EURURO Vol. 71 No. 5

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Our findings draw from a longitudinal multisite registry
of men with PCa treated in community, academic, and
Veterans Affairs centers with extended follow-up. As a
result, we were able to assess more robust oncologic
endpoints, including PCSM, as well as metastatic progres-
sion, which may be of great relevance in clinical counseling.
Furthermore, in contrast to publications focusing on
academic institutions, the CaPSURE cohort may better
simulate the implications of implementing the prognostic
Gleason scoring system on a broad scale. In light of
recognized variations in concordance between biopsy and
RP histology for tertiary referral centers and community
pathologists, validation studies within varied care delivery
systems are valuable before widespread adoption In
this regard, our work appears to be in agreement with a
recent analysis by Loeb et al for data in the Swedish
National Prostate Cancer Registry. In addition, we included
patients managed across treatment types, including AS/
WW and primary ADT, as most clinical decisions occur at
the time of initial biopsy, including outcomes following
conservative or nondefinitive therapy. Notably, relative to
radical prostatectomy, EBRT, primary ADT, and AS/WW
were independently associated with higher PCSM risk in
multivariate Cox proportional hazards analysis in a direc-
tion consistent with prior comparative studies from
CaPSURE .
In this analysis, adjusted pairwise comparisons of
outcome between grade groups II and III, as well as IV
and V, were not significantly different, which may reflect
heterogeneity in the quantity of pattern 4, particularly in
distinctions between group II and group III. We did not
detect significant differences in outcome in the highest
grade category (group V); however, this subset represented
the smallest proportion of the cohort (3.4%). Although
similar to other published validation studies addressing
clinical recurrence endpoints, the statistical power for
detection of distinctions among higher Gleason scores is
therefore limited and may mask differences for the highest
grade group category. For example, prior work supports
more precise calculation of the percentage of pattern 4 and
5 on biopsy specimens that offer more granular insights into
the degree of aggressive histologic patterns within biopsy
specimens . From this perspective, measures to
quantify the percentage of high-grade elements—both
pattern 4 and pattern 5—appear to complement a more
streamlined reporting system .
There are additional limitations that must be acknowl-
edged. For example, pathologic designations were made at
the individual treatment sites without routine central
pathologic review, and dedicated uropathologists were
not routinely used at CaPSURE sites. Therefore, we are
unable to assess whether Gleason scores were assigned in
accordance with the 2005 ISUP modification. To account for
changes in practice patterns over time, statistical models
were adjusted for year of diagnosis, as well as the nature of
the clinical site. However, such measures, including
assignment of cribriform patterns as Gleason 4, avoidance
of Gleason sums 2–4, and the use of tertiary patterns within
biopsy specimens, may have little bearing on the highest
Gleason patterns, and should be applied equally at the
lower end of the histologic spectrum. Furthermore, we were
able to evaluate the discrimination of outcome using
pathologic Gleason scores among the subset of men treated
with RP, which serves to offset the contribution of biopsy
undersampling, and more definitively assess an individual’s
future risk of disease progression .
Owing to the length of clinical follow-up, this study
represents the only one, to our knowledge, that addresses
PCSM as a primary endpoint across the broad spectrum of
management strategies at diagnosis, including both defini-
tive therapy and conservative approaches. By demonstrating
an association with risk of death from PCa across prognostic
Gleason grade groupings, such a system appears valid and is
poised to dramatically improve the communication of
attendant disease risk to patients and clinicians alike.
5. Conclusions
We confirm that the new Gleason grouping system is
associated with distant clinical endpoints across manage-
ment strategies, including active surveillance, watchful-
waiting and non-definitive therapy. No significant distinc-
tion in outcome was detected within the Gleason scores
combined within the highest Grade grouping, however this
represented a small proportion of men within the study
cohort.
Author contributions: Michael S. Leapman had full access to all the data
in the study and takes responsibility for the integrity of the data and the
accuracy of the data analysis.
Study concept and design: Leapman, Cowan, Roberge, Simko, Cooperberg.
Acquisition of data: Cowan, Cooperberg, Leapman.
Analysis and interpretation of data: Cowan, Cooperberg, Leapman.
Drafting of the manuscript: Leapman, Cowan, Roberge, Stohr, Carroll,
Cooperberg.
Critical revision of the manuscript for important intellectual content:
Leapman, Cowan, Roberge, Stohr, Carroll, Cooperberg.
Statistical analysis: Leapman, Cowan, Cooperberg.
Obtaining funding: Carroll, Cooperberg.
Administrative, technical, or material support: Cooperberg, Carroll.
Supervision: Cooperberg, Carroll.
Other: None.
Financial disclosures: Michael S. Leapman certifies that all conflicts of
interest, including specific financial interests and relationships and
affiliations relevant to the subject matter or materials discussed in the
manuscript (eg, employment/affiliation, grants or funding, consultan-
cies, honoraria, stock ownership or options, expert testimony, royalties,
or patents filed, received, or pending), are the following: None.
Funding/Support and role of the sponsor: Work by the authors is funded
by the US Department of Defense Prostate Cancer Research Program
(W81XWH-13-2-0074). The sponsor played no direct role in this study.
Appendix A. Supplementary data
Supplementary data associated with this article can be
found, in the online version, at
.
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