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20 Using Multicore, Transperineal Prostate Mapping Biopsy to Detect, Localize, and Treat the mpMRI…
233
a
d
R R L L
b
e
c
Fig. 20.7 MRI and 3DTPMB images for Pt #6—(a)
T2W, (b) DWI, (c) ADC, (d) Front view, (e) Side angle
view, and (f) Top view. Gleason 3+3 cancer 2/72 cores on
were similar for the US cohort [46]. A cohort of
255 patients with pre-biopsy positive mpMRI
(PIRADS ≥3) had MRTB and STRB as standalone, missing 10% and 13% of csPCa, respec-
f
the left depicted in blue, Gleason 3+4 cancer 2/72 cores
on the left depicted in orange, Gleason 4+4 cancer 1/72
cores on the left depicted in green
tively [47]. Therefore, a combination of MRTB
and STRB remains necessary for the most accurate assessment of histopathologic grade, stage,
and localization of PCa.
234
E. D. Crawford et al.
MRTB and STRB both missed some csPCa
due to their anatomic location [21]. In addition,
lower MRI lesion volumes (p = 0.022), lesion
density (p < 0.001), and PI-RADS scores
(p<0.001) were signicant predictors of MRTB
missing PCa detected by STRB [48]. The interobserver variability due to the level of experience
among radiologists should be considered for
some of these issues. One study observed that
patient-level MRI specicity was experiencedependent, where highly experienced readers had
84.0% specicity versus 55.2% for all others, and
the proportion of agreement on PIRADS v2 score
for index lesions was moderate with κ = 0.42
[49]. There is also a difference in the experience
level of radiologists in private hospitals versus
those in high-volume centers. The proportion of
agreement between readers at a private hospital
was average, with κ=0.41 for PIRADS scores
3–5 and κ=0.51 for PIRADS scores 4–5 [50].
The shortcoming of STRB for missing anterior tumors (transition zone and anterior horn of
peripheral zone), which accounts for 20–30% of
all PCa is well established [51]. Anterior tumors
required signicantly more biopsy sessions to
diagnose (p = 0.007) and had a signicantly
lesser number of positive cores (1.8 versus 2.5,
p=0.001) than posterior tumors. STRB protocol
with bilateral-apical and bilateral-mid transition
zone biopsies can minimize the under-sampling
of anterior lesions [52, 53]. Alternatively, performing systematic biopsies transperineally as
opposed to transrectally can practically eliminate
the under-sampling of the anterior portion of the
prostate. Transperineal systematic biopsies
detected proportionally more anterior tumors
(16.2% vs. 12%, p=0.046) and identied them at
a smaller size (1.4 vs. 2.1 cm3, p = 0.03) and
lower stage (extracapsular extension 13% vs.
28%, p=0.03) compared to STRB [54]. Patients
with clinicopathological features, like the cohort
of patients presented here, can benet from this
approach.
Performance of PCa Biomarkers PCa biomarkers were able to identify csPCa, but there
were several false negative results. PHI and PHID
provided the diagnosis of csPCa in this cohort of
patients. PHI test is also cost-effective [55]. The
PHI cutoff of 27 was cost-effective regardless of
PSA ranges, but especially for patients with PSA
between 2–10 ng/mL. In one study, PHI was
superior to PSA, free PSA, %free PSA, and
p2PSA in detecting cancer but was not effective
at differentiating between csPCa from non-csPCa
[56], whereas PHID was signicantly different
between csPCa and non-csPCa [31]. Four patients
were noted for PHID >0.7 the conrming incidence of csPCa (Table20.2).
In this small patient cohort, SelectMDx
showed two positives (Pt #2 and #6) and two negatives (Pt #3 and #5) who had primarily Gleason
pattern 3 cancer with a small fraction of 5–10%
Gleason pattern 4. In larger cohorts, however, the
SelectMDx test has failed to diagnose less than
10% with high-grade PCa among biopsy-naïve
men while avoiding unnecessary biopsies in 38%
[57]. A meta-analysis of seven studies showed
SelectMDx had a pooled sensitivity, specicity,
PPV, and NPV of 81%, 69.8%, 64.7%, and 85%,
respectively, comparable to mpMRI with 80.8%,
73.4%, 72.4%, and 83.5%, respectively [58].
There can be disagreement between biomarkers due to many factors. The AUC of 4Kscore and
SelectMDx were 0.83 and 0.67, respectively, for
the diagnosis of csPCa, and the two tests provided discordant guidance on whether to proceed
with prostate biopsies in 46% and 38% of
patients, respectively [59]. The 4Kscore was one
of the biomarkers that identied high-grade cancer in Pt #2, and there was concordance between
SelectMDx and 4Kscore. PCA3 has a moderate
sensitivity of 71% and specicity of 68% with an
AUC of 0.75 for diagnosis of any PCa [27].
PCA3 test results were false negatives for the
present cohort, as all results were below the
FDA-approved cutoff of 25 (Table20.2).
While PSA lacks specicity for cancer, PSAD
cutoff ≥0.15 indicates the need for prostate biopsies in men with no MRI lesions [39]. Five
patients in this cohort met these criteria (Tables
20.1 and 20.2). The NPV of a negative mpMRI in
association with a PSAD <0.15 was 95% to rule
out ≥GG2 cancer [43]. Only Pt #3 met these conditions (PSAD=0.12), yet he had GG2 cancer.
20 Using Multicore, Transperineal Prostate Mapping Biopsy to Detect, Localize, and Treat the mpMRI…
235
Depending on the MRI accuracy, this cutoff corresponds to a low probability of ≥GG2 cancer
ranging from 2.6% to 10% [60]. Therefore, prostate biopsy at this cutoff is justied only under
the condition of very poor MRI properties.
PSA Cutoff Since PSA lacks specicity for
PCa, the reliable upper limit of the normal range
for PSA is unknown, where the risk of csPCa is
very low. End-of-study prostate biopsies of the
Prostate Cancer Prevention Trial (PCPT) found
PCa, including high-grade cancers among men
with PSA ≤4.0, PSA levels generally thought to
be in the normal range [61]. The prevalence of
high-grade PCa doubled from 12.5% for PSA
≤0.5 to 25.0% for PSA levels of 3.1 to 4.0.
Retrospective analysis of PSA data in the Health
Alliance Plan of Henry Ford Health System
(HFHS) showed PCa rates were 15-fold higher in
patients with PSA≥1.5ng/mL vs. patients with
PSA<1.5ng/mL (7.85% vs. 0.51%, p<0.001)
[62]. African American patients with PSA
between 1.5–4.0ng/mL had a 19-fold increase in
PCa (p<0.001).
PSA cutoff 1.5 was chosen because this
threshold gave the maximum sensitivity and
specicity for ROC with an area of 0.87 [3].
Thus, PSA <1.5ng/mL, which includes ~70% of
men who have a screening PSA, constitutes a
very low-risk category for developing particularly high-risk disease, and recommendations
were made to screen again in 5years [3]. Even
so, the US Preventive Services Task Force recommended against PSA screening assessing a
grade D but later revised to a grade C, emphasizing an individualized approach to screening [6,
63]. Hence, a shared decision-making procedure
linking the primary care provider (PCP) and urologist is necessary for a timely and denitive diagnosis of csPCa.
Shared Decision-Making Procedure As
alluded to in the beginning, the current clinical
challenge remains an accurate diagnosis of csPCa
that warrants denitive treatment while sparing
those with non-csPCa. Patient examples provided
in this chapter highlighted the difculties associ-
ated with the clinical management of these
patients before their cancer progresses to
advanced stages. Their csPCa remained undetected by multiple TRUS biopsies and
mpMRI. They were eventually diagnosed with
TPMB. The procedure illustrated in Fig. 20.8
outlines the screening process linking PCP and
urologist to guide the patient for successful diagnosis of csPCa if present while sparing those with
benign or indolent disease.
The procedure uses PSA cutoff 1.5 to trigger
risk assessment for the patient using several diagnostic and genetic biomarker tests. PCPs are better suited to order these tests since they order
>90% of PSA tests compared to <10% by urologists [64]. The urine/serum-based biomarkers are
commercially available to determine whether
BPH or PCa is the reason for elevated PSA≥1.5.
The patient and PCP must decide which biomarker tests are benecial depending on his age,
family history, PSA/DRE, symptoms (if any),
and cost.
If the patient has a strong family history of
cancer, then several genetic tests are available to
assess PCa risk. Prompt Prostate Genetic Score
(PSG) is a well-validated Next Generation
Sequencing (NGS) germline test performed on
DNA from buccal swab specimens used to evaluate a man’s individual relative genetic predisposition to developing prostate cancer [65]. Myriad
MyRisk test calculates cell cycle progression
(CCP) score to determine prognostic information
[66, 67]. ProstateNext is a 14-gene panel test that
offers more precision to identify and manage
hereditary prostate cancer [68].
With or without genetic testing, a second biomarker panel of SelectMDx, 4Kscore, PHI, and
ExosomeDx (ExoDx) tests also can be used for
PCa risk assessment [69]. ExoDx is a non-DRE
urine exosome-based assay that measures PCA3
and ERG (V-ets erythroblastosis virus E26 oncogene homologs) RNA levels. Molecular markers
are combined with clinical data (PSA, race, age,
family history) to describe the risk of detecting
≥GG2 cancer on biopsy [70, 71].
If the patient is at low risk, then he is advised
to repeat PSA in 1year. Otherwise, the PCP and
236
Fig. 20.8 Shared decision-making process linking the patient, primary care physician, and urology specialist utilizing
urine, blood, tissue, and imaging biomarkers for diagnosis of prostate cancer
E. D. Crawford et al.
urologist offer shared care for the patient, including options for prostate biopsy (Fig.20.8). Shared
care decisions must also take into consideration
false negative and false positive biomarker test
results. If biopsy ndings are negative, then the
patient can repeat PSA in 1 year. Alternatively,
the patient can request the ConrmMDx test,
which utilizes Glutathione S-Transferase Pi 1
(GSTP1), Adenomatous Polyposis Coli (APC),
and Ras association domain family member 1
(RASSF1) to determine “eld effect”, i.e., a positive ConrmMDx test in a cancer-negative biopsy
suggests that occult cancer was missed during the
prostate biopsy [72]. If the ConrmMDx test is
positive, then the patient can choose to have
mpMRI in an attempt to identify csPCa.
MRI is better suited for patients with at least
one positive genetic or diagnostic biomarker test.
Alternatively, if more than one biomarker test
indicates that a patient is at high risk for csPCa,
mpMRI may be ordered prior to the initial biopsy
to identify potential targets for MRTB.For example, Pt #2 and #6 would have beneted from this
approach, granted systematic TRUS biopsies also
targeted the transition zone since there were no
MRI targets. If the repeat biopsy (MRTB and/or
TRUS) results are inconclusive, then the urologist must provide other options, including TPMB,
to either conrm TRUS biopsy ndings or else
nd out whether there are undetected csPCa like
the patients presented here.
There are a couple of options available
depending on positive histopathological ndings
from an initial biopsy (STRB and/or MRTB) or a
repeat biopsy (STRB, MRTB, and/or TPMB).
Patients with GG3 or higher cancer should consider treatment, whereas patients with ≤GG2
cancer have an option for further risk assessment
using several prognostic biomarkers. These
tissue- based biomarkers use mRNA-based gene
expression classiers: Decipher (GenomeDX
Biosciences), Prolaris (Myriad Genetics), and
Oncotype Dx (Genomic Health) [73, 74].
Decipher is a genomic classier of a 22-gene
panel predicting the probability of metastatic
progression after primary treatment for localized
PCa, whereas Prolaris measures the expression of
31 CCP genes with a score range from 0 to 10, a
high score correlating with tumor aggressiveness
and with the risk of progression. The Oncotype
test analyzes the expression of 17 genes (ve
housekeeping genes and 12 genes related to pros-
20 Using Multicore, Transperineal Prostate Mapping Biopsy to Detect, Localize, and Treat the mpMRI…
237
tate cancer) through RT-PCR on formalin-xed
parafn-embedded biopsy tissue. Oncotype test
integrates with traditional clinical and pathological diagnostic features (PSA, Gleason score,
cTNM) to calculate Genomic Prostate Score
(GPS), which ranges from 0 to 100, to better discriminate between indolent and csPCa. High-risk
patients opting for surgery can use radical prostatectomy (RP) tissues for further risk assessment
using Prolaris RP and Decipher RP tests. By utilizing their RP tissue, Pt #1 and #2 would have
benetted from these two tests, which provide
information on disease progression and expected
clinical outcomes. The Prolaris RP test failed to
analyze tumor samples from Pt #3. Visit the website www.pcmarkers.com/ for more information
regarding these biomarkers.
Summary
Diagnosis of clinically signicant prostate cancer
lesions in a timely manner is of paramount importance to both patients and clinicians.
Clinicopathological features of some patients
make this a challenging endeavor due to the failure of systematic biopsy and multiparametric
MRI to diagnose these lesions. The negative predictive value of multiparametric MRI is insufcient to safely rule out the incidence of clinically
signicant cancer lesions regardless of whether
the patient is symptomatic or not. Prostate cancer
biomarkers provide an alternative to identify
these patients but are subject to false negative and
false positive results. The template-guided transperineal mapping biopsy is the only method currently available for accurate diagnosis of these
lesions. The shared decision-making procedure
links primary care providers with urologists to
provide a systematic approach for diagnosis of
clinically signicant prostate cancer in patients
for optimal treatment choices while sparing those
with benign or indolent disease.
Acknowledgments The work presented in this chapter
was supported in parts by the Jack A.Vickers Prostate
Cancer grant, Bingham Foundation, Schramm Foundation,
and Prostate Biorepository at the University of Colorado
Anschutz Medical Campus. The authors thank Dr. Adrie
van Bokhoven and Dr. M. Scott Lucia, Co-Directors of
Pathology Shared Resources, and supporting staff in the
Departments of Urologic Oncology and Pathology who
were responsible for consenting, collecting, and maintaining records of biological samples from patients.
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Diagnostic Performance
ofPET- Based Targeted Fusion
Biopsy inProstate Cancer
HeyingDuan , PejmanGhanouni,
GeoreyA.Sonn, andAndreiIagaru
21
Introduction
Prostate cancer (PC) is the most frequent noncutaneous cancer in men in the US and the second most frequent cancer in men worldwide [1,
2]. The incidence of higher grade and stage dis-
ease is slowly rising [3]. The tumor biology of
PC is heterogeneous, ranging from clinically
non-signicant, indolent disease (Gleason score
3+ 3) to clinically signicant, more aggressive
cancers (Gleason score≥3+4). The International
Society of Urological Pathology grade group
(ISUP GG) was introduced to better characterize
tumor aggressiveness and is also a prognostic
indicator for the metastatic potential of PC [4, 5].
PC typically manifests as multifocal cancers,
with 80–85% of tumors originating in the peripheral zone, 10–15% in the transition zone, and
5–10% in the central zone [6]. The highest-grade
tumor is termed the index lesion and determines
H. Duan · A. Iagaru (*)
Division of Nuclear Medicine and Molecular
Imaging, Department of Radiology, Stanford
University, Stanford, CA, USA
e-mail: heying@stanford.edu; aiagaru@stanford.edu
P. Ghanouni
Division of Body MRI, Department of Radiology,
Stanford University, Stanford, CA, USA
e-mail: ghanouni@stanford.edu
G. A. Sonn
Department of Urology, Stanford University,
Stanford, CA, USA
e-mail: gsonn@stanford.edu
subsequent management decisions and clinical
outcomes [7, 8]. Indolent disease is increasingly
monitored through active surveillance [9, 10]. At
the same time, more aggressive cancers are typically treated via radical prostatectomy, radiation
therapy, hormonal therapy, chemotherapy, a combination of these, or focal treatment using highintensity focused ultrasound, laser ablation, or
cryoablation [11–13].
The diagnostic pathway of PC did not change
much over two decades: an elevated serum
prostate- specic antigen (PSA) triggers a urological exam with subsequent prostate biopsy.
Transrectal ultrasonography (TRUS)-guided
biopsy, a systematic, non-targeted, 12-core
approach sampling the whole prostate, remains the
most widely used method despite its low sensitivity [14]. Although ultrasound helps visualize the
gland and guide systematic sampling, it cannot
reliably localize tumors for targeted sampling.
This technique misses clinically signicant cancers in 20%, resulting in re-biopsies, and overdetects clinically insignicant cancers that are
often treated unnecessarily [14, 15]. Cancers situated anteriorly or in the apex of the prostate are
particularly challenging to access with TRUS and
are, therefore, not consistently included in the
biopsy template [16]. Transrectal biopsies guided
by TRUS are linked to complications such as urinary tract infection, epididymitis, prostatitis, and
sepsis that necessitate hospitalization [17, 18]. The
Gleason score obtained from biopsy correlates to
© 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_21
241
242
H. Duan et al.
nal pathology after radical prostatectomy in only
53% with TRUS-guided prostate biopsy leading to
under-grading of tumors in 38% and over-grading
in the remaining 9% [19]. The inaccuracy and
morbidity of TRUS-guided systematic biopsies
particularly impact patients with indolent disease
on active surveillance, who undergo repeat prostate biopsies to determine disease progression and
the right time point for treatment. Thus, there is a
clinical need for more sensitive and specic imaging modalities to guide prostate biopsy.
Increasing utilization of multiparametric magnetic resonance imaging (mpMRI) over the last
decade has improved PC diagnosis [14, 20, 21].
MRI utilizes T2-weighted, diffusion-weighted, and
dynamic contrast-enhanced sequences to localize
foci in the prostate suspicious for clinically signicant cancer. While MRI has become the gold standard in pre-biopsy imaging of the prostate, it is
used in a minority of cases. The interpretation of
suspected lesions is based on a standardized scoring system, the Prostate Imaging Reporting and
Data System (PI-RADS) score [22, 23]. PI-RADS
scoring and lesion volume assessment showed
pooled sensitivity and specicity for clinically relevant PC at 89% and 73%, respectively [21].
mpMRI mitigates the limitations of TRUS-guided
biopsies [24]; by now, multiple clinical trials have
shown the superiority of mpMRI-guided targeted
prostate biopsy over TRUS-guided template biopsy
in detecting signicant cancers [25–27]. The
PRECISION trial found that mpMRI-targeted
biopsy detected 38% of clinically signicant PC
compared to TRUS-guided standard 12-core
biopsy with 26% [28]. Conversely, MRI-guided
biopsy decreased the detection of insignicant disease from 22% to 9%. The PROMIS study reported
that mpMRI could be used as a triage tool, which
could avoid prostate biopsy in 25% of patients;
these patients could have PSA follow-up rather
than invasive biopsies with the associated risks and
complications [14]. However, mpMRI has limitations: the PI-RADS score is susceptible to subjective interpretation among radiologists, resulting in
high inter-reader variability [29]. The positive predictive value (PPV) and the negative predictive
value (NPV) are low, with PPV reported to range
between 34 and 68% [14, 30] and NPV between 88
and 91% [31, 32]. This results in unnecessary biopsies and missing around 10% of signicant PC [25,
26, 32–35]. The MRI FIRST trial revealed a 5%
miss rate for signicant disease [26], while the
TRIO study demonstrated a 9% misclassication
rate on mpMRI-targeted biopsy [27]. Given these
limitations of mpMRI missing clinically signicant
disease, especially in challenging areas like the
transition and central zones [36], underestimating
grade and tumor volume by up to threefold [37,
38], and absolute and relative contraindications
such as metal implants and claustrophobia, alternative methods are needed to fulll the three most
important criteria at initial prostate imaging: (1)
stratify aggressive cancers from indolent disease;
(2) guide targeted biopsy of the index tumor for
accurate diagnosis; and (3) provide whole-body
assessment for potential cancer presence beyond
the prostate gland.
In this chapter, we focus on an emerging alternative to TRUS- and mpMRI-guided prostate
biopsy: Positron emission tomography (PET)guided targeted biopsies for localized primary
PC use radiopharmaceuticals that target specic
molecular markers on the PC cell such as
prostate- specic membrane antigen (PSMA) and
gastrin-releasing peptide receptor (GRPR).
Finally, we will give an overview of ongoing trials and an outlook into future directions.
PET-Guided Targeted Prostate Biopsy
Molecular imaging with PET combined with
computed tomography (CT) or MRI provides the
best of two worlds: anatomical and biological
information of the whole body in one scan. PET/
MRI has high soft tissue contrast compared to CT
and is therefore particularly well-suited for imaging of the pelvis and thus staging localized
PC. PET imaging utilizes radiopharmaceuticals
that target specic receptors on the PC cell,
thereby improving cancer detection.
Prostate-Specic Membrane Antigen
(PSMA)
The most widely used radiotracer for imaging of
PC targets PSMA, a type II transmembrane glycoprotein that is highly expressed in 90% of PC