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Chronic Sclerosing Ureteritis and Nephrogenic Adenoma of the Ureter in Analgesic Abuse
Path. Res. Pract. 180, 569-573 (1985)
Chronic Sclerosing Ureteritis and Nephrogenic Adenoma of the Ureter in Analgesic Abuse J. Marek and E. Hradec* Second Department of Pathology (Head: Prof. Dr. J. Dobias) and Urological Clinic (Head: Prof. Dr. E. Hradec), Faculty of General Medicine, Charles University, Prague, CSSR
SUMMARY
A 44-year old women with 8 years of analgesic abuse developed bilateral ureteral stenosis with urine congestion and manifestations of renal insufficiency. The resected parts of the ureters were affected by chronic productive inflammation with pronounced capillarosclerosis characteristic of analgesic abuse and largely responsible for the stenosis of the lumina. In addition there was a nephrogenic adenoma in the left ureter, so far almost exclusively described in the urinary bladder and prostatic urethra. Its relation to the analgesic abuse is under discussion.
Uni- or bilateral stenosis of the upper and middle ureteral segments is not common; when seen, it is mostly the result of either on-going or past ureterolithiasis, urological instrumentation or surgery. Cystic ureteritis with renal pelvis stasis is even less frequent. The cause of the stenosis of these ureteral segments mostly lies outside the ureter most often retroperitoneal fibrosis or tumorous infiltration. In this paper we present a case of bilateral ureteral stenosis due to, on the one hand, chronic sclerosing ureteritis indubitably related to analgesic abuse and, on the other hand, the so-called nephrogenic adenoma.
Case report B. G., a 44-year-old woman architect, was admitted to the urological department because of 3-month-lasting persistent lumbar pain and early signs of renal insufficiency. The patient, of asthenic habitus, had been seven years earlier conservatively treated for a chronic peptic ulcer and for years suffered from migraines, most probably of vertebrogenic origin (blocked position of cervical vertebrae). ,. Dedicated to Prof. Dr. Dr. h.c. Franz Buchner in honor of his 90th birthday, Jan. 20, 1985. © 1985 by Gustav Fischer Verlag, Stuttgart
She convincingly denied any long-term drug-taking, although repeatedly asked point-blank by the physician. Two years prior to admission to the urological department she had been examined because of a left-sided renal colic, including intravenous urography. Except for an incomplete rotation of the left kidney, she presented no pathological signs, the upper urinary tract was slim. At the time of admission, renal insufficiency was caused by bilateral stasis in the upper ureteral segments, confirmed by instrumental ureterography (Fig. 1). Following bilateral transcutaneous nephrostomy the patient was referred for reconstructive surgery with a working diagnosis of retroperitoneal fibrosis. Surgery revealed sclerosed ureteral segments, but unmodified surrounding retroperitoneal connective tissue. She had a resection of the left ureter along a length of 3 cm, of the right ureter 4 cm and bilateral anastomosis. The post-operative course and healing were complication-free. When confronted with biopsy results, the patient admitted to taking, in the last eight years, at least 10 tablets of various analgesic mixtures a day, on the average 150-300 mg of phenacetin in one tablet. On histology both ureters were mildly thickened due to limited periureteral fibrosis and to conspicuous thickening of the lamina propria narrowing the lumen. In the left ureter (Fig. 2), the thickening of the lamina propria was 0344·0338/85/0180-0569$3.50/0
570 .
J. Marek and E. Hradec
Fig. 1. Retrograde pyeloureterogram shows bilateral ureteral stenosis.
Fig. 2. Left ureter with irregular lumen, dense band of sclerotic connective tissue (arrows) and chronic inflammation of lamina propria with tubular structures (arrowheads). HE, cca x 60.
caused, on the one hand, by an externally positioned compact stript of acellular connective tissue of almost scarry appearance and on the other hand, by a layer of connective tissue with chronic inflammatory infiltrations, in which were found tubular formations corresponding to nephrogenic adenoma. These formations, some cystically dilated, were lined with simple cuboid, in places almost columnar epithelium reminiscent of distal nephronal segments and sometimes formed solid cellular strips with only an indication of a lumen (Fig. 3 and 4). They were always
Fig. 4. Tubular structures with cuboidal and columnar epithelium partly with lumina, partly as solid strips. HE, cca x 260.
Fig. 3. Dilated tubules lined with flattened cuboidal epithelium and chronic inflammation of lamina propria. Cuboidal epithelium is also on the surface of the lesion. On the left many thick-walled capillaries. HE, cca x 150.
Fig. 5. Lamina propria with severe capillarosclerosis. HE, cca x 260.
Nephrogenic Adenoma of Ureter . 571
Fig. 6. Ultrastructure of epithelial cells in nephrogenic adenoma. Light cytoplasm with few mitochondria, dense bodies, lipid, ribosomes and glycogen granules. Lead citrate and uranyl acetate, cca X 500.
Fig. 9. Thick basement membrane and complex infoldings in basal regions of epithelial cells. cca X 9600.
Fig. 7. Microvilli and tight junctions in the apical regions of the nephrogenic adenoma epithelial cells. cca = 8000.
Fig. 10. Thickened capillary wall in capillarosclerosis with many dense basement membrane lamellae and endothelial cell in the place of obliterated lumen. cca X 9600.
Fig. 8. Brush-border like microvilli with dense apical vacuoles and tubules. cca X 19200.
separated from the neighbouring interstice by a distinct basement membrane. In these segments the mucosal surface was often not covered with the typical urothelium, but with simple cuboid to columnar epithelium. The external strip of sclerotic connective tissue consisted, on greater magnification, of oval and ribbon-like structures (Fig. 3 and 5), on occasion with a preserved lumen with erythro-
572 .
J. Marek and E. Hradec
cytes; their wall was always conspicuously PAS positive. A closer analysis of these structures demonstrated that they are proliferating capillaries with conspicuous wall hyalinosis and sclerosis resulting in their obliteration. In the right ureter there were only these vascular changes and a chronic productive inflammation. Electron microscopy of formalin-fixed material revealed nephrogenic adenoma cells with light cytoplasm and occasional mitochondria, dense bodies of varying frequency, ribosomes and glycogen granules. Granular endoplasmic reticulum was seen only rarely (Fig. 6). The cells were in the apical region connected by many zonulae occludentes (Fig. 7) and on the free surface the cellular membrane formed many microvilli, on whose base there were sometimes apical vacuoles and tubules (Fig. 8). A thick basement membrane consisted of several layers of dense lamellae, while the cellular membrane formed on the base obvious complex infoldings (Fig. 9). The ultrastructural basis of the thickened capillary walls was a pronounced reduplication of electron-dense lamellae of the basement membrane; they were interwoven, often obliterating the lumen - in its place endothelial remains could be seen (Fig. 10). Discussion The morphological changes seen in the resected ureters are remarkable for two reasons. In the first place, the sclerosis of the lamina propria, which caused ureteral stenosis, was to a large extent due to pronounced hyalinosis and sclerosis of capillary walls. These changes, called capillarosclerosis, are considered in the outlet urinary tract as characteristic of patients with analgesic abuse, primarily of phenacetin, being the most constant finding in a number of morphological changes 15 . The patient admitted only after reconstructive surgery, when the results of histology were known, to having intentionally kept silent about the analgesic abuse. It should be added that she was a highly intelligent and productive person; during her stay in hospital she was disciplined and cooperating very well. The second unusual finding is the presence of tubular epithelial formations in the lamina propria of the left ureter. It is fully in keeping with nephrogenic adenoma, described for the first time in 1949 by Davis in the wall of the urinary bladder6. Since then there have been now and again reports published about isolated cases of this benign lesion - most of them in the bladder1, 4, 5, 8-10, 16, 18-20 and only rarely in the prostatic urethra 2, 14. Ureteral nephrogenic adenoma is somewhat unique - in addition to our case13 only one similar case had been described in literature 12 • Most authors now reject the tumorous or hamartogenic nature of this lesion, suggesting it to be an exceptional form of urothelial metaplasia that accompanies chronic inflammations or traumatic changes 1? For this reason it has lately been called either adenomatoid or nephrogenic metaplasia. Because of the nature and origin of cells, the infrequent ultrastructural findings do not yield clear-cut results most authors speak of an analogy with various segments
of the lower nephron ll , 12, 16, 19. Only Bhagavan and coworkers have demonstrated in some of the investigated material formations corresponding to the proximal convuluted renal tubule2. Our findings are similar in so far that there was almost identical arrangement of basal cellular parts. The brush border was only indicated (Fig. 8), because we succeeded in visualizing solely solid, not fully luminized formations. The ultrastructure of epithelial cells is no doubt influenced by chronic inflammation and intersticial vascular changes. It is thus in no way surprising that the nature of the cytoplasm is reminiscent of the picture of atrophic cells in the proximal convoluted tubule of an ischaemic kidney21. The assessment of cytoplasmic structures was, in our case, somewhat difficult because of imperfect fixation, as only formalin-fixed material was available. Typical mature urothelial structures could be demonstrated neither in our material, nor in literature. The meta- or mesonephric nature of nephrogenic adenoma cells seems to be indicated also by the demonstration of identical PNA-lectin receptor sites in nephrogenic adenoma and embryonic kidney tubules? Nephrogenic adenoma is generally believed to be an entirely benign lesion with limited proliferation activity although in literature we find isolated reports or urinary bladder carcinoma associated with nephrogenic adenoma of the bladder or following closely upon it4,16. The presence of the basement membrane and the absence of mitoses and cellular atypia are the most important points in the differential diagnosis from an adenocarcinoma. The relation of nephrogenic adenoma to analgesic abuse remains unclarified. In the pathogenesis of nef.hro~enic adenoma there has been repeatedly stressed2, 1 ,17-1 the significance of influences that also result in squamous metaplasia and cystic ureteritis: chronic inflammation, long-term concrement irritation, sequellae of trauma or surgery and immunosuppression. For these reasons nephrogenic adenoma is seen as an unusual manifestation of urothelial structural instability, due to long exposure of the urothelium to harmful influences. In our cases in its pathogenesis predominated the chronic inflammation; but phenacetin abuse should also be included among harmful influences because of its well-known carcinogenic action on the urothelium 3 • There are no data in literature on . possible analgesic abuse in nephrogenic adenoma - in our case analgesic abuse would not have been demonstrated, had not the finding of capillarosclerosis led to a closer investigation of the patient's medical history. It is, therefore, recommended to search specifically, in patients presenting with this lesion, for analgesic abuse and either confirm or eliminate a possible association.
References 1 Allan E (1975) Nephrogenic adenoma of the bladder. J Urol 113: 35-41 2 Bhagavan BS, Tiamson EM, Wenk RE, Berger BW, Hamamoto G, Eggleston Je (1981) Nephrogenic adenoma of the urinary bladder and urethra. Human Path 12: 907-916
Letter to the Case . 573 3 Blohme I, Johansson S (1981) Renal pelvic neoplasms and atypical urothelium in patients with end-stage analgesic nephrOfathy. Kidney Int 20: 671-675 Christoffersen J, Meller JE (1972) Adenomatoid tumours of the urinary bladder. Scand J Urol Nephrol 6: 295-298 5 Cremer H, Adolphs HD (1978) The natural history of nephrogenic adenoma of the urinary bladder. Z Krebsforsch 91: 49-53 6 Davis T A (1949) Hamartoma of the urinary bladder. Northwest Med 48: 182-185 7 Devine P, Ucci AA, Krain H, Gavris VE, Bhagavan BS, Heaney JA, Alroy J (1984) Nephrogenic adenoma and embryonic kidney tubules share PNA receptor sites. Amer J Clin Path 81: 728-732 8 Donhuijsen K, Leiteschneider W (1975) Nephrogenic adenoma. A rare epithelial tumor of the urinary bladder. Beitr Path 155: 208-211 9 Friedman NB, Kuhlenbeck H (1950) Adenomatoid tumors of the bladder reproducting renal structures (nephrogenic adenomas) . J Urol 64: 657-670 10 Goldman RL (1972) Nephrogenic metaplasia (nephrogenic adenoma, adenomatoid tumor) of the bladder. J Urol 108: 565-567 11 Imahori S (1980) Nephrogenic adenoma of urinary bladder: a liyht and electron microscopic study. Lab Invest 42: 124-125 1 Lugo M, Petersen RO, Elfenbein IB, Stein BS, Duker NJ (1983) Nephrogenic metaplasia of the ureter. Amer J Clin Path 80: 92-97
13 Marek J, Hradec E (1982) The so called nephrogenic adenoma resulting from the abuse of analgetics. Cas lek ces 121: 1207-1209 (in Czech with English Summary) 14 Martin SA, Santa Cruz DJ (1981) Adenomatoid metaplasia of 8rostatic urethra. Amer J Clin Path 75: 185-189 Mihatsch MJ, Torhorst J, Steinmann E, Hofer H, Stickelberger M, Bianchi L, Berneis K, Zollinger KU (1979) The morphologic diagnosis of analgesic (phenacetin) abuse. Path Res Pract 164: 68-79 16 Molland EA, Trott PA, Paris AMI, Blandy JP (1976) Nephrogenic adenoma: a form of adenomatous metaplasia of the bladder. A clinical and electron microscopical study. Brit J Urol 48: 453-462 17 Mostofi FK (1955) Potentialities of bladder epithelum. J Urol 71: 705-714 18 Navarre RJ, Loening SA, Platz C, Narayana A, Culp DA (1982) Nephrogenic adenoma: a report of 9 cases and review of the literature. J Uro1127: 775-779 19 O'Shea PA, Callaghan JF, Lawlor JB, Reddy VC (1981 ) "Nephrogenic adenoma": an unusual metaplastic change of urothelium. J Uro1125: 249-252 20 Sussman EB, Brice M, Gray GF (1974) Nephrogenic metaplasia of the bladder. J Urolll1: 34-35 21 Zollinger HU, Torhorst J, Riede UN, Toenges vV, Geering B, Rohr HP (1973) Der inkomplette oder Sub-Infarkt der Niere (einseitige zentral-arterielle Schrumpfniere). Pathologischanatomische morphometrische und elektronmikroskopische Untersuchungen. Beitr Path Anat 148: 15-34
Received September 24, 1984· Accepted March 15, 1985
Key words: Nephrogenic adenoma - Capillarosclerosis - Analgesic abuse - Ureteral stenosis Dr. J. Marek, 2nd Department of Pathology, U nemocnice 4, 12852 Prague, CSSR
Letter to the Case E. Kunze Gottingen So-called nephrogenic adenoma is an uncommon peculiar polypoid and/or papillary lesion mainly occurring in the urinary bladder first described by Davis in 19497 • The distinctive feature is the formation of tubular structures limited to the lamina propria with an overlying urothelium. The proliferated tubules are lined by flattened or cuboidal cells frequently showing a hobnail configuration. The intervening interstitial tissue is edenomatous and infiltrated by chronic inflammatory cells. Because of the close morphologic resemblance of the tubular complexes with
either renal distal convoluted or collecting ducts Friedman and Kuhlenbeck 10 coined the term "nephrogenic adenoma". In most cases there is in addition to a tubular a papillary growth pattern at the surface of the lesion showing delicate papillary fronds covered by a single layer of cuboidal or low columnar cells with an abundant, frequently clear cytoplasm4, 6,9-11 , 18,19, 21. There is no cellular atypia. Opinions widely differ as to the nature, pathogenesis and histogenesis of this rare lesion as is best reflected by the different terms used such as "nephrogenic
Chronic Sclerosing Ureteritis and Nephrogenic Adenoma of the Ureter in Analgesic Abuse J. Marek and E. Hradec* Second Department of Pathology (Head: Prof. Dr. J. Dobias) and Urological Clinic (Head: Prof. Dr. E. Hradec), Faculty of General Medicine, Charles University, Prague, CSSR
SUMMARY
A 44-year old women with 8 years of analgesic abuse developed bilateral ureteral stenosis with urine congestion and manifestations of renal insufficiency. The resected parts of the ureters were affected by chronic productive inflammation with pronounced capillarosclerosis characteristic of analgesic abuse and largely responsible for the stenosis of the lumina. In addition there was a nephrogenic adenoma in the left ureter, so far almost exclusively described in the urinary bladder and prostatic urethra. Its relation to the analgesic abuse is under discussion.
Uni- or bilateral stenosis of the upper and middle ureteral segments is not common; when seen, it is mostly the result of either on-going or past ureterolithiasis, urological instrumentation or surgery. Cystic ureteritis with renal pelvis stasis is even less frequent. The cause of the stenosis of these ureteral segments mostly lies outside the ureter most often retroperitoneal fibrosis or tumorous infiltration. In this paper we present a case of bilateral ureteral stenosis due to, on the one hand, chronic sclerosing ureteritis indubitably related to analgesic abuse and, on the other hand, the so-called nephrogenic adenoma.
Case report B. G., a 44-year-old woman architect, was admitted to the urological department because of 3-month-lasting persistent lumbar pain and early signs of renal insufficiency. The patient, of asthenic habitus, had been seven years earlier conservatively treated for a chronic peptic ulcer and for years suffered from migraines, most probably of vertebrogenic origin (blocked position of cervical vertebrae). ,. Dedicated to Prof. Dr. Dr. h.c. Franz Buchner in honor of his 90th birthday, Jan. 20, 1985. © 1985 by Gustav Fischer Verlag, Stuttgart
She convincingly denied any long-term drug-taking, although repeatedly asked point-blank by the physician. Two years prior to admission to the urological department she had been examined because of a left-sided renal colic, including intravenous urography. Except for an incomplete rotation of the left kidney, she presented no pathological signs, the upper urinary tract was slim. At the time of admission, renal insufficiency was caused by bilateral stasis in the upper ureteral segments, confirmed by instrumental ureterography (Fig. 1). Following bilateral transcutaneous nephrostomy the patient was referred for reconstructive surgery with a working diagnosis of retroperitoneal fibrosis. Surgery revealed sclerosed ureteral segments, but unmodified surrounding retroperitoneal connective tissue. She had a resection of the left ureter along a length of 3 cm, of the right ureter 4 cm and bilateral anastomosis. The post-operative course and healing were complication-free. When confronted with biopsy results, the patient admitted to taking, in the last eight years, at least 10 tablets of various analgesic mixtures a day, on the average 150-300 mg of phenacetin in one tablet. On histology both ureters were mildly thickened due to limited periureteral fibrosis and to conspicuous thickening of the lamina propria narrowing the lumen. In the left ureter (Fig. 2), the thickening of the lamina propria was 0344·0338/85/0180-0569$3.50/0
570 .
J. Marek and E. Hradec
Fig. 1. Retrograde pyeloureterogram shows bilateral ureteral stenosis.
Fig. 2. Left ureter with irregular lumen, dense band of sclerotic connective tissue (arrows) and chronic inflammation of lamina propria with tubular structures (arrowheads). HE, cca x 60.
caused, on the one hand, by an externally positioned compact stript of acellular connective tissue of almost scarry appearance and on the other hand, by a layer of connective tissue with chronic inflammatory infiltrations, in which were found tubular formations corresponding to nephrogenic adenoma. These formations, some cystically dilated, were lined with simple cuboid, in places almost columnar epithelium reminiscent of distal nephronal segments and sometimes formed solid cellular strips with only an indication of a lumen (Fig. 3 and 4). They were always
Fig. 4. Tubular structures with cuboidal and columnar epithelium partly with lumina, partly as solid strips. HE, cca x 260.
Fig. 3. Dilated tubules lined with flattened cuboidal epithelium and chronic inflammation of lamina propria. Cuboidal epithelium is also on the surface of the lesion. On the left many thick-walled capillaries. HE, cca x 150.
Fig. 5. Lamina propria with severe capillarosclerosis. HE, cca x 260.
Nephrogenic Adenoma of Ureter . 571
Fig. 6. Ultrastructure of epithelial cells in nephrogenic adenoma. Light cytoplasm with few mitochondria, dense bodies, lipid, ribosomes and glycogen granules. Lead citrate and uranyl acetate, cca X 500.
Fig. 9. Thick basement membrane and complex infoldings in basal regions of epithelial cells. cca X 9600.
Fig. 7. Microvilli and tight junctions in the apical regions of the nephrogenic adenoma epithelial cells. cca = 8000.
Fig. 10. Thickened capillary wall in capillarosclerosis with many dense basement membrane lamellae and endothelial cell in the place of obliterated lumen. cca X 9600.
Fig. 8. Brush-border like microvilli with dense apical vacuoles and tubules. cca X 19200.
separated from the neighbouring interstice by a distinct basement membrane. In these segments the mucosal surface was often not covered with the typical urothelium, but with simple cuboid to columnar epithelium. The external strip of sclerotic connective tissue consisted, on greater magnification, of oval and ribbon-like structures (Fig. 3 and 5), on occasion with a preserved lumen with erythro-
572 .
J. Marek and E. Hradec
cytes; their wall was always conspicuously PAS positive. A closer analysis of these structures demonstrated that they are proliferating capillaries with conspicuous wall hyalinosis and sclerosis resulting in their obliteration. In the right ureter there were only these vascular changes and a chronic productive inflammation. Electron microscopy of formalin-fixed material revealed nephrogenic adenoma cells with light cytoplasm and occasional mitochondria, dense bodies of varying frequency, ribosomes and glycogen granules. Granular endoplasmic reticulum was seen only rarely (Fig. 6). The cells were in the apical region connected by many zonulae occludentes (Fig. 7) and on the free surface the cellular membrane formed many microvilli, on whose base there were sometimes apical vacuoles and tubules (Fig. 8). A thick basement membrane consisted of several layers of dense lamellae, while the cellular membrane formed on the base obvious complex infoldings (Fig. 9). The ultrastructural basis of the thickened capillary walls was a pronounced reduplication of electron-dense lamellae of the basement membrane; they were interwoven, often obliterating the lumen - in its place endothelial remains could be seen (Fig. 10). Discussion The morphological changes seen in the resected ureters are remarkable for two reasons. In the first place, the sclerosis of the lamina propria, which caused ureteral stenosis, was to a large extent due to pronounced hyalinosis and sclerosis of capillary walls. These changes, called capillarosclerosis, are considered in the outlet urinary tract as characteristic of patients with analgesic abuse, primarily of phenacetin, being the most constant finding in a number of morphological changes 15 . The patient admitted only after reconstructive surgery, when the results of histology were known, to having intentionally kept silent about the analgesic abuse. It should be added that she was a highly intelligent and productive person; during her stay in hospital she was disciplined and cooperating very well. The second unusual finding is the presence of tubular epithelial formations in the lamina propria of the left ureter. It is fully in keeping with nephrogenic adenoma, described for the first time in 1949 by Davis in the wall of the urinary bladder6. Since then there have been now and again reports published about isolated cases of this benign lesion - most of them in the bladder1, 4, 5, 8-10, 16, 18-20 and only rarely in the prostatic urethra 2, 14. Ureteral nephrogenic adenoma is somewhat unique - in addition to our case13 only one similar case had been described in literature 12 • Most authors now reject the tumorous or hamartogenic nature of this lesion, suggesting it to be an exceptional form of urothelial metaplasia that accompanies chronic inflammations or traumatic changes 1? For this reason it has lately been called either adenomatoid or nephrogenic metaplasia. Because of the nature and origin of cells, the infrequent ultrastructural findings do not yield clear-cut results most authors speak of an analogy with various segments
of the lower nephron ll , 12, 16, 19. Only Bhagavan and coworkers have demonstrated in some of the investigated material formations corresponding to the proximal convuluted renal tubule2. Our findings are similar in so far that there was almost identical arrangement of basal cellular parts. The brush border was only indicated (Fig. 8), because we succeeded in visualizing solely solid, not fully luminized formations. The ultrastructure of epithelial cells is no doubt influenced by chronic inflammation and intersticial vascular changes. It is thus in no way surprising that the nature of the cytoplasm is reminiscent of the picture of atrophic cells in the proximal convoluted tubule of an ischaemic kidney21. The assessment of cytoplasmic structures was, in our case, somewhat difficult because of imperfect fixation, as only formalin-fixed material was available. Typical mature urothelial structures could be demonstrated neither in our material, nor in literature. The meta- or mesonephric nature of nephrogenic adenoma cells seems to be indicated also by the demonstration of identical PNA-lectin receptor sites in nephrogenic adenoma and embryonic kidney tubules? Nephrogenic adenoma is generally believed to be an entirely benign lesion with limited proliferation activity although in literature we find isolated reports or urinary bladder carcinoma associated with nephrogenic adenoma of the bladder or following closely upon it4,16. The presence of the basement membrane and the absence of mitoses and cellular atypia are the most important points in the differential diagnosis from an adenocarcinoma. The relation of nephrogenic adenoma to analgesic abuse remains unclarified. In the pathogenesis of nef.hro~enic adenoma there has been repeatedly stressed2, 1 ,17-1 the significance of influences that also result in squamous metaplasia and cystic ureteritis: chronic inflammation, long-term concrement irritation, sequellae of trauma or surgery and immunosuppression. For these reasons nephrogenic adenoma is seen as an unusual manifestation of urothelial structural instability, due to long exposure of the urothelium to harmful influences. In our cases in its pathogenesis predominated the chronic inflammation; but phenacetin abuse should also be included among harmful influences because of its well-known carcinogenic action on the urothelium 3 • There are no data in literature on . possible analgesic abuse in nephrogenic adenoma - in our case analgesic abuse would not have been demonstrated, had not the finding of capillarosclerosis led to a closer investigation of the patient's medical history. It is, therefore, recommended to search specifically, in patients presenting with this lesion, for analgesic abuse and either confirm or eliminate a possible association.
References 1 Allan E (1975) Nephrogenic adenoma of the bladder. J Urol 113: 35-41 2 Bhagavan BS, Tiamson EM, Wenk RE, Berger BW, Hamamoto G, Eggleston Je (1981) Nephrogenic adenoma of the urinary bladder and urethra. Human Path 12: 907-916
Letter to the Case . 573 3 Blohme I, Johansson S (1981) Renal pelvic neoplasms and atypical urothelium in patients with end-stage analgesic nephrOfathy. Kidney Int 20: 671-675 Christoffersen J, Meller JE (1972) Adenomatoid tumours of the urinary bladder. Scand J Urol Nephrol 6: 295-298 5 Cremer H, Adolphs HD (1978) The natural history of nephrogenic adenoma of the urinary bladder. Z Krebsforsch 91: 49-53 6 Davis T A (1949) Hamartoma of the urinary bladder. Northwest Med 48: 182-185 7 Devine P, Ucci AA, Krain H, Gavris VE, Bhagavan BS, Heaney JA, Alroy J (1984) Nephrogenic adenoma and embryonic kidney tubules share PNA receptor sites. Amer J Clin Path 81: 728-732 8 Donhuijsen K, Leiteschneider W (1975) Nephrogenic adenoma. A rare epithelial tumor of the urinary bladder. Beitr Path 155: 208-211 9 Friedman NB, Kuhlenbeck H (1950) Adenomatoid tumors of the bladder reproducting renal structures (nephrogenic adenomas) . J Urol 64: 657-670 10 Goldman RL (1972) Nephrogenic metaplasia (nephrogenic adenoma, adenomatoid tumor) of the bladder. J Urol 108: 565-567 11 Imahori S (1980) Nephrogenic adenoma of urinary bladder: a liyht and electron microscopic study. Lab Invest 42: 124-125 1 Lugo M, Petersen RO, Elfenbein IB, Stein BS, Duker NJ (1983) Nephrogenic metaplasia of the ureter. Amer J Clin Path 80: 92-97
13 Marek J, Hradec E (1982) The so called nephrogenic adenoma resulting from the abuse of analgetics. Cas lek ces 121: 1207-1209 (in Czech with English Summary) 14 Martin SA, Santa Cruz DJ (1981) Adenomatoid metaplasia of 8rostatic urethra. Amer J Clin Path 75: 185-189 Mihatsch MJ, Torhorst J, Steinmann E, Hofer H, Stickelberger M, Bianchi L, Berneis K, Zollinger KU (1979) The morphologic diagnosis of analgesic (phenacetin) abuse. Path Res Pract 164: 68-79 16 Molland EA, Trott PA, Paris AMI, Blandy JP (1976) Nephrogenic adenoma: a form of adenomatous metaplasia of the bladder. A clinical and electron microscopical study. Brit J Urol 48: 453-462 17 Mostofi FK (1955) Potentialities of bladder epithelum. J Urol 71: 705-714 18 Navarre RJ, Loening SA, Platz C, Narayana A, Culp DA (1982) Nephrogenic adenoma: a report of 9 cases and review of the literature. J Uro1127: 775-779 19 O'Shea PA, Callaghan JF, Lawlor JB, Reddy VC (1981 ) "Nephrogenic adenoma": an unusual metaplastic change of urothelium. J Uro1125: 249-252 20 Sussman EB, Brice M, Gray GF (1974) Nephrogenic metaplasia of the bladder. J Urolll1: 34-35 21 Zollinger HU, Torhorst J, Riede UN, Toenges vV, Geering B, Rohr HP (1973) Der inkomplette oder Sub-Infarkt der Niere (einseitige zentral-arterielle Schrumpfniere). Pathologischanatomische morphometrische und elektronmikroskopische Untersuchungen. Beitr Path Anat 148: 15-34
Received September 24, 1984· Accepted March 15, 1985
Key words: Nephrogenic adenoma - Capillarosclerosis - Analgesic abuse - Ureteral stenosis Dr. J. Marek, 2nd Department of Pathology, U nemocnice 4, 12852 Prague, CSSR
Letter to the Case E. Kunze Gottingen So-called nephrogenic adenoma is an uncommon peculiar polypoid and/or papillary lesion mainly occurring in the urinary bladder first described by Davis in 19497 • The distinctive feature is the formation of tubular structures limited to the lamina propria with an overlying urothelium. The proliferated tubules are lined by flattened or cuboidal cells frequently showing a hobnail configuration. The intervening interstitial tissue is edenomatous and infiltrated by chronic inflammatory cells. Because of the close morphologic resemblance of the tubular complexes with
either renal distal convoluted or collecting ducts Friedman and Kuhlenbeck 10 coined the term "nephrogenic adenoma". In most cases there is in addition to a tubular a papillary growth pattern at the surface of the lesion showing delicate papillary fronds covered by a single layer of cuboidal or low columnar cells with an abundant, frequently clear cytoplasm4, 6,9-11 , 18,19, 21. There is no cellular atypia. Opinions widely differ as to the nature, pathogenesis and histogenesis of this rare lesion as is best reflected by the different terms used such as "nephrogenic