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Clinical Significance of Benign Glands at Surgical Margins in Robotic Radical Prostatectomy Specimens
Adult Urology Clinical Significance of Benign Glands at Surgical Margins in Robotic Radical Prostatectomy Specimens Shane K. Kohl, Kethandapatti C. Balaji, Lynette M. Smith, Nicholas P. Wilson, Sonny L. Johansson, Samuel P. Sterrett, and Neil A. Abrahams OBJECTIVES
METHODS
RESULTS
CONCLUSIONS
Completion of robotic radical prostatectomy compared with conventional open retropubic radical prostatectomy can result in different alterations in the prostatectomy specimens. One difference appears to be an increased incidence of benign glands at the margins, which has been associated with an increase in postoperative prostatic-specific antigen (PSA) levels. We compared the frequency and clinical significance of benign prostate glands at the surgical margins in radical prostatectomy specimens obtained by robotic versus open retropubic prostatectomy. We reviewed 38 consecutive prostatectomy specimens from patients with biopsy-proven prostate cancer. Of these 38 specimens, 25 (65%) were obtained by robotic resection and 13 (35%) by open retropubic prostatectomy. Each case was analyzed for Gleason score, pathologic stage, including margin status, and the presence or absence of benign glands at the surgical margin. The study endpoint was the postoperative serum PSA level. A significantly greater incidence (P ⫽ 0.035) of benign glands at the surgical margins was found within the robotic group compared with the open retropubic prostatectomy group (54% versus 15%). With a median follow-up of 12.5 months for the robotic group and 24.5 months for the robotic prostatectomy group, only 2 patients, who also had had positive surgical margins, had a continued and persistent increase in the postoperative PSA level after an initial nadir. The early clinical follow-up data of our study have suggested that patients undergoing robotic radical prostatectomy with negative surgical margins achieve a PSA nadir of less than 0.1 ng/mL, irrespective of the presence or absence of benign prostatic tissue at the surgical margins. UROLOGY 69: 1112–1116, 2007. © 2007 Elsevier Inc.
A
t present, more than 200 da Vinci robotic surgical instruments have been installed in medical institutions worldwide, with an estimated 9000 robotic radical prostatectomies performed in 2004.1 Recent early studies have suggested a possible benefit in postoperative outcomes for robotic radical prostatectomy. Among the benefits described have been a decrease in estimated blood loss, postoperative recovery period, and, depending on the series, increased urinary continence and sexual function preservation.2– 6 However, some uncertainty still remains regarding the cancer control efficacy of robotic prostatectomy compared with retropubic surgery. The increase in the use of robotic prostatectomy has been paralleled by studies comparing the clinical and
From the Departments of Pathology and Microbiology, Surgery, Division of Urologic Surgery, and Preventive and Societal Medicine, University of Nebraska Medical Center, Omaha, Nebraska Reprint requests: Neil A. Abrahams, M.D., Department of Pathology and Microbiology, University of Nebraska Medical Center, 987549 Nebraska Medical Center, Omaha, NE 68198. E-mail: [email protected] Submitted: February 28, 2006; accepted (with revisions): February 27, 2007
1112
© 2007 Elsevier Inc. All Rights Reserved
surgical differences of robotic prostatectomy and open retropubic prostatectomy. These studies have focused on the initial experience needed to gain proficiency in this surgically challenging technique, as well as comparing the incidence of surgical complications and overall differences in pathologic stage.2– 4,7,8 No studies to date have been done that have focused purely on the pathologic alterations that robotic surgery has on the radical prostatectomy specimen (RPS) and the effect this might have on the overall clinical management of the disease. At our institution, we routinely report the findings of benign glands at the surgical margin in open retropubic specimens, because this finding can be associated with a postoperative increase in the serum PSA level and, therefore, be confused with tumor recurrence or an undetected positive surgical margin (PSM).9 –11 Some investigators have used the term “incompletely excised prostate gland” to alert the clinician that benign prostatic tissue might have been incompletely excised. For the purposes of this study, a PSM was defined as malignant gland present at the surgical margin and incompletely excised (IE) as benign gland present at the surgical margin. 0090-4295/07/$32.00 doi:10.1016/j.urology.2007.02.048
In this study, we explored whether the method of performing radical prostatectomy (robotic versus conventional retropubic open) influenced the pathologic outcomes, as determined by a focused analysis of the specimens, and compared the frequency and clinical significance of the presence of benign glands at the surgical margins in prostatectomy specimens obtained by the two surgical approaches.
MATERIAL AND METHODS
Clinical Information and Follow-up Data All patients had biopsy-proven prostate adenocarcinoma. The clinical information regarding age and preoperative serum PSA level was obtained from the patients’ medical records. The postoperative serum PSA values were measured at each follow-up visit and documented. A PSA nadir was considered as an immediate postoperative level of less than 0.1 ng/mL. Postoperative serum PSA increases were considered to either represent recurrent disease or residual prostatic tissue, depending on the pathologic stage (PSMs or benign glands present at the surgical margin) and clinical scenario (PSA increasing without a plateau phase).
Surgery To minimize the effect of surgical technique and experience gained over time by the surgeon, as well as to limit any surgical bias in the study, all the procedures were performed by a single surgeon. As such, a cohort of 38 consecutive RPSs (robotic and open prostatectomy performed by the same surgeon) from patients with biopsy-proven prostate cancer were reviewed. The time frame (May 2001 to May 2004) chosen to review the cases was chosen after the surgeon had gained sufficient experience to be categorized as adept in the procedure and had already performed more than 60 cases of robotic prostatectomy and would thus be considered to be at the height of the learning curve.
Pathology In an effort to substantially limit any bias in tissue sampling technique or partial tissue submission, all prostatectomy specimens were reviewed by a single pathologist with subspecialty genitourinary pathology training. In our institution, all radical prostatectomy specimens are entirely embedded for histologic examination, eliminating the possibility of pathologically understaging the disease (undetected PSM). The RPSs were initially weighed and inked and had the apex (approximately 0.4 cm) amputated. After formalin fixation, the entire prostate was submitted according to a standard protocol and map, as previously described and reported.12,13 In brief, the apex was radially sectioned, and the body of the prostate was sectioned transversely at 2 to 3-mm intervals and divided into quarters to fit into the specimen cassettes. The right and left vas deferens and seminal vesicles were removed and two proximal perpendicular sections were submitted. The prostate base (bladder neck) was then divided into the mid, right, and left portions, sectioned perpendicularly to the inked margin, and submitted. The hematoxylin-eosin sections on all blocks were reviewed.
Histologic Evaluation and Pathologic Stage A single genitourinary pathologist reviewed all slides from the RPSs for the study, and each case was analyzed for Gleason score, perineural involvement, pathologic stage information (tumor location, extraprostatic extension, and seminal vesicle invasion), tumor volume, and margin status (PSM), including the presence of benign glands at the margin (IE). In all cases, and in all RPSs from the robotic and open groups, the presence of benign glands at the margin (IE) was evaluated, irrespective of the presence or absence of tumor at the surgical margin (PSM). This was done to control for potential stage bias. All foci of tumor were mapped separately, and the tumor volume was measured, as previously described.13 The extent of the PSMs and IE were measured from the glass slide in millimeters and documented according to the location and number of cross-sections involved. UROLOGY 69 (6), 2007
Statistical Analysis Statistical analysis was performed using Statistical Analysis System software, version 9.1 (SAS Institute, Cary, NC). Tumor size was compared between the surgery methods using a t test. The Wilcoxon rank sum test was used to compare the other continuous variables between the groups. The categorical variables were compared with Fisher’s exact test. Tests with P values less than 0.05 were considered statistically significant.
RESULTS Surgery A single surgeon, with 3 years’ experience with the da Vinci robotic system, who had performed more than 60 robotic prostatectomies, performed 38 consecutive prostatectomies from May 2001 to May 2004. Of these 38, 25 (65%) were robotic and 13 (35%) were open. Pathologic Findings, Histologic Evaluation, and Pathologic Stage The Gleason scores were evenly distributed between the two groups (Table 1). Of the 38 RPSs, the Gleason combined score was 6 or less in 8 robotic cases versus 4 open cases, 7 in 10 robotic cases versus 8 open cases, 8 or more in 6 robotic cases versus only 1 open case. One case was not graded because the patient had received preoperative hormonal therapy and had a marked therapy effect on the tumor. The mean tumor volume was similar in both groups (1.5 ⫾ 0.8 cm for the robotic versus 1.7 ⫾ 0.4 cm for the open group), with a slight increase in the number of tumor foci found in the robotic group (mean 1.80, range 1 to 3) compared with the number found in the open group (mean 1.36, range 1 to 2). Perineural invasion and seminal vesicle invasion were similar in both groups. A slight stage bias toward pT2 was found in both groups, with 69% and 72% of the cases being pT2 in the open and robotic groups, respectively. Because the differences in pathologic stage between the two groups were not statistically significant (P ⫽ 1.0), this variable was not considered to significantly affect the overall differences in the other variables studied. The incidence of PSMs was greater in the robotic group (28%) than in the open group (8%). However, this finding was not statistically significant (P ⫽ 0.22). The PSMs were distributed as follows in the robotic group: five involved the posterolateral aspects of the prostate 1113
Table 1. Summary of clinicopathologic findings between robotic retropubic radical prostatectomy and open retropubic radical prostatectomy Characteristic Follow-up (mo) Median Range Unknown Age (yr) Median Range Preoperative PSA (ng/mL) Median Range Unknown Postoperative PSA (ng/mL) ⬍0.1 ⬎0.1 Stage pT2a-c pT3 Gleason score 6 7 8–9 Tumor size Mean ⫾ SD Range Tumor foci (n) 1 2 3 Perineural invasion No Yes Seminal vesical invasion No Yes EPE present No Yes Tumor at inked margin (PSM) No Yes Extent of positive margin (mm) (n ⫽ 8) Mean Range Benign glands at margin (IE) No Yes Extent of benign glands at margin (mm) (n ⫽ 15) Mean Range
ORRP (n ⫽ 13)
RRRP (n ⫽ 25)
P Value
24.5 8.5–59.5 1
12.5 2.5–23.0 5
0.005
58 49–71
61 48–79
0.52
5.3 4.9–15.2 5
6.3 0.1–24.9 5
0.51
12 (100) 0
18 (90) 2 (10)
0.52
9 (69) 4 (31)
18 (72) 7 (28)
1.0
4 (31) 8 (62) 1 (8)
8 (33) 10 (42) 6 (25)
0.44
1.7 ⫾ 0.4 1.1–2.5
1.5 ⫾ 0.8 0.3–3.5
0.27
7 (64) 4 (36) 0
9 (36) 12 (48) 4 (16)
0.23
2 (15) 11 (85)
11 (44) 14 (56)
0.15
12 (92) 1 (8)
22 (88) 3 (12)
1.0
8 (62) 5 (38)
18 (72) 7 (28)
0.71
12 (92) 1 (8)
18 (72) 7 (28)
0.22
1.5 ⫾ NA NA 11 (85) 2 (15) 3.0 ⫾ 2.1 1.5–4.5
4.4 ⫾ 3.3 1–10
NA
11 (46) 13 (54)
0.035
3.3 ⫾ 2.0 1–6
0.93
ORRP ⫽ open retropubic radical prostatectomy; RRRP ⫽ robotic retropubic radical prostatectomy; PSA ⫽ prostatic-specific antigen; EPE ⫽ extraprostatic extension; PSM ⫽ positive surgical margin; NA ⫽ not available; IE ⫽ incompletely excised. Data presented as mean ⫾ SD or numbers with percentages in parentheses.
superior to the neurovascular bundles and two occurred at the apex. The only PSM in the open group involved the posterolateral aspect of the prostate. A noticeably increased incidence of IE was identified in the robotic group (54%) compared with the open group (15%). This finding was statistically significant (P ⫽ 0.035). The anatomic location of IE was predominantly at the apex in 2 of the open cases and 9 of the robotic cases. In the remaining robotic cases, IE was identified at the prostatic 1114
base. The extent of benign glands at the surgical margin was marginally greater in the robotic group (mean linear length 3.3 ⫾ 2.0 mm) than that in the open group (mean linear length 3.0 ⫾ 2.1 mm; P ⫽ 0.93). Clinical Information and Follow-up Data The median patient age of the robotic group was 61 years versus 58 years for the open group. The postoperative PSA values were measured in all patients for a minimum UROLOGY 69 (6), 2007
of 6 months, except for 6 patients who were lost to follow-up after the 6-week postoperative evaluation period. The median postoperative follow-up duration was 12.5 months for the robotic group and 24.5 months for the open group. The median preoperative PSA level was 6.3 ng/mL in the robotic group and 5.3 ng/mL in the open group. In patients with long-term PSA follow-up, the postoperative PSA nadir (less than 0.1 ng/mL) was achieved in 18 (90%) of 20 patients in robotic group and 12 (100%) of 12 patients in open group. The 2 patients who did not achieve a PSA nadir in the robotic group also had PSMs, accounting for the postoperative serum PSA increase (2.8 ng/mL and 2.6 ng/mL). These 2 patients had pathologic Stage pT2b and pT3b disease, with PSMs located on the right lateral apex and right posterolateral base (Table 1). The stratification of patients according to a PSA level greater 0.2 ng/mL and surgery type is given in Table 1.
COMMENT The robotic method uses laparoscopic techniques complemented by the da Vinci Surgical Robotic Surgical System, which provides three-dimensional visualization and EndoWrist movements with six degrees of freedom, greatly facilitating intracorporeal suturing. The clinical advantages of robotic radical prostatectomy such as decreased intraoperative blood loss and quicker convalescence compared with conventional open methods are being studied. Several recent studies examining the use of the da Vinci Surgical Robotic Surgical System in radical prostatectomy have had promising findings compared with conventional open approaches.2,3,8 One prospective study comparing robotic-assisted prostatectomy (da Vinci surgical system) and open radical retropubic prostatectomy showed longer mean operative times (4.8 hours versus 2.3 hours), less mean blood loss (329 mL versus 970 mL), less postoperative pain, and earlier discharge times for robotic-assisted prostatectomy, with no significant difference in pathologic stage, margin status, or complication rates.2 Differences in surgical techniques and instrumentation can result in alterations of the RPSs. We have observed subtle gross and histologic differences between robotic and retropubic prostatectomy specimens. These have included, at the macroscopic level, the presence of an irregular excisional surface, with multiple foci of cautery artifact and less extraprostatic soft tissue. At the microscopic level, the most noticeable findings have included increased cautery artifact at the surgical margin and the presence of surgeon-induced capsular incision. In addition, specimen processing, slide interpretation, and whether multiple or one pathologist reviews the slides all have influence on the final pathology report, with a substantial impact on treatment.14,15 One study found that approximately 12% of margins could be missed (pathologic understaging), depending on whether the prostate was sectioned at 5-mm versus 2 to 3-mm UROLOGY 69 (6), 2007
intervals.16 In another study, 5 of 7 cases with initial Stage pT2 disease were later upstaged on repeat review of the original slides and additional 2-mm sections.10 To eliminate the pitfalls of surgeon experience, histologic sample bias, and interobserver differences with regard to pathologic interpretation, we selected a cohort of RPSs obtained by a single surgeon and histologically sectioned and reviewed in an identical manner by a single genitourinary pathologist, with the entire prostate submitted for evaluation. Our reported rate of PSMs in the robotic group versus the open group, 28% versus 8%, can be considered definitive and free of any sampling bias. The PSMs in the RPSs from open retropubic surgery have a reported incidence of 15% to 58% and our results are in keeping with the published data.2,14,17–19 The incidence of PSMs in the robotic group (28%) was slightly greater than reported in other studies using robotic-assisted radical prostatectomy (17.5% and 26%).2,3,8 This could be because of the understaging of cases previously reported (the prostate gland was not entirely submitted in previously cited studies) and surgeon experience with the robotic instrument. Benign glands extending to the surgical margins secondary to capsular incision have a reported incidence of 8% to 66%.18,20 The significance regarding their role in postoperative PSA levels has been investigated with mixed results.9,17,20 The main concern of such findings is that the postoperative PSA elevation secondary to the presence of benign glands could potentially lead to false categorization and unnecessary treatment. It has been proposed that if benign glands had an effect on postoperative PSA levels, one would expect low, relatively stable PSA levels, especially when considering that 1 g of benign prostatic hypertrophy tissue has been shown to produce, on average, a 0.31-ng/mL increase in PSA.9 One study examining 351 RPSs from open prostatectomy found an incidence of 27% of IE and that 79% of the patients with Stage pT2 disease and benign glands at the surgical margin had postoperative detectable PSA levels at a mean follow-up of 5 years.21 In other studies, the presence of benign and malignant glands at the surgical margins had less impact on postoperative biochemical progression compared with that of extraprostatic extension.17 To the best of our knowledge, no published studies have focused on the incidence of benign glands at the margin of RPSs from robotic surgery. Therefore, our incidence of 54%, although seemingly high, has no point of comparison. Despite this seemingly high incidence of IE, a PSA postoperative nadir of less than 0.1ng/mL was achieved, irrespective of the presence of benign glands or tumor cells extending to the surgical margins. In the 2 cases with a postoperative increase in the serum PSA level, these elevations were accounted for by the presence of PSMs in both cases, as well as extraprostatic extension in 1 case. The use of electrocautery as a means of dissection in the robotic group was more liberal. This 1115
cautery can allow for several additional millimeters of tissue margin and, as such, it might be that no benign prostatic tissue was left in the prostatic bed. This study had some limitations. The follow-up period was relatively short, and longer follow-up and larger cohorts of patients are needed to clearly establish the significance of benign prostate glands at the surgical margins in robotic specimens. Although the present study identified a significant difference in the rate of the presence of benign glands at the margins of RPSs between the open and robotic methods, a larger sample size would help to validate our initial findings. Also, because of the relatively short follow-up period (12.5 months for the robotic group and 24.5 for the open group), longer follow-up would be desirable before drawing conclusions about the oncologic outcomes.
CONCLUSIONS The results of our study have shown that the incidence of benign prostate glands in patients undergoing robotic radical prostatectomy is significantly increased compared with that after open retropubic prostatectomy (P ⫽ 0.035). Although a greater rate of PSMs was noted for the robotic group compared with the open group, this was not statistically significant (P ⫽ 0.22). The early clinical follow-up results suggest that patients undergoing robotic radical prostatectomy for prostate cancer can achieve a PSA nadir of less than 0.1 ng/mL, irrespective of the presence or absence of benign prostatic tissue at the surgical margins. Furthermore, considerations for the lack of elevated postoperative PSA levels in the setting of PSMs and IE would include destruction of the glands secondary to ischemia and granulation tissue formation and the use of significant electrocautery at the surgical margins. References 1. Perrotti M, and Moran ME: Robotic prostatectomy outcomes. Urol Oncol 23: 341–345, 2005. 2. Menon M, Tewari A, Baize B, et al: Prospective comparison of radical retropubic prostatectomy and robot-assisted anatomic prostatectomy: the Vattikuti Urology Institute experience. Urology 60: 864 – 868, 2002. 3. Menon M, and Tewari A: Robotic radical prostatectomy and the Vattikuti Urology Institute technique: an interim analysis of results and technical points. Urology 61: 15–20, 2003. 4. Ahlering TE, Woo D, Eichel L, et al: Robot-assisted versus open radical prostatectomy: a comparison of one surgeon’s outcomes. Urology 63: 819 – 822, 2004.
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5. Bentas W, Wolfram M, Jones J, et al: Robotic technology and the translation of open radical prostatectomy to laparoscopy: the early Frankfurt experience with robotic radical prostatectomy and one year follow-up. Eur Urol 44: 175–181, 2003. 6. Cathelineau X, Rozet F, and Vallancien G: Robotic radical prostatectomy: the European experience. Urol Clin North Am 31: 693– 699, viii, 2004. 7. Ahlering TE, Skarecky D, Lee D, et al: Successful transfer of open surgical skills to a laparoscopic environment using a robotic interface: initial experience with laparoscopic radical prostatectomy. J Urol 170: 1738 –1741, 2003. 8. Menon M, Shrivastava A, Tewari A, et al: Laparoscopic and robot assisted radical prostatectomy: establishment of a structured program and preliminary analysis of outcomes. J Urol 168: 945–949, 2002. 9. Ravery V: The significance of recurrent PSA after radical prostatectomy: benign versus malignant sources. Semin Urol Oncol 17: 127–129, 1999. 10. Ravery V, de la Taille A, Toublanc M, et al: Prostate specimen reevaluation in patients with organ confined prostate cancer and postoperative biological recurrence. J Urol 155: 1981–1982, 1996. 11. Wood DP Jr, Peretsman SJ, and Seay TM: Incidence of benign and malignant prostate tissue in biopsies of the bladder neck after a radical prostatectomy. J Urol 154: 1443–1446, 1995. 12. Babaian RJ, Troncoso P, Bhadkamkar VA, et al: Analysis of clinicopathologic factors predicting outcome after radical prostatectomy. Cancer 91: 1414 –1422, 2001. 13. Chen ME, Johnston D, Reyes AO, et al: A streamlined threedimensional volume estimation method accurately classifies prostate tumors by volume. Am J Surg Pathol 27: 1291–1301, 2003. 14. Epstein JI: Incidence and significance of positive margins in radical prostatectomy specimens. Urol Clin North Am 23: 651– 663, 1996. 15. Epstein JI, Pizov G, and Walsh PC: Correlation of pathologic findings with progression after radical retropubic prostatectomy. Cancer 71: 3582–3593, 1993. 16. Hall GS, Kramer CE, and Epstein JI: Evaluation of radical prostatectomy specimens: a comparative analysis of sampling methods. Am J Surg Pathol 16: 315–324, 1992. 17. Barocas DA, Han M, Epstein JI, et al: Does capsular incision at radical retropubic prostatectomy affect disease-free survival in otherwise organ-confined prostate cancer? Urology 58: 746 –751, 2001. 18. Boccon-Gibod L, Ravery V, Vordos D, et al: Radical prostatectomy for prostate cancer: the perineal approach increases the risk of surgically induced positive margins and capsular incisions. J Urol 160: 1383–1385, 1998. 19. Watson RB, Civantos F, and Soloway MS: Positive surgical margins with radical prostatectomy: detailed pathological analysis and prognosis. Urology 48: 80 –90, 1996. 20. Shah R, Bassily N, Wei J, et al: Benign prostatic glands at surgical margins of radical prostatectomy specimens: frequency and associated risk factors. Urology 56: 721–725, 2000. 21. Djavan B, Sesterhann I, and Hruby S: Benign prostatic glands in the surgical margin of radical retropubic prostatectomies: redefining PSA nadir. J Urol 163: A624, 2000.
UROLOGY 69 (6), 2007
METHODS
RESULTS
CONCLUSIONS
Completion of robotic radical prostatectomy compared with conventional open retropubic radical prostatectomy can result in different alterations in the prostatectomy specimens. One difference appears to be an increased incidence of benign glands at the margins, which has been associated with an increase in postoperative prostatic-specific antigen (PSA) levels. We compared the frequency and clinical significance of benign prostate glands at the surgical margins in radical prostatectomy specimens obtained by robotic versus open retropubic prostatectomy. We reviewed 38 consecutive prostatectomy specimens from patients with biopsy-proven prostate cancer. Of these 38 specimens, 25 (65%) were obtained by robotic resection and 13 (35%) by open retropubic prostatectomy. Each case was analyzed for Gleason score, pathologic stage, including margin status, and the presence or absence of benign glands at the surgical margin. The study endpoint was the postoperative serum PSA level. A significantly greater incidence (P ⫽ 0.035) of benign glands at the surgical margins was found within the robotic group compared with the open retropubic prostatectomy group (54% versus 15%). With a median follow-up of 12.5 months for the robotic group and 24.5 months for the robotic prostatectomy group, only 2 patients, who also had had positive surgical margins, had a continued and persistent increase in the postoperative PSA level after an initial nadir. The early clinical follow-up data of our study have suggested that patients undergoing robotic radical prostatectomy with negative surgical margins achieve a PSA nadir of less than 0.1 ng/mL, irrespective of the presence or absence of benign prostatic tissue at the surgical margins. UROLOGY 69: 1112–1116, 2007. © 2007 Elsevier Inc.
A
t present, more than 200 da Vinci robotic surgical instruments have been installed in medical institutions worldwide, with an estimated 9000 robotic radical prostatectomies performed in 2004.1 Recent early studies have suggested a possible benefit in postoperative outcomes for robotic radical prostatectomy. Among the benefits described have been a decrease in estimated blood loss, postoperative recovery period, and, depending on the series, increased urinary continence and sexual function preservation.2– 6 However, some uncertainty still remains regarding the cancer control efficacy of robotic prostatectomy compared with retropubic surgery. The increase in the use of robotic prostatectomy has been paralleled by studies comparing the clinical and
From the Departments of Pathology and Microbiology, Surgery, Division of Urologic Surgery, and Preventive and Societal Medicine, University of Nebraska Medical Center, Omaha, Nebraska Reprint requests: Neil A. Abrahams, M.D., Department of Pathology and Microbiology, University of Nebraska Medical Center, 987549 Nebraska Medical Center, Omaha, NE 68198. E-mail: [email protected] Submitted: February 28, 2006; accepted (with revisions): February 27, 2007
1112
© 2007 Elsevier Inc. All Rights Reserved
surgical differences of robotic prostatectomy and open retropubic prostatectomy. These studies have focused on the initial experience needed to gain proficiency in this surgically challenging technique, as well as comparing the incidence of surgical complications and overall differences in pathologic stage.2– 4,7,8 No studies to date have been done that have focused purely on the pathologic alterations that robotic surgery has on the radical prostatectomy specimen (RPS) and the effect this might have on the overall clinical management of the disease. At our institution, we routinely report the findings of benign glands at the surgical margin in open retropubic specimens, because this finding can be associated with a postoperative increase in the serum PSA level and, therefore, be confused with tumor recurrence or an undetected positive surgical margin (PSM).9 –11 Some investigators have used the term “incompletely excised prostate gland” to alert the clinician that benign prostatic tissue might have been incompletely excised. For the purposes of this study, a PSM was defined as malignant gland present at the surgical margin and incompletely excised (IE) as benign gland present at the surgical margin. 0090-4295/07/$32.00 doi:10.1016/j.urology.2007.02.048
In this study, we explored whether the method of performing radical prostatectomy (robotic versus conventional retropubic open) influenced the pathologic outcomes, as determined by a focused analysis of the specimens, and compared the frequency and clinical significance of the presence of benign glands at the surgical margins in prostatectomy specimens obtained by the two surgical approaches.
MATERIAL AND METHODS
Clinical Information and Follow-up Data All patients had biopsy-proven prostate adenocarcinoma. The clinical information regarding age and preoperative serum PSA level was obtained from the patients’ medical records. The postoperative serum PSA values were measured at each follow-up visit and documented. A PSA nadir was considered as an immediate postoperative level of less than 0.1 ng/mL. Postoperative serum PSA increases were considered to either represent recurrent disease or residual prostatic tissue, depending on the pathologic stage (PSMs or benign glands present at the surgical margin) and clinical scenario (PSA increasing without a plateau phase).
Surgery To minimize the effect of surgical technique and experience gained over time by the surgeon, as well as to limit any surgical bias in the study, all the procedures were performed by a single surgeon. As such, a cohort of 38 consecutive RPSs (robotic and open prostatectomy performed by the same surgeon) from patients with biopsy-proven prostate cancer were reviewed. The time frame (May 2001 to May 2004) chosen to review the cases was chosen after the surgeon had gained sufficient experience to be categorized as adept in the procedure and had already performed more than 60 cases of robotic prostatectomy and would thus be considered to be at the height of the learning curve.
Pathology In an effort to substantially limit any bias in tissue sampling technique or partial tissue submission, all prostatectomy specimens were reviewed by a single pathologist with subspecialty genitourinary pathology training. In our institution, all radical prostatectomy specimens are entirely embedded for histologic examination, eliminating the possibility of pathologically understaging the disease (undetected PSM). The RPSs were initially weighed and inked and had the apex (approximately 0.4 cm) amputated. After formalin fixation, the entire prostate was submitted according to a standard protocol and map, as previously described and reported.12,13 In brief, the apex was radially sectioned, and the body of the prostate was sectioned transversely at 2 to 3-mm intervals and divided into quarters to fit into the specimen cassettes. The right and left vas deferens and seminal vesicles were removed and two proximal perpendicular sections were submitted. The prostate base (bladder neck) was then divided into the mid, right, and left portions, sectioned perpendicularly to the inked margin, and submitted. The hematoxylin-eosin sections on all blocks were reviewed.
Histologic Evaluation and Pathologic Stage A single genitourinary pathologist reviewed all slides from the RPSs for the study, and each case was analyzed for Gleason score, perineural involvement, pathologic stage information (tumor location, extraprostatic extension, and seminal vesicle invasion), tumor volume, and margin status (PSM), including the presence of benign glands at the margin (IE). In all cases, and in all RPSs from the robotic and open groups, the presence of benign glands at the margin (IE) was evaluated, irrespective of the presence or absence of tumor at the surgical margin (PSM). This was done to control for potential stage bias. All foci of tumor were mapped separately, and the tumor volume was measured, as previously described.13 The extent of the PSMs and IE were measured from the glass slide in millimeters and documented according to the location and number of cross-sections involved. UROLOGY 69 (6), 2007
Statistical Analysis Statistical analysis was performed using Statistical Analysis System software, version 9.1 (SAS Institute, Cary, NC). Tumor size was compared between the surgery methods using a t test. The Wilcoxon rank sum test was used to compare the other continuous variables between the groups. The categorical variables were compared with Fisher’s exact test. Tests with P values less than 0.05 were considered statistically significant.
RESULTS Surgery A single surgeon, with 3 years’ experience with the da Vinci robotic system, who had performed more than 60 robotic prostatectomies, performed 38 consecutive prostatectomies from May 2001 to May 2004. Of these 38, 25 (65%) were robotic and 13 (35%) were open. Pathologic Findings, Histologic Evaluation, and Pathologic Stage The Gleason scores were evenly distributed between the two groups (Table 1). Of the 38 RPSs, the Gleason combined score was 6 or less in 8 robotic cases versus 4 open cases, 7 in 10 robotic cases versus 8 open cases, 8 or more in 6 robotic cases versus only 1 open case. One case was not graded because the patient had received preoperative hormonal therapy and had a marked therapy effect on the tumor. The mean tumor volume was similar in both groups (1.5 ⫾ 0.8 cm for the robotic versus 1.7 ⫾ 0.4 cm for the open group), with a slight increase in the number of tumor foci found in the robotic group (mean 1.80, range 1 to 3) compared with the number found in the open group (mean 1.36, range 1 to 2). Perineural invasion and seminal vesicle invasion were similar in both groups. A slight stage bias toward pT2 was found in both groups, with 69% and 72% of the cases being pT2 in the open and robotic groups, respectively. Because the differences in pathologic stage between the two groups were not statistically significant (P ⫽ 1.0), this variable was not considered to significantly affect the overall differences in the other variables studied. The incidence of PSMs was greater in the robotic group (28%) than in the open group (8%). However, this finding was not statistically significant (P ⫽ 0.22). The PSMs were distributed as follows in the robotic group: five involved the posterolateral aspects of the prostate 1113
Table 1. Summary of clinicopathologic findings between robotic retropubic radical prostatectomy and open retropubic radical prostatectomy Characteristic Follow-up (mo) Median Range Unknown Age (yr) Median Range Preoperative PSA (ng/mL) Median Range Unknown Postoperative PSA (ng/mL) ⬍0.1 ⬎0.1 Stage pT2a-c pT3 Gleason score 6 7 8–9 Tumor size Mean ⫾ SD Range Tumor foci (n) 1 2 3 Perineural invasion No Yes Seminal vesical invasion No Yes EPE present No Yes Tumor at inked margin (PSM) No Yes Extent of positive margin (mm) (n ⫽ 8) Mean Range Benign glands at margin (IE) No Yes Extent of benign glands at margin (mm) (n ⫽ 15) Mean Range
ORRP (n ⫽ 13)
RRRP (n ⫽ 25)
P Value
24.5 8.5–59.5 1
12.5 2.5–23.0 5
0.005
58 49–71
61 48–79
0.52
5.3 4.9–15.2 5
6.3 0.1–24.9 5
0.51
12 (100) 0
18 (90) 2 (10)
0.52
9 (69) 4 (31)
18 (72) 7 (28)
1.0
4 (31) 8 (62) 1 (8)
8 (33) 10 (42) 6 (25)
0.44
1.7 ⫾ 0.4 1.1–2.5
1.5 ⫾ 0.8 0.3–3.5
0.27
7 (64) 4 (36) 0
9 (36) 12 (48) 4 (16)
0.23
2 (15) 11 (85)
11 (44) 14 (56)
0.15
12 (92) 1 (8)
22 (88) 3 (12)
1.0
8 (62) 5 (38)
18 (72) 7 (28)
0.71
12 (92) 1 (8)
18 (72) 7 (28)
0.22
1.5 ⫾ NA NA 11 (85) 2 (15) 3.0 ⫾ 2.1 1.5–4.5
4.4 ⫾ 3.3 1–10
NA
11 (46) 13 (54)
0.035
3.3 ⫾ 2.0 1–6
0.93
ORRP ⫽ open retropubic radical prostatectomy; RRRP ⫽ robotic retropubic radical prostatectomy; PSA ⫽ prostatic-specific antigen; EPE ⫽ extraprostatic extension; PSM ⫽ positive surgical margin; NA ⫽ not available; IE ⫽ incompletely excised. Data presented as mean ⫾ SD or numbers with percentages in parentheses.
superior to the neurovascular bundles and two occurred at the apex. The only PSM in the open group involved the posterolateral aspect of the prostate. A noticeably increased incidence of IE was identified in the robotic group (54%) compared with the open group (15%). This finding was statistically significant (P ⫽ 0.035). The anatomic location of IE was predominantly at the apex in 2 of the open cases and 9 of the robotic cases. In the remaining robotic cases, IE was identified at the prostatic 1114
base. The extent of benign glands at the surgical margin was marginally greater in the robotic group (mean linear length 3.3 ⫾ 2.0 mm) than that in the open group (mean linear length 3.0 ⫾ 2.1 mm; P ⫽ 0.93). Clinical Information and Follow-up Data The median patient age of the robotic group was 61 years versus 58 years for the open group. The postoperative PSA values were measured in all patients for a minimum UROLOGY 69 (6), 2007
of 6 months, except for 6 patients who were lost to follow-up after the 6-week postoperative evaluation period. The median postoperative follow-up duration was 12.5 months for the robotic group and 24.5 months for the open group. The median preoperative PSA level was 6.3 ng/mL in the robotic group and 5.3 ng/mL in the open group. In patients with long-term PSA follow-up, the postoperative PSA nadir (less than 0.1 ng/mL) was achieved in 18 (90%) of 20 patients in robotic group and 12 (100%) of 12 patients in open group. The 2 patients who did not achieve a PSA nadir in the robotic group also had PSMs, accounting for the postoperative serum PSA increase (2.8 ng/mL and 2.6 ng/mL). These 2 patients had pathologic Stage pT2b and pT3b disease, with PSMs located on the right lateral apex and right posterolateral base (Table 1). The stratification of patients according to a PSA level greater 0.2 ng/mL and surgery type is given in Table 1.
COMMENT The robotic method uses laparoscopic techniques complemented by the da Vinci Surgical Robotic Surgical System, which provides three-dimensional visualization and EndoWrist movements with six degrees of freedom, greatly facilitating intracorporeal suturing. The clinical advantages of robotic radical prostatectomy such as decreased intraoperative blood loss and quicker convalescence compared with conventional open methods are being studied. Several recent studies examining the use of the da Vinci Surgical Robotic Surgical System in radical prostatectomy have had promising findings compared with conventional open approaches.2,3,8 One prospective study comparing robotic-assisted prostatectomy (da Vinci surgical system) and open radical retropubic prostatectomy showed longer mean operative times (4.8 hours versus 2.3 hours), less mean blood loss (329 mL versus 970 mL), less postoperative pain, and earlier discharge times for robotic-assisted prostatectomy, with no significant difference in pathologic stage, margin status, or complication rates.2 Differences in surgical techniques and instrumentation can result in alterations of the RPSs. We have observed subtle gross and histologic differences between robotic and retropubic prostatectomy specimens. These have included, at the macroscopic level, the presence of an irregular excisional surface, with multiple foci of cautery artifact and less extraprostatic soft tissue. At the microscopic level, the most noticeable findings have included increased cautery artifact at the surgical margin and the presence of surgeon-induced capsular incision. In addition, specimen processing, slide interpretation, and whether multiple or one pathologist reviews the slides all have influence on the final pathology report, with a substantial impact on treatment.14,15 One study found that approximately 12% of margins could be missed (pathologic understaging), depending on whether the prostate was sectioned at 5-mm versus 2 to 3-mm UROLOGY 69 (6), 2007
intervals.16 In another study, 5 of 7 cases with initial Stage pT2 disease were later upstaged on repeat review of the original slides and additional 2-mm sections.10 To eliminate the pitfalls of surgeon experience, histologic sample bias, and interobserver differences with regard to pathologic interpretation, we selected a cohort of RPSs obtained by a single surgeon and histologically sectioned and reviewed in an identical manner by a single genitourinary pathologist, with the entire prostate submitted for evaluation. Our reported rate of PSMs in the robotic group versus the open group, 28% versus 8%, can be considered definitive and free of any sampling bias. The PSMs in the RPSs from open retropubic surgery have a reported incidence of 15% to 58% and our results are in keeping with the published data.2,14,17–19 The incidence of PSMs in the robotic group (28%) was slightly greater than reported in other studies using robotic-assisted radical prostatectomy (17.5% and 26%).2,3,8 This could be because of the understaging of cases previously reported (the prostate gland was not entirely submitted in previously cited studies) and surgeon experience with the robotic instrument. Benign glands extending to the surgical margins secondary to capsular incision have a reported incidence of 8% to 66%.18,20 The significance regarding their role in postoperative PSA levels has been investigated with mixed results.9,17,20 The main concern of such findings is that the postoperative PSA elevation secondary to the presence of benign glands could potentially lead to false categorization and unnecessary treatment. It has been proposed that if benign glands had an effect on postoperative PSA levels, one would expect low, relatively stable PSA levels, especially when considering that 1 g of benign prostatic hypertrophy tissue has been shown to produce, on average, a 0.31-ng/mL increase in PSA.9 One study examining 351 RPSs from open prostatectomy found an incidence of 27% of IE and that 79% of the patients with Stage pT2 disease and benign glands at the surgical margin had postoperative detectable PSA levels at a mean follow-up of 5 years.21 In other studies, the presence of benign and malignant glands at the surgical margins had less impact on postoperative biochemical progression compared with that of extraprostatic extension.17 To the best of our knowledge, no published studies have focused on the incidence of benign glands at the margin of RPSs from robotic surgery. Therefore, our incidence of 54%, although seemingly high, has no point of comparison. Despite this seemingly high incidence of IE, a PSA postoperative nadir of less than 0.1ng/mL was achieved, irrespective of the presence of benign glands or tumor cells extending to the surgical margins. In the 2 cases with a postoperative increase in the serum PSA level, these elevations were accounted for by the presence of PSMs in both cases, as well as extraprostatic extension in 1 case. The use of electrocautery as a means of dissection in the robotic group was more liberal. This 1115
cautery can allow for several additional millimeters of tissue margin and, as such, it might be that no benign prostatic tissue was left in the prostatic bed. This study had some limitations. The follow-up period was relatively short, and longer follow-up and larger cohorts of patients are needed to clearly establish the significance of benign prostate glands at the surgical margins in robotic specimens. Although the present study identified a significant difference in the rate of the presence of benign glands at the margins of RPSs between the open and robotic methods, a larger sample size would help to validate our initial findings. Also, because of the relatively short follow-up period (12.5 months for the robotic group and 24.5 for the open group), longer follow-up would be desirable before drawing conclusions about the oncologic outcomes.
CONCLUSIONS The results of our study have shown that the incidence of benign prostate glands in patients undergoing robotic radical prostatectomy is significantly increased compared with that after open retropubic prostatectomy (P ⫽ 0.035). Although a greater rate of PSMs was noted for the robotic group compared with the open group, this was not statistically significant (P ⫽ 0.22). The early clinical follow-up results suggest that patients undergoing robotic radical prostatectomy for prostate cancer can achieve a PSA nadir of less than 0.1 ng/mL, irrespective of the presence or absence of benign prostatic tissue at the surgical margins. Furthermore, considerations for the lack of elevated postoperative PSA levels in the setting of PSMs and IE would include destruction of the glands secondary to ischemia and granulation tissue formation and the use of significant electrocautery at the surgical margins. References 1. Perrotti M, and Moran ME: Robotic prostatectomy outcomes. Urol Oncol 23: 341–345, 2005. 2. Menon M, Tewari A, Baize B, et al: Prospective comparison of radical retropubic prostatectomy and robot-assisted anatomic prostatectomy: the Vattikuti Urology Institute experience. Urology 60: 864 – 868, 2002. 3. Menon M, and Tewari A: Robotic radical prostatectomy and the Vattikuti Urology Institute technique: an interim analysis of results and technical points. Urology 61: 15–20, 2003. 4. Ahlering TE, Woo D, Eichel L, et al: Robot-assisted versus open radical prostatectomy: a comparison of one surgeon’s outcomes. Urology 63: 819 – 822, 2004.
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5. Bentas W, Wolfram M, Jones J, et al: Robotic technology and the translation of open radical prostatectomy to laparoscopy: the early Frankfurt experience with robotic radical prostatectomy and one year follow-up. Eur Urol 44: 175–181, 2003. 6. Cathelineau X, Rozet F, and Vallancien G: Robotic radical prostatectomy: the European experience. Urol Clin North Am 31: 693– 699, viii, 2004. 7. Ahlering TE, Skarecky D, Lee D, et al: Successful transfer of open surgical skills to a laparoscopic environment using a robotic interface: initial experience with laparoscopic radical prostatectomy. J Urol 170: 1738 –1741, 2003. 8. Menon M, Shrivastava A, Tewari A, et al: Laparoscopic and robot assisted radical prostatectomy: establishment of a structured program and preliminary analysis of outcomes. J Urol 168: 945–949, 2002. 9. Ravery V: The significance of recurrent PSA after radical prostatectomy: benign versus malignant sources. Semin Urol Oncol 17: 127–129, 1999. 10. Ravery V, de la Taille A, Toublanc M, et al: Prostate specimen reevaluation in patients with organ confined prostate cancer and postoperative biological recurrence. J Urol 155: 1981–1982, 1996. 11. Wood DP Jr, Peretsman SJ, and Seay TM: Incidence of benign and malignant prostate tissue in biopsies of the bladder neck after a radical prostatectomy. J Urol 154: 1443–1446, 1995. 12. Babaian RJ, Troncoso P, Bhadkamkar VA, et al: Analysis of clinicopathologic factors predicting outcome after radical prostatectomy. Cancer 91: 1414 –1422, 2001. 13. Chen ME, Johnston D, Reyes AO, et al: A streamlined threedimensional volume estimation method accurately classifies prostate tumors by volume. Am J Surg Pathol 27: 1291–1301, 2003. 14. Epstein JI: Incidence and significance of positive margins in radical prostatectomy specimens. Urol Clin North Am 23: 651– 663, 1996. 15. Epstein JI, Pizov G, and Walsh PC: Correlation of pathologic findings with progression after radical retropubic prostatectomy. Cancer 71: 3582–3593, 1993. 16. Hall GS, Kramer CE, and Epstein JI: Evaluation of radical prostatectomy specimens: a comparative analysis of sampling methods. Am J Surg Pathol 16: 315–324, 1992. 17. Barocas DA, Han M, Epstein JI, et al: Does capsular incision at radical retropubic prostatectomy affect disease-free survival in otherwise organ-confined prostate cancer? Urology 58: 746 –751, 2001. 18. Boccon-Gibod L, Ravery V, Vordos D, et al: Radical prostatectomy for prostate cancer: the perineal approach increases the risk of surgically induced positive margins and capsular incisions. J Urol 160: 1383–1385, 1998. 19. Watson RB, Civantos F, and Soloway MS: Positive surgical margins with radical prostatectomy: detailed pathological analysis and prognosis. Urology 48: 80 –90, 1996. 20. Shah R, Bassily N, Wei J, et al: Benign prostatic glands at surgical margins of radical prostatectomy specimens: frequency and associated risk factors. Urology 56: 721–725, 2000. 21. Djavan B, Sesterhann I, and Hruby S: Benign prostatic glands in the surgical margin of radical retropubic prostatectomies: redefining PSA nadir. J Urol 163: A624, 2000.
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