EURURO Vol. 72 No. 5

672 860

culpable of driving transformation and expansion of tumor
clones . Nonetheless, apart from hypoxia, it is lesser
known if other field-wide effects have a role in therapeutic
resistance and tumor aggression. Nimbosus, therefore,
represents a novel and potentially late-occurring ‘‘aggres-
sion’’ field defect, and the weak association of IDC/CA with
hypoxia might suggest for hypoxia as a bystander
phenomenon following genomic instability and SChLAP1
expression in the evolution of IDC/CA+ prostate cancer.
The existence of a prostate cancer nimbosus that most
strongly predicts for failure of primary therapy and
metastatic recurrence argues for a multimodal signature
as an ideal biomarker. In addition to PGA and SChLAP1
expression , a series of other molecular biomarkers
have been proposed ; however, technical and
financial challenges limit their utility in the clinical setting.
Moreover, the prediction accuracy of these molecular tests
can be affected by intratumoral genomic heterogeneity
, as highlighted by the potential disadvantages of
limited sampling and false negatives when employing
SChLAP1 RNA-ISH on TMA for detecting IDC/CA. Given that
IDC and CA subpathologies are hallmarks of nimbosus ,
pathological screening of these lesions represents a simpler
and practical method for identifying patients with aggres-
sive prostate cancer. We propose that modern imaging
(positron emission tomography, functional magnetic reso-
nance imaging, etc.) for surveillance of metastasis, in
conjunction with prospective clinical trials of treatment
Table 2 – Intraductal carcinoma (IDC), cribriform architecture (CA), and percentage of genome alteration (PGA) are prognostic for metastasis
in the pooled cohort
Univariable (N = 829,
events = 52)
Multivariable (clinical + IDC/
CA;
N = 805,events = 49);Harrell’s
C-index = 0.786 (95%
CI = 0.606–0.966)
Multivariable (clinical + IDC/
CA + PGA; N= 422,
events = 36);Harrell’s C-
index = 0.805 (95%
CI = 0.615–0.995)
Pooled Canadian and MSKCC cohorts HR (95% CI) p value HR (95% CI) p value HR (95% CI) p value
Age (continuous) 0.99 (0.95–1.03) 0.59 – –
[3_TD$DIFF]cT [1_TD$DIFF]category
cT2b/c vs cT1/T2a (ref.) 1.16 (0.58–2.31) 0.68 1.07 (0.5–2.27) 0.86 0.97 (0.39–2.38) 0.95
cT3 vs cT1/2a (ref.) 4.01 (1.5–10.72) 0.0057 1.19 (0.4–3.58) 0.76 1.15 (0.32–4.11) 0.83
[4_TD$DIFF]GS
7 vs 6 (ref.) 3.57 (1.53–8.32) 0.0032 – –
8/9 vs 6 (ref.) 7.06 (2.61–19.1) <0.001 – –
ISUP grade
2 vs 1 (ref.) 1.84 (0.71–4.74) 0.21 – –
3 vs 1 8.67 (3.55–21.16) <0.001 3.92 (2.11–7.29) <0.001 3.05 (1.43–6.52) 0.004
4/5 vs 1 7.01 (2.59–18.98) <0.001
PSA (continuous) 1.01 (1–1.01) <0.001 1.01 (1–1.01) <0.001 1.01 (1–1.01) 0.0016
IDC/CA
Present vs absent 3.99 (2.23-7.13) <0.001 3.31 (1.76-6.21) <0.001 2.09 (0.94-4.66) 0.072
PGA (continuous) 1.08 (1.04–1.11) <0.001 1.05 (1.01–1.09) 0.027
CI = confidence interval; GS = Gleason score; HR = hazards ratio; ISUP = International Society of Urological Pathology grading system for prostate cancer based
on GS; MSKCC = Memorial Sloan Kettering Cancer Center; PSA = prostate-specific antigen; ref. = reference.
a ISUP grades 3 and 4/5, and grades 1 and 2 were grouped together for multivariable analyses due to comparable metastasis-free rates (Supplementary ).
Harrell’s C-index for the multivariable clinical only model was 0.761 (95% CI = 0.588–0.935). The p values are generated using Wald’s test.
[(Fig._4)TD$FIG]
Fig. 4 – A prostate cancer nimbosus that is associated with intraductal (IDC) and cribriform (CA) subpathologies. CA = cribriform architecture;
IDC = intraductal carcinoma; PSA = prostate-specific antigen; RNA-ISH = RNA in situ hybridization.
E U R O P E A N U R O L O G Y 7 2 ( 2 0 1 7 ) 6 6 5 – 6 7 4 672