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α-Fetoprotein Producing Undifferentiated Carcinoma of the Bladder
0022-534 7 /94/1523-0958$03.00/0 THE JOURNAL OF UROLOGY Copyright© 1994 by AMERICAN UROLOGICAL AssocIATION, INC.
Vol. 152, 958-960, September 1994
Printed in U.S.A.
a-FETOPROTEIN PRODUCING UNDIFFERENTIATED CARCINOMA OF THE BLADDER KAZUHIKO YAMADA,* YOSHIAKI FUJIOKA, YOSHIO EBIHARA, ISAO KIRIYAMA, HIROSHI SUZUKI AND MASAO AKIMOTO From the Department of Urology, Nippon Medical School, and Departments of Urology and Pathology, Kawakita General Hospital, Tokyo, Japan
ABSTRACT
We report on a rare primary undifferentiated carcinoma of the bladder producing a-fetoprotein in a woman. Definitive features included an aggressive, invasive and rapidly growing tumor with a hepatoid carcinomatous lesion on histological examination. Histopathological findings sug gested that the multipotent transitional cell induces production of a-fetoprotein. The association of an aggressive tumor with the ability to produce this antigen suggests a possible benefit in measuring serum a-fetoprotein levels and examining histological sections for its expression in primary undifferentiated carcinoma of the bladder. Further study may indicate radical cystec tomy when the resected specimen produces a-fetoprotein, particularly if tumors appear to be aggressive and highly vascularized as in our case. KEY WORDS: alpha fetoproteins, bladder, carcinoma, cystectomy
Primary undifferentiated carcinoma of the bladder is an uncommon malignancy, comprising 2% of all bladder malig nancies. To our knowledge we report the first case of a-feto protein producing primary undifferentiated carcinoma of the bladder, and we describe its histopathological characteris tics. CASE REPORT
An 89-year-old woman was admitted to Kawakita General Hospital, Tokyo complaining ofhematuria and irritable blad der in July 1992. Computerized tomography (CT) and cysto scopy showed a 1 cm. solitary papillary tumor on the right wall of the bladder. Histopathology of the specimen from transurethral resection of the bladder tumor revealed grade 3 transitional cell carcinoma with no evidence of muscular invasion. The histopathological appearance ofthis tumor was difficult to distinguish from poorly differentiated adenocarci noma or an undifferentiated carcinoma. Massive hematuria developed 3 months after initial sur gery, and transurethral coagulation and repeat resection were performed. The tumor had recurred grossly at the orig inal site. A total of60 gm. of tumor as well as necrotic tissue and coagula were excised. Histopathological diagnosis was undifferentiated carcinoma of the bladder with features of a hepatoid adenocarcinoma-like structure. Histopathology demonstrated that by the time repeat resection was done the tumor had invaded the deep muscle layer. CT after repeat surgery revealed a thickening of the bladder wall consistent with residual tumor (fig. 1, A). Immunohistochemical stain ing was strongly positive for a-fetoprotein and serum a-feto protein was 12,700 ng./ml. on radioimmunoassay (normal less than 20). CT revealed no evidence of hepatocellular carcinoma, cirrhosis or ovarian tumors (fig. 1, B) and the patient had no gastrointestinal symptoms. We concluded that this lesion represented a primary undifferentiated car cinoma of the bladder which produced systemically detect able a-fetoprotein.
Accepted for publication December 3, 1993. * Current address: Transplantation Biology Research Center, Massachusetts General Hospital, Harvard Medical School, Building 149, 13th St., Charlestown, Massachusetts 02129.
FIG. 1. CT of abdomen after repeat transurethral resection of bladder tumor. A, thickening of bladder wall by residual tumor. B, no evidence of hepatocellular carcinoma or cirrhosis.
Five months after initial surgery radical cystectomy and bilateral cutaneous ureterostomies were performed because repeat CT revealed signs of residual tumor, and a primary a-fetoprotein producing lesion was found in no other organ. Abdominal exploration at cystectomy confirmed a normal liver and ovaries. Although a huge bladder neoplasm was palpated there was no evidence of invasion beyond the blad der. Histopathological examination of the 6.5 X 5.5 cm. pap illary tumor arising from the right wall ofthe bladder showed marked hemorrhage and necrosis. The tumor invaded the deep muscle layer of the bladder wall without reaching the adventitia (fig. 2, A). It was composed of large cells and formed a diffuse pattern (fig. 2, B) with focal areas remark ably similar in appearance to hepatocellular carcinoma (fig. 2, C). Immunohistochemical staining for a-fetoprotein was diffusely positive in the hepatoid carcinomatous lesions and negative in the surrounding areas (fig. 2, D). In addition, part of the tumor showed adenocarcinomatous features. Transi tional cell carcinoma in situ was also found in the mucosa proximal to the main tumor (fig. 3). There were no metasta ses in the regional lymph nodes. Electron microscopy demonstrated the characteristically high frequency of secretory granules within the tumor cells (fig. 4). Convalescence was uneventful and the patient was dis charged from the hospital 1 month after cystectomy. Serum a-fetoprotein decreased steadily and was 617 ng./ml. at that time. The patient was lost to followup.
958
a-FETOPROTEIN PRODUCING UNDIFFERENTIATED CARCINOMA OF BLADDER
959
FIG. 2. A, tumor invading deep muscle layer ofbladder without penetrating adventitia. H & E, reduced from X4. B, tumor demonstrating large cells and diffuse pattern. H & E, reduced from XlO. C, areas within tumor that simulate features ofhepatocellular carcinoma. H & E, reduced from X20. D, immunohistochemical staining for a-fetoprotein is diffusely positive in hepatoid carcinomatous lesions. a-Fetoprotein stain, reduced from X20.
FIG. 3. A, part of tumor shows adenocarcinomatous feature. Reduced from X4. B, in situ transitional cell carcinoma is seen in mucosa proximal to main tumor. H & E, reduced from X 10.
DISCUSSION
It is well known that hepatocellular, 1 testicular2 and ovar ian carcinomas synthesize a-fetoprotein, as do some gastric malignancies, such as hepatoid adenocarcinoma of the stom ach. 3 a-Fetoprotein production by testicular tumors has been associated with a higher rate of recurrence in early stages and a poorer prognosis in advanced stages unless additional chemotherapy is administered. 4• 5 Although a-fetoprotein production by an adenocarcinoma of the ureter has been described, 6 to our knowledge our case represents the first report of this phenomenon in an undifferentiated bladder carcinoma. Our patient was an elderly woman. Matias-Guiu and Guix listed the higher incidence of hepatoid adenocarcinoma of the stomach in older patients as a distinctive feature of that neoplasm. 7 Although this is only a single case, age may be a contributing factor in the development of a-fetoprotein pro ducing undifferentiated bladder carcinoma. In a clinical set ting specimens resected for bladder cancer are not routinely stained for a-fetoprotein but our case suggests characteris tics of a subset of bladder tumors for which staining for the antigen might be useful. These characteristics include a tu-
FIG. 4. Electron micrograph reveals that most tumor cells are characteristically rich in secretory granules.
960
a-FETOPROTEIN PRODUCING UNDIFFERENTIATED CARCINOMA OF BLADDER
mor that is composed of large cells forming a diffuse pattern with focal features similar to hepatocellular carcinoma and immunohistochemical staining for a-fetoprotein that is dif fusely positive in the hepatoid carcinomatous lesion. We thought that adjuvant chemotherapy, such as etopo side and cisplatin, directed against the germ cell tumor may have prevented distant metastasis in our case but patient age, lack of consent to chemotherapy and loss to followup prevented further treatment. The rate of tumorigenesis and the degree ofvascularity indicate a potential benefit in diag nosing these rare lesions at the earliest possible stage to allow for successful therapy. We believe that a pluripotent transitional cell line induces a-fetoprotein production. There fore, if a-fetoprotein levels are measured in older patients undergoing transurethral resection of the bladder tumor for hepatoid carcinomatous lesions, an aggressive tumor may be identified and cure rates improved by performing radical cystectomy. Due to the rarity of this carcinoma we cannot comment on the efficacy of chemotherapy. We look to future reports for confirmation of our observations. Dr. Bryan F. Meyers, Dr. Pierre Gianello and Ms. Danielle Vitiello assisted in revising this manuscript.
REFERENCES 1. Bergstrand, C. G. and Czar, B.: Paper electrophoresis study of human fetal serum protein with demonstration of a new pro tein fraction. Scand. J. Clin. Lab. Invest., 9: 277, 1975. 2. Shirai, T., ltoh, T. and Yoshiki, T.: Immunofluorescent demon stration of alpha-fetoprotein and other plasma proteins in yolk sac tumor. Cancer, 38: 1661, 1976. 3. Ishikura, H., Kirimoto, K., Shamoto, M., Miyamoto, Y., Yamagiwa, H., ltoh, T. and Aizawa, M.: Hepatoid adenocarci nomas of the stomach. An analysis of seven cases. Cancer, 58: 119, 1985. 4. Scardino, P. T., Cox, H. D., Waldmann, T. A., McIntire, K. R., Mittemeyer, B. and Javadpour, N.: The value of serum tumor markers in the staging and prognosis of germ cell tumors of the testis. J. Urol., 118: 994, 1977. 5. Vugrin, D. and Whitmore, W. F., Jr.: The role of chemotherapy and surgery in the treatment of retroperitoneal metastases in advanced nonseminomatous testis cancer. Cancer, 55: 1874, 1985. 6. Hosomi, M., Sagawa, S. and Kotou, Y.: Alpha-fetoprotein-pro ducing adenocarcinoma of the ureter. Urol. Int., 48: 226, 1992. 7. Matias-Guiu, X. and Guix, M.: Hepatoid gastric adenocarcinoma. Path. Res. Pract., 185: 397, 1989.
Vol. 152, 958-960, September 1994
Printed in U.S.A.
a-FETOPROTEIN PRODUCING UNDIFFERENTIATED CARCINOMA OF THE BLADDER KAZUHIKO YAMADA,* YOSHIAKI FUJIOKA, YOSHIO EBIHARA, ISAO KIRIYAMA, HIROSHI SUZUKI AND MASAO AKIMOTO From the Department of Urology, Nippon Medical School, and Departments of Urology and Pathology, Kawakita General Hospital, Tokyo, Japan
ABSTRACT
We report on a rare primary undifferentiated carcinoma of the bladder producing a-fetoprotein in a woman. Definitive features included an aggressive, invasive and rapidly growing tumor with a hepatoid carcinomatous lesion on histological examination. Histopathological findings sug gested that the multipotent transitional cell induces production of a-fetoprotein. The association of an aggressive tumor with the ability to produce this antigen suggests a possible benefit in measuring serum a-fetoprotein levels and examining histological sections for its expression in primary undifferentiated carcinoma of the bladder. Further study may indicate radical cystec tomy when the resected specimen produces a-fetoprotein, particularly if tumors appear to be aggressive and highly vascularized as in our case. KEY WORDS: alpha fetoproteins, bladder, carcinoma, cystectomy
Primary undifferentiated carcinoma of the bladder is an uncommon malignancy, comprising 2% of all bladder malig nancies. To our knowledge we report the first case of a-feto protein producing primary undifferentiated carcinoma of the bladder, and we describe its histopathological characteris tics. CASE REPORT
An 89-year-old woman was admitted to Kawakita General Hospital, Tokyo complaining ofhematuria and irritable blad der in July 1992. Computerized tomography (CT) and cysto scopy showed a 1 cm. solitary papillary tumor on the right wall of the bladder. Histopathology of the specimen from transurethral resection of the bladder tumor revealed grade 3 transitional cell carcinoma with no evidence of muscular invasion. The histopathological appearance ofthis tumor was difficult to distinguish from poorly differentiated adenocarci noma or an undifferentiated carcinoma. Massive hematuria developed 3 months after initial sur gery, and transurethral coagulation and repeat resection were performed. The tumor had recurred grossly at the orig inal site. A total of60 gm. of tumor as well as necrotic tissue and coagula were excised. Histopathological diagnosis was undifferentiated carcinoma of the bladder with features of a hepatoid adenocarcinoma-like structure. Histopathology demonstrated that by the time repeat resection was done the tumor had invaded the deep muscle layer. CT after repeat surgery revealed a thickening of the bladder wall consistent with residual tumor (fig. 1, A). Immunohistochemical stain ing was strongly positive for a-fetoprotein and serum a-feto protein was 12,700 ng./ml. on radioimmunoassay (normal less than 20). CT revealed no evidence of hepatocellular carcinoma, cirrhosis or ovarian tumors (fig. 1, B) and the patient had no gastrointestinal symptoms. We concluded that this lesion represented a primary undifferentiated car cinoma of the bladder which produced systemically detect able a-fetoprotein.
Accepted for publication December 3, 1993. * Current address: Transplantation Biology Research Center, Massachusetts General Hospital, Harvard Medical School, Building 149, 13th St., Charlestown, Massachusetts 02129.
FIG. 1. CT of abdomen after repeat transurethral resection of bladder tumor. A, thickening of bladder wall by residual tumor. B, no evidence of hepatocellular carcinoma or cirrhosis.
Five months after initial surgery radical cystectomy and bilateral cutaneous ureterostomies were performed because repeat CT revealed signs of residual tumor, and a primary a-fetoprotein producing lesion was found in no other organ. Abdominal exploration at cystectomy confirmed a normal liver and ovaries. Although a huge bladder neoplasm was palpated there was no evidence of invasion beyond the blad der. Histopathological examination of the 6.5 X 5.5 cm. pap illary tumor arising from the right wall ofthe bladder showed marked hemorrhage and necrosis. The tumor invaded the deep muscle layer of the bladder wall without reaching the adventitia (fig. 2, A). It was composed of large cells and formed a diffuse pattern (fig. 2, B) with focal areas remark ably similar in appearance to hepatocellular carcinoma (fig. 2, C). Immunohistochemical staining for a-fetoprotein was diffusely positive in the hepatoid carcinomatous lesions and negative in the surrounding areas (fig. 2, D). In addition, part of the tumor showed adenocarcinomatous features. Transi tional cell carcinoma in situ was also found in the mucosa proximal to the main tumor (fig. 3). There were no metasta ses in the regional lymph nodes. Electron microscopy demonstrated the characteristically high frequency of secretory granules within the tumor cells (fig. 4). Convalescence was uneventful and the patient was dis charged from the hospital 1 month after cystectomy. Serum a-fetoprotein decreased steadily and was 617 ng./ml. at that time. The patient was lost to followup.
958
a-FETOPROTEIN PRODUCING UNDIFFERENTIATED CARCINOMA OF BLADDER
959
FIG. 2. A, tumor invading deep muscle layer ofbladder without penetrating adventitia. H & E, reduced from X4. B, tumor demonstrating large cells and diffuse pattern. H & E, reduced from XlO. C, areas within tumor that simulate features ofhepatocellular carcinoma. H & E, reduced from X20. D, immunohistochemical staining for a-fetoprotein is diffusely positive in hepatoid carcinomatous lesions. a-Fetoprotein stain, reduced from X20.
FIG. 3. A, part of tumor shows adenocarcinomatous feature. Reduced from X4. B, in situ transitional cell carcinoma is seen in mucosa proximal to main tumor. H & E, reduced from X 10.
DISCUSSION
It is well known that hepatocellular, 1 testicular2 and ovar ian carcinomas synthesize a-fetoprotein, as do some gastric malignancies, such as hepatoid adenocarcinoma of the stom ach. 3 a-Fetoprotein production by testicular tumors has been associated with a higher rate of recurrence in early stages and a poorer prognosis in advanced stages unless additional chemotherapy is administered. 4• 5 Although a-fetoprotein production by an adenocarcinoma of the ureter has been described, 6 to our knowledge our case represents the first report of this phenomenon in an undifferentiated bladder carcinoma. Our patient was an elderly woman. Matias-Guiu and Guix listed the higher incidence of hepatoid adenocarcinoma of the stomach in older patients as a distinctive feature of that neoplasm. 7 Although this is only a single case, age may be a contributing factor in the development of a-fetoprotein pro ducing undifferentiated bladder carcinoma. In a clinical set ting specimens resected for bladder cancer are not routinely stained for a-fetoprotein but our case suggests characteris tics of a subset of bladder tumors for which staining for the antigen might be useful. These characteristics include a tu-
FIG. 4. Electron micrograph reveals that most tumor cells are characteristically rich in secretory granules.
960
a-FETOPROTEIN PRODUCING UNDIFFERENTIATED CARCINOMA OF BLADDER
mor that is composed of large cells forming a diffuse pattern with focal features similar to hepatocellular carcinoma and immunohistochemical staining for a-fetoprotein that is dif fusely positive in the hepatoid carcinomatous lesion. We thought that adjuvant chemotherapy, such as etopo side and cisplatin, directed against the germ cell tumor may have prevented distant metastasis in our case but patient age, lack of consent to chemotherapy and loss to followup prevented further treatment. The rate of tumorigenesis and the degree ofvascularity indicate a potential benefit in diag nosing these rare lesions at the earliest possible stage to allow for successful therapy. We believe that a pluripotent transitional cell line induces a-fetoprotein production. There fore, if a-fetoprotein levels are measured in older patients undergoing transurethral resection of the bladder tumor for hepatoid carcinomatous lesions, an aggressive tumor may be identified and cure rates improved by performing radical cystectomy. Due to the rarity of this carcinoma we cannot comment on the efficacy of chemotherapy. We look to future reports for confirmation of our observations. Dr. Bryan F. Meyers, Dr. Pierre Gianello and Ms. Danielle Vitiello assisted in revising this manuscript.
REFERENCES 1. Bergstrand, C. G. and Czar, B.: Paper electrophoresis study of human fetal serum protein with demonstration of a new pro tein fraction. Scand. J. Clin. Lab. Invest., 9: 277, 1975. 2. Shirai, T., ltoh, T. and Yoshiki, T.: Immunofluorescent demon stration of alpha-fetoprotein and other plasma proteins in yolk sac tumor. Cancer, 38: 1661, 1976. 3. Ishikura, H., Kirimoto, K., Shamoto, M., Miyamoto, Y., Yamagiwa, H., ltoh, T. and Aizawa, M.: Hepatoid adenocarci nomas of the stomach. An analysis of seven cases. Cancer, 58: 119, 1985. 4. Scardino, P. T., Cox, H. D., Waldmann, T. A., McIntire, K. R., Mittemeyer, B. and Javadpour, N.: The value of serum tumor markers in the staging and prognosis of germ cell tumors of the testis. J. Urol., 118: 994, 1977. 5. Vugrin, D. and Whitmore, W. F., Jr.: The role of chemotherapy and surgery in the treatment of retroperitoneal metastases in advanced nonseminomatous testis cancer. Cancer, 55: 1874, 1985. 6. Hosomi, M., Sagawa, S. and Kotou, Y.: Alpha-fetoprotein-pro ducing adenocarcinoma of the ureter. Urol. Int., 48: 226, 1992. 7. Matias-Guiu, X. and Guix, M.: Hepatoid gastric adenocarcinoma. Path. Res. Pract., 185: 397, 1989.