Disseminated tuberculosis in a patient with recurrent transitional cell ...

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Disseminated tuberculosis in a patient with recurrent transitional cell carcinoma of renal pelvis and bladder following intravesical BCG therapy: A report of a rare case ABSTRACT Bacillus Calmette–Guerin (BCG) has been used as an intravesical instillation for nonmuscle invasive (superficial) bladder cancer for the last 3 decades. Although intravesical BCG therapy is well‑tolerated by most of the patients, adverse reactions have also been reported which are usually local, benign, and self‑limited. Systemic complications such as miliary tuberculosis (TB) are very rare with few documented reports in literature. We hereby report a rare case of disseminated TB in bilateral lungs, adrenal, cervical, mediastinal, and para‑aortic lymph nodesin a patient with recurrent transitional cell carcinoma (TCC) of renal pelvis and urinary bladder. Peculiar feature of this case was the development of TB 2 years following last BCG instillation, which is unlike most of the cases in the literature where TB developed within few weeks of last dose of BCG. KEY WORDS: Bacillus Calmette–Guerin, bladder carcinoma, intravesical therapy, miliary tuberculosis

INTRODUCTION Intravesical immunotherapy with Bacillus Calmette–Guerin (BCG) used for transitional cell carcinoma (TCC) bladder is considered a safe and highly effective treatment modality in superficial bladder tumor.[1] Adverse reactions are rare and usually local, benign, and self‑limited; however, exceptionally, they may be severe. The exact mechanism of such complications is not clear. Mostly, granulomatous inflammation involves multiple organs, but these are negative for acid‑fast bacilli both on special stains as well as culture.[2,3] On search of literature, we came across a few reports of miliary tuberculosis (TB) following BCG therapy.[3‑6] We hereby report a rare case of disseminated TB in bilateral lungs, adrenal, cervical, mediastinal, and para‑aortic lymph nodes, 2 years following cessation of intravesical BCG instillation (which is even rarer) in a patient with recurrent TCC of renal pelvis and urinary bladder.

right radical nephrectomy and ureterectomy. He developed a recurrence in the urinary bladder in 2010. Computed tomography (CT) positron emission tomography (PET) in December 2012 showed hypermetabolic lesions in bladder only. Transurethral resection of bladder tumor (TURBT) was performed, as it was superficial bladder tumor, after 6 weeks six cycles of weekly intravesical BCG instillation was given. Following this, he developed acute BCG cystitis and was managed conservatively. There was no past or family history of TB. He had received BCG vaccine at the time of birth, as per our national immunization program. He remained asymptomatic for 2 years. During this period, he did not have any contact with TB patient. Presently, he was admitted in emergency with acute onset hematuria and passage of clots in urine. He was afebrile, pulse‑ 90/min, and blood pressure ‑ 150/100 mm. Bilateral supraclavicular lymphadenopathy, pedal edema, and pallor present. His abdomen had mild distension with palpable bladder. He had a history of weakness and loss of appetite for last 1.5 month.

Mukta Pujani, Sabina Khan, Sujata Jetley, Prabhat Kumar Raina1 Department of Pathology, 1 Department Surgery, Hamdard Institute of Medical Sciences and Research, New Delhi, India For correspondence: Dr. Sujata Jetley, Professor and Head, Department of Pathology, Hamdard Institute of Medical Sciences and Research (HIMSR), Jamia Hamdard, New Delhi ‑ 110 044, India. E‑mail: drjetley2013@ gmail.com

Access this article online Website: www.cancerjournal.net DOI: 10.4103/0973-1482.151860 PMID: *** Quick Response Code:

CASE REPORT A 66‑year‑old male was diagnosed with TCC of renal pelvis in October, 2008 for which he underwent

Hemoglobin was 8 gm/dl, total leukocyte count of 8,500/mm3 with 72% neutrophils, blood urea 129 mg/dl, serum creatinine 6.8 mg/dl, uric acid

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Pujani, et al.: Disseminated tuberculosis following BCG therapy

9.0 mg/dl, total proteins 6.6 gm/dl, albumin 2.1 gm/dl, and serum calcium 7.6 mg/dl. Chest X‑ray showed a miliary nodular pattern in both lung fields [Figure 1]. Ultrasound scan abdomen showed absent right kidney (post‑surgery), left hydroureteronephrosis, and bladder full of mixed echogenic content (clots). An emergency cystoscopy was performed for clot evacuation with incomplete resection of bladder tumor for left double J (DJ) stenting to relieve ureteric obstruction. Biopsy showed high grade TCC, papillary type with muscle invasion. Noncontrast CT done later showed a large mass lesion in bladder with multiple air foci with perivesical fat streakiness. Bone scan showed increased tracer uptake in multiple dorsal vertebrae and degenerative changes in the skeleton, suspicious of metastasis. Whole‑body CT PET revealed evidence of metabolic active disease involving urinary bladder suggestive of neoplastic pathology. Miliary nodular pattern was noted in both lung fields with splenic F‑18 fluorodeoxyglucose (FDG) uptake more than liver, suggestive of infectious etiology like TB. FDG uptake was also observed in the left adrenal gland and mediastinal and supraclavicular lymph nodes. Patient had systemic features of letharginess and loss of appetite along with palpable supraclavicular lymphadenopathy, which can be present in both advance malignancy and disseminated TB. In view of disseminated disease, fine‑needle aspiration cytology (FNAC) was performed from left supraclavicular lymph nodes which revealed many epithelioid cell granulomas and necrosis. Ziehl–Neelsen (ZN) stain was positive [Figure 2], suggestive of tubercular lymphadenopathy. CT‑guided FNAC was also performed from the lung lesions and tubercular lesions were detected. In view of the deranged renal function, modified dose of antituberculosis therapy (ATT) was started,

Figure 1: Chest X‑ray film showing miliary nodular pattern in both the lung fields

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comprising of rifampicin, isoniazid, and ofloxacin. He was on regular hemodialysis and other supportive treatment. In spite of these, his general condition gradually deteriorated and he expired after 1 month. DISCUSSION BCG was first introduced as an intravesical instillation for nonmuscle, invasive (superficial) bladder cancer by Morales et al., in 1976.[1] BCG is a live, attenuated strain of Mycobacterium bovis and has been reported to be effective in more than 70% of the patients with in situ and stage I disease.[7] Although intravesical BCG therapy is well‑tolerated by most of the patients, a variety of adverse reactions have also been reported. Lamm et al.,[2] studied the frequency of adverse effects in a large subset of patients (2,602) who received BCG immunotherapy. Systemic complications were rarely reported in only 5% of the patients including high fever (> 39°C), hematuria, granulomatous prostatitis, granulomatous pneumonitis, hepatitis, etc. Most of these symptoms are the result of the immune stimulation that is required for effective eradication of cancer cells. The mechanism of action of BCG is based on the role of fibronectin. Live mycobacteria attach to the urothelium, the process being facilitated by fibronectin which is a component of extracellular matrix. BCG–fibronectin–tumor cell interaction also inhibits the tumor cell motility. To prevent BCG‑induced complications, BCG should not be administered till at least 2 weeks after TURBT; as any disruption of the urothelium may propagate the spread of infection. Moreover, BCG therapy should not be used in immunocompromised patients.[2,6]

Figure 2: Cytology smear showing epithelioid cell granuloma (Giemsa, ×400f), inset: Acid fast bacilli (Ziehl–Neelsen (ZN) stain, ×1,000, oil immersion)



Pujani, et al.: Disseminated tuberculosis following BCG therapy

The adverse complications following intravesical BCG instillation can be divided into two groups: Infectious and noninfectious (inflammatory). Noninfectious are more frequently encountered and include abacterial cystitis and dysuria occurring in 80% patients, followed by hematuria in 40%, and low grade fever in 30%.[8] These are usually benign and self‑limiting, but cystitis may facilitate the dissemination of mycobacteria. Systemic complications such as miliary TB is very rare, but is associated with high mortality like in the present case. The mechanism for occurrence of disseminated BCG infection is debatable. One point of view is hematogeneous spread of mycobacteria to distant sites like liver, bone, lung, etc. The presence of epithelioid granulomas in these organs and several reports of positive cultures for M. bovis, support this hypothesis.[4] Another theory favors a hypersensitivity reaction to M. bovis. This was proposed due to inability to demonstrate Mycobacteria on special stains and polymerase chain reaction (PCR) analysis. Moreover, patients respond well when ATT was given in conjunction with steroids. Some authors recommend that if the symptoms of cystitis persist for more than 7 days or if there is clinical deterioration, RIPE therapy (with rifampin, isoniazid, pyridoxine, and ethambutol) and a fluoroquinolone should be administered for a 6–9‑month course along with steroids for 4–6 weeks.[9,10] A variety of tests can be performed to establish the diagnosis like ZN stain, culture, PCR etc.; however, these may not be able to demonstrate the organism in more than half of the cases. In our case, granulomas were detected on cytology and acid‑fast bacilli could be demonstrated on ZN stain. Another peculiar feature in our case was the development of disseminated TB 2 years following BCG therapy. In most of the published reports,[3,5,6,11] the patients developed TB within a short period following BCG instillation. Development of TB after BCG therapy can be early (within 3 months) or late (after 3 months). The late presentation can be accounted for by reactivation of infection after successful control of early dissemination, like in our case. Infection has been documented as late as 3 years following intravesical BCG therapy.[12]

REFERENCES 1. Morales A, Eidinger D, Bruce AW. Intracavitary Bacillus Calmette‑Guérin in the treatment of superficial bladder tumors. J Urol 1976;116:180‑3. 2. Lamm DL, van der Meijden PM, Morales A, Brosman SA, Catalona WJ, Herr HW, et al. Incidence and treatment of complications of bacillus Calmette‑Guérin intravesical therapy in superficial bladder cancer. J Urol 1992;147:596‑600. 3. Manfredi R, Dentale N, Piergentili B, Pultrone C, Brunocilla E. Tubercular disease caused by bacillus of Calmette‑Guerin administered as a local adjuvant treatment of relapsing bladder carcinoma. Pathogenetic, diagnostic and therapeutic issues, and literature review. Archives of Venezuelan pharmacology and therapeutics 2009;28:54‑60. 4. McParland C, Cotton DJ, Gowda KS, Hoeppner VH, Martin WT, Weckworth PF. Miliary Mycobacterium bovis induced by intravesical bacille Calmette‑Guérin immunotherapy. Am Rev Respir Dis 1992;146:1330‑3. 5. Elkabani M, Greene JN, Vincent AL, VanHook S, Sandin RL. Disseminated Mycobacterium bovis after intravesicular bacillus Calmette‑Guérin treatments for bladder cancer. Cancer Control 2000;7:476‑81. 6. Naudžiūnas A, Juškaitė R, Žiaugrytė I, Unikauskas A, Varanauskienė E, Mašanauskienė E. Tuberculosis complications after BCG treatment for urinary bladder cancer. Medicina (Kaunas) 2012;48:563‑5. 7. Schellhammer PF, Ladaga LE, Fillion MB. Bacillus Calmette‑Guérin for superficial transitional cell carcinoma of the bladder. J Urol 1986;135:261‑4. 8. Lockyer W, Gillat DA. BCG immunotherapy for superficial bladder cancer. J R Soc Med 2001;94:119‑23. 9. Kristjansson M, Green P, Manning HL, Slutsky AM, Brecher SM, von Reyn CF, et al. Molecular confirmation of bacillus Calmette‑Guérin as the cause of pulmonary infection following urinary tract instillation. Clin Infect Dis 1993;17:228‑30. 10. To U, Kim J, Chia D. Disseminated BCG: Complications of intravesical bladder cancer treatment. Case Rep Med 2014;2014:362845. 11. Lukacs S, Tschobotko B, Szabo NA, Symes A. Systemic BCG‑Osis as a rare side effect of intravesical BCG treatment for superficial bladder cancer. Case Rep Urol 2013;2013:821526. 12. Gonzalez OY, Musher DM, Brar I, Furgeson S, Boktour MR, Septimus EJ, et al. Spectrum of bacille Calmette‑Gu’erin (BCG) infection after intravesical BCG immunotherapy. Clin Infect Dis 2003;36:140‑8. Cite this article as: Pujani M, Khan S, Jetley S, Raina PK. Disseminated tuberculosis in a patient with recurrent transitional cell carcinoma of renal pelvis and bladder following intravesical BCG therapy: A report of a rare case. J Can Res Ther 2015;11:1028. Source of Support: Nil, Conflict of Interest: None declared.


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