Stesura Seveso


291Archivio Italiano di Urologia e Andrologia 2022; 94, 3

ORIGINAL PAPER

No conflict of interest declared.

cell variant, sarcomatoid variant, plasmacytoid variant,
microcystic variant, micropapillary variant, nested vari-
ant, and small cell type (2). Histologic variants are classi-
fied primarily based on morphology that is associated
with a distinct biological behavior, such as proclivity for
local recurrence and metastasis. Moreover there are vari-
ations in the clinical course including progression pat-
terns and responses to therapy as well as biologic features
in molecular subtypes and DNA alterations (3).
In the past, it was believed that urothelial tumors with
divergent differentiation presented at a later stage of diag-
nosis, and earlier reports indicated a lower survival rate
(4). Recent studies show that patients with squamous or
glandular urothelial tumors have survival rates compara-
ble to those with pure urothelial tumor (3, 5). In a study
by Sefik et al. patients with variant histology were observed
to have proportionally higher T stage compared to nonva-
riant urothelial carcinoma; however there were no signifi-
cant differences for overall survival and cancer-specific
survival (6). A recent study by Pereira et al. evidenced that
although bladder cancers with histological variants are
clearly associated with features of more aggressive behav-
ior, they had not any significant impact in survival
expectancies (7). Therefore, the clinical impact of tumor
with variant histology on the treatment options still
remains under a cloud of doubt in that whether the pres-
ence of variant histology justifies an aggressive treatment
strategy involving early radical cystectomy (8). The final
pathology and prognosis of bladder cancer with variant
histology differ from that of pure urothelial bladder cancer,
and evidence on the response to systemic therapy in these
variant histologies is scarce and divergent (9, 10). Current
guidelines place urothelial carcinoma with variant histol-
ogy in the highest risk category, implying that, despite
lacking high level of evidence, early radical cystectomy
should be considered (11). It is noteworthy, when it comes
to management, evidence in some areas is contradictory
and inconclusive therefore necessitating further investiga-
tion. Our study aims to share our institution experience in
treating bladder cancer with variant histology.

METHODS
A retrospective cohort single center study involving all
patients who were treated for bladder cancer with a his-
tological variant admitted to the Thunder Bay Regional

Purpose: The aim of this study is to report
our experience in managing bladder cancer

in patients with variant pathology. 
Methods: Retrospective data collection for all patients managed
by radical cystectomy over the last 3 years for a variant pathol-
ogy was completed. We specifically included micropapillary and
nested variants. 
Results: Ten patients were identified, with eight having
micropapillary carcinoma (MPC) and two having nested vari-
ants. Nine patients were male. The median age was 75. The two
patients with nested variant were 56 and 62 years old, respec-
tively, whereas all patients with MPC were over the age of 70.
Upon cystectomy of all micropapillary cases, three patients
(37.5%) had positive lymph node invasion and the final patholo-
gy was T2 (two patients), T3 (two patients), and T4 (four
patients). Barring a grade III complication Clavien-Dindo classi-
fication due to wound dehiscence that necessitated secondary
surgical closure, there were no specific perioperative complica-
tions. Given the urethral invasion, cystourethrectomy was per-
formed on the female patient. Within a median 13-month fol-
low-up, three patients developed local recurrence, including two
urethral and one new lateral pelvic mass. 
Conclusions: Considering the muscle invasive nature of
micropapillary and nested bladder cancer, aggressive surgical
management should not be postponed. Moreover, due to notable
prevalence of concurrent and/or recurrent urethral involvement,
initial urethrectomy or early and frequent postoperative ure-
throscopy should be provided. Patients with variant histology
bladder cancer may benefit from early radical cystectomy when
compared to bladder sparing protocols and prostate sparing
 cystectomy treatment options. 

KEY WORDS: Bladder cancer; Urothelial carcinoma; Variant
 histology; Radical cystectomy.

Submitted 30 July 2022; Accepted 20 August 2022

INTRODUCTION
Bladder cancer varies along a wide spectrum of histologi-
cal variants with urothelial cancer accounting for the vast
majority (1, 2). Variant histology accounts for approxi-
mately 25% of bladder tumors that can pose distinctive
diagnosis and therapy challenges to the overall manage-
ment of bladder cancer (2). According to the World
Health Organization 2016 classification, variant histology
of bladder cancer includes urothelial carcinoma with
divergent differentiation, such as lymphoepithelioma-like

Radical cystectomy for bladder urothelial carcinoma 
with aggressive variant histology 

Vahid Mehrnoush, Logan Brennan, Asmaa Ismail, Ahmed Zakaria, Hazem Elmansy,
Walid Shahrour, Owen Prowse, Ahmed Kotb

Urology Department, Northern Ontario School of Medicine, Thunder Bay Regional Health Centre, Ontario, Canada.

DOI: 10.4081/aiua.2022.3.291

Summary



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V. Mehrnoush, L. Brennan, A. Ismail, A. Zakaria, H. Elmansy, W. Shahrour, O. Prowse, A. Kotb

292

Health Science Centre. Our patients were treated with
either a radical cystectomy or a transurethral resection of
the bladder tumor (TURBT) alone, or a TURBT combined
with adjuvant BCG therapy.

RESULTS
Ten patients (9 male and 1 female) were identified, with
eight having micropapillary cancer and two having nest-
ed variants. The median age was 75 (56-84). The two
patients with the nested variant were 56 and 62 years old,
respectively, whereas all patients with micropapillary can-
cer (MPC) were over the age of 70. Of nested variant
patients, one patient had a domal T1 tumor and the other
had a T2 small trigonal tumor.
Localized cancer was confirmed by staging CT scans.
Upon radical cystoprostatectomy, the final pathology for
the first patient was pT2N0, while the second patient was
pT4aN1. Of the patients with MPC, two were reported to
have stage T1 tumors, while six were reported to have
stage T2 tumors on TURBT. Stage T4b was found on CT
scan in two patients. Despite the instillation of intravesi-
cal bacillus Calmette-Gue'rin (BCG) induction course,
upstaging to T2 was reported in both T1 cases. Upon cys-
tectomy for all micropapillary cases, three patients
(37.5%) had positive lymph node invasion and the final
pathology came back T2 (two patients), T3 (two
patients), and T4 (four patients).
Barring a grade III complication Clavien-Dindo classifica-
tion due to wound dehiscence that necessitated second-
ary surgical closure, there were no specific perioperative
complications). Given the urethral invasion, the cys-
tourethrectomy was performed on the female patient.
Within a median 13-month follow-up, three patients
(30%) developed local recurrence, including two urethral
and one new lateral pelvic mass.
Table 1 illustrates the clinical characteristics and out-
comes to the patients and Figures 1 and 2 represent two

cases with micropapillary and nested variant urothelial
carcinoma respectively.

DISCUSSION
The current study is a report on our experience in treating
bladder cancer with aggressive variant histology.
Micropapillary urothelial carcinoma (MPC) was a male-pre-
dominant variant found in our patients. MPC has received
the most attention of the variant histologies in recent years
and may be more familiar to many pathologists than other
variants (8). Clinically, it is an aggressive variant that typi-
cally manifests at an advanced stage and accounts for 2-
5% of urothelial carcinomas (8) which have a poor prog-
nosis (12). The fast progression of non-muscle invasive
micropapillary urothelial carcinoma to muscle invasive or
metastatic bladder carcinoma is concerning and is a well
demonstrated concern in our cases (13).
MPC is tightly linked to lymph vascular invasion and
lymph node metastasis, in that pT1 bladder cancer with
micropapillary variant is frequently upstaged to more
advanced stages during investigation and treatment (12).

Table 1. 
Clinical characteristics and outcomes of all cases.

Median age 75 (56- 84)
Sex Males 9

Females 1
Histology Micropapillary 8

Nested 2
TURBT stage T1 3

T2 7
Final T pathology (cystectomy) T1 0

T2 3
T3 2
T4 5

Final N stage N0 7
N1 3

Urethral invasion No 7
Present at cystectomy 1
Early (within 6 months) 2

Local recurrence (within 1 year) No 7
Urethra 2
Pelvic side wall 1

Figure 1. 
Abdominal axial CT image showing a large cT4 micropapillary
cancer.

Figure 2. 
Abdominal axial CT showing cT1 nested variant.



293Archivio Italiano di Urologia e Andrologia 2022; 94, 3

Radical cystectomy for bladder urothelial carcinoma with aggressive variant histology 

As a result, the European Association of Urology-European
Society of Medical Oncology Guidelines Committees recently
agreed that T1 high-grade bladder urothelial carcinoma
with micropapillary histology should be treated with
immediate radical cystectomy and lymphadenectomy
(11). Therefore, in such cases, most centers consider early
radical cystectomy to be the standard of care; however,
there have been reports of reasonable outcomes in series
in which bladder preservation therapies were used in
highly selected patients with a relatively small micropap-
illary component (14). Although there is still limited evi-
dence on the preferred treatment option, reports show no
statistically significant differences in overall survival
between groups that received neoadjuvant chemotherapy
plus early radical cystectomy vs. radical cystectomy alone
in muscle-invasive micropapillary urothelial carcinoma
(15, 16). On the other hand, evidence is lacking on the
added benefit of neoadjuvant chemotherapy to the treat-
ment of the bladder cancers with variant histology (17).
A study on patients with muscle-invasive urothelial carci-
noma with variant histology comparing neoadjuvant
chemotherapy plus radical cystectomy vs. early radical
cystectomy only showed an improvement in overall sur-
vival and a lower rate of non-organ-confined disease at
the time of radical cystectomy in patients with neuroen-
docrine tumor neoadjuvant chemotherapy. Neoadjuvant
chemotherapy reduced the rate of non-organ-confined
disease but had no effect on overall survival in bladder
tumors with micropapillary differentiation, sarcomatoid
differentiation, or adenocarcinoma (9). Evidence also rec-
ommended that muscle-invasive bladder urothelial carci-
noma with micropapillary or plasmacytoid differentia-
tion, as well as squamous or glandular differentiation,
should be treated with neoadjuvant chemotherapy fol-
lowed by radical cystectomy and concomitant lym-
phadenectomy (11).
The role of adjuvant radiotherapy for muscle-invasive
urothelial carcinoma and variant histologies is controver-
sial. Some evidence recommends that adjuvant radiothera-
py (with or without radiosensitizing chemotherapy) is a
standard treatment for patients with muscle-invasive
urothelial carcinoma with variant histology (11, 18). Other
evidence states that it is prudent to consider adjuvant
radiotherapy to improve local control. This is particularly
important in cases with positive margins like patients with
urothelial carcinoma with squamous and/or glandular dif-
ferentiation who are more likely to have pT3-T4 tumors,
pelvic lymph node involvement, and local or distant metas-
tasis-related to increased mortality when compared to
those with pure urothelial carcinoma (19-21).
It has been reported that the response rate to intravesical
BCG administration for micropapillary variant is poor
(11, 22). 
In a study of 72 patients with MPC, 40 received primary
intravesical BCG and 26 received early radical cystecto-
my. The BCG group were more inclined to recurrence,
progression, and lymph node metastasis at a 75%, 45%,
and 35% rate, respectively 22. While certain patients
with T1 MPC may respond to intravesical BCG, patients
who undergo early radical cystectomy have improved
survival outcome (22). In our center, we tried a BCG
induction course for patients with T1, but due to T2 pro-

gression, they eventually underwent radical cystectomy.
Nested variant urothelial carcinoma is more common in
men over the age of 60, which is similar to the occurrence
of classic urothelial carcinoma; however, it has been
reported in patients ranging in age from 42 to 90 years
(23). In our findings, the nested variant, in contrast to
MPC, were found in younger cases. The nested variant,
according to the 2016 WHO classification, includes
urothelial carcinoma with small tubules and microcysts
(24). It is distinguished by disorderly proliferation of con-
fluent nests with minimal cell atypia (25) which is fre-
quently mistaken for benign cytology that leads to a delay
in the definitive diagnosis. Nested urothelial carcinomas
typically manifest as advanced disease and may be associ-
ated with a poor prognosis when compared to pure
urothelial carcinoma (26). It has similar characteristics
and clinical outcomes to classical urothelial carcinoma,
with little to no difference in recurrence or survival rate
when treated with radical cystectomy in either non mus-
cle invasive or muscle invasive bladder cancer (25). Data
from two matched cohorts revealed that patients with
nested variants had similar oncological outcomes after
radical cystectomy compared to pure urothelial carcino-
ma (27, 28). Although lacking consensus due to a lack of
evidence, it is recommended that T1 high-grade bladder
urothelial carcinoma with nested variants confirmed
(after complete TURBT and/or re-TURBT) should be
treated with immediate radical cystectomy and concomi-
tant lymph node dissection (11).
The treatment of bladder cancer including transurethral
surgery, intravesical chemotherapy and immunotherapy,
radical cystectomy, systemic combination chemotherapy,
and, in some cases, radiation therapy has evolved over
time to the point where clinical risk markers are now
employed to make the best decision for patients. As a
result, variant histology can serve as a risk stratification
factor that can contribute to improved clinical decision
making (17).

CONCLUSIONS
Aggressive surgical treatment for patients with micropapil-
lary and nested muscle invasive bladder cancer should not
be postponed. A large proportion of these patients have
urethral involvement. 
Thus, an initial urethrectomy or early and frequent post-
operative urethroscopy should be included in the treat-
ment and management of variant histology bladder can-
cers. For bladder cancer with variant histology, bladder
sparing protocols and prostate sparing cystectomy may not
be the best treatment options.

KEY MESSAGES
1. Urothelial variant bladder cancer is always upstaged on
radical cystectomy.
2. Radical cystectomy for T1 variant histology should be
offered rather than surveillance.
3. Urethrectomy may be considered at time of radical cys-
tectomy.
4. Urothelial variant histology was a male predominant
finding in our series. 



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Correspondence

Vahid Mehrnoush, MD
vahidmehrnoush7@gmail.com

Logan Brennan
lobrennan@nosm.ca

Asmaa Ismail
asmaaismail0782@gmail.com

Ahmed Zakaria
aszakaria81@yahoo.com

Hazem Elmansy
hazemuro100@yahoo.com

Walid Shahrour
walid.shahrour@gmail.com

Owen Prowse
owen.prowse@tbh.net

Ahmed Kotb (Corresponding Author)
drahmedfali@gmail.com
Urology Department, Northern Ontario School of Medicine, Thunder Bay 
Regional Health Centre, Ontario, Canada