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Effects of Formalin on Bladder Urothelium
Vol. 114. December Printed in U.S.A.
THE JOURNAL OF UROLOGY
Copyright© 1975 by The Williams & Wilkins Co.
EFFECTS OF FORMALIN ON BLADDER UROTHELIUM JOHN R. WHITTAKER*
AND
SELWYN Z. FREED
From the Department of Surgery, Montefiore Hospital and Medical Center and Albert Einstein College of Medicine, New York, New York ABSTRACT
Formalin instillation into canine bladders was followed by serial radiographic and histologic evaluation. A generalized slough of epithelial tissue was seen with the deposition of an amorphous substance. Telangiectasia resulted in moderate bleeding. No ureterovesical junction obstruction was seen and reflux occurring in 60 per cent of the animals reverted to normal. Correlation with clinical experience is made. Intractable hemorrhagic cystitis after radiation therapy or treatment with cyclophosphamide confronts the urologist with a difficult problem. Conservative measures using cauterization of bleeding areas or silver nitrate bladder irrigation are often unsuccessful. Cystectomy to control bleeding is sometimes required but a less aggressive measure would be preferred in these critically ill patients. The clinical experience with formalin instillation into the bladder is quite extensive, more than 80 cases having been reported. Several authors have reported minimal complications with this therapy, although urologic evaluation was scanty or absent. 1 ·• On the other hand, bilateral papillary necrosis, 5 peritoneal extravasation and death, 4 bladder rupture 6 and ureterovesical obstruction'· 8 were among the complications reported subsequently. Fair described a 75 per cent complication rate with 10 per cent formalin but showed an uncomplicated course when 1 or 2 per cent was used. 9 Intravesical formalin instillation for intractable hemorrhagic cystitis has been used in 6 patients at our hospital. Five patients had received deep pelvic radiation for carcinoma and 1 patient had been treated with cyclophosphamide for multiple myeloma. Each patient had preoperative excretory urography (IVP) and a retrograde cystogram. After cystoscopy and evacuation of clots under epidural anesthesia a 3. 7 per cent formalin solution was inserted by gravity until a volume of 120 to 150 cc had been reached. The catheter was left undamped above the level of the pubis. After 15 minutes the bladder was emptied of the formalin and then irrigated with a 10 per cent alcohol solution followed by copious amounts of sterile saline. Two of the patients who had normal preoperative urographic studies showed bilateral ureterohydronephrosis plus bilateral reflux postoperatively. Two other patients, one with right and the other with left reflux preoperatively, had bilateral
reflux postoperatively. The patient with left reflux subsequently required a left nephrectomy for fever, pain and non-function. The right ureter was diverted to a jejuna! loop for ureterovesical obstruction on that side. The patient with right reflux required a second treatment, during which time an extraperitoneal rupture occurred but was treated with bilateral cutaneous ureterostomy. The fifth patient showed some progression of upper tract dilatation but also the interesting finding of a calcified bladder postoperatively (fig. 1). The last patient showed no change in the preoperative and postoperative urogram and cystogram. These complications, as well ::is those reported in the literature, prompted us to evaluate the local effect of formalin on the urothelium of canine bladders, using serial full thickness biopsies. In addition, sequential radiographic evaluation was done to examine changes in the renal collecting system and changes in the competence of the ureterovesical junction. The only previous animal study showed no marked histologic changes or systemic effects on 50 normal mice bladders. 3
Accepted for publication June 20, 1975.
* Current address: 25 Avista Circle, St. Augustine, Florida 32084. 866
MATERIALS AND METHODS
Five adult mongrel dogs weighing 45 to 60 pounds were chosen for study. All were anesthetized with intravenous pentobarbital. An initial cystogram and IVP were done prior to formalin instillation. The vagina was then packed with vaseline gauze and 3.7 per cent formalin solution (10 per cent dilution of 37 per cent formalin) was inserted through a 14F Foley catheter held above the level of the pubic ramus and- not clamped. Average bladder capacity ranged from 70 to 125 cc. The formalin remained in the bladder for 15 minutes, following which the bladder was continuously irrigated with copious amounts of sterile saline. A subsequent cystogram and IVP were done on each dog at 1 week, 1, 2 and 6 months and 1 year post-formalin instillation. In addition, the bladder of each dog was explored through a midline extraperitoneal incision. The bladder was opened anteriorly and a full thickness biopsy was taken at 1 week, 1, 2 and
EFFECTS OF FORMALIN ON BLADDER UROTHELIUM
867
6 months, and 1 year post-formalin instillation. The bladders were reapproximated with a 2-layer closure of 2-zero chromic sutures. The incisions were closed in a standard fashion using a subcuticular skin closure. The biopsies were sent for histologic evaluation. RESULTS
The initial cystograms showed no evidence of reflux and good capacity bladders without calculi, diverticula or filling defects. The IVPs revealed normal tracts with no evidence of obstruction nor and the ureters were seen segmentally to the bladder. No difficulty was experienced during the formalin instillation. A week after instillation of the formalin dog 1 showed radiographic evidence of deep ulcer formation with a wisp of contrast in the perivesical tissues, suggesting early bladder rupture (fig. 2, A). After 1 month this area appeared healed but marked bilateral reflux was noted (fig. 2, B). Dogs 4 and 5 also showed similar bilateral reflux. Dogs 2 and 3 showed no evidence of reflux. Left ureteral reflux had ceased in dog l at 6 months but right reflux persisted. At the end of the year there was no reflux on either side. Dog 4 showed no reflux after the first week and dog 5 showed no reflux after the first month. In none of the 3 dogs with reflux was there Fie. 1. Clinical case of bladder calcification after any evidence of upper tract changes. The IVPs on formalin instillation. all 5 dogs remained normal throughout the study
FIG. 2. Dog 1. A, evidence of deep ulcer formation 1 week after formalin instillation. B, bilateral reflux 1 month after formalin instillation.
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without any evidence of upper tract damage or ureteral obstruction. No systemic effects were noted in any of the animals. Serum electrolytes and blood urea nitrogen remained normal throughout the study. However, each dog showed marked macroscopic hematuria following formalin instillation which persisted 1 to 3 weeks. An exception to this was seen in dog 1, whose hematuria seemed exacerbated after the first post-instillation cystogram. The excessive bleeding seen in this animal may have been promoted by over-distension of a weakened bladder as suggested by the extravasation of contrast medium on a cystogram (fig. 2, A). Serial biopsies 1 week, 1, 2 and 6 months, and 1 year post-formalin instillation were compared to normal canine bladder biopsies (fig. 3, A). These biopsies showed a regular arrangement of urothelial cells, lamina propria and detrusor muscle. A week after instillation of the formalin the bladder on gross inspection appears to have a gray urothelium with blackened areas of hemorrhage and necrosis. Microscopically, the urothelium is entirely disrupted with almost complete lack of normal urothelial cells (fig. 3, B). There is an intense inflammatory reaction with the deposition of an amorphous, almost acellular substance below the urothelium. The subepithelial tissues show multiple telangiectasia and what appears to be young fibroblasts. The inflammatory reaction and edema extend to the superficial muscular layers. At 1 month there is a normal appearance on gross
inspection. Histologically, there is a return of recognizable urothelium (fig. 4, A), although cellular atypia, subepithelial edema and some telangiectasia persist. Two months post-formalin instillation the bladder urothelium shows less atypia but subepithelial edema can still be seen (fig. 4, B). However, at 6 months the normal canine bladder urothelium is again seen with a regular arrangement of urothelial cells, lamina propria and detrusor muscle (fig. 5). Biopsies at 1 year again show a basically normal appearance. DISCUSSION
The suggested modes of action of formalin are "precipitation of cellular protein on the surface of the bladder mucosa" 10 or that formaldehyde solution has an occluding and fixative action upon the small capillaries and telangiectatic tissue produced by radiation or cyclophosphamide therapy. 3 Our histologic studies tend to confirm that there is a generalized slough of the epithelial tissue with the deposition of an amorphous substance, perhaps protein. Telangiectasia can be seen deep to this layer in figure 3, B. Telangiectasia probably accounts for the bleeding seen in our experimental animals. The bladder then appears to heal by the regeneration of a normal-appearing urothelium. Ureterovesical junction obstruction was not observed in any of the experimental animals. Although reflux was seen in 60 per cent of the dogs it did not appear to have the severity seen in our clinical patients. In addition, reflux was noted to
Fm. 3. A, normal canine bladder biopsy. B, canine urothelium 1 week after formalin instillation
EFFECTS OF FORMALIN ON BLADDER UROTHELIUM
869
FIG. 4. Canine urothelium. A, 1 month after formahn instillation. B, 2 months after formalin instillation
Fie. 5. Canine urothelium 6 months after formalin instillation.
disappear in the experimental animals in 1 to 6 months, while reflux persisted in all of our clinical cases. These findings are probably explained in part the fact that each of the patients already had bladders damaged by either radiation or cyclophosphamide therapy. Pre-experimental treatment of the dogs with either radiation or cyclophosphamide may result in the severity of complications seen in clinical cases. The complication of bladder rupture associated with intravesical formalin was noted by McGuire 4 and Scott• and their associates, and again in our series. The possibility of bladder rupture is suggested by the cystogram obtained in dog 1 (fig. 2, A). Again this complication was much more severe in the clinical cases. As previously mentioned all patients had received treatment with either radiation or cyclophosphamide, which may predispose to further damage by formalin. This was not seen in our experiments in which the dogs had no pre-formalin treatment. The use of formalin in a bladder with an incompetent ureterovesical junction has been associated with particularly grave complications, ranging from papillary necrosis and irreversible renal damage to ureteral stricture. In addition, the use of formalin in the same patient on successive occasions often has been associated with complications, particularly when the patients were not evaluated with preoperative urography. The animals in this experiment all had cystograms demonstrating a
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competent ureterovesical junction prior to the mended by Fair, appears to be associated with a instillation of formalin. This study does not in- much reduced complication rate.• clude the results of successive applications of formalin. REFERENCES The literature is quite specific on the concentration of formalin used by each researcher but little 1. Brown, R. B.: A method of management of inoperaattention is given to the determination of this ble carcinoma of the bladder. Med. J. Aust., 1: 23, 1969. concentration. Formaldehyde in its natural state is 2. Firlit, C. F.: Intractable hemorrhagic cystitis seconda gas and its greatest strength in solution is 37 per ary to extensive carcinomatosis: management with cent. Thus, a 10 per cent formalin dilution calcuformalin solution. J. Urol., 110: 57, 1973. lated on the basis of volume is actually 3.7 per 3. Barakat, H. A., Javadpour, N. and Bush, I. M.: cent formaldehyde. As emphasized by Kalish and Management of massive intractable hematuria. A associates, "A 10 per cent dilution of formaldehyde simple method. Urology, 1: 351, 1973. is called 10 per cent by some pharmacies and 3. 7 4. McGuire, E. J., Weiss, R. M., Schiff, M., Jr. and per cent by others".• Lytton, B.: Hermorrhagic radiation cystitis: treatment. Urology, 3: 204, 1974. Although this investigation examines the local effect of formalin on normal bladder urothelium and 5. Kalish, M., Silber, S. J. and Herwig, K. R.: Papillary necrosis. Result of intravesical instillation of forthe effect upon a normal competent ureterovesical malin. Urology, 2: 315, 1973. junction, more work must be done to fully underM. P., Jr., Marshall, S. and Lyon, R. P.: stand the effects of formalin vesical instillation. 6. Scott, Bladder rupture following formalin therapy for Subsequent studies using formalin after prelimihemorrhage secondary to cyclophosphamide thernary radiation or cyclophosphamide therapy are reapy. Urology, 3: 364, 1974. quired. These should be coupled with preoperative 7. Spiro, L. H., Hecht, H., Horowitz, A. and Orkin, L.: and postoperative urographic and histologic evaluaFormalin treatment for massive bladder hemorrhage. Urology, 2: 669, 1973. tion at successive intervals. Clinically, formalin instillation for intractable 8. Fishbein, P. G., McCurdy, D. K., DeFronzo, R. D. and Murphy, J. J.: Irreversible bilateral ureteral hemorrhagic cystitis should be used with great obstruction from intravesical formaldehyde solucaution and only following failure of the more contion. J.A.M.A., 228: 872, 1974. servative measures. IVP and cystography should be 9. Fair, W. R.: Formalin in the treatment of massive carried out prior to each formalin treatment. This bladder hemorrhage, techniques, results, and commode of therapy should usually be reserved for plications. Urology, 3: 573, 1974. those debilitated patients whose prognosis does not 10. Shah, B. C. and Albert, D. J.: Intravesical instillawarrant major surgical intervention. Finally, an tion of formalin for the management of intractable initial trial with 1 per cent formalin, as recomhematuria. J. Urol., 110: 519, 1973.
THE JOURNAL OF UROLOGY
Copyright© 1975 by The Williams & Wilkins Co.
EFFECTS OF FORMALIN ON BLADDER UROTHELIUM JOHN R. WHITTAKER*
AND
SELWYN Z. FREED
From the Department of Surgery, Montefiore Hospital and Medical Center and Albert Einstein College of Medicine, New York, New York ABSTRACT
Formalin instillation into canine bladders was followed by serial radiographic and histologic evaluation. A generalized slough of epithelial tissue was seen with the deposition of an amorphous substance. Telangiectasia resulted in moderate bleeding. No ureterovesical junction obstruction was seen and reflux occurring in 60 per cent of the animals reverted to normal. Correlation with clinical experience is made. Intractable hemorrhagic cystitis after radiation therapy or treatment with cyclophosphamide confronts the urologist with a difficult problem. Conservative measures using cauterization of bleeding areas or silver nitrate bladder irrigation are often unsuccessful. Cystectomy to control bleeding is sometimes required but a less aggressive measure would be preferred in these critically ill patients. The clinical experience with formalin instillation into the bladder is quite extensive, more than 80 cases having been reported. Several authors have reported minimal complications with this therapy, although urologic evaluation was scanty or absent. 1 ·• On the other hand, bilateral papillary necrosis, 5 peritoneal extravasation and death, 4 bladder rupture 6 and ureterovesical obstruction'· 8 were among the complications reported subsequently. Fair described a 75 per cent complication rate with 10 per cent formalin but showed an uncomplicated course when 1 or 2 per cent was used. 9 Intravesical formalin instillation for intractable hemorrhagic cystitis has been used in 6 patients at our hospital. Five patients had received deep pelvic radiation for carcinoma and 1 patient had been treated with cyclophosphamide for multiple myeloma. Each patient had preoperative excretory urography (IVP) and a retrograde cystogram. After cystoscopy and evacuation of clots under epidural anesthesia a 3. 7 per cent formalin solution was inserted by gravity until a volume of 120 to 150 cc had been reached. The catheter was left undamped above the level of the pubis. After 15 minutes the bladder was emptied of the formalin and then irrigated with a 10 per cent alcohol solution followed by copious amounts of sterile saline. Two of the patients who had normal preoperative urographic studies showed bilateral ureterohydronephrosis plus bilateral reflux postoperatively. Two other patients, one with right and the other with left reflux preoperatively, had bilateral
reflux postoperatively. The patient with left reflux subsequently required a left nephrectomy for fever, pain and non-function. The right ureter was diverted to a jejuna! loop for ureterovesical obstruction on that side. The patient with right reflux required a second treatment, during which time an extraperitoneal rupture occurred but was treated with bilateral cutaneous ureterostomy. The fifth patient showed some progression of upper tract dilatation but also the interesting finding of a calcified bladder postoperatively (fig. 1). The last patient showed no change in the preoperative and postoperative urogram and cystogram. These complications, as well ::is those reported in the literature, prompted us to evaluate the local effect of formalin on the urothelium of canine bladders, using serial full thickness biopsies. In addition, sequential radiographic evaluation was done to examine changes in the renal collecting system and changes in the competence of the ureterovesical junction. The only previous animal study showed no marked histologic changes or systemic effects on 50 normal mice bladders. 3
Accepted for publication June 20, 1975.
* Current address: 25 Avista Circle, St. Augustine, Florida 32084. 866
MATERIALS AND METHODS
Five adult mongrel dogs weighing 45 to 60 pounds were chosen for study. All were anesthetized with intravenous pentobarbital. An initial cystogram and IVP were done prior to formalin instillation. The vagina was then packed with vaseline gauze and 3.7 per cent formalin solution (10 per cent dilution of 37 per cent formalin) was inserted through a 14F Foley catheter held above the level of the pubic ramus and- not clamped. Average bladder capacity ranged from 70 to 125 cc. The formalin remained in the bladder for 15 minutes, following which the bladder was continuously irrigated with copious amounts of sterile saline. A subsequent cystogram and IVP were done on each dog at 1 week, 1, 2 and 6 months and 1 year post-formalin instillation. In addition, the bladder of each dog was explored through a midline extraperitoneal incision. The bladder was opened anteriorly and a full thickness biopsy was taken at 1 week, 1, 2 and
EFFECTS OF FORMALIN ON BLADDER UROTHELIUM
867
6 months, and 1 year post-formalin instillation. The bladders were reapproximated with a 2-layer closure of 2-zero chromic sutures. The incisions were closed in a standard fashion using a subcuticular skin closure. The biopsies were sent for histologic evaluation. RESULTS
The initial cystograms showed no evidence of reflux and good capacity bladders without calculi, diverticula or filling defects. The IVPs revealed normal tracts with no evidence of obstruction nor and the ureters were seen segmentally to the bladder. No difficulty was experienced during the formalin instillation. A week after instillation of the formalin dog 1 showed radiographic evidence of deep ulcer formation with a wisp of contrast in the perivesical tissues, suggesting early bladder rupture (fig. 2, A). After 1 month this area appeared healed but marked bilateral reflux was noted (fig. 2, B). Dogs 4 and 5 also showed similar bilateral reflux. Dogs 2 and 3 showed no evidence of reflux. Left ureteral reflux had ceased in dog l at 6 months but right reflux persisted. At the end of the year there was no reflux on either side. Dog 4 showed no reflux after the first week and dog 5 showed no reflux after the first month. In none of the 3 dogs with reflux was there Fie. 1. Clinical case of bladder calcification after any evidence of upper tract changes. The IVPs on formalin instillation. all 5 dogs remained normal throughout the study
FIG. 2. Dog 1. A, evidence of deep ulcer formation 1 week after formalin instillation. B, bilateral reflux 1 month after formalin instillation.
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WHITTAKER AND FREED
without any evidence of upper tract damage or ureteral obstruction. No systemic effects were noted in any of the animals. Serum electrolytes and blood urea nitrogen remained normal throughout the study. However, each dog showed marked macroscopic hematuria following formalin instillation which persisted 1 to 3 weeks. An exception to this was seen in dog 1, whose hematuria seemed exacerbated after the first post-instillation cystogram. The excessive bleeding seen in this animal may have been promoted by over-distension of a weakened bladder as suggested by the extravasation of contrast medium on a cystogram (fig. 2, A). Serial biopsies 1 week, 1, 2 and 6 months, and 1 year post-formalin instillation were compared to normal canine bladder biopsies (fig. 3, A). These biopsies showed a regular arrangement of urothelial cells, lamina propria and detrusor muscle. A week after instillation of the formalin the bladder on gross inspection appears to have a gray urothelium with blackened areas of hemorrhage and necrosis. Microscopically, the urothelium is entirely disrupted with almost complete lack of normal urothelial cells (fig. 3, B). There is an intense inflammatory reaction with the deposition of an amorphous, almost acellular substance below the urothelium. The subepithelial tissues show multiple telangiectasia and what appears to be young fibroblasts. The inflammatory reaction and edema extend to the superficial muscular layers. At 1 month there is a normal appearance on gross
inspection. Histologically, there is a return of recognizable urothelium (fig. 4, A), although cellular atypia, subepithelial edema and some telangiectasia persist. Two months post-formalin instillation the bladder urothelium shows less atypia but subepithelial edema can still be seen (fig. 4, B). However, at 6 months the normal canine bladder urothelium is again seen with a regular arrangement of urothelial cells, lamina propria and detrusor muscle (fig. 5). Biopsies at 1 year again show a basically normal appearance. DISCUSSION
The suggested modes of action of formalin are "precipitation of cellular protein on the surface of the bladder mucosa" 10 or that formaldehyde solution has an occluding and fixative action upon the small capillaries and telangiectatic tissue produced by radiation or cyclophosphamide therapy. 3 Our histologic studies tend to confirm that there is a generalized slough of the epithelial tissue with the deposition of an amorphous substance, perhaps protein. Telangiectasia can be seen deep to this layer in figure 3, B. Telangiectasia probably accounts for the bleeding seen in our experimental animals. The bladder then appears to heal by the regeneration of a normal-appearing urothelium. Ureterovesical junction obstruction was not observed in any of the experimental animals. Although reflux was seen in 60 per cent of the dogs it did not appear to have the severity seen in our clinical patients. In addition, reflux was noted to
Fm. 3. A, normal canine bladder biopsy. B, canine urothelium 1 week after formalin instillation
EFFECTS OF FORMALIN ON BLADDER UROTHELIUM
869
FIG. 4. Canine urothelium. A, 1 month after formahn instillation. B, 2 months after formalin instillation
Fie. 5. Canine urothelium 6 months after formalin instillation.
disappear in the experimental animals in 1 to 6 months, while reflux persisted in all of our clinical cases. These findings are probably explained in part the fact that each of the patients already had bladders damaged by either radiation or cyclophosphamide therapy. Pre-experimental treatment of the dogs with either radiation or cyclophosphamide may result in the severity of complications seen in clinical cases. The complication of bladder rupture associated with intravesical formalin was noted by McGuire 4 and Scott• and their associates, and again in our series. The possibility of bladder rupture is suggested by the cystogram obtained in dog 1 (fig. 2, A). Again this complication was much more severe in the clinical cases. As previously mentioned all patients had received treatment with either radiation or cyclophosphamide, which may predispose to further damage by formalin. This was not seen in our experiments in which the dogs had no pre-formalin treatment. The use of formalin in a bladder with an incompetent ureterovesical junction has been associated with particularly grave complications, ranging from papillary necrosis and irreversible renal damage to ureteral stricture. In addition, the use of formalin in the same patient on successive occasions often has been associated with complications, particularly when the patients were not evaluated with preoperative urography. The animals in this experiment all had cystograms demonstrating a
870
WHITTAKER AND FREED
competent ureterovesical junction prior to the mended by Fair, appears to be associated with a instillation of formalin. This study does not in- much reduced complication rate.• clude the results of successive applications of formalin. REFERENCES The literature is quite specific on the concentration of formalin used by each researcher but little 1. Brown, R. B.: A method of management of inoperaattention is given to the determination of this ble carcinoma of the bladder. Med. J. Aust., 1: 23, 1969. concentration. Formaldehyde in its natural state is 2. Firlit, C. F.: Intractable hemorrhagic cystitis seconda gas and its greatest strength in solution is 37 per ary to extensive carcinomatosis: management with cent. Thus, a 10 per cent formalin dilution calcuformalin solution. J. Urol., 110: 57, 1973. lated on the basis of volume is actually 3.7 per 3. Barakat, H. A., Javadpour, N. and Bush, I. M.: cent formaldehyde. As emphasized by Kalish and Management of massive intractable hematuria. A associates, "A 10 per cent dilution of formaldehyde simple method. Urology, 1: 351, 1973. is called 10 per cent by some pharmacies and 3. 7 4. McGuire, E. J., Weiss, R. M., Schiff, M., Jr. and per cent by others".• Lytton, B.: Hermorrhagic radiation cystitis: treatment. Urology, 3: 204, 1974. Although this investigation examines the local effect of formalin on normal bladder urothelium and 5. Kalish, M., Silber, S. J. and Herwig, K. R.: Papillary necrosis. Result of intravesical instillation of forthe effect upon a normal competent ureterovesical malin. Urology, 2: 315, 1973. junction, more work must be done to fully underM. P., Jr., Marshall, S. and Lyon, R. P.: stand the effects of formalin vesical instillation. 6. Scott, Bladder rupture following formalin therapy for Subsequent studies using formalin after prelimihemorrhage secondary to cyclophosphamide thernary radiation or cyclophosphamide therapy are reapy. Urology, 3: 364, 1974. quired. These should be coupled with preoperative 7. Spiro, L. H., Hecht, H., Horowitz, A. and Orkin, L.: and postoperative urographic and histologic evaluaFormalin treatment for massive bladder hemorrhage. Urology, 2: 669, 1973. tion at successive intervals. Clinically, formalin instillation for intractable 8. Fishbein, P. G., McCurdy, D. K., DeFronzo, R. D. and Murphy, J. J.: Irreversible bilateral ureteral hemorrhagic cystitis should be used with great obstruction from intravesical formaldehyde solucaution and only following failure of the more contion. J.A.M.A., 228: 872, 1974. servative measures. IVP and cystography should be 9. Fair, W. R.: Formalin in the treatment of massive carried out prior to each formalin treatment. This bladder hemorrhage, techniques, results, and commode of therapy should usually be reserved for plications. Urology, 3: 573, 1974. those debilitated patients whose prognosis does not 10. Shah, B. C. and Albert, D. J.: Intravesical instillawarrant major surgical intervention. Finally, an tion of formalin for the management of intractable initial trial with 1 per cent formalin, as recomhematuria. J. Urol., 110: 519, 1973.