EURURO Vol. 72 No. 5

666 860

1. Introduction
In men diagnosed with localized prostate cancer, risk
stratification based on conventional clinical parameters is
imprecise and accounts only for a fraction of interpatient
heterogeneity in treatment responses . Although clini-
copathological indices such as percentage biopsy core
involvement and primary Gleason grade have been
proposed to improve upon existing stratification models,
these factors do not account for the intratumoral spatial
genomic heterogeneity that highlights the biological
complexity of multifocal prostate tumors . To predict
the risks of biochemical relapse and metastasis following
definitive prostatectomy or radiotherapy, a series of
molecular indices have been proposed, including percent-
age of genome alteration (PGA) . Likewise, other
microenvironmental factors such as hypoxia and sub-
pathologies such as intraductal carcinoma (IDC) and
cribriform architecture (CA) have been linked to therapeutic
resistance and disease recurrence . Genomic profiling
of matched primary metastatic tumors has further revealed
the close relationship between tumor clones within the
metastases and IDC, affirming the unfavorable nature of this
subpathology Importantly, our group recently
reported that both IDC and the index tumor share a clonal
ancestry a finding that could suggest that IDC-related
prometastatic tumor clones are, in fact, present during the
early phase of prostate cancer evolution, along with the
development and co-occurrence of multiple aggressive
features within the prostate gland. Herein, we posit a novel
concept of a prostate cancer ‘‘nimbosus’’ (‘‘gathering of
stormy clouds’’; Latin) that is hallmarked by the sub-
pathologies of IDC and CA. Nimbosus highlights the
constellation of unfavorable indices of genomic instability,
increased hypoxia, and SChLAP1 expression that are
associated with prostate cancers harboring these
subpathologies, and importantly, correlates with a poor
prognosis following radical prostatectomy or image-guided
radiotherapy.
2. Patients and methods
2.1. Patient cohorts
The study cohort comprised 1325 men with pathologically confirmed
National Comprehensive Cancer Network (NCCN)-defined low- to high-
risk prostate cancers, who received definitive treatment between
1987 and 2012: (Canadian) 103 radical prostatectomy cases from
CHU de Que´bec-Universite´ Laval (CHUdeQ-UL), and 70 prostatectomy
and 501 image-guided radiotherapy cases from University Health
Network (UHN); 258 prostatectomy cases from Memorial Sloan
Kettering Cancer Center (MSKCC), NY ; and 393 prostatectomy
cases from Erasmus Medical Center (EMC), Rotterdam . An illustra-
tive summary of the Canadian and MSKCC cohorts that were used for the
respective clinical analyses is presented in the Supplementary material
(Supplementary Fig. 1). A tissue microarray (TMA) constructed using
prostatectomy specimens from the EMC cohort was used for RNA in situ
hybridization (RNA-ISH) testing. This cohort comprised men who were
diagnosed with prostate cancer in the scope of the European
Randomized Screening Study for Prostate Cancer . The majority of
patients in our cohorts were hormone naı¨ve at the time of definitive
treatment; 71 patients (14.2%) from the UHN radiotherapy cohort and
seven (2.7%) from the MSKCC cohort received hormonal therapy with
their local treatment. Informed consent was obtained at the time of
clinical follow-up from all patients, and ethics approval was obtained
from all participating institutions.
2.2. Pathological analysis for IDC/CA
All prostate tumors from UHN, MSKCC, and EMC were surveyed for IDC/
CA by expert genitourinary pathologists (C.K., A.G., G.v.L., V.R., and
T.v.d.K.) using previously reported criteria No attempt was made to
distinguish between IDC and CA because of their comparable prognostic
impact .
Outcome measurements and statistical analysis: IDC/CA was separately assessed for
biochemical relapse risk in the Canadian and MSKCC cohorts. Both cohorts were pooled
for analyses on metastasis.
Results and limitation: Presence of IDC/CA independently predicted for increased risks of
biochemical relapse (HRCanadian 2.17, p < 0.001; HRMSKCC 2.32, p = 0.0035) and metastasis
(HRpooled 3.31, p < 0.001). IDC/CA+ cancers were associated with an increased percentage of
genome alteration (PGA [median] 7.2 vs 3.0, p < 0.001), and hypoxia (64.0% vs 45.5%,
p = 0.17). Combinatorial genomic–pathological indices offered the strongest discrimination
for metastasis (C-index 0.805 [clinical + IDC/CA + PGA] vs 0.786 [clinical + IDC/CA] vs
0.761 [clinical]). Profiling of mRNA abundance revealed that long noncoding RNA, SChLAP1,
was the only gene expressed at >3-fold higher (p < 0.0001) in IDC/CA+ than in IDC/CA–
tumors, independently corroborated by increased SChLAP1 RNA in situ hybridization signal.
Optimal treatment intensification for IDC/CA+ prostate cancer requires prospective testing.
Conclusions: The poor outcome associated with IDC and CA subpathologies is associated
with a constellation of genomic instability, SChLAP1 expression, and hypoxia. We posit a
novel concept in IDC/CA+ prostate cancer, ‘‘nimbosus’’ (gathering of stormy clouds, Latin),
which manifests as increased metastatic capacity and lethality.
Patient summary: A constellation of unfavorable molecular characteristics co-occur with
intraductal and cribriform subpathologies in prostate cancer. Modern imaging for surveil-
lance and treatment intensification trials should be considered in this adverse subgroup.
# 2017 European Association of Urology. Published by Elsevier B.V. All rights reserved.
Genomic instability
Hypoxia
SChLAP1
Prognosis
Please visit
to read and
answer questions on-line.
The EU-ACME credits will
then be attributed
automatically.
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 4 666