Original Paper
Urologia
Received: May 28, 2002 Accepted after revision: November 6, 2002
Urol Int 2003;71:285–289 DOI: 10.1159/000072680
Internationalis
Eosinophilic Cystitis A Rare Inflammatory Pathology Mimicking Bladder Neoplasms
Süleyman Kiliç a Rezzan Erguvan b Deniz Ipek a Hasan Gökçe b Ali Günes¸ a N. Engin Aydin b Can Baydinç a Departments of a Urology and b Pathology, Inonu University Medical Faculty, Turgut Özal Medical Center, Malatya, Turkey
Key Words Bladder W Cystitis W Eosinophilic inflammation W Bladder tumors
Abstract Purpose: We present a large series of eosinophilic cystitis including 8 cases; 3 of them had tumor-like lesions. Materials and Methods: The archives of pathology clinic of Inonu University Medical Faculty were reviewed from 1988 to 2002. The characteristics of patients and their diseases were recorded. Data obtained from 180 cases (172 from the literature and 8 from the present series) was assessed. Results: Seven cases had symptoms such as dysuria, frequency, hematuria, suprapubic pain, and difficulty in voiding. One asymptomatic case with history of bladder carcinoma was diagnosed during routine cystoscopy. The findings were microhematuria in 6 cases, macrohematuria in 2, pyuria in 3, urinary infection in 1, eosinophilia in 1, hyperazotemia in 1, and bladder masses in 3. Cystoscopies detected edematous and erythematous areas in 5 cases and lesions mimicking bladder carcinoma in 3. One case did not take further treatment after cystoscopy and biopsy and completely recovered. Four cases underwent medical therapy with nonsteroidal anti-inflammatory drugs and antihistaminics. They became asymptomatic and control cystoscopies showed no abnormal finding. Two of three patients with mass
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lesions recovered after steroid therapy following transurethral resection. The lesion in the third recurred and he improved after a second course of steroid therapy. Conclusions: Eosinophilic cystitis is a rare pathology. Sometimes, it may simulate bladder malignancies. Biopsy is mandatory at diagnosis. Usually, it has a benign course and may be treated with fulguration, analgesics, antihistaminics and steroids, although recurrence is possible. Copyright © 2003 S. Karger AG, Basel
Introduction
Eosinophilic cystitis is a rare inflammatory lesion of the bladder, characterized by massive eosinophilic infiltration of the bladder wall. Its cause is not known definitely. The majority of knowledge about this disorder is based on the case reports. Brown [1] and Palubinskas [2] first reported the disease in 1960. The most common symptoms, such as dysuria, frequency, hematuria, and suprapubic pain are nonspecific. Not frequently, the disease may mimic the bladder carcinoma with clinical, radiographic and cystoscopic features. The definitive diagnosis can be made only by histopathologic examination of biopsy specimens. In this report, we present a large series of eosinophilic cystitis including 8 cases. Three cases had bladder masses mimicking carcinoma clinically and cystoscopically. The
Süleyman Kiliç I˙nönü Üniversitesi Tıp Fakültesi, Turgut Özal Tıp Merkezi, Üroloji AD, Elazıg˘ Yolu 9. km, TR–44069, Malatya (Turkey) Tel. +90 422 3410660-5804, +90 422 3262129, +90 533 2652948 Fax +90 422 3410729, E-Mail
[email protected] or
[email protected]
principal clinical findings, differential diagnosis, etiology, pathogenesis and treatment modalities of this inflammatory disease were discussed.
Materials and Methods To determinate cases with EC, we retrospectively reviewed the archives of the pathology clinic of Inonu University Medical Faculty from 1988 to 2002. Eight cases of eosinophilic cystitis were retrieved. To confirm the diagnosis, pathologists reexamined 5-Ìm-thick slides stained routinely with hematoxylin and eosin. For the purpose of final analysis, the cases’ ages, sexes, histories, presenting symptoms, physical findings, blood and urine tests, radiological investigations, urine cytology findings, cystoscopic and histopathologic appearance of lesions, treatments and outcomes were recorded. Then recorded findings were assessed together with the findings in literature reports concerning eosinophilic cystitis. For this purpose, a literature search was performed using the PubMed database. The database was searched several times up to September 2002, using the MESH subject heading, ‘eosinophilic cystitis’. This effort produced a report that had performed a pooled analysis of 135 cases of the previous literature and was published in 2000 [3]. So this report and available reports that were published after this date [4–12] were retrieved for detailed article review and data extraction. The information about 172 cases in these reports was taken into consideration.
Results
Cases ranged in age from 28 to 77 years (mean 59). Three cases were females and 5 were males. Medical histories documented the intravesical Bacillus CalmetteGuérin instillation performed 2 years ago for superficial transitional cell carcinoma of bladder in 1 male, right leg amputation due to diabetes mellitus in 1 female, urethra stricture in 1 case following the transurethral prostatectomy performed 10 years ago, and intermittent antibiotic (trimethoprim-sulphamethoxazole, ciprofloxacin) therapies during 1 year due to chronic prostatitis in 1 patient. The coexisting pathologies were bronchial asthma in 2 cases and coronary artery disease in 2. No case had a significant allergy history. Seven cases were symptomatic. The predominant symptoms were irritative voiding symptoms (dysuria, frequency, nocturia, urgency) in 4 cases, hematuria (intermittent, macroscopic with or without clot) in 3, suprapubic pain resting with micturition in 4, and infravesical obstruction symptoms in 3; 1 with BPH, 1 with urethral stricture, and 1 with a tumoral lesion at the trigone and bladder neck who had a recent history of urinary retention. The case with TCC history had no symptoms and his pathology was determined incidentally during routine
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cystoscopic surveillance. Physical examination revealed suprapubic tenderness in 4 cases and prostatic enlargement in 1. Blood biochemistries indicated normal values in all except 1 who had high urea (57 mg/dl, normal: 10–40) and creatinine (2.2 mg/dl, normal: 0.5–1.2) due to diabetic nephropathy. One case had peripheral eosinophilia. The urine analysis results available in all cases showed pyuria in 3 that was mere presence of leukocytes in 2 and related to urinary infection in 1; microhematuria in 6, and macroscopic hematuria in 2. The cytology examinations available in 2 cases were negative for malignancy. USG were normal in 5 cases; however, in 3 there were soft-tissue masses in bladder; a 10 ! 15 mm mass on the right side of bladder wall and right wall thickening in a male, a 10 ! 10 mm mass projecting intraluminally over the left wall in a female, and a 30 ! 15 mm mass on the bladder base in a male. IVP and CT were performed to illuminate mass lesions. These examinations demonstrated irregularity of bladder walls, filling defects and tumefactive processes. Especially in 1 case, there was an appearance of invasive bladder carcinoma on CT (fig. 1). Cystoscopies visualized erythematous and edematous mucosal areas in 5 cases; diagnostic cold-cup biopsies in all of them, and, additionally, fulguration for a bleeding mucosal lesion in one were done. In 1 of 3 cases with tumor-like lesion, a mass was palpated at bimanual examination. At cystoscopy, he had a wide, erythematous, solid lesion over the trigone and bladder neck, which was simulating an invasive carcinoma. Cystoscopies of the other two revealed erythematous and papillary mucosal lesions. Tumors in 3 cases were resected transurethrally. Biopsy specimens of all patients revealed the histologic changes of eosinophilic cystitis. Histologically, some cases showed acute, and some others chronic inflammatory infiltrate in the lamina propria. The common finding in all cases was presence of eosinophilic infiltrate. Eosinophils were more notable in acute stage and fewer in the chronic stage confirming the literature [13] (fig. 2). An asymptomatic case underwent medical therapy for 1 month including 120 mg fexofenadine hydrochloride twice daily. Cystoscopies were done every 3 or 6 months during 2 years. No recurrence of TCC or eosinophilic cystitis was established. Other cases were followed for 5–25 months (mean 12.4). Three of them, who had undergone only cystoscopy and cold-cup biopsy, were prescribed 60 mg terfenadine twice daily and 20 mg tenoxicam during 1–3 months. They became symptom-free and control cystoscopies showed no abnormal finding. One case recovered completely following fulguration; therefore, no
Kiliç/Erguvan/Ipek/Gökçe/Günes¸/Aydin/ Baydinç
Fig. 1. In a male patient, CT shows a wide tumoral lesion protruding into the lumen at bladder base and neck, which resembles an invasive carcinoma (black arrow). A Foley catheter balloon is seen at bladder base.
Fig. 2. Acute inflammatory infiltrate rich in
eosinophils is seen in the edematous lamina propria. Black arrow indicates an eosinophil. Congested vessels are also discerned. HE. !200.
further therapy was given. Cases with mass lesion were followed for 6–18 months (mean 13.6). They underwent steroid therapy with oral prednisone (20 mg daily for 4–6 weeks that was tapered to 10 mg daily for 1 week, 5 mg daily for 1 week and 5 mg every other day for 1 week).
Symptomatically and cystoscopically, 2 of them improved completely. But disease recurred in the case with wide tumor at trigone 5 months later. Another course of prednisone was given for 3 months. This therapy achieved complete improvement.
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Discussion
According to a report, the incidence of eosinophilic cystitis for 1,000 bladder biopsies performed for the suspicion of having bladder tumor was 1.7% [3]. In another report, only one case was diagnosed by random bladder biopsy in 150 consecutive patients with unexplained irritable micturition complaints [4]. In our clinic, the disease rate was 2.2% for 365 bladder biopsies that were done in 4 years to evaluate several problems. The disease was reported in all age groups from 5 days to 87 years with a lower frequency in children. Thirtythree of 180 cases were children (22 males and 11 females). Eosinophilic cystitis affected men more often than women. The etiology of eosinophilic cystitis has remained poorly understood in spite of many case reports. In a report in which the data of 83 cases from the literature were reviewed, no underlying cause was recognized in 24 (29%) [5]. However, in the remaining 59, one or more associated conditions were established, such as transitional cell carcinoma of bladder with or without intravesical chemotherapy (mitomycin-C, thiotepa) in 25%, respiratory diseases (asthma and rhinitis) in 16%, bladder outlet obstruction in 13%, various medications (sulphonamides, warfarin, antranillic acid, cyclophosphamide, methicillin) in 8.5%, autoimmune and other related disorders in 8.5%, nonurological parasitic disorder in 2.4%, and eosinophilic enteritis in 2.4%. There were 2 cases with asthma, and 2 with coronary artery disease in our series. The most predominating symptoms were frequency (68.3%), dysuria (61.7%), hematuria (58.96%), pain (48.9%), urinary retention (11.1%), and nocturnal enuresis [4] in 1 case. As in our 1 case, when the lesion was located at or near the bladder neck, it presented as urinary retention [6]. Sometimes asymptomatic cases, as in our specific case, were identified during routine cystoscopic surveillance of bladder carcinoma [5]. In most of the cases, physical examination revealed suprapubic tenderness [3, 5] similarly to present cases. In a report authors pointed out that mass was palpated on anterior rectum or vaginal wall [4]. In our series a mass also was palpable at bimanual examination. Urinalyses of 180 cases usually showed hematuria and/ or pyuria (77%). The ratio of positive urine culture was only 20.5%. Eosinophilia was positive in only 42.5% of 141 cases. Peripheral eosinophilia, although diagnostically helpful if present, is unusual. Eosinophils are rarely identified in the urinary sediment, because they are rapidly degraded or there is little mucosal shedding [5]. In
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pathogenesis, IgE may play a potential role by means of binding to various antigens, activating mast cell degranulation, eosinophil attraction and release of damaging enzymes [5]. Dubucquoi et al. [14] suggested that numerous activated eosinophils synthesized and secreted IL-5 that could enhance the activation of eosinophils and their cytotoxic potential in bladder tissues. Sano et al. [15] suggested that the measurement of eosinophil cationic protein (ECP) in serum and urine was an appropriate marker. IVP and CT have been used to define the abnormal conditions related to disease. These examinations revealed hydronephrosis, filling defects, irregular bladder walls, wall thickening, bladder contracture, and bladder masses in some cases. As in our cases eosinophilic cystitis may be characterized by pseudotumors due to an extensive infiltration of the bladder wall that may resemble an invasive neoplasm. Cystoscopy is a very important examination at diagnosis. At cystoscopy of most cases, edematous, ulcerative, or hyperemic mucosa lesions were defined. 56 cases had tumor-like lesions. 63.7% children presented with a tumor in the bladder. 147 (81.7%) patients were defined as cured after various treatments; such as removal of allergen, cystoscopic fulguration, transurethral resection, steroids, antihistamines, antibiotics, nonsteroidal anti-inflammatory drugs, and partial or total cystectomy and urinary diversion. In children, symptoms subsided spontaneously or during corticosteroid therapy in 22 cases including 17 cases with a bladder mass. Profuse hematuria was treated successfully with intravesical dimethylsulfoxide instillations [7]. In a pediatric case, treatment with cyclosporin-A for 8 months achieved complete clinical, radiological, and histopathological cure with no side effects [8]. However, treatment has not yet been standardized. Most cases may be managed conservatively with spontaneous resolution of bladder pathology and symptoms [4, 5]. But, especially in adults, recurrence is a frequent finding. Because of probable immunologic nature of disease, corticosteroids have become the mainstay of the therapy, especially in patients who have an unresolved disease with anti-inflammatory drugs and antihistamines and have wide tumoral lesions. Only in patients who have a disease intractable to conservative treatments and presenting as profuse hematuria, contracted bladder, uni- or bilateral distal ureteral involvement together with renal failure, partial or total cystectomy and diversion must be considered [3–5, 11]. The most important complications of eosinophilic cystitis are significant hematuria, bladder contraction, distal ureteral involvement, upper tract dilatation and deterio-
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ration of renal functions. Differential diagnosis includes other forms of intractable cystitis, such as interstitial cystitis, tuberculosis and bladder neoplasms.
Conclusions
Eosinophilic cystitis is an inflammatory disease of the bladder. Its definitive etiology is unknown, but probably it has an immunologic origin. Clinically, radiographically,
and cystoscopically, it may mimic other inflammatory type bladder lesions and bladder neoplasms. For the definitive and differential diagnosis, cystoscopic biopsy and histopathologic examination are mandatory. The type of treatment is related to severity of the symptoms, degree of bladder involvement and presence of complications. The disease usually has a benign course and recurrence potential.
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7 Sibert L, Khalaf A, Bugel H, Sfaxi M, Grise P: Intravesical dimethylsulfoxide instillations can be useful in the symptomatic treatment of profuse hematuria due to eosinophilic cystitis. J Urol 2000;164:446–448. 8 Pomeranz A, Elikaim A, Uziel Y, Gottesman G, Rathaus V, Zehavi T, Wolach B: Eosinophilic cystitis in a 4-year-old boy: Successful long-term treatment with cyclosporin A. Pediatrics 2001;108:E113. 9 Gög˘üs¸ C, Türkölmez K, Tolunay O, Gög˘üs¸ O: Eosinophilic cystitis in a case with an initial diagnosis of invasive bladder tumor. Urol Int 2000;64(3):162–164. 10 Kayı˙gil O, Özbag˘ı˙ T, Çakar S, Metin A: Contracted bladder secondary to eosinophilic cystitis. Int Urol Nephrol 2001;33:341–342. 11 Lin HY, Chou YH, Wu WJ, Huang CH, Chai CY: Eosinophilic cystitis: Eight case reports and literature review. Kaohsiung J Med Sci 2002;18:30–34.
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12 Clark T, Chang SS, Cookson MS: Eosinophilic cystitis presenting as a recurrent symptomatic bladder mass following intravesical mitomycin-C therapy. J Urol 2002;167:1795. 13 Reuter VE, Melamed MR: The urothelial tract: renal pelvis, ureter, urinary bladder and urethra; in Sternberg SS (ed): Diagnostic Surgical Pathology, ed 3. China, Lippincott Williams and Wilkins, 1999, vol 2, pp 1853–1891. 14 Dubucquoi S, Janin A, Desreumaux P, Rigot JM, Copin MC, Francois M, Torpier G, Capron M, Gosselin B: Evidence for eosinophils activation in eosinophilic cystitis. Eur Urol 1994;25:254–258. 15 Sano K, Terashima K, Gotoh K, Ijiri R, Tanaka Y: A case of eosinophilic cystitis in a 5-yearold boy. Int J Urol 2000;7:54–56, discussion 57.
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