ORIGINAL RESEARCH • GENITOURINARY IMAGING

A Grading System for the Assessment of Risk of

Extraprostatic Extension of Prostate Cancer at
Multiparametric MRI
Sherif Mehralivand, MD  •  Joanna H. Shih, PhD  •  Stephanie Harmon, PhD  •  Clayton Smith, BA  • 
Jonathan Bloom, MD  •  Marcin Czarniecki, MD  •  Samuel Gold, BS  •  Graham Hale, BS  •  Kareem Rayn, BS  • 
Maria J. Merino, MD  •  Bradford J. Wood, MD  •  Peter A. Pinto, MD  •  Peter L. Choyke, MD  •  Baris Turkbey, MD
From the Department of Urology and Pediatric Urology, University Medical Center, Mainz, Germany (S.M.); Urologic Oncology Branch, National Cancer Institute,
National Institutes of Health, Bethesda, Md (S.M., J.B., S.G., G.H., K.R., P.A.P.); Molecular Imaging Program, National Cancer Institute, National Institutes of Health,
10 Center Dr, MSC 1182, Building 10, Room B3B85, Bethesda, MD 20892-1088 (S.M., C.S., M.C., P.L.C., B.T.); Division of Cancer Treatment and Diagnosis: Bio-
metric Research Program, National Cancer Institute, National Institutes of Health, Rockville, Md (J.H.S.); Clinical Research Directorate/Clinical Monitoring Research
Program, Leidos Biomedical Research, NCI Campus at Frederick, Frederick, Md (S.H.); Laboratory of Pathology, National Cancer Institute, National Institutes of Health,
Bethesda, Md (M.J.M.); and Center for Interventional Oncology, National Cancer Institute and Radiology and Imaging Sciences, Clinical Center, National Institutes of
Health, Bethesda, Md (B.J.W.). Received May 31, 2018; revision requested July 25; final revision received November 19; accepted December 3. Address correspondence
to B.T. (e-mail: turkbeyi@mail.nih.gov).
S.M. supported by Dr. Mildred Scheel Stiftung für Krebsforschung (Bonn, Germany).
This project has been funded in whole or in part with federal funds from the National Cancer Institute, National Institutes of Health, under Contract No. HH-
SN261200800001E. The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention
of trade names, commercial products, or organizations imply endorsement by the U.S. Government.

Conflicts of interest are listed at the end of this article.

See also the editorial by Eberhardt in this issue.

Radiology 2019; 00:1–111 • https://doi.org/10.1148/radiol.2018181278 • Content code:

Purpose:  To evaluate MRI features associated with pathologically defined extraprostatic extension (EPE) of prostate cancer and to
propose an MRI grading system for pathologic EPE.

Materials and Methods:  In this prospective study, consecutive male study participants underwent preoperative 3.0-T MRI from
June 2007 to March 2017 followed by robotic-assisted laparoscopic radical prostatectomy. An MRI-based EPE grading system was
defined as follows: curvilinear contact length of 1.5 cm or capsular bulge and irregularity were grade 1, both features were grade 2,
and frank capsular breach were grade 3. Multivariable logistic regression and decision curve analyses were performed to compare the
MRI grade model and clinical parameters (prostate-specific antigen, Gleason score) for pathologic EPE prediction by using the area
under the receiver operating characteristic curve (AUC) value.

Results:  Among 553 study participants, the mean age was 60 years 6 8 (standard deviation); the median prostate-specific antigen
value was 6.3 ng/mL. A total of 125 of 553 (22%) participants had pathologic EPE at radical prostatectomy. Detection of patho-
logic EPE, defined as number of pathologic EPEs divided by number of participants with individual MRI features, was as follows:
curvilinear contact length, 88 of 208 (42%); capsular bulge and irregularity, 78 of 175 (45%); and EPE visible at MRI, 37 of 56
(66%). For MRI, grades 1, 2, and 3 for detection of pathologic EPE were 18 of 74 (24%), 39 of 102 (38%), and 37 of 56 (66%),
respectively. Clinical features plus the MRI-based EPE grading system (prostate-specific antigen, International Society of Urological
Pathology stage, MRI grade) predicted pathologic EPE better than did MRI grade alone (AUC, 0.81 vs 0.77, respectively; P ,
.001).

Conclusion:  Higher MRI-based extraprostatic extension (EPE) grading categories were associated with a greater risk of pathologic
EPE. Clinical features plus MRI grading had the highest diagnostic performance for prediction of pathologic EPE.
© RSNA, 2019

Online supplemental material is available for this article.

Pcomprehensive risk assessment and staging to ensure

atients diagnosed with prostate cancer benefit from
optimal counseling and treatment planning. Extrapros-
tatic extension (EPE) of tumor is associated with a higher
risk of positive surgical margins, biochemical recurrence,
metastatic disease, and lower cancer-specific survival after
radical prostatectomy (1–4). In patients who elect surgery,
preoperative assessment of the location of pathologic EPE
impacts the surgical strategy because a wider excision with
removal of the neurovascular bundles may be attempted
to increase the likelihood of a negative margin (5,6). De-
spite improved cancer control, this more aggressive surgical
This copy is for personal use only. To order printed copies, contact reprints@rsna.org
approach comes at the cost of higher rates of urinary in-
continence and erectile dysfunction (7). Therefore, having
more accurate assessment of pathologic EPE prior to sur-
gery is of utmost importance to optimize clinical decision
making.
Multiparametric MRI is used to depict and localize sus-
pected prostate cancer lesions primarily for guiding image-
directed biopsies. Besides detection of prostate cancer, there
is a potential role in preoperative staging for depiction of
pathologic EPE and seminal vesicle invasion. Several stud-
ies have reported that multiparametric MRI outperforms
clinical risk calculators in predicting pathologic EPE; the
Assessment of Risk of Extraprostatic Extension of Prostate Cancer at MRI
Abbreviations
AUC = area under the receiver operating characteristics curve, EPE =
extraprostatic extension, ISUP = International Society of Urological
Pathology, PI-RADS = Prostate Imaging Reporting and Data System
Summary
MRI grading for extraprostatic extension combined with clinical
variables (prostate-specific antigen, Gleason score, and digital rectal
examination) showed the highest diagnostic performance for predic-
tion of pathologic extraprostatic extension of prostate cancer.
Implications for Patient Care
nn Curvilinear contact length of more than 1.5 cm, capsular bulge
and irregularity, and MRI-visible extraprostatic extension (EPE)
were the primary features that were associated with greater likeli-
hood of pathologic EPE.
nn An MRI grading system consisting of curvilinear contact length,
capsular bulge, and MRI-visible EPE was developed for prediction
of pathologically defined EPE of prostate cancer.
nn MRI grade 3 was associated with a 66% positive predictive value
and 82% negative predictive value for defining pathologic EPE of
prostate cancer.
combined use of multiparametric MRI and clinical risk further
improve prediction of pathologic EPE (8–11). However, there is
significant interreader variability due to lack of standardization
and because the likelihood of pathologic EPE varies with specific
MRI findings. Pathologic EPE has commonly been reported in
binary terms (ie, “present” or “absent”) despite the fact that MR
findings are rarely definitive for pathologic EPE (12). In such
cases, it is common to create a likelihood scale that estimates
the risk of pathologic EPE rather than providing a definitive,
but possibly inaccurate, binary answer. Recently, studies have
aimed to apply a Likert scale of 1–5 to EPE that showed moder-
ate interreader agreement. However, Likert scales typically lack
objective criteria and therefore are difficult to reproduce (13).
Additionally, few studies have used specific Prostate Imaging Re-
porting and Data System (PI-RADS) terms as criteria in the as-
sessment of pathologic EPE (14–16). To overcome these issues,
a standardized grading system of EPE at multiparametric MRI
would be helpful to improve consistency in reporting and to aid
in training.
Several multiparametric MRI features are associated with
pathologic EPE. These include curvilinear contact length, cap-
sular irregularity and bulge, obliteration of rectoprostatic angle,
asymmetry of the neurovascular bundles, invasion of the peri-
prostatic fat, and seminal vesicle invasion. However, validation
studies for these markers are still sparse (17–20). Hence, the
purpose of our study was to evaluate the diagnostic value of six
well-defined multiparametric MRI features for the prediction of
pathologic EPE. Based on these results, we also introduce a stan-
dardized grading system that predicts the likelihood of patho-
logic EPE at multiparametric MRI.
Materials and Methods
Patient Population
This prospective study was compliant with the Health Insur-
ance Portability and Accountability Act and institutional re-
2 radiology.rsna.org  n  Radiology: Volume 00: Number 0— 2018
view board approval was obtained. The study was funded by
the intramural research program of the National Institutes of
Health. Written informed consent was obtained from all par-
ticipants (NCT00026884 and NCT02594202). All authors
had control of the participants’ data and study information.
A subset of 115 participants from this population were previ-
ously reported (21,22). Those studies focused on detection of
prostate cancer rather than staging. A prospectively maintained
database was queried for participants who underwent prostatec-
tomy at our institution from June 2007 to March 2017. Par-
ticipants with biopsy-confirmed nonmetastatic prostate cancer
who underwent multiparametric MRI and subsequent robotic-
assisted laparoscopic radical prostatectomy were eligible. Exclu-
sion criteria were prior local or neoadjuvant systemic therapy for
prostate cancer or benign prostatic hyperplasia (external beam
radiation therapy, proton-beam therapy, high-intensity focused
ultrasound, brachytherapy, focal laser ablation, transurethral
resection of the prostate, a2-blocker therapy, neoadjuvant an-
drogen deprivation, neoadjuvant enzalutamide, neoadjuvant
prostate immunotherapy). In five participants, multiparametric
MRI was not performed because of contraindications and one
patient underwent an outside multiparametric MRI without a
diagnostic T2 sequence. Three participants in the database who
underwent simple prostatectomy for benign prostatic hyperplasia
and had no prostate cancer at final histopathologic evaluation
were also excluded (Fig 1).
Imaging Technique, Surgery, and Histopathologic
Evaluation
A detailed description of imaging technique, surgery proce-
dure, and histopathologic evaluation is presented in Table E1
and Appendix E1 (online). Briefly, all participants were imaged
with an endorectal coil (BPX-30; Medrad, Pittsburgh, Pa) with
a 3.0-T magnet (Achieva 3.0-T-TX; Philips Healthcare, Best,
the Netherlands). All surgeries were performed by a single ex-
perienced prostate surgeon (P.A.P.). The histopathologic reads
were performed by a genitourinary pathologist (M.J.M.) ac-
cording to the International Society of Urological Pathology
(ISUP) 2014 consensus statement (23).
MRI Evaluation and Reporting
All examinations were interpreted by two genitourinary radiol-
ogists (P.L.C. and B.T., with 15 years and 9 years of experience
in prostate cancer imaging, respectively). All prostate MRI ex-
aminations were prospectively evaluated based on an in-house
prostate MRI interpretation system between June 2007 and
May 2015, which was supplemented with PI-RADS version
2 between May 2015 and March 2017. Reader 1 (P.L.C.) re-
ported the examinations from 2007 to 2009. Reader 2 (B.T.)
started reporting from 2009 to present. All examinations were
read by a single reader; therefore, interreader variability was not
assessed. A validated in-house scoring system (National Insti-
tutes of Health score) was applied to lesions visible at MRI to
assess the underlying risk of prostate cancer at biopsy (24–26).
Pathologic EPE status was prospectively assessed at MRI
based on the presence or absence of secondary indicators of
pathologic EPE. MRI indicators of pathologic EPE used in

Figure 1:  Flowchart shows determination of
final study population. ADT = androgen depriva-
tion therapy, BPH = benign prostatic hyperplasia,
EBRT = external beam radiation therapy, HIFU =
high-intensity focused ultrasound, TURP = trans-
urethral resection of prostate.
this study were as follows: (a) curvilinear contact length with
the capsule, defined as positive when this distance equals or
exceeds 1.5 cm; (b) capsular bulge, defined as a smooth convex
extension of the margin of the prostate into the extraprostatic
space, in continuity with an intraprostatic tumor; (c) EPE vis-
ible at MRI, a well-defined breach of the prostate capsule with
tumor extension into the periprostatic space or invasion of
adjacent anatomic structures such as the rectum, bladder, or
pelvic wall; (d) obliteration of the rectoprostatic angle, defined
as loss of the space between the prostate and the rectum; and
(e) neurovascular asymmetry, defined as an unequal appearance
of the neurovascular bundles in presence of an ipsilateral intra-
prostatic tumor.
Seminal vesicle invasion was reported when there was loss
of the normal high signal within the seminal vesicles, a finding
that increases the risk of pathologic EPE. Capsular irregularity
and bulge and suspicion of EPE at MRI were extracted from
the reports and treated as binary variables (Fig 2). Curvilinear
contact length was not prospectively reported on a consistent
basis and, therefore, was measured retrospectively in the axial
plane by using a Digital Imaging and Communications in
Medicine viewer measuring tool (Carestream Health, Roch-
ester, NY). The 48 participants who were imaged in the first
3 years of our study (June 2007 to June 2010) had prostate
cancer staging and reporting of the previously mentioned pa-
rameters performed retrospectively, because these examinations
were read by a different reader before comprehensive prostate
cancer staging was part of the routine workflow.
Imaging features were implemented in an EPE grading sys-
tem as follows: grade 0, no suspicion for pathologic EPE; grade 1,
either curvilinear contact length or capsular irregularity and
bulge; grade 2, both curvilinear contact length and capsular ir-
regularity and bulge; grade 3, frank EPE visible at MRI or inva-
sion of adjacent anatomic structures. Neurovascular asymmetry
Radiology: Volume 00: Number 0— 2018  n  radiology.rsna.org 3
Mehralivand et al
was a relatively rare finding at multiparametric MRI that may
otherwise indicate EPE; neurovascular asymmetry was not
implemented in our system. Obliteration of the rectoprostatic
angle may also indicate pathologic EPE but only occurs in pos-
teriorly located tumors and was, therefore, excluded in the pro-
posed standardized system to maintain simplicity.
Statistical Analysis
Data acquisition and reporting was consistent with the Standards
of Reporting for MRI-targeted Biopsy Studies, or START, of the
prostate (27). Variables were defined as follows: prostate-specific
antigen, continuous (nanograms per milliliter); suspicion of
EPE at digital rectal examination, binary (0 or 1 [negative or
positive]); ISUP category, categorical (1, Gleason score of 3+3;
2, Gleason score of 3+4; 3, Gleason score of 4+3; 4, Gleason
score of 8; 5, Gleason score of 9–10); MRI-based EPE grade,
categorical (grades 1, 2, or 3); and curvilinear contact length,
capsular irregularity and bulge, obliteration of rectoprostatic
angle, asymmetry of the neurovascular bundles, EPE visible at
MRI or suspicion of seminal vesicle invasion at MRI, all binary
(0 or 1 [negative or positive]).
Sensitivity, specificity, positive predictive value, and negative
predictive value for pathologic EPE were calculated at each clini-
cal and MRI variable threshold. Both univariable and multivari-
able logistic regression models were estimated to correlate with
pathologic EPE.
Four multivariable models were considered: clinical vari-
ables only, MRI-derived EPE grade only, clinical variables
plus MRI-derived EPE grade, and clinical variables plus
MRI features. The last model was used to assess whether it
had an advantage in predictive value over the MRI-derived
EPE grade. Variables included in that model were selected
from the backward variable selection procedure based on the
Akaike information criteria. Diagnostic performance quanti-
fied by using area under the receiver operating characteris-
tic curve (AUC) was compared between nested models with
the likelihood ratio test (28) and between nonnested models
by using the Wald test with bootstrap-based standard errors.
Model fit was assessed with the calibration plot of predicted
risk deciles versus observed risks (28).
Clinical utility of each prediction model was assessed by us-
ing the decision curve analysis, in which net benefit was plotted
against risk threshold for each prediction model along with the
treat-none and treat-all strategy (29,30). Net benefit at each risk
threshold was defined as the difference between the proportion
of true-positive results and weighted proportion of false-positive
results with the weight equal to the ratio of risk threshold to
1 minus risk threshold. The treatment strategy or prediction
model that has the highest net benefit at a given risk threshold
has the highest clinical value.
The 95% confidence intervals of the diagnostic performance
parameters were obtained from 2000 bootstrap samples by ran-
domly sampling participants with replacements. The 95% confi-
dence limits were taken from the 2.5th and 97.5th percentiles of
the bootstrap resampling distribution. All tests were two sided,
and P values , .05 were considered to indicate statistical signifi-
cance. All the statistical and graphical analysis were performed
Assessment of Risk of Extraprostatic Extension of Prostate Cancer at MRI

Figure 2:  Images show indirect (a) curvilinear contact length associated with left midperipheral zone lesion (arrows), (b) capsular
bulge or irregularity associated with left apical-midperipheral zone lesion (arrows), (c) obliteration of rectoprostatic angle associated
with left apical-midperipheral zone lesion (arrows) compared with normal right side, (d) asymmetry of neurovascular bundles associ-
ated with left apical peripheral zone lesion [arrows]) and direct (e) frank breach of prostate capsule associated with right midperiph-
eral zone lesion (arrows) MRI features at axial T2-weighted MRI and (f) seminal vesicle invasion (arrows) at sagittal T2-weighted MRI
associated with pathologic extraprostatic extension.

by using the R software (version 3.4.0; R Foundation for Statisti-
cal computing, Vienna, Austria) (31).
Results
Study Population
A total of 601 consecutive participants underwent robotic-
assisted laparoscopic radical prostatectomy between 2007 and
2017 at our institution. After excluding 48 participants for
reasons described previously, 553 participants remained for fi-
nal analysis (Fig 1). Mean participant age was 60 years (range,
38–76 years), median prostate-specific antigen value was 6.28
ng/mL (range, 0.21–170 ng/mL), and median prostate volume
was 42.07 mL (range, 11–164 mL). Clinical, surgical, and de-
mographic characteristics of the final patient cohort are sum-
marized in Table 1.
Imaging Features
All multiparametric MRI–based EPE features were assessed
before being included in our grading system. The detection
rates for MRI-derived EPE features and grades are summa-
rized in Table 2. The detection rate was 88 of 208 (42%)
for curvilinear contact length, 78 of 175 (45%) for capsu-
lar irregularity and bulge, 31 of 51 (61%) for obliteration of
rectoprostatic angle, 19 of 25 (76%) for asymmetry of the
neurovascular bundles, 37 of 56 (66%) for suspicion of EPE
at MRI, and 12 of 15 (80%) for suspicion of seminal vesicle
invasion at MRI. There was an incremental increase in the
detection rate of EPE with higher grades as follows: grade 1,
18 of 74 (24%); grade 2, 39 of 102 (38%); and grade 3, 37
of 56 (66%) (Fig 3).
Diagnostic measures for all features and grade cutoffs are
summarized in Table 3. Although specificity was moderate to
high for all variables, sensitivity varied. For example, seminal
vesicle invasion at MRI was associated with a high detection rate
(12 of 15 [80%]) and specificity (425 of 428 [99%]) for patho-
logic EPE, but a low sensitivity rate (12 of 125 [10%]).
Relationship of Clinical and MRI Features to
Presence of EPE
Clinical variables of pathologic EPE, imaging features, and
MRI-derived EPE grades were evaluated in a univariable logis-
tic regression for predicting final pathologic EPE. All variables
were significant predictors of pathologic EPE in the univariable
analysis (Table 4).
Clinical variables included log (prostate-specific antigen)
and biopsy ISUP categories as independent predictors for
multivariable analysis. Clinical stage based on digital rectal
examination was not associated with EPE (P = .08) and there-
fore was excluded (Table E2 [online]).

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 Mehralivand et al

Table 1: Participant Demographics and Characteristics Table 2: Diagnostic Accuracy of Individual MRI Param-
eters for Pathologic EPE
Variable Value
Age at MRI (y)* Variable Value
†
60 6 8 (38–76)
Clinical stage Individual MRI features
 cT1c 481 (90.1)   Curvilinear contact length greater than 88/208 (42) [35, 49]
 cT2a 41 (7.7)   1.5 cm
 cT2b 4 (0.7)   Capsular bulge 78/175 (45) [38, 52]
 cT2c 8 (1.5)   Obliteration of rectoprostatic angle 31/51 (61) [48, 75]
Prostate-specific antigen (ng/mL)‡ 6.28 (5.02)   Neurovascular bundle asymmetry 19/25 (76) [59, 91]
Prostate volume at MRI (mL)‡ 42.07 (19)   EPE at MRI 37/56 (66) [53, 78]
Index lesion size at MRI (mm)‡ 15.57 (8)   Seminal vesicle invasion at MRI 12/15 (80) [57, 100]
No. of detected lesions at MRI* 2.12 6 1.16 Proposed MRI-derived EPE grading
NIH score for MRI index lesions (%)   system
 1 36 (7.6)   Grade 1 18/74 (24) [14, 34]
 2 17 (3.6)   Grade 2 39/102 (38) [29, 47]
 3 229 (48.2)   Grade 3 37/56 (66) [53, 78]
 4 65 (13.7) Pathologic grading system*
 5 128 (26.9)   ISUP score of 1 11/106 (10) [5, 17]
Weight at radical prostatectomy (g)‡ 49 (22)   ISUP score of 2 36/182 (20) [14, 26]
ISUP category and Gleason score at radical   ISUP score of 3 10/68 (15) [7, 24]
  prostatectomy   ISUP score of 4 36/93 (39) [29, 48]
  1, 3+3 53 (9.6)   ISUP score of 5 15/25 (60) [39, 79]
  2, 3+4 267 (48.3) Note.—Numerators are numbers of pathologic extraprostatic
  3, 4+3 37 (6.7) extension (EPE) and denominators are numbers of participants.
  4, 8 136 (24.6) Data in parentheses are percentages, with 95% confidence
  5, 9+10 60 (10.8) intervals in brackets. ISUP = International Society of Urological
Pathology.
Cancer involvement at radical prostatectomy 25 (20)
  (%)‡ * ISUP score was missing in 60 participants due to outside
biopsy reports that were not retrievable retrospectively.
Pathologic EPE
 Yes 125 (22.6)
 No 428 (77.4)
Pathologic seminal vesicle invasion the clinical variables to predict the risk of pathologic EPE
 Yes 37 (6.7) (AUC, 0.81 vs 0.81; P = .54), suggesting comparable diagnos-
 No 516 (93.7) tic performance of both models. The calibration plots exhib-
Note.—Unless otherwise specified, data in parentheses are per- ited better fit of the MRI and clinical combined models, as
centages. EPE = extraprostatic extension, ISUP = International well as the MRI-derived EPE grade model, than did the clinical
Society of Urological Pathology, NIH = National Institutes of model (Fig 4).
Health.
* Data are means 6 standard deviation. Decision Curve Analysis
†
Data in parentheses are ranges. Net benefits are displayed in Table 5 and Figure 5. Clinical plus
‡
Data are medians, with interquartile ranges in parentheses. the MRI-derived EPE grade model and clinical plus MRI fea-
tures model had comparable and persistently higher net benefit
The final clinical model was refitted to the data containing 493 than did the other models for risk thresholds greater than or
participants without missing values because 60 participants had to equal to 20%. As an example, at a risk threshold of 25%, the
be excluded due to missing ISUP scores from outside histopatho- net benefit was 6% for the clinical, 9% for the MRI-derived
logic evaluation, which could not be retrieved retrospectively. EPE grade, 10% for the clinical plus the MRI-derived EPE
The MRI-derived EPE grading system trended toward bet- grade, and 10% for clinical plus MRI features model compared
ter diagnostic performance compared with clinical parameters with null for the treat-none strategy (standard treatment) and
(AUC, 0.77 vs 0.71; P = .05) (Table 4). When the MRI-derived 24% for the treat-all strategy (more advanced treatment).
EPE grading system was combined with clinical parameters,
the AUC improved (from 0.71 for the clinical model alone Discussion
to 0.81 for both; P , .001). Furthermore, with the addition Preoperative assessment of the presence of EPE of prostate can-
of the MRI-derived EPE grade, log (protein-specific antigen) cer may result in wider excision with removal of the neurovas-
was no longer associated with EPE (P = .16) and was therefore cular bundles to increase the likelihood of a negative margin.
eliminated from the clinical plus the MRI-derived EPE grade We developed an MRI-derived EPE grading system to predict
model (Table E3 [online]). There was no improvement in AUC pathologically defined EPE of prostate cancer. This grading sys-
when MRI features instead of EPE grade were combined with tem combines MRI features of curvilinear contact length of the

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Assessment of Risk of Extraprostatic Extension of Prostate Cancer at MRI

Figure 3:  Axial T2-weighted MR images show proposed MRI-derived extraprostatic extension (EPE) grading system for prediction of pathologic
EPE (pEPE). MRI features included curvilinear contact length, defined as present when distance exceeded 1.5 cm (arrows); capsular bulge, defined
as smooth convex extension of margin of prostate into extraprostatic space, in continuity with intraprostatic tumor (arrows); and EPE visible at MRI,
a well-defined breach of prostate capsule with tumor extension into periprostatic space or invasion of adjacent anatomic structures such as rectum,
bladder, or pelvic wall (arrows).

Table 3: Diagnostic Measures for Different Cutoffs for MRI Features and ISUP Categories

Variable Sensitivity (%)* Specificity (%)† PPV (%)‡ NPV (%)§

Individual MRI features
  Curvilinear contact length greater 88/125 (70) [62, 79] 308/428 (72) [68, 77] 88/208 (42) [36, 49] 308/345 (89) [86, 92]
  than 1.5 cm
  Capsular bulge 78/125 (62) [54, 71] 331/428 (77) [73, 81] 78/175 (45) [38, 52] 331/378 (88) [84, 91]
  Obliteration of rectoprostatic 31/125 (25) [17, 33] 408/428 (95) [93, 97] 31/51 (61) [48, 75] 408/502 (81) [78, 85]
  angle
  Neurovascular bundle asymmetry 19/125 (15) [9, 22] 422/428 (99) [97, 100] 19/25 (76) [59, 91] 422/528 (80) [77, 83]
  EPE at MRI 37/125 (30) [21, 38] 409/428 (96) [94, 98] 37/56 (66) [53, 79] 409/497 (82) [79, 86]
  Seminal vesicle invasion at MRI 12/125 (10) [5, 15] 425/428 (99) [98, 100] 12/15 (80) [57, 100] 425/538 (79) [76, 82]
Proposed MRI-derived EPE grading
  system
 Grade 1 94/125 (75) [67, 83] 290/428 (68) [63, 72] 94/232 (41) [34, 47] 290/321 (90) [87, 93]
 Grade 2 76/125 (61) [53, 69] 346/428 (81) [77, 84] 76/158 (48) [40, 56] 346/395 (88) [84, 91]
 Grade 3 37/125 (30) [21, 38] 409/428 (96) [94, 98] 37/56 (66) [53, 79] 409/497 (82) [79, 86]
Pathologic grading system
  ISUP score 1 109/109 (99) [97, 100] 18/384 (5) [3, 7] 108/474 (23) [19, 27] 18/19 (95) [82, 100]
  ISUP score 2 97/109 (89) [83, 95] 113/384 (29) [25, 34] 97/368 (26) [22, 31] 113/125 (90) [85, 95]
  ISUP score 3 61/109 (56) [46, 65] 259/384 (67) [64, 72] 61/186 (33) [26, 40] 259/307 (84) [80, 88]
  ISUP score 4 51/109 (47) [37, 56] 317/384 (83) [79, 86] 51/118 (43) [34, 52] 317/375 (85) [81, 88]
  ISUP score of 5 15/109 (14) [8, 21] 374/384 (97) [96, 99] 15/25 (60) [39, 79] 374/468 (80) [76, 83]
Note.—Data in parentheses are percentages, with 95% confidence intervals in brackets. EPE = extraprostatic extension, ISUP = International Society of
Urological Pathology, NPV = negative predictive value, PPV = positive predictive value.
* Numerators are number of participants with individual MRI and clinical variables above and equal to the cutoff value and denominators are number
of pathologic EPE.
†
Numerators are number of participants with individual MRI and clinical variables below the cutoff value and denominators are number of non-EPE.
‡
Numerators are number of EPE and denominators are number of participants with individual MRI and clinical variables above and equal to the
cutoff value.
§
Numerators are number of non-EPE and denominators are number of participants with individual MRI and clinical variables below the cutoff value.

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 Mehralivand et al

Table 4: Univariable and Multivariable Logistic Regression Model for Pathologic EPE Risk Prediction by
Using Different Predictors
Variable b Coefficient Odds Ratio 95% CI P Value
Univariable logistic regression model
  Log (prostate-specific antigen) (ng/mL) 0.82 2.3 1.7, 3.0 ,.001
  Clinical stage 0.66 1.9 1.0, 3.6 .034
  Individual MRI features
   Curvilinear contact length greater than 1.5 cm 1.8 6.1 3.9, 9.4 ,.001
  Capsular bulge 1.7 5.6 3.7, 8.6 ,.001
   Obliteration of rectoprostatic angle 1.9 6.7 3.7, 12.3 ,.001
   Neurovascular bundle symmetry 2.5 12.6 4.9, 32.3 ,.001
   EPE at MRI 2.2 9.1 5.0, 16.5 ,.001
   Seminal vesicle invasion at MRI 2.7 15.0 4.2, 54.1 ,.001
  Proposed MRI-derived EPE grading system
  Grade 0 Reference … … …
  Grade 1 1.1 3.0 1.6, 5.7 .003
  Grade 2 1.8 5.8 3.4, 10.0 ,.001
  Grade 3 2.9 18.2 9.4, 35.4 ,.001
  Pathologic grading system
  ISUP score 3 Reference … … …
   ISUP score of 4 1.2 3.4 2.1, 5.7 ,.001
   ISUP score of 5 2.1 8.2 3.5, 19.1 ,.001
Multivariable logistic regression model
 Clinical*
  (Intercept) 22.7 … … ,.001
   Log (prostate-specific antigen) (ng/mL) 0.56 1.7 1.3, 2.4 .001
   ISUP score of 4 0.96 2.6 1.5, 4.4 ,.001
   ISUP score of 5 1.8 5.9 2.4, 14.6 ,.001
  MRI-derived EPE grade
  (Intercept) 22.4 … … ,.001
   mEPE grade 1 1.3 3.6 1.8, 7.2 ,.001
   mEPE grade 2 1.9 6.7 3.7, 12.1 ,.001
   mEPE grade 3 3.1 22 10.6, 44.5 ,.001
  Clinical plus MRI-derived EPE grade
  (Intercept) 22.6 … … ,.001
   ISUP score of 4 0.87 2.4 1.4, 4.2 .002
   ISUP score of 5 1.8 6.1 2.3, 16.0 ,.001
   mEPE grade 1 1.2 3.3 1.6, 6.8 .001
   mEPE grade 2 1.8 6.0 3.2, 11.0 ,.001
   mEPE grade 3 2.8 17.4 8.3, 36.4 ,.001
  Clinical plus MRI features
  (Intercept) 23.17 … … ,.001
   Log (prostate-specific antigen) (ng/mL)† 0.33 1.4 0.98, 1.98 .068
   ISUP score of 4 0.78 2.2 1.2, 4.0 .01
   ISUP score of 5 1.69 5.4 2.0, 14.6 .001
   Curvilinear contact length greater than 1.5 cm 0.98 2.7 1.3, 5.3 .006
   Capsular bulge† 0.53 1.7 0.83, 3.4 .146
   Obliteration of rectoprostatic angle† 0.65 1.9 0.78, 4.7 .153
   Neurovascular bundle symmetry† 1.02 2.8 0.78, 9.8 .116
  mEPE† 0.67 2.0 0.9, 4.3 .09
Note.—Clinical plus MRI-derived extraprostatic extension (EPE) grade model consists of clinical factors and MRI-derived EPE grade; clinical plus
MRI features model consists of clinical factors and MRI features. CI = confidence interval, ISUP = International Society of Urological Pathology,
mEPE = suspicion of extraprostatic extension at MRI.
* Initial clinical model was eliminated for consideration because of nonsignificant effect of clinical stage. The final clinical model was refitted to
the data containing 493 participants without missing values. (All 60 excluded participants did not have ISUP scores due to outside histopathologic
evaluation that could not be retrieved retrospectively).
†
Combined effect of prostate-specific antigen, capsular bulge, obliteration of rectoprostatic angle, neurovascular bundle symmetry, and mEPE was
significant (P , .001).

Radiology: Volume 00: Number 0— 2018  n  radiology.rsna.org 7

Assessment of Risk of Extraprostatic Extension of Prostate Cancer at MRI

Figure 4:  Calibration plots show mean predicted risk of pathologic extraprostatic extension (EPE) and the 95% confi-
dence interval versus observed proportion of pathologic EPE in each decile of pathologic EPE risk scores calculated from
each multivariable logistic regression model. Clinical plus MRI-derived EPE grade model consists of clinical factors and
MRI-derived EPE grade; clinical plus MRI features model consists of clinical factors and MRI features. Clinical model had
poorer fit and worse ability in discriminating between EPE and non-EPE cases than did other three models, because it
had more observed proportions of EPE lying outside 95% confidence intervals and less spread in predicted risks. Thus,
including MRI-derived EPE grade or MRI features in risk prediction model improves predicted value for EPE.

tumor with the capsules, capsular bulge, and overt direct EPE
(Fig 3). The sensitivity of individual MRI features (eg, oblitera-
tion of rectoprostatic angle, neurovascular bundle asymmetry,
seminal vesical asymmetry) was poor, ranging from 10% to
30% for predicting pathologic status. These findings are rela-
tively late markers of pathologic EPE and only become visible
when the tumor is already at an advanced stage. However, the
combination of clinical features and MRI-derived EPE grade
model was superior to evaluation of clinical features (prostate-
specific antigen and ISUP staging) alone (AUC, 0.81 vs 0.71,
respectively; P , .001). The main advantage of using the MRI-
derived EPE grade system is its simplified approach of report-
ing suspicion of pathologic EPE at multiparametric MRI.
In general, multiparametric MRI is not considered highly
sensitive for detecting pathologic EPE. A recent meta-analysis
of 45 studies revealed a pooled sensitivity of only 57% and a
specificity of 91% for the detection of EPE at multiparametric
MRI (32). However, definitions of EPE at multiparametric MRI
vary among readers and centers. Moreover, the reporting of EPE
is unrealistically binary and it is generally acknowledged that in-
terpretations should estimate the likelihood of pathologic EPE,
rather than state definitively whether it is or is not present. A
previously proposed five-tier system for EPE was not validated in
a clinical study and did not define criteria (33). The definition of
clear, simple, and reproducible criteria for EPE at MRI is there-
fore important to standardizing and clarifying the likelihood
that a finding at MRI will represent EPE at pathologic evalu-
ation. Several imaging features have been linked to pathologic
EPE including curvilinear contact length, capsular irregularity
and bulge, obliteration of rectoprostatic angle, and asymmetry of

8 radiology.rsna.org  n  Radiology: Volume 00: Number 0— 2018

 Mehralivand et al

Table 5: Decision Curve Analysis of the Four Risk Prediction Models

True-Positive Rate against Risk False-Positive Rate against Risk Net Benefit at Risk Threshold
Threshold (%) Threshold (%) (%)*

Independent
Variables in
Model the Model 20% 25% 30% 20% 25% 30% 20% 25% 30%
Clinical Log (PSA), 62 (48, 75) 50 (38, 62) 43 (29, 55) 27 (16, 43) 18 (13, 27) 16 (8, 20) 9 (5, 12) 6 (3, 10) 4 (2, 8)
ISUP
MRI-derived mEPE grade 78 (61, 85) 63 (57, 85) 63 (36, 83) 32 (17, 37) 19 (16, 35) 19 (5, 33) 11 (8, 15) 9 (6, 13) 8 (4, 11)
  EPE grade
Clinical plus ISUP, mEPE 74 (66, 88) 74 (53, 84) 56 (46, 81) 23 (18, 38) 23 (10, 34) 12 (8, 26) 12 (8, 16) 10 (7, 14) 8 (5, 12)
 MRI-derived  grade
EPE grade
Clinical plus ISUP, log (PSA), 78 (65, 84) 70 (56, 81) 62 (50, 77) 24 (15, 33) 20 (10, 27) 14 (8, 23) 13 (9, 16) 10 (7, 14) 9 (6, 13)
  MRI features  individual
MRI features
Note.— Data in parentheses are 95% confidence intervals. Clinical plus MRI-derived extraprostatic extension (EPE) grade models consist
of clinical factors and MRI-derived EPE grade; clinical plus MRI features model consist of clinical factors and MRI features. ISUP = Inter-
national Society of Urological Pathology, mEPE = suspicion of extraprostatic extension at MRI, PSA = prostate-specific antigen.
* Net benefit at each risk threshold was defined as the difference between the proportion of true positive-results and weighted proportion of
false-positives results with the weight equal to the ratio of risk threshold to 1 minus risk threshold.

the neurovascular bundles, whereas a visible breach of the pros-
tate capsule or tumor in the periprostatic fatty tissue are con-
sidered direct and highly reliable signs of pathologic EPE (17).
The PI-RADS version 2 document recommends reporting these
features when evaluating multiparametric MRI prostate exami-
nations for staging, but refrains from assigning a likelihood of
pathologic EPE based on a combination of these findings (34).
One of the few studies of EPE at MRI was published by Yu et
al in 1997 (17). Technological improvements in imaging quality
have occurred since this study. Moreover, their analysis was based
on only 77 patients who underwent radical prostatectomy and
imaging features were assigned retrospectively by three readers
of varying experience. Asymmetry of the neurovascular bundles
and obliteration of rectoprostatic angle were the strongest pre-
dictors of pathologic EPE with high specificity (81%–95% and
81%–95%, respectively) but, as in our study, showed low-to-
moderate sensitivity (21%–38% and 57%–71%, respectively).
Our results are in accordance with other publications sug-
gesting an improved diagnostic accuracy of MRI for pathologic
EPE compared with clinical parameters, and even greater accu-
racy when MRI is combined with clinical information to estimate
pathologic EPE. Gupta et al (10) found a superior AUC for MRI
(AUC, 0.82) in predicting organ-confined disease compared with
Partin tables (AUC, 0.62). However, their analysis was based on a
sample size of 60 patients. Similarly, Feng et al (9) found a small
increase in AUC after the addition of MRI to the Partin tables
(AUC increased from 0.85 to 0.92) and Memorial Sloan-Kettering
Center risk calculators (AUC increased from 0.86 to 0.95) in 112
patients. Tay et al (35) found an increase of AUC in a clinical and
MRI-based model compared with a clinical-based model (AUC,
0.72 vs 0.69) in 120 men. AUC was even higher with special-
ized MRI reading (AUC, 0.91). Morlacco et al (8) showed greater
AUC of a Partin table plus MRI-combined model compared
with Partin tables alone (AUC, 0.73 vs 0.61) in 501 patients. A
similar improvement was shown when comparing Cancer of the
Prostate Risk Assessment, or CAPRA, score combined with MRI
to CAPRA alone (AUC, 0.77 vs 0.69). Our data confirm these
findings; however, here we provide a specific set of MRI criteria
for grading likelihood of pathologic EPE, which has the potential
to better standardize and decrease the subjectivity of diagnosing
pathologic EPE if validated in future multireader studies.
When investigating new diagnostic biomarkers or imaging
modalities, it is important to determine the clinical value when
implementing these into prediction models (29). Furthermore,
with the rise of multimodal treatment strategies for localized
prostate cancer, it is even more important to stage a patient ac-
curately prior to treatment. We applied a decision curve analy-
sis to all four models to compare net benefits to the treat-none
strategy. Treat none and treat all must not be confused in this
context because treat none means standard treatment for lo-
calized prostate cancer (radical prostatectomy, external beam
radiation therapy), whereas treat all refers to more radical or
advanced multimodal therapy (eg, neoadjuvant androgen depri-
vation, wider excision during robotic-assisted laparoscopic radi-
cal prostatectomy, etc). Because of higher adverse-effect profiles,
referring physicians would only recommend a more aggressive
treatment regimen when there is a high risk for locally advanced
prostate cancer. Therefore, we selected high risk thresholds for
our decision curve analysis. There was a consistently higher net
benefit among risk thresholds greater than or equal to 20% for
all models compared with the treat-all and treat-none strategies.
The MRI-derived model based on our grading system resulted in
higher net benefit than did the clinical model, suggesting an im-
proved clinical value. Both clinical plus MRI-combined models
demonstrated similar and only slightly higher net benefit than
did the MRI-derived EPE grade.

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Assessment of Risk of Extraprostatic Extension of Prostate Cancer at MRI

Figure 5:  Graphs show performance of four multivariable logistic regression models. Clinical plus MRI-derived extra-
prostatic extension (EPE) grade model consists of clinical factors and MRI-derived EPE grade; clinical plus MRI features
model consists of clinical factors and MRI features. (a) Receiver operating characteristic curves are shown. Both clinical
plus MRI-combined models had higher area under receiver operating characteristic curves (AUCs) than did MRI-derived
EPE grade model and clinical model. (b) True-positive rate was plotted against risk threshold. Clinical model exhibited
lower true-positive rate than did other three models except for risk threshold less than 15%. (c) False-positive rate was
plotted against risk threshold. False-positive rates did not differ significantly among four models except for risk threshold
less than 15%, whereas false-positive rate in clinical model was much higher. (d) Net benefits (proportion of true-
positive results minus weighted proportion of false-positive results with weight equal to ratio of risk threshold to 1 minus
risk threshold) of two clinical plus MRI-combined models were comparable and higher than were those of MRI-derived
EPE grade or clinical model for risk threshold greater than 10%. Thus, MRI-derived EPE grade can simplify EPE reporting
while maintaining same diagnostic performance as by using all MRI features.

Our study had some limitations. Although the majority of
MRI examinations were reported prospectively, 48 patients
from the initial 3 years of our subject accrual had to be reported
retrospectively in terms of primary and secondary EPE imag-
ing features. Thus, not all of the features were prospectively
identified. However, the retrospective reader was blinded to
the pathologic data, which would mimic a prospective reading.
Furthermore, at our institution, prostate MRI examinations are
read by a single reader; therefore, interreader variability of our
MRI grading system could not be assessed. Because this was a
single-institutional study, external validation is also needed to
assess generalizability of our grading system. We do not know
whether these findings will generalize to other centers due to
differences in patient populations. Finally, all participants in
our study were imaged with an endorectal coil. These results
may not apply to patients imaged without an endorectal coil,
which is a common practice in many centers.
In conclusion, we propose a standardized grading system for
the detection of pathologic extraprostatic extension (EPE) at
multiparametric MRI. The system adds additional diagnostic
value to clinical parameters and provides a graded quantifiable
risk assessment of pathologic EPE. It is based on only a few
imaging features, making it easy to teach, and it should be rela-
tively easy to implement. External validation and multireader
studies are underway to evaluate the generalizability of these
results.

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Author contributions: Guarantors of integrity of entire study, S.M., K.R., B.T.;
study concepts/study design or data acquisition or data analysis/interpretation, all
authors; manuscript drafting or manuscript revision for important intellectual con-
tent, all authors; approval of final version of submitted manuscript, all authors;
agrees to ensure any questions related to the work are appropriately resolved, all
authors; literature research, S.M., C.S., J.B., S.G., G.H., K.R., B.T.; clinical stud-
ies, S.H., C.S., K.R., M.J.M., B.J.W., P.A.P., P.L.C., B.T.; statistical analysis, S.M.,
J.H.S., S.G., K.R., B.T.; and manuscript editing, all authors
Disclosures of Conflicts of Interest: S.M. disclosed no relevant relationships.
J.H.S. disclosed no relevant relationships. S.H. disclosed no relevant relationships.
C.S. disclosed no relevant relationships. J.B. disclosed no relevant relationships. M.C.
disclosed no relevant relationships. S.G. disclosed no relevant relationships. G.H.
disclosed no relevant relationships. K.R. disclosed no relevant relationships. M.J.M.
disclosed no relevant relationships. B.J.W. Activities related to the present article:
institution received funds and equipment related to cooperative research and de-
velopment agreement with Philips Invivo; author received support for travel to
meetings for the study or other purposes from Philips. Activities not related to the
present article: author is employed by the National Institutes of Health (NIH);
has grants/grants pending with NIH Intramural Research Program; has multiple
patents in field; has received payment for licenses and royalties between NIH and
Philips; received payment for travel/accommodations/meeting expenses unrelated
to activities listed from Philips Invivo. Other relationships: disclosed no relevant
relationships. P.A.P. Activities related to the present article: author is a full-time
federal government physician-scientist in the NIH Intramural Research Program.
Activities not related to the present article: has grants/grants pending with the NIH;
has patents (planned, pending, or issued) with the NIH and Philips; has received
payment for licenses and royalties related to cooperative research and development
agreement between the NIH and Philips. Other relationships: disclosed no relevant
relationships. P.L.C. Activities related to the present article: disclosed no relevant
relationships. Activities not related to the present article: has patents (planned,
pending, or issued) with Invivo, Rokuten Aspyrian, ScanMed, and the U.S. govern-
ment; has received payment for royalties from the U.S. government. Other relation-
ships: disclosed no relevant relationships. B.T. disclosed no relevant relationships.
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