Oncology

Prostate-specific Antigen Density Is

a Good Predictor of Upstaging and
Upgrading, According to the New Grading
System: The Keys We Are Seeking May
Be Already in Our Pocket
Aldo Brassetti, Riccardo Lombardo, Paolo Emiliozzi, Antonio Cardi, De Vico Antonio,
Iannello Antonio, Scapellato Aldo, Riga Tommaso, Pansadoro Alberto, and
D’Elia Gianluca
OBJECTIVE To analyze the performance of prostate-specific antigen density (PSAD) as a predictor of upstag-
ing and prognostic grade group (PGG) upgrading.
MATERIALS AND We retrospectively evaluated data on men with prostate cancer (PCa) treated with robot-
METHODS assisted laparoscopic radical prostatectomy (RALP) at our center in 2014-2015. Preoperative PSAD
was calculated. Bioptic and pathologic PGGs were also considered in the analysis. We defined
upgrading as any increase in PGG after RALP; upstaging was the pathologic diagnosis of a clini-
cally unsuspected stage ≥3a PCa.
RESULTS Data on 379 patients were analyzed. Upgrading was found in 41.4% of the patients; 29% of the
patients were upstaged. On multivariable analysis, core involvement and PSAD were found to
be predictors of upgrading (odds ratio [OR] 1.017, 95% confidence interval [CI] 1.001-1.034, P = .039;
and OR 3.638, 95% CI 1.084-12.207, P = .001, respectively). Furthermore, core involvement and
PSAD were predictors of upstaging (OR 1.020, 95% CI 1.020-1.034, P = .003; and OR 5.656,
95% CI 1.285-24.894, P = .022, respectively). PSAD showed areas under the curve of 0.712
(95% CI 0.645-0.780, P = .000) and 0.628 (95% CI 0.566-0.689, P = .000) for the prediction of
upgrading and upstaging, respectively. In a subpopulation of 90 patients theoretically eligible for
active surveillance, 14% were found upstaged and 17% were upgraded. PSAD showed areas under
the curve of 0.894 (95% CI 0.808-0.97, P = .000) and 0.689 (95% CI 0.539-0.840, P = .021) for
the prediction of upgrading and upstaging, respectively.
CONCLUSION PSAD is a valuable predictor of upgrading and upstaging in men with PCa who were
candidates for surgery and is accurate in selecting patients for AS. UROLOGY 111: 129–135, 2018.
© 2017 Elsevier Inc.

P
rostate cancer (PCa) shows an extremely heteroge-
neous clinical course, ranging from indolent and
organ-confined to aggressive and metastatic disease.
An accurate assessment of the tumor characteristics is crucial
so that the appropriate treatment options can be considered.1
D’Amico et al was the first to combine the use of pre-
operative prostate-specific antigen (PSA) levels, clinical
stage (cT), and biopsy Gleason score (bGS) to stratify
Financial Disclosure: The authors declare that they have no relevant financial
interests.
From the Department of Urology, San Giovanni Hospital, Rome, Italy; and the De-
partment of Urology, La Sapienza University of Rome, Italy
Address correspondence to: Aldo Brassetti, M.D., Department of Urology, San Giovanni
Hospital, Via Oslo 7, Fiumicino, Rome 00054, Italy. E-mail: aldo.brassetti@
gmail.com
Submitted: April 10, 2017, accepted (with revisions): July 28, 2017
© 2017 Elsevier Inc.
All rights reserved.
patients with PCa into risk groups.1 Unfortunately, current
methods of clinically assessing PCa grade and stage are not
accurate, and upgrading or upstaging occurs in more than
one-third of the cases.2-4 Recently, Epstein et al proposed
a new grading system to provide a more accurate tumor
stratification, simplifying at the same time patients’ com-
prehension of their disease.5
Some authors proved that prostate-specific antigen density
(PSAD) may be useful in predicting adverse pathologic find-
ings in radical prostatectomy (RP) specimens and unfa-
vorable outcomes after local treatment.6 However, when
assessing the ability of PSAD to predict upgrading and up-
staging, conflicting results were reported.7,8 Moreover, to
our knowledge, no study has yet evaluated the accuracy of
PSAD in predicting upgrading after RP using the new
Epstein grading system.
https://doi.org/10.1016/j.urology.2017.07.071 129
0090-4295
 The aim of the present study was to analyze the perfor-
mance of PSAD as a predictor of upstaging and prognos-
tic grade group (PGG) upgrading.
MATERIALS AND METHODS
Patient Selection
After obtaining institutional review board approval, a retrospec-
tive analysis of our prospectively maintained database of men who
underwent robot-assisted laparoscopic prostatectomy (RALP) at
our center between January 2014 and December 2015 was carried
out. We included patients with a histologically confirmed pros-
tate biopsy diagnosis of PCa (at our institution) within 3 months
before surgery. Patients who underwent neoadjuvant therapy were
excluded from the study. Previous benign prostatic hyperplasia
surgery and treatment with 5α-reductase inhibitors at the time
of surgery were also considered exclusion criteria.
Prostate biopsies were conducted through a transrectal
ultrasound-guided approach. During the sampling, 12 cores were
taken from all the patients, regardless of the size of the gland;
prostate volume (PV) was also evaluated (using the ellipsoid
formula) and PSAD was further calculated.
RALP was performed by experienced surgeons. Extended lymph
node dissection was carried out according to European Associa-
tion of Urology (EAU) guidelines.9
The American Joint Committee on Cancer TNM, sixth edition
(2002), was used for pathologic staging. The Gleason score (GS)
and PGG were also assigned according to the International Society
of Urological Pathology recently described by Epstein et al.10,11
Data Collected
Evaluated variables included age, body mass index (calculated as
weight in kilogram divided by height in meter squared [kg/m2]),
preoperative PSA, PV, PSAD, cT and pathologic stage (pT),
bioptic and pathologic GS and PGG, the number of positive cores,
and the percentage of tumor involvement of each bioptic core.
We defined a PGG ≥3 tumor as a high-grade prostate cancer
(HG-PCa); pT ≥ 3a malignancies were considered locally ad-
vanced diseases. Any increase in PGG between core biopsy and
RP specimen was considered upgrading;12 this increase was con-
sidered clinically relevant when switching from low-grade PCa at
biopsy to HG-PCa after RALP. Upstaging was defined as the patho-
logic diagnosis of a non–organ-confined disease not clinically sus-
pected before RP by means of routine investigation.
Preoperative data were used to identify patients theoretically
eligible for active surveillance (AS) according to EAU guidelines,9
defining a binary variable for the presence or the absence of a
low-risk PCa (>10 years of life expectancy, cT T1/2, bGS ≤6, PSA
≤10 ng/mL, fewer than 3 prostate biopsy cores positive with ≤50%
of cancer in each core).
Statistical Analysis
Statistical analysis was performed using the SPSS 12.0 software.
Evaluation of data distribution showed a non-normal distribu-
tion of the study data set. Differences between groups of pa-
tients in medians for quantitative variables and differences in
distributions for categorical variables were tested with the Kruskal-
Wallis 1-way analysis of variance and chi-square test, respec-
tively. Using multiple logistic regression with the enter method,
the statistically significant variables as assessed in the univari-
ate analysis were entered and investigated as predictors of up-
grading and upstaging. The logistic regression analysis was carried
130
out using only the patients for whom the complete sets of data
were available. The variables considered for entry into the model
included age, the number of positive cores, the percentage of core
involvement, and PSAD (PSA and PV were excluded from the
multivariable model for the risk of multicollinearity). Receiver
operating characteristic (ROC) curves were produced to evalu-
ate the area under the curve (AUC) and the diagnostic perfor-
mance of PSAD as a predictor of upgrading and upstaging. The
diagnostic performance of PSAD was also expressed by the cal-
culation of the sensitivity, the specificity, the positive predic-
tive value (PPV), and the negative predictive value (NPV) at
the best cutoff value of 0.130. A P value of 5% was considered
as the threshold for significance. Data were presented as
mean ± standard deviation and median with interquartile
range.
RESULTS
Overall, 379 patients were enrolled and their character-
istics are described in Table 1. Before surgery, 38 (10%)
patients presented with HG-PCa and 1 of these patients
(0.2%) was suspected to have a locally advanced disease.
On pathologic examination, 83 (22%) were diagnosed with
a high-grade tumor and 109 (29%) with a locally ad-
vanced one.
After RALP, 157 (41.4%) patients were found up-
graded and the rate of clinically relevant upgrading was
14.5% (n = 55). Of 280 patients diagnosed with PGG 1
cancer on biopsy, 145 (51.7%) were upgraded on final pa-
thology; the same happened to 6 of 61 patients (9.8%) with
a bPGG of 2 and to 6 of 30 patients with a bPGG of 3.
Downgrading occurred in 9 patients (2.4%): 7 had a bPGG
of 2 and 2 had a bPGG of 5.
Of all the patients with a bioptic diagnosis of PGG 1
cancer, 61 (22.1%) were diagnosed with a locally ad-
vanced disease; the same happened to 21 patients (34.4%)
with a bPGG of 2, to 20 patients (66.6%) with a bPGG
of 3, and to 7 patients (87.5%) with a bPGG of ≥4.
Patients presenting with upgrading in the pathology
report showed smaller prostates, slightly higher PSA values,
and higher PSAD (Table 1). On multivariable analysis, core
involvement and PSAD were found to be predictors
of upgrading (Table 2). The latter showed an AUC of 0.712
(95% confidence interval [CI] 0.645-0.780, P = .000) for
the prediction of upgrading. At the best cutoff value of
0.13 ng/mL2, the PSAD showed a sensitivity of 83%, a speci-
ficity of 57%, a PPV of 25%, and an NPV of 95%.
Patients presenting with upstaging in the pathology report
showed smaller prostates, a larger number of positive cores,
a higher percentage of core involvement, and higher PSA
values and PSADs (Table 2). The multivariate analysis
showed that core involvement and PSAD were found to
be predictors of upstaging (Table 3). The latter showed
an AUC of 0.628 (95% CI 0.566-0.689, P = .000) for
the prediction of upstaging. At the best cutoff value of
0.13 ng/mL2, the PSAD showed a sensitivity of 62%, a speci-
ficity of 57%, a PPV of 38%, and an NPV of 78%.
Overall 90 patients (24%) were possible candidates for
AS. Of these patients, 13 (14%) presented with upstaging
UROLOGY 111, 2018
 and 15 (17%) presented with upgrading. The predictive

.583

.000

.065

.004

.000

.000

.000
P
accuracy of PSAD in these patients is described in Table 3.

(0.170, 0.120-0.280)
(n = 111, 29%)

0.250 ± 0.313
(8.1, 6.1-12.0)
COMMENTS
(63, 59-68)

(47, 40-56)

(28, 25-31)

(40, 18-55)
28.2 ± 4.0

10.7 ± 9.9
Upstaging

4.5 ± 3.1
63.0 ± 6

51 ± 19

38 ± 20
(4, 2-6)
Bioptic GS and cT, together with the PSA level at diag-
nosis, are widely adopted variables used to stratify pa-
tients with PCa in prognostic groups so that appropriate
treatment options can be considered.1,9 Several studies,
however, have reported a poor concordance between clini-
cal assessment and pathologic findings that might result
in inappropriate therapeutic recommendations.2,3,8,12-16
(0.110, 0.080-0.0.198) Recently, Epstein et al proposed a new grading system
(n = 268, 71%)

0.160 ± 0.123
to provide a more accurate tumor stratification, simplify-
(7.1, 5.5-9.9)
No Upstaging

25.0 ± 20.5
(63, 58-68)

(54, 44-71)

(26, 25-28)
26.6 ± 3.2
59.8 ± 23

(20, 9-40)
8.1 ± 4.1

3.1 ± 2.4
62.6 ± 6

(2, 1-4) ing at the same time patients’ comprehension of their

disease.5 Later on, the ability of this new grading system
to predict surgical, oncological, and biochemical out-
comes was evaluated.14 The present study adds more evi-
dence to the applicability of the new PGG system and
confirms the role of PSAD as a predictor of upgrading.
Table 1. Characteristics of the cohort according to the presence and the absence of upgrading and upstaging

Kvåle et al described an overall 53% concordance rate

between biopsy and pathologic GS and highlighted that
.859

.000

.610

.053

.000

.783

.097
P

upgrading was more common in patients with a low biopsy-

BMI, body mass index; PSA, prostate-specific antigen; PSAD, prostate-specific antigen density; PV, prostate volume.

based GS,3 as further confirmed by Sfoungaristos and

Perimenis.13 Interestingly, Corcoran et al and Epstein et al
(0.190, 0.140-0.300)

reported that patients with a bGS = 7 showed a higher rate

(n = 157, 41.4%)

0.241 ± 0.185
(8.1, 6.7-11.0)

of agreement with final pathology (50.0%-85.2%)2,14 com-

(63, 59-68)

(46, 40-52)

(27, 24-31)

(35, 10-50)
28.2 ± 5.1

10.0 ± 6.0

33.7 ± 23
Upgrading

3.5 ± 2.4
49 ± 19

(3, 2-5)
63 ± 6

pared with patients with a bGS = 6, as confirmed by our

results. In the present series, we found an overall 56% rate
of concordance between bioptic and pathologic PGG:
41.4% of the patients were found upgraded, and 2.6% were
found downgraded. Remarkably, our rate of clinically rel-
evant upgrading was 14.5%, in line with previous find-
Data are presented as mean ± standard deviation (median, interquartile range).

ings by Epstein et al (8.9%),14 Kvåle et al (<10%)3 and

(0.120, 0.090-0.200)
(26.7, 24.8-29.0)
(n = 202, 58.6%)

D’Elia et al (14.1%).15
0.177 ± 0.206
(7.3, 5.5-10.0)
No Upgrading

27.9 ± 21.1
(63, 58-68)

(54, 43-70)

(20, 10-43)
26.9 ± 3.2

Noteworthy is that up to one-third of the patients un-

8.7 ± 6.5

3.6 ± 2.7
62.7 ± 6

58 ± 22

(3, 2-5)

dergoing RP for clinically localized PCa is diagnosed with

a locally advanced disease on pathologic examination.7,8,16
Consistently, in the present series, 109 of 379 men (29%)
were found to harbor a pT ≥ 3a PCa.
In the present series, patients presenting with upgrad-
ing in the pathology report had smaller prostates
(49 ± 19 mL vs 58 ± 22 mL, P = .000), higher PSA values
(26.7, 24.9-29.0)

(0.13, 0.09-0.22)
0.186 ± 0.204
(7.4, 5.5-10.5)

(10.0 ± 6.0 ng/mL vs 8.7 ± 6.5, P = .053), and higher PSADs

57.2 ± 22.1

28.8 ± 21.4
(63, 58-68)

(52, 42-68)

(22, 10-45)
27.1 ± 3.5

8.9 ± 6.5

3.6 ± 2.7
(n = 379)
62.7 ± 6

(3, 2-5)
Overall

(0.241 ± 0.185 ng/mL2 vs 0.177 ± 0.206 ng/mL2, P = .000).

The body mass index and the percentage of core involve-
ment were also higher in this population, but the differ-
ence was not statistically significant. On a multivariable
analysis, core involvement and PSAD were found to be
predictors of upgrading (odds ratio [OR] 1.017, 95% CI
Core involvement (%)

1.001-1.034, P = .039; and OR 3.638, 95% CI 1.084-

12.207, P = .001, respectively). Epstein et al14 and Magheli
PSAD (ng/mL2)

Positive cores

et al17 reported similar results and also demonstrated a sig-

PSA (ng/mL)
BMI (kg/m2)

nificant association between increased age and upgrad-

PV (mL)

ing, in contrast with our findings. On the contrary, other

Age (y)

authors failed to prove any association between PSA levels

and cancer core involvement with upgrading.12,18,19

UROLOGY 111, 2018 131

Table 2. Multivariable analysis for predicting upgrading and upstaging in the pathology report
Patients Upgrading P Upstaging P
Age 371 0.994 .816 1.000 .775
(0.946-0.045) (0.965-1.048)
Positive cores 371 0.901 .153 1.091 .109
(0.780-1.040) (0.983-1.210)
Core involvement 371 1.017 .039 1.020 .003
(1.001-1.034) (1.020-1.034)
PSAD 371 3.638 .037 5.656 .022
(1.084-12.207) (1.285-24.894)
Data are presented as odds ratio (95% confidence interval).

Table 3. Predictive characteristics of PSAD in patients eli-
gible for AS
Upgrading Upstaging
Sensibility 84 40
(%)
Specificity 85 78
(%)
PPV (%) 50 27
NPV (%) 97 87
Accuracy 85 72
(%)
AUC 0.894 (0.808-0.979) 0.689 (0.539-0.840)
AUC, area under the curve; NPV, negative predicting value; PPV,
positive predictive value.
In our cohort, patients with a locally advanced PCa at
the pathologic examination had smaller prostates
(51 ± 19 mL vs 59.8 ± 23, P = .000), a higher percentage
of core involvement (38% ± 20% vs 25.0% ± 20.5%,
P = .000), higher PSA values (10.7 ± 9.9 ng/mL vs 8.1 ± 4.1,
P = .004), and higher PSADs (0.250 ± 0.313 ng/mL2 vs
0.160 ± 0.123 ng/mL2, P = .000). On multivariate analy-
sis, core involvement and PSAD were found to be predic-
tors of upstaging (OR 1.020, 95% CI 1.020-1.034, P = .003;
and OR 5.656, 95% CI 1.285-24.894, P = .022, respec-
tively). Similar pieces of evidence were previously pub-
lished by other authors.7,20
Initially introduced to improve PSA testing sensitivity
and specificity for PCa screening,21 PSAD has clearly shown
a strong relationship with PCa aggressiveness,17 proving to
be helpful in predicting high-grade and extracapsular disease,
seminal vesicle invasion, and lymph node involvement.6
Recent papers, moreover, have supported the inclusion of
PSAD into the risk stratification system for candidates for
AS, proving that it is significantly more accurate than PSA
in predicting upgrading and upstaging in this specific
population.22 Notwithstanding these pieces of evidences,
although widely adopted as a risk stratification tool,23-25
PSAD has not been recognized by the EAU as an AS in-
clusion criteria.9
Overall, in the present series, PSAD proved to be ef-
fective in predicting adverse pathologic features. In the ROC
analysis, PSAD showed AUCs of 0.712 (95% CI 0.645-
0.780, P = .000) and 0.628 (95% CI 0.566-0.689, P = .000)
for the prediction of upgrading and upstaging, respec-
tively. At the best cutoff value of 0.130 ng/mL 2 , the
sensitivity of PSAD was 83% for upgrading and 62% for
upstaging.
In our study, moreover, in a subpopulation of 90 pa-
tients theoretically eligible for AS according to the EAU
guidelines,9 13 (14%) were found upstaged on pathologic
examination and 15 (17%) were upgraded. In this group
of patients, in the ROC analysis, PSAD showed AUCs of
0.894 (95% CI 0.808-0.97, P = .000) and 0.689 (95% CI
0.539-0.840, P = .021) for the prediction of upgrading and
upstaging, respectively.
Our results are consistent with those from recent pro-
spective AS studies that have demonstrated that a more
aggressive disease is found in up to one-third of the pa-
tients eligible, on confirmation biopsy.26,27 Noteworthy is
that Ha et al recently proved that removing the PSAD cri-
terion from those adopted by the National Comprehen-
sive Cancer Network or the Prostate Cancer Research
International Active Surveillance (PRIAS) would expand
eligibility at the expense of the significant increase in the
rate of upgrading and upstaging. Contrariwise, reducing the
PSAD threshold from 0.2 to 0.15 ng/mL2 in the PRIAS
study or adding a PSAD cutoff of 0.15 ng/mL2 to the cri-
teria adopted by the University of California, San Fran-
cisco, would reduce the rate of unexpected adverse pathology
diagnosed at prostatectomy.27
We must acknowledge several limitations to the present
trial.
Firstly, the database was prospectively maintained but
was analyzed retrospectively. Furthermore, in the present
study, no pathologic review of all the specimens was per-
formed, and interpretative modifications might in part affect
the results of our study. However, the lack of a pathologic
review was, common to other studies validating the Epstein
classification.28
Another limitation is that we calculated PSAD taking
into consideration PV values assessed during transrectal ul-
trasound, made by 4 different experienced operators. Even
though a standard protocol was followed, the interobserver
variability may have negatively affected the validity of the
results. Some other authors, to overcome the limitation of
an operator-dependent assessment of the prostate size, re-
curred to the measured volume of the specimen ex vivo
(often before seminal vesicle removal) for the PSAD
calculation.4,7 In our opinion, however, this choice may limit
the clinical applicability of their findings, completely vio-
lating the nature of PSAD as a preoperative prognostic tool.

132 UROLOGY 111, 2018

Some other authors, moreover, suggested a magnetic
resonance-based PV estimation to accurately calculate
PSAD. In the present cohort, however, the results of this
(expensive) radiological investigation were available only
for a limited number of patients, mostly with HR-PCa, and
thus were not taken into consideration for the statistical
analysis. An additional limitation to the use of PSAD as
a prognostic tool is that, because the epithelium-to-
stroma ratio varies among individuals, this parameter may
not accurately estimate the benign prostatic hyperplasia
volume. Assessing the PSA transition zone density may
provide a more valuable information but it is not rou-
tinely evaluated in our outpatient clinic.
Notwithstanding these limitations, our results concur in
demonstrating that PSAD is one of the most valuable
markers to predict upgrading and upstaging in men with
PCa who were candidates for local treatment with cura-
tive intent and is accurate in selecting patients for AS. Al-
though it has not been very helpful in screening and
detecting PCa,29,30 PSAD may have found a new life in
today’s clinical practice, helping the urologist to select pa-
tients who should undergo more expensive tests before de-
ciding on the appropriate treatment options.
Although we agree with the recent interest in identi-
fying new tools31,32 able to further improve our capability
to clinically predict PCa clinical behavior, we recom-
mend a wider use of PSAD, actually relegated to the scrap
heap of prostate markers and PSA derivates, in daily prac-
tice and its inclusion in all AS protocols.
CONCLUSION
PSAD proved to be one of the most valuable markers to
predict upgrading and upstaging in men with PCa who were
candidates for surgery and is accurate in selecting pa-
tients for AS.
Accordingly, we recommend its adoption in urologic daily
practice as a reliable and accurate cancer risk stratifica-
tion tool, and its inclusion in all AS protocols.
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23. van den Bergh RCN, Vasarainen H, van der Poel HG, et al. Short-
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25. Tosoian JJ, JohnBull E, Trock BJ, et al. Pathological outcomes
in men with low risk and very low risk prostate cancer: implica-
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26. Kim TH, Jeon HG, Choo SH, et al. Pathological upgrading and up-
staging of patients eligible for active surveillance according to cur-
rently used protocols. Int J Urol. 2014;21:377-381.
27. Ha Y-S, Yu J, Salmasi AH, et al. Prostate-specific antigen density
toward a better cutoff to identify better candidates for active sur-
veillance. Urology. 2014;84:365-372.
28. Gandaglia G, Karnes RJ, Sivaraman A, et al. Are all grade group 4
prostate cancers created equal? Implications for the applicability of
the novel grade grouping. Urol Oncol Semin Orig Investig.
2017;doi:10.1016/j.urolonc.2017.02.012.
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EDITORIAL COMMENT
The poor concordance between clinical assessment and patho-
logical findings with potential inappropriate therapeutic recom-
mendations in prostate cancer (PCa) is a current challenge. Like
present series, we have already described that patients present-
ing upgrading on pathological report had smaller prostates and
higher PSA, consequently, higher PSAD.1
One must not forget or minimize the selection bias related to
PSA and digital rectal examination (DRE) as the main screen-
ing instruments for PCa. In fact, the PSAD role in predicting
adverse pathology diagnosed at prostatectomy represents a con-
tinuum of its initial mission to identify clinically significant cancers,
limiting over diagnosis in the screening scenario, in which PSAD
still figures as a precious tool.2
In the context of cost effective screening of patients in need
of additional tests, despite the use of new technology, clinical
investigation including DRE will always play a major role in
the diagnosis and prognosis of clinical problems. Nevertheless,
there is a growing trend in the current practice to offer less
basic office evaluation, proposing more complementary exams,
culminating certainly in cost increments with no warranted
benefits.3
While magnetic resonance image (MRI) or trans-rectal ultra-
sound (TRUS) is utilized to measure prostate volume (PV), ab-
dominal ultrasound was proved an equivalent method to TRUS
for measuring the prostate when bladder volume is over 100 ml.4
Likewise ultrasound data, although also an examiner dependent
tool with inter-observer variability, standardizing DRE for a more
accurate clinical impression of prostate volume in the physical
examination will certainly impact clinical practice, room for future
developments.
134
To fill such gap and in line with the authors hope to expand
PSAD use and give it a renewed dignity in today’s daily prac-
tice, we have described surprising accuracy of a scaled standard-
ization of DRE based on fingertips graphical schema.5
On the other hand, following the authors perspective that “the
keys we are seeking may be already in our pocket” and consid-
ering PSA derivatives beyond PSAD given its limitations, a urology
group in the South of Brazil has proposed the use of a “PSA index”
obtained by dividing the value of the PSAD by the value of the
free/total PSA ratio. The rational is based on the premise that
all the PSA derivatives criteria are complementary2 and the lower
the percentage of the free PSA6 and the higher the PSAD,1 the
greater the probability of clinically significant PCa.
A quick evaluation of the proposed “PSA-index” perfor-
mance to predict biopsy results including Gleason Prognostic Grade
Group classification in one of our representative cohorts showed
potential to take the best of PSA as the precious though ago-
nizing tool on PCa screening/prognosis. “PSA-index” area under
the ROC curve is over .75, which might be surprisingly compa-
rable to Vienna, Partin, and Kattan nomograms.
Obviously, many players compete to PCa under-staging/
grading, including biopsy related imperfections involving core
number/quality/length, location, labeling and pathologic
processing.7,8 Definitely, the keys we are seeking may be already
in our pocket and are beyond PSAD. However, further than ques-
tioning are we using it, how far can we go with that?
Leonardo Oliveira Reis, M.D., M.Sc., Ph.D., Pontifical
Catholic University of Campinas (PUC-Campinas), Av. John
Boyd Dunlop, s/n, Campinas, São Paulo CEP: 13060-904,
Brazil
References
1. Reis LO, Zani EL, Freitas LLL, Denardi F, Billis A. Higher prostate
weight is inversely associated with Gleason score upgrading in radical
prostatectomy specimens. Adv Urol. 2013;2013:710421. doi:10.1155/
2013/710421.
2. Reis LO, Zani EL, Alonso JC, Simões FA, Rejowski RF, Ferreira U.
Does the criterion for prostate biopsy indication impact its accuracy?
A prospective population-based outpatient clinical setting study. Actas
Urol Esp. 2011;35:10-14. doi:10.1016/j.acuro.2010.06.011.
3. Lim CH, Quinlan DM. Are doctors examining prostates in univer-
sity hospital? Urology. 2007;70:843-845.
4. Yuen JS, Ngiap JT, Cheng CW, Foo KT. Effects of bladder volume
on transabdominal ultrasound measurements of intravesical pros-
tatic protrusion and volume. Int J Urol. 2002;9:225-229.
5. Reis LO, Simao AF, Baracat J, Denardi F, Gugliotta A. Digital
rectal examination standardization for inexperienced hands:
teaching medical students. Adv Urol. 2013;2013:797096. doi:10.1155/
2013/797096.
6. Faria EF, Carvalhal GF, dos Reis RB, et al. Use of low free to
total PSA ratio in prostate cancer screening: detection rates, clinical
and pathological findings in Brazilian men with serum PSA levels
<4.0 ng/mL. BJU Int. 2012;110(11 Pt B):E653-E657. doi:10.1111/
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https://doi.org/10.1016/j.urology.2017.07.072
UROLOGY 111: 134, 2018. © 2017 Elsevier Inc.
UROLOGY 111, 2018

AUTHOR REPLY
Prostate cancer (PCa) is a major public health concern. Despite
attempts to reduce health-care costs, care expenditures in the
United States in 2024 will account for 20% of the gross domes-
tic product, and the largest single portion of the projected cost
increases will be for PCa care.1
The appropriate treatment options are usually decided upon
the clinical stage, the prognostic grade group, and the prostate-
specific antigen level at diagnosis. Results from prostate biopsy,
however, may differ from the final pathology after radical pros-
tatectomy and, as confirmed by our data, in 1 out of 2 cases, the
choice of the therapeutic approach is based on an inaccurate grade
or stage attribution.
Ours and other studies highlighted that different inexpensive
preoperative variables (age, abnormal digital rectal examina-
tion result, prostate-specific antigen density and percentage of
biopsy core involved in cancer) can efficiently predict upgrad-
ing and upstaging. Nevertheless, despite the need for health-
care expenditure reduction, there is a growing interest in new
technological examinations, thus leading to cost increments with
no warranted benefits.1
Prostate-specific antigen isoforms and the Prostate Health Index
might guide the urologist in decision making. However, strong
supporting pieces of evidences are still warranted to assess their
impact on PCa diagnosis and prognosis.2
Multiparametric magnetic resonance imaging (mpMRI) is revo-
lutionizing the approach to PCa care. It is hypothesized that
mpMRI may provide a more accurate initial staging in patients
on active surveillance and may help in identifying aggressive
cancers, thanks to its high specificity for high-grade PCa (Gleason
score ≥ 3 + 4). In this setting, Alberts reported a 31% upgrad-
ing rate overall. However, a high-grade PCa was identified in only
46.6% of the patients diagnosed with a Prostate Imaging Re-
porting and Data System ≥ 4 intraprostatic lesion. Interestingly,
in this subgroup of patients, a baseline prostate-specific antigen
density of ≥0.15 ng/mL2 was associated with a higher incidence
of aggressive disease (50% vs 24%). 3 Besides providing
an accurate clinical staging, mpMRI is thought to be also
useful in surgical planning, especially when a nerve-sparing
approach is desirable. Rud et al, however, failed to prove
Financial Disclosure: The authors have nothing to disclose.
UROLOGY 111, 2018
the role of magnetic resonance in reducing positive margin
rates.4
On the contrary, the digital rectal examination is nowadays
underperformed: this not only deprives junior doctors of train-
ing opportunities but also leads to nondetection of some PCa cases.5
Staying stuck in the past is surely a huge mistake: new tools
to better define clinical stage are needed to offer patients the ap-
propriate treatment options.
In our opinion, however, in the context of the cost-effective
management of patients with cancer, basic clinical investiga-
tions will always play a role in PCa diagnosis and prognosis.
When you look for the right key to open the door, it often ex-
hibits the signs of the times.
Aldo Brassetti, M.D., and Gianluca D’Elia, M.D., the
Department of Urology, San Giovanni Hospital, Rome, Italy
References
1. Hutchinson R, Lotan Y. Cost consideration in utilization of
multiparametric magnetic resonance imaging in prostate cancer. Transl
Androl Urol. 2017;6:345-354. doi:10.21037/tau.2017.01.13.
2. Guazzoni G, Nava L, Lazzeri M, et al. Prostate-specific antigen (PSA)
isoform p2PSA significantly improves the prediction of prostate
cancer at initial extended prostate biopsies in patients with total
PSA between 2.0 and 10 ng/ml: results of a prospective study in
a clinical setting. Eur Urol. 2011;60:214-222. doi:10.1016/j.eururo
.2011.03.052.
3. Alberts AR, Roobol MJ, Drost F-JH, et al. Risk-stratification based
on magnetic resonance imaging and prostate-specific antigen density
may reduce unnecessary follow-up biopsy procedures in men on active
surveillance for low-risk prostate cancer. BJU Int. 2017;doi:10.1111/
bju.13836.
4. Rud E, Baco E, Klotz D, et al. Does preoperative magnetic resonance
imaging reduce the rate of positive surgical margins at radical pros-
tatectomy in a randomised clinical trial? Eur Urol. 2015;68:487-496.
doi:10.1016/j.eururo.2015.02.039.
5. Hong Lim C, Quinlan DM. Are doctors examining prostates in Uni-
versity Hospital? Urology. 2007;70:843-845. doi:10.1016/j.urology
.2007.07.010.
https://doi.org/10.1016/j.urology.2017.07.073
UROLOGY 111: 135, 2018. © 2017 Elsevier Inc.
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