










































This is an open access article under the terms of a license that permits non-commercial use, provided the original work is properly cited. 
© 2021 The Authors. Société Internationale d'Urologie Journal, published by the Société Internationale d'Urologie, Canada.

Incidence and Predictors of Secondary Upper 
Tract Urothelial Cancer in Patients With High-Risk 
Non-Muscle Invasive Urinary Bladder Cancer and 
its Impact on Imaging Surveillance: A Retrospective 
Analysis With 1501 Patients
Ebrahim Elsaeed Abouelenein,1 Mohamed Elawdy,1 Diaa-Eldin Taha,2 Yasser Osman,1  
Bedeir Ali-El Dein,1 Ahmed Mosbah1 

1 Urology Department, Urology and Nephrology Center, Mansoura University, Egypt 2 Kafr El Sheikh Faculty of Medicine, Kafr El Sheikh University, Egypt

Abstract

Objectives We aimed to study the incidence and predictors of upper tract urothelial cancer (UTUC) in  
patients with high-risk non-muscle invasive bladder cancer (HR-NMIBC).

Methods Patients who had HR-NMIBC were reviewed to identify those who subsequently developed UTUC. 
Complete transurethral resection was performed, and biopsies were collected for histopathology followed by 
intravesical chemoimmunotherapy. Patients were screened annually by computed tomography (CT) for UTUC.

Results Data for 1501 patients were reviewed. UTUC developed in 59 (4%) after a median of 20 months  
after HR-NMIBC. Most patients were symptomatic, but UTUC was discovered on routine follow-up imaging  
in 28%. On bivariate analysis, only multiple bladder tumors and the number of bladder recurrences  
were predictors for UTUC (P = 0.01 and P = 0.008, respectively). Multiple bladder tumors and ≥ 3 bladder  
recurrences remained significant on multivariable analysis.

Conclusion UTUC after HR-NMIBC is uncommon (4%). Despite routine follow-up CT imaging, recurrence 
was detected due to symptoms in most patients, and based on imaging only in 28%. Imaging surveillance can be 
prioritized in patients with multiple bladder tumors and those with ≥ 3 bladder recurrences. For the other patients, 
the benefit of imaging surveillance has to be weighed against the risks.

Introduction

In patients with primary upper tract urothelial cancer (UTUC), secondary bladder recurrence is high (30% to 45%)[1], 
and routine follow-up can be performed easily with a flexible cystoscope during an office visit. However, secondary 
UTUC post non-muscle invasive urinary bladder cancer (NMIBC) is different; it has a low incidence (1% to 4%)[2-4], 
and the follow-up requires lifelong contrast-enhanced imaging.

Key Words Competing Interests Article Information

Upper tract urothelial cancer, transitional 
cell carcinoma, non-muscle invasive bladder 
cancer, bladder cancer, recurrence, predictors

None declared. Received on January 30, 2021 
Accepted on April 3, 2021

Soc Int Urol J. 2021;2(3):151–157

DOI: https://10.48083/NZTC6259

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Whether routine annual computed tomography (CT) 
imaging should be performed on all NMIBC patients 
or if CT should be individualized is still an open issue. 
Some guidelines still recommend routine upper tract 
imaging[5]. However, IVU/CT is reported to have poor 
sensitivity for the detection of UTUC, which is usually 
low grade and low stage[6]. Moreover, most of the UTUC 
patients are symptomatic, and the follow-up procedure 
requires lifelong CT with contrast administration.

In 2 large separately published studies that involved 
more than 1500 and 1000 NMIBC patients, the high-
risk (HR-NMIBC) group constituted the majority of 
the patients[7,8]. Regarding the incidence of secondary 
UTUC, a statistically significant difference was reported 
between low- and high-risk groups (0.6, 4% and 1, 9.8%, 
respectively)[3,4]. Moreover, it was reported that UTUC 
has low incidence in the low- and intermediate-risk 
groups (LE: 2b)[9]. New studies were therefore necessary 
to focus on the high-risk group alone.

We aimed to study the predictors of secondary UTUC 
and survival rates in patients with HR-NMIBC. The 
study may help in stratifying patients to determine who 
requires strict routine upper tract imaging and in whom 
the benefits could outweigh the risks. Our data will 
help in validating the existing knowledge and in patient 
counseling.

Materials and Methods

After institutional board approval (R/18.04.217), a 
retrospective analysis was conducted between January 
2004 and December 2018. The data of patients with 
non-muscle invasive urothelial bladder cancers who 
were managed with transurethral resection (TUR) were 
reviewed. Patients’ files were further reviewed to identify 
those who had developed UTUC on follow-up.

Patients were classified into 3 risk groups according 
to European Association of Urology guidelines[9]: low, 
intermediate, and high. The low-risk group included 
all of the following: primary, solitary, Ta, G1 tumor < 3 
cm, and no CIS. The high-risk group included any of the 
following: T1, G3, CIS, and multiple and recurrent and 
large (> 3 cm) Ta G1G2 tumors. The intermediate-risk 

group included tumors that were not identified in the 
other 2 groups.

Inclusion and exclusion criteria: The high-risk group 
was the only group included in our study, and we 
eliminated those with low- and intermediate-risk 
NMIBC. Additionally, patients who had previous and/or 
concomitant UTUC were eliminated.

Preoperative workup: This included medical history, 
physical examination, and routine laboratory and 
imaging workup. Office f lexible cystoscopy was used 
as an initial tool for the diagnosis of patients who 
had hematuria, persistent irritative lower urinary 
tract symptoms, or any suspicious bladder mass on 
ultrasound.

Operative details: Cystoscopy and bladder tumor 
resection were performed under spinal anesthesia, 
and general anesthesia was used if the spinal failed 
or was contraindicated, or if obturator jerk occurred, 
jeopardizing the resection. Instillation of a single dose 
of intravesical chemotherapy (epirubicin, 50 mg) was 
standard practice as a part of a prospective randomized 
4-year study in our hospital. Its aim was to evaluate the 
effectiveness of the therapy in intermediate- and high-
risk groups[10].

Postoperative care: All patients were kept in the 
hospital, and the urethral catheter was kept in place for 
48 hours unless other recommendations were given in 
cases of deep resection or suspected bladder perforation.

Routine second look TUR for all high-risk patients 
was introduced at our institute in 2010; before 2010, it 
was performed based on surgeon’s recommendations.

Eligible patients received adjuvant intravesical 
instillation of chemotherapy or immunotherapy (bacillus  
Ca lmette-Guérin, BCG) according to European 
Association of Urolog y g uidelines. A ll patients 
underwent routine flexible cystoscopy every 3 months 
for the first 2 years, every 6 months for the next 3 years, 
and then annually. Patients with recurrent tumors were 
scheduled for repeat TUR followed by resumption of 
intravesical immunotherapy. Patients were screened 
annually by CT for any UTUC recurrence.

For tumor grading, the 3-tiered World Health 
Organization grading system[11] was used to determine 
the pathologic grade by different pathologists. The tumor 
was staged according to the 2009 TNM classification.

The primary outcome was development of secondary 
UTUC (dependent variable) in patients who had non-
muscle invasive bladder tumor that was correlated with 
possible risk factors (independent variables) and to study 
its clinical implementation on routine imaging.

Abbreviations 
BCG bacillus Calmette-Guérin
CT computed tomography
IVU intravenous urography
NMIBC non-muscle invasive urinary bladder cancer
TUR transurethral resection
UTUC upper tract urothelial cancer

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TABLE 1. 

Demographics of 1501 patients and bivariate analysis of risk factors for development of  
upper urothelial cancer in patients with non-muscle invasive bladder cancer

Demographics (R/18.04.217) Development of upper urothelial cancer 
n (%), total number (1501) *

P- Value

Value (%) * No, n=1442 Yes, n= 59

Gender

Male 1290 (86) 1240 (96) 50 (4)
0.7

Female 211 (14) 202 (96) 9 (4)

Tumor size

Less than 3cm 780 (52) 757 (97) 23 (3)
0.7

3cm or more 721 (48) 685 (95) 36 (5)

Tumor site

Posterior 330 (22) 320 (97) 10 (3)

0.6

Lateral walls 495 (33) 479 (97) 16 (3)

Anterior, and domal 135 (9) 129 (96)  6 (4)

Trigone and BN 90 (6) 85 (95) 5 (5)

Multicenteric 451 (30) 429 (95) 22 (5)

Tumor number

Single 753 (50) 732 (98) 21 (2)
0.01

Multiple 748 (50) 710 (95) 38 (5)

Tumor stage

Ta 10 (1) 10 (100) –

0.6T1 1470 (98) 1411 (96) 59 (4)

Primary CIS 21 (1) 21 (100)

Tumor grade

Grade I 168 (11) 159 (95) 9 (5)

0.6Grade II 784 (52) 755 (96) 29 (4)

Grade III 549 (37) 528 (96) 21 (4)

CIS

No 1350 (90) 1297 (96) 53 (4)

0.7Yes, concomitant 130 (8) 124 (96) 6 (4)

Yes, primary 21 (2) 21 (100) – –

Number of recurrences

First time 810 (54) 792 (97) 18 (3)

0.008

Previous 1 recurrence 316 (21) 307 (97) 9 (3)

Previous 2 recurrences 180 (12) 171 (95)  9 (5)

Previous 3 recurrences 105 (7) 94 (89) 11 (11)

More than 3 recurrences 90 (6) 78 (86) 12 (14)

* Percentage was given for rows; decimals were deleted for simplification

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Statistical analysis: The data were collected using 
IBM SPSS version 21 (Armonk, NY: IBM Corp.). For 
univariate analysis, frequency and percentage were used 
to express nominal and ordinal variables. Mean and 
standard deviation were used to express scale variables 
with normally distributed data. Median and range were 
used for non-normally distributed data. For bivariate 
analysis, chi-square test was used for nominal variables. 
Multivariate analysis with a logistic regression model 
in a forward LR-selection strategy was generated for 
significant variables in bivariate analysis. In all tests, the 
P value was 2-sided, and significance was set at P < 0.05.

Results

Of 1565 patients, 64 were not compliant to upper 
tract imaging and were eliminated from the analysis, 
leaving 1501 patients eligible for analysis. The mean 
age was 58±11, 90% (1354/1501) were male, and median 
follow-up was 21 months (6 to 210). Nearly half of the 
patients (51%) had a single bladder tumor, and (53%) 
had tumors less than 3cm in diameter and of GII. Upper 
tract urothelial cancer developed in 59 patients (4%). 
Demographic information and NMIBC tumor criteria 
for the remaining patients are shown in Table 1.

Most of the secondary UTUC were in the ureter: 
alone (39/59 = 66%), also in the kidney (10/59 = 17%), 
or in the kidney alone (10/59 = 17%). In the ureteral 
tumor group (n = 49), distal ureteral tumors were 
more common (30/49 = 61%) than multicentric or 
proximal ureter tumors (11/49 = 23% and 8/49 = 16%, 
respectively). The median time for the development of 
UTUC was 20 months (6 to 106 months). Hematuria was 
the most common symptom in this cohort (64%), while 
UTUC was discovered on follow-up imaging in 28% of 
the patients. Cytology was used in detecting UTUC with 
overall diagnostic accuracy of 75%. The other UTUC 
characteristics are shown in Table 2.

Bivariate analysis of the risk factors showed that none 
of the following were predictors for the development 
of secondary UTUC: gender, tumor size, site, tumor 
stage or grade; only bladder tumor number (single 
or multiple) and the number of bladder recurrences 
were the predictors for secondary UTUC (P = 0.01 and 
P = 0.008, respectively), Table 1.

On multivariable analysis, multiple tumors remained 
significant when compared with the presence of 
a single tumor (P = 0.04). Also, as the number of 
previous recurrences increased, the chance of UTUC 
increased; previous recurrences (1 to 2) were not 
predictors (P = 0.5, and P = 0.6, respectively), but 3 or 
more previous recurrences were strongly significant 
predictors for secondary UTUC (P = 0.04 and P = 0.003, 
respectively) Table 3.

TABLE 2. 

Tumor characteristics of 59 patients who had secondary 
UTUC post-surgical management of NMIBC

Characteristics Value          (%) *

Gender

Male 50 (83)

Female 9 (17)

Side of the tumor

Right 41 (70)

Left 18 (30)

Presentation

Symptomatic: 42 (72)

Hematuria + flank pain 39 (66)

Microscopic hematuria, LUTS 
Incidentally on follow-up imaging

3
17

(6)
(28)

Site of the tumor

Ureter 39 (66)

Kidney (pelvi-calyceal) 10 (17)

Kidney and ureter 10 (17)

Tumor grade

Grade I TCC 6 (10)

Grade II TCC 39 (65)

Grade III TCC 14 (25)

Tumor stage

Ta, T1, Tis 41 (70)

T2 12 (20)

T3 6 (10)

The final size in cm, median (range)

Renal pelvis tumors

Length 3 (2–8)

Width 4 (3–10)

Ureteric tumors

Length 4 (1–6)

Width 2 (0.5–3)

Management of UTUC

Nephroureterectomy  
(Laparoscopic and Open)

40 (67)

Endoscopic management 13 (23)

Nephron-sparing (ureterectomy) 6 (10)

*Decimals were removed for simplification

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Discussion

Urothelial cancer is a field-change disease. The multiple 
foci of urothelial cancers on different anatomical sites in 
the urothelium is a common feature of the disease[12]. 
Recurrence, either synchronous or metachronous, is 
an inherent behavior of urothelial cancer. In treating 
NMIBC, which is quite a common tumor, synchronous 
UTUC can be detected at the time of initial evaluation 
of bladder tumor, but metachronous UTUC is of greater 
concern. It requires not only routine radiation exposure 
but also contrast administration that may increase the 
risk of contrast-induced nephropathy, especially in the 
elderly and in those with borderline renal function. 
Moreover, metachronous recurrence has a lifelong risk 
and could present after many years (7 to 15 years)[13]. In 
addition, patients with metachronous recurrence require 
repeated contrast administration, which increases the 
odds of contrast-induced nephropathy. Because of these 
issues, our study and other published studies have aimed 
to identify those at high risk and to determine whether 
the risk outweighs the benefit.

The incidence of secondary UTUC in our series is 4%, 
which is consistent with the majority of published data 
(1% to 4%)[2,3]. This small range in incidence can be 
explained by the different bladder tumor characteristics 
between series, in terms of bladder tumor grade, stage, 
CIS, and recurrence.

The ureter is the site most frequently affected in 
secondary UTUC. In our series, 80% of the cases 
were in the ureter, either alone or with involvement of 
the renal pelvis. Others have reported similar results 
regarding ureteral involvement, especially in the pelvic 
ureter and intramural ureter[4,14]. This observation 
can be explained by vesicoureteral reflux; however, this 
theory cannot explain UTUC recurrence post radical 
cystectomy that was reported with similar incidence 
(3.9%) in a study of 1420 patients[15], or an even higher 
incidence (6.4%) in a large meta-analysis[16]. The theory 
of the panurethral nature of UTUC is therefore more 
widely accepted than the theory that it is due to reflux.

Of 59 patients who had secondary UTUC in our 
series, 72%, were symptomatic, and hematuria, either 
microscopic or macroscopic, was the most common 
complaint. Patients in this situation usually seek medical 
attention and undergo imaging, so UTUC is discovered 
at an early stage. Nevertheless, the issue remains for the 
28% (17/59) who had no symptoms but were discovered 
incidentally with routine imaging to the upper tract.
Sternberg et al., in a series of 935 patients of NMIBC, 
and Picozzi et al., in a large meta-analysis of UTUC 
recurrence post radical cystectomy in more than 13 000 
patients, reported similar percentages (30% and 38%)of 
asymptomatic patients[6,16].

On bivariate analysis, multiple bladder tumors at 
the time of TURBT and bladder recurrences were 
the only predictors for secondary UTUC. This was 
consistent with the findings of Millan-Rodriguez et 
al.[4] and with a series of 375 patients all of whom had 
Ta bladder tumors[2]. The natural behavior of urothelial 
cancer, urothelial instability, field-change disease, and 
multicentricity all explain our findings and those of 
other studies. The results of Cox regression multivariable 
analysis solidified this. Although this was not calculated 
in our series, the recurrence time of bladder tumor could 
indicate more bladder instability. Recurrence within 12 
months increases the risk of UTUC recurrence by 4.5-
fold, as reported by Canales et al.[2]. Other predictors 
were reported in a few studies: tumor grade, CIS, and 
BCG failure[5], tumor morphology (being non-papillary 
increases the risk)[14], and in some cases, no predictors 
were found[17]. A statistically significant difference 
in the incidence of UTUC between low- and high-risk 
NMIBC patients was reported by Hurle et al. (0.6% 
and 4%) and Millan-Rodriguez et al. (1% and 9.8%), 
respectively[3,4]. For that reason, we focused only on the 
high-risk group in our series.

We aimed to address the debate in the literature 
regarding the necessity and frequency of upper tract 
imaging post management of NMIBC. The majority 
of published studies do not support its routine use for 
many reasons (low incidence, low grade and stage, 
lifelong risk), and many patients who developed UTUC 
are symptomatic. Moreover, this imaging requires 
contrast administration with known side effects on the 
kidney. Contrast nephropathy is one of the reasons for 
hospital-acquired renal insufficiency[18], and this is in 

TABLE 3. 

Multivariate logistic regression analysis of the possible 
risk factors

Parameters
Binary logistic regression 

models

Odds 
ratio (OR)

95% CI p -value

Number of tumors

Single Ref

Multicentric 1.7 1.1–2.2 0.04

Number of recurrences

No recurrence Ref

Previous 1 recurrence 1.2 0.6–2.5 0.5

Previous 2 recurrences 1.2 0.5–3 0.6

Previous 3 recurrences 2.4 1.1–6.7 0.04

More than 3 recurrences 3.5 1.6–8.7 0.003

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addition to the radiation exposure and its side effects. 
Stenberg et al. reported more than 3 thousand routine 
imaging scans were conducted for an overall efficiency 
of 0.49%. In our series, more than 4 thousand were 
performed to detect UTUC in 59 patients (4000/59 = 
68), only 17 of whom were asymptomatic (4000/17 = 235)
[5]. Therefore, 235 patients were exposed to imaging in 
order to diagnose 1 asymptomatic patient. Most of the 
comments in the literature recommend imaging for 
symptomatic patients, those with abnormal cytology, or 
those with new urinary tract obstruction.

Urine cy tolog y can be taken through regular 
surveillance by outpatient cystoscopy. It would be 
considered an excellent way to monitor the urothelium, 
and unexplained positive for high grade cells should 
warrant imaging of the UT. Instead of routine imaging, 
Sternberg et al. recommended a combination of history 
and urine cytology with lower side effects[6]. Holmang 
et al. and others recommended routine imaging in the 
case of tumor progression[17,19].

We agree that patients could be more stratified to 
detect those in whom the benefits of routine imaging 
with contrast would outweigh the risks. In the 17 
asymptomatic patients who developed UTUC in our 
series, 9 had 2 or more intravesical recurrences, while 
the remaining 8 presented with silent hydronephrosis. 
Patients with recurrent bladder tumors may require 
routine ultrasonography surveillance for the upper 
tract, while those having 3 or more recurrences require 
a stricter follow-up. These data require more validation 
with prospective studies.

The treatment of recurrent UTUC, post management 
of NMIBC, follows the same standards as primary 
U TUC . Nephrou reterec tomy, whet her open or 
laparoscopic and with excision of the bladder cuff, was 
the primary surgical modality in our series. However, 
distal ureterectomy and ureterovesical reimplantation 
was performed in select patients with localized tumor 
and no other upper urothelial foci of cancers.

The conventional 3-tiered WHO grading system was 
used in our series. There is still limited data regarding 

intraobserver and interobserver variability differences 
between the WHO 1973 and 2004 classification systems. 
The European Association of Urolog y currently 
recommends reporting both WHO 1973 and WHO 
2004/2016 classifications[20].

We preferred spinal over general anesthesia for many 
reasons: the procedure is brief, and the patient is awake 
and can describe any abdominal pain for early detection 
of bladder perforation.

A limitation of our study is its retrospective nature; 
however, with the low incidence of secondary UTUC, 
it is difficult to conduct prospective studies. Also, it has 
been reported that peripheral blood levels of neutrophil 
to lymphocyte ratio are associated with an increased risk 
of disease recurrence in patients who have undergone 
TURBT for NMIBC[21]. Our data lacked information 
on white blood cell count. Also, we did not include the 
time of recurrence of the UTUC in BCG unresponsive 
and refractory populations because the dates of this 
group were absent for many patients and could not be 
retrieved. Despite these limitations, our study included a 
large HR-NMIBC cohort of patients who were treated at 
a single tertiary urology institute.

Conclusion

UTUC post management of high-risk NMIBC is 
uncommon (4%). UTUC was discovered on routine 
follow-up CT in 28% of patients; all others were 
symptomatic. Imaging surveillance should be performed 
in patients with multiple bladder tumors and those with 
3 or more bladder tumor recurrences. For the other 
patients, the benefits of imaging surveillance have to be 
weighed against the risks. The optimum protocol and 
frequency for upper tract imaging is to be determined by 
future prospective studies.

Author Contributions

Ebra him Elsaeed Abouelenein: data col lect ion;  
Mohamed Elawdy: project development, data analysis; 
Diaa-Eldin Taha: data collection; Yasser Osman: 
manuscript writing; Bedeir Ali-El Dein: manuscript 
reviewing; Ahmed Mosbah: manuscript reviewing.

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157SIUJ.ORG SIUJ  •  Volume 2, Number 3  •  May 2021

Incidence and Predictors of Secondary Upper Tract Urothelial Cancer

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