DOI:10.2214/AJR.08.1962
AJR 2009; 192:1494-1500
© American Roentgen Ray Society
Imaging Appearance of Granulomatous Disease After Intravesical Bacille Calmette-Guérin (BCG) Treatment of Bladder Carcinoma
Weining Ma1,
Stella K. Kang2,
Hedvig Hricak1,
Scott R. Gerst1 and
Jingbo Zhang1
1 Department of Radiology, Memorial Sloan-Kettering Cancer Center, 1275 York
Ave., New York, NY 10022.
2 Department of Radiology, NYU Hospitals Center, New York, NY.
Received October 17, 2008;
accepted after revision January 21, 2009.
Address correspondence to W. Ma
(maw{at}mskcc.org).
Abstract
OBJECTIVE. The purpose of our study is to present the radiographic
findings in a series of 16 patients with complications associated with
intravesical bacille Calmette-Guérin (BCG) treatment of bladder
cancer.
CONCLUSION. Intravesical BCG-related complications such as
granulomatous disease may show imaging findings mimicking primary or
metastatic tumors in patients with bladder cancer. Radiologists should
consider this possibility when imaging abnormalities are encountered in
bladder cancer patients treated with intravesical BCG so that appropriate
management can be administered and unnecessary procedures avoided.
Keywords: bladder carcinoma • CT, kidney • CT, prostate gland • CT, urinary bladder • granulomatous disease • intravesical bacille Calmette-Guérin (BCG) treatment • kidney disease • MRI, prostate gland • MRI, urinary bladder • prostate gland disease • urinary bladder disease
Introduction
Intravesical instillation of immunotherapeutic bacille
Calmette-Guérin (BCG) is an important adjunct to transurethral
resection of bladder tumor in patients with superficial disease to reduce the
risk of recurrence and progression. Indications for use of intravesical BCG
depend on the potential of a particular tumor to progress. Thus, multifocal
Ta, T1, and carcinoma in situ frequently necessitate intravesical BCG
treatment [1]. Although adverse
effects of BCG therapy are rare and most patients treated with intravesical
BCG do not present with any side effects, both localized and systemic
complications may result from such treatment, and they occur more frequently
and severely than those seen after vaccination for tuberculosis. The most
common local complications that occur include cystitis, hematuria, bladder
contracture, granulomatous prostatitis, epididymoorchitis, and ureteral
obstruction. Fewer than 5% of patients may have mild, short-lived symptoms
such as malaise, low-grade fever, cystitis, and hematuria. Rarely, systemic
infections such as granulomatous nephritis and abscesses, pneumonitis,
hepatitis, osteomyelitis, and other life-threatening adverse events may occur.
Life-threatening BCG sepsis can occur but has been reported in only 0.4% of
patients [2].
Diagnosis of complications related to intravesical instillation of BCG is
based on clinical presentation related to timing of recent instillations,
imaging findings, and biopsy. The organism is usually not isolated. Although
the complications of intravesical BCG treatment are well-described, to our
knowledge there is a paucity of articles on the radiologic findings in these
cases. Our article aims to describe the radiologic findings in patients with
confirmed granulomatous disease associated with intravesical BCG treatment of
bladder cancer.
Materials and Methods
Subjects
This HIPAA-compliant retrospective study was approved by our institutional
review board, and informed consent was waived. A search of electronic medical
records in our hospital for the period between 2004 and 2006 identified a
total of 491 patients who received intravesical BCG treatment of bladder
cancer. Among them, a total of 16 patients (all men; mean age, 69 years; age
range, 45–89 years) who had received intravesical BCG treatment of
bladder carcinoma subsequently either developed granulomatous disease proven
by biopsy or presented with clinical symptoms suspicious for complications
related to BCG treatment. The patients had received adequate imaging follow-up
to indicate the diagnosis of BCG-related complications.
Eight of 16 patients experienced one or more adverse reactions during or
just after BCG treatment, including systemic symptoms (such as fever, chills,
or night sweats) in four patients, urinary symptoms (dysuria, urinary
frequency, or hematuria) in four patients, flank pain in one patient, prostate
abnormality (enlargement of the prostate, prostate nodule, or elevated
prostate-specific antigen [PSA]) in five patients. The other eight patients
did not have documented symptoms after BCG treatment, but abnormalities were
found on follow-up imaging studies. Biopsy or surgical pathology results were
available in all patients.
Imaging Method and Analysis
All 16 patients underwent CT on helical scanners (LightSpeed, GE
Healthcare). Among them, four patients underwent routine contrast-enhanced CT
after administration of oral and IV contrast material with 5-mm slice
thickness during the portal venous phase. Twelve patients underwent CT
urography, which included unenhanced images, contrast-enhanced images during
the renal parenchymal phase, and delayed excretory phase images of the abdomen
and pelvis at 2.5-mm slice thickness. For the CT urography, no oral contrast
material was administered. Four of the patients also underwent MRI of the
abdomen and pelvis (including endorectal prostate MRI), and two patients
underwent MRI of the pelvis only. All MRI examinations were performed on a
1.5-T scanner (Signa, GE Healthcare). In addition, five patients underwent
11C-acetate PET with IV administration of 19.8 mCi (732.6 MBq) of
11C-acetate. All imaging studies were retrospectively reviewed on a
PACS (Centricity, GE Healthcare) by two fellowship-trained body imaging
radiologists in consensus.
Results
Table 1 summarizes the
clinical history and imaging findings of these patients. Imaging abnormalities
were found mostly in the urinary system, including the kidneys, urinary
bladder, and prostate gland.
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TABLE 1: Imaging Findings in Cases of Complicated Intravesical Bacille
Calmette-Guérin (BCG) Treatment of Bladder Carcinoma
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In the kidneys, five patients were found to have enhancing lesions on
contrast-enhanced CT. Although some of these renal lesions were segmental in
appearance and associated with minimal perinephric stranding that may be
suggestive of pyelonephritis, some were quite expansile and masslike in
appearance, mimicking tumor (Figs.
1A,
1B,
1C,
1D and
2A,
2B,
2C,
2D,
2E,
2F). Among these, two patients
presented with fevers, and one had flank pain as well. One patient had urinary
frequency. The other two patients did not present with any symptoms and were
incidentally found to have imaging abnormalities in the kidneys on follow-up
examinations. No renal biopsy was performed in any of these patients. The
presumed diagnosis of BCG-related complication involving the kidneys was made
in three patients because the symptoms and size of renal lesions improved
after anti-BCG treatment or without any treatment. In two patients who did not
present with any symptoms, one patient's renal lesions improved after
ciprofloxacin (Cipro, Bayer HealthCare) treatment of presumed pyelonephritis
and the other patient's renal lesions improved without any treatment. That
patient had biopsy-proven granulomatous disease elsewhere in the urinary
tract.
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Fig. 1A —65-year-old man who presented with fever, chills, and night
sweats after intravesical bacille Calmette-Guérin treatment of bladder
cancer. Axial contrast-enhanced CT images of abdomen show enhancing masses in
left kidney (arrows).
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Fig. 1B —65-year-old man who presented with fever, chills, and night
sweats after intravesical bacille Calmette-Guérin treatment of bladder
cancer. Axial contrast-enhanced CT images of abdomen show enhancing masses in
left kidney (arrows).
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Fig. 1C —65-year-old man who presented with fever, chills, and night
sweats after intravesical bacille Calmette-Guérin treatment of bladder
cancer. Axial contrast-enhanced CT images of abdomen 3 months after treatment
(rifampin, isoniazid, and steroids) show decreased sizes of renal masses
(arrows). No renal biopsy was performed. However, patient's clinical
symptoms resolved after treatment in addition to improved imaging findings
shown here.
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Fig. 1D —65-year-old man who presented with fever, chills, and night
sweats after intravesical bacille Calmette-Guérin treatment of bladder
cancer. Axial contrast-enhanced CT images of abdomen 3 months after treatment
(rifampin, isoniazid, and steroids) show decreased sizes of renal masses
(arrows). No renal biopsy was performed. However, patient's clinical
symptoms resolved after treatment in addition to improved imaging findings
shown here.
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Fig. 2A —58-year-old man who presented with fever and right flank pain
after intravesical bacille Calmette-Guérin treatment of bladder cancer.
Axial contrast-enhanced CT images of abdomen show enhancing masses in right
kidney (arrows).
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Fig. 2B —58-year-old man who presented with fever and right flank pain
after intravesical bacille Calmette-Guérin treatment of bladder cancer.
Axial contrast-enhanced CT images of abdomen show enhancing masses in right
kidney (arrows).
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Fig. 2C —58-year-old man who presented with fever and right flank pain
after intravesical bacille Calmette-Guérin treatment of bladder cancer.
Axial contrast-enhanced CT images of abdomen 6 months after treatment
(rifampin, isoniazid, and ethambutol) show decreased sizes of renal masses
(arrows).
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Fig. 2D —58-year-old man who presented with fever and right flank pain
after intravesical bacille Calmette-Guérin treatment of bladder cancer.
Axial contrast-enhanced CT images of abdomen 6 months after treatment
(rifampin, isoniazid, and ethambutol) show decreased sizes of renal masses
(arrows).
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Fig. 2E —58-year-old man who presented with fever and right flank pain
after intravesical bacille Calmette-Guérin treatment of bladder cancer.
Axial contrast-enhanced CT image of pelvis shows thickening in right bladder
wall (arrow).
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Fig. 2F —58-year-old man who presented with fever and right flank pain
after intravesical bacille Calmette-Guérin treatment of bladder cancer.
Axial contrast-enhanced CT image of pelvis 6 months after treatment (rifampin,
isoniazid, and ethambutol) shows decreased thickening in right bladder wall
(arrow). No renal biopsy was performed. However, bladder biopsy
showed granulomatous cystitis, and patient's symptoms and imaging findings
improved after treatment.
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In the bladder, thickened bladder wall with focal nodularity was seen on CT
or MRI in 11 patients (Figs.
2A,
2B,
2C,
2D,
2E,
2F and
3A,
3B,
3C,
3D,
3E). This imaging finding is
very difficult to differentiate from bladder tumor, especially in this patient
population with a known history of bladder cancer. The diagnosis of
granulomatous cystitis was made on either bladder biopsy or surgical pathology
in eight patients. Two patients had noninvasive urothelial carcinoma in the
bladder, and one patient had reactive atypia and inflammatory changes in the
bladder wall. Two additional patients had granulomatous disease involving the
bladder that was not detected by imaging.
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Fig. 3A —70-year-old man who presented with enlarged prostate after
intravesical bacille Calmette-Guérin treatment of bladder cancer. Axial
T2-weighted MR image of pelvis shows diffusely decreased T2 signal in
peripheral zone of prostate gland (arrow).
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Fig. 3B —70-year-old man who presented with enlarged prostate after
intravesical bacille Calmette-Guérin treatment of bladder cancer.
Sagittal T2-weighted MR image of pelvis shows nodular thickening of posterior
bladder wall (arrow).
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Fig. 3C —70-year-old man who presented with enlarged prostate after
intravesical bacille Calmette-Guérin treatment of bladder cancer. Axial
T2-weighted image of pelvis shows bilateral enlarged external iliac lymph
nodes (arrows).
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Fig. 3D —70-year-old man who presented with enlarged prostate after
intravesical bacille Calmette-Guérin treatment of bladder cancer. Axial
11C-acetate PET image shows increased tracer uptake in left
external iliac lymphadenopathy (arrow).
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Fig. 3E —70-year-old man who presented with enlarged prostate after
intravesical bacille Calmette-Guérin treatment of bladder cancer. Axial
11C-acetate PET image shows increased tracer uptake in prostate
gland (arrow). Subsequent surgical pathology from cystoprostatectomy
showed extensive granulomatous prostatitis and cystitis as well as granulomas
in pelvic lymph nodes.
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Fig. 4 —69-year-old man who presented with new palpable prostate
nodules, elevated prostate-specific antigen (7.35 ng/mL), fever, dysuria, and
increased urinary frequency after intravesical bacille Calmette-Guérin
treatment of bladder cancer. Axial T2-weighted MR image of prostate with
endorectal coil shows mild diffuse T2 hypointensity in prostate gland and
discrete nodule of decreased T2 signal intensity in posterior peripheral zone
with mild bulging of posterior prostate contour (arrow). Subsequent
prostate biopsy showed granulomatous prostatitis in prostate nodule and
granulomas diffusely present throughout rest of prostate.
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Fig. 5A —66-year-old man who completed bacille Calmette-Guérin
(BCG) treatment of bladder cancer without complaints or symptoms. Axial
contrast-enhanced CT image of pelvis shows prominently sized prostate
gland.
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Fig. 5B —66-year-old man who completed bacille Calmette-Guérin
(BCG) treatment of bladder cancer without complaints or symptoms. Axial
T2-weighted MR image of pelvis shows mild, diffuse decrease in T2 signal in
prostate gland.
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Fig. 5C —66-year-old man who completed bacille Calmette-Guérin
(BCG) treatment of bladder cancer without complaints or symptoms. Axial
11C-acetate PET image shows increased tracer uptake in prostate
gland. Subsequent surgical pathology from radical cystoprostatectomy showed
diffuse granulomatous prostatitis and focal adenocarcinoma with Gleason score
of 6 in anterior prostate gland.
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The prostate showed nonspecific enlargement on CT in six patients, five of
whom underwent MRI, which showed either diffusely decreased T2 signal in the
prostatic peripheral zone or well-defined focal T2 hypointense nodules, some
of which corresponded to the site of induration by digital rectal examination
(Figs. 3A,
3B,
3C,
3D,
3E,
4,
5A,
5B,
5C). These findings mimic
those in patients with either diffuse or focal prostatic carcinoma. Biopsy
showed granulomatous prostatitis or granulomatous changes in these five
patients. One of these patients also had prostate carcinoma on pathology.
Granulomatous prostatitis was also found on biopsy in other patients who did
not undergo pelvic MRI.
It should be noted that 11C-acetate PET may show increased
metabolic activity in all the previously described imaging abnormalities
(Figs. 3A,
3B,
3C,
3D,
3E and
5A,
5B,
5C), further complicating the
differentiation between benign versus malignant disease.
Furthermore, pelvic lymphadenopathy was present in one patient, seen as
enlarged lymph nodes on CT and MRI and with increased tracer uptake on
11C-acetate PET, mimicking metastatic disease in patients with a
known diagnosis of bladder cancer (Fig.
3A,
3B,
3C,
3D,
3E). These lymph nodes were
confirmed to contain focal granulomas on surgical pathology.
Discussion
Intravesical BCG therapy is commonly used for the treatment of bladder
cancer. The live attenuated strain of Mycobacterium bovis is used as
an adjuvant therapy after transurethral resection of the bladder tumor.
Because these patients often undergo repeated imaging studies to monitor
treatment response and evaluate the extent of disease, it is important to
recognize the spectrum of imaging findings that may be encountered after BCG
treatment and not to mistake these findings for a primary or metastatic
neoplastic process.
Our study showed that BCG-related complications may manifest as focal
imaging abnormalities, especially in the genitourinary organs. Clinically,
BCG-induced cystitis is the most common local complication
[2]. Symptoms such as urinary
frequency, urgency, and dysuria are often present and accompanied by a
low-grade fever. Our study showed that BCG cystitis can manifest as a
thickened bladder wall with focal nodularity that cannot be differentiated
from the appearance of bladder cancer.
Attenuated BCG may also be spread by contaminated urine to other
genitourinary structures, causing granulomatous prostatitis,
epididymoorchitis, renal abscess, and ureteral obstruction. Some studies
describe a high proportion of men with granulomatous prostatitis after BCG
treatment [3,
4]. Although often
asymptomatic, acute granulomatous prostatitis can cause urinary retention and
induration. Furthermore, the PSA level is elevated in about 75% of men treated
with BCG, although most of these cases are asymptomatic
[5]. Our study showed that
granulomatous prostatitis may present as diffusely or focally decreased T2
signal in the prostate gland on MRI. Because BCG-related granulomatous
prostatitis cannot be reliably distinguished from prostate cancer by digital
rectal examination or imaging, it is important to consider this differential
diagnosis, and definitive diagnosis may need to be made by biopsy.
Our study showed that BCG treatment can also cause focal renal lesions
mimicking renal masses or other abnormalities such as pyelonephritis.
Depending on the nature of the reaction, these renal lesions may represent
either abscesses or granulomas
[6,
7]. The development of a
granulomatous renal mass is extremely rare, occurring in less than 0.1% of
BCG-treated patients [2]. The
mechanism of renal granuloma formation after intravesical BCG therapy
(vesicoureteral reflux versus systemic spread) remains unclear and
controversial [8]. For renal
abscess or granulomas, treatment with rifampin and isoniazid is recommended
for 3–6 months [2]. It is
therefore essential to consider the possibility of post-BCG treatment reaction
in the kidneys of bladder cancer patients treated with BCG so that appropriate
management can be undertaken and unnecessary invasive procedures avoided.
Mainly because the radioactive tracer used for 18F-FDG PET is
excreted by urine, this technique has not been widely used for staging or
detection of recurrence in patients with urinary tumors. As a result,
evaluation of the urinary system is frequently difficult. Because it is not
excreted by the urinary system, 11C-acetate may have great
potential in evaluating urinary tumors and is undergoing active investigation.
Unfortunately, a few cases in our study showed that the uptake of
11C-acetate is not specific to tumor. Granulomatous disease or
inflammatory processes in the urinary organs, such as bladder, prostate, and
kidney, can be associated with increased tracer uptake. Furthermore, patients
with bladder cancer treated with BCG can develop enlarged lymph nodes in the
pelvis with increased tracer uptake on PET, causing further confusion in
interpretation of the imaging findings. It is important to consider that under
these circumstances, the abnormal pelvic lymph node may not necessarily
represent nodal metastasis from the patient's known bladder cancer.
Our investigation has the limitations of a retrospective study, including
selection bias and interpretation bias. It is very likely that some patients
with BCG-related complications were not included in our study because they did
not undergo imaging or biopsy due to lack of symptoms. In addition, the
diagnosis of BCG-related complications in our series was based on clinical and
imaging follow-up in several patients. Nevertheless, this was a descriptive
study of the radiographic findings in patients with BCG-related
complications.
As discussed, it is clinically important for the radiologist to consider
the possibility of BCG reaction when local or disseminated masses are
visualized on follow-up imaging in bladder cancer patients. If clinical
concern for metastatic disease or another primary tumor is high, a biopsy may
be needed to provide a definitive diagnosis. Otherwise, empirical therapy
using antituberculous drugs, with or without prednisone, should be
administered when clinically indicated, regardless of failure to isolate the
organism in culture. Disseminated infection complications are generally
treated effectively with antituberculous drugs, whereas hypersensitivity
reactions have been reported to be highly responsive to steroids alone
[9,
10]. Repeat imaging of these
patients after conservative therapy to document improvement of imaging
abnormalities would be helpful for confirming the diagnosis and excluding
progression of tumor.
In conclusion, we have reported a small group of patients with
complications from intravesical BCG treatment of bladder cancer that can be
encountered on imaging and may lead to the misdiagnosis of primary or
metastatic tumors. It is important for the radiologist to consider this
differential diagnosis when interpreting the imaging studies so that
appropriate treatment can be administered and unnecessary invasive procedures
avoided.
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Abstract
Introduction
