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Case report: The sonographic appearance of cyclophosphamide-induced acute haemorrhagic cystitis
Clinical Radiology (1990) 41, 28%290
Case Report: The Sonographic Appearance of Cyclophosphamide-induced Acute Haemorrhagic Cystitis A. K U M A R and S. A G G A R W A L
Department of Radio-Diagnosis, All India Institute of Medical Sciences, Ansari Nagar, New Delhi 110029, India
The ultrasound findings in a case of cyelophosphamideinduced acute haemorrhagic cystitis are reported. Radiologists should be familiar with these findings as the drug is used widely and the complication is not infrequent.
Cyclophosphamide is currently one o f the m o s t widely used cytotoxic drugs. Its immunosuppressive action has also m a d e it p o p u l a r for use in transplantation and several a u t o i m m u n e disorders. It has been estimated that almost 200 000 patients per year receive the drug in the USA alone (Ehrlich et al., 1984). M a j o r side-effects o f the drug include nausea and vomiting, bone m a r r o w suppression, sterility, alopecia, a sterile haemorrhagic cystitis, and urothelial carcinoma (Klein and Smith, 1983). The cystitis m a y be either acute or chronic and m a y present even after cessation o f the drug (Renert et al., 1973). It has been reported to occur in 10-40% o f patients (Watson and Notley, 1973). U n c o n trolled h a e m o r r h a g e m a y have a mortality up to 4% (Pyeritz et al., 1978). On occasion, it m a y be further complicated by the development o f urinary bladder calculi ( F o a d and Hess, 1976) or o f gas gangrene which may be fatal (Galloway, 1984).
(a)
CASE R E P O R T A 9-year-old boy with known acute lymphoblastic leukaemia presented with fever, dysuria, haematuria, and vomiting while on a course of cytotoxic chemotherapy following a relapse. The drugs that he had been receiving last were cyclophosphamide and asparaginase in standard doses. The patient also gave a short history of cough which had lately increased in severity and become productive. Investigations revealed anaemia, leucopenia, and thromboeytopenia. A chest radiograph revealed pneumonitis. The patient was given intravenous antibiotics, fluids, and blood and platelet transfusions. Urine culture was sterile. An ultrasound examination performed 3 days later for persistent, unresponsive haematuria revealed mucosal thickening. This was more marked and irregular superiorly and anteriorly where a lobulated hypoechoic mass protruded into the bladder (Fig. la, b). The patient's condition deteriorated suddenly a few hours later, and he died. No autopsy was performed. DISCUSSION The s y m p t o m s o f cyctophosphamide-induced cystitis are non-specific and include dysuria, frequency, a n d , either microscopic or gross haematuria. Cystoscopy m a y reveal mucosal oedema, hyperemia, telangiectasia, haemorrhage, ulceration, and necrosis (Ehrlich et al., 1984). Current opinion holds acrolein, a metabolite o f Correspondence to: Dr Alka Kumar, Department of Radiology, Victoria General Hospital, Halifax, Nova Scotia B3H 2Y9, Canada.
(b) Fig. 1 - Transverse (a) and sagittal (b) bladder sonograms show a considerably thickened, lobulated, and hypoechoic mucosa of the anterior and superior walls. The bladder lumen is markedly reduced. cyclophosphamide, responsible for the cystitis (Ehrlich et al., 1984; H o w s et al., 1984; Shaw and G r a h a m , 1987). Recently, 2-mercaptoethane sulfonate sodium (mesna), a drug that combines with acrolein to form a non-toxic product, has shown promise in the prevention of cystitis (Ehrlich et al., 1984; H o w s et al., 1984; Shaw and G r a h a m , 1987) but does not abolish it altogether (Hows et al., 1984; Shaw and G r a h a m , 1987). D e h y d r a t i o n m a y increase the likelihood o f the development o f cystitis, and this was p r o b a b l y the case in our patient. The findings on intravenous u r o g r a p h y include nodu-
289
290
CLINICAL RADIOLOGY
lar defects in the b l a d d e r wall in the acute stage, a n d a small c a p a c i t y b l a d d e r , ureteral o b s t r u c t i o n , a n d vesic o u r e t e r a l reflux in c h r o n i c cases ( R e n e r t et al., 1973). These l a t t e r changes reflect the fibrosis a n d scarring a c c o m p a n y i n g l o n g s t a n d i n g , u n t r e a t e d cystitis. A t s o n o g r a p h y , the m u c o s a o f the a n t e r i o r a n d superior walls was thickened, l o b u l a t e d , a n d h y p o e c h o i c , reflecting the gross o e d e m a , b u t the b l a d d e r outline was s m o o t h . T h e b l a d d e r c a p a c i t y was m a r k e d l y reduced. Suzuki et al. (198 8) r e p o r t e d diffuse thickening o f the wall o f the u r i n a r y b l a d d e r in two p a t i e n t s with c y c l o p h o s p h a m i d e - i n d u c e d cystitis. H o w e v e r , o u r findings indicate t h a t at least initially the changes m a y be localised r a t h e r t h a n diffuse. O t h e r f o r m s o f cystitis that m a y p r o d u c e s o n o g r a p h i c m a s s lesions in the b l a d d e r , such as catheteri n d u c e d cystitis ( A b u - Y o u s e f et al., 1984) a n d viral a n d bacterial cystitis (Rifkin et al., 1983), were differentiated in that (a) there was n o h i s t o r y o f catheterisation in o u r patient, a n d (b) the urine was sterile. R e c o g n i t i o n o f the s o n o g r a p h i c a p p e a r a n c e should n o t be difficult in the a p p r o p r i a t e clinical setting a n d will help avert unnecessary a d d i t i o n a l studies.
REFERENCES
Abu-Yousef, MM, Narayana, AS & Brown, RC (1984). Catheterinduced cystitis: evaluation by cystosonography. Radiology, 151, 471-473.
Ehrlich, RM, Freedman, A, Goldsobel, AB & Stiehm, ER (1984). The use of sodium 2-mercaptoethane sulfonate to prevent cyclophospha. mide cystitis. Journal of Urology, 131, 960-962. Foad, BSI & Hess, EV (1976). Urinary bladder complications with cyclophosphamide therapy. Archives of Internal Medicine, 136, 616619. Galloway, NTM (1984). Gas gangrene of the bladder complicating cyclophosphamide cystitis. British Journal of Urology, 56, 100-101. Hows, JM, Mehta, A, Ward, Let al. (1984). Comparison of mesna with forced diuresis to prevent cyclophosphamide induced haemorrhagic cystitis in marrow transplantation: a prospective randomised study. British Journal of Cancer, 53, 753-756. Klein, FA & Smith, MJV (1983). Urinary complications of cyclophosphamide therapy: etiology, prevention, and management. Southern Medical Journal, 76, 1413-1416. Pyeritz, RE, Droller, M J, Bender, WL & Saral, R (1978). An approach to the control of massive haemorrhage in cyclophosphamide. induced cystitis by intravenous vasopress!n: a case report. Journal of Urology, 120, 253-254. Renert, WA, Berdon, WE & Baker, DH (1973). Haemorrhagic cystitis and vesicoureteral reflux secondary to cytotoxic therapy for childhood malignancies. American Journal of Roentgenology, 117, 664669. Rifkin, MD, Kurtz, BM, Pasto, ME & Goldberg, NN (1983). Unusual presentations of cystitis. Journal of Ultrasound in Medicine, 2, 25-28. Shaw, IC & Graham, MI (1987). Mesna--a short review. Cancer Treatment Reviews, 14, 67 86. Suzuki, T, Yasumoto, M, Shibuya, H & Suzuki, S (1988). Sonography of cyclophosphamide haemorrhagic cystitis: a report of two cases. Journal of Clinical Ultrasound, 16, 183-186. Watson, NA & Notley, RG (1973). Urological complications of cyclophosphamide. British Journal of Urology, 45, 606-609.
Case Report: The Sonographic Appearance of Cyclophosphamide-induced Acute Haemorrhagic Cystitis A. K U M A R and S. A G G A R W A L
Department of Radio-Diagnosis, All India Institute of Medical Sciences, Ansari Nagar, New Delhi 110029, India
The ultrasound findings in a case of cyelophosphamideinduced acute haemorrhagic cystitis are reported. Radiologists should be familiar with these findings as the drug is used widely and the complication is not infrequent.
Cyclophosphamide is currently one o f the m o s t widely used cytotoxic drugs. Its immunosuppressive action has also m a d e it p o p u l a r for use in transplantation and several a u t o i m m u n e disorders. It has been estimated that almost 200 000 patients per year receive the drug in the USA alone (Ehrlich et al., 1984). M a j o r side-effects o f the drug include nausea and vomiting, bone m a r r o w suppression, sterility, alopecia, a sterile haemorrhagic cystitis, and urothelial carcinoma (Klein and Smith, 1983). The cystitis m a y be either acute or chronic and m a y present even after cessation o f the drug (Renert et al., 1973). It has been reported to occur in 10-40% o f patients (Watson and Notley, 1973). U n c o n trolled h a e m o r r h a g e m a y have a mortality up to 4% (Pyeritz et al., 1978). On occasion, it m a y be further complicated by the development o f urinary bladder calculi ( F o a d and Hess, 1976) or o f gas gangrene which may be fatal (Galloway, 1984).
(a)
CASE R E P O R T A 9-year-old boy with known acute lymphoblastic leukaemia presented with fever, dysuria, haematuria, and vomiting while on a course of cytotoxic chemotherapy following a relapse. The drugs that he had been receiving last were cyclophosphamide and asparaginase in standard doses. The patient also gave a short history of cough which had lately increased in severity and become productive. Investigations revealed anaemia, leucopenia, and thromboeytopenia. A chest radiograph revealed pneumonitis. The patient was given intravenous antibiotics, fluids, and blood and platelet transfusions. Urine culture was sterile. An ultrasound examination performed 3 days later for persistent, unresponsive haematuria revealed mucosal thickening. This was more marked and irregular superiorly and anteriorly where a lobulated hypoechoic mass protruded into the bladder (Fig. la, b). The patient's condition deteriorated suddenly a few hours later, and he died. No autopsy was performed. DISCUSSION The s y m p t o m s o f cyctophosphamide-induced cystitis are non-specific and include dysuria, frequency, a n d , either microscopic or gross haematuria. Cystoscopy m a y reveal mucosal oedema, hyperemia, telangiectasia, haemorrhage, ulceration, and necrosis (Ehrlich et al., 1984). Current opinion holds acrolein, a metabolite o f Correspondence to: Dr Alka Kumar, Department of Radiology, Victoria General Hospital, Halifax, Nova Scotia B3H 2Y9, Canada.
(b) Fig. 1 - Transverse (a) and sagittal (b) bladder sonograms show a considerably thickened, lobulated, and hypoechoic mucosa of the anterior and superior walls. The bladder lumen is markedly reduced. cyclophosphamide, responsible for the cystitis (Ehrlich et al., 1984; H o w s et al., 1984; Shaw and G r a h a m , 1987). Recently, 2-mercaptoethane sulfonate sodium (mesna), a drug that combines with acrolein to form a non-toxic product, has shown promise in the prevention of cystitis (Ehrlich et al., 1984; H o w s et al., 1984; Shaw and G r a h a m , 1987) but does not abolish it altogether (Hows et al., 1984; Shaw and G r a h a m , 1987). D e h y d r a t i o n m a y increase the likelihood o f the development o f cystitis, and this was p r o b a b l y the case in our patient. The findings on intravenous u r o g r a p h y include nodu-
289
290
CLINICAL RADIOLOGY
lar defects in the b l a d d e r wall in the acute stage, a n d a small c a p a c i t y b l a d d e r , ureteral o b s t r u c t i o n , a n d vesic o u r e t e r a l reflux in c h r o n i c cases ( R e n e r t et al., 1973). These l a t t e r changes reflect the fibrosis a n d scarring a c c o m p a n y i n g l o n g s t a n d i n g , u n t r e a t e d cystitis. A t s o n o g r a p h y , the m u c o s a o f the a n t e r i o r a n d superior walls was thickened, l o b u l a t e d , a n d h y p o e c h o i c , reflecting the gross o e d e m a , b u t the b l a d d e r outline was s m o o t h . T h e b l a d d e r c a p a c i t y was m a r k e d l y reduced. Suzuki et al. (198 8) r e p o r t e d diffuse thickening o f the wall o f the u r i n a r y b l a d d e r in two p a t i e n t s with c y c l o p h o s p h a m i d e - i n d u c e d cystitis. H o w e v e r , o u r findings indicate t h a t at least initially the changes m a y be localised r a t h e r t h a n diffuse. O t h e r f o r m s o f cystitis that m a y p r o d u c e s o n o g r a p h i c m a s s lesions in the b l a d d e r , such as catheteri n d u c e d cystitis ( A b u - Y o u s e f et al., 1984) a n d viral a n d bacterial cystitis (Rifkin et al., 1983), were differentiated in that (a) there was n o h i s t o r y o f catheterisation in o u r patient, a n d (b) the urine was sterile. R e c o g n i t i o n o f the s o n o g r a p h i c a p p e a r a n c e should n o t be difficult in the a p p r o p r i a t e clinical setting a n d will help avert unnecessary a d d i t i o n a l studies.
REFERENCES
Abu-Yousef, MM, Narayana, AS & Brown, RC (1984). Catheterinduced cystitis: evaluation by cystosonography. Radiology, 151, 471-473.
Ehrlich, RM, Freedman, A, Goldsobel, AB & Stiehm, ER (1984). The use of sodium 2-mercaptoethane sulfonate to prevent cyclophospha. mide cystitis. Journal of Urology, 131, 960-962. Foad, BSI & Hess, EV (1976). Urinary bladder complications with cyclophosphamide therapy. Archives of Internal Medicine, 136, 616619. Galloway, NTM (1984). Gas gangrene of the bladder complicating cyclophosphamide cystitis. British Journal of Urology, 56, 100-101. Hows, JM, Mehta, A, Ward, Let al. (1984). Comparison of mesna with forced diuresis to prevent cyclophosphamide induced haemorrhagic cystitis in marrow transplantation: a prospective randomised study. British Journal of Cancer, 53, 753-756. Klein, FA & Smith, MJV (1983). Urinary complications of cyclophosphamide therapy: etiology, prevention, and management. Southern Medical Journal, 76, 1413-1416. Pyeritz, RE, Droller, M J, Bender, WL & Saral, R (1978). An approach to the control of massive haemorrhage in cyclophosphamide. induced cystitis by intravenous vasopress!n: a case report. Journal of Urology, 120, 253-254. Renert, WA, Berdon, WE & Baker, DH (1973). Haemorrhagic cystitis and vesicoureteral reflux secondary to cytotoxic therapy for childhood malignancies. American Journal of Roentgenology, 117, 664669. Rifkin, MD, Kurtz, BM, Pasto, ME & Goldberg, NN (1983). Unusual presentations of cystitis. Journal of Ultrasound in Medicine, 2, 25-28. Shaw, IC & Graham, MI (1987). Mesna--a short review. Cancer Treatment Reviews, 14, 67 86. Suzuki, T, Yasumoto, M, Shibuya, H & Suzuki, S (1988). Sonography of cyclophosphamide haemorrhagic cystitis: a report of two cases. Journal of Clinical Ultrasound, 16, 183-186. Watson, NA & Notley, RG (1973). Urological complications of cyclophosphamide. British Journal of Urology, 45, 606-609.