Pembrolizumab-Associated Immune-Related Cystitis Mimicking Urothelial Malignancy as Part of a Multi-organ Immune-Related Adverse Event (irAE) Phenotype in a Patient With Metastatic Squamous Cell Lung Cancer: A Case Report and Literature Review.

Immune checkpoint inhibitors (ICIs) have revolutionized the treatment of metastatic non-small-cell lung cancer (NSCLC) but can cause a broad spectrum of immune-related adverse events (irAEs) affecting multiple organ systems. Although common irAEs are well characterized, immune-related cystitis is rare and may pose a significant diagnostic challenge, particularly when urine cytology demonstrates atypical urothelial cells that mimic high-grade urothelial carcinoma. We present the case of a 55-year-old man with metastatic squamous cell carcinoma of the lung who developed hematuria and non-bacterial cystitis during pembrolizumab therapy in the setting of multiple other irAEs, including hypophysitis resulting in secondary adrenal insufficiency and hypothyroidism. Following the onset of hematuria, computed tomography (CT) of the abdomen and pelvis demonstrated an acute cystitis picture. Importantly, there was no evidence of urinary calculi or progression of pelvic metastatic disease to otherwise explain his symptoms. Urine cytology subsequently showed marked urothelial atypia concerning for high-grade urothelial carcinoma, creating a significant diagnostic dilemma. Cystoscopic evaluation, however, revealed a normal bladder mucosa without erythema, lesions, or findings suggestive of carcinoma in situ; no biopsy was performed. The absence of an identifiable urothelial malignancy or bacterial infection, together with the temporal association with pembrolizumab and the patient's concurrent multisystem irAEs, supported an immune-related etiology. This case highlights the potential for ICI-associated cystitis to produce cytologic atypia that closely mimics high-grade urothelial carcinoma and underscores the importance of integrating cytomorphologic findings with clinical history, radiologic and cystoscopic findings, microbiologic studies, and treatment history to avoid misdiagnosis. Recognition of this rare irAE is essential for appropriate management and prevention of unnecessary interventions.