Stesura Seveso


311Archivio Italiano di Urologia e Andrologia 2014; 86, 4

REVIEW

Repeated biopsy in the detection of prostate cancer: 
When and how many cores

Vincenzo Scattoni, Andrea Russo, Ettore Di Trapani, Umberto Capitanio, 
Giovanni La Croce, Francesco Montorsi

Department of Urology, University Vita-Salute, Scientific Institute San Raffaele, Milan, Italy

Purpose: We performed an analysis of
the literature about the optimal prostate

biopsy (PBX) scheme in the repeated setting
Methods: We performed a clinical and critical literature
review by searching Medline Database from January
2005 up to January 2014. Electronic searches were limit-
ed to the English language. The keywords were: prostate
cancer, prostate biopsy, transrectal  ultrasound, transper-
ineal prostate biopsy. 
Results: The recommended approach in repeated setting is
still the extended scheme (EPBx) (12 cores). An approach
with more than 12 cores according to the clinical charac-
teristics of the patients may optimize cancer detection.
Saturation PBx (> 20 cores) clearly improves cancer
detection if clinical suspicion persists after previous nega-
tive biopsy. Nevertheless  international guidelines do not
strongly recommended SPBx in all situations of repeated
setting. EPBx or SPBX may be, in the future, substituted
by multiparametric MRI-targeted biopsies.
Conclusions: Since the scenario in which a PBx is chang-
ing, the issue about the number and location of the cores
in PBx is still a matter of debate in repeated setting.  
At present, EPBx are still the gold standard even if SPBx
seems to be necessary in many cases. However, random
PBx does not represent the approach of the future, but
rather imaging targeted biopsy. 

KEY WORDS: Prostate cancer; Prostate biopsy; Transrectal
ultrasound; Ttransperineal prostate biopsy.

Submitted 3 October 2014; Accepted 31 October 2014

Summary

No conflict of interest declared.

tocol in each patient, or whether to modify the protocol
for different clinical situations. Moreover, it is still contro-
versial whether the detection rate may increase with addi-
tional biopsies or whether it is necessary to modify the
locations where the cores are taken (1, 3).

METHODS
We performed a clinical and critical review of electronic
databases by searching Medline, Web of Knowledge and
the Cochrane Library from January 2005 up to January
2014 to identify all relevant studies. Electronic searches
were limited to the English language, and the keywords
prostate cancer, prostate biopsy, transrectal ultrasound,
transperineal prostate biopsy were used. Two independ-
ent authors performed all aspects of the search strategy,
screening the titles and abstracts of all articles and then
reviewing the full-text articles in detail. 

PROSTATE BIOPSY STRATEGY IN THE REPEAT SETTING
Candidates to repeat PBx include patients with a prior
negative PBx but with a persistent suspicion of PCa on the
basis of repeated PSA values and/or DRE findings (and
other markers such us %FPSA, complexed PSA, PSAD,
PSA velocity and urinary PCA3 score), previous peculiar
hystological diagnosis (such as atypical small acinar prolif-
eration of prostate - ASAP or high-grade prostatic intraepithe-
lial neoplasia - HGPIN), candidates to active surveillance or
to focal therapy. How and how many cores should be
taken in these different scenarios is still unclear and
schemes may significantly change in the different patients. 
Based on the findings that even initial extended PBx (EPBx)
miss almost a third of cancers, a SPBx has been adopted to
improve PCa DR in patients with suspicious clinical find-
ings following previous negative standard PBx. 
There is now good evidence in the literature that SPBx are
superior than EPBx in this setting. Zaytoun et al. reported
their experience at Cleveland Clinic where they compared
EPBx with SPBx in a clearly defined, heterogeneous pop-
ulation of patients undergoing repeat biopsy after a single
prior biopsy that failed to diagnose PCa (2). They showed
that office-based SPBx significantly increases DR in repeat
biopsy compared to EPBx. SPBx detected almost one-
third more cancers. For patients with benign initial biop-

DOI: 10.4081/aiua.2014.4.311

Presented at 19th National Congress SIEUN, Fermo 2014

INTRODUCTION
Management of patients with negative biopsy often pres-
ents a dilemma. Urologists know well that a negative
biopsy does not mean the absence of cancer, and a sec-
ond biopsy is one of the options. The saturation prostate
biopsy (SPBx) was initially introduced to improve prostate
cancer (Pca) detection rates (DR) in the repeat setting
because initial 10- to 12-core biopsy schemes may miss
almost a third of cancers (1). 
Nevertheless, the most efficient scheme with the optimal
number and location of cores has not been defined yet (1).
It is not clear when and how to perform a second biopsy,
whether it is necessary to perform the same sampling pro-

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Archivio Italiano di Urologia e Andrologia 2014; 86, 4

V. Scattoni, A. Russo, E. Di Trapani, U. Capitanio, G. La Croce, F. Montorsi

312

sy, SPBx demonstrated significantly greater PCa detection.
For previous ASAP and/or HGPIN, a trend for higher PCa
DR was demonstrated in the saturation group but did not
reach statistical significance.
Similarly, Scattoni et al. recently tried to identify the optimal
combination of sampling sites (number and location) to
detect PCa in patients previously submitted to an initial
negative prostatic biopsy (3). They prospectively per-
formed a transrectal ultrasound (TRUS)-guided systematic
24-core PBx in 340 consecutive patients after a first nega-
tive biopsy (at least 12 cores). Subsequently, they set the
cancer-positive rate of the 24-core PBx at 100% and calcu-
lated PCa DR for 255 possible combinations of sampling
sites. They reported that the more cores taken, the higher
the cancer DR. They showed a continuum of improvement
of the cancer DR when increasing the number of cores,
even if the cancer DR of the 24 cores was significantly
higher than only the mean DR rates of 14-core schemes.
Moreover, at a given number of cores, the DR rates varied
significantly according to the different combination of sites
considered. All of these studies demonstrate that SPBx pro-
vides a higher cancer DR than the extended approach in
the repeat setting and that the higher the number of cores,
the higher the number of cancers detected.
Nevertheless the regular use of SPBx in clinical practice
is not approved (4-5). The National Comprehensive
Cancer Network (NCCN) suggests performing a second
extended protocol after an initial negative extended
scheme and suggests considering SPBx only in patients
with a high risk of cancer after multiple negative biop-
sies. The 2013 European Association of Urology (EAU)
guidelines on PCa do not indicate the template that
should be used. Consequently, the ideal strategy for a
second PBx procedure has yet to be fully elucidated. 
Recently, interest has increased in defining more efficient
biopsy schemes for PCa detection with the minimum num-
ber of cores. Different variables, both clinical and not clin-
ical, may have an impact on the cancer DR. Apart from the
clinical characteristics of the patients, some procedural
characteristics may have an even greater impact on the can-
cer DR. Intuitively, adding more biopsies to prostatic areas
not sampled by common extended schemes should
increase the DR. It should be noted, however, that increas-
ing the number of biopsy cores is not the solution to the
problem and that the relationship between the number of
biopsy cores and the resulting cancer DR does not correlate
linearly. As a matter of fact, the curve of saturation tends to
plateau, and the increase of cores taken in the template is
not equivalent to the increase of cancer detected. 
Kawakami et al. analyzed the PCa detection rate by using a
three-dimensional (3D) 26-core systematic super-EPBx
protocol (6). In these analyses, subset biopsy schemes
were determined by recursive partitioning to achieve a
maximum cancer detection rate at a given number of
biopsy cores through a single transrectal approach, a sin-
gle transperineal approach, or a 3D combination of tran-
srectal and transperineal approaches. They were able to
extract a 3D 14-core biopsy protocol that could detect
95% of cancers with the fewest number of cores.
Nevertheless, their approach has the disadvantage of
requiring general anesthesia to perform the double
approach (transrectal and transperineal). Moreover, they

have not specified the most advantageous biopsy protocol
according to the clinical characteristics of the patients. 
All of these data demonstrate that cancer detection is
influenced not only by the number of cores but also by
the exact location of the cores. 
The report by Delongchamps et al. is a reminder that the
urologist needs to do a better job of biopsying the
prostate (7). A fairly extensive 36-core biopsy performed
in 48 autopsied prostates (median volume: 35 ml) missed
5 of 12 (42%) cancers found on whole-mount patholog-
ic analysis. In fact, the 36-core biopsy offered no benefit
over an 18-core protocol in terms of PCa detection (7). 
Adopting a scheme that is able to maximize the DR with
the fewest number of cores represents a possible new
modality of performing PBx. This approach is clinically
preferable to adopting a saturation scheme that is unable
to increase the cancer DR with the same proportion of
increasing numbers of cores. Scattoni et al. recently
demonstrated that both the number and the location of
biopsy cores taken affect cancer DR in a repeated biopsy
setting (3). They also showed that the “optimal” repeat
biopsy scheme varies according to the clinical characteris-
tics of the patients. Analysis revealed that for patients with
previous ASAP diagnosis, the most advantageous scheme
was a combination of a 14-core biopsy (without TZ biop-
sies). For patients with no previous ASAP diagnosis and
percentage of free prostate-specific antigen (%fPSA) of
10% or less, the most advantageous scheme was a 14-core
biopsy (including four TZ biopsies). The most advanta-
geous sampling scheme for patients with no previous
ASAP and %fPSA greater than 10% was a combination of
a 20-core biopsy (including 4 TZ biopsies). Moreover, the
number of repeated biopsy is controversial, also because
the DR is inversely related to the subsequent procedure. 
Djavan et al. reported in 2001 an original work on the risk
of PCa on repeat biopsies performed 6 weeks after an ini-
tial negative set. These investigators found that cancer
detection rates on biopsies 1, 2, 3 and 4 were 22%, 10%,
5% and 4%, respectively, and that 58%, 60.9%, 86.3% and
100% of patients who had RP had organ confined disease
on biopsies 1, 2, 3 and 4. The investigators concluded that
biopsy 2 in all cases of a negative finding on biopsy 1 seems
justified (8). Similarly, Campos-Fernandes et al. in a cohort
with extended biopsies found that 18%, 17%, and 14% of
patients had PCa in second, third, and fourth biopsies,
respectively. PCa detected at these sets of biopsies was sig-
nificant in 85% of cases (9). Detection of clinically insignif-
icant PCa (according to Epstein’s criteria) is an inevitable
risk of repeat biopsy, and its association with the number
of biopsy cores is an issue of considerable debate.
Moreover, SPBx has been evaluated as a staging tool to
improve the characterization of low-volume and well-dif-
ferentiated PCa, but whether SPBx improves prediction of
tumor insignificance remains open to debate. It should be
also noted that, in general, cancer missed on initial prostate
biopsy is likely to be smaller or more insignificant than
those cancers identified on first attempt. In this context,
the real issue with PCa detection is not overdiagnosis, since
only diagnosis or misdiagnosis exist, but rather potential
overtreatment. 
Detection and treatment of PCa should always be consid-
ered independent processes, and concern about overdetec-

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tion must be weighed against the risk of missing clinically
significant cancers. 
Finally, in patients with a diagnosis of PCa candidate to
active surveillance SPBx is preferable even if not mandato-
ry, while in cases of focal therapy SPBx may not be suffi-
cient and considered a surrogate to transperineal grid tem-
plate biopsy. However, the optimal number and location of
prostate biopsies in patients in active surveillance with a
low grade and low volume PCa and patients who are can-
didate to focal therapy has not been established. 
Several benefits appear to be associated with an image
guided approach to prostate biopsy. In summary, fewer
men are biopsied overall, a greater proportion of men with
clinically significant prostate cancer are biopsied, and fewer
men are attributed a diagnosis of clinically insignificant.
Even if the randomized EPBX and SPBx remain the gold
standard, many patients demand advances beyond the
‘‘old-fashioned’’ randomized biopsy, which is not consid-
ered the “future”. Nowadays, multiparametric MRI
(mpMRI) has demonstrated to have a high degree of accu-
racy for the detection of clinically significant prostate can-
cer and can be used to define a target area before prostate
biopsy. In the last five years, the role of image-guided tar-
geted biopsy has grown. The likelihood of detecting can-
cer in such a visible lesion is definitely higher than with a
randomized biopsy if the detection rate per core is con-
sidered. MpMRI-targeted biopsies have demonstrated
superiority over systematic randomized biopsies for the
detection of clinically significant disease and representa-
tion of disease burden, while deploying fewer cores. There
is evidence that the Gleason score obtained in a targeted
biopsy reflects the true Gleason score better than the
Gleason score obtained by a randomized PBx (10).
Hambrock et al. have demonstrated that MRI-guided biop-
sies significantly improve pretreatment risk stratification
by obtaining cores that are representative of the true
Gleason grade (11). In a recent review about MpMRI-tar-
geted biopsies, men with a clinical suspicion of prostate
cancer, a biopsy of the prostate that used MRI to inform
the sampling was associated with a detection rate of clini-
cally significant prostate cancer of 42%. This approach
might permit a reduction in the number of men who need
to undergo biopsy if they are deemed to have a normal
MRI. The efficiency of the targeted sampling appeared
superior to the standard approach (70% vs 40%). Since
the randomized PBx was associated with a diagnosis of
insignificant prostate cancer in 10% of men biopsied, this
cancer diagnosis might have been avoided if men had
undergone targeted biopsy alone (11). The authors also
concluded that adopting MpMRI-targeted biopsies rather
than randomized PBX, fewer men are biopsied overall, a
greater proportion of men with clinically significant
prostate cancer are biopsied, and fewer men are attributed
a diagnosis of clinically insignificant prostate cancer. On
the contrary, other authors have shown that in cases com-
bining targeted and randomized biopsies during one PBx
session, a substantial number of cancers were detected in
only the randomized cores (12). Relying on the targeted
biopsy alone would have led to a significant rate of under-
detection in these studies. There is no doubt that EPBx
might better characterize PCa volume and cancer extent
than just a targeted biopsy: the positive cores give us infor-
mation on not only the cancer extent but also the number

of negative cores. Targeted biopsies seem to reflect the true
Gleason score, yet they might underestimate the extent of
the cancer. Probably the combination of both targeted and
extended biopsies will show the most appropriate infor-
mation about the correct cancer characteristics.

CONCLUSIONS
The issue about the number and location of the cores is
still a matter of debate in repeat setting also because the
scenarios in which PBx is required are changing. At pres-
ent, SPBx seems to be necessary in most of the cases.
However, random prostate PBx do not represent the future
while imaging target biopsy are becoming more popular. 

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313Archivio Italiano di Urologia e Andrologia 2014; 86, 4

The optimal number of cores in the detection of prostate cancer after an initial negative biopsy

Correspondence
Vincenzo Scattoni, MD (Corresponding Author)
scattoni.vincenzo@hsr.it
Andrea Russo, MD - Ettore Di Trapani, MD - Umberto Capitanio, MD
Giovanni La Croce, MD - Francesco Montorsi, MD
Department of Urology, University Vita-Salute, Scientific Institute H 
San Raffaele. Via Olgettina 60 - 20132 Milan, Italy

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