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Malakoplakia of the Bladder: Case Report1
MALAKOPLAKIA OF THE BLADDER CASE REPORT 1
DORRIN F. RUDNICK
AND
ALEX B. RAGINS
From the Urological, the Surgical Pathology Departments of the Cook County Hospital, and the Cook County Graduate School of Medicine, Chicago, Illinois.
Malakoplakia is one of the rarest lesions of the urinary bladder and has seldom been diagnosed on cystoscopic examination. This disease was first accurately described in 1903 by Hansemann. Prior to that time, Michaelis and Gutmann, who were the first to notice so-called "inclusion bodies," reported a similar condition, but were inclined to call it a malignant tumor. The last paper was written in 1934 by Chisholm and Tudhope. The first case recognized by cystoscopic examination was reported by Blum, who treated the lesion successfully by fulguration. Subsequent cases have been reported by Thomson-Walker and Barrington, Folsom, Dickson, Gray and Kidd, and others. Our case was observed cystoscopically during a routine urinary tract examination. Case report, R. C., a 53 year old white Polish female, entered the Cook County Hospital on May 15, 1938 with the tentative diagnosis of perinephric abscess. With the aid of an interpreter, it was learned that for the past year she had been very constipated, with evacuations only about every fourth day. Aside from this complaint she felt perfectly well until 3 weeks before admission. She began to lose her appetite and developed some lower back pain which was most marked on the left. She also had suprapubic pains and a burning sensation during urination. Frequency of urination increased particularly at night when the patient at times found it necessary to get up every half hour to urinate. During this 3-week period, the urine was always creamcolored and cloudy. In the last 3 days preceding hospitalization the pain became more severe and on the day prior to admission she vomited a half cupful of "bright red blood." The past history was essentially negative. Her menopause occurred 4 years before this illness. About 20 years prior to admission, she fractured both wrists and right leg. Some deformity persisted. The temperature was 99.4°F.; pulse 118; respirations 24; and the blood pressure was 140/102. 1 Read before meeting of North Central Branch Society, American Urological Association, September 30, 1938. 108
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Her teeth were few and carious; tongue clear, and tonsils small. The lungs showed no abnormalities; heart borders were within normal limits, sounds rapid with an occasional extrasystole and no murmurs. Tenderness was elicited on Murphy's percussion in both lumbar regions, but was most marked in the left side. The abdomen was slightly distended; kidneys and spleen not palpable. Generalized tenderness was elicited on both slight and deep pressure over the entire abdomen, most marked, however, in the epigastrium and left lateral and lumbar regions. A sense of resistance was felt in the epigastrium. On percussion the upper abdomen was flat. Tympany was present in the lower abdomen. Exquisite tenderness was elicited over the last sacral vertebra. On pelvic examination Bartholin and Skenes glands were negative. The vagina admitted 2 fingers with difficulty. The cervix was not felt. The
FIG.
1. Cystoscopic drawing of malakoplakic areas as seen on posterior wall of bladder
uterus appeared to be surrounded by adhesions. The entire suprapubic region was tender. No masses were palpated. Rectal examination revealed large external hemorrhoids. Otherwise the rectum was negative. Examination of the extremities revealed radial deviation of both hands, more marked in the right (Walrus-hand deformity). A transverse scar was present on the dorsum of the right wrist. A tentative diagnosis of pyelitis with possible infection of the entire urinary tract was made, pending further workup. Cystoscopy (May 15, 1938): A No. 24 McCarthy cystoscope was passed easily and 120 cc. of very cloudy urine was removed from the bladder. The urinary bladder was washed clear with difficulty. On the posterior wall near the fundus were located 4 small papillary-like tumor masses (fig. 1). The one nearest the trigone was symmetrically round and about 1 cm. in diameter. It was light canary yellow in color and was surrounded by a small but distinct
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DORRIN F. RUDNICK AND. ALEX B. RAGINS
hyperemic halo. There was slight pitting in the center of the mass. The other 3 lesions were similar but not symmetrical in outline. The patient was uncooperative, and after biopsies were taken further work-up was impossible. A catheterized specimen of bladder urine removed at the time of the cystoscopic examination revealed B. coli, B. proteus, and B. mucosus capsulatus. The blood Wassermann was negative. X-ray examination of the right forearm revealed an old fracture in the lower one-third of the right radius with a sharp medial angulation and some overriding. There was a wide separation between the radius and ulna at the lower end and a marked deformity of the wrist. There was also a suggestion of an old fracture of the styloid process of the left ulna. A plain film of the abdomen revealed slight arthritic changes in the sacroiliac areas and a suggestion of a stone in the left renal area. X-ray examination of the gastro-intestinal tract was entirely negative. The chest revealed a bilateral increase in the hilar markings with some calcification in the hilar lymph nodes. Blood urea-nitrogen was 16 mgm. per 100 ccm., and blood-sugar 91 mgm. The electrocardiograph showed a left axis deviation with a notched and slurred QRS. complex, and T1-T2-and T3 were all upright. (N.E., left ventricular preponderance.) The biopsy of the urinary bladder, stained with hemalum and eosin, revealed islands of large polyhedral cells, in the submucosa, with ample pale-pinkstaining, finely granular, and, in places, markedly vacuolated cytoplasm (fig. 2). Their nuclei were large, round to oval in shape, and contained a moderate amount of granular chromatin. Many of the nuclei contained distinct nucleoli. In places these cells were covered by a layer of normal transitional cell epithelium. In the cytoplasm of many of these cells, small, round, bluish staining bodies were seen, some of which showed distinct laminations. The bodies varied in size from 2 to 7 microns in diameter, and at times appeared to push the nucleus of the cell to the periphery. Some of the cells contained as many as S inclusion bodies. When stained with the Kossa stain, these bodies appeared to be almost wholly calcium (fig. 3, a). An iron stain (Prussian-blue reaction) revealed but few of the bodies to be composed of iron pigment (fig. 3, b). These polygonal cells were separated, in certain areas, by a large number of lymphocytes and plasma cells which were well demonstrated by the methylgreen-pyronin stain which stained the cytoplasm of the plasma cells and lymphoid cells a distinct pink. Throughout the masses of polygonal cells there were numerous thin-walled blood capillaries filled with a few polymorphonuclear leucocytes and red blood cells.
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The free surface of the polygonal cellular masses lay adjacent to and was covered by a layer of intact transitional epithelial cells infiltrated by single polymorphonuclear leucocytes. With the Heideheim azo-carmin stain these epithelial cells stained a distinct homogeneous pinkish red, whereas the polygonal cells stained a bluish pink, demonstrating a distinctly granular and vacuolated cytoplasm. In addition there was a definite layer of blue staining connective tissue separating the polygonal cells from the transitional epithelial cells. The inclusion-bodies appeared blue with the azo-carmin stain, and the blood vessels were surrounded by a layer of blue staining connective tissue. At the base of these plaques the connective tissue was markedly increased and contained large sized blood vessels and arterioles.
FIG. 2. Showing many polyhedral cells with granular and vacuolated cytoplasm. In places faint inclusion bodies may be seen. Darker staining cells are lymphocytes and plasma cells. Hemalum-eosin stain. X 276.
The differentiation of cells was still better demonstrated by staining the section for reticulum fibers after a quick method described by Gomori. Here single islands of polyhedral cells were surrounded by a fine network of reticulum fibers, whereas the epithelial cells, quite characteristically, had no surrounding fibers (fig. 3, c). In addition, as with the Azan stain, there was a thin layer of reticulum fibers, which served as a sharp line of demarkation between the epithelial cells and the large polyhedral cells. The elastin stain for elastic tissue fibrils revealed many fibrils about the larger blood vessels at the base of the plaque. None, however, were present about the polyhedral cells. Gram, Weigert, Ziehl-Nielsen, and dilute carbofuchsin stains were made for bacteria but none were found.
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DORRIN F. RUDNICK AND ALE:X B. RAGINS
Sudan 3 stain reveakd fine fat granules in only a few of the polyhedral cells. Examination of unstained sections through the polarizing microscope for double refractile fat bodies was negative.
a
FrG. 3. A, Kossa stain showing intracellular inclusions to be composed of calcium which in places sho.ys distinct lamellae. B, Iron stain showing some of bodies containing iron. Note iron bodies in marked-off areas. C, Reticulum stain showing reticulum fibers surrounding some of polyhedral cells, and also showing separation of polyhedral from epithelial cells.
In view of the above microscopic and cystoscopic findings a diagnosis of malakoplakia was made. In an attempt to establish an etiologic basis for the malakoplakia, cystoscopy was repeated June 1, 1938. A No. 24 French cystoscope was passed
MALAKOPLAKIA OF THE BLADDER
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with ease and 2 ounces of a cloudy urine were removed from the bladder, Many washings were required to get a clear medium. The bladder was regular in contour. The vesical picture was exactly the same as previously described in detail under date of May 15, 1938. The orifices of the right and left ureters were both red and edematous. The efflux from the left ureteral orifice was grossly turbid; from the right ureteral orifice it appeared clear. The vesical mucosa was light absorbing. Catheters passed easily on both sides and catheterized specimens from both ureters were sent to the bacteriologic laboratories for culture and study.
FrG. 4. X-ray showing staghorn stone in left renal pelvis
Phenolsulphonphthalein dye given intravenously appeared in 5 minutes in excellent concentration from the right kidney but did not appear from the left kidney after 30 minutes of observation. Bilateral retrograde pyelograms were made. X-ray examination revealed a large staghorn calculus in the region of the left kidney pelvis (fig. 4). The iliopsoas margin on the left side was obscured. The renal pelvis on the right side was well visualized and appeared normal. The left ureter showed some dilatation. Bacteriologic examination of the urine specimens submitted was reported
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DORRIN F. RUDNICK AND ALEX B. RAGINS
as follows: A direct smear from the left ureteral urine showed many pus cells with Gram-positive diplococci suggestive of staphylococci and also many Gramnegative forms, particularly Gram-negative bacilli. Ziehl-Nielsen stain failed to show acid-fast organisms. Primary cultures revealed a growth of B. proteus, B. coli, and Staph. albus. Subcultures revealed a pure strain of B. mucosus capsulatus. Guinea pig inoculations for tubercle bacilli were negative. A direct smear of the contents of the right ureter showed no organisms and cultures revealed no growth. In view of the above findings it was thought advisable to remove the left kidney. A nephrectomy and partial ureterectomy was performed by one of us (D.F.R.) June 11, 1939. The specimen consisted of a left kidney measuring 10 x 5.5 x 5.5 cm. On sectioning, the capsule was found to be firmly adherent to the cortex, and covered in places by fat tissue. The cortex was narrowed and varied in thickness from 2 to 4 mm. It was light purple gray and mottled by darker purplish gray to purplish red areas. The pelvis was distended, and the calices were :flattened. The mucous membrane was markedly thickened and granular. In the lumen of the renal pelvis extending into the calices was an irregular staghorn stone measuring 5.5 x 4 x 2 gm. in its greatest dimensions. The free surface of this stone was brownish gray and granular. Attached to the pelvis was a portion of the ureter measuring 7 cm. long, the wall of which was markedly thickened. No evidence of malakoplakia was found in the mucosa of the pelvis of the kidney or in the ureter. On microscopic examination the capsule of the kidney was markedly thickened and was composed of edematous fibrous connective tissue infiltrated by many round cells. At the junction of the capsule and cortex of the kidney· there were large hemorrhagic areas. Many of the glomeruli were partially to completely hyalinized, while others showed slight atrophy of the glomerular tufts. Bowman's capsule was markedly thickened in many places. The convoluted tubuli, as well as the collecting tubuli were widely separated by a marked increase of connective tissue fibers heavily infiltrated by round cells and in places by red blood corpuscles. The lining epithelium of the tubuli was flattened, and many of the nuclei had undergone either karyorexis or karyolysis. Many of their lumina contained hyaline casts or epithelial cells. The submucosa of the renal pelvis, as well as that of the ureter, was heavily infiltrated by lymphocytes, large mononuclear cells, and a few eosinophilic cells. The blood capillaries were dilated and filled with blood. The mucosa proper, particularly in the pelvis of the kidney, was replaced by small areas of infected chronic granulation tissue. Otherwise, the mucosa was thickened by a moderate increase in the number of transitional epithelial cells. A diagnosis of chronic pyelonephritis and ureteritis associated with nephrolithiasis was made. Following the operation the patient made an uneventful recovery except for
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an acute dacrocystitis which developed 3 weeks later. One month after the operation her symptoms of back pains, dysuria, frequency, and chills disappeared. Cystoscopy, about 1 month after the nephrectomy, revealed a complete disappearance of the plaques of malakoplakia described previously, except for 1 area which was considerably smaller and flatter than those previously seen. That the lesions herein described are of a granulomatous nature and are not true neoplasms is fairly well demonstrated by the above histological description and clinical course. Particularly conclusive are (1) the definite demarkation between the polygonal cells (which we are inclined to call histiocytes, since they contain calcium bodies and to some extent iron granules) and the transitional epithelium of the bladder mucosa; and (2) the disappearance of the plaques following the removal of the diseased kidney. Since the first description of malakoplakia by Hansemann practically all investigators have believed these lesions to be granulomatous in nature and infectious in origin. There seems to be quite a difference of opinion as to the causative agents involved in their production. Hansemann emphasized the fact that there was no infection of the urinary bladder in the 2 cases that he reported. In 1 instance the patient died of pulmonary tuberculosis, and in the second, death resulted from a carcinoma of the gall bladder. He did, however, find (in the nodules) clumps of bacteria which resembled B. coli, which he did not consider to be an etiologic factor. Schaudinn did not believe that the inclusion bodies were parasites. In the cases reported by Michaelis and Gutmann, Chisholm and Tudhope, Blum, Walker and Barrington, and Folsom a definite history of cystitis was given. Pappenheimer found Gram-negative bacteria resembling B. coli, as did Landsteiner and Stoerck. They were of the opinion that these organisms were of definite etiologic significance. Minelli and Gierke merely considered them a possible etiologic factor. The bacteriologic studies in our case seemed to point to a Gramnegative bacillus which, when isolated, proved to be the bacillus mucosus capsulatus. This was found in the purulent material from the left kidney, and upon removal of the left kidney the patches all disappeared, except one, and the urinary bladder symptoms vanished. An interesting observation was made by Dickson, Gray, and Kidd, who, in addition to finding the Friedlander bacillus, were able to demonstrate, on repeated occasions, what they thought were mycotic parasites
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DORRIN F. RUDNICK AND ALEX B. RAGINS
which appeared as monilia-like spores. On observing a moist preparation over a period of 38 hours, they noticed that the inclusion bodies in cells obtained from the urinary sediment resembled Michaelis-Gutmann bodies and produced budding forms. We failed to find, in our case, a similar organism. As to the origin of the polygonal cells, we are inclined to call them histiocytes, since they have the power of phagocytosis, as demonstrated by the calcium and iron body inclusions. We can not make a definite statement as to the source of these inclusions although one may suppose that they are derived from the broken down red blood corpuscles, or what is more likely, the absorption of calcium oxalate or calcium phosphate granules. Albright states that in an alkaline urine associated with urea-splitting organisms, such as B. proteus, calcium phosphates or calcium oxalates may be precipitated with ease. In our case, bacillus proteus was found. Wells calls these bodies calcospherites, i.e., small calcareous spheres usually of concentric structure. He states that they seem to be the result of the formation of insoluble calcium salts in the presence of colloidal substances, just as urinary and other concretions are formed about an organic nucleus. It seems to him that an ulcerated lesion in the urinary tract offers ideal conditions for the formation of calcospherites in the tissues. The properties and composition of the bodies found are just what would be expected of calcospherites formed in such an environment as might be furnished by the slow diffusion of cystitis urine into edematous and inflamed vesical mucosa. Landsteiner and Stoerck believed these cells to be derived from the interstitial wandering cells, whereas Gierke and Ellenreider state that they look more like epithelioid cells which come from the connective tissue and blood capillaries. Malakoplakia usually occurs in adults past the age of forty and is more frequent in females than in males. The youngest case hitherto reported was an eight year old girl (Oppermann). Malakoplakia is so infrequent that the treatment has not been standardized. There is no question that the removal of the source of infection can cause the disappearance of the lesions, as occurred in our case. Folsom, Blum, and Dickson, Gray, and Kidd have had fair results by fulguration. The lesions have also been treated with potassium iodide and autogeneous vaccines.
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CONCLUSIONS
A case of malakoplakia is reported ina 53 year old white woman associated with a chronic ascending unilateral pyelonephritis, nephrolithiasis, and chronic ureteritis. The plaques were composed of large polygonal cells containing Michaelis-Gutmann bodies and also large accumulations of lymphocytes and plasma cells. They were entirely distinct from the transitional epithelium covering them, as shown by various differential stains. Bacteriologic studies revealed the chief organism to be the bacillus mucosus capsulatus of Friedlander, which was isolated from the urinary bladder and left ureter. Upon removal of the left kidney and ureter, all of the symptoms and the malakoplakia disappeared.
55 E. Washington St., Chicago, Ill. REFERENCES ALBRIGHT: Some medical aspects of the renal stone problem. New Eng. J. Med., 217: 1063, 1937. BLUM: Malakoplakia Vesicae. Wien. Med. Woch., 68: 347, 1918; Ztschr. f. Urol., 12: 401, 1918. CHISOLM AND TuDHOPE: Malakoplakia of urinary bladder. Edinburgh M. J., 41: 626, 1924. DICKSON, GRAY AND KIDD: Malakoplakia vesicae: An investigation of certain mycotic infections of genito-urinary tract. Urol. and Cutan. Rev., 31: 611, 1927. ELLENREIDER, A. R.: Quoted by Folsom. FOLSOM, A. I.: Malakoplakia of urinary bladder. J. A. M.A., 73: 1112, 1919. GIERKE: Ueber Malakoplakia der Harnblase. Mtinchen med. Woch., 62: 1388, 1905. Gi:iMi:iRI, G.: Silver impregnation of reticulum in paraffin sections. Am. J. Path., 31: 993, 1937. voN HANSEMANN: Uber Malakoplakia der Harnblase. Virchow's Arch., 173: 302, 1903. LANDSTEINER AND STOERCK: Uber eine eigenartige Form Chronischer Cystitis ( v .Hansemann). Beitr. z. path. Anat. u. z. allg. Path. 36: 131, 1904. MICHAELIS AND GUTMANN: Uber Einschlusse in Blasentumoren. Ztschr. f. klin. Med., 47: 208, 1902. MINELLI, S.: Uber die Malakoplakia der Harnblase. Vinchow's Arch., 184: 157, 1906. OPPERMAN: Malakoplakia der Harnblase bei einem achtjahrigen Madschen. Ztschr. f. U rol., 18: 164, 1924. PAPPENHEIMER, A. M.: Malakoplakia of urinary bladder. Proc. New York Paih. Soc., p. 65, 1906-07. SCHAUDINN: Quoted by v.Hansemann. THOMSON-WALKER, J. AND BARRINGTON: Proc. Royal Soc. London, 16: 32, 1922-23. WELLS, H. G.: Giant cells in cystitis. Arch. Path., 26: 32, 1938.
DORRIN F. RUDNICK
AND
ALEX B. RAGINS
From the Urological, the Surgical Pathology Departments of the Cook County Hospital, and the Cook County Graduate School of Medicine, Chicago, Illinois.
Malakoplakia is one of the rarest lesions of the urinary bladder and has seldom been diagnosed on cystoscopic examination. This disease was first accurately described in 1903 by Hansemann. Prior to that time, Michaelis and Gutmann, who were the first to notice so-called "inclusion bodies," reported a similar condition, but were inclined to call it a malignant tumor. The last paper was written in 1934 by Chisholm and Tudhope. The first case recognized by cystoscopic examination was reported by Blum, who treated the lesion successfully by fulguration. Subsequent cases have been reported by Thomson-Walker and Barrington, Folsom, Dickson, Gray and Kidd, and others. Our case was observed cystoscopically during a routine urinary tract examination. Case report, R. C., a 53 year old white Polish female, entered the Cook County Hospital on May 15, 1938 with the tentative diagnosis of perinephric abscess. With the aid of an interpreter, it was learned that for the past year she had been very constipated, with evacuations only about every fourth day. Aside from this complaint she felt perfectly well until 3 weeks before admission. She began to lose her appetite and developed some lower back pain which was most marked on the left. She also had suprapubic pains and a burning sensation during urination. Frequency of urination increased particularly at night when the patient at times found it necessary to get up every half hour to urinate. During this 3-week period, the urine was always creamcolored and cloudy. In the last 3 days preceding hospitalization the pain became more severe and on the day prior to admission she vomited a half cupful of "bright red blood." The past history was essentially negative. Her menopause occurred 4 years before this illness. About 20 years prior to admission, she fractured both wrists and right leg. Some deformity persisted. The temperature was 99.4°F.; pulse 118; respirations 24; and the blood pressure was 140/102. 1 Read before meeting of North Central Branch Society, American Urological Association, September 30, 1938. 108
MALAKOPLAKIA OF THE BLADDER
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Her teeth were few and carious; tongue clear, and tonsils small. The lungs showed no abnormalities; heart borders were within normal limits, sounds rapid with an occasional extrasystole and no murmurs. Tenderness was elicited on Murphy's percussion in both lumbar regions, but was most marked in the left side. The abdomen was slightly distended; kidneys and spleen not palpable. Generalized tenderness was elicited on both slight and deep pressure over the entire abdomen, most marked, however, in the epigastrium and left lateral and lumbar regions. A sense of resistance was felt in the epigastrium. On percussion the upper abdomen was flat. Tympany was present in the lower abdomen. Exquisite tenderness was elicited over the last sacral vertebra. On pelvic examination Bartholin and Skenes glands were negative. The vagina admitted 2 fingers with difficulty. The cervix was not felt. The
FIG.
1. Cystoscopic drawing of malakoplakic areas as seen on posterior wall of bladder
uterus appeared to be surrounded by adhesions. The entire suprapubic region was tender. No masses were palpated. Rectal examination revealed large external hemorrhoids. Otherwise the rectum was negative. Examination of the extremities revealed radial deviation of both hands, more marked in the right (Walrus-hand deformity). A transverse scar was present on the dorsum of the right wrist. A tentative diagnosis of pyelitis with possible infection of the entire urinary tract was made, pending further workup. Cystoscopy (May 15, 1938): A No. 24 McCarthy cystoscope was passed easily and 120 cc. of very cloudy urine was removed from the bladder. The urinary bladder was washed clear with difficulty. On the posterior wall near the fundus were located 4 small papillary-like tumor masses (fig. 1). The one nearest the trigone was symmetrically round and about 1 cm. in diameter. It was light canary yellow in color and was surrounded by a small but distinct
110
DORRIN F. RUDNICK AND. ALEX B. RAGINS
hyperemic halo. There was slight pitting in the center of the mass. The other 3 lesions were similar but not symmetrical in outline. The patient was uncooperative, and after biopsies were taken further work-up was impossible. A catheterized specimen of bladder urine removed at the time of the cystoscopic examination revealed B. coli, B. proteus, and B. mucosus capsulatus. The blood Wassermann was negative. X-ray examination of the right forearm revealed an old fracture in the lower one-third of the right radius with a sharp medial angulation and some overriding. There was a wide separation between the radius and ulna at the lower end and a marked deformity of the wrist. There was also a suggestion of an old fracture of the styloid process of the left ulna. A plain film of the abdomen revealed slight arthritic changes in the sacroiliac areas and a suggestion of a stone in the left renal area. X-ray examination of the gastro-intestinal tract was entirely negative. The chest revealed a bilateral increase in the hilar markings with some calcification in the hilar lymph nodes. Blood urea-nitrogen was 16 mgm. per 100 ccm., and blood-sugar 91 mgm. The electrocardiograph showed a left axis deviation with a notched and slurred QRS. complex, and T1-T2-and T3 were all upright. (N.E., left ventricular preponderance.) The biopsy of the urinary bladder, stained with hemalum and eosin, revealed islands of large polyhedral cells, in the submucosa, with ample pale-pinkstaining, finely granular, and, in places, markedly vacuolated cytoplasm (fig. 2). Their nuclei were large, round to oval in shape, and contained a moderate amount of granular chromatin. Many of the nuclei contained distinct nucleoli. In places these cells were covered by a layer of normal transitional cell epithelium. In the cytoplasm of many of these cells, small, round, bluish staining bodies were seen, some of which showed distinct laminations. The bodies varied in size from 2 to 7 microns in diameter, and at times appeared to push the nucleus of the cell to the periphery. Some of the cells contained as many as S inclusion bodies. When stained with the Kossa stain, these bodies appeared to be almost wholly calcium (fig. 3, a). An iron stain (Prussian-blue reaction) revealed but few of the bodies to be composed of iron pigment (fig. 3, b). These polygonal cells were separated, in certain areas, by a large number of lymphocytes and plasma cells which were well demonstrated by the methylgreen-pyronin stain which stained the cytoplasm of the plasma cells and lymphoid cells a distinct pink. Throughout the masses of polygonal cells there were numerous thin-walled blood capillaries filled with a few polymorphonuclear leucocytes and red blood cells.
MALAKOPLAKIA OF THE BLADDER
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The free surface of the polygonal cellular masses lay adjacent to and was covered by a layer of intact transitional epithelial cells infiltrated by single polymorphonuclear leucocytes. With the Heideheim azo-carmin stain these epithelial cells stained a distinct homogeneous pinkish red, whereas the polygonal cells stained a bluish pink, demonstrating a distinctly granular and vacuolated cytoplasm. In addition there was a definite layer of blue staining connective tissue separating the polygonal cells from the transitional epithelial cells. The inclusion-bodies appeared blue with the azo-carmin stain, and the blood vessels were surrounded by a layer of blue staining connective tissue. At the base of these plaques the connective tissue was markedly increased and contained large sized blood vessels and arterioles.
FIG. 2. Showing many polyhedral cells with granular and vacuolated cytoplasm. In places faint inclusion bodies may be seen. Darker staining cells are lymphocytes and plasma cells. Hemalum-eosin stain. X 276.
The differentiation of cells was still better demonstrated by staining the section for reticulum fibers after a quick method described by Gomori. Here single islands of polyhedral cells were surrounded by a fine network of reticulum fibers, whereas the epithelial cells, quite characteristically, had no surrounding fibers (fig. 3, c). In addition, as with the Azan stain, there was a thin layer of reticulum fibers, which served as a sharp line of demarkation between the epithelial cells and the large polyhedral cells. The elastin stain for elastic tissue fibrils revealed many fibrils about the larger blood vessels at the base of the plaque. None, however, were present about the polyhedral cells. Gram, Weigert, Ziehl-Nielsen, and dilute carbofuchsin stains were made for bacteria but none were found.
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DORRIN F. RUDNICK AND ALE:X B. RAGINS
Sudan 3 stain reveakd fine fat granules in only a few of the polyhedral cells. Examination of unstained sections through the polarizing microscope for double refractile fat bodies was negative.
a
FrG. 3. A, Kossa stain showing intracellular inclusions to be composed of calcium which in places sho.ys distinct lamellae. B, Iron stain showing some of bodies containing iron. Note iron bodies in marked-off areas. C, Reticulum stain showing reticulum fibers surrounding some of polyhedral cells, and also showing separation of polyhedral from epithelial cells.
In view of the above microscopic and cystoscopic findings a diagnosis of malakoplakia was made. In an attempt to establish an etiologic basis for the malakoplakia, cystoscopy was repeated June 1, 1938. A No. 24 French cystoscope was passed
MALAKOPLAKIA OF THE BLADDER
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with ease and 2 ounces of a cloudy urine were removed from the bladder, Many washings were required to get a clear medium. The bladder was regular in contour. The vesical picture was exactly the same as previously described in detail under date of May 15, 1938. The orifices of the right and left ureters were both red and edematous. The efflux from the left ureteral orifice was grossly turbid; from the right ureteral orifice it appeared clear. The vesical mucosa was light absorbing. Catheters passed easily on both sides and catheterized specimens from both ureters were sent to the bacteriologic laboratories for culture and study.
FrG. 4. X-ray showing staghorn stone in left renal pelvis
Phenolsulphonphthalein dye given intravenously appeared in 5 minutes in excellent concentration from the right kidney but did not appear from the left kidney after 30 minutes of observation. Bilateral retrograde pyelograms were made. X-ray examination revealed a large staghorn calculus in the region of the left kidney pelvis (fig. 4). The iliopsoas margin on the left side was obscured. The renal pelvis on the right side was well visualized and appeared normal. The left ureter showed some dilatation. Bacteriologic examination of the urine specimens submitted was reported
114
DORRIN F. RUDNICK AND ALEX B. RAGINS
as follows: A direct smear from the left ureteral urine showed many pus cells with Gram-positive diplococci suggestive of staphylococci and also many Gramnegative forms, particularly Gram-negative bacilli. Ziehl-Nielsen stain failed to show acid-fast organisms. Primary cultures revealed a growth of B. proteus, B. coli, and Staph. albus. Subcultures revealed a pure strain of B. mucosus capsulatus. Guinea pig inoculations for tubercle bacilli were negative. A direct smear of the contents of the right ureter showed no organisms and cultures revealed no growth. In view of the above findings it was thought advisable to remove the left kidney. A nephrectomy and partial ureterectomy was performed by one of us (D.F.R.) June 11, 1939. The specimen consisted of a left kidney measuring 10 x 5.5 x 5.5 cm. On sectioning, the capsule was found to be firmly adherent to the cortex, and covered in places by fat tissue. The cortex was narrowed and varied in thickness from 2 to 4 mm. It was light purple gray and mottled by darker purplish gray to purplish red areas. The pelvis was distended, and the calices were :flattened. The mucous membrane was markedly thickened and granular. In the lumen of the renal pelvis extending into the calices was an irregular staghorn stone measuring 5.5 x 4 x 2 gm. in its greatest dimensions. The free surface of this stone was brownish gray and granular. Attached to the pelvis was a portion of the ureter measuring 7 cm. long, the wall of which was markedly thickened. No evidence of malakoplakia was found in the mucosa of the pelvis of the kidney or in the ureter. On microscopic examination the capsule of the kidney was markedly thickened and was composed of edematous fibrous connective tissue infiltrated by many round cells. At the junction of the capsule and cortex of the kidney· there were large hemorrhagic areas. Many of the glomeruli were partially to completely hyalinized, while others showed slight atrophy of the glomerular tufts. Bowman's capsule was markedly thickened in many places. The convoluted tubuli, as well as the collecting tubuli were widely separated by a marked increase of connective tissue fibers heavily infiltrated by round cells and in places by red blood corpuscles. The lining epithelium of the tubuli was flattened, and many of the nuclei had undergone either karyorexis or karyolysis. Many of their lumina contained hyaline casts or epithelial cells. The submucosa of the renal pelvis, as well as that of the ureter, was heavily infiltrated by lymphocytes, large mononuclear cells, and a few eosinophilic cells. The blood capillaries were dilated and filled with blood. The mucosa proper, particularly in the pelvis of the kidney, was replaced by small areas of infected chronic granulation tissue. Otherwise, the mucosa was thickened by a moderate increase in the number of transitional epithelial cells. A diagnosis of chronic pyelonephritis and ureteritis associated with nephrolithiasis was made. Following the operation the patient made an uneventful recovery except for
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an acute dacrocystitis which developed 3 weeks later. One month after the operation her symptoms of back pains, dysuria, frequency, and chills disappeared. Cystoscopy, about 1 month after the nephrectomy, revealed a complete disappearance of the plaques of malakoplakia described previously, except for 1 area which was considerably smaller and flatter than those previously seen. That the lesions herein described are of a granulomatous nature and are not true neoplasms is fairly well demonstrated by the above histological description and clinical course. Particularly conclusive are (1) the definite demarkation between the polygonal cells (which we are inclined to call histiocytes, since they contain calcium bodies and to some extent iron granules) and the transitional epithelium of the bladder mucosa; and (2) the disappearance of the plaques following the removal of the diseased kidney. Since the first description of malakoplakia by Hansemann practically all investigators have believed these lesions to be granulomatous in nature and infectious in origin. There seems to be quite a difference of opinion as to the causative agents involved in their production. Hansemann emphasized the fact that there was no infection of the urinary bladder in the 2 cases that he reported. In 1 instance the patient died of pulmonary tuberculosis, and in the second, death resulted from a carcinoma of the gall bladder. He did, however, find (in the nodules) clumps of bacteria which resembled B. coli, which he did not consider to be an etiologic factor. Schaudinn did not believe that the inclusion bodies were parasites. In the cases reported by Michaelis and Gutmann, Chisholm and Tudhope, Blum, Walker and Barrington, and Folsom a definite history of cystitis was given. Pappenheimer found Gram-negative bacteria resembling B. coli, as did Landsteiner and Stoerck. They were of the opinion that these organisms were of definite etiologic significance. Minelli and Gierke merely considered them a possible etiologic factor. The bacteriologic studies in our case seemed to point to a Gramnegative bacillus which, when isolated, proved to be the bacillus mucosus capsulatus. This was found in the purulent material from the left kidney, and upon removal of the left kidney the patches all disappeared, except one, and the urinary bladder symptoms vanished. An interesting observation was made by Dickson, Gray, and Kidd, who, in addition to finding the Friedlander bacillus, were able to demonstrate, on repeated occasions, what they thought were mycotic parasites
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which appeared as monilia-like spores. On observing a moist preparation over a period of 38 hours, they noticed that the inclusion bodies in cells obtained from the urinary sediment resembled Michaelis-Gutmann bodies and produced budding forms. We failed to find, in our case, a similar organism. As to the origin of the polygonal cells, we are inclined to call them histiocytes, since they have the power of phagocytosis, as demonstrated by the calcium and iron body inclusions. We can not make a definite statement as to the source of these inclusions although one may suppose that they are derived from the broken down red blood corpuscles, or what is more likely, the absorption of calcium oxalate or calcium phosphate granules. Albright states that in an alkaline urine associated with urea-splitting organisms, such as B. proteus, calcium phosphates or calcium oxalates may be precipitated with ease. In our case, bacillus proteus was found. Wells calls these bodies calcospherites, i.e., small calcareous spheres usually of concentric structure. He states that they seem to be the result of the formation of insoluble calcium salts in the presence of colloidal substances, just as urinary and other concretions are formed about an organic nucleus. It seems to him that an ulcerated lesion in the urinary tract offers ideal conditions for the formation of calcospherites in the tissues. The properties and composition of the bodies found are just what would be expected of calcospherites formed in such an environment as might be furnished by the slow diffusion of cystitis urine into edematous and inflamed vesical mucosa. Landsteiner and Stoerck believed these cells to be derived from the interstitial wandering cells, whereas Gierke and Ellenreider state that they look more like epithelioid cells which come from the connective tissue and blood capillaries. Malakoplakia usually occurs in adults past the age of forty and is more frequent in females than in males. The youngest case hitherto reported was an eight year old girl (Oppermann). Malakoplakia is so infrequent that the treatment has not been standardized. There is no question that the removal of the source of infection can cause the disappearance of the lesions, as occurred in our case. Folsom, Blum, and Dickson, Gray, and Kidd have had fair results by fulguration. The lesions have also been treated with potassium iodide and autogeneous vaccines.
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CONCLUSIONS
A case of malakoplakia is reported ina 53 year old white woman associated with a chronic ascending unilateral pyelonephritis, nephrolithiasis, and chronic ureteritis. The plaques were composed of large polygonal cells containing Michaelis-Gutmann bodies and also large accumulations of lymphocytes and plasma cells. They were entirely distinct from the transitional epithelium covering them, as shown by various differential stains. Bacteriologic studies revealed the chief organism to be the bacillus mucosus capsulatus of Friedlander, which was isolated from the urinary bladder and left ureter. Upon removal of the left kidney and ureter, all of the symptoms and the malakoplakia disappeared.
55 E. Washington St., Chicago, Ill. REFERENCES ALBRIGHT: Some medical aspects of the renal stone problem. New Eng. J. Med., 217: 1063, 1937. BLUM: Malakoplakia Vesicae. Wien. Med. Woch., 68: 347, 1918; Ztschr. f. Urol., 12: 401, 1918. CHISOLM AND TuDHOPE: Malakoplakia of urinary bladder. Edinburgh M. J., 41: 626, 1924. DICKSON, GRAY AND KIDD: Malakoplakia vesicae: An investigation of certain mycotic infections of genito-urinary tract. Urol. and Cutan. Rev., 31: 611, 1927. ELLENREIDER, A. R.: Quoted by Folsom. FOLSOM, A. I.: Malakoplakia of urinary bladder. J. A. M.A., 73: 1112, 1919. GIERKE: Ueber Malakoplakia der Harnblase. Mtinchen med. Woch., 62: 1388, 1905. Gi:iMi:iRI, G.: Silver impregnation of reticulum in paraffin sections. Am. J. Path., 31: 993, 1937. voN HANSEMANN: Uber Malakoplakia der Harnblase. Virchow's Arch., 173: 302, 1903. LANDSTEINER AND STOERCK: Uber eine eigenartige Form Chronischer Cystitis ( v .Hansemann). Beitr. z. path. Anat. u. z. allg. Path. 36: 131, 1904. MICHAELIS AND GUTMANN: Uber Einschlusse in Blasentumoren. Ztschr. f. klin. Med., 47: 208, 1902. MINELLI, S.: Uber die Malakoplakia der Harnblase. Vinchow's Arch., 184: 157, 1906. OPPERMAN: Malakoplakia der Harnblase bei einem achtjahrigen Madschen. Ztschr. f. U rol., 18: 164, 1924. PAPPENHEIMER, A. M.: Malakoplakia of urinary bladder. Proc. New York Paih. Soc., p. 65, 1906-07. SCHAUDINN: Quoted by v.Hansemann. THOMSON-WALKER, J. AND BARRINGTON: Proc. Royal Soc. London, 16: 32, 1922-23. WELLS, H. G.: Giant cells in cystitis. Arch. Path., 26: 32, 1938.