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98
A. Villers et al.
GG1 tumors could be dened as index lesions.
The histologic grading and the concept of index
lesion as a driver of cancer progression are
addressed in separate chapters of this textbook
(Identifying and Characterizing the Index Lesion.
The Role of Molecular Techniques to Distinguish
Low Grade from Lethal Cancers).
The validation of selection criteria such as
tumor volume and grade can be assessed in two
ways: (1) assessing outcomes of FT series at
1 year through per-protocol MRI and biopsies
during follow-up or (2) assessing cases treated by
radical prostatectomy specimens and retrospectively applying eligibility criteria for FT.
1. Assessing outcomes of FT series at 1year by
per-protocol MRI, biopsies, and during follow- up. In a review of HIFU studies, a median
of 85% of patients with no clinically signicant cancer in the treated area was reported
[4]. In a multicenter UK cohort of 1379
patients with a median follow-up of 32
(17–58) months, 7-year failure-free survival
dened as avoidance of no evidence of disease to require salvage whole-gland or systemic treatment or metastases was in
intermediate- and high-risk cancers 68%
(95% [CI] 62–75%) and 65% (95% CI
56–74%; p = 0.3), respectively. Thirty-nine
patients received ADT after focal therapy
associated with salvage therapy, and three
patients developed metastases.
2. Assessing radical prostatectomy specimens
for which, cases were retrospectively selected
for FT. A European multicenter cohort of
patients who underwent MRI-targeted and
systematic biopsies followed by radical prostatectomy was studied [5]. The Imperial
College of London eligibility criteria for FT
were applied: (1) unifocal MRI lesion with
Prostate Imaging Reporting and Data System
score of 3–5; (2) prostate-specic antigen
(PSA) ≤20ng/ml; (3) cT2–3a stage on MRI;
and (4) International Society of Urological
Pathology grade group (GG) 1 and ≤6mm or
GG 2–3. A total of 334 patients were included.
The primary outcome was unfavorable disease at RP, dened as GG ≥4, and/or lymph
node invasion, and/or seminal vesicle invasion, and/or contralateral clinically signicant
cancer. Overall, 43 patients (13%) had unfavorable disease on RP pathology. The model
(novel nomogram predicting the probability
of unfavorable disease at radical prostatectomy) included PSA, clinical stage on digital
rectal examination, maximum lesion diameter
on MRI, and had an AUC of 73%. The addition of other MRI or biopsy information did
not signicantly improve the model
performance.
Role ofSpatial Distribution
ofCancers According totheZone
ofOrigin andVolume
Modeling studies estimate that approximately
30% of low-volume cancers are located anteriorly [6]. Anterior cancers originate in the transition zone (TZ), and these may be compressed
further anteriorly during benign prostatic hyperplastic (BPH) growth, giving rise to cancers
located in the anterior bro-muscular stoma
(AFMS) [7].
Prevalence According totheZone
ofOrigin andVolume. Patterns
ofSpread
Nevoux etal. analyzed a series of cystoprostatectomy specimens performed for bladder cancer
from 345 consecutive patients without clinically
manifest prostate cancer [6]. In the 96 prostates
with prostate cancer, 215 cancer foci were identied (mean 2.24 cancers per prostate). Of the 215
cancers, 90% were <0.5 cc and 79% <0.2 cc
(Fig.9.1). Overall, 88% of cancer foci were clinically insignicant with a tumor volume<0.5cc
and no Gleason patterns 4–5. Seventy-ve percent of the cancer foci were in the peripheral
zone (PZ), while the remainder were within the
transition zone (TZ). One-third of cancer foci
were anteriorly located beyond the conventional
area sampled by posterior biopsies. One-fth of
cancer foci were within 6 mm of the apex.
9 Understanding Tumor Biology and Pathology: Cancer Grade, Volume, and Spatial Location…
99
Fig. 9.1 Spatial distribution of (a) 146 prostate cancers
<0.1cc and (b) 24 prostate cancers 0.2-0.5cc on sagittal
and transverse prostate sections for an average 45 cc
Limitations include that cystoprostatectomy cancer foci are biologically at an earlier stage than
screening-detected cancers.
In a series of 108 RP specimens, Haffner etal.
out of 188 PZ cancers, 179 were <4 cc and 168
<2 cc [8]. PZ cancers tend to remain conned to
their zone of origin for tumor volumes <2 cc.
Between 2 and 4cc, some cancers partly spread
into the TZ or AFMS.In total, 64% and 90% of
PZ cancers, <4cc were located in the lower and
posterior half of the gland, respectively.
Additionally, 10% were located in the anterior
horn of the PZ.Cancers <2cc were conned to
one lobe in 164 of 168 (98%) cases and not conned in 3 of 11 (27%) in cancers measuring
2-4 cc in volume. Only cancer ≥2 cc involved
both apex and base in the sagittal plane.
Bouye analyzed a series of 91 prostates with
TZ/AFMS foci. Overall, 79 foci were< 4cc and
69 were<2cc [7]. Additionally, 50% and 70% of
cancers <4cc were located in the anterior third and
inferior half of the TZ and/or AFMS, respectively.
The authors sub-classied three varieties of small
cancers <2cc according to their location related to
the boundaries of the histological zones: TZ type 1
(40%) represented cancers conned to one TZ
lobe; TZ type 2 (35%) represented cancers mostly
in one TZ lobe but crossing its anterior boundary;
and type 3 AFMS (25%) represents cancers conned to the AFMS.Specic insights into the pattern of spread and case selection of TZ/AFMS foci
gland. Dots represent the center of each cancer focus. PZ
cancers are in red and TZ /AFMS in green. (Adapted from
Nevoux etal. [6])
are addressed in a separate chapter of this textbook
(Focal Therapy for Anterior Cancers).
Cancer Laterality andFocality
In the analysis of a series of cystoprostatectomy
specimens by Nevoux etal., the mean number
of cancer foci per prostate was 2.24.
Multifocality was observed in 48% of cases. In
instances of multifocality, the second cancer
was located in the same lobe in 21% of cases
and in the contralateral lobe in 79% (Fig.9.2)
[6]. In multifocal cases, distances between the
largest foci and the following two largest foci
according to their centers and nearest limits are
shown in Table9.1.
The question remains regarding how this distribution observed in autopsy or unselected specimens of prostatectomies translates into clinical
series. Okabe et al. concluded that among men
with a clinical suspicion of prostate cancer
receiving MRI, 28.7% had a single targeted
biopsy-conrmed lesion, and 10.4% had multifocality on MRI [9]. However, many MRIundetected contralateral cancer foci were
identied. Only 6.0% of biopsy-naïve men
remained with a single GG2 MRI lesion potentially amenable to FT.
In summary, PZ (foci <2cc), TZ/AFMS cancer contours and locations can be predictable and
100
UNILATERAL 21 % BILATERAL 79 %
UNIFOCAL
A. Villers et al.
42 %
a
b
MULTIFOCAL
58 %
c
d
Fig. 9.2 Average transverse section of a 45cc prostate at
mid-gland depicting a model of distribution of 215 separate prostate cancers in 96 cystoprostatectomy specimens
demonstrating unifocal (a, b) and multifocal (c, d) unilateral (c) bilateral (d) tumors. Among the unilateral and
multifocal cases (c), cancers were in the same anterior or
posterior part of the gland in 50% of cases. (a) posterior
Table 9.1 Distances between the largest lesions and the following two largest lesions according to their centers and
nearest limits and their laterality (lesion 1 is the largest lesion, lesion 2 is the second largest lesion, and lesion 3 is the
third largest lesion in the same specimen) (Adapted from [6])
Mean distance (range), mm Unilateral lesions All multifocal lesions
Between the centers of the largest
surfaces of lesions 1 and 2
Between nearest contour borders of
the largest surfaces of lesions 1 and
2
Between the centers of the largest
surfaces of lesions 1 and 3
Between nearest contour borders of
the largest surfaces of lesions 1 and
3
18 (8–29) 23 (8–39)
11 (3–23) 15 (3–35)
17 (11–23) 22 (6–49)
12 (7–18) 16 (0–35)
insignicant cancer of 0.1 cc that could be detected by
posterior systematic biopsies (SB). (b) anterior insignicant cancer of 0.1cc undetectable by posterior SB. (c, d)
unilateral (c) and bilateral (d) multifocal cancers with a
large PZ cancer of 0.7 cc and a smaller TZ cancer of
0.1cc. (Adapted from Nevoux etal. [6])
9 Understanding Tumor Biology and Pathology: Cancer Grade, Volume, and Spatial Location…
101
conform to histological zonal boundaries.
Understanding the origin of cancer and its intraprostatic pattern of dissemination is crucial for
imaging, diagnosis, and guidance for biopsy and
focal therapy. Further studies will be necessary to
better understand the molecular events and potential intra-prostatic spread of cancers.
Concept ofSafety Margin inFT
FT should consider treating the histologically
malignant part rather than solely relying on imaging
data based on pathologic evidence. Priester etal. at
UCLA demonstrated that MRI consistently underestimates the size and extent of prostate tumors in
114 men who all had MRI before radical prostatectomy, with patient-specic mold processing of the
specimen [10]. At nal pathology assessment, 222
tumors were evident on whole-mount sections, 118
of which had been identied on MRI.For the 118
ROIs, the mean volume was 0.8cc, and the longest
3D diameter was 17 mm. However, for matched
pathologic tumors, most of which were GG≥2, the
mean volume was 2.5cc, and the longest 3D diameter was 28mm. The median tumor had a 13.5mm
maximal extent beyond the MRI contour, and 80%
of cancer volume from matched tumors was outside
of ROI boundaries. Size estimation was most accurate in the axial plane and least accurate along the
base-apex axis. Prostate cancer foci had an average
diameter 11 mm longer and a volume 3 times
greater than T2-weighted MRI segmentations.
These results may have important implications for
an improvement of the accuracy, especially along
the cranio-caudal axis. The latest report of this
group updates results showing an index cancer
detection rate by MRI in 224/285 (78.6%) tumors
validated by whole-mount histopathology
(WMHP). The median maximal diameter of PCa
index tumors was on MRI of 1.3 cm whole on
WMHP-2.0 cm with a poor Pearson correlation
coefcient of 0.45 (p<0.05).
A properly optimized targeted biopsy can
rene candidate selection, margin evaluation, and
side effect reduction. Priester etal. [10] recommended that a planning biopsy should be done to
determine disease extent in all patients undergo-
ing partial gland ablation (PGA) as cancer has
been noted to extend up to 15mm from the lesion
border on imaging.
Le Nobin et al. searched the accuracy of
MRI before prostatectomy in 33 patients [11].
The concordance was conducted between
lesion borders traced by radiologists on MRI
pictures and MRI and three-dimensional reconstructions created from high-resolution digitalized slides of radical prostatectomy
specimens and co- registered to imaging using
advanced software. Tumors were compared
between histology and imaging by the
Hausdorff distance and stratied by the MRI
suspicion score, Gleason score, and lesion
diameter. Distances between the largest lesions
and the following two largest lesions according
to their centers and nearest limits and their laterality are shown in Table 9.1. The results
showed a boundary underestimation in larger
lesions with an imaging suspicion score of 4 or
greater (mean 3.49±2.1mm, p<0.001) and a
GG ≥7 (mean 2.48±2.8mm, p 1/4 0.035). A
simulated treatment volume based on the MRI
boundary missed an average of 14.8% of tumor
volume compared to that based on the histological boundary (Fig. 9.3). Adjustment of
simulated treatment volume to a 9mm treatment margin achieved complete histological
tumor destruction in 100% of patients that can
have a clinical application. The exact limits of
an appropriate treatment zone have not been
well established in prospective studies.
Fig. 9.3 MRI lesion encompassed by histological lesion.
The red outline indicates histological boundaries. Small
2-headed arrows indicate Housdorff distance. Large
2-headed arrows indicate Hausdorff Max. (Adapted from
Le Nobin etal. [11])
102
A. Villers et al.
Extra-Prostatic Extension (EPE) Is
Not anAbsolute Contraindication
toFT
When considering therapy for any given prostate
cancer focus, the possibility of EPE must be
taken into account. A concern for FT is its
application to a unilateral pT3a tumor. EPE is a
signicant pathological parameter identied after
RP that can inuence disease-free recurrence.
Mouraviev et al. reported that among 1184
patients with low-risk PCa, EPE occurred in
19.2%, as conrmed by pathological assessment
of RP specimens [12]. Only some of these
patients, theoretically, with unilateral or unifocal
PCa and large EPE, may not be eligible for
FT. Most of them can still potentially benet
from FT since several technologies, such as cryoablation, can extend its therapeutic effect beyond
the gland boundary, thereby treating EPE. Tay
etal. retrospectively reviewed 120 men with clinically localized PCa undergoing mpMRI and
radical prostatectomy to assess EPE [13].
Radiologic prediction of pECE from standard
radiologic reports (standard read) and by a specialized reader blinded to clinical and pathologic
ndings (specialized read) was used. The incremental benet of standard read and specialized
read by sequential addition to a baseline clinical
parameter-only logistic regression model predicting pECE was determined. The sensitivity and
specicity of standard read were 77% and 44%,
respectively, whereas those of specialized read
were 86% and 81%. This second opinion may be
useful when considering active surveillance,
nerve-sparing surgery, or focal therapy.
References
1. Bommelaere T, Villers A, Puech P, et al. Risk estimation of metastatic recurrence after prostatectomy:
a model using preoperative magnetic resonance
imaging and targeted biopsy. Eur Urol Open Sci.
2022;41:24–34.
2. Deleuze C, Dickinson L, Orczyk C. Re: Thomas
Bommelaere, Arnauld Villers, Philippe Puech, etal.
Risk estimation of metastatic recurrence after prostatectomy: a model using preoperative magnetic resonance imaging and targeted biopsy. Eur Urol Open
Sci 2023.
3. Lebastchi AH, George AK, Polascik TJ, et al.
Standardized nomenclature and surveillance methodologies after focal therapy and partial gland ablation
for localized prostate cancer: an international multidisciplinary consensus. Eur Urol. 2020;78:371–8.
4. Hopstaken JS, Bomers JGR, Sedelaar MJP, et al. An
updated systematic review on focal therapy inlocalized prostate cancer: what has changed over the past 5
years? Eur Urol. 2022;81:5–33.
5. Mjaess G, Peltier A, Roche J-B, etal. A novel nomogram to identify candidates for focal therapy among
patients with localized prostate cancer diagnosed via
magnetic resonance imaging-targeted and systematic biopsies: a European multicenter study. Eur Urol
Focus. 2023;9:992–9.
6. Nevoux P, Ouzzane A, Ahmed HU, etal. Quantitative
tissue analyses of prostate cancer foci in an unselected
cystoprostatectomy series. BJU Int. 2012;110:517–23.
7. Bouyé S, Potiron E, Puech P, et al. Transition zone
and anterior stromal prostate cancers: zone of origin
and intraprostatic patterns of spread at histopathology.
Prostate. 2009;69:105–13.
8. Haffner J, Potiron E, Bouyé S, etal. Peripheral zone
prostate cancers: location and intraprostatic patterns of
spread at histopathology. Prostate. 2009;69:276–82.
9. Okabe Y, Patel HD, Rac G, et al. Multifocality of
prostate cancer and candidacy for focal therapy
based on magnetic resonance imaging. Urology.
2022;169:141–9.
10. Priester A, Natarajan S, Khoshnoodi P, etal. Magnetic
resonance imaging underestimation of prostate cancer geometry: use of patient specic molds to correlate images with whole mount pathology. J Urol.
2017;197:320–6.
11. Julien LN, Rosenkrantz AB, Arnauld V, etal. Image
guided focal therapy for magnetic resonance imaging visible prostate cancer: dening a 3-dimensional
treatment margin based on magnetic resonance
imaging histology co-registration analysis. J Urol.
2015;194:364–70.
12. Mouraviev V, Mayes JM, Sun L, etal. Prostate cancer
laterality as a rationale of focal ablative therapy for
the treatment of clinically localized prostate cancer.
Cancer. 2007;110:906–10.
13. Tay KJ, Gupta RT, Brown AF, et al. Dening the
incremental utility of prostate multiparametric magnetic resonance imaging at standard and specialized
read in predicting extracapsular extension of prostate
cancer. Eur Urol. 2016;70:211–3.
Identifying andCharacterizing
theIndex Lesion
FrancescoCei, MasatomoKaneko, AndreAbreu,
andGiovanniEnricoCacciamani
10
Introduction
Prostate cancer is a heterogeneous disease that
can be unifocal or multifocal according to the
number of cancerous lesions inside the gland.
Pathology studies on prostatectomy specimens
have always shown that low-risk prostate cancer
in almost 70–80% of cases is multifocal [1, 2].
This is the reason why tissue-sparing treatment
in prostate cancer traditionally has never been
performed despite being extremely common in
other solid cancers like kidney, breast, or thyroid. However, thanks to improved screening
and prostate cancer detection, a greater amount
F. Cei
Center for Image-Guided Surgery, Focal Therapy and
Articial Intelligence for Prostate Cancer, USC
Institute of Urology Catherine and Joseph Aresty
Department of Urology, Norris Comprehensive
Cancer Center, Keck School of Medicine, University
of Southern California, Los Angeles, CA, USA
Division of Experimental Oncology/Unit of Urology,
URI, IRCCS Ospedale San Raffaele, Milan, Italy
e-mail: francesco.cei@med.usc.edu
M. Kaneko · A. Abreu · G. E. Cacciamani (*)
Center for Image-Guided Surgery, Focal Therapy and
Articial Intelligence for Prostate Cancer, USC
Institute of Urology Catherine and Joseph Aresty
Department of Urology, Norris Comprehensive
Cancer Center, Keck School of Medicine, University
of Southern California, Los Angeles, CA, USA
e-mail: masatomo.kaneko@med.usc.edu;
andre.abreu@med.usc.edu;
giovanni.cacciamani@med.usc.edu
of patients present with early-stage cancer and
potentially can be perfect candidates for focal
therapy (FT) [3].
The index lesion is the tumor focus that contains the largest volume, the highest Gleason
grade; and, theoretically, is the main determinant
of the cancer prognosis. In this chapter we are
going to discuss the implications of multi and
unifocal cancer, the role of the index lesion,
together with possible challenges and
controversies.
Tumor Unifocality andMultifocality
While a clear denition of tumor multifocality
exists for breast cancer (i.e., the presence of two
or more synchronous ipsilateral neoplasms separated by benign tissues in the same or different
quadrants of the breast [4]), no denitive characterization has been established for multifocal
prostate cancer. Villers et al. [5] introduced an
initial denition, identifying multifocal prostate
cancer as a tumor featuring a dominant focus,
termed the index lesion, accompanied by a secondary smaller lesion of lower grade. To enhance
discrimination between two lesions, a distance
threshold of 3mm from the second closest lesion
was introduced [6].
Historically, the prevalence of multifocality in
prostate cancer, coupled with the challenge faced
by urologists in reliably detecting such cases, led
© 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_10
103
104
a
b
F. Cei et al.
to a therapeutic focus on radical prostatectomy
(RP) and radiation therapy (RT) [7]. The concern
of missing out on clinically signicant cancer
tumors outside the index lesion hindered the
application of FT in low-risk patients. However,
the current trend is to minimize treatment-related
morbidity while upholding oncological safety.
This shift is pushed by the earlier diagnosis of
prostate cancer at an initial stage, with an increasing number of studies reporting a higher percentage of patients having unifocal prostate cancer or
a “biological unifocal tumor.” The latter is dened
as multifocal prostate cancer with clinically nonsignicant disease [8]. Figure 10.1 shows three
real case scenarios of unifocal, multifocal, and
biological monofocal prostate cancer.
Several studies suggest that 10–40% of
patients diagnosed with low-risk prostate cancer
exhibit unifocal diseases. Interestingly Song etal.
reported in a cohort of Korean patients a rate of
unifocal prostate cancer of 67%, signicantly
higher in comparison to western prostate adeno-
Fig. 10.1 Three real life case scenario of unifocal, multifocal and biological unifocal tumor. (a) Unifocal tumor:
PSA 5.4, PV 23.9cc, PSA density 0.23ng/ml2, PIRADS
5 (Left Apex Peripheral Zone). Gleason Score 4+4 from
the target. Systematic cores from contralateral side were
benign. (b) Multifocal tumor: PSA 13.1, PV 47.8 cc,
PSA density 0.27 ng/ml
Zone Lesion) and PIRADS 3 (Left Transition Zone
Lesion). Gleason Score 4+3 from the Right Peripheral
2
, PIRADS 5 (Right Peripheral
Zone target and Gleason Score 3 + 4 from the Left
Transition Zone target. (c) Biological unifocal tumor:
PSA 4.5, PV 63cc, PSA density 0.07ng/ml
(Right Mid Transition Zone Lesion) and PIRADS 4 (Left
Mid Peripheral Zone Lesion). Gleason Score 3+ 4 from
the right Transition Zone target and Gleason Score 3+3
(clinically non-signicant prostate cancer) from the Right
Peripheral Zone target
2
, PIRADS 5
c
10 Identifying andCharacterizing theIndex Lesion
Fig. 10.1 continued
105
carcinoma [9]. However, the substantial variability observed among these studies is attributed to
the methodology employed in processing radical
prostatectomy specimens, specically the thickness of pathology slides. For instance, the slicing
of samples at 6mm instead of 3mm may result in
an inaccurate characterization of a tumor as unifocal. It has been estimated that the use of 6mmthick pathology slides leads to the loss of
approximately 17% of additional small foci
within the prostate [10]. Moreover, a notable bias
is associated with pathologist interpretation.
Achieving a comprehensive scan of the entire
prostate would require an evaluation of approximately 2500 pathology slides, a task impractical
within the clinical role of a pathologist [11].
Additionally, the accurate denition of the number of lesions is highly dependent on the subjective interpretation of the pathologist, given that
the majority of prostate cancer lesions do not
exhibit perfect ovoid shapes but rather present a
nonhomogeneous morphology [12].
tumor within the prostate determines the natural
progression of the disease [13]. This theory is
grounded in the observation that the pathological
attributes of the index lesion, such as Gleason
grade, dimensions, and extraprostatic extension,
typically dictate the prognosis of the disease [14].
Research indicates that the estimated volume of
3
the index lesion falls between 0.3 and 1.5cm
,
constituting almost 90% of the total tumor volume [13, 15].
Crucially, Karvatakis etal. demonstrated that
in multifocal prostate cancers, key histopathological features—namely Gleason grade, extraprostatic extension, and seminal vesicle
invasion—are determined by the index lesion
[16]. Furthermore, studies conducted on patients
undergoing active surveillance reveal that tumors
with a size of 0.5cm
3
exhibit a volume doubling
time of 48months [17]. Given this characteristic
and considering that lymph node metastasis is
typically observed when the tumor volume
reaches at least 4 cm3, it becomes plausible to
classify these lesions as nonsignicant cancers.
The FLAME trial showed that it is possible to
Signicance andDebate
Surrounding theIndex Lesion
Theory
improve biochemical disease-free survival in
patients with intermediate- and high-risk prostate
cancer undergoing whole-gland external beam
radiotherapy by adding a focal boost to the main
In recent years, signicant efforts have been dedicated to substantiating the index lesion theory,
according to which the largest and highest-grade
intraprostatic lesion dened at the multiparametric magnetic resonance imaging (mpMRI). This
Phase III randomized clinical trial proved the
106
F. Cei et al.
prognostic benet of adopting a more aggressive
approach toward treating the index lesion [18].
However, the discussion on this topic remains
intensely debated. In a survey involving 425 urologists, only 45% subscribed to the “index lesion
theory,” with a notably higher acceptance rate
among professionals in academic centers [15].
Despite the conventional belief that small
lesions possess low biological potential, emerging studies suggest that even lesions as small as
0.1 cm3 can manifest invasiveness and aggressiveness. For instance, Ruitjer etal. reported that
14% of nonindex lesions exhibited extraprostatic
invasion [19]. Another study identied men with
lymph nodal metastasis despite prostatic lesions
smaller than 0.2cm3 [20]. Finally, a study encompassing 239 patients with a tumor volume less
than 0.5 cm3 revealed rates of 18% exhibiting
poor differentiation, 5% with extraprostatic
extension, 1% with positive lymph node metastasis, and 3% experiencing oncological progression within 5 years of diagnosis [21]. These
ndings collectively suggest that tumor volume
alone may not reliably estimate the prognosis and
natural history of the disease. This also raises a
discussion on whether all index lesions should be
considered clinically signicant and whether all
clinically signicant lesions are actually index
lesions.
Role ofImaging inDening Index
Lesions
For decades, patient selection for FT has been
slowed down by the absence of a reliable imaging
technology capable of accurately identifying the
index lesion. Early case series on FT relied on
patients diagnosed through transrectal ultrasound
(TRUS)-guided biopsy, a method known for its
inherent randomness and resulting in data fraught
with inaccuracies in terms of tumor volume,
localization, and grade [22]. The landscape
changed signicantly with the introduction of
mpMRI.Now, our ability to recognize and dene
the index lesion has markedly improved, along
with the capacity to appropriately select candidates for FT.
The negative predictive value of mpMRI in
forecasting the absence of a signicant lesion has
been reported to range from 63% to 98% [23,
24]. In a separate study, the sensitivity, negative
predictive value, and negative likelihood ratios of
mpMRI for detecting lesions larger than 4 mm
and/or Gleason score≥3+4 were reported to be
58–73%, 84–89%, and 0.3–0.5, respectively [25].
Furthermore, mpMRI has assumed a central role
in the biopsy process, with a growing number of
urologists in tertiary referral centers opting for
MRI-targeted biopsies.
The key to appropriately using FT lies in the
selection of ideal patients. This heavily relies on
the diagnostic accuracy of mpMRI, biopsies, and
available biomarkers. Beyond patient selection,
mpMRI plays a crucial role in the delivery of FT,
providing optimal navigation within the prostate
to treat target lesions and facilitating the oncological post-operative follow-up of patients
undergoing the procedure in conjunction with
validated biomarkers [26]. Despite this great
improvement in characterizing index lesions, the
accuracy of mpMRI in identifying prostate cancer multifocality is poor. Indeed, mpMRI misses
low-volume csPCa in approximately 30% of
patients. The detection rate for csPCa at TRUS-Bx
was 8% for PI-RADS 2, 15% for PI-RADS 3,
36% for PI-RADS 4, and 58% for PI-RADS 5
lesions [27]. Despite this limitation, the main
future challenge for mpMRI is the ability to diagnose cancer without the need for biopsy proof.
Emmett etal. proved that the addition of PSMAPET/CT to MRI improved the MRI sensitivity
(83% vs. 97%) and NPV (from 72% to 91%),
thus providing a more effective strategy for safely
avoiding biopsy compared with relying on MRI
alone [28]. This can theoretically bring us to a
signicant change in the workup of prostate cancer diagnosis, but for the time being, the use of
MRI and targeted biopsies is the most efcient
diagnostic pathway to provide an acceptable
mapping of the prostatic gland and perform FT
without taking oncological risks.
a
b
10 Identifying andCharacterizing theIndex Lesion
107
Dual Nature ofProstate Cancer:
Monoclonal Vs. Multiclonal
Hypotheses andTheir Impact
onFocal Therapy Development
Tumors can arise through either a monoclonal or
polyclonal process. The monoclonal hypothesis
states that all cancer foci originate from the same
cancer stem cells, attributing the cancerogenic
process to a single transformative event. This
implies that a solitary cancer cell possesses the
capability to spread throughout the organ, giving
rise to genetically similar clones. Subsequent
genetic mutations, occurring as part of cancer
evolution, contribute to divergence. Conversely,
the multiclonality hypothesis suggests that each
cancer focus results from an independent tumorigenic event, rendering cancer cells within distinct
lesions genetically distinct and exhibiting few
similarities in their molecular prole [29, 30]
(Fig.10.2).
To address this question, molecular and microsatellite alteration analyses are imperative [31].
However, the scientic community has yet to
provide a denitive answer, with studies over the
years yielding conicting results.
Boyd etal. proposed that neoplastic cells can
disseminate from a common origin, nding a
consistent genetic prole among all cancer foci
analyzed. This implies that multifocal cases may
stem from a single prostate cancer precursor
clone progressing to multifocal invasive prostate
cancer [32]. In line with this perspective, 15years
ago, Liu et al. analyzed samples from 94 cancer
specimens obtained from deceased patients with
metastatic prostate cancer. These patients underwent autopsies as part of the Project to Eliminate
Lethal Prostate Cancer (PELICAN) rapid autopsy
program at Johns Hopkins Medical Institutions.
In 2009, the authors concluded that a single precursor cell was responsible for generating metastatic disease, leading to the assumption of a
monoclonal origin of lethal metastatic prostate
cancer [33]. Similarly, Grasso et al. sequenced
the exomes of 50 lethal, heavily pre-treated metastatic castration-resistant prostate cancers
(CRPCs) obtained at rapid autopsy. Their
sequencing results identied a common cell of
origin in lethal CRPC [34].
Conversely, other studies suggest the polyclonal origin of prostate cancer. One study examining the genomic prole differences between
prostatic intraepithelial neoplasms (PINs) and
their matched carcinoma foci revealed signicant
genetic heterogeneity in both PIN and prostate
carcinoma, suggesting independent origins of
multiple PIN foci within the same prostate [35].
Evaluating allelic heterogeneity of the BRCA1
locus on chromosome 17q21, researchers found
different foci within the same prostate specimen
to have distinct allelic proles, while cancer cells
within the same lesions exhibited a consistent
Fig. 10.2 Monoclonal vs Multiclonal hypotheses of multifocal prostate cancer (a) Monoclonal: a single transforming event occurs in one cell with the spread of this
clone through the organ resulting in topographically dis-
tinct but genetically related tumors. (b) Multiclonal: each
cancer foci are composed of multiple genetically distinct
cancer cell clones