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Nephrogenic Adenoma Associated with Intravesical Bacillus Calmette-Guerin Treatment: A Report of 2 Cases
0022-534 7/86/1352-0359$02.00/0 THE JOURNAL OF UROLOGY
Vol. 135, February
Copyright © 1986 by The Williams & Wilkins Co.
Printed in U.S.A.
NEPHROGENIC ADENOMA ASSOCIATED WITH INTRAVESICAL BACILLUS CALMETTE-GUERIN TREATMENT: A REPORT OF 2 CASES MAGDA M. STILMANT* AND MIKE B. SIROKY From the Departments of Pathology and Urology, Veterans Administration Medical Center, Boston, Massachusetts
ABSTRACT
Nephrogenic adenoma, a rare metaplastic change of urothelium, was observed in 2 patients after intravesical bacillus Calmette-Guerin instillation. The lesion has not been reported previously in relation to bacillus Calmette-Guerin immunotherapy. We discuss the pathogenesis of nephrogenic adenoma and suggest that the marked prolonged cystitis induced by bacillus Calmette-Guerin has an etiological role. The lesion known as nephrogenic adenoma of the bladder is relatively uncommon and was described initially in 1949 by Davis who thought the lesion represented a hamartoma. 1 The term nephrogenic adenoma was suggested the following year by Friedman and Kuhlenbeck, who reported 8 cases with detailed morphological description. 2 Recently, Ritchey and associates described 8 cases and found only 55 cases reported in the literature. 3 However, the incidence of nephrogenic adenoma is probably much higher than the number of cases described in the literature. For example, Davis had seen approximately 100 cases as of 1980 at the Armed Forces Institute of Pathology. 4 Although Friedman and Kuhlenbeck reported the lesion as an adenomatoid tumor reproducing renal structures 2 , thus, representing a hamartoma, recent studies have concluded that it is a metaplastic response of the transitional epithelium to chronic irritation or infection, 3 • 5 or trauma. 6 It also has been observed following kidney transplantation 7 (with surgical trauma and cytomegalovirus infection cited as possible etiological factors) and after radiation. 5 We report 2 cases of nephrogenic adenoma after intravesical instillation of bacillus Calmette-Guerin (BCG) for transitional cell carcinoma of the bladder. MATERIALS AND METHODS
Of 8 patients with transitional cell carcinoma of the bladder treated with intravesical BCG 2 had nephrogenic adenoma. Treatment consisted of 1 ampule of Tice strain BCGt (1 to 8 X 108 organisms) diluted with 60 cc saline solution and instilled in the bladder via a Foley catheter. The solution was retained in the bladder for 1½ to 2 hours. The treatment was performed at regular intervals, initially weekly for 6 weeks, followed by biweekly instillations for 3 months and monthly thereafter for a total of 2 years. Both patients had undergone multiple bladder biopsies. The tissues obtained at biopsy were fixed in 10 per cent buffered formalin and processed for histology using conventional methods. CASE REPORTS
Case J. H. K., a 71-year-old man with a 10-year history of recurrent superficial bladder tumors, had carcinoma in situ of the bladder diagnosed by biopsy in July 1980. He received 80 Accepted for publication July 26, 1985. * Requests for reprints: Laboratory Services (113), Veterans Administration Medical Center, 150 S. Huntington Ave., Boston, Massachusetts 02130. t Antigen Supply House, Northbridge, California 91324. 359
mg. doxorubicin hydrochloride intravesically weekly times 3. Carcinoma in situ was again diagnosed in March 1982 and the patient received 40 mg. mitomycin C intravesically weekly times 24. Subsequent biopsies in June, September and December 1982, and in March 1983 showed no tumor but indicated varying degrees of acute and chronic inflammation and focal necrosis. BCG treatment was initiated in March. Cystoscopy 3 months later showed diffuse mucosal erythema. Three random biopsies performed at that time revealed fibrino purulent exudate and marked inflammation of the bladder mucosa. Multiple biopsies in September, after approximately 6 months of BCG treatment, showed marked chronic inflammation, granulation tissue, erosion and regeneration of the surface epithelium, as well as focal dysplasia of the transitional mucosa. In June 1984 routine biopsies of the bladder were characterized by severe acute and chronic inflammation. No tumor was noted by cystoscopy. In December, about 21 months after beginning BCG therapy, routine surveillance cystoscopy revealed a suspicious lesion at the dome of the bladder. The patient was essentially asymptomatic and was near the end of the 2-year BCG treatment protocol. Biopsy of the bladder lesion revealed marked acute and chronic cystitis and granulation tissue, with prominent capillaries and irregular glandular spaces in the submucosa, which had well defined basement membranes and tall atypical columnar cells characteristic of nephrogenic adenoma (fig. 1). No recurrence of transitional cell carcinoma in situ was observed in the biopsy. Case 2. L. R., a 68-year-old man, had a grade 1/111 superficial transitional cell carcinoma of the bladder diagnosed in November 1980. Cystoscopically, the lesion was a 0.8 cm. sessile tumor on the left lateral wall. Surveillance cystoscopy every 3 months was negative until March 1982 when a small tumor was noted on the right posterior wall. Histologically, the tumor was of low grade and there was no evidence of invasion into the muscle. A third recurrence was noted in July 1983 with similar histology. In addition, random bladder biopsies revealed severe dysplasia bordering on carcinoma in situ. BCG treatment was initiated immediately following the biopsy in July. Followup biopsies 3 months after beginning BCG treatment revealed moderate acute and chronic inflammation of the bladder mucosa and submucosa with no evidence of tumor recurrence. Cystoscopy in January 1984 revealed a small lesion near the left ureteral orifice. The patient had mild dysuria as the only symptom. The lesion was biopsied and consisted histologically of irregular glandular structures in the submucosa with an intact overlying transitional epithelium free of atypia. The glands
360
STILMANT AND SIROKY
FIG. 1. Case 1. Two glandular spaces (arrows) with thick basement membranes and tall atypical cell lining, characteristic of nephrogenic adenoma. Background contains blood vessels and many inflammatory cells. H & E, reduced from X200. Inset is higher power of aforementioned large gland and shows cellular atypia. H & E, reduced from X375.
FIG. 2. Case 2. Several glands with poorly defined basement membranes and atypical cuboidal cell lining. Background shows edema and marked inflammation. H & E, reduced from X200.
were characterized by poorly defined thin basement membranes and were lined by a single row of atypical cuboidal cells. The intervening stroma contained many polymorphonuclear leukocytes and mononuclear cells. Diagnosis was nephrogenic adenoma (fig. 2). No transitional cell tumor was seen. Comment: Although we have observed a small granuloma in the bladder mucosa after BCG treatment in another patient, no granulomas were seen in any of the bladder biopsies after BCG therapy in either of our patients with nephrogenic adenoma. DISCUSSION
Nephrogenic adenoma is a lesion of the bladder, representing a metaplastic response of the transitional epithelium to chronic irritation or trauma. 3 • 5 Clinically, the patient usually presents with irritation, hematuria and pyuria. At biopsy metaplastic tubules, superficially resembling renal proximal tubules,2 are seen in the submucosa, which usually is covered by intact, normal transitional epithelium. The tubular proliferation may be florid and the lining cells often appear quite atypical. A
pseudo-infiltrative pattern may be erroneously diagnosed as invasive adenocarcinoma. However, although recurrences are not uncommon 4 the lesion usually is benign 2·4 and its malignant potential is unknown. Davis, who reported approximately 100 cases at the Armed Forces Institute of Pathology, had not seen any of these lesions recur as malignant tumor. 4 There is good evidence that the lesion is not nephrogenic in origin. Ultrastructural examination, as well as the absence of Tamm-Horsfall protein, has led Bhagavan and associates to suggest a mesonephric rather than a metanephric homology. 8 The term nephrogenic adenoma, introduced by Friedman and Kuhlenbeck in 1950, 2 is unfortunate since the lesion is neither an adenoma nor nephrogenic. Adenomatous metaplasia9 is a more accurate description but the older terminology is well entrenched in the literature and is widely accepted by pathologists as well as urologists. Rarely, infiltrative adenocarcinoma of the bladder is associated with nephrogenic adenoma. 9 • 10 However, there is no evidence of a causal relationship per se between the 2 types of lesions. Perhaps less rare is the association of nephrogenic adenoma with transitional cell carcinoma of the bladder. 5 • 8 • 11 In these cases the development of nephrogenic adenoma usually followed resection of a transitional cell tumor and probably was a result of surgical trauma. Both of our patients had had multiple biopsy procedures before the development of nephrogenic adenoma and it is impossible to rule out trauma as an etiological factor. However, we have only rarely observed nephrogenic adenoma in other patients with multiple biopsies and, thus, we suspect that the marked prolonged cystitis secondary to BCG instillation had a major role. The close temporal relationship to BCG therapy also supports this hypothesis. We have seen no mention in the literature of nephrogenic adenoma in ECG-treated patients. For example, Lamm and associates recently reviewed the complications of intravesical BCG therapy in 140 patients and did not document the development of this lesion in any. 12 However, some have expressed concern about the possible long-term ill-effects of this therapy_1a We believe that nephrogenic adenoma may have been overlooked or misdiagnosed as cystitis cystica and glandularis in the past when biopsy material from ECG-treated patients was examined. It is likely that more such cases will be recognized as the number of ECG-treated patients increases. REFERENCES 1. Davis, T. A.: Hamartoma of the urinary bladder. Northwest. Med., 48: 182, 1949. 2. Friedman, N. B. and Kuhlenbeck, H.: Adenomatoid tumors of the bladder reproducing renal structures (nephrogenic adenomas). J. Urol., 64: 657, 1950. 3. Ritchey, M. L., Novicki, D. E. and Schultenover, S. J.: Nephrogenic adenoma of bladder: a report of 8 cases. J. Urol., 131: 537, 1984. 4. Davis, C. J., Jr.: Case for diagnosis. Milit. Med., 145: 242 and 258, 1980. 5. Navarre, R. J., Jr., Loening, S. A., Platz, C., Narayana, A. and Culp, D. A.: Nephrogenic adenoma: a report of9 cases and review of the literature. J. Urol., 127: 775, 1982. 6. Leonard, S. A., Silverman, A. J., Longston, J. W. and Fuselier, H. A.: Postoperative nephrogenic adenoma of bladder. Urology, 7: 327, 1976. 7. Beaudry, C., Bartrand, P.-E., Laplante, L., Houde, M., Lamoureux, C., Laverdiere, M. and Dandavino, R.: Nephrogenic adenoma of the bladder after kidney transplantation: spontaneous improvement with azathioprine removal; surgical trauma and cytomegalovirus infection as possible etiologic factors. J. Urol., 130: 1183, 1983. 8. Bhagavan, B. S., Tiamson, E. M., Wenk, R. E., Berger, B. W., Hamamoto, G. and Eggleston, J. C.: Nephrogenic adenoma of the urinary bladder and urethra. Hum. Path., 12: 907, 1981. 9. Molland, E. A., Trott, P. A., Paris, A. M. I. and Blandy, J. P.: N ephrogenic adenoma: a form of adenomatous metaplasia of the
l'JEPHROGENIC ADEI\IOfv!lt ASSOCIATED '·WITH BACILLUS CALfviETT:S-GUERIN TR,EATIY!E~JT
bladder. A clinical and electron microscopical study. Brit. J. UroL, 48: 453, 1976. 10. Christoffersen, J. and M,;ller, J.E.: Adenomatoid tumours of the urinary bladder. Scand. J. Urol. NephroL, 6: 295, 1972. 11. Berger, B. W., Bhagavan, B. S., Reiner, W., Engel, R. and Lepor, H.: Nephrogenic adenoma: clinical features and therapeutic con-
361
siderations. J. Urol., 126: 824, 1981. 12. Lamm, D. L., Stogdill, V. D., Stogdill, B. J. and Crispen, R. G.: Complications of bacillus Calmette-Guerin immunotherapy in 1,278 patients with bladder cancer. J. Urol., 135: 272, 1986. 13. Connolly, J. G.: Re: Immunotherapy of superficial bladder cancer. Letter to the Editor. J. Urol., 130: 368, 1983.
Vol. 135, February
Copyright © 1986 by The Williams & Wilkins Co.
Printed in U.S.A.
NEPHROGENIC ADENOMA ASSOCIATED WITH INTRAVESICAL BACILLUS CALMETTE-GUERIN TREATMENT: A REPORT OF 2 CASES MAGDA M. STILMANT* AND MIKE B. SIROKY From the Departments of Pathology and Urology, Veterans Administration Medical Center, Boston, Massachusetts
ABSTRACT
Nephrogenic adenoma, a rare metaplastic change of urothelium, was observed in 2 patients after intravesical bacillus Calmette-Guerin instillation. The lesion has not been reported previously in relation to bacillus Calmette-Guerin immunotherapy. We discuss the pathogenesis of nephrogenic adenoma and suggest that the marked prolonged cystitis induced by bacillus Calmette-Guerin has an etiological role. The lesion known as nephrogenic adenoma of the bladder is relatively uncommon and was described initially in 1949 by Davis who thought the lesion represented a hamartoma. 1 The term nephrogenic adenoma was suggested the following year by Friedman and Kuhlenbeck, who reported 8 cases with detailed morphological description. 2 Recently, Ritchey and associates described 8 cases and found only 55 cases reported in the literature. 3 However, the incidence of nephrogenic adenoma is probably much higher than the number of cases described in the literature. For example, Davis had seen approximately 100 cases as of 1980 at the Armed Forces Institute of Pathology. 4 Although Friedman and Kuhlenbeck reported the lesion as an adenomatoid tumor reproducing renal structures 2 , thus, representing a hamartoma, recent studies have concluded that it is a metaplastic response of the transitional epithelium to chronic irritation or infection, 3 • 5 or trauma. 6 It also has been observed following kidney transplantation 7 (with surgical trauma and cytomegalovirus infection cited as possible etiological factors) and after radiation. 5 We report 2 cases of nephrogenic adenoma after intravesical instillation of bacillus Calmette-Guerin (BCG) for transitional cell carcinoma of the bladder. MATERIALS AND METHODS
Of 8 patients with transitional cell carcinoma of the bladder treated with intravesical BCG 2 had nephrogenic adenoma. Treatment consisted of 1 ampule of Tice strain BCGt (1 to 8 X 108 organisms) diluted with 60 cc saline solution and instilled in the bladder via a Foley catheter. The solution was retained in the bladder for 1½ to 2 hours. The treatment was performed at regular intervals, initially weekly for 6 weeks, followed by biweekly instillations for 3 months and monthly thereafter for a total of 2 years. Both patients had undergone multiple bladder biopsies. The tissues obtained at biopsy were fixed in 10 per cent buffered formalin and processed for histology using conventional methods. CASE REPORTS
Case J. H. K., a 71-year-old man with a 10-year history of recurrent superficial bladder tumors, had carcinoma in situ of the bladder diagnosed by biopsy in July 1980. He received 80 Accepted for publication July 26, 1985. * Requests for reprints: Laboratory Services (113), Veterans Administration Medical Center, 150 S. Huntington Ave., Boston, Massachusetts 02130. t Antigen Supply House, Northbridge, California 91324. 359
mg. doxorubicin hydrochloride intravesically weekly times 3. Carcinoma in situ was again diagnosed in March 1982 and the patient received 40 mg. mitomycin C intravesically weekly times 24. Subsequent biopsies in June, September and December 1982, and in March 1983 showed no tumor but indicated varying degrees of acute and chronic inflammation and focal necrosis. BCG treatment was initiated in March. Cystoscopy 3 months later showed diffuse mucosal erythema. Three random biopsies performed at that time revealed fibrino purulent exudate and marked inflammation of the bladder mucosa. Multiple biopsies in September, after approximately 6 months of BCG treatment, showed marked chronic inflammation, granulation tissue, erosion and regeneration of the surface epithelium, as well as focal dysplasia of the transitional mucosa. In June 1984 routine biopsies of the bladder were characterized by severe acute and chronic inflammation. No tumor was noted by cystoscopy. In December, about 21 months after beginning BCG therapy, routine surveillance cystoscopy revealed a suspicious lesion at the dome of the bladder. The patient was essentially asymptomatic and was near the end of the 2-year BCG treatment protocol. Biopsy of the bladder lesion revealed marked acute and chronic cystitis and granulation tissue, with prominent capillaries and irregular glandular spaces in the submucosa, which had well defined basement membranes and tall atypical columnar cells characteristic of nephrogenic adenoma (fig. 1). No recurrence of transitional cell carcinoma in situ was observed in the biopsy. Case 2. L. R., a 68-year-old man, had a grade 1/111 superficial transitional cell carcinoma of the bladder diagnosed in November 1980. Cystoscopically, the lesion was a 0.8 cm. sessile tumor on the left lateral wall. Surveillance cystoscopy every 3 months was negative until March 1982 when a small tumor was noted on the right posterior wall. Histologically, the tumor was of low grade and there was no evidence of invasion into the muscle. A third recurrence was noted in July 1983 with similar histology. In addition, random bladder biopsies revealed severe dysplasia bordering on carcinoma in situ. BCG treatment was initiated immediately following the biopsy in July. Followup biopsies 3 months after beginning BCG treatment revealed moderate acute and chronic inflammation of the bladder mucosa and submucosa with no evidence of tumor recurrence. Cystoscopy in January 1984 revealed a small lesion near the left ureteral orifice. The patient had mild dysuria as the only symptom. The lesion was biopsied and consisted histologically of irregular glandular structures in the submucosa with an intact overlying transitional epithelium free of atypia. The glands
360
STILMANT AND SIROKY
FIG. 1. Case 1. Two glandular spaces (arrows) with thick basement membranes and tall atypical cell lining, characteristic of nephrogenic adenoma. Background contains blood vessels and many inflammatory cells. H & E, reduced from X200. Inset is higher power of aforementioned large gland and shows cellular atypia. H & E, reduced from X375.
FIG. 2. Case 2. Several glands with poorly defined basement membranes and atypical cuboidal cell lining. Background shows edema and marked inflammation. H & E, reduced from X200.
were characterized by poorly defined thin basement membranes and were lined by a single row of atypical cuboidal cells. The intervening stroma contained many polymorphonuclear leukocytes and mononuclear cells. Diagnosis was nephrogenic adenoma (fig. 2). No transitional cell tumor was seen. Comment: Although we have observed a small granuloma in the bladder mucosa after BCG treatment in another patient, no granulomas were seen in any of the bladder biopsies after BCG therapy in either of our patients with nephrogenic adenoma. DISCUSSION
Nephrogenic adenoma is a lesion of the bladder, representing a metaplastic response of the transitional epithelium to chronic irritation or trauma. 3 • 5 Clinically, the patient usually presents with irritation, hematuria and pyuria. At biopsy metaplastic tubules, superficially resembling renal proximal tubules,2 are seen in the submucosa, which usually is covered by intact, normal transitional epithelium. The tubular proliferation may be florid and the lining cells often appear quite atypical. A
pseudo-infiltrative pattern may be erroneously diagnosed as invasive adenocarcinoma. However, although recurrences are not uncommon 4 the lesion usually is benign 2·4 and its malignant potential is unknown. Davis, who reported approximately 100 cases at the Armed Forces Institute of Pathology, had not seen any of these lesions recur as malignant tumor. 4 There is good evidence that the lesion is not nephrogenic in origin. Ultrastructural examination, as well as the absence of Tamm-Horsfall protein, has led Bhagavan and associates to suggest a mesonephric rather than a metanephric homology. 8 The term nephrogenic adenoma, introduced by Friedman and Kuhlenbeck in 1950, 2 is unfortunate since the lesion is neither an adenoma nor nephrogenic. Adenomatous metaplasia9 is a more accurate description but the older terminology is well entrenched in the literature and is widely accepted by pathologists as well as urologists. Rarely, infiltrative adenocarcinoma of the bladder is associated with nephrogenic adenoma. 9 • 10 However, there is no evidence of a causal relationship per se between the 2 types of lesions. Perhaps less rare is the association of nephrogenic adenoma with transitional cell carcinoma of the bladder. 5 • 8 • 11 In these cases the development of nephrogenic adenoma usually followed resection of a transitional cell tumor and probably was a result of surgical trauma. Both of our patients had had multiple biopsy procedures before the development of nephrogenic adenoma and it is impossible to rule out trauma as an etiological factor. However, we have only rarely observed nephrogenic adenoma in other patients with multiple biopsies and, thus, we suspect that the marked prolonged cystitis secondary to BCG instillation had a major role. The close temporal relationship to BCG therapy also supports this hypothesis. We have seen no mention in the literature of nephrogenic adenoma in ECG-treated patients. For example, Lamm and associates recently reviewed the complications of intravesical BCG therapy in 140 patients and did not document the development of this lesion in any. 12 However, some have expressed concern about the possible long-term ill-effects of this therapy_1a We believe that nephrogenic adenoma may have been overlooked or misdiagnosed as cystitis cystica and glandularis in the past when biopsy material from ECG-treated patients was examined. It is likely that more such cases will be recognized as the number of ECG-treated patients increases. REFERENCES 1. Davis, T. A.: Hamartoma of the urinary bladder. Northwest. Med., 48: 182, 1949. 2. Friedman, N. B. and Kuhlenbeck, H.: Adenomatoid tumors of the bladder reproducing renal structures (nephrogenic adenomas). J. Urol., 64: 657, 1950. 3. Ritchey, M. L., Novicki, D. E. and Schultenover, S. J.: Nephrogenic adenoma of bladder: a report of 8 cases. J. Urol., 131: 537, 1984. 4. Davis, C. J., Jr.: Case for diagnosis. Milit. Med., 145: 242 and 258, 1980. 5. Navarre, R. J., Jr., Loening, S. A., Platz, C., Narayana, A. and Culp, D. A.: Nephrogenic adenoma: a report of9 cases and review of the literature. J. Urol., 127: 775, 1982. 6. Leonard, S. A., Silverman, A. J., Longston, J. W. and Fuselier, H. A.: Postoperative nephrogenic adenoma of bladder. Urology, 7: 327, 1976. 7. Beaudry, C., Bartrand, P.-E., Laplante, L., Houde, M., Lamoureux, C., Laverdiere, M. and Dandavino, R.: Nephrogenic adenoma of the bladder after kidney transplantation: spontaneous improvement with azathioprine removal; surgical trauma and cytomegalovirus infection as possible etiologic factors. J. Urol., 130: 1183, 1983. 8. Bhagavan, B. S., Tiamson, E. M., Wenk, R. E., Berger, B. W., Hamamoto, G. and Eggleston, J. C.: Nephrogenic adenoma of the urinary bladder and urethra. Hum. Path., 12: 907, 1981. 9. Molland, E. A., Trott, P. A., Paris, A. M. I. and Blandy, J. P.: N ephrogenic adenoma: a form of adenomatous metaplasia of the
l'JEPHROGENIC ADEI\IOfv!lt ASSOCIATED '·WITH BACILLUS CALfviETT:S-GUERIN TR,EATIY!E~JT
bladder. A clinical and electron microscopical study. Brit. J. UroL, 48: 453, 1976. 10. Christoffersen, J. and M,;ller, J.E.: Adenomatoid tumours of the urinary bladder. Scand. J. Urol. NephroL, 6: 295, 1972. 11. Berger, B. W., Bhagavan, B. S., Reiner, W., Engel, R. and Lepor, H.: Nephrogenic adenoma: clinical features and therapeutic con-
361
siderations. J. Urol., 126: 824, 1981. 12. Lamm, D. L., Stogdill, V. D., Stogdill, B. J. and Crispen, R. G.: Complications of bacillus Calmette-Guerin immunotherapy in 1,278 patients with bladder cancer. J. Urol., 135: 272, 1986. 13. Connolly, J. G.: Re: Immunotherapy of superficial bladder cancer. Letter to the Editor. J. Urol., 130: 368, 1983.