










































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.

Key Words Competing Interests Article Information

Bladder cancer, histological variants, lymph 
node dissection, lymph node metastasis

None declared. Received on April 18, 2021 
Accepted on July 4, 2021

Soc Int Urol J.2021;2(5):282–298

DOI: 10.48083/DHHV3158

282 SIUJ  •  Volume 2, Number 5  •  September 2021 SIUJ.ORG

ORIGINAL RESEARCH

Dissecting Patterns of Care in Patients  
With Variant Histology of Bladder Cancer  
and Lymph Node Invasion
Marco Bandini,1* Filippo Pederzoli,1* Andrea Necchi,2 Roger Li,3 Roberta Lucianò,4 Giuseppe Basile,1 
Simone Scuderi,1 Riccardo Leni,1 Alberto Briganti,1 Andrea Salonia,1 Francesco Montorsi,1  
Andrea Gallina,1 Philippe E. Spiess3

1 Unit of Urology, Urological Research Institute (URI), San Raffaele Hospital, Vita-Salute San Raffaele University, Milan, Italy 2 Unit of Oncology, San Raffaele Hospital, 
Vita-Salute San Raffaele University, Milan, Italy 3 Moffitt Cancer Center and Research Institute, Tampa, United States 4 Department of Pathology, IRCCS Ospedale  
San Raffaele, Milan, Italy * Marco Bandini and Filippo Pederzoli equally contributed to the manuscript.

Abstract

Objectives Lymph node invasion (LNI) is related to long-term survival in patients with muscle-invasive bladder 
cancer. However, in the case of variant histology (VH), data on pelvic lymph node dissection (PLND) and LNI are 
sparse. We described the pattern of care of PLND in patients with VHs of bladder cancer, exploring predictors of LNI.

Methods Using the 2001–2016 SEER registry, 20 767 bladder cancer patients who underwent PLND were identified. 
Included histological variants were pure urothelial carcinoma (UC), micropapillary UC, sarcomatoid UC, 
lymphoepithelioma-like UC, adenocarcinoma, sarcoma, giant and spindle cell carcinoma, squamous cell carcinoma 
(SCC), and neuroendocrine tumor. Uni- and multivariable logistic regression analyses tested for LNI predictors. 
Cox regression was used to test for predictors of overall mortality (OM) among both LNI positive and LNI negative 
patients.

Results Overall, 2464 (11.9%) harbored a VH. On multivariate analysis, only micropapillary UC was associated 
with higher risk (OR = 3.39) of LNI. This association was maintained when only the subset of patients treated without 
perioperative chemotherapy were analyzed (OR = 3.30). Similarly, higher T stage (T2 stage OR = 2.24; T3–4 stage 
OR = 9.44) and the use of chemotherapy (OR = 2.29) were associated with a higher risk of LNI. Among patients with 
LNI (5299, 25.5%), SCC (HR = 1.87), T3–4 stage (HR = 1.94), age at diagnosis (HR = 1.01) and geographic region 
(south) (HR = 1.22) were predictors of higher risk of OM. Conversely, chemotherapy (HR = 0.69) and number of 
removed LN (HR = −0.99) were associated with lower risk of OM. Finally, in a subgroup of patients without LNI, 
sarcomatoid UC (HR = 1.58) and giant and spindle cell carcinoma (HR = 1.83) were the only VH predictors of OM.

Conclusions We described different patterns of care in patients with VHs of bladder cancer. Micropapillary UC was 
an independent risk factor for LNI. Among patients harboring LNI, those with SCC VH had higher OM compared 
to pure UC. Conversely, sarcomatoid UC and giant and spindle cell carcinoma were predictors of OM in patients 
without nodal involvement.

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Introduction

Lymph node metastases may occur in up to one fourth 
of patients with muscle-invasive urothelial cancer 
of the bladder (MIBC)[1], and their presence is an 
important indicator of long-term survival and cancer 
recurrence[2–4]. Therefore, radical cystectomy with 
pelvic lymph node dissection (PLND) is the standard 
treatment for MIBC[5,6].

While general agreement exists with respect to pure 
urothelial carcinoma, fragmentary evidence suggests 
caution in generalizing these findings to all the other 
histological variants of urothelial carcinoma and non-
urothelial histology[7–11]. Histological variants are 
present in up to 25% of cystectomy specimens, and 
they have been traditionally associated with aggressive 
behavior[12–14]. Here, paucity of data about the use and 
the role of the PLND and the prevalence of lymph node 
metastases in these histological subtypes makes it difficult 
to determine a standard of care.

Given the lack of consensus, the European Association 
of Urology (EAU) partnered with the European Society of 
Medical Oncology (ESMO) and provided recommendations 
to guide specialists in this setting[7]. However, novel 
studies must address several gaps in the management of 
variant histology bladder cancer, including the different 
patterns of lymph node involvement according to the 
specific histology.

Using a population-based registry, we provided a 
description of the PLND patterns and the prevalence of 
lymph node invasion (LNI) in bladder cancer of urothelial 
and variant histology. Additionally, we explored potential 
predictors of lymph node metastasis.

Materials and Methods
Study Population
Within the Surveillance, Epidemiology, and End Results 
(SEER) database (2001–2016)[15], we selected patients 
aged 18 years or older with histologically confirmed 
bladder cancer (International Classification of Disease 
for Oncology [ICD-O] site codes C670-679), excluding 

patients with urachal tumors (ICD-O site code C677) 
(Supplementary Figure 1; available at siuj.org). For the 
purpose of our analysis, we focused on patients with 
bladder cancer and non-systemic metastasis (T0-4N0-3) 
who underwent any form of treatment to the primary 
tumor, as well as PLND, and who harbored the following 
primary bladder histological variants (Supplementary 
Table 1; available at siuj.org): urothelial carcinoma 
(UC), micropapillary UC, lymphoepithelioma-like 
UC, sarcomatoid UC, adenocarcinoma, squamous cell 
carcinoma (SCC), giant and spindle cell carcinoma, 
neuroendocrine tumor and sarcoma[16]. These selection 
criteria yielded an initial study population of 20767 
patients.

Variables Definition
The variables considered included variant histology 
together with the presence of LNI. Study covariates 
included age at the time of bladder cancer diagnosis, 
sex, race (White, Black, Hispanic, Asian, and other), 
marital status (married, never married, previously 
married, unk nown), geographica l region (West, 
Midwest, North-East, South), socioeconomic status 
(high versus low), administration of perioperative 
chemotherapy (either neoadjuvant or adjuvant), local 
treatment modality (radical cystectomy [RC], partial 
cystectomy, transurethral resection of the bladder 
[TURB] only, radiotherapy, trimodal therapy [TMT], no 
local treatment, other/unknown), T stage (T0/x, T<2, T2, 
T3–4), tumor grade (G1–4, unknown), number of lymph 
nodes removed (NNR), number of positive lymph nodes 
(NPN), and lymph node density (LN density).

Statistical Analysis
Descript ive stat ist ics i ncludes f requencies a nd 
proportions for categorical variables. Means, medians, 
and ranges were reported for continuously coded 
variables. Chi-square was used to test the statistical 
significance in proportions’ differences. The t test and 
Kruskal-Wallis test examined the statistical significance 
of differences in means and medians[17]. Univariable 
and multivariable logistic regression analyses were 
used to test for predictors of LNI among patients who 
received PLND among several covariates. Sub-analyses 
focused on patients treated with RC. Univariable and 
multivariable Cox regression analyses were used to test 
for predictors of overall mortality (OM) among patients 
with LNI. Moreover, we performed sensitivity analyses 
focusing on patients who did not receive perioperative 
chemotherapy to mitigate the possible effect of either 
neoadjuvant or adjuvant chemotherapy treatments on 
both LNI and OM prediction. Finally, univariable and 
multivariable Cox regression analyses were also used 
to test for predictors of OM among patients without 
nodal disease (N0). P-values were adjusted using the 
conservative Bonferroni correction method, which 

283SIUJ.ORG SIUJ  •  Volume 2, Number 5  • September 2021

Dissecting Patterns of Care in Patients With Variant Histology of Bladder Cancer and Lymph Node Invasion

Abbreviations 
LNI lymph node invasion
MIBC muscle-invasive urothelial cancer
OM overall mortality
PLND pelvic lymph node dissection
SCC squamous cell carcinoma
SEER Surveillance, Epidemiology, and End Results
TURB transurethral resection of the bladder
UC urothelial carcinoma

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multiplies the raw P-values by the number of tests. For 
all statistical analyses, R software environment (version 
3.6.1) was used. All tests were 2-sided with a level of 
significance set at P < 0.05.

Results
Overall descriptive characteristics
Overall, we identified 20 767 patients diagnosed with 
bladder cancer between 2001 and 2016 who underwent 
PLND (Table 1). Among them, 18 303 (88.1%) patients 
had UC, 889 (4.3%) SCC, 592 (2.9%) adenocarcinoma, 
382 (1.8%) neu roendocr i ne t u mor, 283 (1.4%) 
sarcomatoid UC, 177 (0.9%) micropapillary UC, 85 
(0.4%) giant and spindle cell carcinoma, 38 (0.2%) 
lymphoepithelioma-like UC and 18 (< 0.1%) sarcoma. 
The vast majority of patients were diagnosed with T ≥ 
2 disease (17 843, 85.9%), without major differences 
across the histologic subtypes. RC represented the 
main primary treatment in all groups. Among non-RC 
primary treatments, a high percentage (132, 22.3%) of 
partial cystectomies was performed in adenocarcinoma 
patients (Figure 1). Perioperative chemotherapy was  
evenly administered in t he dif ferent histologic 
subty pes, with patients with lymphoepithelioma-
like UC (25, 65.8%), neuroendocrine tumor (250, 
65.4%) and micropapillary UC (91, 51.4%) being most 
frequently treated with chemotherapy. The median 
number of removed lymph nodes ranged from 11 to 
19 in all the study groups (Figure 2): patients with 
lymphoepithelioma-like UC had the highest number of 
lymph nodes removed (median 19, interquartile range 
[IQR]: 7–26), while patients with giant and spindle cell 
carcinoma had the lowest (11, 5–19).

LNI Cohort
In the study population, LNI was reported in 5299 (25.5%) 
patients (Supplementary Table 2; available at siuj.org), 
specifically 88 (49.7%) micropapillary UC, 117 (30.6%) 
neuroendocrine tumor, 175 (29.6%) adenocarcinoma, 
11 (28.9%) lymphoepithelioma-like UC, 72 (25.4%) 
sarcomatoid UC, 4596 (25.1%) UC, 220 (24.7%) SCC, 
17 (20.0%) giant and spindle cell carcinoma, 3 (16.7%) 
sarcoma. Patients with LNI had a higher stage disease 
(T3–4 stage 77.0% versus 41.6%; P < 0.001) and were 
more frequently treated with chemotherapy (55.1% versus 
32.9%; P < 0.001) than patients without malignant nodal 
involvement (Table  2). Among different histological 
variants, UC (3.1%) and micropapillary UC (3.4%) 
presented the highest rates of LNI in non-muscle-
invasive disease. Compared with UC (19.9%), all the 
other histological variants had lower rates of LNI in T2 
disease, with the exception of micropapillary UC, which 
presented higher (27.3%) rates of LNI (Supplementary 
Table 2; available at siuj.org). At multivariate logistic 

regression analysis (Table 3), only micropapillary UC 
was associated with a higher risk (OR [95%CI] = 3.39 
[2.43–4.74]; P < 0.001, Bonferroni adjusted P < 0.001) of 
LNI among the histological variants. Similarly, higher 
T stage (T2 stage OR [95%CI] = 2.24 [1.88–2.69], 
P  <  0.001, Bonferroni adjusted P < 0.001; T3–4 stage 
OR [95%CI]  =  9.44 [7.98–11.2], P < 0.001, Bonferroni 
adjusted P < 0.001), and the use of chemotherapy (OR 
[95%CI]  =  2.29 [2.13–2.46]; P < 0.001, Bonferroni 
adjusted P < 0.001) were associated with a higher risk of 
LNI. Analyses restricted to the population who received 
RC are shown in Supplementary Table 3 (available at siuj.
org).

Sensitivity analysis of LNI among patients without 
perioperative chemotherapy treatment
Overall, 12 761 (61.4%) patients did not receive either 
neoadjuvant or adjuvant chemotherapy. Particularly,  
11 187 (87.7%) patients had UC, 683 (5.4%) SCC, 402 (3.2%) 
adenocarcinoma, 132 (1.0%) neuroendocrine tumor, 182 
(1.4%) sarcomatoid UC, 86 (0.7%) micropapillary UC, 
63 (0.5%) giant and spindle cell carcinoma, 13 (0.1%) 
lymphoepithelioma-like UC and 13 (0.1%) sarcoma, 
as shown in Supplementary Table  4 (available at siuj.org). 
Among these, LNI was reported in 2380 (18.6%) 
patients (Supplementary Table 5; available at siuj.org). At 
multivariate logistic regression analysis (Supplementary 
Table 6; available at siuj.org), both micropapillary UC 
(OR [95%CI] = 3.30 [2.01–5.37]; P < 0.001, Bonferroni 
adjusted P < 0.001) and higher T stage (T2 stage OR 
[95%CI] = 3.31 [2.54–4.37]; P  <  0.001, Bonferroni 
adjusted P < 0.001; T3–4 stage OR [95%CI] = 15.39 
[12–20.1]; P < 0.001, Bonferroni adjusted P < 0.001) were 
confirmed to be associated with a higher risk of LNI.

Overall Mortality Data
When considering patients with LNI, median OM rate 
was 24 months (IQR 23–25) with a median follow-up of  
22 months (IQR 9–42.7) regardless of histology variant. 
OM rates according to variant histology in patients with 
LNI is reported in Supplementary Table 7 (available at  
siuj.org). Among patients with LNI (Table 4), predictors of 
higher risk of OM were SCC (hazard ratio, HR [95%CI] = 
1.87 [1.56–2.24]; P < 0.001, Bonferroni adjusted P < 0.001), 
histology, T3–4 stage (HR [95%CI] = 1.94 [1.52–2.47];  
P < 0.001, Bonferroni adjusted P = 0.03), age at diagnosis 
(HR [95%CI] = 1.01 [1.01–1.01]; P < 0.001, Bonferroni 
adjusted P < 0.001), never married (HR [95%CI] = 1.24 
[1.11–1.39]; P < 0.001, Bonferroni adjusted P < 0.001), and 
South Region (HR [95%CI] = 1.22 [1.10–1.35]; P < 0.001, 
Bonferroni adjusted P < 0.001). Conversely, chemotherapy 
(HR [95%CI] = 0.69 [0.64–0.74]; P < 0.001, Bonferroni 
adjusted P < 0.001) and number of removed LN (HR 
[95%CI] = 0.99 [0.99–0.99]; P < 0.001, Bonferroni 
adjusted P = 0.03) were associated with lower risk of OM. 

284 SIUJ  •  Volume 2, Number 5  •  September 2021 SIUJ.ORG

ORIGINAL RESEARCH

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Analyses restricted to the population who received RC 
are shown in Supplementary Table 8 (available at siuj.org).

Sensitivity analysis of overall mortality among 
patients without perioperative chemotherapy 
treatment 
Among patients with LNI and no perioperative 
chemotherapy treatment (n = 2380, Supplementary 
Table 9; available at siuj.org), SCC (HR [95%CI] = 2.06 
[1.64–2.59]; P < 0.001, Bonferroni adjusted P  <  0.001) 
was conf irmed to be the only histolog y variant 
predictor of OM. Moreover, number of removed LN 
(HR [95%CI] = 0.98 [0.98–0.99]; P < 0.001), Bonferroni 
adjusted P < 0.001) was associated with lower risk of OM.

Sensitivity analysis of overall mortality among 
patients without LNI 
When considering patients without lymph node 
invasion (n = 15 468, Supplementary Table 10; available 
at siuj.org), sarcomatoid UC (HR [95%CI] = 1.58 [1.28–
1.94]); P < 0.001, Bonferroni adjusted P = 0.001) and 
giant and spindle cell carcinoma (HR [95%CI]  =  1.83 
[1.29–2.59]; P < 0.001, Bonferroni adjusted P  =  0.026) 
were the only histology variants predictors of OM, 
as compared to the LNI cohort. Conversely, both 
chemotherapy (HR [95%CI] = 0.89 [0.83–0.95]; P < 
0.001, Bonferroni adjusted P = 0.015) and number 
of removed LN (HR [95%CI] = 0.99 [0.99–0.99];  
P < 0.001, Bonferroni adjusted P < 0.001) were confirmed 
to be associated with lower risk of OM.

Discussion 
In this study, we explored the patterns of care associated 
with the diagnosis of a non-pure urothelial carcinoma 
of the bladder in the SEER database. We focused our 
attention on the LNI distribution according to the 
histological diagnosis in PLND patients, eventually 
exploring potential predictors of lymph node metastasis.

In general, histological variants are considered more 
aggressive than pure UC, which requires an aggressive 
therapeutic management even in case of non-muscle-
invasive disease. For instance, the micropapillary, 
plasmacytoid and sarcomatoid variants of urothelial 
carcinoma have a worse prognosis than comparable 
high-grade, pure UC[18–21]. Therefore, the European 
Association of Urology (EAU) guidelines have included 
them in the highest risk group of non-muscle-invasive 
bladder cancer, for which radical cystectomy +/₋ 
neoadjuvant treatments should be considered[19]. Our 
study confirmed the aggressiveness of some variants in 
terms of overall mortality when considering patients 
with LNI, reporting a higher OM risk for SCC among 
all the VHs considered, regardless of perioperative 
chemotherapy treatment. Conversely, among patients 
without LNI, sarcomatoid UC and giant and spindle 

cell carcinoma were associated with higher OM risk. 
Moreover, the survival advantage for bladder cancer 
patients linked to lymphadenectomy at the time of 
radical surgery has been shown by several studies[22], 
including a registr y-based analysis[23], and it is 
supported by the fact that up to 25% of patients with 
organ-confined muscle-invasive bladder cancer have 
metastatic nodal disease[24].

It is still debated whether the presence of histological 
variants affects the incidence of lymph node metastasis, 
potentially affecting progression and survival. Kim et 
al. analyzed the outcomes of a cohort of 132 patients 
with bladder cancer showing squamous differentiation, 
41 with glandular differentiation, and 13 with both 
variants[25]. The presence of differentiations, compared 
with a control cohort of pure UC patients, was associated 
with a higher rate of extravesical disease (pT3-T4 stage 
70% versus 38%; P < 0.001) and lymph node involvement 
(20% versus 15%; P = 0.05), but it did not affect 10-year 
cancer-specific survival (52% versus 51%; P = 0.71). 
Similarly, a long-term analysis of a cohort of 52 patients 
with nested variant reported a positive association 
between the nested variant and the presence of locally 
advanced disease and lymph node metastases[26]. 
Nevertheless, the presence of nested variant did not 
influence either 10-year recurrence-free survival (80% 
versus 83%; P = 0.46) or cancer-specific survival (41% 
versus 46%; P = 0.75), when compared with pure UC 
patients. Another recent cohort study[27] of 525 bladder 
cancer patients treated with open radical cystectomy at 
a single tertiary center reported a histological variant 
in 131 patients (25.0%). Their data suggested that the 
presence of a variant histology was associated with a 
more advanced and biologically aggressive malignancy, 
including a higher frequency of lymphovascular invasion 
and nodal disease at radical cystectomy. Conversely, 
other studies did not find an association between 
histological variants and LNI, as reported by Marks et al. 
in their cohort of 138 patients with nodal metastases[28]. 
A variant histology was present in 96 patients, and 
the presence of variant histology was not associated 
with either the presence of lymph node metastases or 
extranodal extension. In our analysis, we found that the 
presence micropapillary UC was an independent risk 
factor for LNI after multivariate correction, and also 
after accounting for the possible effect of perioperative 
chemotherapy on nodal disease status. Micropapillary 
morphology in solid malignancies is known to have 
a distinct propensity for lymphovascular invasion, 
which can lead to a higher rate of LNI compared with 
the non-micropapillary histological variants[29,30]. 
Therefore, these observations suggest the need for 
further studies involving an accurate analysis of the 
biological, pathological, and clinical factors of the 
urothelial and non-urothelial bladder cancer variants 

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TABLE 1. 

Descriptive characteristics of the overall population of study (n = 20 767) according to  
the different histological subtypes 

Urothelial 
carcinoma 
(n = 18303)

Micropapillary UC 
(n = 177)

Lymphoepithelioma-like UC 
(n = 38)

Sarcomatoid UC 
(n = 283)

Adenocarcinoma  
(n = 592)

Giant and 
spindle-cell 
carcinoma  

(n = 85)

Squamous cell 
carcinoma  

(n = 889)

Neuroendocrine 
tumor 

(n = 382)

Sarcoma
(n = 18)

Age at diagnosis, median (IQR) 68 (61–76) 70 (61–76) 68 (62–75) 69 (61–76) 63 (54–71) 71 (59–77) 68 (58–76) 68 (61–75) 75 (61–78)

Female sex, n (%) 4163 (22.7) 31 (17.5) 9 (23.7) 91 (32.2) 226 (38.2) 27 (31.8) 439 (49.4) 70 (18.3) 6 (33.3)

Race, n (%) 
 White
 Black
 Hispanic
 Asiatic
 Other

15165 (82.8)
1055 (5.8)
1158 (6.3)
828 (4.5)
97 (0.5)

153 (86.4)
5 (2.8)
8 (4.5)
10 (5.6)
1 (0.6)

28 (73.7)
4 (10.5)
2 (5.3)
4 (10.5)

0 (0)

225 (79.5)
20 (7.1)
19 (6.7)
18 (6.4)
1 (0.4)

410 (69.3)
81 (13.7)
59 (10)
36 (6.1)

6 (1)

70 (82.4)
3 (3.5)
8 (9.4)
3 (3.5)
1 (1.2)

707 (79.5)
75 (8.4)
74 (8.3)
26 (2.9)
7 (0.8)

319 (83.5)
15 (3.9)
27 (7.1)
19 (5)
2 (0.5)

14 (77.8)
1 (5.6)
3 (16.7)

0 (0)
0 (0)

Socioeconomic status, n (%)
 High
 Low

9144 (49.9)
9159 (50.1)

86 (48.6)
91 (51.4)

18 (47.4)
20(52.6)

131 (46.3)
152 (53.7)

314 (53)
278 (47)

47 (55.3)
38 (44.7)

442 (49.7)
447 (50.3)

192 (50.3)
190 (49.7)

12 (66.7)
6 (33.3)

Region, n (%)
 West
 Midwest
 North-East
 South

9927 (54.2)
2104 (11.5)
3146 (17.2)
3126 (17.1)

84 (47.5)
30 (16.9)

16 (9)
47 (26.6)

24 (63.2)
3 (7.9)

5 (13.2)
6 (15.8)

129 (45.6)
45 (15.9)
48 (17)

61 (21.6)

327 (55.2)
47 (7.9)

112 (18.9)
106 (17.9)

46 (54.1)
6 (7.1)

19 (22.4)
14 (16.5)

463 (52.1)
103 (11.6)
155 (17.4)
168 (18.9)

204 (53.4)
38 (9.9)
74 (19.4)
66 (17.3)

13 (72.2)
0 (0)

3 (16.7)
2 (11.1)

Marital status, n (%)
 Married
  Never married
  Previously married
 Unknown

11771 (64.3)
2005 (11)

3870 (21.1)
657 (3.6)

117 (66.1)
17 (9.6)

36 (20.3)
7 (4)

28 (73.7)
6 (15.8)
4 (10.5)

0 (0)

175 (61.8)
27 (9.5)

73 (25.8)
8 (2.8)

345 (58.3)
102 (17.2)
118 (19.9)
27 (4.6)

45 (52.9)
12 (14.1)
24 (28.2)

4 (4.7)

493 (55.5)
124 (13.9)
242 (27.2)
30 (3.4)

260 (68.1)
46 (12)

63 (16.5)
13 (3.4)

12 (66.7)
2 (11.1)
4 (22.2)

0 (0)

Treatment, n (%)
 Radical cystectomy
 Partial cystectomy
 TURB only
 Radiotherapy
 TMT
 No local treatment
 Other/Unknown

16155 (88.3)
796 (4.4)
684 (3.7)

8 (0)
101 (0.6)
37 (0.2)

522 (2.9)

159 (89.8)
7 (4)

3 (1.7)
0 (0)

3 (1.7)
0 (0)

5 (2.8)

33 (86.8)
2 (5.3)
2 (5.3)
0 (0)
0 (0)
0 (0)

1 (2.6)

254 (89.8)
14 (4.9)
3 (1.1)
0 (0)
0 (0)
0 (0)

12 (4.2)

389 (65.7)
132 (22.3)

13 (2.2)
0 (0)

8 (1.4)
3 (0.5)
47 (7.9)

72 (84.7)
5 (5.9)
3 (3.5)
0 (0)

1 (1.2)
0 (0)

4 (4.7)

730 (82.1)
59 (6.6)
20 (2.2)
1 (0.1)
2 (0.2)
8 (0.9)
69 (7.8)

317 (83)
29 (7.6)
11 (2.9)

0 (0)
4 (1)

1 (0.3)
20 (5.2)

16 (88.9)
0 (0)
0 (0)
0 (0)
0 (0)
0 (0)

2 (11.1)

CT: chemotherapy; IQR: interquartile range; LN: lymph node; LNI: lymph node invasion; NNR: number of lymph nodes removed; TMT: trimodal therapy;  
TURB: transurethral resection of the bladder; UC: urothelial carcinoma

continued on page 288

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TABLE 1. 

Descriptive characteristics of the overall population of study (n = 20 767) according to  
the different histological subtypes 

Urothelial 
carcinoma 
(n = 18303)

Micropapillary UC 
(n = 177)

Lymphoepithelioma-like UC 
(n = 38)

Sarcomatoid UC 
(n = 283)

Adenocarcinoma  
(n = 592)

Giant and 
spindle-cell 
carcinoma  

(n = 85)

Squamous cell 
carcinoma  

(n = 889)

Neuroendocrine 
tumor 

(n = 382)

Sarcoma
(n = 18)

Age at diagnosis, median (IQR) 68 (61–76) 70 (61–76) 68 (62–75) 69 (61–76) 63 (54–71) 71 (59–77) 68 (58–76) 68 (61–75) 75 (61–78)

Female sex, n (%) 4163 (22.7) 31 (17.5) 9 (23.7) 91 (32.2) 226 (38.2) 27 (31.8) 439 (49.4) 70 (18.3) 6 (33.3)

Race, n (%) 
 White
 Black
 Hispanic
 Asiatic
 Other

15165 (82.8)
1055 (5.8)
1158 (6.3)
828 (4.5)
97 (0.5)

153 (86.4)
5 (2.8)
8 (4.5)
10 (5.6)
1 (0.6)

28 (73.7)
4 (10.5)
2 (5.3)
4 (10.5)

0 (0)

225 (79.5)
20 (7.1)
19 (6.7)
18 (6.4)
1 (0.4)

410 (69.3)
81 (13.7)
59 (10)
36 (6.1)

6 (1)

70 (82.4)
3 (3.5)
8 (9.4)
3 (3.5)
1 (1.2)

707 (79.5)
75 (8.4)
74 (8.3)
26 (2.9)
7 (0.8)

319 (83.5)
15 (3.9)
27 (7.1)
19 (5)
2 (0.5)

14 (77.8)
1 (5.6)
3 (16.7)

0 (0)
0 (0)

Socioeconomic status, n (%)
 High
 Low

9144 (49.9)
9159 (50.1)

86 (48.6)
91 (51.4)

18 (47.4)
20(52.6)

131 (46.3)
152 (53.7)

314 (53)
278 (47)

47 (55.3)
38 (44.7)

442 (49.7)
447 (50.3)

192 (50.3)
190 (49.7)

12 (66.7)
6 (33.3)

Region, n (%)
 West
 Midwest
 North-East
 South

9927 (54.2)
2104 (11.5)
3146 (17.2)
3126 (17.1)

84 (47.5)
30 (16.9)

16 (9)
47 (26.6)

24 (63.2)
3 (7.9)

5 (13.2)
6 (15.8)

129 (45.6)
45 (15.9)
48 (17)

61 (21.6)

327 (55.2)
47 (7.9)

112 (18.9)
106 (17.9)

46 (54.1)
6 (7.1)

19 (22.4)
14 (16.5)

463 (52.1)
103 (11.6)
155 (17.4)
168 (18.9)

204 (53.4)
38 (9.9)
74 (19.4)
66 (17.3)

13 (72.2)
0 (0)

3 (16.7)
2 (11.1)

Marital status, n (%)
 Married
  Never married
  Previously married
 Unknown

11771 (64.3)
2005 (11)

3870 (21.1)
657 (3.6)

117 (66.1)
17 (9.6)

36 (20.3)
7 (4)

28 (73.7)
6 (15.8)
4 (10.5)

0 (0)

175 (61.8)
27 (9.5)

73 (25.8)
8 (2.8)

345 (58.3)
102 (17.2)
118 (19.9)
27 (4.6)

45 (52.9)
12 (14.1)
24 (28.2)

4 (4.7)

493 (55.5)
124 (13.9)
242 (27.2)
30 (3.4)

260 (68.1)
46 (12)

63 (16.5)
13 (3.4)

12 (66.7)
2 (11.1)
4 (22.2)

0 (0)

Treatment, n (%)
 Radical cystectomy
 Partial cystectomy
 TURB only
 Radiotherapy
 TMT
 No local treatment
 Other/Unknown

16155 (88.3)
796 (4.4)
684 (3.7)

8 (0)
101 (0.6)
37 (0.2)

522 (2.9)

159 (89.8)
7 (4)

3 (1.7)
0 (0)

3 (1.7)
0 (0)

5 (2.8)

33 (86.8)
2 (5.3)
2 (5.3)
0 (0)
0 (0)
0 (0)

1 (2.6)

254 (89.8)
14 (4.9)
3 (1.1)
0 (0)
0 (0)
0 (0)

12 (4.2)

389 (65.7)
132 (22.3)

13 (2.2)
0 (0)

8 (1.4)
3 (0.5)
47 (7.9)

72 (84.7)
5 (5.9)
3 (3.5)
0 (0)

1 (1.2)
0 (0)

4 (4.7)

730 (82.1)
59 (6.6)
20 (2.2)
1 (0.1)
2 (0.2)
8 (0.9)
69 (7.8)

317 (83)
29 (7.6)
11 (2.9)

0 (0)
4 (1)

1 (0.3)
20 (5.2)

16 (88.9)
0 (0)
0 (0)
0 (0)
0 (0)
0 (0)

2 (11.1)

CT: chemotherapy; IQR: interquartile range; LN: lymph node; LNI: lymph node invasion; NNR: number of lymph nodes removed; TMT: trimodal therapy;  
TURB: transurethral resection of the bladder; UC: urothelial carcinoma

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TABLE 1. 

Descriptive characteristics of the overall population of study (n = 20 767) according to  
the different histological subtypes 

Urothelial 
carcinoma 
(n = 18303)

Micropapillary UC 
(n = 177)

Lymphoepithelioma-like UC 
(n = 38)

Sarcomatoid UC 
(n = 283)

Adenocarcinoma  
(n = 592)

Giant and 
spindle-cell 
carcinoma  

(n = 85)

Squamous cell 
carcinoma  

(n = 889)

Neuroendocrine 
tumor 

(n = 382)

Sarcoma
(n = 18)

Perioperative CT, n (%)
 Yes
 No/Unknown

7116 (38.9)
11187 (61.1)

91 (51.4)
86 (48.6)

25 (65.8)
13 (34.2)

101 (35.7)
182 (64.3)

190 (32.1)
402 (67.9)

22 (25.9)
63 (74.1)

206 (23.2)
683 (76.8)

250 (65.4)
132 (34.6)

5 (27.8)
13 (72.2)

T stage, n (%)
 T0/x
 T<2
 T2
 T3–4

110 (0.6)
2563 (14)

6694 (36.6)
8936 (48.8)

0 (0)
23 (13)

64 (36.2)
90 (50.8)

0 (0)
4 (10.5)
12 (31.6)
22 (57.9)

2 (0.7)
25 (8.8)

81 (28.6)
175 (61.8)

6 (1)
76 (12.8)
137 (23.1)
373 (63)

1 (1.2)
4 (4.7)

25 (29.4)
55 (64.7)

17 (1.9)
52 (5.8)

188 (21.1)
632 (71.1)

1 (0.3)
36 (9.4)

129 (33.8)
216 (56.5)

1 (5.6)
3 (16.7)
3 (16.7)
11 (61.1)

Grade, n (%)
 G1
 G2
 G3
 G4
 Gx

114 (0.6)
614 (3.4)

5577 (30.5)
11169 (61)
829 (4.5)

0 (0)
2 (1.1)
39 (22)

127 (71.8)
9 (5.1)

0 (0)
0 (0)

8 (21.1)
26 (68.4)
4 (10.5)

1 (0.4)
3 (1.1)
85 (30)

175 (61.8)
19 (6.7)

21 (3.5)
149 (25.2)
241 (40.7)
115 (19.4)
66 (11.1)

0 (0)
1 (1.2)

22 (25.9)
48 (56.5)
14 (16.5)

58 (6.5)
344 (38.7)
308 (34.6)
136 (15.3)
43 (4.8)

1 (0.3)
3 (0.8)

101 (26.4)
200 (52.4)
77 (20.2)

0 (0)
0 (0)

4 (22.2)
11 (61.1)
3 (16.7)

LNI, n (%) 4596 (25.1) 88 (49.7) 11 (28.9) 72 (25.4) 175 (29.6) 17 (20) 220 (24.7) 117 (30.6) 3 (16.7)

NNR, median (IQR) 12 (6–22) 15 (9–26) 19 (7–26) 13 (6–22) 11 (6–21) 11 (5–19) 11 (6–20) 12 (7–23) 13 (6–23)

LN density, mean 7.8 21 8.9 7.1 11.1 4.7 8.7 9.7 1.5

CT: chemotherapy; IQR: interquartile range; LN: lymph node; LNI: lymph node invasion; NNR: number of lymph nodes removed; TMT: trimodal therapy;  
TURB: transurethral resection of the bladder; UC: urothelial carcinoma

, Cont’d 

to define the best multidisciplinary (surgery, radiation 
therapy, chemotherapy, and innovative treatment 
strategies) approach for each histological subtype, with 
a particular emphasis on immunotherapy and targeted 
therapies[31–34].

It is clear that the time has come to gain a clear, 
ordered and practice-changing knowledge about these 
rare entities. Single- and small multi-institutional 
studies are generally unable to collect enough cases 
belonging to the different subtypes, potentially resulting 
in underpowered findings. Although retrospective 
registry-based analyses have access to greater numbers, 

they are frequently incomplete and suffer from the lack 
of or underreporting of variables that may have had an 
impact on patient outcomes. With respect to bladder 
cancer variants, the lack of centralized pathological 
review of the cases, as well as the possible under 
recognition of rare histological entities outside high-
volume centers, may hamper the generalization of the 
study conclusions. For all these reasons, to further 
advance the knowledge in the field of bladder cancer, 
centralized initiatives are needed to create prospective, 
centralized, multicenter bladder cancer registries, like 
the BRaVeRY (BladdeR Variants RegistrY) protocol 
sponsored by the EAU Research Foundation[35]. With 

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TABLE 1. 

Descriptive characteristics of the overall population of study (n = 20 767) according to  
the different histological subtypes 

Urothelial 
carcinoma 
(n = 18303)

Micropapillary UC 
(n = 177)

Lymphoepithelioma-like UC 
(n = 38)

Sarcomatoid UC 
(n = 283)

Adenocarcinoma  
(n = 592)

Giant and 
spindle-cell 
carcinoma  

(n = 85)

Squamous cell 
carcinoma  

(n = 889)

Neuroendocrine 
tumor 

(n = 382)

Sarcoma
(n = 18)

Perioperative CT, n (%)
 Yes
 No/Unknown

7116 (38.9)
11187 (61.1)

91 (51.4)
86 (48.6)

25 (65.8)
13 (34.2)

101 (35.7)
182 (64.3)

190 (32.1)
402 (67.9)

22 (25.9)
63 (74.1)

206 (23.2)
683 (76.8)

250 (65.4)
132 (34.6)

5 (27.8)
13 (72.2)

T stage, n (%)
 T0/x
 T<2
 T2
 T3–4

110 (0.6)
2563 (14)

6694 (36.6)
8936 (48.8)

0 (0)
23 (13)

64 (36.2)
90 (50.8)

0 (0)
4 (10.5)
12 (31.6)
22 (57.9)

2 (0.7)
25 (8.8)

81 (28.6)
175 (61.8)

6 (1)
76 (12.8)
137 (23.1)
373 (63)

1 (1.2)
4 (4.7)

25 (29.4)
55 (64.7)

17 (1.9)
52 (5.8)

188 (21.1)
632 (71.1)

1 (0.3)
36 (9.4)

129 (33.8)
216 (56.5)

1 (5.6)
3 (16.7)
3 (16.7)
11 (61.1)

Grade, n (%)
 G1
 G2
 G3
 G4
 Gx

114 (0.6)
614 (3.4)

5577 (30.5)
11169 (61)
829 (4.5)

0 (0)
2 (1.1)
39 (22)

127 (71.8)
9 (5.1)

0 (0)
0 (0)

8 (21.1)
26 (68.4)
4 (10.5)

1 (0.4)
3 (1.1)
85 (30)

175 (61.8)
19 (6.7)

21 (3.5)
149 (25.2)
241 (40.7)
115 (19.4)
66 (11.1)

0 (0)
1 (1.2)

22 (25.9)
48 (56.5)
14 (16.5)

58 (6.5)
344 (38.7)
308 (34.6)
136 (15.3)
43 (4.8)

1 (0.3)
3 (0.8)

101 (26.4)
200 (52.4)
77 (20.2)

0 (0)
0 (0)

4 (22.2)
11 (61.1)
3 (16.7)

LNI, n (%) 4596 (25.1) 88 (49.7) 11 (28.9) 72 (25.4) 175 (29.6) 17 (20) 220 (24.7) 117 (30.6) 3 (16.7)

NNR, median (IQR) 12 (6–22) 15 (9–26) 19 (7–26) 13 (6–22) 11 (6–21) 11 (5–19) 11 (6–20) 12 (7–23) 13 (6–23)

LN density, mean 7.8 21 8.9 7.1 11.1 4.7 8.7 9.7 1.5

CT: chemotherapy; IQR: interquartile range; LN: lymph node; LNI: lymph node invasion; NNR: number of lymph nodes removed; TMT: trimodal therapy;  
TURB: transurethral resection of the bladder; UC: urothelial carcinoma

the creation of this multicenter registry, it will be 
possible to capture for the first time the therapeutic and 
surgical management of urothelial-histological variants 
and non-urothelial-histological variants in a real-life 
setting.

Despite its novelty, our study is not devoid of 
limitations. First, the presented retrospective SEER 
data[15] are influenced by inherent selection biases, as 
well as by the lack of variables that may have an impact 
on LNI, such as lymphovascular invasion, treatment 
choice, and patient eligibility for chemotherapy. One 
of the main limitations of our study is related to the 

impossibility of distinguishing between neoadjuvant 
a nd adjuva nt chemot herapy t reat ment. Is wel l 
recognized, neoadjuvant chemotherapy could affect 
lymph node positivity rates, and patients who have 
neoadjuvant chemot herapy genera lly have more 
favorable oncological outcomes than patients who 
do not. As well, neoadjuvant treatments could be 
used differentially between histological variants. 
Nevertheless, micropapillary UC was confirmed to 
be the only histological variant predictor of LNI, even 
when patients who had not received any perioperative 
chemotherapy treatment were considered. Furthermore, 
SCC histology was found to be associated with a higher 

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risk of OM than any of the other VHs considered, 
regardless of perioperative chemotherapy use, probably 
due to the inherent pathobiological behavior of this type 
of VH. Moreover, the SEER database does not allow 
identification of the reason for PLND, and some patients 
may have received PLND for staging purposes or have 
had aborted procedures, which have also been reported 
for prostate cancer[36]. Further, the SEER database does 
not include all the histological variants of bladder cancer 
identified by the 2016 World Health Organization 
classification of tumors of the urinary tract[37]; our 
analysis is therefore limited to the coded entities. The 
SEER database does not provide a central pathological 
review, which may have an impact on the accuracy of 
the reported variants, as bladder cancer variants are 
commonly underrecognized outside tertiary, high-
volume centers[38,39]. Additionally, the SEER database 
does not discriminate between the histologic diagnosis 
at transurethral resection of the bladder tumor and the 
histologic diagnosis at partial or radical cystectomy and 
does not provide a quantitative evaluation of the variant 
component compared with the total tumor volume. 
Finally, the high heterogeneity of local treatments 
considered may have affected the detection rate of 
variant histology included in this study.

Conclusions
We described different patterns of care according to the 
histological variants in bladder cancer using the SEER 
database. In particular, we analyzed the rate at which 
PLND was performed and the prevalence of LNI, as is 

well as the potential predictors of each. We found that 
the presence of micropapillary UC was an independent 
risk factor for LNI after multivariate correction, 
regardless of perioperative chemotherapy treatment. 
Additionally, among patients with LNI, SCC histology 
was associated with higher OM compared with pure 
UC. Our analysis highlights the need for international 
collaborations to advance knowledge with respect to 
urothelial and non-urothelial bladder cancer variants.

FIGURE 1. 

Radar plot showing the main clinical and pathological 
characteristics in the study population according to 
histological variant 

FIGURE 2. 

Violin plot showing the number of removed lymph nodes 
(above) and wave plot (below) showing the lymph node 
density, according to histological variant 

LEL: lymphoepithelioma-like; SCC: squamous cell 
carcinoma; UC: urothelial carcinoma

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TABLE 2. 

Descriptive characteristics according to the lymph node invasion status in the study population (n = 20 767)

Overall 
(n = 20 767)

No LNI 
(n = 15 468)

LNI 
(n = 5299)

P value

Age at diagnosis, median (IQR) 68 (60–76) 69 (61–76) 68 (60–75) < 0.001

Sex, n (%) 
 Male
 Female

15 705 (75.6)
5062 (24.4)

11 844 (76.6)
3624 (23.4)

3861 (72.9)
1438 (27.1)

< 0.001

Race, n(%) 
 White
 Black
 Hispanic
 Asiatic
 Other

17 089 (82.3)
1260 (6.1)
1359 (6.5)
944 (4.5)
115 (0.6)

12 811 (82.8)
873 (5.6)
984 (6.4)
712 (4.6)
88 (0.6)

4278 (80.7)
387 (7.3)
375 (7.1)
232 (4.4)
27 (0.5)

< 0.001

Socioeconomical status, n (%)
 High
 Low

10 385 (50.1)
10 382 (49.9)

7730 (50)
7738 (50)

2655 (50.1)
2644 (49.9)

0.9

Region, n (%)
 West
 Midwest
 North-East
 South

11 217 (54.0)
2376 (11.4)
3578 (17.2)
3596 (17.3)

8363 (54.1)
1804 (11.7)
2674 (17.3)
2627 (17.0)

2854 (53.9)
572 (10.8)
904 (17.1)
969 (18.3)

0.1

Histology, n (%)
 Urothelial carcinoma
 Micropapillary UC
 Lymphoepithelioma-like UC
 Sarcomatoid UC
 Adenocarcinoma
 Giant and spindle cell carcinoma
 Squamous cell carcinoma
 Neuroendocrine tumor
 Sarcoma

18 303 (88.1)
177 (0.9)
38 (0.2)
283 (1.4)
592 (2.9)
85 (0.4)

889 (4.3)
382 (1.8)
18 (0.1)

13 707 (88.6)
89 (0.6)
27 (0.2)
211 (1.4)
417 (2.7)
68 (0.4)

669 (4.3)
265 (1.7)
15 (0.1)

4596 (86.7)
88 (1.7)
11 (0.2)
72 (1.4)

175 (3.3)
17 (0.3)

220 (4.2)
117 (2.2)

3 (0.1)

< 0.001

Marital status, n (%)
 Married
 Never married
 Previously married
 Unknown

13 242 (63.8)
2339 (11.3)
4440 (21.4)

746 (3.6)

9983 (64.5)
1683 (10.9)
3226 (20.9)

576 (3.7)

3259 (61.5)
656 (12.4) 
1214 (22.9)
170 (3.2)

< 0.001

CT: chemotherapy; IQR: interquartile range; LN: lymph node; LNI: lymph node invasion; NNR: number of lymph nodes removed; TMT: trimodal therapy; 
TURB: transurethral resection of the bladder; UC: urothelial carcinoma

continued on page 292

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Dissecting Patterns of Care in Patients With Variant Histology of Bladder Cancer and Lymph Node Invasion

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TABLE 2. 

Descriptive characteristics according to the lymph node invasion status in the study population (n = 20 767)

Overall 
(n = 20 767)

No LNI 
(n = 15 468)

LNI 
(n = 5299)

P value

Treatment, n (%)
 Radical cystectomy
 Partial cystectomy
 TURB only
 Radiotherapy
 TMT
 No local treatment
 Other/Unknown

18 125 (87.3)
1044 (5)
739 (3.6)

9 (0)
119 (0.6)
49 (0.2)

682 (3.3)

13 677 (88.4)
911 (5.9)
473 (3.1)

2 (0)
40 (0.3)
19 (0.1)

346 (2.2)

4448 (83.9)
133 (2.5)
266 (5.0)

7 (0.1)
79 (1.5)
30 (0.6)

336 (6.3)

< 0.001

Perioperative CT, n (%)
 Yes
 No/Unknown

8006 (38.6)
12 761 (61.4)

5087 (32.9)
10381 (67.1)

2919 (55.1)
2380 (44.9)

< 0.001

T stage, n (%)
 T0/x
 T<2
 T2
 T3–4

138 (0.7)
2786 (13.4)
7333 (35.3)
10 510 (50.6)

87 (0.6)
2628 (17.0)
6325 (40.9)
6428 (41.6)

51 (1.0)
158 (3.0)

1008 (19.0)
4082 (77.0)

< 0.001

Grade, n (%)
 G1
 G2
 G3
 G4
 Gx

195 (0.9)
1116 (5.4)

6385 (30.7)
12007 (57.8)

1064 (5.1)

167 (1.1)
936 (6.1)

4579 (29.6)
8949 (57.9)
837 (5.4)

28 (0.5)
180 (3.4)

1806 (34.1)
3058 (57.7)
227 (4.3)

< 0.001

NNR, median (IQR) 12 (6–22) 12 (6–22) 13 (6.5–21) 0.4

Positive LN, median (IQR) 0 (0–1) 0 (0) 2 (1–4) < 0.001

CT: chemotherapy; IQR: interquartile range; LN: lymph node; LNI: lymph node invasion; NNR: number of lymph nodes removed; TMT: trimodal therapy; 
TURB: transurethral resection of the bladder; UC: urothelial carcinoma

, Cont’d

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TABLE 3. 

Univariable and multivariable logistic regression analysis predicting lymph node invasion  
in the overall population (n = 20 767)

Univariate Multivariate

  OR (95%CI)   P value OR (95%CI)   P value AdjustedP value*

Histology
 Urothelial carcinoma
 Micropapillary UC
 Lymphoepithelioma-like UC
 Sarcomatoid UC
 Adenocarcinoma
 Giant and spindle cell carcinoma
 Neuroendocrine tumor
 Squamous cell carcinoma
 Sarcoma

–
2.95 (2.19–3.97)
1.22 (0.58–2.39)
1.02 (0.77–1.33)
1.25 (1.05–1.50)
0.75 (0.42–1.24)
1.32 (1.06–1.64)
0.98 (0.84–1.14)
0.60 (0.14–1.81)

< 0.001
0.6
0.9

0.01
0.3
0.01
0.8
0.4

Reference
3.39 (2.43–4.74)
0.84 (0.38–1.76)
0.89 (0.66–1.18)
1.22 (0.99–1.50)
0.60 (0.33–1.03)
1.04 (0.81–1.32)
0.90 (0.75–1.08)
0.45 (0.10–1.48)

< 0.001
0.7
0.4

0.06
0.07
0.8
0.3
0.2

< 0.001
1
1
1
1
1
1
1

Age at diagnosis (years) 0.99 (0.99–1.00) < 0.001 0.99 (0.99–1.00) 0.04 1

Sex
 Male
 Female

–
1.22 (1.14–1.31) < 0.001

Reference
1.12 (1.03–1.22) 0.006 0.2

Race
 White
 Black
 Hispanic
 Asiatic
 Other

–
1.32 (1.17–1.50)
1.14 (1.01–1.29)
0.98 (0.84–1.13)
0.92 (0.59–1.40)

< 0.001
0.04
0.7
0.7

Reference
1.17 (1.01–1.34)
1.16 (1.01–1.34)
0.98 (0.83–1.16)
0.85 (0.52–1.35)

0.03
0.03
0.8
0.5

1
1
1
1

Socioeconomic status
 Low
 High

–
1.01 (0.94–1.07) 0.9

Reference
0.99 (0.92–1.06) 0.7 1

Region
 West
 Midwest
 North-East
 South

–
0.93 (0.84–1.03)
0.99 (0.91–1.08)
1.08 (0.99–1.18)

0.2
0.8

0.07

Reference
0.84 (0.74–0.94)
0.93 (0.84–1.02)
1.02 (0.92–1.12)

0.003
0.1
0.7

0.1
1
1

Marital status
 Married
 Never married
 Previously married
 Unknown

–
1.19 (1.08–1.32)
1.15 (1.07–1.25)
0.90 (0.76–1.08)

< 0.001
< 0.001

0.3

Reference
1.13 (1.01–1.26)
1.12 (1.03–1.23)
1.04 (0.86–1.26)

0.03
0.008

0.7

1
0.3
1

CI: confidence interval; CT: chemotherapy; OR: odd ratio; NNR: number of lymph nodes removed; UC: urothelial carcinoma
* P values were adjusted using the conservative Bonferroni correction method which multiplies the raw P-values by the number of tests

continued on page 294

293SIUJ.ORG SIUJ  •  Volume 2, Number 5  • September 2021

Dissecting Patterns of Care in Patients With Variant Histology of Bladder Cancer and Lymph Node Invasion

http://SIUJ.org


, Cont’d

TABLE 3. 

Univariable and multivariable logistic regression analysis predicting lymph node invasion  
in the overall population (n = 20 767)

Univariate Multivariate

  OR (95%CI)   P value OR (95%CI)   P value AdjustedP value*

Perioperative CT
 No
 Yes

–
2.50 (2.35–2.67) < 0.001

Reference
2.29 (2.13–2.46) < 0.001 < 0.001

Treatment
 No local treatment
 Radical cystectomy
 Partial cystectomy
 TURB only
 Radiotherapy
 TMT
 Other/Unknown

–
0.21 (0.11–0.36)
0.09 (0.05–0.17)
0.36 (0.19–0.63)
2.21 (0.48–15.9)
1.25 (0.62–2.48)
0.62 (0.33–1.11)

< 0.001
< 0.001
< 0.001

0.4
0.5
0.1

Reference
0.18 (0.09–0.34)
0.09 (0.04–0.18)
0.57 (0.29–1.07)
1.42 (0.27–11.23)
0.76 (0.35–1.61)
0.32 (0.16–0.62)

< 0.001
< 0.001

0.09
0.7
0.5

< 0.001

< 0.001
< 0.001

1
1
1

0.03

T stage
 T < 2
 T2
 T3–4
 T0/x

–
2.65 (2.23–3.16)
10.6 (8.98–12.5)
9.74 (6.63–14.2)

< 0.001
< 0.001
< 0.001

Reference
2.24 (1.88–2.69)
9.44 (7.98–11.2)
6.21 (4.08–9.35)

< 0.001
< 0.001
< 0.001

< 0.001
< 0.001
< 0.001

Grade
 G1
 G2
 G3
 G4
 Gx

–
1.15 (0.76–1.80)
2.35 (1.60–3.60)
2.04 (1.39–3.11)
1.62 (1.07–2.52)

0.5
< 0.001
< 0.001

0.03

Reference
0.78 (0.50–1.27)
1.50 (0.98–2.37)
1.33 (0.87–2.10)
1.16 (0.74–1.87)

0.3
0.07
0.2
0.5

1
1
1
1

NNR 1.00 (0.99–1.00) 0.5 1.00 (0.99–1.00) 0.3 1

CI: confidence interval; CT: chemotherapy; OR: odd ratio; NNR: number of lymph nodes removed; UC: urothelial carcinoma
* P values were adjusted using the conservative Bonferroni correction method which multiplies the raw P-values by the number of tests

294 SIUJ  •  Volume 2, Number 5  •  September 2021 SIUJ.ORG

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TABLE 4. 

Univariable and multivariable Cox regression analyses predicting overall mortality  
among patients with lymph node invasion (n = 5299)  

Univariate Multivariate

  HR (95%CI)  P value HR (95%CI)  P value Adjusted  P value*

Histology
 Urothelial carcinoma
 Micropapillary UC
 Lymphoepithelioma-like UC
 Sarcomatoid UC
 Adenocarcinoma
 Giant and spindle cell carcinoma
 Neuroendocrine tumor
 Squamous cell carcinoma
 Sarcoma

–
0.97 (0.72–1.30)
0.46 (0.11–1.82)
1.55 (1.16–2.08)
1.17 (0.97–1.42)
0.69 (0.29–1.66)
1.33 (1.06–1.68)
2.03 (1.72–2.40)
4.69 (1.17–18.8)

0.84
0.27

< 0.001
0.10
0.40
0.01

< 0.001
0.03

Reference
1.09 (0.81–1.47)
0.47 (0.12–1.87)
1.37 (1.02–1.84)
1.10 (0.90–1.34)
0.67 (0.28–1.60)
1.34 (1.06–1.70)
1.87 (1.56–2.24)
4.84 (1.21–19.4)

0.55
0.28
0.04
0.36
0.36
0.01

< 0.001
0.03

1
1
1
1
1

0.35
< 0.001

1

Age at diagnosis (years) 1.01 (1.01–1.01) <0.001 1.01 (1.01–1.01) < 0.001 < 0.001

Sex
 Male
 Female

–
1.12 (1.04–1.21) < 0.001

Reference
1.04 (0.96–1.13) 0.37 1

Race
 White
 Black
 Hispanic
 Asiatic
 Other

–
1.27 (1.12–1.45)
0.93 (0.81–1.08)
0.97 (0.82–1.15)
1.02 (0.62–1.67)

< 0.001
0.33
0.76
0.94

Reference
1.18 (1.03–1.36)
0.97 (0.84–1.13)
1.04 (0.88–1.24)
1.04 (0.63–1.70)

0.02
0.73
0.65
0.89

0.7
1
1
1

Socioeconomic status
 Low
 High

–
1.01 (0.94–1.08) 0.77

Reference
1.00 (0.93–1.08) 0.96 1

Region
 West
 Midwest
 North-East
 South

–
1.07 (0.95–1.21)
1.15 (1.04–1.27)
1.28 (1.16–1.41)

0.23
< 0.001
< 0.001

Reference
1.10 (0.97–1.25)
1.05 (0.95–1.17)
1.22 (1.10–1.35)

0.12
0.33

< 0.001

1
1

< 0.001

Marital status
 Married
 Never married
 Previously married
 Unknown

–
1.27 (1.14–1.41)
1.21 (1.11–1.32)
0.94 (0.76–1.18)

< 0.001
< 0.001

0.61

Reference
1.24 (1.11–1.39)
1.10 (1.01–1.21)
0.90 (0.71–1.12)

<0.001
0.03
0.34

<0.001
1
1

CI: confidence interval; CT: chemotherapy; HR: hazard ratio; NNR: number of lymph nodes removed; TMT: trimodal therapy;  
TURB: transurethral resection of the bladder; UC: urothelial carcinoma
* P values were adjusted using the conservative Bonferroni correction method which multiplies the raw P-values by the number of tests

continued on page 296

295SIUJ.ORG SIUJ  •  Volume 2, Number 5  • September 2021

Dissecting Patterns of Care in Patients With Variant Histology of Bladder Cancer and Lymph Node Invasion

http://SIUJ.org


TABLE 4. 

Univariable and multivariable Cox regression analyses predicting overall mortality  
among patients with lymph node invasion (n = 5299)  

Univariate Multivariate

  HR (95%CI)  P value HR (95%CI)  P value Adjusted  P value*

Perioperative CT
 No
 Yes

–
0.65 (0.61–0.70) < 0.001

Reference
0.69 (0.64–0.74) < 0.001 < 0.001

Treatment
 No local treatment
 Radical cystectomy
 Partial cystectomy
 TURB only
 Radiotherapy
 TMT
 Other/Unknown

–
0.77 (0.46–1.27)
0.67 (0.38–1.16)
0.92 (0.54–1.56)
3.08 (1.19–7.93)
0.82 (0.46–1.46)
0.94 (0.56–1.59)

0.30 
0.15 
0.76 
0.02 
0.51 
0.82 

Reference
0.83 (0.48–1.45)
0.65 (0.36–1.18)
1.12 (0.63–1.98)
3.82 (1.46–9.98)
1.13 (0.61–2.09)
0.98 (0.55–1.75)

0.51
0.16 
0.70 
0.01 
0.70 
0.96 

1
1
1

0.35
1
1

T stage
T<2
T2
T3–4
T0/x

–
1.05 (0.82–1.35)
1.83 (1.45–2.33)
1.64 (1.04–2.56)

0.70
<0.001

0.03

Reference
1.12 (0.87–1.45)
1.94 (1.52–2.47)
1.32 (0.81–2.15)

0.37
<0.001

0.27

1
0.03

1

Grade
G1
G2
G3
G4
Gx

–
1.36 (0.80–2.29)
1.15 (0.70–1.88)
1.00 (0.61–1.63)
1.08 (0.64–1.81)

0.25
0.59
0.99
0.78

Reference
0.95 (0.56–1.62)
1.05 (0.64–1.72)
0.99 (0.61–1.63)
0.98 (0.58–1.66)

0.86
0.85
0.98
0.94

1
1
1
1

NNR 0.99 (0.99–0.99) <0.001 0.99 (0.99–0.99) <0.001 0.03

CI: confidence interval; CT: chemotherapy; HR: hazard ratio; NNR: number of lymph nodes removed; TMT: trimodal therapy;  
TURB: transurethral resection of the bladder; UC: urothelial carcinoma
* P values were adjusted using the conservative Bonferroni correction method which multiplies the raw P-values by the number of tests

, Cont’d

296 SIUJ  •  Volume 2, Number 5  •  September 2021 SIUJ.ORG

ORIGINAL RESEARCH

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