Bladder Rupture After Chronic Hemorrhagic Cystitis in a Stem Cell Transplantation Recipient

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A 45-year-old female patient was diagnosed with acute myeloid leukemia (defined as high-risk erythroleukemia, French-American-British classification M6a). She underwent stem cell transplantation soon after her first remission. She had a history of systemic lupus erythematosus with onset at 17 years. She had been treated with cyclophosphamide at 50 mg/d for 13 years because of exacerbation of systemic lupus erythematosus. A bone marrow transplantation was performed with a conventional regimen using a human leukocyte antigen-matched unrelated donor. The posttransplantation course was stable, and graft-versus-host disease (GVHD) was not observed.
On day 207 after transplantation, she complained of hematuria during outpatient clinic care. BK viral DNA was detected in her urine, and she was consequently diagnosed with BK virus hemorrhagic cystitis. On days 200 to 290, she was treated with oral prednisolone at 15 to 25 mg/d for her chronic skin GVHD symptoms. We treated her hematuria supportively; however, chronic cystitis continued. On day 291, she was admitted to Kagawa University hospital because of incontinence after a protracted hematuria episode continuing for 3 months. After admission, her hematuria progressed to grossly bloody urine; thereafter, a urinary catheter was placed. The patient received intravenous immunoglobulin therapy (10 g). Continuous vesicoclysis prevented urinary tract obstruction with coagula; however, on day 298, the patient complained of acute abdominal pain. The patient's computed tomography revealed bladder rupture (Figure 1A) presenting with peritonitis. The patient underwent emergent cystectomy with total hysterectomy. The surgery was successful, and bilateral ureterostomy sustained her renal function. Pathological study of the resected bladder indicated transmural degeneration of smooth muscle cells in the bladder wall with lymphocyte infiltration (Figure 1B). No inclusion bodies were found in the histopathological samples. Pathological diagnosis for BK virus staining was negative. However, BKV PCR was positive in the patient's urine sample just before bladder rupture and resected bladder mucosa.
Bladder perforation resulting from chronic cystitis after stem cell transplantation is a rare but lethal event. Contributing risk factors for hemorrhagic cystitis are adenovirus infection,1 GVHD,2 cyclophosphamide preconditioning, and transplantation-related microangiopathy.3 However, a recent review suggested that reactivation of the BK virus plays a major role in hemorrhagic cystitis after engraftment.4 One of the pivotal large cohort studies reported more than 90% contribution of BK virus to hemorrhagic cystitis.5 Almost all cases of hemorrhagic cystitis were resolved by supportive therapy, including bladder irrigation.6 Detailed case reports, such as ours, with pathological evidence, are quite rare. Although pathological detection of the BK virus was negative in the patient's resected tissue, we realized that BK virus hemorrhagic cystitis could trigger bladder membranous layer destruction and degeneration. We assumed that bladder perforation is an end-stage complication after chronic hemorrhagic cystitis, where the BK virus has been eliminated. We speculated that prolonged chronic cystitis after stem cell transplantation (in this case for more than 3 months) caused fibrosis into the bladder wall and was one of the risk factors for bladder rupture.
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