Immune Checkpoint Inhibitor–Induced Ureteritis and Cystitis in Patients With Lung Cancer and Uterine Malignancies: A Case Series and Literature Review

Abstract

Immune checkpoint inhibitors (ICIs) have demonstrated significant efficacy across various cancers but can cause immune-related adverse events (irAEs). While common irAEs such as dermatitis, pneumonitis, and colitis are well-documented, rare events like cystitis and ureteritis remain underrecognized. We report 3 cases of ICI-induced cystitis and ureteritis. The first case involves a 67-year-old female with lung cancer who developed immune-related cystitis and ureteritis after 3 cycles of pembrolizumab, with recurrence 8 months after discontinuation. Both episodes presented with hematuria, urinary frequency, and dysuria, and were responsive to corticosteroid treatment. The second case involves a 37-year-old female with cervical cancer who developed a truncal rash, hematuria, urinary frequency, and dysuria after the first cycle of cadonilimab, a PD-1/CTLA-4 bispecific antibody. Her condition worsened with rising serum creatinine levels. Imaging revealed bladder wall thickening and ureteral dilation. Partial symptom relief followed oral corticosteroids, but complete resolution was achieved with intravesical corticosteroid irrigation. The third case describes a 35-year-old female with endometrial cancer who presented with similar urinary symptoms and flank pain after 4 cycles of pembrolizumab. Rapid creatinine elevation necessitated ureteral stent placement, which failed to alleviate symptoms. After exclusion of infectious etiologies, immune-related cystitis/ureteritis was diagnosed. Symptoms resolved with intravenous corticosteroids. This report underscores the importance of early recognition and management of rare urinary irAEs to avoid unnecessary interventions and prolonged interruption of anti-tumor therapy. It also highlights intravesical methylprednisolone as a potential treatment modality that warrants further investigation.

Immune checkpoint inhibitors (ICIs), including cytotoxic T-lymphocyte–associated protein 4 (CTLA-4) inhibitors, programmed cell death protein 1 (PD-1) inhibitors, and programmed death ligand 1 (PD-L1) inhibitors, have revolutionized cancer therapy. Recently, novel bispecific antibodies, such as cadonilimab,¹ which targets both PD-1 and CTLA-4, have shown promising results. The indications for these agents are rapidly expanding across various malignancies and treatment settings, offering new therapeutic options for patients.² However, the use of ICIs has been accompanied by the emergence of immune-related adverse events (irAEs), which are often distinct from traditional chemotherapy-related toxicities and can affect virtually any organ system.³ As the use of ICIs becomes more widespread, clinicians are increasingly encountering not only common but also rare irAEs. The spectrum of organ systems affected by irAEs is very broad; toxicities can affect almost any organ, with varying frequencies and severities. Although any organ system can be affected, immune-related adverse events most commonly involve the gastrointestinal tract, endocrine glands, skin, and liver. Less often, the central nervous system and cardiovascular, pulmonary, musculoskeletal, and hematologic systems are involved. The previous events were well-documented. This report focuses on 3 rare cases of ICI-induced cystitis and ureteritis and includes a comprehensive literature review (Table 1) to enhance understanding of this rare irAE. The importance of early recognition and glucocorticoid-based interventions for mitigating urinary tract damage is emphasized.

TABLE 1.

Cases of Immune Checkpoint Inhibitor-Related Cystitis/Ureteritis

Patient ID	Age	Sex	Primary cancer	Country	ICIs	ICI cycle	Symptoms	Type of irAE	Grade*	Histopathologic findings	Treatment	Outcome	Reference
1	47	M	NSCLC	Japan	Nivolumab	18	Pollakiuria, dysuria	Cystitis	2	Hemorrhages; allergy-related cystitis	Bladder hydrodistension	Improved	4
2	61	F	Melanoma	France	Ipilimumab, nivolumab	6	Diarrhea, pollakiuria, urgency, nocturia	Cystitis	3	Hyperemia, edema, lymphocyte cell infiltration	Oral PSL 0.5 mg/kg/d	Improved	5
3	70	M	SDC	Japan	Pembrolizumab	2	Dysuria, hematuria	Cystitis	3	Mucosal bleeding, CD8+ lymphocyte infiltration	Bladder hydrodistension	Improved	6
4	78	F	NSCLC	Japan	Pembrolizumab	6	Pollakiuria, nocturia, dysuria	Cystitis	NA	Hyperemia, edema, CD8+/TIA-1+ lymphocytes infiltration, PD-L1+	PSL 25 mg/d, tapered over 8 wk	Improved	7
5	48	M	ICC	China	Nivolumab1, atezolizumab2	3, 3	Urinary tract irritation	cystitis	NA	Chronic inflammation	Steroid hormones 2 mg/kg/d	Improved	8
6	62	M	NSCLC	Japan	Nivolumab	3	Diarrhea, dysuria, pollakiuria, hematuria	Cystitis	3	Hyperemia, bleeding, mucosal epithelium sloughed off, slight lymphocytic infiltration	MP 500 mg/d*3d, switched to PSL 0.5 mg/kg/d	Improved	9
7	49	M	Esophageal carcinoma	China	Tislelizumab	6	Gross hematuria, pollakiuria, dysuria, low back pain	Cystitis, ureteritis	NA	Hyperemia, Bladder urothelial damage, granulation tissue, immune cell infiltration	Bilateral ureteral stenting, MP 60 mg/d (equivalent Pred 1.5 mg/kg/d)	Improved	10
8	62	F	GC	China	Sintilimab	3	Urinary irritation	Cystitis, ureteritis	NA	NA	MP 60 mg/d, tapered over 3 mo	Improved	10
9	49	M	GC	China	Nivolumab	2	Hematuria, pollakiuria, dysuria, fever	Cystitis, ureteritis	NA	NA	MP 60 mg/d (equivalent Pred 1.7 mg/kg/d)	Improved	10
10	53	M	NSCLC	China	Sintilimab	3	Hematuria, pollakiuria, dysuria, low back pain	Cystitis, ureteritis	3	Hyperemia, lymphocyted inflammation interstitial hyperplasia	MP 80 mg/d, tapered over 8 wk	Improved	11
11	67	F	Breast cancer	Japan	Atezolizumab	4	Dysuria, urgency	Cystitis	2-3	Hyperemia, PD-L1+. CD8+ and/or TIA-1+lymphocytes infiltration	PSL 40 mg/d (equivalent 1 mg/kg/d)	Improved, but died due to pneumonia	12
12	60	M	Lung cancer	Japan	Nivolumab	77	Glans penile pain, dysuria	Cystitis	NA	NA	MP 60 mg/d, infliximab 5 mg/kg	Improved	13
13	51	M	SCLC	China	Nivolumab	5	Pollakiuria, urgency, dysuria	Cystitis	NA	Hyperemia, edema, CD8+ lymphocytes infiltration	MP 80 mg twice daily, tapered over 6 wk	Improved, but died due to cancer progression	14
14	58	M	ICC	China	Pembrolizumab, toripalimab	2	Pollakiuria, urgency, dysuria, gross hematuria	Cystitis	NA	Hyperemia, active and chronic inflammation	MP 120 mg/d*5d→80 mg/d*3d	Improved	15
15	56	M	SCLC	China	Pembrolizumab	6	Pollakiuria, urgency, dysuria	Cystitis	NA	Hyperemia, CD8+/TIA-1+ lymphocytes, and many neutrophil infiltrations	MP 40 mg	Improved	16
16	56	M	GC	China	Sintilimab	5	Pollakiuria, dysuria, urinary incontinence	Cystitis	2	Hyperemia, edema, CD8+ lymphocytes infiltration, PD-L1 strongly expressed	Chai-Ling-Tang	Improved	17
17	27	M	Thymic carcinoma	China	Tislelizumab	6	Bellyache, paroxysmal lumbago	Cystitis, ureteritis	NA	NA	MP 1 mg/kg/d, tapered over 5 wk	Improved	18

^*Grade is according to Common Terminology Criteria for Adverse Events (CTCAE) v5.0.

GC indicates gastric carcinoma; ICC, intrahepatic cholangiocarcinoma; MP, methylprednisolone; NA, not applicable; NSCLC, non-small cell lung cancer; PSL, prednisolone; SCLC, small cell lung cancer; SDC, salivary duct carcinoma; TIA-1, T-cell intracellular antigen 1.

CASE 1

A 67-year-old female was diagnosed with lung adenocarcinoma with brain metastasis in January 2022 at Peking Union Medical College Hospital, harboring an EGFR 19del mutation. Additional findings included ATM, RB1, and TP53 positivity, a TMB of 8.6 Muts/Mb, and PD-L1 negativity. She received first-line treatment with osimertinib, achieving partial response (PR) in both pulmonary and intracranial lesions. In September 2022, progression was noted in the pulmonary lesions with new bone metastasis, prompting a switch to second-line treatment with osimertinib, pemetrexed, and carboplatin. After 4 cycles, she transitioned to pembrolizumab plus pemetrexed as maintenance therapy. Intracranial lesions showed complete response (CR), but the pulmonary lesions continued to progress.

In March 2023, the patient started third-line therapy with anlotinib and pembrolizumab. Four days after treatment initiation (and following a cumulative total of 3 pembrolizumab cycles), she developed hematuria, dysuria, and urinary frequency. Urinalysis revealed elevated white and red blood cells, while repeated urine cultures remained negative. Her serum creatinine also increased to 153 μmol/L. Computed tomography (CT) imaging showed mild dilation of the upper segments of both ureters. Although empirical antibiotics temporarily reduced urinary leukocytes, her symptoms recurred. Immune-related cystitis and ureteritis were suspected, and cystoscopy was recommended for further evaluation; however, the patient declined due to fear of discomfort. Two weeks after symptom onset, she was started on oral prednisone at 40 mg daily, and anti-tumor therapy was discontinued. As symptoms improved only gradually, the prednisone dose was increased to 80 mg daily, leading to rapid resolution of symptoms. Steroids were then tapered over a 12-week course. After symptom resolution, urinalysis showed normalized leukocyte levels but persistent hematuria (red blood cells: 700 cells/μL). Her serum creatinine also returned to normal, decreasing to 73 μmol/L. Due to concerns that anlotinib might increase the risk of bleeding, both anlotinib and pembrolizumab were permanently discontinued, and osimertinib was resumed. Despite clinical improvement, follow-up CT after steroid withdrawal still revealed bilateral upper ureteral dilation with wall thickening.

In July 2023, the patient exhibited rapid progression of the pulmonary lesions, with biopsy confirming pathologic transformation to small cell lung cancer (SCLC), accompanied by multiple metastases to the liver, adrenal glands, and bones. Fourth-line chemotherapy with etoposide and carboplatin was initiated while continuing osimertinib. On November 8, she developed fever, abdominal distension, and decreased urine output. Urinalysis revealed elevated white blood cells (70 cells/μL), red blood cells (200 cells/μL), and proteinuria (≥3 g/L) despite negative urine cultures, with symptom improvement following ertapenem. Palliative radiotherapy to the L4 vertebra and right ischial bone metastases was administered on November 11 for pain relief, but within 24 hours, she developed gross hematuria (“wash meat” appearance) with worsened urinary frequency, urgency, and a rise in serum creatinine to 113 μmol/L. Repeat urinalysis showed marked elevations in red blood cells (peaking at 20,646 cells/μL) and white blood cells (up to 85 cells/μL), despite adequate antimicrobial therapy. Given the location and dose of radiotherapy, radiation-induced cystitis/urititis was considered unlikely. A diagnosis of recurrent immune-related cystitis/urititis was made, potentially triggered by radiotherapy and infection. Eighteen days after symptom onset, she was treated with intravenous methylprednisolone 40 mg daily, resulting in significant improvement in hematuria and normalization in serum creatinine. Urinary red blood cell counts decreased from 20,646 to 2410 cells/μL, and leukocytes returned to negative. After 12 days, therapy was transitioned to oral prednisone 40 mg daily, tapered by 10 mg weekly over 6 weeks. Unfortunately, the patient succumbed to tumor progression 2 months later. Her clinical course is illustrated in Figure 1.

FIGURE 1.

Clinical course of case 1. A 67-year-old female was diagnosed with lung cancer in January 2022. First-line treatment led to shrinkage of pulmonary (A and B) and brain lesions (L and M). Disease progressed in October 2022, and second-line therapy was initiated (C and D). Further progression occurred in March 2023, prompting third-line treatment (E and F), during which immune-related cystitis/ureteritis first developed. In July 2023, pathologic transformation to small cell lung cancer was observed, and fourth-line therapy was started (G and H). Recurrence of immune-related cystitis/ureteritis occurred following urinary tract infection and radiotherapy to bone metastases (N). Disease progression continued in January 2024 (I–K), and the patient passed away. Pem indicates pemetrexed; Carbo, carboplatin; OSI, osimertinib; Pembro, pembrolizumab; VP-16, etoposide.

CASE 2

A 37-year-old female presented with contact bleeding on May 18, 2024, and was subsequently diagnosed with stage IIIC cervical cancer at Peking Union Medical College Hospital. Concurrent chemoradiotherapy was initiated on June 6, 2024, consisting of external beam radiation therapy (EBRT) and weekly cisplatin (60 mg/m²) as a radiosensitizer. Cadonilimab was introduced 3 weeks after the start of treatment. Four days after the first infusion, the patient developed pruritus followed by a rapidly spreading rash on the trunk (Fig. 2A). By day 7 after infusion, she experienced urinary irritation symptoms, including urinary frequency, dysuria, hematuria, and lower abdominal pain. An immune-related rash was suspected, and oral prednisone (40 mg daily) was prescribed, leading to rapid resolution of the rash. However, the patient discontinued corticosteroids after 5 days without medical consultation, and her urinary symptoms worsened thereafter.

FIGURE 2.

Clinical course of case 2. A, Immune-related dermatitis with trunk-distributed rash. B, Imaging findings of the bladder and kidney. Day 0 (D0) indicates the onset of symptoms of immune-related cystitis/ureteritis. Red arrows highlight abnormal findings: bladder wall thickening and hydronephrosis. C, Therapy and clinical findings of case 2. CT indicates computed tomography; MRI, magnetic resonance imaging; sCr, serum creatinine.

On day 3 of urinary symptoms, ultrasonography showed normal kidney, ureter, and bladder structures, but urinalysis revealed elevated white blood cells (70–125 cells/μL), red blood cells (200 cells/μL), and proteinuria (3 g/L). Repeated urine cultures were largely negative except for a single positive result for Gardnerella vaginalis. Antibiotic therapy was escalated from ceftriaxone to ertapenem. Despite adequate and prolonged antibiotic treatment, the urinary symptoms continued to worsen. Ten days after the onset of urinary symptoms, imaging studies, including CT and ultrasonography, revealed bilateral ureteral dilatation with wall thickening, hydronephrosis, and bladder wall thickening (Fig. 2B), accompanied by elevated serum creatinine levels (maximum 215 μmol/L). Bilateral nephrostomies were performed due to acute obstructive uropathy, resulting in normalization of creatinine. However, the patient continued to suffer from severe dysuria and lower abdominal pain, which significantly affected her daily activities.

She was referred to the Respiratory Outpatient Department, where immune-related cystitis and ureteritis were clinically suspected. She was subsequently admitted to the inpatient department of Beijing Water Conservancy Hospital for further management. Oral prednisone 40 mg daily was reinitiated; however, her symptoms improved slowly, and she continued to experience significant lower abdominal pain. Given the suspected marked local bladder inflammation, intravesical instillation therapy was added, consisting of methylprednisolone (80 mg in 250 mL normal saline, twice daily). Following bladder irrigation, the patient reported noticeable relief of abdominal pain and dysuria. Bladder capacity gradually improved, and urinalysis showed normalized protein levels and reduced erythrocyte counts.

On day 8 of corticosteroid therapy, the patient resumed and completed intracavitary brachytherapy for cervical cancer. A complete response (CR) was achieved according to the Response Evaluation Criteria in Solid Tumors (RECIST) 1.1. Corticosteroids were tapered over 8 weeks (Fig. 2C). At a 1-month follow-up after cessation of corticosteroid therapy, urinalysis showed persistent leukocyturia, and the patient reported mild post-void pain and nocturia (2–3 episodes per night). At 6 months, urinalysis normalized, although CT imaging still showed bladder wall thickening and ureteral dilatation with wall thickening. By the 1-year follow-up, CT demonstrated complete resolution of abnormalities, with normal renal, ureteral, and bladder structures.

CASE 3

A 35-year-old female was initially evaluated for abnormal vaginal bleeding and diagnosed with endometrial cancer in January 2024. She underwent surgical treatment, and postoperative pathology revealed clear cell carcinoma, staged as IIIA. After surgery, she received adjuvant chemotherapy with albumin-bound paclitaxel and carboplatin. Pembrolizumab was added after 2 cycles. In April 2024, she underwent pelvic radiotherapy while continuing immunotherapy.

After 4 cycles of immunotherapy, she developed urinary frequency, urgency, dysuria, and fever. Initially, radiation cystitis was suspected, and she was treated with dexamethasone (5 mg daily) and antibiotics for 7 days. Her symptoms temporarily improved but subsequently worsened, with progression to gross hematuria and flank pain. CT imaging revealed bilateral hydronephrosis, elevated serum creatinine, and marked increases in urinary leukocytes and erythrocytes. Multiple urine cultures were repeatedly negative. Bilateral ureteral stents were placed, resulting in normalization of serum creatinine and relief of flank pain. However, urinary symptoms recurred intermittently despite a temporary improvement of symptoms and pyuria with antibiotic treatment. Repeated urine cultures remained negative throughout.

Eleven weeks after symptom onset, her urinary symptoms worsened significantly, with gross hematuria becoming the predominant feature. Urinalysis revealed a marked elevation of red blood cells (2360 cells/μL), white blood cells (68 cells/μL), and proteinuria (0.15 g/L), while serum creatinine remained normal. CT imaging demonstrated left-sided hydronephrosis despite the ureteral stent being in place. The patient presented to the Respiratory Outpatient Department of Peking Union Medical College Hospital, where immune-related cystitis and ureteritis were suspected. She was subsequently transferred to the inpatient department of Beijing Water Conservancy Hospital, where intravenous methylprednisolone 80 mg daily was initiated. By the second day of treatment, the patient showed marked symptomatic improvement, allowing for dose reduction to 40 mg daily.

During treatment, the patient attempted one session of methylprednisolone bladder irrigation but was unable to tolerate the procedure due to ureteral discomfort and declined further sessions. After 1 week of intravenous corticosteroids, the regimen was transitioned to oral prednisone (40 mg daily), with a structured weekly taper over 8 weeks. By day 12 of corticosteroid therapy, urinalysis had normalized, showing urinary leukocyte counts at 1.7 cells/µL, erythrocytes at 0.5 cells/µL, and resolution of proteinuria. Hemoglobin levels also improved significantly, increasing from 107 g/L to 123 g/L. Bladder function normalized, with a single voided volume of 300 mL. The patient was deemed clinically stable and discharged. The clinical course is depicted in Figure 3. Pembrolizumab was resumed more than one month after discharge, with no recurrence of cystitis or ureteritis.

FIGURE 3.

Clinical course of case 3. Therapy and clinical findings of case 3. Day 0 (D0) indicates the onset of symptoms of immune-related cystitis/ureteritis. Pembro indicates pembrolizumab; DEX, dexamethasone; MP, methylprednisolone; Pred, prednisone; sCr, serum creatinine.

DISCUSSION

We reported 3 cases of cystitis and ureteritis occurring during immunotherapy. All patients presented with urinary frequency, urgency, dysuria, and gross hematuria. Urinalysis revealed significant elevations in red and white blood cells. Postrenal urinary obstruction developed, leading to a rapid increase in serum creatinine levels. Symptoms improved significantly following corticosteroid therapy, with one patient, in addition, receiving bladder irrigation with methylprednisolone.

Immune-related ureteritis and cystitis are rare but clinically significant irAEs, typically occurring within the first 6 cycles of ICI therapy. Diagnosis is usually made by exclusion, with common symptoms including urinary frequency, urgency, dysuria, and hematuria. In cases of ureteritis, imaging findings such as ureteral dilatation, wall thickening, and a rapid increase in serum creatinine may suggest immune-related involvement. Sterile pyuria, elevated urinary leukocytes with repeatedly negative urine cultures, should prompt suspicion for immune-related cystitis, especially when symptoms are unresponsive to antibiotics or antispasmodics. Cystoscopy often reveals mucosal hyperemia and edema, and biopsy findings typically demonstrate lymphocytic infiltration with occasional eosinophils⁴ or neutrophils.^10,16 It is worth noting, however, that while cystoscopic biopsy can support the diagnosis, it is not definitive on its own. During the acute symptomatic phase, the risks and benefits of invasive procedures should be carefully considered.

Although the exact pathophysiology remains unclear, significant evidence implicates lymphocytic infiltration as a key feature.^{6,7,11,12,14,16,17} In our cases, histopathologic confirmation was unavailable; however, the consistent presence of sterile pyuria, lack of response to antibiotics, and rapid improvement with corticosteroids support an immune-mediated etiology. In our cases, CT imaging revealed ureteral wall thickening and dilation, likely due to inflammatory infiltration, which progressed to obstructive uropathy. These findings align with previous reports, emphasizing the importance of integrating clinical, imaging, and histopathologic data for accurate diagnosis and timely management.

Distinguishing immune-mediated cystitis from radiation-induced cystitis can be challenging due to overlapping symptoms such as dysuria, frequency, urgency, and hematuria. Acute radiation cystitis typically occurs during or shortly after radiation therapy, is usually mild, self-limiting, and resolves after treatment cessation.¹⁹ In cases 2 and 3, cystitis and ureteritis developed during or shortly after radiotherapy, within the expected timeframe for acute radiation cystitis, but the progressive symptom worsening after radiotherapy cessation was inconsistent with its self-limiting nature. In case 2, the radiation oncologist also judged that the radiation field and dose were insufficient to induce radiation cystitis. Careful review of the treatment history, radiation exposure, and symptom progression is essential, and multidisciplinary evaluation helps guide accurate diagnosis and management.

While most reported cases of immune-related cystitis and ureteritis respond well to systemic corticosteroids, we explored the use of intravesical methylprednisolone irrigation as a novel treatment approach. This method delivers corticosteroids directly to the site of inflammation, potentially improving therapeutic efficacy while minimizing systemic steroid exposure. In case 2, intravesical methylprednisolone was administered along with saline bladder irrigation. The irrigation volume was gradually increased based on patient tolerance; although bladder pressure was not measured, the irrigation volume was insufficient to achieve the pressure required for bladder hydrodistension, unlike previous reports^4,6 that successfully used this method to treat immune-related cystitis.

Alternative treatments may be considered for refractory cases. For instance, Fukunaga et al¹³ reported successful resolution of steroid-refractory cystitis with infliximab, suggesting the potential role of anti-cytokine therapies. Identifying whether the inflammatory process is primarily localized or driven by systemic cytokines and immune cell subtypes is critical. Comprehensive evaluations, including lymphocyte counts, lymphocyte subsets, C-reactive protein (CRP) levels, and cytokine profiles, are essential for characterizing the underlying immune pathology. Furthermore, careful monitoring of potential adverse effects, such as infection, is important for developing personalized treatment strategies.

A limitation of our report is the absence of histopathologic confirmation. Nevertheless, our cases provide valuable real-world data for recognizing and managing rare immune-related cystitis and ureteritis. In all cases, cystitis and ureteritis occurred within the first 4 cycles of immunotherapy, with imaging showing bladder and ureteral wall thickening; in case 2, concurrent immune-related dermatitis was also observed. These features—early onset, radiologic abnormalities, and multiorgan irAEs involvement—collectively support the diagnosis of immune-related cystitis and ureteritis. Intravesical methylprednisolone irrigation, as employed in case 2, may represent a promising adjunct therapy for patients with severe localized symptoms. Further studies are needed to confirm its efficacy and establish standardized protocols. Future research should also focus on the role of inflammatory markers and cytokine profiles to guide mechanism-based treatment strategies for immune-related cystitis and ureteritis.

CONCLUSION

We report 3 cases of ICI-induced cystitis and ureteritis: 1 in a patient with lung cancer and 2 in patients with uterine malignancies. All cases responded well to corticosteroid therapy, with one patient showing significant improvement after intravesical methylprednisolone irrigation. Prompt recognition and management of these rare irAEs are essential for improving patient outcomes and avoiding unnecessary interventions. Intravesical methylprednisolone irrigation warrants further research as a promising therapeutic option for immune-related cystitis.