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Agreement of Gleason Score on Prostate Biopsy and Radical Prostatectomy Specimen: Is There Improvement With Increased Number of Biopsy Cylinders and the 2005 Revised Gleason Scoring?
Original Study
Agreement of Gleason Score on Prostate Biopsy and Radical Prostatectomy Specimen: Is There Improvement With Increased Number of Biopsy Cylinders and the 2005 Revised Gleason Scoring? Charles Van Praet,1 Louis Libbrecht,2 Frederiek D’Hondt,1 Karel Decaestecker,1 Valérie Fonteyne,3 Stephanie Verschuere,2 Sylvie Rottey,4 Marleen Praet,2 Pieter De Visschere,5 Nicolaas Lumen,1on behalf of the Uro-Oncology Group Ghent Abstract For prostate cancer diagnoses we simultaneously incorporated the 2005 modified Gleason score (GS) and increased the standard number of biopsy cylinders to 8 to 12. This provided better Gleason score concordance between biopsy and radical prostatectomy (RP) specimens (n [ 193) than before this change of practice (n [ 135), although concordance rate (54%) remained rather poor. More tumors are labeled intermediate-/ high-grade using the modified Gleason score. Introduction: The objectives of this study were to assess the agreement of GS on biopsy compared with RP specimens and to assess whether an increased number of biopsy cylinders and the 2005 International Society of Urological Pathology (ISUP) GS modification improved this agreement. Materials and Methods: Pathological data of biopsy and RP specimens were analyzed in 328 consecutive patients, before (group 1; n ¼ 135) and after (group 2; n ¼ 193) implementation of the 2005 ISUP modification. Additionally, patients had more biopsy cylinders taken in group 2 (mean 10 vs. 6.9). The agreement of GS between biopsy and RP specimens was evaluated using the kappa coefficient. GS was pooled into 3 grades: low- (GS 6), intermediate- (GS ¼ 7), and high-grade (GS 8) prostate cancer. Results: Kappa coefficient for GS in group 1 and 2 was 0.261 and 0.341, respectively. For tumor grade, this was 0.308 and 0.359 for group 1 and 2, respectively. For RP specimens, there was more agreement between biopsy and RP GS in group 2 compared with group 1 (53.9% vs. 37.8%). Upgrading was almost exclusively (89.5%) seen in patients with biopsy GS 6 and was lower in group 2 (25.4% vs. 48.1%) because of classification of more intermediate- and high-grade tumors using the 2005 ISUP modification. Taking > 6 biopsy cylinders was associated with better GS and tumor grade agreement. Conclusion: Extended biopsy template and the 2005 ISUP modification resulted in an improved agreement between biopsy GS and RP GS and a shift toward more aggressive tumors. Clinical Genitourinary Cancer, Vol. 12, No. 3, 160-6 ª 2014 Elsevier Inc. All rights reserved. Keywords: Biopsy, Gleason score, Pathology, Prostatectomy, Prostatic neoplasms
Introduction Prostate biopsy histopathology is a key step in diagnosing prostate cancer (PC).1,2 The Gleason score (GS)3 is universally accepted as a grading system for histopathology obtained from prostate biopsy and radical prostatectomy (RP).1 At the 2005 International 1
Department of Urology Department of Pathology 3 Department of Radiotherapy 4 Department of Medical Oncology 5 Department of Radiology Ghent University Hospital, Ghent, Belgium 2
160
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Society of Urological Pathology (ISUP) Consensus Conference several changes were introduced to the Gleason scoring system (for an overview, see Epstein et al4). The biopsy GS (b-GS) is an independent prognostic factor, used in several preoperative nomograms and risk group stratifications, finally affecting the therapeutic Submitted: Aug 7, 2013; Revised: Oct 8, 2013; Accepted: Nov 8, 2013; Epub: Nov 12, 2013 Address for correspondence: Charles Van Praet, MD, Department of Urology, Ghent University Hospital, De Pintelaan 185, 9000 Ghent, Belgium Fax: þ32-9-332-38-89; e-mail contact: [email protected]
1558-7673/$ - see frontmatter ª 2014 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.clgc.2013.11.008
decision-making.5,6 Therefore, a strong agreement between b-GS and RP GS is important. With the original Gleason scoring system, there was an important discrepancy between b-GS and RP GS.7 Furthermore, contemporary PC management has changed a lot because of screening, multiple cylinder biopsies, introduction of immunohistochemistry, and new insights in treatment. These factors triggered a change in clinical practice at our center: from 2006, the standard biopsy template consisted of 8 to 12 cylinders and we implemented the revised Gleason scoring system from the 2005 ISUP Consensus Conference.4 The scope of this study was to evaluate the agreement between b-GS and RP GS to determine whether our change in clinical practice improved this agreement.
Figure 1 Patients Were Divided into 2 Groups According to Year of Radical Prostatectomy. Biopsy Gleason Score (B-GS) and Radical Prostatectomy Gleason Score (RP-GS) was Assessed in all Patients
Materials and Methods From 1997, data on patients with PC undergoing RP were collected into a database. A search of this database (dated March 1, 2013) revealed 328 patients in whom pathological data of prostate biopsy and RP were available. Patient characteristics includes age, prostate-specific antigen (PSA) at biopsy, and prostate volume. Tumor characteristics included number of harvested and PC-invaded cylinders, clinical T-stage, b-GS, and RP GS. GS was pooled into 3 tumor grades: low-, intermediate-, and high-grade PC (Gleason 6, 7, and 8). Until 2006, the original GS was used for pathological analysis of prostate biopsies and RP specimens, whereas from 2006 the ISUP modification was used. Starting from 2009, RP specimens were evaluated using whole-mount sections. Specimens were evaluated by general surgical pathologists under supervision and with daily consultation of urological pathologists (L.L. and M.P.). All biopsies were performed using transrectal ultrasound (TRUS). Until 2006, sextant biopsy was performed. Additional cylinder(s) were only taken in case of a suspicious lesion on imaging or rectal examination. Starting from 2006, a minimum of 8 cylinders for small prostates (< 30 mL) and 10 to 12 for larger prostates were taken. Again, additional cylinder(s) were taken in case of suspicious lesion(s). Because of the change in scoring system and practice of prostate biopsy, patients were divided into 2 groups (Fig. 1): before 2006 (group 1; n ¼ 135) and starting
from 2006 (group 2; n ¼ 193). Continuous and categorical data were evaluated using Student t test and c2 test, respectively. Agreement between b-GS and RP GS sum was calculated using linear weighted kappa statistics8 and incidence of upgrading (RP GS sum > b-GS sum) and downgrading (RP-GS sum < b-GS sum) was calculated. Cases with b-GS 7 were further stratified into Gleason 3þ4 and 4þ3. Univariate logistic regression was used to identify predictors of GS and tumor grade agreement, upgrading, and downgrading. A P value < .05 indicated statistical significance. Ghent University Hospital’s ethics committee approved the study (EC UZG 2011/495).
Results Patients in group 2 were older compared with group 1 (62.7 vs. 60.7 years; P ¼ .0068) and had more biopsy cylinders harvested (10 vs. 6.9; P < .0001) (Table 1). Gleason score distribution and tumor grading differed significantly between groups (Table 2). No b-GS < 6 was scored in group 2. In group 1, 98 patients (72.6%) had a low-grade tumor compared to 68 patients (35.2%) in group 2 (P < .0001). There were fewer intermediate- and high-grade tumors in group 1 (25 [18.5%] vs. 90 [46.6%]; P < .0001 and 12 [8.9%] vs. 35 [18.2%];
Table 1 Patient and Tumor Characteristics for the Total Patient Population and for Each Group All Patients (n [ 328)
Group 1 (n [ 135)
Group 2 (n [ 193)
P
Age, Years
61.9 (6.6)
60.7 (6.2)
62.7 (6.7)
.0068
PSA, ng/mL
11.6 (13.1)
12.5 (13.5)
10.9 (12.8)
.274
Prostate Volume, mL
39.1 (20.4)
37.3 (15.2)
39.5 (21.6)
.396
T1
173 (52.7)
69 (51.1)
104 (53.9)
T2
148 (45.1)
63 (46.7)
85 (44.0)
T3
7 (2.1)
3 (2.2)
4 (2.1)
Characteristic
Clinical T-Stage .884
Prostate Biopsy <.0001
Cylinders, n
9.4 (3.2)
6.9 (2.5)
10.0 (3.0)
Cylinders invaded, n
3.4 (2.3)
2.9 (2.1)
3.5 (2.4)
.125
Cylinders invaded, %
37.8 (24.5)
44.8 (29.8)
36.1 (22.8)
.077
Results are presented as mean ( SD) or n (%). Group 1 ¼ before and group 2 ¼ after introduction of the 2005 ISUP modification. Bold values represent P < .05. Abbreviation: PSA ¼ prostate-specific antigen.
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Contemporary Gleason Score Agreement Table 2 Distribution of Biopsy Gleason Score (b-GS) and Radical Prostatectomy Specimen Gleason Score (RP GS) per Gleason Score and Tumor Grade Gleason Score
All Patients (n [ 328)
Group 1 (n [ 135)
Group 2 (n [ 193)
P
166 (50.6)
98 (72.6)
68 (35.2)
<.0001
1
1
0
b-GS 6 (low grade) 2 3
5
5
0
4
10
10
0
5
40
40
0
6
110
42
68
7 (intermediate grade)
115 (35.1)
25 (18.5)
90 (46.6)
3þ4
84 (73.0)
14 (56.0)
70 (77.8)
4þ3
22 (19.1)
2 (8.0)
20 (22.2)
Unknown
9 (7.8)
9 (36.0)
0
8 (high grade)
47 (14.3)
12 (8.9)
35 (18.2)
8
23
6
17
9
21
5
16
10
3
1
2
<.0001
.0284
RP GS 6 (low grade)
116 (35.4)
68 (50.4)
48 (24.9)
2
0
0
0
3
2
2
0
4
1
1
0
5
23
18
5
6 7 (intermediate grade) 3þ4
90
47
43
162 (49.4)
51 (37.8)
111 (57.5)
107 (66.0)
20 (39.2)
87 (78.4) 24 (21.6)
4þ3
27 (16.7)
3 (5.9)
Unknown
28 (17.3)
28 (54.9)
0
8 (high grade)
50 (15.2)
16 (11.2)
34 (17.6)
8
32
11
21
9
18
5
13
10
0
0
0
<.0001
.0007
.203
Results are presented as n or n (%). Bold values represent P < .05.
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P ¼ .0284, respectively). Similarly, for RP GS, significantly more low-grade tumors and fewer intermediate-grade tumors were observed in group 1 compared with group 2 (68 [50.4%] vs. 48 [24.9%]; P < .0001 and 51 [37.8%] vs. 111 [57.5%]; P ¼ .0007, respectively). For the whole study population, kappa coefficient between b-GS and RP GS was 0.344. Kappa coefficient for tumor grade was 0.381. When comparing group 1 with group 2 there was an improvement in kappa coefficient for GS (0.261 vs. 0.341) and tumor grade (0.308 vs. 0.359). For GS, a perfect match between biopsy and RP was significantly more frequent in group 2 compared with group 1 (104 [53.9%] vs. 51 patients [37.8%]; P ¼ .0057) (Table 3). For tumor grade, GS agreement did not differ between groups. In group 1, 65 patients (48.1%) had an upgrade of the GS compared to 49 patients (25.4%) in group 2 (P < .0001). When stratified according to tumor grade, however, upgrading did not differ significantly between groups. Upgrading occurred mostly in cases with b-GS 6 (102 out of 114 cases [89.5%]). Downgrading
Clinical Genitourinary Cancer June 2014
did not differ significantly. A subanalysis of b-GS 7 showed that most patients presented with b-GS 3þ4 (84 [73.0%]) rather than 4þ3 (22 [19.1%]), before and after 2006 (Table 2). There were more patients with perfect concordance between b-GS and RP GS with b-GS 3þ4 (48 [57.1%]) than with b-GS 4þ3 (8 [36.4%]), but this was not statistically significant (P ¼ .134). Upgrading was more frequent in b-GS 3þ4 (17 patients [20.2%]), including 9 patients (52.9%) with RP GS 4þ3. Downgrading was more frequent in b-GS 4þ3 (13 patients [59.1%]), including 10 patients (76.9%) with RP GS 3þ4. When considering the total group, patients with > 6 cylinders had less GS upgrading (24.1% vs. 42.5%; P ¼ .018) and tumor grade upgrading (20.9% vs. 37.5%; P ¼ .025) than patients with 6 cylinders. Univariate logistic regression (Table 4) confirmed that an increased number of cylinders predicted for less tumor grade upgrading (odds ratio [OR], 0.89 with 95% confidence interval [CI], 0.80-0.99; P ¼ .041), with > 6 cylinders as a significant cutoff
Charles Van Praet et al Table 3 Agreement Between b-GS and RP GS and Tumor Grade Gleason Score Equal
All Patients (n [ 328)
Group 1 (n [ 135)
Group 2 (n [ 193)
P
155 (47.2%)
51 (37.8%)
104 (53.9%)
.0057
b-GS <7
57 (34.3%)
32 (32.7%)
25 (36.8%)
.702
b-GS ¼ 7
81 (70.4%)
14 (56.0%)
67 (74.4%)
.123
b-GS 3þ4
48 (57.1%)
7 (50.0%)
41 (58.6%)
.767
b-GS 4þ3
8 (36.4%)
1 (50.0%)
7 (35.0%)
.726
b-GS >7
17 (36.2%)
5 (41.7%)
12 (34.3%)
.912
114 (34.8%)
65 (48.1%)
49 (25.4%)
<.0001
b-GS <7
102 (61.4%)
61 (62.2%)
41 (60.3%)
.927
b-GS ¼ 7
8 (7.0%)
3 (12.0%)
5 (5.6%)
.368
b-GS 3þ4
17 (20.2%)
1 (7.1%)
16 (22.9%)
.331
b-GS 4þ3
1 (4.5%)
0
1 (5.0%)
.145
Upgrading
b-GS >7
4 (8.5%)
1 (8.3%)
3 (8.6%)
1
59 (18.0%)
19 (14.1%)
40 (20.7%)
.162
b-GS <7
7 (4.2%)
5 (5.1%)
2 (2.9%)
.773
b-GS ¼ 7
26 (22.6%)
8 (32.0%)
18 (20.0%)
.318
b-GS 3þ4
19 (22.6%)
6 (42.8%)
13 (18.6%)
.103
b-GS 4þ3
13 (59.1%)
1 (50.0%)
12 (60.0%)
.631
b-GS >7
26 (55.3%)
6 (50.0%)
20 (57.1%)
.926 .937
Downgrading
Tumor Grade Equal
194 (59.2%)
79 (58.5%)
115 (59.6%)
Upgrading
88 (26.8%)
42 (31.1%)
46 (23.8%)
.182
Downgrading
46 (14.0%)
14 (10.4%)
32 (16.6%)
.152
b-GS and RP GS are either equal (perfect match), or show upgrading (RP GS > b-GS) or downgrading (RP GS < b-GS). For Gleason score agreement, patients were also stratified according to b-GS. Nine Gleason 7 patients not evaluable because of missing data on separate Gleason patterns. Results are presented as n (%). Bold values represent P < .05. Abbreviations: b-GS ¼ biopsy Gleason score; RP GS ¼ radical prostatectomy Gleason score.
for tumor grade (OR, 0.44; 95% CI, 0.21-0.91; P ¼ .027) and GS upgrading (OR, 0.43; 95% CI, 0.30-0.61; P ¼ .020). To discriminate between the effect of the ISUP modification and the increased number of cylinders, we assessed group 1 separately. Taking > 6 cylinders predicted for more GS agreement (OR, 3.95; 95% CI, 1.13-13.71; P ¼ .031) and better tumor grade agreement (OR, 5.09; 95% CI, 1.32-19.65; P ¼ .018). An increased number of positive cylinders predicted for more tumor grade agreement in all patients (OR, 1.15; 95% CI, 1.01-1.31; P ¼ .031) and in group 2 (OR, 1.18; 95% CI, 1.02-1.37; P ¼ .025). Increased percentage of positive cylinders only predicted for better tumor grade agreement in group 2 (OR, 1.02; 95% CI, 1.00-1.03; P ¼ .046).
Discussion Prostate biopsy is the key step in PC diagnosis and accurate PC grading is essential for appropriate treatment decision-making. The 2005 ISUP modification aimed to improve the GS agreement by creating a more universally accepted grading system, adapted to contemporary PC management. This revised Gleason scoring for prostate biopsy and for RP specimens proved to be a strong independent prognostic factor predicting the risk of biochemical recurrence after RP.9 Starting from 2006, we changed clinical practice at our center. First, our standard biopsy template of 6 cylinders was extended to 8 to 12 cylinders. Second, we adopted the 2005 ISUP modification for Gleason scoring.
We demonstrated that the 2005 ISUP modification resulted in a shift of GS distribution: GS 6 was observed in most patients before the ISUP modification on biopsy and RP specimens. However, after the ISUP modification, most patients had a GS 7. Other studies reported similar findings10,11: b-GS 6 decreased from 48% to 68% before to 22% to 49% after the ISUP modification. Accordingly, b-GS ¼ 7 increased from 26% before to 39% to 68% after the ISUP modification. It is unlikely that the increase in the amount of patients with GS 7 is explained by the fact that PC has become more aggressive in the past years. On the contrary, because of the introduction of PSA testing, more patients are found with more localized and less aggressive PC.12 Moreover, our study started several years after introduction of PSA testing and almost all patients were diagnosed with PC after an elevated PSA was detected. The shift in distribution toward higher GS and tumor grades is thus mainly explained by the ISUP modification. Indeed, one of the crucial modifications is that almost all cribriform patterns should be diagnosed as a pattern 4, thus widening the scope of pattern 4 and limiting that of pattern 3.4 This is important to acknowledge the difficulty in comparing data assessing patient outcomes in PC over time. In the current study, the agreement for GS and tumor grade improved after the ISUP modification, although this agreement remained only “fair” (ie, kappa, 0.2-0.4).8 This degree of agreement is in line with a previous meta-analysis on GS agreement, in which
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Contemporary Gleason Score Agreement Table 4 Univariate Logistic Regression for All Patients and for Group 1 and 2 Separately Factor
Biopsy Cylinders, n
>6 Biopsy Cylinders Positive Cylinders, n Positive Cylinders, %
Prostate Volume
All Patients (n [ 328) Gleason score Agreement
1.03 (0.95-1.12)
1.66 (0.83-3.31)
1.09 (0.97-1.22)
1.01 (0.99-1.02)
Upgrading
0.90 (0.82-1.00)
0.43 (0.30-0.61)
0.89 (0.78-1.03)
1.00 (0.99-1.01)
1.00 (0.99-1.02) 1.00 (0.99-1.01)
Downgrading
1.07 (0.97-1.18)
1.49 (0.59-3.81)
1.00 (0.87-1.15)
0.99 (0.98-1.01)
0.99 (0.98-1.01)
1.06 (0.97-1.16)
1.67 (0.84-3.32)
1.15 (1.01-1.31)
1.01 (0.99-1.02)
1.00 (0.99-1.01)
Tumor grade Agreement Upgrading
0.89 (0.80-0.99)
0.44 (0.21-0.91)
0.88 (0.76-1.03)
1.00 (0.99-1.01)
1.00 (0.99-1.02)
Downgrading
1.03 (0.93-1.15)
1.39 (0.51-3.83)
0.91 (0.77-1.09)
0.99 (0.97-1.01)
0.99 (0.98-1.01)
Group 1 (n [ 135) Gleason score Agreement
1.23 (0.95-1.60)
3.95 (1.13-13.71)
1.06 (0.80-1.42)
1.00 (0.98-1.02)
0.98 (0.95-1.02)
Upgrading
0.90 (0.69-1.15)
0.46 (0.14-1.60)
0.91 (0.67-1.22)
1.00 (0.98-1.02)
1.02 (0.98-1.06)
Downgrading
0.79 (0.52-1.19)
0.21 (0.02-1.97)
1.08 (0.70-1.65)
1.01 (0.98-1.04)
1.00 (0.95-1.05)
Agreement
1.70 (1.14-2.54)
5.09 (1.32-19.65)
1.03 (0.77-1.38)
0.99 (0.96-1.01)
0.97 (0.94-1.01)
Upgrading
0.63 (0.43-0.94)
0.27 (0.06-1.15)
0.93 (0.67-1.29)
1.01 (0.99-1.04)
1.03 (0.99-1.07)
Downgrading
0.79 (0.51-1.23)
0.28 (0.03-2.70)
1.08 (0.70-1.65)
1.01 (0.98-1.04)
1.01 (0.95-1.06)
Tumor grade
Group 2 (n [ 193) Gleason Score Agreement
0.98 (0.89-1.08)
e
1.09 (0.96-1.24)
1.01 (1.00-1.03)
1.01 (0.99-1.02)
Upgrading
0.94 (0.84-1.07)
e
0.91 (0.77-1.06)
1.00 (0.98-1.01)
1.00 (0.98-1.01)
Downgrading
1.08 (0.97-1.21)
e
0.98 (0.84-1.14)
0.99 (0.97-1.01)
0.99 (0.98-1.01)
Agreement
1.02 (0.92-1.13)
e
1.18 (1.02-1.37)
1.02 (1.00-1.03)
1.00 (0.99-1.02)
Upgrading
0.94 (0.83-1.07)
e
0.88 (0.74-1.04)
0.99 (0.98-1.01)
1.00 (0.98-1.02)
Downgrading
1.04 (0.92-1.17)
e
0.88 (0.72-1.07)
0.98 (0.96-1.00)
0.99 (0.97-1.01)
Tumor Grade
Results are presented as odds ratio (95% confidence interval). Statistically significant results (P < .05) are presented in bold.
164
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a kappa coefficient of 0.37 was observed.13 However, this metaanalysis did not take into account a difference before and after the ISUP modification. In our study, since 2006 the rate of patients with a perfect GS match has significantly increased from 38% to 54%. Montironi et al reported a perfect match between b-GS and RP GS in 43% based on a compilation of data before the ISUP modification, which is in line with the results in group 1.7 Other series report concordance rates with the original GS ranging from 32% to 64% that significantly increased to 44% to 70% when the ISUP modification was used.14,15 Although we demonstrated an improved GS agreement, after b-GS stratification, this improvement was no longer statistically significant. Indeed, this improvement is mostly because of a reduced incidence of b-GS 6, which in our series has the poorest b-GS and RP GS concordance rate. Also, after adjustment for tumor grade, the improvement of this concordance rate became no longer statistically significant. Before introduction of the ISUP modification many patients with b-GS 6 had an upgrade of GS, but remained classified as having a low-grade tumor. This can be explained by the ISUP recommendation that diagnosing a Gleason pattern of 1 to 2 should “rarely, if ever be done.”4 The main reason for this recommendation was the fact that a bGS 4 correlates very poorly with RP GS.7 This was also observed
Clinical Genitourinary Cancer June 2014
in our series in which most patients (13 of 16) with b-GS 4 were upgraded to RP GS > 4. Upgrading was significantly less in group 2, but b-GS stratification again shows this is because of a reduction in b-GS 6 cases after the ISUP modification. In our series b-GS 6 was associated with a 60% chance of upgrading, before and after the ISUP modification, which is at the upper bound of what is reported in other series.14-18 Compared with upgrading, downgrading was less frequent, before and after the ISUP modification.7,13-15 Downgrading might be explained by the fact that tangentially sectioned small glands of pattern 3 on biopsy were overgraded as Gleason pattern 4. Alternatively, in some cases the assigned biopsy Gleason pattern 4 might have been accurate with such small foci of pattern 4 in the RP specimen that it was either not recorded or unsampled deeper within the paraffin block. The GS of biopsy and RP specimen might not be the same for several reasons. Borderline grades and pathological errors are possible explanations.7 Most frequently, a sampling error (ie, when a higher grade is missed on biopsy) has been proposed.13,17,19 Studies have demonstrated that increasing the number of biopsies reduces upgrading.20-23 Contemporary guidelines recommend an extended biopsy template (10-12 cylinders), which has a PC
Charles Van Praet et al detection rate of 80%, instead of sextant biopsies to avoid the additional risk of upgrading.1,24 This recommendation is strengthened by our significantly lower chance of GS and tumor grade upgrading when > 6 biopsy cylinders were taken. However, because most cases with > 6 biopsy cylinders were diagnosed after 2005, this effect might be attributed to the 2005 ISUP modification. Therefore, we analyzed the effect of an extended biopsy template in group 1 (before the ISUP modification) separately. We found that an increased number of cylinders predicted for more tumor grade agreement and less upgrading, with a cutoff of > 6 cylinders associated with more agreement. This is in line with the literature before the ISUP modification.23 Because of the concomitant introduction of our extended biopsy template and the ISUP modification, all patients in group 2 had > 6 biopsy cylinders taken and we cannot reliably assess the effect of an extended biopsy template on GS agreement with the current revised Gleason scoring system. In our current practice, however, an increased number or percentage of positive cylinders predicted for more tumor grade agreement on univariate logistic regression. Indeed, a greater tumor volume in contemporary biopsies is associated with more accurate staging.20 Although upgrading nowadays is less common, in our series there is, however, a slight trend toward more downgrading after the ISUP modification. From a clinical point of view, this is safer and thus considered as acceptable. In our opinion it is better to apply an aggressive but curative treatment for a post hoc less aggressive tumor than to apply an insufficient treatment for a post hoc more aggressive tumor. Upgrading and downgrading has significant implications for patients in whom a change in tumor grade would affect their management. Indeed, tumor grade is a cornerstone in risk group stratification.5 Active surveillance or focal therapy (brachytherapy or high-intensity focused ultrasound) would be a less appropriate treatment choice if upgrading occurs or might have been an option if downgrading occurred. Furthermore, the tumor grade influences the need for pelvic lymphadenectomy and androgen deprivation therapy concomitant with external beam radiotherapy.1 From a prognostic point of view, upgrading is associated with greater risk of adverse pathologic features and biochemical progression.4,11,12 In contrast, downgrading was associated with better biochemical recurrence-free survival.11,12 Finally, considering the different prognoses suggested by several studies, we looked at GS 7 independently to assess b-GS and RP GS agreement in case of GS 3þ4 or 4þ3 on biopsy.25,26 There is better agreement for 3þ4 than for 4þ3. Up to 60% of patients with GS 4þ3 had downgrading, most of them to GS 3þ4 (83%). Upgrading of GS 4þ3, however, is infrequent (5%), which indicates that generally the relative volume of pattern 4 tumor is overestimated. This is not surprising: in case only 1 biopsy cylinder presents more Gleason pattern 4 than pattern 3, the biopsy result is labeled GS 4þ3, despite that several other cylinders might harbor an abundance of Gleason pattern 3 and little pattern 4. On RP analysis, however, such a case would be classified as 3þ4. Further techniques to improve PC detection rate and b-GS accuracy have been proposed, one of which is increasing the number of biopsy cylinders up to 20 to 50 (saturation biopsies). This can be performed transrectally or transperineally with the use of a stereotactic grid, which is more suitable for template biopsies.27
Transperineal biopsy also allows for better access to the anterior zone of the prostate and has a very low risk of infective complications.28 However, the need for general anesthesia makes this less convenient for the patient and for the urologist. Currently, saturation biopsy is usually restricted for repeat biopsies after initial negative biopsy.29 Instead of template biopsies with increased sampling rate, image-guided targeted biopsy seems a more appealing alternative. Multiparametric magnetic resonance imaging (MRI)targeted biopsy or TRUS-guided biopsy after MRI (with or without MRI/TRUS fusion) have been described. This approach detects as many clinically significant tumors as standard biopsy but reduces to a third the number of men biopsied and the number of biopsy cylinders (mean, 3.8).30 Additionally, fewer clinically insignificant tumors will be detected when adopting MRI.30 A suspicious MRI also predicts for b-GS upgrading after standard biopsy.31 Hambrock et al reported a highest Gleason pattern concordance between RP specimen and MRI-guided biopsy (n ¼ 34) in 88% of patients compared with 55% (P ¼ .001) using standard 10-cylinder biopsy (n ¼ 64).32 These data indicate MRI is valuable in decision-making as to whether the patient should undergo (repeat) biopsy and can improve b-GS accuracy. Our report has some shortcomings because we retrospectively analyzed GS agreement in 2 separate patient cohorts. However, the fact that only age but not tumor characteristics (except for, of course, GS distribution) differed in both groups adds strength to our findings. The older age in group 2 can be explained by the increasing life expectancy which lowered our threshold for performing RP in older patients.
Conclusion We demonstrated that the ISUP modification resulted in a shift of GS distribution toward more aggressive tumors, on biopsy and on RP. Overall, there is only a fair agreement between b-GS and RP GS. With the ISUP modification and an extended biopsy template, more patients had a perfect match between b-GS and RP GS. GS upgrading was less prevalent because of a reduced incidence of low-grade tumors.
Clinical Practice Points The 2005 ISUP modification leads to diagnosis of more inter-
mediate- and high-grade PC. The 2005 ISUP modification resulted in a better concordance
between biopsy and RP GS, although this concordance remained rather poor. Since upgrading (RP GS > b-GS) is most prevalent in low-grade PC, upgrading is less common nowadays.
Disclosure The authors have stated that they have no conflicts of interest.
References 1. Heidenreich A, Bellmunt J, Bolla M, et al. EAU guidelines on prostate cancer. Part 1: screening, diagnosis, and treatment of clinically localised disease. Eur Urol 2011; 59:61-71. 2. Lumen N, Fonteyne V, De Meerleer G, et al. Screening and early diagnosis of prostate cancer: an update. Acta Clin Belg 2012; 67:270-5. 3. Gleason DF. Classification of prostatic carcinomas. Cancer Chemother Rep 1966; 50:125-8.
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Contemporary Gleason Score Agreement 4. Epstein JI, Allsbrook WC Jr., Amin MB, et al. The 2005 International Society of Urological Pathology (ISUP) Consensus Conference on Gleason Grading of Prostatic Carcinoma. Am J Surg Pathol 2005; 29:1228-42. 5. D’Amico AV, Whittington R, Malkowicz SB, et al. Biochemical outcome after radical prostatectomy, external beam radiation therapy, or interstitial radiation therapy for clinically localized prostate cancer. JAMA 1998; 280:969-74. 6. Lughezzani G, Briganti A, Karakiewicz PI, et al. Predictive and prognostic models in radical prostatectomy candidates: a critical analysis of the literature. Eur Urol 2010; 58:687-700. 7. Montironi R, Mazzuccheli R, Scarpelli M, et al. Gleason grading of prostate cancer in needle biopsies or radical prostatectomy specimens: contemporary approach, current clinical significance and sources of pathology discrepancies. BJU Int 2005; 95:1146-52. 8. Viera AJ, Garrett JM. Understanding interobserver agreement: the kappa statistic. Fam Med 2005; 37:360-3. 9. Pierorazio PM, Walsh PC, Partin AW, et al. Prognostic Gleason grade grouping: data based on the modified Gleason scoring system. BJU Int 2013; 111:753-60. 10. Billis A, Guimaraes MS, Freitas LL, et al. The impact of the 2005 International Society of Urological Pathology consensus conference on standard Gleason grading of prostatic carcinoma in needle biopsies. J Urol 2008; 180:548-52, discussion 52-3. 11. Helpap B, Egevad L. The significance of modified Gleason grading of prostatic carcinoma in biopsy and radical prostatectomy specimens. Virchows Arch 2006; 449:622-7. 12. Lumen N, Fonteyne V, De Meerleert G, et al. Population screening for prostate cancer: an overview of available studies and meta-analysis. Int J Urol 2012; 19:100-8. 13. Cohen MS, Hanley RS, Kurteva T, et al. Comparing the Gleason prostate biopsy and Gleason prostatectomy grading system: the Lahey Clinic Medical Center experience and an international meta-analysis. Eur Urol 2008; 54:371-81. 14. Uemura H, Hoshino K, Sasaki T, et al. Usefulness of the 2005 International Society of Urologic Pathology Gleason grading system in prostate biopsy and radical prostatectomy specimens. BJU Int 2009; 103:1190-4. 15. Ozok HU, Sagnak L, Tuygun C, et al. Will the modification of the Gleason grading system affect the urology practice? Int J Surg Pathol 2010; 18:248-54. 16. Mehta V, Rycyna K, Baesens BM, et al. Predictors of Gleason Score (GS) upgrading on subsequent prostatectomy: a single institution study in a cohort of patients with GS 6. Int J Clin Exp Pathol 2012; 5:496-502. 17. Epstein JI, Feng Z, Trock BJ, et al. Upgrading and downgrading of prostate cancer from biopsy to radical prostatectomy: incidence and predictive factors using the modified Gleason grading system and factoring in tertiary grades. Eur Urol 2012; 61:1019-24.
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18. Kim KH, Lim SK, Shin TY, et al. Upgrading of Gleason score and prostate volume: a clinicopathological analysis. BJU Int 2013; 111:1310-6. 19. Corcoran NM, Hovens CM, Hong MK, et al. Underestimation of Gleason score at prostate biopsy reflects sampling error in lower volume tumours. BJU Int 2012; 109:660-4. 20. Capitanio U, Karakiewicz PI, Valiquette L, et al. Biopsy core number represents one of foremost predictors of clinically significant gleason sum upgrading in patients with low-risk prostate cancer. Urology 2009; 73:1087-91. 21. Serkin FB, Soderdahl DW, Cullen J, et al. Patient risk stratification using Gleason score concordance and upgrading among men with prostate biopsy Gleason score 6 or 7. Urol Oncol 2010; 28:302-7. 22. Thomas C, Pfirrmann K, Pieles F, et al. Predictors for clinically relevant Gleason score upgrade in patients undergoing radical prostatectomy. BJU Int 2012; 109: 214-9. 23. San Francisco IF, DeWolf WC, Rosen S, et al. Extended prostate needle biopsy improves concordance of Gleason grading between prostate needle biopsy and radical prostatectomy. J Urol 2003; 169:136-40. 24. Haas GP, Delongchamps NB, Jones RF, et al. Needle biopsies on autopsy prostates: sensitivity of cancer detection based on true prevalence. J Natl Cancer Inst 2007; 99:1484-9. 25. Burdick MJ, Reddy CA, Ulchaker J, et al. Comparison of biochemical relapse-free survival between primary Gleason score 3 and primary Gleason score 4 for biopsy Gleason score 7 prostate cancer. Int J Radiat Oncol Biol Phys 2009; 73:1439-45. 26. Kang DE, Fitzsimons NJ, Presti JC Jr., et al. Risk stratification of men with Gleason score 7 to 10 tumors by primary and secondary Gleason score: results from the SEARCH database. Urology 2007; 70:277-82. 27. Moran BJ, Braccioforte MH, Conterato DJ. Re-biopsy of the prostate using a stereotactic transperineal technique. J Urol 2006; 176:1376-81, discussion 81. 28. Pepe P, Aragona F. Prostate biopsy: results and advantages of the transperineal approach-twenty-year experience of a single center. World J Urol Published online June 7, 2013. 29. Maccagnano C, Gallina A, Roscigno M, et al. Prostate saturation biopsy following a first negative biopsy: state of the art. Urol Int 2012; 89:126-35. 30. Moore CM, Robertson NL, Arsanious N, et al. Image-guided prostate biopsy using magnetic resonance imaging-derived targets: a systematic review. Eur Urol 2013; 63:125-40. 31. Borofsky MS, Rosenkrantz AB, Abraham N, et al. Does suspicion of prostate cancer on integrated T2 and diffusion-weighted MRI predict more adverse pathology on radical prostatectomy? Urology 2013; 81:1279-83. 32. Hambrock T, Hoeks C, Hulsbergen-van de Kaa C, et al. Prospective assessment of prostate cancer aggressiveness using 3-T diffusion-weighted magnetic resonance imaging-guided biopsies versus a systematic 10-core transrectal ultrasound prostate biopsy cohort. Eur Urol 2012; 61:177-84.
Agreement of Gleason Score on Prostate Biopsy and Radical Prostatectomy Specimen: Is There Improvement With Increased Number of Biopsy Cylinders and the 2005 Revised Gleason Scoring? Charles Van Praet,1 Louis Libbrecht,2 Frederiek D’Hondt,1 Karel Decaestecker,1 Valérie Fonteyne,3 Stephanie Verschuere,2 Sylvie Rottey,4 Marleen Praet,2 Pieter De Visschere,5 Nicolaas Lumen,1on behalf of the Uro-Oncology Group Ghent Abstract For prostate cancer diagnoses we simultaneously incorporated the 2005 modified Gleason score (GS) and increased the standard number of biopsy cylinders to 8 to 12. This provided better Gleason score concordance between biopsy and radical prostatectomy (RP) specimens (n [ 193) than before this change of practice (n [ 135), although concordance rate (54%) remained rather poor. More tumors are labeled intermediate-/ high-grade using the modified Gleason score. Introduction: The objectives of this study were to assess the agreement of GS on biopsy compared with RP specimens and to assess whether an increased number of biopsy cylinders and the 2005 International Society of Urological Pathology (ISUP) GS modification improved this agreement. Materials and Methods: Pathological data of biopsy and RP specimens were analyzed in 328 consecutive patients, before (group 1; n ¼ 135) and after (group 2; n ¼ 193) implementation of the 2005 ISUP modification. Additionally, patients had more biopsy cylinders taken in group 2 (mean 10 vs. 6.9). The agreement of GS between biopsy and RP specimens was evaluated using the kappa coefficient. GS was pooled into 3 grades: low- (GS 6), intermediate- (GS ¼ 7), and high-grade (GS 8) prostate cancer. Results: Kappa coefficient for GS in group 1 and 2 was 0.261 and 0.341, respectively. For tumor grade, this was 0.308 and 0.359 for group 1 and 2, respectively. For RP specimens, there was more agreement between biopsy and RP GS in group 2 compared with group 1 (53.9% vs. 37.8%). Upgrading was almost exclusively (89.5%) seen in patients with biopsy GS 6 and was lower in group 2 (25.4% vs. 48.1%) because of classification of more intermediate- and high-grade tumors using the 2005 ISUP modification. Taking > 6 biopsy cylinders was associated with better GS and tumor grade agreement. Conclusion: Extended biopsy template and the 2005 ISUP modification resulted in an improved agreement between biopsy GS and RP GS and a shift toward more aggressive tumors. Clinical Genitourinary Cancer, Vol. 12, No. 3, 160-6 ª 2014 Elsevier Inc. All rights reserved. Keywords: Biopsy, Gleason score, Pathology, Prostatectomy, Prostatic neoplasms
Introduction Prostate biopsy histopathology is a key step in diagnosing prostate cancer (PC).1,2 The Gleason score (GS)3 is universally accepted as a grading system for histopathology obtained from prostate biopsy and radical prostatectomy (RP).1 At the 2005 International 1
Department of Urology Department of Pathology 3 Department of Radiotherapy 4 Department of Medical Oncology 5 Department of Radiology Ghent University Hospital, Ghent, Belgium 2
160
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Society of Urological Pathology (ISUP) Consensus Conference several changes were introduced to the Gleason scoring system (for an overview, see Epstein et al4). The biopsy GS (b-GS) is an independent prognostic factor, used in several preoperative nomograms and risk group stratifications, finally affecting the therapeutic Submitted: Aug 7, 2013; Revised: Oct 8, 2013; Accepted: Nov 8, 2013; Epub: Nov 12, 2013 Address for correspondence: Charles Van Praet, MD, Department of Urology, Ghent University Hospital, De Pintelaan 185, 9000 Ghent, Belgium Fax: þ32-9-332-38-89; e-mail contact: [email protected]
1558-7673/$ - see frontmatter ª 2014 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.clgc.2013.11.008
decision-making.5,6 Therefore, a strong agreement between b-GS and RP GS is important. With the original Gleason scoring system, there was an important discrepancy between b-GS and RP GS.7 Furthermore, contemporary PC management has changed a lot because of screening, multiple cylinder biopsies, introduction of immunohistochemistry, and new insights in treatment. These factors triggered a change in clinical practice at our center: from 2006, the standard biopsy template consisted of 8 to 12 cylinders and we implemented the revised Gleason scoring system from the 2005 ISUP Consensus Conference.4 The scope of this study was to evaluate the agreement between b-GS and RP GS to determine whether our change in clinical practice improved this agreement.
Figure 1 Patients Were Divided into 2 Groups According to Year of Radical Prostatectomy. Biopsy Gleason Score (B-GS) and Radical Prostatectomy Gleason Score (RP-GS) was Assessed in all Patients
Materials and Methods From 1997, data on patients with PC undergoing RP were collected into a database. A search of this database (dated March 1, 2013) revealed 328 patients in whom pathological data of prostate biopsy and RP were available. Patient characteristics includes age, prostate-specific antigen (PSA) at biopsy, and prostate volume. Tumor characteristics included number of harvested and PC-invaded cylinders, clinical T-stage, b-GS, and RP GS. GS was pooled into 3 tumor grades: low-, intermediate-, and high-grade PC (Gleason 6, 7, and 8). Until 2006, the original GS was used for pathological analysis of prostate biopsies and RP specimens, whereas from 2006 the ISUP modification was used. Starting from 2009, RP specimens were evaluated using whole-mount sections. Specimens were evaluated by general surgical pathologists under supervision and with daily consultation of urological pathologists (L.L. and M.P.). All biopsies were performed using transrectal ultrasound (TRUS). Until 2006, sextant biopsy was performed. Additional cylinder(s) were only taken in case of a suspicious lesion on imaging or rectal examination. Starting from 2006, a minimum of 8 cylinders for small prostates (< 30 mL) and 10 to 12 for larger prostates were taken. Again, additional cylinder(s) were taken in case of suspicious lesion(s). Because of the change in scoring system and practice of prostate biopsy, patients were divided into 2 groups (Fig. 1): before 2006 (group 1; n ¼ 135) and starting
from 2006 (group 2; n ¼ 193). Continuous and categorical data were evaluated using Student t test and c2 test, respectively. Agreement between b-GS and RP GS sum was calculated using linear weighted kappa statistics8 and incidence of upgrading (RP GS sum > b-GS sum) and downgrading (RP-GS sum < b-GS sum) was calculated. Cases with b-GS 7 were further stratified into Gleason 3þ4 and 4þ3. Univariate logistic regression was used to identify predictors of GS and tumor grade agreement, upgrading, and downgrading. A P value < .05 indicated statistical significance. Ghent University Hospital’s ethics committee approved the study (EC UZG 2011/495).
Results Patients in group 2 were older compared with group 1 (62.7 vs. 60.7 years; P ¼ .0068) and had more biopsy cylinders harvested (10 vs. 6.9; P < .0001) (Table 1). Gleason score distribution and tumor grading differed significantly between groups (Table 2). No b-GS < 6 was scored in group 2. In group 1, 98 patients (72.6%) had a low-grade tumor compared to 68 patients (35.2%) in group 2 (P < .0001). There were fewer intermediate- and high-grade tumors in group 1 (25 [18.5%] vs. 90 [46.6%]; P < .0001 and 12 [8.9%] vs. 35 [18.2%];
Table 1 Patient and Tumor Characteristics for the Total Patient Population and for Each Group All Patients (n [ 328)
Group 1 (n [ 135)
Group 2 (n [ 193)
P
Age, Years
61.9 (6.6)
60.7 (6.2)
62.7 (6.7)
.0068
PSA, ng/mL
11.6 (13.1)
12.5 (13.5)
10.9 (12.8)
.274
Prostate Volume, mL
39.1 (20.4)
37.3 (15.2)
39.5 (21.6)
.396
T1
173 (52.7)
69 (51.1)
104 (53.9)
T2
148 (45.1)
63 (46.7)
85 (44.0)
T3
7 (2.1)
3 (2.2)
4 (2.1)
Characteristic
Clinical T-Stage .884
Prostate Biopsy <.0001
Cylinders, n
9.4 (3.2)
6.9 (2.5)
10.0 (3.0)
Cylinders invaded, n
3.4 (2.3)
2.9 (2.1)
3.5 (2.4)
.125
Cylinders invaded, %
37.8 (24.5)
44.8 (29.8)
36.1 (22.8)
.077
Results are presented as mean ( SD) or n (%). Group 1 ¼ before and group 2 ¼ after introduction of the 2005 ISUP modification. Bold values represent P < .05. Abbreviation: PSA ¼ prostate-specific antigen.
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Contemporary Gleason Score Agreement Table 2 Distribution of Biopsy Gleason Score (b-GS) and Radical Prostatectomy Specimen Gleason Score (RP GS) per Gleason Score and Tumor Grade Gleason Score
All Patients (n [ 328)
Group 1 (n [ 135)
Group 2 (n [ 193)
P
166 (50.6)
98 (72.6)
68 (35.2)
<.0001
1
1
0
b-GS 6 (low grade) 2 3
5
5
0
4
10
10
0
5
40
40
0
6
110
42
68
7 (intermediate grade)
115 (35.1)
25 (18.5)
90 (46.6)
3þ4
84 (73.0)
14 (56.0)
70 (77.8)
4þ3
22 (19.1)
2 (8.0)
20 (22.2)
Unknown
9 (7.8)
9 (36.0)
0
8 (high grade)
47 (14.3)
12 (8.9)
35 (18.2)
8
23
6
17
9
21
5
16
10
3
1
2
<.0001
.0284
RP GS 6 (low grade)
116 (35.4)
68 (50.4)
48 (24.9)
2
0
0
0
3
2
2
0
4
1
1
0
5
23
18
5
6 7 (intermediate grade) 3þ4
90
47
43
162 (49.4)
51 (37.8)
111 (57.5)
107 (66.0)
20 (39.2)
87 (78.4) 24 (21.6)
4þ3
27 (16.7)
3 (5.9)
Unknown
28 (17.3)
28 (54.9)
0
8 (high grade)
50 (15.2)
16 (11.2)
34 (17.6)
8
32
11
21
9
18
5
13
10
0
0
0
<.0001
.0007
.203
Results are presented as n or n (%). Bold values represent P < .05.
162
-
P ¼ .0284, respectively). Similarly, for RP GS, significantly more low-grade tumors and fewer intermediate-grade tumors were observed in group 1 compared with group 2 (68 [50.4%] vs. 48 [24.9%]; P < .0001 and 51 [37.8%] vs. 111 [57.5%]; P ¼ .0007, respectively). For the whole study population, kappa coefficient between b-GS and RP GS was 0.344. Kappa coefficient for tumor grade was 0.381. When comparing group 1 with group 2 there was an improvement in kappa coefficient for GS (0.261 vs. 0.341) and tumor grade (0.308 vs. 0.359). For GS, a perfect match between biopsy and RP was significantly more frequent in group 2 compared with group 1 (104 [53.9%] vs. 51 patients [37.8%]; P ¼ .0057) (Table 3). For tumor grade, GS agreement did not differ between groups. In group 1, 65 patients (48.1%) had an upgrade of the GS compared to 49 patients (25.4%) in group 2 (P < .0001). When stratified according to tumor grade, however, upgrading did not differ significantly between groups. Upgrading occurred mostly in cases with b-GS 6 (102 out of 114 cases [89.5%]). Downgrading
Clinical Genitourinary Cancer June 2014
did not differ significantly. A subanalysis of b-GS 7 showed that most patients presented with b-GS 3þ4 (84 [73.0%]) rather than 4þ3 (22 [19.1%]), before and after 2006 (Table 2). There were more patients with perfect concordance between b-GS and RP GS with b-GS 3þ4 (48 [57.1%]) than with b-GS 4þ3 (8 [36.4%]), but this was not statistically significant (P ¼ .134). Upgrading was more frequent in b-GS 3þ4 (17 patients [20.2%]), including 9 patients (52.9%) with RP GS 4þ3. Downgrading was more frequent in b-GS 4þ3 (13 patients [59.1%]), including 10 patients (76.9%) with RP GS 3þ4. When considering the total group, patients with > 6 cylinders had less GS upgrading (24.1% vs. 42.5%; P ¼ .018) and tumor grade upgrading (20.9% vs. 37.5%; P ¼ .025) than patients with 6 cylinders. Univariate logistic regression (Table 4) confirmed that an increased number of cylinders predicted for less tumor grade upgrading (odds ratio [OR], 0.89 with 95% confidence interval [CI], 0.80-0.99; P ¼ .041), with > 6 cylinders as a significant cutoff
Charles Van Praet et al Table 3 Agreement Between b-GS and RP GS and Tumor Grade Gleason Score Equal
All Patients (n [ 328)
Group 1 (n [ 135)
Group 2 (n [ 193)
P
155 (47.2%)
51 (37.8%)
104 (53.9%)
.0057
b-GS <7
57 (34.3%)
32 (32.7%)
25 (36.8%)
.702
b-GS ¼ 7
81 (70.4%)
14 (56.0%)
67 (74.4%)
.123
b-GS 3þ4
48 (57.1%)
7 (50.0%)
41 (58.6%)
.767
b-GS 4þ3
8 (36.4%)
1 (50.0%)
7 (35.0%)
.726
b-GS >7
17 (36.2%)
5 (41.7%)
12 (34.3%)
.912
114 (34.8%)
65 (48.1%)
49 (25.4%)
<.0001
b-GS <7
102 (61.4%)
61 (62.2%)
41 (60.3%)
.927
b-GS ¼ 7
8 (7.0%)
3 (12.0%)
5 (5.6%)
.368
b-GS 3þ4
17 (20.2%)
1 (7.1%)
16 (22.9%)
.331
b-GS 4þ3
1 (4.5%)
0
1 (5.0%)
.145
Upgrading
b-GS >7
4 (8.5%)
1 (8.3%)
3 (8.6%)
1
59 (18.0%)
19 (14.1%)
40 (20.7%)
.162
b-GS <7
7 (4.2%)
5 (5.1%)
2 (2.9%)
.773
b-GS ¼ 7
26 (22.6%)
8 (32.0%)
18 (20.0%)
.318
b-GS 3þ4
19 (22.6%)
6 (42.8%)
13 (18.6%)
.103
b-GS 4þ3
13 (59.1%)
1 (50.0%)
12 (60.0%)
.631
b-GS >7
26 (55.3%)
6 (50.0%)
20 (57.1%)
.926 .937
Downgrading
Tumor Grade Equal
194 (59.2%)
79 (58.5%)
115 (59.6%)
Upgrading
88 (26.8%)
42 (31.1%)
46 (23.8%)
.182
Downgrading
46 (14.0%)
14 (10.4%)
32 (16.6%)
.152
b-GS and RP GS are either equal (perfect match), or show upgrading (RP GS > b-GS) or downgrading (RP GS < b-GS). For Gleason score agreement, patients were also stratified according to b-GS. Nine Gleason 7 patients not evaluable because of missing data on separate Gleason patterns. Results are presented as n (%). Bold values represent P < .05. Abbreviations: b-GS ¼ biopsy Gleason score; RP GS ¼ radical prostatectomy Gleason score.
for tumor grade (OR, 0.44; 95% CI, 0.21-0.91; P ¼ .027) and GS upgrading (OR, 0.43; 95% CI, 0.30-0.61; P ¼ .020). To discriminate between the effect of the ISUP modification and the increased number of cylinders, we assessed group 1 separately. Taking > 6 cylinders predicted for more GS agreement (OR, 3.95; 95% CI, 1.13-13.71; P ¼ .031) and better tumor grade agreement (OR, 5.09; 95% CI, 1.32-19.65; P ¼ .018). An increased number of positive cylinders predicted for more tumor grade agreement in all patients (OR, 1.15; 95% CI, 1.01-1.31; P ¼ .031) and in group 2 (OR, 1.18; 95% CI, 1.02-1.37; P ¼ .025). Increased percentage of positive cylinders only predicted for better tumor grade agreement in group 2 (OR, 1.02; 95% CI, 1.00-1.03; P ¼ .046).
Discussion Prostate biopsy is the key step in PC diagnosis and accurate PC grading is essential for appropriate treatment decision-making. The 2005 ISUP modification aimed to improve the GS agreement by creating a more universally accepted grading system, adapted to contemporary PC management. This revised Gleason scoring for prostate biopsy and for RP specimens proved to be a strong independent prognostic factor predicting the risk of biochemical recurrence after RP.9 Starting from 2006, we changed clinical practice at our center. First, our standard biopsy template of 6 cylinders was extended to 8 to 12 cylinders. Second, we adopted the 2005 ISUP modification for Gleason scoring.
We demonstrated that the 2005 ISUP modification resulted in a shift of GS distribution: GS 6 was observed in most patients before the ISUP modification on biopsy and RP specimens. However, after the ISUP modification, most patients had a GS 7. Other studies reported similar findings10,11: b-GS 6 decreased from 48% to 68% before to 22% to 49% after the ISUP modification. Accordingly, b-GS ¼ 7 increased from 26% before to 39% to 68% after the ISUP modification. It is unlikely that the increase in the amount of patients with GS 7 is explained by the fact that PC has become more aggressive in the past years. On the contrary, because of the introduction of PSA testing, more patients are found with more localized and less aggressive PC.12 Moreover, our study started several years after introduction of PSA testing and almost all patients were diagnosed with PC after an elevated PSA was detected. The shift in distribution toward higher GS and tumor grades is thus mainly explained by the ISUP modification. Indeed, one of the crucial modifications is that almost all cribriform patterns should be diagnosed as a pattern 4, thus widening the scope of pattern 4 and limiting that of pattern 3.4 This is important to acknowledge the difficulty in comparing data assessing patient outcomes in PC over time. In the current study, the agreement for GS and tumor grade improved after the ISUP modification, although this agreement remained only “fair” (ie, kappa, 0.2-0.4).8 This degree of agreement is in line with a previous meta-analysis on GS agreement, in which
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Contemporary Gleason Score Agreement Table 4 Univariate Logistic Regression for All Patients and for Group 1 and 2 Separately Factor
Biopsy Cylinders, n
>6 Biopsy Cylinders Positive Cylinders, n Positive Cylinders, %
Prostate Volume
All Patients (n [ 328) Gleason score Agreement
1.03 (0.95-1.12)
1.66 (0.83-3.31)
1.09 (0.97-1.22)
1.01 (0.99-1.02)
Upgrading
0.90 (0.82-1.00)
0.43 (0.30-0.61)
0.89 (0.78-1.03)
1.00 (0.99-1.01)
1.00 (0.99-1.02) 1.00 (0.99-1.01)
Downgrading
1.07 (0.97-1.18)
1.49 (0.59-3.81)
1.00 (0.87-1.15)
0.99 (0.98-1.01)
0.99 (0.98-1.01)
1.06 (0.97-1.16)
1.67 (0.84-3.32)
1.15 (1.01-1.31)
1.01 (0.99-1.02)
1.00 (0.99-1.01)
Tumor grade Agreement Upgrading
0.89 (0.80-0.99)
0.44 (0.21-0.91)
0.88 (0.76-1.03)
1.00 (0.99-1.01)
1.00 (0.99-1.02)
Downgrading
1.03 (0.93-1.15)
1.39 (0.51-3.83)
0.91 (0.77-1.09)
0.99 (0.97-1.01)
0.99 (0.98-1.01)
Group 1 (n [ 135) Gleason score Agreement
1.23 (0.95-1.60)
3.95 (1.13-13.71)
1.06 (0.80-1.42)
1.00 (0.98-1.02)
0.98 (0.95-1.02)
Upgrading
0.90 (0.69-1.15)
0.46 (0.14-1.60)
0.91 (0.67-1.22)
1.00 (0.98-1.02)
1.02 (0.98-1.06)
Downgrading
0.79 (0.52-1.19)
0.21 (0.02-1.97)
1.08 (0.70-1.65)
1.01 (0.98-1.04)
1.00 (0.95-1.05)
Agreement
1.70 (1.14-2.54)
5.09 (1.32-19.65)
1.03 (0.77-1.38)
0.99 (0.96-1.01)
0.97 (0.94-1.01)
Upgrading
0.63 (0.43-0.94)
0.27 (0.06-1.15)
0.93 (0.67-1.29)
1.01 (0.99-1.04)
1.03 (0.99-1.07)
Downgrading
0.79 (0.51-1.23)
0.28 (0.03-2.70)
1.08 (0.70-1.65)
1.01 (0.98-1.04)
1.01 (0.95-1.06)
Tumor grade
Group 2 (n [ 193) Gleason Score Agreement
0.98 (0.89-1.08)
e
1.09 (0.96-1.24)
1.01 (1.00-1.03)
1.01 (0.99-1.02)
Upgrading
0.94 (0.84-1.07)
e
0.91 (0.77-1.06)
1.00 (0.98-1.01)
1.00 (0.98-1.01)
Downgrading
1.08 (0.97-1.21)
e
0.98 (0.84-1.14)
0.99 (0.97-1.01)
0.99 (0.98-1.01)
Agreement
1.02 (0.92-1.13)
e
1.18 (1.02-1.37)
1.02 (1.00-1.03)
1.00 (0.99-1.02)
Upgrading
0.94 (0.83-1.07)
e
0.88 (0.74-1.04)
0.99 (0.98-1.01)
1.00 (0.98-1.02)
Downgrading
1.04 (0.92-1.17)
e
0.88 (0.72-1.07)
0.98 (0.96-1.00)
0.99 (0.97-1.01)
Tumor Grade
Results are presented as odds ratio (95% confidence interval). Statistically significant results (P < .05) are presented in bold.
164
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a kappa coefficient of 0.37 was observed.13 However, this metaanalysis did not take into account a difference before and after the ISUP modification. In our study, since 2006 the rate of patients with a perfect GS match has significantly increased from 38% to 54%. Montironi et al reported a perfect match between b-GS and RP GS in 43% based on a compilation of data before the ISUP modification, which is in line with the results in group 1.7 Other series report concordance rates with the original GS ranging from 32% to 64% that significantly increased to 44% to 70% when the ISUP modification was used.14,15 Although we demonstrated an improved GS agreement, after b-GS stratification, this improvement was no longer statistically significant. Indeed, this improvement is mostly because of a reduced incidence of b-GS 6, which in our series has the poorest b-GS and RP GS concordance rate. Also, after adjustment for tumor grade, the improvement of this concordance rate became no longer statistically significant. Before introduction of the ISUP modification many patients with b-GS 6 had an upgrade of GS, but remained classified as having a low-grade tumor. This can be explained by the ISUP recommendation that diagnosing a Gleason pattern of 1 to 2 should “rarely, if ever be done.”4 The main reason for this recommendation was the fact that a bGS 4 correlates very poorly with RP GS.7 This was also observed
Clinical Genitourinary Cancer June 2014
in our series in which most patients (13 of 16) with b-GS 4 were upgraded to RP GS > 4. Upgrading was significantly less in group 2, but b-GS stratification again shows this is because of a reduction in b-GS 6 cases after the ISUP modification. In our series b-GS 6 was associated with a 60% chance of upgrading, before and after the ISUP modification, which is at the upper bound of what is reported in other series.14-18 Compared with upgrading, downgrading was less frequent, before and after the ISUP modification.7,13-15 Downgrading might be explained by the fact that tangentially sectioned small glands of pattern 3 on biopsy were overgraded as Gleason pattern 4. Alternatively, in some cases the assigned biopsy Gleason pattern 4 might have been accurate with such small foci of pattern 4 in the RP specimen that it was either not recorded or unsampled deeper within the paraffin block. The GS of biopsy and RP specimen might not be the same for several reasons. Borderline grades and pathological errors are possible explanations.7 Most frequently, a sampling error (ie, when a higher grade is missed on biopsy) has been proposed.13,17,19 Studies have demonstrated that increasing the number of biopsies reduces upgrading.20-23 Contemporary guidelines recommend an extended biopsy template (10-12 cylinders), which has a PC
Charles Van Praet et al detection rate of 80%, instead of sextant biopsies to avoid the additional risk of upgrading.1,24 This recommendation is strengthened by our significantly lower chance of GS and tumor grade upgrading when > 6 biopsy cylinders were taken. However, because most cases with > 6 biopsy cylinders were diagnosed after 2005, this effect might be attributed to the 2005 ISUP modification. Therefore, we analyzed the effect of an extended biopsy template in group 1 (before the ISUP modification) separately. We found that an increased number of cylinders predicted for more tumor grade agreement and less upgrading, with a cutoff of > 6 cylinders associated with more agreement. This is in line with the literature before the ISUP modification.23 Because of the concomitant introduction of our extended biopsy template and the ISUP modification, all patients in group 2 had > 6 biopsy cylinders taken and we cannot reliably assess the effect of an extended biopsy template on GS agreement with the current revised Gleason scoring system. In our current practice, however, an increased number or percentage of positive cylinders predicted for more tumor grade agreement on univariate logistic regression. Indeed, a greater tumor volume in contemporary biopsies is associated with more accurate staging.20 Although upgrading nowadays is less common, in our series there is, however, a slight trend toward more downgrading after the ISUP modification. From a clinical point of view, this is safer and thus considered as acceptable. In our opinion it is better to apply an aggressive but curative treatment for a post hoc less aggressive tumor than to apply an insufficient treatment for a post hoc more aggressive tumor. Upgrading and downgrading has significant implications for patients in whom a change in tumor grade would affect their management. Indeed, tumor grade is a cornerstone in risk group stratification.5 Active surveillance or focal therapy (brachytherapy or high-intensity focused ultrasound) would be a less appropriate treatment choice if upgrading occurs or might have been an option if downgrading occurred. Furthermore, the tumor grade influences the need for pelvic lymphadenectomy and androgen deprivation therapy concomitant with external beam radiotherapy.1 From a prognostic point of view, upgrading is associated with greater risk of adverse pathologic features and biochemical progression.4,11,12 In contrast, downgrading was associated with better biochemical recurrence-free survival.11,12 Finally, considering the different prognoses suggested by several studies, we looked at GS 7 independently to assess b-GS and RP GS agreement in case of GS 3þ4 or 4þ3 on biopsy.25,26 There is better agreement for 3þ4 than for 4þ3. Up to 60% of patients with GS 4þ3 had downgrading, most of them to GS 3þ4 (83%). Upgrading of GS 4þ3, however, is infrequent (5%), which indicates that generally the relative volume of pattern 4 tumor is overestimated. This is not surprising: in case only 1 biopsy cylinder presents more Gleason pattern 4 than pattern 3, the biopsy result is labeled GS 4þ3, despite that several other cylinders might harbor an abundance of Gleason pattern 3 and little pattern 4. On RP analysis, however, such a case would be classified as 3þ4. Further techniques to improve PC detection rate and b-GS accuracy have been proposed, one of which is increasing the number of biopsy cylinders up to 20 to 50 (saturation biopsies). This can be performed transrectally or transperineally with the use of a stereotactic grid, which is more suitable for template biopsies.27
Transperineal biopsy also allows for better access to the anterior zone of the prostate and has a very low risk of infective complications.28 However, the need for general anesthesia makes this less convenient for the patient and for the urologist. Currently, saturation biopsy is usually restricted for repeat biopsies after initial negative biopsy.29 Instead of template biopsies with increased sampling rate, image-guided targeted biopsy seems a more appealing alternative. Multiparametric magnetic resonance imaging (MRI)targeted biopsy or TRUS-guided biopsy after MRI (with or without MRI/TRUS fusion) have been described. This approach detects as many clinically significant tumors as standard biopsy but reduces to a third the number of men biopsied and the number of biopsy cylinders (mean, 3.8).30 Additionally, fewer clinically insignificant tumors will be detected when adopting MRI.30 A suspicious MRI also predicts for b-GS upgrading after standard biopsy.31 Hambrock et al reported a highest Gleason pattern concordance between RP specimen and MRI-guided biopsy (n ¼ 34) in 88% of patients compared with 55% (P ¼ .001) using standard 10-cylinder biopsy (n ¼ 64).32 These data indicate MRI is valuable in decision-making as to whether the patient should undergo (repeat) biopsy and can improve b-GS accuracy. Our report has some shortcomings because we retrospectively analyzed GS agreement in 2 separate patient cohorts. However, the fact that only age but not tumor characteristics (except for, of course, GS distribution) differed in both groups adds strength to our findings. The older age in group 2 can be explained by the increasing life expectancy which lowered our threshold for performing RP in older patients.
Conclusion We demonstrated that the ISUP modification resulted in a shift of GS distribution toward more aggressive tumors, on biopsy and on RP. Overall, there is only a fair agreement between b-GS and RP GS. With the ISUP modification and an extended biopsy template, more patients had a perfect match between b-GS and RP GS. GS upgrading was less prevalent because of a reduced incidence of low-grade tumors.
Clinical Practice Points The 2005 ISUP modification leads to diagnosis of more inter-
mediate- and high-grade PC. The 2005 ISUP modification resulted in a better concordance
between biopsy and RP GS, although this concordance remained rather poor. Since upgrading (RP GS > b-GS) is most prevalent in low-grade PC, upgrading is less common nowadays.
Disclosure The authors have stated that they have no conflicts of interest.
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