1976;38:1498-1502. 76. Cardamakis E, Relakis K, Ginopoulos P, et al. Treatment of penile intraepithelial neoplasia (PIN) with interferon alpha-2a, CO2 laser (vaporization) and 5-uorouracil 5% (5-FU). Eur J Gynaecol Oncol. 1997;18:410-413. 77. Tolia BM, Castro VL, Mouded IM, et al. Bowens disease of shaft of penis: successful treatment with 5-uorouracil. Urology. 1976; 7:617-619. 78. Kaspari M, Gutzmer R, Kiehl P, et al. Imiquimod 5% cream in the treatment of human papillomavirus-16-positive erythroplasia of Queyrat. Dermatology. 2002;205:67-69. 79. Orengo I, Rosen T, Guill CK. Treatment of squamous cell carcinoma in situ of the penis with 5% imiquimod cream: a case report. J Am Acad Dermatol. 2002;47(suppl):S225-S228. 80. Schroeder TL, Sengelmann RD. Squamous cell carcinoma in situ of the penis successfully treated with imiquimod 5% cream. J Am Acad Dermatol. 2002;46:545-548. 81. Danielsen AG, Sand C, Weismann K. Treatment of Bowens disease of the penis with imiquimod 5% cream. Clin Exp Dermatol. 2003;28(suppl 1):7-9. 82. Malek RS. Laser treatment of premalignant and malignant squamous cell lesions of the penis. Lasers Surg Med. 1992;12:246253. 83. Tietjen DN, Malek RS. Laser therapy of squamous cell dysplasia and carcinoma of the penis. Urology. 1998;52:559-565. 84. Axcrona K, Brennhovd B, Alfsen GC, et al. Photodynamic therapy with methyl aminolevulinate for atypical carcinoma in situ of the penis. Scand J Urol Nephrol. 2007;41:507-510. 85. Britton JE, Goulden V, Stables G, et al. Investigation of the use of the pulsed dye laser in the treatment of Bowens disease using 5-aminolaevulinic acid phototherapy. Br J Dermatol. 2005;153: 780-784. 86. Stables GI, Stringer MR, Robinson DJ, et al. Erythroplasia of Queyrat treated by topical aminolaevulinic acid photodynamic therapy. Br J Dermatol. 1999;140:514-517.

S34

UROLOGY 76 (Supplement 2A), August 2010

87. Knoll LD, Segura JW, Benson RC Jr, et al. Bowenoid papulosis of the penis: successful management with neodymium:YAG laser. J Urol. 1988;139:1307-1309. 88. Sonnex TS, Ralfs IG, Plaza de Lanza M, et al. Treatment of erythroplasia of Queyrat with liquid nitrogen cryosurgery. Br J Dermatol. 1982;106:581-584. 89. van Bezooijen BP, Horenblas S, Meinhardt W, et al. Laser therapy for carcinoma in situ of the penis. J Urol. 2001;166:1670-1671. 90. Palminteri E, Berdondini E, Lazzeri M, et al. Resurfacing and reconstruction of the glans penis. Eur Urol. 2007;52:893-898. 91. Hadway P, Corbishley CM, Watkin NA. Total glans resurfacing for premalignant lesions of the penis: initial outcome data. BJU Int. 2006;98:532-536. 92. Bargman H. Pseudoepitheliomatous, keratotic, and micaceeous balanitis. Cutis. 1985;35:77-79. 93. Beljaards RC, van Dijk E, Hausman R. Is pseudoepitheliomatous, micaceous and keratotic balanitis synonymous with verrucous carcinoma? Br J Dermatol. 1987;117:641-646. 94. Bart RS, Kopf AW. On a dilemma of penile horns, pseudoepitheliomatous, hyperkeratotic and micaceous balanitis? J Dermatol Surg Oncol. 1977;3:580-582. 95. Gray MR, Ansell ID. Pseudo-epitheliomatous hyperkeratotic and micaceous balanitis: evidence for regarding it as pre-malignant. Br J Urol. 1990;66:103-104.

96. Solivan GA, Smith KJ, James WD. Cutaneous horn of the penis: its association with squamous cell carcinoma and HPV-16 infection. J Am Acad Dermatol. 1990;23(5 Pt. 2):969-972. 97. Yeager JK, Findlay RF, McAleer IM. Penile verrucous carcinoma. Arch Dermatol. 1990;126:1208-1210. 98. Cruz Guerra NA, Senz MJ, Ursa Sarmiento I, et al. [Malignant recurrence of a penile cutaneous horn]. Arch Esp Urol. 2005;58:61-63. 99. Fields T, Drylie D, Wilson J. Malignant evolution of penile horn. Urology. 1987;30:65-66. 100. Mihara Y, Mihara M, Hagari Y, et al. Lichen sclerosus et atrophicus: a histological, immunohistochemical and electron microscopic study. Arch Dermatol Res. 1994;286:434-442. 101. Scurry J. Does lichen sclerosus play a central role in the pathogenesis of human papillomavirus negative vulvar squamous cell carcinoma? The itch-scratch-lichen sclerosus hypothesis. Int J Gynecol Cancer. 1999;9:89-97. 102. Bingham JS. Carcinoma of the penis developed in lichen sclerosus et atrophicus. Br J Vener Dis. 1978;54:350-351. 103. Weigand DA. Lichen sclerosus et atrophicus, multiple dysplastic keratoses and squamous-cell carcinoma of the glans penis. J Dermatol Surg Oncol. 1980;6:45-50. 104. Liatsikos EN, Perimenis P, Dandinis K, et al. Lichen sclerosus et atrophicus: ndings after complete circumcision. Scand J Urol Nephrol. 1997;31:453-456.

UROLOGY 76 (Supplement 2A), August 2010

S35