Trigonitis is a pathological process of the bladder trigone characterized by nonkeratinizing squamous metaplasia (see the image below). Anatomically, the trigone occupies the region between the ureteric ridge and the bladder neck. Histologically, the bladder trigone is normally lined by urothelium, a type of transitional epithelial tissue found throughout the urinary tract.[1]
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Nonkeratinizing squamous metaplasia. Stratified squamous metaplasia is usually seen in the bladder neck and trigone. Note the lack of densely eosinoph....
Trigonitis was first described in 1905 by Heymann, who called the disorder cystitis trigoni.[2] Subsequently, Cifuentes described trigonitis as a true trigonal membrane.[3] It is also referred to in the scientific literature as pseudomembranous trigonitis or vaginal metaplasia.
Squamous metaplasia of the trigone has been observed almost exclusively in women of childbearing age. It is almost nonexistent in children. Although the exact etiology of trigonitis is unknown, the condition usually occurs in response to an irritative insult to the bladder trigone (eg, from a long-term indwelling catheter) or an infectious process.
Patients with squamous metaplastic changes in the bladder may be asymptomatic or may present with irritative voiding symptoms. Diagnosis of trigonitis requires cystoscopy (see Workup). Asymptomatic patients do not require treatment. Several treatment approaches have been tried in patients with symptomatic trigonitis, including medications and surgery. See Treatment.
Trigonitis is a benign lesion that does not carry malignant potential. Expertise and scientific data indicate that follow-up cystoscopy after diagnosis is not required. However, urologists should make it a point of emphasis to distinguish trigonitis from keratinizing squamous metaplasia, also known as leukoplakia, which does carry malignant potential.
For patient education information, see Bladder Cancer.
Trigonitis, although its name suggests inflammation, is a metaplastic process. The precise underlying cause is not known, but squamous metaplasia in the bladder usually occurs in response to irritation (eg, from a long-term indwelling catheter) or infection. Given that nonkeratinizing squamous metaplasia is commonly found in adult women of childbearing age, a hormonal component is often considered likely.
In a study of bladder biopsies performed in women with pseudomembranous trigonitis and women who underwent cystoscopy for staging gynecological cancer, estrogen and progesterone receptors were found in the trigone in association with squamous metaplastic changes.[4] In a more extensive mapping study of the female lower urinary tract, both estrogen and progesterone receptors were found in squamous epithelial tissue, including the transitional cell epithelium in the trigone and proximal urethra that had undergone squamous metaplastic changes.[5]
In the first case report of pseudomembranous trigonitis in a patient with Klinefelter syndrome (a 16-year-old boy), the findings of raised estrogen levels in conjunction with increased expression of estrogen receptors in the trigone area, but not the remainder of the bladder, suggest that estrogen could be an etiological driver, much like the association of Klinefelter syndrome with estrogen-driven cancers such as breast cancer.[6] Trigonitis has been reported in men receiving estrogen therapy for the treatment of prostate cancer.[7]
However, whether hormonal influences lead to squamous metaplasia is unclear. Other authors have suggested that squamous cell metaplasia is not associated with increased estrogen activity.[8] Kvist et al did not find estrogen receptors in 36 historically collected samples of squamous metaplasia of the bladder urothelium, although these authors posited that if only relatively few receptors had been present initially, they might have been destroyed in the tissue preparation process.[8]
Instead, other explanations focus on the potential role of chronic inflammation and/or a deficient urothelium. In one autopsy study of adult women, histological evidence of chronic inflammation was found significantly more often in bladders with squamous metaplasia. The authors suggest that squamous metaplasia is not a consequence of chronic inflammation but rather that its surface characteristics may predispose to chronic infection.[9]
Squamous metaplasia is observed over edematous or inflamed lamina propria.[10] Electron microscopy of the keratinizing variant has demonstrated that squamous metaplastic cells lack the tight junctions seen in normal transitional epithelial cells, which might allow urine to permeate the subepithelial layers, resulting in ongoing inflammation.[11]
Bacterial cystitis has been associated with the development of trigonitis in cases of recurrent urinary tract infections. The literature regarding interstitial cystitis suggests that the mucosal coating of the bladder surface, also known as the glycosaminoglycan (GAG) layer, plays a profound role in preventing urinary solutes from permeating into the urothelium of the bladder wall.[12] Restriction of the characteristic lesion to the trigone of the bladder is possibly due to the estrogenic effect. This restriction could be explained by the fact that the trigone is anatomically and embryologically distinct from the remainder of the bladder.[13]
Defects in this protective mechanism, or injuries resulting from chronic irritation or recurrent infections, may result in chronic inflammatory changes leading to metaplasia. However, not all individuals with squamous metaplasia are symptomatic, and not all symptomatic patients have squamous metaplasia, which complicates understanding of this elusive disease process.
The frequency of trigonitis differs in various reports, but the literature consistently shows that trigonitis occurs almost exclusively in women of childbearing age. Nonkeratinizing squamous metaplasia of the bladder neck and trigone can be seen in 50-70% of premenopausal women and is considered a normal variant.[11]
In a study by Wiener et al that examined 100 grossly normal bladders at autopsy, 46% of premenopausal and postmenopausal women were to found to have squamous metaplasia; in comparison, only 7% of men were found to have squamous metaplasia of the bladder.[14] In an autopsy study of bladders from 106 women who had died of diseases unrelated to the urinary tract, 72% exhibited squamous metaplasia in the trigone.[9] Other reports suggest that trigonitis occurs in approximately 40% of adult women and approximately 5% of men.[15] Trigonitis may also be seen in men receiving hormonal therapy for prostate cancer.[7]
Patients with squamous metaplastic changes in the bladder may be asymptomatic or may present with irritative voiding symptoms (generally characterized by frequency, urgency, and dysuria), recurrent urinary tract infections (UTIs), hematuria, or pelvic pain.[16] Specific attention should be directed at establishing the presence and pattern of specific voiding symptoms.
Patients with trigonitis typically complain of persistent burning pain or nagging discomfort that is deep to the symphysis pubis and radiates down the urethra. The pain is worse with urination. This contrasts with the presentation of interstitial cystitis; those patients typically feel the pain across the lower abdomen.[17]
A complete genitourinary exam may be helpful in ruling out other causes of symptoms that bring the patient to medical attention. However, it is important to realize that trigonitis can only be confirmed by cystoscopy.
Cystoscopy is necessary to make the diagnosis of trigonitis. Urinalysis and urine culture can be performed to exclude infection, as is often done prior to cystoscopy.
Imaging studies are not necessary to confirm the diagnosis. However, in one study of transabdominal ultrasonography, asymptomatic women with cystoscopically confirmed trigonitis had thickening of the mucosa around the bladder neck, compared with women who had cystoscopically normal bladders.[19]
In a study of 114 women with recurrent urinary tract infection who underwent transvaginal bladder ultrasound (TBU) for diagnosis of chronic trigonitis, Ribeiro-Filho and colleagues reported that thickening of trigone mucosa (> 3 mm) was detected in all patients. Additional findings were irregular and interrupted mucosa lining (96.4%), free debris in the urine (85.9%), increased blood flow on Doppler study (81.5%), mucosa shedding, and tissue flaps. In a control group of 25 age-matched women with no history of urinary tract infection or urological conditions, trigone mucosa thickness was ≤3 mm and no debris was present in the urine. The diagnostic agreement index for chronic trigonitis between TBU and cystoscopy was 100%.[20]
Cystoscopy is necessary to make the diagnosis. Grossly, the lesion appears as a glistening, fluffy white patch of bladder mucosa with well-defined borders. See the image below.
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Cystoscopic appearance of trigonitis as a well-defined white area overlying the trigone.
Biopsy of suspected trigonitis can usually be deferred, as trigonitis has a distinct gross appearance under cystoscopy. However, a lower threshold for biopsy is warranted when there is a higher likelihood that the lesions are leukoplakia, such as in the following cases:
Male patients
Females with hematuria
Pediatric patients
Patients with a similar-appearing lesion outside of the confines of the trigone
Nonkeratinizing squamous metaplasia of the trigone is composed of stratified squamous epithelium that often contains abundant glycogen. The basal cell layer has prominent nuclei with condensed chromatin and nucleoli. The surface cells are linked by desmosomes and are longitudinally oriented. Jost et al found the mitotic index within these lesions to be 0.17%, higher than the expected value of 0%.[21] See the image below.
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Nonkeratinizing squamous metaplasia. Stratified squamous metaplasia is usually seen in the bladder neck and trigone. Note the lack of densely eosinoph....
Asymptomatic patients do not require treatment for trigonitis. A urologist may be consulted in symptomatic cases. Several treatment approaches have been tried in patients with symptomatic trigonitis, including medications and surgery. Because it presents a constant source of irritation, long-term indwelling instrumentation of the bladder should be discouraged if better alternatives for bladder drainage are feasible.
Antibiotic therapy with a course of doxycycline proved effective in a study of 103 women with cystoscopically confirmed trigonitis and irritative voiding symptoms. In addition to vaginal tablets to eradicate microbial reservoirs, the women received doxycycline at 100 mg twice daily for 2 weeks, followed by 100 mg daily for 2 weeks. Sexual partners were also treated with doxycycline 100 mg twice daily for 2 weeks, and the use of condoms was recommended during the entire treatment period. Following the treatment, 30% of patients considered themselves cured and 41% reported symptom improvement. On follow-up cystoscopy in 31 patients, trigonitis was completely resolved in 8 cases and improved in 12 cases.[22]
A European trial reported improvement in trigonitis symptoms with intravesical instillations of sodium hyaluronate, a derivative of hyaluronic acid that replaces the deficient glycosaminoglycan (GAG) layer in the bladder wall. The 37 women in the trial received sodium hyaluronate once weekly for 10 weeks and then once monthly for the next 10 months. However, clinical improvement did not clearly relate with improvement in cystoscopic and biopsy findings.[15] The US Food and Drug Administration (FDA) has not approved sodium hyaluronate for intravesical instillation.
Endoscopic treatment with an Nd:YAG laser was studied in women with urethral syndrome and biopsy-confirmed squamous metaplasia of the bladder refractory to medical treatment. Patients (n=62) were randomized to end-firing or side-firing Nd:YAG laser treatment at 30 W. Although results, as assessed by the Urogenital Distress Inventory short form (UDI-6), were significantly better in the side-firing group, follow-up cystoscopy and biopsy found that squamous metaplastic lesions were no longer present in patients of either group with symptom improvement, but white lesions in the bladder neck and trigone were seen in patients whose symptoms were unchanged or worsened.[23]
In a retrospective study of 33 women with longstanding recurrent urinary tract infections (UTIs) refractory to antibiotic treatment who underwent cystoscopy with fulguration of trigonitis (CFT), 76% had a complete cystoscopic resolution of the trigonal lesions at 6 months postoperatively. The patients with complete resolution had a significantly decreased need for antibiotic treatment for UTI-related symptoms and/or positive urine cultures, compared with the group with residual trigonitis following CFT.[24]
Similar results were reported in a prospective study of electrofulguration (EF) of trigonal lesions in women with recurrent UTIs refractory to antibiotic treatment. Of the 73 patients treated with EF, 96% were UTI free during first year following treatment and 53% during the second year of follow-up.[25]
Wellman W Cheung, MD, FACS, Clinical Professor, Department of Urology and Department of Obstetrics and Gynecology, State University of New York Downstate Medical School
Disclosure: Received grant/research funds from Astallas for pi.
Coauthor(s)
Raymond Khargi, MD, Resident Physician in Urologic Surgery, SUNY Downstate College of Medicine
Disclosure: Nothing to disclose.
Specialty Editors
Francisco Talavera, PharmD, PhD, Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference
Disclosure: Received salary from Medscape for employment. for: Medscape.
Chief Editor
Edward David Kim, MD, FACS, Professor of Urology, Department of Urology, University of Tennessee Graduate School of Medicine; Consulting Staff, University of Tennessee Medical Center
Disclosure: Nothing to disclose.
Additional Contributors
Leonard Gabriel Gomella, MD, FACS, The Bernard W Godwin Professor of Prostate Cancer Chairman, Department of Urology, Associate Director of Clinical Affairs, Kimmel Cancer Center, Jefferson Medical College of Thomas Jefferson University
Disclosure: Received consulting fee from GSK for consulting; Received honoraria from Astra Zeneca for speaking and teaching; Received consulting fee from Watson Pharmaceuticals for consulting.
Sophia Kawa Chiu, MD, MA, MSc, Resident Physician, Department of Urology, State University of New York Downstate Medical Center
Disclosure: Nothing to disclose.
Acknowledgements
The authors and editors of Medscape Reference gratefully acknowledge the contributions of previous author Scott Rutchik, MD, to the development and writing of this article.
Stavropoulos M, Papatsoris AG, Konstantinidis C, and Chrisofos M. Pseudomembranous Trigonitis: A Common but Underrecognized Urological Entity. Advances in Urology. 2010. 2010:
Hussain SA, Alhalabi F, and Zimmern PE. Long-term efficacy of fulguration of trigonitis for recurrent urinary tract infections in women. Urol Sci. September 2015. 26(3):197-201.
Nonkeratinizing squamous metaplasia. Stratified squamous metaplasia is usually seen in the bladder neck and trigone. Note the lack of densely eosinophilic layer, representing keratin, at the luminal side.
Keratinizing squamous metaplasia of the bladder.
Cystoscopic appearance of trigonitis as a well-defined white area overlying the trigone.
Nonkeratinizing squamous metaplasia. Stratified squamous metaplasia is usually seen in the bladder neck and trigone. Note the lack of densely eosinophilic layer, representing keratin, at the luminal side.
Keratinizing squamous metaplasia of the bladder.
Cystoscopic appearance of trigonitis as a well-defined white area overlying the trigone.
Nonkeratinizing squamous metaplasia. Stratified squamous metaplasia is usually seen in the bladder neck and trigone. Note the lack of densely eosinophilic layer, representing keratin, at the luminal side.
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