The spectrum of eosinophilic cystitis in males: case series and literature review.
Abstract: * Context.--Eosinophilic cystitis (EC) is an inflammatory condition of the bladder that has been linked to food allergens, infectious agents, drugs, and other genitourinary conditions. Like interstitial cystitis, EC has a strong female predominance. It is characterized by an intense eosinophilic infiltrate in the acute phase and fibrosis in the chronic phase.

Objectives.--To document and focus on specific features of EC in males and highlight the relationship between clinical and histopathologic findings.

Design.--The bladder biopsies of male patients were reviewed. Eight cases of EC were selected.

Results.--Several known associations were noted as well as unreported features and associations such as CharcotLeyden crystals, celiac disease, lupus anticoagulant, and additional viral and bacterial agents.

Conclusions.--Eosinophilic cystitis represents a response to a variety of agents and may often be overlooked. The temporally biphasic morphologic features are the hallmark of this condition. Because clinical and imaging studies are not specific, a high index of clinical suspicion is often crucial to the correct diagnosis and proper management of EC.

(Arch Pathol Lab Med. 2009;133:289-294)
Article Type: Report
Subject: Cystitis (Risk factors)
Cystitis (Diagnosis)
Cystitis (Demographic aspects)
Allergens (Health aspects)
Kidneys (Biopsy)
Kidneys (Usage)
Authors: Popescu, Oana-Eugenia
Landas, Steve K.
Haas, Gabriel P.
Pub Date: 02/01/2009
Publication: Name: Archives of Pathology & Laboratory Medicine Publisher: College of American Pathologists Audience: Academic; Professional Format: Magazine/Journal Subject: Health Copyright: COPYRIGHT 2009 College of American Pathologists ISSN: 1543-2165
Issue: Date: Feb, 2009 Source Volume: 133 Source Issue: 2
Accession Number: 230151964
Full Text: Eosinophilic cystitis (EC) is an inflammatory condition first described more than 85 years ago. (1) Eosinophilic cystitis was regarded as a consequence of food allergens, (1) although other factors (inhalants, bacteria, viruses, and parasites) drew consideration. (2-4) Later, other allergenic agents were implicated such as condom antigens, contraceptive jellies, iodine, and anesthetic ointments. (5) Brown, in 1960, referred to the condition as eosinophilic granuloma of the bladder and asserted a relatedness to Hand-Schuler-Christian and Letterer-Siwe diseases. (6) With time other factors were proposed as putative initiators of EC, including parasitic infestation with Toxocara cati, (7) Echinococcus granulosus, (8) and Sparganum. (9) Extrapelvic infectious and inflammatory conditions were also noted: extensive skin infections with omphalitis, (10) infected urachal remnant, (11) and hypersensitivity to chromate catgut sutures. (12) A variety of medications including salicylazosulfapyridine, tranilast, Coumadin, and intravesical thiotepa and mitomycin were also implicated. (13-17) Finally, prostatic hyperplasia, and surgeries or tumors of the bladder and prostate were associated with EC. (12,18-21) Eosinophilic cystitis has been reported at all ages (5 days to 87 years), 20% of cases occurring in children.21 It shows a striking female predominance of 87%. (4) Other studies (21,22) showing equal sex incidence or slight male pre dominance reflect study group composition rather than actual incidence rates. Only one previous study has focused exclusively on male patients. (23) Eosinophilic cystitis in males has the same age distribution but appears to be related to different pathological genitourinary conditions and less associated with systemic or other organ conditions. (7,17,19-21,23,24) Clinical onset is commonly marked by urinary frequency, dysuria, gross hematuria, and suprapubic pain during micturition. Less frequent manifestations include microscopic hematuria, urinary retention, gastrointestinal symptoms (vomiting, diarrhea, tenesmus, bloody stool), urgency, incontinence, fever, skin rash, pneumaturia, and nocturnal enuresis. (1-26)

Urine cultures in EC are positive in some cases. (6,15,20,24,27) Cystoscopy findings are variable: ulcers, exudates, edematous bullae, or polyps (which may simulate malignancy). (2-10,12-27) Imaging studies (computed tomography scan, ultrasonography) may reveal thickening of the bladder wall and occasional mucosal polyps mimicking papillary tumors. (28-32)

Yamada and Taguchi (33,34) described the clinical features of 15 patients with contracted bladders. Four of their patients had distinct histopathologic changes in the bladder including a leukocytic infiltrate rich in lymphocytes, plasma cells, and eosinophils. The other 11 had renal tuberculosis and bladder lesions ascribed to mycobacterial infection. Although the authors did not indicate a threshold separating these groups, the inflammatory infiltrate, particularly the eosinophilia, was stressed. They regarded the first group as part of an interstitial cystitis phenomenon and discussed possible mechanisms of immune system dysregulation (autoimmunity, connective tissue disease, allergy, postinfectious antigenic cross-reactivity) and other factors that might be contributing factors.

The histopathologic features of EC may be classified as either "acute" or "chronic" phase. (2-4,21,23) The acute phase presents with tissue eosinophilia, mucosal edema and hyperemia, and muscle necrosis. In the chronic phase eosinophilia is not conspicuous, chronic inflammation is present to a variable degree, and scarring may be prominent. Early reports noted abundant eosinophils in 5% of the patients, these reflecting the early stage of disease. (2-4) Massive eosinophilic infiltrates are noted in areas adjacent to muscle necrosis (in the acute phase) but are absent in areas of muscle wall scarring (chronic phase). Mast cells and plasma cells may also be prominent in the chronic phase and squamous metaplasia and cystitis cystica have been reported. (23)

The biphasic nature of EC manifests the underlying mechanisms. In the acute phase antigen-antibody complexes attract eosinophils, (35,36) which release potent cationic proteins (such as urine eosinophil cationic protein) in high concentration that serve to enhance local inflammation and associated myonecrosis. (37) The acute phase of EC is triggered by a wide variety of injurious stimuli with resultant inflammation, oxidative stress, and creation of a cytokine-rich microenvironment, a potent recruiter of eosinophils and basophils. (38-40) In the wake of the intense proinflammatory storm of the acute phase, eosinophils secrete interleukins 5 and 12. These activate natural killer cells and T lymphocytes, favoring transition from a [T.sub.H]2 to a [T.sub.H]1 immune response (41) and the beginning of the chronic, smoldering phase of low-grade inflammation and fibrosis. The most frequent complication of EC is unilateral or bilateral hydroureteronephrosis, possibly due to inflammation obstructing the intramural ureter. Less frequent complications include uremia, (15) eosinophilic ureteritis, eosinophilic cholangitis, (42,43) retroperitoneal fibrosis, (44) spontaneous bladder perforation with persistent vesical fistula, (45) and vesicoureteral reflux. (15,20,42-46) Therapy begins with removal of any identifiable offending antigen that affords a 96% cure rate. (21) Antihistamines and corticosteroids have proven efficacious. (21-23) In severe cases electrocoagulation, (47) endoscopic resection of bladder mass, (20,27) partial cystectomy, (7,12,20,30,45) radical cystectomy with reconstruction, (27) or prostatectomy (19,44,47) have been required.

MATERIALS AND METHODS

Between 1984 and 2005 (inclusive) 10 341 bladder specimens (biopsies or resections) were identified in the anatomic pathology archives of the State University of New York Upstate Medical University, Syracuse. Nine hundred forty-seven of these noted cystitis in male patients. These specimens and corresponding medical records were reviewed in accordance with institutional review board guidelines. We looked for the features of acute and/ or chronic stage EC in all biopsies as morphologically consistent with EC if the infiltrate exceeded an average of 1 or more eosinophils per high-power field (HPF). A minimum of 10 HPFs were observed to avoid potential spurious inclusion of inappropriate cases (some biopsies had limited material). Bladder biopsies with marked and extensive eosinophilic infiltrate were selected. Individual biopsies were regarded as morphologically consistent with EC if the infiltrate exceeded an average of 1 or more eosinophils per HPF. Biopsies with fewer eosinophils but with clinical history of chronic or repeated repetitive episodes of bladder pain were examined for the presence of fibrosis, mast cells, plasma cells, and eosinophils. Clinical features were reviewed in patients with bladder eosinophilia to exclude interstitial cystitis, a distinct clinical entity that may exhibit morphologic overlap with the chronic phase of EC. (48) However, features such as mucosal ulceration covered by fibrin and a mononuclear infiltrate rich in mast cells are characteristic to interstitial cystitis but are not encountered in the chronic phase of EC. The chronic phase of EC presents with an inflammatory infiltrate containing a variable number of eosinophils and there is muscular fibrosis but no necrosis. Also, the acute phase of EC may present with focal muscular necrosis but this is associated with a prominent eosinophilic infiltrate in which mast cells are inconspicuous.

Eight cases of EC were identified. Patient ages, clinical symptoms, morphologic features, associated conditions, endoscopic findings, therapeutic approaches, and outcomes for all 8 were investigated and are presented in the Table.

RESULTS

Ages ranged from 18 months to 79 years. All patients had at least 1 eosinophil per HPF (X40 magnification). This is an equivalent density to the one reported by Yamada and Taguchi. 49 Most patients had one or more associated genitourinary conditions such as prostatic hyperplasia (patients 4 and 7), lithiasis (patients 2 and 5), indwelling Foley catheter (patients 1 and 3), urinary tract infections (patients 1, 6, and 7), irritable bladder symptoms (patients 3 and 4), and urethral strictures (patient 7). Associated surgeries included abdominal perineal colectomy (patient 3, rectal carcinoma), transurethral resection of the prostate (patient 3, hyperplasia), and bladder neck resection (patient 3, outlet obstruction). Associated malignancies included genitourinary primaries as urothelial carcinoma (patients 2, 3, and 7), rhabdomyosarcoma (patient 6), and malignancies involving other systems including chronic myelogenous leukemia (patient 8) and rectal carcinoma (patient 3). Atopic/allergic conditions such as asthma (patient 7), celiac disease (patient 4), and febrile transfusion reaction (patient 6) were also noted. Patient 3 exhibited a lupus anticoagulant, discovered during the EC episode. All but one patient had repeated episodes of EC. Patient 5 had only one episode of EC related to bladder calculi, resolving without further bladder complaints. Although all 8 patients had biopsy-proven EC, not all EC episodes prompted biopsy. All patients (except patients 2 and 4) had bladder biopsy during the acute phase only. Patient 3 illustrates the clinical presentation, episodic occurrence, and morphology typical of EC (Figure 1). Patients 2 and 4 had several bladder biopsies performed (6 and 3, respectively). The initial biopsies showed numerous eosinophils, edema, hemorrhage, and rare foci of necrosis. These findings were followed in subsequent biopsies by fibrosis of the bladder wall with predominance of plasma cells, mast cells, and only rare eosinophils. Patient 6 showed foci of both acute and chronic phase, simultaneously (Figures 2 and 3). The outcome of most of our patients was favorable; after appropriate management, the symptoms resolved. However, patient 3 experienced continued genitourinary issues, with bladder symptoms for more than 9 years with late development of penile pain.

[FIGURES 1-4 OMITTED]

COMMENT

Eosinophilic cystitis is a rare condition, one that may go unrecognized, especially in the chronic phase and especially in males. Eosinophilic cystitis should, however, be a diagnostic consideration in all patients with frequent and unexplained bladder or other genitourinary complaints. Correlation of all patient bladder biopsy material (current and previous) with clinical history is necessary for arrival at a correct impression and management plan. Eosinophilic cystitis is not a distinct diagnostic entity but rather represents a response to a variety of agents and is encountered in an ever-growing number of conditions. Most reports of EC are based on individual cases or small series although more comprehensive studies have been conducted. (4,22) Hellstrom et al (23) studied EC in 16 male patients. Study of the literature regarding EC in male patients shows a strong association with genitourinary conditions compared with female patients but there are no differences regarding age distribution and clinical outcome. Our study bears out the findings of prior reports and validates the criteria of Yamada and Taguchi (49) who reported 20 or more eosinophils per five X20 fields (comparable eosinophil density). A prominent eosinophilic infiltrate (at least 1 eosinophil per HPF in at least 10 HPFs or Yamada and Taguchi (49) criteria) associated with edema and occasional muscle necrosis are features of the acute phase of EC. Less numerous eosinophils with lymphocytes, plasma cells, and mast cells and muscle fibrosis define the chronic phase of EC. New observations include Charcot-Leyden crystals (Figure 4) and association with celiac disease, lupus anticoagulant, and new viral and bacterial infectious agents. Charcot-Leyden crystals, often encountered in asthma or other eosinophilic disorders, have not previously been noted (by light microscopy) in EC (1 report describes them, ultrastructurally). (33) Association with celiac disease, likewise, has not been previously reported. Celiac disease is related to gluten intolerance. The numerous bouts of EC, viewed on a background of celiac disease (patient 4), suggest a possible underlying immunologic dysfunction at work in both processes. Association of lupus anticoagulant, a condition related to antiphospholipid antibodies, and EC has not been previously reported. Antiphospholipid antibodies may play a role in the generation of EC or may be generated secondary to the tissue damage occurring in EC, although no mechanism linking EC and lupus anticoagulant is known. BK virus infection of the urinary bladder has not been previously reported in association with EC. Hemorrhagic cystitis is the clinical correlate of BK viral bladder infection and is a well-known complication following allogeneic hematopoietic stem cell transplantation. (50) Numerous reports of hemorrhagic cystitis exist, but none has correlated the clinical with the pathologic findings, recognizing the biphasic temporal pattern of EC. Enterobacter and Proteus mirabilis are 2 microbial agents not previously observed in association with EC. Cultures revealed both organisms in the setting of a bladder mass (patient 6) thought initially to be recurrent rhabdomyosarcoma. Many of the clinical, imaging, and morphologic findings and outcomes in our study are concordant with previous reports. Several patients (patients 1, 6, and 7) had repeated bacterial urinary tract infections. Five (patients 2, 3, 4, 5, and 7) exhibited association of EC with prostatic hyperplasia, bladder stones, prostate or bladder surgery, or medication as detailed in the Table. In the literature most cases of urothelial carcinoma-associated EC have developed after chemotherapy. Only one report notes EC at the time of diagnosis of urothelial carcinoma, prior to chemotherapy. (17) Two of our EC patients presented with urothelial carcinoma, one with recurrent invasive carcinoma and one with carcinoma in situ, the latter patient prior to any intravesical chemotherapy. Patients 2 and 4 illustrate, through serial biopsies, the characteristic temporal pattern of morphologic findings in EC. The initial biopsies revealed marked eosinophilic infiltrates with occasional foci of necrosis and ulceration. Subsequent biopsies showed a predominantly eosinophilic infiltrate but with increasing numbers of lymphocytes and plasma cells. Later biopsies showed many plasma cells and marked fibrosis as well as some mast cells and only scattered to rare eosinophils.

Current thought regarding therapy is summarized in a recent management algorithm, (51) which calls for withdrawal of any identifiable precipitating factor. If none is evident, laboratory studies (urinalysis and culture) and cystoscopy with biopsy are recommended. Nonsteroidal anti-inflammatory agents and antihistamines are favored first-line agents. In refractory cases corticosteroids, cyclosporine, and azathioprine are recommended considerations. Ultimately, if medical management fails, cystectomy may be necessary. Longterm follow-up is recommended for all patients.

Eosinophilic cystitis remains an important, albeit infrequent condition in males evaluated for diverse genitourinary tract symptomatologies. Accurate diagnosis is critical because EC therapy is unique and, with identification and withdrawal of precipitating agents, treatment is curative in most individuals. Diagnosis hinges on clinical assessment and histopathology, recalling the temporally biphasic morphologic features. Presence of Charcot-Leyden crystals may offer a clue in acute phase biopsies. Finally, a diagnosis of EC should raise consideration of the possibility of concurrent associated malignancy or other associated conditions.

We acknowledge and are deeply appreciative of the help provided by Taro Iguchi, MD, PhD.

Accepted for publication July 21, 2008.

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Oana-Eugenia Popescu, MD; Steve K. Landas, MD; Gabriel P. Haas, MD

From the Division of Anatomic Pathology, Children's and Women's Health Centre of British Columbia, Vancouver (Dr Popescu); and the Departments of Pathology and Urology (Dr Landas) and Urology (Dr Haas), State University of New York Upstate Medical University, Syracuse.

The authors have no relevant financial interest in the products or companies described in this article.

Reprints: Steve K. Landas, MD, Department of Pathology and Urology, State University of New York Upstate Medical University, 750 E Adams St, Syracuse, NY 13210 (e-mail: landas@upstate.edu).
Age of Patients, History, Clinical Symptoms, Associated
Conditions, Endoscopic Imaging, Morphologic Features,
Therapeutic Approach, and Outcome *

Patient   Age     History
  No.

  1       27 y    Paraplegia (after MVA) UTI with Klebsiella
  2       34 y    Urothelial carcinoma, high grade of the
                  bladder, instillations with mitomycin and
                  thiotepa, bladder stones
  3       79 y    Chronic indwelling Foley catheter, [beta]
                  thalassemia trait, rectal carcinoma,
                  transurethral resection of prostate
  4       61 y    Numerous episodes of irritable bladder
                  symptoms (during 6 y), celiac sprue with
                  a few exacerbations, prostatic hypertrophy
  5       52 y    Negative for any medical or surgical
                  history
  6       18 mo   Embryonal rhabdomyosarcoma of the pros-
                  tate and bladder neck, UTI with Klebsiella
                  pneumoniae and Enterococcus
  7       79 y    Asthma, coronary artery disease, multiple
                  UTIs positive for Escherichia coli,
                  multiple upper respiratory infections,
                  prostatic hypertrophy, postresection
                  urothelial carcinoma, high grade
  8       39 y    Chronic myelogenous leukemia following
                  allogeneic peripheral blood stem cell
                  transplant

Patient   Symptoms or Associated              Image by Endoscopy
  No.     Conditions

  1       Hematuria, indwelling Foley         Diffuse hemorrhagic
          catheter, Coumadin                  edema  of all bladder
                                              walls and  deviation
                                              of the left ureter
  2       NA (follow-up for carcinoma)        NA
  3       Urinary retention, urethral         Erythematous bladder
          voiding symptoms, frequency and     wall
          urgency, lupus anticoagulant
  4       Frequency, urgency, and             NA
          pelvic/perineal pain
  5       Right ureteral calculus,            Bladder neck
          persistent pain                     contracture
  6       Fever and pancytopenia, febrile     Bladder neck mass
          transfusion reaction (premedicat-   (2.5 cm in the
          ed with an antihistaminic); urine   largest dimension)
          culture positive for Enterobacter
          and Proteus mirabilis
  7       Decreased urinary stream            Small papillary
                                              urothelial carcinoma
  8       Burning on urination, hematuria,    Numerous erythematous
          BK virus infection                  patches at the dome
                                              and the posterior
                                              bladder wall

* MVA indicates motor vehicle accident; UTI, urinary tract infection;
NA, not applicable; and EC, eosinophilic cystitis.

Extended

Biopsy of Acute Phase                   Biopsy of Chronic Phase

Intense eosinophilic infiltrate         NA
extending from the  mucosa into
the muscular wall, small areas of
necrosis and Charcot-Leyden
crystals were noted
I. Recurrent urothelial carcinoma       V. Plasma cells, mast cells,
and numerous eosinophils in the         and a few eosinophils, and
lamina propria, few iron-laden          moderate fibrosis later-
macrophages, areas of ulceration        marked fibrosis with rare
and necrosis                            inflammatory cells
II-IV. Marked eosinophilic infiltrate
of the bladder wall. In addition, a     VI. Marked fibrosis with rare
few iron-laden macrophages were noted   inflammatory cells (2 y after
as well as areas of ulceration and      the first biopsy)
necrosis
Urothelial carcinoma in situ, marked    NA
eosinophilic  infiltrate extending
deep in the submucosa and the
muscular layer
I. Eosinophilic infiltrate extending    III. Fibrosis of the bladder
deep in the lamina propria              wall with numerous plasma
                                        cells as well as scattered
II. Mixed inflammatory infiltrate       eosinophils and mast
composed of eosinophils, plasma         cells--2 y after the second
cells, and a few lymphocytes            biopsy
Numerous eosinophils in the bladder     NA
wall
Edema, fibrosis, foci of necrosis,      NA
numerous eosinophils and chronic
inflammatory cells
Multiple foci of necrosis, an intense   NA
eosinophilic infiltrate
Ulceration with granulation tissue,     NA
hemorrhage, and edema, areas with a
dense eosinophilic infiltrate and
areas with fibrosis

Biopsy of Acute Phase                   Therapy             Outcome

Intense eosinophilic infiltrate         Stopped Coumadin,   Cleared in
extending from the  mucosa into         fulguration         a few days
the muscular wall, small areas of
necrosis and Charcot-Leyden
crystals were noted
I. Recurrent urothelial carcinoma       None for EC         No symp-
and numerous eosinophils in the                             toms after
lamina propria, few iron-laden
macrophages, areas of ulceration
and necrosis
II-IV. Marked eosinophilic infiltrate
of the bladder wall. In addition, a
few iron-laden macrophages were noted
as well as areas of ulceration and
necrosis
Urothelial carcinoma in situ, marked    Transurethral       Residual
eosinophilic  infiltrate extending      resection of        penile pain
deep in the submucosa and the           the bladder neck
muscular layer
I. Eosinophilic infiltrate extending    None                No symp-
deep in the lamina propria                                  toms after

II. Mixed inflammatory infiltrate
composed of eosinophils, plasma
cells, and a few lymphocytes
Numerous eosinophils in the bladder     Removal of          No symp-
wall                                    calculus            toms after
Edema, fibrosis, foci of necrosis,      Spasmolytic         No symp-
numerous eosinophils and chronic        medication,         toms after
inflammatory cells                      antibiotics
Multiple foci of necrosis, an intense   Dissection of       No symp-
eosinophilic infiltrate                 urethral            toms after
                                        strictures
Ulceration with granulation tissue,     None                No symp-
hemorrhage, and edema, areas with a                         toms after
dense eosinophilic infiltrate and
areas with fibrosis
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