MYCOBACTERIUM BOVIS VERTEBRAL OSTEOMYELITIS AND PSOAS ABSCESS AFTER INTRAVESICAL BCG THERAPY FOR BLADDER CARCINOMA DOUGLAS S. KATZ, M.D. HARRY WOGALTER, M.D. ROBERT E D’ESPOSITO, M.D. BURKE A. CUNHA, M.D.
From the Department of Urology and the Infectious Disease Division, Winthrop-University Hospital, Mineola, and the School of Medicine, State University of New York, Stony Brook, New York ABSTRACT-Systemic complications of intravesicular BCG for bladder carcinoma are uncommon, and include fever, pneumonia, hepatitis, arthralgias, or skin rash. Local complications of BCG therapy for bladder cancer include cystitis, prostatitis, epididymo-orchitis, granulomatous lymphadenitis, or ureteral obstruction. We believe this is the first case of Mycobacterium bovis vertebral osteomyelitis and psoas abscess complicating intravesicular BCG therapy for bladder carcinoma.
Treatment with intravesicular Bacillus Calmette-Guerin (BCG) for superficial bladder carcinoma was first used successfully in 1976 by Morales and associates.’ BCG is currently the most effective therapy for superficial bladder cancer.2-4 Intravesical therapy prevents tumor recurrence after transurethral resection, while minimizing systemic toxicity.5 While side effects such as hematuria, dysuria, increased urinary frequency, and an influenza-like syndrome are common, intravesicular BCG therapy is considered safe and extravesical complications are rare.3.4 We report a case of Mycobacterium bovis spinal osteomyelitis and psoas abscess following intravesical BCG administration. Case Report A sixty-seven-year-old man presented to Winthrop-university Hospital with two episodes of macroscopic hematuria associated with slight suprapubic pain. Intravenous urethrography revealed a 2-cm filling defect on the left side of the bladder, and cystoscopic examination revealed a plum-sized neoplasm blocking the left
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ureteral orifice. After resection, pathologic examination identified a superficial papillary transitional cell carcinoma, predominantly grade 1, confined to the mucosa. Past history was significant only for smoking and a transurethral removal of bladder stones seven years prior to admission. There was no history of tuberculosis or vaccination with BCG. Physical examination was unremarkable. Intravesical thiotepa was administered, and one month later, monthly intravesical BCG therapy (40 mg per installation, Connaught strain) was begun and continued for a year, and no percutaneous BCG was given. Cystoscopic examinations at three, twelve, and fifteen months were negative for tumor recurrence, and no side effects were initially observed. Sixteen months after his initial presentation, he was readmitted to Winthrop-University Hospital complaining of several months of mild lower back pain that became constant and severe for three weeks. The pain radiated to the right thigh and buttock and was unrelieved by bedrest or codeine. He also noted right leg and
63
FIGURE 2. CT-guided psoas biopsy; vertebral destruction and adjacent left psoas abscess demonstrated.
FIGURE 1. Lumbosacral spine film shows extensive vertebral and disk space destruction.
foot weakness and anorexia. He denied bowel or bladder dysfunction, or fever and chills. On physical examination, he appeared weak and in some distress. Positive findings included exquisite point tenderness over the right lumbosacral joint area. Knee and ankle reflexes were absent bilaterally, and sensorimotor function in the right L5 and Sl dermatomes were decreased. Admission laboratory tests were normal except for 25-50 white blood cells in the urine. Urine cultures grew >lOO,OOO colonies of Enterobacter aerogenes, and oral trimethoprimsulfamethoxazole (TMP-SMX) was begun. Lumbosacral spine films showed extensive destructive changes of the L4-L5 intervertebral disk space and adjoining vertebral bodies (Fig. 1). Additionally, a left psoas mass with low attenuation areas was seen on computerized tomography (CT) scan (Fig. 2). Tl-weighted magnetic resonance imaging (MRI) confirmed the extent of tissue destruction (Fig. 3). On T2weighted images, the involved areas showed
64
FIGURE 3. Tl-weighted and CT findings.
MRI confirms plain film
marked increased signal. The bladder appearance was normal. CT-guided biopsy specimens of the left psoas mass and the L4-L5 disk space showed scant inflammatory cells. Smears for acid-fast bacilli were negative, but cultures were positive for M. bovis. Therapy with isonicotine hydrazine (INH), rifampin, and pyridoxine was begun. Laminotomy of the L5-Sl and L4-L5 interspaces was performed with excision of the fourth lumbar disk. After several weeks, an anterior spinal decompression, anterior lumbar fusion of L3 to L5 with a fibular bone graft, and drainage of the psoas abscess was done. Excised tissue had areas of necrotic bone with
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granulation tissue and both caseating and noncaseating granulomas with Langerhans-type giant cells, and smears for acid-fast bacilli were positive. Two months later, the patient was discharged to a rehabilitation facility for physical therapy, and antituberculous therapy was continued . Comment BCG is a live, freeze-dried, attenuated strain of M. bovis, first used in more than one billion people as a vaccine to prevent tuberculosis. 3 Localized abscesses and regional lymphadenopathy from BCG vaccination are rare complications.e Severe or systemic complications of BCG therapy for superficial bladder cancer are uncommon, and rare fatal infections and disseminated granulomas have occurred.3 Lamm and associates4 noted a 91 percent incidence of cystitis in 1,278 patients. Much less common were fever > 103 “F (in 3.9 % ), granulomatous prostatitis (1.3 % ), systemic infection with pneumonitis or hepatitis (0.9%), arthritis or arthralgias (0.5%), skin rash (0.4%), skin abscess (0.4%), and ureteral obstruction (0.3 % ) . Also, epididymo-orchitis occurred (0.2 % ), as well as hypotension (0.1% ), bladder contracture (0.2%), and cytopenia (0.1%). Orihuela and associates’ reported severe cystitis in 10 of 107 patients, severe flu-like symptoms in 6, and regional granulomatous lymphadenitis in 2 patients. They noted that most acute reactions were mild and self-limited.’ Oates and associates8 reported a series of 32 patients with indications for biopsy or aspiration cytology of the prostate after BCG treatment, and 13 of these showed granulomatous changes. Others have reported granulomatous renal masses in association with BCG therapy.g Most’recently, ArmstronglO identified a patient with fever, myalgias, rhabdomyolysis, and anuric renal failure, and another patient with a subcutaneous chest wall nodule that contained a nonviable acid-fast bacilli. BCG osteomyelitis is a rare complication of vaccination with BCG for tuberculosis prophylaxis, and it has never been reported from BCG installation for superficial bladder cancer. The majority of cases have come from Scandinavia, where infants were routinely vaccinated with BCG before 1975.” BCG-induced osteomyelitis has been estimated at 1 per 80,000 children vaccinated, and most often presents as a single osteolytic lesion in the metaphysis of long bones.“m13 Culture is frequently negative, and
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in one group of 77 cases of suspected BCG osteomyelitis, in only 42 could M. bovis be grown. l4 Tuberculous spondylitis, or Potts disease of the spine, results from hematogenous spread of bacilli, presents with nonspecific symptoms of insidious pain, weight loss, and anorexia, and there may be local swelling and spinal tenderness on palpation. Diagnosis is difficult or delayed, and x-ray films usually show vertebral body destruction with involvement of adjacent intervertebral disksI T-2-weighted MRI scans show high-signal intensity of both the vertebrae and the disks.le A combination of stains and culture for acid-fast bacilli with pathologic examination of tissue confirms the diagnosis. Permanent neurologic damage may occur if therapy is not started early enough. Therapy with antituberculous chemotherapy is indicated but rationale for surgery is controversial.15 BCG spondylitis is rare following BCG vaccination. A thirteen-year-old Swedish girl in whom lumbosacral BCG spondylitis developed following BCG vaccination is one of only a few cases in the literature. l1 Bottinger and associates reported 6 cases of spondylitis in a series of 190 patients with BCG osteomyelitis.‘2 The incidence of skeletal involvement in tuberculosis is 1 percent, and the spine is the most frequent site involved.” Why the spine is so rarely affected in BCG osteomyelitis is unknown.13 Strausser and Quindlen17 noted Pott’s disease in 1 case of BCG spondylitis after intralesional BCG therapy in a patient with melanoma. The association of tuberculous psoas abscess with spinal tuberculosis is well known.18 A psoas abscess usually results from contiguous spread of a gastrointestinal or skeletal process. Tuberculous psoas abscess presents with nonspecific symptoms including fever, chills, weight loss, and hip pain on hyperextension. la BCG osteomyelitis has not been previously reported as a complication of intravesicular BCG therapy for superficial transitional cell bladder carcinoma. Furthermore, to our knowledge, a BCG psoas abscess has never been reported from any form of administered BCG. We report a case of BCG spinal osteomyelitis and psoas abscess following intravesical BCG biopsy-proved by acid-fast smears, and culture of M. bovis. Our patient required major surgical interventions and was left with residual neurologic deficits. The risk of systemic complications may increase with each additional
65
installation of BCG a patient receives.4 As reports of severe reactions and serious complications of BCG therapy increase, urologists must remain aware of the potential problems with intravesicular BCG therapy. lo Infectious Disease Division Winthrop-University Hospital Mineola, New York 11501 (DR. CUNHA) References I. Morales A, Eidinger D, and Bruce AW: Intracavitary Bacillus Calmette-Guerin in the treatment of superficial bladder tumors, J Urol 116: 180 (1976). 2. Lamm DL, et al: Prospective randomized comparison of intravesical with percutaneous Bacillus Calmette-Guerin versus intravesical Bacillus Calmette-Guerin in superficial bladder cancer, J Urol 145: 738 (1991). 3. Diagnostic and therapeutic technology assessment (DATTA): BCG immunotherapy in bladder cancer: a reassessment, JAMA 259: 2153 (1988). 4. Lamm DL, et al: Complications of Bacillus CalmetteGuerin immunotherapy in 1,278 patients with bladder cancer, J Urol 135: 272 (1986). 5. Soloway MS: Introduction and overview of intravesical therapy for superficial bladder cancer, Urology 31: 95 (1988). 6. Rosenberg EB, et al: Systemic infection following BCG
66
therapy, Arch Intern Med 134: 769 (1974). 7. Orihuela E. et al: Toxicitv of intravesical BCG and its management in patients with superficial bladder tumors, Cancer 60: 326 (1987). prostatitis following Bacil8. Oaks RD, et al: Granulomatous lus Calmette-Guerin immunotherapy of bladder cancer, J Urol 140: 751 (1988). 9. Stanisic TH, Brewer ML, and Graham AR: Intravesical Bacillus Calmette-Guerin therapy and associated granulomatous renal masses, J Urol 135: 356 (1986). 10. Armstrong RW: Complications after intravesical installation of Bacillus Calmette-Guerin: rhabdomyolysis and metastatic infection, J Urol 145: 1264 (1991). 11. Sandstrom S: Multifocal sclerotic BCG spondylitis in a 13year-old girl, Pediatr Radio1 13: 239 (1983). 12. Bottiger M, Romanus V, deverdier C, and Boman G: Osteitis and other complications caused by generalized BCG-itis, Acta Pediatr Stand 71: 471 (1982). 13. Mortensson W, Eklot 0, and Jorulf H: Radiologic aspects of BCG-osteomvelitis in infants and children. Acta Radio1 17: 471 (1982). ’ 14. Schopfer K, et al: BCG osteomyelitis: case report and review, Helv Paediatr Acta 37: 73 (1982). 15. Shivaram U, Wollschlager C, Khan F, and Khan A: Spinal tuberculosis revisited, South Med J 78: 681 (1985). 16. deRoos A, van Persijn van Meerten EL, and Bluemm RG: MRI of tuberculosis spondylitis, AJR 146: 79 (1986). 17. Strausser JL, and Quindlen EA: Pott’s disease following BCG therapy of melanoma, Cancer 48: 1154 (1981). 18. Lowe BA, and Smith AV: Primary psoas abscess, J Urol 137: 485 (1987). 2
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From the Department of Urology and the Infectious Disease Division, Winthrop-University Hospital, Mineola, and the School of Medicine, State University of New York, Stony Brook, New York ABSTRACT-Systemic complications of intravesicular BCG for bladder carcinoma are uncommon, and include fever, pneumonia, hepatitis, arthralgias, or skin rash. Local complications of BCG therapy for bladder cancer include cystitis, prostatitis, epididymo-orchitis, granulomatous lymphadenitis, or ureteral obstruction. We believe this is the first case of Mycobacterium bovis vertebral osteomyelitis and psoas abscess complicating intravesicular BCG therapy for bladder carcinoma.
Treatment with intravesicular Bacillus Calmette-Guerin (BCG) for superficial bladder carcinoma was first used successfully in 1976 by Morales and associates.’ BCG is currently the most effective therapy for superficial bladder cancer.2-4 Intravesical therapy prevents tumor recurrence after transurethral resection, while minimizing systemic toxicity.5 While side effects such as hematuria, dysuria, increased urinary frequency, and an influenza-like syndrome are common, intravesicular BCG therapy is considered safe and extravesical complications are rare.3.4 We report a case of Mycobacterium bovis spinal osteomyelitis and psoas abscess following intravesical BCG administration. Case Report A sixty-seven-year-old man presented to Winthrop-university Hospital with two episodes of macroscopic hematuria associated with slight suprapubic pain. Intravenous urethrography revealed a 2-cm filling defect on the left side of the bladder, and cystoscopic examination revealed a plum-sized neoplasm blocking the left
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JULY 1992
I
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40, NUMBER
1
ureteral orifice. After resection, pathologic examination identified a superficial papillary transitional cell carcinoma, predominantly grade 1, confined to the mucosa. Past history was significant only for smoking and a transurethral removal of bladder stones seven years prior to admission. There was no history of tuberculosis or vaccination with BCG. Physical examination was unremarkable. Intravesical thiotepa was administered, and one month later, monthly intravesical BCG therapy (40 mg per installation, Connaught strain) was begun and continued for a year, and no percutaneous BCG was given. Cystoscopic examinations at three, twelve, and fifteen months were negative for tumor recurrence, and no side effects were initially observed. Sixteen months after his initial presentation, he was readmitted to Winthrop-University Hospital complaining of several months of mild lower back pain that became constant and severe for three weeks. The pain radiated to the right thigh and buttock and was unrelieved by bedrest or codeine. He also noted right leg and
63
FIGURE 2. CT-guided psoas biopsy; vertebral destruction and adjacent left psoas abscess demonstrated.
FIGURE 1. Lumbosacral spine film shows extensive vertebral and disk space destruction.
foot weakness and anorexia. He denied bowel or bladder dysfunction, or fever and chills. On physical examination, he appeared weak and in some distress. Positive findings included exquisite point tenderness over the right lumbosacral joint area. Knee and ankle reflexes were absent bilaterally, and sensorimotor function in the right L5 and Sl dermatomes were decreased. Admission laboratory tests were normal except for 25-50 white blood cells in the urine. Urine cultures grew >lOO,OOO colonies of Enterobacter aerogenes, and oral trimethoprimsulfamethoxazole (TMP-SMX) was begun. Lumbosacral spine films showed extensive destructive changes of the L4-L5 intervertebral disk space and adjoining vertebral bodies (Fig. 1). Additionally, a left psoas mass with low attenuation areas was seen on computerized tomography (CT) scan (Fig. 2). Tl-weighted magnetic resonance imaging (MRI) confirmed the extent of tissue destruction (Fig. 3). On T2weighted images, the involved areas showed
64
FIGURE 3. Tl-weighted and CT findings.
MRI confirms plain film
marked increased signal. The bladder appearance was normal. CT-guided biopsy specimens of the left psoas mass and the L4-L5 disk space showed scant inflammatory cells. Smears for acid-fast bacilli were negative, but cultures were positive for M. bovis. Therapy with isonicotine hydrazine (INH), rifampin, and pyridoxine was begun. Laminotomy of the L5-Sl and L4-L5 interspaces was performed with excision of the fourth lumbar disk. After several weeks, an anterior spinal decompression, anterior lumbar fusion of L3 to L5 with a fibular bone graft, and drainage of the psoas abscess was done. Excised tissue had areas of necrotic bone with
UROLOGY
I JULY1992 / VOLUME40,NUMBERl
granulation tissue and both caseating and noncaseating granulomas with Langerhans-type giant cells, and smears for acid-fast bacilli were positive. Two months later, the patient was discharged to a rehabilitation facility for physical therapy, and antituberculous therapy was continued . Comment BCG is a live, freeze-dried, attenuated strain of M. bovis, first used in more than one billion people as a vaccine to prevent tuberculosis. 3 Localized abscesses and regional lymphadenopathy from BCG vaccination are rare complications.e Severe or systemic complications of BCG therapy for superficial bladder cancer are uncommon, and rare fatal infections and disseminated granulomas have occurred.3 Lamm and associates4 noted a 91 percent incidence of cystitis in 1,278 patients. Much less common were fever > 103 “F (in 3.9 % ), granulomatous prostatitis (1.3 % ), systemic infection with pneumonitis or hepatitis (0.9%), arthritis or arthralgias (0.5%), skin rash (0.4%), skin abscess (0.4%), and ureteral obstruction (0.3 % ) . Also, epididymo-orchitis occurred (0.2 % ), as well as hypotension (0.1% ), bladder contracture (0.2%), and cytopenia (0.1%). Orihuela and associates’ reported severe cystitis in 10 of 107 patients, severe flu-like symptoms in 6, and regional granulomatous lymphadenitis in 2 patients. They noted that most acute reactions were mild and self-limited.’ Oates and associates8 reported a series of 32 patients with indications for biopsy or aspiration cytology of the prostate after BCG treatment, and 13 of these showed granulomatous changes. Others have reported granulomatous renal masses in association with BCG therapy.g Most’recently, ArmstronglO identified a patient with fever, myalgias, rhabdomyolysis, and anuric renal failure, and another patient with a subcutaneous chest wall nodule that contained a nonviable acid-fast bacilli. BCG osteomyelitis is a rare complication of vaccination with BCG for tuberculosis prophylaxis, and it has never been reported from BCG installation for superficial bladder cancer. The majority of cases have come from Scandinavia, where infants were routinely vaccinated with BCG before 1975.” BCG-induced osteomyelitis has been estimated at 1 per 80,000 children vaccinated, and most often presents as a single osteolytic lesion in the metaphysis of long bones.“m13 Culture is frequently negative, and
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JULY 1992
/
VOLUME
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in one group of 77 cases of suspected BCG osteomyelitis, in only 42 could M. bovis be grown. l4 Tuberculous spondylitis, or Potts disease of the spine, results from hematogenous spread of bacilli, presents with nonspecific symptoms of insidious pain, weight loss, and anorexia, and there may be local swelling and spinal tenderness on palpation. Diagnosis is difficult or delayed, and x-ray films usually show vertebral body destruction with involvement of adjacent intervertebral disksI T-2-weighted MRI scans show high-signal intensity of both the vertebrae and the disks.le A combination of stains and culture for acid-fast bacilli with pathologic examination of tissue confirms the diagnosis. Permanent neurologic damage may occur if therapy is not started early enough. Therapy with antituberculous chemotherapy is indicated but rationale for surgery is controversial.15 BCG spondylitis is rare following BCG vaccination. A thirteen-year-old Swedish girl in whom lumbosacral BCG spondylitis developed following BCG vaccination is one of only a few cases in the literature. l1 Bottinger and associates reported 6 cases of spondylitis in a series of 190 patients with BCG osteomyelitis.‘2 The incidence of skeletal involvement in tuberculosis is 1 percent, and the spine is the most frequent site involved.” Why the spine is so rarely affected in BCG osteomyelitis is unknown.13 Strausser and Quindlen17 noted Pott’s disease in 1 case of BCG spondylitis after intralesional BCG therapy in a patient with melanoma. The association of tuberculous psoas abscess with spinal tuberculosis is well known.18 A psoas abscess usually results from contiguous spread of a gastrointestinal or skeletal process. Tuberculous psoas abscess presents with nonspecific symptoms including fever, chills, weight loss, and hip pain on hyperextension. la BCG osteomyelitis has not been previously reported as a complication of intravesicular BCG therapy for superficial transitional cell bladder carcinoma. Furthermore, to our knowledge, a BCG psoas abscess has never been reported from any form of administered BCG. We report a case of BCG spinal osteomyelitis and psoas abscess following intravesical BCG biopsy-proved by acid-fast smears, and culture of M. bovis. Our patient required major surgical interventions and was left with residual neurologic deficits. The risk of systemic complications may increase with each additional
65
installation of BCG a patient receives.4 As reports of severe reactions and serious complications of BCG therapy increase, urologists must remain aware of the potential problems with intravesicular BCG therapy. lo Infectious Disease Division Winthrop-University Hospital Mineola, New York 11501 (DR. CUNHA) References I. Morales A, Eidinger D, and Bruce AW: Intracavitary Bacillus Calmette-Guerin in the treatment of superficial bladder tumors, J Urol 116: 180 (1976). 2. Lamm DL, et al: Prospective randomized comparison of intravesical with percutaneous Bacillus Calmette-Guerin versus intravesical Bacillus Calmette-Guerin in superficial bladder cancer, J Urol 145: 738 (1991). 3. Diagnostic and therapeutic technology assessment (DATTA): BCG immunotherapy in bladder cancer: a reassessment, JAMA 259: 2153 (1988). 4. Lamm DL, et al: Complications of Bacillus CalmetteGuerin immunotherapy in 1,278 patients with bladder cancer, J Urol 135: 272 (1986). 5. Soloway MS: Introduction and overview of intravesical therapy for superficial bladder cancer, Urology 31: 95 (1988). 6. Rosenberg EB, et al: Systemic infection following BCG
66
therapy, Arch Intern Med 134: 769 (1974). 7. Orihuela E. et al: Toxicitv of intravesical BCG and its management in patients with superficial bladder tumors, Cancer 60: 326 (1987). prostatitis following Bacil8. Oaks RD, et al: Granulomatous lus Calmette-Guerin immunotherapy of bladder cancer, J Urol 140: 751 (1988). 9. Stanisic TH, Brewer ML, and Graham AR: Intravesical Bacillus Calmette-Guerin therapy and associated granulomatous renal masses, J Urol 135: 356 (1986). 10. Armstrong RW: Complications after intravesical installation of Bacillus Calmette-Guerin: rhabdomyolysis and metastatic infection, J Urol 145: 1264 (1991). 11. Sandstrom S: Multifocal sclerotic BCG spondylitis in a 13year-old girl, Pediatr Radio1 13: 239 (1983). 12. Bottiger M, Romanus V, deverdier C, and Boman G: Osteitis and other complications caused by generalized BCG-itis, Acta Pediatr Stand 71: 471 (1982). 13. Mortensson W, Eklot 0, and Jorulf H: Radiologic aspects of BCG-osteomvelitis in infants and children. Acta Radio1 17: 471 (1982). ’ 14. Schopfer K, et al: BCG osteomyelitis: case report and review, Helv Paediatr Acta 37: 73 (1982). 15. Shivaram U, Wollschlager C, Khan F, and Khan A: Spinal tuberculosis revisited, South Med J 78: 681 (1985). 16. deRoos A, van Persijn van Meerten EL, and Bluemm RG: MRI of tuberculosis spondylitis, AJR 146: 79 (1986). 17. Strausser JL, and Quindlen EA: Pott’s disease following BCG therapy of melanoma, Cancer 48: 1154 (1981). 18. Lowe BA, and Smith AV: Primary psoas abscess, J Urol 137: 485 (1987). 2
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