==== Front IJU Case Rep IJU Case Rep 10.1002/(ISSN)2577-171X IJU5 IJU Case Reports 2577-171X John Wiley and Sons Inc. Hoboken 10.1002/iju5.12588 IJU512588 IJUCR-2023-0006.R1 Case Report Case Reports Successful treatment of immune‐related cystitis with bladder hydrodistension Hydrodistension for immune‐related cystitis T Anraku et al. Anraku Tsutomu https://orcid.org/0000-0002-2128-7886 1 3 chin2jp@yahoo.co.jp Hashidate Hideki 2 Imai Tomoyuki 1 Kawakami Yoshiaki 1 1 Department of Urology Niigata City General Hospital Niigata Japan 2 Department of Pathology Niigata City General Hospital Niigata Japan 3 Present address: Department of Urology, Molecular Oncology Niigata University Asahimachi‐dori 1‐757, Chuo‐ku Niigata City Niigata 951‐8510 Japan * Correspondence: Tsutomu Anraku, Niigata City General Hospital, 463‐7 shumoku, Chuo‐ku, Niigata‐City, Niigata, Japan. Email: chin2jp@yahoo.co.jp 03 4 2023 7 2023 6 4 10.1002/iju5.v6.4 211215 19 1 2023 19 3 2023 © 2023 The Authors. IJU Case Reports published by John Wiley & Sons Australia, Ltd on behalf of Japanese Urological Association. https://creativecommons.org/licenses/by/4.0/ This is an open access article under the terms of the http://creativecommons.org/licenses/by/4.0/ License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited. Introduction Although immune checkpoint inhibitors offer significant therapeutic benefits to patients with advanced cancer, they can also cause a variety of immune‐related adverse events. As immune checkpoint inhibitors are being widely used, rare immune‐related adverse events are being reported. Case presentation A 70‐year‐old man with advanced salivary duct carcinoma was treated with pembrolizumab following radiotherapy. After receiving two doses of pembrolizumab, the patient experienced symptoms such as micturition pain and hematuria. Immune‐related cystitis was suspected, and the patient underwent a bladder biopsy and bladder hydrodistension. Histological analysis revealed non‐neoplastic bladder mucosa with CD8‐positive lymphocyte‐dominant inflammatory cell infiltration, consistent with immune‐related cystitis. The patient's bladder symptoms improved postoperatively without steroid administration. Conclusion Although steroids are commonly administered to treat immune‐related adverse events, bladder hydrodistension may be a promising treatment option for immune‐related cystitis to avoid administration of steroids, which may impair the therapeutic effect of immune checkpoint inhibitors. hydrodistension immune checkpoint inhibitor immune‐related cystitis interstitial cystitis steroid source-schema-version-number2.0 cover-dateJuly 2023 details-of-publishers-convertorConverter:WILEY_ML3GV2_TO_JATSPMC version:6.3.0 mode:remove_FC converted:02.07.2023 ==== Body pmc Keynote message Immune‐related cystitis is a rare irAE. It is often successfully treated with steroids, but bladder hydrodistension may also be helpful. It may be worth trying bladder hydrodistension for immune‐related cystitis to avoid the side effects of steroids. Abbreviations & Acronyms BPS bladder pain syndrome CR complete response CT computed tomography HPF high power field IC interstitial cystitis ICI immune checkpoint inhibitor irAE immune‐related adverse event MP methylprednisolone N/A not available PD progressive disease PR partial response PSL prednisolone SD stable disease TIA‐1 T‐cell intracellular antigen 1 Introduction ICIs have revolutionized cancer treatment and have become an integral part of the standard of care for many cancers. However, ICIs often trigger side effects due to autoimmune mechanisms, which are referred to as irAEs. IrAEs can affect many organs throughout the body, and the probability of developing irAEs ranged from 54% to 76% in a meta‐analysis. 1 Meanwhile, irAEs rarely affect the bladder, and only 12 cases of immune‐related cystitis have been reported so far. 2 , 3 , 4 , 5 , 6 , 7 , 8 , 9 , 10 , 11 , 12 Steroids are recommended for the treatment of irAEs according to the guidelines, 13 and most cases of immune‐related cystitis are also treated with steroids. However, whether steroids impair the therapeutic effect of ICIs remains controversial. 14 Previously, a case of immune‐related cystitis in which bladder symptoms improved after bladder biopsy was reported. 5 In that report, the authors noted that unintentional bladder hydrodistension during the biopsy might have contributed to the improvement in bladder symptoms. Herein, we describe a case of immune‐related cystitis that was successfully treated with bladder hydrodistension. Case presentation A 70‐year‐old man with a history of hypertension, but not on oral medication, was diagnosed with salivary duct carcinoma (T4bN0M0, stage IVB). The patient received 70 Gy of radiotherapy, followed by immunotherapy with pembrolizumab at a dose of 200 mg every 3 weeks. Two weeks after the second administration of pembrolizumab, the patient developed fatigue, micturition pain, urinary frequency, and gross hematuria. CT revealed a thickened bladder wall and strongly enhanced bladder mucosa (Fig. 1), and cystoscopy revealed diffuse mucosal edema and bladder redness. Urinalysis revealed a red blood cell count of >100/HPF and a white blood cell count of 20–29/HPF. No causative bacteria were detected in the urine cultures, and the urine cytology was negative. Despite the discontinuation of pembrolizumab and administration of antibiotics and anticholinergic drugs, the urinary tract pain worsened to grade 3 based on the Common Terminology Criteria for Adverse Events v5.0. He urinated more than 30 times a day and his functional bladder capacity was less than 50 milliliters. Bladder biopsy and bladder hydrodistension under spinal anesthesia were performed approximately 2 months after the onset of the symptoms. Before the biopsy, the bladder was distended three times with saline at a pressure of 80 cm H2O for 3 min. The maximum bladder capacities during the distensions were 120, 140, and 140 mL. Mucosal bleeding in the posterior wall of the bladder was observed after the first distension (Video S1). Histological analysis showed non‐neoplastic bladder mucosa with epithelial detachment, interstitial edema, vascular hyperplasia, and inflammatory cell infiltration (Fig. 2). Immunohistochemical analysis revealed the infiltrated inflammatory cells to be positive for CD3 and CD8, partially positive for CD4 and CD20, indicating that cytotoxic T cells were predominant (Fig. 3). Based on the clinical course, we diagnosed immune‐related cystitis and considered the administration of steroids. However, the patient's symptoms were alleviated when the urethral catheter was removed on the second day after the endoscopic surgery. CT performed a month after surgery showed mild shrinkage of the parotid tumor. The patient underwent a repeat needle biopsy of the tumor, and no viable cancer cells were observed in the histopathological analysis. He has been monitored carefully, and there has been no recurrence of cancer or bladder symptoms 11 months after surgery. Fig. 1 Pelvic imaging with contrast‐enhanced CT. The bladder wall is thickened with contrast enhancement of the mucosa (arrowhead). Fig. 2 Hematoxylin and eosin staining of the bladder tissue. Non‐neoplastic bladder mucosa with epithelial detachment, interstitial edema, vascular hyperplasia, and inflammatory cell infiltration is observed in a hematoxylin–eosin‐stained specimen of the bladder. Scale bar indicates 200 μm. Fig. 3 Immunohistochemical results in the bladder tissue. (a) CD3; (b) CD4; (c) CD8; (d) CD20. Scale bar indicates 200 μm. Discussion The applications of ICIs have expanded to various cancers. As the use of ICI increases, there will be more opportunities to experience various irAEs. Therefore, familiarity with irAE management is crucial for clinical oncologists. Common irAEs include endocrine, gastrointestinal, lung, skin, and musculoskeletal disorders. It has been reported that the frequency or breakdown of irAEs varies according to the ICI class, cancer type, and race. 15 , 16 Immune‐related cystitis is a rare irAE, which has been reported in only 13 cases so far, including the current case (Table 1). Most of them have been reported in Asia, 2 , 3 , 4 , 5 , 6 , 7 , 8 , 10 , 11 , 12 suggesting that immune‐related cystitis may be more common among Asians. Table 1 Clinical information on the reported cases of immune‐related cystitis Authors Age Sex Country Symptoms Primary cancer ICIs ICI cycle Best response Treatment for immune‐related cystitis ICI discontinuation ICI rechallenge Pathological findings Ozaki et al. 2 62 M Japan Urinary frequency, micturition pain, macroscopic hematuria Lung cancer Nivolumab 3 PD MP 500 mg × 3 days, followed by PSL 0.5 mg/kg and tapered Yes Nivolumab with PSL Epithelial detachment, interstitial edema, slight lymphocytic infiltration Shimatani et al. 3 50 M Japan Urinary frequency, micturition pain Lung cancer Nivolumab 7 PD PSL 1 mg/kg/day Yes Nivolumab N/A Shimatani et al. 3 60 M Japan Urinary frequency, dysuria Lung cancer Nivolumab 12 SD ICI discontinuation Yes Nivolumab N/A Ueki et al. 4 78 F Japan Urinary frequency, micturition pain Lung cancer Pembrolizumab 6 PR PSL 0.5 mg/kg/day Yes No Infiltration of CD8+ and/or TIA‐1+ lymphocytes, PD‐L1+ urothelium Yajima et al. 5 47 M Japan Urinary frequency, micturition pain Lung cancer Nivolumab 18 PR Bladder biopsy No N/A Eosinophil‐ and plasma cell‐dominant infiltration Tu et al. 6 53 M China Urinary frequency, micturition pain, macroscopic hematuria Lung cancer Sintilimab 3 PR MP 1 mg/kg/day Yes No Lymphocyte‐dominant inflammation, interstitial tissue hyperplasia Zhu et al. 7 51 M China Urinary frequency, urgency, dysuria Lung cancer Nivolumab 5 CR MP 160 mg/day Yes No Infiltration of CD3+ and CD8+ lymphocytes Zhu et al. 8 48 M China Urinary tract irritation Intrahepatic cholangiocarcinoma Nivolumab 3 PD Steroid hormones Yes Atezolizumab Chronic inflammation, mucosal erosion, proliferation of granulation tissues and fibroblasts Schneider et al. 9 61 F France Urinary frequency, bladder pain, urgency, diarrhea Melanoma (i) Pembrolizumab (ii) Ipilimumab and nivolumab (iii) Nivolumab (i) 2 (ii) 2 (iii) 4 PR PSL 0.5 mg/kg/day Yes No Regular epithelial layer with lymphocyte infiltration in intraepithelial and subepithelial connective tissue with lymphoid follicle Wang et al. 10 56 M China Urinary frequency, micturition pain, urinary incontinence Gastric cancer Sintilimab 5 CR Chai‐Ling‐Tang (Sairei‐To) No N/A Numerous infiltration of CD3+ and CD8+ cells into the urothelium, PD‐L1+ urothelium and subepithelial inflammatory cells Obayashi et al. 11 67 F Japan Urinary frequency, urinary tract pain Breast cancer Atezolizumab 4 PR PSL 60 mg/body Yes N/A Infiltration of CD8+ and/or TIA‐1+ lymphocytes, PD‐L1+ urothelium Fukunaga et al. 12 60 M Japan Penile pain, micturition pain Lung cancer Nivolumab 77 CR MP 1 mg/kg/day Infliximab 5 mg/kg Yes No N/A Anraku et al. [present case] 70 M Japan Urinary frequency, micturition pain, macroscopic hematuria Salivary duct carcinoma Pembrolizumab 2 SD Hydrodistension Yes No CD3+ and CD8+ lymphocyte‐dominant infiltration, epithelial detachment, interstitial edema, vascular hyperplasia In the current study, histopathology of the bladder showed CD8‐positive lymphocyte‐dominant infiltration, similar to previously reported cases of immune‐related cystitis. 4 , 7 This finding suggests that some antigens in the bladder are attacked by the immune system, which is consistent with immune‐related cystitis. In another case, an allergic mechanism was considered because eosinophil and plasma cell‐dominant infiltration was observed in the bladder histopathology. 5 Although the precise mechanism of immune‐related cystitis remains unknown, steroids are most commonly administered as an effective treatment, similar to that for other irAEs. However, it may be better if irAEs can be treated without steroids, mainly for two reasons. First, there is concern that steroids may impair the anti‐tumor activity of ICIs owing to their immunosuppressive effects. 17 Second, steroids induce side effects, such as hyperglycemia, hypertension, gastroduodenal ulcers, and infection. Based on the case report by Yajima et al., in which the potential effectiveness of bladder hydrodistension for immune‐related cystitis was mentioned, we successfully treated the current case with bladder hydrodistension and avoided steroid administration. Although the precise mechanism of bladder hydrodistension remains unclear, one possible cause is that ischemia due to increased bladder wall tension leads to the degeneration of sensory nerve fibers. 18 Bladder hydrodistension is usually performed to treat IC/BPS. IC/BPS presents with chronic bladder symptoms in the absence of confusable diseases. 19 It is divided into Hunner‐type IC and BPS, the former characterized by Hunner lesions and inflammation of the bladder mucosa and the latter having neither of these features. Although no Hunner lesion was observed in cystoscopy in the current case, the clinical course and histological findings were similar to those of Hunner‐type IC, which is associated with autoimmune mechanisms in some cases. Furthermore, many animal models of autoimmune cystitis have been reported to mimic Hunner‐type IC. 20 The efficacy of bladder hydrodistension usually lasts for only a few months. 19 Careful follow‐up is required in the current case. In conclusion, we present a case of immune‐related cystitis successfully treated with bladder hydrodistension. Although steroids are effective in the treatment of irAEs, bladder hydrodistension may be a promising treatment option for immune‐related cystitis. Further studies are required to elucidate the pathophysiology and management of this disease. Author contributions Tsutomu Anraku: Conceptualization; writing – original draft. Hideki Hashidate: Investigation; supervision; validation. Tomoyuki Imai: Supervision. Yoshiaki Kawakami: Supervision. Conflict of interest The authors declare no conflict of interest. Approval of the research protocol by an Institutional Reviewer Board Not applicable. Informed consent Written informed consent was obtained from the patient for the publication of this case report. Registry and the Registration No. of the study/trial Not applicable. Supporting information Video S1. Video of the bladder hydrodistension. The bladder was distended three times at a pressure of 80 cm H2O for 3 min. Mucosal bleeding in the posterior wall of the bladder was observed after the first distension. Click here for additional data file. ==== Refs References 1 Xu C , Chen YP , Du XJ et al. 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