The value of the 2005 International Society of Urological Pathology (ISUP) modified Gleason grading system as a predictor of biochemical recurrence after radical prostatectomy

UROLOGY - ORIGINAL PAPER

The value of the 2005 International Society of UrologicalPathology (ISUP) modified Gleason grading system as a predictorof biochemical recurrence after radical prostatectomy

Athanase Billis • Maisa M.Q. Quintal • Luciana Meirelles • Leandro L.L. Freitas •

Larissa B.E. Costa • Joao F.L. Bonfitto • Betina L. Diniz • Paola H. Poletto •

Luıs A. Magna • Ubirajara Ferreira

Received: 21 June 2013 / Accepted: 27 September 2013 / Published online: 6 October 2013

� Springer Science+Business Media Dordrecht 2013

Abstract

Purpose To compare time and risk to biochemical

recurrence (BR) after radical prostatectomy of two chro-

nologically different groups of patients using the standard

and the modified Gleason system (MGS).

Methods Cohort 1 comprised biopsies of 197 patients

graded according to the standard Gleason system (SGS) in

the period 1997/2004, and cohort 2, 176 biopsies graded

according to the modified system in the period 2005/2011.

Time to BR was analyzed with the Kaplan–Meier product-

limit analysis and prediction of shorter time to recurrence

using univariate and multivariate Cox proportional hazards

model.

Results Patients in cohort 2 reflected time-related chan-

ges: striking increase in clinical stage T1c, systematic use

of extended biopsies, and lower percentage of total length

of cancer in millimeter in all cores. The MGS used in

cohort 2 showed fewer biopsies with Gleason score B6 and

more biopsies of the intermediate Gleason score 7. Time to

BR using the Kaplan–Meier curves showed statistical sig-

nificance using the MGS in cohort 2, but not the SGS in

cohort 1. Only the MGS predicted shorter time to BR on

univariate analysis and on multivariate analysis was an

independent predictor.

Conclusions The results favor that the 2005 International

Society of Urological Pathology modified system is a

refinement of the Gleason grading and valuable for con-

temporary clinical practice.

Keywords Prostate � Prostatic neoplasms �Adenocarcinoma � Needle biopsy � Prostatectomy

Introduction

The Gleason grading system is the most commonly used

grading system for prostate carcinoma in the world [1–5].

At an International Society of Urological Pathology (ISUP)

consensus conference in 2005, the Gleason grading system

for prostatic carcinoma underwent a major revision [6].

Since the 2005 consensus, very few studies have vali-

dated the prognostic value for the prediction of time to

biochemical recurrence (BR) after radical prostatectomy

(RP) of the modified Gleason grading system [7–13]. In a

previous study, we revised needle prostatic biopsies

A. Billis (&) � M. M.Q.Quintal � L. Meirelles �L. L.L.Freitas � L. B.E.Costa � J. F.L.Bonfitto �B. L. Diniz � P. H. Poletto � L. A. Magna � U. Ferreira

School of Medicine, State University of Campinas (Unicamp),

Campinas, SP, Brazil

e-mail: [email protected]

M. M.Q.Quintal


L. Meirelles


L. L.L.Freitas


L. B.E.Costa


J. F.L.Bonfitto


B. L. Diniz


P. H. Poletto


L. A. Magna


U. Ferreira


123

Int Urol Nephrol (2014) 46:935–940

DOI 10.1007/s11255-013-0579-8

(NPBs) according to the modified Gleason system (MGS)

[9]. Concordance of pattern and change of prognostic

groups were highlighted. The revised Gleason grading

identified fewer number of patients with Gleason score B6

and a higher number of patients with Gleason score 7 and

C8. Only the modified Gleason grading system was sig-

nificantly associated with time to biochemical progression-

free outcome after RP using the Kaplan–Meier curves.

In this study, we compared the time and risk to BR after

RP of two chronologically different groups of patients:

patients with NPB graded according to the standard Glea-

son system (SGS) before 2005 and patients with NPB

graded after the 2005 ISUP MGS.

Methods

In this retrospective study, we compared the Gleason score

on 366 NPB from two consecutive patient cohorts sub-

mitted to retropubic RP by one surgeon (UF). Two groups

of biopsies were analyzed by an experienced uropatholo-

gist (AB): Cohort 1 comprised 191 patients with NPB

graded according to the SGS [1–5] in the period January

1997–April 2004, and cohort 2, 175 patients with NPB

graded according to the 2005 ISUP MGS [6] in the period

April 2005–February 2011.

Several clinical features and pathological findings on

needle biopsy were studied: age, race, preoperative serum

prostate-specific antigen (PSA), clinical stage, number of

NPB cores, number of cores with carcinoma, total cancer

extent in millimeter in all cores, and percentage of cancer

extent in all cores. Standard and 2005 ISUP modified

Gleason score values on NPB were categorized as B6, 7,

and C8.

Linear carcinoma extent in millimeter on NPB was

measured using a single Olympus (Olympus Optical Co.,

Ltd., Tokyo, Japan) micrometer eyepiece with a linear

array. In cases of discontinuous foci 1 mm apart, the tumor

was considered as continuous and the measure included

1 mm. In discontinuous foci more than 1 mm apart, the

final extent was the sum of the measures. According to

race, patients were considered Whites and African Brazil-

ians. In Brazil, African Brazilians include Mulattos (White

and African Brazilian admixture). Three patients of

oriental ancestry were excluded. Clinical stage included

T1c and T2.

After RP, serum PSA was measured every 3 months during

year 1, every 6 months during year 2, and annually thereafter.

No patient in this series received radiotherapy or androgen

manipulation before or after surgery except patients with BR.

Total serum PSA was measured using the previously vali-

dated Immulite� PSA kit. Postoperative BR was considered

as an initial PSA C0.2 ng/mL, with a second confirmatory

level of PSA [0.2 ng/mL according to the American Uro-

logical Association recommendation [14]. Patients without

BR were censored at last follow-up. The study was approved

by our institutional committee of ethics.

Radical prostatectomy surgical specimens were step

sectioned at 3–5 mm intervals and embedded in paraffin. A

mean of 32 paraffin blocks were processed. Sections

(6 lm) of each block were stained with hematoxylin and

eosin. Each transverse section of the prostate was subdi-

vided into two anterolateral and two posterolateral quad-

rants. Using the cone method, eight sections from the

bladder neck and eight from the apex were obtained.

Positive surgical margin was defined as cancer cells in

contact with the inked specimen surface. Extraprostatic

extension (pT3a) was diagnosed when cancer was seen in

adipose tissue and in case of a desmoplastic response when a

protuberance corresponding to tumor extension into peri-

prostatic tissue was seen. Seminal vesicle invasion (pT3b)

occurred when there was involvement of the muscular coat.

Tumor extent at RP was evaluated by a previously

described semiquantitative point-count method [15]. Briefly,

each quadrant of the transverse sections was drawn on paper

and contained eight equidistant points. During microscopic

examination of the slides, the tumor area was drawn on the

correspondent quadrant on the paper. At the end of exami-

nation, the number of positive points represented an estimate

of tumor extent.

Statistical analysis

Data were analyzed using the Fisher’s exact test and the

chi-square test to compare proportions, the Mann–Whitney

test to compare means, and Kaplan–Meier product-limit

analysis for time to BR (TBR) using the log-rank test for

comparison between the groups. Univariate and multivar-

iate Cox stepwise logistic regression models were used to

identify significant predictors of shorter TBR. The p values

were two-sided at the significance level of \0.05. All sta-

tistical analyses were performed using PASW� Statistics

18.0.

Results

Clinicopathologic findings

Comparing cohort 1 and cohort 2, there was no significant

difference in age (p = 0.533), race (p = 0.792), number of

cores with carcinoma (p = 0.357), total length of cancer in

millimeter in all cores (p = 0.203), and tumor extent at RP

(p = 0.889). There was significant difference in preoperative

serum PSA (p = 0.045), clinical stage (p \ 0.001), number

of biopsy cores (p \ 0.001), percentage of total length of

936 Int Urol Nephrol (2014) 46:935–940

123

cancer in millimeter in all cores (p = 0.032), Gleason score

on NPB (p = 0.032), positive surgical margins (p = 0.021),

and pathologic stage (p = 0.031). Mean preoperative PSA,

mean percentage of total length of cancer in millimeter in all

cores, and clinical stage T2 were higher in cohort 1. Mean

number of cores, Gleason score 7, clinical stage T1c, positive

surgical margins, and pathological stage[T2 were higher in

cohort 2.

Time to biochemical recurrence

Cohort 1 (biopsies with standard Gleason grading)

After RP, 74 (41.6 %) patients had BR at a mean follow-up

of 25 months (median 11, range 3–129). Of the remaining

patients, 104 (58.4 %) who were censored remained at risk

at a mean follow-up of 68 months (median 45, range

3–155), while 13 had no serum PSA data available.

At 5 years of follow-up, 64 % of patients with Gleason

score B6 on NPB were BR free, 49 % with Gleason score

7, and 38 % with Gleason score C8 (log-rank p = 0.364,

Fig. 1).

Cohort 2 (biopsies with 2005 ISUP modified Gleason

grading)

After RP, 50 (29.2 %) patients had BR at a mean fol-

low-up of 13 months (median 8, range 3–95). Of the

remaining patients, 121 (70.8 %) who were censored

remained at risk at a mean follow-up of 40 months

(median 40, range 3–95), while four had no serum PSA

data available.

At 5 years of follow-up, 75 % of patients with Gleason

score B6 on NPB were BR free, 54 % with Gleason score

7, and 37 % with Gleason score C8 (log-rank p = 0.012,

Fig. 2).

Risk of shorter time to biochemical recurrence

Clinical characteristics and pathologic findings on needle

prostatic biopsy were analyzed.

Cohort 1 (biopsies with standard Gleason grading)

On univariate Cox regression analysis, only percentage of

total cancer extent in millimeter in all cores (p = 0.006)

and preoperative serum PSA (\0.001) significantly pre-

dicted shorter TBR. Total cancer extent in millimeter in all

cores was in the limit of significance (p = 0.052)

(Table 1).

On multivariate analysis using the backward stepwise

logistic regression method, only preoperative serum PSA

was an independent predictor of shorter TBR (p = 0.001)

(Table 1).

months

7

6

8

P=0.364

Fig. 1 Kaplan–Meier product-limit analysis showing time to PSA

biochemical progression-free outcome by Gleason score B6, 7, and

C8 on biopsies graded by the SGS in the period 1997–2004. Cum,

cumulative

months

6

7

8

6 vs 7 vs 8 P=0.012 6 vs 7 P=0.016

7 vs 8 P=0.015

Fig. 2 Kaplan–Meier product-limit analysis showing time to PSA

biochemical progression-free outcome by Gleason score B6, 7, and

C8 on biopsies graded by the ISUP 2005 MGS in the period

2005–2011. Cum, cumulative

Int Urol Nephrol (2014) 46:935–940 937

123

Cohort 2 (biopsies with 2005 ISUP modified Gleason

grading)

On univariate Cox regression analysis, only Gleason score

on NPB significantly predicted shorter TBR (p = 0.021)

(Table 2).

On multivariate analysis using the backward stepwise

logistic regression method, only Gleason score on NPB

was an independent predictor of shorter TBR (p = 0.018)

(Table 2).

Comment

Patients in cohort 2 (from 2005 to 2011) reflect time-

related changes in clinicopathologic findings: striking

higher number of clinical stage T1c (68.8 %), higher

number of biopsy cores as a consequence of routinely used

extended biopsies, and lower percentage of total length of

cancer in millimeter in all cores. However, clinical stage

T1c represents a heterogeneous group of patients according

to pathologic stage. Comparing to patients in cohort 1, in

spite of no difference in total tumor extent in RP, there was

a higher number of pathologic stage pT3a/pT3b. We

hypothesize that extraprostatic extent may be related to

topography of the index tumor and not to total tumor

extent. A possibility is that in cohort 2, by chance, the

topography of index tumor favored extraprostatic extent.

Gleason score was significantly different comparing

standard grading in cohort 1 and the MGS grading in

cohort 2. Gleason score B6 decreased from 70.2 % in

cohort 1 to 57.7 % in cohort 2, and Gleason score 7

increased from 24.6 to 37.1 %. This was due to the

important modifications proposed by the 2005 ISUP

modified Gleason grading [6].

To check the discriminatory power of the MGS, we

compared the biochemical PSA progression-free outcome

in cohort 1 and cohort 2 according to Gleason score. The

Kaplan–Meier curve in cohort 1 SGS showed no significant

difference in TBR among patients stratified according to

Gleason score (log-rank, p = 0.364) (Fig. 1). In cohort 2

MGS, there was a significant difference (log-rank,

p = 0.012) (Fig. 2).

In univariate Cox analysis in cohort 1 (Table 1), Glea-

son score was not predictive of shorter TBR (p = 0.375).

Only percentage of total cancer extent in millimeter in all

Table 2 Cox univariate and multivariate proportional hazard ana-

lysis of several clinicopathologic factors predicting shorter time to BR

after RP in cohort 2 (2005 ISUP modified Gleason grading on needle

prostatic biopsy)

Predictors HR (95 % CI) Wald

test

P value

Univariate

Clinical stage 1.004 (0.548–1.839) 0.000 0.989

Age 0.996 (0.957–1.037) 0.034 0.854

Race 0.714 (0.320–1.592) 0.679 0.410

Preoperative PSA 1.019 (0.985–1.055) 1.180 0.277

Percentage of total cancer

extent in millimeter in all

cores

1.010 (0.993–1.026) 1.352 0.245

Total cancer extent in

millimeter in all cores

1.017 (0.994–1.039) 2.080 0.149

Number of cores with

carcinoma

1.103 (0.981–1.242) 2.675 0.102

Gleason score on NPB 1.995 (1.111–3.583) 5.340 0.021

Multivariate

Percentage of cancer

extent in millimeter in all

cores

1.003 (0.976–1.030) 0.041 0.840



0.989 (0.951–1.029) 0.278 0.598


carcinoma

1.046 (0.920–1.189) 0.464 0.496



NPB needle prostatic biopsy; HR hazard ratio; CI confidence interval

Table 1 Cox univariate and multivariate proportional hazard analy-

ses of several clinicopathologic factors predicting shorter time to BR

after RP in cohort 1 (standard Gleason grading on needle prostatic

biopsy)

Predictors HR (95 % CI) Wald

test

P value

Univariate

Age 1.012 (0.975–1.050) 0.370 0.543

Race 0.792 (0.434–1.445) 0.578 0.447

Clinical stage 1.223 (0.751–1.991) 0.656 0.418



carcinoma

1.084 (0.977–1.202) 2.322 0.128



1.025 (1.000–1.051) 3.783 0.052

Percentage of total

cancer extent in


1.014 (1.004–1.025) 7.464 0.006

Preoperative PSA 1.056 (1.032–1.079) 22.842 \0.001

Multivariate



millimeterm in all cores

0.986 (0.932–1.042) 0.267 0.605


carcinoma

1.047 (0.930–1.179) 0.585 0.444

Percentage of total

cancer extent in all cores

1.010 (0.999–1.021) 3.135 0.077


NPB needle prostatic biopsy; HR hazard ratio; CI confidence interval

938 Int Urol Nephrol (2014) 46:935–940

123

cores (p = 0.006) and preoperative serum PSA (p \ 0.001)

were significantly predictive. Total cancer extent in milli-

meter in all cores was in the limit of significance

(p = 0.052). In multivariate Cox analysis, only preopera-

tive serum PSA was independent predictor of shorter TBR

(p = 0.001). In Cohort 2, Gleason score was significantly

predictive of shorter TBR in univariate analysis

(p = 0.021) and independent predictor in multivariate

analysis (p = 0.018) (Table 2). Comparing to cohort 1,

preoperative PSA, percentage, and total cancer extent in

millimeter in all cores were not significantly predictive of

shorter TBR in univariate analysis. One possible explana-

tion for this is the short follow-up time in cohort 2, which is

one limitation of the study. Furthermore, incorporating in

the Cox model variables such as preoperative PSA veloc-

ity, PSA density, or others, the results could be different.

Therefore, other studies are needed incorporating addi-

tional variables.

Our results are in accordance with other authors. Berney

et al. [7] comprised a pathological review within a multi-

center study of patients with clinically localized prostate

cancer diagnosed in the UK from 1991 to 1996 and treated

by watchful-waiting or hormonal therapy alone. The

diagnosis of prostate cancer was revised, and the disease-

specific survival was considered the main outcome mea-

sure. In multivariate analysis, the revised Gleason score

was a more accurate predictor of prognosis than the ori-

ginal score.

Mitchell et al. [8] described the changes in the Gleason

grading system over time and evaluated how a shift in

Gleason grading affected the overall predictive accuracy of

the system in predicting biochemical disease-free survival

after RP. The patients were divided into two time cohorts

(1998–1997 and 1998–2004). A shift toward greater

Gleason sums over time was confirmed using the Chi-

square test (p \ 0.001), and a significant difference was

observed in biochemical disease-free survival between the

two time cohorts for those with Gleason 6 cancer

(p \ 0.01).

Uemura et al. [10] evaluated the prognostic value of the

MGS. The biopsies graded with the SGS of 103 patients

subsequently submitted to RP were revised according to

the MGS. The SGS and the MGS were associated with BR-

free survival after RP. Patients were divided into three

groups based on Gleason score: B6, 7, and C8. These

groups differed significantly using the MGS after RP

(p = 0.022). The biopsies graded according to the SGS

showed no such association.

Tsivian et al. [11] reviewed 204 NPB of patients who

underwent a RP for T2–T3 prostate cancer between 1995

and 1997. The previous SGS was reassigned in a blinded

fashion by a single uropathologist in 2008 using the MGS.

Gleason score was categorized into risk groups: low \7,

moderate =7, and high [7. Gleason score distribution dif-

fered significantly between the mid-1990s and the 2008

grading, with the average reevaluated Gleason score higher

than the initial one (6.14 vs. 6.39, p \ 0.001). Biochemical

disease-free survival curves of the SGS could not distin-

guish between moderate- and high-risk groups, although

the MGS curves showed statistically significant differences

between all risk groups.

Dong et al. [12] graded surgical specimens on the basis

of the SGS and the MGS. A total of 806 patients with

prostate cancer of SGS score 3 ? 3 = 6 or 3 ? 4 = 7 and

MGS score 6–8 were analyzed with a median overall fol-

low-up of 12.6 years. In the study population, 34 % of

patients with SGS score 3 ? 3 = 6 prostate cancer were

upgraded to MGS score 7 or 8. Compared to patients with

MGS score 3 ? 3 = 6 and patients with SGS 3 ? 4 = 7,

the upgraded patients were at intermediate risk of bio-

chemical progression (paired log-rank p B 0.03). The

authors conclude that the results validate the prognostic

value of the MGS and suggest that the recognition of an

intermediate-risk histological pattern may be useful in the

prognosis of patients with prostate cancer.

Delahunt et al. [13] compared the distribution and pre-

dictive performance of the SGS and the MGS criteria of

prostate carcinoma accessioned by the Trans-Tasman

Radiation Oncology Group RADAR trial. The predictive

performance of each of the four Gleason scores assigned to

each case was evaluated using the nadir prostate-specific

antigen (nPSA) as clinical end point. On comparison of the

prognostic gradients of the grade groupings, SGS scoring

outperformed modified MGS. This is the only study that is

not in accordance with our results. An important difference

to be considered is the fact that Delahunt et al. considered

as end point the PSA nadir that is not currently considered

the best end point for predicting failure after radiotherapy.

Following radiotherapy for prostate cancer, serum PSA

values decrease to a nadir although not to the same extent

as those following RP. Treatment failure is considered only

after three subsequent rises in serum PSA.

Conclusion

Comparing to patients in cohort 1 (from 1997 to 2004),

patients in cohort 2 (from 2005 to 2011) reflect time-related

changes: striking increase in clinical stage T1c, systematic

use of extended biopsies, and lower percentage of total

length of cancer in millimeter in all cores. The 2005 ISUP

MGS applied in cohort 2 showed fewer biopsies with

Gleason score B6 and more biopsies of the intermediate

Gleason score 7. Time to BR using the Kaplan–Meier

curves showed statistical significance using the MGS in

cohort 2, but not the SGS in cohort 1. Only MGS predicted

Int Urol Nephrol (2014) 46:935–940 939

123

shorter TBR after RP on univariate Cox analysis and on

multivariate analysis was an independent predictor. The

results favor that the 2005 ISUP modified system is a

refinement of the Gleason grading and valuable for con-

temporary clinical practice.

Conflict of interest The authors declare that there is no conflict of

interest.

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The value of the 2005 International Society of Urological Pathology (ISUP) modified Gleason grading system as a predictor of biochemical recurrence after radical prostatectomy