EUROPEAN UROLOGY 60 (2011) 291–303
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Collaborative Review – Prostate Cancer
The Contemporary Concept of Significant Versus Insignificant
Prostate Cancer
Guillaume Ploussard a,b,*, Jonathan I. Epstein c, Rodolfo Montironi d,e, Peter R. Carroll f,
Manfred Wirth g, Marc-Oliver Grimm h, Anders S. Bjartell i, Francesco Montorsi j,
Stephen J. Freedland k, Andreas Erbersdobler l, Theodorus H. van der Kwast m
a
Department of Urology, Saint-Louis Hospital, APHP, Paris, France
b
INSERM 955, Team 7, University Paris 12, Créteil, France
c
Department of Pathology, Johns Hopkins Medical Institutions, Baltimore, MD, USA
d
Institute of Pathological Anatomy and Histopathology, Polytechnic University of the Marche Region, Ancona, Italy
e
Arizona Cancer Centre, College of Medicine, University of Arizona Health Sciences Centre, Tucson, AZ, USA
f
Department of Urology, UCSF School of Medicine, Helen Diller Family Comprehensive Cancer Centre, San Francisco, CA, USA
g
Department of Urology, University Hospital Carl Gustav Carus, Technical University of Dresden, Dresden, Germany
h
Urologischen Klinik und Poliklinik, Universitätsklinikum Jena, Jena, Germany
i
Department of Urology, Skåne University Hospital, Malmö, Sweden
j
Department of Urology, Universita Vita Salute San Raffaele, Milan, Italy
k
Department of Surgery, Durham VA Medical Centre, and the Duke Prostate Centre, Division of Urological Surgery, Departments of Surgery and
Pathology, Duke University, Durham, NC, USA
l
Institute of Pathology, University of Rostock, Rostock, Germany
m
Department of Pathology, University Health Network and University of Toronto, Toronto, ON, Canada
Article info
Abstract
Article history:
Accepted May 2, 2011
Published online ahead of
print on May 17, 2011
Context: The notion of insignificant prostate cancer (Ins-PCa) has progressively emerged in the past
two decades. The clinical relevance of such a definition was based on the fact that low-grade, smallvolume, and organ-confined prostate cancer (PCa) may be indolent and unlikely to progress to biologic
significance in the absence of treatment.
Objective: To review the definition of Ins-PCa, its incidence, and the clinical impact of Ins-PCa on the
contemporary management of PCa.
Evidence acquisition: A review of the literature was performed using the Medline, Scopus, and Web of
Science databases with no restriction on language up to September 2010. The literature search used the
following terms: insignificant, indolent, minute, microfocal, minimal, low volume, low risk, and prostate cancer.
Evidence synthesis: The most commonly used criteria to define Ins-PCa are based on the pathologic
assessment of the radical prostatectomy specimen: (1) Gleason score 6 without Gleason pattern 4 or
5, (2) organ-confined disease, and (3) tumour volume < 0.5 cm3. Several preoperative criteria and
prognostication tools for predicting Ins-PCa have been suggested. Nomograms are best placed to
estimate the risk of progression on an individualised basis, but a substantial proportion of men with a
high probability of harbouring Ins-PCa are at risk for pathologic understaging and/or undergrading.
Thus, there is an ongoing need for identifying novel and more accurate predictors of Ins-PCa to
improve the distinction between insignificant versus significant disease and thus to promote the
adequate management of PCa patients at low risk for progression.
Conclusions: The exciting challenge of obtaining the pretreatment diagnostic tools that can really
distinguish insignificant from significant PCa should be one of the main objectives of urologists in the
following years to decrease the risk of overtreatment of Ins-PCa.
Keywords:
Prostate cancer
Insignificant
Active surveillance
Indolent
Significant
Prediction
Tumour volume
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# 2011 European Association of Urology. Published by Elsevier B.V. All rights reserved.
* Corresponding author. CHU Saint-Louis, Urology, 1 avenue Claude Vellefaux, Paris, 75010, France.
E-mail address: g.ploussard@gmail.com (G. Ploussard).
0302-2838/$ – see back matter # 2011 European Association of Urology. Published by Elsevier B.V. All rights reserved.
doi:10.1016/j.eururo.2011.05.006
292
1.
EUROPEAN UROLOGY 60 (2011) 291–303
Introduction
As a consequence of the stage and grade migration of prostate
cancer (PCa) resulting from widespread use of prostatespecific antigen (PSA) testing in combination with extendedcore prostate biopsy strategies, the notion of insignificant PCa
(Ins-PCa) has progressively emerged in the last two decades.
The clinical relevance of such a definition was based on
previous studies that suggested that low-grade, smallvolume, and organ-confined PCa may be indolent and
unlikely to progress to biologic significance in the absence
of treatment [1]. An accurate definition of insignificant disease
may help the clinician better manage patients after radical
treatment and propose alternative therapies (active surveillance) more confidently. Given the sharp increase in PCa
diagnoses and the increasing concerns of overtreatment, the
identification and definition of insignificant cancers is a high
priority. In this article, we review the definition of insignificant prostate cancers, their incidence, and their clinical impact
on the contemporary management of PCa.
2.
Evidence acquisition
A review of the literature was performed using the Medline,
Scopus, and Web of Science databases. We identified
original articles, reviews, and editorials with no restriction
on language up to September 2010. The literature search
used the following terms: insignificant, indolent, minute,
microfocal, minimal, low volume, low risk, and prostate cancer.
The selected articles were reviewed and summarised with
the consensus of all the authors of this review article.
3.
Evidence synthesis
3.1.
Current definition of insignificant prostate cancer
3.1.1.
What is the right terminology?
low-grade, small-volume, and organ-confined PCa that is
unlikely to progress to clinical and biologic significance
without treatment. In clinical practice, an Ins-PCa is a PCa
diagnosed in the absence of cancer-related symptoms that
would not have caused disease-specific morbidity or
mortality during the patient’s life if left untreated.
Stamey et al. first put forward the concept of Ins-PCa [9].
Their analysis was based on the tumour volume of
incidental PCa found in 139 cystoprostatectomy specimens
from patients with bladder cancer, and they proposed a
volume threshold of 0.5 cm3 of the largest tumour to define
subclinical disease. Patients were carefully evaluated to rule
out palpable PCa, and 88% of prostate tumours had a
dominant tumour nodule volume <0.2 cm3. They used the
prevalence of clinically significant PCa in the population to
conclude that tumours <0.5 cm3 are unlikely to become
clinically significant within the life span of the patient and
need not be treated. In subsequent works, Epstein et al.
validated this threshold, and their definition of Ins-PCa
based on radical prostatectomy (RP) specimens is the most
widely used one definition [1,10].
In the initial definition, Epstein et al. noted that in
tumours <0.2 cm3 (‘‘insignificant’’), they never found any
cancer with ‘‘capsular penetration,’’ although a few were
positive for capsular penetration in the set between 0.2 and
0.5 cm3 (‘‘minimal’’). In 1994, the conservative threshold of
0.2 cm3 was proposed to determine an expectant policy, but
to date, the current view is to use a more liberal definition,
and 0.5 cm3 is already considered too stringent.
To date, the most commonly used criteria to define InsPCa are based on the pathologic assessment of the RP
specimen (Fig. 1 and 2) and include three well-established
prognostic factors, as described by Ohori et al. and Epstein
et al.: (1) a Gleason score 6 without Gleason pattern 4 or 5,
[()TD$FIG]
The term and the definition used for insignificant cancer of the
prostate varies greatly in the literature, and various terms are
used somewhat interchangeably: indolent, minimal, minute,
low volume, and microfocal [2]. The terms insignificant and
indolent are the most common terms reported in the
literature, but slight differences between the two should be
emphasised. An indolent cancer is more likely defined by strict
pathologic characteristics and thus has been frequently
preferred in nomograms to define cancer detected by
pathologic criteria alone without integrating other important
variables such as patient age [3–7]. Indolent PCa refers to a
cancer that would never—regardless of the lifespan of the
patient—become clinically manifest according to its pathologic features. Insignificant prostate cancer is a subset of
indolent cancers that also factors in patient age and
comorbidity. Therefore, the term insignificant PCa may better
reflect the natural history of the disease in an individual
patient [8].
3.1.2.
Current definitions
Despite variations in the definition of insignificant disease,
the intellectual concept of Ins-PCa is well established: a
Fig. 1 – Whole-mount section of a low-volume but significant prostate
cancer in the peripheral zone (haematoxylin and eosin staining plus
immunostaining).
EUROPEAN UROLOGY 60 (2011) 291–303
[()TD$FIG]
Fig. 2 – Whole-mount section of an insignificant prostate cancer
(haematoxylin and eosin staining plus immunostaining).
(2) organ-confined disease (no extraprostatic extension,
seminal vesicle invasion [SVI], or lymph node involvement
[LNI]); and (3) a tumour volume <0.5 cm3 [1,10,11]. The
categorisation of the tumour was based on the mass with
the largest tumour volume (ie, the dominant, or index
tumour) [1].
3.1.3.
Factors influencing the definition of insignificance
Some factors have to be taken into account when defining
the significance of PCa based on RP specimens. First, the
pathologic sampling of the RP specimen has to be complete.
The specimens should ideally be step-sectioned at 3-mm
intervals. Slices 5 mm in thickness may not be adequate for
the evaluation of prognostic factors such as extraprostatic
extension and microscopic bladder neck invasion. The
method currently recommended by the International
Society of Urological Pathology (ISUP) is called a cone
technique, and it samples to the apex and the base (vs a
shaved approach). Another methodologic confounder is
how tumour volume is calculated [12]. The independent
prognostic value of planimetry and volume estimation
methods in determining tumour volume has been reported
in various studies [13–16]. However, the study of tumour
volume as a prognostic factor has been hampered by the
lack of a convenient and accurate method for determining
PCa volume (standard quantitative methods, planimetry)
[12]. The total tumour volume or the volume of the largest
or dominant tumour have both been calculated and used in
the literature [7,10,16]. Thus, differences in tumour volume
measurements between studies may limit comparisons
between different study findings. The first reports of Stamey
and Epstein included only the dominant tumour nodule
[1,9].
An additional point worth discussing is the update on
Gleason grading made during the ISUP consensus confer-
293
ence in 2005 [17]. This update, although barely recognised
by most urologists, led to a significant upgrade of tumours
towards a Gleason 4 pattern in prostatectomy specimens as
well as in biopsies. This definition differs from Gleason’s
original description of pattern 4, which consisted almost
entirely of cribriform patterns without depicting fused
glands or ill-defined glands with poorly formed glandular
lumina. In addition, currently, virtually all cribriform glands
are considered Gleason pattern 4, as opposed to the original
Gleason system, which included cribriform Gleason pattern
3. Because most ‘‘definitions’’ of insignificant prostate cancers
rely on Gleason grading and were made before 2005, this
update may result in a decrease in diagnosed Ins-PCa. There is
some controversy in the literature about the prognostic
difference between Gleason score 6 cancers with or without
grade 4. Some authors did not found strong differences in
biochemical recurrence (BCR) between the two groups
[13,18–20]. Otherwise, Epstein et al. have found in all their
studies that in RP specimens, Gleason score 6 cancers with
tertiary (<5%) pattern 4 had a worse prognosis than pure
Gleason score 3 + 3 = 6 cancers [20]. Their findings emphasised that 3 + 3 and 3 + 4 behaved differently in terms of
pathologic stage and biochemical progression.
Immunohistochemistry with markers against basal
cells (high-molecular cytokeratin, p63), PSA, and alphamethyl-coenzyme A racemase can be helpful for the
diagnosis of small foci in PCa. These antibodies have to
be used judiciously in light of the morphology on routine
haematoxylin and eosin–stained sections, as all of these
ancillary tests have significant false-positive and falsenegative results.
Zonal tumour location is an important feature for the
detection of PCa as well as for its prognosis. About 20% of
cancers are predominantly located in the transition zone
[21,22]. These tumours are often missed by conventional
core biopsy techniques, because routine biopsy protocols do
not sample the transition zone. However, these transition
zone tumours constitute the majority of the so-called
incidental prostate cancers detected in transurethral resection specimens performed for benign prostatic hyperplasia.
Clinical studies demonstrate that transition zone cancers
are less likely to develop PSA recurrence after RP as
compared to peripheral zone tumours of equal size [21].
Cancers originating in the transition zone are more likely to
behave in an indolent fashion and therefore could more
easily be defined as insignificant.
3.2.
Incidence of insignificant prostate cancer in clinical,
screening, and autopsy series
3.2.1.
Clinical and screening series
The reported incidences of Ins-PCa in RP specimens from
clinical and screening settings are listed in Table 1. The rates
range from 2.3% to 25% in unselected RP specimens [23–48].
Higher rates are reported in series including only clinical
stage T1c and/or Gleason score 6 (3 + 3) PCa. Some of the
variations in the incidence of Ins-PCa may be attributable to
several factors, such as patient selection or the impact of
clinical or screening practices.
294
EUROPEAN UROLOGY 60 (2011) 291–303
Table 1 – Reported incidences of insignificant prostate cancer in radical prostatectomy specimens in the literature
Reference
Epstein et al, 1994 [1]
Irwin and Trapasso, 1994 [23]
Terris et al, 1995 [24]
Cupp et al, 1995 [25]
Goto et al, 1996 [26]
Elgamal et al, 1997 [27]
Carter et al, 1997 [28]
Epstein et al, 1998 [10]
Noguchi et al, 2001 [29]
Grossklaus et al, 2001 [30]
Chan et al, 2001 [31]
Kattan et al, 2003 [7]
DiMarco et al, 2003 [32]
Augustin et al, 2003 [33]
Anast et al, 2004 [34]
Miyake et al, 2005 [35]
Ochiai et al, 2005 [36]
Loeb et al, 2006 [37]
Steyerberg et al, 2007 [6]
Shukla-Dave et al, 2007 [38]
No. of
patients
Cohort
Setting
157
28
92
130
170
90
240
163
222
135
217
409
274
1254
152
195
207
1410
247
220
Clinical
Clinical
Clinical
Clinical
Clinical
Clinical
Clinical
Clinical
Clinical
Clinical
Clinical
Clinical
Clinical
Clinical
Clinical
Clinical
Clinical
Screening
Screening
Clinical
OC + GS <7 + <0.5
<0.5 cm3
<1 cm3
<0.5 cm3
OC + GS <7 + <0.5
GS <7 + <0.5 cm3
OC + GS <7 + <0.5
GS <7 + <0.5 cm3
<0.5 cm3
<0.5 cm3
OC + GS <7 + <0.5
OC + GS <7 + <0.5
OC + GS <7 + <0.5
GS <7 + <0.5 cm3
OC + GS <7 + <0.5
<0.5 cm3
GS <7 + <0.5 cm3
OC + GS <7 + <0.5
OC + GS <7 + <0.5
OC + GS <7 + <0.5
Clinical
Screening
OC + GS <7 + <0.5 cm3
OC + GS <7 + <0.5 cm3
Clinical
Clinical
Clinical
Clinical
Clinical
Clinical
Screening
Clinical
Clinical
GS <7 + <0.5 cm3
OC + GS <7 + <0.5 cm3
OC + GS <7 + <0.5 cm3
PSA <10 + OC + GS <7 + <0.5 cm3
OC + GS <7 + <0.5 cm3
OC + GS <7 + <0.5 cm3
OC + GS <7 + <0.5 cm3
GS <7 + <0.5 cm3
OC + GS <7 + <0.5 cm3
Nakanishi et al, 2007 [39]
Postma et al, 2007 [40]
258
550
T1c
T1c–T2
T1c–T2
Overall
Overall
T1c
T1c
T1c
T1c
Overall
Overall
T1c–T2a
bGS 6
Overall
T1c
Overall
Overall
Overall
T1c–T2a
T1c–T2a, bGS 6,
PSA <20
1 positive core
Overall
Van Oort et al, 2009 [41]
Capitanio et al, 2008 [42]
Chun et al, 2008 [43]
Sengupta et al, 2008 [44]
Dong et al, 2008 [3]
Lee et al, 2010 [45]
Loeb et al, 2010 [46]
Raventós et al, 2010 [47]
Helfand et al, 2010 [48]
502
1358
1132
6496
296
746
1073
280
629
Overall
Overall
Overall
Overall
T1c–T2a, bGS 6
bGS 6
Overall
Overall
Overall
Definition of
Ins-PCa
cm3
cm3
cm3
cm3
cm3
cm3
cm3
cm3
cm3
cm3
Percent of
Ins-PCa, %
26
12
16
2.3
10
20
29
31
10
25
24.4
20
28
5.8
25.7
14.4
21.7
6.6
49
41
51.6
Round 1: 32%
Round 2: 42%
12.8
5
5.7
5.5
27.4
25.3
6
11.8
6
Ins-PCa = insignificant prostate cancer; OC = organ confined; GS = Gleason score; bGS = biopsy Gleason score; PSA = prostate-specific antigen.
3.2.2.
Autopsy series
Autopsy series are interesting, because they provide insight
into the true prevalence of PCa. Unfortunately, few of them
have investigated the frequency of low-grade and lowvolume PCa that would be pathologically described as InsPCa in living patients. This rate in a small autopsy series of
48 cases was estimated to be 10.4% [49]. The term Ins-PCa
should be strictly used in living patients, because any cancer
found at the autopsy is clinically insignificant by definition.
In a subsequent series of 164 autopsy specimens, 25
incidences of PCa (15.4%) were found, including 9 low-grade
and low-volume PCa instances that would be pathologically
described as Ins-PCa in living patients (36% of PCa cases) [50].
Stamatiou et al. have previously found that most of the
impalpable cancers found in autopsy studies were potentially insignificant tumours [51]. They reported 70.7% lowvolume (<1 cm3) PCa in a series of 40 PCa cases diagnosed
from 212 autopsy specimens. In another autopsy series from
57 men without clinically suspected PCa, the prostates were
completely embedded and sectioned in 3-mm steps using the
cone method. Interestingly, tumour volumes were also
measured with computer-assisted planimetry. Eleven cancers were insignificant according to the criteria (no Gleason 4,
volume <0.5 c3, diploid), representing 59.7% of all cancers
detected and 19.3% of all prostates examined [52]. Appar-
ently, there is a wide variation in the proportion of lowvolume PCa among the few available autopsy studies.
Konety et al. have examined changes in the prevalence of
autopsy-detected PCa over time in an American population
[53]. They found a 3-fold decrease in the prevalence of
autopsy-detected latent PCa during the 1991–2001 period as
compared to the earlier, pre-PSA 1955–1960 period. This
decrease in prevalence was associated with a downward
stage and grade migration of the latent cancers. The adoption
of early detection of PCa in a population even affects the grade
and stage distribution of the latent, autopsy-detected PCa
instances. It is therefore likely that the proportion of Ins-PCa
among the latent cancers would increase in PSA-tested
populations. The frequency of small latent carcinomas has
been estimated at about 12% in the 1970 s and did not vary
with age [54]. Rates for larger latent carcinomas increased
sharply with age and showed an area-to-area variation
resembling that of clinical carcinoma of prostate.
3.3.
Pretreatment tools for predicting insignificant prostate
cancer
3.3.1.
Epstein criteria
In 1994, Epstein et al. published pretreatment criteria
significantly predictive of Ins-PCa identified in RP specimens
295
EUROPEAN UROLOGY 60 (2011) 291–303
Table 2 – Percent of insignificant prostate cancer (Ins-PCa) in radical prostatectomy specimens in patients with suspected Ins-PCa according
to the preoperative Epstein criteria
No. of patients
Preoperative Epstein criteria
–
Percent of Ins-PCa at RP
Percent of Ins-PCa at RP
Percent of Ins-PCa at RP
PSA density 0.1–0.15
<3 mm of cancer in one core
Updated Epstein criteria*
73
–
–
–
–
–
Epstein et al, 1994 [1]
Carter et al, 1997 [28]
Bastian et al, 2004 [55]
157
64
237
PSA density <0.1
No grade 4 or 5
<3 positives cores
<50% cancer per core
73
–
–
Jeldres et al, 2008 [56]
Lee et al, 2010 [45]
Lee et al, 2010 [57]
366
136
131
–
–
–
–
75
84**
(91.6***)
76**
37 (58**)
69.5**
Ins-PCa = insignificant prostate cancer; RP = radial prostatectomy; PSA = prostate-specific antigen.
Updated Epstein criteria: PSA density <0.15 ng/ml per gram, Gleason score 6, fewer than three positive cores, <50% of cancer involvement in any core.
Gleason score 6 and organ-confined disease in RP specimen.
***
Organ-confined disease in RP specimen.
*
**
using PSA and needle biopsy findings [1]: no Gleason pattern
4 or 5, less than three core samples involved of a sextant
biopsy, and no core sample >50% involved. The best model
for predicting Ins-PCa in RP specimens was obtained by the
two following preoperative criteria combinations: (1) PSA
density <0.1 ng/ml per gram, no Gleason pattern 4 or 5, less
than three positives cores, and <50% of cancer involvement
per core; and (2) PSA density between 0.1 and 0.15 ng/ml per
gram and <3 mm of cancer in one core (Table 2). The positive
and negative predictive values of this model were 95% and
66%, respectively. These two current preoperative definitions
of Ins-PCa have been extensively evaluated in the literature. It
is noteworthy to emphasise that analyses from Epstein et al.
were based on an index tumour volume <0.2 cm3 (associated
with the absence of Gleason pattern >3 and of non–organconfined disease) as the threshold for defining Ins-PCa. The
threshold of 0.5 cm3 characterised a ‘‘minimal’’ PCa. The
predictive value of the preoperative Epstein criteria did not
vary, as the model also correctly identified 73% of these
minimal PCa instances. However, these results emphasised
that the definition of Ins-PCa at diagnosis on biopsies was
slightly different from the criteria used to define Ins-PCa at
final pathology in RP specimens.
In 2004, an update of the preoperative Epstein criteria
was reported in a contemporary analysis of T1c PCa [55].
The updated criteria consist of PSA density 0.15 ng/ml per
gram, Gleason score 6, fewer than three positive cores, and
<50% of cancer involvement in any core. To date, these are
the most widely used preoperative criteria for predicting
Ins-PCa, and more recent attempts to predict Ins-PCa after
positive biopsies and before surgery are based on this
updated definition [45,56,57].
The Epstein criteria are not perfect and misclassify
about 30% of patients who would have unfavourable
pathologic features in RP specimen. This risk ranges from
16% to 42% in selected series (Table 2). In the study by Lee
et al, only 37% of men who fulfilled the preoperative
Epstein biopsy criteria had Ins-PCa as defined by the
current definition of Ins-PCa in RP specimens [45].
Nevertheless, the authors emphasised that the preoperative contemporary Epstein criteria were highly predictive
for favourable disease (58% of organ-confined and Gleason
6 PCa) and cure by RP. The European study by Jeldres et al.
demonstrated a rate of organ-confined disease of 91.7%
when the updated Epstein criteria were used. Conversely,
the rate of Gleason 7–10 cancers was substantially higher
in this study cohort compared with the rate found in the
reference cohort from Bastian et al. (24% vs 9%), which
yielded a substantially lower overall accuracy (76%) than
the one reported by Bastian et al. (84%). These discrepancies can be explained by several factors, such as grade
misclassification, number of cores obtained at biopsy, or
ethnical considerations.
However, it is noteworthy that predicting favourable
disease at RP should not be the main end point of interest,
because most definitions of Ins-PCa will result in low-risk
disease at surgery, and the main aim of insignificance
definition is to avoid surgery or other treatment modalities.
3.3.2.
Other predictive models
Several authors have put forward alternative preoperative
models to better predict Ins-PCa [23–27,29,34,36,47,58].
Ochiai et al. found that the combination of a tumour length
<2 mm, a Gleason score 3 + 3, and a prostate volume
>50 ml best predicted Ins-PCa [36]. Overall, the sensitivity
and the specificity of these predictive models ranged from
23% to 77% and from 75% to 98%, respectively. These
findings underline the need for developing more accurate
models to identify Ins-PCa.
More stringent biopsy criteria have also been tested in
the literature, especially the ‘‘minute’’ or ‘‘microfocal’’ PCa
that was defined by a single neoplastic microfocus at
biopsies involving 5% or 1 mm in one core. Unfortunately, the diagnosis of ‘‘minute’’ PCa did not completely
eliminate the risk of misclassification of a significant PCa,
and the smallest focus of cancer on needle biopsy is not a
guarantee of clinically insignificant PCa. In their systematic
review and meta-analysis, Harnden et al. observed that
between 33% and 84% of patients with minute PCa on
biopsies had at least one adverse pathologic feature in the
RP specimen and were considered to have a significant and
potentially progressive PCa [59].
296
EUROPEAN UROLOGY 60 (2011) 291–303
Table 3 – Predictive accuracy of published nomograms for the prediction of insignificant prostate cancer in the literature
No. of patients
Variables
–
Setting
–
Kattan et al, 2003 [7]
409
Clinical
Steyerberg et al, 2007 [6]
490
Screening
Nakanishi et al, 2007 [39]
Roemeling et al, 2007 [5]
Dong et al, 2008 [3]
258
825
296
Clinical
Screening
Clinical
Chun et al, 2008 [43]
1132
Clinical
No cores
–
6
6
10–13*
6
5–34
Median:11
6–10
Predictive accuracy
Kattan
Steyerberg
Nakanishi
Chun
Base: PSA, clinical stage,
bGS
Medium: + volume
and % positive cores
Full: + tumour length
Base: 0.64
Medium: 0.74
Full: 0.79
Base: 0.61
Medium: 0.72
Full: 0.76
–
–
Full: 0.78
Recalibration
of the Kattan
nomogram
Age, PSA density,
tumour length
PSA, bGS,
tumour length,
% positive cores
–
–
–
–
–
–
0.73
–
–
–
–
–
–
0.90
0.81
–
65%**
0.77
–
PSA = prostate-specific antigen; bGS = biopsy Gleason score.
Only one positive core in all patients included.
**
Calculated probability of indolent cancer.
*
3.3.3.
Nomograms based on clinicopathologic variables
Several authors have generated preoperative predictive
models to better identify potentially insignificant PCa. The
main nomograms that have been reported and validated in
predicting Ins-PCa are listed in Table 3.
The first nomogram for the prediction of Ins-PCa was
reported by Kattan et al. [7]. The study cohort included
patients who underwent RP for clinical T1c–T2a PCa. The
authors developed three different nomograms (base,
medium, and full models) by integrating additional biopsy
features. The full model predicted the presence of an InsPCa with an area under the curve (AUC) of 0.79. This good
discriminatory ability has been externally validated in two
clinical settings and one European screening [3,6,43]. A
recalibration of this reference nomogram was performed by
Steyerberg for a screening setting (European Randomized
Study of Screening for Prostate Cancer [ERSPC]), and then
validated by Roemeling et al. [5,6]. These nomograms are
slightly superior to the original Epstein criteria in their
ability to predict Ins-PCa [5,6]. Recently, Chun et al.
proposed a new nomogram based on a single-centre
experience [43]. In this cohort of 1132 men, this model
surpassed the Kattan nomogram for the prediction of InsPCa (AUC: 0.90 vs 0.81). This nomogram was based on a
European study population and awaits external validation.
Except for the nomogram of Chun et al, which reported a
high accuracy of 90%, previous nomograms are only slightly
superior to the original Epstein criteria in their ability to
predict Ins-PCa. Moreover, despite the good discrimination,
a significant proportion of patients (63%) who were
considered by the nomogram of Chun et al. to have a high
probability of Ins-PCa eventually harboured more aggressive PCa in the RP specimens (Gleason score 7–10, non–
organ-confined disease). This study also provided an
external validation of the Kattan nomogram. However,
45% of patients who were considered to have Ins-PCa using
the Kattan nomogram had an ‘‘aggressive’’ PCa in the final
pathologic assessment. Thus, the study showed that
regardless of which nomogram is used to predict Ins-PCa,
a significant number of patients remain understaged.
3.3.4.
Impact of various factors on predictive models
3.3.4.1. Study population and prostate-specific antigen screening.
Differences in study population are likely the predominant
factor responsible for variability in predictive values among
nomograms [4,6]. Some of the variations in the prediction of
Ins-PCa may be attributable to patient selection. For
example, the nomogram developed by Nakanishi et al.
was restrictive and incorporated only those patients with a
single positive core at biopsy [39]. Stage and grade
distribution at biopsy as well as the rate of Ins-PCa in RP
specimens observed in European men differs from their
North American counterparts. It has been shown that the
Epstein criteria defined from an American cohort perform
less well in European men [60].
PSA screening has resulted in an increase in low-risk PCa
at diagnosis. Several authors found an increasing trend of
low-risk and insignificant PCa in the past decades
[33,61,62]. Earlier studies evaluating the prediction of
Ins-PCa are characterised by different clinical profiles of PCa
compared with those noted to date. PCa diagnosed in a
screening setting has a substantially higher likelihood of
being indolent than those identified in a clinical setting
(Tables 1 and 3). As emphasised by the ERSPC study data, a
calibration factor may correct differences among patients
from different settings or regions that are not captured by
the characteristics in the reference model [5,6].
3.3.4.2. Biopsy core number. One of the reasons for the lack of
correlation between preoperative potentially and definitive
Ins-PCa may be sampling error or bias when biopsy findings
are not representative of the overall tumour burden. This
consideration argues for the need for more extensive
sampling to exclude undersampled, significant cancer.
EUROPEAN UROLOGY 60 (2011) 291–303
Studies have demonstrated that the increase in biopsy core
number from sextant biopsies to extended schemes,
including additional far lateral biopsies (10–12 cores),
improved the PCa detection rate but does not detect more
Ins-PCa [63]. The majority of PCa detected in these lateral
cores were clinically significant. The percent of positive
cores has been shown to predict extraprostatic extension,
recurrence, and death after RP. Tumour volume as assessed
by extended biopsy does predict outcome [64]. Saturation
biopsies have been evaluated as a staging tool to improve
the characterisation of low-volume and well-differentiated
PCa, but whether they improve prediction of tumour
insignificance remains open to debate. It is also noteworthy
that insufficient prostate sampling increases the chance of
undergrading the tumour, leading to a false increase in InsPCa prevalence. Grossklaus et al. suggested in a small series
of PCa patients that the prediction of Ins-PCa was not
improved by an extended biopsy scheme versus sextant
biopsies [30].
Epstein et al. have emphasised the benefit of saturation
biopsies in the measurement of tumour extent and grade
and thus in the evaluation of Ins-PCa [65]. Using a
saturation biopsy scheme, the false-positive rate for the
diagnosis of Ins-PCa only ranged from 8% to 11.5% according
to the algorithm chosen. However, this was an ex vivo study,
and transfer to clinical practice might have limitations. An
autopsy series from 164 prostates found that taking
additional cores in cases of microfocal PCa identified on
sextant biopsies helped differentiate significant from
insignificant PCa [50]. However, results of autopsy series
based on the true prevalence of PCa suggested that 40% of
PCa would stay undetected regardless of the number of
locations from which biopsies were taken. In men with a
diagnosis of microfocal and potentially insignificant PCa on
primary biopsy, authors found that the reevaluation by an
extended 32-core biopsy scheme was helpful in identifying
70% of men who had significant tumours based on the
repeat saturation biopsy findings [66]. Cancers originating
in the transition zone are more likely to behave in an
indolent fashion and therefore could more easily be defined
as insignificant. Thus, extended biopsy schemes, including
cores in the transition zone, might increase the prevalence
of diagnosed Ins-PCa. However, to date, no published series
has confirmed this statement.
3.4.
Impact of the dichotomy of significant vs insignificant
prostate cancer in clinical practice
3.4.1.
Diagnosis of potentially insignificant prostate cancer before
definitive therapy
Stage and grade migration of PCa increases the proportion of
men undergoing overtreatment, which can place them at
unnecessary risk for complications. In the ERSPC, PSA
screening has been shown to reduce specific mortality by
20%, and it was estimated that 48 men needed to be treated
to prevent one death [67]. The number needed to treat
(NNT) has recently been estimated at 29 and 18 by
extrapolating the follow-up to 10 and 12 yr, respectively
[68]. In the Göteborg randomised, population-based PCa
297
screening trial, authors have shown that PCa mortality was
reduced almost by half over 14 yr and that the NNT was at
least as high as in breast cancer screening programmes [69].
The ability to identify Ins-PCa prior to definitive therapy
and patients harbouring tumours that pose no risk to life
and health is critically needed. Although clinical and
pathologic predictors of Ins-PCa can be identified, it remains
to be established whether such patients can be safely
managed conservatively. Despite the imperfection of
predictive tools, the preoperative definition of a potentially
insignificant PCa provides a starting point in identifying
patients eligible for active surveillance or organ-sparing
therapies. Thus, it remains difficult to select the optimal
active surveillance candidate, and cancer characteristics are
only part of the story, which must also factor in patients’ age
and life expectancy irrespective of PCa.
Although the Epstein definition of Ins-PCa is the most
widely used tool in defining potentially insignificant PCa,
this definition has not been thoroughly incorporated as an
active surveillance selection criterion in most active
surveillance protocols. Only the active surveillance programme from the Johns Hopkins Hospital included it as an
entry criterion. Midterm follow-up from this institution has
recently been reported [70]. Overall, 102 (35%) of 290 men
developed unfavourable findings on surveillance biopsy at
last follow-up and were recommended to undergo treatment (median follow-up: 3 yr). Of men who underwent
treatment, 45 (44%) elected to undergo RP. The authors
emphasised that most events with more unfavourable
findings on repeat biopsy after active surveillance occurred
1 to 2 yr after diagnosis, suggesting undersampling of more
aggressive tumours rather than progression of indolent
tumours [71]. Even with more unfavourable findings on
repeat biopsy, 27% of PCa instances were Ins-PCa at RP.
However, one-third of these PCa instances were non–organconfined disease with adverse pathology. Patients enrolled
in active surveillance programmes should be informed that
they may harbour more aggressive disease, with a risk of
non–organ-confined PCa [72].
3.4.2.
The risk of clinical progression in men with insignificant
prostate cancer in radical prostatectomy specimens
Patients treated by surgery for Ins-PCa pathologically
defined in an RP specimen should be at zero risk of
systemic progression or death from cancer in the postoperative course. If this were true, they might require less
intense postoperative surveillance. However, the oncologic
follow-up of men with pathologically confirmed Ins-PCa
after RP has not been thoroughly investigated [41,42,44]
(Table 4). One of the explanations of this shortcoming in the
current literature may be the fact that the stringency of
criteria results in small cohorts of patients. Yet this analysis
is critically important before considering active surveillance
in patients with potentially insignificant PCa at diagnosis.
The absence of a strong difference between oncologic
outcomes of clinical PCa and Ins-PCa or poor rates of PSA
failure after RP in Ins-PCa patients would cast a shadow of
doubt on the validity of the clinical definition of insignificant
PCa. In one of the first reports of Epstein et al, the authors
298
EUROPEAN UROLOGY 60 (2011) 291–303
Table 4 – Oncologic outcomes after radical prostatectomy in patients with pathologically confirmed insignificant prostate cancer
Postma et al, 2007 [40]
Sengupta et al, 2008 [44]
Capitanio et al, 2008 [42]
Van Oort et al, 2009 [41]
No. of
patients
Percent of Ins-PCa
at RP, % (n)
Follow-up,
yr
5-yr RFS, %
Rate of metastatic disease
during follow-up, %
550
6496
1358
502
33 (182)
5.5 (354)
5 (69)
12.8 (64)
5.6
9.2
3
3.3
94
87
100
90
0
0.3
0
0
Ins-PCa = insignificant prostate cancer; RP = radical prostatectomy; RFS = recurrence-free survival.
reported that no patients with a tumour volume <0.5 cm3
demonstrated progression following RP [10].
In line with this finding, from a series of 1358 PCa
patients who underwent RP, Capitanio et al. found Ins-PCa
in only 65 patients. None of them developed PSA failure
after a relatively short follow-up of 3 yr [42]. Analysis of PSA
follow-up in a larger cohort of Ins-PCa patients (354 cases)
by Sengupta et al. [44] revealed that patients with Ins-PCa
have a 13% risk of PSA failure at 10 yr after surgery. The risks
of metastatic progression (0.3%) or specific death (0%) after
RP were negligible over a follow-up approaching 10 yr.
Although these low-risk and low-volume PCa patients were
at low risk for progression, this risk was comparable to that
faced by men with low-risk PCa as defined by the d’Amico
criteria. In a smaller cohort of Ins-PCa patients, van Oort at
al also reported a 10% 5-yr risk of BCR [41]. Pathologic
differences in the assessment of RP specimens may explain
the discrepancies between studies. Sengupta et al. used
limited sampling with a not-otherwise-specified technique
compared to the whole-mounted 3-mm step sections that
Capitanio et al. used. Their calculations of tumour volume
also differed and increased the importance of technical
considerations when assessing the insignificance of PCa.
These discrepancies between studies emphasise the need
for future studies addressing this important topic and the
fact that the natural history of pathologically confirmed InsPCa may require further assessment to optimise their
management.
To date, the current classification of significant and
insignificant PCa does not seem to perfectly predict the
biologic behaviour of cancer after definitive treatment, and
the prognostic value of tumour volume as a key predictor of
outcome remains debated in the literature [73]. Thus, there
is a need to find more precise and replicable tools to better
predict the insignificance of these tumours, because
pathologic assessment will always have a certain degree
of differences around the world and because adequate
accuracy in predicting Ins-PCa cannot be achieved by
relying on basic predictors.
One series that included men treated by radiation
therapy compared the biochemical control among patients
at low risk for progression to patients with potentially
insignificant PCa as defined by the pretreatment Epstein
criteria [74]. No significant differences in terms of BCR-free
survival were found between these two groups in a 7-yr
follow-up (89% vs 84%). However, only 42 patients with
Ins-PCa were included. Altogether, these findings do not
argue for less close surveillance in treated Ins-PCa
patients.
3.5.
Improving the prediction of truly insignificant prostate
cancer
The lack of perfect performance in models predictive for InsPCa justifies the assessment of novel tools. There is an
ongoing need for identifying truly biologically significant
PCa that cannot be accurately predicted by the currently
available tools. The aim of such extended diagnostic
strategies in initial management would be to reduce the
risk of misclassification of a clinically significant disease.
3.5.1.
Urinary prostate cancer antigen 3 score
Some studies have evaluated the correlation between
prostate cancer antigen 3 (PCA3) score and RP findings
[75–79]. A significant association between PCA3 score and
tumour volume has also been emphasised [75,76,78,79].
Whitman et al. also found an association between PCA3 and
extraprostatic extension, whereas Nakanishi et al. demonstrated a significant link between PCA3 and high Gleason
score. Hessels et al. did not confirm the latter findings in
their recent study [77], but their patient cohort included
few men with favourable features: 40% had pT3 disease, and
only 10 cancers had a volume <0.5 cm3. In a160-case series,
Auprich et al. confirmed PCA3 score as a valuable predictor
of pathologically confirmed Ins-PCa. PCA3 scores were
significantly lower in Ins-PCa, and the addition of the PCA3
score in multivariable models increased the accuracy of InsPCa prediction [78].
Recently, another prospective study assessed the impact
of the PCA3 assay in a cohort of low-risk PCa patients [79].
The findings suggested that the PCA3 score was strongly
indicative of tumour volume and accordingly a determinant
for significance of PCa according to the current Epstein
definition. The risk of having a significant PCa was increased
3-fold in men with a PCA3 score 25 compared with men
with a PCA3 score <25.
3.5.2.
Magnetic resonance imaging
Although magnetic resonance imaging (MRI) has become an
increasing commonly used imaging tool for characterisation of low-volume PCa, its predictive value has not been
thoroughly assessed among PCa patients eligible for active
surveillance [80]. T2-weighted standard images have a low
specificity, especially for detecting PCa in the transition
zone. In addition, the use of routine T2-weighted images
may underestimate the detection of low-risk or low-volume
PCa [81].
Other MRI parameters may have greater prognostic
importance than standard T2-weighted sequences, howev-
EUROPEAN UROLOGY 60 (2011) 291–303
er. The diagnostic performance of MRI in PCa detection is
improved by the addition of an apparent diffusion coefficient map to T2-weighted imaging [82]. Diffusion-weighted
MRI has been shown to discriminate cancer tissue from
benign peripheral tissue as well as low-risk PCa from highor intermediate-risk PCa [83]. Recent data also suggest that
MRI combined with magnetic resonance spectroscopic
imaging (MRSI) could be relevant for assessment of lowrisk patients [84].
Futures studies should also investigate whether 3.0-T
MRI provides greater predictive value and help to better
assign patients to active surveillance. The 3.0-T MRI
improves spectral resolutions of prostate imaging on T2weighted sequences. One potential advantage is adequate
imaging without endorectal coil. However, his additional
value for cancer staging has to be proven. Recent
recommendations from a European consensus meeting
concluded that T2-weighted, dynamic, contrast-enhanced,
and diffusion-weighted MRI were the key sequences
incorporated into the minimum requirements, especially
concerning the exclusion of clinically significant disease as
defined by a lesion size >0.5 cm3 (approximately 10 mm) in
the peripheral zone [85]. Shukla-Dave et al. found that new
models that combined clinical and biopsy data with MRI
and MRSI findings performed better than the clinical
models for predicting the probability of Ins-PCa in RP
specimens [38,86]. The reported accuracy of this combined
model as measured by the AUC improved to 0.85 compared
with 0.73 for the Kattan nomogram.
3.5.3.
Prostate-specific antigen velocity
In a large retrospective study from 1073 RP specimens, Loeb
et al. suggested PSA velocity as a useful additional tool in
predicting Ins-PCa. Patients with a preoperative PSA
velocity >0.4 ng/ml per year were 50% less likely to have
Ins-PCa in RP specimens (10% vs 5%) [46]. Sengupta et al. also
reported that the PSA doubling time was an independent
predictor of Ins-PCa in a multivariate model taking into
account age, biopsy Gleason score, and clinical stage [44].
Unfortunately, findings from the ERSPC study failed to
identify PSA velocity as an independent predictor of clinically
significant PCa. In this screening trial, the use of PSA velocity
led to appreciable numbers of missed indolent but also
significant PCa [87,88]. In the active surveillance Johns
Hopkins cohort, PSA kinetics during follow-up did not
reliably predict biopsy progression in 290 men who were
included in the active surveillance programme. In this study,
PSA velocity was an unreliable trigger for differed treatment
and a poor indicator of clinically significant PCa [70].
3.5.4.
Genetic variants
The analysis of PCa risk alleles has been reported to be
potentially interesting in identifying Ins-PCa [89,90].
Helfand et al. suggested that men with significant PCa
had a greater frequency of any of five risk alleles studied (at
chromosomes 8q24 and 17) than patients with Ins-PCa
[89]. However, no single risk allele was able to distinguish
an Ins-PCa instance, and only a cumulative effect was
observed.
299
New research methods are also emerging, and highthroughput technologies will facilitate high-dimensional
biomarker discovery. Future approaches will probably integrate proteomic, transcriptomic, and multiplex approaches to
detect novel biomarkers and aim to identify combinations of
multiple biomarkers to optimise the preoperative characterisation of PCa and better differentiate indolent from aggressive
cancers.
3.6.
Is the current definition of insignificant prostate cancer
still timely in the era of active surveillance?
To date, there is a rationale for the debate about a more
liberal definition of insignificant disease. In a large multicentre analysis of 24 414 patients, Stephenson et al. found
that only 0.003% of men with organ-confined Gleason
score–6 disease died from PCa within 15 yr of RP [91]. Other
authors suggested that tumour volume did not independently influence the oncologic outcome in Gleason score–6
PCa [92]. It also should be noted that the proportion of men
with pathologically confirmed Ins-PCa is relatively small
and that the employment of the current strict definition of
insignificant PCa will not critically decrease the rate of
overtreatment. It is quite possible that using 0.5-cm3 cancer
volume as a cut-off for clinically significant PCa is too small,
and it is important to note that this cut-off is based on a
single study [9].
Recently, Wolters et al. aimed to reassess the tumour
volume threshold [93]. Using lifetime risk rates for the
ERSPC population-based screened cohort, they found that
the index tumour volume threshold of 0.5 ml reported by
Stamey could be confirmed with a total tumour volume
threshold of 0.7 ml. However, as grade and stage were the
most important prognostic factors for PCa aggressiveness,
they demonstrated that clinically insignificant PCa may
include index tumours with volumes up to at least 1.3 ml
(and a total tumour volume of 2.5 ml) for patients with lowgrade, low-stage disease.
The criteria used in most active surveillance protocols
are currently less stringent than those used to define an InsPCa, and most patients included in active surveillance
protocols who were reclassified as higher risk over time
remained curable by delayed therapy. Nevertheless, a nonnegligible proportion of PCa continues to be classified as
insignificant, where clinically significant and potentially
life-threatening disease may be found at RP. In active
surveillance protocols, studies comparing entry criteria
have emphasised the risk of misclassification and the
limitations of currently available active surveillance criteria
[94]. Recent studies of repeat biopsies in men under active
surveillance have also emphasised the risk of encountering
upgraded and/or upstaged disease [95]. Long-term followup of active surveillance series might modify the definition
of insignificant PCa with the identification of prognostic
factors of disease progression.
As mentioned, most published active surveillance series
have used entry criteria different from the current
definition of insignificant PCa that were largely based on
centre experiences with no hard data. The most current
300
EUROPEAN UROLOGY 60 (2011) 291–303
active surveillance criteria are a Gleason score 6, PSA 10
ng/ml, and clinical stage T1–T2a disease, with additional
biologic or biopsy criteria depending on institutional
preferences. Other characteristics may include multiple
pathologic biopsy parameters, such as <33% of biopsy cores,
fewer than two positive cores, and/or <50% of cancer
involvement [96,97]. This consideration argues for a more
liberal definition of insignificant PCa. Only the Johns Hopkins
active surveillance cohort required fulfilment of the Epstein
criteria for eligibility, but the use of these criteria has not
been validated in other active surveillance programmes,
and their utility for this purpose may be questioned.
4.
Conclusions
Supervision: Epstein, Montironi, Carroll, Wirth, Grimm, Bjartell, Montorsi,
Freedland, Erbersdobler, van der Kwast.
Other (specify): None.
Financial disclosures: I certify that all conflicts of interest, including
specific financial interests and relationships and affiliations relevant to the
subject matter or materials discussed in the manuscript (eg, employment/
affiliation, grants or funding, consultancies, honoraria, stock ownership or
options, expert testimony, royalties, or patents filed, received, or pending),
are the following: None.
Funding/Support and role of the sponsor: None.
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Author contributions: Guillaume Ploussard had full access to all the data in
the study and takes responsibility for the integrity of the data and the
accuracy of the data analysis.
Study concept and design: Bjartell, Montorsi.
Acquisition of data: Ploussard.
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Administrative, technical, or material support: None.
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