PRIMARY LOCALIZED
RIAD N. FARAH, DANIEL GERALD PHILIP
OF BLADDER
M.D.
0. BENSON, FINE,
AMYLOIDOSIS
M.D.
M.D.
J. DORMAN,
From the Departments Henry Ford Hospital,
M.D. of Urology, Pathology, Detroit, Michigan
and Medicine,
ABSTRACT - Primary amyloidosis of the bladder is a rare disease, most frequently confused with bladder carcinoma. Our experience in defining the lesion during surgery is presented. The etiology is discussed.
Primary localized amyloidosis of the bladder is of special interest because, both in symptoms and gross appearance, it resembles an infiltrating neoplasm. Accurate diagnosis depends on biopsy. The benign lesions usually respond well to surgical treatment: transurethral resection with or without fulguration, or segmental cystectomy. Case Report A fifty-two-year-old white man was admitted to Henry Ford Hospital with a two-year history of intermittent painless hematuria which had increased in frequency and severity during the past few months. Although the patient had no history of acute or chronic illness, he reported that three of his four children had died of Hurler disease before the age of twenty-one. Physical examination showed this patient to be in good general health. Findings on a liver spleen scan were negative. Routine laboratory studies (complete blood count, sedimentation electrolytes, blood urea nitrogen, rate, creatinine, fasting and two-hour blood sugar, VDRL, total T4, and uric acid) were within normal limits except for microscopic hematuria. The intravenous urogram was normal. A sternal bone marrow smear showed slight elevation of plasmacytes (2.8 per cent). The serum protein electrophoretic pattern was normal. Analysis of serum immunoglobulins revealed elevation of IgA. Immunochemical analysis of the urine
200
demonstrated no free kappa or lambda Bence Jones proteins. Cystoscopy disclosed a sessile, irregular, gray-yellow lesion about 3 cm. in diameter on the right lateral wall of the bladder close to the dome which on biopsy was found to be amyloid deposition. Transurethral resection of the amyloid mass failed to control the bleeding, and a segmental cystectomy was performed using diluted povidone-iodine solution (Betadine) to fill the bladder and localize the amyloid deposit by staining it blue. The postoperative course was uneventful. Cystoscopy three months later showed a well-healed scar and no evidence of recurrence. However, during the next twelve months, the patient had two episodes of hematuria and new areas of amyloid deposition were found on the dome of the bladder which were treated by fulguration, In an attempt to determine if the amyloid was confined to the bladder, biopsies were taken from a number of other sites. Pathology Specimens examined included biopsies of the urinary bladder, the segmentally resected urinary bladder, and biopsies of the stomach, rectum, duodenum, and the right transverse carpal ligament and median nerve (obtained when the patient underwent surgery for carpal tunnel
UROLOGY
/ FEBRUARY
1979 / VOLUME
XIII,
NUMBER 2
FIGURE 1. (A) Subepithelial (SE) area of urinary bladder is greatly thickened principally due to deposition of amyloid which spares area immediately beneath urothelium that is occupied by inflammatory cell infiltrate. (B) Magni$cation of area V (A) better illustrates irregular ajibri11a.ramyloid deposits which have replaced normal connective tissue fm this zone of urinary bladder. (Hematoxylin and eosin, original magnijcations x i’Oand x 300, respectively.)
FIGURE 2. (A and B) Polarization of sections showing same area seen in Fig. 1 B. Bright areas, birefringence of some of Congo red positive amyloid seen in A, are in contrast to almost negative birefringence seen in B and helps to identify small focal amyloid deposits in arterial wall. Birefringence in B is considered due to connective tissue. (Polarized Congo red [A] and polarized hematoxylin and eosin [B], original magnijcations x 300.)
syndrome). Stains used for histologic examination included hematoxylin eosin, Congo red, crystal violet, Van Gieson, and thioflavin T; the last being examined with ultraviolet light. Only the urinary bladder was found to be abnormal. The resected segment of bladder wall was thicker and more rigid than normal with the mucosa and muscular wall being 0.8 and 1.2 cm., respectively. The mucosa was finely granular, and the muscular portion of the bladder wall was attributable to a combination of inflammatory cells and the deposition of an afibrillar eosin-stained material (Fig. 1A). The inflammatory infiltrate was pleomorphic, consisting of plasma cells, lymphocytes, and histiocytes in that order of frequency. They were principally in the immediate subepithelial region and only rarely extended along a vascular channel into
UROLOGY
/ FEBRUARY1979
/ VOLUMEXIII, NUMBER2
the superficial muscle layer of the bladder. The afibrillar eosin-stained material appeared to be a greater factor in the production of the gross bladder changes than the inflammatory cell infiltrate. It, too, was most abundant in the subepithelial portion of the bladder wall, presenting diffusely as irregular, varying-sized masses which had replaced most of the connective tissue in this portion of the bladder wall but spared the blood vessel walls except for infrequent focal small areas (Figs. 1 and 2). The cells interspersed among the deposits were predominantly histiocytes and fibrocytes. Only rarely were cells of the type found in the zone immediately beneath the urothelium seen. The smooth muscle of the bladder wall was much less altered by the afibrillar deposits. Their detection required careful searching and where
201
FIGURE 3. (A and B) Suspected amyloid in intermuscular connective tissue (CT) and smooth muscle (SM) of bladder wall (A) was verijied by birefringence of Congo red positive amyloid (B). (Hematoxylin and eosin [A] and polarized C on g o red [B], original mugnijkation x 300.)
present they principally replaced intermuscular connective tissue and less commonly individual or small groups of smooth muscle fibers (Fig. 3). The afibrillar material stained in the typical fashion of amyloid with all the special stains utilized. The Van Gieson and polarized Congo red-stained sections were particularly helpful in distinguishing the amyloid from collagen something not found possible in all areas with the hematoxylin eosin and crystal violet stains, and the Congo red stain without polarization (Figs. 2 and 3). Comment Classification of amyloidosis has been discussed by Symmers’ in his extensive review. Primary localized amyloidosis, which we believe this case to be an example of, has been reported in the upper and lower respiratory tracts, the urinary bladder and urethra, and the skin and orificial mucosa. The reports of urinary bladder involvement from 1897 to 1971 have been analyzed by Kinzel, Harrison, and Utz’ and by Malek, Greene, and Farrow; subsequent cases have been reported. 4-6 Involvement of other regions of the lower urogenital tract-urethra’,’ and seminal vesicles*-” has also been reported. Many investigations into the chemical composition of amyloid have been carried out and are summarized by Glenner, Ein, and Terry.” Virchow’s concept of amyloid being mainly carbohydrate in nature, investigations since have shown it to be a variable mixture of carbohydrate and proteins with some of the latter having similarities to immunoglobulins. The absence of physical and laboratory findings which would support generalized amyloidosis or a disease process which has been indicated as playing a role in the production of amyloidosis, lends credance to our considering
202
this case one of primary amyloid involvement of the urinary bladder. Although the present case had the carpel tunnel syndrome, which has been in primary systemic reported to occur amyloidosis, l2 we were unable to demonstrate amyloid in the tissue removed for the correction of the syndrome. The slight increase of plasma cells in the marrow in the present case is likewise not believed to be sufficient evidence of a cause and effect relation to the amyloid in the urinary bladder - at least not any indication of multiple myeloma. The painless gross hematuria and involvement of the right lateral bladder wall observed in this case have been findings common to almost every case reported of urinary bladder amyloidosis.2’3 Department of Urology 2799 West Grand Boulevard Detroit, Michigan 48202 (DR. FARAH) References 1. Symmers WSC: Primary amyloidosis; a review, J. Clin. Pathol. 9: 187 (1956). 2. Kinzel RC, Harrison EG, and Utz DP: Primary localized amyloidosis of the bladder, J. Urol. 85: 785 (1961). 3. Malek RS, Greene LF, and Farrow GM: Amyloidosis of the urinary bladder, Br. J. Ural. 43: 189 (1971). 4. Hofer RA, et al: Primary localized amyloidosis of the bladder, Stand. J. Urol. Nephrol. 8: 193 (1974). 5. Strong-GH, Kelsey D, and Hoch W: Primary amyloid disease of the bladder. I. Urol. 112: 463 (1974). 6. Au KK, and G&augh JH: Primary amyloidosis of the bladder, ibid. 114: 786 (1975). 7. Ullman AS, Fine G, and Johnson AL: Localized amyloidosis of the urethra, ibid. 92: 42 (1%4). 8. Car& CK, McLaughlin AP, and Gittes RF: Amyloidosis of the lower genitourinary tract, ibid. 115: 423 (1976). 9. McDonald JH, and Heckel NJ: Primary amyloidosis of the lower genitourinary tract, ibid. 75: 122 (1956). 10. Krane RJ, Klugo RC, and Olsson CA: Seminal vesicle amyloidosis, Urology 2: 70 (1973). 11. Glenner GG, Ein E, and Terry WD: The immunoglobulin origin of amyloid, Am. J. Med. 52: 141 (1972). 12. Barth WF, Willerson JT, Waldmann TA, and Decker JL: Primary amyloidosis, ibid. 47: 359 (1969).
UROLOGY
/
FEBRUARY
1979
/
VOLUME XIII,
NUMBER 2
RIAD N. FARAH, DANIEL GERALD PHILIP
OF BLADDER
M.D.
0. BENSON, FINE,
AMYLOIDOSIS
M.D.
M.D.
J. DORMAN,
From the Departments Henry Ford Hospital,
M.D. of Urology, Pathology, Detroit, Michigan
and Medicine,
ABSTRACT - Primary amyloidosis of the bladder is a rare disease, most frequently confused with bladder carcinoma. Our experience in defining the lesion during surgery is presented. The etiology is discussed.
Primary localized amyloidosis of the bladder is of special interest because, both in symptoms and gross appearance, it resembles an infiltrating neoplasm. Accurate diagnosis depends on biopsy. The benign lesions usually respond well to surgical treatment: transurethral resection with or without fulguration, or segmental cystectomy. Case Report A fifty-two-year-old white man was admitted to Henry Ford Hospital with a two-year history of intermittent painless hematuria which had increased in frequency and severity during the past few months. Although the patient had no history of acute or chronic illness, he reported that three of his four children had died of Hurler disease before the age of twenty-one. Physical examination showed this patient to be in good general health. Findings on a liver spleen scan were negative. Routine laboratory studies (complete blood count, sedimentation electrolytes, blood urea nitrogen, rate, creatinine, fasting and two-hour blood sugar, VDRL, total T4, and uric acid) were within normal limits except for microscopic hematuria. The intravenous urogram was normal. A sternal bone marrow smear showed slight elevation of plasmacytes (2.8 per cent). The serum protein electrophoretic pattern was normal. Analysis of serum immunoglobulins revealed elevation of IgA. Immunochemical analysis of the urine
200
demonstrated no free kappa or lambda Bence Jones proteins. Cystoscopy disclosed a sessile, irregular, gray-yellow lesion about 3 cm. in diameter on the right lateral wall of the bladder close to the dome which on biopsy was found to be amyloid deposition. Transurethral resection of the amyloid mass failed to control the bleeding, and a segmental cystectomy was performed using diluted povidone-iodine solution (Betadine) to fill the bladder and localize the amyloid deposit by staining it blue. The postoperative course was uneventful. Cystoscopy three months later showed a well-healed scar and no evidence of recurrence. However, during the next twelve months, the patient had two episodes of hematuria and new areas of amyloid deposition were found on the dome of the bladder which were treated by fulguration, In an attempt to determine if the amyloid was confined to the bladder, biopsies were taken from a number of other sites. Pathology Specimens examined included biopsies of the urinary bladder, the segmentally resected urinary bladder, and biopsies of the stomach, rectum, duodenum, and the right transverse carpal ligament and median nerve (obtained when the patient underwent surgery for carpal tunnel
UROLOGY
/ FEBRUARY
1979 / VOLUME
XIII,
NUMBER 2
FIGURE 1. (A) Subepithelial (SE) area of urinary bladder is greatly thickened principally due to deposition of amyloid which spares area immediately beneath urothelium that is occupied by inflammatory cell infiltrate. (B) Magni$cation of area V (A) better illustrates irregular ajibri11a.ramyloid deposits which have replaced normal connective tissue fm this zone of urinary bladder. (Hematoxylin and eosin, original magnijcations x i’Oand x 300, respectively.)
FIGURE 2. (A and B) Polarization of sections showing same area seen in Fig. 1 B. Bright areas, birefringence of some of Congo red positive amyloid seen in A, are in contrast to almost negative birefringence seen in B and helps to identify small focal amyloid deposits in arterial wall. Birefringence in B is considered due to connective tissue. (Polarized Congo red [A] and polarized hematoxylin and eosin [B], original magnijcations x 300.)
syndrome). Stains used for histologic examination included hematoxylin eosin, Congo red, crystal violet, Van Gieson, and thioflavin T; the last being examined with ultraviolet light. Only the urinary bladder was found to be abnormal. The resected segment of bladder wall was thicker and more rigid than normal with the mucosa and muscular wall being 0.8 and 1.2 cm., respectively. The mucosa was finely granular, and the muscular portion of the bladder wall was attributable to a combination of inflammatory cells and the deposition of an afibrillar eosin-stained material (Fig. 1A). The inflammatory infiltrate was pleomorphic, consisting of plasma cells, lymphocytes, and histiocytes in that order of frequency. They were principally in the immediate subepithelial region and only rarely extended along a vascular channel into
UROLOGY
/ FEBRUARY1979
/ VOLUMEXIII, NUMBER2
the superficial muscle layer of the bladder. The afibrillar eosin-stained material appeared to be a greater factor in the production of the gross bladder changes than the inflammatory cell infiltrate. It, too, was most abundant in the subepithelial portion of the bladder wall, presenting diffusely as irregular, varying-sized masses which had replaced most of the connective tissue in this portion of the bladder wall but spared the blood vessel walls except for infrequent focal small areas (Figs. 1 and 2). The cells interspersed among the deposits were predominantly histiocytes and fibrocytes. Only rarely were cells of the type found in the zone immediately beneath the urothelium seen. The smooth muscle of the bladder wall was much less altered by the afibrillar deposits. Their detection required careful searching and where
201
FIGURE 3. (A and B) Suspected amyloid in intermuscular connective tissue (CT) and smooth muscle (SM) of bladder wall (A) was verijied by birefringence of Congo red positive amyloid (B). (Hematoxylin and eosin [A] and polarized C on g o red [B], original mugnijkation x 300.)
present they principally replaced intermuscular connective tissue and less commonly individual or small groups of smooth muscle fibers (Fig. 3). The afibrillar material stained in the typical fashion of amyloid with all the special stains utilized. The Van Gieson and polarized Congo red-stained sections were particularly helpful in distinguishing the amyloid from collagen something not found possible in all areas with the hematoxylin eosin and crystal violet stains, and the Congo red stain without polarization (Figs. 2 and 3). Comment Classification of amyloidosis has been discussed by Symmers’ in his extensive review. Primary localized amyloidosis, which we believe this case to be an example of, has been reported in the upper and lower respiratory tracts, the urinary bladder and urethra, and the skin and orificial mucosa. The reports of urinary bladder involvement from 1897 to 1971 have been analyzed by Kinzel, Harrison, and Utz’ and by Malek, Greene, and Farrow; subsequent cases have been reported. 4-6 Involvement of other regions of the lower urogenital tract-urethra’,’ and seminal vesicles*-” has also been reported. Many investigations into the chemical composition of amyloid have been carried out and are summarized by Glenner, Ein, and Terry.” Virchow’s concept of amyloid being mainly carbohydrate in nature, investigations since have shown it to be a variable mixture of carbohydrate and proteins with some of the latter having similarities to immunoglobulins. The absence of physical and laboratory findings which would support generalized amyloidosis or a disease process which has been indicated as playing a role in the production of amyloidosis, lends credance to our considering
202
this case one of primary amyloid involvement of the urinary bladder. Although the present case had the carpel tunnel syndrome, which has been in primary systemic reported to occur amyloidosis, l2 we were unable to demonstrate amyloid in the tissue removed for the correction of the syndrome. The slight increase of plasma cells in the marrow in the present case is likewise not believed to be sufficient evidence of a cause and effect relation to the amyloid in the urinary bladder - at least not any indication of multiple myeloma. The painless gross hematuria and involvement of the right lateral bladder wall observed in this case have been findings common to almost every case reported of urinary bladder amyloidosis.2’3 Department of Urology 2799 West Grand Boulevard Detroit, Michigan 48202 (DR. FARAH) References 1. Symmers WSC: Primary amyloidosis; a review, J. Clin. Pathol. 9: 187 (1956). 2. Kinzel RC, Harrison EG, and Utz DP: Primary localized amyloidosis of the bladder, J. Urol. 85: 785 (1961). 3. Malek RS, Greene LF, and Farrow GM: Amyloidosis of the urinary bladder, Br. J. Ural. 43: 189 (1971). 4. Hofer RA, et al: Primary localized amyloidosis of the bladder, Stand. J. Urol. Nephrol. 8: 193 (1974). 5. Strong-GH, Kelsey D, and Hoch W: Primary amyloid disease of the bladder. I. Urol. 112: 463 (1974). 6. Au KK, and G&augh JH: Primary amyloidosis of the bladder, ibid. 114: 786 (1975). 7. Ullman AS, Fine G, and Johnson AL: Localized amyloidosis of the urethra, ibid. 92: 42 (1%4). 8. Car& CK, McLaughlin AP, and Gittes RF: Amyloidosis of the lower genitourinary tract, ibid. 115: 423 (1976). 9. McDonald JH, and Heckel NJ: Primary amyloidosis of the lower genitourinary tract, ibid. 75: 122 (1956). 10. Krane RJ, Klugo RC, and Olsson CA: Seminal vesicle amyloidosis, Urology 2: 70 (1973). 11. Glenner GG, Ein E, and Terry WD: The immunoglobulin origin of amyloid, Am. J. Med. 52: 141 (1972). 12. Barth WF, Willerson JT, Waldmann TA, and Decker JL: Primary amyloidosis, ibid. 47: 359 (1969).
UROLOGY
/
FEBRUARY
1979
/
VOLUME XIII,
NUMBER 2
