Open Journal of Urology, 2013, 3, 210-216 Published Online September 2013 (
Characteristics of Prostate Cancers Missed by Biopsies:
Evaluation of Cumulative Tumor Volume Missed
According to Cancer True Prevalence*
Nicolas B. Delongchamps1#, Gustavo de la Roza2, Paul Perrin3, Michaël Peyromaure1, Gabriel P. Haas4
1Department of Urology, Cochin Hospital, Paris Descartes University, Paris, France
2Department of Pathology, Upstate Medical University, Syracuse, USA
3Department of Urology, Lyon South Hospital, Lyon, France
4Astellas Pharma Global Development, Inc., Deerfield, USA
Received May 14, 2013; revised June 16, 2013; accepted June 22, 2013
Copyright © 2013 Nicolas B. Delongchamps et al. This is an open access article distributed under the Creative Commons Attribution
License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
Purpose: To characterize missed prostate tumors and their cumulative volume with various biopsy regimens to deter-
mine optimal biopsy schemes. Methods: We performed 6, 12 and 18-core needle biopsies on 165 and 36-core biopsies
on 47 autopsy prostates, respectively. The 6-core biopsy included 6 cores from the mid peripheral zone (MPZ), the
12-core biopsy included 6 cores from the MPZ and lateral PZ (LPZ), and the 18-core biopsies included 6 cores from the
MPZ, LPZ and central zone (CZ). The 36-core biopsies included 12 cores in each of these 3 areas. We analyzed the
sensitivity of biopsies at each site and evaluated the cumulative volume of cancers and tumor foci missed. Results:
Whole-mount analysis identified 59 cancers, 110 tumor foci, and a total cumulative tumor volume of 43 cm3. The per-
centage of tumor foci and corresponding cumulative volume missed with 6, 12, 18 and 36-core biopsies were of 79%
and 58%, 64% and 48%, 57% and 26%, and 42% and 17%, respectively (p < 0.05). 12-core biopsies from the MPZ and
LPZ performed best for clinically significant cancers detection. However, increasing the number of cores over the
6-core biopsy cutoff increased solely the detection of tumor foci < 0.5 cm3. Conclusion: Twelve biopsies from the MPZ
and LPZ detected most of the clinically significant cancers while missing most of the tumor foci. These missed tumors
represented only a small amount of the overall cancer volume.
Keywords: Prostate Cancer; Prevalence; Biopsy; Clinical Significance
1. Introduction
The trend among clinicians has been performed more
prostate biopsies to detect more prostate cancers. Sextant
biopsies have been all but abandoned, and most studies
recommend extended biopsy protocols of 12 cores [1-3].
Although these efforts have undoubtedly led to increased
detection of cancer, they have also led to the over diag-
nosis of small and well-differentiated tumors, designated
as clinically insignificant [4,5]. Even undetected, they
may not be of immediate threat, and should they be de-
tected, not to be managed with radical and possibly mor-
bid treatment. This issue recently came under increased
scrutiny as a consequence of the recent recommendations
by the Task Force for Preventive Medicine [6]. Notwith-
standing the evidence that PSA screening followed by
early stage treatment may reduce mortality [7-9], they
concluded that the use of PSA was harmful because it
caused increased morbidity and over treatment of indo-
lent tumors.
While recommendations from the Task Force for Pre-
ventive Medicine focused on the adverse effects of PSA
screening, they did not address the role of prostate biopsy
as a staging tool. Also, we have to be concerned not only
with the ability of the biopsy to detect cancer, but also
with the potential characteristics of cancers missed. We
previously reported cancer detection rates obtained with
different ex-vivo biopsy protocols performed on autop-
sied prostates [10]. Based on the cancer true prevalence,
we found that 12 biopsies targeting the mid peripheral
*Funding: National Institute on Aging (AG021389 to G.P.H.); National
Cancer Institute (CA097751 to G.P.H.); National Institutes of Health
(2U42RR006042-13). This study or its publication did not receive
financial support from Astellas Pharma Global Development, Inc.
#Corresponding author.
opyright © 2013 SciRes. OJU
zone (MPZ) and lateral peripheral zone (LPZ) performed
best for cancer detection. In the current study, we per-
formed post hoc sub-analyses of our data to evaluate the
performance of sextant, 12-core, 18-core and 36-core
biopsies to detect cancer, with emphasis on the charac-
terization of missed tumor foci and their cumulative
2. Method
2.1. Tissue Collection
We prospectively collected 261 consecutive prostate
glands from deceased men that were provided by the
University Hospital, Syracuse, NY, the Onondaga Coun-
ty Medical Examiner, Syracuse, NY and by the National
Disease Research Interchange, Philadelphia, PA. This
study was approved by the Institutional Review Board,
and the tissue suppliers obtained informed consent from
the next of kin. The decedents had no known history of
prostate cancer. At autopsy, the entire prostate gland,
together with the seminal vesicles, were excised within
24 hours post-mortem by an experienced medical exam-
iner or pathologist, en-block, and placed in 10% neutral
buffered formalin. Prostatic tissue was not entirely re-
moved in 49 (20%) of the prostates autopsied; these sub-
jects were excluded, leaving 212 prostate glands avail-
able for analysis.
2.2. Prostate Biopsy
All biopsies were performed in a manner that mimicked
clinical biopsy with a standard 18F spring-loaded biopsy
gun. The needle was inserted through the posterior sur-
face of the hand-held gland, and bilateral samples were
taken from the apex, mid gland, and base. The first 165
autopsied glands were biopsied using an 18-core biopsy
protocol (Figure 1). The first six cores, corresponding to
the sextant biopsy protocol, were taken from the mid
peripheral zone (MPZ). The next six cores were taken
with the needle inserted into the central zone (CZ). The
last six cores were taken from the lateral peripheral zone
(LPZ). The last 47 autopsied glands were biopsied using
a saturation biopsy protocol of 36 cores: the first 18 cores
were taken in a similar fashion and 6 additional cores
were taken in each of the 3 locations (Figure 1).
2.3. Whole Mount Prostate Processing and
Histological Evaluation
After the biopsies were taken, the glands were fixed in
formalin for at least 72 hours. The glands were cut into
4-mm sections perpendicular to the posterior plane, la-
belled, embedded in paraffin, and further sectioned to
produce 5-μm whole-mount sections that were stained
with hematoxylin and eosin. A single pathologist ana-
Figure 1. Schema of the anatomic sites of prostate biopsies
taken from the 212 men postmortem. The first six biopsy
cores (1-6) were taken from the mid peripheral zone (MPZ),
the next six cores (7-12) from the central zone (CZ), and the
last six cores (13-18) from the lateral peripheral zone (LPZ).
In the last 47 glands, 6 additional biopsy cores were taken
in each of these 3 mentioned areas.
lyzed the biopsies and whole-mount slides in a blinded
fashion. The total number of tumor foci and their loca-
tions were recorded. An area of carcinoma was consid-
ered to be a separate focus if it was separated from the
nearest adjacent focus by a low-power field diameter (4.5
mm), as previously described [11]. Each tumor focus was
graded according to the modified Gleason grading sys-
tem [12].
2.4. Digital Reconstruction and Measurement of
Tumor Volume
The surface of each tumor focus was determined by com-
puterized planimetry, using an image analysis program
[10,13]. Tumor volume was calculated by multiplying
each tumor surface by the section thickness (4 mm) and
by 1.5 to compensate for tissue shrinkage [14]. Tumors
were considered clinically insignificant if they were or-
gan-confined (<pT3) with an index tumor volume of less
than 0.5 cm3 and Gleason score 6 or less [4,5]. The cu-
mulative tumor volume detected was calculated as the
sum of the volumes of each individual tumor foci de-
tected by biopsies. The cumulative cancer volume de-
tected was calculated as the sum of the volumes of each
cancer identified by biopsies.
2.5. Statistical Methods
Tumors missed by biopsies were compared with those
Copyright © 2013 SciRes. OJU
detected using the student t-test and the χ2 test for quan-
titative and qualitative variables, respectively. McNemar
and χ2 tests were used to compare the sensitivity of can-
cer detection, the number of missed foci and their cumu-
lative volume between 6-, 12-, and 18- and 36-core biop-
sies. Sensitivity of biopsy results were calculated using
as the standard either the presence of any prostate cancer
or of clinically significant cancer on whole-mount analy-
sis. All statistical tests were two-sided, and P values less
than 0.05 were considered to be statistically significant.
Statistical analyses were conducted using MedCalc®.
3. Results
Pathologic evaluation of step sectioned prostates identi-
fied 59 prostates with cancer, and 110 tumor foci with a
cumulative volume of 43 cm3. In the sub group of 47
autopsied glands biopsied with 36-core saturation biop-
sies, 12 cancers and 22 tumor foci were identified on step
sectioned prostates, with a cumulative tumor volume of
4.7 cm3. Table 1 summarizes their characteristics and
compares them between cancers detected and missed.
Detection rates of significant and insignificant cancers
were not statistically different between large (>50 cm3)
and small (50 cm3) glands, whatever biopsy protocol
tested (p > 0.1).
Sextant prostate biopsies from the MPZ detected 18/59
(30%) cancers and 23/110 (21%) tumor foci. Of the 87
tumor foci missed, 7 (8%) were >0.5 cm3, 19 (22%) were
0.2 - 0.5 cm3 and 61 (70%) were <0.2 cm3. Thirteen
(15%) of the missed tumors were Gleason score > 6. The
cumulative tumor volume missed on sextant biopsy was
of 25.1 cm3 (58%).
12-core biopsies from the MPZ and LPZ together de-
tected 31/59 (52%) cancers and 40/110 (36%) tumor foci.
Of the 70 tumor foci missed, 4 (6%), 15 (21%), and 51
(73%) were >0.5 cm3, 0.2 - 0.5 cm3 and <0.2 cm3, re-
spectively. Nine (13%) of the missed tumors were Glea-
son score > 6. The cumulative tumor volume missed on
12-core biopsies was of 20.6 cm3 (48%).
18-core biopsies from the MPZ, LPZ and CZ detected
32/59 (54%) cancers and 47/110 (43%) tumor foci. Of
the 63 tumor foci missed, 3 (5%), 13 (21%) and 47 (75%)
were >0.5 cm3, 0.2 - 0.5 cm3 and <0.2 cm3, respectively.
Eight (13%) of the missed tumors were Gleason score >
6. The cumulative tumor volume missed on 18-core bi-
opsies was of 11.3 cm3 (26%) (Table 2).
36-core biopsies from the MPZ, LPZ and CZ detected
7/12 (58%) cancers and 15/22 (68%) tumor foci. Of the 7
tumor foci missed, 0, 1 (14%) and 6 (86%) were >0.5
cm3, 0.2 - 0.5 cm3 and <0.2 cm3, respectively. One (14%)
of the missed tumors was Gleason score > 6. The cumu-
lative tumor volume missed on 36-core biopsies was of
0.8 cm3 (17%).
The sensitivity of 12-core biopsies for cancer detection
was significantly higher than for sextant biopsies alone
(p < 0.0009). The sensitivities of biopsies from the MPZ
for clinically significant and insignificant cancer were
50% and 15%, respectively, compared with 77% and
33% for those from the MPZ and LPZ combined (p =
0.02 and p = 0.04, respectively). Increasing sampling
over the 12-core cut-off decreased significantly the num-
ber of tumor foci missed as well as their cumulative vol-
ume, without increasing any further cancer detection rate
(Figure 2). However, as shown in Figure 3, increased
sampling over the 6-core cut-off decreased significantly
the number of small tumor foci missed (<0.5 cm3) but not
that of large (>0.5 cm3). The number of missed tumor
foci with a Gleason score > 6 decreased with additional
biopsies, but the difference was not statistically signifi-
cant (p = 0.2).
4. Discussion
In the large ongoing debate over prostate cancer screen-
ing, urologists mainly focus on cancers detected and their
management. These cancers represent however only the
tip of the iceberg. Estimation of tumors that are “missed”
with particular biopsy regimens, the location of such tu-
mors, and their histological characteristics and signifi-
cance is therefore of critical importance.
Our analysis confirmed that performing more than 12
biopsies did not increase cancer detection any further.
Although 64% of tumor foci and more than half (54%) of
the cancers present were missed by 12-core biopsies,
they corresponded to a small amount of the overall can-
cer volume. The percentage of cumulative tumor volume
missed with 12-core biopsies was high (48%), but a sig-
nificant number of the missed foci were located in glands
diagnosed with cancer thanks to other contiguous or dis-
tant tumor foci detected by biopsies. As a result, only
14% of the overall cancer volume was truly missed with
12-core biopsies. Moreover, our results suggested that
missed foci were significantly smaller than those de-
tected and that they had a lower Gleason score. These
findings are in accordance with earlier published studies
suggesting that 12 cores directed to the peripheral zone
of the prostate seem to have a high performance while
minimizing the number of unnecessary cores [1-3]. Bi-
opsies within the central zone have a low likelihood of
detecting cancer in the absence of positive results from
the peripheral zone of the gland [1,15].
Once having recognized that 12 biopsies from the
MPZ and LPZ performed best and detected most of the
significant cancers, the next question would concern the
need for additional biopsy sampling for cancer charac-
terization. The potential benefit of additional biopsies
would have to be balanced against the increased morbid-
ity of the procedure. Biopsy-related morbidity is also a
major issue highlighted by the Task Force for Preventive
Copyright © 2013 SciRes. OJU
Copyright © 2013 SciRes. OJU
Table 1. Baseline characteristics of all patients and pathologic characteristics of pros t a t e c a ncers.
Characteristic Median (IQR) or number (%)
All men (N = 212)
Age (years) 64.5 (54 - 73)
Gland volume (cm3) 49 (30 - 55)
White 194 (91%)
Black 9 (4.5%)
Hispanic 1 (0.5%)
Unknown 8 (4%)
Prostate cancers (N = 59)
Pathological stage
pT2a 34 (58%)
pT2b 3 (5%)
pT2c 14 (24%)
pT3a 8 (13%)
Gleason score
6 41 (69%)
7 18 (31%)
Volume (cm3)
ITV 0.222 (0.074 - 0.530)
TTV 0.296 (0.074 - 0.768)
Tumor foci volume 0.115 (0.046 - 0.315)
Clinical significance
Significant 26 (44%)
Insignificant 33 (56%)
Tumor foci location
MPZ only 30 (27%)
LPZ only 41 (37%)
MPZ and LPZ 11 (10%)
CZ only 24 (22%)
MPZ and CZ 3 (3%)
CZ, MPZ and LPZ 1 (1%)
Medicine [6] and has increased these past 10 years [16].
The rate of hospital admission within 30 days of having
prostate biopsies was reported to be as high as 4%,
mainly for infection-related reasons [16]. In our analysis,
18 and 36-core biopsies allowed a significant increase in
tumor foci detection and in their cumulative volume,
improving therefore staging for each individual patient.
However, this increased detection yielded only tumor
foci < 0.5 cm3. Additionally, the number of missed
poorly differentiated tumor foci (Gleason score > 6) de-
creased with additional sampling, but the difference was
not significant (p = 0.2). These findings support the con-
cept that cancers are not missed by biopsies because of
suboptimal technique, but rather because they are smaller
and earlier in their development. In clinical practice,
these cancers may be detected later with repeated biop-
sies [17]. Knowing the existence and characteristics of
such secondary foci is of low value if a radical treatment
is immediately intended. Conversely, to develop and in-
crease the possibilities of active surveillance and focal
therapies, performing an initial accurate cancer mapping
of the prostate may be of crucial importance, especially
when 12-core biopsies reveal only small amount of low
grade cancer. This initial staging could then serve as a re-
ference for potential re-biopsy strategies.
Our study has several limitations, the most important
being the absence of pre-mortem PSA data available.
PSA screening is indeed the first step before considering
prostate biopsies. Another limitation is our “histological”
definition of clinical significance, which did not take into
consideration age, comorbidities, and other individual
5. Conclusion
Twelve biopsies from the MPZ and LPZ detected most of
Table 2. Pathological characteristics of cancers detected and missed with 18-core biopsies.
Prostate cancers
Detected (n = 32) Missed (n = 27) p value
Median (IQR) ITV (cm3) 0.485 (0.265 - 0.845) 0.081 (0.047 - 0.215) 0.02
Median (IQR) TTV (cm3) 0.638 (0.333 - 1.057) 0.087 (0.051 - 0.215) 0.005
Gleason score
3 + 3 19 (59%) 21 (78%)
3 + 4 13 (41%) 6 (22%) 0.2
Number of foci
Unifocal 9 (28%) 21 (78%)
Multifocal 23 (72%) 6 (22%) 0.0002
Significant 21 (66%) 5 (18%)
Insignificant 11 (34%) 22 (82%) 0.0005
Tumor foci
Detected (n = 47) Missed (n = 63) p value
Median (IQR) tumor volume (cm3) 0.296 (0.096 - 0.572) 0.081 (0.031 - 0.197) 0.003
Number of tumor foci
Volume 0.2 cm3 20 47
Volume [0.2 - 0.5] cm3 14 13
Volume 0.5 cm3 13 3
Gleason score
3 + 3 30 55
3 + 4 17 8 0.005
MPZ 10 (21%) 20 (32%) 0.3
LPZ 17 (37%) 24 (38%) 1
CZ 7 (15%) 17 (27%) 0.2
MPZ + LPZ 9 (19%) 2 (3%) 0.008
MPZ + CZ 3 (6%) 0
MPZ + LPZ + CZ 1 (2%) 0
Figure 2. Rates of missed cancers and individual tumor foci, and corresponding volumes, according to biopsy protocol.
Copyright © 2013 SciRes. OJU
Figure 3. Rates of missed individual tumor foci according to their volume.
the clinically significant cancers while missing as much
as 48% of cancers. These missed cancers represented
however only 13% of the overall volume of cancer.
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