Pediatr Radiol (2000) 30: 131±138

Ó Springer-Verlag 2000 R E V I E W A RTIC LE

Mary Beth McCarville Imaging findings of hemorrhagic

Fredric Alan Hoffer
Jeffrey Rae Gingrich cystitis in pediatric oncology patients
Jesse Jay Jenkins III

Received: 24 May 1999

Accepted: 20 September 1999
)
M. B. McCarville ( ) ´ F. A. Hoffer
Department of Diagnostic Imaging,
St. Jude Children's Research Hospital,
332 North Lauderdale Street, Memphis,
TN 38105±2794, and The University
of Tennessee, 800 Madison Avenue,
Memphis, TN 38163
J. R. Gingrich
Department of Surgery,
Division of Urology,
St. Jude Children's Research Hospital,
332 North Lauderdale Street, Memphis,
TN 38105±2794, and The University of
Tennessee, 800 Madison Avenue,
Memphis, TN 38163
J. J. Jenkins III
Department of Pathology,
St. Jude Children's Research Hospital,
332 North Lauderdale Street, Memphis,
TN 38105±2794, and The University of
Tennessee, 800 Madison Avenue,
Memphis, TN 38163
Abstract In pediatric oncology pa-
tients, hemorrhagic cystitis may be a
life-threatening complication of
bone-marrow transplantation, che-
motherapy, and/or radiation thera-
py. The inciting agent in urine can
affect the entire urothelium from
the renal collecting system to the
bladder, and the severity of disease
can vary. The radiologist often plays
a key role in the diagnosis, follow-
up, and occasionally the treatment
of hemorrhagic cystitis and its com-
plications. This review discusses the
imaging findings in the kidneys and
bladder in patients with hemorrhag-
ic cystitis both before and after
treatment for this disease. Findings
on two-dimensional sonography,
color Doppler and power Doppler
sonography, computed tomography,
magnetic resonance imaging, ante-
grade pyleography, and cystography
are presented.

ditional dose, 2 Gy; total dose, 14 Gy) received by the

Introduction
Hemorrhagic cystitis results from damage to the bladder
transitional epithelium and blood vessels by toxins, vi-
ruses, irradiation, drugs, or disease [1]. In the pediatric
oncology population, most cases are associated with
the use of cyclophosphamide and total-body irradiation
as preparative therapy for bone-marrow transplanta-
tion. At our institution, the incidence of hemorrhagic
cystitis is lower for HLA-matched sibling bone-marrow
transplant recipients (10 %) than for matched unrelated
donor recipients (33 %) [2]. This difference is thought to
be, in part, due to additional total-body irradiation (ad-
matched unrelated donor recipients. The cause of hem-
orrhagic cystitis is often difficult to determine because
forced hydration or intravesical saline irrigation used
to treat this disease precludes adequate urine collection
for bacterial and viral cultures. The time required for
development of hemorrhagic cystitis after completion
of chemotherapy or radiation therapy varies, ranging
from a few weeks to several years. Although rarely fatal,
hemorrhagic cystitis can result in a long hospital stay,
protracted use of blood products, and impaired bladder
and renal function [2, 3]. The use of blood products, in-
cluding platelets and packed red blood cells, exposes
132
b Fig. 2 a, b This 14-year-old boy underwent bone-marrow trans-
c
Fig. 1 a±c This 12-year-old girl underwent bone-marrow transplan-
tation for chronic myelogenous leukemia. a Transverse sonogram
of the bladder shows focal areas of thickening and/or adherent
clot (arrows). b Transverse power Doppler sonogram of the blad-
der reveals diffuse hypervascularity of the bladder wall. c Cysto-
scopic photograph shows a focus of telangiectasia. Cystoscopic
examination revealed numerous telangiectatic foci in the bladder
mucosa
b
plantation for aplastic anemia. a Transverse color Doppler sono-
gram of the bladder shows focal area of active bleeding from the
anterior bladder wall (arrow). b Cystoscopic photograph shows fo-
cal hemorrhagic mucosa in an area corresponding to the focus of
bleeding revealed by color Doppler sonography
these immunocompromised patients to additional infec-
tious agents and compounds problems involved in fluid
management.
Between July 1997 and March 1999, we imaged 18
patients who had hemorrhagic cystitis of significant se-
verity to require consultation or intervention by urolog-
ic surgeons. Fifteen of these patients were bone-marrow
transplant recipients, and all patients had received cy-
clophosphamide. In this review, imaging features seen
on two-dimensional (2D) sonography, color Doppler
and power Doppler sonography, computed tomography
(CT), magnetic resonance (MR) imaging, antegrade
pyelography, or cystography illustrate the spectrum of
disease that may involve the bladder and upper urinary
tracts both before and after treatment of hemorrhagic
cystitis. Correlation with cystoscopic and pathologic
findings are presented in selected cases.

b
Fig. 3 a, b This 6-year-old boy underwent bone-marrow transplan-
tation for acute lymphoblastic leukemia. a Transverse sonogram
shows diffusely thickened bladder wall measuring 0.96 cm. Power
Doppler images showed marked hypervascularity of the entire
bladder wall. b Factor VIII stain of full thickness bladder biopsy
demonstrates hypervascularity of the suburothelial layer. Note the
stain in the walls of the vessels (arrows)
Pathophysiology and treatment
Cyclophosphamide (Cytoxan), often used as a prepara-
tive therapy before bone-marrow transplantation, is the
most common cause of hemorrhagic cystitis in both chil-
dren and adults, and the effects of cyclophosphamide on
the urothelium are a primary limiting factor in its use
[4]. The hepatic metabolite of cyclophosphamide, ac-
rolein, causes sloughing, thinning, and inflammation of
the bladder urothelium [1].
Uroprotective measures for patients receiving cyclo-
phosphamide include intravenous administration of
2-mercaptoethane sulfonate (mesna), hyperhydration
with forced diuresis, and occasionally Foley catheter
placement to decrease exposure of the urothelium to
the toxic agent. If these preventive measures fail, first-
line therapy for hemorrhagic cystitis is placement of a
133
Fig. 4 This 5-year-old girl was treated with cyclophosphamide and
radiation (59 Gy) for bladder rhabdomyosarcoma. Short tau inver-
sion recovery (flip angle, 180 ; TR/TE, 4080/30) coronal MR
image of the bladder shows bladder wall thickening and hyperin-
tense foci (arrows) consistent with inflammation or edema. Cystos-
copy revealed multiple ectatic, engorged, suburothelial blood
vessels
large-bore urethral catheter and intravesical saline irri-
gation [1]. If bleeding persists or is serious enough to re-
sult in clot retention, then additional treatment is
required because large clots prohibit effective contrac-
tion of the detrusor muscle and thereby prevent com-
pression of large, bleeding intramural blood vessels.
Further treatment options depend on whether the blad-
der disease is focal or diffuse. If disease is focal, the le-
sion can be cauterized to control bleeding. If disease is
diffuse, intravesical sclerotherapy can be performed
with alum, silver nitrate or formalin, after evacuation
of intraluminal clot. These agents immobilize or coagu-
late proteins, which usually results in a sloughing of the
bladder urothelium and coagulation of suburothelial
blood vessels [1, 3, 4]. Hyperbaric oxygen therapy, em-
piric conjugated estrogen therapy, and intravesical pros-
taglandin therapy have all been reported to have
varying success rates [1]. Other more invasive measures
of controlling hemorrhagic cystitis include urinary di-
version (percutaneous nephrostomy), unilateral inter-
nal iliac artery embolization or ligation and, if
necessary, cystectomy [1].
Bladder disease
The bladder is the organ most susceptible to disease be-
cause of prolonged surface contact with the inciting
agent in urine. Patients with hemorrhagic cystitis usually
experience urinary urgency, frequency, suprapubic pain,
134

a b

c d

Fig. 5 a±e This 19-year-old boy underwent bone-marrow trans-

plantation for acute lymphoblastic leukemia. a Cystoscopic photo-
graph taken before sclerotherapy shows diffuse ulceration of the
bladder mucosa. b Cystoscopic photograph taken after intravesical
instillation of 1 % formalin shows denuded urothelium with granu-
lation tissue. c Transverse power Doppler sonogram taken
3 months after sclerotherapy shows that the bladder is filled with
clot (arrows) and an absence of flow to the bladder wall. d Post
mortem histology of bladder shows absence of urothelial layer,
thrombosis of suburothelial vessels (solid arrows) and surface
granulation tissue (open arrows). e Autopsy specimen demon-
e strates diffuse thickening of the walls of the bladder and distal ure-
ters

Fig. 6 This 15-year-old boy underwent bone-marrow transplanta-
tion for aplastic anemia. Intraoperative cystogram shows left vesi-
coureteral reflux (black arrow) and a large intraluminal filling
defect (white arrows) consistent with blood clot
and passage of blood clots [5]. At our institution, renal/
bladder ultrasonography is routinely performed to eval-
uate patients with suspected hemorrhagic cystitis. Imag-
ing findings vary with the severity of disease. According
to the criteria of Jequier and Rosseau, the normal sono-
graphic bladder wall thickness in children is 3 mm for a
distended bladder and 5 mm for a nondistended bladder
[6]. In early hemorrhagic cystitis, the bladder wall may
be either focally or diffusely thickened. When the dis-
ease is focal, 2D sonograms show focal areas of blad-
der-wall thickening, and power Doppler sonograms
show hypervascularity of the bladder wall (Fig. 1 a,b).
With color Doppler sonography, it is possible to see fo-
cal areas of active bleeding (Fig. 2 a). If ultrasound im-
ages suggest a focal process, it may be amenable to
endoscopic cauterization; therefore, ultrasound findings
influence the decision to treat conservatively or to
proceed more quickly to cystoscopy. Cystoscopy may
confirm focal areas of bladder wall thickening, hyper-
vascularity, and bleeding (Figs. 1 c, 2 b) that can be cau-
terized.
When bladder disease is diffuse, the patient may re-
quire a trial of intravesical saline irrigation and platelet
transfusion for thrombocytopenia. If hematuria persists,
intravesical sclerotherapy should be considered. Diffuse
thickening and hypervascularity of the bladder wall can
be detected by 2D and power Doppler sonography
(Fig. 3 a). MR images will show inflammation or edema
of the bladder wall (Fig. 4 a) [7, 8]. Histologic studies
show a prominence of vessels in the suburothelial layer
(Fig. 3 b), and cystoscopic examination reveals multiple
engorged vessels that may cause the entire bladder mu-
135
cosa to appear indurated (Fig. 5 a) [9]. If intravesical
sclerotherapy is needed, a cystogram is necessary to de-
termine the bladder volume and to determine whether
vesicoureteral reflux is present. When reflux is present
(Fig. 6), the ureteral orifice should be occluded with a
Fogarty balloon to prevent damage to the ureter and
kidneys during instillation of the sclerosing agent.
Sclerotherapy denudes the bladder of its mucosa
(urothelium), causing the bladder to appear pale during
cystoscopic examination (Fig. 5 b). Histologic studies
performed after sclerotherapy show that the urothelial
layer is absent and that suburothelial vessels are ex-
posed and thrombosed (Fig. 5 d). Power Doppler sono-
grams indicate diminished blood flow to the bladder
wall; however, significant bladder hemorrhage may per-
sist after sclerotherapy, presumably because of tiny ex-
posed suburothelial vessels (Fig. 5 c). Because the
bladder may become distended by blood clot, it may be
difficult to distinguish the bladder wall from intralumi-
nal clot on sonograms and CT images (Figs. 7, 8). In
this instance, MR imaging may best reveal the muscular
layer of the bladder wall (Fig. 9). However, when the
bladder is filled with clot, no imaging modality will
clearly distinguish intramural hemorrhage from intralu-
minal clot.
Upper-tract disease
Although the bladder is the organ most susceptible to
the inciting agent in urine, the entire urothelial surface
is at risk; lesions of the renal pelvis and ureter have
been reported [4]. In our experience the most common
finding in the upper tracts is hydronephrosis caused by
reflux or obstruction, which may be present with blad-
der-wall thickening alone or in association with bladder
clot. Additionally, sonograms may show suburothelial
thickening in the renal pelvis (Fig. 10) due to inflam-
mation caused by the inciting agent. Perinephric fluid
collections may occur (Fig. 11) because of either hemor-
rhage or forniceal rupture in a fragile and obstructed
collecting system. Debris resulting from hemorrhagic
pyelitis or papillary necrosis may collect within and dis-
tend the renal collecting system, and this can be demon-
strated on sonograms, MR images, and antegrade
pyelograms (Fig. 12a±c). During placement of nephros-
otomy tubes, one may see extravasation of contrast ma-
terial from the collecting system, a reflection of the
friability of the upper tracts in this disease (Fig. 13).
Conclusion
Patients with hemorrhagic cystitis may have focal or
diffuse bladder disease, which ranges in severity from
mild to severe. Imaging findings often influence treat-
136
7 8
9 10
11
Fig. 7 This 10-year-old girl developed hemorrhagic cystitis after
bone-marrow transplantation. Her bladder perforated after sclero-
therapy. CT image of the pelvis after repair of the bladder perfora-
tion shows the bladder to be distended by clot. The positions of the
bilateral ureteral stents (curved arrow), suprapubic Foley catheter
(open arrow) and transurethral Foley catheter (straight black ar-
row) suggest that there is probably intramural hemorrhage or
thickening as well as intraluminal clot
Fig. 8 This 12-year-old girl was treated with intravesical silver ni-
trate and formalin for hemorrhagic cystitis. Transverse sonogram
shows that the bladder is distended by clot. Note difficulty in dis-
tinguishing the bladder wall
Fig. 9 This 15-year-old boy underwent bone-marrow transplanta-
tion and was later treated for hemorrhagic cystitis with two intra-
vesical installations of 0.5 % silver nitrate. Coronal T1-weighted
(TR/TE, 550/15) MR image shows that the bladder is filled with
clot. Methemoglobin (white arrow) appears bright, and deoxyhe-
moglobin(open arrow) appears dark. Note that the muscular layer
of the bladder wall (black arrows) and the intraluminal clot can
be visualized separately
Fig. 10 This 19-year-old boy underwent bone-marrow transplanta-
tion and was later treated for hemorrhagic cystitis. Longitudinal
sonogram of the right kidney shows suburothelial edema and
thickening (arrow)
Fig. 11 This 10-year-old girl underwent bone-marrow transplanta-
tion and was later treated for hemorrhagic cystitis. Longitudinal
sonogram of the right kidney shows subcapsular fluid collection
(arrows) that may be due to hemorrhage or forniceal rupture in a
fragile and obstructed collecting system
 137

b
Fig. 12 a±c This 15-year-old boy underwent bone-marrow trans-
plantation and was later treated for hemorrhagic cystitis. a Longi-
tudinal sonogram of the right kidney shows the calyces to be filled
with debris (arrows). b Coronal T1-weighted (TR/TE, 559/15) im-
age of the kidneys shows mixed high- and low-signal material in
the right renal collecting system consistent with hemorrhage and
possibly papillary necrosis. c Image obtained during nephrostomy
tube placement shows large amount of debris in collecting system
(open arrows). The location of filling defects in calyces (black ar-
rows) is consistent with papillary necrosis. The obstructed proxi-
mal ureter (white arrow) is probably due to sloughed debris and
blood clot

ment decisions. We have found 2D and color Doppler

sonography to be of value in determining whether
disease is focal or diffuse. Because power Doppler
sonography is a sensitive method for detecting hyper-
vascularity in the bladder wall, this tool is useful in esti-
mating the severity of disease. When sclerotherapy is
considered, a cystogram should be performed to evalu-
ate for the presence of vesicoureteral reflux so that, if
necessary, the ureter can be occluded prior to sclero- Fig. 13 This 10-year-old girl underwent bone-marrow transplanta-
therapy to prevent damage to the ureter and kidney tion and was later treated for hemorrhagic cystitis. Fluoroscopic
by the sclerosing agent. Because the inciting agent in image obtained 2 days after nephrostomy tube placement shows
urine can affect the entire urothelium from the kidneys extravasation of contrast material from the renal pelvis (arrows)
138

to the bladder, the kidneys in patients with hemorrhag- imaging be performed for patients suspected of having
ic cystitis must be evaluated. We recommend that re- hemorrhagic cystitis and in the follow-up of those who
nal/bladder 2D and power Doppler ultrasound are treated for this disease.

References
1. West NJ (1997) Prevention and treat-
ment of hemorrhagic cystitis. Pharma-
cotherapy 17: 696±706
2. Hongeng S, Krance RA, Bowman LC,
et al (1997) Outcomes of transplanta-
tion with matched-sibling and unrelat-
ed-donor bone marrow in children with
leukaemia. Lancet 350: 767±771
3. Hill DE, Kramer SA (1994) Specific in-
fections of the genitourinary tract. In:
Kelalis PP, King LR, Belman AB (eds)
Clin Pediatr Urol, 3rd edn. Saunders,
Philadelphia, pp 266±268
4. Haas GP (1994) Cytoxan cystitis. In:
Current urologic therapy. Saunders,
Philadelphia, pp 266±268
5. Levine LA, Richie JP (1989) Urological
complications of cyclophosphamide.
J Urol 141: 1063±1069
6. Jequier S, Rousseau O (1987) Sono-
graphic measurements of the normal
bladder wall in children. Am J Roen-
tengol 149: 563±566
7. Worawattanakul S, Semelka RC, Kele-
kis NL (1997) Post-radiation hemor-
rhagic cystitis: MR findings. Magn
Reson Imaging 15: 1103±1106
8. Kazuro S, Carrington BM, Quivey JM,
et al (1990) Postirradiation changes in
the pelvis: assessment with MR imag-
ing. Radiology 175: 805±813
9. Brugieres L, Hartmann O, Travagli JP,
et al (1989) Hemorrhagic cystitis fol-
lowing high-dose chemotherapy and
bone marrow transplantation in chil-
dren with malignancies: incidence, clin-
ical course, and outcome. J Clin Oncol
7: 194±199