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Primary Amyloidosis of the Urinary Bladder
C.Y. Huang, et al
CASE REPORT
Primary Amyloidosis of the Urinary Bladder Chao-Yuan Huang, Chia-Tung Shun,1 Kuo-How Huang, Jun Chen, Yeong-Shiau Pu* Amyloidosis is a systemic disease that usually occurs in the gastrointestinal tract or in muscular or adipose tissue. Primary amyloidosis of the urinary bladder is a rare disease that can mimic bladder cancer on cystoscopic examination as well as in its clinical presentation of painless gross hematuria. This report describes a 49year-old male with repeated painless gross hematuria, who underwent transurethral resection of a suspected bladder tumor. Pathologic examination revealed papillary urothelial hyperplasia with vascular ectasia and no signs of malignancy. Massive gross hematuria occurred 2.5 years later. Cystoscopy showed multiple papillary lesions with yellowish-brown submucosal plaques on the posterior bladder wall. A second transurethral tumor resection was performed and histologic examination revealed plasma cell infiltration and eosinophilic amorphous deposits in the subepithelial stroma and vascular wall. The deposits were positive for Congo red and apple-green birefringence under polarized light examination but negative for Masson’s trichrome stain, indicating that they were not fibrotic in nature. Hence, the diagnosis of amyloidosis of the urinary bladder was confirmed. Screening for amyloidosis was negative in other organ systems and the patient has remained disease-free up to the last follow-up 4 years after the second transurethral resection. Amyloidosis should be considered in the differential diagnosis of patients with recurrent hematuria who have symptoms characteristic of bladder cancer but negative pathologic study for malignancy. Correct diagnosis relies on clinical alertness and the use of a special staining technique during pathologic examination. [J Formos Med Assoc 2006;105(2): 164–167] Key Words: amyloid, hematuria, urothelial carcinoma
Amyloidosis is characterized by extracellular deposits of the fibrillar protein, amyloid. Primary amyloidosis of the urinary bladder resembles urothelial carcinoma of the bladder or urethra on cystoscopic examination and in its clinical presentation of gross or microscopic hematuria. Few 1–4 cases of this rare condition have been reported. Amyloid deposits in the bladder may be a primary disease or a secondary manifestation of systemic amyloidosis. Diagnosis can be made by histopathologic examination following biopsy or resection of bladder lesions. This report presents the first case of primary amyloidosis of the urinary bladder documented in Taiwan.
Case Report A 49-year-old man experienced repeated episodes of painless gross hematuria within 3 weeks prior to visiting our clinic in June 1998. His medical history was unremarkable except for a 10-year history of essential hypertension with regular medical control. The patient had no history of smoking or alcohol intake. Urinalysis showed numerous red blood cells, a pH of 7.0, trace proteinuria and no sugar or white blood cell sediment. Other urinalysis parameters were unremarkable. Urine culture also showed negative results. Voided urine cytology series was negative for malignancy. Renal ultra-
©2006 Elsevier & Formosan Medical Association 1
Department of Urology, National Taiwan University Hospital, and Department of Forensic Medicine, College of Medicine, National Taiwan University, Taipei, Taiwan, R.O.C. Received: December 14, 2004 Revised: February 5, 2005 Accepted: May 10, 2005
164
*Correspondence to: Dr. Yeong-Shiau Pu, Department of Urology, National Taiwan University Hospital, 7, ChungShan South Road, Taipei 100, Taiwan, R.O.C. E-mail: [email protected]
J Formos Med Assoc | 2006 • Vol 105 • No 2
Urinary bladder amyloidosis
sonography was unremarkable. Urinary bladder ultrasonography revealed a lesion with an uneven surface at the left posterior bladder wall. Cystoscopy also showed multiple large (up to 2 cm) papillary lesions with covering blood clots on the posterior bladder wall. Biopsy of the lesion showed plasma cell infiltration and eosinophilic amorphous deposits in the subepithelial stroma. Eosinophilic amorphous deposits were also seen in the vascular wall. Transurethral resection of the papillary lesions was performed, which revealed dark-brown contents and recent hemorrhage beneath the mucosa. Pathologic examination revealed papillary urothelial hyperplasia with vascular ectasia and old hemorrhage with no evidence of malignancy. However, the patient continued to experience intermittent, painless gross hematuria in the following 2.5 years. Cystoscopy performed during this period only revealed scar tissue, while biopsies showed urothelial hyperplasia and chronic inflammation. Results of repeated voided urine cytology tests, excretory urography and renal ultrasonography were all unremarkable. An episode of massive, painless gross hematuria occurred in January 2001. Cystoscopy revealed recurrent multiple papillary lesions with blood clots covering the lateral bladder wall, where diffuse yellowish-brown submucosal plaques with fragile mucosa were also seen. Transurethral resection of the lesions was performed for a second time. Pathologic examination revealed mild urothelial hyperplasia with underlying amorphous, eosinophilic substance deposition in the stroma and vascular wall (Figure 1). The deposits were positive for Congo red and apple-green birefringence under polarized light examination (Figure 2). The deposits were not fibrotic in nature, as evidenced by negative Masson’s trichrome stain. Hence, the diagnosis of amyloidosis of the urinary bladder was confirmed. Retrospective review and special staining of the specimen obtained from the first transurethral resection suggested that severe cauterization might have masked the correct diagnosis of amyloidosis. Endoscopy of the upper gastrointestinal tract, colonofibroscopy, abdominal ultraJ Formos Med Assoc | 2006 • Vol 105 • No 2
A
B
C
Figure 1. (A) Amorphous, eosinophilic amyloid my deposits within the bladder’s submucosal layer (hematoxylin & eosin, × 40). (B) Vascular wall amyloid deposits (hematoxylin & eosin, × 400). (C) Amyloid deposits in submucosal connective tissue (hematoxylin & eosin, × 400).
sonography, serum electrolyte and liver enzyme tests, a hemogram and electrophoresis of serum protein all had normal findings. As there were no apparent skin lesions or symptoms, the patient refused further subcutaneous abdominal fat pad aspiration. After the transurethral resection, no further episodes of massive gross hematuria were noted, except for a few episodes of self-limiting
A
B
Figure 2. (A) Special stains reveal perivascular deposits (arrow) positive for Congo red (× 200). (B) Visualization of the specimen under polarized light reveals applegreen birefringence (arrow) (× 200).
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mild hematuria. Follow-up cystoscopy 48 months after surgery only revealed uneven bladder mucosa with engorged vessels at the previous site of operation.
Discussion Systemic amyloidosis is a common condition that affects various organ systems, including the gastrointestinal tract, cardiac and striated muscle and adipose tissue. While the etiology of amyloidosis is unknown, several theories suggest a chronic monoclonal inflammatory response or an immu5 nologic mechanism. Systemic amyloidosis is commonly associated with chronic granulomatous disease, multiple myeloma or rheumatoid dis6 ease. However, primary amyloidosis can occur anywhere along the urinary tract and has been reported in the kidney, renal pelvis, ureters, penis 4,7–9 and even in the seminal vesicles. Primary amyloidosis of the bladder is rare, and an initial examination may be easily confused with urothelial carcinoma due to a similar clinical presentation of painless gross hematuria.1–4 Caldamone et al reviewed 46 cases of primary localized amyloidosis of the urinary bladder in 1980. 4 There were 20 males and 26 females. The age distribution was from 28 to 80 years, with a mean age of 53 years. In all but five cases, the major presenting symptom was painless gross hematuria (80%).4 Findings from cystoscopic examination may also mimic malignant pathologic findings, as fungating, erythematous, hemorrhagic and, sometimes, papillary lesions are frequently noted. As in the current case, endoscopic examination may show amyloid deposits as yellowish-brown submucosal plaques. This case illustrates the typical clinical manifestations and gross features of primary amyloidosis of the bladder. Most patients with focal amyloid deposits in the bladder can be successfully managed with one or more transurethral resections.2 Follow-up of patients is necessary due to the high likelihood of recurrence. In this case, the patient did not experience recurrent severe gross hematuria during the 4 166
years after the second transurethral resection. The patient’s occasional mild hematuria was successfully managed by conservative medical treatment. Medical regimens that include colchicine, nitrofurazone and dimethyl sulfoxide as primary or 10,11 adjuvant therapy have had variable results. More aggressive procedures such as cystectomy or ligation of the internal iliac arteries for massive 12 hemorrhage control are, at times, necessary. Although bladder amyloidosis has been correctly diagnosed by cystoscopy in some reported cases, definitive diagnosis depends on histopathologic examination of the biopsy or resected specimen. Histologic examination shows proteinaceous amorphous eosinophilic deposits in the extracellular spaces. Diagnosis is confirmed by fluorescent apple-green birefringence after Congo red staining and visualization of the specimen under polarized light.4 In conclusion, primary bladder amyloidosis is a rare cause of painless gross hematuria, and can have similar cystoscopic features as urothelial carcinoma. Pathologic examination and special staining can help to confirm the diagnosis. Conservative therapy, such as endoscopic resection, is usually adequate. Medical treatment with systemic or intravesical agents has demonstrated some benefit in selected patients. Massive hemorrhage rarely requires a more aggressive approach such as surgical treatment. An initial diagnosis of bladder amyloidosis should prompt an evaluation of other organ systems, as this could be the first manifestation of a chronic, extensive disease.
References 1. Grainger R, O’Riordan B, Cullen A, et al. Primary amyloidosis of lower urinary tract. Urology 1988;31:14–6. 2. Mark IR, Goodlad J, Lloyd-Davies RW. Localized amyloidosis of the genitourinary tract. J R Soc Med 1995;88:320–4. 3. Auge BK, Haluszka MM. Primary amyloidosis of the bladder. J Urol 2000;163:1867–8. 4. Caldamone AA, Elbadawi A, Moshtagi A, et al. Primary localized amyloidosis of urinary bladder. Urology 1980;15: 174–80. 5. Cohen AS. Amyloidosis. N Engl J Med 1967;277:522–30. 6. Symmers WS. Primary amyloidosis: a review. J Clin Pathol
J Formos Med Assoc | 2006 • Vol 105 • No 2
Urinary bladder amyloidosis
1956;9:187–211. 7. Gardner KD Jr, Castellino RA, Kempson R, et al. Primary amyloidosis of the renal pelvis. N Engl J Med 1971;284: 1196–8. 8. Gulmi FA, Mooppan UM, Gomez-Leon G, et al. Primary localized amyloidosis of ureter. Urology 1988;32:161–4. 9. Krane RJ, Klugo RC, Olsson CA. Seminal vesicle amyloidosis. Urology 1973;2:70–2.
J Formos Med Assoc | 2006 • Vol 105 • No 2
10. Livingstone RR, Sarembock LA, Barnes RD, et al. Colchicine therapy in primary amyloidosis of the bladder: a case report. J Urol 1989;142:1570–1. 11. Nurmi MJ, Ekfors TO, Rajala PO, et al. Intravesical dimethyl sulfoxide instillations in the treatment of secondary amyloidosis of the bladder. J Urol 1990;143:808–10. 12. Malek RS, Greene LF, Farrow GM. Amyloidosis of the urinary bladder. Br J Urol 1971;43:189–200.
167
CASE REPORT
Primary Amyloidosis of the Urinary Bladder Chao-Yuan Huang, Chia-Tung Shun,1 Kuo-How Huang, Jun Chen, Yeong-Shiau Pu* Amyloidosis is a systemic disease that usually occurs in the gastrointestinal tract or in muscular or adipose tissue. Primary amyloidosis of the urinary bladder is a rare disease that can mimic bladder cancer on cystoscopic examination as well as in its clinical presentation of painless gross hematuria. This report describes a 49year-old male with repeated painless gross hematuria, who underwent transurethral resection of a suspected bladder tumor. Pathologic examination revealed papillary urothelial hyperplasia with vascular ectasia and no signs of malignancy. Massive gross hematuria occurred 2.5 years later. Cystoscopy showed multiple papillary lesions with yellowish-brown submucosal plaques on the posterior bladder wall. A second transurethral tumor resection was performed and histologic examination revealed plasma cell infiltration and eosinophilic amorphous deposits in the subepithelial stroma and vascular wall. The deposits were positive for Congo red and apple-green birefringence under polarized light examination but negative for Masson’s trichrome stain, indicating that they were not fibrotic in nature. Hence, the diagnosis of amyloidosis of the urinary bladder was confirmed. Screening for amyloidosis was negative in other organ systems and the patient has remained disease-free up to the last follow-up 4 years after the second transurethral resection. Amyloidosis should be considered in the differential diagnosis of patients with recurrent hematuria who have symptoms characteristic of bladder cancer but negative pathologic study for malignancy. Correct diagnosis relies on clinical alertness and the use of a special staining technique during pathologic examination. [J Formos Med Assoc 2006;105(2): 164–167] Key Words: amyloid, hematuria, urothelial carcinoma
Amyloidosis is characterized by extracellular deposits of the fibrillar protein, amyloid. Primary amyloidosis of the urinary bladder resembles urothelial carcinoma of the bladder or urethra on cystoscopic examination and in its clinical presentation of gross or microscopic hematuria. Few 1–4 cases of this rare condition have been reported. Amyloid deposits in the bladder may be a primary disease or a secondary manifestation of systemic amyloidosis. Diagnosis can be made by histopathologic examination following biopsy or resection of bladder lesions. This report presents the first case of primary amyloidosis of the urinary bladder documented in Taiwan.
Case Report A 49-year-old man experienced repeated episodes of painless gross hematuria within 3 weeks prior to visiting our clinic in June 1998. His medical history was unremarkable except for a 10-year history of essential hypertension with regular medical control. The patient had no history of smoking or alcohol intake. Urinalysis showed numerous red blood cells, a pH of 7.0, trace proteinuria and no sugar or white blood cell sediment. Other urinalysis parameters were unremarkable. Urine culture also showed negative results. Voided urine cytology series was negative for malignancy. Renal ultra-
©2006 Elsevier & Formosan Medical Association 1
Department of Urology, National Taiwan University Hospital, and Department of Forensic Medicine, College of Medicine, National Taiwan University, Taipei, Taiwan, R.O.C. Received: December 14, 2004 Revised: February 5, 2005 Accepted: May 10, 2005
164
*Correspondence to: Dr. Yeong-Shiau Pu, Department of Urology, National Taiwan University Hospital, 7, ChungShan South Road, Taipei 100, Taiwan, R.O.C. E-mail: [email protected]
J Formos Med Assoc | 2006 • Vol 105 • No 2
Urinary bladder amyloidosis
sonography was unremarkable. Urinary bladder ultrasonography revealed a lesion with an uneven surface at the left posterior bladder wall. Cystoscopy also showed multiple large (up to 2 cm) papillary lesions with covering blood clots on the posterior bladder wall. Biopsy of the lesion showed plasma cell infiltration and eosinophilic amorphous deposits in the subepithelial stroma. Eosinophilic amorphous deposits were also seen in the vascular wall. Transurethral resection of the papillary lesions was performed, which revealed dark-brown contents and recent hemorrhage beneath the mucosa. Pathologic examination revealed papillary urothelial hyperplasia with vascular ectasia and old hemorrhage with no evidence of malignancy. However, the patient continued to experience intermittent, painless gross hematuria in the following 2.5 years. Cystoscopy performed during this period only revealed scar tissue, while biopsies showed urothelial hyperplasia and chronic inflammation. Results of repeated voided urine cytology tests, excretory urography and renal ultrasonography were all unremarkable. An episode of massive, painless gross hematuria occurred in January 2001. Cystoscopy revealed recurrent multiple papillary lesions with blood clots covering the lateral bladder wall, where diffuse yellowish-brown submucosal plaques with fragile mucosa were also seen. Transurethral resection of the lesions was performed for a second time. Pathologic examination revealed mild urothelial hyperplasia with underlying amorphous, eosinophilic substance deposition in the stroma and vascular wall (Figure 1). The deposits were positive for Congo red and apple-green birefringence under polarized light examination (Figure 2). The deposits were not fibrotic in nature, as evidenced by negative Masson’s trichrome stain. Hence, the diagnosis of amyloidosis of the urinary bladder was confirmed. Retrospective review and special staining of the specimen obtained from the first transurethral resection suggested that severe cauterization might have masked the correct diagnosis of amyloidosis. Endoscopy of the upper gastrointestinal tract, colonofibroscopy, abdominal ultraJ Formos Med Assoc | 2006 • Vol 105 • No 2
A
B
C
Figure 1. (A) Amorphous, eosinophilic amyloid my deposits within the bladder’s submucosal layer (hematoxylin & eosin, × 40). (B) Vascular wall amyloid deposits (hematoxylin & eosin, × 400). (C) Amyloid deposits in submucosal connective tissue (hematoxylin & eosin, × 400).
sonography, serum electrolyte and liver enzyme tests, a hemogram and electrophoresis of serum protein all had normal findings. As there were no apparent skin lesions or symptoms, the patient refused further subcutaneous abdominal fat pad aspiration. After the transurethral resection, no further episodes of massive gross hematuria were noted, except for a few episodes of self-limiting
A
B
Figure 2. (A) Special stains reveal perivascular deposits (arrow) positive for Congo red (× 200). (B) Visualization of the specimen under polarized light reveals applegreen birefringence (arrow) (× 200).
165
C.Y. Huang, et al
mild hematuria. Follow-up cystoscopy 48 months after surgery only revealed uneven bladder mucosa with engorged vessels at the previous site of operation.
Discussion Systemic amyloidosis is a common condition that affects various organ systems, including the gastrointestinal tract, cardiac and striated muscle and adipose tissue. While the etiology of amyloidosis is unknown, several theories suggest a chronic monoclonal inflammatory response or an immu5 nologic mechanism. Systemic amyloidosis is commonly associated with chronic granulomatous disease, multiple myeloma or rheumatoid dis6 ease. However, primary amyloidosis can occur anywhere along the urinary tract and has been reported in the kidney, renal pelvis, ureters, penis 4,7–9 and even in the seminal vesicles. Primary amyloidosis of the bladder is rare, and an initial examination may be easily confused with urothelial carcinoma due to a similar clinical presentation of painless gross hematuria.1–4 Caldamone et al reviewed 46 cases of primary localized amyloidosis of the urinary bladder in 1980. 4 There were 20 males and 26 females. The age distribution was from 28 to 80 years, with a mean age of 53 years. In all but five cases, the major presenting symptom was painless gross hematuria (80%).4 Findings from cystoscopic examination may also mimic malignant pathologic findings, as fungating, erythematous, hemorrhagic and, sometimes, papillary lesions are frequently noted. As in the current case, endoscopic examination may show amyloid deposits as yellowish-brown submucosal plaques. This case illustrates the typical clinical manifestations and gross features of primary amyloidosis of the bladder. Most patients with focal amyloid deposits in the bladder can be successfully managed with one or more transurethral resections.2 Follow-up of patients is necessary due to the high likelihood of recurrence. In this case, the patient did not experience recurrent severe gross hematuria during the 4 166
years after the second transurethral resection. The patient’s occasional mild hematuria was successfully managed by conservative medical treatment. Medical regimens that include colchicine, nitrofurazone and dimethyl sulfoxide as primary or 10,11 adjuvant therapy have had variable results. More aggressive procedures such as cystectomy or ligation of the internal iliac arteries for massive 12 hemorrhage control are, at times, necessary. Although bladder amyloidosis has been correctly diagnosed by cystoscopy in some reported cases, definitive diagnosis depends on histopathologic examination of the biopsy or resected specimen. Histologic examination shows proteinaceous amorphous eosinophilic deposits in the extracellular spaces. Diagnosis is confirmed by fluorescent apple-green birefringence after Congo red staining and visualization of the specimen under polarized light.4 In conclusion, primary bladder amyloidosis is a rare cause of painless gross hematuria, and can have similar cystoscopic features as urothelial carcinoma. Pathologic examination and special staining can help to confirm the diagnosis. Conservative therapy, such as endoscopic resection, is usually adequate. Medical treatment with systemic or intravesical agents has demonstrated some benefit in selected patients. Massive hemorrhage rarely requires a more aggressive approach such as surgical treatment. An initial diagnosis of bladder amyloidosis should prompt an evaluation of other organ systems, as this could be the first manifestation of a chronic, extensive disease.
References 1. Grainger R, O’Riordan B, Cullen A, et al. Primary amyloidosis of lower urinary tract. Urology 1988;31:14–6. 2. Mark IR, Goodlad J, Lloyd-Davies RW. Localized amyloidosis of the genitourinary tract. J R Soc Med 1995;88:320–4. 3. Auge BK, Haluszka MM. Primary amyloidosis of the bladder. J Urol 2000;163:1867–8. 4. Caldamone AA, Elbadawi A, Moshtagi A, et al. Primary localized amyloidosis of urinary bladder. Urology 1980;15: 174–80. 5. Cohen AS. Amyloidosis. N Engl J Med 1967;277:522–30. 6. Symmers WS. Primary amyloidosis: a review. J Clin Pathol
J Formos Med Assoc | 2006 • Vol 105 • No 2
Urinary bladder amyloidosis
1956;9:187–211. 7. Gardner KD Jr, Castellino RA, Kempson R, et al. Primary amyloidosis of the renal pelvis. N Engl J Med 1971;284: 1196–8. 8. Gulmi FA, Mooppan UM, Gomez-Leon G, et al. Primary localized amyloidosis of ureter. Urology 1988;32:161–4. 9. Krane RJ, Klugo RC, Olsson CA. Seminal vesicle amyloidosis. Urology 1973;2:70–2.
J Formos Med Assoc | 2006 • Vol 105 • No 2
10. Livingstone RR, Sarembock LA, Barnes RD, et al. Colchicine therapy in primary amyloidosis of the bladder: a case report. J Urol 1989;142:1570–1. 11. Nurmi MJ, Ekfors TO, Rajala PO, et al. Intravesical dimethyl sulfoxide instillations in the treatment of secondary amyloidosis of the bladder. J Urol 1990;143:808–10. 12. Malek RS, Greene LF, Farrow GM. Amyloidosis of the urinary bladder. Br J Urol 1971;43:189–200.
167