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Urologic manifestations of wegener granulomatosis
UROLOGIC
MANIFESTATIONS
OF
WEGENER GRANULOMATOSIS T. W. HENSLE, M.D. 14. E . M I T C H E L L , k4.D. K. K. CROOKS, ,M.D. D. ROBINSON, M.D. From the Urologic and Medical Services, Massachusetts General Hospital, and the Departments of Surgery and Medicine, Harvard Medical School, Boston, Massachusetts
ABSTRACT - Wegener granulomatosis is a disease characterized by necrotixing granulomatous ungiitis inGoluing the upper and lower respiratory tracts and the kidneys. The introduction of cyclophosphamide in the treatment of Wegener granulomatosis has dramatically altered the rapidly fatal course of the disease and has altered our thinking regarding its management. Recently we haoe cared for 3 patients who demonstrated a dramatic spectrum of urinary tract pthology related to W:egr>ner granulomatosis. The cases presented offer three points for consideration b!y the urologist: (1) the manifestations of the disease in the genitourinary tract can be c,aried and can present in a dramatic fashion; (2) the rapid progression of renal failure and the nearly uniform mortalitly associated with the disease haoe changed largely because of the use of cycll7p}lo,fphalnitle; and (3) our upproach toward patients w-ith renal failure on the basis of Wegencr granulomatosis can be altered, and renal transplantation is certainly feasible with the increased longez.ity afforded these patients by cyclophosphamide. ___-.-__-
Case Reports
W’egener granulomatosis is a disease characterized b,r necrotizing granulomatous angiitis involving the upper and lower respiratory tracts and kidneys. First described in 1939’ the condition has been confirmed as a disease entity bv manv authors.‘*3 Pathologically, the necrotizing angiitis causes a segmental focal granulomatous glomerulonephritis in the kidney (Fig. .2,3 Although renal involvement is common ;i!3 per cent of reported cases) and renal failure is the most common cause of death in Wegner granulomatosis, other involvement of the genitourinary tract has been rarely reported. Only 2 cases with necrosis of the penis4a5 and 1 case with prostatic involvement’ have been reported in the urologic literature. We report 3 recent cases of LT’egener granulomatosis demonstrating a spectrum of urologic disease and present supportive data for a therapeutic modalit!, which has largely changed the nearly uniform mortality once associated u,ith this disease.
I’RoLo(:J
YOVESIBER
197X
/ VOLLrhlE X I I .
NI!MBEH
Case 1 ‘4 sixty-year-old white woman \vas admitted in February, 1977, with fatigue, weakness, fever, and sinusitis. For two years prior to admission she had been managed with alternateday prednisone for a poorly understood vasculitis characterized by retinal artery occlusion, migratory arthralgias, peripheral neuropathy, microscopic hematuria, and mild chronic renal failure. A previous left renal biopsy had revealed focal necrotizing glomerulitis with crescents but no granulomas (Fig. 2‘1. On physical examination the patient appeared to be ill; her temperature was 39.(3” C., pulse 90 per minute, and blood pressure I70/70 mm. Hg. She was obese, with facial plethora and abdominal striae; howe\.er, there were no masses. or costovertebral angle tenderness. On neurologic examination she did ha\Te evidence of a mild peripheral neuropath!,.
5
5i5:3
- ..--.
._- FIGURE 1. Granulomatous destroyed glomerulus.
reaction
FIGURE 2. Segmental crescent formation.
surrounding
glomerular
necrosis
with
FIGURE 3. (A) Chest x-ray j i l m u>ith seoeral r o u n d e d pulmonary densities in right and lower lobes. upper (B) Left antegrade pyelogram shouing ureteral obstruction a t a r e a o f pelrjic brim. (C) Contrast study done through internal drainage catheters ten days after transureterosix ureterostomy. (D) IVP months after transureteroureterostomy.
Laboratory values revealed a hematocrit of 35, white blood cell count of 16,000, and an erythrocyte sedimentation rate of 131 mm. per hour. She had proteinuria (2-t) with numerous white blood cells, bacteria (3+), and a urine culture grew Escherichia coli > 105. Blood urea nitrogen was 30 mg./lOO ml. with a creatinine of 2.6 mg./lOO ml. and creatinine clearance of 20L./day. Serum electrolytes were normal. Chest x-ray film showed several 2-cm. nodular densities in the right upper and lower lobes . was clouding of the right (Fig. 3A). Th ele antrum noted in views of her maxillary sinus, and there was a delayed nephrogram on the left with what appeared to be an obstruction of the left ureter at the pelvic brim on intravenous pyelogram (IVP). 554
Two days after a Caldwell-Luc procedure to her right maxillary antrum, a left retrograde pyelogram confirmed an extrinsic narrowing of the left ureter at the pelvic brim (Fig. 3B). An exploratory procedure was done, and the patient was found to have a dense fibrotic reaction around the distal left ureter with transmural involvement of the ureteral wall. A left to right transureteroureterostomy was performed (Fig. 3C). Pathology revealed a necrotizing vasculitis with probable granuloma (Fig. 4), typical of Wegener granulomatosis. Postoperatively steroids were tapered and cyclophosphamide therapy was started. Twelve months after surgery the patient had a creatinine of 1.6 mg./ 100 ml., sterile urine, and no evidence of disease progression (Fig. 3D).
UROLOGY
/
NOVEMBER1978
/
VOLUMEXII,
NUMBER5
FlGVRE 5. Sclccticc renal clrtcv-iograms. (A) Right side .shotcing ruptuwd aneurysm o.f distal renal urtrry, bleedi n g i n t o large pr>rinephric hcmatoma. a n d i Bj lc>ft side ret-ruling mrrltipl
A
NtIf’lit’!{.FIli.F.
t\vrn t ?~-foul--yc~ar--old
IllilIl w a s in g o o d
health until six Lreeks prior to admission Lvhen
he noted the onsc+ of nasal congestion. ldood~ nasal discharge. f&ue, a n d a low-grade fever w.hich \vere u n r e s p o n s i v e t o t h e us11a1 dt>congestant a n d antibiotic therap!.. The patient mxs fimnd to have a necrotic lesion of the nasal mucosa bvith radiographic opacifications of the maxillarv sinuses. R e s u l t s o f a n a s a l mu~osa biopsy I.t”VVillVCl 21 necrotizing angiitis consistent IYhile i n t h e w i t h Tf’egcner granulomatosis. recovery- roon~, the patient became hypotensive (HO/40 mm. Hg), a n d h i s h e m a t o c r i t d r o p p e d from 42 to 20. A right flank mass developed. rin emergent! urograin demonstrnted a normal left kidne) and an enlarged right renal orltline. The patient WY~S stabilized, and after receiving 14 units of blood, a11 emergency selecti1.e arte~riograin w’as performed. Several large distal artrr!, aneuryslns were noted on the right Lvith a large subcapsular hematoma secondar~~ to a ruptured (listal artery aneurysm (Fig. FjA). The left kidlie!, also showed multiple distal arttar!, ancwrysnlal changes (Fig. SB).
The bleeding point was selecti\:el>~ (‘mbolized with multiple Gelfoam fragments Ct~~cl the, p a t i e n t ’ s l~lood r e q u i r e m e n t rapidly tlc~creasetl; howe\-er. h e hecame ac~lltt~l!. h! pt’rtellsive (ZOO/130 mm. Hg). T h i s \\as controllt~d initiall>\frith nitroprusside, a n d l a t e r \rith propranolol and spironolactone (Aldactonr’j. 10r1e da!, after embolization, ~!,clophosph;ll”icle wan 1~~~gu11 a n d and IVP eleven days later showed gooc~ fiinction Materally with only- ;I small cwrtical defect in the right upper pole. Twelve months at‘tcr emI)olizatiotl his I~lood urea nitrogen and creatinine \jwe ,, normal. There has hectn w proqression o f ’ \Vegener granulotn2~tosls 011 chtamotherapy. c (I.(‘(’ .3 -4 fift),-eight-),c,ar-ol~l \vhite ~voti1ii11 h a d t h e acute o n s e t o f a f e b r i l e illncw punctuate(l 1))
TABLE
I. Ten cases of biopsy-procetl Wegener granulomatosis
hemoptysis and hematuria in early 1973. She was noted to have several nodular lesions in her left upper lobe and underwent a left upper lobectomy in February, 1974, which revealed Wegener granulomatosis. Renal involvement was confirmed at this time by renal biopsy, and the patient was placed on hemodialysis for renal failure. Postoperatively cyclophosphamide therapy was begun; over the next few months her puhnonary lesions resolved and her renal failure stabilized. The patient was readmitted to the hospital in December, 1975, for renal transplantation with a cadaveric renal allograft. Postoperatively she did well; cyclophosphamide therapy was tapered and she was continued on steroids. At present the patient continues to do well and has no evidence of recurrence of her primary disease. Comment Over the past decade at the Massachusetts General Hospital we have seen 10 patients with biopsy-proved Wegener granulomatosis (Table I). The male to female ratio was equal in contrast to the usual 3: 2 male predominance generally reported; however, the age at presentation (fourth to sixth decade)2 was consistent. The presenting complaint at the time of initial hospitalization was related to upper respiratory tract involvement (sinusitis, epistaxis, or otitis media) in 7 of 10 patients (70 per cent). Pulmonary disease was present in only 6 patients (60 per cent); however, 90 per cent (9-10) had evidence of urinary tract involvement. Renal involvement was most frequently seen and was most commonly manifested by micro-
3.56
scopic hematuria. Five of the patients had reduced renal function, and in 4 patients the renal failure was fulminant requiring hemodialysis. Transplantation was required in one case (Case 3). The introduction of cyclophosphamide in the treatment of Wegener granulomatosis has largely changed the nearly uniform mortality previously seen with the untreated form of this disease.8,Y Corticosteroids, which had previously been the primary therapy, proved ineffective in controlling the renal form of the disease, whereas upper respiratory and pulmonary lesions were less difficult to control with these agents. The efficiency of cyclophosphamide has not been studied in a prospective controlled manner to date; there are, however, increasing numbers of reports of long-term survivals in patients with renal involvement treated with cyclophosphamide alone or cyclophosphamide in conjunction with corticosteroids. The optimal dose schedule and proper route and frequency of administration for cyclophosphamide have not been clearly established; however, there is now such strong, positive evidence in terms of patient survival that the withholding of cyclophosphamide in patients with renal involvement secondary to Wegener granulomatosis would be considered unwise. Massachusetts General Hospital Department of Urology Boston, Massachusetts (DR. CROOKS) References 1. VVegener F: Uber eine eigeartige rhinogerr Granulomatose mit besonderer Beterligung des Arteriensystems und der Nieren, Beitr. Pathol. 102: 36 (1939). 2. Fauci A, and Wolff SM: Wegener’s granulomatosis: studies in eighteen patients and a review of the literature, hledicinr 52: 535 (1973). 3. Wolff SM, Fauci AS, Hern RG, and Dale DC: \Vegener granulomatosis, Ann. Intern. \fed. 81: 513 (1974). 4. Osada T, Inoue T, Hirano A, and Tanaka K: Wegener’s granulomatosis with penile necrosis, Jap. J, Clin. Ural. 28: 549 (1974). 5. Matsuda S, Mitsukawa S, Ishii N, and Shirai 11: A case of Wegener’s granulomatosis with necrosis of the penis, Tohoku J. Exp. Med. 118: 145 (1976). 6. Yalowitz P.4, Freene LF, Sheps SG, and Carlin MR: Wegener’s granulomatosis involving the prostate gland: report of a case, J. Ural. 96: 801 (1966). 7. Lundstrom B, et al: N’ephroangiography in Wegener’s granulomatosis - a comparison with panartenitis nodosa, Acta Radiol. Diag. 16: 641 (1975). 8. Raitt JW: Wegener’s granulomatosis: treatment with cytoxic agents and adrenocorticoids, Ann. Intern. Med. 74: 344 (1971). 9. Novack SN, and Pearson CSI: Cyclophosphamide therapy in Wegener’s granulomatosis. N. Engl. J, Med. 284: 938 (1971).
UROLOGY / NOVEMBER 1978 i \‘OLUME
XII, NUMBER 5
MANIFESTATIONS
OF
WEGENER GRANULOMATOSIS T. W. HENSLE, M.D. 14. E . M I T C H E L L , k4.D. K. K. CROOKS, ,M.D. D. ROBINSON, M.D. From the Urologic and Medical Services, Massachusetts General Hospital, and the Departments of Surgery and Medicine, Harvard Medical School, Boston, Massachusetts
ABSTRACT - Wegener granulomatosis is a disease characterized by necrotixing granulomatous ungiitis inGoluing the upper and lower respiratory tracts and the kidneys. The introduction of cyclophosphamide in the treatment of Wegener granulomatosis has dramatically altered the rapidly fatal course of the disease and has altered our thinking regarding its management. Recently we haoe cared for 3 patients who demonstrated a dramatic spectrum of urinary tract pthology related to W:egr>ner granulomatosis. The cases presented offer three points for consideration b!y the urologist: (1) the manifestations of the disease in the genitourinary tract can be c,aried and can present in a dramatic fashion; (2) the rapid progression of renal failure and the nearly uniform mortalitly associated with the disease haoe changed largely because of the use of cycll7p}lo,fphalnitle; and (3) our upproach toward patients w-ith renal failure on the basis of Wegencr granulomatosis can be altered, and renal transplantation is certainly feasible with the increased longez.ity afforded these patients by cyclophosphamide. ___-.-__-
Case Reports
W’egener granulomatosis is a disease characterized b,r necrotizing granulomatous angiitis involving the upper and lower respiratory tracts and kidneys. First described in 1939’ the condition has been confirmed as a disease entity bv manv authors.‘*3 Pathologically, the necrotizing angiitis causes a segmental focal granulomatous glomerulonephritis in the kidney (Fig. .2,3 Although renal involvement is common ;i!3 per cent of reported cases) and renal failure is the most common cause of death in Wegner granulomatosis, other involvement of the genitourinary tract has been rarely reported. Only 2 cases with necrosis of the penis4a5 and 1 case with prostatic involvement’ have been reported in the urologic literature. We report 3 recent cases of LT’egener granulomatosis demonstrating a spectrum of urologic disease and present supportive data for a therapeutic modalit!, which has largely changed the nearly uniform mortality once associated u,ith this disease.
I’RoLo(:J
YOVESIBER
197X
/ VOLLrhlE X I I .
NI!MBEH
Case 1 ‘4 sixty-year-old white woman \vas admitted in February, 1977, with fatigue, weakness, fever, and sinusitis. For two years prior to admission she had been managed with alternateday prednisone for a poorly understood vasculitis characterized by retinal artery occlusion, migratory arthralgias, peripheral neuropathy, microscopic hematuria, and mild chronic renal failure. A previous left renal biopsy had revealed focal necrotizing glomerulitis with crescents but no granulomas (Fig. 2‘1. On physical examination the patient appeared to be ill; her temperature was 39.(3” C., pulse 90 per minute, and blood pressure I70/70 mm. Hg. She was obese, with facial plethora and abdominal striae; howe\.er, there were no masses. or costovertebral angle tenderness. On neurologic examination she did ha\Te evidence of a mild peripheral neuropath!,.
5
5i5:3
- ..--.
._- FIGURE 1. Granulomatous destroyed glomerulus.
reaction
FIGURE 2. Segmental crescent formation.
surrounding
glomerular
necrosis
with
FIGURE 3. (A) Chest x-ray j i l m u>ith seoeral r o u n d e d pulmonary densities in right and lower lobes. upper (B) Left antegrade pyelogram shouing ureteral obstruction a t a r e a o f pelrjic brim. (C) Contrast study done through internal drainage catheters ten days after transureterosix ureterostomy. (D) IVP months after transureteroureterostomy.
Laboratory values revealed a hematocrit of 35, white blood cell count of 16,000, and an erythrocyte sedimentation rate of 131 mm. per hour. She had proteinuria (2-t) with numerous white blood cells, bacteria (3+), and a urine culture grew Escherichia coli > 105. Blood urea nitrogen was 30 mg./lOO ml. with a creatinine of 2.6 mg./lOO ml. and creatinine clearance of 20L./day. Serum electrolytes were normal. Chest x-ray film showed several 2-cm. nodular densities in the right upper and lower lobes . was clouding of the right (Fig. 3A). Th ele antrum noted in views of her maxillary sinus, and there was a delayed nephrogram on the left with what appeared to be an obstruction of the left ureter at the pelvic brim on intravenous pyelogram (IVP). 554
Two days after a Caldwell-Luc procedure to her right maxillary antrum, a left retrograde pyelogram confirmed an extrinsic narrowing of the left ureter at the pelvic brim (Fig. 3B). An exploratory procedure was done, and the patient was found to have a dense fibrotic reaction around the distal left ureter with transmural involvement of the ureteral wall. A left to right transureteroureterostomy was performed (Fig. 3C). Pathology revealed a necrotizing vasculitis with probable granuloma (Fig. 4), typical of Wegener granulomatosis. Postoperatively steroids were tapered and cyclophosphamide therapy was started. Twelve months after surgery the patient had a creatinine of 1.6 mg./ 100 ml., sterile urine, and no evidence of disease progression (Fig. 3D).
UROLOGY
/
NOVEMBER1978
/
VOLUMEXII,
NUMBER5
FlGVRE 5. Sclccticc renal clrtcv-iograms. (A) Right side .shotcing ruptuwd aneurysm o.f distal renal urtrry, bleedi n g i n t o large pr>rinephric hcmatoma. a n d i Bj lc>ft side ret-ruling mrrltipl
A
NtIf’lit’!{.FIli.F.
t\vrn t ?~-foul--yc~ar--old
IllilIl w a s in g o o d
health until six Lreeks prior to admission Lvhen
he noted the onsc+ of nasal congestion. ldood~ nasal discharge. f&ue, a n d a low-grade fever w.hich \vere u n r e s p o n s i v e t o t h e us11a1 dt>congestant a n d antibiotic therap!.. The patient mxs fimnd to have a necrotic lesion of the nasal mucosa bvith radiographic opacifications of the maxillarv sinuses. R e s u l t s o f a n a s a l mu~osa biopsy I.t”VVillVCl 21 necrotizing angiitis consistent IYhile i n t h e w i t h Tf’egcner granulomatosis. recovery- roon~, the patient became hypotensive (HO/40 mm. Hg), a n d h i s h e m a t o c r i t d r o p p e d from 42 to 20. A right flank mass developed. rin emergent! urograin demonstrnted a normal left kidne) and an enlarged right renal orltline. The patient WY~S stabilized, and after receiving 14 units of blood, a11 emergency selecti1.e arte~riograin w’as performed. Several large distal artrr!, aneuryslns were noted on the right Lvith a large subcapsular hematoma secondar~~ to a ruptured (listal artery aneurysm (Fig. FjA). The left kidlie!, also showed multiple distal arttar!, ancwrysnlal changes (Fig. SB).
The bleeding point was selecti\:el>~ (‘mbolized with multiple Gelfoam fragments Ct~~cl the, p a t i e n t ’ s l~lood r e q u i r e m e n t rapidly tlc~creasetl; howe\-er. h e hecame ac~lltt~l!. h! pt’rtellsive (ZOO/130 mm. Hg). T h i s \\as controllt~d initiall>\frith nitroprusside, a n d l a t e r \rith propranolol and spironolactone (Aldactonr’j. 10r1e da!, after embolization, ~!,clophosph;ll”icle wan 1~~~gu11 a n d and IVP eleven days later showed gooc~ fiinction Materally with only- ;I small cwrtical defect in the right upper pole. Twelve months at‘tcr emI)olizatiotl his I~lood urea nitrogen and creatinine \jwe ,
TABLE
I. Ten cases of biopsy-procetl Wegener granulomatosis
hemoptysis and hematuria in early 1973. She was noted to have several nodular lesions in her left upper lobe and underwent a left upper lobectomy in February, 1974, which revealed Wegener granulomatosis. Renal involvement was confirmed at this time by renal biopsy, and the patient was placed on hemodialysis for renal failure. Postoperatively cyclophosphamide therapy was begun; over the next few months her puhnonary lesions resolved and her renal failure stabilized. The patient was readmitted to the hospital in December, 1975, for renal transplantation with a cadaveric renal allograft. Postoperatively she did well; cyclophosphamide therapy was tapered and she was continued on steroids. At present the patient continues to do well and has no evidence of recurrence of her primary disease. Comment Over the past decade at the Massachusetts General Hospital we have seen 10 patients with biopsy-proved Wegener granulomatosis (Table I). The male to female ratio was equal in contrast to the usual 3: 2 male predominance generally reported; however, the age at presentation (fourth to sixth decade)2 was consistent. The presenting complaint at the time of initial hospitalization was related to upper respiratory tract involvement (sinusitis, epistaxis, or otitis media) in 7 of 10 patients (70 per cent). Pulmonary disease was present in only 6 patients (60 per cent); however, 90 per cent (9-10) had evidence of urinary tract involvement. Renal involvement was most frequently seen and was most commonly manifested by micro-
3.56
scopic hematuria. Five of the patients had reduced renal function, and in 4 patients the renal failure was fulminant requiring hemodialysis. Transplantation was required in one case (Case 3). The introduction of cyclophosphamide in the treatment of Wegener granulomatosis has largely changed the nearly uniform mortality previously seen with the untreated form of this disease.8,Y Corticosteroids, which had previously been the primary therapy, proved ineffective in controlling the renal form of the disease, whereas upper respiratory and pulmonary lesions were less difficult to control with these agents. The efficiency of cyclophosphamide has not been studied in a prospective controlled manner to date; there are, however, increasing numbers of reports of long-term survivals in patients with renal involvement treated with cyclophosphamide alone or cyclophosphamide in conjunction with corticosteroids. The optimal dose schedule and proper route and frequency of administration for cyclophosphamide have not been clearly established; however, there is now such strong, positive evidence in terms of patient survival that the withholding of cyclophosphamide in patients with renal involvement secondary to Wegener granulomatosis would be considered unwise. Massachusetts General Hospital Department of Urology Boston, Massachusetts (DR. CROOKS) References 1. VVegener F: Uber eine eigeartige rhinogerr Granulomatose mit besonderer Beterligung des Arteriensystems und der Nieren, Beitr. Pathol. 102: 36 (1939). 2. Fauci A, and Wolff SM: Wegener’s granulomatosis: studies in eighteen patients and a review of the literature, hledicinr 52: 535 (1973). 3. Wolff SM, Fauci AS, Hern RG, and Dale DC: \Vegener granulomatosis, Ann. Intern. \fed. 81: 513 (1974). 4. Osada T, Inoue T, Hirano A, and Tanaka K: Wegener’s granulomatosis with penile necrosis, Jap. J, Clin. Ural. 28: 549 (1974). 5. Matsuda S, Mitsukawa S, Ishii N, and Shirai 11: A case of Wegener’s granulomatosis with necrosis of the penis, Tohoku J. Exp. Med. 118: 145 (1976). 6. Yalowitz P.4, Freene LF, Sheps SG, and Carlin MR: Wegener’s granulomatosis involving the prostate gland: report of a case, J. Ural. 96: 801 (1966). 7. Lundstrom B, et al: N’ephroangiography in Wegener’s granulomatosis - a comparison with panartenitis nodosa, Acta Radiol. Diag. 16: 641 (1975). 8. Raitt JW: Wegener’s granulomatosis: treatment with cytoxic agents and adrenocorticoids, Ann. Intern. Med. 74: 344 (1971). 9. Novack SN, and Pearson CSI: Cyclophosphamide therapy in Wegener’s granulomatosis. N. Engl. J, Med. 284: 938 (1971).
UROLOGY / NOVEMBER 1978 i \‘OLUME
XII, NUMBER 5