EURURO Vol. 72 No. 3

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further elucidate the particular behavior of contemporary
GS6 (grade group 1 ) to determine the optimal
management strategy for these patients. Historically,
>90% of men diagnosed with GS6 underwent treatment
although contemporary rates have decreased to 50% in
regional studies Prostate cancer treatment with
radiation or surgery can lead to significant morbidity with
regard to erectile dysfunction, urinary incontinence, and
bowel urgency . For patients with pure GS6, these
adverse effects may outweigh cancer control if the disease
itself rarely, if ever, metastasizes or is associated with
adverse pathology at radical prostatectomy (RP).
Many patients with GS6 in the past are now graded as
GS7 by contemporary guidelines. Among the modifications
in the 2005 ISUP consensus were the classification of poorly
formed and large cribriform glands as pattern 4, and the
grading of some variant morphologies . In 2014, a further
ISUP consensus was held to further update Gleason grading
including assigning pattern 4 to any cribriform and
glomeruloid glands, enhanced definition of pattern 4 versus
3, and establishing a cut-off (<5%) for tertiary pattern
. We hypothesize that patients with pure GS6 (grade
group 1) have very low rates of adverse pathology on RP.
2. Patients and methods
Utilizing two institutional review board (IRB)-approved institutional
prostate cancer databases containing data on 7817 patients who
underwent RP in the period 2003–2014, we identified 2502 (32%) with
GS6 on surgical pathology. Of these, 75 (3%) patients had GS6 with
extraprostatic extension (EPE, pT3a) or seminal vesicle invasion (SVI,
pT3b). In total, for 60 of the 75 (80%) with pT3 disease, pathology slides
were available for contemporary review. Both partial and complete
embedding of the prostate gland were practiced at both institutions. At
Northwestern Memorial Hospital, RP submission was 100% in the period
2011–2016 and 80–90% in the period 2003–2010. At the University of
Chicago Medical Center, the median and mean prostate sampling rates in
a subset of RP with recorded submission were 90% and 80%, respectively
. To confirm similar high sampling in this study, the pathology
reports of the 1108 cases of GS6 fromUniversity of Chicagowere reviewed.
Percent embedding was available in 567/1108 (51%). In this cohort,
complete (100%) embedding was performed in 230/567 (41%) and partial
embedding in 337/567 (59%). Of the cases with partial embedding, mean
and median were 87% and 90%, respectively. To assess for potential
downgrading, 153 patients with (GS 7) pT3b were identified, 132 (86%)
with slides available for review. Pathologic re-grading and re-stagingwere
performed by two expert genitourinary pathologists, one from each
institution (G.P.P. and X.J.Y.), whowere blinded to patient information and
previous pathology readings, except for the previously reported Gleason
score and pathologic stage. The pathologists were aware of the purpose of
the study. Repeat grading evaluation was performed applying the
modifications from the 2005 and 2014 ISUP Gleason grading criteria
with the type of Gleason pattern 4 architecture and presence of variant
morphology. For-restaging, definitions of EPE and SVI were based on the
2009 ISUP consensus
All statistical significance levels were two-sided, and the threshold
for statistical significance was p < 0.05. Analysis of variance was used for
comparing the distribution of continuous variables between the cohorts.
Fisher’s exact test was used to compare proportions of categorical
variables. Statistical computations were performed using Stata 13
(StataCorp, College Station, TX, USA) and the SPSS statistics package 22.0
(IBM Corp, Armonk, NY, USA).
3. Results
Among patients with GS6 identified following RP in the
period 2003–2014, none had positive lymph nodes or pT4
. Lymph-node dissections were performed in
1003 of 2502 (40%) patients with GS6. There were
60 GS6 with pT3a–b, of which 50 (83%) were upgraded
). The incidence of GS6 with pT3a on initial
pathologic review decreased following the 2005 ISUP
Gleason grading consensus, being present in 10.8% and
11.8% of GS6 cases in 2003 and 2004, respectively, while
from 2005 to 2014 pT3a was reported in 0–3.3% of GS6
cases. Of the 50 upgraded cases previously identified as GS6,
after applying current ISUP consensus, 47 (94%) were
Gleason 3 + 4, two (4%) were Gleason 4 + 3, and one (2%)
was Gleason 4 + 4. Of the upgraded cases, 12 (24%) had
minor (<5%) components of pattern 4, which under the
2014 ISUP consensus is considered as Gleason 3 + 4 or grade
group 2 . Of the original 60 GS6 pT3 cases, eight (13%)
were reclassified as pT2 or pT2 + because only intrapro-
static incision was present or no EPE was identified Of
the types of Gleason pattern 4, poorly formed glands were
the most common type identified, being present in 91% of
upgraded cases, followed by fused (82%) and cribriform
(35%) glands. Ductal adenocarcinoma (6%) and mucinous
carcinoma with Gleason 4 patterns (3%) were rare reasons
for upgrading. Of the 60 GS6 cases with pT3a originally
reported, 49 were upgraded. Of these, 20 (44%) were
upgraded because percent pattern 4 is no longer reported as
a tertiary grade when present in 5% or less of the tissue, and
29 (56%) because of newly identified features. In summary,
upgrading was in part due both to updated classifications
and to new identification of higher-grade elements not
previously seen.
After re-review, seven cases of GS6 with pT3a were
observed, representing 0.28% of the entire GS6 cohort (95%
confidence interval [CI] 0.07–0.49%), all with focal EPE (non-
established) . With available follow-up to date
(median 20 mo), there have been no documented cases of
biochemical recurrence in these patients. Among the re-
examined cohort, no cases with GS6 and stage pT3b were
observed (95% CI 0.0–0.15%). Of the 132 GS 7 pT3b cases
that underwent contemporary review, none were down-
graded to GS6 . One specimen was downstaged to
pT2 because no SVI was present.
4. Discussion
Using contemporary pathologic standards, among
2502 men with pure GS6 (grade group 1 ) at RP,
0.28% had focal EPE and none had SVI. To our knowledge,
the absence of SVI in true GS6 is a novel finding. In addition,
no patients with GS6 had positive lymph nodes or pT4
disease. This is consistent with Ross et al who identified no
lymph-node metastases in a contemporary cohort of around
14 000 men who underwent RP with GS6 prostate cancer on
surgical pathology . Nevertheless, there are some
concerns because a significant minority of men with GS6
on biopsy are found to have higher-grade elements at
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