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12 Can Understanding and Utilizing the Tumor Microenvironment Enhance the Therapeutic Ecacy…
119
particular, an effect of HIFU [16, 20]. Microwave
ablation and laser ablation are also heat-based
techniques; thus, one may assume that the effects
will be similar. Cryoablation generally has similar effects as it also causes cell destruction, but
many of the tumor antigens may be preserved,
thus increasing the probability of their recognition by APCs. There is also an activation of apoptosis. This is called a cryo-immunological
response [19].
Irreversible electroporation (IRE) is a nonthermal- based soft tissue destruction resulting in
cell membrane rupture due to the formation of
multiple pores after a high-voltage electric current. This leads to a massive efux of intracellular components and a wide availability of
membrane antigens. IRE is known to impact less
of the vascular and scaffolding structures; therefore, it permits faster and higher immune cells
(CD3+ cells and macrophages) inltration into
treated (tumor) area when compared to the techniques directly creating a necrotic lesion. There
was, on the other hand, a lower proportion of
MDSCs after IRE. Like in the heat techniques,
there was a production of DAMP, such as ATP
and HSP, after IRE application in preclinical
models [21].
All treatment modalities of FT also induce
natural inammatory reactions following index
lesion treatment. It remains unknown if such
inammation plays a role or not in further PCa
occurrence or progression of non-index lesions.
However, there are reports on the effect of
vascular- targeted photodynamic therapies which,
unlike other energies, may not induce typical
inammation, but rather increase inltration of
M2 macrophages and MDSC (having immunosuppressive features), which can be a future target of pharmacological manipulation [22].
Modifying theTME
Androgen Manipulation
The easiest way for TME manipulation is androgen deprivation therapy (ADT). The effect of
ADT has been known for more than 80 years.
ADT is typically used in advanced or metastatic
prostate cancer and potentiates the effect of radiation therapy [23]. The effect of ADT is a direct
blockade of testosterone production, thus resulting in the absence of its stimulatory effect on
prostatic cells (both PCa and non-PCa) and
resulting apoptotic activation.
However, there is a paradox, because there is a
clear initial benet of ADT and later castration
resistance. ADT has an immunosuppressive signature on TME with a reduction of CD4+ and
CD8+ T cells, M1:M2 ratios in favor of immunosuppressive M2 macrophages, and also an
increase of MDSC density [24]. ADT also has a
pro-inammatory effect and leads to chronic
inammation. This is demonstrated by increased
production of IL-1, but also of IL-6 [2]. It has
been described that IL-1 also represses the activity of androgen receptors, which could promote
PCa progression in the long term [25]. It has been
described that CAF, as a known part of PCa
tumorigenesis, are upregulated following ADT
initiation [26].
FT therapy is not typically used for the treatment of advanced PCa, although trials such as
IP2-ATLANTA (combining focal therapy and
hormonal treatment) are on the way to assess the
effect of minimally invasive ablative treatment in
patients with metastatic PCa [27].
Modication oftheInammatory
Activity
Chronic inammation in the prostate may result
in tissue damage, and epigenetic changes may
also indirectly modify TME, thus favoring PCa
occurrence, its progression, or potentially metastatic spread [2]. One of the main chronic signaling pathways is led by a transcription factor
NF-κB, activated by tumor necrosis factor-alpha
(TNF-α). Upon NF-κB activation, a release of
further cytokines such as IL-6, Il-8, and VEGF
occurs. IL-6 is produced by prostate cancer cells,
tumor-associated macrophages, and broblasts.
It stimulates tumor proliferation and expression
of anti-apoptotic genes of the Bcl-family. IL-8 is
produced by prostate stromal cells and inltra-
120
P. Macek et al.
tion macrophages; it promotes cell proliferation
and inhibits apoptosis [2].
On a cellular level, the inammation is noted
as a prostatic inammatory atrophy (PIA), and
morphological studies showed its transition to
prostatic intraepithelial neoplasia (PIN), benign
prostatic hyperplasia, or cancer [28, 29]. Some
authors have shown that anti-inammatory medication may reduce the incidence of PCa in
COX-2 and aspirin users [30]. The data are,
however, conicting, and there is currently no
chemoprevention in use [31]. Aspirin may
reduce inammation, has an impact on polyamine prostatic metabolism, and may induce
apoptosis by promoting TNFα-related apoptosisinducing ligand- mediated cell death [32]. There
are also limited data on the potential synergistic
effect of COX inhibition and radiotherapy, which
might be applicable for a combination with
brachytherapy [33].
Others have shown the absence of efcacy of
COX-2 on inammation before prostatectomy
[34]. However, the latter is a relatively short
study lasting for only 4weeks before prostatectomy, and authors have focused mainly on the
histological indicators of apoptosis, which is
probably not the best surrogate to show longlasting anti-inammatory effects. So far, there
are no clear data on the efcacy of chemoprevention for PCa, and data on 5-alpha reductase inhibitors are contradictory due to the potential
selection of high-grade cancers.
There are reports that physical activity might
inuence the tumor microenvironment either
directly or indirectly by decreasing inammatory
status. Physical activity is recognized as one of
the preventive measures for multiple cancers, and
it is alike in prostate cancer [35]. It has been
reported that acute physical exercise increases
the levels of NK cells, NKT-like cells, and cytotoxic CD8+ T- lymphocytes in the peripheral circulation [36]. Preclinical studies in mice have
found a reduction of IL-6, TNF-α, and NF-κB
after physical activity [37].
There is also emerging information on the role
of the prostate microbiota as an inammation
theory is studied in prostate cancer initiation,
promotion, and progression [38]. The most com-
monly found bacteria in the prostate are E. coli
and N. gonorrhoeae. They both contain lipopolysaccharide endotoxin, which may promote
epithelial- mesenchymal transition, which is
related to tumor invasiveness and progression
[39]. ADT may activate tumor microbiota, which
in turn may add to the production of androgen
receptors, thus contributing to castration resistance. And antibiotic treatment may mitigate
such effects [40].
Other Approaches andOngoing
Research
PCa is known to be rather immunologically cold
environment. Therefore, there is very little effect
of currently available immunotherapy, such as
PD-1/PD-1L or CTLA4 blockade. In the eld of
castration-resistant prostate cancer (CRPC),
there are current rials testing the efcacy of two
specic approaches linked to prostate-specic
membrane antigen (PSMA). One group of trials
is those who use PSMA as target for CAR-T (chimeric antigen receptor T-cell) therapy that may
improve a recognition of prostate cells as immunological targets with IL-23 or TNF-beta as cotargets [41]. Another group of studies is aimed at
exploring of possible use of bi-specic antibodies (with two binding scFv domains) that have an
afnity to tumor-associated antigens and CD3 T
cells. Pasotuxizumab and acapatamab are examples of such tested products [41]. Although these
approaches linked to PSMA recognition and/or
targeting are currently experimental only for
CRPC without a clear future, it is not impossible
that they could be potentially useful inlocalized
tumors and/or focal therapy (imaging targets,
energy concentration, post-FT control, and other
potential uses).
As focal therapy is linked with specic lesion
targeting, any approach improving exact PCa targeting during treatment would certainly be welcomed. Such an option is studies with
TME-activated nanoprobes constructed of pentagonal gold prisms (PGP) covered by calcium
carbonate that binds IR820 photosensitizer and
docetaxel on its surface (nanoparticles “PGP/
12 Can Understanding and Utilizing the Tumor Microenvironment Enhance the Therapeutic Ecacy…
121
CaCO3@IR820/DTX-HA”). This may ensure
targeted CHT delivery with specic activation
following near-infrared light activation [42].
Other types of experimental nanoparticles are
poly-tetramethylene glycol nanoparticles (polyTTG) which have a negative surface charge and
are loaded with docetaxel, which is released upon
contact with the tumor environment. Such an
approach may overcome currently known poor
availability or usual chemotherapy in PCa [43].
Conclusion
Focal therapy in prostate cancer is aimed at selective impact on the tumor population with minimal
impact on healthy prostate or other tissues. Current
energy-based treatment is certainly well established, and its efcacy in well-selected patients is
also good. However, expanding knowledge of
tumor microenvironment may potentially allow us
to combine energy and drug delivery to potentiate
its effect, improve precision, or overcome currently known resistance to therapy. It is also possible that tumor microenvironment targeting may
allow targeted pharmacological treatment of localized disease events with energy ablation.
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Dierences Between MRI-Visible
Vs. MRI-Invisible Cancers: Biology
andOutcomes
AlecZhu andJimC.Hu
13
Introduction
The advent of multiparametric magnetic resonance imaging (MRI) drastically shifted the diagnosis and management of localized prostate
cancer. MRI enhances detection and risk stratication of prostate cancer, with prior studies demonstrating the utility of pre-biopsy MRI to
improve diagnostic accuracy and aid in treatment
decision-making [1, 2]. While long-term prostate
cancer outcomes with MRI use are lacking, its
utilization has increased signicantly over the
past decade [3], and the American Urological
Association and European Association of
Urology [4, 5] professional societies incorporated pre-biopsy MRI into their guidelines.
However, MRI detection of prostate cancer is
limited since up to one-third of clinically signicant cancer (Gleason Grade Group ≥2) foci are
not visible on MRI [6–8], and the biological basis
of MRI visibility is not well understood. In this
chapter, we explore the current evidence of the
biological underpinnings of MRI visibility in
prostate cancer, including the genetic and pathophysiologic markers that contribute to MRI conspicuity. We also review the prognostic
signicance of MRI-visible vs. MRI-invisible
A. Zhu · J. C. Hu (*)
Department of Urology, NewYork-Presbyterian
Hospital/Weill Cornell Medical Center,
New York, NY, USA
e-mail: alz9028@nyp.org; jch9011@med.cornell.edu
cancer as well as potential outcomes of various
treatments, like partial gland ablation, for localized prostate cancer in men with MRI-visible and
MRI-invisible cancers.
Multiparametric Imaging
oftheProstate
Prostate cancer lesion identication and characterization with MRI utilizes several imaging
sequences in combination. Multiparametric MRI
consists of three individual imaging sequences:
T2-weighted imaging, diffusion-weighted imaging (DWI) with an apparent diffusion coefcient
(ADC), and a dynamic contrast-enhanced (DCE)
phase [9]. The T2-weighted phase is helpful in
delineating normal prostate zonal anatomy and
detects cancer as areas of low signal intensity.
Additionally, cancer within the transition zone is
best assessed using the T2-weighted sequence.
The DWI sequence measures the movement of
water molecules and generates signal contrast
based on differences in Brownian motion, and
this signal contrast is quantied by ADC maps.
Typically, an area suspicious for prostate cancer
(increased cell density) will have focally
restricted free-water diffusion and will have a
high signal on DWI along with a low signal on
the corresponding ADC sequence. The ADC
value of an area of interest, which can be measured by the radiologist, further enhances the
© 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_13
123
124
A. Zhu and J. C. Hu
characterization of a lesion given its association
PI-RADS 1—presence of clinically signicant
with pathologic outcomes on biopsy; lower ADC
values correlate with higher Gleason risk scores
PI-RADS 2—presence of clinically signicant
[10]. Additional images with DCE can also be
obtained if a patient receives an intravenous
PI-RADS 3—presence of clinically signicant
injection of contrast (gadoliniumdiethylenetriamine penta-acetic acid), which
PI-RADS 4—presence of clinically signicant
illustrates areas of abnormal vascularity that may
be indicative of prostate cancer. The combination
PI-RADS 5—presence of clinically signicant
of imaging ndings determined by multiparametric MRI determines the likelihood of nding
clinically signicant prostate cancer. However,
the utility of DCE sequences as part of the multiparametric MRI protocol is debated and may not
provide signicant value over biparametric MRI,
which excludes DCE sequences, in detecting
prostate cancer [11]. The PRostate Imaging using
Mri +/− contrast Enhancement (PRIME) trial is
currently underway and will examine whether
biparametric MRI is non-inferior to multiparametric MRI in the detection of clinically signicant prostate cancer [12]. The advantages of
avoiding contrast administration include lower
costs, shorter scan times, and avoiding potential
neurotoxicity.
Other considerations include the MRI magnet
strength as well as the insertion of an endorectal
coil. A eld strength of 1.5Tesla or higher is considered necessary for prostate imaging, and highvolume centers frequently use magnet strengths
of 3 Tesla, given the increased eld strength
allows for improved image resolution and faster
scanning. Additionally, endorectal coils were
previously believed to increase the spatial resolution of prostate imaging after its introduction in
good performance for the detection of clinically
signicant prostate cancer. With increasing
PI-RADS scores, the probability of nding clinically signicant prostate cancer increases.
Kasivisvanathan et al. demonstrated that the
chances of detecting clinically signicant cancer
on targeted biopsies were 12%, 60%, and 83%
for PI-RADS v2 scores of 3, 4, and 5, respectively, in men with no prior biopsy [1]. In a systematic review of 3857 patients across 21 studies,
the pooled sensitivity of PI-RADS v2 was 89%
and specicity was 73% for prostate cancer
detection [17]. However, MRI utilizing the
PI-RADS system may not capture all foci of
prostate cancer. On a per-lesion basis, the sensitivity of MRI for detecting clinically signicant
cancer at the index lesion was lower at around
75% [18, 19]. In a study of 100 patients who had
preoperative MRI imaging and subsequent radical prostatectomy, MRI detected clinically signicant cancer in 99% of patients, but in 26% of
patients, at least one clinically important tumor
was missed [20].
1989 [13]. However, recent studies demonstrate
that magnet eld strength and endorectal coils
may not play a signicant role in the MRI’s abil-
Determinants ofMRI Visibility
ity to detect prostate cancer [14, 15].
A system of prostate MRI reporting termed
the Prostate Imaging Reporting and Data System
(PI-RADS) was developed by the International
Prostate MRI Working Group to standardize MRI
examinations and reporting, with the most
updated version, PI-RADS v2.1, published in
2019 [16]. Individual lesions are characterized on
a 5-point scale to indicate the likelihood of clinically signicant cancer in the lesion of interest:
The nature of MRI-invisible prostate cancer
remains an area of investigation. Existing studies
report that tumor visibility is associated with cancer location, tumor volume, and tumor Gleason
grade group [15, 21, 22]. A study of 830 patients
from Germany who underwent prostate MRI for
elevated PSA found that the majority of tumors
missed on MRI were low-grade lesions and small
in size [23]. Additionally, in a study of men who
cancer is very unlikely.
cancer is unlikely.
cancer is equivocal.
cancer is likely.
cancer is very likely.
Overall, the PI-RADS scale demonstrates
13 Dierences Between MRI-Visible Vs. MRI-Invisible Cancers: Biology andOutcomes
125
had preoperative MRI lesions conrmed by
whole-mount histopathology, Le etal. found that
overall MRI sensitivity for tumor detection was
47%, and MRI had increased sensitivity for larger
(>1.0 cm) tumors, higher-grade (Gleason
grade≥7) tumors, and index tumors [24]. Here,
we explore the genetic and pathophysiologic
underpinnings that contribute to MRI visibility of
prostate cancer.
Genetic Markers ofMRI Visibility
Studies have sought to characterize genes associated with MRI visibility. Transcriptomic analyses
found that many genes are differentially expressed
between MRI-visible and MRI-invisible tumors,
and genes associated with aggressive disease
appear to also be associated with MRI visibility
[25]. For example, the CENPF gene, which is
associated with metastatic prostate cancer [26],
was found to have enhanced expression in MRIvisible tumors [27]. With the induction of
microRNA-101, which negatively inhibits
CENPF, there was decreased expression of
CENPF as well as reduced MRI visibility in an
invivo model [27]. Additionally, the loss of the
PTEN gene, which is associated with more
aggressive prostate cancer [28, 29], was associated with lower ADC values on prostate MRI
[30] and was more frequently found in tumors
identied by MRI-targeted biopsies [31]. In a
genomic proling study, Houlahan etal. compared 20 tumors characterized as PI-RADS 5 vs.
20 tumors not visible on MRI (PI-RADS <3).
The authors found that PI-RADS 5 tumors had
elevated levels of RNA transcripts, such as
SChLAP1 and small nucleolar RNAs [32]. The
long noncoding RNA, SChLAP1, has been linked
to prostate cancer progression as well as aggressive pathologic features like intraductal carcinoma and cribriform architecture [33, 34].
Certain genes involved in the cellular pathways of prostate cancer development are also
associated with MRI visibility. For instance,
increased immune and inammatory responses
may be associated with radiomic features that
enhance tumor visibility [35]. Additionally,
Salami et al. identied a nine-gene signature
associated with cellular organization (actin laments and cytoskeleton organization) that was
able to predict MRI visibility with a sensitivity of
75% and specicity of 100% in a validation
cohort [36]. MRI-visible tumors tended to have
decreased expression of cellular organization
genes compared to MRI-invisible tumors.
Genomic Biomarkers
Commercial biomarker assays are used to facilitate the diagnosis and risk stratication of prostate cancer, and studies have described their
association with prostate cancer visibility on
MRI. Among pre-biopsy biomarkers, prostate
cancer antigen 3 (PCA3), a urine test performed
after digital rectal examination in men with at
least one prior benign prostate biopsy, has been
evaluated for its relationship to MRI visibility.
The PCA3 score is signicantly correlated with
the presence of visible lesions on prostate MRI
[37]. Additionally, higher PCA3 scores are sig-
nicantly associated with higher PI-RADS
scores as well as higher Gleason grade group on
targeted biopsy [38]. The tissue-based genomic
assays of Decipher and Oncotype have also been
shown to be related to MRI conspicuity. The
Decipher genomic classier (GC) utilizes a
22-gene panel on biopsy tissue to help decisionmaking on curative treatment versus active surveillance. Studies demonstrate tumors with
higher Decipher scores are more likely to be
MRI-visible [39, 40]. The Oncotype Genomic
Prostate Score (GPS) is a tissue-based 17-gene
assay also utilized in patients with low- or intermediate-risk prostate cancer being considered
for active surveillance. Leapman etal. evaluated
GPS results in men who had undergone prostate
MRI and found that GPS scores correlated with
MRI-visible status, and ADC values were negatively correlated GPS scores [41]. Lastly, the
Prolaris test, which examines 31 cell cycle progression (CCP) genes, correlates with PI-RADS
scores but there is conicting evidence on its
relationship to MRI- visible and MRI-invisible
lesions [42, 43].
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A. Zhu and J. C. Hu
Genomic Heterogeneity
While studies suggest that MRI-visible tumors
may harbor more aggressive disease given differences in their genetic proles compared to MRIinvisible tumors, there is also intratumor
transcriptomic heterogeneity, which carries the
risk of tumor misclassication [44]. For example,
the percentage of genomic alterations, which confer lower or higher levels of risk, may differ in two
different biopsy cores taken from the same MRIvisible lesion. Additionally, MRI-invisible lesions
may also harbor aggressive genetic features.
Some MRI-invisible lesions were reported to contain copy number variations in genes, including
RB1, TP53, and MYC, which are found in metastatic castration-resistant prostate cancers [45].
Histopathological Dierences
Beyond tumor grade and volume, proteomic differences exist between MRI-visible and MRIinvisible lesions, which may contribute to
MRI-visible tumors having more complex tumor
architecture than MRI-invisible tumors. In a
study of 12 patients who had MRI images mapped
to whole-mount radical prostatectomy specimens, MRI-visible tumors were found to have
higher cell density and microvascular density
than MRI-invisible tumors [46]. These ndings
were further corroborated by Miyai et al. who
evaluated 59 radical prostatectomy specimens
and characterized tumors as MRI-visible or MRIinvisible. The authors found that MRI-visible
tumors had increased proportions of cancer cells
in the specimen and decreased proportion of stromal and luminal spaces [47]. Additionally, the
cellular and structural characteristics of MRIinvisible tumors seem to resemble normal prostate tissue [46, 48]. As previously discussed,
tumor identication on prostate MRI depends on
characterizations of T2-weighted imaging,
diffusion- weighted imaging, and contrast
enhancement. These histopathological ndings
demonstrate how the high tissue density of prostate cancer tissues likely contributes to its visibility on MRI.
The histopathological subtypes of prostate
cancer may also play a role in its conspicuity. In
a study of 83 tumors from 22 radical prostatectomy specimens, Truong et al. found that the
majority (66%) of cribriform pattern cancers
were MRI-invisible, and cribriform tumors
needed to be larger in size before becoming visible on MRI relative to other histologic types [49].
Conversely, Tonttila et al. found that 91% of
tumors containing cribriform or ductal architecture were MRI-visible [50]. The differences in
results from these two studies may be due to sampling differences. While most of the cribriform
tumors missed on MRI were pure cribriform patterns in Truong etal.’s study, only a small proportion of tumors missed on MRI in the Tonttila
etal. study had cribriform architecture, and none
of the missed tumors had a pure cribriform pattern [51]. Recent evidence in a study of 188 prostate cancer patients demonstrated that 96% of
tumors with any cribriform pattern or 100% of
tumors with large cribriform patterns were visible on MRI, and lower ADC values were predictive of cribriform pathology [52]. Another rare,
aggressive subtype of prostate cancer is the ductal type. A study of 11 patients revealed the
T2-weighted signal of ductal carcinoma was similar to that of low-grade cancers but signicantly
different to that of high-grade cancers [53].
Overall, the current literature shows conicting
evidence regarding lesion conspicuity of cribriform histopathology on MRI, whereas ductal carcinoma tends to be MRI-invisible.
Outcomes Associated withMRIVisible andMRI-Invisible Tumors
The characterization of MRI-visible and MRIinvisible lesions is an important clinical consideration, particularly if MRI-visible lesions are
biologically more aggressive than MRI-invisible
lesions. Elucidating the prognostic signicance
of MRI-visible and MRI-invisible lesions can
help determine the need for prostate biopsy and
select the appropriate management strategy,
including options such as active surveillance and
focal therapy.
13 Dierences Between MRI-Visible Vs. MRI-Invisible Cancers: Biology andOutcomes
127
Among individuals with suspicion of prostate
cancer, the detection of clinically signicant
prostate cancer while minimizing diagnosis of
non-clinically signicant cancer is critical. The
12-core transrectal ultrasound-guided systematic
biopsy was traditionally the most frequently used
method for diagnosing prostate cancer. However,
this nontargeted approach led to missed diagnoses and inappropriate risk stratication discovered at the time of radical prostatectomy [54–56].
Targeted Biopsy Outcomes
Prostate MRI is frequently combined with
ultrasound- guided technologies to perform targeted prostate biopsies, which enhance lesion
localization and risk stratication of localized
disease. Multiple studies demonstrated that MRItargeted biopsies detect higher rates of highgrade cancers than systematic biopsies alone [1,
2, 57, 58]. However, there is controversy if sys-
tematic biopsy needs to be performed in addition
to MRI-targeted biopsy in men with suspicious
MRI lesions. A study by Ahdoot et al. demonstrated the combined approach of both targeted
and systematic biopsies yields a 9.9% greater
detection of cancer as well as the lowest rate of
upgrading at radical prostatectomy than either
approach alone [59]. However, a randomized trial
comparing targeted biopsy alone to targeted plus
systematic biopsies among patients with suspicious MRI lesions (PI-RADS 3–5) found that
omitting systematic biopsy decreased the probability of nding clinically insignicant cancers
by 50% but also reduced the chance of nding
clinically signicant cancers by 27% [60].
Although the decreased detection of clinically
signicant cancers was not statistically signicant, the study was not powered to detect this
difference.
In men at increased risk for prostate cancer but
with negative MRI ndings, there is no clear consensus if systematic biopsy can be completely
omitted. A systematic review of 42 studies found
that the negative predictive value of a negative
MRI (PI-RADS 1–2) to detect clinically signicant cancer among biopsy-naïve patients was
91% [61]. Additionally, a Cochrane review of 18
studies found that omitting biopsies in patients
with PI-RADS 1–2 lesions would have avoided
30% of all biopsy procedures while missing 11%
of clinically signicant cancers [62]. Guidelines
from the European Association of Urology propose an “MR pathway” as an option whereby
patients with positive MRI undergo MRI-targeted
biopsy and patients with negative MRI are not
biopsied at all [63]. However, guidelines from the
AUA continue to recommend systematic biopsy
in men with an elevated risk of clinically signicant cancer in the absence of suspicious ndings
on MRI [4], given the risk of missing clinically
signicant cancers.
Outcomes After Active Surveillance
The prognostic signicance of MRI-visible
lesions has been evaluated in men being considered for active surveillance. In a cohort of 194
patients diagnosed with low-risk prostate cancer
who underwent MRI and subsequent templatemapping biopsy, higher MRI scores were predictive of upgrading to a higher Gleason score on the
sequent biopsy [64]. In another study by Dianat
etal., 84 men with MRI-visible and 12 men with
MRI-invisible lesions were compared on an
active surveillance regimen. Adverse pathology
was found on surveillance biopsy in 41% of men
with MRI-visible tumors compared to 8.3% of
men with MRI-invisible tumors [65]. However,
the shorter follow-up duration in the MRIinvisible group may have contributed to its more
favorable outcomes.
Outcomes After Radical Prostatectomy
In men who undergo radical prostatectomy, the
presence of lesions on MRI may also predict biochemical recurrence. Park et al. analyzed 282
patients who underwent radical prostatectomy
and had preoperative MRI with a median
follow- up of 26 months. On adjusted analyses,
the combined presence of tumors on T2-weighted,
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A. Zhu and J. C. Hu
DWI, and DCE phases was signicantly associated with biochemical recurrence, but the isolated ndings of tumors on T2-weighted and
DWI or T2-weighted and DCE phases were not
associated with biochemical recurrence [66].
However, the study was limited by lack of pathologic correlation with preoperative MRI
ndings.
Outcomes inPartial Gland Ablation
The increased utilization of prostate MRI for
diagnosis and treatment planning has coincided
with a rise in partial gland ablation as an alternative treatment option for prostate cancer. If partial
gland ablation is considered, contemporary
expert consensus recommends treatment of clinically signicant prostate cancer diagnosed via
targeted biopsy of MRI-visible lesions [67].
However, men with MRI-invisible tumors may
also be considered for treatment. An analysis by
Zhu etal. evaluated treatment outcomes of partial
gland cryoablation in 58 men with MRI-visible
lesions and 17 men with MRI-invisible lesions.
All men had Gleason grade group ≥2, and the
median follow-up was 44months. Prostate cancer recurrence on surveillance biopsy was 39%
vs. 19% at 12 months and 47% vs. 31% at
24months for the MRI-visible and MRI-invisible
groups, respectively, and differences were not
statistically signicant (p = 0.2 at 12 months,
p=0.4 at 24months) [68]. While results suggest
that patients with MRI-invisible lesions may
experience similar outcomes to those with MRIvisible lesions after partial gland cryoablation,
the study was limited by a small sample size and
limited follow-up time.
Conclusions
Studies elucidating the genomic basis and
pathophysiology of MRI-visible and MRIinvisible disease present a new frontier in which
imaging may be used to improve risk stratication and patient selection for appropriate treatment options, given the prognostic implications
of visible or invisible prostate cancer. If MRI
visibility correlates with disease aggressiveness,
as suggested by prior studies, then certain
patients with MRI-invisible lesions may be
omitted for biopsy or considered for less aggressive treatments. However, existing studies evaluating genomic associations and
histopathological outcomes of MRI-visible disease are limited in that many do not appropriately match visible and invisible lesions by
percent of Gleason pattern 4, cribriform architecture, and extra-prostatic extension [69].
Without appropriate balance in tumor characteristics, the outcomes derived from these studies
may be confounded by the presence of these
high-risk features. Future work in this area
would benet from the careful matching of visible and invisible lesions to determine the true
prognostic value of MRI visibility.
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