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Squamous Cell Carcinoma of the Ureterovesical Junction after Renal Transplantation
THE ,Joum~AL OF lJHOLOGY
Vol. 114, October
Copyright© 197.5 by The Williams & Wilkins Co.
Printed in U.S.A.
SQUAMOUS CELL CARCINOMA OF THE URETEROVESICAL JUNCTION AFTER RENAL TRANSPLANTATION RALPH E. DUNCA;\/,* RICHARD H. KEYS, DALE W. HEN>IETT, ARTHUR T. EVANS, ,JAMES P. FIDLER AND ,J. WESLEY ALEXA>IDER From the Diuision of Urologv and Departmmt of Surgery, l !niuPrsitv of Cincinnati Medical Center, Cincinnati, Ohio
ABSTRACT
A case of squamous cell carcinoma of the bladder occurring at the ureterovesical junction in a renal transplant recipient is presented. References are made to ureteral obstruction in transplanted kidneys, the broader field of squamous cell carcinoma of the bladder in non-transplanted patients and the relationship of malignancy to transplantation. We anticipate that an ever increasing number of these unusual cases will be forthcoming in the urological literature as renal transplantation develops. Neoplasm arising de novo in patients who have received renal allografts is not uncommon_ 1.' Although a case of transitional cell carcinoma oft he bladder occurring in a renal transplant recipient has been reported, 3 squamous cell carcinoma of the bladder at the ureterovesical reimplantation site is unique. The first such case is reported herein. CASE REPORT
A 52-year-old white woman with end stage chronic pyelonephritis underwent bilateral nephrectomy and splenectomy in March 1971 in preparation for renal transplantation. She was maintained on hemodialysis. In May 1971 she received an A-match related donor renal allograft. Steroid-induced diabetes mellitus and severe osteoporosis post-transplantation were such that the patient was maintained on 12/i mg. azathioprine daily as the only immunosuppressive agent. The prevailing blood urea nitrogen (BUN) and serum creatinine were 22 and 1.2 mg. per cent, respectively, :l years after transplantation. In November 1974 the patient complained of pain over the renal allograft 2 weeks in duration. Physical examination revealed an enlarged, tense kidney but was otherwise normal. Admission hematocrit was 44.5 per cent, hemoglobin 14.9 gm. and leukocyte count 8,500 per cu. mm. Urinalysis was normal except for 2 red and 10 to Ui white blood cells per high power field. A voided urine culture yielded 5,000 Escherichia coli colonies per ml. BU:\l was ;37 and serum creatinine 2.2 mg. per cent. The serum electrolytes were sodium Jfi:l, potassium 4.:3, chloride 112 and bicarbonate 28 mEq. per 1. The urinary electrolytes were sodium ii4 and potassium 27 mEq. per 1. The creatinine clearance was 40 ml. per minute. The 24-hour urinary protein Accepted for publication March 7. 197ii. * Requests for reprints: Division of Urology, University of Cincinnati Medical Center, Cincinnati, Ohio 4.'i26,. 6:!8
was ;;27 mg. An excretory urogram (IVP) demonstrated ureterectasis and pyelocaliectasis, and a mass lesion was seen at the ureterovesical junction (fig. u. Cystoscopic exam in at ion revealed considerable bullous edema in the area of the ureteral reimplantation and the orifice was not discernible. Biopsy tissue of this area was interpreted by the pathologist as squamous cell carcinoma. Surgical exploration of the transplanted renal unit and bladder was performed. A 2 by 1.2 cm. tumor involved the bladder and ureter at the site of reimplantation
Fie:. 1. Preoperative lVP with hydronephrosis and rnass lesion in area of ureterovesical .iunction.
SQUAMOUS CELL CARCINOMA AFTER RENAL TRANSPLANTATION
and the ureteral orifice would admit only a small probe (fig. 2). No extravesical spread of tumor was appreciated at this time. Frozen sections of 2 iliac lymph nodes were examined by the pathologist and were free of tumor. Although several treatment options were considered at the time of operation, segmental resection of the involved area of bladder and distal donor ureter was performed. The ureteroneocystotomy was recreated into the dome of the remaining bladder. Microscopic examination of the specimen showed a well differentiated squamous cell carcinoma involving the wall of the bladder and orifice of the transplanted ureter (fig. 3). The tumor penetrated to the superficial portion of the muscularis. There was surrounding squamous metaplasia. All margins of the specimen were free of tumor. Postoperatively the BUN and serum creatinine returned to preoperative levels. Before discharge from the hospital 100 mg. cyclophosphamide daily was substituted for azathioprine. It is too early to determine the ultimate course of this patient.
FIG.
orifice.
2. Surgical specimen with probe through ureteral
629
DISCUSSION
Urological complications occurring late ( more than l month) after renal transplantation are less common than those encountered in the first posttransplant month.' Distal ureteral stenosis is the most common late complication hut periureteral fibrosis. nephrolithiasis , perinephric and periureteral abscess. lymphocele and fungus ball causing ureteral obstruction have all been described. s- , 6 De novo neoplasm arising in transplant recipients would necessarilv be a late complication. Our case adds intrinsic tu.mor as a cause of ureteral obstruction to the aforementioned list. Whether the tumor in our case originated in the donor ureter or the recipient bladder is not known. The tumor was confined within the bladder. involving the ureteral orifice only superficially. We believe this tumor originated in the bladder. In a series of patients with squamous cell carcinoma of the bladder. Bessette and associates recently reported that hematuria was present in all patients. 17 Weight loss. hack or pelvic pain. or frank urinarv obstruction was present in 26 per cent of patien.ts and indicated advanced disease. A history of genitourinary disease (urethral stricture. calculous disease or chronic urinar:-: tract infection) was given hy 72 per cent of the patients. Infiltration or penetration of '.umor was evident in 98 per cent of the patients on initial presentation. Non-visualization or hydronephrosis occurred in 64 per cent of the patients. Pathological examination showed moderatelv differentiated tumors with focal keratinizat ion· in 65 per cent of the specimens. More women (40 per cent) were found to have squamous cell carcinoma of the bladder in this group of patients as compared to 25 per cent in reported series of transitional cell bladder tumors. Our patient would seem to conform to most of the aforementioned criteria. The critical location of the lesion may have contributed to an early diagnosis. Her chance of 1-:-,·ear survival based on this
FIG. 3. Well differentiated squamous cell carcinoma at ureterovesical junction with tumor invasion of bladder muscularis (low power). Adjacent squamous metaplas,a can be seen (arrow).
630
DUNCAN AND ASSOCIATES
study would be 31 per cent (irrespective of the influence of immunotherapy). Statistics presented in an earlier study by Newman and associates ' " corroborate this expectation of survival. Immunosuppressive agents enhance malignant growth. ' 9 In patients with competent immune mechanisms the occurrence of squamous cell carcinoma represents only 6 per cent of bladder cancers.2° Azathioprine and cyclophosphamide are known oncogens.2' Cyclophosphamide was substituted for azathioprine because of the possible carcinogenic effect of t he latter in our patient. Cyclophosphamide cystitis has been associated with progressive bladder changes which may give rise to transitional cell carcinoma of the bladder 2 2-2• but we are unable to find any association between cyclophosphamide and squamous cell carcinoma of the bladder or between azathioprine and bladder tumors. Squamous metaplasia of the bladder is a common finding in female subjects and is not generally believed to be a precursor to squamous cell carcinoma of the bladder. 25 The proximity of squamous metaplasia to the malignancy in our case is striking.
M .: Seconda ry pyeloureterosto my in renal trans-
plant recipients. ,J. Urol., 110: 166, 197:,. 9. Prout, G. R. , Jr., Hume, D. M. , Lee. H . M . a nd Willi a ms, G . M.: Som e urological aspect s of 93 consec utive renal homotra ns plan t.s in modified rec ipients . J. Urol.. 97: 409, 1967 . 10. Krane, R. J ., Cho. S. I. and Olsson. C. A.: Renaltransplant uret eral obstruction s imulating retroperitoneal fibrosis. J.A.M.A. , 225: 607, 197:i. 11. Kuss. R. , Poisson. ,J., Thibault. P. and Gluckman. ,J. C.: Le retabliss em ent de la vo ie exc retrice dans l'allotransplantation rena le par anastomose uretero-ureterale et ses complications (a propos de 120 cas ). Urol. Int.. 28: 91 , 197:3. 12. Smith. M. ,J.: Anuria in the recipient. Transplant. Proc. , 4: 651. 197:2. 13. Olsson, C . A., Mannic k, J. A. , Schmitt , G. W. Idelson. H. A., Williams. L. F. , ,Jr., Lemann. J., ,Jr.. Ha rrin gton. ,J. T. and Nabseth . D. C.: Nephrosto my in rena l trans plantation. Amer. ,J. Surg., 121: 467 . 197 1. 14. Zazgo rnik. J .. Schm idt, P., Kotza urek, R. and Kop sa, H.: Perinephric abscess with ureteric obstruction a fter renal transplantation. Lancet. 1: 381, 197:1. 15. Kearney. G. P ., Murray, ,J. E. and Harrison, J. H.: Perinephric pseudocyst: a complication of renal trans pl a nt ation. ,J. Urol. , 109: 802, 1973 . Drs. G . Chedid and J. Lee assisted with t he 16. Shelp, W. D., Wen, S. F. and Weinstein. A. B.: pathology. Uret eropelv ic obstruction ca us ed by Candida pyelitis in homotransplant.ed kidney. Arch. Intern . REFERENCES Med. , 117: 401, 1966. 1. Penn , I. and Starzl, T. E.: Malignant tumors aris ing 17. Bessette. P. L. , Abell , M. R. and Herwig, K. R.: A de novo in immunosuppressed organ transplant clinicopathologic study of squamous cell carcirecipients. Transplantation , 14: 407. 1972. noma of the bladder. J. Urol. , 112: 66, 1974. 2. Hoover, R. and Fraumeni, J. F. , Jr.: Risk of cancer in 18. Newman, D. M. , Brown, J. R. , Jay, A. C. and renal-transplant recipients. Lancet, 2: 55, 1973. Pontius, E . E .: Squa mous cell carcinoma of the 3 . Biggs , A. W.: Carcinoma of t he bl adder in a rena l bladde r. J. Urol. , 100: 470, 1968. 19. Fahey, J . L.: Cancer in the immunosuppressed trans plant patient. J. Urol., 109: 417, 197:>. 4. Rattazzi, L. C ., Simmons, R. L., Miller. J ., Cas a li, R. pa tient. Ann. Intern. M ed. , 75: :no, 1972. and Najarian, J. S. : Acute ureteric obstruct ion of 20. Melicow, M. M .: Tumors of the bladder: a multifackidney transplant. Management of late cometed problem . J. Urol. , 112: 467, 1974. 21. Decker, ,J. L .: T oxicity of immunos uppressive drugs plications. Urology, 4: 384. 1974. in man. Arth ritis Rheum., 16: 89, 1973. 5. Martin, D. C., Mims, M. M .. Kaufman , ,J. ,J. and Goodwin , W. E.: The ureter in renal transplant a - 22. Worth, P . H.: Cyclophosphamide and t he bladder. (Letter to the Edit.or.) Hrit. M ed. ,J. , 3: 182, 1971. tion. J . Urol. , 101: 680. 1969. 6. Starzl, T. E. , Groth, C . G. , Putnam, C . W., P enn , I.. 23 . Phillips, F . S., Sternberg, S. S. , Croni n, A. P. and H algrimson , C. G. , Flat.mark, A. , Gecelt er, L. , Vidal, P . M .: Cyclophospha mide and urinary bladder t oxic ity. Cancer Res., 21: 1577, 1961. Brettschneider, L . and Stonington, 0 . G.: Urologica l complications in 216 human recipients of rena l 24 . Dale, G. A. a nd Smith, R. B.: Trans itiona l cell transplants. Ann. Surg., 172: 1, 1970. carcinoma of the bladder associated with cyclo7. Fjeldborg, 0. and Kim, C. H.: Ureteral complicaphosphamide. J. Urol., 112: 603. 1974. tions in human renal transplantation. An analys is 25. Widran , ,J ., Sa nchez, R. and Gruhn , J .: Squamous metaplasia of t he bl adder: a study of 450 patients . of 180 cases. Urol. Int. , 27: 41 7. 1972. J. Urol., 112: 479, 1974. 8. Presto, A. J. , III, Middleton , R. G . and Bateman , J .
Vol. 114, October
Copyright© 197.5 by The Williams & Wilkins Co.
Printed in U.S.A.
SQUAMOUS CELL CARCINOMA OF THE URETEROVESICAL JUNCTION AFTER RENAL TRANSPLANTATION RALPH E. DUNCA;\/,* RICHARD H. KEYS, DALE W. HEN>IETT, ARTHUR T. EVANS, ,JAMES P. FIDLER AND ,J. WESLEY ALEXA>IDER From the Diuision of Urologv and Departmmt of Surgery, l !niuPrsitv of Cincinnati Medical Center, Cincinnati, Ohio
ABSTRACT
A case of squamous cell carcinoma of the bladder occurring at the ureterovesical junction in a renal transplant recipient is presented. References are made to ureteral obstruction in transplanted kidneys, the broader field of squamous cell carcinoma of the bladder in non-transplanted patients and the relationship of malignancy to transplantation. We anticipate that an ever increasing number of these unusual cases will be forthcoming in the urological literature as renal transplantation develops. Neoplasm arising de novo in patients who have received renal allografts is not uncommon_ 1.' Although a case of transitional cell carcinoma oft he bladder occurring in a renal transplant recipient has been reported, 3 squamous cell carcinoma of the bladder at the ureterovesical reimplantation site is unique. The first such case is reported herein. CASE REPORT
A 52-year-old white woman with end stage chronic pyelonephritis underwent bilateral nephrectomy and splenectomy in March 1971 in preparation for renal transplantation. She was maintained on hemodialysis. In May 1971 she received an A-match related donor renal allograft. Steroid-induced diabetes mellitus and severe osteoporosis post-transplantation were such that the patient was maintained on 12/i mg. azathioprine daily as the only immunosuppressive agent. The prevailing blood urea nitrogen (BUN) and serum creatinine were 22 and 1.2 mg. per cent, respectively, :l years after transplantation. In November 1974 the patient complained of pain over the renal allograft 2 weeks in duration. Physical examination revealed an enlarged, tense kidney but was otherwise normal. Admission hematocrit was 44.5 per cent, hemoglobin 14.9 gm. and leukocyte count 8,500 per cu. mm. Urinalysis was normal except for 2 red and 10 to Ui white blood cells per high power field. A voided urine culture yielded 5,000 Escherichia coli colonies per ml. BU:\l was ;37 and serum creatinine 2.2 mg. per cent. The serum electrolytes were sodium Jfi:l, potassium 4.:3, chloride 112 and bicarbonate 28 mEq. per 1. The urinary electrolytes were sodium ii4 and potassium 27 mEq. per 1. The creatinine clearance was 40 ml. per minute. The 24-hour urinary protein Accepted for publication March 7. 197ii. * Requests for reprints: Division of Urology, University of Cincinnati Medical Center, Cincinnati, Ohio 4.'i26,. 6:!8
was ;;27 mg. An excretory urogram (IVP) demonstrated ureterectasis and pyelocaliectasis, and a mass lesion was seen at the ureterovesical junction (fig. u. Cystoscopic exam in at ion revealed considerable bullous edema in the area of the ureteral reimplantation and the orifice was not discernible. Biopsy tissue of this area was interpreted by the pathologist as squamous cell carcinoma. Surgical exploration of the transplanted renal unit and bladder was performed. A 2 by 1.2 cm. tumor involved the bladder and ureter at the site of reimplantation
Fie:. 1. Preoperative lVP with hydronephrosis and rnass lesion in area of ureterovesical .iunction.
SQUAMOUS CELL CARCINOMA AFTER RENAL TRANSPLANTATION
and the ureteral orifice would admit only a small probe (fig. 2). No extravesical spread of tumor was appreciated at this time. Frozen sections of 2 iliac lymph nodes were examined by the pathologist and were free of tumor. Although several treatment options were considered at the time of operation, segmental resection of the involved area of bladder and distal donor ureter was performed. The ureteroneocystotomy was recreated into the dome of the remaining bladder. Microscopic examination of the specimen showed a well differentiated squamous cell carcinoma involving the wall of the bladder and orifice of the transplanted ureter (fig. 3). The tumor penetrated to the superficial portion of the muscularis. There was surrounding squamous metaplasia. All margins of the specimen were free of tumor. Postoperatively the BUN and serum creatinine returned to preoperative levels. Before discharge from the hospital 100 mg. cyclophosphamide daily was substituted for azathioprine. It is too early to determine the ultimate course of this patient.
FIG.
orifice.
2. Surgical specimen with probe through ureteral
629
DISCUSSION
Urological complications occurring late ( more than l month) after renal transplantation are less common than those encountered in the first posttransplant month.' Distal ureteral stenosis is the most common late complication hut periureteral fibrosis. nephrolithiasis , perinephric and periureteral abscess. lymphocele and fungus ball causing ureteral obstruction have all been described. s- , 6 De novo neoplasm arising in transplant recipients would necessarilv be a late complication. Our case adds intrinsic tu.mor as a cause of ureteral obstruction to the aforementioned list. Whether the tumor in our case originated in the donor ureter or the recipient bladder is not known. The tumor was confined within the bladder. involving the ureteral orifice only superficially. We believe this tumor originated in the bladder. In a series of patients with squamous cell carcinoma of the bladder. Bessette and associates recently reported that hematuria was present in all patients. 17 Weight loss. hack or pelvic pain. or frank urinarv obstruction was present in 26 per cent of patien.ts and indicated advanced disease. A history of genitourinary disease (urethral stricture. calculous disease or chronic urinar:-: tract infection) was given hy 72 per cent of the patients. Infiltration or penetration of '.umor was evident in 98 per cent of the patients on initial presentation. Non-visualization or hydronephrosis occurred in 64 per cent of the patients. Pathological examination showed moderatelv differentiated tumors with focal keratinizat ion· in 65 per cent of the specimens. More women (40 per cent) were found to have squamous cell carcinoma of the bladder in this group of patients as compared to 25 per cent in reported series of transitional cell bladder tumors. Our patient would seem to conform to most of the aforementioned criteria. The critical location of the lesion may have contributed to an early diagnosis. Her chance of 1-:-,·ear survival based on this
FIG. 3. Well differentiated squamous cell carcinoma at ureterovesical junction with tumor invasion of bladder muscularis (low power). Adjacent squamous metaplas,a can be seen (arrow).
630
DUNCAN AND ASSOCIATES
study would be 31 per cent (irrespective of the influence of immunotherapy). Statistics presented in an earlier study by Newman and associates ' " corroborate this expectation of survival. Immunosuppressive agents enhance malignant growth. ' 9 In patients with competent immune mechanisms the occurrence of squamous cell carcinoma represents only 6 per cent of bladder cancers.2° Azathioprine and cyclophosphamide are known oncogens.2' Cyclophosphamide was substituted for azathioprine because of the possible carcinogenic effect of t he latter in our patient. Cyclophosphamide cystitis has been associated with progressive bladder changes which may give rise to transitional cell carcinoma of the bladder 2 2-2• but we are unable to find any association between cyclophosphamide and squamous cell carcinoma of the bladder or between azathioprine and bladder tumors. Squamous metaplasia of the bladder is a common finding in female subjects and is not generally believed to be a precursor to squamous cell carcinoma of the bladder. 25 The proximity of squamous metaplasia to the malignancy in our case is striking.
M .: Seconda ry pyeloureterosto my in renal trans-
plant recipients. ,J. Urol., 110: 166, 197:,. 9. Prout, G. R. , Jr., Hume, D. M. , Lee. H . M . a nd Willi a ms, G . M.: Som e urological aspect s of 93 consec utive renal homotra ns plan t.s in modified rec ipients . J. Urol.. 97: 409, 1967 . 10. Krane, R. J ., Cho. S. I. and Olsson. C. A.: Renaltransplant uret eral obstruction s imulating retroperitoneal fibrosis. J.A.M.A. , 225: 607, 197:i. 11. Kuss. R. , Poisson. ,J., Thibault. P. and Gluckman. ,J. C.: Le retabliss em ent de la vo ie exc retrice dans l'allotransplantation rena le par anastomose uretero-ureterale et ses complications (a propos de 120 cas ). Urol. Int.. 28: 91 , 197:3. 12. Smith. M. ,J.: Anuria in the recipient. Transplant. Proc. , 4: 651. 197:2. 13. Olsson, C . A., Mannic k, J. A. , Schmitt , G. W. Idelson. H. A., Williams. L. F. , ,Jr., Lemann. J., ,Jr.. Ha rrin gton. ,J. T. and Nabseth . D. C.: Nephrosto my in rena l trans plantation. Amer. ,J. Surg., 121: 467 . 197 1. 14. Zazgo rnik. J .. Schm idt, P., Kotza urek, R. and Kop sa, H.: Perinephric abscess with ureteric obstruction a fter renal transplantation. Lancet. 1: 381, 197:1. 15. Kearney. G. P ., Murray, ,J. E. and Harrison, J. H.: Perinephric pseudocyst: a complication of renal trans pl a nt ation. ,J. Urol. , 109: 802, 1973 . Drs. G . Chedid and J. Lee assisted with t he 16. Shelp, W. D., Wen, S. F. and Weinstein. A. B.: pathology. Uret eropelv ic obstruction ca us ed by Candida pyelitis in homotransplant.ed kidney. Arch. Intern . REFERENCES Med. , 117: 401, 1966. 1. Penn , I. and Starzl, T. E.: Malignant tumors aris ing 17. Bessette. P. L. , Abell , M. R. and Herwig, K. R.: A de novo in immunosuppressed organ transplant clinicopathologic study of squamous cell carcirecipients. Transplantation , 14: 407. 1972. noma of the bladder. J. Urol. , 112: 66, 1974. 2. Hoover, R. and Fraumeni, J. F. , Jr.: Risk of cancer in 18. Newman, D. M. , Brown, J. R. , Jay, A. C. and renal-transplant recipients. Lancet, 2: 55, 1973. Pontius, E . E .: Squa mous cell carcinoma of the 3 . Biggs , A. W.: Carcinoma of t he bl adder in a rena l bladde r. J. Urol. , 100: 470, 1968. 19. Fahey, J . L.: Cancer in the immunosuppressed trans plant patient. J. Urol., 109: 417, 197:>. 4. Rattazzi, L. C ., Simmons, R. L., Miller. J ., Cas a li, R. pa tient. Ann. Intern. M ed. , 75: :no, 1972. and Najarian, J. S. : Acute ureteric obstruct ion of 20. Melicow, M. M .: Tumors of the bladder: a multifackidney transplant. Management of late cometed problem . J. Urol. , 112: 467, 1974. 21. Decker, ,J. L .: T oxicity of immunos uppressive drugs plications. Urology, 4: 384. 1974. in man. Arth ritis Rheum., 16: 89, 1973. 5. Martin, D. C., Mims, M. M .. Kaufman , ,J. ,J. and Goodwin , W. E.: The ureter in renal transplant a - 22. Worth, P . H.: Cyclophosphamide and t he bladder. (Letter to the Edit.or.) Hrit. M ed. ,J. , 3: 182, 1971. tion. J . Urol. , 101: 680. 1969. 6. Starzl, T. E. , Groth, C . G. , Putnam, C . W., P enn , I.. 23 . Phillips, F . S., Sternberg, S. S. , Croni n, A. P. and H algrimson , C. G. , Flat.mark, A. , Gecelt er, L. , Vidal, P . M .: Cyclophospha mide and urinary bladder t oxic ity. Cancer Res., 21: 1577, 1961. Brettschneider, L . and Stonington, 0 . G.: Urologica l complications in 216 human recipients of rena l 24 . Dale, G. A. a nd Smith, R. B.: Trans itiona l cell transplants. Ann. Surg., 172: 1, 1970. carcinoma of the bladder associated with cyclo7. Fjeldborg, 0. and Kim, C. H.: Ureteral complicaphosphamide. J. Urol., 112: 603. 1974. tions in human renal transplantation. An analys is 25. Widran , ,J ., Sa nchez, R. and Gruhn , J .: Squamous metaplasia of t he bl adder: a study of 450 patients . of 180 cases. Urol. Int. , 27: 41 7. 1972. J. Urol., 112: 479, 1974. 8. Presto, A. J. , III, Middleton , R. G . and Bateman , J .