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Keywords:

  • positive surgical margins;
  • positive surgical margins localization;
  • positive surgical margins size;
  • prognosis;
  • radical prostatectomy

Abstract

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. References

Objectives:  To evaluate the prognostic value of positive surgical margins (PSM) in radical prostatectomy (RPE) specimens in relation to multifocality, localization and size.

Methods:  A total of 1036 patients who underwent RPE and staged pT2–3a,pN0,M0 were evaluated. None had received adjuvant or neoadjuvant therapy. All specimens were routinely processed by complete whole mount sectioning. Exact number, localization and size of PSM were reassessed, and patients were followed up for a mean of 60 months.

Results:  A total of 267 patients (26%) showed PSM (20% pT2, 48% pT3a). Preoperative prostate-specific antigen, Gleason score (GS) and PSM were independent predictors of biochemical recurrence (BCR). BCR-free survival rates for patients with and without PSM were 59% and 80%, respectively (HR 2.1; P < 0.001). PSM were related to biochemical failure in pT2 and pT3a tumors (P = 0.001 and P = 0.015). A total of 64% of solitary PSM were apical. Multifocality, localization and size of PSM had no significant impact on BCR.

Conclusions:  Solitary apical and small PSM in RPE have a significant impact on BCR-free survival in localized stages.


Introduction

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. References

Radical prostatectomy (RPE) is one of the standard procedures for curative treatment of localized prostate cancer (PCA). Positive surgical margins (PSM) have been reported in 10–36% of contemporary series, and remnant tumor is suggested to compromise a cure.1–16 Although overall PSM (R1 vs R0) is a prognosticator of biochemical recurrence (BCR) in addition to tumor stage and Gleason score (GS) in some series,12–15 others report no clinical relevance, especially of solitary and small PSM.1,11

Adjuvant radiotherapy, androgen deprivation therapy and active surveillance with subsequent salvage-therapy in BCR have been suggested for the management of PSM.14–22 Despite the lack of solid data, many urologists tend towards expectative management in solitary and small PSM in localized stages. Previous analyses of the impact of PSM on BCR are contradictory and of limited comparability as a result of heterogeneous tumor stages and adjuvant strategies included.1–16 To date, only one larger series comprising patients at all tumor stages without adjuvant treatment has been published; however, not analyzing PSM details, that is, localization and size.13 In all previous series, RPE specimens underwent standard histopathological processing, usually consisting of the removal of ink-stained apical margins (3–5 mm) followed by serial sectioning perpendicular to the ink and embedding in conventional blocks. Three sections of each prostate side are usually embedded in conventional blocks, with one transverse slice cut perpendicular to the rectal surface.23,24 In contrast, complete processing consists of removal of all ink-stained surgical margins and embedding the entire gland for subsequent whole-mount sections with 4-mm slices of the whole specimen.

Although standard processing provides sufficient assessment in routine management, whole-mount sectioning and processing of the entire gland has been reported to significantly improve histopathological accuracy.23,24 Its use has been suggested for research purposes by current guidelines of the American Urological Association.25 To date, there is only one analysis aside from the present series using data from complete processing; van Oort et al. related the oncological outcome in PSM to its length.26 Although in the mentioned analysis a comparison with patients void of PSM was not carried out, the purpose of the present study was to analyze the influence of multifocality, localization and size of PSM in completely processed specimens on BCR in patients with pT2–3a,pN0,M0 PCA not undergoing adjuvant or neoadjuvant therapy and to compare outcome between patients with and without PSM. Hence, this is the initial report using completely processed RPE specimens and comprising data from a markedly homogeneous series.

Methods

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. References

From 1993 to 2007, 1412 open RPE were carried out in two tertiary urological centres. Histopathological and clinical data were collected prospectively (Vivantes-Klinikum im Friedrichshain, Berlin, Germany and Vivantes-Klinikum Am Urban, Berlin, Germany). All cases underwent dissection of the external iliac and obturator lymph nodes as defined by institutional protocol. Central histopathological processing of RPE-specimens was defined by a prospective protocol. All specimens underwent complete 4 mm whole mount sectioning as previously described.27 The apex was dissected separately and sectioned in a parasagittal manner. To histologically assess surgical margins, the entire surface of the completely embedded prostate gland was inked. PSM was strictly defined as any direct contact of carcinoma (tumor glands) to the ink without any intervening connective tissue, and all foci and localizations were noted and recorded. Four regions of PSM-localizations were differentiated: the apex, base, anterior and posterolateral region. The exact length of PSM was assessed as previously described; the greatest extent of apical PSM was measured in the parasagittal sections. In cases with multifocal positive margins, all separate PSM foci were added. The size of PSM was categorized in ≤3 versus <3 mm. In the present series, we used 3 mm as the cut-off in concordance with Babaian et al.22 All specimens were staged according to the sixth amendment of the Tumor, Nodes and Metastasis (TNM)-staging system. GS was categorized in GS ≤ 6, GS 7 and GS 8–10. BCR was defined as two consecutive prostate-specific antigen (PSA)-values ≥0.2 ng/mL after the third postoperative month.

Inclusion criteria for this retrospective analysis were defined as follows: PCA staged pT2–3a,pN0,M0, lymphadenectomy ≥6 nodes and absence of any adjuvant or neoadjuvant androgen deprivation therapy and/or radiotherapy. A total of 1036 (267 with PSM) patients met these criteria, and pathological and clinical data were assessed. Overall, 376 patients were excluded from the trial (i.e. 26.6% of the whole study group); 346 patients exceeded tumor stages pT2–3a,pN0,M0, and 30 patients showed tumor stages pT2–3a,pN0,M0 but underwent adjuvant or neoadjuvant androgen deprivation therapy and/or radiotherapy because of patient preference.

Statistical analyses were carried out using spss version 16.0 (SPSS, Chicago, IL, USA). Significant differences concerning BCR were calculated using the Kaplan–Meier method, significance was evaluated by the two-sided log–rank test. To identify independent prognostic factors in a multivariable analysis for BCR, we used the Cox proportional hazards model. P-values less than.05 were considered significant for all tests and taken when achieved in the univariable analysis as inclusion criteria for the multivariable model. The final analysis included the variables age (continuous), PSA (continuous), clinical tumor stage (cT1c, cT2, cT3a), pathological tumor stage (pT2a/b, pT2c, pT3a), Gleason score (<7, 7, 8–10), PSM (no vs yes) and year of surgery (1993–1997, 1998–2002, 2003–2007). For the evaluation of BCR, patients were surveyed at the time of their last BCR-free follow-up appointment.

Results

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. References

All clinical and histopathological parameters are shown in Table 1. A total of 267/1036 patients (26%) showed PSM. In tumors staged pT2 and pT3a, PSM rates were 21% (n = 172/837) and 48% (n = 95/199), respectively (P < 0.001). A total of 64% of all solitary PSM were located at the apex (150/235), 3% showed multifocal PSM and 29% (n = 299) underwent a unilateral or bilateral nerve sparing procedure with assessment of PSM by fresh-frozen biopsies of the neurovascular bundle during surgery. Two of these patients showed PSM (2/299; 1%) in definitive histology. No correlation could be shown between prostate volume and multifocality, localization and size of PSM.

Table 1.  Clinical and pathological parameters (n = 1036)
Parametern (%)
  1. GS, Gleason score; PSA, prostate-specific antigen; PSM, positive surgical margin; RPE, radical prostatectomy; TRUS, transrectal ultrasonography.

Age, mean (range), years63.7 (44–79)
PSA, mean (range), ng/mL10.9 (0.1–132)
Prostate volume, mean (range), cm3, TRUS31.9 (5–450)
Lymph nodes, mean (range)13.5 (6–47)
Clinical tumor stage (cT) 
 cT1c447 (43.1%)
 cT2564 (54.4%)
 cT3a25 (2.4%)
Pathological tumor stage (pT) 
 pT2a/b, pN0268 (25.9%)
 pT2c, pN0569 (54.9%)
 pT3a, pN0199 (19.2%)
GS, RPE 
 GS ≤6684 (66.0%)
 GS 7294 (28.4%)
 GS 8–1058 (5.6%)
PSM 
 No PSM769 (74.2%)
 PSM267 (25.8%)
PSM localization 
 No PSM769 (74.2%)
 Apex150 (14.5%)
 Basis18 (1.7%)
 Anterior region0
 Posterolateral region67 (6.5%)
 Multifocal32 (3.1%)
PSM – extent 
 No PSM769 (74.2%)
 ≤3 mm122 (11.8%)
 <3 mm145 (14.0%)
Year of surgery 
 1993–1997150 (14.5%)
 1998–2002327 (31.5%)
 2003–2007559 (54.0%)

The median follow up was 52 months (mean 60, range 1–156); BCR-free survival rates of patients with and without PSM after 7 years were 59% and 80%, respectively (HR 2.06; 95% CI 1.56–2.72; P < 0.001; Table 2). In pT2 tumors, BCR-free survival rates after 7 years with and without PSM were 68% and 82% (P = 0.001), and in pT3a 46% and 72% (P = 0.015), respectively.

Table 2.  Univariate logistic regression analysis of the influence of assessed parameters on biochemical recurrence
ParameterHR (95% CI)P-value
  1. GS, Gleason score; PSA, prostate-specific antigen; PSM, positive surgical margin; RPE, radical prostatectomy.

Age, per year1.01 (0.99–1.03)0.476
PSA, per ng/mL1.02 (1.01–1.03)<0.001
Prostate volume, per cm31.00 (0.99–1.01)0.126
Clinical tumor stage (cT)  
 cT1c1.00 (reference)0.667
 cT21.07 (0.79–1.45)0.279
 cT3a1.24 (0.84–1.84)
Tumor stage (pT)  
 pT2a/b, pN01.00 (reference)0.596
 pT2c, pN01.11 (0.77–1.59)<0.001
 pT3a, pN01.42 (1.17–1.73)
GS, RPE  
 GS ≤61.00 (reference)<0.001
 GS 75.60 (4.12–7.61)<0.001
 GS 8–102.77 (2.14–3.57)
PSM  
 No PSM1.00 (reference)<0.001
 PSM2.06 (1.56–2.72)
Tumor stage and PSM  
 pT2, PSM-1.00 (reference)0.001
 pT2, PSM+1.85 (1.30–2.63)0.041
 pT3a, PSM-1.26 (1.01–1.57)
 pT3a, PSM+1.42 (1.26–1.61)<0.001
PSM localization  
 No PSM1.00 (reference)<0.001
 PSM, solitary apical2.15 (1.55–2.99)0.001
 PSM, other1.39 (1.14–1.68)
PSM – extent  
 No PSM1.00 (reference)<0.001
 ≤3 mm2.04 (1.42–2.92)<0.001
 <3 mm1.44 (1.21–1.71)
Year of surgery  
 1993–19971.00 (reference)0.695
 1998–20020.93 (0.65–1.33)0.682
 2003–20070.96 (0.77–1.19)

BCR-rates of solitary and multifocal PSM did not differ (HR 0.97; 95% CI 0.48–1.94; P = 0.93). Localization of PSM was not related to BCR (solitary apical PSM vs PSM at other location with HR 0.91; 95% CI 0.59–1.41; P = 0.67; Fig. 1), neither was the size of PSM (≤3 vs <3 mm; HR 1.0; 95% CI 0.66–1.55; P = 0.96; Fig. 2). Furthermore, the combination of extent and localization of PSM was void of influence, as BCR of patients with solitary apical R1 ≤3 versus PSM other did not differ (P = 0.6; Fig. 3).

image

Figure 1. Biochemical recurrence (BCR) in dependence of positive surgical margins (PSM) multifocality and localization (inline image) R0; (inline image) R1-A; (inline image) R1-P; (inline image) R1-B; (inline image) R1-M. R1-A, PSM apical; R1-B, PSM base; R1-M, PSM multifocal; R1-P, PSM postolateral.

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image

Figure 2. Biochemical recurrence (BCR) in dependence of positive surgical margins (PSM) extent. (inline image) R0; (inline image) R1 ≤3 mm; (inline image) >3 mm.

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image

Figure 3. Biochemical recurrence (BCR) in dependence of solitary apical positive surgical margins (PSM) and ≤3 mm versus any other (R1-SA and < = 3 mm = PSM solitary apical and ≤3 mm, R1-O = PSM other). (inline image) R0; (inline image) R1-SA and ≤3 mm; (inline image) R1-O.

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Of all parameters evaluated, only preoperative PSA, GS and overall PSM were independently predictive of BCR (Tables 2,3). PSM had a greater impact on BCR than tumor stage (pT2 vs pT3a) (Table 3 and Fig. 4).

Table 3.  Multivariate logistic regression analysis of the influence of assessed parameters on biochemical recurrence
ParameterHR (95%CI)P-value
  1. GS, Gleason score; n.s., not significant; PSA, prostate-specific antigen; PSM, positive surgical margin; RPE, radical prostatectomy.

PSA (per ng/mL)1.01 (1.01–1.02)0.002
Tumor Stage (pT) (pT3a,pN0 vs pT2, pN0) n.s.
GS, RPE (GS 8–10 vs GS 7 vs GS ≤6)3.01 (2.53–3.79)<0.001
PSM (any vs no PSM)1.35 (1.01–1.80)0.045
image

Figure 4. Biochemical recurrence (BCR) in dependence of tumor stage. (inline image) pT2, R0; (inline image) pT2, R1; (inline image) pT3a, R0; (inline image) pT3a, R1.

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Discussion

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. References

PSM is defined as any contact of tumor cells with the ink-stained surface of RPE-specimens.16 Although most series report overall PSM to be an independent prognostic factor for BCR, others do not (Table 4). On the one hand, remnant tumor is highly suggestive of unsuccessful cancer therapy; on the other hand, however, just 20% of overall PSM will result in BCR.12 Various theories try to explain this phenomenon: (i) tumor cells adjacent to resection sites are damaged during surgery; (ii) remnant tumor cells are impaired by debris formation and reparative processes; (iii) the growth of tumor cells depends on the microenvironment provided by the main tumor mass; and (iv) PSM is in fact the last layer and the tumor does not continue into adjacent tissue.12 To better guide clinical management, attempts have been made to define relevant clinically subsets of PSM using three characteristics: (i) multifocality; (ii) localization; and (iii) size of PSM. Previous series on these issues are contradictory (Tables 4,5).

Table 4.  Review of literature on prognostic impact of positive surgical margin localization on biochemical recurrence after radical prostatectomy
ReferencenTumor stagesPSM (%)Prognostic impact of PSMPrognostic impact of PSM localization
  1. BCP, biochemical recurrence; n.a., not assessed; PSM, positive surgical margin.

Watson (1996)1215All stages34.0n.a.No independent impact
Blute (1997)22712pT2, pN025.7Independent impactPSM at base with impact vs apex/posterolateral/anterior
Öbek (1999)3495All stages30.5No independent impactPSM at base with impact vs apex/posterolateral/anterior
Grossfeld (2000)41294All stages35.9No independent impact (assessed in n = 380)No independent impact
Sofer (2002)5734All stages28.6n.a.No independent impact
Salomon (2003)6371pT2, pN016.1n.a.PSM at apex with impact vs base/posterolateral
Sebe (2003)7436pT2, pN015.1n.a.PSM at apex with impact vs any other localization
Aydin (2004)8164pT2-3a, pN0, R1n.a.n.a.PSM at apex with impact vs any other localization
Pettus (2004)9498pT2-3a, pN019.6Independent impactNo independent impact
Eastham (2007)102442All stages11.2Independent impact on BCRPostolateral PSM with impact vs apex/base/anterior
Saether (2008)11219All stages26.5No independent impact on BCRNo independent impact
Pfitzenmaier (2008)12406All stages17.2Independent impact on BCRNo independent impact
Shikanov (2009)131398All stages17.4Independent impact on BCRNo independent impact
Stephenson (2009)147160All stages21.0Independent impact on BCRNo independent impact
Godoy (2009)151308All stages9.8Independent impact on BCRAnterior/base PSM with impact vs apex/posterolateral
Resnick (2009)162410All stages18.8n.a.No independent impact
Present series1036pT2-3a, pN025.8Independent impact on BCRNo independent impact
Table 5.  Review of literature on prognostic impact of positive surgical margin size on biochemical recurrence after radical prostatectomy
ReferencenTumor stagesPSM (%)Cut-off of PSM extentPrognostic impact of PSM extent
  1. BCP, biochemical recurrence; n.a., not assessed; PSM, positive surgical margin.

Watson (1996)1215All stages34.0Focal vs extensiveNo independent impact
Saether (2008)11219All stages26.5<6 mm vs≥6 mmNo independent impact
Shikanov (2009)131398All stages17.4≤1 mm vs <1 mmIndependent impact
Stephenson (2009)147160All stages21.0focal vs extensiveIndependent impact
Babaian (2001)22265pT2-3b, pN0n.a.≤3 mm vs <3 mmIndependent impact for tumor stages pT2 and pT3b
Emerson (2005)28369All stages23.3LinearNo independent impact
Van Oort (2010)26267All stages, PSM onlyn.a.Independent impact on BCRNo independent impact
Present series1036pT2-3a, pN025.8≤3 mm vs <3 mmNo independent impact

Concerning multifocality, some authors describe an independent risk of BCR in multifocal PSM,3,5,14,16 whereas others do not (Table 4).1,4,9,11–13,15 Concerning localization of PSM, nine out of 16 evaluable studies did not show an influence on BCR (Table 4).1–16 In particular, the impact of apical PSM is uncertain,17–19 and accordingly some surgeons value solitary apical PSM as clinically irrelevant. In analogy to those findings, the impact of the size of PSM is uncertain as well, as some reports describe an independent influence on BCR,13,14,22,26 whereas others do not1,11,28 (Table 5). In the present series, any PSM was independently related to BCR regardless of multifocality, localization or size.

How do these findings relate to previous series? Concerning the impact of overall PSM on BCR, it has to be taken into consideration that the interpretation of previous reports is hampered by the varying use of neoadjuvant or adjuvant androgen deprivation and/or radiotherapy in all series published to date. In contrast, the present series is the largest homogeneous series of patients with pT2–3a PCA without neo- and/or adjuvant treatment and, hence, reflects the natural history of PSM in localized PCA. Patients with pT2–3a tumors adjuvantly treated in the entire database (n = 32, data not shown), but excluded from further analysis, did not differ in any other parameter assessed, and, hence, respective bias can be excluded.

Concerning the impact of localization of PSM on BCR, it has to be taken into account that the anterior region, base and apex of the prostate lack a distinct fascia, and tumors located close to the prostatic surface in these areas defy an easy staging.29 The present series, however, was entirely assessed by whole-mount sectioning and complete processing of the prostate significantly increasing preciseness of histopathological assessment.23,24 There is just one further analysis using whole-mount sectioning in patients with PSM. BCR-risk, however, was only related to characteristics of PSM, but not to patients without PSM.26

Concerning the impact of size of PSM on BCR, the comparability of various reports is limited by different thresholds used to differentiate small from large sizes of PSM, which usually range from 1 to 3 mm.13,22 In contrast, van Oort et al. found an impact of the length of PSM on BCR to be significant when dichotomized at 10 mm.26 In the present series, the size of PSM was dichotomized (≤3 vs <3 mm); a prognostic value for further thresholds was not assessed (Table 2). The limited number of PSM below 3 mm defied continuous evaluation (PSM 3 mm: n = 104, PSM <3 mm: n = 18).

Two findings are notable. For one, pathological tumor stage had no impact of BCR in multivariable analysis as opposed to PSM. It has to be taken into account, however, that only stages pT2a–3a were analysed, whereas stage pT3b was not. Second, even patients with tumors staged pT2 with PSM showed BCR 7 years after RPE in almost one-third of cases; hence, their risk was similar to tumors staged pT3a without PSM (68 vs 72%; P = 0.543; Fig. 4).

Yet some limitations of the present data warrant consideration. For one, the present data do not include GS at PSM, which might have some impact.30 Second, almost 26% PSM in tumors staged pT2–3a,pN0,M0 seem rather high as compared with some data published in the current literature.1–16,22,28 However, this rate might be explained by the methodology of complete whole-mount processing resulting in increased accuracy of assessment.23,24,31 Furthermore, it has to be considered that our data derive from two mid-size institutions not carrying out robotic or laparoscopic RPE, whereas lower rates of PSM have been reported for those surgical approaches and high volume centres alike.32 However, the open approach and the size of the contributing institutions in this series reflect the most common setting of current surgical PCA management in Europe and, thus, might put emphasis on the broad clinical relevance of the present findings. Third, the only end-point assessed was BCR not accounting for the clinical relevance of local recurrence, cancer-specific and overall survival. However, despite the mean follow-up duration of 60 months, the available period was still insufficient for assessment of these parameters, resulting in the decision to aim at BCR in concordance with all previous data. Although the value of BCR as a clinically valid end-point as opposed to metastasis-free and cancer-specific survival is arguable, radical prostatectomy aims at a cure, and BCR is the proof of failing this goal.33,34

The present series comprises intermediate-term data of more than 1000 patients not undergoing adjuvant treatment with pT2–pT3a,pN0 PCA assessed by complete whole-mount sectioning. Results from the present study show that even solitary apical and small PSM influence BCR. These findings should raise respective awareness.

References

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. References
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