Primary Urinary Cytodiagnosis of a Bladder Small-Cell Carcinoma Susan Rollins, M.D., and G. Berry Schumann, M.D.
A small-cell undifferentiated tumor of the bladder in a 69-yrold man with asymptomatic hematuria is described. Urine cytology showed abundant, small, round-to-oval hyperchromatic cells with coarse chromatin, nuclear molding, and high nuclear/cytoplasmic ratios. A primary cytodiagnosis of smallcell undifferentiated cancer with associated severe urothelial atypia was made. Immunohistochemical stains were negative for neuron-specific enolase, leukocyte common antigen, chromogranin. epithelial membrane antigen, prostatic acid phosphatase, and prostate-specific phosphatase. The diagnosis was confirmed histologically by studies performed on cystoscopic bladder biopsy material. Diagn Cytopathol 1991;1:19-82. Key Words: Bladder; Cytology; Small-cell undifferentiated carcinoma; Oat-cell carcinoma; Neuroendocrine differentiation; Immunocytochemistry; Ultrastructure; Urine
Small-cell undifferentiated tumors composed of small anaplastic cells with high nuclear/cytoplasmic ratios and scanty cytoplasm have been reported in a variety of body sites, the most common being the lung.'92The bladder is an unusual location for these tumors. To date, 30 smallcell undifferentiated carcinomas of the urinary bladder have been reported in the histology literat~re."~-'~ To our knowledge, this is the first case of primary small-cell tumor of the urinary bladder diagnosed by exfoliative cytology.
Case Report A 69-yr-old man presented with painless hematuria. He had no prior history of urinary tract infection, genitourinary trauma, or tumor. Review of systems disclosed no other symptoms. The patient had a 25 pack-yr smoking history. Physical examination was unremarkable; the
Received August 7, 1989. Accepted March 2, 1990. From the Cytopathology Division, Department of Pathology, University of Utah Health Sciences Center, Salt Lake City, UT, and St. Louis University School of Medicine, Department of Pathology, St. Louis, MO. Address reprint requests to G. Berry Schumann, M.D., Director, Cytopathology and Cytotechnology, Department of Pathology, University of Utah Health Sciences Center, 50 N. Medical Dr, Salt Lake City, UT 84132. 0 1991 WILEY-LISS, INC.
prostate was normal in size and no masses were palpated. Results of a complete blood count and chemistry profile were all within normal limits. The first urine specimen sent for cytology showed abundant small undifferentiated cells. Chest roentgenogram showed chronic obstructive airway disease, old granulomatous disease, and no evidence of tumor. Computerized tomography (CT) of the chest and head were unremarkable. Intravenous urogram showed a large lobulated mass involving the left side of the bladder with extension along the inferior aspect of the bladder wall; the upper urinary tract was normal. CT of the abdomen and pelvis showed an abnormal soft-tissue density within the bladder, thickening of the anterior bladder wall, and possible perivesicular fat infiltration. There was no evidence of adenopathy. A second urine specimen was sent for cytology. On this occasion, abundant small undifferentiated cells and a smaller population of severely atypical urothelial cells were seen. The diagnosis of primary small-cell undifferentiated cancer of the bladder was rendered and treatment was begun. A cystoscopic bladder biopsy was performed. A 4-cmdiameter mass located in the anterior and left lateral bladder wall was seen. The mass had a relatively smooth surface; no papillations were seen. A small amount of necrotic-looking debris overlaid part of the mass. Histologically, the tumor consisted of small undifferentiated cells. Soon thereafter, a radical cystectomy was done. Histology revealed a small-cell undifferentiated carcinoma with transmural extension through the bladder wall and into the perivesicle adipose tissue. The right and left pelvic lymph nodes and the right and left ureteral distal margins of resection showed no evidence of malignancy. Six months after the radical cystectomy, metastatic disease was identified in the right lung, right axilla, abdomen, and retroperitoneum. After three courses of chemotherapy with vincristine, cytoxan sulfate, and Adriamycin at I-mo intervals, the above named sites of tumor had almost totally regressed. At the present time, 9 mo Diagnostic Cytopathology,Vol7, No I
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ROLLINS AND SCHUMANN
after the beginning of chemotherapy, no new lesions have appeared.
Methods and Materials Urine was sent for cytologic diagnosis on two separate occasions. Cytocentrifuge preparations were made and stained by the modified Papanicolaou method. Immunocytochemical stains for epithelial membrane antigen (EMA; Dako, Santa Barbara, CA), leukocyte common antigen (T-200; Dako), neuron-specific enolase (NSE; Dako), chromogranin (Hybritech, San Diego, CA), S-100 (Dako), prostatic acid phosphatase (PRAP; Dako), and prostatespecific phosphatase (PSA; Dako) were performed on cytocentrifuge preparations. Urine fixed in Karnovsky's fixative was processed for electron microscopy. Tissue obtained by cystoscopic bladder biopsy was fixed in 10% buffered formalin and embedded in paraffin. Tissue sections were stained with hematoxylin-eosin, and immunocytochemical stains for cytokeratins (AE-1-3; protease digestion with trypsin), NSE, S-100, T-200, chromogranin, PRAP, and PSA were performed using the strep-avidin method with 3-amino-9 ethyl carbazole (AEC) as the ~hromogen.'~ Tissue was also sent for electron microscopy.
Results Cytopathology Cytocentrifuge preparations of both urine samples yielded abundant undifferentiated malignant cells (Fig. 1). These cells were small, with scant cytoplasm, coarse nuclear chromatin, high nuclear/cytoplasmic ratios, and nuclear molding. In the second urine sample, a second population of cells showing features of severe urothelial atypia was present (Fig. 2). A diagnosis of small-cell undifferentiated tumor with associated Severe urothelial atypia was rendered.
Fig. 1. Malignant cells derived from small-cell cancer. Note the cluster of malignant cells with characteristic hyperchromatic, molded nuclei (Papanicolaou, x 1,000).
Histopathology
Immunohistochemistry
Thirty-four grams of bladder tissue were received. Light microscopy showed cells similar to the small undifferentiated cells seen in the urine cytology specimens (Fig. 3). The tumor was composed of sheets and lobules of small, relatively uniform, round-to-fusiform, hyperchromatic cells with scanty cytoplasm. The tumor cells replaced the normal surface transitional cells and extended deep into the muscularis propria. Focal extension into the perivesical adipose tissue was present. Numerous mitotic figures and necrosis were present. In summary, the histologic features were similar to those of the common small-cell carcinoma of the lung. Much of the bladder surface was denuded and necrotic; however, areas of urothelial atypia were identified overlying the tumor.
EMA, T-200, AE-1-3, NSE, S-100, chromogranin, PRAP, and PSA were done on both the cytologic preparations and the paraffin-embedded histologic material. All markers were negative in both the cytology and histology specimens.
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Electron Microscopy Electron micrographs of the cytologic material were unhelpful due to cellular degeneration. Electron micrographs of the tissue biopsy showed cells that were relatively uniform and round to polygonal, with oval, moderately irregular nuclei with peripheral dense chromatin. Tight junctions and junctional complexes were not present. The cytoplasm contained a few organelles consisting
URINARY DIAGNOSIS OF BLADDER CARCINOMA
Fig. 2. Urine cytology specimen containing urothelial atypia (Papanicolaou, x 1,000).
theory on the histogenesis of these tumors, which is that they arise from a proliferating mucosal stem cell rather than a specific neuroendocrine prec~rsor.~.’ SCUCs of the lung are associated with a smoking history. Patients’ smoking history has been documented in 7 of the 30 previously reported cases of SCUC of the bladder; of these seven patients, three did not smoke and four did. The patient in our report has a 25 pack-yr smoking history. Further studies must be done to determine whether the occurrence of SCUC of the bladder is linked with cigarette smoking. This is the first case of a SCUC from any location diagnosed by urine cytology. In this case, atypical urothelial cells were shed into the urine; thus, we suspected that the primary tumor was in the urinary bladder. The diagnosis of SCUC of the bladder was confirmed by cystoscopic biopsy. The clinical course of our patientearly widespread metastases and good response to chemo-
mainly of mitochondria and rough endoplasmic reticulum. Scattered electron-dense granules were present in the cells; they had eccentrically located homogenous electron-dense cores and were thought to represent neurosecretory granules, thus confirming the diagnosis of smallcell tumor with neuroendocrine differentiation.
Discussion It is important to recognize small-cell undifferentiated carcinomas. The vast majority of these tumors occur in the lung; in this location, they have a distinct biologic behavior with early invasion and metastases, frequent association with paraendocrine syndromes, and sensitivity to particular chemotherapy regimens. In a review of the literature, 30 cases of small-cell carcinoma of the bladder diagnosed on histologic material were identified.3 It appears from these cases that small-cell carcinoma of the bladder, like its pulmonary counterpart, is an aggressive tumor; metastases typically develop early in the clinical course and median survival after diagnosis is approximately 5 n-10.~ Small-cell undifferentiated carcinomas (SCUCs) of the bladder usually occur in elderly men who present with gross hematuria. In a series of patients described by Mills et al.,3 over one half of the patients were over 70 yr of age. On cystoscopy, the tumors tend to be single, large, polypoid intraluminal masses that may or may not be ulcerated. This gross appearance differs from the appearance of the more common papillary and infiltrative transitional-cell carcinomas of the bladder. Neuroendocrine differentiation can be demonstrated in most SCUCs of the urinary bladder by immunocytochemistry or ultrastructure; however, whether or not neuroendocrine differentiation is found, these tumors tend to have an aggressive course. We support the current favored
Fig. 3. Histologic section showing small-cell cancer of the bladder (hematoxylin-eosin,x 430).
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therapy-was similar to that of the other patients reported in the literature. Lesions that need to be excluded when small undifferentiated cells are seen in the urine include metastatic SCUC"; SCUC of the kidney'*'6 and the pr~state'~''-'~; carcinoid tumor of the bladder,20*21 the and the urethra2'; lymphoma; transitional-cell carcinoma-insitu; severe urothelial atypia; and follicular cystitis. We believe that an accurate diagnosis of SCUC can be made on urine cytology when the cytologic, immunocytochemical, and/or ultrastructural features of the cells are analyzed. Since treatment and prognosis differ for the above entities, an accurate diagnosis is essential.
Acknowledgment T h e authors thank Susan Creighton, C.T. (A.S.C.P.), and C. J a y Marshall, M.D., for their assistance in writing this article and Cheryl Shurtleff for typing the manuscript.
References 1. Ibrahim NBN, Briggs JC, Corbishley CM. Extrapulmonary oat cell carcinoma. Cancer 1984;54:1645-61. 2. Richardson RL, Weiland LH. Undifferentiated small cell carcinomas at extrapulmonary sites. Semin Oncol 1982;9:484-96. 3. Mills SE, Wolfe JT, Weiss MA, et al. Small cell undifferentiated carcinoma of the urinary bladder. Am J Surg Pathol 1987;11:606-17. 4. Reyes CV, Sonera I. Small cell carcinoma of the urinary bladder with hypercalcemia. Cancer 1985;56:2530-3. 5. Abenoza P, hlanivel C, Sibley RK. Adenocarcinoma with neuroendocrine differentiation of the urinary bladder. Arch Pathol Lab Med 1986;110: 1062-6. 6. Partanen S, Asikainen U. Oat cell carcinoma of the urinary bladder with ectopic adrenocorticotropic hormone production. Hum Pathol 1985;16:313-5. 7. Kim CK, Lin JI, Tseng CH. Small cell carcinoma of urinary bladder. Urology 1984;24(4):384-6. 8. Ordonez NG, Khorsand J, Ayala AG, Sneige N. Oat cell carcinoma of the urinary tract: an immunohistochemical and electron microscopic study. Cancer 1986;58:2519-30.
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9. Cramer SF, Aikawa M, Cebelin M. Neurosecretory granules in the small cell invasive carcinoma of the urinary bladder. Cancer 1981;47: 724-30. 10. Lee JYY, Tang CK, Rodriguez F. Anaplastic carcinoma of urinary bladder with oat cell features. Urology 1986;27:474-6. 11. Davis BH, Ludwig ME, Cole SR, Pastuzak WT. Small cell neuroendocrine carcinoma of the urinary bladder: report of three cases with ultrastructural analysis. Ultrastruct Pathol 1983;4:197-204. 12. Williams MR, Dunn M, Ansell ID. Primary oat cell carcinoma of the urinary bladder. Br J Urol 1986;58:225. 13. Aoyoma H, Yoshida K, Kondo, et al. Primary carcinoid tumor of the urinary bladder (report of a case). Jpn J Urol 1978;69:124-33. 14. Taylor CR. Immunomicroscopy: a diagnostic tool for the surgical pathologist. Philadelphia: Saunders, 1986:43-69. 15. Coltart RS, Stewart S, Brown CH. Small cell carcinoma of the bronchus: a rare cause of haematuria from a metastasis in the urinary bladder. J R SOC Med 1985;78:1053-4. 16. Capella C, Eusebi V, Rosai J. Primary oat cell carcinoma of the kidney. Am J Surg Pathol 1984;8:855-61. 17. Wenk RE, Bhagavan BS, Levy R, Miller D, Weisburger W. Ectopic ACTH, prostatic oat cell carcinoma, and marked hypernatremia. Cancer 1977;40:773-8. 18. Tetu B, Ro JY, Ayala AG, Johnson DE, Logothetis CJ, Ordonez NG. Small cell carcinoma of the prostate. Part 1. A clinicopathologic study of 20 cases. Cancer 1987;59:1803-9. 19. Bleichner JC, Chun B, Klappenbach S. Pure small cell carcinoma of the prostate with fatal liver metastasis. Arch Pathol Lab Med 1986;llO: 1041-4. 20. Yang C, Krzyzaniak K, Brown WJ, Kurtz SM. Primary carcinoid tumor of urinary bladder. Urology 1985;26:594-7. 21. Colby TV. Carcinoid tumor of the bladder. A case report. Arch Pathol Lab Med 1980;104:199-200. 22. Montasser AY, Ong MG, Mehta VT. Carcinoid tumor of the prostate associated with adenocarcinoma. Cancer 1979;44:307-10. 23. Wasserstein PW, Goldman RL. Primary carcinoid of prostate. Urology 1979;13:318-20. 24. Azumi N, Shibuya H, Ishikura M. Primary prostatic carcinoid tumor with intracytoplasmic prostatic acid phosphatase and prostatespecific antigen. Am J Surg Pathol 1984;8:545-50. 25. Sylora HO, Diamond HM, Kaufman M, Straus F, Lyons ES. Primary carcinoid of the urethra. J Urol 1975;114:150-3.
A small-cell undifferentiated tumor of the bladder in a 69-yrold man with asymptomatic hematuria is described. Urine cytology showed abundant, small, round-to-oval hyperchromatic cells with coarse chromatin, nuclear molding, and high nuclear/cytoplasmic ratios. A primary cytodiagnosis of smallcell undifferentiated cancer with associated severe urothelial atypia was made. Immunohistochemical stains were negative for neuron-specific enolase, leukocyte common antigen, chromogranin. epithelial membrane antigen, prostatic acid phosphatase, and prostate-specific phosphatase. The diagnosis was confirmed histologically by studies performed on cystoscopic bladder biopsy material. Diagn Cytopathol 1991;1:19-82. Key Words: Bladder; Cytology; Small-cell undifferentiated carcinoma; Oat-cell carcinoma; Neuroendocrine differentiation; Immunocytochemistry; Ultrastructure; Urine
Small-cell undifferentiated tumors composed of small anaplastic cells with high nuclear/cytoplasmic ratios and scanty cytoplasm have been reported in a variety of body sites, the most common being the lung.'92The bladder is an unusual location for these tumors. To date, 30 smallcell undifferentiated carcinomas of the urinary bladder have been reported in the histology literat~re."~-'~ To our knowledge, this is the first case of primary small-cell tumor of the urinary bladder diagnosed by exfoliative cytology.
Case Report A 69-yr-old man presented with painless hematuria. He had no prior history of urinary tract infection, genitourinary trauma, or tumor. Review of systems disclosed no other symptoms. The patient had a 25 pack-yr smoking history. Physical examination was unremarkable; the
Received August 7, 1989. Accepted March 2, 1990. From the Cytopathology Division, Department of Pathology, University of Utah Health Sciences Center, Salt Lake City, UT, and St. Louis University School of Medicine, Department of Pathology, St. Louis, MO. Address reprint requests to G. Berry Schumann, M.D., Director, Cytopathology and Cytotechnology, Department of Pathology, University of Utah Health Sciences Center, 50 N. Medical Dr, Salt Lake City, UT 84132. 0 1991 WILEY-LISS, INC.
prostate was normal in size and no masses were palpated. Results of a complete blood count and chemistry profile were all within normal limits. The first urine specimen sent for cytology showed abundant small undifferentiated cells. Chest roentgenogram showed chronic obstructive airway disease, old granulomatous disease, and no evidence of tumor. Computerized tomography (CT) of the chest and head were unremarkable. Intravenous urogram showed a large lobulated mass involving the left side of the bladder with extension along the inferior aspect of the bladder wall; the upper urinary tract was normal. CT of the abdomen and pelvis showed an abnormal soft-tissue density within the bladder, thickening of the anterior bladder wall, and possible perivesicular fat infiltration. There was no evidence of adenopathy. A second urine specimen was sent for cytology. On this occasion, abundant small undifferentiated cells and a smaller population of severely atypical urothelial cells were seen. The diagnosis of primary small-cell undifferentiated cancer of the bladder was rendered and treatment was begun. A cystoscopic bladder biopsy was performed. A 4-cmdiameter mass located in the anterior and left lateral bladder wall was seen. The mass had a relatively smooth surface; no papillations were seen. A small amount of necrotic-looking debris overlaid part of the mass. Histologically, the tumor consisted of small undifferentiated cells. Soon thereafter, a radical cystectomy was done. Histology revealed a small-cell undifferentiated carcinoma with transmural extension through the bladder wall and into the perivesicle adipose tissue. The right and left pelvic lymph nodes and the right and left ureteral distal margins of resection showed no evidence of malignancy. Six months after the radical cystectomy, metastatic disease was identified in the right lung, right axilla, abdomen, and retroperitoneum. After three courses of chemotherapy with vincristine, cytoxan sulfate, and Adriamycin at I-mo intervals, the above named sites of tumor had almost totally regressed. At the present time, 9 mo Diagnostic Cytopathology,Vol7, No I
79
ROLLINS AND SCHUMANN
after the beginning of chemotherapy, no new lesions have appeared.
Methods and Materials Urine was sent for cytologic diagnosis on two separate occasions. Cytocentrifuge preparations were made and stained by the modified Papanicolaou method. Immunocytochemical stains for epithelial membrane antigen (EMA; Dako, Santa Barbara, CA), leukocyte common antigen (T-200; Dako), neuron-specific enolase (NSE; Dako), chromogranin (Hybritech, San Diego, CA), S-100 (Dako), prostatic acid phosphatase (PRAP; Dako), and prostatespecific phosphatase (PSA; Dako) were performed on cytocentrifuge preparations. Urine fixed in Karnovsky's fixative was processed for electron microscopy. Tissue obtained by cystoscopic bladder biopsy was fixed in 10% buffered formalin and embedded in paraffin. Tissue sections were stained with hematoxylin-eosin, and immunocytochemical stains for cytokeratins (AE-1-3; protease digestion with trypsin), NSE, S-100, T-200, chromogranin, PRAP, and PSA were performed using the strep-avidin method with 3-amino-9 ethyl carbazole (AEC) as the ~hromogen.'~ Tissue was also sent for electron microscopy.
Results Cytopathology Cytocentrifuge preparations of both urine samples yielded abundant undifferentiated malignant cells (Fig. 1). These cells were small, with scant cytoplasm, coarse nuclear chromatin, high nuclear/cytoplasmic ratios, and nuclear molding. In the second urine sample, a second population of cells showing features of severe urothelial atypia was present (Fig. 2). A diagnosis of small-cell undifferentiated tumor with associated Severe urothelial atypia was rendered.
Fig. 1. Malignant cells derived from small-cell cancer. Note the cluster of malignant cells with characteristic hyperchromatic, molded nuclei (Papanicolaou, x 1,000).
Histopathology
Immunohistochemistry
Thirty-four grams of bladder tissue were received. Light microscopy showed cells similar to the small undifferentiated cells seen in the urine cytology specimens (Fig. 3). The tumor was composed of sheets and lobules of small, relatively uniform, round-to-fusiform, hyperchromatic cells with scanty cytoplasm. The tumor cells replaced the normal surface transitional cells and extended deep into the muscularis propria. Focal extension into the perivesical adipose tissue was present. Numerous mitotic figures and necrosis were present. In summary, the histologic features were similar to those of the common small-cell carcinoma of the lung. Much of the bladder surface was denuded and necrotic; however, areas of urothelial atypia were identified overlying the tumor.
EMA, T-200, AE-1-3, NSE, S-100, chromogranin, PRAP, and PSA were done on both the cytologic preparations and the paraffin-embedded histologic material. All markers were negative in both the cytology and histology specimens.
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Diagnostic Cytopathology,Vol7,No I
Electron Microscopy Electron micrographs of the cytologic material were unhelpful due to cellular degeneration. Electron micrographs of the tissue biopsy showed cells that were relatively uniform and round to polygonal, with oval, moderately irregular nuclei with peripheral dense chromatin. Tight junctions and junctional complexes were not present. The cytoplasm contained a few organelles consisting
URINARY DIAGNOSIS OF BLADDER CARCINOMA
Fig. 2. Urine cytology specimen containing urothelial atypia (Papanicolaou, x 1,000).
theory on the histogenesis of these tumors, which is that they arise from a proliferating mucosal stem cell rather than a specific neuroendocrine prec~rsor.~.’ SCUCs of the lung are associated with a smoking history. Patients’ smoking history has been documented in 7 of the 30 previously reported cases of SCUC of the bladder; of these seven patients, three did not smoke and four did. The patient in our report has a 25 pack-yr smoking history. Further studies must be done to determine whether the occurrence of SCUC of the bladder is linked with cigarette smoking. This is the first case of a SCUC from any location diagnosed by urine cytology. In this case, atypical urothelial cells were shed into the urine; thus, we suspected that the primary tumor was in the urinary bladder. The diagnosis of SCUC of the bladder was confirmed by cystoscopic biopsy. The clinical course of our patientearly widespread metastases and good response to chemo-
mainly of mitochondria and rough endoplasmic reticulum. Scattered electron-dense granules were present in the cells; they had eccentrically located homogenous electron-dense cores and were thought to represent neurosecretory granules, thus confirming the diagnosis of smallcell tumor with neuroendocrine differentiation.
Discussion It is important to recognize small-cell undifferentiated carcinomas. The vast majority of these tumors occur in the lung; in this location, they have a distinct biologic behavior with early invasion and metastases, frequent association with paraendocrine syndromes, and sensitivity to particular chemotherapy regimens. In a review of the literature, 30 cases of small-cell carcinoma of the bladder diagnosed on histologic material were identified.3 It appears from these cases that small-cell carcinoma of the bladder, like its pulmonary counterpart, is an aggressive tumor; metastases typically develop early in the clinical course and median survival after diagnosis is approximately 5 n-10.~ Small-cell undifferentiated carcinomas (SCUCs) of the bladder usually occur in elderly men who present with gross hematuria. In a series of patients described by Mills et al.,3 over one half of the patients were over 70 yr of age. On cystoscopy, the tumors tend to be single, large, polypoid intraluminal masses that may or may not be ulcerated. This gross appearance differs from the appearance of the more common papillary and infiltrative transitional-cell carcinomas of the bladder. Neuroendocrine differentiation can be demonstrated in most SCUCs of the urinary bladder by immunocytochemistry or ultrastructure; however, whether or not neuroendocrine differentiation is found, these tumors tend to have an aggressive course. We support the current favored
Fig. 3. Histologic section showing small-cell cancer of the bladder (hematoxylin-eosin,x 430).
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therapy-was similar to that of the other patients reported in the literature. Lesions that need to be excluded when small undifferentiated cells are seen in the urine include metastatic SCUC"; SCUC of the kidney'*'6 and the pr~state'~''-'~; carcinoid tumor of the bladder,20*21 the and the urethra2'; lymphoma; transitional-cell carcinoma-insitu; severe urothelial atypia; and follicular cystitis. We believe that an accurate diagnosis of SCUC can be made on urine cytology when the cytologic, immunocytochemical, and/or ultrastructural features of the cells are analyzed. Since treatment and prognosis differ for the above entities, an accurate diagnosis is essential.
Acknowledgment T h e authors thank Susan Creighton, C.T. (A.S.C.P.), and C. J a y Marshall, M.D., for their assistance in writing this article and Cheryl Shurtleff for typing the manuscript.
References 1. Ibrahim NBN, Briggs JC, Corbishley CM. Extrapulmonary oat cell carcinoma. Cancer 1984;54:1645-61. 2. Richardson RL, Weiland LH. Undifferentiated small cell carcinomas at extrapulmonary sites. Semin Oncol 1982;9:484-96. 3. Mills SE, Wolfe JT, Weiss MA, et al. Small cell undifferentiated carcinoma of the urinary bladder. Am J Surg Pathol 1987;11:606-17. 4. Reyes CV, Sonera I. Small cell carcinoma of the urinary bladder with hypercalcemia. Cancer 1985;56:2530-3. 5. Abenoza P, hlanivel C, Sibley RK. Adenocarcinoma with neuroendocrine differentiation of the urinary bladder. Arch Pathol Lab Med 1986;110: 1062-6. 6. Partanen S, Asikainen U. Oat cell carcinoma of the urinary bladder with ectopic adrenocorticotropic hormone production. Hum Pathol 1985;16:313-5. 7. Kim CK, Lin JI, Tseng CH. Small cell carcinoma of urinary bladder. Urology 1984;24(4):384-6. 8. Ordonez NG, Khorsand J, Ayala AG, Sneige N. Oat cell carcinoma of the urinary tract: an immunohistochemical and electron microscopic study. Cancer 1986;58:2519-30.
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9. Cramer SF, Aikawa M, Cebelin M. Neurosecretory granules in the small cell invasive carcinoma of the urinary bladder. Cancer 1981;47: 724-30. 10. Lee JYY, Tang CK, Rodriguez F. Anaplastic carcinoma of urinary bladder with oat cell features. Urology 1986;27:474-6. 11. Davis BH, Ludwig ME, Cole SR, Pastuzak WT. Small cell neuroendocrine carcinoma of the urinary bladder: report of three cases with ultrastructural analysis. Ultrastruct Pathol 1983;4:197-204. 12. Williams MR, Dunn M, Ansell ID. Primary oat cell carcinoma of the urinary bladder. Br J Urol 1986;58:225. 13. Aoyoma H, Yoshida K, Kondo, et al. Primary carcinoid tumor of the urinary bladder (report of a case). Jpn J Urol 1978;69:124-33. 14. Taylor CR. Immunomicroscopy: a diagnostic tool for the surgical pathologist. Philadelphia: Saunders, 1986:43-69. 15. Coltart RS, Stewart S, Brown CH. Small cell carcinoma of the bronchus: a rare cause of haematuria from a metastasis in the urinary bladder. J R SOC Med 1985;78:1053-4. 16. Capella C, Eusebi V, Rosai J. Primary oat cell carcinoma of the kidney. Am J Surg Pathol 1984;8:855-61. 17. Wenk RE, Bhagavan BS, Levy R, Miller D, Weisburger W. Ectopic ACTH, prostatic oat cell carcinoma, and marked hypernatremia. Cancer 1977;40:773-8. 18. Tetu B, Ro JY, Ayala AG, Johnson DE, Logothetis CJ, Ordonez NG. Small cell carcinoma of the prostate. Part 1. A clinicopathologic study of 20 cases. Cancer 1987;59:1803-9. 19. Bleichner JC, Chun B, Klappenbach S. Pure small cell carcinoma of the prostate with fatal liver metastasis. Arch Pathol Lab Med 1986;llO: 1041-4. 20. Yang C, Krzyzaniak K, Brown WJ, Kurtz SM. Primary carcinoid tumor of urinary bladder. Urology 1985;26:594-7. 21. Colby TV. Carcinoid tumor of the bladder. A case report. Arch Pathol Lab Med 1980;104:199-200. 22. Montasser AY, Ong MG, Mehta VT. Carcinoid tumor of the prostate associated with adenocarcinoma. Cancer 1979;44:307-10. 23. Wasserstein PW, Goldman RL. Primary carcinoid of prostate. Urology 1979;13:318-20. 24. Azumi N, Shibuya H, Ishikura M. Primary prostatic carcinoid tumor with intracytoplasmic prostatic acid phosphatase and prostatespecific antigen. Am J Surg Pathol 1984;8:545-50. 25. Sylora HO, Diamond HM, Kaufman M, Straus F, Lyons ES. Primary carcinoid of the urethra. J Urol 1975;114:150-3.
