EURURO Vol. 71 No. 4

546 692

1. Introduction
Radical cystectomy (RC) is the mainstay of treatment for
muscle-invasive bladder cancer (BC) . The main goal of
RC is to completely remove the tumor-bearing bladder with
negative surgical margins in order to provide optimal
cancer control. Urothelial carcinoma (UC) is considered a
pan-urothelial disease Therefore, the remnant urothe-
lium in the upper tracts and urethra remains at life-long risk
for recurrence after RC.
In this regard, the carcinogenesis of multifocal lesions in
UC is still controversial. According to the oligoclonal theory
or field cancerization, multifocal UC is a result of different
genomic events at different time points in the urothelium,
whereas the clonal theory considers that multifocal
urothelial tumours arise by tumor spread or implantation
in the urothelial layer and are genetically identical
A better understanding of the cancerogenic potential of
the remnant urothelium after RC is prerequisite for any
individualized and evidence-based follow-up strategy of
patients at risk of secondary urothelial tumors (SUTs). The
present analysis aims to synthesize the available evidence
on the incidence, diagnosis, treatment, and outcomes of
patients with SUTs after RC in order to address the issue as
to whether it is possible to identify patients who are likely
to develop SUTs and profit from early detection and
treatment.
2. Evidence acquisition
A systematic literature search was conducted according to
the Preferred Reporting Items for Systematic Reviews and
Meta-analyses statement to identify studies reporting on
malignant diseases of the remnant urothelium after RC
between 1970 and 2016. The PubMed database was
searched along with a free-text hand search using one or
several combinations of the following items: BC, remnant,
radical cystectomy, upper urinary tract, upper tract urothe-
lial carcinoma, urethral carcinoma, upper tract recurrence,
urethral recurrence, and urothelium. A total of 1069 studies
were initially identified. The selection process was con-
ducted in three stages. The first stage was performed via
initial screening of the title to identify eligible publications
including a search of respective publications in journals not
listed in PubMed to avoid missing any eligible study. In the
second stage, publications were screened for eligibility
according to the abstracts. The third stage was performed via
full-text reading of the respective publications. For this
systematic review, we excluded: (1) non-English articles, (2)
review articles (without systematic review or meta-analy-
sis), (3) editorial reports and case reports, and (4) repeated
publications to avoid publication bias. We decided to
exclude review articles as the interpretation of published
results without systematic assessment or meta-analysis of
data does not offer significant novel insights into the issue of
diagnosis and treatment of secondary urothelial tumors.
A total of 57 papers were finally considered for evidence
synthesis ). Notably, these studies are
retrospective which inevitably inherit the risk of selection
bias for which this review cannot control. A Consolidated
Standards of Reporting Trials diagram is provided in
3. Evidence Synthesis
3.1. Incidence and clinicopathological risk factors for secondary
urothelial recurrences
3.1.1. Risk factors for secondary upper tract urothelial carcinoma
Generally, secondary tumors of the upper tract are consid-
ered as late oncological events, occurring after a median of
24–36 mo after RC For this reason, it is important to
evaluate clinical and pathological risk factors which may
help to assess the intensity of follow-up. In 2012, a meta-
analysis was published which aimed to address risk
factors for upper tract urothelial carcinoma (UTUC) after RC.
The study cohort consisted of 13 185 patients (included from
22 retrospective studies) treated with RC for BC between
1970 and 2010. The follow-up interval ranged between
0.4 mo and 349 mo and the rates of UTUC between 0.8% and
6.4% ). A significantly higher risk for secondary UTUC
was reported for the following subgroups: nonmuscle
invasive tumor stages and carcinoma in situ (CIS) at RC,
histologically confirmed negative lymph nodes (pN0), tumor
multifocality and history of multifocal BC, a prior history of
UTUC prior to RC, a positive ureteral or urethral margin at RC,
and the presence of low-grade tumors (G1) . The latter
finding seems to be contraintuitive from a biological
standpoint. However, in the context of patients treated with
RC for BC those who are at low risk of cancer-related death
(ie, those with nonmuscle invasive disease) or exhibit
histological features of pan-urothelial disese (ie, CIS) are the
ones at particular risk for subsequent upper tract tumors
during the long-term follow-up compared with those who
present with advanced disease at surgery and are more likely
to die from metastatic disease which usually occurs in the
1st 2 yr after RC . Recently, urethral margin status on
permanent section was also found to be an independent
prognosticator for metachronous UTUC whereas frozen
section analysis (FSA) of the distal ureteral margin was only
associated with recurrence in univariable but not multivari-
able analysis . Similarly, in another large retrospective
study on 1420 RC patients, CIS of the bladder, a history of
recurrent BC, nonmuscle invasive bladder cancer stage, and
tumor involvement of the distal ureter were reported to be
independently associated with the risk for secondary UTUC.
Indeed, while for the total cohort the overall rate of UTUC
was very low (0.8%), its prevalence increased to 13.5% for
patients with three to four risk factors
3.1.2. Risk factors for secondary urethral tumors
As for SUTs of the upper tract, the median time to secondary
urethral tumors has been reported to range between 13 mo
and 28 mo in men and 30 months in women
. Secondary urethral tumors after RC are relatively rare
(incidence: 0.8–6.1%; ) and associated with a trend
towards lower 5-yr cancer-specific survival compared with
patients without urethral tumors (63% vs 71%; p = 0.11)
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