URETERITIS CYSTICA AFTER TREATMENT
OF
CYCLOPHOSPHAMIDE-INDUCED HEMORRHAGIC SOROOSH
CYSTITIS
MAHBOUBI,
JOHN N. DUCKEIT,
M.D.
M.D.
THOMAS J. SPACKMAN,
M.D.
From the Departments of Radiology and Urology, Children’s Hospital of Philadelphia, University of Pennsylvania Medical School, Philadelphia, Pennsylvania
ABSTRACT - A case is presented in which ureteritis cystica developed following formalin instillation for treatment of cyclophosphamide-induced hemorrhagic cystitis. It is not known whether this complication, not previously reported, is a result of the cyclophosphamide, the formalin, or a combination of both. Patients being considered fm fn-malin instillation should be studied by cystography fn- evaluation of vesicoureteral rejux. Alternative methods to fwmalin instillation should be considered in patients with reflux.
Several recent reports have described the occurrence of hemorrhagic cystitis and vesicoureteral reflux after the systemic administration of cyclophosphamide as a cancer chemotherapeutic agent. l-3 This article reports a case of ureteritis cystica which resulted after cyclophosphamide-induced hemorrhagic cystitis was treated by formalin lavage of the urinary bladder. The cause of the ureteritis is considered, and methods of avoiding the complication of treatment are discussed. Case Report At seven years of age, this boy was initially diagnosed as having acute lymphocytic leukemia. With combination chemotherapy, complete remission was achieved and maintained for three and a half years. Therapy was then stopped for five months, at which time relapse occurred. Remission was again induced and maintained for another five years. During this time he received vincristine, methotrexate, daunomycin, 6mercaptopurine, and a total of 4 Cm. of cyclophosphamide, and he remained completely asymptomatic throughout.
UROLOGY
/ MAY 1976 / VOLUME
VII,
NUMBER 5
At the age of fifteen he began having microscopic hematuria which persisted despite discontinuance of cyclophosphamide. Over the ensuing six months the hematuria became more severe and finally resulted in a massive hemorrhagic cystitis. His hemoglobin dropped from 12 Gm. to 6.5 Gm. per 100 ml., and he required transfusion with six units of blood. An intravenous pyelogram demonstrated a small bladder with mucosal irregularity (Fig. 1A). The findings were compatible with cyclophosphamide-induced hemorrhagic cystitis, but no cystogram was done at that time for evaluation of vesicoureteral reflux. For treatment of the severe urinary hemorrhage, a solution of lo-per cent formalin was instilled into the patient’s bladder for fifteen minutes. The therapy was successful in producing hemostasis, and the urine remained free of blood on subsequent examinations. Over the next several months he complained of left flank pain intermittently, and an intravenous pyelogram three months after formalin treatment showed left hydroureteronephrosis to the level of the bony pelvis. A cystogram demonstrated bilateral
521
(A) Intravenous pyelogram shows irregularity of bladder wall withfilling defect, narrowing of distal FIGURE 1. ureters, and some fullness of collecting system on left. (B) lntravenous pyelogram shows progress of hydronephrosis and hydroureter on left. (C) Left retrograde pyeloureterogram shows irregularity and narrowing of distal ureter with some fullness of proximal ureter and calyceal system secondary to ureteritis.
vesicoureteral reflux. The left flank pain was controlled with analgesics, and surgical drainage of the partially obstructed collecting system was not necessary. Nine months after formalin instillation, a repeat intravenous pyelogram showed progressive left hydroureteronephrosis (Fig. 1B). At cystoscopy there was evidence of small telangiectatic capillaries, but the bladder mucosa otherwise appeared normal. A left retrograde pyelogram showed irregular narrowing of the distal third of the ureter (Fig. 1C). The proximal ureter was dilated with multiple small mucosal irregularities similar to ureteritis cystica. A 4 F catheter was passed with ease all the way to the kidney, and there was no evidence of rigid stenosis of the distal ureter. Removal of the catheter from the ureter was followed by bloody drainage, indicating friability of the ureteral mucosa. Because of the extent of the ureteral involvement and the absence of a rigid stricture, the planned reimplantation was deferred. The patient has continued to have periodic low-grade backache, and repeat intravenous pyelogram fifteen months after formalin treatment showed no changes in the degree of obstruction on the left.
522
Comment Since its development in 1957, the use of cyclophosphamide as a cancer chemotherapeutic agent has been associated with a 5 to 10 per cent risk of hemorrhagic cystitis as a complication. The drug goes through several metabolic conversions in the body, and breakdown products are excreted in the urine. It is believed that hemorrhagic cystitis results from direct contact of breakdown products with bladder mucosa while urine is stored within the bladder. Cystitis may develop during treatment or as long as several years after cyclophosphamide is discontinued. An additional urinary complication of systemic cyclophosphamide therapy is vesicoureteral refl~x.‘,~ It is postulated that this phenomenon is secondary to elevation and distortion of the bladder trigone which results from the bladder inflammation. Formalin instilled into the bladder has been used for the control of hemorrhagic cystitis since Brown4 first described the method in 1969. It acts directly on the bladder mucosa causing coagulation of proliferating telangiectatic capillaries. The initial tissue destruction produces sloughing of the mucosa which is then replaced by a more normal mucosal lining. It is not uncommon
UROLOGY
/ MAY 1976 / VOLUME
VII, NUMBER 5
to have transient partial ureterovesical junction obstruction after formalin treatment, presumably resulting from the inflammatory reaction in the bladder wall. By contrast with the formalin treatment used in our patient, the current recommended dosage is a 4-per cent solution instilled for thirty minutes. The ease of passage of the ureteral catheter through the distal ureter in our patient and the evident friability of the ureter-al mucosa suggest that the abnormality represented active inflammation from cyclophosphamide toxicity rather than a fibrotic reaction caused by the formalin. It is likely that cyclophosphamide breakdown products within the ureter resulted in a direct toxic effect on the ureteral mucosa. An alternative possibility is that the patient was refluxing at the time of the formalin instillation and that the changes in the ureter were secondary to the effect of the formalin itself. Whatever the cause, this patient does represent a complication of cyclophosphamide therapy or formalin instillation or both. It is recommended that patients with cyclophosphamide-
UROLOGY
/ MAY 1976 / VOLUME VII, NUMBER 5
induced hemorrhagic cystitis be studied by cystography for evaluation ofvesicoureteral reflux before formalin treatment is initiated. In patients with reflux formalin should be used judiciously, and alternative methods of therapy should be considered. 34th Street and Civic Center Boulevard Philadelphia, Pennsylvania 191O4 (DR. MAHBOUBI) References JOHNSON, W., and MEADOWS, D.: Urinary bladder fibrosis and telangectasia associated with long term cyclophosphamide therapy, N. Engl. J. Med. 284: 290 (1971). MARSH, I. P., BARD, V. M., and POLLACK, D. J.: Cyclophosphamide necrosis of bladder causing calcification, contracture and reflux, treated by colocystoplasty, Br. J. Urol. 43: 324 (1971). RENERT, W. A., BERDON, W., and BAKER, D. H.: Hemorrhagic cystitis and vesicoureteral reflux secondary to cytotoxic therapy for childhood malignancies, Am. J. Roent. Radium Ther. Nucl. Med. 117: 664 (1973). BROWN, R. B.: Method of management of inoperable carcinoma of the bladder, Med. J. Aust. 1: 23 (1969).
523
OF
CYCLOPHOSPHAMIDE-INDUCED HEMORRHAGIC SOROOSH
CYSTITIS
MAHBOUBI,
JOHN N. DUCKEIT,
M.D.
M.D.
THOMAS J. SPACKMAN,
M.D.
From the Departments of Radiology and Urology, Children’s Hospital of Philadelphia, University of Pennsylvania Medical School, Philadelphia, Pennsylvania
ABSTRACT - A case is presented in which ureteritis cystica developed following formalin instillation for treatment of cyclophosphamide-induced hemorrhagic cystitis. It is not known whether this complication, not previously reported, is a result of the cyclophosphamide, the formalin, or a combination of both. Patients being considered fm fn-malin instillation should be studied by cystography fn- evaluation of vesicoureteral rejux. Alternative methods to fwmalin instillation should be considered in patients with reflux.
Several recent reports have described the occurrence of hemorrhagic cystitis and vesicoureteral reflux after the systemic administration of cyclophosphamide as a cancer chemotherapeutic agent. l-3 This article reports a case of ureteritis cystica which resulted after cyclophosphamide-induced hemorrhagic cystitis was treated by formalin lavage of the urinary bladder. The cause of the ureteritis is considered, and methods of avoiding the complication of treatment are discussed. Case Report At seven years of age, this boy was initially diagnosed as having acute lymphocytic leukemia. With combination chemotherapy, complete remission was achieved and maintained for three and a half years. Therapy was then stopped for five months, at which time relapse occurred. Remission was again induced and maintained for another five years. During this time he received vincristine, methotrexate, daunomycin, 6mercaptopurine, and a total of 4 Cm. of cyclophosphamide, and he remained completely asymptomatic throughout.
UROLOGY
/ MAY 1976 / VOLUME
VII,
NUMBER 5
At the age of fifteen he began having microscopic hematuria which persisted despite discontinuance of cyclophosphamide. Over the ensuing six months the hematuria became more severe and finally resulted in a massive hemorrhagic cystitis. His hemoglobin dropped from 12 Gm. to 6.5 Gm. per 100 ml., and he required transfusion with six units of blood. An intravenous pyelogram demonstrated a small bladder with mucosal irregularity (Fig. 1A). The findings were compatible with cyclophosphamide-induced hemorrhagic cystitis, but no cystogram was done at that time for evaluation of vesicoureteral reflux. For treatment of the severe urinary hemorrhage, a solution of lo-per cent formalin was instilled into the patient’s bladder for fifteen minutes. The therapy was successful in producing hemostasis, and the urine remained free of blood on subsequent examinations. Over the next several months he complained of left flank pain intermittently, and an intravenous pyelogram three months after formalin treatment showed left hydroureteronephrosis to the level of the bony pelvis. A cystogram demonstrated bilateral
521
(A) Intravenous pyelogram shows irregularity of bladder wall withfilling defect, narrowing of distal FIGURE 1. ureters, and some fullness of collecting system on left. (B) lntravenous pyelogram shows progress of hydronephrosis and hydroureter on left. (C) Left retrograde pyeloureterogram shows irregularity and narrowing of distal ureter with some fullness of proximal ureter and calyceal system secondary to ureteritis.
vesicoureteral reflux. The left flank pain was controlled with analgesics, and surgical drainage of the partially obstructed collecting system was not necessary. Nine months after formalin instillation, a repeat intravenous pyelogram showed progressive left hydroureteronephrosis (Fig. 1B). At cystoscopy there was evidence of small telangiectatic capillaries, but the bladder mucosa otherwise appeared normal. A left retrograde pyelogram showed irregular narrowing of the distal third of the ureter (Fig. 1C). The proximal ureter was dilated with multiple small mucosal irregularities similar to ureteritis cystica. A 4 F catheter was passed with ease all the way to the kidney, and there was no evidence of rigid stenosis of the distal ureter. Removal of the catheter from the ureter was followed by bloody drainage, indicating friability of the ureteral mucosa. Because of the extent of the ureteral involvement and the absence of a rigid stricture, the planned reimplantation was deferred. The patient has continued to have periodic low-grade backache, and repeat intravenous pyelogram fifteen months after formalin treatment showed no changes in the degree of obstruction on the left.
522
Comment Since its development in 1957, the use of cyclophosphamide as a cancer chemotherapeutic agent has been associated with a 5 to 10 per cent risk of hemorrhagic cystitis as a complication. The drug goes through several metabolic conversions in the body, and breakdown products are excreted in the urine. It is believed that hemorrhagic cystitis results from direct contact of breakdown products with bladder mucosa while urine is stored within the bladder. Cystitis may develop during treatment or as long as several years after cyclophosphamide is discontinued. An additional urinary complication of systemic cyclophosphamide therapy is vesicoureteral refl~x.‘,~ It is postulated that this phenomenon is secondary to elevation and distortion of the bladder trigone which results from the bladder inflammation. Formalin instilled into the bladder has been used for the control of hemorrhagic cystitis since Brown4 first described the method in 1969. It acts directly on the bladder mucosa causing coagulation of proliferating telangiectatic capillaries. The initial tissue destruction produces sloughing of the mucosa which is then replaced by a more normal mucosal lining. It is not uncommon
UROLOGY
/ MAY 1976 / VOLUME
VII, NUMBER 5
to have transient partial ureterovesical junction obstruction after formalin treatment, presumably resulting from the inflammatory reaction in the bladder wall. By contrast with the formalin treatment used in our patient, the current recommended dosage is a 4-per cent solution instilled for thirty minutes. The ease of passage of the ureteral catheter through the distal ureter in our patient and the evident friability of the ureter-al mucosa suggest that the abnormality represented active inflammation from cyclophosphamide toxicity rather than a fibrotic reaction caused by the formalin. It is likely that cyclophosphamide breakdown products within the ureter resulted in a direct toxic effect on the ureteral mucosa. An alternative possibility is that the patient was refluxing at the time of the formalin instillation and that the changes in the ureter were secondary to the effect of the formalin itself. Whatever the cause, this patient does represent a complication of cyclophosphamide therapy or formalin instillation or both. It is recommended that patients with cyclophosphamide-
UROLOGY
/ MAY 1976 / VOLUME VII, NUMBER 5
induced hemorrhagic cystitis be studied by cystography for evaluation ofvesicoureteral reflux before formalin treatment is initiated. In patients with reflux formalin should be used judiciously, and alternative methods of therapy should be considered. 34th Street and Civic Center Boulevard Philadelphia, Pennsylvania 191O4 (DR. MAHBOUBI) References JOHNSON, W., and MEADOWS, D.: Urinary bladder fibrosis and telangectasia associated with long term cyclophosphamide therapy, N. Engl. J. Med. 284: 290 (1971). MARSH, I. P., BARD, V. M., and POLLACK, D. J.: Cyclophosphamide necrosis of bladder causing calcification, contracture and reflux, treated by colocystoplasty, Br. J. Urol. 43: 324 (1971). RENERT, W. A., BERDON, W., and BAKER, D. H.: Hemorrhagic cystitis and vesicoureteral reflux secondary to cytotoxic therapy for childhood malignancies, Am. J. Roent. Radium Ther. Nucl. Med. 117: 664 (1973). BROWN, R. B.: Method of management of inoperable carcinoma of the bladder, Med. J. Aust. 1: 23 (1969).
523
