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outcomes, but it is uncertain if this trial will be able to
add significant upgrade/upstage information using whole-
specimen pathology as the gold standard.
The present study is not devoid of limitations. First, our
findings come from a cohort of RP-treated men andmay only
indirectly be generalized to the population of AS men.
Despite that, the use of stringent inclusion/exclusion criteria,
and the inclusion limited men fit for surgery enhance the
applicability of these results to a contemporary subset of
men with newly diagnosed FIR GS 3 + 4 PCa. Our results refer
mostly to the PCa population during the PSA screening era.
Also in the small percentage (11.8%) of patients operated on
in 2013–2014, after the formal US Preventive Services Task
Force recommendation against PSA screening we did
not observe any significant difference in patient features.
Perhaps it is too early to see any effect of this change in our
cohort; however, our results might be interpreted differently
in the context of nonscreened populations. The retrospective
nature and the lack of a single pathologist reexamination of
all the cases are other potential limitations. However, the
single-institution analysis of all the biopsy and RP specimens
was carried out by a very limited number of fully trained
uropathologists. This enhances internal validity but could
make our assumptions slightly less generalizable to centers
when the complete review of the material is not a
consuetude. Finally, the short follow-up for a considerable
number of patients prevented us from presenting survival
data.
Our results show that the risk of harboring unfavorable
disease among FIR GS 3 + 4 patients may be up to 25%.
However, downgrade is not an uncommon event. Overall,
these findings underscore the need for appropriate counsel-
ing when a management decision is made and suggest that
additional risk-assessing tools might be useful to improve
the prediction models. Recently, 3-T multiparametric
magnetic resonance imaging (mpMRI) using the Prostate
Imaging Reporting and Data System has emerged as an
independent predictor of downgrade in patients with biopsy
GS 3 + 4 . It is yet to be determined whether this
technique may be helpful in the prediction of unfavorable
features. Genetic biomarkers also look promising in this
setting. The Genomic Prostate Score (GPS) has proved
more efficacious than clinical variables alone to predict
adverse tumor features at RP when used on biopsy
samples, yet this retrospective cohort included a small
fraction (23%) of GS 3 + 4 patients, and the diagnostic
accuracy is still not ideal. However, the test has now
entered the 2016 NCCN guidelines for patient counseling
after the initial diagnosis.
5. Conclusions
Based on the risk of upgrade and upstage at RP, AS is a viable
option for a subset of FIR GS 3 + 4, but there is clearly room
for improvement of risk-predictive strategies and patient
selection. Further investigation with the use of biologically
based tests, genomic classifiers, and mpMRI, as well as
prospective AS results in this population, are expected to
shed more light in this clinical setting.
Author contributions: R. Jeffrey Karnes 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: Karnes, Morlacco, Gearman.
Acquisition of data: Morlacco, Rangel.
Analysis and interpretation of data: Morlacco, Rangel, Cheville, Karnes.
Drafting of the manuscript: Morlacco, Gearman, Karnes.
Critical revision of the manuscript for important intellectual content:
Morlacco, Cheville, Rangel, Gearman, Karnes.
Statistical analysis: Rangel, Morlacco.
Obtaining funding: None.
Administrative, technical, or material support: None.
Supervision: Karnes, Cheville.
Other (specify): None.
Financial disclosures: R. Jeffrey Karnes 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: None.
Appendix A. Supplementary data
Supplementary data associated with this article can be
found, in the online version, at
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