Discussion
The Gleason grading system has been shown to be the most important
determinant of tumor aggressiveness, disease outcome, and mortality from
prostate cancer (19). Gleason Score
discordance can confound optimal treatment allocation of patients
diagnosed with prostate cancer and place them at risk of worse
oncological outcomes. MRI targeted biopsies, which utilise previously
taken MRI images of suspected cancer and fuse them with real-time
ultrasound images, are reported to be able to detect high grade cancers
better than systematic biopsies and TRUS (6-9, 20,21). However, several
recent studies have reported a mismatch in the biopsy and radical
prostatectomy Gleason Score (10,11, 22). Despite the improved detection
of clinically significant cancers with MRI targeted biopsies,
considerable disparity
exists in the literature regarding MRI targeted biopsy’s ability to
better detect RP pathology in biopsy-naive men over conventional TRUS
biopsies (10,11,22). We performed this study in order to investigate if
targeted prostate biopsy has a performance superior to untargeted biopsy
in determining the optimal agreement between biopsy and surgical Gleason
Score. Our findings suggest that in the overall patient cohort, combined
TBx+SBx provides improved detection rates particularly for higher-grade
disease over either systematic or MRI-targeted biopsy or TRUS-Bx alone.
However, superiority in significant cancer detection did not reflect
accurate Gleason Grade Group in the whole prostate gland at final
surgical pathology due to selective sampling of higher grade areas
within an otherwise low grade cancer. MRI targeted biopsy was better in
the prediction of the result of final histopathological analysis for
ISUP 1 and ISUP 4 than systematic biopsies or TRUS-Bx. Our analysis of
biopsy techniques according to ISUP Grade groups showed increased
downgrading in MRI fusion biopsy and increased upgrading in TRUS-Bx.
In this cohort of patients, combined TBx+SBx biopsy provided more
accurate diagnosis than MRI targeted or systematic biopsy alone.
Consistent with earlier studies, we found higher cancer detection rates
on TBx when compared to SBx (7,9, 23). However, 13 out of 127 prostate
cancers (10.2%) were missed by TBx alone. Missed cancers by TBx may
reflect the underlying limitation of mpMRI which might result from
factors such as PCa not visible on mpMRI, varying inter-reader agreement
on the mpMRI results and/or missing the target lesion in biopsy.
Our results have shown that MRI targeted biopsies are significantly
better for the detection of clinically significant PCa (ISUP 2 or
higher) than TRUS-Bx. Almost half of the cancers detected by TRUS-Bx
were in ISUP grade 1 category. When TBx alone is compared to SBx alone
for the detection rate of significant prostate cancer diagnosis, overall
targeted biopsy alone tends to detect more significant PCa but this
superiority does not reach statistical difference. In the present study,
SBx had superior performance to TRUS-Bx in determining high grade
cancers. This could be a result of the cognitive fusion bias within the
SBx that the urologist performing the SBx was aware of the localization
of the suspicious lesion on mpMRI. In our study, if a pure TBx strategy
omitting SBx is applied, this will lead to missing significant prostate
cancer in 11 patients. Our results support the notion that in order to
obtain the most accurate assessment of the entire prostate gland
especially for patients at risk of significant disease, SBx remains
necessary, in addition to the TBx due to limitations of mpMRI
performance/reading and of precision during lesion targeting.
In this study, combined TBx+SBx showed significantly better concordance
than any biopsy method alone in ISUP Grade 1. Also, combined TBX+SBx
prostate
biopsy resulted in significantly less pathologic upgrading in ISUP 1
grade group as compared with TRUS-Bx
at prostatectomy
(38.7% vs 62.1%). Men under active surveillance in ISUP Grade 1 group
diagnosed by TRUS-Bx are at significantly greater risk of subsequent
reclassification by confirmatory biopsies. It has been reported that up
to 40% of men potentially suitable for AS had unfavorable disease at RP
and these high rates of adverse pathologic findings which can
underestimate aggressiveness of the disease (24-26). Upgrading is
particularly a great concern in the context of active surveillance.
Pathologic upgrading has been shown to be associated with adverse
outcomes, including higher rates of biochemical recurrence (27,28). A
recent study by our group has shown that men suitable for AS, but
elected immediate RP, proved to have a GS upgrade rate of 30.6% and a
pathological upstaging rate of 13.2% (29). In the present study, our
results clearly suggest that TRUS-Bx based active surveillance decision
should be questioned unless confirmatory mpMRI TBx+SBx is done. In the
active surveillance scenario, it is imperative to decrease the risk of
missing a high-grade disease and delaying a radical treatment, providing
more confidence to the urologist and the patient with conservative
management of PCa. Based on our data, multiparametric MRI TBx+SBx is the
best available strategy to stratify men to AS with reliable eligibility
and should be included in the AS protocols for a more accurate grading
of PCa.
Among all biopsy methods, the lowest concordance was achieved in ISUP
Grade 4. Combined TBx+SBx showed significantly better concordance than
TRUS-Bx in ISUP Grade 4. At this group, TRUS-Bx showed increased
upgrading (47.1%) but in contrast TBx+SBx showed increased downgrading
(54.6%). Downgrading may be due to oversampling that small foci of
Gleason 5 detected at biopsy but not documented at radical prostatectomy
(4). In ISUP Grade 4, SBx was better than TRUS-Bx. This, again, shows
that inadequate diagnostic biopsy sampling is high in TRUS-Bx and most
of the SBx are not blind and affected by MRI cognition.
Our study has demonstrated that TRUS-Bx concordance was superior for
ISUP 2,3 and 5 Grade Groups than TBx+SBx. In all ISUP groups except 1
and 4, TRUS-Bx showed better performance in predicting final pathology
with higher concordance. MRI Targeted biopsies are more prone to
downgrading and TRUS biopsies are more upgraded. In the present study,
downgrading was higher in TBx+ SBx biopsy group compared to conventional
TRUS-Bx. Downgrading may occur for several reasons, including
over-sampling of the very small (less than 5%) foci of Gleason pattern
4 or 5 cancer (4, 30). There is a risk of oversampling with increased
number of targets registered by radiologist and increased number of
biopsy cores taken at discretion of the biopsy performer. A very small
foci of Gleason pattern 4 or 5 tumor might be missed by the routine
radical prostatectomy pathologic examination or might be noted as the
presence of a tertiary Gleason pattern if these small tumors are
detected. It is reported that the issue of accounting for tertiary grade
patterns is significant as can be seen in almost 20% of RP specimens
(4). An increased number of target lesions on mpMRI and thus,an
increased number of core biopsy per lesion may cause needle biopsy to
sample a tertiary higher grade pattern in the RP, which is not recorded
in the standard GS reporting, resulting in apparent overgrading on the
needle biopsy. Our results suggest that if the physician is assigning
the patient as high risk group solely based on biopsy pathology, there
would be a risk of overtreating quite a few patients. Having increased
the percentage of surgical pathology downgrading, MRI fusion biopsy
implies a high rate of overdiagnosis of Gleason sum 8 scores on biopsy,
potentially leading to suboptimal treatment strategies and patient
distress.
Although conventional TRUS-Bx is a blind, nontargeted and not always
anatomically systematic biopsy, our findings portray that TRUS-Bx is
superior but not yet significant over SBx in accurate prediction of
final pathology. However, there is a difference of 7.6% and 22.4 % for
ISUP 1 and 4 grades between the schemes respectively favoring SBx. This
may be a result of cognitive impact of MRI findings that the unblind
nature of systematic biopsies after mpMRI were probably contaminated by
MRI findings and not even described to be so, in practice it influences
and orients biopsy.
The major limitations of our study are its retrospective nature and
analysis. Another limitation is that TBx data was obtained from 5
different centers performed by 7 different urologists using different
MRI and MRI-US Fusion devices. Failure of mpMRI fusion biopsy due to
mpMRI incorrect image registration or mismatch of image planes,
inaccurate sampling and intralesional Gleason Score heterogeneity may
have impacted our results. Another important limitation is that there
was no centralized pathological examination, multicentric pathological
examinations by uropathologists at respective centers. However, our data
reflects the real-life nationwide picture.
In conclusion, our results have shown that MRI-targeted biopsies are
significantly better for the detection of clinically significant PCa
(ISUP 2 or higher) than TRUS-Bx. However, superiority in significant
cancer detection appears at least in part as a result of oversampling of
higher grade areas within an otherwise low grade cancer and may not
reflect accurate Gleason Grade Group in the whole prostate gland at
final surgical pathology due to increased downgrading. There is a risk
of overtreatment if biopsy Gleason Group was taken as a unique parameter
for treatment decision. TRUS-Bx has superior concordance with radical
prostatectomy for ISUP 2,3,5 grade groups, but increased upgrading
should also be taken into account leading to undertreatment. MRI
Targeted biopsies combined with systematic biopsies has the greatest
concordance in ISUP Grade 1 which is of utmost importance for active
surveillance indicating that active surveillance decision should be
based on MRI targeted + systematic biopsies either at initial diagnosis
or in confirmatory biopsy.