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Signet ring cell adenocarcinoma of prostate
CASE REPORT
SIGNET
RING CELL ADENOCARCINOMA OF PROSTATE
CYNTHIA SMITH, B.S. RICHARD M. FEDDERSEN, M.D. LYNN DRESSLER, M.S.
THOMAS MCCONNELL, M.D MICHAEL MILROY, M.D. ANTHONY Y. SMITH, M.D.
From the Division of Urology, Department of Pathology, and Center for Molecular and Cellular Diagnostics, University of New Mexico School of Medicine, Albuquerque, New Mexico
ABSTRACT-Primary signet ring cell adenocarcinoma of the prostate is a rare malignancy with a total of 13 cases reported to date in the English literature. We report a very unusual case of signet ring adenocarcinoma of the prostate occurring in a patient who presented initially with irritative voiding symptoms and a bladder mass. Results of immunohistochemical, flow cytometric, and cytogenetic analyses of the tumor are presented.
Mutinous adenocarcinomas of the prostate, defined as those in which more than 25 percent of the tumor shows pools of mucin, are rare tumors.i,’ Mutinous prostate cancers only rarely contain signet ring cells. Primary signet ring adenocarcinomas of the prostate are therefore more rare, with only 13 well-documented cases reported to date.3-8 Uyama and Moriwaki6 reported the first case of signet ring adenocarcinoma of the prostate in 1979. A seventeen-year experience at the M.D. Anderson Hospital identified an additional 8 patients.4 Four additional case reports are found in the literature.3.5.7,8 We present a very unusual case of signet ring adenocarcinoma of the prostate which occurred in a patient with irritative voiding symptoms and an apparent bladder mass. Results of immunohistochemical and previously unreported flow cytometric and cytogenetic analyses are presented. CASE REPORT A sixty-two-year-old man presented with microhematuria and irritative voiding symptoms. Physical examination revealed a large prostate which was clinically benign. There was no evidence of adenopathy. A serum prostate-specific antigen (PSA) was 4.6 ng/mL (normal O-4 ng/mL) and the serum prostatic acid phosphatase (PAP) was 1.7 ng/mL (normal O-2.2 ng/mL). An intravenous Submitted: September vember 4. 199.3
UROLOGY
2, 1993,
accepted
(with
revisions):
/ MARCH1994 / VOLUME43, NUMLWR 3
No-
urogram showed mild right hydronephrosis and a filling defect in the bladder base. A cystoscopy and transurethral resection of a right lateral wall bladder mass revealed an invasive adenocarcinoma composed primarily of signet ring cells. Immunohistochemical stains of the resected specimen for PSA and PAP were negative. A metastatic workup, including abdominal computed tomography (CT) scan, chest x-ray film, and whole body bone scan, showed no evidence of metastatic disease. Since the tumor was believed to be a bladder primary, a radical cystoprostatectomy was recommended. Independently obtained second opinions from multiple urologic oncologists in other parts of the country all recommended the same. Perioperative sigmoidoscopy revealed no mucosal lesions. The patient underwent an uncomplicated radical cystoprostatectomy and ileal conduit urinary diversion. The poorly circumscribed tumor measured 5 cm in largest diameter and involved the trigone, right ureteral orifice, and superior aspect of the prostate. Light microscopy revealed an adenocarcinema. A search of the prostate revealed neoplastic glands, cords of cells, and solid cell masses which were histologically recognizable as prostatic adenocarcinoma. The most prevalent patterns were Gleason grades 5 and 3, with morphologic transitions between the two (Fig. lA, B). Half of the cells in the high-grade areas contained prominent intracytoplasmic mucin vacuoles that indented the nuclei, including occasional fully 397
FIGURE 1. [A) lntraprostatic differentiated adenocarcinoma, Gleason grade 3. (B) Transition from neoplastic glands (solid arrows) to circumscribed solid cell masses (open arrows, Gleason grade 5) with scattered cytoplasmic mucin droplets. (C] Perivesical soft tissue contains irregular cell masses suspended in pools of extracellular mucin. (D) Detail from a lymph node metastasis. Aggregates and individual signet ring cells are suspended in extracellular mucin. (Hematoxylin and eosin, original magnifications from x 150 to x 400.)
developed signet ring cells. Accumulations of extracellular mucin were small and focal within the prostate. The tumor extended directly through the bladder wall and infiltrated the bladder submucosa and perivesical fat. Several iliac lymph nodes contained metastatic deposits. At all of these extraprostatic sites which comprised the bulk of the tumor, clusters of neoplastic cells including large numbers of signet ring cells were suspended in pools of extracellular mucin (Fig. lC, D). This pattern alternated in roughly equal proportions with solid nests and cords of mucin containing neoplastic and signet ring cells, indistinguishable from the high-grade patterns observed within the prostate. More than 40 percent of the tumor was comprised of this mutinous adenocarcinoma, with signet ring cells prominent in the extraprostatic sites (Fig. 1D). Both intracellular and extracellular mucin at all sites stained strongly with PAS-diastase, and weakly with mucicarmine.
398
Thorough sampling of bladder and urethral epithelia revealed no columnar metaplasia or preneoplastic changes. Immunohistochemical stains for PSA were repeated as well as stains for carcinoembryonic antigen (CEA). Positive staining for both antigens was demonstrated (Fig. 2). PSA reactivity was strong in the well-differentiated components within the prostate, and weak to moderate in the high-grade areas. Conversely, CEA was most prevalent in the least differentiated components. Flow cytometric analysis of the prostatic portion of the tumor, bladder component, and one of the positive lymph nodes was performed. While the positive node revealed an aneuploid population with high S phase fraction of 19.9 percent, the primary tumor and involved bladder showed a diploid DNA content with lower S phase fractions of 6.3 percent and 11.9 percent, respectively. Gbanded chromosome analysis of the bladder component revealed that eleven of twenty metaphases UROLOGY
/
MARCH 1994
/ VOLUME43, NUMBER 3
FIGURE 2. (A) Neoplastic glands show strong cytoplasmic PSA staining. (B) Solid patterns of carcinoma show focal (solid arrows) or negative (open arrows) PSA reaction; a residual non-neoplastic gland is strongly positive. (C) Luminal membrane pattern of CEA expression characterizes a minority of the infiltrating glands. (D) Areas of high-grade mutinous differentiation show diffuse cytoplasmic staining for CEA. [lmmunohistochemical staining for PSA [A and B] and CEA [C and D]; original magnifications, x 100 to x 200.) -
were 46,XY and nine of twenty showed loss of the Y chromosome. No other numerical or structural abnormalities were noted. At nine months, the patient had evidence of skeletal metastases by bone scan and he died twelve months postoperatively despite hormonal therapy. Serum PSA and PAP levels remained normal postoperatively COMMENT Most reported cases of signet ring adenocarcinoma of the prostate have presented with advanced disease. Of the 13 cases previously reported, 7 of the patients have succumbed to disease within five years of diagnosis and several have died within weeks or months.3s5 The clinical presentation has been similar to that of other advanced prostate cancers although 2 patients have presented initially with supraclavicular lymphadenopathy4,5 Retrotrigonal spread masquerading as a bladder primary and the unsuspicious prostate examination are unusual features of the present case. In spite of advanced presentation, the serum acid phosphatase may be normal as seen in this case.4 In all previously reported antemortem cases treatment has consisted of observation in very advanced cases or some combination of hormonal or radiation therapy.3-8 The diagnosis of signet ring cell adenocarcinoma of the prostate may be difficult to make, UROLOGY
/
MARCH 1994
I VOLUME43, NUMBFR.1
owing to its rarity and because it is not a pathologically homogeneous entity. In the present case, more than 40 percent of the pathologic specimen was composed of nests of mucin-positive signet ring cells surrounded by large pools of extracellular mucin. In the 8 cases collected from M.D. Anderson Hospital, the signet ring cells were negative for cytoplasmic mucin and CEA, and positive for PSA. In contrast, this case and 5 others contained large intracellular mucin droplets.3-5.7,8 In the present case and in that reported by Remmele et al,,5 some signet ring cells were CEA positive and PSA negative. This phenotype is more common in primary tumors of the gastrointestinal tract. Specific measures to exclude a bowel lesion are mandatory before concluding such a tumor has originated in the prostate, which in this case consisted of a negative sigmoidoscopy and exploratory laparotomy for other sites. However, the signet ring and other neoplastic prostatic cells which stained positive for PSA, coupled with the finding of morphologic transitions between both well-differentiated prostate cancer and signet ring cancer, were helpful to establish the diagnosis and origin of the tumor. Signet ring adenocarcinomas of the bladder also occur. However, these tumors may be associated with urothelial atypia, Von Brunn’s nests, or glandular metaplasia, features not observed in this patient9
399
This case illustrates that negative PSA and PAP staining of biopsy material may not exclude the diagnosis of signet ring adenocarcinoma of the prostate and may cause confusion as to whether the tumor is of prostatic or bladder origin. Regardless of the subtype of signet ring carcinoma, identifying areas of more differentiated prostatic adenocarcinoma has been emphasized by Ro et aK4 in arriving at the correct diagnosis. On the other hand, the presence or absence of intracellular mucin does not seem to be a consistent finding for the signet ring adenocarcinomas of the prostate that are described in the literature.3-8 This patient’s tumor also showed features of mutinous carcinoma of the prostate with clusters of neoplastic and signet cells suspended in large pools of extracellular mucin. Mutinous prostate carcinoma is rare when defined as a tumor with greater than 25 percent of the total specimen showing pools of mucin, and accounts for less than 0.4 percent of prostate cancers. Approximately 62 cases exist in the worlds literature.‘,2 The vast majority of these tumors are devoid of signet ring cells and the absence of intracytoplasmic mucin helps to distinguish prostatic primary disease from other mutinous cancers in most cases.’ We could identify only 2 other well-documented cases of prostatic mutinous carcinoma that contained signet ring cells.5,6 Flow cytometry has not been previously reported for this histology, although aneuploidy has been found more commonly in poorly differentiated, more advanced prostate cancers and has been correlated with decreased survival.” An aneuploid population was observed only in the involved node and may represent a more aggressive clone of the tumor not detectable in the prostate or bladder specimens. Loss of the Y chromosome in both blood and bone marrow has been associated with advancing age.” In both bladder and prostate cancers, loss of a Y chromosome with or
400
without other changes has been reported and is believed to be clinically significant. In bladder cancer, patients with -Y have decreased survival compared with those whose tumor cells retain the Y chromosome. l1 Anthony Y. Smith, M.D. Division of Urology University of New Mexico School of Medicine Albuquerque, New Mexico 87131 REFERENCES 1. Ro JY, Grignon DJ, Ayala AG, Fernandez PL, Ordonez NG, and Wishnow Kl: Mutinous adenocarcinoma of the prostate: histochemical and immunohistochemical studies. Human Path01 21: 593-600,199O. 2. Epstein Jl, and Lieberman PH: Mutinous adenocarcinoma of the prostate gland. Am J Surg Path01 9: 299-308, 1985. 3. Giltman Ll: Signet ring adenocarcinoma of the prostate. J Ural 126: 134-135,198l. 4. Ro JY, El-Naggar A, Ayala AG, Mody DR, and Ordonez NG: Signet-ring-cell carcinoma of the prostate: electron-microscopic and immunohistochemical studies of eight cases. Am J Surg Path01 12: 453-460, 1988. 5. Remmele W, Weber A, and Harding P: Primary signetring cell carcinoma of the prostate. Human Path01 19: 478-480,1988. 6. Uyama T, and Moriwaki S: Papillary and mucus-forming adenocarcinomas of prostate. Urology 13: 432-434, 1979. 7. Uchijima Y, lto H, Takahashi M, and Yamashina M: Prostate mutinous adenocarcinoma with signet ring cell. Urology 36: 267-268, 1990. 8. Hejka AG, and England DM: Signet ring cell carcinoma of prostate. lmmunohistochemical and ultrastructural study of a case. Urology 34: 155-158, 1989. 9. Braun EV, Ah M, Fayemi AO, and Beaugard E: Primary signet-ring cell carcinoma of the urinary bladder: review of the literature and report of a case. Cancer 47: 1430-1435, 1981. 10. Fordham MV, Burdge AH, Matthews J, Williams G, and Cooke T: Prostatic carcinoma cell DNA content measured by flow cytometry and its relation to clinical outcome. Br J Surg 73: 40&403,1986. 11. Sandberg AA: The Chromosomes in Human Cancer and Leukemia, 2nd ed., New York, Elsevier Science Publishing, 1990, pp 28-29,232,591,811,823-827.
UROLOGY
I MARCH1994 I VOLUME43, NUMBER3
SIGNET
RING CELL ADENOCARCINOMA OF PROSTATE
CYNTHIA SMITH, B.S. RICHARD M. FEDDERSEN, M.D. LYNN DRESSLER, M.S.
THOMAS MCCONNELL, M.D MICHAEL MILROY, M.D. ANTHONY Y. SMITH, M.D.
From the Division of Urology, Department of Pathology, and Center for Molecular and Cellular Diagnostics, University of New Mexico School of Medicine, Albuquerque, New Mexico
ABSTRACT-Primary signet ring cell adenocarcinoma of the prostate is a rare malignancy with a total of 13 cases reported to date in the English literature. We report a very unusual case of signet ring adenocarcinoma of the prostate occurring in a patient who presented initially with irritative voiding symptoms and a bladder mass. Results of immunohistochemical, flow cytometric, and cytogenetic analyses of the tumor are presented.
Mutinous adenocarcinomas of the prostate, defined as those in which more than 25 percent of the tumor shows pools of mucin, are rare tumors.i,’ Mutinous prostate cancers only rarely contain signet ring cells. Primary signet ring adenocarcinomas of the prostate are therefore more rare, with only 13 well-documented cases reported to date.3-8 Uyama and Moriwaki6 reported the first case of signet ring adenocarcinoma of the prostate in 1979. A seventeen-year experience at the M.D. Anderson Hospital identified an additional 8 patients.4 Four additional case reports are found in the literature.3.5.7,8 We present a very unusual case of signet ring adenocarcinoma of the prostate which occurred in a patient with irritative voiding symptoms and an apparent bladder mass. Results of immunohistochemical and previously unreported flow cytometric and cytogenetic analyses are presented. CASE REPORT A sixty-two-year-old man presented with microhematuria and irritative voiding symptoms. Physical examination revealed a large prostate which was clinically benign. There was no evidence of adenopathy. A serum prostate-specific antigen (PSA) was 4.6 ng/mL (normal O-4 ng/mL) and the serum prostatic acid phosphatase (PAP) was 1.7 ng/mL (normal O-2.2 ng/mL). An intravenous Submitted: September vember 4. 199.3
UROLOGY
2, 1993,
accepted
(with
revisions):
/ MARCH1994 / VOLUME43, NUMLWR 3
No-
urogram showed mild right hydronephrosis and a filling defect in the bladder base. A cystoscopy and transurethral resection of a right lateral wall bladder mass revealed an invasive adenocarcinoma composed primarily of signet ring cells. Immunohistochemical stains of the resected specimen for PSA and PAP were negative. A metastatic workup, including abdominal computed tomography (CT) scan, chest x-ray film, and whole body bone scan, showed no evidence of metastatic disease. Since the tumor was believed to be a bladder primary, a radical cystoprostatectomy was recommended. Independently obtained second opinions from multiple urologic oncologists in other parts of the country all recommended the same. Perioperative sigmoidoscopy revealed no mucosal lesions. The patient underwent an uncomplicated radical cystoprostatectomy and ileal conduit urinary diversion. The poorly circumscribed tumor measured 5 cm in largest diameter and involved the trigone, right ureteral orifice, and superior aspect of the prostate. Light microscopy revealed an adenocarcinema. A search of the prostate revealed neoplastic glands, cords of cells, and solid cell masses which were histologically recognizable as prostatic adenocarcinoma. The most prevalent patterns were Gleason grades 5 and 3, with morphologic transitions between the two (Fig. lA, B). Half of the cells in the high-grade areas contained prominent intracytoplasmic mucin vacuoles that indented the nuclei, including occasional fully 397
FIGURE 1. [A) lntraprostatic differentiated adenocarcinoma, Gleason grade 3. (B) Transition from neoplastic glands (solid arrows) to circumscribed solid cell masses (open arrows, Gleason grade 5) with scattered cytoplasmic mucin droplets. (C] Perivesical soft tissue contains irregular cell masses suspended in pools of extracellular mucin. (D) Detail from a lymph node metastasis. Aggregates and individual signet ring cells are suspended in extracellular mucin. (Hematoxylin and eosin, original magnifications from x 150 to x 400.)
developed signet ring cells. Accumulations of extracellular mucin were small and focal within the prostate. The tumor extended directly through the bladder wall and infiltrated the bladder submucosa and perivesical fat. Several iliac lymph nodes contained metastatic deposits. At all of these extraprostatic sites which comprised the bulk of the tumor, clusters of neoplastic cells including large numbers of signet ring cells were suspended in pools of extracellular mucin (Fig. lC, D). This pattern alternated in roughly equal proportions with solid nests and cords of mucin containing neoplastic and signet ring cells, indistinguishable from the high-grade patterns observed within the prostate. More than 40 percent of the tumor was comprised of this mutinous adenocarcinoma, with signet ring cells prominent in the extraprostatic sites (Fig. 1D). Both intracellular and extracellular mucin at all sites stained strongly with PAS-diastase, and weakly with mucicarmine.
398
Thorough sampling of bladder and urethral epithelia revealed no columnar metaplasia or preneoplastic changes. Immunohistochemical stains for PSA were repeated as well as stains for carcinoembryonic antigen (CEA). Positive staining for both antigens was demonstrated (Fig. 2). PSA reactivity was strong in the well-differentiated components within the prostate, and weak to moderate in the high-grade areas. Conversely, CEA was most prevalent in the least differentiated components. Flow cytometric analysis of the prostatic portion of the tumor, bladder component, and one of the positive lymph nodes was performed. While the positive node revealed an aneuploid population with high S phase fraction of 19.9 percent, the primary tumor and involved bladder showed a diploid DNA content with lower S phase fractions of 6.3 percent and 11.9 percent, respectively. Gbanded chromosome analysis of the bladder component revealed that eleven of twenty metaphases UROLOGY
/
MARCH 1994
/ VOLUME43, NUMBER 3
FIGURE 2. (A) Neoplastic glands show strong cytoplasmic PSA staining. (B) Solid patterns of carcinoma show focal (solid arrows) or negative (open arrows) PSA reaction; a residual non-neoplastic gland is strongly positive. (C) Luminal membrane pattern of CEA expression characterizes a minority of the infiltrating glands. (D) Areas of high-grade mutinous differentiation show diffuse cytoplasmic staining for CEA. [lmmunohistochemical staining for PSA [A and B] and CEA [C and D]; original magnifications, x 100 to x 200.) -
were 46,XY and nine of twenty showed loss of the Y chromosome. No other numerical or structural abnormalities were noted. At nine months, the patient had evidence of skeletal metastases by bone scan and he died twelve months postoperatively despite hormonal therapy. Serum PSA and PAP levels remained normal postoperatively COMMENT Most reported cases of signet ring adenocarcinoma of the prostate have presented with advanced disease. Of the 13 cases previously reported, 7 of the patients have succumbed to disease within five years of diagnosis and several have died within weeks or months.3s5 The clinical presentation has been similar to that of other advanced prostate cancers although 2 patients have presented initially with supraclavicular lymphadenopathy4,5 Retrotrigonal spread masquerading as a bladder primary and the unsuspicious prostate examination are unusual features of the present case. In spite of advanced presentation, the serum acid phosphatase may be normal as seen in this case.4 In all previously reported antemortem cases treatment has consisted of observation in very advanced cases or some combination of hormonal or radiation therapy.3-8 The diagnosis of signet ring cell adenocarcinoma of the prostate may be difficult to make, UROLOGY
/
MARCH 1994
I VOLUME43, NUMBFR.1
owing to its rarity and because it is not a pathologically homogeneous entity. In the present case, more than 40 percent of the pathologic specimen was composed of nests of mucin-positive signet ring cells surrounded by large pools of extracellular mucin. In the 8 cases collected from M.D. Anderson Hospital, the signet ring cells were negative for cytoplasmic mucin and CEA, and positive for PSA. In contrast, this case and 5 others contained large intracellular mucin droplets.3-5.7,8 In the present case and in that reported by Remmele et al,,5 some signet ring cells were CEA positive and PSA negative. This phenotype is more common in primary tumors of the gastrointestinal tract. Specific measures to exclude a bowel lesion are mandatory before concluding such a tumor has originated in the prostate, which in this case consisted of a negative sigmoidoscopy and exploratory laparotomy for other sites. However, the signet ring and other neoplastic prostatic cells which stained positive for PSA, coupled with the finding of morphologic transitions between both well-differentiated prostate cancer and signet ring cancer, were helpful to establish the diagnosis and origin of the tumor. Signet ring adenocarcinomas of the bladder also occur. However, these tumors may be associated with urothelial atypia, Von Brunn’s nests, or glandular metaplasia, features not observed in this patient9
399
This case illustrates that negative PSA and PAP staining of biopsy material may not exclude the diagnosis of signet ring adenocarcinoma of the prostate and may cause confusion as to whether the tumor is of prostatic or bladder origin. Regardless of the subtype of signet ring carcinoma, identifying areas of more differentiated prostatic adenocarcinoma has been emphasized by Ro et aK4 in arriving at the correct diagnosis. On the other hand, the presence or absence of intracellular mucin does not seem to be a consistent finding for the signet ring adenocarcinomas of the prostate that are described in the literature.3-8 This patient’s tumor also showed features of mutinous carcinoma of the prostate with clusters of neoplastic and signet cells suspended in large pools of extracellular mucin. Mutinous prostate carcinoma is rare when defined as a tumor with greater than 25 percent of the total specimen showing pools of mucin, and accounts for less than 0.4 percent of prostate cancers. Approximately 62 cases exist in the worlds literature.‘,2 The vast majority of these tumors are devoid of signet ring cells and the absence of intracytoplasmic mucin helps to distinguish prostatic primary disease from other mutinous cancers in most cases.’ We could identify only 2 other well-documented cases of prostatic mutinous carcinoma that contained signet ring cells.5,6 Flow cytometry has not been previously reported for this histology, although aneuploidy has been found more commonly in poorly differentiated, more advanced prostate cancers and has been correlated with decreased survival.” An aneuploid population was observed only in the involved node and may represent a more aggressive clone of the tumor not detectable in the prostate or bladder specimens. Loss of the Y chromosome in both blood and bone marrow has been associated with advancing age.” In both bladder and prostate cancers, loss of a Y chromosome with or
400
without other changes has been reported and is believed to be clinically significant. In bladder cancer, patients with -Y have decreased survival compared with those whose tumor cells retain the Y chromosome. l1 Anthony Y. Smith, M.D. Division of Urology University of New Mexico School of Medicine Albuquerque, New Mexico 87131 REFERENCES 1. Ro JY, Grignon DJ, Ayala AG, Fernandez PL, Ordonez NG, and Wishnow Kl: Mutinous adenocarcinoma of the prostate: histochemical and immunohistochemical studies. Human Path01 21: 593-600,199O. 2. Epstein Jl, and Lieberman PH: Mutinous adenocarcinoma of the prostate gland. Am J Surg Path01 9: 299-308, 1985. 3. Giltman Ll: Signet ring adenocarcinoma of the prostate. J Ural 126: 134-135,198l. 4. Ro JY, El-Naggar A, Ayala AG, Mody DR, and Ordonez NG: Signet-ring-cell carcinoma of the prostate: electron-microscopic and immunohistochemical studies of eight cases. Am J Surg Path01 12: 453-460, 1988. 5. Remmele W, Weber A, and Harding P: Primary signetring cell carcinoma of the prostate. Human Path01 19: 478-480,1988. 6. Uyama T, and Moriwaki S: Papillary and mucus-forming adenocarcinomas of prostate. Urology 13: 432-434, 1979. 7. Uchijima Y, lto H, Takahashi M, and Yamashina M: Prostate mutinous adenocarcinoma with signet ring cell. Urology 36: 267-268, 1990. 8. Hejka AG, and England DM: Signet ring cell carcinoma of prostate. lmmunohistochemical and ultrastructural study of a case. Urology 34: 155-158, 1989. 9. Braun EV, Ah M, Fayemi AO, and Beaugard E: Primary signet-ring cell carcinoma of the urinary bladder: review of the literature and report of a case. Cancer 47: 1430-1435, 1981. 10. Fordham MV, Burdge AH, Matthews J, Williams G, and Cooke T: Prostatic carcinoma cell DNA content measured by flow cytometry and its relation to clinical outcome. Br J Surg 73: 40&403,1986. 11. Sandberg AA: The Chromosomes in Human Cancer and Leukemia, 2nd ed., New York, Elsevier Science Publishing, 1990, pp 28-29,232,591,811,823-827.
UROLOGY
I MARCH1994 I VOLUME43, NUMBER3