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The Eradication of Intraurethral Condyloma Acuminata with 5 Per Cent 5-Fluorouracil Cream
Vol. 113, February Printed in U.S.A.
THE JOURNAL OF UROLOGY
Copyright© 1975 by The Williams & Wilkins Co.
THE ERADICATION OF INTRAURETHRAL CONDYLOMA ACUMINATA WITH 5 PER CENT 5-FLUOROURACIL CREAM STEPHEN P. DRETLER
AND
LESTER A. KLEIN
From the Departments of Urology, Massachusetts General Hospital, Beth Israel Hospital and Harvard Medical School, Boston, Massachusetts
Although the prolapsing, glistening, cauliflowerlike lesions of intraurethral condyloma acuminata appear innocuous, they are commonly associated with urethral irritation and infection, have resulted in total urinary tract obstruction and fistula formation, 1 and have so extensively involved the urethra and bladder that penectomy 2 and cystectomy have been required.•. 4 To date, treatment of intraurethral condyloma acuminata has been unsatisfactory. Excision and electrodesiccation have resulted in urethral stricture and have not prevented recurrence. Podophyllin, while effective in external genital condylomas, is extremely cytotoxic, harmful to normal epithelium and unsuitable for intraurethral use. Other agents used for external condylomas, such as sulfa cream, 5 ammoniated mercury• and chloroquine 7 are not effective for intraurethral lesions. Recently, the use of thio-tepa has been suggested but this method requires long-term treatment with multiple appli-' cations and does not cause total eradication. 8 Similarly, liquid solutions of colchicine have been used successfully in a few patients but require repeated physician instillation over a number of months and may cause urethral inflammation and pain. 9 The search for an agent which would rapidly, safely and effectively eradicate intraurethral conAccepted for publication July 19, 1974. Read at annual meeting of American Urological Association, St. Louis, Missouri, May 19-23, 1974. 1 Morrow, R. P., Jr., McDonald, J. R. and Emmett, J. L.: Condylomata acuminata of the urethra. J. Urol., 68: 909, 1952. 2 Lindner, H. J. and Pasquier, C. M., Jr.: Condylomata acuminata of the urethra. J. Urol., 72: 875, 1954. • Kleiman, H. and Lancaster, Y.: Condyloma acuminata of the bladder. J. Urol., 88: 52, 1962. 4 Lewis, H. Y., Wolf, P. L. and Pierce, J. M.: Condyloma acuminatum of the bladder. J. Urol., 88: 248, 1962. 'Gardner, H. L. and Kaufman, R. J:I.: Tum~rs of the vulva and vagina. Condylomata acummata. Chn. Obst. Gynec., 8: 938, 1965. • Grace, D. A., Ochsner, J. A., McLain, C. R. and Smith, J. P.: Vulva condylomata acuminata in prepubertal females. J.A.M.A., 201: 137, 1967. 7 Murphy, J. C. and Petty, S.: Chloroquine treatmei:t of warts; a double-blind clinical study. Rocky Mountam Med. J., 62: 25, 1965. 'Halverstadt, D. B. and Parry, W. L.: Thiotepa in the management of intraurethral condylomata acuminata. J. Urol., 101: 729, 1969. • Gigax, J. H. and Robison, J. R.: The. success~! treatment of intraurethral condyloma acummata with colchicine. J. Urol., 105: 809, 1071.
dyloma acuminata led to a trial usage of 5 per cent 5-fluorouracil cream (5-FU). * MATERIALS AND METHODS
From 1970 to 1974, 20 patients with intraurethral condyloma acuminata were treated with intraurethral instillation of 5 per cent 5-FU cream. Of these patients 15 had lesions localized to the urethral meatus, 4 had meatal and more proximal urethral lesions and 1 had condylomas in the penile and bulbous urethra but none at the meatus. Each patient with meatal condylomas was provided with a 25 gm. tube of 5 per cent 5-FU cream and a cone-shaped applicator of a type usually used for instillation of local anesthetic. The patients were instructed to instill approximately 2 cc cream into the meatus after each voiding and at bedtime, being careful to avoid contact of 5-FU and other skin surfaces, especially fingers, prepuce and scrotum. To prevent contact of scrotal skin and 5-FU, patients were supplied with a scrotal support with a penile aperture. Initially, treatment was continued for 7 days but since patient response varied applications were given for the length of time necessary to eradicate visible condylomas, usually 3 to 8 days. Patients with more proximal urethral lesions were instructed to instill volumes of 5-FU cream sufficient to fill the entire urethra. This was a difficult task to accomplish and 2 of the 5 patients with proximal urethral condylomas required repeated physician instillation so that the 5-FU would reach the affected areas. RESULTS
Of the 20 patients 19 have had total eradication of intraurethral condyloma acuminata by instillations of 5 per cent 5-FU cream. The patient who failed to achieve total eradication had condylomas proximal to the urinary sphincter in the prostatic urethra and required transurethral fulguration (case 3). Followup ranged from 6 months to 4 years. Another meatal condyloma developed in 1 patient 6 months following treatment and was successfully retreated. It is not known whether this represented recurrence or reinfection. Meatal inflammation, adherence of adjacent denuded meatal mucosa and spraying of the urinary stream following eradication of meatal condylomas were noted in 4 patients. However, all of
* Efudex, Roche Laboratories, Nutley, New Jersey. 195
196
DRETLER AND KLEIN
these patients had normal urination following a single passage of No. 24F Van Buren sound through the distal 4 cm. of urethra. None had meatal stricture. One patient had severe dysuria, urethral irritation and could not void following deep urethral instillation of 5-FU but the lesions were extensive, involving the entire urethral mucosa from the meatus to the bladder neck (case 3). Superficial scrotal ulcerations resulting from prolonged and repeated contact of 5-FU and scrotal skin developed in 2 patients. The erosions healed without scarring after brief treatment with saline dressings and hydrocortisone ointment. The use of a scrotal support with penile aperture has averted this complication in the remaining patients. There have been no instances of meatal scarring or urethral strictures and no evidence of systemic absorption manifested by changes in white blood cell, red blood cell or platelet count. CASE REPORTS
Case 1. R. W., a 25-year-old white man, presented early in the series with the chief complaint of dysuria. Physical examination revealed a cluster of condyloma acuminata at the urethral meatus
(fig. 1, A). Panendoscopic examination showed the remainder of the urethra to be free of lesions. Accordingly, the patient was given the previously outlined instructions for the application of 5-FU to the meatus. Two weeks later he was re-examined and all meatal lesions were gone (fig. 1, B). However, repeat endoscopic examination showed linear streaks of condylomas at 3 and 9 o'clock along the course of the penile urethra. The patient was then instructed to instill a greater volume of 5-FU so that these new lesions could be eradicated. Two weeks later all lesions had disappeared. Case 2. P. W., a 37-year-old white man, presented with the chief complaint of difficulty voiding and urethral bleeding. Urologic history included membranous urethral rupture resulting from a pelvic fracture. Physical examination revealed no evidence of meatal condylomas. Endoscopic examination revealed a membranous urethral stricture, and multiple bulbous and penile condylomas (fig. 2, A). The patient was instructed to instill 5-FU so that it filled the penile and bulbous urethra. He was successful in eradicating most but not all of the lesions. Therefore, the patient returned for biweekly office instillations for 3 weeks. Repeated endoscopic examination 6 weeks after the initial
FIG. 1. A, retraction of meatus results in protrusion of submeatal condylomas. B, meatal condylomas have disappeared after applications of 5-FU. Area of condyloma necrosis and denuded meatal mucosa is visible.
ERADICATION OF INTRAURETHRAL CONDYLOMA ACUMINATA
197
Fm. 2. Photographs taken through panendoscope. A, multiple filamentous condyloma in proximal penile urethra. B, small areas of mucosa! elevation marking sites of origin of necrotic condylomas. Note that remainder of urethrv.l mucosa is normal.
treatment showed only small mucosal elevations, marking the healing sites of disappearing lesions and 1 small condyloma which was successfully retreated (fig. 2, B). At no time did the patient have meatal ulceration, urethral pain, evidence of urethral inflammation or difficulty voiding. Case 3. D. M., a 27-year-old white man, had recently undergone endoscopic examination with excision and electrodesiccation of meatal condylomas. Shortly thereafter dysuria and decreased urinary stream developed and he was referred for further urologic treatment. At physical examination no meatal lesions were visible but by endoscopic examination the patient was noted to have almost total involvement of penile, bulbous and prostatic urethra by condyloma acuminata (fig. 3). He was given 5-FU cream and instructed to fill the urethra as previously described. Five days later severe dysuria developed. The 5-FU treatment was discontinued and endoscopic examination was done. Surprisingly, all bulbous urethral lesions and all but a patch of mid penile urethral condylomas had disappeared, leaving only small mucosa! elevations marking the sites of origin. However, condylomas in the prostatic urethra were still present (fig. 4) and were fulgurated. After urethral inflammation had subsided a second course of 5-FU instillation was administered. This eradicated the remaining penile condylomas but resulted in urethral edema and difficulty voiding requiring 4 days of catheterization.
FrG. 3. Endoscopic view of bulbous urethra almost totally occluded by condyloma acuminata.
DISCUSSION
5-FU is a compound which blocks the rnethylation reaction of deoxyuridylic acid to thymidylic acid. The effect is to create a thymine deficiency and, thus, interfere with deoxyribonucleic acid and to a lesser extent ribonucleic acid synthesis. The action of the drug is much more marked on rapidly metabolizing cells since these take up this competitive inhibitor at a more rapid pace. Since the drug is non-toxic when applied to most skin areas it has
FIG. 4. Endoscopic view of condyloma protrudes from membranous urethra through area of urinary sphincter.
198
DRETLER AND KLEIN
widespread use for the treatment of dermatologic lesions, notably basal cell carcinoma and penile lesions such as Bowen's disease and erythroplasia of Queyrat. 10 Since condyloma acuminata, although nonmalignant, are rapidly metabolizing growths, it is not surprising that they respond to treatment with 5-FU. With necrosis and subsequent disappearance of condylomas an area of denuded urethral mucosa occurs and this erosion accounts for the urethral edema and meatal irritation. The larger the surface area covered by condylomas the greater the area of erosion and urethral reaction. With extensive penile and bulbous urethral condylomas one can expect considerable superficial mucosal denudation. However, these erosions heal rapidly and no strictures result. Endoscopic examinations performed after treatment with 5-FU showed no evidence of damage to the normal urethral mucosa. Since the patient described in case 1 had proximal urethral condylomas following endoscopic examination, it seemed probable that passage of the panendoscope seeded the meatal condylomas along the course of the urethra. Although it is recognized that the appearance of these new intraurethral lesions may have been fortuitous, endoscopic examination is no longer performed until all meatal condylomas have been eradicated. Since the patient in case 3 had endoscopic examination at the 10 Williams, A. C. and Klein, E.: Experiences with local chemotherapy and immunotherapy in premalignant and malignant skin lesions. Cancer, 25: 450, 1970.
time of initial fulguration of meatal lesions and, subsequently, had severe penile, bulbous and prostatic urethral involvement, the precaution of delayed endoscopy appears justified. Condylomas in the prostatic urethra occurred in 1 patient (case 3) and were unable to be eradicated by intraurethral 5-FU. It is likely that the force of injection was not sufficient to overcome sphincter pressure and allow large enough volume of 5-FU to be in contact with the prostatic urethra for an adequate period. It must be emphasized that patient response to intraurethral 5-FU instillation is variable and treatment should be done, not for a specific number of days, but until the lesions show regression. Furthermore, precautions must be taken to avoid contact of 5-FU with scrotal skin, to delay endoscopic examination until meatal lesions have been eradicated and to prevent adherence of adjacent denuded meatal mucosa by frequent retraction of meatal edges or, if necessary, the passage of a Van Buren sound. SUMMARY
Twenty patients have had successful eradication of intraurethral condyloma acuminata by the in-traurethral instillation of 5 per cent 5-fluorouraci:t cream. Avoidable complications are scrotal irritation and meatitis. Endoscopic examination is delayed until distal lesions have been eradicated, The method is safe, inexpensive, painless and effective.
THE JOURNAL OF UROLOGY
Copyright© 1975 by The Williams & Wilkins Co.
THE ERADICATION OF INTRAURETHRAL CONDYLOMA ACUMINATA WITH 5 PER CENT 5-FLUOROURACIL CREAM STEPHEN P. DRETLER
AND
LESTER A. KLEIN
From the Departments of Urology, Massachusetts General Hospital, Beth Israel Hospital and Harvard Medical School, Boston, Massachusetts
Although the prolapsing, glistening, cauliflowerlike lesions of intraurethral condyloma acuminata appear innocuous, they are commonly associated with urethral irritation and infection, have resulted in total urinary tract obstruction and fistula formation, 1 and have so extensively involved the urethra and bladder that penectomy 2 and cystectomy have been required.•. 4 To date, treatment of intraurethral condyloma acuminata has been unsatisfactory. Excision and electrodesiccation have resulted in urethral stricture and have not prevented recurrence. Podophyllin, while effective in external genital condylomas, is extremely cytotoxic, harmful to normal epithelium and unsuitable for intraurethral use. Other agents used for external condylomas, such as sulfa cream, 5 ammoniated mercury• and chloroquine 7 are not effective for intraurethral lesions. Recently, the use of thio-tepa has been suggested but this method requires long-term treatment with multiple appli-' cations and does not cause total eradication. 8 Similarly, liquid solutions of colchicine have been used successfully in a few patients but require repeated physician instillation over a number of months and may cause urethral inflammation and pain. 9 The search for an agent which would rapidly, safely and effectively eradicate intraurethral conAccepted for publication July 19, 1974. Read at annual meeting of American Urological Association, St. Louis, Missouri, May 19-23, 1974. 1 Morrow, R. P., Jr., McDonald, J. R. and Emmett, J. L.: Condylomata acuminata of the urethra. J. Urol., 68: 909, 1952. 2 Lindner, H. J. and Pasquier, C. M., Jr.: Condylomata acuminata of the urethra. J. Urol., 72: 875, 1954. • Kleiman, H. and Lancaster, Y.: Condyloma acuminata of the bladder. J. Urol., 88: 52, 1962. 4 Lewis, H. Y., Wolf, P. L. and Pierce, J. M.: Condyloma acuminatum of the bladder. J. Urol., 88: 248, 1962. 'Gardner, H. L. and Kaufman, R. J:I.: Tum~rs of the vulva and vagina. Condylomata acummata. Chn. Obst. Gynec., 8: 938, 1965. • Grace, D. A., Ochsner, J. A., McLain, C. R. and Smith, J. P.: Vulva condylomata acuminata in prepubertal females. J.A.M.A., 201: 137, 1967. 7 Murphy, J. C. and Petty, S.: Chloroquine treatmei:t of warts; a double-blind clinical study. Rocky Mountam Med. J., 62: 25, 1965. 'Halverstadt, D. B. and Parry, W. L.: Thiotepa in the management of intraurethral condylomata acuminata. J. Urol., 101: 729, 1969. • Gigax, J. H. and Robison, J. R.: The. success~! treatment of intraurethral condyloma acummata with colchicine. J. Urol., 105: 809, 1071.
dyloma acuminata led to a trial usage of 5 per cent 5-fluorouracil cream (5-FU). * MATERIALS AND METHODS
From 1970 to 1974, 20 patients with intraurethral condyloma acuminata were treated with intraurethral instillation of 5 per cent 5-FU cream. Of these patients 15 had lesions localized to the urethral meatus, 4 had meatal and more proximal urethral lesions and 1 had condylomas in the penile and bulbous urethra but none at the meatus. Each patient with meatal condylomas was provided with a 25 gm. tube of 5 per cent 5-FU cream and a cone-shaped applicator of a type usually used for instillation of local anesthetic. The patients were instructed to instill approximately 2 cc cream into the meatus after each voiding and at bedtime, being careful to avoid contact of 5-FU and other skin surfaces, especially fingers, prepuce and scrotum. To prevent contact of scrotal skin and 5-FU, patients were supplied with a scrotal support with a penile aperture. Initially, treatment was continued for 7 days but since patient response varied applications were given for the length of time necessary to eradicate visible condylomas, usually 3 to 8 days. Patients with more proximal urethral lesions were instructed to instill volumes of 5-FU cream sufficient to fill the entire urethra. This was a difficult task to accomplish and 2 of the 5 patients with proximal urethral condylomas required repeated physician instillation so that the 5-FU would reach the affected areas. RESULTS
Of the 20 patients 19 have had total eradication of intraurethral condyloma acuminata by instillations of 5 per cent 5-FU cream. The patient who failed to achieve total eradication had condylomas proximal to the urinary sphincter in the prostatic urethra and required transurethral fulguration (case 3). Followup ranged from 6 months to 4 years. Another meatal condyloma developed in 1 patient 6 months following treatment and was successfully retreated. It is not known whether this represented recurrence or reinfection. Meatal inflammation, adherence of adjacent denuded meatal mucosa and spraying of the urinary stream following eradication of meatal condylomas were noted in 4 patients. However, all of
* Efudex, Roche Laboratories, Nutley, New Jersey. 195
196
DRETLER AND KLEIN
these patients had normal urination following a single passage of No. 24F Van Buren sound through the distal 4 cm. of urethra. None had meatal stricture. One patient had severe dysuria, urethral irritation and could not void following deep urethral instillation of 5-FU but the lesions were extensive, involving the entire urethral mucosa from the meatus to the bladder neck (case 3). Superficial scrotal ulcerations resulting from prolonged and repeated contact of 5-FU and scrotal skin developed in 2 patients. The erosions healed without scarring after brief treatment with saline dressings and hydrocortisone ointment. The use of a scrotal support with penile aperture has averted this complication in the remaining patients. There have been no instances of meatal scarring or urethral strictures and no evidence of systemic absorption manifested by changes in white blood cell, red blood cell or platelet count. CASE REPORTS
Case 1. R. W., a 25-year-old white man, presented early in the series with the chief complaint of dysuria. Physical examination revealed a cluster of condyloma acuminata at the urethral meatus
(fig. 1, A). Panendoscopic examination showed the remainder of the urethra to be free of lesions. Accordingly, the patient was given the previously outlined instructions for the application of 5-FU to the meatus. Two weeks later he was re-examined and all meatal lesions were gone (fig. 1, B). However, repeat endoscopic examination showed linear streaks of condylomas at 3 and 9 o'clock along the course of the penile urethra. The patient was then instructed to instill a greater volume of 5-FU so that these new lesions could be eradicated. Two weeks later all lesions had disappeared. Case 2. P. W., a 37-year-old white man, presented with the chief complaint of difficulty voiding and urethral bleeding. Urologic history included membranous urethral rupture resulting from a pelvic fracture. Physical examination revealed no evidence of meatal condylomas. Endoscopic examination revealed a membranous urethral stricture, and multiple bulbous and penile condylomas (fig. 2, A). The patient was instructed to instill 5-FU so that it filled the penile and bulbous urethra. He was successful in eradicating most but not all of the lesions. Therefore, the patient returned for biweekly office instillations for 3 weeks. Repeated endoscopic examination 6 weeks after the initial
FIG. 1. A, retraction of meatus results in protrusion of submeatal condylomas. B, meatal condylomas have disappeared after applications of 5-FU. Area of condyloma necrosis and denuded meatal mucosa is visible.
ERADICATION OF INTRAURETHRAL CONDYLOMA ACUMINATA
197
Fm. 2. Photographs taken through panendoscope. A, multiple filamentous condyloma in proximal penile urethra. B, small areas of mucosa! elevation marking sites of origin of necrotic condylomas. Note that remainder of urethrv.l mucosa is normal.
treatment showed only small mucosal elevations, marking the healing sites of disappearing lesions and 1 small condyloma which was successfully retreated (fig. 2, B). At no time did the patient have meatal ulceration, urethral pain, evidence of urethral inflammation or difficulty voiding. Case 3. D. M., a 27-year-old white man, had recently undergone endoscopic examination with excision and electrodesiccation of meatal condylomas. Shortly thereafter dysuria and decreased urinary stream developed and he was referred for further urologic treatment. At physical examination no meatal lesions were visible but by endoscopic examination the patient was noted to have almost total involvement of penile, bulbous and prostatic urethra by condyloma acuminata (fig. 3). He was given 5-FU cream and instructed to fill the urethra as previously described. Five days later severe dysuria developed. The 5-FU treatment was discontinued and endoscopic examination was done. Surprisingly, all bulbous urethral lesions and all but a patch of mid penile urethral condylomas had disappeared, leaving only small mucosa! elevations marking the sites of origin. However, condylomas in the prostatic urethra were still present (fig. 4) and were fulgurated. After urethral inflammation had subsided a second course of 5-FU instillation was administered. This eradicated the remaining penile condylomas but resulted in urethral edema and difficulty voiding requiring 4 days of catheterization.
FrG. 3. Endoscopic view of bulbous urethra almost totally occluded by condyloma acuminata.
DISCUSSION
5-FU is a compound which blocks the rnethylation reaction of deoxyuridylic acid to thymidylic acid. The effect is to create a thymine deficiency and, thus, interfere with deoxyribonucleic acid and to a lesser extent ribonucleic acid synthesis. The action of the drug is much more marked on rapidly metabolizing cells since these take up this competitive inhibitor at a more rapid pace. Since the drug is non-toxic when applied to most skin areas it has
FIG. 4. Endoscopic view of condyloma protrudes from membranous urethra through area of urinary sphincter.
198
DRETLER AND KLEIN
widespread use for the treatment of dermatologic lesions, notably basal cell carcinoma and penile lesions such as Bowen's disease and erythroplasia of Queyrat. 10 Since condyloma acuminata, although nonmalignant, are rapidly metabolizing growths, it is not surprising that they respond to treatment with 5-FU. With necrosis and subsequent disappearance of condylomas an area of denuded urethral mucosa occurs and this erosion accounts for the urethral edema and meatal irritation. The larger the surface area covered by condylomas the greater the area of erosion and urethral reaction. With extensive penile and bulbous urethral condylomas one can expect considerable superficial mucosal denudation. However, these erosions heal rapidly and no strictures result. Endoscopic examinations performed after treatment with 5-FU showed no evidence of damage to the normal urethral mucosa. Since the patient described in case 1 had proximal urethral condylomas following endoscopic examination, it seemed probable that passage of the panendoscope seeded the meatal condylomas along the course of the urethra. Although it is recognized that the appearance of these new intraurethral lesions may have been fortuitous, endoscopic examination is no longer performed until all meatal condylomas have been eradicated. Since the patient in case 3 had endoscopic examination at the 10 Williams, A. C. and Klein, E.: Experiences with local chemotherapy and immunotherapy in premalignant and malignant skin lesions. Cancer, 25: 450, 1970.
time of initial fulguration of meatal lesions and, subsequently, had severe penile, bulbous and prostatic urethral involvement, the precaution of delayed endoscopy appears justified. Condylomas in the prostatic urethra occurred in 1 patient (case 3) and were unable to be eradicated by intraurethral 5-FU. It is likely that the force of injection was not sufficient to overcome sphincter pressure and allow large enough volume of 5-FU to be in contact with the prostatic urethra for an adequate period. It must be emphasized that patient response to intraurethral 5-FU instillation is variable and treatment should be done, not for a specific number of days, but until the lesions show regression. Furthermore, precautions must be taken to avoid contact of 5-FU with scrotal skin, to delay endoscopic examination until meatal lesions have been eradicated and to prevent adherence of adjacent denuded meatal mucosa by frequent retraction of meatal edges or, if necessary, the passage of a Van Buren sound. SUMMARY
Twenty patients have had successful eradication of intraurethral condyloma acuminata by the in-traurethral instillation of 5 per cent 5-fluorouraci:t cream. Avoidable complications are scrotal irritation and meatitis. Endoscopic examination is delayed until distal lesions have been eradicated, The method is safe, inexpensive, painless and effective.