- Email: [email protected]
Operable Prostatic Carcinoma: Correlations Among Clinical Stage, Pathological Stage, Gleason Histological Score and Early Disease-Free Survival
0022-534 7/85/1331-0049$02,0G/O VoL 133,
THE JOURNAL OF UROLOGY
Copyright© 1985 by The Wiiliams & VJilkins Co,
Printed in
OPERABLE PROSTATIC CARCINOMA: CORRELATIONS AMONG CLINICAL STAGE, PATHOLOGICAL STAGE, GLEASON HISTOLOGICAL SCORE AND EARLY DISEASE-FREE SURVIVAL JACKSON E. FOWLER, JR. AND STACEY E. MILLS From the Departments of Urology and Pathology, University of Virginia School of Medicine, Charlottesville, Virginia
ABSTRACT
We investigated the relationships among clinical and pathological stages, Gleason histological score and early disease-free survival of 75 patients with localized prostatic carcinoma treated by radical prostatectomy. Carcinoma was confined histologically to the prostate in 81 per cent of the patients with clinical stage A2, 79 per cent with BlN, 38 per cent with Bl and O per cent with B2 tumors. The Gleason score correlated directly with clinical and pathological stages, estimated extent of intraprostatic tumor and invasive capacity of the primary tumor. Of the tumors with a Gleason score of 8 or more 81 per cent extended beyond the prostatic capsule. Of 12 patients who suffered distant metastases 9 had tumors that extended beyond the prostatic capsule and 5 had tumors with Gleason scores of 8 or more. clinically free of tumor with a median followup of 52 months (range 5 to 149 months) postoperatively, while 6 died without evidence of tumor 13 to 156 months (median 26 months) postoperatively. Radiographical evidence of distant metastases developed 4 to 106 months postoperatively (median 41 months) in 12 patients and 1 suffered a local recurrence 84 months postoperatively. One other patient is known to have a local recurrence but osseous metastases also were documented when this recurrence was detected. Clinical stage was assessed retrospectively by review of the medical records. A total of 16 patients had stage A2 tumors (clinically undetectable carcinoma involving more than 5 per cent of the prostatic tissue removed for the treatment of symptomatic bladder outlet obstruction). In 11 of these patients the tumor was estimated to involve 33 per cent or less of the resected tissue. There were 24 patients with clinical stage BlN tumors (a discrete, solitary nodule not more than 1.5 cm. in diameter confined to 1 lobe of the prostate), while 24 had clinical stage Bl tumors (palpable induration greater than 1.5 cm. in diameter but involving less than 1 lobe of the prostate) and 11 had clinical stage B2 tumors (palpable induration confined to the prostate but involving 1 entire lobe or both lobes). Of the latter 11 patients 9 had clinical involvement of both prostatic lobes. Histological sections of the primary tumors were reviewed by 1 of us (S. E. M.) without knowledge of the corresponding clinical stage. Two pathological stages were recognized: 1) disease confined to the prostate (tumors confined to the parenchyma of the prostate or that invaded but did not penetrate the capsule of the prostate) and 2) extracapsular extension (tumors with microscopically verified penetration through the prostatic capsule into the surrounding periprostatic fat or with seminal vesicle invasion). The volume of the primary tumor was estimated grossly by determining whether there was unilateral or bilateral involvement of the gland. Each tumor was scored histologically via the system described by Gleason and associates. 9 • 10 Statistical analyses. We determined the correlation coefficients between the Gleason histological scores, and both the clinical stages of the palpable tumors and the degree of local invasiveness of the primary tumors. Statistical significance was calculated from the t statistic. Predictive values were determined by standard methods.
The possibility of cure after an extirpative operation for localized adenocarcinoma of the prostate is related to the pathological stage and histological grade of the primary tumor, and to the presence or absence of regional lymph node metastases.1-10 We investigated the relationships among clinical and pathological stages, Gleason histological score and early disease-free survival of men with localized prostatic carcinoma who were treated by radical prostatectomy. Correlations between pathological stage, and both clinical stage and Gleason score were examined closely, since pathological stage is the only parameter that cannot be established with certainty before removal of the prostate. PATIENTS AND METHODS
A total of 81 patients with nonfocal carcinoma confined to the prostate on clinical examination underwent radical prostatectomy at our institution between 1967 and 1983. The majority of the patients (81 per cent) were treated during the last 10 years. Six patients (5 with clinical stage Bl and 1 with a stage A2 tumors) were excluded from analysis because histological sections of the primary tumor were unavailable for review (3) or were inadequate for assessment of histological stage and grade (3). The remaining 75 patients had normal serum acid phosphatase levels. Preoperative bone scans showed no evidence of metastatic disease in 73 patients, whereas radiographical bone surveys were interpreted as normal in 2. Patient age ranged from 46 to 73 years (mean age 60.7 years). Fifty-eight patients underwent radical perinea! prostatectomy, 12 underwent radical retropubic prostatectomy with pelvic lymphadenectomy, 3 underwent radical retropubic prostatectomy only, and 2 underwent pelvic lymphadenectomy and subsequent radical perinea! prostatectomy. Frozen section examination of the pelvic lymph nodes was not done routinely and during the study period an anticipated radical prostatectomy never was withheld because of pelvic lymph node metastases. Four patients were treated with androgen deprivation and 1 was treated with pelvic radiation therapy immediately after radical prostatectomy. Two patients were lost to followup. None of the remaining 68 patients received further treatment unless recurrent tumor was documented. Of these 68 patients 49 are Accepted for publication September 20, 1984.
49
50
FOWLER AND MILLS TABLE
1. Clinical versus pathological stage of primary tumor Pathological Stage Disease Confined to Prostate
No.
Clinical Stage
No Capsular Involvement No.(%)
4 (25) 10 (42) 6 (25)
9 (56) 9 (38) 3 (13)
16 24 24
A2 BlN Bl B2
Extracapsular Extension Capsular Penetration* No.(%)
Capsular Invasion No.(%)
2/1 4/1 9/2 5/1
11
(13) (17) (38) (45)
Seminal Vesicle Invasiont No.(%) 1 1 6 6
(6) (4) (25) (55)
* Number of specimens with capsular penetration/number without pathologically identifiable seminal vesicles. t All tumors with seminal vesicle invasion had coexisting capsular penetration.
TABLE 2.
Clinical and pathological stages versus Gleason histological score BlN
A2
Bl
B2
Clinical Stage Pathological Stage
Disease Confined Extracapsular Disease Confined Extracapsular Disease Confined Extracapsular Disease Confined Extracapsular Extension to Prostate Extension to Prostate Extension to Prostate Extension to Prostate
Gleason score: 4 5 6 7 8 9 10
TABLE 3.
4 4 1 4 1 2
1
2 4 4 6 1 2
Gleason histological score versus tumor invasiveness Disease Confined to Prostate
Extracapsular Extension
Gleason Score No Capsular Involvement 4 5 6 7 8 9 10
6 7 2 5 1
Capsular Invasion
Capsular Penetration
5 4 8 1 2
1 2 2 (2) 8 (1) 2 5 (2)
3
4 1 3
1
1
1
Seminal Vesicle Invasion
4 4 5 1
Numbers in parentheses indicate number of specimens with capsular penetration that did not have pathologically identifiable seminal vesicles.
RESULTS
Clinical versus pathological stage. Correlations between the clinical and pathological stages are shown in table 1. In 5 cases the seminal vesicles were not identifiable in the surgical specimen but each tumor had extracapsular extension owing to capsular penetration. All 14 tumors with seminal vesicle invasion had coexisting capsular penetration. All 3 stage A2 tumors with extracapsular extension were associated with transurethral resection specimens with more than 33 per cent of the tissue involved with carcinoma. There was bilateral involvement of the prostate in 16 of the 24 stage BlN tumors (68 per cent), 23 of the 24 stage Bl tumors (96 per cent) and all 11 stage B2 tumors. The incidence of extracapsular extension among the palpable tumors correlated directly with clinical stage. Clinical and pathological stages versus Gleason score. Nine per cent of the tumors had Gleason scores of 4 or less, 63 per cent had Gleason scores of 5 to 7 and 28 per cent had Gleason scores of 8 or more (table 2). The correlation coefficient between the clinical stage of the palpable tumors and the Gleason scores was 0.32 (p <0.05). Gleason scores of 8 or more were seen in 19
1 7 2 4
1 1 2 3 3 1
per cent of the stage A2, 17 per cent of BlN, 29 per cent of Bl and 64 per cent of B2 tumors. None of the 9 palpable tumors that were confined histologically to 1 side of the prostate or the 13 stage A2 tumors associated with tumor involvement of 33 per cent or less of the resected tissue had a Gleason score of 8 or more. Over-all, the highest predictive value for extracapsular extension (84 per cent) was found for Gleason scores of 8 or more. When stratified by clinical stage, a greater proportion of tumors with extracapsular extension compared to those that were confined to the prostate had Gleason scores of 8 or more. This relationship between local invasiveness and Gleason score also was evident when the tumors were stratified relative to the presence or absence of capsular invasion, capsular penetration and seminal vesicle invasion (table 3). Gleason scores of 8 or more were present in 5 per cent of the tumors with no capsular invasion, 15 per cent with capsular invasion, 35 per cent with capsular penetration and 71 per cent with seminal vesicle invasion. The correlation coefficient between these histological estimates of tumor invasiveness and the Gleason score was 0.59 (p <0.01). If the 5 specimens with capsular penetration but without pathologically identifiable seminal vesicles actually had seminal vesicle invasion, 33 per cent of the tumors with capsular penetration and 63 per cent with seminal vesicle invasion would have had Gleason scores of 8 or more. Survival free of disease. Of the 68 patients who received no additional anticancer therapy postoperatively distant metastases developed in 3 (20 per cent) with stage A2 tumors, 1 (4 per cent) with a stage BlN tumor, 6 (29 per cent) with stage Bl tumors and 2 (22 per cent) with stage B2 tumors. Distant metastases were associated with O to 20 tumors that did not invade the prostatic capsule, 3 of 18 (17 per cent) that invaded the prostatic capsule, 3 of 19 (16 per cent) that penetrated the prostatic capsule and 6 of 11 (55 per cent) that invaded the seminal vesicles, as well as O of 27 tumors (O per cent) with Gleason scores of 6 or less, 7 of 25 tumors (28 per cent) with a Gleason score of 7 and 5 of 16 tumors (31 per cent) with Gleason scores of 8 or more.
51
OPERABLE PROSTATIC CARCINOMA DISCUSSION
Substantial evidence exists that local extension of tumor beyond the confines of the prostate, poor tumor differentiation and pelvic lymph node metastases are associated with an unfavorable prognosis after radical prostatectomy. 1- 10 The latter parameter was not investigated systematically in this study and data have suggested that the incidence of extracapsular extension among patients treated by radical prostatectomy may be reduced if those with pelvic lymph node metastases are excluded selectively. 11 • 12 Nonetheless, extracapsular extension may be associated with uninvolved pelvic lymph nodes 12 and it is logical to believe that complete excision of the primary tumor will be compromised in these patients. Therefore, assessment of the likelihood of extracapsular extension remains important in the selection of patients for radical prostatectomy. Many of our insights concerning the relationship between clinical and pathological stages of prostatic carcinoma, and between pathological stage and potential for cure with radical prostatectomy, are derived from the clinicopathological investigations of Jewett and associates. 1 These investigators demonstrated that the likelihood of seminal vesicle invasion among prostatic carcinomas manifested by "a palpably discrete nodule of firm or stoney consistency limited to a part of one lateral lobe, averaging 1 cm or a little more in diameter, with compressible prostatic tissue always on two and sometimes on three sides", was approximately 17 per cent. Furthermore, they found that disease-free survival following radical prostatectomy was substantially greater among patients with tumors that did not invade the seminal vesicles. Penetration of the prostatic capsule alone was not of prognostic significance. However, the rigid definition of a clinical stage Bl prostatic cancer as defined by Jewett and associates has been abandoned largely in more recent studies dealing with radical prostatectomy. Presently, clinical stage Bl tumors usually are defined as palpable induration confined to less than 1 lobe of the prostate, regardless of over-all dimension. 4 • 8 • 12 Our data suggest that the "Jewett nodule" or, as suggested by Catalona and Scott, a clinical stage BlN tumor, is less likely to be associated with seminal vesicle invasion specifically, and extracapsular extension in general, than a larger clinical stage Bl tumor.13 All of our clinical stage B2 tumors had extracapsular extension, in contrast to only 66 and 40 per cent, respectively, of the stage B2 tumors excised regardless of pelvic lymph node status reported by Elder and associates,7 and Catalona and Stein. 8 These differences may reflect the fact that almost all of our stage B2 tumors involved clinically both lobes of the prostate. The biological characteristics of prostatic neoplasms that predispose to palpable induration or nodularity, and that determine the extent of induration within the confines of the gland, are not known. Paradoxically, Byar and associates demonstrated that the majority of palpably unilateral prostatic tumors are bilaternl pathologically. 2 In our study 81 per cent of stages BIN and Bl tumors involved both sides of the prostate on histological examination. However, there was a direct correlation between the estimated area of palpable induration, or clinical stage, and the Gleason score (r = 0.32, p <0.05), and between the Gleason score and local invasiveness of the tumor (r = 0.59, p <0.01). Together, these observations suggest a relationship between invasive potential and propensity for prostatic induration. This relationship may explain the established prognostic value of a clinical staging system that is based largely on the estimated extent of the tumor within the prostate but that actually correlates poorly with this parameter. The efficacy of radical prostatectomy in the treatment of stage A2 prostatic cancer is yet to be established. Reported surgical series with long-term followup generally have not differentiated stage Al from stage A2 tumors. Moreover, some advocates of radical prostatectomy argue that the potential technical difficulties associated with radical prostatectomy fol-
lowing partial prostatectomy, and the increased incidence of less differentiated tumors and pelvic lymph node metastases compared to clinical stage Bl tumors, favor alternative treatments.' Our limited experience suggests that the likelihood of extracapsular extension among stage A2 tumors with Gleason scores of less than 8, or with less than 33 per cent of previously excised tissue involved with cancer, is low. Similar observations concerning the incidence of extracapsular extension in patients with stage A2 tumors treated by radical prostatectomy have been reported previously. 14 - 16 These findings and evidence that the incidence of incontinence following radical prostatectomy for stage A2 tumors parallels that for stage B tumors 14 · 17 provide a rationale for continued exploration of the efficacy of surgical therapy for stage A2 lesions. Of the tumors with Gleason scores of 8 or more 81 per cent had extracapsular extension. An extraordinarily high incidence of pelvic lymph node metastases has been associated with Gleason scores of 8 or more. 18• 19 However, in our and other series the majority of clinically localized prostatic tumors had Gleason scores of 5 to 7. 9 • 18' 19 The practical importance of the Gleason score in predicting extracapsular extension also is limited by the direct relationship between the Gleason score and the clinical stage. Therefore, among stages BIN and B2 tumors, in which the likelihoods of extracapsular extension are low and high, respectively, the Gleason score is not particularly helpful for predicting the presence or absence of extracapsular extension, On the other hand, in stages A2 and Bl tumors, in which the presence or absence of extracapsular extension cannot be predicted with a high degree of certainty, the Gleason score assumes greater clinical importance. The preliminary disease-free survival in our patients are consistent with the concept that extracapsular extension and Gleason scores of 8 or more are associated with a high risk of treatment failure after radical prostatectomy. The observation that 55 per cent of the patients with seminal vesicle invasion but only 16 per cent of those with capsular penetration only have suffered distant metastases supports the findings of Jewett and associates. 1 The duration of post-treatment observation is far too brief for meaningful conclusions concerning the efficacy of treatment in our series. Nonetheless, the relationships between pathological stage, and both clinical stage and Gleason histological score provide data that should be useful when considering the advisability of radical prostatectomy in patients with localized prostatic carcinoma. REFERENCES
1. Jewett, H. J., Bridge, R. W., Gray, G. F., Jr. and Shelley, W. M.:
2.
3.
4. 5. 6. 7. 8.
The palpable nodule of prostatic cancer: results 15 years after radical excision. J.A.M.A., 203: 403, 1968. Byar, D. P., Mostofi, F. K. and the Veterans Administration Cooperative Urological Research Group: Carcinoma of the prostate: prognostic evaluation of certain pathologic features in 208 radical prostatectomies examined by the step-section technique. Cancer, 30: 5, 1972. Vickery, A. L., Jr. and Kerr, W. S., Jr.: Carcinoma of the prostate treated by radical prostatectomy. A clinicopathological survey of 187 cases followed for 5 years and 148 cases followed for 10 years. Cancer, 16: 1598, 1963. Walsh, P. C. and Jewett, H.J.: Radical surgery forprostatic cancer. Cancer, suppl. 7, 45: 1906, 1980. Boxer, R. J., Kaufman, J. J. and Goodwin, W. E.: Radical prostatectomy for carcinoma of the prostate: 1951-1976. A review of 329 patients. J. Urol., 117: 208, 1977. Prout, G. R., Jr., Heaney, J. A., Griffin, P. P., Daly, J. J. and Shipley, W. U.: Nodal involvement as a prognostic indicator in patients with prostatic carcinoma. J. Urol., 124: 226, 1980. Elder, J. S., Jewett, H. J. and Walsh, P. C.: Radical perinea! prostatectomy for clinical stage B2 carcinoma of the prostate. J. Urol., 127: 704, 1982. Catalona, W. J. and Stein, A. J.: Staging errors in clinically localized prostatic cancer. J. Urol., 127: 452, 1982.
52
FOWLER AND MILLS
\J. Gleason, D. F., Mellinger, G. T. and The Veterans Administration
10.
11. 12. 13.
Cooperative Urological Research Group: Prediction of prognosis for prostatic adenocarcinoma by combined histological grading and clinical staging. J. Urol., 111: 58, 1974. Gleason, D. F.: Histologic grading and clinical staging of prostatic carcinoma. In: Urologic Pathology: The Prostate. Edited by M. Tannenbaum. Philadelphia: Lea & Febiger, chapt. 9, p. 171, 1977. Middleton, R. G. and Smith, J. A., Jr.: Radical prostatectomy for stage B2 prostatic cancer. J. Urol., 127: 702, 1982. Catalona, W. J., Fleischmann, J. and Menon, M.: Pelvic lymph node status as predictor of extracapsular tumor extension in clinical stage B prostatic cancer. J. Urol., 129: 327, 1983. Catalona, W. J. and Scott, W. W.: Carcinoma of the prostate. In: Campbell's Urology, 4th ed. Edited by J. H. Harrison, R. F. Gittes, A. D. Perlmutter, T. A. Stamey and P. C. Walsh. Philadelphia: W. B. Saunders Co., vol. 2, sect. IX, chapt. 31, pp. 10851124, 1979.
14. Bass, R. B., Jr. and Barrett, D. M.: Radical retropubic prostatectomy after transurethral prostatic resection. J. Urol., 124: 495, 1980. 15. Parfitt, H. E., Jr., Smith, J. A., Jr., Seaman, J. P. and Middleton, R. G.: Surgical treatment of stage A2 prostatic carcinoma: significance of tumor grade and extent. J. Urol., 129: 763, 1983. 16. Golimbu, M., Schinella, R., Morales, P. and Kurusu, S.: Differences in pathological characteristics and prognosis of clinical A2 prostatic cancer from Al and B disease. J. Urol., 119: 618, 1978. 17. Linder, A., deKernion, J.B., Smith, R. B. and Katske, F. A.: Risk of urinary incontinence following radical prostatectomy. J. Urol., 129: 1007, 1983. 18. Kramer, S. A., Spahr, J., Brendler, C. B., Glenn, J. F. and Paulson, D. F.: Experience with Gleason's histopathologic grading in prostatic cancer. J. Urol., 124: 223, 1980. 19. Thomas, R., Lewis, R. W., Sarma, D. P., Coker, G. B., Rao, M. K. and Roberts, J. A.: Aid to accurate clinical staging-histopathologic grading in prostatic cancer. J. Urol., 128: 726, 1982.
THE JOURNAL OF UROLOGY
Copyright© 1985 by The Wiiliams & VJilkins Co,
Printed in
OPERABLE PROSTATIC CARCINOMA: CORRELATIONS AMONG CLINICAL STAGE, PATHOLOGICAL STAGE, GLEASON HISTOLOGICAL SCORE AND EARLY DISEASE-FREE SURVIVAL JACKSON E. FOWLER, JR. AND STACEY E. MILLS From the Departments of Urology and Pathology, University of Virginia School of Medicine, Charlottesville, Virginia
ABSTRACT
We investigated the relationships among clinical and pathological stages, Gleason histological score and early disease-free survival of 75 patients with localized prostatic carcinoma treated by radical prostatectomy. Carcinoma was confined histologically to the prostate in 81 per cent of the patients with clinical stage A2, 79 per cent with BlN, 38 per cent with Bl and O per cent with B2 tumors. The Gleason score correlated directly with clinical and pathological stages, estimated extent of intraprostatic tumor and invasive capacity of the primary tumor. Of the tumors with a Gleason score of 8 or more 81 per cent extended beyond the prostatic capsule. Of 12 patients who suffered distant metastases 9 had tumors that extended beyond the prostatic capsule and 5 had tumors with Gleason scores of 8 or more. clinically free of tumor with a median followup of 52 months (range 5 to 149 months) postoperatively, while 6 died without evidence of tumor 13 to 156 months (median 26 months) postoperatively. Radiographical evidence of distant metastases developed 4 to 106 months postoperatively (median 41 months) in 12 patients and 1 suffered a local recurrence 84 months postoperatively. One other patient is known to have a local recurrence but osseous metastases also were documented when this recurrence was detected. Clinical stage was assessed retrospectively by review of the medical records. A total of 16 patients had stage A2 tumors (clinically undetectable carcinoma involving more than 5 per cent of the prostatic tissue removed for the treatment of symptomatic bladder outlet obstruction). In 11 of these patients the tumor was estimated to involve 33 per cent or less of the resected tissue. There were 24 patients with clinical stage BlN tumors (a discrete, solitary nodule not more than 1.5 cm. in diameter confined to 1 lobe of the prostate), while 24 had clinical stage Bl tumors (palpable induration greater than 1.5 cm. in diameter but involving less than 1 lobe of the prostate) and 11 had clinical stage B2 tumors (palpable induration confined to the prostate but involving 1 entire lobe or both lobes). Of the latter 11 patients 9 had clinical involvement of both prostatic lobes. Histological sections of the primary tumors were reviewed by 1 of us (S. E. M.) without knowledge of the corresponding clinical stage. Two pathological stages were recognized: 1) disease confined to the prostate (tumors confined to the parenchyma of the prostate or that invaded but did not penetrate the capsule of the prostate) and 2) extracapsular extension (tumors with microscopically verified penetration through the prostatic capsule into the surrounding periprostatic fat or with seminal vesicle invasion). The volume of the primary tumor was estimated grossly by determining whether there was unilateral or bilateral involvement of the gland. Each tumor was scored histologically via the system described by Gleason and associates. 9 • 10 Statistical analyses. We determined the correlation coefficients between the Gleason histological scores, and both the clinical stages of the palpable tumors and the degree of local invasiveness of the primary tumors. Statistical significance was calculated from the t statistic. Predictive values were determined by standard methods.
The possibility of cure after an extirpative operation for localized adenocarcinoma of the prostate is related to the pathological stage and histological grade of the primary tumor, and to the presence or absence of regional lymph node metastases.1-10 We investigated the relationships among clinical and pathological stages, Gleason histological score and early disease-free survival of men with localized prostatic carcinoma who were treated by radical prostatectomy. Correlations between pathological stage, and both clinical stage and Gleason score were examined closely, since pathological stage is the only parameter that cannot be established with certainty before removal of the prostate. PATIENTS AND METHODS
A total of 81 patients with nonfocal carcinoma confined to the prostate on clinical examination underwent radical prostatectomy at our institution between 1967 and 1983. The majority of the patients (81 per cent) were treated during the last 10 years. Six patients (5 with clinical stage Bl and 1 with a stage A2 tumors) were excluded from analysis because histological sections of the primary tumor were unavailable for review (3) or were inadequate for assessment of histological stage and grade (3). The remaining 75 patients had normal serum acid phosphatase levels. Preoperative bone scans showed no evidence of metastatic disease in 73 patients, whereas radiographical bone surveys were interpreted as normal in 2. Patient age ranged from 46 to 73 years (mean age 60.7 years). Fifty-eight patients underwent radical perinea! prostatectomy, 12 underwent radical retropubic prostatectomy with pelvic lymphadenectomy, 3 underwent radical retropubic prostatectomy only, and 2 underwent pelvic lymphadenectomy and subsequent radical perinea! prostatectomy. Frozen section examination of the pelvic lymph nodes was not done routinely and during the study period an anticipated radical prostatectomy never was withheld because of pelvic lymph node metastases. Four patients were treated with androgen deprivation and 1 was treated with pelvic radiation therapy immediately after radical prostatectomy. Two patients were lost to followup. None of the remaining 68 patients received further treatment unless recurrent tumor was documented. Of these 68 patients 49 are Accepted for publication September 20, 1984.
49
50
FOWLER AND MILLS TABLE
1. Clinical versus pathological stage of primary tumor Pathological Stage Disease Confined to Prostate
No.
Clinical Stage
No Capsular Involvement No.(%)
4 (25) 10 (42) 6 (25)
9 (56) 9 (38) 3 (13)
16 24 24
A2 BlN Bl B2
Extracapsular Extension Capsular Penetration* No.(%)
Capsular Invasion No.(%)
2/1 4/1 9/2 5/1
11
(13) (17) (38) (45)
Seminal Vesicle Invasiont No.(%) 1 1 6 6
(6) (4) (25) (55)
* Number of specimens with capsular penetration/number without pathologically identifiable seminal vesicles. t All tumors with seminal vesicle invasion had coexisting capsular penetration.
TABLE 2.
Clinical and pathological stages versus Gleason histological score BlN
A2
Bl
B2
Clinical Stage Pathological Stage
Disease Confined Extracapsular Disease Confined Extracapsular Disease Confined Extracapsular Disease Confined Extracapsular Extension to Prostate Extension to Prostate Extension to Prostate Extension to Prostate
Gleason score: 4 5 6 7 8 9 10
TABLE 3.
4 4 1 4 1 2
1
2 4 4 6 1 2
Gleason histological score versus tumor invasiveness Disease Confined to Prostate
Extracapsular Extension
Gleason Score No Capsular Involvement 4 5 6 7 8 9 10
6 7 2 5 1
Capsular Invasion
Capsular Penetration
5 4 8 1 2
1 2 2 (2) 8 (1) 2 5 (2)
3
4 1 3
1
1
1
Seminal Vesicle Invasion
4 4 5 1
Numbers in parentheses indicate number of specimens with capsular penetration that did not have pathologically identifiable seminal vesicles.
RESULTS
Clinical versus pathological stage. Correlations between the clinical and pathological stages are shown in table 1. In 5 cases the seminal vesicles were not identifiable in the surgical specimen but each tumor had extracapsular extension owing to capsular penetration. All 14 tumors with seminal vesicle invasion had coexisting capsular penetration. All 3 stage A2 tumors with extracapsular extension were associated with transurethral resection specimens with more than 33 per cent of the tissue involved with carcinoma. There was bilateral involvement of the prostate in 16 of the 24 stage BlN tumors (68 per cent), 23 of the 24 stage Bl tumors (96 per cent) and all 11 stage B2 tumors. The incidence of extracapsular extension among the palpable tumors correlated directly with clinical stage. Clinical and pathological stages versus Gleason score. Nine per cent of the tumors had Gleason scores of 4 or less, 63 per cent had Gleason scores of 5 to 7 and 28 per cent had Gleason scores of 8 or more (table 2). The correlation coefficient between the clinical stage of the palpable tumors and the Gleason scores was 0.32 (p <0.05). Gleason scores of 8 or more were seen in 19
1 7 2 4
1 1 2 3 3 1
per cent of the stage A2, 17 per cent of BlN, 29 per cent of Bl and 64 per cent of B2 tumors. None of the 9 palpable tumors that were confined histologically to 1 side of the prostate or the 13 stage A2 tumors associated with tumor involvement of 33 per cent or less of the resected tissue had a Gleason score of 8 or more. Over-all, the highest predictive value for extracapsular extension (84 per cent) was found for Gleason scores of 8 or more. When stratified by clinical stage, a greater proportion of tumors with extracapsular extension compared to those that were confined to the prostate had Gleason scores of 8 or more. This relationship between local invasiveness and Gleason score also was evident when the tumors were stratified relative to the presence or absence of capsular invasion, capsular penetration and seminal vesicle invasion (table 3). Gleason scores of 8 or more were present in 5 per cent of the tumors with no capsular invasion, 15 per cent with capsular invasion, 35 per cent with capsular penetration and 71 per cent with seminal vesicle invasion. The correlation coefficient between these histological estimates of tumor invasiveness and the Gleason score was 0.59 (p <0.01). If the 5 specimens with capsular penetration but without pathologically identifiable seminal vesicles actually had seminal vesicle invasion, 33 per cent of the tumors with capsular penetration and 63 per cent with seminal vesicle invasion would have had Gleason scores of 8 or more. Survival free of disease. Of the 68 patients who received no additional anticancer therapy postoperatively distant metastases developed in 3 (20 per cent) with stage A2 tumors, 1 (4 per cent) with a stage BlN tumor, 6 (29 per cent) with stage Bl tumors and 2 (22 per cent) with stage B2 tumors. Distant metastases were associated with O to 20 tumors that did not invade the prostatic capsule, 3 of 18 (17 per cent) that invaded the prostatic capsule, 3 of 19 (16 per cent) that penetrated the prostatic capsule and 6 of 11 (55 per cent) that invaded the seminal vesicles, as well as O of 27 tumors (O per cent) with Gleason scores of 6 or less, 7 of 25 tumors (28 per cent) with a Gleason score of 7 and 5 of 16 tumors (31 per cent) with Gleason scores of 8 or more.
51
OPERABLE PROSTATIC CARCINOMA DISCUSSION
Substantial evidence exists that local extension of tumor beyond the confines of the prostate, poor tumor differentiation and pelvic lymph node metastases are associated with an unfavorable prognosis after radical prostatectomy. 1- 10 The latter parameter was not investigated systematically in this study and data have suggested that the incidence of extracapsular extension among patients treated by radical prostatectomy may be reduced if those with pelvic lymph node metastases are excluded selectively. 11 • 12 Nonetheless, extracapsular extension may be associated with uninvolved pelvic lymph nodes 12 and it is logical to believe that complete excision of the primary tumor will be compromised in these patients. Therefore, assessment of the likelihood of extracapsular extension remains important in the selection of patients for radical prostatectomy. Many of our insights concerning the relationship between clinical and pathological stages of prostatic carcinoma, and between pathological stage and potential for cure with radical prostatectomy, are derived from the clinicopathological investigations of Jewett and associates. 1 These investigators demonstrated that the likelihood of seminal vesicle invasion among prostatic carcinomas manifested by "a palpably discrete nodule of firm or stoney consistency limited to a part of one lateral lobe, averaging 1 cm or a little more in diameter, with compressible prostatic tissue always on two and sometimes on three sides", was approximately 17 per cent. Furthermore, they found that disease-free survival following radical prostatectomy was substantially greater among patients with tumors that did not invade the seminal vesicles. Penetration of the prostatic capsule alone was not of prognostic significance. However, the rigid definition of a clinical stage Bl prostatic cancer as defined by Jewett and associates has been abandoned largely in more recent studies dealing with radical prostatectomy. Presently, clinical stage Bl tumors usually are defined as palpable induration confined to less than 1 lobe of the prostate, regardless of over-all dimension. 4 • 8 • 12 Our data suggest that the "Jewett nodule" or, as suggested by Catalona and Scott, a clinical stage BlN tumor, is less likely to be associated with seminal vesicle invasion specifically, and extracapsular extension in general, than a larger clinical stage Bl tumor.13 All of our clinical stage B2 tumors had extracapsular extension, in contrast to only 66 and 40 per cent, respectively, of the stage B2 tumors excised regardless of pelvic lymph node status reported by Elder and associates,7 and Catalona and Stein. 8 These differences may reflect the fact that almost all of our stage B2 tumors involved clinically both lobes of the prostate. The biological characteristics of prostatic neoplasms that predispose to palpable induration or nodularity, and that determine the extent of induration within the confines of the gland, are not known. Paradoxically, Byar and associates demonstrated that the majority of palpably unilateral prostatic tumors are bilaternl pathologically. 2 In our study 81 per cent of stages BIN and Bl tumors involved both sides of the prostate on histological examination. However, there was a direct correlation between the estimated area of palpable induration, or clinical stage, and the Gleason score (r = 0.32, p <0.05), and between the Gleason score and local invasiveness of the tumor (r = 0.59, p <0.01). Together, these observations suggest a relationship between invasive potential and propensity for prostatic induration. This relationship may explain the established prognostic value of a clinical staging system that is based largely on the estimated extent of the tumor within the prostate but that actually correlates poorly with this parameter. The efficacy of radical prostatectomy in the treatment of stage A2 prostatic cancer is yet to be established. Reported surgical series with long-term followup generally have not differentiated stage Al from stage A2 tumors. Moreover, some advocates of radical prostatectomy argue that the potential technical difficulties associated with radical prostatectomy fol-
lowing partial prostatectomy, and the increased incidence of less differentiated tumors and pelvic lymph node metastases compared to clinical stage Bl tumors, favor alternative treatments.' Our limited experience suggests that the likelihood of extracapsular extension among stage A2 tumors with Gleason scores of less than 8, or with less than 33 per cent of previously excised tissue involved with cancer, is low. Similar observations concerning the incidence of extracapsular extension in patients with stage A2 tumors treated by radical prostatectomy have been reported previously. 14 - 16 These findings and evidence that the incidence of incontinence following radical prostatectomy for stage A2 tumors parallels that for stage B tumors 14 · 17 provide a rationale for continued exploration of the efficacy of surgical therapy for stage A2 lesions. Of the tumors with Gleason scores of 8 or more 81 per cent had extracapsular extension. An extraordinarily high incidence of pelvic lymph node metastases has been associated with Gleason scores of 8 or more. 18• 19 However, in our and other series the majority of clinically localized prostatic tumors had Gleason scores of 5 to 7. 9 • 18' 19 The practical importance of the Gleason score in predicting extracapsular extension also is limited by the direct relationship between the Gleason score and the clinical stage. Therefore, among stages BIN and B2 tumors, in which the likelihoods of extracapsular extension are low and high, respectively, the Gleason score is not particularly helpful for predicting the presence or absence of extracapsular extension, On the other hand, in stages A2 and Bl tumors, in which the presence or absence of extracapsular extension cannot be predicted with a high degree of certainty, the Gleason score assumes greater clinical importance. The preliminary disease-free survival in our patients are consistent with the concept that extracapsular extension and Gleason scores of 8 or more are associated with a high risk of treatment failure after radical prostatectomy. The observation that 55 per cent of the patients with seminal vesicle invasion but only 16 per cent of those with capsular penetration only have suffered distant metastases supports the findings of Jewett and associates. 1 The duration of post-treatment observation is far too brief for meaningful conclusions concerning the efficacy of treatment in our series. Nonetheless, the relationships between pathological stage, and both clinical stage and Gleason histological score provide data that should be useful when considering the advisability of radical prostatectomy in patients with localized prostatic carcinoma. REFERENCES
1. Jewett, H. J., Bridge, R. W., Gray, G. F., Jr. and Shelley, W. M.:
2.
3.
4. 5. 6. 7. 8.
The palpable nodule of prostatic cancer: results 15 years after radical excision. J.A.M.A., 203: 403, 1968. Byar, D. P., Mostofi, F. K. and the Veterans Administration Cooperative Urological Research Group: Carcinoma of the prostate: prognostic evaluation of certain pathologic features in 208 radical prostatectomies examined by the step-section technique. Cancer, 30: 5, 1972. Vickery, A. L., Jr. and Kerr, W. S., Jr.: Carcinoma of the prostate treated by radical prostatectomy. A clinicopathological survey of 187 cases followed for 5 years and 148 cases followed for 10 years. Cancer, 16: 1598, 1963. Walsh, P. C. and Jewett, H.J.: Radical surgery forprostatic cancer. Cancer, suppl. 7, 45: 1906, 1980. Boxer, R. J., Kaufman, J. J. and Goodwin, W. E.: Radical prostatectomy for carcinoma of the prostate: 1951-1976. A review of 329 patients. J. Urol., 117: 208, 1977. Prout, G. R., Jr., Heaney, J. A., Griffin, P. P., Daly, J. J. and Shipley, W. U.: Nodal involvement as a prognostic indicator in patients with prostatic carcinoma. J. Urol., 124: 226, 1980. Elder, J. S., Jewett, H. J. and Walsh, P. C.: Radical perinea! prostatectomy for clinical stage B2 carcinoma of the prostate. J. Urol., 127: 704, 1982. Catalona, W. J. and Stein, A. J.: Staging errors in clinically localized prostatic cancer. J. Urol., 127: 452, 1982.
52
FOWLER AND MILLS
\J. Gleason, D. F., Mellinger, G. T. and The Veterans Administration
10.
11. 12. 13.
Cooperative Urological Research Group: Prediction of prognosis for prostatic adenocarcinoma by combined histological grading and clinical staging. J. Urol., 111: 58, 1974. Gleason, D. F.: Histologic grading and clinical staging of prostatic carcinoma. In: Urologic Pathology: The Prostate. Edited by M. Tannenbaum. Philadelphia: Lea & Febiger, chapt. 9, p. 171, 1977. Middleton, R. G. and Smith, J. A., Jr.: Radical prostatectomy for stage B2 prostatic cancer. J. Urol., 127: 702, 1982. Catalona, W. J., Fleischmann, J. and Menon, M.: Pelvic lymph node status as predictor of extracapsular tumor extension in clinical stage B prostatic cancer. J. Urol., 129: 327, 1983. Catalona, W. J. and Scott, W. W.: Carcinoma of the prostate. In: Campbell's Urology, 4th ed. Edited by J. H. Harrison, R. F. Gittes, A. D. Perlmutter, T. A. Stamey and P. C. Walsh. Philadelphia: W. B. Saunders Co., vol. 2, sect. IX, chapt. 31, pp. 10851124, 1979.
14. Bass, R. B., Jr. and Barrett, D. M.: Radical retropubic prostatectomy after transurethral prostatic resection. J. Urol., 124: 495, 1980. 15. Parfitt, H. E., Jr., Smith, J. A., Jr., Seaman, J. P. and Middleton, R. G.: Surgical treatment of stage A2 prostatic carcinoma: significance of tumor grade and extent. J. Urol., 129: 763, 1983. 16. Golimbu, M., Schinella, R., Morales, P. and Kurusu, S.: Differences in pathological characteristics and prognosis of clinical A2 prostatic cancer from Al and B disease. J. Urol., 119: 618, 1978. 17. Linder, A., deKernion, J.B., Smith, R. B. and Katske, F. A.: Risk of urinary incontinence following radical prostatectomy. J. Urol., 129: 1007, 1983. 18. Kramer, S. A., Spahr, J., Brendler, C. B., Glenn, J. F. and Paulson, D. F.: Experience with Gleason's histopathologic grading in prostatic cancer. J. Urol., 124: 223, 1980. 19. Thomas, R., Lewis, R. W., Sarma, D. P., Coker, G. B., Rao, M. K. and Roberts, J. A.: Aid to accurate clinical staging-histopathologic grading in prostatic cancer. J. Urol., 128: 726, 1982.