R EVI E W A R T IC L E
BJUI
‘Insignificant’ prostate cancer on
prostatectomy and cystoprostatectomy:
variation on a theme ‘low-volume/
low-grade’ prostate cancer?
BJU INTERNATIONAL
Kiril Trpkov*, Asli Yilmaz*, Tarek A. Bismar*,† and
Rodolfo Montironi‡
*Department of Pathology and Laboratory Medicine, Calgary Laboratory Services and
†
Department of Oncology, University of Calgary, Calgary, Alberta, Canada, and ‡Pathological
Anatomy, Polytechnic University of the Marche Region, School of Medicine, United
Hospitals, Ancona, Italy
Accepted for publication 9 March 2010
Although ‘insignificant’ prostate cancer has been examined separately in radical prostatectomy
(RP) and radical cystoprostatectomy (RCP) studies, it is not entirely clear whether cancers
designated as ‘insignificant’ on RP and RCP represent the same, similar or different forms of
prostate cancer. Insignificant prostate cancer has been traditionally defined based on the
pathological findings in the whole prostate gland. In addition to the pathological determinants
of ‘insignificant’ prostate cancer, it is also important to account for the biological and the
clinical context of the disease, as well as patient age and health status to designate a prostate
cancer ‘insignificant’. This review examines and compares prostate cancers described as
‘insignificant’ on RP and RCP. We conclude that in most cases these low-volume/low-grade
prostate cancers represent an early stage and clinically ‘silent’ disease, which are only detected
in different clinical settings.
KEYWORDS insignificant prostate cancer, indolent prostate cancer, incidental prostate cancer, minimal
prostate cancer, prostatectomy, cystoprostatectomy
INTRODUCTION The improved public awareness and widespread screening for PSA in the last couple of decades,
in a large part because men actively seek medical evaluations and PSA testing, have contributed
to the earlier detection of prostate cancer during the natural history of the disease. Therefore,
prostate cancer encountered in clinical practice based on PSA screening has undergone stage
migration, resulting in earlier stage disease at diagnosis and surgery, with increasing detection
of smaller tumour volumes on biopsy and radical prostatectomy (RP) [1,2]. In addition to PSA
screening, extended biopsy schemes were adopted in many centres during the last decade as a
standard of care, which has increased the prostate cancer detection rates by ≈30% compared
with sextant biopsy schemes [3,4]. Although the most recent trend for smaller tumour volume
detection on RP was attributed to extended biopsy templates in several studies [4–7], others
have found no difference in tumour volume or increased incidence of low-volume cancer
(<0.5 cm3) on extended biopsy compared with sextant biopsy schemes [8]. The changes in
prostate cancer as a primarily screen-detected disease constantly reinvigorate the controversies
of over-diagnosis and over-treatment of a subset of potentially indolent prostate cancers,
which are incidentally diagnosed on needle biopsy [9,10]. A proportion of these slowly
progressing cancers represent low-grade, organ-limited disease, which may not require
immediate curative treatment and, in some instances, the treatment can be delayed indefinitely,
through regular clinical monitoring using active surveillance.
A separate issue is the clinical significance
of the incidentally detected prostate
cancers in patients undergoing radical
cystoprostatectomy (RCP), primarily because
of bladder malignancy. Indeed, many of the
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incidental prostate cancers detected on RCP
reflect potentially insignificant and clinically
indolent or ‘silent’ disease, not apparent
before surgery. These unsuspected prostate
cancers on RCP are probably similar to the
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‘INSIGNIFICANT’ PROSTATE CANCER
autopsy detected cancers, which are in the
overwhelming majority also clinically silent
during life and are also more frequent in older
men. The aim of the present review is to
reassess and compare the prostate cancers
detected on RP and RCP that are labelled
‘insignificant’.
WHAT IS AN ‘INSIGNIFICANT’ PROSTATE
CANCER AND WHY AN ACCEPTABLE
DEFINITION IS NEEDED?
Unfortunately, there is no universally
accepted definition of ‘insignificant’ prostate
cancer because of the different perception of
the disease significance from a pathological,
biological, clinical and patient age
perspective. The ‘insignificance’ of the disease
is also relative to the social and public
healthcare context, because the diagnosis of
cancer conveys immediate significance to the
patient, the family and the healthcare system
in terms of required resources. The term
clinically or biologically ‘insignificant cancer’
indicates a low-volume, low-grade tumour
with somewhat varying definitions used in
published studies. In theory, every tumour
starts with a few cells that gradually grow
2 that these patients can be identified with
reasonable accuracy
3 that delayed intervention does not appear
to put those patients who re-classify as
higher risk over time at significant risk
4 that the psychological burden of
surveillance is acceptable.
The definition of ‘insignificant’ prostate
cancer generally implies a disease that is
clinically or biologically insignificant, but the
definition has somewhat varied and evolved
over time. The most commonly used
pathological parameters to define
‘insignificant’ cancer include:
• tumour volume of <0.5 cm3
• Gleason score of ≤6, with absence of
Gleason grades 4 and 5
• cancer that is confined to the prostate (i.e.
negative for extraprostatic extension with no
seminal vesicle or lymph node involvement,
and usually negative margins).
In fact, the tumour volume threshold of
0.5 cm3 for insignificant prostate cancers
was based on the initial analysis by Stamey
et al. [13] who examined prostate glands
obtained from 139 consecutively sampled
RCP specimens and found that 55 (40%)
had incidental
(unsuspected)
prostate cancer.
‘ “insignificant cancer” indicates a low-volume,
Because
low-grade tumour with somewhat varying
epidemiological
data suggested that
definitions used in published studies’
the largest 8% of
into a larger tumour and all tumours are at
cancers were those that become clinically
some stage biologically ‘insignificant’ [11].
significant, the authors concluded that
Ultimately, if patients live long enough, every tumour volumes above the 92nd percentile,
tumour will grow and potentially become
ranging in size from 0.5 to 6.1 cm3 were
clinically ‘significant’. Klotz [12] has argued,
clinically significant and suggested that
based on the results of the recent long-term tumours measuring <0.5 cm3 are unlikely to
studies of conservative management, that:
reach a significant size within the life-span
of the individual and spread to the regional
1 widespread screening results in a diagnosis nodes [13]. Epstein et al. [14] in 1994
of prostate cancer in many patients with
examined the pathological tumour features
clinically insignificant disease
in 157 men with clinical stage T1c cancer
©
treated by RP. In the final pathology, they
established two groups of prostate cancers:
(i) insignificant (tumour volume <0.2 cm3,
organ-confined, Gleason score of <7) and (ii)
minimal (tumour volume 0.2–0.5 cm3,
organ-confined, Gleason score of <7). Later,
both categories were combined and the
absence of Gleason grades 4 and 5 and
extraprostatic spread were added to the
tumour volume threshold of 0.5 cm3, which
resulted in the generally accepted and
widely used pathological definition of
‘insignificant prostate cancer’ [15].
The pathological definition of prostate cancer
as clinically ‘insignificant’, if used in clinical
practice, has to take into account other
important variables, such as patient age. For
example, a potentially insignificant cancer
may be clinically significant for a healthy 50year-old man with long life expectancy, while
being insignificant for an 80-year-old man in
poor general health with confounding
comorbidities [16]. Because the pathological
definition of ‘insignificant’ prostate cancer
has not been formally validated, some have
argued that pathological definition of
‘insignificant’ cancer should be tested
clinically with data of actual patient followup to support the notion of long-term disease
insignificance [17]. In a recent series from the
Mayo Clinic, patients deemed by the authors
to have ‘insignificant’ cancers were at low risk
of systemic progression or death from cancer
over a 5–10-year period, which was
nevertheless comparable to the low-risk faced
by men with significant prostate cancer, and
no significant differences in outcome were
found [17]. The term ‘indolent’ prostate
cancer has been preferred to describe cancers
prospectively detected by nomograms, still
relying on the established pathological
criteria for cancer insignificance [18,19].
Some authors have also advocated trials
to establish an accurate definition of
‘insignificant’ prostate cancer, which would
allow validation of potential biological
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T R P K O V ET AL.
markers predictive of tumour progression
and investigation of possible preventive
interventions, such as dietary and lifestyle
changes, in preventing tumour progression
and delaying or eliminating the need for
curative intervention [20]. Other questions
that may be answered through trials are
whether the cure rates for patients who
progress and undergo delayed therapy with
curative intent is as good as the cure rate for
those who choose immediate treatment and
what are the psychological, economic, and
health-related quality of life consequences of
active surveillance [20]. Accurately defining
an ‘insignificant’ prostate cancer will
ultimately help in resolving the crucial clinical
challenge in balancing on one hand, the
appropriate curative treatments for earlierstage, but clinically significant lower grade
and stage cancers, and, on the other,
conservatively managing the truly biologically
insignificant cancers, which may not be
harmful in the short term.
Some methodological issues relating to
the pathological definition of insignificant
cancer in these types of studies are worth
considering. Tumor volume calculations in
some studies represent the total tumour
volume [18], while others used the volume of
the largest or dominant tumour [15,21],
which somewhat hampers the comparison
between studies. Tumor volume has also been
calculated using different, but largely
comparable, methods or formulas. In addition,
some studies provide only tumour volume
estimates as a percentage of gland
involvement, determined by visual inspection,
which was also shown to strongly correlated
with the actual tumour volume calculated by
grid-morphometric analysis [22].
‘INSIGNIFICANT’ PROSTATE CANCER
ON RCP
In a landmark study published in 1993,
Stamey et al. [13] detected 40% unsuspected
or incidental prostate cancers on RCP and this
study also established the tumour volume
threshold of 0.5 cm3
for insignificant
prostate cancers.
‘Prostate cancers detected on RCP are typically Prostate cancers
small, organ-confined, peripheral-zone cancers of detected on RCP are
typically small,
lower Gleason score’
organ-confined,
peripheral-zone
cancers of lower Gleason score. They do not
produce clinical symptoms and are usually
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not diagnosed on DRE or by laboratory tests
before surgery performed for bladder
malignancy. Preoperatively, 90% of patients
with available PSA data who underwent RCP,
had PSA values of ≤4 ng/mL [23]. There was
variable incidence of incidental prostate
cancer in the RCP specimens. Its clinical
significance also remains questionable,
because the outcome of the patients depends
almost exclusively on the prognosis of the
bladder tumours. The reported incidence of
unsuspected prostate cancer on RCP, as
shown in Table 1 [24–48] (modified from
Damiano et al. [49]), varies widely from 4%
[40], documented in an Oriental study
population from Taiwan, up to 60% [43], with
an overall weighted incidence of 29.3%. The
frequency of prostate cancers on RCP that
were considered ‘insignificant’ ranges from
30% [38] to 90% [33], although there are
differences between the studies regarding the
definition of ‘clinical significance’ of prostate
cancer. Based on the aggregate reported data,
only a third (32.8%) of the incidental prostate
cancers on RCP were considered ‘significant’,
while two-thirds (67.2%) were ‘insignificant’;
of note, the data of actual tumour volume
were not provided in many studies. This
variability may be also due to different study
populations, use of different criteria for
determining ‘significant’ cancer and the
variations in the pathology sampling method
relating to the slice thickness and complete vs
partial sampling of the specimens. In recent
study by Mazzucchelli et al. [48] one of the
largest and most detailed series of 248
completely sampled RCPs, there were 123
(49.6%) incidental prostate cancers of which
81.3% were clinically ‘insignificant’.
Terris et al. [50] reported a significant
difference in the preoperative PSA level
between patients who had incidental prostate
cancer on RCP: 3.4 ng/mL in patients with
incidental prostate cancer vs 0.4 ng/mL in
those without. This finding was supported by
Winkler et al. [43] who reported preoperative
PSA level of 3.1 ng/mL in patients with
incidental prostate cancer vs 1.1 ng/mL in
those without (P < 0.06), although a reliable
preoperative PSA level distinction between
patients with and without prostate cancers
was not documented in other studies
[35,38,39].
The great majority of patients with incidental
prostate cancers on RCP had no clinical
consequences because of their prostate
cancers and their prognosis was almost
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‘INSIGNIFICANT’ PROSTATE CANCER
TABLE 1 Incidental and significant prostate cancer found in published RCP series*
Reference/year
Winfield et al. [24]/1987
Pritchett et al. [25]/1988
Montie et al. [26]/1989
Kabalin et al. [27]/1989
Abbas et al. [28]/1996
Moutzouris et al. [29]/1999
Aydin et al. [30]/1999
Yang et al. [31]/1999
Conrad et al. [32]/2001
Prange et al. [33]/2001
Cindolo et al. [34]/2001
Ward et al. [35]/2004
Revelo et al. [36]/2004
Kouriefs et al. [37]/2005
Delongchamps et al. [38]/2005
Ruffion et al. [39]/2005
Lee et al. [40]/2006
Rocco et al. [41]/2006
Abdelhady et al. [42]/2007
Winkler et al. [43]/2007
Hosseini et al. [44]/2007
Weizer et al. [45]/2007
Esgueva et al. [46]/2008
Saad et al. [47]/2008
Mazzucchelli et al. [48]/2009
Overall
No. of
samples
80
165
84
66
40
59
121
49
133
85
165
129
121
128
141
100
248
63
204
97
50
35
120
425
248
3156
Mean age
of patients,
years
63.7
65
62
64
64.3
66.5
67.1
67.8
60
64
69
69
67.4
NA
62
62
63
67
67
NA
62.5
65
NA
59
68
64.8
Prostate cancer, n (%)
Significant (%
of incidental
Incidental
prostate cancer)†
22 (28)
11 (50)
45 (27.3)
NA
39 (46)
6 (15)
25 (38)
3 (12)
18 (45)
NA
16 (27)
NA
17 (14)
NA
16 (33)
NA
58 (43.6)
11 (19)
41 (48)
4 (10)
17 (10.3)
NA
30 (23.3)
18 (60)
50 (41.3)
24 (48)
23 (18)
NA
20 (14.2)
14 (70)
51 (51)
6 (12)
10 (4)
NA
34 (54)
12 (35)
58 (28.4)
18 (31)
58 (60)
31 (53)
7 (14)
4 (57)
16 (46)
4 (25)
41 (34.2)
25 (61)
90 (21.2)
36 (40)
123 (49.6)
23 (18.7)
925 (29.3)
250 (32.8)
*Modified from Damiano et al. [49]; †Weighted average based only on studies with reported significant
prostate cancer. NA, not available.
Ohori et al. [51] compared the unsuspected
prostate cancers found on RCP to the
clinically detected cancers on RP and found
that unsuspected cancers on RCP had
significantly smaller volumes, lower Gleason
scores and pathological stages: 83% were
≤0.5 cm3, 89% had only Gleason grades
1–3 and 97% were organ-confined. Most of
these tumours
(78%) were
considered
‘The reported incidence of “insignificant” prostate ‘unimportant’ and
cancer in studies from the USA ranges from 5.5% although 22% of
cancers were
to 29% in men undergoing RP’
regarded
‘important’, they
represented potentially curable disease. These
appears to be completely dependent on the
findings were confirmed in a more recent
bladder malignancy, the confounding
study, in which incidentally detected cancers
variables in the studies were the limited data
on RCP showed less aggressive pathological
sets, the short patient follow-up and the
parameters, including lower Gleason scores
retrospective study design.
exclusively dependent on the bladder
malignancy. In studies with documented
patient follow-up, there were only two local
recurrences for prostate cancer [29,42]; one
patient had progression with lung metastasis
[42], but no death related to prostate cancer
was recorded [25,28,29,34,37,38,48].
Although the prognosis in these patients
©
and pathological stages and had fewer
positive margins [52]. Although incidental
cancers on RCP had somewhat different and
‘less aggressive’ marker expression profile
than clinically detected cancers on RP,
regarding the nuclear and nucleolar size,
Ki-67 proliferation index, HER2 gene
amplification and protein expression, AMACR
(racemase) and endothelin 1 and its receptors,
these differences appeared more quantitative
that qualitative and showed a significant
overlap, which mirrored the differences in the
standard pathological parameters [52–55].
Concomitant bladder and prostate cancer
occur significantly more frequently than each
cancer individually in the general population
[56–59], which raises the possibility of a
common or dependent carcinogenetic
pathway for both cancers. However, the
influence of a diagnostic bias in this setting is
an important variable because the detection
of bladder cancer leads to detection of an
incidental prostate cancer through a more
detailed clinical and/or pathological
examination. To our knowledge, no study
to date has examined the ability to
preoperatively predict an incidental or
‘insignificant’ prostate cancer on RCP,
performed due to bladder malignancy.
‘INSIGNIFICANT’ PROSTATE CANCER ON RP
AFTER POSITIVE NEEDLE CORE BIOPSY
The reported incidence of ‘insignificant’
prostate cancer in studies from the USA
ranges from 5.5% to 29% in men undergoing
RP, higher numbers being reported in cancers
with clinical stage T1c or impalpable cancer,
as shown in Table 2 [14,15,17–19,60–70]
(modified from Anast et al. [68]). The
incidence of clinically ‘insignificant’ cancer
reported in the Johns Hopkins Hospital RP
series was as high as 26% and 29% [14,65] in
patients with clinical stage T1c, but lower
values of 9% and 10% were reported in series
from the Mayo Clinic and Stanford,
respectively [17,66]. Potentially ‘insignificant’
cancers were detected in 14.4% of patients in
a study from Japan [69], while in Europe,
Augustin et al. [67] reported an overall
incidence of 5.8% (8.3% in stage T1c). The
highest prevalence of indolent cancer of 49%
was found in a screening setting; the same
group found 20% prevalence of indolent
cancer in a clinical setting [19].
In a study of 1000 consecutive RP between
1983 and 1995, the frequency of indolent
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TABLE 2 Insignificant prostate cancer on RP in previously published studies
Reference/year
Epstein et al. [14]/1994
Irwin et al. [61]/1994
Terris et al. [62]/1995
Cupp et al. [63]/1995
Goto et al. [60]/1997
Elgamal et al. [64]/1997
Carter et al. [65]/1997
Epstein et al. [15]/1998
Noguchi et al. [66]/2001
Kattan et al. [18]/2003
Augustin et al. [67]/2003
Anast et al. [68]/2004
Miyake et al. [69]/2005
Steyerberg et al. [19]/2007
Chun et al. [70]/2008
Sengupta et al. [17]/2008
No. of patients
157
28*
92†
130
170
90
72‡
163§
222
409
480¶
152
195
247††
1132
678
433
21
6496‡‡
2106
3834
428
Clinical stage
T1c
T1c–T2
T1c–T2
T1c–T2
T1c–T3
T1c
T1c
T1c
T1c
T1c–T2a
T1c
T1c
T1c–T2
T1c–T2a
T1c–T3
T1c
T2
T3
T1–T4
T1c
T2
T3–4
Criteria for ‘insignificant’ cancer on RP
<0.5 cm3 + OC + Gleason score <7
<0.5 cm3 tumour volume
<1.0 cm3
<0.5 cm3
<0.5 cm3 + OC + Gleason score <7
<0.5 cm3 + negative margins + Gleason score <7
<0.5 cm3 + OC + Gleason score <7
<0.5 cm3
<0.5 cm3
<0.5 cm3 + OC + Gleason score <7
<0.5 cm3 + Gleason score <7
<0.5 cm3 + OC + Gleason score <7
<0.5 cm3
<0.5 cm3 + OC + Gleason score <7
<0.5 cm3 + OC + no Gleason 4 or 5
‘Insignificant’ cancers, %
26
12
16
2.3
10
20
31
31
10
20
8.3
25.7
14.4
49
5.7
7.5
3
5
5.5
9
4
0.7
<0.5 cm3 + OC + Gleason score <7, PSA <10 ng/mL
Updated and modified from Anast et al. [68]. OC, organ-confined; *only 28 patients analyzed with biopsy Gleason ≤4 and ≤3 mm from an initial group of 188
patients with cancer; †15 patients with transitional zone cancer and 29 patients with isoechoic tumours on ultrasonography were excluded; ‡probability of cancer
<0.5 cm3; §subset of patients of those previously included in studies by Epstein et al. [14] and Carter et al. [65]; ¶analysis limited to men with biopsy Gleason score
≤6 from an initial group of 1254 men; ††patients selected from a screening programme (Rotterdam section of European Randomized Study on screening for
Prostate Cancer); ‡‡includes 106 cases clinical stage T1a–b.
potentially ‘insignificant’ tumours. In 52 of
these cases, the total tumour volume was
additionally measured by digital image
analysis; 49 of 52 (94.2%) cases had tumour
volumes of <0.5 cm3 and only three (5.8%)
had tumour volumes
of >0.5 cm3 (none
were >1 cm3). In a
‘The pathological definition of “insignificant”
subset of 1376
prostate cancer essentially determines the disease patients with a
after a definitive surgery’
normal DRE (stage
T1c), 163 (11.8%)
had potentially ‘insignificant’ tumours. In 38
the ‘insignificant’ cancer did not show
patients with total tumour volume calculated
significant linear correlation with the
by digital imaging in this group, 35 (92.1%)
increased rate of cancers detected exclusively
had tumour volumes <0.5 cm3 and only three
due to PSA level elevation (i.e. stage T1c
cancers).
(7.9%) had tumour volumes of >0.5 cm3
(none were >1 cm3).
In a recent unpublished analysis of 2145
completely sampled RPs after a positive 10core biopsy, performed between 2000 and
PRETREATMENT PREDICTION OF
2008 at the University of Calgary, 242 (11.3%)
‘INSIGNIFICANT’ PROSTATE CANCER ON RP
contained tumours volume measuring ≤5% of
the gland, with no Gleason grades 4 and 5 or
The pathological definition of ‘insignificant’
other adverse RP findings, thus representing
prostate cancer essentially determines the
cancer was 9% and subsequently increased to
14.7% between 1996 and 1998 [71]. Augustin
et al. [67] also found an increasing trend of
‘insignificant’ cancer, from 5% before 1999 to
9.5% in 2002 over a period of 10.5 years, but
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disease after a definitive surgery. This
underscores a need for reliable and accurate
pretreatment prediction of potentially
‘insignificant’ or ‘indolent’ tumours for
clinical decision making, because tumour
volume cannot be accurately and reliably
measured before surgery using the
currently available noninvasive imaging
methods.
Several investigators have generated models
based on preoperative parameters to predict
‘insignificant’ cancers, as shown in Table 2
(reviewed in Anast et al. [68]). The common
preoperative parameters used to predict
pathologically defined ‘insignificant’ cancer
on RP included Gleason score ≤6, cancer on
biopsy measuring in length of ≤3 mm,
combined with PSA level, PSA density or free
PSA level [6,14,15,60,61,63,66–68]. In brief,
these studies showed variable sensitivity from
23% to 77% and specificity from 75% to 99%
for the prediction models applied. However,
earlier studies used different modifications of
a six-core (sextant) biopsy scheme. The
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‘INSIGNIFICANT’ PROSTATE CANCER
differences between the studies, pertaining to
study design and method, preoperative
parameters examined and study results,
preclude adopting uniformly accepted clinical
recommendations based on these models.
Additional limitations in most of the earlier
studies that used sextant biopsies were the
lack of independent validation and the clinical
setting in an earlier PSA screening era,
characterized by different clinical profile of
prostate cancer.
One of the key landmarks used in predicting
‘insignificant’ cancer on RP was a small
volume or minimal prostate cancer on biopsy.
Minimal or microfocal prostate cancer on
biopsy was usually defined as cancer
involving ≤5% of one core or ≤1 mm cancer
length of one core [72–74]; others have used
cancer extent ≤×40 microscopic field
(‘minute’ cancer) [75]. Single microfocal
cancers on biopsy are more likely to occur in a
previously PSA-tested and biopsied patient
population [74]. Minimal cancer on needle
biopsy, defined as ≤1 mm or ≤5% of one core,
is not a rare finding in the diagnostic practice.
In a contemporary series of 1017 consecutive
prostate cancers diagnosed on a 10-core
biopsy (sextant plus additional lateral cores at
the mid and base), one in 10 (10.4%) of all
cancers represented minimal cancer on biopsy
and one in four (24.3%) represented a singlecore positive biopsy [76]. In a model with a
specific focus of predicting a pathologically
defined ‘insignificant’ cancer on RP after a
single core positive biopsy, the following
variables were used: tumour length of
<2 mm, Gleason score ≤3 zyxfouronexyz 4,
and prostate volume of >50 cm3 [77]. The
authors showed that even in studies using
the most restrictive criteria with smallest
maximum length of cancer on biopsy and
maximum Gleason score of 6, there was an
extraprostatic disease in a median (range) of
13.5 (4–45)% of patients, positive margins in
11 (5–19)% and PSA recurrence in 8.5 (0–
26)%. However, most of the evaluated studies
used sextant or variable biopsy strategies,
which limited the analysis. The authors
concluded that a significant proportion of
patients with microfocal cancer on biopsy,
regardless of how it was defined, show
adverse pathological findings on RP with
subsequent significant risk of PSA recurrence
and they argued strongly against delayed
treatment even in patients with minimal
cancer on biopsy [80]. In contrast, one of the
largest studies using a prospective active
surveillance with delayed intervention
showed an overall patient survival of 85% and
disease-specific survival of 99.3% after a
median follow-up of 8 years [81]. Although
the criteria used in this study were not the
most stringent, even among the worst patient
subset in the cohort treated by surgery, i.e.
those patients re-classified as higher risk over
time, most remained curable by delayed
therapy.
PREDICTION OF ‘INSIGNIFICANT’
PROSTATE CANCER USING
CONTEMPORARY EPSTEIN CRITERIA
More recent attempts to redefine and
predict an ‘insignificant clinical’ prostate
cancer before surgery were based on the
updated Epstein criteria, which included PSA
density of <0.15 ng/
mL, Gleason sum of
‘minimal cancer on biopsy . . . does not necessarily ≤6, prostate
carcinoma in <3
translate into a small tumour volume in the
cores on biopsy (i.e.
prostate of an individual patient’
1 or 2 cores
positive), with
cancer not
exceeding 50% of any core [82]. When these
authors showed a positive predictive value
criteria were applied to the Johns Hopkins
(PPV) of 70.4%, negative predictive value
Hospital RP patient cohort, 91.6% of
(NPV) of 71.1% and diagnostic accuracy of
patients were found to have organ-confined
70.6% [77]. However, minimal cancer on
disease and only 9.7% of patients had
biopsy, as shown in several studies, mostly
Gleason scores 7 or 8 on RP [82]; no data
based on six-core biopsy, does not necessarily
were provided as to the correlation with
translate into a small tumour volume
‘insignificant’ cancer on RP based on the
in the prostate of an individual patient
[14,63,66,72,73,78,79]. A meta-analysis based traditional pathological definition. However,
using the same criteria others have found
on a systematic literature review explored the
adverse RP findings in 24% of European
predictive potential of minimal or small
men [83] and 30.5% in Korean men [84],
volume prostate cancer on biopsy [80]. The
©
which was largely due to RP upgrading from
Gleason sum of ≤6–7 and, to a smaller
extend, to cancer upstaging (mostly pT3a
extraprostatic disease on RP). Another recent
USA study from the Cleveland Clinic
examined the validity of the contemporary
Epstein criteria and concluded that although
they were highly predictive of an organconfined disease and an absence of
biochemical failure for up to 6 years after
RP, they were insufficiently robust to predict
biologically insignificant disease, defined by
the classic pathological criteria, primarily
because of underestimating Gleason 7 on
RP, and, to a smaller extent, the
extraprostatic disease on RP [85]. In part of
their analysis, they introduced a more liberal
definition of ‘insignificant’ prostate cancer
on RP (organ-confined disease, Gleason
score of ≤6 of any tumour volume), but
found that the updated criteria had a PPV of
only 58% even for the more liberally defined
‘insignificant’ prostate cancer. The rationale
for introducing a more liberal definition was
derived from a multi-institutional pooled
analysis of 24414 patients treated by RP
between 1987 and 2006, which showed that
only 1 of 3756 patients (0.003%) with
organ-confined Gleason score ≤6 disease
died from prostate cancer within 15 years
[86] and the evidence that tumour volume
does not upstage the disease in the great
majority of patients with Gleason 6 disease
[87,88]. The authors from the Cleveland
Clinic concluded that:
• a substantial portion of men fulfilling the
Epstein contemporary criteria, which is
currently the most widely used approach
to predict ‘insignificant’ cancer at the time
of diagnosis, are at risk for pathological
under-staging, under-grading or disease
progression
• that these criteria define only a potential
for biological insignificance
• that there is an ongoing need for
identifying truly biologically insignificant
tumours, which can not be fully characterized
by the currently available tools [85].
PRETREATMENT PREDICTION OF
‘INSIGNIFICANT’ PROSTATE CANCER
USING NOMOGRAMS
Several years ago, Kattan et al. [18] developed
nomograms for predicting small, potentially
‘indolent’ tumours, incorporating
pretreatment variables, such as clinical stage,
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T R P K O V ET AL.
Gleason grade, PSA level, gland volume and
the amount of cancer in a systematic biopsy
specimen. Their nomograms demonstrated
good discriminatory variables with an area
under the receiver operating characteristics
curve (AUC) of 0.64–0.79. A subsequent
attempt to validate these nomograms on an
independent data set, initially showed a poor
calibration, and, thus it was updated resulting
in adequate discriminative ability (AUC 0.76)
[19].
Recently, another nomogram-based approach
to predict ‘insignificant’ prostate cancer was
developed using PSA level, clinical stage,
biopsy Gleason sum, cancer length and
percentage of positive cores [70]. The authors
claimed a predictive accuracy of 90% for the
model, but no external validation was
performed. More importantly, as much as
63% of patients, considered as high
probability for ‘insignificant’ prostate cancer,
were misclassified and harboured adverse
findings (Gleason score 7–10, extraprostatic
extension, seminal vesicle or lymph node
invasion).
The term ‘low-volume/low-grade’ has been
recently proposed and favoured for those
cancers fulfilling the classic pathological
definition of ‘insignificant’ cancer [7,11,89]. A
nomogram was generated, based on the
aggregate data from two institutions, to
preoperatively predict ‘low-volume/lowgrade’ prostate cancer, which applied only to
men who had one positive cancer core
on extended (≥10 cores) biopsy [89].
Preoperative predictors in this nomogram
included patient age, PSA density and cancer
length (but not Gleason score), which
resulted in a good disease discrimination
(AUC 0.73).
Indeed, despite the accuracy of 64% to 79%
in the proposed nomograms [18,19,89,90],
the ability to predict potentially
‘insignificant’ disease preoperatively is still
far from perfect. It nevertheless provides a
reasonable starting point to select patients
for active surveillance in the current practice,
based on statistical probabilities, patient
preference and an ongoing commitment by
the clinician. This strategy includes active
patient follow-up with regular PSA
evaluations, regular or clinically driven
repeat biopsies and initiation of definitive
treatment when and if necessary upon
tumour progression, to achieve delayed but
complete patient cure.
310
DO PATIENTS WITH ‘MINIMAL OR MINUTE’
CANCER ON RP ALWAYS PRESENT
WITH FAVOURABLE PREOPERATIVE AND
BIOPSY FINDINGS?
Another approach in investigating
preoperative correlates of ‘minimal or minute’
cancer on RP would be to use pathologically
defined ‘minimal’ disease on RP as a starting
point and to correlate it with the preoperative
clinical and biopsy variables. The specific
objective would be to evaluate whether
‘minute’ cancers on RP invariably correspond
with extremely favourable biopsy and
preoperative clinical findings. In such a study
of 151 RPs at the Johns Hopkins Hospital,
showing only ‘minute cancer’ (defined as
prostate cancer involving only one to three RP
slides with Gleason score 6 (3 + 3) and no
focus of cancer measuring >2 mm), the
biopsy and the clinical preoperative findings
were typically favourable, but no ideal
correlation was established between the
preoperative and the RP findings [91]. The
discrepancies were reflected in the cancer
extent on biopsy with 24.5% of patients
having >1 positive core, PSA levels of >10 ng/
mL in 4.8%, PSA density of >0.15 ng/mL in
13%, free PSA of <10 ng/mL in 9.7% and
suspicious DRE in 14.6% [91]. There were ≥3
positive cores in 6% of the patients and >50%
cancer involvement in at least one of the
positive cores was identified in 2% of the
patients [91]. In a similar recent study from
our institution, we evaluated 114 RP
specimens which contained ‘minimal’
tumours, defined as ≤1% of the whole gland
volume; they represented 6.5% of a cohort of
1754 RPs [92]. The median gland volume in
these patients with ‘minimal’ cancers on RP
was 52 cm3. There was an abnormal DRE in
23% of patients and 17% had abnormal
ultrasound findings. In 18.7% patients the
PSA level was >10 ng/mL and 29% had a PSA
density od >0.15 ng/mL. On biopsy, 22%
of patients had cancer in >1 core (3.6%
had ≥3 positive cores). The median cancer
involvement on biopsy was 0.9% of the total
biopsy core sample and the median cancer
length on biopsy was 1.4 mm [92].
In conclusion, regardless whether a ‘minimal’
cancer on biopsy or ‘minimal’ cancer on RP is
used as a starting point, no perfect correlation
between the two can be achieved because of
the sampling limitations and error. The lack of
correlation between minimal cancer on biopsy
and minimal cancer on RP, which is driven by
the sampling limitation and error is inherent
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‘INSIGNIFICANT’ PROSTATE CANCER
to the current practice, because even an
extended (or saturation) biopsy samples <1%
of the whole prostate gland, and even a
‘complete’ or in toto pathological gland
sampling evaluates overall <1% of the gland
tissue [93].
ROLE OF MOLECULAR AND OTHER
EMERGING MARKERS IN DEFINING
‘INSIGNIFICANT’ PROSTATE CANCER
It is apparent that predicting ‘insignificant’
prostate cancer is not perfect using the
clinical and biopsy parameters alone, which
creates a need to incorporate molecular and
other markers to improve on this task.
Emerging molecular markers are expected
to potentially aid in refining and further
clarifying what prostate cancer and
insignificant cancer represent from a
molecular perspective. Of the ever growing
number of biomarkers that exist, to date, only
a few show promise to be potentially relevant
in characterizing prostate cancer further. One
of the promising molecular markers is ERG
gene rearrangement, which was recently
identified as the most common gene
rearrangement specific to prostate cancer
[94,95]. The incidence of ERG gene
rearrangement in prostate cancer is variable
and ranges between 15 and 60%, depending
on the detection methods used and the
studied patient cohorts [96–98]. This
variability may indicate a role for ERG gene
rearrangement in segregating significant
from insignificant tumours, which is reflected
in the tumour aggressiveness. Indeed, in
some reports, ERG gene rearrangement is
this marker in discriminating between the
minimal and non-minimal cancers in that
study. Although other emerging molecular
markers may play a role in distinguishing
clinically insignificant from significant
cancers, such as ‘Prostate CAncer gene 3’
(PCA3) [101] and early prostate cancer
antigen 2 (EPCA-2) [102], at present,
traditional pathological and clinical
parameters, such as grade, stage, tumour
volume, PSA level and its derivatives are the
cornerstones used in clinical practice.
Another novel research venue uses
molecular imaging of prostate cancer
based on molecular signatures for prostate
cancer discovered through genomics,
proteomics, metabolomics and
bioinformatics (reviewed in [103]). This
approach allows physicians to visualize
tumours using various imaging techniques
and to monitor the expression and activities
of key molecular signatures that are closely
associated with the early biological events
of human cancer. Selection and targeting of
suitable molecular signatures may also help
to not only detect the presence of cancer
at its early and curable stage, but also to
understand the underlying pathogenesis of
human cancer.
EMERGING TREATMENT OPTIONS
FOR PATIENTS WITH LOW-RISK
PROSTATE CANCER
In many instances, patients considered
preoperatively to harbour potentially
‘insignificant’ prostate cancer, as well as some
patients who do not
fulfil all criteria for
‘insignificant’
‘There are apparent clinical and pathological
prostate cancer, can
similarities between cancers considered
be considered
‘insignificant’ on RCP and RP’
within the low-risk
cancer category.
These low-risk
patients face and will face a difficult choice
associated with aggressive clinical behaviour
between the risk of morbidity from RP or
[97,98], while in other studies an association
radiotherapy, and the risks of an ongoing
with favourable prognosis has been reported
anxiety brought by watchful waiting and
[99]. Recently, TMPRSS2-ERG gene fusion has
active surveillance. Thus, there is a need for an
been found in 47% of ‘minute’ (or minimal)
organ-sparing therapy that definitively treats
prostate cancers on RP, defined as total
the largest tumour, achieves excellent
tumour volume of ≤0.5 cm3, Gleason score <7
oncological outcomes, and preserves the
and organ-confined disease with no evidence
patient’s quality of life. One of those emerging
of margin, seminal vesicle or lymph node
options is focal cryoablation, which is a
positivity [100]. This was comparable with the
promising minimally invasive therapy that
ERG fusion rate of 58% in non-minimal
might ultimately satisfy this growing need
cancers, which argued against the value of
©
[104,105]. For example, for patients with
unilateral positive biopsies, a recently
proposed approach involved simulated focal
therapy with regionally targeted cancer
ablation in a subtotal fashion (either by
cryotherapy or high-intensity focused
ultrasound). Comparing two simulated
regional template strategies (hemi-prostate
and ‘hockey-stick’), the authors concluded
that regional ablation would have
successfully treated all clinically significant
prostate tumours in 64% and 81% of patients
using the hemi-prostate or ‘hockey-stick’
templates, respectively [106]. Most ‘out-offield’ cancers (i.e. outside of the treatment
zone) were considered clinically insignificant
(low volume <0.5 cm3 and low grade Gleason
score ≤6).
‘INSIGNIFICANT’ CANCER ON RP AND RCP:
VARIATION ON A THEME LOW-GRADE/
LOW-VOLUME PROSTATE CANCER?
There are apparent clinical and pathological
similarities between cancers considered
‘insignificant’ on RCP and RP. Both are
generally reflective of an early stage, low
tumour volume disease, which usually bears
no significant clinical consequences for the
patients on follow-up. In both instances,
patients typically present with low PSA levels
and PSA densities. However, the preoperative
parameters, such as PSA level and PSA
density are difficult to compare in a
systematic fashion between ‘insignificant’
cancers on RCP and RP, because they are
generally not recorded or are incomplete in
RCP series of incidentally detected cancers.
Another similarity includes the cancer
distribution, which in both instances
typically involves the peripheral zone of the
prostate.
However, there are also some differences
between the cancers labelled ‘insignificant’
on RCP and RP. While most incidental
cancers on RCP may be considered
‘insignificant’, only a minority of all prostate
cancers on RP represent an ‘insignificant’
disease, using the accepted pathological
definition. Another potential difference
between these cancers on RP and RCP may
relate to the prostate gland size or volume.
More recent RP studies have documented
larger gland size (>50 cm3) for prostates
containing ‘insignificant’ cancers compared
with prostates with ‘significant’ cancers
[18,67,77]. This is nevertheless difficult to
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T R P K O V ET AL.
evaluate and compare in a systematic
fashion regarding the prostate gland size for
cancers considered ‘insignificant’ on RCP,
because these studies generally do not
provide prostate size data.
Although the ‘insignificant’ cancers on RP and
RCP are typically detected in patients aged
60–69 years, cancers detected on RCP are
usually found in patients who are 5–10 years
older than patients are with cancers detected
on RP. The age-difference in the two patient
populations, probably reflects the lead-time
bias from more frequent PSA screening and
the stage migration occurring in clinical
practice for cancers detected on RP. Because
cancers considered ‘insignificant’ on RP and
RCP peak in the 60–69 years age group, it
would be pertinent to compare their
incidences with the corresponding cohorts of
men in the same age group in the general
population, which are documented in autopsy
and organ donor studies. In an autopsy study
of men who died of trauma from Wayne State
University [107], there was an incidental (or
latent) prostate cancer in 70% of AfricanAmerican and 65% of Caucasian men in the
age group 60–69 years. In another autopsy
study examining specifically the incidence of
prostate cancer in cadaveric organ donors, a
lower incidence of 35% was documented in
the same age group 60–69 years [108]. The
rate of 35% of incidental cancers in cadaveric
donors is closer to the documented rates of
incidental cancers on RCP (overall 29.3%;
Table 1). In the study of prostate cancer in
cadaveric organ donors, the mean (range)
Gleason score of prostate cancer in the age
group 60–69 years was 6.5 (6–7). Although
the authors concluded that many of the
cancers detected in cadaveric donors may be
clinically ‘insignificant’ with a Gleason score
≤6 and have small tumour volumes, no
specific data were provided in both studies as
to what proportion of these cancers fulfilled
the pathological criteria for ‘insignificant’
cancer.
‘insignificant’ are probably biologically similar,
but different from most clinically ‘significant’
prostate cancers found on RP, which
represent later and more advanced stage
disease. We feel that a more neutral term
‘low-volume/low-grade prostate cancer’ may
be currently more appropriate until a
universally accepted definition of
‘insignificant’ prostate cancer is achieved
and a clear distinction of insignificant vs
significant disease is established, based on
clinical, pathological, molecular or other
parameters, in order to appropriately manage
patients harbouring this type of disease.
312
9
10
CONFLICT OF INTEREST
None declared.
11
12
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clinical settings, which explains some of
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Correspondence: Kiril Trpkov, Anatomical
Pathology, Rockyview Hospital, Department of
Pathology and Laboratory Medicine, Calgary
Laboratory Services and University of Calgary,
7007-14 Street S.W., Calgary, Alberta, Canada,
T2V 1P9.
e-mail: kiril.trpkov@cls.ab.ca
Abbreviations: RP, radical prostatectomy;
RCP, radical cystoprostatectomy; PPV,
positive predictive value; NPV, negative
predictive value; AUC, area under the
receiver operating characteristics curve.
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