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Primary and secondary prostatic adenocarcinoma of the urinary bladder
Primary and Secondary Prostatic Adenocarcinoma of the Urinary Bladder KIEN T. MAI, MD, FRCPC, JASON C. FORD, MD, CHRISTOPHER MORASH, MD, FRCSC, AND RONALD GERRIDZEN, MD, FRCSC Urinary bladder involvement by prostatic adenocarcinoma (PAC) is not well characterized in the literature. Fifteen consecutive cases of PAC diagnosed in the urinary bladder over a period of 10 years were reviewed. All bladder and prostate slides from each patient were evaluated. Eleven patients (group A) had synchronous PAC in the prostate. In these patients, bladder PAC occurred 2 to 11 years after the initial diagnosis of PAC in the prostate and tended to have a higher Gleason score than the original prostatic PAC. Four cases of bladder PAC in group A had areas with features of urothelial carcinoma, with focal positive immunoreactivity for thrombomodulin in 2 cases. Two patients (group B) had undergone radical prostatectomy for PAC 15 years earlier. The lesions in the urinary bladder in both cases showed histopathologic features similar to those seen in the previous prostatic malignancies. Two patients (group C) had histories of previously resected urothelial carcinoma. Bladder PAC was diag-
nosed at routine follow-up, and repeated prostate biopsy up to 2 years after the diagnosis of bladder PAC showed no evidence of prostatic PAC. PAC in the urinary bladder may be either primary or secondary. Secondary PAC is usually associated with high-grade and high-stage carcinoma in the prostate and may mimic transitional cell carcinoma. Primary bladder lesions may or may not be associated with a history of PAC in the prostate. The prognosis of patients with the primary carcinoma is favorable. HUM PATHOL 32:434-440. Copyright © 2001 by W.B. Saunders Company Key words: prostatic adenocarcinoma, urinary bladder, prostatespecific antigen. Abbreviations: PAC, prostatic adenocarcinoma; TURP, transurethral resection of the prostate; PAP, prostatic acid phosphatase; PSA, prostate-specific antigen; CK, cytokeratin; CEA, carcinoembryonic antigen; UC, urothelial carcinoma.
Prostatic adenocarcinoma (PAC) is usually a multifocal disease occurring in the prostate.1,2 In the course of evolution of this tumor, the carcinoma may spread to various structures, including the perineural space, prostatic capsule, periprostatic tissue, and seminal vesicles. It may also metastasize to regional lymph nodes and other distant sites. Involvement of the urinary bladder by PAC occasionally occurs.3 However, it is understood that bladder mucosa may display focal prostate-like metaplasia.4-8 Cases of prostatic polyp5,9 and PAC10 arising primarily in the urinary bladder mucosa have been reported. In this study, we report cases of PAC diagnosed in the urinary bladder in patients with and without associated PAC in the prostate.
(TURP) tissue, and radical prostatectomy from these patients were also obtained for review. All bladder specimens were obtained by transurethral resection. All TURP and radical prostatectomy specimens were submitted in toto. Grading of PAC in the prostate and the urinary bladder was performed in accordance with the Gleason scoring system. The size of the tumor in the TURP specimens was roughly determined by the proportion of “chips” involved. For the radical prostatectomy specimens, the volume of the carcinoma was calculated by the combined total involved surface areas multiplied by the thickness of the section (0.3 cm) and the coefficient of retraction in formalin (1.5).11 PAC was staged according to the definitions from the Joint Committee on Cancer.12 Immunostaining was performed using the peroxidase–antiperoxidase technique as well as antigen retrieval (microwave treatment at high energy in pH 5.6 citrate buffer). Antisera used were as follows: prostatic acid phosphatase (PAP; Dako, Denmark; monoclonal, dilution 1:400), prostate-specific antigen (PSA; Dako, monoclonal, dilution 1:400), cytokeratin (CK) 7 (Dako; dilution 1:200), cytokeratin 20 (Dako; dilution 1:200), carcinoembryonic antigen (CEA; Dako; polyclonal, dilution 1:2,000), and thrombomodulin (Dako; dilution 1:50).
MATERIALS AND METHODS Fifteen consecutive cases of PAC diagnosed in the urinary bladder (including the bladder neck) were retrieved from the surgical pathology files of the Ottawa Hospital— Civic Campus covering a period of 10 years. Specimens labeled “urinary bladder” or “bladder neck” but containing prostate tissue as evidenced by prostatic epithelium or corpora amylacea were excluded from the study. Slides of previous prostate needle biopsy, transurethral resection of prostate From the Division of Anatomical Pathology, Department of Laboratory Medicine, and Division of Urology, Department of Surgery, The Ottawa Hospital—Civic Campus; and Department of Pathology and Laboratory Medicine, University of Ottawa, Ottawa, Ontario, Canada. Accepted for publication January 17, 2001. Address correspondence and reprint requests to Kien T. Mai, MD, FRCPC, Anatomical Pathology, The Ottawa Hospital—Civic Campus, 1053 Carling Ave, Ottawa, Ontario, Canada, K1Y 4E9. Copyright © 2001 by W.B. Saunders Company 0046-8177/01/3204-0011$35.00/0 doi:10.1053/hupa.2001.23518
RESULTS Tables 1 and 2 summarize the clinical and pathologic data as well as the immunohistochemical results of the 15 cases in the study. These cases were divided into 3 groups on the basis of clinical history. Group A These 11 patients had PAC in the prostate treated with radical prostatectomy (1 patient) and with TURP (10 patients), with or without hormone therapy including antiandrogen therapy and orchidectomy. Four cases (cases 6, 7, 10, and 11 from Tables 1 and 2) were
434
PROSTATIC ADENOCARCINOMA OF THE URINARY BLADDER (Mai et al)
TABLE 1. Clinical and Pathologic Features of the Cases in the Study PAC in the Prostate
Case Group A 1 (Fig 1) 2 3 4 5 6 7 8 9 10 11 Group B 12 (Fig 2) 13 Group C 14 (Fig 3) 15
Age (yr)
Gleason/Size
g g g g g g g g g g
PAC in the Urinary Bladder
Stage
Treatment
Interval After Diagnosis (yr)
Gleason/Size
Outcome
T4 T4 T3 T3 T3 T1b* T4* T1b T3 T1b* T2*
TURP/Ra TURP/O TURP/P TURP/O TURP/O TURP/Ra O/Ra TURP O/TURP TURP/Ra P
3 2 11 2 9 7 4 2 2 2 10
10/90% of 4 g 9/90% of 8 g 8/70% of 10 g 9/90% of 8 g 7/50% of 4 g 8/90% of 16 g 9/50% of 8 g 8/90% of 4 g 10/90% of 8 g 9/30% of 5 g 9/90% of 10 g
DOD, 1 yr DOD, 1.5 yr N, Li B, 2 yr DOD, 1 yr DOD, 4 yr DOD, 2.5 yr D MI, 5 yr DOD, 3 yr D CVA, 1 yr DOD, 7 yr B, Li, 5 yr
15 15
6/50% of 4 g 7/50% of 2 g
Alive, 4 yr Alive, 3 yr
0 0
6/⬍2 g tissue 7/⬍2 g tissue
Alive, 3 yr Alive, 5 yr
85 67 50 60 74 75 85 60 72 66 70
8/80% of 16 7/50% of 20 7/70% of 15 9/80% of 10 8/80% of 30 7/50% of 10 6/30% of 10 7/80% of 20 9/80% of 20 6/30% of 15 7/4.5 cm3
52 69
7/NA 7/3 cm3
T2 T2
P P
71 68
NA NA
NA NA
NA NA
Abbreviations: Ra, radiotherapy; O, orchidectomy; P, radical prostatectomy; DOD, dead of disease; D MI, dead of myocardial infarct; D CVA, dead of cerebrovascular accident; N, B, Li, metastases in node, bone, liver, respectively; NA, not available. * Patient had needle biopsy.
initially diagnosed by needle biopsies of the prostate. The remaining cases were initially diagnosed by TURP. At the time of initial diagnosis, most of the prostatic PACs had a Gleason score greater than 6 out of 10 and involved extraprostatic tissue. At the time of diagnosis of PAC in the urinary bladder, 10 of the 11 cases of bladder PAC had Gleason scores greater than 7. Four of the cases had areas with some features of transitional cell carcinoma (urothelial carcinoma; UC), including abundant and thick cytoplasm and rare glandular lumens. However, the bladder PAC usually formed con-
fluent masses of invasive cells with mild to moderate anisonucleosis and nuclear pleomorphism, as well as prominent single nucleoli. Furthermore, these lesions were not associated with overlying UC in situ and were immunoreactive for PAP and PSA (Fig 1A, B, C). Group B Group B included 2 cases, each with a history of prostatic PAC treated with radical prostatectomy 15 years before the diagnosis of PAC in the urinary blad-
TABLE 2. Immunohistochemical Features of the Cases in the Study PAC in the Prostate* Case Group A 1 (Fig 1) 2 3 4 5 6 7 8 9 10 11 Group B 12 (Fig 2) 13 Group C 14 (Fig 3) 15
PAC in the Urinary Bladder*
PSA/PAP
CK7
CK20
CEA
TM
PSA/PAP
CK7
CK20
CEA
TM
3 3 3 3 3 3 3 3 3 3 3
2 0 0 0 0 0 2 0 0 0 0
0 1 0 0 1 0 0 1 0 0 0
0 0 0 0 0 0 0 0 0 0 0
0 0 0 0 0 0 0 0 0 0 0
2 3 3 3 2 3 3 3 2 3 3
1 0 0 1 0 0 2 0 0 0 0
0 1 0 0 2 0 0 1 0 0 0
0 0 0 0 0 0 0 0 0 0 0
2 1 0 0 0 2 1 0 0 0 0
3 3
0 0
0 0
0 0
0 0
3 3
0 0
0 0
0 0
0 0
NA NA
NA NA
NA NA
NA NA
NA NA
3 3
2 0
0 0
0 0
0 0
Abbreviations: TM, thrombomodulin; NA, not available. * 3, Strong and extensive immunoreactivity; 2, moderate and focal reactivity; 1, very weak and/or focal reactivity.
435
FIGURE 1. A high-grade prostatic PAC arising secondarily in the urinary bladder. (A) Low-magnification photomicrograph, showing the carcinoma consisting of solid nests and trabeculae of cells mimicking transitional cell carcinoma in the stroma as well as on the mucosal surface. (B) Immunostaining for PSA showing positive reactivity. (C) Immunostaining for thrombomodulin showing focal moderate positive reactivity.
FIGURE 2. PAC with ductal features. (A) Low magnification of the PAC involving the urinary bladder. Note the cribriform pattern and the overlying atrophic urothelium. (B) Immunostaining for PSA showing positive reactivity. (C) Low magnification of the PAC with ductal features in the prostate of the same patient, treated with radical prostatectomy 15 years earlier. Note the similar appearance of the carcinomas in both locations.
FIGURE 3. PAC in the urinary bladder in a patient without a history of malignancy in the prostate. This may represent a primary lesion arising within the bladder (see discussion). (A, B) Low and medium magnifications. (C) Immunostaining for PSA showing positive reactivity.
PROSTATIC ADENOCARCINOMA OF THE URINARY BLADDER (Mai et al)
der. There was no evidence of metastatic or recurrent disease apart from the PAC in the urinary bladder. The lesions in the urinary bladder in both cases showed histopathologic features similar to those seen in the respective prostates. These 2 cases had more favorable outcomes than most cases in group A (Fig 2A, B, C; Table 1). Group C Group C included 2 cases with no history of PAC in the prostate. Both cases occurred in patients with a history of resected UC, followed by repeat cystoscopy and biopsy (Fig 3A, B, C; Table 1). The bladder PAC occurred at 3 and 5 years, respectively, of postresection follow-up. Repeat needle biopsy of the prostate 1 and 2 years after the diagnosis of PAC in the urinary bladder showed no evidence of PAC in the prostate. The outcomes in these 2 cases, similar to those from group B, were more favorable than those from group A. Immunostaining for PAP and PSA showed moderate to strong positive reactivity in the urinary bladder lesions (Figs 1B, 2B, 3C). In the cases of PAC in the urinary bladder with focal light microscopic features of UC, immunostaining for thrombomodulin showed focal weak to moderate immunoreactivity in 3 cases (Fig 1C). Immunoreactivity results for CK7 and CK20 and CEA are shown in Table 2. DISCUSSION In this study, most cases of PAC involving the urinary bladder represented lesions developing after the progression of high-grade and high-stage PAC originating in the prostate. Because all cases in group A were associated with extensive prostatic PAC, it is likely that these carcinomas in the urinary bladder developed as a result of contiguous extension of PAC from the prostate into the bladder neck and trigone.3 All patients in this group developed distant metastases, and at least 7 of the 11 died of the disease. As a result of transformation to higher-grade carcinoma, a number of cases of PAC in the bladder may mimic UC, even to the extent of showing immunohistochemical properties of UC such as positive reactivity for thrombomodulin that has been documented as a marker for UC.13-15 These PACs with some UC features could be differentiated from “true” UC by (1) the absence of transitional cell carcinoma in situ within the overlying surface urothelium, which is usually associated with invasive UC; (2) the presence of single or small nests of infiltrating UC in the context of a predominant pattern of large masses of identifiable PAC tumor cells; (3) the frequent marked cytologic atypia and anisocytosis of neoplastic cells within the areas resembling UC; (4) the presence of multiple nucleoli in “true” UC, in contrast to the single large nucleolus in PAC; and (5) the positive immunoreactivity for PSA and PAP, the negative or focal reactivity for thrombomodulin, and the negative reactivity for CEA within those areas resembling UC.
True UC of the urinary bladder may show focal positive reactivity for PAP but not for PSA,16 only rarely shows negative reactivity for thrombomodulin,17-19 and frequently shows positive reactivity for CEA.19 The results of immunostaining for CK7 and 20 in this series were similar to the findings in previous studies.20,21 These immunostains were not contributory to the differential diagnosis between carcinoma from prostate versus urinary bladder. For the group C lesions, because of the absence of PAC in the prostate and the favorable clinical course after resection of the urinary bladder lesion, it is likely that the bladder PAC represents a primary PAC arising within the urinary bladder. It is not clear whether group B lesions represent secondary or new primary tumors. In the group B cases, the long period free of disease after the treatment of PAC in the prostate and the favorable clinical outcomes argue in favor of these lesions representing new primary PAC. So too does the fact that the bladder PAC had a similar grade to the prostate PAC in group B, rather than the generally increased grade in group A that would be expected with simple tumor progression from a prostatic primary tumor. Buchholz et al22 reported a case of PAC occurring in the urinary bladder neck after radical prostatectomy. They considered the lesion a late recurrence of the PAC in the prostate. However, the interval after prostatectomy was only 14 months in their example, compared with 2 to 11 years in the 11 cases in group A of this study. The urinary bladder has the potential to transform into benign prostatic epithelium, showing positive reactivity for PSA and PAP. Therefore, this prostatic tissue in the urinary bladder may be the site of development of PAC. Such a lesion has been reported in patients with and without previous TURP.4,10 The potential of malignant transformation of the bladder mucosa associated with positive reactivity for PSA and PAP could be enhanced in patients who had PAC because of inherent predisposing factors. In conclusion, secondary PACs are occasionally diagnosed in the urinary bladder and usually associated with high-grade and high-stage carcinoma in the prostate. Primary PAC in the urinary bladder may occur de novo in patients with a history of intravesical instrumentation or present as a urinary bladder lesion without accompanying PAC in the prostate in patients with a history of PAC in the prostate. They are of lower grade and are more localized than the secondary PAC. REFERENCES 1. Bostwick DG, Shan A, Qian J, et al: Independent origin of multiple foci of prostatic intraepithelial neoplasia: Comparison with matched foci of prostate carcinoma. Cancer 83:1995-2002, 1998 2. Haggman M, Nordin B, Mattson S, et al: Morphometric studies of intra-prostatic volume relationships in localized prostatic cancer. Br J Urol 80:612-617, 1997 3. Conolly JA, Shinohara K, Presti JC Jr, et al: Local recurrence after radical prostatectomy: Characteristics in size, location, and relationship to prostatic-specific antigen and surgical margins. Urology 47:225-231, 1996
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4. Delladetsima J, Theodorou C, Dapolla Y, et al: Prostatic-type epithelium in urinary bladder. Clinical, histologic, and immunohistochemical study. Urology 36:445-448, 1990 5. Ishikawa J, Yasuno H, Higuchi A, et al: Benign polyp with prostatic-type epithelium of the urinary bladder. A case report. Hinyokika Kiyo 36:1463-1465, 1990 6. Nowels K, Kent E, Rinsho K, et al: Prostate specific antigen and acid phosphatase-reactive cells in cystitis cystica and glandularis. Arch Pathol Lab Med 112:734-737, 1988 7. Remick DG Jr, Kumar NB: Benign polyps with prostatic-type epithelium of the urethra and the urinary bladder. A suggestion of histogenesis based on histologic and immunohistochemical studies. Am J Surg Pathol 8:833-839, 1984 8. Yajima I, Yamaguchi K, Akimoto M: Ectopic prostatic tissue in the bladder. Hinyikika Kiyo 39:761-764, 1993 9. Chow TC, Tsui MS: Prostatic-type polyps of the lower urinary tract: three histogenetic types? Histopathology 11:789-801, 1987 10. Hoang C, Wassef M, Cortesse A, et al: [Papillary “endometrial” adenocarcinoma of the bladder neck. Light and electron microscopy and immunohistochemistry]. Adenocarcinome papillaire “endometrioide” du col vesical. Microscopie optique et electronique et immunohistochimie. Ann Pathol 5:125-129, 1985 11. Schmid HP, McNeal JE: An abbreviated standard procedure for accurate tumor volume estimation in prostate cancer. Am J Surg Pathol 16:184-191, 1992 12. Beahrs OH, Henson DG, Hutter RVP, et al (eds): Manual for Staging of Cancer (ed 4). Philadelphia, PA, Lippincott, 1992, pp 181-186 13. Ogawa H, Yonezawa S, Maruyama I, et al: Expression of
thrombomodulin in squamous cell carcinoma of the lung: Relationship to lymph node metastasis and prognosis of the patients. Cancer Lett 149:95-103, 2000 14. Ordonez NG: Thrombomodulin expression in transitional cell carcinoma. Am J Clin Pathol 110:385-390, 1998 15. Tabata M, Sugihara K, Yonezawa S, et al: An immunohistochemical study of thrombomodulin in oral squamous cell carcinoma and its association with invasive and metastatic potential. J Oral Pathol Med 26:258-264, 1997 16. Epstein JI, Kuhajda FP, Lieberman PH: Prostatic specific acid phosphatase immunoreactivity in adenocarcinoma. HUM PATHOL 17:939-942, 1986 17. Ordonez NG: Thrombomodulin expression in transitional cell carcinoma. Am J Clin Pathol 110:385-390, 1998 18. Ordonez NG: Value of thrombomodulin immunostaining in the diagnosis of transitional cell carcinoma: A comparative study with carcinoembryonic antigen. Histopathology 31:517-524, 1997 19. Oxley J, Abbott C: Thrombomodulin immunostaining and ductal carcinoma of the prostate. Histopathology 33:391-392, 1998 20. Bassily NH, Vallorosi CJ, Akdas G, et al: Coordinate expression of cytokeratins 7 and 20 in prostate adenocarcinoma and bladder urothelial carcinoma. Am J Clin Pathol 113:383-388, 2000 21. Torenbeek R, Lagendijk JH, Van Diest PJ, et al: Value of a panel of antibodies to identify the primary origin of adenocarcinomas presenting as bladder carcinoma. Histopathology 32:20-27, 1998 22. Buchholz NP, Moch H, Mihatsch MJ: Late urinary bladder metastases after radical resection of prostatic carcinoma. Urol Int 53:50-52, 1994
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nosed at routine follow-up, and repeated prostate biopsy up to 2 years after the diagnosis of bladder PAC showed no evidence of prostatic PAC. PAC in the urinary bladder may be either primary or secondary. Secondary PAC is usually associated with high-grade and high-stage carcinoma in the prostate and may mimic transitional cell carcinoma. Primary bladder lesions may or may not be associated with a history of PAC in the prostate. The prognosis of patients with the primary carcinoma is favorable. HUM PATHOL 32:434-440. Copyright © 2001 by W.B. Saunders Company Key words: prostatic adenocarcinoma, urinary bladder, prostatespecific antigen. Abbreviations: PAC, prostatic adenocarcinoma; TURP, transurethral resection of the prostate; PAP, prostatic acid phosphatase; PSA, prostate-specific antigen; CK, cytokeratin; CEA, carcinoembryonic antigen; UC, urothelial carcinoma.
Prostatic adenocarcinoma (PAC) is usually a multifocal disease occurring in the prostate.1,2 In the course of evolution of this tumor, the carcinoma may spread to various structures, including the perineural space, prostatic capsule, periprostatic tissue, and seminal vesicles. It may also metastasize to regional lymph nodes and other distant sites. Involvement of the urinary bladder by PAC occasionally occurs.3 However, it is understood that bladder mucosa may display focal prostate-like metaplasia.4-8 Cases of prostatic polyp5,9 and PAC10 arising primarily in the urinary bladder mucosa have been reported. In this study, we report cases of PAC diagnosed in the urinary bladder in patients with and without associated PAC in the prostate.
(TURP) tissue, and radical prostatectomy from these patients were also obtained for review. All bladder specimens were obtained by transurethral resection. All TURP and radical prostatectomy specimens were submitted in toto. Grading of PAC in the prostate and the urinary bladder was performed in accordance with the Gleason scoring system. The size of the tumor in the TURP specimens was roughly determined by the proportion of “chips” involved. For the radical prostatectomy specimens, the volume of the carcinoma was calculated by the combined total involved surface areas multiplied by the thickness of the section (0.3 cm) and the coefficient of retraction in formalin (1.5).11 PAC was staged according to the definitions from the Joint Committee on Cancer.12 Immunostaining was performed using the peroxidase–antiperoxidase technique as well as antigen retrieval (microwave treatment at high energy in pH 5.6 citrate buffer). Antisera used were as follows: prostatic acid phosphatase (PAP; Dako, Denmark; monoclonal, dilution 1:400), prostate-specific antigen (PSA; Dako, monoclonal, dilution 1:400), cytokeratin (CK) 7 (Dako; dilution 1:200), cytokeratin 20 (Dako; dilution 1:200), carcinoembryonic antigen (CEA; Dako; polyclonal, dilution 1:2,000), and thrombomodulin (Dako; dilution 1:50).
MATERIALS AND METHODS Fifteen consecutive cases of PAC diagnosed in the urinary bladder (including the bladder neck) were retrieved from the surgical pathology files of the Ottawa Hospital— Civic Campus covering a period of 10 years. Specimens labeled “urinary bladder” or “bladder neck” but containing prostate tissue as evidenced by prostatic epithelium or corpora amylacea were excluded from the study. Slides of previous prostate needle biopsy, transurethral resection of prostate From the Division of Anatomical Pathology, Department of Laboratory Medicine, and Division of Urology, Department of Surgery, The Ottawa Hospital—Civic Campus; and Department of Pathology and Laboratory Medicine, University of Ottawa, Ottawa, Ontario, Canada. Accepted for publication January 17, 2001. Address correspondence and reprint requests to Kien T. Mai, MD, FRCPC, Anatomical Pathology, The Ottawa Hospital—Civic Campus, 1053 Carling Ave, Ottawa, Ontario, Canada, K1Y 4E9. Copyright © 2001 by W.B. Saunders Company 0046-8177/01/3204-0011$35.00/0 doi:10.1053/hupa.2001.23518
RESULTS Tables 1 and 2 summarize the clinical and pathologic data as well as the immunohistochemical results of the 15 cases in the study. These cases were divided into 3 groups on the basis of clinical history. Group A These 11 patients had PAC in the prostate treated with radical prostatectomy (1 patient) and with TURP (10 patients), with or without hormone therapy including antiandrogen therapy and orchidectomy. Four cases (cases 6, 7, 10, and 11 from Tables 1 and 2) were
434
PROSTATIC ADENOCARCINOMA OF THE URINARY BLADDER (Mai et al)
TABLE 1. Clinical and Pathologic Features of the Cases in the Study PAC in the Prostate
Case Group A 1 (Fig 1) 2 3 4 5 6 7 8 9 10 11 Group B 12 (Fig 2) 13 Group C 14 (Fig 3) 15
Age (yr)
Gleason/Size
g g g g g g g g g g
PAC in the Urinary Bladder
Stage
Treatment
Interval After Diagnosis (yr)
Gleason/Size
Outcome
T4 T4 T3 T3 T3 T1b* T4* T1b T3 T1b* T2*
TURP/Ra TURP/O TURP/P TURP/O TURP/O TURP/Ra O/Ra TURP O/TURP TURP/Ra P
3 2 11 2 9 7 4 2 2 2 10
10/90% of 4 g 9/90% of 8 g 8/70% of 10 g 9/90% of 8 g 7/50% of 4 g 8/90% of 16 g 9/50% of 8 g 8/90% of 4 g 10/90% of 8 g 9/30% of 5 g 9/90% of 10 g
DOD, 1 yr DOD, 1.5 yr N, Li B, 2 yr DOD, 1 yr DOD, 4 yr DOD, 2.5 yr D MI, 5 yr DOD, 3 yr D CVA, 1 yr DOD, 7 yr B, Li, 5 yr
15 15
6/50% of 4 g 7/50% of 2 g
Alive, 4 yr Alive, 3 yr
0 0
6/⬍2 g tissue 7/⬍2 g tissue
Alive, 3 yr Alive, 5 yr
85 67 50 60 74 75 85 60 72 66 70
8/80% of 16 7/50% of 20 7/70% of 15 9/80% of 10 8/80% of 30 7/50% of 10 6/30% of 10 7/80% of 20 9/80% of 20 6/30% of 15 7/4.5 cm3
52 69
7/NA 7/3 cm3
T2 T2
P P
71 68
NA NA
NA NA
NA NA
Abbreviations: Ra, radiotherapy; O, orchidectomy; P, radical prostatectomy; DOD, dead of disease; D MI, dead of myocardial infarct; D CVA, dead of cerebrovascular accident; N, B, Li, metastases in node, bone, liver, respectively; NA, not available. * Patient had needle biopsy.
initially diagnosed by needle biopsies of the prostate. The remaining cases were initially diagnosed by TURP. At the time of initial diagnosis, most of the prostatic PACs had a Gleason score greater than 6 out of 10 and involved extraprostatic tissue. At the time of diagnosis of PAC in the urinary bladder, 10 of the 11 cases of bladder PAC had Gleason scores greater than 7. Four of the cases had areas with some features of transitional cell carcinoma (urothelial carcinoma; UC), including abundant and thick cytoplasm and rare glandular lumens. However, the bladder PAC usually formed con-
fluent masses of invasive cells with mild to moderate anisonucleosis and nuclear pleomorphism, as well as prominent single nucleoli. Furthermore, these lesions were not associated with overlying UC in situ and were immunoreactive for PAP and PSA (Fig 1A, B, C). Group B Group B included 2 cases, each with a history of prostatic PAC treated with radical prostatectomy 15 years before the diagnosis of PAC in the urinary blad-
TABLE 2. Immunohistochemical Features of the Cases in the Study PAC in the Prostate* Case Group A 1 (Fig 1) 2 3 4 5 6 7 8 9 10 11 Group B 12 (Fig 2) 13 Group C 14 (Fig 3) 15
PAC in the Urinary Bladder*
PSA/PAP
CK7
CK20
CEA
TM
PSA/PAP
CK7
CK20
CEA
TM
3 3 3 3 3 3 3 3 3 3 3
2 0 0 0 0 0 2 0 0 0 0
0 1 0 0 1 0 0 1 0 0 0
0 0 0 0 0 0 0 0 0 0 0
0 0 0 0 0 0 0 0 0 0 0
2 3 3 3 2 3 3 3 2 3 3
1 0 0 1 0 0 2 0 0 0 0
0 1 0 0 2 0 0 1 0 0 0
0 0 0 0 0 0 0 0 0 0 0
2 1 0 0 0 2 1 0 0 0 0
3 3
0 0
0 0
0 0
0 0
3 3
0 0
0 0
0 0
0 0
NA NA
NA NA
NA NA
NA NA
NA NA
3 3
2 0
0 0
0 0
0 0
Abbreviations: TM, thrombomodulin; NA, not available. * 3, Strong and extensive immunoreactivity; 2, moderate and focal reactivity; 1, very weak and/or focal reactivity.
435
FIGURE 1. A high-grade prostatic PAC arising secondarily in the urinary bladder. (A) Low-magnification photomicrograph, showing the carcinoma consisting of solid nests and trabeculae of cells mimicking transitional cell carcinoma in the stroma as well as on the mucosal surface. (B) Immunostaining for PSA showing positive reactivity. (C) Immunostaining for thrombomodulin showing focal moderate positive reactivity.
FIGURE 2. PAC with ductal features. (A) Low magnification of the PAC involving the urinary bladder. Note the cribriform pattern and the overlying atrophic urothelium. (B) Immunostaining for PSA showing positive reactivity. (C) Low magnification of the PAC with ductal features in the prostate of the same patient, treated with radical prostatectomy 15 years earlier. Note the similar appearance of the carcinomas in both locations.
FIGURE 3. PAC in the urinary bladder in a patient without a history of malignancy in the prostate. This may represent a primary lesion arising within the bladder (see discussion). (A, B) Low and medium magnifications. (C) Immunostaining for PSA showing positive reactivity.
PROSTATIC ADENOCARCINOMA OF THE URINARY BLADDER (Mai et al)
der. There was no evidence of metastatic or recurrent disease apart from the PAC in the urinary bladder. The lesions in the urinary bladder in both cases showed histopathologic features similar to those seen in the respective prostates. These 2 cases had more favorable outcomes than most cases in group A (Fig 2A, B, C; Table 1). Group C Group C included 2 cases with no history of PAC in the prostate. Both cases occurred in patients with a history of resected UC, followed by repeat cystoscopy and biopsy (Fig 3A, B, C; Table 1). The bladder PAC occurred at 3 and 5 years, respectively, of postresection follow-up. Repeat needle biopsy of the prostate 1 and 2 years after the diagnosis of PAC in the urinary bladder showed no evidence of PAC in the prostate. The outcomes in these 2 cases, similar to those from group B, were more favorable than those from group A. Immunostaining for PAP and PSA showed moderate to strong positive reactivity in the urinary bladder lesions (Figs 1B, 2B, 3C). In the cases of PAC in the urinary bladder with focal light microscopic features of UC, immunostaining for thrombomodulin showed focal weak to moderate immunoreactivity in 3 cases (Fig 1C). Immunoreactivity results for CK7 and CK20 and CEA are shown in Table 2. DISCUSSION In this study, most cases of PAC involving the urinary bladder represented lesions developing after the progression of high-grade and high-stage PAC originating in the prostate. Because all cases in group A were associated with extensive prostatic PAC, it is likely that these carcinomas in the urinary bladder developed as a result of contiguous extension of PAC from the prostate into the bladder neck and trigone.3 All patients in this group developed distant metastases, and at least 7 of the 11 died of the disease. As a result of transformation to higher-grade carcinoma, a number of cases of PAC in the bladder may mimic UC, even to the extent of showing immunohistochemical properties of UC such as positive reactivity for thrombomodulin that has been documented as a marker for UC.13-15 These PACs with some UC features could be differentiated from “true” UC by (1) the absence of transitional cell carcinoma in situ within the overlying surface urothelium, which is usually associated with invasive UC; (2) the presence of single or small nests of infiltrating UC in the context of a predominant pattern of large masses of identifiable PAC tumor cells; (3) the frequent marked cytologic atypia and anisocytosis of neoplastic cells within the areas resembling UC; (4) the presence of multiple nucleoli in “true” UC, in contrast to the single large nucleolus in PAC; and (5) the positive immunoreactivity for PSA and PAP, the negative or focal reactivity for thrombomodulin, and the negative reactivity for CEA within those areas resembling UC.
True UC of the urinary bladder may show focal positive reactivity for PAP but not for PSA,16 only rarely shows negative reactivity for thrombomodulin,17-19 and frequently shows positive reactivity for CEA.19 The results of immunostaining for CK7 and 20 in this series were similar to the findings in previous studies.20,21 These immunostains were not contributory to the differential diagnosis between carcinoma from prostate versus urinary bladder. For the group C lesions, because of the absence of PAC in the prostate and the favorable clinical course after resection of the urinary bladder lesion, it is likely that the bladder PAC represents a primary PAC arising within the urinary bladder. It is not clear whether group B lesions represent secondary or new primary tumors. In the group B cases, the long period free of disease after the treatment of PAC in the prostate and the favorable clinical outcomes argue in favor of these lesions representing new primary PAC. So too does the fact that the bladder PAC had a similar grade to the prostate PAC in group B, rather than the generally increased grade in group A that would be expected with simple tumor progression from a prostatic primary tumor. Buchholz et al22 reported a case of PAC occurring in the urinary bladder neck after radical prostatectomy. They considered the lesion a late recurrence of the PAC in the prostate. However, the interval after prostatectomy was only 14 months in their example, compared with 2 to 11 years in the 11 cases in group A of this study. The urinary bladder has the potential to transform into benign prostatic epithelium, showing positive reactivity for PSA and PAP. Therefore, this prostatic tissue in the urinary bladder may be the site of development of PAC. Such a lesion has been reported in patients with and without previous TURP.4,10 The potential of malignant transformation of the bladder mucosa associated with positive reactivity for PSA and PAP could be enhanced in patients who had PAC because of inherent predisposing factors. In conclusion, secondary PACs are occasionally diagnosed in the urinary bladder and usually associated with high-grade and high-stage carcinoma in the prostate. Primary PAC in the urinary bladder may occur de novo in patients with a history of intravesical instrumentation or present as a urinary bladder lesion without accompanying PAC in the prostate in patients with a history of PAC in the prostate. They are of lower grade and are more localized than the secondary PAC. REFERENCES 1. Bostwick DG, Shan A, Qian J, et al: Independent origin of multiple foci of prostatic intraepithelial neoplasia: Comparison with matched foci of prostate carcinoma. Cancer 83:1995-2002, 1998 2. Haggman M, Nordin B, Mattson S, et al: Morphometric studies of intra-prostatic volume relationships in localized prostatic cancer. Br J Urol 80:612-617, 1997 3. Conolly JA, Shinohara K, Presti JC Jr, et al: Local recurrence after radical prostatectomy: Characteristics in size, location, and relationship to prostatic-specific antigen and surgical margins. Urology 47:225-231, 1996
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