NEPHROGENIC ADENOMA OF URINARY BLADDER ASSOCIATED WITH MALAKOPLAKIA
N . V . RAGHAVAIAH, M .D . H . NORMAN NOE, M .D . DAVID M . PARHAM, M . D . WILLIAM M . MURPHY, M .D . From the Departments of Urology and Pathology, University of Tennessee for Health Sciences, Memphis, Tennessee
ABSTRACT -A case of nephrogenic adenoma occurring in a twelve-year-old black female child, associated with recurrent Escherichia coli urinary tract infection is described . The patient was followed for over six years and treated with repeated cystoscopic examinations and fulgurations of the lesion . Five years after the initial diagnosis, malakoplakia of the bladder developed in association with nephrogenic adenoma . There was no evidence of invasion of the bladder by the lesion during these six years . Electron microscopic study of nephrogenic adenoma indicated its origin from the urotheliumn . Nephrogenic adenoma of the bladder is to be considered as a benign mntaplastic lesion of the urothelium and is to he treated with repeated cystoscopic fulgurations .
Nephrogenic adenoma of the bladder is a rare lesion of the vesical urothelium . Although 32 cases have been reported in the literature, the nature and histogenesis of the lesion have not been definitely established . Malakoplakia of the urinary bladder is a benign, recurrent, inflammatory lesion, and its association with nephrogenic adenoma of the bladder has not been reported . The ultrastructure of this lesion was studied in an attempt to understand the nature and histogenesis of this condition . Case Report A twelve-year-old black female was admitted to the urology service in 1972, with a history of gross, total, painless hematuria, and frequency of micturition . At the age of six years, she had been evaluated for recurrent urinary tract infection and was found to have a refluxing duplicated collecting system on the right side with marked hydronephrosis of the lower pole segment . Lower pole nephroureterectomy and reimplantation of the ureter of the upper pole of the kidney was performed with good result .
Clinical examination of the patient during her 1972 admission was unremarkable except for deep suprapubic tenderness . Urinalysis revealed gross hematuria, and the urine culture grew Escherichia coli . Excretory urogram was unremarkable except for the evidence of previous surgery on the right kidney . Cystourethroscopy revealed multiple papillary lesions measuring 5 in m . to 1 .5 cm . scattered over the trigone and near the right ureteric orifice . Transurethral punch biopsy and fulguration of the lesions were performed . Microscopic examination of the lesion revealed nephrogenic adenoma . The patient was treated with long-term suppressive antibiotic therapy and repeated cystoscopic examinations every six months . The lesions recurred from time to time in different locations of the bladder . Excretory urograms were repeated every year . She had symptomatic improvement with this treatment, and excretory urograms were unchanged and normal during this period . In 1975, six years after the initial diagnosis of nephrogenic adenoma, she had another attack of
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hematuria, during which time she was two months' pregnant . Cystoscopic examination revealed recurrence of papillary lesions over the trigone and dome of the bladder . They were fulgurated after obtaining cold punch biopsies . The biopsy specimens were studied both with light microscope and Philips 200 Electron microscope which revealed malakoplakia in association with nephrogenic adenoma . Pathologic Findings Multiple fragments of bladder mucosa and underlying soft tissue were examined microscopically . The urothelium was irregularly thickened with focal nodules of hyperplastic urothelial cells projecting into the lamina propria . In some areas these cells had columnar forms, basally located nuclei, and clear apical cytoplasm . Chronic inflammatory cells were scattered diffusely throughout the lamina propria, and lymphoid follicles with germinal center formation were observed in some areas . A focal area of histoeystic proliferation was observed in the lamina propria of one fragment . The histocvtes were densely packed with small round nuclei with dense chromatin . The cytoplasm was foamy and lightly basophilic with irregular cellular borders . The cytoplasm of many histocvtes contained small round inclusions con-
sistent with Michaelis-Guttman bodies . These inclusions stained positively with periodic acidSchiff, Von Kossa calcium, and Prussian blue iron (Fig . 1A) . In several fragments papillomatous lesions, lined by simple cuboidal epithelium, were identified . Tubular structures lined by comparable epithelial cells and resembling renal tubules were embedded in the adjacent lamina propria (Fig . 1B) . Ultrastructurally these structures were composed of cuhoidal and low columnar cells with microvillous luminal surface . Zonular occludens were present at the apical junctions of adjoining cells . The intercellular spaces were widened in some areas . Lateral cell processes protruded into these spaces . The basal portions of these cells formed complex intertwining processes set upon a thin basement membrane . The epithelial cells consisted of a bimodal population of light and dark cells . The light cells contained round to irregular nuclei with various degrees of chromatin density . Oblong
FIGURE 1 . (A) Close-up view of lamina propria of urinary bladder showing densely packed infiltrate of histiocystes with scattered fibroblasts, Numerous round intracystoplasmic inclusions composed of concentric variably staining spheres (Michaelis-Guttman bodies) are visible 'arrows) . (Periodic acid-schiff, original magnification x 300) . (B) View of urinary bladder showing tumor composed of papillary fronds and projections lined by simple cuboidal epithelium . Underlying lamina propria is replaced by tubular structures lined by similar epithelium and resembling distal convoluted tubules . (llematoxylinn and eosin, original magnification x 150.)
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FIGURE 2 . (A) Ultrastructural view of nephrogenic adenoma composed of single layer of low columnar cells with a tnicrovillous surface and an irregular, infolded base, Mitochondria, lysosomes, Golgi complexes, and granular endoplamic reticulum are visible . (B) Ultrastructural view of nephrogenic adenoma containing low columnar cells with both lightly and darkly staining cells . Endoplasraic reticulum of dark cells is dilated and forms complex intracellular spaces . (Original magnifications x 3,300 .) mitochondria and lysosomes bearing no consistent spacial orientations were identified . Granular endoplasmic reticulum was prominent and in some areas was dilated, forming dilated intracellular spaces . Active secretion was not observed . The cells also contained Golgi complexes and polyribosomes, glycogen, and lipid were absent (Fig . 2A) . The dark cells contained similar organelles but differed in that the dilatation of the endoplasmic reticulmn and partial lysis of the basal portions were more prominent (Fig. 2B) . Comment Friedman and Kuhlenbeckz coined the term "nephrogenic adenorna" to describe a bladder lesion which resembled histologically the loop of Henle, distal convoluted tubules, or collecting tubules of the kidney . Since then 32 cases have been reported ."' Clinical features of the lesion were well documented in the previous reports . It occurred most commonly in males (78 per cent) during the third decade of life, The ages of the patients ranged from twelve to sixty-eight years, the youngest patient being twelve years of age, as described here . The most common presenting complaint was bladder irritative symptoms in the form of dysuria, frequency, and urgency (58 per cent), and gross, painless, total, and recurrent attacks
of hematuria (48 per cent) . In 2 patients, nephrogenic adenoma was an incidental finding during a routine autopsy . Forty-eight per cent of the patients had a history of trauma (operative or otherwise) to the bladder prior to the detection of the lesion . Most often it was an operative trauma . Forty per cent of the patients suffered from chronic urinary tract infection with E . coli . Nineteen per cent of the patients had stone disease of the kidney, and 10 per cent had prolonged catheter drainage of the bladder before the lesion was diagnosed . In most of the patients, physical examination and excretory urograms were normal . Cystoscopic examination showed multiple small papillary lesions situated in and around the trigone, and near the ureteric orifices . The dome and lateral walls were affected less often ." The light microscopic appearance of nephrogenic adenoma was well documented .' 5 .6,13 It consisted of tubular and cystic structures lined by a single layer of cuboidal or columnar epithelium resembling distal convoluted tubule, loops of Henle, and collecting tubules . This appearance differed from normal renal tissue in that, structures resembling glomeruli, Bowman capsule, and proximal convoluted tubules were absent in nephrogenic adenoma . All had mixed stromal inflammatory cell infiltrates . The electron microscopic appearance of nephrogenic adenoma indicated that the cells are
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immature and not totally characteristic of any commonly cited tissues of origin . The findings are most consistent with urothelium' 5 and are least compatible either with fetal mesonephros or its mature derivatives . The only other available report on ultrstructure of this lesion also indicates that nephrogenic adenoma probably originates from urothelium . 13 The nature and histogenesis of this lesion have not been established . There are two main theories of its histogenesis . 13 (1) The embryologic theory suggests that these tumors take origin from mesodermally developed trigone of the bladder, and they represent embryonic rests or choristomas of mesodermally derived elements .' .2 (2) The inflammatory theory postulates that these tumors represent an unusual metaplastic reaction of the urothelium to chronic inflammation and irritation 7,8,11,11,11 A combinaation of these two theories was attempted by Goldman . 16 In his opinion, the tumor represents a metaplastic change in the urothelium of the bladder derived from mesoderm, as would be found in the region of trigone or, as local mesothelial islands in entodermally derived areas of the bladder. However, the ultrastructure of nephrogenic adenoma indicates that this lesion probably originates from urothelium and not from the mesodermal derivatives . The nature of the lesion is also debated . Although, in 90 per cent of the cases the lesion was considered benign, 3 cases of malignant transformation of this lesion were described . , '" llit 2 of 3 malignant lesions, nephrogenic adenoma was probably an associated lesion with carcinoma of the bladder . Recently Gordon and Kerr' 2 suggested its relationship to the failure of the immunologic surveillance mechanism because of its occurrence in a patient with renal transplantation and chronic immunosuppressive therapy . The chronic nature of the lesion with a benign noninvasive course for over six years as in the present patient, indicates its benign nature . Its association with malakoplakia which is also a benign unetaplastic lesion of the urotheliuin, 16 indicates that nephrogenic
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adenoma also probably is a benign metaplasia of the urothelium either due to chronic sepsis or irritation or trauma to the bladder . Of 32 cases . 2 were incidental findings during autopsy, 2 were treated with subtotal cystectomy and ileocecocystoplasty' 213 and 2 were treated with total cystectorny and deal conduit .'' Twenty-six patients were treated with transurethral resection and/or hd,guration of these lesions, either repeatedly or in one sitting . with satisfactory results . Department of Urology Memphis, (DR .
P .O . Box 63635 Tennessee 38163 RAGHAVAIAH)
References 1 . Davis TA: Hamartoma of the urinary bladder . Northwest \led, 48 : 182 (1949) . 2 . Friedman NB, and Kuhlenheck H : Ade :mnatoid tumors of the bladder reproducing renal stmetures (nephrogenic adenonas), JUml . 64 : 657 (1950) . 3 . Mostofi FK : Potentialities of bladder epithelium, ibid. 71 : 705 (1954) . 4 . Ilasen II B: Nephrogenic adenoma of the hi adder, ibid, 88 : 629 (1962) . 5 . Christoffeison J, and Moller JI : : Adenomatoid tumors of the urinary bladder, Scand . J . Urol . Nephrol . 6 : 295 (1972) . 6 . Goldman RL: Nephrogenic metaplasia (nephrngenic adenoma, adenomatoid tumor) of the bladder. J . Urol . 108 : 565 (M72) . 7 . Kalloor GJ, and Shaw RE : Nephrogenic adenoma of the bladder, Br . J, Urol . 46 : 91 (1973) . 8 . Taneja OP, el al : Nephrogenic adenonr.a of the urinary bladder, ibid . 46 : 97 (1974) . 9 . Sussmau EB, Mitchell B, and Gray GF : Nephrogenic metaplasia of the bladder, J . Urol, 111 : 34 (1974) . 10 . Kaany E, and Wemer SL : Nephrogenic adenoma of the bladder . Urology 4 : 343 (1974) . 11 . Allen E : Nephrogeucadenomaofthe bladder, J . Urnl . 113 : 35 (1975) . 12 . Cordon HL, and Ken' SG : Nephrogenic adenoma of the bladder in immunosuppressed renal transplantation . Urology 5 : 275 (1975) . 13 . Mollaud EA . Trott PA, Paris AML and Blandy JP : Nephrogenic adenoma a form of adenomatous metaplasia of the bladder; a clinical and microscopic study . Br . J . Urol, 48: 453 (1976) . 14 . Kaswick )A, Waisman J, and Goodwin ME : Nephrogenic metaplasia (adenonatoid tumors) of bladder, Urology 8 : 283 (1976) . 15 . Fulker MJ . Cooper EH . and Tanaka T . Proliferation and ultrastructure of papillary transitional cell can inoma of the human bladder, Cancer 27 : 71 (1971) . 16 . O'Dea MJ, Malek RS, and Farrow GM : Malacoplakia of the urinary tract challenges and frustrations with 10 cases, j . Urol . 118 : 739 i 1977) .