Incidence of positive surgical margins after biopsy-selected nerve-sparing radical prostatectomy

ADULT UROLOGY CME ARTICLE ELSEVIER

INCIDENCE

OF POSITIVE SURGICAL MARGINS BIOPSY-SELECTED NERVE-SPARING RADICAL PROSTATECTOMY

AFTER

MARKUS GRAEFEN, PETER HAMMERER, UWE MICHL, JOACHIM NOLDUS, ALEXANDER HAESE, ROLF-PETER HENKE, EDITH HUIAND, AND HARTWIG HULAND

ABSTRACT Objectives. The selection criteria for a nerve-sparing radical prostatectomy (NSRP) are not thoroughly investigated and are based mainly on preoperative digital rectal examinations and intraoperative findings. At our institution NSRP is performed only on patients whose preoperative systematic sextant biopsy of the prostate showed only unilateral cancer. To prove the safety of these criteria, we analyzed the incidence of positive surgical margins and tumor progression rate in patients who were selected for an NSRP only by the result of the biopsy. Methods. Preoperative systematic sextant biopsies revealed unilateral cancer in 69 preoperatively potent men of 289 consecutive prostatic cancer patients (23.9%); contralateral NSRP was performed on these 69 patients. The prostate specimens were investigated by using a 3-mm step-section technique to identify positive surgical margins. Tumor progression was defined as a prostate-specific antigen (PSA) level greater than 0.4 ng/mL in the native and greater than 0.025 ng/mL in the suprasensitive postoperative blood test. Mean follow-up was 15 months (range 6 to 24). Results. In 69 patients who underwent NSRP, 1 1 positive margins (15.9%) were found. Only 3 patients (4.3%) had a positive margin on the nerve-sparing side. In 220 patients who underwent non-NSRP 59 positive margins (26.8%) were detected. PSA recurrence rate after 12 months was similar in patients with NSRP and non-NSRP. Analysis of systematic sextant biopsies gives safe selection criteria because in approximately 95% the surgical margin on the nerve-sparing side will be negative. Conclusions. Basing the indication for an NSRP on the results of preoperative systematic biopsies was safe according to margin status and postoperative PSA, when all patients with tumor in one of the three biopsy cores of each side of the prostate were excluded from an NS technique on that side. Such a strict approach will exclude approximately 30% of patients from NSRP unnecessarily because of tumor findings on a prostate side where the cancer is still organ-confined. Less strict criteria, including patients with only well-differentiated cancer and a maximum of one positive biopsy on the evaluated side, seem to be as safe as the described selection. However, data on these patients need further evaluation. UROLOGY 51: 437-442, 1998. 0 1998, Elsevier Science Inc. All rights reserved.

nerve-sparing modification of radical retropubit prostatectomy (RP) was introduced by P. C. Walsh and associates in 1983.l Its purpose was to preserve erectile potency by excising the prostate without injuring the neurovascular bundles that contain the cavernous nerves and vessels.

A

From the Department of Urology and Pathology, University Clinic Eppendorf, Hamburg, Germany Reprint requests: Markus Graefen, M.D., Department of Urology, University Clinic Eppendorj, Martinistrusse 52, 20246 Hamburg, Germany Submitted: December 30,1996, accepted (with revisions): September 2,1997 0 1998, ELSEVIER SCIENCEINC. RIGHTS

where the cancer has already left the capsule will therefore most likely lead to an artificial positive margin, which might have been avoided by a wide excision of then neurovascular bundle. DRE and imaging (nuclear magnetic resonance [ NMRI , transrectal ultrasonography, and computed tomography [CT] scan) are unreliable in predicting the stage of prostate cancer. In the absence of any established safe selection criteria, we rather favor a very strict selection approach because it is not yet proved if nerve-sparing surgery is indeed safe in all pT2 and pT3a tumors. We have reported on the use of very strict selection criteria that are based on the assumption that unilateral nerve-sparing is safe with respect to margin status and postoperative prostate-specific antigen (PSA) recurrence when it is used in patients who have negative specimens in all three biopsies of one side of the prostate.ll In the present study, we used the result of systematic sextant biopsies of the prostate as selection criteria for a nerve-sparing radical prostatectomy (NSRP). We studied 289 consecutive patients of which 69 men (23.9%) underwent a unilateral NSRP. We compared the incidence of positive surgical margins and pathologic outcome in these patients with those who underwent a non-NSRP with comparable pathologic stage, tumor volume, and Gleason score. Postoperative potency rate was evaluated by using an anonymous questionnaire. The rate of postoperative recurrence, as indicated by increasing PSA concentration in native and supersensitive measure, was analyzed. We also looked at the incidence of urinary incontinence 6 and 12 months postoperatively to evaluate whether nerve sparing could have any influence on postoperative continence. MATERIAL

AND METHODS

A total of 289 consecutive patients with biopsy-proved prostate cancer at clinical Stage Tl and T2 underwent pelvic lymphadenectomy and RP from February 1992 to June 1995 at our institution. All patients underwent preoperative systematic sextant biopsy of the prostate. In 69 of those patients, we performed a unilateral nerve-sparing technique. Bilateral sparing of the neurovascular bundle was not performed. The mean (*SD) age of the patients who underwent the nerve-sparing technique was 59.4 2 6 years (range 48 to 71), and that of those who underwent the non-nerve-sparing technique was 63.4 -C 7.3 years (range 47 to 73) (Table I). Bone scan yielded negative results on all patients. Ultrasonographically guided systematic sextant biopsies were used to identify the nerve-sparing side. Only if all three biopsies of one side were negative for tumor, the nerve-sparing technique was used in preoperatively potent patients. Radical RP with a modified Walsh technique was used if frozen section revealed negative lymph nodes. All specimens were inked over the entire surface, fixed in formalin for at least 24 hours, and processed with a 3-mm step-section technique. 12 In brief, the seminal vesicles, apex, and base of the prostate specimen were amputated, and the remainder was serially blocked at 3-mm intervals along trans438

TABLE I. Me 50-59 60-69 Mean * Numbers

SD

Age of patients

No. Non-NerveSparing (n 220)

No. NerveSparing = 69)

6 (2.7)* (21.4) 128 39 (17.7) 63.4 7

(5.8) 29 33 (47.8) (4.3) 59.4 6

in parentheses are percents.

verse planes parallel to the initial apical and basal sections. The Gleason system was used for histologic grading,13 and the staging was according to the second revision of the fourth edition of the TNM classification. In all specimens, the cancer volume was calculated by using a computer-assisted volumetric program developed in our department of pathology.14 After radical prostatectomy, all patients were seen regularly at our outpatient department. Follow-up investigations, including physical and ultrasonographic investigation and blood samples, were performed at least twice a year. None of the patients received any additional therapy before PSA relapse was proved. To detect serum PSA, we used a simple PSA test in addition to a supersensitive method developed in our laboratory. The supersensitive assay is described elsewhere.i5 In brief, it includes a manipulation of serum through lyophilization and concentration by a factor of 4, which increases sensitivity by a factor of 4 (Microparticle Enzyme Assay; Abbott IMX). This PSA assay was considered positive if it yielded a PSA concentration of more than 0.025 ng/mL. Earlier studies showed that the supersensitive assay could detect tumor recurrence an average of 1 year earlier than the standard assay.i5 To assess postoperative potency, an anonymous questionnaire addressing erectile function was sent to all patients who underwent NSRP. We also investigated whether preservation of the neurovascular bundle has an influence on urinary continence 6 and 12 months postoperatively. Information on the grade of incontinence was obtained during the outpatient consultation. We considered patients continent if they did not require a protective pad to keep clothing dry. Patients who were dry under virtually all normal circumstances but who elected to wear a pad as a precaution in case of occasional leakage were also considered to be continent. We defined three grades of incontinence: grade 1, “dry” patients; grade 2, patients whose coughing or straining leads to urinary leakage; and grade 3, patients with urinary leakage even at low physical activity.

RESULTS Thirty-six of the 69 patients who underwent an NSRP were at pathologic Stage pT2. No positive surgical margin was found in these patients (Table II). Sixty-five of the 220 non-NSRP patients were at Stage pT2; 1 had a positive margin. The average cancer volume was 2.13 +- 1.55 cm3 in the NSRP group and 2.66 ? 1.59 cm3 in the non-NSRP group. The difference was not statistically significant (P = 0.239, B = 0.748). Similarly, for the patients who had unilateral capsular penetration (histologic Stage pT3a), the difference between NSRP and non-NSRP patients according to margin status was not statistically significant (P = 0.294, z = 0.728). Twenty-seven of UROLOGY

51 (3), I998

TABLE II.

Incidence of positive surgical margins aRer radical prostatectomy No. of Non-Nerve-Sparing

Stages pT2 (organ confined) pT3a (unilateral capsular penetration) pT3b (bilateral capsular penetration) pT3c (infiltration of seminal vesicles)

l/65 23/78 10/14 25/63

No. of Nerve-Sparing

P Value *

O/36 (0) 1O/27 (37.0) o/o l/6 (16.7)

0.239 0.294 -

(1.5)+ (39.5) (71.4) (39.7)

0.273

* Wilcoxon test. ’ Numbers in parentheses are percents.

Freedom of recurrence aiter radical prostatectomy at Stages pT2, pT3a, and pT3c (PSA less than 0.4 nglmL)

TABLE III.

No. of Non-Nerve-Sparing

pT2 pT3a pT3c

at Postop Month:

No. of Nerve-Sparing

at Postop Month:

6

12

18

24

6

12

18

24

34734 (lOO)* 47/48 (97.9) 37/43 (86)

25725 (100) 35/37 (94.6) 26/32 (81.3)

16716 (100) 17/20 (85) 14/22 (63.6)

12712 (100) 7/l 0 (70) 6/l 2 (50)

18/18 (100) 19/l 9 (100) 2/3 (66.7)

14114 (100) 13/l 4 (92.9) l/2 (50)

7/7 (100) 576 (83.3) -

4/4 (100) 3/5 (60) -

Stages

KEY: PSA

= prostate-specijc antigen; postop = postoperative. * Numbers in parentheses are percents.

TABLE IV.

Freedom of recurrence after radical prostatectomy at Stages pT2, pT3a, and pT3c (PSA less than 0.025 nglmL) No. of Non-Nerve-Sparing

Stages pT2 pT3a pT3c

6 34/34(100)* 46/48 (95.8) 35/43 (81.4)

KEY: PSA

12 25125 (100) 34/37 (91.9) 24/32 (75)

= prostate-specijic antigen; pomp * Numbers in parentheses are percents.

at Postop Month: 18

6

15/16(93.8) 11/12 (91.7) 18/18(100) 16/20 (80) 7/10 (70) 19/l 9 (100) 1 l/22 (50) 4/14 (33.3) 2/3 (66.7)

12

at Postop Month: 18

24

13/14(92.2) 7/7 (100) 4/4(100) 12/l 4 (85.7) 5/6 (83.3) 3/5 (60) l/2 (50) -

= postoperative.

the patients who underwent NSRP were at Stage pT3a. In 10 patients a positive margin was detected; however, in only 2 of these patients it was found only on the nerve-sparing side of the prostate. In 7 patients margin was positive on the side where the neurovascular bundle was excised, and in 1 patient a bilateral positive margin was found. Average cancer volume was 4.71 ? 3.1 cm3 in the NSRP group and 6.95 ? 6.42 cm3 in the non-NSRP group. A nerve-sparing technique was not used in patients at Stage pT3b, because a significant amount of cancer, which led to bilateral capsular penetration, was revealed preoperatively by the systematic biopsy in all these cases. The 14 patients at this stage underwent a non-NSRP, and in 10 (71%) a positive margin was detected. An infiltration of the seminal vesicles (Stage pT3c) was seen in 69 patients: in the 6 patients from the NSRP group (average cancer volume 10.62 + 8.6 cm3>, margin status was positive in 1 patient. However, this was detected on the side where the neurovascular bundle was excised and therefore not due to the nerve-sparing technique. In the 63 patients who underwent a nonUROLOGY 51 (31, 1998

24

No. of Nerve-Sparing

NSRP (average cancer volume 13.3 2 9.8 cm3>, a positive margin was found in 25 (39.7%). Again, the difference in the incidence of positive margins was not statistically significant (P = 0.273, z = 0.872). Rates of recurrence in NSRP and non-NSRP patients at various clinical stages and after various periods of postoperative follow-up are shown in Table III. Statistical analysis was performed by using Wilcoxon’s test. No statistically significant differences in the incidence of biochemical relapse was found between the two surgical approaches. The same analysis was performed by using an ultrasensitive PSA test. PSA recurrence by this approach is diagnosed roughly a year earlier with this test than with a native PSA determination, so tumor progression was generally detected in a higher percentage of patients. Again, no significant difference was seen between the NSRP and the nonNSRP patients (Table IV). Table V shows the rates of continence in both groups of patients 6 and 12 months after surgery at Stages pT2 and pT3. The difference between the two groups was not statistically significant (P = 0.43). In a multivariate analysis, we could not find 439

TABLE V. Postoperative urinary continence and surgical technique after radical prostatectomy (stage pl’2 and pT3) No. of Non-Nerve-Sparing

No. of Nerve-Sparing

6-mo follow-up(n = 171) Grade 102 (75) O/l 20(14.7) 2 14(10.3) 3 136(100)

27 (77.1) 4(11.4) 4 (11.4) 35 (100)

12-mo follow-up(n = 150) Grade 102 (84.3) O/l 11 (9.1) 2 8 (6.6) 3 121 (100)

26 2 2 29

*Numbers

(89.7) (6.9) (6.9) (100)

in parentheses me percents

any influence of the nerve-sparing technique on postoperative continence.16 COMMENT The frequency of radical prostatectomy to cure localized prostate cancer has increased in the last few years. The combination of preoperative investigations, such as DRE, transrectal ultrasonographic examination, PSA measurement, percentage of free PSA, and systematic prostate biopsies, is useful in selecting patients whose disease is at lower clinical and pathologic stage. Especially for younger patients the possibility of postoperative erectile dysfunction is often hard to accept, and attempts to preserve potency should be made whenever they are safe. Reliable selection criteria are necessary to allow adequate and safe application of a nerve-sparing surgical approach without compromising the removal of the cancer. However, no objective and accepted selection criteria exist, and the reported studies addressing the results of the nerve-sparing modification are based on patients selected by DRE, PSA, or intraoperative findings. Van den Ouden et al.17 reported no higher incidence of positive surgical margins in patients who underwent NSRP in a study in which 108 of 172 prostatectomy patients underwent NSRP; the surgical technique was selected intraoperatively. Catalona and Bigg3 reported that complete tumor excision, as defined by organ-confined tumor, was achieved in 41% of patients who underwent unilateral and in 59% of patients who underwent bilateral nerve-sparing procedures. However, they estimated that 55% of positive margins were due to improper application of the nerve-sparing technique. In their series the decision whether to preserve or excise the neurovascular bundle was based 440

on DRE and intraoperative findings. In an editorial comment concerning that article, Stamey18 stated that the NSRP should be used with caution and that the decision to spare or to perform a wide excision of the neurovascular bundle should be made preoperatively. We agree with the opinion that a preoperative decision whether the nervesparing approach will be performed or not is desired because this is important information when a patient with prostate cancer is advised about treatment options. In another study Catalona and Dresnerlg reported no statistically significant difference in the incidence of positive surgical margins between patients who underwent an NSRP and a non-NSRP control group. However, 18% of the patients at Stages Tl and T2a and 57% of the patients at Stage T2b had positive surgical margins; the incidence might have been lower with better selection criteria. In various reports on the results of nerve-sparing surgery Walsh et al.8 and Eggleston and Walsh9 stated that there was no indication that it compromised the adequacy of cancer removal, which they stated to be determined primarily by the extent of the cancer rather than the operative technique. However, the impact of positive surgical margins on biochemical relapse after RP still remains unclear. In a multivariate evaluation of pathologic parameters Epstein et al .20 found that analysis of surgical margin enhanced prediction of biochemical relapse after RP, although it was less influential than Gleason grade. Scardin found the surgical margin status to be an independent predictor of biochemical relapse. In a recent study Ohori et ~1.2~ could show that, in patients with moderate cancer and only unilateral capsular penetration, margin status had a significant impact on the outcome after RP. These data emphasize that an artificial positive margin, produced by sparing the neurovascular bundle on a side of the prostate where the capsule is already penetrated by the tumor, will most probably adversely affect the outcome. Therefore, it is crucial to recognize the side of the prostate where the cancer is non-organ-confined preoperatively. Additionally, one has to be aware that our series is difficult to compare with a series from the United States because, in general, the percentage of patients with capsular penetration of the cancer is higher at our institution than in the above-mentioned studies. Therefore, objective selection criteria for our patients are needed to avoid positive surgical margins due to an improper indication for this technique. Another aim of this study is to present objective and reproducible selection criteria. The selection criteria noted above are based on rather subjective investigations, such as DRE and intraoperative findings, which implies that a surgeon would need UROLOGY 51 (3),1998

enormous clinical experience to obtain similar results. Our selection criteria are based on a simple, reliable, and objective procedure that can be safely applied to patients without the need of many years of clinical experience. We believe that performing a systematic sextant biopsy is the best tool today for estimating tumor extent preoperatively to support the choice of a surgical technique. This is documented by the fact that none of our patients who underwent NSRP had a bilateral capsular penetration (Stage pT3b). In all the patients who had significant tumor bilaterally, this was detected by the biopsy preoperatively, and those patients underwent a non-NSRP. We believe that systematic sextant biopsy detects large low differentiated prostate cancer, because there will be bilateral positive biopsies in these cases, which implies that the findings in systematic sextant biopsy are proper criteria for the selection of a nervesparing or non-nerve-sparing procedure. It is appropriate in patients whose PSA recurrence is affected by margin status, because it identifies small and welldifferentiated cancers. Those are exactly the criteria demanded by other investigators for the application of a nerve-sparing procedure.3,9J8 Nevertheless, we have found 2 patients with positive margins due to a nerve-sparing technique (both at Stage pT3a with a moderately differentiated cancer). The positive surgical margins might have been avoided if a non-nerve-sparing technique would have been performed. One of the 2 patients is now PSA positive and treated with additional hormone therapy; the other still remains PSA negative. In these 2 patients the sextant biopsy failed to detect substantial cancer preoperatively on the nerve-sparing side. The disadvantage of our method is an overestimation of clinically relevant extension of the carcinoma when it is used as strictly as we use it. We are not preserving the neurovascular bundle when there is any positive biopsy on that side. Because of this strict application, we have not performed any bilateral nerve-sparing procedure so far. When pathologic workup of the prostate reveals an organ-confined cancer without capsular penetration and this man has been excluded from an NSRP because of bilateral tumor finding in the systematic sextant biopsy, one could assume that this was done unnecessarily. This happens in approximately 30% of those patients who undergo a nonNSRP at our institution. Loch et ~1.~~showed that in the most prostatic specimens from patients with biopsy-proved bilateral prostate cancer, an additional incidental carcinoma causes positive biopsies on one side. Therefore, excluding, for example, patients with only one positive biopsy and a low Gleason score on the affected side from a nerve-sparing procedure might be too strict; we have no way so far to distinguish UROLOGY 51 (31, 1998

between clinically relevant and incidental tumor in the biopsy core. In a running study, we try to create an algorithm, including preoperative investigations, to recognize patients with organ-confined disease preoperatively-in all these patients, an NSRP would be a safe procedure. Consistent with our findings, Daniels et al4 showed that contralatera1 negative biopsies in patients with unilateral palpable disease predicted low volume, localized tumor and a negligible likelihood of positive surgical margins when a contralateral nerve-sparing approach was used. All patients in our study had negative biopsies on the nerve-sparing side, and bilateral tumor extension was found in 82% of prostate specimens; this shows that negative findings do not imply the absence of prostate cancer but the absence of clinically relevant tumor extension. We are now preparing another series in which NSRP was performed again on the basis of the result of the biopsy but less strict. In some cases the neurovascular bundle was preserved also when only one of the three ipsilateral cores showed low differentiated cancer. This approach seems to be as safe as the described strict approach but includes more patients. No positive surgical margin was found on the nerve-sparing side so far. However, only a few patients were operated on according to these selection criteria, and the data are preliminary. The benefit of the nerve-sparing technique needs to be seen in the light of the above-mentioned data on an adverse effect of a positive surgical margin on the outcome of RP. A patient who underwent an NSRP with a positive margin on the side where the bundle was preserved will face a higher likelihood of tumor recurrence than a patient whose wide excision will leave negative margins with the same pathologic features. There have been numerous studies on the recovery of erectile function after a nerve-sparing operation2J*6~8~20; they have generally reported high recovery rates (30% to 81%). Interestingly, the latest data on postoperative potency are less enthusiastic than earlier reports. Reviewing the published reports, one encounters the problem that postoperative potency and erectile function are not clearly defined. In addition, for some reason chart reviews in general lead to better results than anonymous questionnaires. The data in the presented reports on erectile function are mainly based on chart reviews. In a very careful recent study, Geary et al.24 found that only 13.3% of patients were potent after a unilateral preservation of the neurovascular bundle and reported that less than half of those patients were satisfied with their erectile function. In an earlier series from our institution we reported postperative potency in approximately 33 O /o.25 However, our data were based on a chart review. For the present study we evalu441

ated postoperative erectile function by an anonymous questionnaire. Twelve of the reported 69 patients (17.4%) who underwent a unilateral NSRP stated they were able to have postoperative sexual intercourse without any artificial aid. We expect that this rate will improve in the future by a more sparing technique, especially in the area of the seminal vesicles. Nevertheless, complete tumor excision is by far the most important aim of radical prostatectomy; to us it seems more important to heal a patient and risk his impotence than to accept the risk of a positive surgical margin due to an improper application of a surgical technique. Like many earlier investigators, we showed that preserving the neurovascular bundle does not influence postoperative urinary continence.2,26 In a multivariate analysis, we could not find an influence of the nerve-sparing technique on postoperative continence. We found that the postoperative continence is mainly influenced by the function of the external spincter muscle, which is routinely tested at our institution preoperatively.‘6 CONCLUSIONS We reported on the results of systematic sextant biopsiy as safe and easy selection criteria for the appropriate application of NSRP: in 4.3% of patients, positive margins were found on the nervesparing side. On the assumption that all non-NSRP patients who had pT2 tumors were candidates for a nerve-sparing approach (65 of 220 patients or 29.5%), we excluded those patients unnecessarily from NSRP, because of nonrelevant tumor findings in preoperative biopsies. However, the safety of the selection criteria was shown. We excluded some patients unnecessarily, but a strict and safe indication is better than exclusion of all patients from a nerve-sparing approach because of fear of positive margins or, in contrast, risking PSA recurrence because of positive margins after improper preoperative and intraoperative assessment. REFERENCES 1. Walsh PC, Lepor H, and Eggleston JC: Radical prostatectomy with preservation of sexual function: anatomical and pathological considerations. Prostate 4: 473-485, 1983. 2. Catalona WJ, and Basler JW: Return of erections and urinary continence following nerve sparing radical retropubic prostaectomy. J Ural 150: 905-907, 1993. 3. Catalona WJ, and Bigg SW Nerve-sparing radical prostatectomy: evaluation of results after 250 patients. J Urol 143: 538-543,199o. 4. Daniels GF Jr, McNeal JE, and Stamey TA: Predictive value of contralateral biopsies in unilaterally palpable prostate cancer. J Uroll47: 870-874, 1992. 5. Leandri P, Rossignol G, Gautier JR, and Ramon J: Radical retropubic prostatectomy: morbitidy and quality of life. Experience in 620 consecutive cases. J Urol 147: 883-887, 1992. 6. Quinlan DM, Epstein JI, Carter BS, and Walsh PC: Sex442

ual function following radical prostatectomy: influence of preservation of neurovascular bundles. J Urol145: 998-1002, 1991. 7. Rossignol G, Leandri P, Gautier JR, and Ramon J: Radical prostatectomy in stage A carcinoma of the prostate. Eur Urol21: 269-273,1992. 8. Walsh PC, Epstein JI, and Lowe FC: Potency following radical prostatectomy with wide unilateral excision of the neurovascular bundle. J Urol 138: 823-827, 1987. 9. Eggleston JC, and Walsh PC: Radical prostatectomy with preservation of sexual function: pathological findings in the first 100 cases. J Urol 134: 1146-1148, 1985. 10. Villers A, McNeal JE, Redwine EA, Freiha FS, and Stamey TA: The role of perineural space invasion in the local spread of prostatic adenocarcinoma. J Urol 142: 763-768, 1989. 11. Huland H, Hiibner D, and Henke RP: Systematic biopsies and digital rectal examination to identify the nerve-sparing side for radical prostatectomy without risk of positive margin in patients with clinical stage T2, NO prostatic carcinoma. Urology 44: 211-214,1994. 12. McNeal JE, Redwine EA, Freiha FS, and Stamey TA: Zonal distribution of prostatic adenocarcinoma: correlation with histologic pattern and direction of spread. Am J Path01 12: 897, 1988. 13. Gleason DF, and Veterans Administration Cooperative Urological Research Group: Histologic grading and clinical staging of prostate carcinoma, in Tannenbaum M (Ed): Urologic Pathology: The Prostate. Philadelphia, Lea 61 Febiger, 1997, pp 171-197. 14. Henke RP, Kruger E, Ayhan N, Htibner D, Hammerer P, and Huland H: Immunhistochemical detection of P53 protein in human prostatic cancer. J Urol152: 1297-1301, 1994. 15. Huland E, Haese A, Htibner D, and Huland H: Supersensitive detection of PSA and the followup after radical prostatectomy. J Urol 151: 130A, 1994. 16. Hammerer P, Michl U, Meyer-Moldenhauer H, and Huland H: Urethral closure pressure changes with age in men. J Urol156: 1741-1743,1996. 17. van den Ouden D, Bentvelsen FM, Boeve ER, and Schroder FH: Positive margins after radical prostatectomy: correlation with local recurrence and distant progression. Br J Uro172: 489-494,1993. 18. Stamey TA: Editorial comment. J Urol143: 543,199O. 19. Catalona WJ, and Dresner SM: Nerve-sparing radical prostatectomy: extraporstatic tumor extension and preservation of erectile function. J Urol 134: 1149-1151, 1985. 20. Epstein JI, Pizov G, and Walsh PC: Correlation of pathologic findings with progression after radical retropubic prostatectomy. Cancer 71: 3582-3593, 1993. 21. Scardino P: Prostate Cancer Treatment: Stage by Stage. Seminar 9655, AUA 1996. 22. Ohori M, Wheeler TM, Kattan MW, Goto Y, and Scardino PT: Prognostic significance of positive surgical margins in radical prostatectomy specimens. J Urol 154: 18181824,1995. 23. Loch T, McNeal JE, and Stamey TA: Interpretation of bilateral positive biopsies in prostate cancer. J Urol 154: 1078-1083,1995. 24. Geary ES, Dendinger TE, Freiha FS, and Stamey TA: Nerve sparing radical prostatectomy: a different view. J Urol 154: 145-149,1995. 25. Hammerer P, Htibner D, Gonnermann D, and Huland H: Perioperative und postoperative Komplikationen der pelvinen Lymphadenektomie und radikalen Prostatektomie bei 320 konsekutiven Patienten. Urologe (A) 34: 334-342,1995. 26. Narayaan P: Nerve sparing and continence preservation during radical prostatectomy. Urol Int 46: 266-274, 1991. UROLOGY

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