SEXUALLY TRANSMITTED PAPILLOMAVIRAL INFECTION IN THE MALE VII. Is Cancer of Penis Sexually Thansmitted? SAMUEL K. ROSEMBERG, M.D. GILBERT HERMAN, M.D., PII.D. EDNA ELFONT, PH.D. From the Department of Surgery, Divisions of Urology and Pathology, Sinai Hospital of Detroit, Detroit, Michigan
ABSTRACT-Four cases are reported oJ squamous cell carcinoma oj the genital tract in males. The close association oj HPV 16118 with in situ squamous carcinoma affecting the penis is demonstrated. The Jirst documented case oj a primary penile squamous cell carcinoma with metastatic deposits yielding positive HPV 16118 isolates as shown by in situ DNA hybridization again demonstrates a close association oj this virus to malignancy in humans. The clinical implications oj these findings strongly suggest that squamous cell carcinoma oj the penis is a sexually transmitted disease. A thorough examination oj both sexual partners is necessary when Bowenoid papulosis or penile carcinoma is present, since the female partner is at high risk Jor cervical neoplasia.
Carcinoma of the penis accounts for 0.3 to 1.0 percent of cancer in the male population in the United States. l High incidences are reported in tropical areas such as Puerto Rico, Mexico, Paraguay, Venezuela, China, Uganda, and India,2.3 and in the hot, humid regions of South America, Africa, and the Far East squamous cell carcinoma may account for 10-20 percent of malignant tumors in males. 4 The disease has been infrequently reported in Jews who have been circumcised, consequently there is a low incidence of cancer in Israel with less than 0.1 cases per 100,000 males, supporting the prophylactic use of circumcision. 5 The presence of phimosis or paraphimosis is the one factor most consistently implicated as the etiology of carcinoma of the penis, suggesting the production of a carcinogen under the foreskin, and/or the fact that Mycobacterium smegmatis may convert the smegma sterols into carcinogenic sterols. 6 The role of human papilloma virus infections in human genital cancer has been suggested UROLOGY I MAY 1991
I VOLUME XXXVII, NUMBER 5
previously by Zurhausen, et al. 7 and others, 8 and since the epidemiologic features of this type of cancer point to a number of parameters such as dependence on the number of sexual partners, early onset of sexual relations, existence of marital clusters, and correlation in the incidence between cervical and penile cancer to an infectious etiology, the human papilloma virus with its oncogenic potential seems to be the most rational causal candidate in penile carcinogenesis. The venereal nature of the cervical squamous neoplasia is sharply suggested by epidemiologic and demographic studies. There is a significant excess of deaths from cancer of the cervix in women who are the wives of men with penile cancer. 9 Kessler 10 demonstrated a fourfold increased risk of cervical neoplasia in women whose husbands had been previously married to another woman in whom cervical neoplasia had developed. Campion in 1987 11 reported on the high prevalence of subclinical penile HPV infection in the sexual partners of women with 437
cervical intraepithelial neoplasia (CIN), finding that 49 percent had histologically proved HPV infection detectable only after application of acetic acid, with a 9 percent incidence of carcinoma in situ. Penile carcinoma has been reported in association with recalcitrant penile condylomata. 11 Both of these conditions are associated with an increased risk of cervical neoplasia in the sexual partner. 9 HPV 16 DNA has been detected in 49 percent of penile carcinomas, and HPV 18 in 5 percent. 13 The finding by Campion of 9 percent penile carcinoma in situ in the sexual partners of women with CIN III is a cause for concern, and in considering the etiology of penile carcinogenesis, subclinical penile HPV infection seems to prove the ground-floor etiology of this neoplasia. Case Reports
Case 1 A twenty-seven-year-old man presented with a seven-month history of brownish nodulartype lesions on the penile shaft; he was asymptomatic. Physical examination revealed multiple flat, papular, brownish lesions scattered throughout the penile shaft. Biopsy of these areas revealed acanthosis of the dermis, hyperkeratosis, and parakeratosis. The stratum spinosum contained enlarged nuclei, pleomorphism, and multinuc1eation. Hybridization studies revealed HPV 16/18.·
Case 2 A thirty-one-year-old man presented with a twelve-month history of persistent reddish brown penile lesions. He had been asymptomatic, and his previous history had included treatment of venereal warts (HPV) several years prior to the appearance of these lesions. Hybridization studies revealed HPV 16118.·
Case 3 A forty-four-year-old white man, whose sexual partner had been found to have CIN III complained of the asymptomatic development of brownish papules on the shaft of his penis. Surgical biopsy revealed acanthosis, hyperkeratosis, cytolOgic atypia, and pleomorphism compatible with Bowenoid papulosis. Hybridization studies yielded HPV 16/18.· "Dot Blot Hybridization, as performed by ViraType Life Thchnologies, Gaithersburg, Maryland. '
438
1. Case 4. (A) Suprapubic catheter, bilateral, inguinal adenopathy, suprapubic mass, and partial penectomy with massive scrotal edema. (B) Perineal neoplasm extends into anal region with focal ulceration oj mucosa, and massive scrotal edema.
FIGURE
Case 4 A sixty-two-year-old black man with a long h~tory of s9uamous ~ll car?inoma of the penis WIth extensIve local dIsease mvolving perineum and rectum, after a partial penectomy, entered. the hospital complaining of rectal pain. A suprapublic catheter had been placed six years prior to bypass the neoplastic urethral obstructi?n. While under supportive care, the patient dIed. The autopsy demonstrated recurrent carcinoma involving the penile stump with extensive perineal infiltration (Fig. 1). Fistulous tracks between the perineal tumor and urinary bladder were found. Metastatic neoplasm was found in periaortic lymph nodes, hilar lymph nodes, mediastinal lymph nodes, lung parenchyma bilaterally, periesophageal tissue, cerebellum, and pleural surfaces. Routine light microscopy showed the recurrent carcinoma and all metastatic deposits to be a poorly differentiated squamous cell carcinoma (Fig. 2). A formalin-fixed paraffin-embedded portion of tissue was submitted for in situ DNA hybridization using a commercial human papilloma UROLOGY
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FICURE 2. Case 4. Histologic sections of (A) penile slUmp with moderately diifferentiated squamous cell CQf'anotnQ invading into cavernous tissue (lower areo), and (B) lung showing pleural involvement with metastatic squamous carcinoma as well as intrapulmonary metastasis (lower left).
virus detection kit (Vira'!Ype). In situ hybridization of the primary tumor had hundreds of individual neoplastic cells with positive nuclear staining for HPV type 16/18 with pleural deposits having similar reaction (Fig. 3). Weaker focal positive hybridization for HPV type 6/11 was found in the primary recurrent penile lesion and believed to be cross-hybridization rather than a second HPV infection.14 Bowenoid papulosis of the genital skin was first described in 1977 by Kopf et al.15 The name Bowenoid papulosis of the genitalia appears to be the most adequate, because it stresses the multifocal and papular type of the lesions. The disease occurs in young, sexually active adults, with its course being variable. Some cases have regressed spontaneously,18 and in some patients the Bowenoid papules have been converted into large plaques typical of Bowen's disease or squamous carcinoma. 17 At the present time, it has been demonstrated that UROLOGY I MAY 1991 I VOLUME XXXVII, NUMBER 5
these lesions are caused by the human papilloma virus type 16. 18 Hurwitz, et al. 111 have recently reported clinical and histologic evidence of suspected femaleto-male transmission of Bowenoid papulosis of the penis from a woman with condylomata acuminata, squamous cell carcinoma in situ, and focally invasive squamous cell carcinoma of the vulva. Bowenoid papulosis of the penis and carcinoma in situ of the cervix have been seen concomitantly in sexual partners. IlO The clinical differentiation of Bowenoid papulosis from Bowen's disease of the genitalia is based on the older age of the patients (over 40) in Bowen's disease. Bowen's disease usually presents as a solitary nonpigmented lesion, with a slow progressive clinical course and no tendency toward spontaneous remission. Our findings of HPV 16/18 in the original lesion in Case 4, coupled with similar virologic identification in metastatic deposits in the 439
pleura and lung, confirm the fact that the human papilloma virus appears to be intimately involved with the induction or the development of squamous cell carcinoma of the male genitalia. Animal models have shown HPV to serve as an inducer of carcinoma with environmental factors serving as potent promoters. Rabbits infected with the cottontail rabbit papillomavirus when exposed to coal tars develop skin carcinoma in 25 percent within twelve months.21 Cattle exposed to Bovine Papillomavirus-4 develop intestinal, bladder, and esophageal carcinoma when fed a diet of Bracken fern. 22 In man, the hereditary skin disorder of epidermodysplasia verruciform is will show a progression of cutaneous warts to invasive squamous carcinoma in ultraviolet (UV) damaged skin.2:I In human genital malignancies there has been a close association of papilloma virus DNA isolates from primary malignancies of the cervix, penis, and vulva. The incidence of isolates is up to 89 percent of cervical carcinoma harboring HPV 16/18. 24 HPV 18 is a constant isolate of the immortalized cervical cancer cell line of HELA cells, and HPV 16 is an isolate of the Caski cell line. HPV 16 also has been isolated in both cervical primary carcinomas and the metastatic nodal deposits.24 Case 4 represents the first documentation of a primary penile squamous carcinoma with metastatic deposits yielding positive HPV 16/18 isolates as demonstrated by in situ DNA hybridization. Again the close association of this virus to a human malignancy is demonstrated, which further supports the role of HPV virus as a causal rather than casual factor in human oncogenesis. The first 3 cases once again demonstrate the close association of HPV 16/18 with in situ squamous carcinoma variants or precursor lesions affecting the penis. These cases further confirm the findings of other published investigations. 18 It is well known that the foreskin is excellent tissue for human papillomavirus infection and replication, and that in the normal uncircumcised male this is a sexually acquired infection. A probable oncogenic cofactor is M. smegmatis conversion of smegma sterols into carcinogens to potentiate the development of penile neoplasia, which is consistent with other animal models and other HPV human-associated malignancies. 440
The clinical implications of these findings strongly suggest that squamous cell carcinoma of the penis is sexually transmitted. A thorough evaluation of both sexual partners is necessary when Bowenoid papulosis or penile carcinoma is present because the female partner is at high risk for cervical neoplasia. 17100 W. 1Welve Mile Road Southfield, Michigan 48076 (DR. ROSEMBERG) References 1. Barney JD: Epithelioma of the penis, an analysis oE 100 cases, Ann Surg 46: 890 (1907). 2. Hoppmann H}, and Fraley EE: Squamous cell carcinoma of the penis, J Uro1120: 393 (1978). 3. Persky L: Epidemiology of cancer of th~ penis, Recent ResUlts Cancer Res 60: 97 (1977). 4. Lichtenauer P, et all On the classification of penis car. cinoma and its ten-year survival, Recent Results Cancer Res 60. 110 (1977). • 5. Dean AL Jr: Epithelioma of the penis, J Uro133: 252 (1935). 6. Sobel II, and Plaut A: The assimilation of cholesterol by My_ cobacterium smegmatis, J Bacteriol57: 377 (1949). 7. Zurhausen II, et all Papillomavirus infections and human genital cancer, Gynecol Onco112: 124 (1981). 8. Rotkin FD: A comparison review of key epidemiological studies in cervical cancer related to current searches for trans. missable agents, Cancer Res 33: 1353 (1973). 9. Martinez I: Relationship of squamous cell carcinoma oE the cervix uteri to squamous carcinoma of the penis, Cancer 24: 777 (1969). 10. Kessler I: Venereal factors in human cervical cancer. Can. cer 39: 1912 (1977). 11. Campion MJ, et 01: Subclinical penile human papillamavirus infection in consorts of women with cervical neoplasia· a clue to the high-risk male, Colposc Gyn Laser Surg 5: 11 (1987) 12. Cartwright RA: Carcinoma oE the penis and cervix, Lancet 11 97 (1980). 13. McCana OJ, et al: Human papilloma virus types 16 and 18 in carcinoma ofthe penis from Brazil, Int J Cancer 37: 55 (1986) 14. Lorincz A: Personal communication, 1988. Life TechnolO:gies, Gaithersburg, Maryland. 15. Kopf AW, et all Thmor Conference No. 11. Multiple Bow neold papules of the penis: a new entity?, J Dermatol Surg Oncoi 3: 265 (1977). 16. Lloyd KM: Multicentric pigmented Bowen's disease of the groin, Arch DermatolIOl: 48 (1970). 17. DeVillez RL, et 01: Bowenoid papules of the genitalia· a case progressing to Bowen's disease, J Am Acad Dermatol 3: i49 (1980). 18. Gross G, et 01: Bowenoid papulosis, Arch Dermatol 1211 858 (1985). 19. Hurwitz R, et all Bowenoid papulosis and squamous cell carcinoma of the genitalia: suspected sexual transmission Cutis 39: 193 (1987). ' 20. Houser B, et 01: HPV-l6-related Bowenoid papulosis, Lan. cet 11 106 (1985). 21. Rous P, and Kidd JG: The carcinogenic effect of papilloma virus on the tarred skin of rabbits: I. Description of the phenomenon, J Exp Med 671399 (1938). 22. Jarrett WFH, et 01: High incidence area of cattle cancer with a possible interaction between an environmental carcinogen and a papilloma virus, Nature 274: 215 (1978). 23. Jablonska S, Dabrowski J, and Jakubowicz K: Epidermodysplasia verruciform is as a model in studies on the role of pa. povaviruses in oncogenesis, Cancer Res 32: 583 (1972). 24. Grissman L: Papillomaviruses and their association with cancer in animals and in man, Cancer Surv 3: 161 (1984).
UROLOGY I
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ABSTRACT-Four cases are reported oJ squamous cell carcinoma oj the genital tract in males. The close association oj HPV 16118 with in situ squamous carcinoma affecting the penis is demonstrated. The Jirst documented case oj a primary penile squamous cell carcinoma with metastatic deposits yielding positive HPV 16118 isolates as shown by in situ DNA hybridization again demonstrates a close association oj this virus to malignancy in humans. The clinical implications oj these findings strongly suggest that squamous cell carcinoma oj the penis is a sexually transmitted disease. A thorough examination oj both sexual partners is necessary when Bowenoid papulosis or penile carcinoma is present, since the female partner is at high risk Jor cervical neoplasia.
Carcinoma of the penis accounts for 0.3 to 1.0 percent of cancer in the male population in the United States. l High incidences are reported in tropical areas such as Puerto Rico, Mexico, Paraguay, Venezuela, China, Uganda, and India,2.3 and in the hot, humid regions of South America, Africa, and the Far East squamous cell carcinoma may account for 10-20 percent of malignant tumors in males. 4 The disease has been infrequently reported in Jews who have been circumcised, consequently there is a low incidence of cancer in Israel with less than 0.1 cases per 100,000 males, supporting the prophylactic use of circumcision. 5 The presence of phimosis or paraphimosis is the one factor most consistently implicated as the etiology of carcinoma of the penis, suggesting the production of a carcinogen under the foreskin, and/or the fact that Mycobacterium smegmatis may convert the smegma sterols into carcinogenic sterols. 6 The role of human papilloma virus infections in human genital cancer has been suggested UROLOGY I MAY 1991
I VOLUME XXXVII, NUMBER 5
previously by Zurhausen, et al. 7 and others, 8 and since the epidemiologic features of this type of cancer point to a number of parameters such as dependence on the number of sexual partners, early onset of sexual relations, existence of marital clusters, and correlation in the incidence between cervical and penile cancer to an infectious etiology, the human papilloma virus with its oncogenic potential seems to be the most rational causal candidate in penile carcinogenesis. The venereal nature of the cervical squamous neoplasia is sharply suggested by epidemiologic and demographic studies. There is a significant excess of deaths from cancer of the cervix in women who are the wives of men with penile cancer. 9 Kessler 10 demonstrated a fourfold increased risk of cervical neoplasia in women whose husbands had been previously married to another woman in whom cervical neoplasia had developed. Campion in 1987 11 reported on the high prevalence of subclinical penile HPV infection in the sexual partners of women with 437
cervical intraepithelial neoplasia (CIN), finding that 49 percent had histologically proved HPV infection detectable only after application of acetic acid, with a 9 percent incidence of carcinoma in situ. Penile carcinoma has been reported in association with recalcitrant penile condylomata. 11 Both of these conditions are associated with an increased risk of cervical neoplasia in the sexual partner. 9 HPV 16 DNA has been detected in 49 percent of penile carcinomas, and HPV 18 in 5 percent. 13 The finding by Campion of 9 percent penile carcinoma in situ in the sexual partners of women with CIN III is a cause for concern, and in considering the etiology of penile carcinogenesis, subclinical penile HPV infection seems to prove the ground-floor etiology of this neoplasia. Case Reports
Case 1 A twenty-seven-year-old man presented with a seven-month history of brownish nodulartype lesions on the penile shaft; he was asymptomatic. Physical examination revealed multiple flat, papular, brownish lesions scattered throughout the penile shaft. Biopsy of these areas revealed acanthosis of the dermis, hyperkeratosis, and parakeratosis. The stratum spinosum contained enlarged nuclei, pleomorphism, and multinuc1eation. Hybridization studies revealed HPV 16/18.·
Case 2 A thirty-one-year-old man presented with a twelve-month history of persistent reddish brown penile lesions. He had been asymptomatic, and his previous history had included treatment of venereal warts (HPV) several years prior to the appearance of these lesions. Hybridization studies revealed HPV 16118.·
Case 3 A forty-four-year-old white man, whose sexual partner had been found to have CIN III complained of the asymptomatic development of brownish papules on the shaft of his penis. Surgical biopsy revealed acanthosis, hyperkeratosis, cytolOgic atypia, and pleomorphism compatible with Bowenoid papulosis. Hybridization studies yielded HPV 16/18.· "Dot Blot Hybridization, as performed by ViraType Life Thchnologies, Gaithersburg, Maryland. '
438
1. Case 4. (A) Suprapubic catheter, bilateral, inguinal adenopathy, suprapubic mass, and partial penectomy with massive scrotal edema. (B) Perineal neoplasm extends into anal region with focal ulceration oj mucosa, and massive scrotal edema.
FIGURE
Case 4 A sixty-two-year-old black man with a long h~tory of s9uamous ~ll car?inoma of the penis WIth extensIve local dIsease mvolving perineum and rectum, after a partial penectomy, entered. the hospital complaining of rectal pain. A suprapublic catheter had been placed six years prior to bypass the neoplastic urethral obstructi?n. While under supportive care, the patient dIed. The autopsy demonstrated recurrent carcinoma involving the penile stump with extensive perineal infiltration (Fig. 1). Fistulous tracks between the perineal tumor and urinary bladder were found. Metastatic neoplasm was found in periaortic lymph nodes, hilar lymph nodes, mediastinal lymph nodes, lung parenchyma bilaterally, periesophageal tissue, cerebellum, and pleural surfaces. Routine light microscopy showed the recurrent carcinoma and all metastatic deposits to be a poorly differentiated squamous cell carcinoma (Fig. 2). A formalin-fixed paraffin-embedded portion of tissue was submitted for in situ DNA hybridization using a commercial human papilloma UROLOGY
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FICURE 2. Case 4. Histologic sections of (A) penile slUmp with moderately diifferentiated squamous cell CQf'anotnQ invading into cavernous tissue (lower areo), and (B) lung showing pleural involvement with metastatic squamous carcinoma as well as intrapulmonary metastasis (lower left).
virus detection kit (Vira'!Ype). In situ hybridization of the primary tumor had hundreds of individual neoplastic cells with positive nuclear staining for HPV type 16/18 with pleural deposits having similar reaction (Fig. 3). Weaker focal positive hybridization for HPV type 6/11 was found in the primary recurrent penile lesion and believed to be cross-hybridization rather than a second HPV infection.14 Bowenoid papulosis of the genital skin was first described in 1977 by Kopf et al.15 The name Bowenoid papulosis of the genitalia appears to be the most adequate, because it stresses the multifocal and papular type of the lesions. The disease occurs in young, sexually active adults, with its course being variable. Some cases have regressed spontaneously,18 and in some patients the Bowenoid papules have been converted into large plaques typical of Bowen's disease or squamous carcinoma. 17 At the present time, it has been demonstrated that UROLOGY I MAY 1991 I VOLUME XXXVII, NUMBER 5
these lesions are caused by the human papilloma virus type 16. 18 Hurwitz, et al. 111 have recently reported clinical and histologic evidence of suspected femaleto-male transmission of Bowenoid papulosis of the penis from a woman with condylomata acuminata, squamous cell carcinoma in situ, and focally invasive squamous cell carcinoma of the vulva. Bowenoid papulosis of the penis and carcinoma in situ of the cervix have been seen concomitantly in sexual partners. IlO The clinical differentiation of Bowenoid papulosis from Bowen's disease of the genitalia is based on the older age of the patients (over 40) in Bowen's disease. Bowen's disease usually presents as a solitary nonpigmented lesion, with a slow progressive clinical course and no tendency toward spontaneous remission. Our findings of HPV 16/18 in the original lesion in Case 4, coupled with similar virologic identification in metastatic deposits in the 439
pleura and lung, confirm the fact that the human papilloma virus appears to be intimately involved with the induction or the development of squamous cell carcinoma of the male genitalia. Animal models have shown HPV to serve as an inducer of carcinoma with environmental factors serving as potent promoters. Rabbits infected with the cottontail rabbit papillomavirus when exposed to coal tars develop skin carcinoma in 25 percent within twelve months.21 Cattle exposed to Bovine Papillomavirus-4 develop intestinal, bladder, and esophageal carcinoma when fed a diet of Bracken fern. 22 In man, the hereditary skin disorder of epidermodysplasia verruciform is will show a progression of cutaneous warts to invasive squamous carcinoma in ultraviolet (UV) damaged skin.2:I In human genital malignancies there has been a close association of papilloma virus DNA isolates from primary malignancies of the cervix, penis, and vulva. The incidence of isolates is up to 89 percent of cervical carcinoma harboring HPV 16/18. 24 HPV 18 is a constant isolate of the immortalized cervical cancer cell line of HELA cells, and HPV 16 is an isolate of the Caski cell line. HPV 16 also has been isolated in both cervical primary carcinomas and the metastatic nodal deposits.24 Case 4 represents the first documentation of a primary penile squamous carcinoma with metastatic deposits yielding positive HPV 16/18 isolates as demonstrated by in situ DNA hybridization. Again the close association of this virus to a human malignancy is demonstrated, which further supports the role of HPV virus as a causal rather than casual factor in human oncogenesis. The first 3 cases once again demonstrate the close association of HPV 16/18 with in situ squamous carcinoma variants or precursor lesions affecting the penis. These cases further confirm the findings of other published investigations. 18 It is well known that the foreskin is excellent tissue for human papillomavirus infection and replication, and that in the normal uncircumcised male this is a sexually acquired infection. A probable oncogenic cofactor is M. smegmatis conversion of smegma sterols into carcinogens to potentiate the development of penile neoplasia, which is consistent with other animal models and other HPV human-associated malignancies. 440
The clinical implications of these findings strongly suggest that squamous cell carcinoma of the penis is sexually transmitted. A thorough evaluation of both sexual partners is necessary when Bowenoid papulosis or penile carcinoma is present because the female partner is at high risk for cervical neoplasia. 17100 W. 1Welve Mile Road Southfield, Michigan 48076 (DR. ROSEMBERG) References 1. Barney JD: Epithelioma of the penis, an analysis oE 100 cases, Ann Surg 46: 890 (1907). 2. Hoppmann H}, and Fraley EE: Squamous cell carcinoma of the penis, J Uro1120: 393 (1978). 3. Persky L: Epidemiology of cancer of th~ penis, Recent ResUlts Cancer Res 60: 97 (1977). 4. Lichtenauer P, et all On the classification of penis car. cinoma and its ten-year survival, Recent Results Cancer Res 60. 110 (1977). • 5. Dean AL Jr: Epithelioma of the penis, J Uro133: 252 (1935). 6. Sobel II, and Plaut A: The assimilation of cholesterol by My_ cobacterium smegmatis, J Bacteriol57: 377 (1949). 7. Zurhausen II, et all Papillomavirus infections and human genital cancer, Gynecol Onco112: 124 (1981). 8. Rotkin FD: A comparison review of key epidemiological studies in cervical cancer related to current searches for trans. missable agents, Cancer Res 33: 1353 (1973). 9. Martinez I: Relationship of squamous cell carcinoma oE the cervix uteri to squamous carcinoma of the penis, Cancer 24: 777 (1969). 10. Kessler I: Venereal factors in human cervical cancer. Can. cer 39: 1912 (1977). 11. Campion MJ, et 01: Subclinical penile human papillamavirus infection in consorts of women with cervical neoplasia· a clue to the high-risk male, Colposc Gyn Laser Surg 5: 11 (1987) 12. Cartwright RA: Carcinoma oE the penis and cervix, Lancet 11 97 (1980). 13. McCana OJ, et al: Human papilloma virus types 16 and 18 in carcinoma ofthe penis from Brazil, Int J Cancer 37: 55 (1986) 14. Lorincz A: Personal communication, 1988. Life TechnolO:gies, Gaithersburg, Maryland. 15. Kopf AW, et all Thmor Conference No. 11. Multiple Bow neold papules of the penis: a new entity?, J Dermatol Surg Oncoi 3: 265 (1977). 16. Lloyd KM: Multicentric pigmented Bowen's disease of the groin, Arch DermatolIOl: 48 (1970). 17. DeVillez RL, et 01: Bowenoid papules of the genitalia· a case progressing to Bowen's disease, J Am Acad Dermatol 3: i49 (1980). 18. Gross G, et 01: Bowenoid papulosis, Arch Dermatol 1211 858 (1985). 19. Hurwitz R, et all Bowenoid papulosis and squamous cell carcinoma of the genitalia: suspected sexual transmission Cutis 39: 193 (1987). ' 20. Houser B, et 01: HPV-l6-related Bowenoid papulosis, Lan. cet 11 106 (1985). 21. Rous P, and Kidd JG: The carcinogenic effect of papilloma virus on the tarred skin of rabbits: I. Description of the phenomenon, J Exp Med 671399 (1938). 22. Jarrett WFH, et 01: High incidence area of cattle cancer with a possible interaction between an environmental carcinogen and a papilloma virus, Nature 274: 215 (1978). 23. Jablonska S, Dabrowski J, and Jakubowicz K: Epidermodysplasia verruciform is as a model in studies on the role of pa. povaviruses in oncogenesis, Cancer Res 32: 583 (1972). 24. Grissman L: Papillomaviruses and their association with cancer in animals and in man, Cancer Surv 3: 161 (1984).
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