Eleven men were identified as having urogenital involvement related to WG. Their mean age at diagnosis was 53 years (range, 21–70 yr). Upper respiratory tract manifestations were present in all patients but 1 (90%), pulmonary opacities were present in 9 (81%), glomerulonephritis in 5 (45%), ocular manifestations in 3 (27%), mono- or polyneuropathy in 3 (27%), cutaneous involvement in 5 (45%), articular manifestations in 7 (63%), and involvement of the central nervous system in 2 (18%) patients. The main urogenital and extra-urogenital features are listed in Table 1. The median follow-up from the onset of urogenital manifestations was 56 months (range, 2–156 mo).
Urogenital involvement was present at the onset of WG in 9 cases, it was the first clinical evidence of WG in 2 (Patients 1, 10), and it was a symptom of WG relapse in 6 cases (Patients 1, 3, 4, 6, 9, 11).
Prostatitis and orchitis were the most common manifestations, and were observed in 4 patients, occurring simultaneously in 2 of these cases (Patients 5, 11). Prostatitis was revealed by dysuria, urinary frequency, and occasionally gross hematuria. Two patients presented with acute urinary retention (Patients 5, 9). Their prostates were enlarged and tender, with a hypoechoic lesion that mimicked an abscess in 1 patient (Patient 5; see Figure 1). Orchitis caused unilateral testicular pain with enlargement and redness of the testis in 4 patients (Patients 5, 6, 8, 11). Two patients presented with an asymptomatic renal pseudotumor (Patients 2, 7) (Figure 3). One patient developed penile ulceration at initial presentation (Patient 1), 1 patient presented with epididymitis at the time of WG diagnosis (Patient 3), and 1 patient had ureteral stenosis as the sole manifestation of relapse (Patient 4).
Therapy and Outcome
All patients but 1 received glucocorticoid therapy and an intravenous CYC regimen as their initial treatment (Table 2). A complete response to the systemic manifestations was observed in 10 patients, and 1 died 2 months after treatment initiation. Two patients (20%) had a partial urogenital response. Patient 1 was treated with MTX and prednisone without success. He was then given intravenous CYC and glucocorticoids, which resulted in a rapid and complete response.
Three patients underwent surgical procedures at the time of diagnosis: suprapubic cystostomy for acute urinary retention (Patient 5), radical prostatectomy because of symptomatic prostatic involvement and suspicion of prostatic cancer (Patient 10), and nephrectomy for suspected carcinoma (Patient 2). Patient 5 underwent suprapubic catheterization; the catheter was removed after 6 months.
Three patients had surgical procedures during follow-up: a ureteral double J stent for unilateral ureteral stenosis, then resection of the stricture with end-to-end anastomosis (Patient 4), and transurethral resection of the prostate because of persistent dysuria (Patients 5, 9).
Seven patients (63%) experienced 13 recurrences of WG under maintenance therapy. Four patients experienced urogenital relapse (36%) that was isolated (n = 2) or was associated (n = 2) with other lesions caused by WG. All but 1 urogenital relapse occurred in patients receiving immunosuppressive agents. Patient 1 had recurrence of penile ulceration while receiving azathioprine. A change of treatment to IVIg, MTX, and prednisone resulted in marked clinical improvement, with resolution of the genital ulcerations. Patient 3 had 2 recurrences of epididymitis: 1 while receiving azathioprine and the other while treatment free. Among the 4 patients with prostatitis, 2 experienced recurrence of urogenital symptoms related to WG while receiving mycophenolate mofetil (Patients 9, 11), 2 patients underwent transurethral prostatic resection because of persistent dysuria despite immunosuppressive therapy (Patients 5, 9), and 3 suffered recurrent infections of the urinary tract (Patients 5, 9, 11).
Within the median follow-up of 56 months, 3 patients died. However, death was not related to urogenital factors. One patient died rapidly during the initial flare-up of WG from severe neurologic involvement (Patient 7). The second patient died from metastatic carcinoma of the upper airway while in remission from WG (Patient 4). The third patient committed suicide while in stable remission at 13 years postdiagnosis (Patient 2). At the end of follow-up, all other 8 patients were free of urogenital manifestations related to WG. However, Patient 5 had undergone a second transurethral resection of the prostate because of persistent dysuria: a prostate histologic examination showed adenocarcinoma.
Involvement of the urogenital system in WG is considered uncommon and has been the subject of only a few reports. We report 11 patients with urogenital manifestation of WG identified among the approximately 1700 patients in the FVSG database. Given the study design, our series cannot pretend to be exhaustive and does not allow us to deduce the incidence of urogenital tract involvement in WG. Nevertheless, the small number of patients found in the current study confirms the infrequency of this condition reported in previous series. For example, no urogenital manifestation was reported in a series of 85 patients with WG followed at the National Institutes of Health (NIH, Bethesda, MD) for 21 years.17 In another study of 158 patients, biopsy-proven WG in the urethra, cervix, and vagina was noted in less than 1% of the cases.27
Authors from 2 tertiary centers (Lê Thi Huong et al28 and Davenport et al12) reported, more than 10 years ago, that the clinical features and treatment of patients with WG affects the urogenital tract. Unlike what is usually observed in “classic” WG, which affects women and men equally in large cohorts,27 in the present series, as in those earlier reports, almost all the patients were male.
It is noteworthy that in most of the cases from the present series, regardless of the patients’ age, urogenital involvement was an initial manifestation or was the first clinical evidence of WG. In previous series,12,28 it preceded the diagnosis of WG in 5 of 16 cases (31%) and occurred at the time of diagnosis in 8 patients (50%). Based on their results, Davenport et al12 advocate ANCA testing for patients who present with chronic or recurrent urogenital manifestations, especially if the patient’s past or present history suggests the presence of vasculitis. In the present series, ANCA testing was positive in 9 of 11 cases. However, in the particular setting of urogenital manifestations, physicians should be aware that patients with tuberculosis could be falsely diagnosed as having WG on the basis of an ANCA test alone.20 Indeed, although ANCA test results can be used by clinicians as adjunct evidence for the diagnosis of WG in patients with limited urogenital manifestations, these results should be viewed in the context of the patient’s complete clinical picture and the prevalence of WG in the clinical setting in which the patient is seen.
Prostatitis is considered the most common urogenital manifestation of WG, and was observed in 3 of the 8 patients in the study by Lê Thi Huong et al28 and in 4 of our patients. In previous series of WG patients, prostatic involvement has been reported in 2.3%–7.4% of cases.55,64 However, when considering granulomatous prostatitis, Stillwell et al56 reported that only 4 cases in a series of 200 cases appeared to be manifestations of WG. In this setting, infectious agents, such as mycobacteria, fungi and spirochetes, the Brucellaceae family, Schistosoma species, and Echinococci species; and noninfectious causes of granulomatous prostatitis, including transurethral resection, allergic and simple granulomatous prostatitis, as well as sarcoidosis, should be excluded.56
As noted in the current series, the clinical course of WG in the prostate includes urinary frequency, dysuria, gross hematuria, and, as in 2 of our cases, acute urinary retention.28,55 On physical examination, the prostate appeared firm, enlarged, and indurated, and sometimes had an indurated area mimicking carcinoma,28,55,60,66 or a necrotic area mimicking an abscess,28,29 as in Case 5. Prostate serum antigen may be slightly elevated.41 Although obstructive urinary symptoms are considered to improve rapidly with medical therapy, 2 of our patients underwent prostate resection during follow-up because of persistent dysuria.
Unilateral orchitis was observed in 4, and epididymitis in 1 of our patients. In previous series, only 3 cases had testicular involvement;12,28 these 3 patients were not reported as having typical granulomatous inflammation of the testes. To our knowledge only 1 other diagnosis of WG made from testicular pathology has been reported,2 as in our Case 5. Other testicular involvement in WG includes embolic testicular infarction secondary to nonbacterial thrombotic endocarditis45 and testicular infarction.6 WG limited to the epididymitis is very rare, with only 2 cases previously reported.3,42
A renal mass was observed in 2 of our 11 patients. The presence of a solitary or multiple renal masses resembling carcinoma in patients suffering from WG is rare: to our knowledge, only 13 cases have been reported.10,16,33,36,37,50–54,59,62,63 The inflammatory nature of these tumors has always been confirmed by histology and necrotizing vasculitis. Such a presentation should be investigated, as a case-control study58 found a link between WG and renal carcinoma, with an odds ratio of 8.7 compared to a control group of patients with rheumatoid arthritis. Although a more recent (2009) case-control study18 did not find clear evidence of an increased prevalence of preceding cancer in their WG cohort, the simultaneous occurrence of these 2 diseases has been reported in several other cases.57 These data emphasize, in such setting, the importance of confirming the diagnosis of suspected WG that presents with a renal mass after histologic examination and/or repeating imaging studies, so that appropriate treatment of mass lesions can be undertaken. However, a fine-needle biopsy during an abdominal CT scan should be avoided in patients with a strong suspicion of renal carcinoma. In doubtful cases, nephron-sparing surgery should be considered rather than total nephrectomy.
Ureteral stenosis was observed in 1 of our patients. This complication is rare: 17 cases (including ours) are reported in the literature.1,5,8,12,22,23,26,28,32,35,40,41,47–49 In most cases, ureteral involvement is an initial manifestation of WG. Ureteral stenosis is rarely reported as a recurrent feature of WG.48 This feature is usually revealed by urinary infection or hematuria.28 In 2 cases,35 a retroperitoneal pseudotumor encompassed both ureters and caused anuria. In most of these cases, stenosis was excised by surgery, and a pathologic examination revealed the histopathologic features of WG.
We report 1 patient who had penile ulceration due to angiitis, which revealed WG. To our knowledge, 17 cases of severe ureteral or urethropenile involvement have been previously described.4,12,14,15,21,24,28,31,39,43,46,55,61,65 As in the patient reported here, penile ulceration due to WG generally occurs as the presenting symptom, but may also be a sign of relapse. Urethropenile ulceration may mimic neoplasia and can be complicated by severe necrosis, which may require amputation.14,61
It is noteworthy that 2 urogenital localizations were observed either simultaneously or successively in 2 of our patients. Other urogenital manifestations of WG, not described in the current study, include uterine cervical involvement,7,38 bladder necrotic pseudotumor,19,24,28 and bladder neuropathy.25 It can be difficult to distinguish CYC toxicity from specific WG bladder involvement in patients with known WG. Cystoscopy is required for any durable urinary symptom in a WG patient who is or has been treated with CYC, to distinguish toxic from specific cystitis, and to exclude transitional carcinoma caused by this cytotoxicity.
Combined glucocorticoid and CYC therapy is the basic treatment for WG.11 A decisive step toward treating WG has been to develop a staged induction-maintenance strategy that reduces cumulative exposure to CYC. This strategy uses CYC to induce remission, followed by a less toxic immunosuppressant, such as azathioprine or MTX.44 This therapeutic regimen has been found to achieve either partial or complete remission in 91% and 75% of patients, respectively.27 However, induction relapses occur in approximately half of WG patients.9,27 But, as shown in the current study and in the study by Lê Thi Huong et al,28 urogenital manifestations respond rapidly to treatment with CYC and glucocorticoids. One patient who failed to respond to MTX and prednisone improved under CYC. Seven of our 11 patients (63%) experienced relapses under maintenance therapy, and 4 had urogenital recurrence (36%). Most urogenital manifestations can be resolved promptly with pharmaceutical therapy, although some patients need surgical procedures (for example, prostatic transurethral resection) because of persistent symptoms after receiving immunosuppressants.
In conclusion, symptomatic urogenital involvement is a rare feature of WG, but is probably underestimated because it is difficult to diagnose in some cases (such as ureteral stenosis and uterine cervical or testicular involvement). Because urogenital manifestations can be the first clinical symptom of WG, physicians should be aware of these presentations. Some presentations, such as the presence of a renal or prostate mass that mimics cancer, should be assessed to avoid unnecessary radical surgery.
Urogenital symptoms seem to be highly sensitive to CYC and glucocorticoid therapy. One-third of patients had urogenital relapse while on maintenance treatment. In this setting, CYC urothelial toxicity and urinary infection may occur in the course of WG and may mimic other manifestations, which should be excluded. However, most relapses rapidly resolve with medical treatment. Surgical procedures, such as a prostatic transurethral resection, can be useful in patients with persistent symptoms.
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