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Severe Cyclophosphamide-Induced Hemorrhagic Cystitis Successfully Treated by Total Cystectomy with Ileal Neobladder Substitution: A Case Report
0022-534 7/93/1506-1909$03.00/0 Vol. 150, 1909-1910, December 1993
THE JOURNAL OF UROLOGY
Printed in U.S.A.
Copyright© 1993 by AMERICAN UROLOGICAL ASSOCIATION, INC.
SEVERE CYCLOPHOSPHAMIDE-INDUCED HEMORRHAGIC CYSTITIS SUCCESSFULLY TREATED BY TOTAL CYSTECTOMY WITH ILEAL NEOBLADDER SUBSTITUTION: A CASE REPORT TOSHIKAZU OKANEYA, KAZUHIKO KONTANI, ITSUKI KOMIYAMA
AND
TORU TAKEZAKI
From the Department of Urology, Yamanashi Prefecture Central Hospital, Kofu, Japan
ABSTRACT
A 45-year-old woman with intractable cyclophosphamide-induced hemorrhagic cystitis was successfully treated with total cystectomy and ileal neobladder substitution. To our knowledge this is the first reported reconstruction of the lower urinary tract in a patient with acute hemorrhagic cystitis using a neobladder. Neobladder substitution is contraindicated if the urethra or bladder neck is involved in the disease, although neither was involved in our patient. Whether these lesions are generally left intact has not been discussed previously. If a neobladder can be used, life threatening hemorrhagic cystitis should be treated with total cystectomy accompanied by immediate neobladder substitution. KEY WORDS:
cyclophosphamide, cystitis, bladder, ileum
Gross hematuria develops in 2 to 40% of patients treated with cyclophosphamide. 1 This adverse effect generally is dose dependent and is likely to be improved only with cessation of the drug or vesical irrigation with alum. However, in some cases bleeding cannot be improved by conservative therapy and it can become life threatening. 1• 2 Recently, we treated a patient with life threatening intractable hemorrhagic cystitis. The bladder was irreversibly deteriorated, although the bladder neck and urethra were intact. We successfully replaced the bladder with an ileal neobladder with which she could urinate via the urethra. We describe the procedure and discuss the results. CASE REPORT
A 45-year-old woman received cyclophosphamide following right mastectomy for breast cancer in November 1985. Microscopic hematuria was noted initially at periodic followup on January 21, 1992. The accumulated doses of oral cyclophosphamide were 89.6 gm. Although cyclophosphamide was discontinued, gross hematuria developed on January 31. Coagulant drugs failed to resolve the hematuria. On September 18 the patient was hospitalized for severe anemia demonstrated by hemoglobin 3.2 gm./dl. (normal 11.1 to 15.1) due to continuing hemorrhagic cystitis. Extensive blood transfusion was administered with transurethral coagulation attempted on October 6, after vesical irrigation with epinephrine had failed to stop the bleeding. Gross hematuria did not resolve. On October 31 cystotomy was performed followed by removal of a packed blood clot because clot retention could not be managed via the urethra. On November 4 the patient suddenly complained of dyspnea and became distressed. Chest xray demonstrated lung edema, and she was intubated and placed on a respirator. On November 9 lung edema was relieved and she was removed from respiratory control. On November 17 total cystectomy was performed. Preoperative blood transfusion comprised as much as 9,000 ml. Clot retention was observed perioperatively. The bladder wall had lost its elasticity, and mucosal inflammation and deterioration were marked. However, the bladder neck and urethra appeared to be intact. These findings confirmed the plausibility of neobladder substitution. Thus, during total cystectomy the urethra was divided at the bladder neck (fig. 1). Neither the ovaries, uterus nor vagina was extirpated. We isolated 65 cm. of distal ileum and the neobladder was created using Hautmann's method. 3 The Accepted for publication May 28, 1993.
FIG. 1. Extirpated bladder. Ulcerative change and bleeding are prominent on bladder mucosa.
ureter and the neobladder were anastomosed using the Le DueCamey method. 4 Pathological specimens of the bladder showed marked migration of inflammatory cells, marked clot embolism in capillary vessels mainly of lamina propria, a moderate degree of epithelial denudation and a moderate degree of fibrosis in the muscular layer (fig. 2). Convalescence was uneventful. The urethral catheter was removed on postoperative day 21. The patient was able to urinate via the urethra thereafter with a mild degree of abdominal straining. She did not complain of urinary incontinence. She was discharged home 30 days postoperatively with no recurrence of urinary bleeding (fig. 3). No hydronephrosis or residual urine was noted on excretory urography at 2-month followup (fig. 4). DISCUSSION
In our patient severe hemorrhagic cystitis could not be managed by conservative therapy and, therefore, it required a more aggressive approach. The condition was life threatening due to massive blood loss and consequent lung edema. The bladder had deteriorated and had lost elasticity. For these reasons we decided to perform emergency total cystectomy. Stillwell and Benson reported that of 100 patients with cyclophosphamide-induced hemorrhagic cystitis 5 underwent total cystectomy because the bleeding could not be managed by other modalities. 1 Urinary diversion, such as the ileal conduit, has been constructed in almost all cystectomized patients
1909
1910
CYCLOPHOSPHAMIDE CYSTITIS TREATED BY CYSTECTOMY WITH NEOBLADDER
FIG. 4. Excretory urogram 2 months postoperatively reveals absence of hydronephrosis.
FIG. 2. Pathological specimen of bladder demonstrates epithelial denudation and clot embolism in capillary vessels. H & E, reduced from Xl5.
CPMBTF
respirator
-
12 IO
8
:;;;
o1 6
cystitis induced by cyclophosphamide. The upper urinary tract, including the renal pelvis and ureter, is usually not cyclophosphamide involved, although no description appears in the literature concerning the involvement of the urethra or bladder neck. In this regard, it should be determined whether the bladder neck or urethra should be spared, since it is important to decide how the lower urinary tract should be reconstructed. According to Andriole et al total cystectomy should be avoided because severe hemorrhagic cystitis might be improved by transient urinary diversion. 6 Conversely, Levine and Richie reported that bladder carcinoma developed in approximately 7 to 14 % of their patients who had hemorrhagic cystitis following cyclophosphamide therapy. 7 These findings demonstrate that we should not hesitate to perform total cystectomy if intractable hemorrhagic cystitis can be treated successfully with total cystectomy and neobladder substitution.
.,:;,
:::c
REFERENCES 2 0
92.1.21
92.IO.I
92.ll.l
92.12.1
Date
FIG. 3. Clinical course. CPM, cyclophosphamide. BTF, blood transfusion. Hb, hemoglobin. TUC, transurethral coagulation. OP, operation.
but successful colocystoplasty for cyclophosphamide-induced contracted bladder was reported by Marsh et al. 5 They stated that the bladder neck and urethra were not involved despite marked fibrotic change in the bladder wall on cystoscopy. Because similar findings were also observed in our case, we avoided urinary diversion and performed neobladder substitution. To our knowledge this is the first report of neobladder construction in a patient with acute phase severe hemorrhagic
1. Stillwell, T. J. and Benson, R. C., Jr.: Cyclophosphamide-induced hemorrhagic cystitis-a review of 100 patients. Cancer, 61: 451, 1988. 2. Johnson, W.W. and Meadows, D. C.: Urinary-bladder fibrosis and telangiectasis associated with long-term cyclophosphamide therapy. New Engl. J. Med., 284: 290, 1971. 3. Hautmann, R. E., Egghart, G., Frohneberg, D. and Miller, K.: The ilea! neobladder. J. Urol., 139: 39, 1988. 4. Le Due, A., Camey, M. and Teillac, P.: An original antireflux ureteroileal implantation technique: long-term followup. J. Urol., 137: 1156, 1987. 5. Marsh, F. P., Vince, F. P., Pollock, D. J. and Blandy, J. P.: Cyclophosphamide necrosis of bladder causing calcification, contracture and reflux: treated by colocystoplasty. Brit. J. Urol., 43, 324, 1971. 6. Andriole, G. L., Yuan, J. J. J. and Catalona, W. J.: Cystotomy, temporary urinary diversion and bladder packing in the management of severe cyclophosphamide-induced hemorrhagic cystitis. J. Urol., 143: 1006, 1990. 7. Levine, L. A. and Richie, J. P.: Urological complications of cyclophosphamide. J. Urol., 141: 1063, 1989.
THE JOURNAL OF UROLOGY
Printed in U.S.A.
Copyright© 1993 by AMERICAN UROLOGICAL ASSOCIATION, INC.
SEVERE CYCLOPHOSPHAMIDE-INDUCED HEMORRHAGIC CYSTITIS SUCCESSFULLY TREATED BY TOTAL CYSTECTOMY WITH ILEAL NEOBLADDER SUBSTITUTION: A CASE REPORT TOSHIKAZU OKANEYA, KAZUHIKO KONTANI, ITSUKI KOMIYAMA
AND
TORU TAKEZAKI
From the Department of Urology, Yamanashi Prefecture Central Hospital, Kofu, Japan
ABSTRACT
A 45-year-old woman with intractable cyclophosphamide-induced hemorrhagic cystitis was successfully treated with total cystectomy and ileal neobladder substitution. To our knowledge this is the first reported reconstruction of the lower urinary tract in a patient with acute hemorrhagic cystitis using a neobladder. Neobladder substitution is contraindicated if the urethra or bladder neck is involved in the disease, although neither was involved in our patient. Whether these lesions are generally left intact has not been discussed previously. If a neobladder can be used, life threatening hemorrhagic cystitis should be treated with total cystectomy accompanied by immediate neobladder substitution. KEY WORDS:
cyclophosphamide, cystitis, bladder, ileum
Gross hematuria develops in 2 to 40% of patients treated with cyclophosphamide. 1 This adverse effect generally is dose dependent and is likely to be improved only with cessation of the drug or vesical irrigation with alum. However, in some cases bleeding cannot be improved by conservative therapy and it can become life threatening. 1• 2 Recently, we treated a patient with life threatening intractable hemorrhagic cystitis. The bladder was irreversibly deteriorated, although the bladder neck and urethra were intact. We successfully replaced the bladder with an ileal neobladder with which she could urinate via the urethra. We describe the procedure and discuss the results. CASE REPORT
A 45-year-old woman received cyclophosphamide following right mastectomy for breast cancer in November 1985. Microscopic hematuria was noted initially at periodic followup on January 21, 1992. The accumulated doses of oral cyclophosphamide were 89.6 gm. Although cyclophosphamide was discontinued, gross hematuria developed on January 31. Coagulant drugs failed to resolve the hematuria. On September 18 the patient was hospitalized for severe anemia demonstrated by hemoglobin 3.2 gm./dl. (normal 11.1 to 15.1) due to continuing hemorrhagic cystitis. Extensive blood transfusion was administered with transurethral coagulation attempted on October 6, after vesical irrigation with epinephrine had failed to stop the bleeding. Gross hematuria did not resolve. On October 31 cystotomy was performed followed by removal of a packed blood clot because clot retention could not be managed via the urethra. On November 4 the patient suddenly complained of dyspnea and became distressed. Chest xray demonstrated lung edema, and she was intubated and placed on a respirator. On November 9 lung edema was relieved and she was removed from respiratory control. On November 17 total cystectomy was performed. Preoperative blood transfusion comprised as much as 9,000 ml. Clot retention was observed perioperatively. The bladder wall had lost its elasticity, and mucosal inflammation and deterioration were marked. However, the bladder neck and urethra appeared to be intact. These findings confirmed the plausibility of neobladder substitution. Thus, during total cystectomy the urethra was divided at the bladder neck (fig. 1). Neither the ovaries, uterus nor vagina was extirpated. We isolated 65 cm. of distal ileum and the neobladder was created using Hautmann's method. 3 The Accepted for publication May 28, 1993.
FIG. 1. Extirpated bladder. Ulcerative change and bleeding are prominent on bladder mucosa.
ureter and the neobladder were anastomosed using the Le DueCamey method. 4 Pathological specimens of the bladder showed marked migration of inflammatory cells, marked clot embolism in capillary vessels mainly of lamina propria, a moderate degree of epithelial denudation and a moderate degree of fibrosis in the muscular layer (fig. 2). Convalescence was uneventful. The urethral catheter was removed on postoperative day 21. The patient was able to urinate via the urethra thereafter with a mild degree of abdominal straining. She did not complain of urinary incontinence. She was discharged home 30 days postoperatively with no recurrence of urinary bleeding (fig. 3). No hydronephrosis or residual urine was noted on excretory urography at 2-month followup (fig. 4). DISCUSSION
In our patient severe hemorrhagic cystitis could not be managed by conservative therapy and, therefore, it required a more aggressive approach. The condition was life threatening due to massive blood loss and consequent lung edema. The bladder had deteriorated and had lost elasticity. For these reasons we decided to perform emergency total cystectomy. Stillwell and Benson reported that of 100 patients with cyclophosphamide-induced hemorrhagic cystitis 5 underwent total cystectomy because the bleeding could not be managed by other modalities. 1 Urinary diversion, such as the ileal conduit, has been constructed in almost all cystectomized patients
1909
1910
CYCLOPHOSPHAMIDE CYSTITIS TREATED BY CYSTECTOMY WITH NEOBLADDER
FIG. 4. Excretory urogram 2 months postoperatively reveals absence of hydronephrosis.
FIG. 2. Pathological specimen of bladder demonstrates epithelial denudation and clot embolism in capillary vessels. H & E, reduced from Xl5.
CPMBTF
respirator
-
12 IO
8
:;;;
o1 6
cystitis induced by cyclophosphamide. The upper urinary tract, including the renal pelvis and ureter, is usually not cyclophosphamide involved, although no description appears in the literature concerning the involvement of the urethra or bladder neck. In this regard, it should be determined whether the bladder neck or urethra should be spared, since it is important to decide how the lower urinary tract should be reconstructed. According to Andriole et al total cystectomy should be avoided because severe hemorrhagic cystitis might be improved by transient urinary diversion. 6 Conversely, Levine and Richie reported that bladder carcinoma developed in approximately 7 to 14 % of their patients who had hemorrhagic cystitis following cyclophosphamide therapy. 7 These findings demonstrate that we should not hesitate to perform total cystectomy if intractable hemorrhagic cystitis can be treated successfully with total cystectomy and neobladder substitution.
.,:;,
:::c
REFERENCES 2 0
92.1.21
92.IO.I
92.ll.l
92.12.1
Date
FIG. 3. Clinical course. CPM, cyclophosphamide. BTF, blood transfusion. Hb, hemoglobin. TUC, transurethral coagulation. OP, operation.
but successful colocystoplasty for cyclophosphamide-induced contracted bladder was reported by Marsh et al. 5 They stated that the bladder neck and urethra were not involved despite marked fibrotic change in the bladder wall on cystoscopy. Because similar findings were also observed in our case, we avoided urinary diversion and performed neobladder substitution. To our knowledge this is the first report of neobladder construction in a patient with acute phase severe hemorrhagic
1. Stillwell, T. J. and Benson, R. C., Jr.: Cyclophosphamide-induced hemorrhagic cystitis-a review of 100 patients. Cancer, 61: 451, 1988. 2. Johnson, W.W. and Meadows, D. C.: Urinary-bladder fibrosis and telangiectasis associated with long-term cyclophosphamide therapy. New Engl. J. Med., 284: 290, 1971. 3. Hautmann, R. E., Egghart, G., Frohneberg, D. and Miller, K.: The ilea! neobladder. J. Urol., 139: 39, 1988. 4. Le Due, A., Camey, M. and Teillac, P.: An original antireflux ureteroileal implantation technique: long-term followup. J. Urol., 137: 1156, 1987. 5. Marsh, F. P., Vince, F. P., Pollock, D. J. and Blandy, J. P.: Cyclophosphamide necrosis of bladder causing calcification, contracture and reflux: treated by colocystoplasty. Brit. J. Urol., 43, 324, 1971. 6. Andriole, G. L., Yuan, J. J. J. and Catalona, W. J.: Cystotomy, temporary urinary diversion and bladder packing in the management of severe cyclophosphamide-induced hemorrhagic cystitis. J. Urol., 143: 1006, 1990. 7. Levine, L. A. and Richie, J. P.: Urological complications of cyclophosphamide. J. Urol., 141: 1063, 1989.