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org
1676
| GENITOURINARY IMAGING

Artificial Intelligence–assisted
Prostate Cancer Diagnosis:
Radiologic-Pathologic Correlation
Lidia Alcalá Mata, MD
Juan Antonio Retamero, MD The classic prostate cancer (PCa) diagnostic pathway that is based
Rajan T. Gupta, MD on prostate-specific antigen (PSA) levels and the findings of digital
Roberto García Figueras, MD, PhD rectal examination followed by systematic biopsy has shown mul-
Antonio Luna, MD, PhD tiple limitations. The use of multiparametric MRI (mpMRI) is now
RADIOLOGY-PATHOLOGY COLLECTION

widely accepted in men with clinical suspicion for PCa. In addition,

Abbreviations: ADC = apparent diffusion
coefficient, AI = artificial intelligence, CAD =
computer-aided diagnosis, csPCa = clinically
significant PCa, DRE = digital rectal examina-
tion, DWI =diffusion-weighted imaging, EAU =
European Association of Urology, ISUP = In-
ternational Society of Urological Pathology,
mpMRI = multiparametric MRI, MRI-TBx =
MRI-targeted biopsy, ncsPCa = non–clinically
significant PCa, NLP = natural language pro-
cessing, PCa = prostate cancer, PI-RADS =
Prostate Imaging Reporting and Data System,
PSA = prostate-specific antigen, TRUS-Bx =
transrectal US-guided biopsy
RadioGraphics 2021; 41:1676–1697
https://doi.org/10.1148/rg.2021210020
Content Codes:
From the Department of Radiology, Clínica Las
Nieves, HT Médica, Calle Carmelo Torres Núm
2, 23007 Jaén, Spain (L.A.M., A.L.); Paige.AI,
New York, NY (J.A.R.); Department of Radiol-
ogy, Duke University Medical Center, Durham,
NC (R.T.G.); and Department of Radiology,
Complexo Hospitalario Universitario de San-
tiago de Compostela, Santiago de Compostela,
Spain (R.G.F.). Recipient of a Certificate of
Merit award for an education exhibit at the 2020
RSNA Annual Meeting. Received January 31,
2021; revision requested March 9 and received
May 26; accepted May 27. For this journal-based
SA-CME activity, the authors J.A.R., R.T.G.,
and A.L. have provided disclosures (see end of
article); all other authors, the editor, and the re-
viewers have disclosed no relevant relationships.
Address correspondence to L.A.M. (e-mail:
l.alcala.o@htime.org).
©
RSNA, 2021
clinical information, PSA density, risk calculators, and genomic and
other “omics” biomarkers are being used to improve risk stratifica-
tion. On the basis of mpMRI and MRI-targeted biopsies (MRI-
TBx), new diagnostic pathways have been established, aiming to
improve the limitations of the classic diagnostic approach. However,
these pathways still show limitations associated with mpMRI and
MRI-TBx. Definitive PCa diagnosis is made on the basis of histo-
pathologic Gleason grading, which has demonstrated an excellent
correlation with clinical outcomes. However, Gleason grading is
done subjectively by pathologists and involves poor reproducibility,
and PCa may have a heterogeneous distribution of histologic pat-
terns. Thus, important discrepancies persist between biopsy tumor
grading and final whole-organ pathologic assessment after radi-
cal prostatectomy. PCa offers a unique opportunity to establish
a real radiologic-pathologic correlation, as whole-mount radical
prostatectomy specimens permit a complete spatial relationship
with mpMRI. Artificial intelligence is increasingly being applied to
radiologic and pathologic images to improve clinical accuracy and
efficiency in PCa diagnosis. This review delineates current PCa di-
agnostic pathways, with a focus on the role of mpMRI, MRI-TBx,
and pathologic analysis. An overview of the expected improvements
in PCa diagnosis derived from the use of artificial intelligence, inte-
grated radiologic-pathologic systems, and decision support tools for
multidisciplinary teams is provided.
An invited commentary by Purysko is available online.
Online supplemental material is available for this article.
©
RSNA, 2021 • radiographics.rsna.org

SA-CME LEARNING OBJECTIVES

Introduction
After completing this journal-based SA-CME Prostate cancer (PCa) is the second most diagnosed cancer and the
activity, participants will be able to:
fourth cause of cancer-related death in men worldwide (1). Despite
„ State the different current diagnostic
pathways for prostate cancer, including
its high incidence, no screening programs have resulted in signifi-
their advantages and limitations. cant mortality decrease (2,3). The most widespread tools used in
Describe the existing AI tools that
„ determining patient risk are serum prostate-specific antigen (PSA)
streamline the prostate cancer diagnostic and digital rectal examination, followed by systematic transrectal
process. US-guided biopsy (TRUS-Bx), which samples regions of the gland
Explain the benefits of digital patho-
„ systematically without a defined target.
logic analysis and integrated radiologic-
pathologic diagnosis in prostate cancer.
See rsna.org/learning-center-rg.
RG  •  Volume 41  Number 6 Alcalá Mata et al  1677

TEACHING POINTS
„ The use of MRI to help determine which patients undergo
MRI-TBx is known as the MRI pathway. Alternatively, MRI
combined with TRUS-Bx is used in the combined biopsy path-
way, in which patients with negative MRI findings undergo
TRUS-Bx, and those with suspicious lesions at MRI undergo
both TRUS-Bx and MRI-TBx.
„ Deep learning and CNNs are currently the most used in the
development of AI tools for clinical diagnosis. Also, radiomics
involves the extraction of quantitative data from radiologic
images and, when combined with machine learning tech-
niques, it permits the identification of image characteristics
beyond those obtained by radiologists.
„ There are two main disadvantages to the development of
these AI tools. First, the large amount of labeled data neces-
sary for adequate AI training requires notable input and time
from experienced radiologists. Second, the false-positive rate
of these tools is up to 50%, which requires radiologist input
during reading to validate or reject the lesions presented by
AI.
Figure 1.  Outline of PCa early detection program objectives.
„ The advantages of a digital pathology workflow are multiple,
The main objective of an early detection program is to increase
including improved efficiency and better user experience the csPCa detection rate while decreasing the detection rate for
compared with light microscopy. Digital histologic images ncsPCa. The purpose is to reduce overtreatment and its com-
can be viewed anywhere by using a computer instead of a mi- plications, the number of unnecessary examinations (MRI and
croscope, which makes them accessible beyond the pathol- biopsy), and the morbidity and costs derived from them.
ogy laboratory. Also, digital pathology permits the application
of AI tools to histologic images to aid diagnosis, as it occurs
in radiology. Therefore, digital pathology is the foundation of reading systems like Prostate Imaging Reporting
computational pathology and CAD in pathology.
and Data System (PI-RADS) version 2.1 (8,9).
„ To solve this problem and facilitate the diagnosis, treatment,
In spite of these limitations, the use of mpMRI
and follow-up of patients with PCa by multidisciplinary teams,
decision support tools are created, based on, and validated
is widely accepted in men suspected of having
by clinical guidelines or expert management. These tools fa- csPCA in both biopsy-naive patients and those
cilitate finding relevant data in the clinical history, including who have undergone TRUS-Bx. Currently, the
analytical values, previous studies, histologic results, and treat- role of MRI-targeted biopsy (MRI-TBx) is grow-
ments received.
ing, although there is variability in the timing and
type of biopsy to be used.
The use of MRI to help determine which
PCa is a heterogeneous disease with vari- patients undergo MRI-TBx is known as the
able prevalence and a wide range of prognoses MRI pathway. Alternatively, MRI combined with
(4). Therefore, it is important to differentiate TRUS-Bx is used in the combined biopsy path-
between indolent or non–clinically significant way, in which patients with negative MRI find-
PCa (ncsPCa), which does not increase mortal- ings undergo TRUS-Bx, and those with suspi-
ity, requires no immediate treatment, and can be cious lesions at MRI undergo both TRUS-Bx and
managed with active surveillance, and clinically MRI-TBx (10).
significant PCa (csPCa), which can become The current lack of uniformity in PCa diagno-
metastatic, can cause death, and requires defini- sis is partly due to differences between U.S. and
tive treatment. The emphasis should be directed European guidelines, with differences regarding
at detecting the latter, aiming to decrease its un- timing and use of imaging techniques, risk calcu-
derdiagnosis and undertreatment, while reduc- lators, and MRI-guided biopsy (11).
ing the detection rate of the former to minimize Historically, Gleason grading has demonstrated
overdiagnosis and unnecessary treatment (Fig an excellent correlation with clinical outcomes.
1). Age, ethnicity, genetic mutations, and clinical Several revisions have improved patient risk strati-
history are helpful data in determining csPCa fication and better predicted their outcome. On
patient risk. Also, PSA density, genomic and the basis of the Gleason score, the International
other “omics” biomarkers, and risk calculators Society of Urological Pathology (ISUP) consensus
may play a key role (5–7). guideline recommends grade grouping to facilitate
Multiparametric MRI (mpMRI) is gaining im- communication of pathologic diagnoses to urolo-
portance in csPCa diagnosis, although it requires gists and patients (Table 1) (12). However, some
experienced radiologists and has a steep learn- unresolved areas regarding diagnosis and quanti-
ing curve despite the existence of standardized fication of high-grade patterns remain (13). Also,
1678  October Special Issue 2021 radiographics.rsna.org
Gleason grading is subjectively done by patholo-
gists and involves inter- and intrareader vari-
ability and poor reproducibility (14). In addition,
PCa may be multifocal and have a heterogeneous
Gleason pattern distribution within the same
patient (15). Likewise, mpMRI often underes-
timates pathologic tumor size, particularly in
lesions with lower PI-RADS scores and smaller
size (16). Tumor heterogeneity and mpMRI
limitations, along with biopsy error, lead to dis-
crepancies between biopsy tumor grade and final
whole-organ pathologic assessment after radical
prostatectomy (17).
Artificial intelligence (AI) is being applied to
medical imaging, both in radiology and pathology
(18). The purpose is to increase clinical efficiency
and the interpretability of results and support
decision making, both in the detection and risk
stratification of disease in patients with PCa, and
after treatment follow-up. In mpMRI PCa diagno-
sis, several AI tools may help radiologists in auto-
matic prostate gland segmentation as well as lesion
detection and characterization (19). Similarly,
there is growing evidence of improving diagnostic
performance when pathologists are aided by AI
(20,21). Also, PCa offers a unique opportunity to
establish radiologic-pathologic correlation, as radi-
cal prostatectomy specimens permit a complete
spatial relationship with mpMRI. Thus, AI-based
tools and integrated radiologic-pathologic di-
agnosis, along with clinical and biomarker data,
show promise in reducing interreader variability,
both among radiologists and pathologists, and
solve some of the multiple weak links that exist in
PCa diagnosis. AI-assisted decision support tools
for multidisciplinary teams may facilitate com-
munication among radiologists, pathologists, and
urologists and analyze multimodal data by using
algorithms that are able to manage large datasets.
These solutions may recognize hidden relation-
ships among different biomarkers and suggest the
most appropriate therapy (20,22).
This review delineates current PCa diagnostic
pathways with a focus on the role of mpMRI,
MRI-TBx, and pathologic analysis. It also pro-
vides an overview of the role of AI in PCa radiol-
ogy and pathology. Finally, the future of PCa
diagnosis and management based on integrated
diagnostic systems is discussed.
General Concepts of AI
AI is the field of computer science that develops
systems capable of performing tasks that are
commonly associated with human intelligence
(18). It is gaining interest in image analysis ap-
plied to radiology and pathology, thanks to its
ability to automatically extract information from
medical images and make diagnostic predictions.
Table 1: ISUP Grades and Gleason Scores
ISUP Grade Gleason Score
1 2–6
2 7 (3+4)
3 7 (4+3)
4 8 (4+4), (3+5), (5+3)
5 9–10 (4+5), (5+4), (5+5)
Source.—Reference 12.
Natural language processing (NLP) tools
read, understand, and classify data in text such
as clinical history or diagnostic reports. Machine
learning creates mathematical algorithms that can
automatically learn from certain tasks, requir-
ing minimal or no human intervention (23). In
supervised learning, computers learn from train-
ing data that were previously labeled by humans,
along with the expected results. A greater amount
and variability of data used during the training
stage typically results in better learning and more
accurate outputs. Algorithms then undergo a vali-
dation process whereby unlabeled data are intro-
duced, and algorithmic output is contrasted with
the results generated by human operators. Ideally,
this validation is done by exposing algorithms to
data from multiple sources. After validation, the
algorithm is calibrated to adjust to local variables,
to improve accuracy and increase sensitivity and
specificity (18). In unsupervised learning, the
system learns directly from unlabeled raw data
without human-made annotations, separating
the samples into different classes on the basis of
the characteristics of the training data and the
random variables under study (20).
Subtypes of machine learning include deep
learning, neural networks, and convolutional
neural networks (CNNs), in which the systems
are formed by layers that interact with each other
and can learn complex processes. Deep learning
and CNNs are currently the most used in the de-
velopment of AI tools for clinical diagnosis (23).
Also, radiomics involves the extraction of quan-
titative data from radiologic images, and when
combined with machine learning techniques, it
permits the identification of image characteristics
beyond those obtained by radiologists.
AI-based tools may improve the diagnosis,
prognosis, and treatment of PCa (Fig 2, Table 2).
Machine learning solutions can perform auto-
matic prostatic mpMRI segmentation, identify
suspicious areas, propose a PI-RADS score,
and estimate risk of histologic aggressiveness.
Algorithms have demonstrated a similar area
under the curve (AUC) to humans in the char-
acterization of csPCa with mpMRI by using the
RG  •  Volume 41  Number 6 Alcalá Mata et al  1679

Figure 2.  Diagram shows the treatment process in patients with potential PCa risk and the possible role of AI (machine learning
[ML], deep learning, and radiomics) in this process. NLP tools can be used to help enroll patients in the screening program. Risk calcu-
lators based on big data suggest tests to be performed. AI also assists the diagnostic process by automatically detecting and classifying
lesions according to PI-RADS version 2.1. Automatic prostatic and suspicious lesion segmentation with mpMRI can be done before
MRI-TBx. The histologic assessment of the biopsy sample, tumor detection, and the corresponding Gleason score can be aided by AI
algorithms. In addition, the whole process can be visualized and managed by multidisciplinary teams through integrated diagnostic
platforms (decision support tools) that can propose next diagnostic and treatment steps according to updated clinical guidelines by
using optimization and planning algorithms. DRE = digital rectal examination.

PI-RADS system (19). Also, machine learning
algorithms can optimize fusion MRI/US biopsies
by improving image alignment and considering
prostate gland deformation during the procedure
(20). Another growing area in AI is the identifi-
cation and validation of genetic signatures and
other “omics” biomarkers that can help in the
diagnosis and prognosis of PCa (6). Computer-
aided diagnosis (CAD) in PCa histopathologic
analysis by using AI is expected to reduce reading
times, improving reproducibility and accuracy
(20,32). AI may play a role in PCa treatment,
building three-dimensional models that could
be integrated in augmented and virtual reality
solutions, improving tumor visualization during
surgery or image-guided focal therapy procedures
and providing a more accurate lesion segmenta-
tion and its relationship with neighboring organs
to optimize radiation therapy treatments (33).
Screening and Early PCa Detection
Current Status
The use of PSA as a screening tool for PCa
detection led to an incidence increase of PCa
(20%–50%), which was mostly associated with
ncsPCa, and was accompanied by a rise in
biopsy and treatment-related complications but
without an overall survival increase or mortal-
ity rate reduction (2,3,34). For this reason, the
U.S. Preventive Services Task Force (USPSTF)
recommended no further PSA testing in the
general population in 2012 (grade D recom-
mendation) (3). In 2017, the revised USPSTF
recommendation advised that men between the
ages of 50 and 69 years be informed of the risks
and benefits of PSA screening for PCa (grade C
recommendation), recommending PSA determi-
nations only after patients are informed of their
individual risk for csPCa. This introduces the
concept of early PCa detection, becoming es-
sential to quantify individual csPCa patient risk
to minimize overdiagnosis, overtreatment, and
associated morbidity (2).
Epidemiologic factors that increase the
likelihood of csPCa include ethnicity (ie, Black
patients [49%] and White patients [26%]), tumor
volume, younger age of onset, and BRCA2 muta-
tion carriers (35,36). Furthermore, the genomic
landscape of csPCa is complex and heteroge-
neous and is associated with TP53 and DNA
repair gene aberrations. Therefore, the genomic
analysis of primary PCa biopsies shows promise
for early identification of tumors that evolve into
more aggressive variants (37).
There are discrepancies and similarities
regarding risk factor management between the
European Association of Urology (EAU) and
their U.S. counterpart, the National Comprehen-
sive Cancer Network (NCCN) (38,39) (Table
3). Both guidelines agree that patients undergo-
ing early detection programs should be informed
1680  October Special Issue 2021 radiographics.rsna.org

Table 2: Advantages and Limitations of AI Solutions in PCa Diagnosis

AI Solution Tool Type Advantages Limitations

Automatic risk factor NLP Greater sensitivity and specificity in Software costs
detection in clinical identifying patients at risk for csPCa Integration with EMR may
history (PSA or DRE) Less clinician time required be challenging
Fewer false-negative findings due to EMR language heteroge-
human oversight neity may lead to false-
negative findings
PCa diagnostic predic- CNNs Higher sensitivity, specificity, PPV, Multiple tools using differ-
tion tools, combining NPV, and AUC in PCa prediction ent variables may reach
PSA with other ana- than with conventional tools similar results
lytical, genetic, and Decreased false-positive findings due
“omics” biomarkers to high PSA
Potential to reduce unnecessary
biopsies
May help decrease false-positive rate
in screening programs
Integration of several biomarkers
may lead to improve PCa diagno-
sis, risk stratification, and outcome
Risk calculator Logistic regression Fewer unnecessary biopsies Result variability depends
models Detect patients at risk in need of on choice of tool
Big data biopsy with negative findings at Variable heterogeneity
imaging (ethnicity, genetic vari-
Fewer unnecessary MRI studies ants, mpMRI data)
CAD for MRI lesion CNNs Fewer false-negative findings Low PPV due to high
detection and clas- Radiomics Less radiologist time required, accel- false-positive rate
sification Texture analysis erated learning curve for nonex- Large amount of labeled
pert radiologists data required for train-
Increased sensitivity in detection of ing
TZ lesions, increased sensitivity in Data heterogeneity
PI-RADS 3 lesions No regulatory clearance
for diagnostic use
Automatic segmenta- Machine learning Less radiologist time Radiologist needs to check
tion of prostate gland Texture analysis Provide quantitative data such as segmentation accuracy
and suspicious lesions prostate and lesion volume Limited results in mpMRI
with T2-weighted Generate files needed to perform of suboptimal quality
sequences MRI-TBx Imprecise in posttreatment
prostates or those with
heterogeneous signal
intensity
Real-time 3D deform- Machine learning Improved results in MRI/US fusion Need for controlled rate of
able image registra- Radiomics biopsy elastic deformation
tion algorithms Permits precise radiation therapy Expensive integration
planning software
Aids robotic surgery
AI in pathology Machine learning Improves sensitivity, specificity, Relies on digital pathology
predictive values, and diagnostic Software integration may
concordance be difficult
Better biomarker quantification
AI-assisted decision Machine learning Better communication among radiol- Software costs
support tools NLP ogists, pathologists, and urologists Difficult workflow integra-
Optimization and Proposes management plan follow- tion
planning ing automatically updated clinical Tools under development
Big data guidelines and not yet cleared for
Time savings with uncomplicated primary diagnosis
cases in tumor boards
Sources.—References 6, 23, and 24–31. AUC = area under the curve, CAD = computer-aided diagnosis, CNN =
convolutional neural network, EMR = electronic medical record, FDA = U.S. Food and Drug Administration,
NPV = negative predictive value, PPV = positive predictive value, 3D = three-dimensional, TZ = transitional zone.
RG  •  Volume 41  Number 6 Alcalá Mata et al  1681
Table 3: Patient Populations Included in PCa Early Detection Programs
NCCN Criteria
Men aged 45–75 years
NA
African American men aged ≥40 years
Men aged >40 years carrying BRCA2 or BRCA1 muta-
tions
Sources.—References 38 and 39.
Note.— EAU = European Association of Urology, NA = not applicable, NCCN = National Comprehensive
Cancer Network.
about what that program consists of, its risks and
benefits, and the exclusion of patients with low
life expectancy.
Future of PCa Screening
It is essential to find tools to decrease the high
false-positive rate associated with elevated PSA
levels in PCa diagnosis. Several studies have shown
that CNN models using different combinations
of data on age, total and free PSA, digital rectal
examination (DRE), and prostate volume can
significantly diminish the false-positive findings
linked to elevated PSA and help prevent unneces-
sary biopsies (24,40,41).
After the USPSTF’s recommendation to elim-
inate routine PSA testing, the incidence of PCa
during the following 5 years in the United States
increased at the expense of regional and distant
disease (by 1.5% and 3.5%, respectively) and a
decrease in the proportion of local-stage disease
(7.6%) (42). This indicates the need for a new
strategy in the treatment of men between 50 and
69 years of age and younger men with additional
risk factors. A promising strategy introduces
screening intervals based on PCa risk and biopsy
recommendation after a risk-based calculation by
using risk calculators and mpMRI. This approach
promotes follow-up in patients with low or inter-
mediate PCa risk (43) (Figs 3–5).
Another promising approach to improve selec-
tion of at-risk patients is the use of NLP tools in
primary care that can automatically detect risk-
factor data in the patients’ clinical record and cre-
ate alerts to enroll these patients in an early detec-
tion program. Similarly, they can classify patients
into risk groups automatically after obtaining PSA
levels and DRE findings (23).
Clinical and Analytical Diagnosis
of PCa
Current Status
The two main problems are the accurate dis-
tinction between patients who should undergo
EAU Criteria
Men aged ≥50 years
Men aged ≥45 years with family history of PCa
Men of African descent aged ≥45 years old
Men aged >40 years carrying BRCA2 mutations
biopsy and low-risk patients who should avoid
it, and the choice of biopsy type that optimizes
csPCa detection.
Classic independent indicators of the need
for biopsy such as abnormal DRE and elevated
PSA levels show evident limitations (43). When
csPCa is suspected, there is mixed evidence on
the use of screening biomarkers such as Pros-
tate Health Index (PHI), SelectMDx, 4KScore,
ExoDx Prostate Test, or prostate cancer antigen 3
(PCA3) before biopsy (38,39). The most updated
guidelines suggest mpMRI before biopsy (38,39).
Patients with a PI-RADS score less than or equal
to 2 at mpMRI have low PCa suspicion and, if
the patient agrees, a biopsy may not be necessary.
Patients with a PI-RADS score greater than or
equal to 3 should undergo a TRUS-Bx together
with MRI-TBx of the suspicious lesion, accord-
ing to EAU guidelines (39). This contrasts with
the PI-RADS version 2.1 guideline for patients
with a PI-RADS score of 3, who may undergo
biopsy only if deemed appropriate according to
clinical data and risk stratification (9) (Fig 3).
Clinical guidelines support an mpMRI-based ap-
proach, but some issues need to be addressed to
make this technique more broadly used (11,43–
45) (Table 4).
To refine PCa diagnosis, new tools such as risk
calculators or PSA density have been introduced.
Risk calculators are multivariable-based tools for
the prediction of individual PCa and csPCa risk
and help clarify the need for biopsy. They calcu-
late individual risk for each patient on the basis
of populational big data after histologic verifica-
tion. Risk calculators present greater discrimina-
tion power in PCa prediction than do PSA levels
and DRE alone, with concordance between 70%
and 77% (7). There are many risk calculators
for PCa, although those with the highest csPCa
prediction are the European Randomized Study
of Screening for Prostate Cancer (ERSPC) risk
calculator, which was created from a European
patient population, and the Prostate Cancer Pre-
vention Trial (PCPT) risk calculator, which was
1682  October Special Issue 2021 radiographics.rsna.org

Figure 3.  Early detection strategy

algorithm for csPCa with risk strati-
fication by using mpMRI according
to current clinical guidelines.

Figure 4. Proposed
strategy algorithm in
early csPCa detection
that is based on risk
stratification by using
a risk calculator (RC)
and PSA density (PSAd)
before mpMRI. This
approach could avoid
unnecessary mpMRI in
low-risk patients (or-
ange pathway).

created from a North American study, with the
ERSPC risk calculator seemingly having greater
PCa prediction (7).
Another important tool in PCa diagnosis is
PSA density (total PSA divided by prostatic
volume), which is a csPCa predictive marker that,
although not currently included in clinical guide-
lines, is used in active surveillance and unofficially
used in mpMRI interpretations at some centers. It
can now be calculated by AI tools and included in
the patient’s report. Its usefulness as a csPCa risk
predictor is gaining interest since it is easy to ac-
quire, and there is growing evidence demonstrat-
ing the relationship between elevated PSA density
values and csPCa. PSA density values greater than
0.10 ng/mL2 are associated with a detection rate of
77% of PCa with a Gleason score greater than or
equal to 7 (5).
Future of Clinical PCa Diagnosis
mpMRI is a tool to help improve risk strati-
fication in patients with suspected csPCa, but
RG  •  Volume 41  Number 6 Alcalá Mata et al  1683

Figure 5.  Proposed strategy flowchart for early csPCa detection based on risk stratification by using a risk calculator
(RC) and PSA density (PSAd) before and after mpMRI. This approach could avoid unnecessary mpMRI in low-risk pa-
tients and unnecessary biopsies in patients with PI-RADS 3 lesions with low risk of csPCa and, more importantly, could
avoid underdiagnosing csPCa in patients with negative MRI findings at medium or high risk of csPCA (orange pathway).

Table 4: Problems Arising from mpMRI Pathway

Problem Prevalence
Low accessibility and high cost of mpMRI NA
Overdiagnosis of ncsPCa in PI-RADS 3 lesions Up to 92%
csPCa undiagnosed because of false-negative findings at 4%–8%
mpMRI (PI-RADS ≤2)
False-positive findings at mpMRI (acute prostatitis, 67% by PI-RADS 3, 31% by PI-RADS 4, and 6% with
atypical hyperplastic nodules in TZ, bleeding areas in PI-RADS 5
PZ)
Increased complications (hematuria and hematosper- Increase in complication risk of 1.11% per core taken
mia) after TRUS-Bx plus MRI-TBx
mpMRI reading requires experienced radiologists and NA
has a steep learning curve
Sources.—References 8,11, and 43–45.
Note.—NA = not applicable, PZ = peripheral zone, TZ = transitional zone.

unnecessary mpMRI should be avoided. Recent
publications advocate the use of risk calcula-
tors in this regard. European guidelines recom-
mended the use of risk calculators in patients
with PSA values between 2 and 10 ng/mL
(39,43). Risk calculators can act as gatekeepers
in improving patient stratification before and
after mpMRI. Before mpMRI, risk calculators
could identify low-risk patients, helping avoid
probable mpMRI false-positive findings that
may lead to unnecessary biopsy (Fig 4). After
mpMRI, risk calculators could avoid unneces-
sary biopsies in patients with indeterminate-risk
lesions (PI-RADS 3), who could benefit from
follow-up (Fig 5). More importantly, they could
help identify high-risk patients with negative
mpMRI findings (PI-RADS ≤ 2), in which a
TRUS-Bx should be considered, helping avoid
underdiagnosis of csPCa in patients with false-
negative findings at mpMRI (10,11,44,46).
1684  October Special Issue 2021 radiographics.rsna.org

Figure 6.  mpMRI and subsequent MRI-TBx in a 64-year-old White man with no previous
biopsy, a PSA level of 5.46 ng/mL, normal DRE findings, normal transrectal US findings, a
prostatic volume of 42 mL, and low risk according to risk calculators. (A) Axial T2-weighted
multiparametric MR image shows a hypointense 10.8-mm lesion with partially occult borders
that was detected in the right anterior midglandular transitional zone (a region of interest
[ROI]) with a PI-RADS score of 3. (B, C) Axial diffusion-weighted MR image (B) depicts marked
lesion diffusion restriction, demonstrating high signal intensity with a b value of 1500 sec/mm2
(an ROI) and with low signal intensity on a corresponding ADC map (an ROI) (C), which corre-
sponded to a PI-RADS score of 4. (D) MRI-TBx of the lesion was performed with MRI/US fusion
biopsy. The biopsy needle was in the center of the lesion. (E) Low-power photomicrograph of
a core-needle biopsy sample shows a Gleason 3+3 adenocarcinoma in the main core (oval).
(Hematoxylin-eosin [H-E] stain; original magnification, 31.) (F) The algorithm highlights zones
of a Gleason 3 pattern while ghosting out the benign surrounding tissue (31). Histologic im-
ages obtained with Paige Prostate (Paige.AI).

Interestingly, PSA density combined with

mpMRI findings has improved PI-RADS nega-
tive predictive value (NPV) and has the promise
to help reduce unnecessary biopsies (10,11,44,47).
Patients at low risk of csPCa as determined by
both variables could benefit from clinical follow-
up, thus avoiding probable mpMRI false-positive of biopsies would be avoided and overdiagnosis of
findings that would lead to unnecessary biopsy ncsPCa reduced by 45% (Fig 6).
(11). According to Boesen et al (48), restricting Both risk calculators and PSA density should
biopsy to patients with a PSA density greater than also be used routinely after mpMRI when the re-
or equal to 0.15 ng/mL2 and a PI-RADS MRI sult is a PI-RADS score that is less than or equal
score greater than or equal to 4 is the best strategy, to 3, potentially avoiding unnecessary biopsies
as only 5% of csPCas would be missed, but 41% in this group who would benefit from multidis-
RG  •  Volume 41  Number 6 Alcalá Mata et al  1685

Table 5: mpMRI Protocol

Sequence When to Perform Sequence Parameters

T2WI Always At least 2D RARE T2WI in two planes
(axial and sagittal or coronal) and 3D
RARE T2WI
DWI Always At least two b values (one low: 0 or 50
sec/mm2; one intermediate: 800 or
1000 sec/mm2) and calculated or ac-
quired high b values ≥1400 sec/mm2
ADC map Always Created only from a low b value (50 sec/
mm2 preferably) and a b value of 800
or 1000 sec/mm2
DCE-MRI Negative prior biopsy results and unexplained high PSA Same plane as in DWI
In active surveillance or have undergone treatment Temporal resolution ≤15 sec
Previous biparametric MRI and persisting PCa suspicion
Negative prior biopsy results and strong family history or
genetic predisposition
Metallic prostheses present
Source.—Reference 9.
Note.—DCE = dynamic contrast-enhanced, RARE = rapid acquisition with relaxation enhancement, T2WI =
T2-weighted imaging, 2D = two-dimensional.

ciplinary team follow-up (10,11,44). The use of
risk calculators and PSA density is potentially
more important in identifying high-risk patients
with negative mpMRI findings (PI-RADS ≤ 2), in
which a TRUS-Bx could be considered, avoiding
csPCa underdiagnosis in that group due to false-
negative mpMRI findings (11). This approach
can be considered a refinement of the combined
biopsy pathway of PCa diagnosis.
Novel “omics” biomarkers may help improve
PCa diagnosis and risk stratification. Here, AI has
a role in the identification and validation of new
biomarkers, as machine learning tools accelerate
the identification of new applications (ie, high
Ki67 expression may be used to select candidates
for focal therapy) (6,49).
Multiparametric MRI
Current Situation
At present, mpMRI should be performed in men
who are suspected of having csPCa in both bi-
opsy-naive patients and after TRUS-Bx, accord-
ing to PI-RADS version 2.1 recommendation
(Table 5) (9,50). mpMRI improves the detection
and location of PCa with an ISUP grade greater
than or equal to 2, with a sensitivity of 91% and
specificity of 37%. For tumors with an ISUP
grade greater than or equal to 3, the sensitivity
of mpMRI is 97% and specificity is 35%, with a
low detection rate of ISUP grade 1 PCa (< 30%)
(51). Also, mpMRI is necessary to perform MRI-
TBx, which significantly increases the detection
rate of csPCa in comparison with TRUS-Bx (38).
mpMRI allows initial tumor staging in the case of
positive biopsy results (9).
Future of mpMRI in PCa Diagnosis
A very promising field is the use of AI in the
development of diagnostic probabilistic maps,
which can identify lesions at mpMRI and es-
tablish a correlation with histologic grading and
clinical outcome (20). The shortage of experi-
enced radiologists can potentially be alleviated
by AI algorithms, reducing time required by the
radiologist and minimizing false-negative find-
ings that are associated with more inexperienced
readers. Alternatively, these solutions can be used
as an independent second reader to help improve
interreader reproducibility.
Radiomics has been used in the development
of CAD tools for PCa detection and PI-RADS
classification of mpMRI lesions. Furthermore,
these solutions can provide information on tu-
mor heterogeneity that has histologic correlation
by examining edge characteristics and texture
analysis (52).
CAD tools typically use texture analysis and
radiomics with one or several MRI sequences,
analyzing lesion borders and signal intensity more
commonly with T2-weighted sequences or diffu-
sion-weighted imaging (DWI) and corresponding
apparent diffusion coefficient (ADC) maps. They
are built by using supervised learning, in which
experienced radiologists label the lesions and
score them according to PI-RADS. These data
can be correlated with histologic results, which are
then used in the AI training process. Later, new
1686  October Special Issue 2021 radiographics.rsna.org

Figure 7.  CAD AI in prostatic MRI (MR

Prostate AI included in syngo.via Fron-
tier; Siemens Healthineers). The AI tool
assists with mpMRI reading and prostate
gland segmentation, including the pe-
ripheral zone and transitional zone, and
the detection and classification of lesions
with a PI-RADS score of 3 or greater by
using T2-weighted, DWI, and postcon-
trast dynamic contrast-enhanced (DCE)
sequences. The AI tool creates both rigid
and elastic registers of the sequences to
generate synthetic or calculated b values
of 1500 sec/mm2 and ADC maps from
original b values of 50 and 1000 sec/
mm2. (A) On these images, the automatic
glandular segmentation is done, which
is then validated or manually edited by
the radiologist. (B) After validation, the
prostatic volume is calculated, and detec-
tion and analysis of suspicious lesions are
performed. Information offered includes
volume, greater diameter, average ADC
value, 10th percentile of the ADC map,
average Ktrans value, and lesion location.
(C) An automatic PI-RADS scoring in the
three analyzed sequences is then done,
and a global PI-RADS scoring is gener-
ated. (D) The radiologist validates this
classification, and a report is automati-
cally generated with the data listed in the
legend for B, which includes key images
highlighting the lesion in the quadrant
map. Both gland segmentation and suspi-
cious lesions can be exported to the hard-
ware to perform MRI-TBx.

unlabeled training data may be presented to the
algorithm (Fig 7) (20,52).
However, there are two main disadvantages to
the development of these AI tools. First, the large
amount of labeled data necessary for adequate
AI training requires notable input and time from
experienced radiologists (25,53). Second, the
false-positive rate of these tools is up to 50%,
which requires radiologist input during reading
to validate or reject the lesions presented by AI
(25,53). Another hurdle to perform quantitative
analysis of mpMRI is the heterogeneity of data
that is due to differences in acquisition protocols,
magnet field strengths, and MRI system ven-
dors. To minimize these variations, some authors
propose the normalization of data to ensure that
intensity values within the prostate gland are
consistent among different studies (54).
There is growing evidence, including from
meta-analyses, describing significant robustness
in the mpMRI detection rate of suspicious lesions
(between 75%–80%) by CAD tools in clinical
trials, which perform similarly to radiologists
(19,26). In a multicenter multireader study, CAD
sensitivity was similar to that of a radiologist but
was associated with a reading time reduction.
Moderately experienced readers required 6.3
minutes, but this time was reduced to 4.4 min-
utes when CAD assisted (27). For experienced
readers, this was 3.5 minutes without CAD as-
sistance, which was reduced to 2.7 minutes with
CAD assistance. The sensitivity of index lesion
detection (PI-RADS ≥3) was 78%, but where
CAD stood out was in the increase in sensitivity
in the detection of transition zone lesions by less
experienced readers, reaching 83.8% compared
to 66.9% without CAD (Fig E1).
Although in most series, the sensitivity for de-
tection and classification of PI-RADS lesions with
a score greater than or equal to 3 and the specific-
ity for PI-RADS lesions with a score greater than
or equal to 4 is similar to that of radiologists, posi-
RG  •  Volume 41  Number 6 Alcalá Mata et al  1687

Figure 8.  False-positive findings in CAD-aided interpretation of mpMRI in a 67-year-old man with a PSA level of 12.1 ng/mL (same
patient as in Figure E2). (A–D) The algorithm (MR Prostate AI) detected a small hypointense bandlike lesion (orange region of interest
[ROI]) at T2-weighted MRI in the apical posterolateral left peripheral zone (A), with high signal intensity at DWI (B), intermediate
ADC values (C), and without early enhancement at dynamic contrast-enhanced (DCE) MRI (D), suggesting an inflammatory or
benign nature. (E) The lesion was assigned a PI-RADS 2 score by a radiologist but was misclassified as PI-RADS 3 by the algorithm.

tive predictive value is low because of false-positive
findings, which would increase the number of
unnecessary biopsies (25). As algorithms continue
to improve, the false-positive rate should continue
to decrease (53) (Fig 8) (Fig E2).
Recent studies point to the association be-
tween MRI signal intensity with T2-weighted
sequences, DWI characteristics, and the density
of the tissue composition, which is derived from
the automatic segmentation of stromal tissue,
epithelium, epithelial nuclei, and lumen that per-
mit the creation of radiopathomic maps. A study
has shown that increased epithelial-map density
and decreased lumen-mapping density were
associated with high-grade PCa (55). Another
study concludes that increased epithelial volume
and decreased stromal and lumen map volumes
that are determined by using hybrid multidimen-
sional MRI are associated with higher-grade PCa,
making this a promising tool in the prediction of
aggressive PCa (56,57) (Fig 9).
In summary, the literature shows how AI
tools can accurately identify suspicious prostatic
lesions at mpMRI and can reasonably estimate
PI-RADS and Gleason scores (27,28,58–60).
Improvements are expected once AI algorithms
can be trained with the relevant digital pathologic
slides, given the spatial correlation between radi-
cal prostatectomy specimens and mpMRI (61).
Biopsy
Current Status
Transrectal or transperineal TRUS-Bx is the
mainstay of PCa diagnosis. Given the low sensi-
tivity of this approach in csPCa detection and the
1688  October Special Issue 2021 radiographics.rsna.org

Figure 9.  Radiopathomic maps from mpMRI that were generated with an AI-based radiomic tool (hybrid
multidimensional MRI) in a 56-year-old patient with Gleason 4+3 adenocarcinoma in the right peripheral zone.
(A–C) Stroma volume map (A), lumen volume map (B), and epithelium volume map (C) depict the malignant
lesion (arrow) as having reduced stroma and lumen volume (36.4% and 7.8%, respectively) and elevated epi-
thelium volume (55.8%) compared with surrounding benign tissue. (D) Axial turbo spin-echo T2-weighted MR
image. The hybrid multidimensional MRI map was correctly predicted as csPCa on the cancer map and was a
hypointense region in the corresponding turbo spin-echo T2-weighted MR image (arrow). (Case courtesy of
Aritrick Chatterjee, PhD, Department of Radiology, University of Chicago, Chicago, Ill.)

introduction of mpMRI in the diagnostic path-
way, new biopsy methods have emerged, such as
MRI-TBx, ranging from cognitive biopsy (visu-
ally registered targeted biopsy), MRI/US fusion
biopsy, to in-bore previous MRI-guided biopsy
(Figs 10, 11). Therefore, the role of TRUS-Bx is
under review. MRI/US fusion biopsy and MRI-
guided biopsy have demonstrated an increase of
30% and of 38%, respectively, in csPCa detec-
tion compared with TRUS-Bx, explaining their
increasing adoption (62). Also, the use of MRI-
TBx seems more consistent with the Gleason
score in prostatectomy specimens in lesions with
a PI-RADS score greater than or equal to 3 than
in TRUS-Bx (63). However, some controversy
remains about the best biopsy route (transrectal
or transperineal), the optimal number of cores
per lesion, the best technical solution to perform
MRI-TBx, and whether it is performed alone or
combined with TRUS-Bx (39).
At present, the recommended approach in
the EAU and NCCN guidelines is to perform
TRUS-Bx plus MRI-TBx for lesions with a
PI-RADS score greater than or equal to 3 in
patients without previous biopsies, as perform-
ing both together seems to increase the PCa
detection rate by 9.9%, compared with any
single-technique approach (63). However, in
patients with previous negative biopsy, com-
bined biopsy is not recommended (51). TRUS-
Bx is still important in patients with negative
MRI findings and high csPCa suspicion, and in
patients with PI-RADS score 3 lesions with-
out previous biopsy. However, a meta-analysis
involving approximately 14 000 patients con-
cluded that excluding TRUS-Bx in these pa-
tients was associated with a decrease in ncsPCa
diagnosis without affecting the diagnosis of
csPCa (64). Furthermore, it has been suggested
that PI-RADS score 4 lesions should have only
MRI-TBx sampling of the target lesion and the
penumbra area (prostatic tissue surrounding the
lesion), since in small lesions, the sampling error
rate can be high, and this ensures that the suspi-
cious area is biopsied. In large PI-RADS score
5 lesions, only MRI-TBx of the lesion has been
recommended, but this is an evolving topic (Fig
12) (11).
Another question is the difference in csPCa
detection between different MRI-TBx tech-
niques. In MRI/US fusion biopsy, in vivo US
acquisitions are overlaid on previously segmented
RG  •  Volume 41  Number 6 Alcalá Mata et al  1689

Figure 10.  Biopsy types.

(A) TRUS-Bx is the usual biopsy
technique. To compensate for the
poor sensitivity of TRUS-Bx in the
detection of suspicious lesions, the
systematic TRUS-Bx uses sextant
sampling. Six cylinders are ob-
tained from the right peripheral
zone and six from the left, with no
routine sampling of the transitional
zone. (B) Cognitive biopsy is per-
formed after mpMRI with positive
findings. In this case, the suspi-
cious lesion was located in the left
anterior midglandular transitional
zone (arrow). The operator then
performed a transrectal US-guided
biopsy of the area, in which the
mpMRI lesion was located, al-
though in this case, the lesion was
not visualized at US. This tech-
nique is indicated when the equip-
ment to perform MRI-TBx is not
available. (C) In MRI/US fusion bi-
opsy, the gland and suspected le-
sion are first segmented at mpMRI
by using specific software, and the
target lesion is then biopsied by
using hardware that permits the
fusion of in vivo US and previous
mpMRI acquisitions. (MRI/US fu-
sion biopsy performed with Uro-
Nav fusion biopsy system; Philips
Healthcare.) (D) Cognitive biopsy.
The operator then performed a
transrectal US-guided biopsy of
the area, in which the mpMRI le-
sion was located, although in this
case, the lesion was not visualized
at US. This technique is indicated
when the equipment to perform
MRI-TBx is not available.

MRI images of the targeted areas. Currently, dif-
ferent commercial MRI/US fusion biopsy systems
use different biopsy routes and show different
technical characteristics and clinical results (65).
One advantage of MRI/US fusion biopsy
over in-bore MRI-guided biopsy is that it can
be combined in a single procedure with TRUS-
Bx. In addition, in-bore MRI-guided biopsy is a
biopsy technique that is of limited use at present
because of its high cost and restricted avail-
ability, but with promising results for certain
lesions. In-bore MRI-guided biopsy shows a
higher csCPa detection rate of 25% compared
with MRI/US fusion biopsy in patients with
previous biopsy, lesions smaller than 10 mm,
or lesions located in the apex or prostatic base,
which may be difficult to reach in patients with
a large prostate (66,67). Also, the fact that these
biopsies are obtained in the same position as
the original MRI examination should be associ-
ated with a better histologic correlation. Thus,
in patients with biopsied lesions with a Gleason
score of 3, but high suspicion at mpMRI with
a Gleason score of 4, an in-bore MRI-guided
biopsy should be considered (67).
Future of MRI-TBx
Although the analysis of MRI/US fusion bi-
opsy systems is beyond the scope of this review,
there is room for improvement in the alignment
1690  October Special Issue 2021 radiographics.rsna.org

Figure 11.  In-bore MRI biopsy in a 64-year-old-man with a PSA level of 4.36 ng/mL and no
previous biopsy. (A–C) Axial T2-weighted MR image (A), axial diffusion-weighted MR image
with a b value of 1000 sec/mm2 (B), and axial ADC map obtained with mpMRI (C) reveal a left
peripheral zone–based medial-lateral lesion measuring 4 mm with a PI-RADS 4 score (arrow).
The needle position was represented in real time by the orange line overlaid from the needle
guide and showed the optimal path after the guide was remotely repositioned. (D, E) Axial
diffusion-weighted MR image (D) and sagittal T2-weighted image (E) show the needle track
and core that were obtained with a remote-controlled manipulator (Soteria Medical), which
are represented by the red line. Two cores were taken, revealing a Gleason 3+3 pattern in
both. The cores consisted of 50% and 70% tumor content, respectively. (Case courtesy of Joan
Carles Vilanova, MD, PhD, Clínica Girona, Girona, Spain.)

Figure 12.  Biopsy indication according to MRI results (blue track). New trends are currently emerging on the biopsy
type of choice in PI-RADS 4 lesions, in which the detection rate of csPCA with MRI-TBx due to saturation sampling of
the lesion and its penumbra zone would be similar to that of a combined biopsy (MRI-TBx and TRUS-Bx). In PI-RADS 5
lesions, given their large size, the existence of csPCA in other locations is unlikely, so sampling that lesion only would be
indicated, thus avoiding the complication risk associated with sampling other regions (orange track).

between both imaging modalities and in target
location, particularly of lesions located anteri-
orly or very apically, where the prostatic gland
deformation during the procedure may compli-
cate biopsy.
Prostate gland segmentation is a repetitive task
that is required for prostate volume measure-
ment, radiation therapy planning, and MRI-TBx.
AI-based solutions can label anatomic structures,
helping to perform an accurate prostate segmen-
tation in mpMRI, while considering the deform-
able prostate pseudocapsule. Other AI tools help
speed up mpMRI reading by performing auto-
matic prostatic segmentation and detecting and
classifying lesions with a PI-RADS score of 3 or
higher. Both gland segmentation and suspicious
lesion data can be exported to the hardware to
perform MRI-TBx. In MRI/US fusion biopsy, AI
may help improve prostatic segmentation in both
mpMRI and US, and more importantly during
RG  •  Volume 41  Number 6 Alcalá Mata et al  1691

Figure 13.  MRI/US fusion biopsy workflow with real-time 3D deformable image registration algorithms. MRI/US fusion biopsy re-
quires prior software-specific segmentation of the prostatic gland at T2-weighted imaging, which can be performed automatically as
in this example (A), and of the suspicious lesion (B), which is usually done manually or semi-automatically (DynaCAD; Philips Health-
care). These segmentations are transferred to the biopsy hardware, which is a US scanner with an electromagnetic field generator and
a navigation sensor mounted on the ultrasound translator. (Fig 13 continues on next page.)

image registration, whereby prostatic segmenta- Pathology

tion and targets in T2-weighted sequences are
fused with the US images in real time (64). The
use of real-time 3D deformable image registra-
tion algorithms can improve MRI/US fusion
biopsy results (29,68) (Fig 13).
AI can also help PCa treatment. The coregis-
tration of cancer lesions at mpMRI, as detected
by a radiomics-based machine learning classi-
fier together with CT, can help generate accu-
rate radiation therapy plans (69). Also, cancer
regions detected by a machine learning algo-
rithm at mpMRI can be fused with real-time
US to be automatically displayed to surgeons,
providing valuable information during robotic
surgery (70).
Current Status
A necessary step for the integration between
radiologic and pathologic characteristics is the
digital transformation of pathology. Pathology
relies on the glass slide as the primary diagnos-
tic medium. Digital pathology consists of the
creation of a digital replica of this glass slide,
called a whole-slide image, by using a scanning
device. Only recently, technologic and regulatory
changes have permitted the digitization of pathol-
ogy. In 2017, the U.S. Food and Drug Admin-
istration (FDA) permitted the use of the first
digital pathology solution for primary diagnosis
(71). The adoption of digital pathology is still in
1692  October Special Issue 2021 radiographics.rsna.org

Figure 13. (Continued from pre-

vious page.)  (C) The segmented
T2-weighted images and US im-
ages are fused together by using
an elastic and rigid registration
(UroNav fusion biopsy system; Phil-
ips Healthcare). The purple outline
is the segmented MRI prostatic
contour, which adapts to the de-
formity of the prostate during the
US examination (caused by the
transrectal probe and sedation)
and checks in real time its appropri-
ate positioning during the duration
of the examination. (D) The green
outline shows the contours of the
segmented lesion at MRI, display-
ing the biopsy needle position
in real time, and taking between
three and five cores per target.

its infancy, with few centers worldwide having
reported their digital transformation.
Core-needle biopsy evaluation is the main his-
topathologic assessment in PCa and is one of the
most frequent specimen types in surgical pathol-
ogy. The histologic evaluation is typically done by
using hematoxylin-eosin–stained tissue sections,
which are examined under conventional micros-
copy, and involves the detection of cancer and its
corresponding Gleason grading. This process is
affected by several problems that could benefit
from CAD. Increasing workloads and decreasing
pathologist numbers worldwide put pressure on
the existing workforce, as it is critical that diagnos-
tic quality standards are met.
Future of Pathologic Diagnosis of PCa
The advantages of a digital pathology workflow
are multiple, including improved efficiency and
better user experience compared with light mi-
croscopy (72,30). Digital histologic images can
be viewed anywhere by using a computer instead
of a microscope, which makes them accessible
beyond the pathology laboratory. Also, digital
pathology permits the application of AI tools to
histologic images to aid diagnosis, as it occurs
in radiology. Therefore, digital pathology is the
foundation of computational pathology and CAD
in pathology.
Specific problem areas in PCa diagnosis that
are likely to benefit from CAD are reducing
false-negative rates in histopathologic diagnosis
and better Gleason grading, as this is a subjective
process with suboptimal concordance, particu-
larly when done by general pathologists instead
of specialists (73,74) (Fig 14). Clinical-grade AI
systems in PCa already exist and have demon-
strated increased pathologist sensitivity and opti-
RG  •  Volume 41  Number 6 Alcalá Mata et al  1693
mal negative predictive value and have led to the
reevaluation of lesions that were misdiagnosed
clinically as benign (32,21). This illustrates how
AI could complement pathologists in tasks that
are difficult and time consuming. Therefore, the
role of technology in the future of histopathologic
PCa diagnosis seems warranted to help alleviate
problems such as intra- and interreader variabil-
ity and long reading times.
Figure 14.  False-negative histopathologic findings re-
vealed by AI in a 74-year-old man with a PSA level of 4.3
ng/mL. (A) Coronal T2-weighted MR image that was ana-
lyzed by MR Prostate AI shows a 13.7-mm lenticular lesion
located in the right anterior apical transitional zone, which
was hypointense at T2-weighted imaging. (B) Fusion of the
lesion heat map and the T2-weighted image shows how
the level of suspiciousness (LoS) calculated by the algorithm
is 85 on a scale from 1 to 100 and is therefore suggestive
of malignancy, with a PI-RADS score of 4. (C) Low-power
photomicrograph of a prostatic core-needle biopsy speci-
men shows abundant prostatic adenocarcinoma, acinar
type. The primary histologic diagnosis was Gleason score
3+3. (H-E stain; original magnification, 32.) (D) Tumor
probability heat map includes an algorithm that highlights
tumor areas according to their mathematical probability
of being malignant. One of the drawbacks of this feature
is that the tissue details are no longer visible. The quanti-
fication window (arrow) displays the tumor size and per-
centage of tumor present in the core, as calculated by AI.
(E, F) Gleason pattern 3 detection (E) and Gleason pat-
tern 4 (F) detection maps can highlight different tumor
areas according to the Gleason pattern. The tumor areas
are clearly visible now and stand out from the benign tissue
background. This facilitates visual assessment of the overall
Gleason score that is also calculated by AI and displayed
(arrow). In this case, AI indicated a Gleason score of 3+4,
which was discordant with the primary histologic diagnosis,
which was subsequently reviewed and updated. Histologic
images were obtained with Paige Prostate Clinical.
Radiopathologic Integration and
Integrated Diagnostics
Current Status
The PCa diagnostic process has some weak links.
False-positive findings in mpMRI interpretation,
associated with prostatitis foci, extruded stromal
nodules and hyperplastic nodules, or nodules with
hemorrhagic content in the transitional zone that
1694  October Special Issue 2021 radiographics.rsna.org
Figure 15.  An example of a tumor board decision support tool (AI-Pathway Companion; Siemens Healthineers) that reflects all
clinical data of the patient and the actions performed. This application also suggests possible management pathways according to
clinical guidelines.
are classified as PI-RADS lesions with a score of
3 or greater, generate a multitude of equivocal
biopsies. Erroneous segmentation of suspicious
lesions may lead to biopsying the wrong location
at MRI-TBx. Inadequate biopsy sampling may
occur in lesions located in regions difficult to
reach transrectally with MRI/US fusion biopsy,
especially in patients with a large prostate, with
an outcome of false-negative findings or discor-
dant radiologic-histopathologic results.
The biopsy processing in the pathology labora-
tory consists of fixing the obtained tissue core in
formalin, which is then embedded in a paraffin
block. This is a 3D structure, and sampling only
its most superficial levels may result in most of
the tissue remaining unsampled, and thus unex-
amined by the pathologist. A biopsy result that
is discrepant with the radiologic findings should
prompt a thorough examination of the tissue
remaining in the paraffin block. Finally, histologic
interpretation errors may result in cancer foci
being either incorrectly graded or missed entirely,
which could lead to underdiagnosis of mpMRI
lesions that are suggestive of csPCa.
Future
A joint radiology-pathology tumor board would
help detect and resolve these diagnostic inconsis-
tencies before a final joint report is issued, thus
reducing confusion and distress in clinicians and
patients, similar to what occurs in the treatment
of breast cancer (31) (Fig E3). An appropri-
ate way to help speed up radiologists’ mpMRI
learning curve could be based on integrated
radiologic-pathologic diagnosis, so lesions with
intermediate PI-RADS scores or those situated
in more complex locations could be discussed in
a multidisciplinary setting to clarify diagnostic
disparities. Similarly, in disease with a PI-RADS
score of 4 or greater with radiologic-pathologic
disagreement, any diagnostic errors such as
mpMRI false-positive findings or biopsy sam-
pling errors could be resolved. Finally, it is im-
portant to ponder the type of biopsy, considering
that saturation biopsies of suspicious lesions with
mpMRI could reduce the number of procedures,
thus reducing the risk of complications.
Cancer centers are recommended to discuss all
their cases in multidisciplinary teams. However,
the time available for complex cases is reduced by
standard case management. To solve this problem
and facilitate the diagnosis, treatment, and follow-
up of patients with PCa by multidisciplinary
teams, decision support tools are created, based
on, and validated by clinical guidelines or expert
management (22). These tools facilitate find-
ing relevant data in the clinical history, includ-
ing analytical values, previous studies, histologic
RG  •  Volume 41  Number 6 Alcalá Mata et al  1695
results, and treatments received. Currently, novel
NLP tools can locate relevant data in the patient
file such as family history, PSA levels, mpMRI
findings, and pathologic reports and generate
alerts, as well as suggesting actions based on up-
dated clinical guidelines. Finally, these platforms
integrate data from different sources (ie, clinical
history, laboratory, genomics, or medical images),
providing the opportunity to apply AI solutions
that analyze these data and compare them with
populational big data to improve individual risk
stratification and better predict patient outcomes,
in a practical example of personalized and preci-
sion medicine (22,75) (Fig 15).
Conclusion
PCa diagnosis is experiencing a revolution with
the introduction of mpMRI and MRI-TBx,
which is known as the MRI pathway. mpMRI is
essential in the detection and characterization of
csPCa, and MRI-TBx is gaining an important
role in PCa diagnosis at the expense of the more
common TRUS-Bx. However, TRUS-Bx still
plays an important role in PCa diagnosis when
combined with mpMRI, which constitutes the
so-called combined biopsy pathway. As such,
the introduction of these diagnostic approaches
results in frequent and substantial changes in
PCa management clinical guidelines. Further
refinement of these diagnostic pathways may be
granted because of the integration of risk calcula-
tors, analytical methods (ie, PSA density), and
genomic and other “omics” biomarkers.
AI is gaining an ever-increasing importance
in PCa management. AI tools facilitate prostate
gland segmentation, lesion detection, and classifi-
cation at mpMRI, limiting interreader variability
and mitigating the potential lack of expertise of
less-experienced radiologists. Digital pathology is
the basis for radiologic-pathologic integration and
of CAD in pathology, helping improve efficiency,
diagnostic accuracy, and concordance. The role of
machine learning tools is expected to grow in ra-
diologic and pathologic PCa diagnosis, facilitating
radiologic-pathologic integration. Finally, the use
of decision support tools and AI-based analysis of
fused data may be the next step in the PCa diag-
nostic pathway, as their use is expected to improve
risk stratification and patient outcome.
Disclosures of Conflicts of Interest.—J.A.R. Activities related
to the present article: disclosed no relevant relationships. Activi-
ties not related to the present article: current employee of Paige.
AI; holds stock options with Paige.AI; former employee of
Philips. Other activities: disclosed no relevant relationships.
R.T.G. Activities related to the present article: disclosed no rele-
vant relationships. Activities not related to the present article: con-
sultant to Invivo and DxTx Medical. Other activities: disclosed
no relevant relationships. A.L. Activities related to the present
article: editorial board member of RadioGraphics (not involved
in the handling of this article). Activities not related to the present
article: lectured for Siemens Healthineers, Philips, and Canon;
received royalties from Springer for book editing. Other activi-
ties: disclosed no relevant relationships.
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