Demystifying Cystitis Cystica—Case Series With Comprehensive Review of Literature

Cystitis cystica (CC) is a hyperproliferative condition affecting the bladder mucosa, in which the submucosally invaginated masses of transitional epithelial cells, also called the “Brunn nests,” undergo cavitation to form fluid-filled cystic cavities. Proliferative or reactive changes occurring in von Brunn nests, which acquire luminal spaces, become cystically dilated (cystitis cystica,CC), undergo glandular metaplasia (cystitis cystica et glandularis, CCG, CG, CCEG), or intestinal metaplasia (IM). The exact incidence of this condition is unknown. Various predisposing factors, such as chronic urinary tract infections (UTIs), mechanical irritation (ie, calculi), in-dwelling catheters, neurogenic bladders, chronic bladder outlet obstruction, and bladder exstrophy, are frequently associated with diffuse CC changes in the bladder mucosa.1 Mostly, presentation is asymptomatic and diagnosed on cystoscopy for evaluation of unrelated causes. There have been various case reports in the past related to progression to malignancy, especially for IM and CCG variants2,3 Despite being recognized since the 1760s, the natural history of CC remains largely unclear. Although some studies have linked it to bladder cancer, others regard it as a chronic inflammatory condition with minimal clinical relevance.4 Concerns persist regarding its potential as a premalignant lesion, recurrence rates, and the risk of ureteric orifice involvement with upper tract deterioration, bladder neck contracture post-transurethral resection of bladder tumour (TURBT) given its usual location in the trigone and bladder neck region. Limited research has explored the natural history, including recurrence, the necessity for additional procedures, and the risk of chronic renal failure. This study aims to address these gaps by examining the clinical spectrum of patients with histopathologically confirmed CC, focusing on the effect of various factors on recurrence, additional interventions, upper tract deterioration, and its association with malignancy.869+426986652c v MATERIALS AND METHODS All patients diagnosed with CC, confirmed histopathologically between July 2021 and December 2024, presenting to our tertiary care hospital, were included in this study. Patients who were not on regular follow-up, lost to follow-up, or had less than 6 months of follow-up were excluded from this study. Demographic details, presenting complaints, comorbidities, predisposing factors like UTI, chronic catheterization (>1 year), bladder outlet obstruction (AUA symptom score), uroflowmetry and post void residual volume (PVR), association with malignancy, location of cystitis changes (on cystoscopy), and associated upper tract changes (on ultrasound, CT urography) were noted. All patients underwent TURBT as a part of the initial treatment of bladder mass. All patients diagnosed with bladder cancer were managed according to European Association of Urology guidelines.5 Patients exhibiting upper tract changes or elevated creatinine levels underwent double J stent (DJS) placement during cystoscopy or TURBT. Pyridium was administered orally 1 hour before the procedure to enhance intraoperative visualization of the ureteric orifice. If the ureteric orifice was not visualized or if DJS placement was unsuccessful, a percutaneous nephrostomy (PCN) was performed. All patients were followed up with symptom score, uroflowmetry, PVR assessment, kidney function tests, and ultrasound every 3 monthly for first year and 6 monthly thereafter. Any abnormality on the above investigations was evaluated with cystoscopy. Any recurrence was resected and followed up with the same pathologist to rule out any changes in histopathology/development of malignancy. Any ancillary procedure requirement, like DJS, PCN insertion, was noted. Patient Consent Written informed consent for participation and publication of anonymized clinical data was obtained from all patients. Consent forms are available with the authors and will be provided to the editors on request. This study was conducted in accordance with the ethical principles outlined in the Declaration of Helsinki. The study protocol was reviewed and approved by the Institutional Ethics Committee (Approval No. AIIMS/IEC/25/447; dated July 30, 2025). Statistical Analysis Data were entered in an Excel chart, and categorical variables were described as frequency and proportion, whereas continuous variables were expressed as mean ± SD or median with the IQR as applicable. Statistical analysis was performed using IBM SPSS STATISTICS (Version 25.0). Univariate and multivariate logistic regression analyses were used to identify independent risk factors for CC recurrence. RESULTS A total of 32 patients were included in the study—27 male (87%) and 5 female (Figure 1), and their baseline characteristics are shown in Table 1.Figure 1.: Age distribution of patients. Table 1. - Baseline Characteristics of Patients Patient characteristics Number (n = 32) Age distribution Mean age: 45.6 y (17-74 y) Sex Male: 27 Female: 5 Comorbidities HTN-5 DM-3 Others: 2 Smoking 40% (n = 13) Presenting complaints Hematuria: 9 (28%) LUTS: 20 (62.5%) Asymptomatic: 6 (18%) Average duration of symptoms 11.64 mo Cystitis changes Trigone: 59% (n = 19) Diffuse involvement: 18% (n = 6) Others: 22% (n = 7) Orifice involvement on cystoscopy 28% (n = 9) Upper tract changes at presentation 15% (n = 5) Histopathological diagnosis CC: 19 (59%) CCG: 11 (34%) IM: 2 (6%) Associated with urinary bladder cancer 6 (18.75%) CC, cystitis cystica; CCG, cystitis cystica et glandularis; DM, diabetes mellitus; HPE, histopathological diagnosis; HTN, hypertension; IM, intestinal metaplasia; LUTS, lower urinary tract symptoms. Around 31% of our patients had comorbidities in terms of hypertension (HTN), diabetes mellitus (DM), and hypothyroidism. A history of smoking was seen in around 40% of cases. The major presenting complaint seen in our study was lower urinary tract symptoms (62.5%), followed by hematuria (28%), whereas 18% patients were incidentally diagnosed on USG for an unrelated cause. Predominant histopathological subtype was CC—59%, followed by cystitis cystica et glandularis (CCG; typical)—34% and IM in 6% cases (Figure 2). Predominant CC changes were seen in the trigonal region in 59% cases, with diffuse involvement seen in 18% cases (Figure 3).Figure 2.: Hematoxylin and eosin slide staining of cystitis cystica and cystitis glandularis. A, Urothelial mucosa shows vague glandular pattern of urothelial cells with cystitis cystica change (H&E, ×20). B, Urothelial mucosa disposing in gland (cystitis glandularis) and few are cystically dilated (cystitis cystica) with bland nuclear morphology (H&E, ×200). C, Urothelial mucosa exhibiting in gland and nest form adjacent to mucosa (H&E, ×40). D, Urothelial mucosa showing glandular structure with inward papillary projections and lined by transitional urothelial lining with bland nuclear morphology (H&E, ×200). H&E indicates hematoxylin and eosin staining.Figure 3.: Cystoscopy appearance of cystitis cystica. A, Cystoscopy appearance of cystitis cystica. B, Reimplanted ureteric orifice in case of recurrent trigonal cystitis cystica.Predisposing Factors Various postulated predisposing factors for CC were identified and studied. These include recurrent UTI, chronic catheter or stents, and bladder outlet obstruction (Table 2). Table 2. - Distribution of Various Risk Factors in Various Patients Predisposing factors No. of patients, No. (%) Recurrent UTI 12 (37.5) Chronic catheter 4 (12.5) Long-standing DJ stent 1 (3.1) Bladder outlet obstruction 12 (37.5) Urethral stricture 2 HBN 5 BPE 2 Dysfunctional voiding 3 No predisposing factor identified 9 (32) BPE, benign prostatic enlargement; HBN, high bladder neck; UTI, urinary tract infections. Histopathological diagnosis revealed CC in 19 cases (59%), CCG in 11 cases (34%), and cystitis glandularis with IM in 2 cases (6%); however, among 6 cases associated with malignancy (urothelial), 2 were of IM, 2 of CCG, and 2 were of CC on HPE (Table 3). Table 3. - Histopathological Diagnosis in Various Patients Histopathological report No. of patients, No. (%) CC 19 (59) CCG 11 (34) CC-IM 2 (6) CC, cystitis cystica; CCG, cystitis cystica et glandularis; CC-IM, cystitis cystica with intestinal metaplasia. Management All patients underwent transurethral resection of bladder growth, with subsequent management tailored to their predisposing factors. Two patients with benign prostatic enlargement underwent transurethral resection of the prostate, whereas 2 patients with urethral strictures received direct visual internal urethrotomy. Among 5 patients with high bladder neck, 4 were treated with bladder neck incision and 1 was managed medically. Three patients with dysfunctional voiding were placed on conservative management (biofeedback, pelvic floor relaxation exercises, sitz bath, stool softeners/laxatives). Those with recurrent UTIs received long-term antibiotic prophylaxis with nitrofurantoin at a dosage of 50 mg once daily for 3 to 6 months.6 During cystoscopy, 9 patients presented with involvement of the ureteric orifices, and 5 exhibited upper tract changes. All 5 patients had their ureteric orifices successfully opened during TURBT and were placed on DJ stents. However, 2 of these patients ultimately required PCN insertion followed by ureteric reimplantation because of upper tract changes associated with multiple recurrences. Follow-Up and Recurrence All patients were followed with symptom score, uroflowmetry, kidney function test, and ultrasound every 3 months for first year and 6 months thereafter. Any abnormality on the above investigations was evaluated with cystoscopy. If recurrence was seen on cystoscopy, the patient underwent another TURBT with complete resection of CC changes. The mean follow-up duration was 44.8 months (3.7 years), and the median follow-up was 39 months (3.25 years). Of 26 patients, 10 had recurrence (38.5%): 8 had recurrence after 1 year and 2 patients had recurrence within 1 year, after excluding patients with carcinoma bladder. Recurrence rates were 55.55% in the CCG group (n = 5/9) and 29.4% in the CC group (n = 5/17). Various factors were studied for recurrence of CC, like age < 50 years, male sex, duration of symptoms > 1 year, history of smoking, prolonged catheterization (>1 year), recurrent UTI, bladder outlet obstruction, CG or CC-IM on histopathology report, and removal of predisposing factors. On application of univariate analysis on the above factors, recurrent UTI and inability to identify or remove predisposing factors were found to be significant predictors for CC recurrence. Required Ancillary Procedures DJS were placed in all 5 patients who had their ureteric orifices successfully opened during TURBT. PCN was required for 2 of these patients because of upper tract changes associated with multiple recurrences. Ureteric reimplantation was also performed for these 2 patients after PCN insertion (Table 4). Table 4. - Ancillary Procedures Summary Procedure No. of patients Purpose DJS 5 To ensure proper drainage in patients with ureteric orifice involvement PCN 2 Required for patients with upper tract changes due to multiple recurrences Ureteric reimplantation 2 Performed for patients in whom ureteric orifice could not be opened on TURBT BNI 4 Conducted for patients with HBN to alleviate obstruction DVIU 2 Used for patients with urethral strictures to relieve urinary obstruction TURP 2 Performed on patients with benign prostatic enlargement to relieve urinary obstruction BNI, bladder neck incision; DVIU, direct visual internal urethrotomy; DJS, double J stents; HBN, high bladder neck; PCN, percutaneous nephrostomy; TURP, transurethral resection of prostate. DISCUSSION Demography CC is a hyperproliferative condition likely due to a local immune response to chronic inflammatory stimulus. It represents a varied spectrum from CC, cystitis cystica et glandularis (CCG) typical type, and CCG with IM.1 CC, as seen from this study, is more prevalent in men (82%), with a mean age group of 45.6 years (17-74 years), which corresponds with the literature as shown by previous studies in Table 5. Table 5. - Review of Literature Showing Characteristics of Various Studies S. no. Studies No. of patients Age group (in y) Follow up HPE subtype Progression to bladder cancer Association between CG and bladder cancer Recurrence 1 Parker7 40 20-82 1-6 y CC-32, CG-8 None 1 case Not studied 2 Davies and Castro8 12 42-82 Not mentioned CG-12 None 2 Not studied 3 Corica et al9 53 37.7 y (range 3-73) 12 y IM-53 None 1 Not studied 4 Smith et al10 136 3 wk to 92 y 4.4 y (median 2.6 y) CCEG-117, IM-19 1 36 (33%) Not studied 5 Rau et al11 11 41.27 Not mentioned CGIT-8, CG-3 Not studied 1 Not studied 6 Yi et al4 166 9 to 86 y Mean-3.38 y, median 4.22 y CCEG-155, IM-11 None 15 (9%) Not studied 7 Xin et al12 89 57 y (range 23-81) 104 mo (range 6-255) IM-89 1 None 4.4% (4) 8 Agrawal et al13 64 35.625 (24-48) Mean-4 y 9 mo (median 5 y 5 mo) CG-52, IM-12 None None Not studied 9 Hu et al14 278 Mean age-50.64 ± 13.06 y 27 mo (14-57 mo) CG-232, IM-32 None None 59.35% 10 Garg et al15 10 33.4 ± 14.0 32.8 (±7.5) mo CG-10 None Nil 80%, number of recurrences 1.5 (±1.1) 11 Current study, 2025 32 45.6 y (17-74 y) Mean-44.8 mo (3.7 y) CC-19, CCEG-11, IM-2 None 6 (18.75%) Overall-38.5%, CC-29.4%, CG-55.55% Median-39 mo (3.25 y) CC, cystitis cystica; IM, intestinal metaplasia. Risk Factors and Recurrence The mean duration of our follow-up was 44.8 months (3.7 years), and the median follow-up was 39 months (3.25 years). Overall recurrence rates from our study came out to be 38.5% to 55.55% in the CCG group (n = 5/9) and 29.4% in the CC group. Similar results were found in a study conducted by Hu et al,14 which showed recurrence rates of CCG to be 59.35%, although the study conducted by Garg et al15 showed recurrence rates of CCG to be 80% which can be due to the reason that we evaluated only symptomatic recurrences. Among the factors studied for recurrence, recurrent UTI and inability to identify or remove predisposing factors came as significant risk factors for recurrence of CC. According to a study conducted by Hu et al,14 urinary infection, long-term indwelling catheter usage, urinary calculus, atypical hyperplasia, and histological subtype were related to CCG recurrence. Malignant Transformation and Association There have been several case reports of malignant transformation of cystitis cystica et glandularis (CCG) to adenocarcinoma of the bladder.16-18 However, there is ample evidence with several series having long follow-up demonstrating no risk of malignant transformation (Table 3). Our study also showed no transformation to malignancy after a mean follow-up of 3.7 years. However, there has been an 18.75% association of urothelial malignancy with CC, as demonstrated by a few studies, as shown in Table 5. Thus, whether CCG acts as a risk factor for malignancy needs to be evaluated further. Based on our retrospective study and review of the literature, we propose a management algorithm for patients with CC (Figure 4).Figure 4.: Management algorithm of cystitis cystica. IPSS indicates International Prostate Symptom Score; PVR, post void residual volume; NSAIDS, nonsteroidal ant inflammatory drugs; TURBT, transurethral resection of bladder tumour.To date, this study remains the most comprehensive study that evaluates the complete spectrum of CC. Molecular Markers Bryan et al reported that in the IM type of CCG, β-catenin production is localized in the nucleus rather than at the membrane, as observed in the typical type of CCG. Similarly, nuclear β-catenin localization has been identified in Barrett esophagus, a known preneoplastic condition for esophageal carcinoma, suggesting a comparable pathway for malignant transformation in the IM type of CCG.19 In addition, Morton et al20 demonstrated significant telomere shortening in the IM type of CCG, along with chromosomal abnormalities similar to those seen in urothelial carcinoma, further supporting a chromosomal-level association. Several studies have shown differential expression of various markers in typical CCG and intestinal type of CCG like expression of CDx2 and CK20 in intestinal CCG than that in typical CCG, CK7, an intermediate weight cytokeratin, which is rarely expressed in intestinal CCG, but positively expressed in all cases of typical CCG, also MUC2 and MUC5AC were specifically expressed in intestinal CCG, while MUC1 and CD10 were specifically expressed in typical CCG.21,22 CONCLUSION CC and its variants, particularly CCG and IM, exhibit a notable risk of recurrence, especially in the presence of unresolved predisposing factors such as recurrent UTIs. Importantly, although some literature suggests a potential premalignant role for CCG and IM, this study found no evidence of malignant transformation over a mean follow-up of 3.7 years, aligning with other long-term series. Effective management should prioritize the identification and correction of underlying risk factors to minimize recurrence and potential upper tract complications. LIMITATIONS OF THE STUDY Despite being a comprehensive investigation, our study is limited by its relatively small sample size, which may affect the statistical power and generalizability of the findings. To effectively evaluate the spectrum of CC across various regions, a multicenter, multi-institutional study is warranted. In addition, the retrospective nature of this study may introduce biases and limit the ability to establish causality, further underscoring the need for prospective studies to validate our findings. Our study also lacked a review of medical management for patients with CC, which remains relatively unexplored. FUNDING The authors did not receive any funding or support from organizations or agencies for the submitted work. CONFLICT OF INTEREST DISCLOSURES The authors declare that they have no conflicts of interest relevant to the content of this article. They have no financial interests, personal relationships, or proprietary interests that could have influenced the work. Conflict of Interest disclosure forms have been completed by all authors as required by journal policy. ETHICS STATEMENT This study was conducted in accordance with the ethical principles outlined in the Declaration of Helsinki. The study protocol was reviewed and approved by the Institutional Ethics Committee (Approval No. AIIMS/IEC/25/447; dated July 30, 2025). Written informed consent was obtained from all participants before inclusion. DATA AVAILABILITY STATEMENT The data sets generated and/or analyzed during this study are not publicly available because of patient confidentiality restrictions, but are available from the corresponding author on reasonable request. AUTHOR CONTRIBUTIONS Conceptualization: Agarwal, Mittal. Data curation: Panwar. Formal analysis: Panwar. Investigation: Singh, Kumar. Methodology: Singh. Supervision: Mittal, Panwar, Singh, Mujahid. Resources: Mujahid. Validation: Saxena. Visualization: Saxena. Writing – original draft: Agarwal. Writing—review & editing: Agarwal.