Bladder cancer is the 6th most common cancer in the United States accounting for 2.9% of cancer deaths.(1) Risk factors include exposure to tobacco, aromatic amines, arsenic, and cyclophosphamide, schistosomiasis, family history of bladder cancer, pelvic irradiation, excessive consumption of poultry and pork, and obesity.(2, 3, 4, 5) Of these, tobacco exposure is associated with the highest risk.(6) Incidence of bladder cancer increases with age and the median age of diagnosis is 73 years.(7) Painless hematuria is the most common presenting symptom. Histologically, bladder tumors can be classified as urothelial and non-urothelial. Urothelial cancer also known as transitional cancers are the most common type, accounting for 90% of all bladder cancers.(8) Management options are dependent on the depth of tumor invasion.(8) For muscle invasive tumors, radical cystectomy and chemotherapy is the mainstay. For superficial tumors which includes carcinoma in situ and non-muscle invasive tumors, trans urethral resection of bladder tumor followed by intravesical chemotherapy or BCG are the treatment options.
BCG primarily used as a vaccine for protection against severe and disseminated tuberculosis infection was discovered by bacteriologist-veterinarian duo, Albert Calmette and Camille Guérin. It was found that development of bacterial infections in patients with lymphosarcoma was known to cause disease remission, which resulted in the use of bacterial extracts as adjuvant therapy for head and neck tumors.(9) Further studies showed that patients with active tuberculosis infections were less likely to develop cancer and that cancer survivors had a higher incidence of tuberculosis infection compared to those who succumbed to cancer.(10) Soon studies were published demonstrating the usage of BCG in treatment of systemic lymphoblastic leukemias, primary cutaneous melanomas, and metastatic melanomas.(11, 12) Treatment efficacy was observed to be better with small, localized tumors, and with tumors that had direct contact with BCG. Based on these findings, Morales et al(13) used intravesical BCG as adjuvant therapy for superficial urothelial carcinomas which was a major success. Theories behind its anti-cancer effects are still evolving and the most studied include anti-proliferative and cytotoxic effects on tumor cells.(14, 15)
As with every immunotherapy, use of BCG is associated with side effects. Fever following BCG installation is the most common. Though it is indicative of good immune activation, it may also be the initial sign of sepsis. Allergic reactions include arthralgias, cramps, and rash. Local side effects are noted in majority of patients and result due to direct irritation of the urogenital lining. These include chemical cystitis, bladder contracture, epididymitis, prostate abscess, and urethral strictures.(16, 17, 18) Systemic complications occur due to BCG dissemination and are rare. It can be seen in immunocompromised individuals such as pregnant women, patients with diabetes, hematologic malignancies, or AIDS. Another risk factor associated with dissemination is a breach in the urothelium which promotes hematogenous spread and is commonly seen in the setting of catheterization.(19) Systemic complications include spondylodiscitis, mycotic pseudoaneurysm, pneumonitis, peritonitis, and granulomatous inflammation involving kidneys, prostate, liver, and lymph nodes. (18, 20, 21, 22) However, viable bacteria are not always identified. In such cases, a type 4 hypersensitivity reaction to BCG has been postulated.(23, 24) Granulomatous cardiomyopathy is a rare entity and can be seen in tuberculosis infection. They are known to cause ventricular tachycardia and arrythmias.(25) To our best knowledge, BCG therapy causing cardiac granulomas is extremely rare and has not been reported before.
We present a BCG-treated urothelial cancer patient with postmortem findings of multiple granulomas in the brain, heart, lungs, bladder and kidneys, most likely due to systemic BCG-osis. AFB stain was negative for viable microorganisms favoring the hypersensitivity reaction rather than direct infection. An immunodeficiency state demonstrated by CMV pulmonary infection could have been a predisposing factor. Arrythmias induced by granulomatous myocarditis was the cause of his death. Though there have been few cases of systemic BCG-osis causing fatal sepsis leading to death, a cardiac cause of death from this complication is unique.