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Bladder Leiomyosarcoma Following Cyclophosphamide Therapy for Lupus Nephritis
0022 ~5347/90 /l 431-0119$02<80 /0 'THE JOURNAL OF UROLOGY
Vol. 143,
Copyright© 1990 by AMERICAN UROLOGICAL ASSOCIATION, INC.
Printed in
BLADDER LEIOMYOSARCOMA FOLLOW'ING CYCLOPHOSPHAMIDE THERAPY FOR LUPUS NEPHRITIS JAMES B. THRASHER, GARY J. MILLER
AND
JOHN N. WETTLAUFER
From the Department of Surgery, Division of Urology, Fitzsimons Army Medical Center, Aurora, and Department of Pathology and Department of Surgery, Division of Urology, University of Colorado Medical Center, Denver, Colorado
ABSTRACT
We report 2 cases of leiomyosarcoma of the bladder that occurred after long-term cyclophosphamide chemotherapy for lupus nephritis and rheumatoid arthritis. One patient had a tumor at the end of an 11-year course of chemotherapy and 1 approximately 7 years after completing a 7-year course of chemotherapy. Patient 1 underwent left partial cystectomy and patient 2 underwent cystectomy with ileal conduit urinary diversion. In patient l the tumor was a typical leiomyosarcoma and patient 2 had a myxoid variant. Both patients were free of disease at 4 months and 3 years, respectively. Whereas previous reports of the carcinogenic effects of cyclophosphamide have been questioned, since the induced tumors occurred in patients being treated for other neoplasms (lymphoproliferative and myeloproliferative disorders), the disease in both of our patients followed cyclophosphamide therapy for nonneoplastic disorders. (J. Ural., 143: 119-121, 1990) Cyclophosphamide, an alkylating agent, has been used extensively in cancer chemotherapy as well as for a variety of nonneoplastic disorders. Its use in the treatment of rheumatoid arthritis, systemic lupus erythematosus and Wegener's granulomatosis has been widespread since its introduction in 1957. However, in the late 1970s it became evident that cyclophosphamide caused epithelial neoplasms of the bladder urothelium, and in 1978 Beyer-Boon and associates described stromal changes in 28 patients who had hemorrhagic cystitis after treatment with cyclophosphamide. 1 Despite the temporal association of cyclophosphamide chemotherapy and subsequent bladder neoplasms, some question the role of cyclophosphamide in the induction of these neoplasms. Since cyclophosphamide has been used so often to treat myeloproliferative and lymphoproliferative disorders, some argue that second malignancies that occur are associated with the primary neoplasm rather than being induced by cyclophosphamide. 2 There have been 2 previous :reports of bladder leiomyosarcoma after cyclophosphamide therapy. 3 ' 4 Both cases are well documented temporally and histologically but they also occurred after treatment for Hodgkin's disease. This again raises the question of the lymphoma being associated with a second, primary malignancy. We report 2 cases of leiomyosarcoma arising in the bladder after long-term treatment with cyciophosphamide for lupus nephritis and rheumatoid arthritis. MATERIALS AND METHODS
Only formalin-fixed, paraffin-embedded material was available for retrospective analysis. The presence of extracellular acidic mucosubstances was evaluated with alcian blue at pH 2.5. 5 Muscle-specific actin antibodies, antibodies against desmin, vimentin and epithelial membrane antigen, and cytokeratin antibody (UCD 10.11) were used. Immunohistochemical localizations were performed with the peroxidase-antiperoxidase technique. 6 Sections stained for the presence of cytokeratin, desmin, epithelial membrane antigen and muscle-specific actin antibodies were preincubated with 0.05% pronase at 25 degrees for 15 minutes. Mitotic figures were counted in 50 random fields with a Zeiss standard microscope with a 40X Accepted for publication August 4, 1989. The views of the authors do not purport to reflect the position of the Army or the Department of Defense.
plan objective and lOX wide field occulars for a 15 mm. 2 effective field area. CASE REPORTS
Case 1. A 51-year-old white woman was treated with steroids and cyclophosphamide for rheumatoid arthritis and lupus nephritis. She received 100 mg. cyclophosphamide orally per day from December 1976 to March 1988. The patient tolerated treatments relatively well until October 1987, when she began to experience episodes of gross painless hematuria. Cystoscopy revealed hemorrhagic cystitis. The hematuria worsened in March 1988, requiring intravesical formalin to stop the persistent bleeding. In September she presented with recurrent gross painless hematuria and biopsy of a smooth bladder wall mass revealed leiomyosarcoma. The patient was referred to our hospital, where no evidence of metastatic spread of the tumor was found. Subsequently, she underwent left partial cystectomy in December. Grossly, the lesion appeared to be approximately 1 cm. in diameter with a whitish color and was indurated to palpation. A 5 X 2 X LS cm. segment of the bladder was resected with a wide margin of normal-appearing tissue. A third of the bladder was excised with surgical margins free of tumor. Microscopithe neoplasm was composed of hypercellular smooth muscle fascicles with pleornorphic nuclei and irregular chromatin clumping (part A of figure). There were 22 mitoses in 50 fields. Immunohistochemical stains revealed the presence of desmin, muscle-specific actin and vimentin in the malignant cells. In addition, the majority of cells were reactive with antibodies against cytokeratin in the distribution of paranuclear dots. The entire tumor revealed no epithelial membrane antigen reaction. The patient was free of disease 4 months postoperatively. Case 2. A 60-year-old white woman was treated with high dose steroids and cyclophosphamide for rheumatoid arthritis and lupus nephritis. She received 150 mg. cyclophosphamide orally per day for the majority of a 7-year period, with a decrease to 100 mg. per day for the last 6 months. The patient responded well and the cyclophosphamide was discontinued in 1978. In June 1985 she noticed 3 separate episodes of gross painless hematuria. A 0.5 cm. polypoid lesion on the right lateral wall of the bladder was resected transurethrally and diagnosed as superficial transitional cell carcinoma. She had a recurrence of the same type in September and received a brief course of
119
120
THRASHER, MILLER AND WETTLAUFER
A, case 1. Leiomyosarcoma shows fascicular arrangement of tumor cells and presence of mitotic figures (arrows). B, case 2. Leiomyosarcoma shows prominence of nucleoli and frequent mitotic figures (arrows). C, case 2. Myxoid component demonstrates loose myxoid stroma and lack of mitotic figures. H & E, reduced from X350.
thiotepa. The bleeding continued and in January 1986 at our institution a large polypoid lesion was resected transurethrally from the right side of the bladder and diagnosed as eosinophilic cystitis. Repeat biopsy of a mass in the same region in April was interpreted as leiomyosarcoma of the bladder. Subsequent metastatic evaluation was negative. Partial cystectomy was attempted but due to inability to obtain unequivocally uninvolved frozen section margins total cystectomy with ileal conduit diversion was performed. Grossly, the partial resection specimen contained a 6 X 3 cm. mass with surgical margins free of tumor. Microscopically, the neoplasm was a heterogeneous mixture of 2 morphological patterns. In some areas the neoplastic cells resembled smooth muscle myocytes (part B of figure) with amphophilic to eosinophilic cytoplasm. The cells contained elongate pleomorphic nuclei with prominent nucleoli. Rare 40X fields contained 3 to 4 mitotic figures but in 50 fields a total of only 12 was found. In other areas the neoplastic cells were arranged in a loose, myxoid stroma (part C of figure). The extracellular matrix of these areas was intensely alcianophilic. Mitoses were rare (3 in 50 fields) in these areas. Immunoperoxidase staining revealed the presence of vimentin, desmin and muscle-specific actin in the neoplastic cells. Again, occasional neoplastic cells also reacted positively for cytokeratin in a perinuclear fashion. No reaction with epithelial membrane antigen was seen. The patient was free of disease 3 years postoperatively. DISCUSSION
In a review of bladder malignancies after cyclophosphamide therapy in 1978, Pearson and Soloway concluded that there was insufficient data to identify cyclophosphamide definitely as a carcinogen. 2 They noted that most often cyclophosphamide was used in the treatment of myeloproliferative and lymphoproliferative disorders that had long been associated with second primary malignancies. Subsequent to their report many documented cases of bladder neoplasms have been associated with the use of cyclophosphamide for neoplastic and nonneoplastic conditions. However, almost all of these bladder neoplasms have been carcinomas. In addition to carcinoma, cyclophosphamide also has been
implicated in the induction of sarcoma of the bladder. One fibrosarcoma 7 and 2 leiomyosarcomas 3 ' 4 have been reported. All of these tumors were associated with concurrent Hodgkin's disease. Our 2 cases are leiomyosarcomas and have no association with lymphoproliferative disorders. Case 1 is a typical leiomyosarcoma with a characteristic myxoid phenotype and a moderate mitotic rate. However, case 2 is a myxoid variant8 with prominent areas of alcianophilic stroma, nuclear atypia and a relatively low mitotic rate. The differential diagnoses of such lesions have become complex and remain somewhat controversial. With respect to spindle cell neoplasms, a variety of lesions, including carcinomas, pseudosarcomas and postoperative spindle cell nodules, must be considered. The latter is germane particularly with respect to case 2, since the lesion in this patient was diagnosed 3 months after transurethral removal of a polypoid inflammatory lesion. In an attempt to clarify the diagnosis of such lesions, Wick and associates studied the immunohistochemical distribution of cytoskeletal components in various spindle cell lesions. 9 They suggested that the presence of cytokeratin is unique to postoperative spindle cell nodules and carcinomas. However, others have reported that 10 to 90% of all smooth muscle neoplasms can contain antigens that cross-react with antikeratin antibodies. 10• 11 Both of our cases reacted positively for cytokeratin but did not react with epithelial membrane antigen. Therefore, it would seem that presently the diagnosis of leiomyosarcoma is made best by confirming the expression of myogenic antigens (for example desmin and muscle-specific actin) in neoplasms with significant nuclear atypia and/or an elevated mitotic count. We report 2 cases of leiomyosarcoma of the bladder after cyclophosphamide therapy for nonneoplastic disorders. Both patients presented with gross painless hematuria many years after initiating oral cyclophosphamide for lupus nephritis and rheumatoid arthritis, and both had cystoscopic and microscopic evidence of cyclophosphamide-induced hemorrhagic changes of the bladder urothelium. In view of the expanding body of literature associating cyclophosphamide with subsequent bladder neoplasms, it may be prudent to re-evaluate the use of cyclophosphamide in disorders
BLADDER LEIOrv1Y08ARC0IvIA FOLLDVVIJ>JG CYCLOPHOSF-HAiviIDE
such as systemic erythematosus and rheumatoid arthritiso Cyclophospharnide remains one of the cornerstones of therapy for systemic lupus erythematosus despite the current lack of prospective studies demonstrating safety and effectiveness. However, its use in severe cases of rheumatoid arthritis could be substituted with other immunosuppressant agents, such as azathioprine, methotrexate or chlorambucil, if they are deemed necessary. The risks of a cyclophosphamide-induced malignancy may outweigh the benefits of treatment in nonneoplastic disorders. Reports in the literature support the premise that the treatment of choice for leiomyosarcoma of the bladder is partial cystectomy when the location and size of the tumor allow for adequate surgical margins. 12- 14 Our patient 2 would have undergone partial cystectomy but due to uncertainty regarding the involvement of surgical margins we elected to perform total cystectomy. The final pathological report revealed that the remaining bladder had, in fact, been free of disease after the initial partial resection. In conclusion, we present 2 cases of leiomyosarcoma of the bladder after cyclophosphamide therapy for nonneoplastic disorders. We support the idea that controlled studies in patients receiving cyclophosphamide are needed to delineate the dose and duration most likely to produce carcinogenic effects but we reiterate the need to monitor closely the use of this carcinogen, especially in nonneoplastic disorders. Robert Cardiff, University of California, Davis, California, donated the cytokeratin antibody. REFERENCES
l. Beyer-Boon, M. E., De Voogt, H.J. and Schaberg, A.: The effects
of cyclophosphamide treatment on the epithelium and stroma of the urinary bladder. Eur. J. Cancer, 14: 1029, 1978. 2. Pearson, R. M. and Soloway, M. S.: Does cyclophosphamide induce bladder cancer? Urology, 11: 437, 1978.
121
3. Rowland, R. G. and Eble, J. N.: Bladder leiomyosarcoma and pelvic fibroblastic tumor following cyclophosphamide therapy. J. Urol., 130: 344, 1983. 4. Seo, I. S., Clark, S. A., McGovern, F. D., Clark, D. L. and Johnson, E. H.: Leiomyosarcoma of the urinary bladder 13 years after cyclophosphamide therapy for Hodgkin's disease. Cancer, 55: 1597, 1985. 5. Lev, R. and Spicer, S. S.: Specific staining of sulphate groups with alcian blue at low pH. J. Histochem. Cytochem., 12: 309, 1964. 6. Sternberger, L.A., Hardy, P. H., Jr., Cuculis, J. J. and Meyer, H. G.: The unlabeled antibody enzyme method of immunohistochemistry: preparation and properties of soluble antigen-antibody complex (horesradish peroxidase-antihorseradish peroxidase) and its use in identification of spirochetes. J. Histochem. Cytochem., 18: 315, 1970. 7. Rupprecht, L. and Blessing, M. H.: Fibrosarcoma of the bladder after seven year chemotherapy for Hodgkin's disease in childhood. Dtsch. Med. Wchnschr., 98: 1663, 1973. 8. Young, R. H., Proppe, K H., Dickersin, G. R. and Scully, R. E.: Myxoid leiomyosarcoma of the urinary bladder. Arch. Path. Lab. Med., 111: 359, 1987. 9. Wick, M. R., Brown, B. A., Young, R.H. and Mills, S. E.: Spindlecell proliferations of the urinary tract. An immunohistochemical study. Amer. J. Surg. Path., 12: 379, 1988. 10. Brown, D. C., Theaker, J. M., Banks, P. M., Gatter, K C. and Mason, D. Y.: Cytokeratin expression in smooth muscle and smooth muscle tumours. Histopathology, 11: 477, 1987. 11. Norton, A. J., Thomas, J. A. and Isaacson, P. G.: Cytokeratinspecific monoclonal antibodies are reactive with tumours of smooth muscle derivation. An immunocytochemical and biochemical study using antibodies to intermediate filament cytoskeletal proteins. Histopathology, 11: 487, 1987. 12. Swartz, D. A., Johnson, D. E., Ayala, A. G. and Watkins, D. L.: Bladder leiomyosarcoma: a review of 10 cases with 5-year followup. J·. Urol., 133: 200, 1985. 13. Wilson, T. M., Fauver, H. E. and Weigel, J. W.: Leiomyosarcoma of urinary bladder. Urology, 13: 565, 1979. 14. Mackenzie, A. R., Whitmore, W. F., Jr. and Melamed, M. R.: Myosarcomas of the bladder and prostate. Cancer, 22: 833, 1968.
Vol. 143,
Copyright© 1990 by AMERICAN UROLOGICAL ASSOCIATION, INC.
Printed in
BLADDER LEIOMYOSARCOMA FOLLOW'ING CYCLOPHOSPHAMIDE THERAPY FOR LUPUS NEPHRITIS JAMES B. THRASHER, GARY J. MILLER
AND
JOHN N. WETTLAUFER
From the Department of Surgery, Division of Urology, Fitzsimons Army Medical Center, Aurora, and Department of Pathology and Department of Surgery, Division of Urology, University of Colorado Medical Center, Denver, Colorado
ABSTRACT
We report 2 cases of leiomyosarcoma of the bladder that occurred after long-term cyclophosphamide chemotherapy for lupus nephritis and rheumatoid arthritis. One patient had a tumor at the end of an 11-year course of chemotherapy and 1 approximately 7 years after completing a 7-year course of chemotherapy. Patient 1 underwent left partial cystectomy and patient 2 underwent cystectomy with ileal conduit urinary diversion. In patient l the tumor was a typical leiomyosarcoma and patient 2 had a myxoid variant. Both patients were free of disease at 4 months and 3 years, respectively. Whereas previous reports of the carcinogenic effects of cyclophosphamide have been questioned, since the induced tumors occurred in patients being treated for other neoplasms (lymphoproliferative and myeloproliferative disorders), the disease in both of our patients followed cyclophosphamide therapy for nonneoplastic disorders. (J. Ural., 143: 119-121, 1990) Cyclophosphamide, an alkylating agent, has been used extensively in cancer chemotherapy as well as for a variety of nonneoplastic disorders. Its use in the treatment of rheumatoid arthritis, systemic lupus erythematosus and Wegener's granulomatosis has been widespread since its introduction in 1957. However, in the late 1970s it became evident that cyclophosphamide caused epithelial neoplasms of the bladder urothelium, and in 1978 Beyer-Boon and associates described stromal changes in 28 patients who had hemorrhagic cystitis after treatment with cyclophosphamide. 1 Despite the temporal association of cyclophosphamide chemotherapy and subsequent bladder neoplasms, some question the role of cyclophosphamide in the induction of these neoplasms. Since cyclophosphamide has been used so often to treat myeloproliferative and lymphoproliferative disorders, some argue that second malignancies that occur are associated with the primary neoplasm rather than being induced by cyclophosphamide. 2 There have been 2 previous :reports of bladder leiomyosarcoma after cyclophosphamide therapy. 3 ' 4 Both cases are well documented temporally and histologically but they also occurred after treatment for Hodgkin's disease. This again raises the question of the lymphoma being associated with a second, primary malignancy. We report 2 cases of leiomyosarcoma arising in the bladder after long-term treatment with cyciophosphamide for lupus nephritis and rheumatoid arthritis. MATERIALS AND METHODS
Only formalin-fixed, paraffin-embedded material was available for retrospective analysis. The presence of extracellular acidic mucosubstances was evaluated with alcian blue at pH 2.5. 5 Muscle-specific actin antibodies, antibodies against desmin, vimentin and epithelial membrane antigen, and cytokeratin antibody (UCD 10.11) were used. Immunohistochemical localizations were performed with the peroxidase-antiperoxidase technique. 6 Sections stained for the presence of cytokeratin, desmin, epithelial membrane antigen and muscle-specific actin antibodies were preincubated with 0.05% pronase at 25 degrees for 15 minutes. Mitotic figures were counted in 50 random fields with a Zeiss standard microscope with a 40X Accepted for publication August 4, 1989. The views of the authors do not purport to reflect the position of the Army or the Department of Defense.
plan objective and lOX wide field occulars for a 15 mm. 2 effective field area. CASE REPORTS
Case 1. A 51-year-old white woman was treated with steroids and cyclophosphamide for rheumatoid arthritis and lupus nephritis. She received 100 mg. cyclophosphamide orally per day from December 1976 to March 1988. The patient tolerated treatments relatively well until October 1987, when she began to experience episodes of gross painless hematuria. Cystoscopy revealed hemorrhagic cystitis. The hematuria worsened in March 1988, requiring intravesical formalin to stop the persistent bleeding. In September she presented with recurrent gross painless hematuria and biopsy of a smooth bladder wall mass revealed leiomyosarcoma. The patient was referred to our hospital, where no evidence of metastatic spread of the tumor was found. Subsequently, she underwent left partial cystectomy in December. Grossly, the lesion appeared to be approximately 1 cm. in diameter with a whitish color and was indurated to palpation. A 5 X 2 X LS cm. segment of the bladder was resected with a wide margin of normal-appearing tissue. A third of the bladder was excised with surgical margins free of tumor. Microscopithe neoplasm was composed of hypercellular smooth muscle fascicles with pleornorphic nuclei and irregular chromatin clumping (part A of figure). There were 22 mitoses in 50 fields. Immunohistochemical stains revealed the presence of desmin, muscle-specific actin and vimentin in the malignant cells. In addition, the majority of cells were reactive with antibodies against cytokeratin in the distribution of paranuclear dots. The entire tumor revealed no epithelial membrane antigen reaction. The patient was free of disease 4 months postoperatively. Case 2. A 60-year-old white woman was treated with high dose steroids and cyclophosphamide for rheumatoid arthritis and lupus nephritis. She received 150 mg. cyclophosphamide orally per day for the majority of a 7-year period, with a decrease to 100 mg. per day for the last 6 months. The patient responded well and the cyclophosphamide was discontinued in 1978. In June 1985 she noticed 3 separate episodes of gross painless hematuria. A 0.5 cm. polypoid lesion on the right lateral wall of the bladder was resected transurethrally and diagnosed as superficial transitional cell carcinoma. She had a recurrence of the same type in September and received a brief course of
119
120
THRASHER, MILLER AND WETTLAUFER
A, case 1. Leiomyosarcoma shows fascicular arrangement of tumor cells and presence of mitotic figures (arrows). B, case 2. Leiomyosarcoma shows prominence of nucleoli and frequent mitotic figures (arrows). C, case 2. Myxoid component demonstrates loose myxoid stroma and lack of mitotic figures. H & E, reduced from X350.
thiotepa. The bleeding continued and in January 1986 at our institution a large polypoid lesion was resected transurethrally from the right side of the bladder and diagnosed as eosinophilic cystitis. Repeat biopsy of a mass in the same region in April was interpreted as leiomyosarcoma of the bladder. Subsequent metastatic evaluation was negative. Partial cystectomy was attempted but due to inability to obtain unequivocally uninvolved frozen section margins total cystectomy with ileal conduit diversion was performed. Grossly, the partial resection specimen contained a 6 X 3 cm. mass with surgical margins free of tumor. Microscopically, the neoplasm was a heterogeneous mixture of 2 morphological patterns. In some areas the neoplastic cells resembled smooth muscle myocytes (part B of figure) with amphophilic to eosinophilic cytoplasm. The cells contained elongate pleomorphic nuclei with prominent nucleoli. Rare 40X fields contained 3 to 4 mitotic figures but in 50 fields a total of only 12 was found. In other areas the neoplastic cells were arranged in a loose, myxoid stroma (part C of figure). The extracellular matrix of these areas was intensely alcianophilic. Mitoses were rare (3 in 50 fields) in these areas. Immunoperoxidase staining revealed the presence of vimentin, desmin and muscle-specific actin in the neoplastic cells. Again, occasional neoplastic cells also reacted positively for cytokeratin in a perinuclear fashion. No reaction with epithelial membrane antigen was seen. The patient was free of disease 3 years postoperatively. DISCUSSION
In a review of bladder malignancies after cyclophosphamide therapy in 1978, Pearson and Soloway concluded that there was insufficient data to identify cyclophosphamide definitely as a carcinogen. 2 They noted that most often cyclophosphamide was used in the treatment of myeloproliferative and lymphoproliferative disorders that had long been associated with second primary malignancies. Subsequent to their report many documented cases of bladder neoplasms have been associated with the use of cyclophosphamide for neoplastic and nonneoplastic conditions. However, almost all of these bladder neoplasms have been carcinomas. In addition to carcinoma, cyclophosphamide also has been
implicated in the induction of sarcoma of the bladder. One fibrosarcoma 7 and 2 leiomyosarcomas 3 ' 4 have been reported. All of these tumors were associated with concurrent Hodgkin's disease. Our 2 cases are leiomyosarcomas and have no association with lymphoproliferative disorders. Case 1 is a typical leiomyosarcoma with a characteristic myxoid phenotype and a moderate mitotic rate. However, case 2 is a myxoid variant8 with prominent areas of alcianophilic stroma, nuclear atypia and a relatively low mitotic rate. The differential diagnoses of such lesions have become complex and remain somewhat controversial. With respect to spindle cell neoplasms, a variety of lesions, including carcinomas, pseudosarcomas and postoperative spindle cell nodules, must be considered. The latter is germane particularly with respect to case 2, since the lesion in this patient was diagnosed 3 months after transurethral removal of a polypoid inflammatory lesion. In an attempt to clarify the diagnosis of such lesions, Wick and associates studied the immunohistochemical distribution of cytoskeletal components in various spindle cell lesions. 9 They suggested that the presence of cytokeratin is unique to postoperative spindle cell nodules and carcinomas. However, others have reported that 10 to 90% of all smooth muscle neoplasms can contain antigens that cross-react with antikeratin antibodies. 10• 11 Both of our cases reacted positively for cytokeratin but did not react with epithelial membrane antigen. Therefore, it would seem that presently the diagnosis of leiomyosarcoma is made best by confirming the expression of myogenic antigens (for example desmin and muscle-specific actin) in neoplasms with significant nuclear atypia and/or an elevated mitotic count. We report 2 cases of leiomyosarcoma of the bladder after cyclophosphamide therapy for nonneoplastic disorders. Both patients presented with gross painless hematuria many years after initiating oral cyclophosphamide for lupus nephritis and rheumatoid arthritis, and both had cystoscopic and microscopic evidence of cyclophosphamide-induced hemorrhagic changes of the bladder urothelium. In view of the expanding body of literature associating cyclophosphamide with subsequent bladder neoplasms, it may be prudent to re-evaluate the use of cyclophosphamide in disorders
BLADDER LEIOrv1Y08ARC0IvIA FOLLDVVIJ>JG CYCLOPHOSF-HAiviIDE
such as systemic erythematosus and rheumatoid arthritiso Cyclophospharnide remains one of the cornerstones of therapy for systemic lupus erythematosus despite the current lack of prospective studies demonstrating safety and effectiveness. However, its use in severe cases of rheumatoid arthritis could be substituted with other immunosuppressant agents, such as azathioprine, methotrexate or chlorambucil, if they are deemed necessary. The risks of a cyclophosphamide-induced malignancy may outweigh the benefits of treatment in nonneoplastic disorders. Reports in the literature support the premise that the treatment of choice for leiomyosarcoma of the bladder is partial cystectomy when the location and size of the tumor allow for adequate surgical margins. 12- 14 Our patient 2 would have undergone partial cystectomy but due to uncertainty regarding the involvement of surgical margins we elected to perform total cystectomy. The final pathological report revealed that the remaining bladder had, in fact, been free of disease after the initial partial resection. In conclusion, we present 2 cases of leiomyosarcoma of the bladder after cyclophosphamide therapy for nonneoplastic disorders. We support the idea that controlled studies in patients receiving cyclophosphamide are needed to delineate the dose and duration most likely to produce carcinogenic effects but we reiterate the need to monitor closely the use of this carcinogen, especially in nonneoplastic disorders. Robert Cardiff, University of California, Davis, California, donated the cytokeratin antibody. REFERENCES
l. Beyer-Boon, M. E., De Voogt, H.J. and Schaberg, A.: The effects
of cyclophosphamide treatment on the epithelium and stroma of the urinary bladder. Eur. J. Cancer, 14: 1029, 1978. 2. Pearson, R. M. and Soloway, M. S.: Does cyclophosphamide induce bladder cancer? Urology, 11: 437, 1978.
121
3. Rowland, R. G. and Eble, J. N.: Bladder leiomyosarcoma and pelvic fibroblastic tumor following cyclophosphamide therapy. J. Urol., 130: 344, 1983. 4. Seo, I. S., Clark, S. A., McGovern, F. D., Clark, D. L. and Johnson, E. H.: Leiomyosarcoma of the urinary bladder 13 years after cyclophosphamide therapy for Hodgkin's disease. Cancer, 55: 1597, 1985. 5. Lev, R. and Spicer, S. S.: Specific staining of sulphate groups with alcian blue at low pH. J. Histochem. Cytochem., 12: 309, 1964. 6. Sternberger, L.A., Hardy, P. H., Jr., Cuculis, J. J. and Meyer, H. G.: The unlabeled antibody enzyme method of immunohistochemistry: preparation and properties of soluble antigen-antibody complex (horesradish peroxidase-antihorseradish peroxidase) and its use in identification of spirochetes. J. Histochem. Cytochem., 18: 315, 1970. 7. Rupprecht, L. and Blessing, M. H.: Fibrosarcoma of the bladder after seven year chemotherapy for Hodgkin's disease in childhood. Dtsch. Med. Wchnschr., 98: 1663, 1973. 8. Young, R. H., Proppe, K H., Dickersin, G. R. and Scully, R. E.: Myxoid leiomyosarcoma of the urinary bladder. Arch. Path. Lab. Med., 111: 359, 1987. 9. Wick, M. R., Brown, B. A., Young, R.H. and Mills, S. E.: Spindlecell proliferations of the urinary tract. An immunohistochemical study. Amer. J. Surg. Path., 12: 379, 1988. 10. Brown, D. C., Theaker, J. M., Banks, P. M., Gatter, K C. and Mason, D. Y.: Cytokeratin expression in smooth muscle and smooth muscle tumours. Histopathology, 11: 477, 1987. 11. Norton, A. J., Thomas, J. A. and Isaacson, P. G.: Cytokeratinspecific monoclonal antibodies are reactive with tumours of smooth muscle derivation. An immunocytochemical and biochemical study using antibodies to intermediate filament cytoskeletal proteins. Histopathology, 11: 487, 1987. 12. Swartz, D. A., Johnson, D. E., Ayala, A. G. and Watkins, D. L.: Bladder leiomyosarcoma: a review of 10 cases with 5-year followup. J·. Urol., 133: 200, 1985. 13. Wilson, T. M., Fauver, H. E. and Weigel, J. W.: Leiomyosarcoma of urinary bladder. Urology, 13: 565, 1979. 14. Mackenzie, A. R., Whitmore, W. F., Jr. and Melamed, M. R.: Myosarcomas of the bladder and prostate. Cancer, 22: 833, 1968.