World J Urol DOI 10.1007/s00345-014-1243-3
ORIGINAL ARTICLE
Location, extent, and multifocality of positive surgical margins for biochemical recurrence prediction after radical prostatectomy Guillaume Ploussard • Sarah J. Drouin • Julie Rode • Yves Allory Dimitri Vordos • Andras Hoznek • Claude-Cle´ment Abbou • Alexandre de la Taille • Laurent Salomon
•
Received: 27 November 2013 / Accepted: 13 January 2014 Ó Springer-Verlag Berlin Heidelberg 2014
Abstract Purpose To study the prognostic value of extent, number, and location of positive surgical margins (PSM). Methods A total of 1,504 consecutive adjuvant treatment naive and node-negative radical prostatectomy men were included in a prospective database including extent, number, and location of PSM. Mean follow-up was 33 months. Endpoint was biochemical progression-free (bPFS) survival. The impact of margin status and characteristics was assessed in time-dependent analyses using Cox regression and Kaplan–Meier methods. Results PSM was reported in 26.7 % of patients. The predominant PSM locations were apex and posterior locations. Median PSM length was 4.0 mm. The 2-year bPFS was 73.7 % in PSM patients as compared to 93.0 % in NSM patients (p \ 0.001). The rate and extent of PSM increased significantly with pathologic stage (p \ 0.001). The extent of PSM length was linearly correlated with bPFS (p = 0.017, coefficient: -0.122). In univariable analysis, extent and number of PSM were significantly
Guillaume Ploussard and Sarah J. Drouin have contributed equally to this work. G. Ploussard (&) S. J. Drouin J. Rode Y. Allory D. Vordos A. Hoznek C.-C. Abbou A. de la Taille L. Salomon Department of Urology and Pathology, Hospital Henri Mondor, 51 Avenue du Mare´chal de Lattre de Tassigny, 94010 Cre´teil, France e-mail: [email protected] L. Salomon e-mail: [email protected]
linked to outcomes. None of PSM subclassifications significantly influenced the bPFS rates in the subgroup of pT2 disease patients. Conversely, stratification by PSM location (apex vs. other locations, p = 0.008), by PSM number (p = 0.006), and by PSM length (p \ 0.001) showed significant differences in pT3-4 cancer patients. In that subgroup, PSM length also added to bPFS prediction using PSM status only in multivariable models (p = 0.005). Conclusions PSM subclassifications do not improve the biochemical recurrence prediction in organ-confined disease. In non-organ-confined disease, PSM length (C3 mm), multifocality (C3 sites), and apical location are significantly linked to poorer outcomes and could justify a more aggressive adjuvant treatment approach. Keywords Radical prostatectomy Margin Prostate cancer PSA failure Oncologic outcomes
Introduction Local control after radical prostatectomy (RP) depends on well-established biological and pathological predictive factors including the margin status. Incidence of positive surgical margins (PSM) varies markedly between different series and ranges between 10 and 60 % being in part a reflection of patient selection, surgical technique, experience of surgeons, and methodology of pathological specimen analyses [1–3]. The risk of PSM increases with increasing PSA, pathological Gleason score and local extent of the disease. PSM has been clearly demonstrated to be one of the main predictive factors for biochemical failure, disease progression, and cancer mortality [4–8]. Prognostic subclassification could improve oncologic outcome prediction and future management. Several factors
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such as location (apical vs. others), length, number of margins (unifocal vs. multifocal) have been studied to stratify the risk of disease recurrence in cancers with PSM [9–11]. An International Society of Urological Pathology conference recommended that pathologists mention the linear extent of PSM in routine reports [12]. However, the additional value of such subclassifications as compared to simple positive/negative margins report is not strongly established. Moreover, to the best of our knowledge, the combined prognostic values of location, number, and extent of PSM have not been assessed together in a single study. In the present series, we studied the impact of PSM status and characteristics (including PSM number, location, and extent) as predictive factor for biochemical recurrence after RP in adjuvant treatment-naı¨ve patients. We also aimed to evaluate whether the prognostic impact of such PSM features varied according to the pathological stage of the disease.
Table 1 Patient cohort characteristics and positive surgical margins parameters n = 1,504 Age, years Median (IQR)
Patient selection From our prospective database, we extracted data from consecutive men who had undergone RP for localized prostate cancer 2005 and 2011 at the Department of Urology, Hospital Henri Mondor, Cre´teil, France. All patients underwent extraperitoneal laparoscopic radical prostatectomy by three well-experienced senior surgeons (CCA, LS, ADLT). Prostatectomy specimens were analyzed as whole mounts and reviewed by a single uropathologist. Standard lymphadenectomy was performed prior to the completion of the vesicourethral anastomosis in case of Gleason score [6 and/or PSA level [10 ng/ml. Low-risk PCa and preoperatively potent patients underwent conventional nervesparing procedure. Patients who had received neoadjuvant therapy or adjuvant therapy before PSA relapse (n = 31) were excluded from analyses. These 31 patients have been included in a prospective trial assessing the role of adjuvant chemotherapy in high-risk cases. Patients with positive lymph nodes (n = 38) were also excluded from analyses. Finally, 1,504 men were included. All patients were followed at our institution and medical visits were scheduled at 1, 3, and 6 months and then within a 6-month interval after RP. Mean follow-up after RP was 33 months (1–71 months; IQR: 22–47). The hospital’s ethics committee approved the study and the good clinical practice criteria were respected.
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62.6
63.0
0.280
8.1
12.0
\0.001
49.9
44.7
\0.001
43.0 (32–58)
pTNM stage pT2
63.1 %
70.0 %
43.8 % \0.001
pT3a
29.4 %
24.7 %
42.3 %
pT3b-T4
7.6 %
5.3 %
13.9 %
6
33.1 %
39.6 %
14.4 % \0.001
7
57.8 %
53.9 %
69.4 %
8–10
9.1 %
6.6 %
Gleason score
PSM
Materials and methods
p value
7.0 (5–10)
Prostate volume, mL Median (IQR)
PSM
62.7 (58.1–67.7)
PSA, ng/mL Median (IQR)
NSM
Overall
26.7 %
pT2
18.5 %
pT3a pT3b-4
38.5 % 48.7 %
Nerve-sparing surgery
84.0 %
Progression
11.4 %
Follow-up, months Median (IQR)
16.2 %
0%
100 %
87.1 %
79.9 %
0.002
25.3 % \0.001
6.4 % 33.3
33.5
0.810
30 (19–44)
n = 402
PSM cohort
pT2
pT3-4 %
n
%
%
Anterior
43
10.7
13.7
8.4
Posterior
103
25.6
26.9
24.8
p value
PSM location
Lateral
32
8.0
7.4
8.4
Apex Base
168 56
41.8 13.9
48.0 4.0
36.7 21.7
Solitary
275
68.4
70.9
67.0
Multiple, including
127
31.6
29.1
33.1
2
104
25.9
25.7
25.6
3–4
23
5.7
3.4
7.5
\0.001
PSM number 0.216
PSM length \3 mm
151
37.6
42.1
33.8
C3 mm
251
62.4
57.9
66.2
4.9
8.3
0.101
PSM length, mm Median (IQR)
4.0 (2–8)
0.001
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Study outcomes The primary outcome of the study was the biochemical recurrence-free survival (PFS) in patients according to the surgical margins status. Biochemical progression was defined by two consecutive PSA measurements[0.2 ng/ml at least 3 months after radical prostatectomy. No patient received adjuvant treatment before biological progression. Database and statistical analyses Data were collected prospectively into a database, including preoperative clinical and biological characteristics, patient demographics, surgical data, and postoperative parameters. Pathologic Gleason score, surgical margin (SM) status (PSM: positive SM; vs. NSM: negative SM), margin characteristics (extent, location, number), pTNM stage were recorded. All pathologic specimens were reviewed by a single senior uropathologist with criteria clearly defined at the beginning of the study. Gleason score was graded according to the 2005 ISUP consensus conference [13]. Positive margins were defined as the presence of tumor tissue on the inked surface of the specimen. Length of PSM was calculated in each case. The number of PSM was reported. The location (anterior, apex, base, lateral, posterior) of the predominant PSM was also noted. Patients with PSA failure were considered for salvage treatment. The impact of margin status and characteristics was assessed in time-dependent analyses using Cox regression models and illustrating by hazards ratio and their 95 % CI. Length of PSM was assessed as quantitative and qualitative variable (1–2 vs. C3 mm). This cutoff was chosen according to recent literature findings [14, 15]. The biochemical progression-free (bPFS) survival was estimated using the Kaplan–Meier method. Survival curves were stratified by the margin status and characteristics, and compared using the log-rank test. A double-sided p value \0.05 was considered statistically significant. All data were analyzed using SPSS version.16.0 software (SPSS, Chicago, Illinois, USA).
Results Characteristics of the cohort are listed in Table 1. Briefly, pT3a and pT3b-4 stage were noted in 29.5 and 7.6 % of specimens, respectively. Biochemical progression was reported in 11.4 % of cases with a median time to recurrence of 4 months (IQR: 1–18). Margin status and characteristics are shown in Table 1. The predominant PSM locations were apex (41.8 %) and posterior location (25.6 %). Single PSM was reported in
Table 2 Univariable Cox proportional hazards model for risk of biochemical recurrence in the overall cohort HR Age
1.02
95 % CI
p value
0.99–1.04
0.211
PSA, ng/mL \10
Ref 1
10–20
1.94
1.38–2.74
\0.001
[20
3.99
2.60–6.12
\0.001
pT2 pT3a
Ref 1 3.55
2.46–5.11
\0.001
pT3b-T4
10.91
7.34–16.23
\0.001
pTNM stage
Gleason score 6
Ref 1
7
4.17
2.34–7.44
\0.001
8–10
21.87
12.01–39.83
\0.001
Nerve-sparing surgery
0.354
0.25–0.50
\0.001
PSM
4.48
3.30–6.08
\0.001
PSM location NSM
Ref 1
Anterior
4.26
2.12–8.55
\0.001
Posterior
3.06
1.80–5.20
\0.001
Lateral
4.10
1.97–8.52
\0.001
Apex
4.95
3.44–7.13
\0.001
5.63
3.35–9.45
\0.001
Base PSM number NSM
Ref 1
Solitary
4.16
2.97–5.81
\0.001
Multiple
5.17
3.42–7.79
\0.001
\0.001
PSM number NSM
Ref 1
1
4.16
2.97–5.81
2
4.54
2.89–7.12
\0.001
3 or more
9.50
4.55–19.85
\0.001
PSM length NSM
Ref 1
\3 mm
2.91
1.86–4.55
\0.001
C3 mm
5.70
4.11–7.90
\0.001
two-thirds of PSM cases. Median PSM length was 4.0 mm. An extensive PSM (C3 mm) was noted in 62.4 % of cases. The rate of PSM increased significantly with pathologic stage of the disease (p \ 0.001): 16.0 % in pT2, 33.6 % in pT3a, and 40.2 % in pT3b cancers. The majority of NSM patients had a pT2 stage (70 %), whereas 56.2 % of PSM patients had at least a pT3 disease (p \ 0.001). The PSM rate increased with pTNM stage: 18.5 % in pT2, 38.5 % in pT3a, and 48.7 % in pT3b cancers (p \ 0.001). Patients with pT3 disease had also more extensive PSM (8.3 vs. 4.9 mm, p = 0.001) and more frequently PSM at base (21.7 vs. 4 %, p \ 0.001) as
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Fig. 1 The bPFS curves stratified by PSM extent and by PSM number
compared to pT2 cancer patients. Prostate volume, PSA level, and Gleason score were also independently correlated with PSM rate. Table 2 shows predictive factors for biochemical progression using a univariable Cox regression analysis. As expected, PSA, pTNM, margin status (PSM vs. NSM), and Gleason score were significantly predictive for progression (p \ 0.001). Each PSM location was significantly predictive for progression with HR ranging from 3 to 5.6. Nevertheless, PSM at apex and base were the most powerful locations for progression as compared to PSM at anterior, posterior, and lateral locations. Solitary or multiple PSM were both significantly associated with outcomes. However, one or two PSM had comparable predictive values (HR 4.2 and 4.5), whereas 3 or more PSM was more significantly linked to progression (HR 9.5). The risk of progression also increased with PSM length, by 2.9-fold in case of\3 mm-PSM (p \ 0.001) and by 5.7-fold in case of C3 mm-PSM (p \ 0.001). The extent of PSM length was linearly and inversely correlated with bPFS (p = 0.017, Pearson’s coefficient: -0.122). Kaplan–Meier models were assessed to illustrate and compare bPFS. The 2-year bPFS was 73.7 % in PSM patients as compared to 93.0 % in NSM patients (p \ 0.001). Figure 1 illustrates stratification of survival curves of the overall cohort by margin characteristics. The PSM length was significantly predictive for different bPFS
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rates (p = 0.001). The presence of at least 3 PSM was also predictive for survival (p = 0.029). Location was not significantly associated with different survival curves even the apical location (p = 0.378). Survival subgroup analyses were performed after stratification by pT stage (Fig. 2). None of PSM characteristics (PSM number, length, location) significantly influenced the bPFS rates in the subgroup of patients having a pT2 disease. Conversely, stratification by PSM location (apex vs. other locations, p = 0.008), by PSM number (1–2 vs. C3 sites, p = 0.006), and by PSM length (p \ 0.001) showed significant differences in bPFS curves in the subgroup of pT3-4 cancer patients. To assess the potential diagnostic yield provided by each margin parameter (length, location, number) as compared to well-defined prognostic margin status (NSM vs. PSM), we used a multivariable Cox model in the overall cohort (Table 3). In the overall cohort, PSM length (C3 mm) was independently predictive for poorer bPFS (HR 1.9, p = 0.004), whereas differences did not reach significance concerning PSM number and PSM location. In the subgroup of pT2 cancer patients, only the margin status was predictive for bPFS as PSM length, number, and location failed to independently predict survival. In the subgroup of pT3-4 cancer patients, there were trends toward poorer bPFS rates in case of multifocal PSM and apical location, but differences did not reach significance. Other locations, including base, did not significantly influenced bPFS.
World J Urol Fig. 2 The bPFS curves stratified by PSM extent in organ-confined (above; p) and non-organ-confined disease (below)
Nevertheless, in that subgroup of non-organ-confined disease, PSM length also independently predicted bPFS (p = 0.005).
Discussion Local control after RP depends on the presence and extent of extraprostatic disease, seminal vesicle invasion, unfavorable Gleason score, and high preoperative PSA level [16, 17]. Literature also supports evidence that the margin
status is a strong predictor of prostate cancer progression and survival, and one of the most influential factors used to determine adjuvant treatment for prostate cancer [4, 5, 18]. Several factors such as location (apical vs. others), PSM length, and number of margins (unifocal vs. multifocal) have been studied to stratify the risk of disease recurrence in cancers with PSM [9–11]. However, conflicting results are reported and the additional value of such subclassifications as compared to simple positive/negative margins report is not established. In univariable analysis, we confirmed that PSM number and extent were significantly
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World J Urol Table 3 Multivariable Cox proportional hazards model for risk of biochemical recurrence in the overall cohort (multivariable model corrected for age, PSA level, Gleason score, nerve-sparing surgery, margin status, clinical stage, prostate volume) Overall cohort n = 1,504
PSM number 0–2 3 or more PSM length \3 mm C3 mm PSM location Other than apex Apex
pT2 n = 949
p value
HR
95 % CI
p value
HR
95 % CI
p value
HR
95 % CI
0.170
Ref 1 1.68
0.80–3.50
0.837
Ref 1 1.10
0.45–2.71
0.066
Ref 1 2.02
0.95–4.29
0.004
Ref 1 1.91
1.23–2.97
0.492
Ref 1 1.33
0.59–3.01
0.005
Ref 1 2.16
1.26–3.68
0.074
Ref 1 1.43
0.97–2.11
0.789
Ref 1 0.90
0.40–2.00
0.079
Ref 1 1.50
0.95–2.35
linked to bPFS. Interestingly, the bPFS was also inversely and linearly correlated with the PSM extent. An International Society of Urological Pathology conference recommended that pathologists mention the linear extent of PSM in routine reports [12]. The impact of PSM/NSM margin status also depends on the pathologic extent of the positive margin [11, 19–23]. The additional value of PSM number remained uncertain as compared to standard margin status reporting NSM versus PSM [22, 23]. Previously, Stephenson et al. [10] also demonstrated the influence of PSM extent and number on biochemical failure, but they failed to show that these subclassifications of PSM according to their extent had empirical usefulness. Indeed, they did not find any enhancement of nomogram accuracy after incorporating it in addition to the simple PSM/NSM status [10]. Moreover, no stratification by pathological stage has been performed in such studies. Our findings suggested that in organ-confined disease, PSM margin status independently predicted outcomes, but PSM subclassifications did not improve this bPFS prediction. This meant that even if the majority of patients with PSM and pT2 disease will never manifest biochemical progression, a focal and solitary PSM could lead to recurrence. Conversely, in non-organ-confined disease, PSM may occur at a location away from the site of extraprostatic extension that could be the main issue explaining the predictive value of the extent and the number of PSM for PSA failure. The prognostic value of PSM location is controversial. Eastham et al. [24] suggested that a posterolateral PSM was associated with a higher risk of biochemical recurrence. Due to the absence of capsule at the prostate apex, various reports also suggested that apical PSM did not confer poorer oncologic outcomes [25, 26]. We did not find any significant differences in oncologic outcome regarding PSM location except in non-organ-confined disease. In that
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pT3 n = 555
setting, an apical location conferred a significant poorer bPFS as compared to other PSM locations. Importantly, data were collected prospectively from a large single-center cohort of consecutive patients who did not receive adjuvant therapy before PSA failure. To date, the impact of systematic adjuvant radiotherapy (ART) in PSM cancers remains controversial. Three randomized controlled trials have addressed the impact of ART in patients with pT3 prostate cancer and in those with PSMs [27–29]. The data from these randomized trials concordantly showed that ART improved biochemical-free survival rates and local control in patients with locally advanced prostate cancer after RP. However, to date, ART has not been shown to improve overall survival compared with surveillance and salvage radiation. Thus, adequate selection of patients for ART is still hampered by the lack of strong predictors and immediate ART for all PSM is difficult to justify. Our results could justify a more aggressive adjuvant approach in non-organ-confined prostate cancer with extensive (C3 mm) and multifocal (C3 sites) PSM cancers. Several limitations should be highlighted. The pathologic definition of PSM seems straight forward: ‘‘A tumor extending to the inked surface of the prostatectomy specimen that the surgeon has cut across’’. The definition of surgical margins is now supposed to be based on a consensus. However, even for dedicated uropathologists with considerable experience, the presence of crush, thermal, or electrocautery artifacts can complicate surgical margins interpretation. We also chose to integrate only specimens evaluated according to the 2005 ISUP consensus. Variables from the database were collected prospectively, including margins features, but reviewed in a retrospective manner introducing analyses bias. Median follow-up of the cohort was relatively short at the time of analysis, limiting the ability to analyse associations between biochemical
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progression and clinical outcomes. However, PSA failure and the time to biochemical progression are established to be associated with an increased risk of progression to metastatic disease and specific death [30].
Conclusions Analysis of the margin status provides clinically relevant prognostic value that may assist in the postoperative management of prostate cancer patients. However, subclassifications taking into account extent, number, or location of PSM do not improve the biochemical recurrence prediction in organ-confined disease. Conversely, in non-organ-confined disease, PSM length (C3 mm), multifocality (C3 sites), and apical location are significantly linked to poorer recurrence-free survival. Our results could justify a more aggressive adjuvant treatment approach in non-organ-confined prostate cancer with extensive PSM cancers.
Conflict of interest
None.
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ORIGINAL ARTICLE
Location, extent, and multifocality of positive surgical margins for biochemical recurrence prediction after radical prostatectomy Guillaume Ploussard • Sarah J. Drouin • Julie Rode • Yves Allory Dimitri Vordos • Andras Hoznek • Claude-Cle´ment Abbou • Alexandre de la Taille • Laurent Salomon
•
Received: 27 November 2013 / Accepted: 13 January 2014 Ó Springer-Verlag Berlin Heidelberg 2014
Abstract Purpose To study the prognostic value of extent, number, and location of positive surgical margins (PSM). Methods A total of 1,504 consecutive adjuvant treatment naive and node-negative radical prostatectomy men were included in a prospective database including extent, number, and location of PSM. Mean follow-up was 33 months. Endpoint was biochemical progression-free (bPFS) survival. The impact of margin status and characteristics was assessed in time-dependent analyses using Cox regression and Kaplan–Meier methods. Results PSM was reported in 26.7 % of patients. The predominant PSM locations were apex and posterior locations. Median PSM length was 4.0 mm. The 2-year bPFS was 73.7 % in PSM patients as compared to 93.0 % in NSM patients (p \ 0.001). The rate and extent of PSM increased significantly with pathologic stage (p \ 0.001). The extent of PSM length was linearly correlated with bPFS (p = 0.017, coefficient: -0.122). In univariable analysis, extent and number of PSM were significantly
Guillaume Ploussard and Sarah J. Drouin have contributed equally to this work. G. Ploussard (&) S. J. Drouin J. Rode Y. Allory D. Vordos A. Hoznek C.-C. Abbou A. de la Taille L. Salomon Department of Urology and Pathology, Hospital Henri Mondor, 51 Avenue du Mare´chal de Lattre de Tassigny, 94010 Cre´teil, France e-mail: [email protected] L. Salomon e-mail: [email protected]
linked to outcomes. None of PSM subclassifications significantly influenced the bPFS rates in the subgroup of pT2 disease patients. Conversely, stratification by PSM location (apex vs. other locations, p = 0.008), by PSM number (p = 0.006), and by PSM length (p \ 0.001) showed significant differences in pT3-4 cancer patients. In that subgroup, PSM length also added to bPFS prediction using PSM status only in multivariable models (p = 0.005). Conclusions PSM subclassifications do not improve the biochemical recurrence prediction in organ-confined disease. In non-organ-confined disease, PSM length (C3 mm), multifocality (C3 sites), and apical location are significantly linked to poorer outcomes and could justify a more aggressive adjuvant treatment approach. Keywords Radical prostatectomy Margin Prostate cancer PSA failure Oncologic outcomes
Introduction Local control after radical prostatectomy (RP) depends on well-established biological and pathological predictive factors including the margin status. Incidence of positive surgical margins (PSM) varies markedly between different series and ranges between 10 and 60 % being in part a reflection of patient selection, surgical technique, experience of surgeons, and methodology of pathological specimen analyses [1–3]. The risk of PSM increases with increasing PSA, pathological Gleason score and local extent of the disease. PSM has been clearly demonstrated to be one of the main predictive factors for biochemical failure, disease progression, and cancer mortality [4–8]. Prognostic subclassification could improve oncologic outcome prediction and future management. Several factors
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such as location (apical vs. others), length, number of margins (unifocal vs. multifocal) have been studied to stratify the risk of disease recurrence in cancers with PSM [9–11]. An International Society of Urological Pathology conference recommended that pathologists mention the linear extent of PSM in routine reports [12]. However, the additional value of such subclassifications as compared to simple positive/negative margins report is not strongly established. Moreover, to the best of our knowledge, the combined prognostic values of location, number, and extent of PSM have not been assessed together in a single study. In the present series, we studied the impact of PSM status and characteristics (including PSM number, location, and extent) as predictive factor for biochemical recurrence after RP in adjuvant treatment-naı¨ve patients. We also aimed to evaluate whether the prognostic impact of such PSM features varied according to the pathological stage of the disease.
Table 1 Patient cohort characteristics and positive surgical margins parameters n = 1,504 Age, years Median (IQR)
Patient selection From our prospective database, we extracted data from consecutive men who had undergone RP for localized prostate cancer 2005 and 2011 at the Department of Urology, Hospital Henri Mondor, Cre´teil, France. All patients underwent extraperitoneal laparoscopic radical prostatectomy by three well-experienced senior surgeons (CCA, LS, ADLT). Prostatectomy specimens were analyzed as whole mounts and reviewed by a single uropathologist. Standard lymphadenectomy was performed prior to the completion of the vesicourethral anastomosis in case of Gleason score [6 and/or PSA level [10 ng/ml. Low-risk PCa and preoperatively potent patients underwent conventional nervesparing procedure. Patients who had received neoadjuvant therapy or adjuvant therapy before PSA relapse (n = 31) were excluded from analyses. These 31 patients have been included in a prospective trial assessing the role of adjuvant chemotherapy in high-risk cases. Patients with positive lymph nodes (n = 38) were also excluded from analyses. Finally, 1,504 men were included. All patients were followed at our institution and medical visits were scheduled at 1, 3, and 6 months and then within a 6-month interval after RP. Mean follow-up after RP was 33 months (1–71 months; IQR: 22–47). The hospital’s ethics committee approved the study and the good clinical practice criteria were respected.
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62.6
63.0
0.280
8.1
12.0
\0.001
49.9
44.7
\0.001
43.0 (32–58)
pTNM stage pT2
63.1 %
70.0 %
43.8 % \0.001
pT3a
29.4 %
24.7 %
42.3 %
pT3b-T4
7.6 %
5.3 %
13.9 %
6
33.1 %
39.6 %
14.4 % \0.001
7
57.8 %
53.9 %
69.4 %
8–10
9.1 %
6.6 %
Gleason score
PSM
Materials and methods
p value
7.0 (5–10)
Prostate volume, mL Median (IQR)
PSM
62.7 (58.1–67.7)
PSA, ng/mL Median (IQR)
NSM
Overall
26.7 %
pT2
18.5 %
pT3a pT3b-4
38.5 % 48.7 %
Nerve-sparing surgery
84.0 %
Progression
11.4 %
Follow-up, months Median (IQR)
16.2 %
0%
100 %
87.1 %
79.9 %
0.002
25.3 % \0.001
6.4 % 33.3
33.5
0.810
30 (19–44)
n = 402
PSM cohort
pT2
pT3-4 %
n
%
%
Anterior
43
10.7
13.7
8.4
Posterior
103
25.6
26.9
24.8
p value
PSM location
Lateral
32
8.0
7.4
8.4
Apex Base
168 56
41.8 13.9
48.0 4.0
36.7 21.7
Solitary
275
68.4
70.9
67.0
Multiple, including
127
31.6
29.1
33.1
2
104
25.9
25.7
25.6
3–4
23
5.7
3.4
7.5
\0.001
PSM number 0.216
PSM length \3 mm
151
37.6
42.1
33.8
C3 mm
251
62.4
57.9
66.2
4.9
8.3
0.101
PSM length, mm Median (IQR)
4.0 (2–8)
0.001
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Study outcomes The primary outcome of the study was the biochemical recurrence-free survival (PFS) in patients according to the surgical margins status. Biochemical progression was defined by two consecutive PSA measurements[0.2 ng/ml at least 3 months after radical prostatectomy. No patient received adjuvant treatment before biological progression. Database and statistical analyses Data were collected prospectively into a database, including preoperative clinical and biological characteristics, patient demographics, surgical data, and postoperative parameters. Pathologic Gleason score, surgical margin (SM) status (PSM: positive SM; vs. NSM: negative SM), margin characteristics (extent, location, number), pTNM stage were recorded. All pathologic specimens were reviewed by a single senior uropathologist with criteria clearly defined at the beginning of the study. Gleason score was graded according to the 2005 ISUP consensus conference [13]. Positive margins were defined as the presence of tumor tissue on the inked surface of the specimen. Length of PSM was calculated in each case. The number of PSM was reported. The location (anterior, apex, base, lateral, posterior) of the predominant PSM was also noted. Patients with PSA failure were considered for salvage treatment. The impact of margin status and characteristics was assessed in time-dependent analyses using Cox regression models and illustrating by hazards ratio and their 95 % CI. Length of PSM was assessed as quantitative and qualitative variable (1–2 vs. C3 mm). This cutoff was chosen according to recent literature findings [14, 15]. The biochemical progression-free (bPFS) survival was estimated using the Kaplan–Meier method. Survival curves were stratified by the margin status and characteristics, and compared using the log-rank test. A double-sided p value \0.05 was considered statistically significant. All data were analyzed using SPSS version.16.0 software (SPSS, Chicago, Illinois, USA).
Results Characteristics of the cohort are listed in Table 1. Briefly, pT3a and pT3b-4 stage were noted in 29.5 and 7.6 % of specimens, respectively. Biochemical progression was reported in 11.4 % of cases with a median time to recurrence of 4 months (IQR: 1–18). Margin status and characteristics are shown in Table 1. The predominant PSM locations were apex (41.8 %) and posterior location (25.6 %). Single PSM was reported in
Table 2 Univariable Cox proportional hazards model for risk of biochemical recurrence in the overall cohort HR Age
1.02
95 % CI
p value
0.99–1.04
0.211
PSA, ng/mL \10
Ref 1
10–20
1.94
1.38–2.74
\0.001
[20
3.99
2.60–6.12
\0.001
pT2 pT3a
Ref 1 3.55
2.46–5.11
\0.001
pT3b-T4
10.91
7.34–16.23
\0.001
pTNM stage
Gleason score 6
Ref 1
7
4.17
2.34–7.44
\0.001
8–10
21.87
12.01–39.83
\0.001
Nerve-sparing surgery
0.354
0.25–0.50
\0.001
PSM
4.48
3.30–6.08
\0.001
PSM location NSM
Ref 1
Anterior
4.26
2.12–8.55
\0.001
Posterior
3.06
1.80–5.20
\0.001
Lateral
4.10
1.97–8.52
\0.001
Apex
4.95
3.44–7.13
\0.001
5.63
3.35–9.45
\0.001
Base PSM number NSM
Ref 1
Solitary
4.16
2.97–5.81
\0.001
Multiple
5.17
3.42–7.79
\0.001
\0.001
PSM number NSM
Ref 1
1
4.16
2.97–5.81
2
4.54
2.89–7.12
\0.001
3 or more
9.50
4.55–19.85
\0.001
PSM length NSM
Ref 1
\3 mm
2.91
1.86–4.55
\0.001
C3 mm
5.70
4.11–7.90
\0.001
two-thirds of PSM cases. Median PSM length was 4.0 mm. An extensive PSM (C3 mm) was noted in 62.4 % of cases. The rate of PSM increased significantly with pathologic stage of the disease (p \ 0.001): 16.0 % in pT2, 33.6 % in pT3a, and 40.2 % in pT3b cancers. The majority of NSM patients had a pT2 stage (70 %), whereas 56.2 % of PSM patients had at least a pT3 disease (p \ 0.001). The PSM rate increased with pTNM stage: 18.5 % in pT2, 38.5 % in pT3a, and 48.7 % in pT3b cancers (p \ 0.001). Patients with pT3 disease had also more extensive PSM (8.3 vs. 4.9 mm, p = 0.001) and more frequently PSM at base (21.7 vs. 4 %, p \ 0.001) as
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Fig. 1 The bPFS curves stratified by PSM extent and by PSM number
compared to pT2 cancer patients. Prostate volume, PSA level, and Gleason score were also independently correlated with PSM rate. Table 2 shows predictive factors for biochemical progression using a univariable Cox regression analysis. As expected, PSA, pTNM, margin status (PSM vs. NSM), and Gleason score were significantly predictive for progression (p \ 0.001). Each PSM location was significantly predictive for progression with HR ranging from 3 to 5.6. Nevertheless, PSM at apex and base were the most powerful locations for progression as compared to PSM at anterior, posterior, and lateral locations. Solitary or multiple PSM were both significantly associated with outcomes. However, one or two PSM had comparable predictive values (HR 4.2 and 4.5), whereas 3 or more PSM was more significantly linked to progression (HR 9.5). The risk of progression also increased with PSM length, by 2.9-fold in case of\3 mm-PSM (p \ 0.001) and by 5.7-fold in case of C3 mm-PSM (p \ 0.001). The extent of PSM length was linearly and inversely correlated with bPFS (p = 0.017, Pearson’s coefficient: -0.122). Kaplan–Meier models were assessed to illustrate and compare bPFS. The 2-year bPFS was 73.7 % in PSM patients as compared to 93.0 % in NSM patients (p \ 0.001). Figure 1 illustrates stratification of survival curves of the overall cohort by margin characteristics. The PSM length was significantly predictive for different bPFS
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rates (p = 0.001). The presence of at least 3 PSM was also predictive for survival (p = 0.029). Location was not significantly associated with different survival curves even the apical location (p = 0.378). Survival subgroup analyses were performed after stratification by pT stage (Fig. 2). None of PSM characteristics (PSM number, length, location) significantly influenced the bPFS rates in the subgroup of patients having a pT2 disease. Conversely, stratification by PSM location (apex vs. other locations, p = 0.008), by PSM number (1–2 vs. C3 sites, p = 0.006), and by PSM length (p \ 0.001) showed significant differences in bPFS curves in the subgroup of pT3-4 cancer patients. To assess the potential diagnostic yield provided by each margin parameter (length, location, number) as compared to well-defined prognostic margin status (NSM vs. PSM), we used a multivariable Cox model in the overall cohort (Table 3). In the overall cohort, PSM length (C3 mm) was independently predictive for poorer bPFS (HR 1.9, p = 0.004), whereas differences did not reach significance concerning PSM number and PSM location. In the subgroup of pT2 cancer patients, only the margin status was predictive for bPFS as PSM length, number, and location failed to independently predict survival. In the subgroup of pT3-4 cancer patients, there were trends toward poorer bPFS rates in case of multifocal PSM and apical location, but differences did not reach significance. Other locations, including base, did not significantly influenced bPFS.
World J Urol Fig. 2 The bPFS curves stratified by PSM extent in organ-confined (above; p) and non-organ-confined disease (below)
Nevertheless, in that subgroup of non-organ-confined disease, PSM length also independently predicted bPFS (p = 0.005).
Discussion Local control after RP depends on the presence and extent of extraprostatic disease, seminal vesicle invasion, unfavorable Gleason score, and high preoperative PSA level [16, 17]. Literature also supports evidence that the margin
status is a strong predictor of prostate cancer progression and survival, and one of the most influential factors used to determine adjuvant treatment for prostate cancer [4, 5, 18]. Several factors such as location (apical vs. others), PSM length, and number of margins (unifocal vs. multifocal) have been studied to stratify the risk of disease recurrence in cancers with PSM [9–11]. However, conflicting results are reported and the additional value of such subclassifications as compared to simple positive/negative margins report is not established. In univariable analysis, we confirmed that PSM number and extent were significantly
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World J Urol Table 3 Multivariable Cox proportional hazards model for risk of biochemical recurrence in the overall cohort (multivariable model corrected for age, PSA level, Gleason score, nerve-sparing surgery, margin status, clinical stage, prostate volume) Overall cohort n = 1,504
PSM number 0–2 3 or more PSM length \3 mm C3 mm PSM location Other than apex Apex
pT2 n = 949
p value
HR
95 % CI
p value
HR
95 % CI
p value
HR
95 % CI
0.170
Ref 1 1.68
0.80–3.50
0.837
Ref 1 1.10
0.45–2.71
0.066
Ref 1 2.02
0.95–4.29
0.004
Ref 1 1.91
1.23–2.97
0.492
Ref 1 1.33
0.59–3.01
0.005
Ref 1 2.16
1.26–3.68
0.074
Ref 1 1.43
0.97–2.11
0.789
Ref 1 0.90
0.40–2.00
0.079
Ref 1 1.50
0.95–2.35
linked to bPFS. Interestingly, the bPFS was also inversely and linearly correlated with the PSM extent. An International Society of Urological Pathology conference recommended that pathologists mention the linear extent of PSM in routine reports [12]. The impact of PSM/NSM margin status also depends on the pathologic extent of the positive margin [11, 19–23]. The additional value of PSM number remained uncertain as compared to standard margin status reporting NSM versus PSM [22, 23]. Previously, Stephenson et al. [10] also demonstrated the influence of PSM extent and number on biochemical failure, but they failed to show that these subclassifications of PSM according to their extent had empirical usefulness. Indeed, they did not find any enhancement of nomogram accuracy after incorporating it in addition to the simple PSM/NSM status [10]. Moreover, no stratification by pathological stage has been performed in such studies. Our findings suggested that in organ-confined disease, PSM margin status independently predicted outcomes, but PSM subclassifications did not improve this bPFS prediction. This meant that even if the majority of patients with PSM and pT2 disease will never manifest biochemical progression, a focal and solitary PSM could lead to recurrence. Conversely, in non-organ-confined disease, PSM may occur at a location away from the site of extraprostatic extension that could be the main issue explaining the predictive value of the extent and the number of PSM for PSA failure. The prognostic value of PSM location is controversial. Eastham et al. [24] suggested that a posterolateral PSM was associated with a higher risk of biochemical recurrence. Due to the absence of capsule at the prostate apex, various reports also suggested that apical PSM did not confer poorer oncologic outcomes [25, 26]. We did not find any significant differences in oncologic outcome regarding PSM location except in non-organ-confined disease. In that
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pT3 n = 555
setting, an apical location conferred a significant poorer bPFS as compared to other PSM locations. Importantly, data were collected prospectively from a large single-center cohort of consecutive patients who did not receive adjuvant therapy before PSA failure. To date, the impact of systematic adjuvant radiotherapy (ART) in PSM cancers remains controversial. Three randomized controlled trials have addressed the impact of ART in patients with pT3 prostate cancer and in those with PSMs [27–29]. The data from these randomized trials concordantly showed that ART improved biochemical-free survival rates and local control in patients with locally advanced prostate cancer after RP. However, to date, ART has not been shown to improve overall survival compared with surveillance and salvage radiation. Thus, adequate selection of patients for ART is still hampered by the lack of strong predictors and immediate ART for all PSM is difficult to justify. Our results could justify a more aggressive adjuvant approach in non-organ-confined prostate cancer with extensive (C3 mm) and multifocal (C3 sites) PSM cancers. Several limitations should be highlighted. The pathologic definition of PSM seems straight forward: ‘‘A tumor extending to the inked surface of the prostatectomy specimen that the surgeon has cut across’’. The definition of surgical margins is now supposed to be based on a consensus. However, even for dedicated uropathologists with considerable experience, the presence of crush, thermal, or electrocautery artifacts can complicate surgical margins interpretation. We also chose to integrate only specimens evaluated according to the 2005 ISUP consensus. Variables from the database were collected prospectively, including margins features, but reviewed in a retrospective manner introducing analyses bias. Median follow-up of the cohort was relatively short at the time of analysis, limiting the ability to analyse associations between biochemical
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progression and clinical outcomes. However, PSA failure and the time to biochemical progression are established to be associated with an increased risk of progression to metastatic disease and specific death [30].
Conclusions Analysis of the margin status provides clinically relevant prognostic value that may assist in the postoperative management of prostate cancer patients. However, subclassifications taking into account extent, number, or location of PSM do not improve the biochemical recurrence prediction in organ-confined disease. Conversely, in non-organ-confined disease, PSM length (C3 mm), multifocality (C3 sites), and apical location are significantly linked to poorer recurrence-free survival. Our results could justify a more aggressive adjuvant treatment approach in non-organ-confined prostate cancer with extensive PSM cancers.
Conflict of interest
None.
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![[Positive surgical margins after radical prostatectomy].](/assets/img/hold.png)
