PD-1/PD-L1 Inhibitor-Related Cystitis: Clinical Features, Diagnostic Exclusion, and Outcomes in an Eight-Patient Case Series with a Targeted Literature Review

Technical Summary: PD-1/PD-L1 Inhibitor-Related Cystitis

Problem Statement
Immune checkpoint inhibitors (ICIs), specifically those targeting PD-1 and PD-L1, have revolutionized oncology but are associated with immune-related adverse events (irAEs) affecting nearly any organ system. While cutaneous, gastrointestinal, and pulmonary irAEs are well-characterized, urinary tract irAEs, particularly immune checkpoint inhibitor-related cystitis (ICI-RC), remain under-recognized. ICI-RC presents a significant diagnostic challenge because its clinical phenotype—urinary frequency, urgency, dysuria, and sterile pyuria—mimics bacterial cystitis, tumor progression, radiation injury, urolithiasis, and chemotherapy-induced hemorrhagic cystitis. This overlap often leads to misdiagnosis, resulting in unnecessary empirical antibiotic therapy and delayed recognition of the immune-mediated etiology. There is a lack of standardized diagnostic criteria and a limited understanding of the clinical course and management of this rare condition.

Methodology
This study employed a retrospective case series design involving eight patients treated at Wuhu Hospital Affiliated to East China Normal University between 2021 and 2024. All patients had a history of malignancy treated with PD-1/PD-L1 inhibitor-based regimens and subsequently developed new lower urinary tract symptoms.

• Diagnostic Protocol: Diagnosis was approached as a process of exclusion. Patients underwent comprehensive evaluation including symptom assessment, urinalysis, urine culture, inflammatory markers (procalcitonin, blood leukocytes), and contrast-enhanced pelvic computed tomography (CT) or CT urography (CTU). Cystoscopy, urine cytology, and mucosal biopsy were performed when clinically indicated (e.g., hematuria, focal wall thickening, or prior urothelial carcinoma).
• Classification: Cases were stratified into "Definite" or "Probable" ICI-RC based on the strength of evidence. "Definite" required histopathological or cystoscopic confirmation of non-malignant inflammation alongside negative cultures and exclusion of alternatives. "Probable" required compatible symptoms, negative cultures, supportive imaging/urinalysis, and clinical improvement after ICI interruption/steroids, but lacked histopathological confirmation.
• Treatment Strategy: Management involved ICI interruption or discontinuation followed by corticosteroid therapy. The observed regimen utilized intravenous methylprednisolone (initially 120 mg/day, tapered to 80 mg/day) followed by oral dexamethasone.
• Literature Review: A targeted search of PubMed, Web of Science, and Google Scholar was conducted to contextualize the findings with existing original reports of PD-1/PD-L1 inhibitor-related cystitis or ureteritis.

Key Results

• Cohort Demographics: The cohort consisted of seven men and one woman with a median age of 65 years. Primary malignancies included lung cancer (4 patients), bladder, esophageal, breast, and gastric cancers.
• Clinical Presentation: All patients presented with urinary frequency, urgency, and dysuria without fever. The median time from ICI initiation to symptom onset was 5 months (range: 2–36 months).
• Diagnostic Findings: Urine cultures were negative in all cases, and procalcitonin levels were normal, ruling out bacterial infection. Seven patients exhibited leukocyturia. Contrast-enhanced imaging revealed inflammatory bladder changes in all patients.
• Classification: One patient (Patient 1) met the criteria for Definite ICI-RC based on cytological, cystoscopic, and histopathological confirmation (showing inflammation without malignancy). The remaining seven patients were classified as Probable ICI-RC.
• Outcomes: All patients underwent ICI interruption/discontinuation and received corticosteroids. This led to the improvement of urinary symptoms and the disappearance or marked reduction of leukocyturia in follow-up analyses. No patient required cystectomy, long-term bladder drainage, transfusion, or bladder irrigation.
• Data Limitations: The study noted that exact CTCAE grades, precise time to symptom relief, steroid taper durations, and rechallenge outcomes were not uniformly documented across the cohort.

Contributions and Significance
The paper claims to provide a detailed clinical phenotype and diagnostic exclusion process for PD-1/PD-L1 inhibitor-related cystitis, filling a gap in the literature regarding this rare urinary irAE. Its primary contributions include:

1. Diagnostic Framework: It outlines a rigorous exclusion-based diagnostic approach, emphasizing the necessity of ruling out infection, malignancy, radiation injury, stones, tuberculosis, and chemotherapy toxicity before attributing symptoms to ICI-RC.
2. Clinical Phenotype Characterization: It reinforces that ICI-RC typically presents as sterile pyuria with inflammatory imaging findings, distinct from bacterial cystitis, and can occur at any time during treatment (up to 36 months post-initiation).
3. Management Evidence: The case series supports the efficacy of ICI interruption and corticosteroid therapy in resolving symptoms and reducing leukocyturia, while noting that the specific steroid dosing used reflects local practice rather than a universally validated standard.
4. Contextualization: By integrating a targeted literature review, the authors situate their findings within the broader spectrum of reported cases, including those involving ureteritis and renal involvement.

Modesty and Limitations
The authors explicitly state that the proposed diagnostic approach and treatment regimen should be interpreted as preliminary. They acknowledge that the study is a small, single-center retrospective series with a limited sample size (n=8), which restricts generalizability and prevents formal risk-factor analysis or comparative efficacy studies. Furthermore, the lack of standardized prospective data collection (e.g., CTCAE grading, recurrence monitoring) means the study cannot reliably estimate recurrence risks or the safety of ICI rechallenge. The authors conclude that while their findings suggest a management pathway, larger multicenter studies are required to validate diagnostic criteria, treatment strategies, and long-term outcomes.