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URETHRAL SLOUGH: A RARE AND PREVIOUSLY UNREPORTED COMPLICATION OF INTRAVESICAL MITOMYCIN
0022-5347/00/1644-1305/0 THE JOURNAL OF UROLOGY® Copyright © 2000 by AMERICAN UROLOGICAL ASSOCIATION, INC.®
Vol. 164, 1305, October 2000 Printed in U.S.A.
URETHRAL SLOUGH: A RARE AND PREVIOUSLY UNREPORTED COMPLICATION OF INTRAVESICAL MITOMYCIN JEFFREY D. BRADY, DEAN G. ASSIMOS
AND
GERALD H. JORDAN*
From the Department of Urology, Wake Forest School of Medicine, Winston-Salem, North Carolina, and Department of Urology, Eastern Virginia Medical School, Devine Center for Genitourinary Reconstruction, Norfolk, Virginia KEY WORDS: mitomycin, drug therapy, urethra, catheterization
Intravesical mitomycin is rarely associated with significant toxicity. We report 2 cases of corpus spongiosum necrosis following intravesical mitomycin therapy for superficial urothelial carcinoma. CASE REPORTS
Case 1. P. O., a 52-year-old man, was started on a course of intravesical mitomycin for recurrent superficial urothelial carcinoma 2 weeks following complete resection. He had no evidence of urethral stricture on prior endoscopy. On the fourth instillation of 40 mg. mitomycin severe pain developed at catheterization and diffuse perineal inflammation developed immediately afterwards. The patient was referred with necrosis of the corpus spongiosum and was treated with a perineal urethrostomy. He was lost to followup. Case 2. W. W., a 62-year-old man, had an 18-year history of steroid dependent systemic lupus erythematosus and superficial bladder carcinoma. Following multiple recurrences, 60 mg. intravesical mitomycin were initiated. There was marked difficulty with urethral catheterization beginning with the third weekly instillation of a 6-week course. The last catheterization and instillation were associated with significant pain. The patient also complained of constant perineal pain, vague pelvic pain, dysuria and right testicular pain. Symptoms persisted and endoscopy revealed a long narrow caliber urethral stricture, which later proved to be a 7 cm. necrotic segment of corpus spongiosum. A suprapubic catheter was placed and the devitalized tissue was de´brided. The patient was referred and treated with a perineal urethrostomy. Recurrence of superficial bladder cancer was treated with a 7-week course of mitomycin through the perineal urethrostomy with no side effects. The patient died of unrelated causes approximately 7 years following the urethrostomy. DISCUSSION
Intravesical mitomycin is an attractive alternative to bacillus Calmette-Guerin for the treatment of high grade superficial urothelial carcinoma. The ability to reduce tumor recurrence has been established in multiple series and the current American Urological Association Bladder Cancer Clinical Guideline supports its use for high grade disease. A naturally occurring antitumor antibiotic isolated from Streptomyces, mitomycin functions as an alkylating agent by inhibiting DNA synthesis, and its molecular weight (324 daltons) limits intravesical absorption and prevents systemic toxicity. Local side effects are largely related to tissue injury caused by direct contact with the drug. Chemical cystitis, the most
common complaint, has a 6% to 41% incidence.1 Bacterial cystitis or flu-like symptoms have been reported in 20% of treated patients. Palmar desquamation and/or genital rash has been reported in approximately 5% of patients and may be due to contact dermatitis or delayed type hypersensitivity. This condition can be prevented by cleansing the hands and perineum carefully, and avoiding contact with urine following treatment. Allergic reactions, perivesical inflammation, reduced bladder capacity, bladder wall calcification, ureteral stricture development and myelosuppression are uncommonly reported side effects.1 Proper placement of the urethral catheter during instillation of immunotherapy or chemotherapy is paramount. Systemic toxicity associated with bacillus Calmette-Guerin following traumatic catheterization has been well documented. Mitomycin instillation through a urethral false passage exposes the submucosa and corpus spongiosum to the direct cytotoxic effects of the chemotherapeutic agent. The destructive effect of mitomycin on local tissue has been described. In the bladder a marked necrotic inflammatory process and severe epithelial denudation may follow the administration of topical mitomycin. The histological response may extend deep into the bladder wall.2 Local complications have been described following intravenous mitomycin. Cellulitis at the injection site has been reported. Necrosis, with subsequent sloughing of tissue, following mitomycin extravasation at the injection site has been described.3 Mitomycin instillation into the subepithelium or spongy tissue of the corpus spongiosum produces a similar histological response and, if severe enough, progresses to necrosis and urethral slough. CONCLUSIONS
Intravesical mitomycin is rarely associated with significant morbidity, although it should be recognized as a possible consequence. Correct catheter placement must be verified before administration of chemotherapy. While our patients did not have a history of coexistent urethral stricture, those who do may be at significant risk. For those patients or any patient for whom stricture is a possibility endoscopic placement of the catheter may be required. Instillation of mitomycin into the subepithelium of a false passage in our patients appeared to cause necrosis of the corpus spongiosum and urethral slough. Urethral reconstruction could have been performed but was not elected by either of our patients.
Accepted for publication May 19, 2000. *Financial interest and/or other relationship with Pfizer-AMS, TAP Pharmaceuticals, Thermatrix, Vivus Inc., Schering, Mentor, Advise Biotechnics/Biospecifics.
1305
REFERENCES
1. Soloway, M. S. and Perito, P. E.: Superficial bladder cancer: diagnosis, surveillance and treatment. J Cell Biochem Suppl, 16I: 120, 1992 2. Lopez-Beltran, A.: Bladder treatment. Immunotherapy and chemotherapy. Urol Clin North Am, 26: 535, 1999 3. Physician’s Desk Reference, 53rd ed. Montale.: Medical Economics Company, Inc., p. 787, 1999
Vol. 164, 1305, October 2000 Printed in U.S.A.
URETHRAL SLOUGH: A RARE AND PREVIOUSLY UNREPORTED COMPLICATION OF INTRAVESICAL MITOMYCIN JEFFREY D. BRADY, DEAN G. ASSIMOS
AND
GERALD H. JORDAN*
From the Department of Urology, Wake Forest School of Medicine, Winston-Salem, North Carolina, and Department of Urology, Eastern Virginia Medical School, Devine Center for Genitourinary Reconstruction, Norfolk, Virginia KEY WORDS: mitomycin, drug therapy, urethra, catheterization
Intravesical mitomycin is rarely associated with significant toxicity. We report 2 cases of corpus spongiosum necrosis following intravesical mitomycin therapy for superficial urothelial carcinoma. CASE REPORTS
Case 1. P. O., a 52-year-old man, was started on a course of intravesical mitomycin for recurrent superficial urothelial carcinoma 2 weeks following complete resection. He had no evidence of urethral stricture on prior endoscopy. On the fourth instillation of 40 mg. mitomycin severe pain developed at catheterization and diffuse perineal inflammation developed immediately afterwards. The patient was referred with necrosis of the corpus spongiosum and was treated with a perineal urethrostomy. He was lost to followup. Case 2. W. W., a 62-year-old man, had an 18-year history of steroid dependent systemic lupus erythematosus and superficial bladder carcinoma. Following multiple recurrences, 60 mg. intravesical mitomycin were initiated. There was marked difficulty with urethral catheterization beginning with the third weekly instillation of a 6-week course. The last catheterization and instillation were associated with significant pain. The patient also complained of constant perineal pain, vague pelvic pain, dysuria and right testicular pain. Symptoms persisted and endoscopy revealed a long narrow caliber urethral stricture, which later proved to be a 7 cm. necrotic segment of corpus spongiosum. A suprapubic catheter was placed and the devitalized tissue was de´brided. The patient was referred and treated with a perineal urethrostomy. Recurrence of superficial bladder cancer was treated with a 7-week course of mitomycin through the perineal urethrostomy with no side effects. The patient died of unrelated causes approximately 7 years following the urethrostomy. DISCUSSION
Intravesical mitomycin is an attractive alternative to bacillus Calmette-Guerin for the treatment of high grade superficial urothelial carcinoma. The ability to reduce tumor recurrence has been established in multiple series and the current American Urological Association Bladder Cancer Clinical Guideline supports its use for high grade disease. A naturally occurring antitumor antibiotic isolated from Streptomyces, mitomycin functions as an alkylating agent by inhibiting DNA synthesis, and its molecular weight (324 daltons) limits intravesical absorption and prevents systemic toxicity. Local side effects are largely related to tissue injury caused by direct contact with the drug. Chemical cystitis, the most
common complaint, has a 6% to 41% incidence.1 Bacterial cystitis or flu-like symptoms have been reported in 20% of treated patients. Palmar desquamation and/or genital rash has been reported in approximately 5% of patients and may be due to contact dermatitis or delayed type hypersensitivity. This condition can be prevented by cleansing the hands and perineum carefully, and avoiding contact with urine following treatment. Allergic reactions, perivesical inflammation, reduced bladder capacity, bladder wall calcification, ureteral stricture development and myelosuppression are uncommonly reported side effects.1 Proper placement of the urethral catheter during instillation of immunotherapy or chemotherapy is paramount. Systemic toxicity associated with bacillus Calmette-Guerin following traumatic catheterization has been well documented. Mitomycin instillation through a urethral false passage exposes the submucosa and corpus spongiosum to the direct cytotoxic effects of the chemotherapeutic agent. The destructive effect of mitomycin on local tissue has been described. In the bladder a marked necrotic inflammatory process and severe epithelial denudation may follow the administration of topical mitomycin. The histological response may extend deep into the bladder wall.2 Local complications have been described following intravenous mitomycin. Cellulitis at the injection site has been reported. Necrosis, with subsequent sloughing of tissue, following mitomycin extravasation at the injection site has been described.3 Mitomycin instillation into the subepithelium or spongy tissue of the corpus spongiosum produces a similar histological response and, if severe enough, progresses to necrosis and urethral slough. CONCLUSIONS
Intravesical mitomycin is rarely associated with significant morbidity, although it should be recognized as a possible consequence. Correct catheter placement must be verified before administration of chemotherapy. While our patients did not have a history of coexistent urethral stricture, those who do may be at significant risk. For those patients or any patient for whom stricture is a possibility endoscopic placement of the catheter may be required. Instillation of mitomycin into the subepithelium of a false passage in our patients appeared to cause necrosis of the corpus spongiosum and urethral slough. Urethral reconstruction could have been performed but was not elected by either of our patients.
Accepted for publication May 19, 2000. *Financial interest and/or other relationship with Pfizer-AMS, TAP Pharmaceuticals, Thermatrix, Vivus Inc., Schering, Mentor, Advise Biotechnics/Biospecifics.
1305
REFERENCES
1. Soloway, M. S. and Perito, P. E.: Superficial bladder cancer: diagnosis, surveillance and treatment. J Cell Biochem Suppl, 16I: 120, 1992 2. Lopez-Beltran, A.: Bladder treatment. Immunotherapy and chemotherapy. Urol Clin North Am, 26: 535, 1999 3. Physician’s Desk Reference, 53rd ed. Montale.: Medical Economics Company, Inc., p. 787, 1999