Correspondence *James Buchanan Brady Urological Institute, The Johns Hopkins Medical Institutions, 600 North Wolfe Street, Marburg 150, Baltimore, MD 21287, USA

Email msemins1@jhmi.edu

The case

A 32-year-old healthy Chinese woman who had recently suffered a miscarriage underwent pelvic ultrasonography as part of her evaluation, which revealed a highly vascular, nonmobile, 1.0 1.2 1.7 cm midline polypoid mass that arose from the posterior inferior wall of the bladder. The patient denied gross hematuria and voiding complaints, apart from a subtle increase in urinary frequency. She did have microscopic hematuria approximately 1.5 years before her current presentation, which was diagnosed as a urinary tract infection, and was subsequently treated. Her past medical history was notable for hepatitis A and Bacillus Calmette–Guérin vaccination. She had no history of smoking or industrial exposure to carcinogens. Physical examination findings were unremarkable, with a soft, nontender abdomen, and normal pelvic examination results, with no masses palpated. Urinalysis and urine culture were negative. Her comprehensive metabolic panel results, liver functions tests, complete blood count, and coagulation profile were unremarkable. She had a negative pregnancy test. Cystoscopy by the Department of Obstetrics and Gynecology confirmed the bladder mass, and the patient was referred to our department for further evaluation and management. Cytology revealed benign urothelial and squamous cells with numerous rod-shaped micro-organisms of uncertain etiology. Intravenous pyelography was performed, which revealed a 1 2 cm filling defect in the mid posterior bladder; however, normal nephrographic findings and excretion with no upper urinary tract defects was noted (Figure 1). The patient's collecting systems were minimally distended bilaterally, secondary to a full bladder. Cystoscopy was performed and transurethral resection of a small papillary lesion on the left aspect of the trigone was carried out. No other abnormalities were noted. Pathology revealed a benign fibroepithelial polyp with prominent cystitis glandularis (Figure 2). There was no muscularis propria present. The patient underwent repeat cystoscopy 4 months later, which was normal. Surveillance was scheduled for 3 months later, but she was lost to follow-up.

Figure 1 Intravenous pyelogram

The arrow indicates the filling defect within the bladder.

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Figure 2 Accumulation of epithelial cells separated from the surface epithelium by a stromal border, also known as a von Brunn cell nest

In cystitis glandularis, the central cells degenerate and there is a central lumen surrounded by a continuous layer of columnar epithelium.^{3, 10} Hematoxylin and eosin stain, magnification 20.

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Discussion of diagnosis

Cystitis glandularis is a rare proliferative disorder of the mucus-producing glands within the mucosa and submucosa of the urinary bladder epithelium. Histologically, it is characterized by mucosal and submucosal foci of bladder transitional cells thought to have undergone glandular metaplasia.¹ Cystitis glandularis is a benign condition that is believed to be a premalignant lesion.

Many different etiologies of cystitis glandularis have been proposed including avitaminosis, allergy to toxins and hormonal imbalance, but two hypotheses predominate in the literature.² Firstly, the hypothesis that cystitis glandularis is a result of abnormal embryologic development where bladder embryonic rests that originate from either urachus or intestinal epithelium are displaced during separation of the rectum from the urogenital sinus.^{3, 4} Many researchers support this theory; however, some note that it is inadequate because cystitis glandularis also occurs in the ureter and renal pelvis.² The second major hypothesis is the metaplastic theory, whereby the vesical mucosa undergoes a series of progressive changes secondary to inflammation—beginning with epithelial hyperplasia. Von Brunn nests then form, followed by degeneration of the central cells, which leaves a central lumen with metaplasia of the surrounding cells to a columnar phenotype consistent with cystitis glandularis.⁵ Further progression, which is a long term process, is thought to result in adenocarcinoma. Venous and lymphatic stasis with subsequent mucosal edema is also believed to have a role in progression to adenocarcinoma; such stasis can arise with chronic inflammation or obstruction, such as occurs in pelvic lipomatosis. The vascular congestion results in an altered extracellular milieu rich in protein-containing fluid, which provides an amenable environment for tissue and hemorrhagic vessels to proliferate within the stroma. The damaged urothelium then sloughs off and regenerates with hyperplasia and subsequent glandular metaplasia.^{6, 7, 8}

The prevalence of clinically overt cystitis glandularis in the general US population has been quoted as 0.9–1.9%.^{5, 6, 9} Autopsy series that looked for von Brunn cell nests, cystitis cystica and cystitis glandularis, however, found that 50–100% of samples have these histologic changes.^{6, 10} These findings have led to the belief that cystitis glandularis is a normal variant of bladder epithelium or an incidentally observed histologic entity rather than a precursor to malignancy.⁴ Notably, however, these autopsy series had no gross findings, but instead were only microscopic findings. These microscopic findings could represent a normal variant, whereas clinically evident disease with macroscopic findings suggests a progression of the condition and premalignant lesions.

Chronic bladder inflammation is thought to be the main risk factor in the development of clinically important cystitis glandularis.¹ Chronic urinary tract infections, inflammation caused by urolithiasis, outflow obstruction and long-term indwelling catheter (urethral or suprapubic) drainage are also well-known risk factors for development of cystitis glandularis.² Individuals with spinal cord injury are at particularly increased risk because of chronic catheter use in this group.¹¹ Another well-known association is pelvic lipomatosis, which is a rare proliferative condition that causes increased deposition of fat around the bladder, rectum and prostate. Interestingly, cystitis glandularis is found in 75% of patients with pelvic lipomatosis.⁶

Symptoms of chronic bladder irritation are the most common complaints that precede diagnosis. Irritative voiding symptoms such as urgency, frequency, and dysuria are often present. Patients might also present with bacteruria, gross hematuria, or chronic, recurrent urinary tract infections. Occasionally they complain of voiding mucus.¹ Lesions often occur at the trigone and vesical neck; obstructive symptoms are, therefore, not uncommon, and cases may even masquerade as a bladder tumor.^{12, 13} Often, as in this case, patients present with an incidentally diagnosed, asymptomatic bladder mass.

After the medical history and physical examination there are many diagnostic investigations that should be undertaken. Blood pressure should be measured, since many patients with obstructive uropathy might develop hypertension if untreated. In addition, laboratory tests, such as a basic metabolic panel to measure renal function and a complete blood count to confirm the stability of hemoglobin, as well as to look for leukocytosis, should be done. Since chronic urinary tract infection is common, urinalysis and urine culture should be performed; mycobacterial culture can rule out genitourinary tuberculosis. CT or intravenous pyelography should be done to locate any obstruction associated with hydronephrosis and hydroureterosis, as well as any masses, bladder-wall thickening, and pelvic lipomatosis (which appears as a pear-shaped bladder on intravenous pyelography). Urodynamic studies have been performed in some patients with recurrent and extensive disease and can reveal a poorly compliant, small-capacity bladder, with elevated voiding pressures. Furosemide renography and Whitaker tests can confirm persistent obstruction.¹⁴ Results of these latter tests may indicate a need for more aggressive intervention. Cystoscopy with biopsy can confirm the diagnosis. A gross appearance that resembles a cobblestone pattern is usually observed. The vesical neck and trigone are the areas most often involved, with the lateral recesses and the dome also commonly affected.⁹

Other conditions that resemble cystitis glandularis are simple chronic inflammatory changes, cystitis cystica, squamous metaplasia, fibroepithelial polyps, genitourinary tuberculosis, transitional cell carcinoma, squamous cell carcinoma, adenocarcinoma, or metastatic disease. Differentiation between these conditions is important, as the final diagnosis will affect how aggressively the patient is treated, whether surgically, with antibiotics, antitubercular drugs, chemotherapy, radiation therapy, or observation. Biopsy with culture is the best way to distinguish these entities.

Treatment and management

The main goals of cystitis glandularis treatment are to relieve the symptoms and signs of the condition, such as irritative voiding symptoms, obstruction and bleeding. By treating the lesions one also aims to prevent the sequelae of chronic disease, such as chronic renal failure from obstructive uropathy and malignant transformation to adenocarcinoma.

Various treatment options are available that range from conservative to aggressive. The first step in management of the condition, given the association of cystitis glandularis with inflammation, is the elimination of any contributing source of chronic bladder irritation. This step could mean eradication of urinary tract infection with long-term antibiotic treatment, removal of mechanical irritation, for example by replacement of chronic indwelling catheters with clean intermittent catheterization, or treatment of stones.⁹ Transurethral resection of bladder lesions with fulguration can ablate tissues that give rise to tumors. Management with nephrostomy tubes may be initially necessary for severe ureteral obstruction before definitive therapy is undertaken. The likelihood of success with these conservative measures is very good for small, focal lesions, although recurrence can occur.

There are other, more-aggressive therapeutic options available for patients with treatment-refractory disease who continue to experience incapacitating symptoms from bladder irritability and contracture, persistent ureteral obstruction that leads to chronic renal failure, hemorrhage, or extensive and progressive lesions.⁹ Bladder augmentation has been performed for patients with decreased bladder capacity, but this surgery does not, unfortunately, eradicate irritative symptoms or obstruction. Ureteral reimplantation can be performed to treat obstruction, but patients still have voiding symptoms after this procedure. Radical cystectomy is the most aggressive yet successful surgery that is performed in very select cases of patients with nonmalignant disease for reasons discussed above.¹⁴ Pelvic lipomatosis could itself be an indication for aggressive therapy since 40% of patients with this condition develop progressive uremia from ureteral obstruction within 5 years after diagnosis, which often requires some form of urinary diversion.⁷ With aggressive therapy, the likelihood of success is excellent, although there are associated risks of erectile dysfunction, bladder-neck contracture or incontinence with continent reservoir creation, and other general complications related to major surgery and anesthesia. Other unsuccessful interventions that have been tried include long-term antibiotics, steroids, dieting, neodymium:yttrium aluminum garnet laser ablation, intravesical hydrocortisone instillation, radiation therapy and chemotherapy.¹⁴

The natural history of clinically relevant cystitis glandularis is not known. There are many researchers who believe the condition is chronic and quiescent; however, on the basis of literature that describes cases with malignant transformation, there are many (including Nesbitt in 1956) who profess that cystitis glandularis is a precursor to adenocarcinoma.^{3, 9} The progression to cancer might be a long-term process, as exemplified by many of the representative cases; however, since the association does exist despite the current lack of definitive evidence, cystitis glandularis requires close follow-up with surveillance cystoscopy at regular intervals for an indefinite time.⁵ If new lesions are found, resection with biopsy should be performed.

Efficacy of treatment can be assessed by evaluation of the patient's symptoms, laboratory studies, imaging techniques and repeat cystoscopy. If there is treatment failure with conservative measures, aggressive treatment (as discussed above) with cystectomy and urinary diversion should be considered.

Conclusions

This case demonstrates the continued challenge to understand the rare disorder, cystitis glandularis, and its clinical relevance as a precursor to malignancy. There is still no definitive evidence that a proportion of cystitis glandularis lesions undergo conversion to carcinoma—only a small number of cystitis glandularis cases that demonstrate malignant transformation are reported in the literature. The only factor that has been shown to correlate with carcinoma is the duration of chronic inflammation, and even this correlation is not reliable. With a particularly young patient, like this one, this diagnostic challenge presents difficult management decisions for the physician.

The association between chronic inflammatory insult and cancer is not a novel concept. Inflammation has been shown to have a role in the risk of cancer development in studies of many organ systems, particularly the genitourinary tract. Inflammatory changes caused by Schistosoma hematobium worms are associated with the development of squamous cell carcinoma of the bladder.¹⁵ This outcome is thought to be caused by mechanical and toxic effects on bladder mucosa as well as chronic secondary bacterial infection. Scientists are now studying the role of chronic inflammation in the development of prostate cancer, and have found it to be a significant risk factor.¹⁶ Bryan et al. compared cystitis glandularis and its progression to adenocarcinoma with Barrett's metaplasia of the esophagus, a well-accepted precursor to malignancy.¹⁷ They studied specific signaling pathways involving beta-catenin and the proinflammatory cytokine TNF (tumor necrosis factor); both showed significant changes in cystitis glandularis, which suggests that there could be a common pathway to malignancy transformation. In addition, the role of chronic inflammation in the development of multiple gastrointestinal cancers and lung cancer is now becoming apparent.¹⁴ Continued research into and good data collection from cystitis glandularis cases will hopefully unveil a molecular profile that could identify those at high risk of cancer conversion, so that management and follow-up can be tailored to individual patients.

Acknowledgments

The authors would like to thank Jonathan Epstein, MD and the Department of Pathology for help with selection of this case, and with preparation of the histologic slide featured in the figure section.

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Subject areas under which this article appears: Female urology | Urinary incontinence, urodynamics and lower urinary tract dysfunction