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21 Diagnostic Performance ofPET-Based Targeted Fusion Biopsy inProstate Cancer
253
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91. Gondoputro W, Doan P, Katelaris A, Scheltema MJ,
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Optimizing Biopsy Core Quality
forDiagnosis
KennethA.Iczkowski
22
Introduction
Contemporary prostate biopsy is a signicant
challenge because of a frequently large number
of biopsies per patient, and prostate biopsies
often constitute half of a subspecialized genitourinary pathologist’s workload. Diagnostic yield
and reported results depend on
• Sampling approach,
• Amount of tissue sampled (individual core
length, aggregate core length, number of fragments, number of cores collected, and identication of extra-prostatic tissue),
• Histotechnologist’s skill, number of needle
cores embedded per cassette, number of tissue
cuts per slide, and
• Manner of reporting ndings.
Quality assurance requires comparing a labo-
ratory’s performance and cancer yield with
national benchmarks.
Approach
The transrectal approach is still used for most
modern prostate biopsy protocols, but this is
changing as the transperineal approach becomes
more widely used. Two areas are difcult to
sample this way. The transition zone of the prostate, anterior to the urethra, is distant from most
needle trajectories through the rectum
(Fig.22.1). The anterior horn of the peripheral
zone may be the only site of cancer (Fig.22.2),
and its far anterolateral location hinders sampling. Special sampling of these two areas using
perineal biopsies may be more effective than
transrectal ones.
K. A. Iczkowski (*)
Department of Pathology and Laboratory Medicine,
University of California—Davis,
Sacramento, CA, USA
e-mail: kaiczkowski@ucdavis.edu
© The Author(s), under exclusive license to Springer Nature Switzerland AG 2024
T. J. Polascik et al. (eds.), Imaging and Focal Therapy of Early Prostate Cancer,
https://doi.org/10.1007/978-3-031-66754-1_22
Fig. 22.1 The peripheral zone is a crescent shape wrapping around the transition zone
255
256
K. A. Iczkowski
sion (EPE), which changes the stage at prostatectomy from T2 to T3a [2]. A meta-analysis showed
targeted biopsies, compared to systematic biopsies, lead to a higher Gleason grade, causing an
upgrading in risk group classication in 12–18%
of patients [3]. Also, the frequency of Gleason
upgrading at radical prostatectomy was lower in
targeted biopsies (20%) as compared to systematic biopsies (42%) [4].
Fig. 22.2 Cancer in the peripheral zone’s left anterior
horn is easily visible in this gross specimen as a yellow
discoloration. This cancer could be missed on needle
sampling
Sampling
The number of prostate sites sampled is an important consideration. Twenty years ago, urologists
would commonly sample 1 to 3 left cores and 1 to
3 right cores, then submit them in vials marked
“right” and “left.” The emergence of the 6-site,
“systematic” sextant biopsy technique improved
the sensitivity of prostate cancer detection.
Studies from 2006 showed that sampling 10 to 14
sites, submitted separately, was superior to the
sextant technique [1] both in terms of sensitivity
for cancer and accuracy of Gleason grading. This
also facilitates schematic mapping of the extent
of the cancer.
By 2014, it was evident that MRI-targeted
biopsy detected more clinically signicant cancer
than systematic biopsy. In recent years, MRItargeted biopsies have become more common.
Zhao etal. showed that targeted biopsies tend to
show longer cancer core length and higher
Gleason scores than systematic biopsies. This
results from their intentionally oversampling
areas of high suspicion rather than directing each
biopsy to a different area of the prostate. Gleason
score on targeted biopsy, but not systematic
biopsy, was a predictor of extra-prostatic exten-
Core Length
Sampling begins with the procurement of needle
core biopsies in a systematic (6- or 12-site) or
targeted (MRI-guided) format. Core length can
vary among samples from different patients and
from the same patient (Fig.22.3). Two decades
ago, we showed that there can be a wide range of
core lengths obtained from various practices and
patients that are submitted to a processing site.
In 1847 men biopsied, a total length of all tissue
showed a ninefold variation, 108±27mm (range
30–275) and 81 ± 22 mm (30–228) in two
cohorts [5].
Length affects diagnostic sensitivity. The optimum for needle biopsy core length is
10–15mm.Those core lengths of 5–7mm or less
were less sensitive than the longer cores, and this
adversely affected the cancer detection rate [5].
Short cores of only a few millimeters usually
contain only bromuscular stroma and are not
contributory at all toward diagnosis.
We also calculated tissue length according to
the anatomic site of the biopsies. Biopsies from
the apex were signicantly shorter (p=0.0001)
than those from the mid-gland and base. The
apex had twice as many cores (<10mm) as the
mid-gland. Anecdotally, the apex may be the
hardest site to biopsy because of spatial constraints as one approaches the urogenital diaphragm. Not only were apical cores shorter than
mid-gland or base cores in our study, but apical
22 Optimizing Biopsy Core Quality forDiagnosis
Fig. 22.3 Three
prostate core samples
from the same patient
differ dramatically in
length
core length correlated strongly with cancer or
non-benign detection. Since the apex accounts
for 64% of margin positivity at prostatectomy
[6], apical biopsy adequacy demands special
attention.
257
Histologic Submission
Submission of too much tissue per cassette can
easily lead to core fragmentation (Fig. 22.4) or
core crossover (Fig.22.5), which impairs tissue
evaluation by the pathologist. Laboratories
should avoid this suboptimal result by processing
one core per cassette (or one sampling site per
cassette if there are up to 3 cores per site).
However, processing of three cores per cassette
from different sites in one cassette can be facilitated by differential inking of the three cores
(Fig. 22.6). A study showed that the diagnostic
yield of this approach was not inferior to one core
per cassette (Fig.22.7) [7] regarding suspicious/
premalignant ndings and rate of cancer
detection. Compared cancer yield from submitting 1 core/cassette (3–6 slices/2 slides) versus 3
cores/cassette (3 slices/2 slides) with differential
inks applied.
Fig. 22.4 Marked fragmentation of prostatic and rectal
tissues makes it difcult to measure the length of cancer
(millimeters) if it is present
Thus, some laboratories have conserved
resources (glass slides, blocks, and storage space)
by adopting this approach, with results as shown
(Fig.22.8).
258
K. A. Iczkowski
Fig. 22.5 Double crossover of cores hinders evaluation
and should be avoided
Fig. 22.7 The diagnostic yield from submitting 3 samples per cassette was not inferior to that from submitting 1
per cassette. There were similar rates of benign (46.2%,
Fig. 22.6 Differential inking of cores (green, blue, and
black) enables placement of apex, mid, and base to be
placed into the same cassette (totaling ve cores) and
evaluated separately
46.7%), ASAP (8.2%, 6.3%), HGPIN (4.5%, 4.4%), and
cancer (41.1%, 42.6%) diagnoses
22 Optimizing Biopsy Core Quality forDiagnosis
Fig. 22.8 Submission
of 1 versus 3 cores per
cassette. Three tissue
cuts per slide
Fig. 22.9 Slide
prepared from Lumea
BxChip™ Matrix.Most
of the purple seen here
is the tissue separators.
These serve to create
straight lanes for
placement of up to 6
tissue cores per slide,
optimizing tissue
integrity, layout, and
orientation (proximal
rectal end versus distal
end) while conserving
resources
259
BxChip™
The Lumea Company has introduced a method
of submitting six prostate cores in a “Sectionable
Matrix” (Fig.22.9). The purpose is to hold multiple biopsy cores in the same plane of section
and keep the cores straight and separate without
crossing over and in the same optical focal plane.
Moreover, there are arrows embedded in the separators, which preserve specimen orientation
(rectal end versus distal tip). If 12 total cores are
taken, then one BxChip™ holds the cores for
one side of the prostate, and the second for the
other side, so 2 BxChip™s get used for a typical
case.
From the pathologist’s perspective, this submission format really does improve specimen
processing and purportedly increases the assessable tissue yield [8], so it maximizes the information that can be derived from the tissue.
260
K. A. Iczkowski
Reporting Results
With many sites and cores sampled at once, how
is reporting to be optimized for patient care?
Iczkowski and Bostwick in 1999 established,
through a survey of urologists and pathologists,
that there was a preference for issuance of a separate line diagnosis for each sextant site instead of
condensing all diagnoses into one line with one
Gleason score [9]. This has been standard practice for many years. Some laboratories use a tabular format to organize this information.
The practice of issuing a merged interpretation
for the overall Gleason score is called a “global”
Gleason score. A survey in 2019 disclosed that this
global score is frequently given in Europe but less
often in North America, where urologists tend to
rely on the highest Gleason score in any one of a set
of biopsy samples [10]. However, for MRI-targeted
specimens containing >1 core but different Gleason
scores, compiling all scores into a “global” score
was recommended by the International Society of
Urological Pathology [11].
References
1. Elabbady AA, Khedr MM. Extended 12-core prostate biopsy increases both the detection of prostate
cancer and the accuracy of Gleason score. Eur Urol.
2006;49:49–53.
2. Raskolnikov D, Rais-Bahrami S, Turkbey B, et al.
Current ability of multiparametric prostate magnetic resonance imaging and targeted biopsy to
improve the detection of prostate cancer. Urol Pract.
2014;1(1):13–21.
3. Padhani AR, Schoots IG. Prostate cancer screening—stepping forward with MRI. Eur Radiol.
2023;33:6670–6.
4. Zhao Y, Seng FM, Huang H, et al. Prostate cancers
detected by magnetic resonance imaging-targeted
biopsies have a higher percentage of Gleason pattern 4 component and are less likely to be upgraded
in radical prostatectomies. Arch Path Lab Med.
2019;143:86–91.
5. Iczkowski KA, Casella G, Seppala RJ, Jones GL,
Mishler BA, Qian J, Bostwick DG.Needle core length
in sextant biopsy inuences prostate cancer detection
rate. Urology. 2002;59:698–703.
6. Shah O, Melamed J, Lepor H.Analysis of apical soft
tissue margins during radical retropubic prostatectomy. J Urol. 2001;165:1943–8.
7. Bostwick DG, Kahane H. Adequate histologic sectioning of prostate needle biopsies. Ann Diagn Pathol.
2013;17:357–60.
8. Wojno K, Al-Jundi R, Mazurco A, Hamzawy
HA.Mp16- BxChip™ clinical tissue array increases
cancer detection rate and amount of tissue available
for pathologist review. J Urol. 2016;195:e168. https://
doi.org/10.1016/juro.2016.02.2584.
9. Iczkowski KA, Bostwick DG.Sampling, submission,
and report format for multiple prostate biopsies: a
1999 survey. Urology. 2000;55(4):568–71.
10. Iczkowski KA, van Leenders GJ, Berney DM, etal.
Geographic differences in prostate cancer grading
practice between USA and non-USA urologic pathologists, #97. In: United States & Canadian academy
of Pathology’s 109th annual meeting, Los Angeles,
March 2, 2020, vol. 930; 2020. p.903.
11. van Leenders GJLH, van der Kwast TH, Grignon
DJ, Evans AJ, Kristiansen G, Kweldam CF, Litjens
G, McKenney JK, Melamed J, Mottet N, Paner GP,
Samaratunga H, Schoots IG, Simko JP, Tsuzuki T,
Varma M, Warren AY, Wheeler TM, Williamson
SR, Iczkowski KA, ISUP Grading Workshop
Panel Members. The 2019 International Society of
Urological Pathology (ISUP) Consensus Conference
on grading of prostatic carcinoma. Am J Surg Pathol.
2020 Aug;44(8):e87–99.
Part VI
Patient Selection and Ablation
Treatment Schema
Patient Selection: What Tumors
Should BeTreated Based onGrade,
Size, Location, Genetics andRisk
Category?
FabianFalkenbach, ArdalanAhmad,
JamesS.Wysock, GeorgSalomon,
andHerbertLepor
23
Introduction
Optimal patient selection for focal treatment
aims to identify patients with clinically signicant prostate cancer (PCa) that, if left untreated,
would cause cancer-specic morbidity and mortality but in whom focal therapy (FT) has a high
chance of postponing or even prohibiting cancer
progression or need for radical treatment. The
potential treatment burden should be counterbalanced by the potential oncologic benets and
omission of the radical approach and its associated toxicity. Owing to the increasing implementation of prostate-specic antigen (PSA)
screening and MRI-guided prostate biopsy, small
deposits of clinically signicant PCa are detected
earlier, and conventional treatment algorithms
may trigger overtreatment [1]. Therefore, FT
F. Falkenbach (*) · G. Salomon
Martini-Klinik Prostate Cancer Center, University
Medical Center Hamburg-Eppendorf,
Hamburg, Germany
e-mail: f.falkenbach@uke.de; g.salomon@uke.de
A. Ahmad
Division of Urology, Department of Surgery,
University Health Network Princess Margaret Cancer
Center, Toronto, ON, Canada
e-mail: Ardalan.Ahmad@uhn.ca
J. S. Wysock · H. Lepor
Department of Urology, NYU Langone Health, NYU
School of Medicine, New York, NY, USA
e-mail: james.wysock@nyumc.org;
Herbert.lepor@nyulangone.org
may be a key strategy for reducing overtreatment
and exploiting the full potential of ultra-early
detection through optimal patient selection [2, 3].
Grade andSize: Tumor Factors
• Gleason Grade Groups (GGG) 2 and 3 are
ideal candidates for focal therapy (FT).
• However, GGG should be considered as a spec-
trum: high-volume GGG 1, as well as small
deposits of GGG 4, may also be treated by FT.
• Size acts as a surrogate for tumor aggressive-
ness within GGG.
Historically, focal therapy (FT) has been an
alternative for patients suitable for active surveillance (AS) because systematic transrectal biopsy
hinders diagnostic accuracy [4], extensive transperineal template/mapping biopsies never
reached the standard of care because of the additional effort required, anesthesia, and slightly
higher post-procedure morbidity [5, 6], and new
treatment modalities are typically applied rst in
less aggressive disease [3, 7]. For instance, in an
early landmark study on HIFU by Blana etal.,
most patients had a Gleason Score <7 and PSA
≤10 ng/ml [8]. MRI-guided biopsy has increased
the detection of clinically signicant prostate
cancer (PCa) at an early stage [9–12] and currently represents a guideline recommendation for
the initial diagnosis [13, 14]. Moreover, growing
© The Author(s), under exclusive license to Springer Nature Switzerland AG 2024
T. J. Polascik et al. (eds.), Imaging and Focal Therapy of Early Prostate Cancer,
https://doi.org/10.1007/978-3-031-66754-1_23
263
264
F. Falkenbach et al.
evidence of the long-term indolent nature of lowrisk PCa has emerged [15]. Today, AS is more
accepted, and overtreatment is considered the
main risk for low-risk PCa [13]. Therefore,
patients with GGG 2 and 3 are ideal candidates for FT. FT complements AS in a changing
world [2, 3, 16]. This shift in FT has been greatly
endorsed by an international panel recommendation over recent years [3, 17–25]. However, consensus statements are heterogeneous, long-term
randomized data for FT are scarce, and globally
accepted guidelines are still missing [26]. The
eligibility criteria are often insufcient [27]. This
may be partly explained by the fact that PCa is a
growth process; the disease burden is a spectrum.
Therefore, clear cutoff values for or against the
FT based on GGG are insufcient. A holistic
approach addressing tumor, treatment, and
patient factors should be applied [28]. Several
strategies for assessing tumor factors prior to
treatment have been described.
First, cancer volume is associated with
increased disease aggressiveness. There is no
denite maximum tumor volume for FT, and cancer volumetry has changed over time. In the preMRI era, the cancer characteristics of the cores
(such as maximum cancer percentage per core,
maximum cancer core length, and number of
involved cores) were used [3].
For instance, the 2017 Delphi consensus recommends a maximum cancer involvement of
20% of the prostate volume [23], and the German
guidelines recommend FT for patients with a
maximum of 50% positive biopsy cores from
only one lobe [29]. Other classic thresholds
include a maximal cancer percentage per core of
less than 20%, maximal cancer length in each
core below 7 mm, and maximal core involvement
of <33%. In MRI fusion biopsy, the cancer core
length correlates with pathological cancer volume during radical prostatectomy (RP) [30].
Interestingly, in this study, the targeted cancer
core length was a better predictor of the actual
pathological cancer dimension than lesion size
measured on MRI. The maximum cancer core
length on targeted biopsy correlates with both
cancer volume and pathological stage at RP [31].
In fact, it appears reasonable to treat high volume
GGG 1 only disease. High-volume GGG1 is
associated with an increased upstaging risk [32].
One in ve patients with low-risk PCa at biopsy
and ≥50% positive biopsy cores had advanced
disease at RP [32]. Furthermore, the ultra-low
incidence of GGG1 metastasis is mainly established by the Gleason grades dened in RP specimens [33, 34]. In AS cohorts diagnosed by
systematic biopsy, approximately half of the
patients harbor signicant PCa at RP [35]. Even
in modern series, such as the PRIAS trial,
415/1480 men (28%) showed reclassication at
repeat biopsy [36].
Gleason pattern 4 (and above) tissue is the
main driver of disease and metastatic progression. Gleason Pattern 4 tissues harbor more
molecular hallmarks of cancer [37] and drive
failure of AS [38], and the percentage of Gleason
pattern 4 in intermediate-risk PCa at biopsy or
RP has strong prognostic implications
(“Quantitative Gleason Grading”) [39]. In fact,
the MRI-guided biopsy path produces articial
stage migration while achieving higher congruence between biopsy and RP specimens [40], i.e.,
low-volume GGG 4 disease in fusion biopsies
may represent GGG 3 in conventional biopsy
sampling [1]. Recent data from the MRI era
showed good medium-term cancer control after
FT in mainly intermediate- and high-risk patients.
In this study, the failure-free survival after 7 years
in intermediate- and high-risk cancers was 68%
(95% CI: 62–75%) and 65% (95% CI: 56–74%),
respectively, without a signicant difference
between the groups (p = 0.3) [41]. In conclusion,
low- volume GGG 4 may also be a good candidate for FT.
Second, cancer volume and aggressiveness
can also be appropriated using a range of different imaging modalities, such as MRI.The 2017
Delphi Consensus, among others, recommends
multiparametric MRI for all patients prior to FT
[23, 29] and tumor foci of <1.5 or <3 mL (for
hemigland ablation) on MRI should be treated
with FT [23]. Lesion measurements should be
based on the diffusion weighted imaging-apparent diffusion coefcient(DWI-ADC) sequence/
map of MRI [42, 43] and should be considered
cautiously because they often underestimate the