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Review – Prostate Cancer
Extended and Saturation Prostatic Biopsy in the
Diagnosis and Characterisation of Prostate Cancer:
A Critical Analysis of the Literature
Vincenzo Scattoni a,*, Alexandre Zlotta b, Rodolfo Montironi c, Claude Schulman d,
Patrizio Rigatti a, Francesco Montorsi a
a
Department of Urology, University Vita-Salute, Scientific Institute San Raffaele, Milan, Italy
Division of Urology, Mount Sinai and Princess Margaret Hospitals, University of Toronto, Toronto, Ontario, Canada
c
Section of Pathological Anatomy, United Hospitals, Marche Polytechnic University, Ancona, Italy
d
Department of Urology, Erasme Hospital, University Clinics of Brussels, Brussels, Belgium
b
Article info
Abstract
Article history:
Accepted August 3, 2007
Published online ahead of
print on August 17, 2007
Objective: To review and critically analyse all the recent literature on the detection and characterisation of prostate cancer by means of extended and saturation
protocols.
Methods: A systematic review of the literature was performed by searching
MedLine from January 1995 to April 2007. Electronic searches were limited to
the English language, and the key words ‘‘prostate cancer,’’ ‘‘diagnosis,’’ ‘‘transrectal ultrasound (TRUS),’’ ‘‘prostate biopsy,’’ and ‘‘prognosis’’ were used.
Results: The prostate biopsy technique has changed significantly since the original Hodge sextant biopsy protocol. Several types of local anaesthesia are now
available, but periprostatic nerve block (PPNB) has proved to be the most effective
method to reduce pain during TRUS biopsy. It remains controversial whether
PPNB should be associated with other medications. The optimal extended protocol (sextant template with at least four additional cores) should include six
standard sextant biopsies, with additional biopsies (up to 12 cores) taken more
laterally (anterior horn) to the base and medially to the apex. Repeat biopsies
should be based on saturation biopsies (number of cores 20) and should include
the transition zone, especially in a patient with an initial negative biopsy. As a
means of increasing accuracy of prostatic biopsy and reducing unnecessary
prostate biopsy, colour and power Doppler imaging, with or without contrast
enhancement, and elastography now can be successfully adopted, but their
routine use is still controversial.
Conclusion: Extended and saturation biopsy schemes should be performed at first
and repeat biopsy, respectively. The widespread use of local anaesthesia makes
the procedures more comfortable.
Keywords:
Diagnosis
Prognosis
Prostate biopsy
Prostatic neoplasms
Transrectal ultrasound
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# 2007 European Association of Urology. Published by Elsevier B.V. All rights reserved.
* Corresponding author. Department of Urology, University Vita-Salute,
Scientific Institute H San Raffaele, Via Olgettina 60, 20132 Milan, Italy.
Tel. +39 02 2643 2311; Fax: +39 02 2643 2735.
E-mail address: [email protected] (V. Scattoni).
0302-2838/$ – see back matter # 2007 European Association of Urology. Published by Elsevier B.V. All rights reserved.
doi:10.1016/j.eururo.2007.08.006
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1.
european urology 52 (2007) 1309–1322
Introduction
Widespread use of serum prostate-specific antigen
(PSA) has certainly increased prostate cancer detection and resulted in considerable stage migration [1].
Such results would not have been achieved without
the contemporary refinements of the technique of
prostate biopsy (PBx). After the initial introduction
of the sextant PBx technique proposed by Hodge,
little refinement of the technique was made until
Stamey [2] suggested directing the biopsies more
laterally. It is now recognised that even lateral
sextant biopsies can miss up to 30% of cancers
because more extended prostatic biopsy (EPBx)
schemes result in higher cancer detection rates
[3–7]. As defined by the National Comprehensive
Cancer Network, an EPBx is essentially a sextant
template with at least four additional cores from the
lateral peripheral zone as well as biopsies directed to
lesions found on palpation or imaging.
At present, little controversy exists in the urologic
community regarding the usefulness of EPBx compared with sextant biopsy in increasing the detection rate of prostate cancer. Data from both
academic and community practices demonstrate a
high cancer detection rate (42–44%) with a 12-core
biopsy template in patients undergoing initial
biopsy [8].
Nevertheless, prostate cancer detection is still
an area currently fraught with many unanswered
questions and significant controversy. Even if several
different EPBx techniques have been recently presented, the optimal protocol needed to identify all
patients with prostate cancer at the earliest stage
possible for optimal treatment, outcome, and survival is still not known. Moreover, the significance of a
Fig. 1 – Drawing shows the sites of injection of lidocaine to
perform a periprostatic nerve block (PPNB).
PBx has changed over the years. Today, a PBx is not
only a method to diagnose prostate cancer, but it has
become an informative method for an accurate
morphologic characterisation of prostate cancer,
including its volume and Gleason score.
We have reviewed the available literature on this
topic and compared the efficacy and safety of the
different schemes with respect to the number of
cores and sampling locations. A systematic review
of the literature was performed by searching MedLine from January 1995 to April 2007. Electronic
searches were limited to the English language,
and the key words ‘‘prostate cancer,’’ ‘‘diagnosis,’’
‘‘transrectal ultrasound (TRUS),’’ ‘‘prostate biopsy,’’
and ‘‘prognosis’’ were used.
2.
Anaesthesia during transrectal prostate
biopsy and antibiotic prophylaxis
2.1.
Anaesthesia during TRUS
Anaesthesia during TRUS PBx is now considered the
gold standard; it is recommended by recently
published guidelines, and we are close to the point
in which absence of anaesthesia would be considered malpractice [9].
Intrarectal local anaesthesia (IRLA) with lidocaine
gel (2%) has had controversial results compared with
placebo [10,11]. In a recent meta-analysis [12], five
studies involving 466 patients and comparing IRLA
with placebo showed that IRLA was associated with
pain reduction, but the effect size was not statistically significant. Moreover, in randomised studies,
IRLA was reported to be inferior to periprostatic
nerve block (PPNB) with lidocaine injection [13–20].
In several articles, it has been shown that PPNB was
superior to IRLA in reducing pain during PBx in
different randomised studies (Table 1). Even if the
superiority of PPNB versus IRLA is evident, it
remains unclear which dosage and PPNB technique
should be used.
As for the site and amount of anaesthetic
infiltration, a study using a placebo and six groups
of escalating doses of 1% lidocaine (2.5, 5, and 10 ml)
infiltration revealed that the best pain relief was
obtained with 10 ml lidocaine infiltrated solely at
the neurovascular bundle region (single site) or to
the neurovascular bundle and apical regions (double
site). Therefore, the authors recommended singlesite, 10-ml infiltration in the region of the neurovascular bundle [21].
Various infiltration sites have been described,
including the apex only [22,23], bilateral neurovascular bundle regions only (defined variously as
Table 1 – Randomised studies comparing PPNB and IRLA
Authors
No. of patients
Dose and type of drug
No. of core biopsies
Results
*
23 (PPNB) vs. 27 (GEL)
20 ml lidocaine 1% (10 ml to junction of seminal
vesicle and prostate + 5 ml into genitourinary
diaphragm + 5 ml between rectal wall and
prostate) vs. 10 ml 2% lidocaine jelly intrarectally
8 up to 15 (mean 12)
Overall pain : 0.5 vs. 4.2 ( p < 0.0001); biopsy
pain 0.5 vs. 4.2 ( p < 0.0001)
*
Pain evaluation: 10-point VAS: insertion of
TRUS probe, anaesthetic instillation, biopsy,
and overall pain procedure
Adamakis et al. [14]
40 (sonographic gel) vs.
78 (GEL) vs. 80 (PPNB)
10 ml sonographic gel intrarectally vs. 10 ml 5%
prilocaine-lidocaine cream (EMLA1) vs. 10 ml 2%
lidocaine to junction of seminal vesicle and
prostate
10-core biopsies
Mean pain*: 5.1 vs. 4.8 vs. 2.5; statistically
significant difference in group 3 and 1
( p < 0.001) and in group 3 and 2 ( p < 0.001);
no statistically significant difference in
groups 1 and 2 ( p = 0.18)
*
Pain evaluation: 11-point VAS biopsy pain
Lynn et al. [15]
30 (PPNB) vs. 27 (GEL) vs.
14 (gel-placebo) vs. 15
(placebo-injection)
10 ml 1% lignocaine periprostatic nerve plexus
injection vs. 11 ml 2% lignocaine gel intrarectally
vs. 10 ml gel-placebo rectally vs. 10 ml normal
saline periprostatic nerve plexus injection
Sextant prostate
biopsies
Mean pain*: 0.5 vs. 2.7 vs. 4.8 vs. 4.3;
statistically significant difference in only
group 1 ( p < 0.001)
*
Pain evaluation: 10 point-VAS
Song et al. [16]
30 (GEL) vs. 30 (PPNB) vs.
30 (injection-placebo)
20 ml 2% lidocaine gel intrarectally vs. 5 ml
2% lidocaine to junction of seminal vesicle
and prostate vs. 5 ml normal saline to
junction of seminal vesicle and prostate
10-core biopsies
Biopsy pain*: 5.5 vs. 3.6 vs. 5.8; statistically
significant difference in group 2 vs. group 3
( p < 0.0001)
*
Pain evaluation: 10-point VAS pain during biopsy
Alavi et al. [17]
75 (PPNB) vs. 75 (GEL)
10 ml 1% injected into periprostatic nerve
plexus vs. 10 ml 2% Turbojet lidocaine
intrarectally
6–14 (average 6.8
vs. 6.6)
Mean pain*: 2.4 vs. 3.7 ( p = 0.00002)
*
Pain evaluation: 11 point-VAS (Wayne State
University-VAS)
Stirling et al. [18]
50 (no anaesthetic) vs.
50 (PPNB) vs. 50 (GEL)
No anaesthetic vs. 5 ml 1% lidocaine
periprostatic injection vs. 10 ml 2%
lidocaine gel intrarectally
Minimum 8 (average 9.6 vs.
9.4 vs. 9.3)
Mean pain*: 3.8 vs. 2.6 vs. 3.1 ( p < 0.05)
*
Entire procedure pain evaluation: 11-point VAS
Rodriguez et al. [19]
43 (GEL) vs. 53 (PPNB)
10 ml 2% lidocaine gel intrarectally vs.
10 ml 1% lidocaine solution injected at
the prostate apex
6–14 (mean 7 vs. 8)
Mean pain*: 2.76 vs. 1.73* ( p = 0.001)
Mean pain*: 2.26 vs. 1.62** ( p < 0.001)
*
Pain evaluation: *10-point VAS and **5-point VAS
Öbek et al. [20]
75 (no anaesthetic) vs.
75 (PPNB) vs. 75
(GEL + PPND) vs. 75
tramadol
No anaesthetic vs. 5 ml 2% lidocaine
injection lateral to junction of seminal
vesicle and prostate vs. 10 ml 2% lidocaine
gel perianal/rectal + 5 ml 2% lidocaine
periprostatic infiltration vs. tramadol
1.5 mg/kg e.v.
12-core biopsies
Mean pain*: 4.6 vs. 2.57 vs. 2.03 vs. 3.11;
statistically significant difference only between
group 3 and group 4 ( p = 0.006).
*
Pain evaluation: 11-point VAS
european urology 52 (2007) 1309–1322
Matlaga et al. [13]
PPNB = periprostatic nerve block; IRLA = intrarectal local anaesthesia; GEL = intrarectal anaesthetic gel; VAS = visual analog pain scale; TRUS = transrectal ultrasound.
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european urology 52 (2007) 1309–1322
basolateral, posterolateral, periprostatic nerve
plexus, prostate-vesicular junction injections) [17,
24,25], apex, and neurovascular bundle [22,23], and
three locations (base, mid, and apex) posterolaterally [26] and lateral to the tip of the seminal vesicles
[27] (Fig. 1). Even if infiltration of the neurovascular
bundle region seems essential for effective anaesthesia, apical infiltration alone has been reported to
provide significant pain relief [22,23]. Recently, it has
been demonstrated that the combination of PPNB
and periapical local anaesthesia is not superior to
PPNB alone in reducing pain during PBx [28].
The issue of whether PPNB should be associated
with IRLA or oral medication has been recently
discussed by some authors [20,29]. Öbek et al [20]
have demonstrated that the combination of PPNB
and IRLA was superior to PPNB alone and concluded
that this combined local anaesthesia could be
considered a new gold standard. Pendleton et al
[29] recently reported that oral administration of
75 mg tramadol/650 mg acetaminophen 3 h before
PPNB appears to provide more effective pain control
than PPNB alone without causing any additional
complications.
There is no doubt that the introduction of PPNB
has allowed EPBx to be performed easily in the office
and, furthermore, the number of biopsies taken to
be increased (from 10 to 18 or 20) without increasing
the discomfort and pain of the patients. Despite the
Fig. 2 – Histologic slide shows an intracapsular prostate
cancer on the left side. The arrows show the directions of
the biopsies. The classic Hodge biopsies as well as the
Stamey biopsies (more lateral) are not in the optimal
direction to detect the tumour that is localised very
laterally in the subcapsular position. Only lateral biopsies
are useful to detect the prostate cancer. LH = lateral horn, a
site where the tumor is often situated; TZ = transition
zone; T = prostate cancer.
variability of location and dosage of infiltration, the
PPNB is, nowadays, the most effective method to
reduce pain during TRUS biopsy. It is controversial
whether PPNB should be associated with IRLA or oral
medication.
2.2.
Antibiotic prophylaxis
Although published guidelines recommend prophylaxis for patients undergoing TRUS PBx because of
the risk of urosepsis, the choice of antibacterial
agent and duration of dosing are not consistent with
the published recommendations and vary widely
among urologists [9]. The antimicrobial prophylaxis
is started the day before the EPBx and, in some cases,
continued for 2–5 d [9]. The incidence of infection
complications seems to be lower with longer
duration of therapy in some but not all studies
[30–32]. Schaeffer et al [32] have recently reported
that a longer course (3 d) of antimicrobial prophylaxis (ciprofloxacin extended-release 1000) might be
more beneficial than a short course (1–d).
3.
Initial prostatic biopsy: from sextant to
extended and saturation biopsy
Over the last few years, interest has increased in
defining a more efficient biopsy scheme for detecting prostate cancer. Intuitively, adding more biopsies to prostatic areas not sampled by standard
sextant schemes should increase the detection rate
for prostate cancer. However, it is not clear whether
the increased detection rate is simply due to the
additional biopsies or to the location from which the
cores are taken. Although biopsies of the transitional zone have been reported to add little to cancer
detection [33–42], it would appear that the addition
of far lateral biopsies improves the detection rate of
adenocarcinoma (Fig. 2). Several researchers [6–8]
have evaluated the diagnostic yield of lateral
biopsies within an EPBx. It has been reported that
laterally directed biopsies, which are aimed at
sampling also the lateral horn, yield about a 25%
increase in the ability to detect prostate cancer
[4,7,35]. The apex and the base of the peripheral
gland are the sites at which prostate cancer is most
likely to be located and at which the biopsies should
be directed, whereas the midline biopsies have been
demonstrated to have the lowest probability of
being positive [7,35]. Most of the studies have
demonstrated that EPBx has proven to be significantly superior to the sextant protocol in cancer
detection, without significant morbidity and without increasing the number of insignificant cancer
european urology 52 (2007) 1309–1322
cases [36]. There is no doubt that the direction and
number of biopsies performed determine the procedure’s sensitivity. For these reasons the EPBx that
optimises the detection rate should include six
standard sextant biopsies with additional biopsies
weighted more laterally at the base (lateral horn)
and medially to the apex. The necessity of biopsying
single hypoechoic lesions seems to be no longer
necessary because the visible lesion itself is as likely
to be the source of cancer as the next adjacent area
[37].
More recently, some investigators have advocated even more aggressive biopsy schemes with
>10–12 cores up to a saturation biopsy (24 cores)
and reported even higher cancer detection rates
[7,35].
Despite the use of an extended protocol, an
increase in sampling error can occur in some
patients, especially those with large prostate glands.
It is well known that prostate volume is one of the
factors that may influence the prediction of cancer
at first biopsy and that a significant inverse
relationship exists between the cancer detection
rate and prostate volume [38]. Recently, it has been
demonstrated that a scheme with eight cores turned
out to be appropriate in patients with prostates
< 30 cc. On the other hand, in prostates > 50 cc, an
extended procedure with >12–14 cores was considered mandatory, even if the authors were not able
to define the exact number of cores [39]. In a study
of 303 patients comparing, directly in the same
patient, the 6-, 12-, 18- and 21-core protocols, it was
shown that a 21-sample needle biopsy procedure
increased the prostate cancer detection rate [7]. The
authors have reported a prostate cancer detection
improvement of about 25% and 11% when
12- versus 6-core and 21- versus 12-core protocols
were compared, respectively. Interestingly, they
have demonstrated that the improvement was
most marked in patients with a prostate volume
of >40 cc. Unfortunately, these results should be
interpreted with caution because most of the
patients had already undergone a previous prostatic biopsy. Recently, it was shown that 14-core
biopsies are superior to 8-core biopsies for patients
with prostate volumes of 30–40 cc. A core number
> 14 may be needed to detect cancer for prostate
volumes in excess of 40 cc [40]. In an EPBx that
included lesion-directed biopsies plus a 14-core
biopsy scheme, the difference in the cancer detection rates of the sextant and the 8-core biopsy
schemes was larger in cases with prostate volumes
< 50 cc than in those with prostate volumes > 50 cc,
whereas the difference in the detection rates of
8-core and 14-core biopsies was smaller in patients
1313
with prostate volumes < 50 cc than in those with
prostate volumes > 50 cc [41].
On the other hand, it has been demonstrated that
the saturation technique as an initial PBx strategy
does not improve cancer detection [42]. Jones et al
[42] have suggested that further efforts at extended
biopsy strategies beyond 10–12 cores are not appropriate as an initial biopsy strategy. In a recent
systematic review, Eichler et al [43] have shown that
there is no significant benefit in taking > 12 cores
and that methods requiring 18 cores have a poor
side-effect profile. Moreover, a transperineal (TP)
6-core biopsy has a detection rate similar to that of a
12-core biopsy in patients presenting with PSA levels
> 10 ng/ml and abnormal digital rectal examination
(DRE) findings [44].
In conclusion, it is now reasonable to consider a
sampling with 12 cores of the peripheral gland as
adequate even if limiting the number of cores to 12
in larger prostate is of concern.
4.
The risk of over-diagnosis
The issue of nonsignificant prostate cancer is
becoming more and more important because one
possible disadvantage of the initial EPBx could
escalate the risk of detecting small, possibly lowgrade, and clinically insignificant cancers. Even if
the definition of clinically insignificant prostate
cancer is controversial and poorly defined, evidence
in the literature suggests that EPBx has really
contributed to the detection of more cancers of
smaller volume and of little clinical relevance, with
the potential for over-diagnosis or over-treatment.
Nevertheless, the concern of over-detection must be
weighed against the risk of missing clinically
significant malignancy and cancer detection does
not need necessarily a linked treatment because
men with low-volume and low-grade diseases may
also be managed expectantly.
There is no doubt that the recent stage migration
of prostate cancer has been witnessed by regular
increases in the proportion of patients with moderately differentiated low-volume tumour and a
significant decrease in the volume of the cancers
removed at surgery [45]. Recently, Master et al [46]
demonstrated that a greater number of biopsies
were associated with smaller tumour volumes at
radical prostatectomy. Boccon-Gibod et al [47] have
reported that 30% of patients with microfocal
prostate cancer on EPBx have the risk of having
insignificant tumour and of being over-treated.
Moreover, no parameter was able to identify on an
individual basis the patients harbouring a prostate
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european urology 52 (2007) 1309–1322
cancer potentially amenable to surveillance with
delayed therapy.
Nevertheless, using an initial EPBx, Siu et al [36]
have demonstrated that it is possible not only to
enhance tumour detection but also to ultimately
lead to the finding of clinically significant disease.
Similarly, Singh et al [6] have shown no apparent
significant association between the increased number of cores and the finding of smaller and clinically
insignificant cancer. Meng et al [48] have recently
demonstrated that performing more extensive
biopsies does not significantly increase the number
of lower-risk tumours identified. They have
reported that there are no differences in disease
characteristics and biochemical-free survival
among men with a biopsy number between 6 and
17. Unfortunately, some methodologic flaws, such
as a short median follow-up of just 2.2 yr, diminish
the value of their results. Even if the authors
concluded that increasing the number of cores does
not affect the detection of lower-risk tumours, the
usefulness of improved and earlier identification of
cancers in altering the natural history remains
uncertain.
Thus, even if the use of EPBx is recommended, the
risk of detecting insignificant tumour should not be
neglected. Nevertheless, saturation biopsies/rebiopsies, which are now used as part of active surveillance protocols, have recently proved to provide
helpful information about quantitative and qualitative histology to predict the clinical significance of
prostate cancer [49,50].
20% [51]. Djavan et al [51] reported cancer detection
rates on subsequent sets of biopsies one, two, three,
and four of 22%, 10%, 5%, and 4%, respectively, in
men with total serum PSA level of 4–10 ng/ml.
Recently, different researchers have demonstrated that saturation biopsy techniques aimed at
greatly increasing the number of samples and
varying the distribution of biopsy sites may provide
a higher cancer detection rate (Table 2). The
detection rate of prostate cancer ranged from 17%
to 41%, and the likelihood of clinically insignificant
cancers was not significantly increased compared
with initial or repeat biopsy [52–58]. Saturation
biopsies have a safe profile and are particularly
useful in larger-volume prostates. Borboroglu et al
[52] used an extensive TR saturation technique to
obtain an average of 22.5 cores/patient and reported
a cancer detection rate of 30%. A larger series with a
different TR saturation biopsy scheme was reported
by Stewart et al [53], who reported a cancer detection
rate of 34%. Recently, Walz et al [57] reported a high
prostate cancer detection rate of 41% with a 24-core
protocol. Similarly to the initial biopsy protocol, it
has been proven that more time and effort should be
spent on lateral biopsies, which increase the cancer
detection rate, whereas parasagittal biopsy provides
a low yield on repeat PBx [56].
Although saturation biopsy is becoming more
often the preferred repeat biopsy scheme, as yet no
clear criteria indicate when to perform a rebiopsy in
patients with persistently elevated levels of PSA.
6.
5.
Repeat biopsy: from extended to saturation
biopsy
The management of patients with persistently
elevated levels of PSA in whom a first set of prostate
biopsies has been negative for cancer is a daily
problem for urologists. The cancer detection rate on
repeat not-extended biopsy ranges between 10% and
Transrectal versus TP
The TP PBx is unusual, especially in the United
States, even if some institutions in European and
Asian countries perform TP PBx exclusively. Theoretically, the direction of the TP biopsies might be
better than the transrectal (TR) route because they
sample longitudinally the peripheral zone of the
prostate. Initially the TP route was demonstrated to
Table 2 – Comparison of saturation biopsy studies in patients undergoing rebiopsy
Author
Year
No. of
patients
Mean/median
PSA, ng/ml
Borboroglu et al. [52]
Stewart et al. [53]
Fleshner et al. [54]
Rabets et al. [55]
Patel et al. [56]
Pinkstaff et al. [58]
Walts et al. [57]
2000
2001
2002
2004
2004
2005
2006
57
224
37
116
100
210
161
8.6
8.7
22.4
9.2
9.4
13.6
9.4
PSA = prostate-specific antigen.
No. of
cores
22.5
23
32–38
22.8
20–24
21.2
24.2
Cancer
detection rate
30%
34%
13.5%
29%
25%
37%
41%
european urology 52 (2007) 1309–1322
be less accurate than the TR approach in identifying
all the hypoechoic lesions [59]. Subsequently,
the same group of authors [60] also reported that
TP-guided sextant biopsies were less accurate than
TRUS-guided sextant biopsies in detecting prostate
cancer. In a simulation experiment, Vis et al [61]
have shown that the two approaches did not differ
in prostate cancer detection. Emiliozzi et al [62] were
the first to compare in vivo the two different
approaches, and they have shown that the sextant
TP biopsy seems superior to TR biopsy in detecting
prostate cancer. The same authors [62] and Takenaka et al [63] have subsequently reported that the
12-core TP PBx is superior to 6-core biopsy and have
shown that the number of cores may have a greater
impact on cancer detection than the route of the
PBx.
In the last few years, the concept of extended
biopsies has been equally applied to the TP
approach, with results similar to those achieved
with the TR approach in patients underoig rebiopsy
procedures. The demonstration that the two
approaches were equivalent in cancer detection
was obtained only from reports of some Japanese
urologists who had performed TR and TP biopsies
in the same patients. Watanabe et al [64] compared
6-core TR and 6-core TP biopsies, and Kawakami
et al [65] compared 12-core TR and 14-core TP
biopsies. Both studies have shown that the overall
cancer detection rate did not differ for the two
approaches when the same number of cores were
used, even if the two approaches combined were
better than a single approach.
7.
The role of nomograms
Detection of prostate cancer detection can be
improved either with a better sampling of prostate
cancer or by improving the indication for a PBx. The
notion that combined input of multiple predictors
usually exceeds that of most informative single
variables has led to the development of artificial
neural networks or nomograms to predict the
probability of having cancer. Artificial neural networks have limited clinical applicability, and they
have proven to be less accurate than nomograms in
predicting the outcome of an initial biopsy [66].
Recently, different authors have reported nomograms based on extended biopsy protocol [66,67].
Chun et al [68] developed a useful nomogram based
on a cohort of 2900 men exposed to 10 biopsy cores.
Predictors included age, DRE, PSA, percent free PSA,
and sampling density (ie, ratio of gland volume and
the number of planned biopsy cores), which were
1315
included in multivariable logistic regression models
predicting presence of prostate cancer. The nomogram was 77% accurate and also allowed the
definition of the ideal ratio between gland volume
and the number of planned biopsy cores that would
yield the ideal biopsy rate.
Within the repeat biopsy setting, a novel nomogram including only patients undergoing extended
biopsy schemes at final repeat biopsy has been
reported with an accuracy of 77%, which exceeded
the accuracies of previously published nomograms
[69].
Therefore, nomograms represent a valid methodologic approach for detection of prostate cancer
both at initial and repeat biopsy, if correct criteria
are met. The availability of such high-quality predictive models should encourage the clinician to
adopt these tools in everyday clinical practice.
8.
Improving cancer detection by means of
Doppler imaging
Standard grey-scale TRUS technology has limited
specificity and sensitivity for prostate cancer detection because of its inability to detect isoechoic
neoplasms. To increase its accuracy and utility,
researchers have investigated a number of alternatives, including colour Doppler TRUS (CDUS), power
Doppler imaging (PDI) with and without intravenous
contrast administration, and, recently, elastography
[65]. Increased microvascularity accompanies cancer
growth, and neovascularity may be detectable by
CDUS and PDI because of abnormal blood flow
patterns in larger feeding vessels.
Some studies have shown that CDUS did not add
significant information to grey-scale TRUS in
detecting early stages of prostate cancer, whereas
others have demonstrated varying degrees of
benefit [70,71]. Overall, the sensitivity of CDUS for
the diagnosis of prostate cancer ranged between
49% and 87%, and specificity ranged between 38%
and 93% [71]. PDI is considered the next generation
of colour Doppler imaging because it has the
advantage of increased sensitivity for detecting
small, low-flow blood vessels. Halpern et al [72]
have shown that PDI may be useful for targeted
biopsies when the number of biopsy passes must be
limited but that there is no substantial advantage of
PDI over CDUS. Remzi et al [73] have recently
reported that PDI has a high negative predictive
value and may help to reduce the number of
unnecessary biopsies because a normal power
Doppler TRUS signal might exclude the presence
of a prostate cancer.
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european urology 52 (2007) 1309–1322
Contrast-enhanced colour Doppler (CECD) is an
ultrasound-based technology for imaging of the
prostate that is used after intravenous administration of gas-encapsulated microbubbles. This
methodology allows for better prostate cancer
visualisation and for targeted biopsies to isoechoic
areas that generally become hypervascular after
contrast infusion. Halpern et al [74] have reported
significantly improved sensitivity, from 38% to 65%,
for detecting prostate cancer with preserved specificity at approximately 80%. Recently, different
authors have demonstrated that targeted biopsy
with CECD detects a number of tumours equal to
that of systematic biopsies with less than half the
number of cores [74–76]. Unfortunately, the poor
discrimination of benign from malignant tissue,
which is due to the CECD ultrasound signal arising
from areas of benign disease such as benign
prostatic hyperplasia, has diminished the specificity
of this technology.
Recently, it has been reported that short-term
oral therapy with a 5a-reductase inhibitor combined
with dutasteride may improve prostate cancer
detection if used with CECD ultrasound [77]. Despite
these promising results, CECD has not yet gained
popularity because of its low specificity, complexity,
and high cost.
Some investigators [70] reported the use of
sonography with manual compression of the prostate gland with the TR probe to generate elastograms. The basis for improved detection of cancer is
that the elasticity of the neoplastic tissue is less
compared with normal prostate tissue. The limited
amount of data available on the ability of elastography to detect prostate cancer show that a targeted
biopsy detects as many cancers as a systematic
biopsy with less than half the number of biopsy cores,
but more clinical trails are needed to determine the
exact role of this advantage for TRUS [70].
9.
Gleason concordance on EPBx
Different studies have demonstrated that the ability
to predict the final Gleason score by means of
standard sextant biopsy is quite poor with a
concordance rate between the biopsy and prostatectomy Gleason scores of only 28–48% [78]. On
average, the Gleason score is under-graded in 43% of
cases (Table 3).
The use of EPBx has been beneficial in the
pretreatment decision-making process because an
increased number of biopsies increase the Gleason
concordance. San Francisco et al [79] reported an
improvement in the concordance rate from 63% to
72%. Mian et al [80] reported that the rate of
upgrading to a worsening risk category was significantly reduced with EPBx. Numao et al [81]
recently reported that a 26-core systematic biopsy
can more accurately predict the presence of Gleason
pattern 4/5 on surgical specimen compared with
transrectal 12-core PBx.
Table 3 – Grade of discordance, biopsy upgrading and downgrading with not-extended and extended protocols according
to different authors
Authors
Year
No. of cores
taken
Grade of
discordance
San Francisco et al. [79]
2003
9
10
37%
24%
12%
10%
25%
14%
King et al. [78]
2004
6
10
38%
37%
25%
12%
12%
25%
Emiliozzi et al. [94]
2004
6
12
51%
30%
11%
6%
39%
24%
Coogan et al. [95]
2005
6
8
10
58.9
60
42.5
19.6%
23%
11%
39.2%
36.9%
31.5%
Mian et al. [80]
2006
6
12
52%
32%
41%
17%
NR
NR
Numao et al. [81]
2006
TP 14
TR 12
3D 26
15%
17%
7.7%
NR
NR
2%
51%
48%
26%
Elabbady et al. [5]
2006
6
12
50%
24.8%
NR
NR
NR = not reported; TP = transperineal; TR = transrectal; 3D = three-dimensional.
Biopsy
upgrading
Biopsy
downgrading
european urology 52 (2007) 1309–1322
King et al distinguished between any upgrading
and significant upgrading (Gleason sum increases
either from 6 to 7 or from 7 to 8) and suggested
that significant upgrading represents a clinically
meaningful entity. Different authors [81–83] have
demonstrated that, with more EPBx, the risk of
significant upgrading decreases because of higher
sampling density and more accurate pathologic
biopsy evaluation. The two largest published
cohorts [86,87] showed a rate of overall Gleason
sum upgrading of 29.3% and 32.6% and a rate of
significant upgrading of 32% and 28.2%, respectively.
Because significant Gleason sum upgrading
between biopsy and final pathology may have an
impact on treatment decision-making, predictive
nomograms have been developed as prognostic
models capable of predicting the probability of
significant upgrading [84,85].
10.
Quantitative histology on EPBx
The amount of tumour in prostate needles can be
expressed by the number of positive cores or by the
amount of tumour per core. This parameter is an
extremely important pathologic parameter and a
predictor of a lethal phenotype of prostate cancer or
a clinically insignificant cancer (Tables 4 and 5)
[86,87]. The extent of involvement of needle cores by
prostatic adenocarcinoma has been shown to
correlate (albeit not perfectly) with the Gleason
Table 4 – Prostate biopsy reporting
Parameters that should be reported
1. Number and total length of the cores (exclude those <1 cm
and those without epithelial component)
2. Number of cores with cancer (percentage of cores involved)
3. Longest single length of tumour (report also the location)
4. Total tumour length in all cores
5. Mean tumour length in all cores (reported as a percentage):
total tumour length divided by total length of cores
multiplied by 100 (ie, overall percentage of cancer in all
biopsies)
6. Number of cores with perineural invasion (extent: focal,
multifocal) and calibre of nerve bundles
7. Number of cores with vascular invasion
8. Composite (global) Gleason score for all cores for the patient
9. Number and location of cores with atypical glands,
suspicious for cancer
10. HGPIN (extent; focality: focal or multifocal; number of
cores involved; laterality: unilateral or bilateral)
Each core (slide) is reported individually (see the example below):
1. Prostate biopsy of 1.4 cm occupied for 7 mm (50% of the core
length) by acinar adenocarcinoma, Gleason score 3 + 3 = 6.
Perineural invasion is present.
2. Prostate biopsy of 1.3 cm with normal prostate tissue
HGPIN = high-grade prostatic intraepithelial neoplasia.
1317
score, pathologic stage, surgical margins, but,
especially, with tumour volume [88]. As the number
of positive cores and the amount of tumour per core
increase, the larger the tumour volume is likely to
be. The extent of needle core involvement, including bilateral involvement, has also been shown to
predict biochemical recurrence, postprostatectomy
progression, and radiation therapy failure in univariate analysis and often in multivariate analysis
[89,90]. It is a parameter included in some recent
nomograms created to predict pathologic stage and
seminal vesicle invasion after radical prostatectomy and radiation therapy failure. Although the
correlation for high tumour burden in needle
biopsies is directly proportional to the likelihood
of an adverse outcome, low tumour burden in
needle biopsies is not necessarily an indicator of
low-volume and low-stage cancer in the prostatectomy specimen. For instance, an apparently
favourable report with only one or two cores
positive for cancer or a limited extent of <3 mm
of cancer does not act as a guarantee for either
organ-confined prostate cancer or insignificant
cancer after radical prostatectomy [91]. As with
the other parameters, a combination of the extent of
involvement of needle cores with the Gleason score,
location of the tumour, and serum PSA levels
increases the prognostic and predictive power of
this parameter [91].
In one study [91], the percentage of cancer in
biopsies from the base correlated with extraprostatic extension. In other studies, a Gleason score of
7–9 cancer in the midprostate or base biopsies
correlated with the risk of seminal vesicle invasion
and lymph node metastasis, and a tumour volume
of >50% in base biopsies correlated with a prediction
of extraprostatic extension at the neurovascular
bundle and posterior lateral region [92]. Moreover,
the amount of cancer in apex biopsies has been
shown to correlate with apical margin positivity [93].
The number and percentage of positive biopsy cores
have also proven to improve the ability to predict
lymph node invasion in patients undergoing radical
prostatectomy and extended pelvic lymph node
dissection (Table 6) [86].
There is lack of consensus in the literature with
regards to the best method of reporting the extent of
tumour involvement. It is recommended that the
report should provide the number of involved cores.
Typically, small foci are reported as <1% or <5%, and
so forth, of needle core biopsies, and linear length is
reported in increments of 0.5 mm. The correlation,
as alluded to before with prognosis, is with greater
involvement of the cores, and studies have shown
various cut-off values (33%, 34–50%, and 51–100%,
1318
european urology 52 (2007) 1309–1322
Table 5 – Preoperative parameters predicting the presence of insignificant prostate cancer according to different authors
Authors
Origin of
cohort
% of IPCa
Biopsy
protocol
Preoperative parameters predicting the
presence of IPCa
Epstein et al. [96]
United States
26%
Sextant
Gleason sum 6
Adenocarcinoma present in fewer than
3 of 6 cores
No more than 50% malignant involvement in each
positive biopsy core
PSA density < 0.15 ng/ml/g
Goto et al. [97]
United States
10%
Sextant
Quantitative analysis of the extent of cancer
PSA, PSA density, and grade
Carter et al. [98]
United States
17%
Sextant
PSA density
Quantitative histology (number of cores involved
with cancer and percentage of cancer within the core)
Epstein et al. [99]
United States
30%
Sextant
Needle biopsy findings
Free/total PSA levels
Kattan et al. [100]
United States
20%
6
Nomograms incorporating pretreatment variables
(clinical stage, Gleason grade, PSA, and the amount
of cancer in a systematic biopsy specimen)
Ochiai et al. [101]
United States
22%
Extended (10–11 cores)
Combination of tumour length < 2 mm, Gleason
score 3 + 4, and prostate volume > 50 cc
Augustin et al. [102]
Europe
6%
Sextant
PSA density
Percent of cancer per biopsy
Chun et al. [68]
Europe
6%
6
Preoperative nomograms (predictor variables: PSA,
clinical stage, biopsy Gleason scores, core cancer
length, and percent of positive biopsy cores)
Miyake et al. [103]
Japan
14%
8
Gleason score < 7
Percent positive biopsy core < 15%
IPCa = insignificant prostate cancer defined as tumour < 0.5 cc and no Gleason 4 and 5 at final pathology; PSA = prostate-specific antigen.
or 20%, 21–55% and >56%, etc) to be of significance
[93]. Because literal translation of these findings to
clinical cases would be difficult and not really
necessary, reporting the percentage of cancer
involvement in increments of 5% or 10% is appropriate.
11.
Table 6 – Importance of knowing the specific location of
the biopsy and the location of cancer
1. Tumour involvement of base biopsies may influence
bladder-neck–sparing radical prostatectomy.
2. Extensive cancer in base biopsies correlates with extraprostatic
extension.
3. Dominant side of prostate biopsy correlates with ipsilateral
positivity of surgical margins and extraprostatic extension.
4. Knowledge of location of cancer may help target additional
tissue or block sampling in cases with no apparent cancer in
radical prostatectomy sections.
5. Knowledge of biopsy site helps recognise potential diagnostic
pitfalls (eg, seminal vesicle epithelium or central zone
epithelium, seen most frequently in base biopsies and the
rare Cowper’s glands in apex biopsies).
6. Knowledge of biopsy site and location of cancer allows detailed
correlation with digital rectal examination and imaging studies.
7. Laterality is useful in planning of nerve-sparing radical
prostatectomy.
8. Map distribution of prostate cancer is useful for planning the
field of radiation therapy (eg, in brachytherapy).
Conclusions
Despite years of research, the exact number of
biopsies to be taken to (1) detect significant prostate
cancers, (2) predict the actual tumour volume, and
(3) rule out insignificant prostate cancer is still
largely unknown. Despite development of PDI,
CDUS, and CECD, which allow performance of
targeted biopsies, the current trend is to use, more
and more often, EPBx (10- to 12-core biopsy without
the transition zone) as the initial biopsy strategy.
Moreover, the inability to better determine who
needs to undergo biopsy and the reliance on Gleason
score are the two main factors that contribute to the
dependence on a greater number of biopsies. In men
with persistent suspicion of prostate cancer after
several negative biopsies, more extensive protocols
(>12 cores) up to saturation biopsy represent a
necessary diagnostic procedure that has proven to
have a safe profile. The issue of whether an increase
in number of biopsy cores taken results in the
european urology 52 (2007) 1309–1322
detection of more tumours with a lower-risk feature
remains controversial.
[15]
Conflicts of interest
[16]
The authors have nothing to disclose.
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