Background & Objectives: We aimed to evaluate the risk of progression in high-grade T1 (HGT1) tumors using tumor budding (TB) and other standard clinical and histological features. TB is defined as an isolated cancer cell or a cluster composed of fewer than 5 cells scattered in the stroma and is usually used as a strong predictor of lymph node metastasis in T1 colorectal cancer. Methods: This is an observational longitudinal cohort study involving 168 consecutive patients with HGT1 between 2013 and 2016. Cox regression was performed to analyze the relationship between the clinical and histological features and progression. All slides were blindly assessed by 2 genitourinary pathologists. Budding was determined to be positive when the number of buds was equal to or greater than 6. Results: The median age was 75 years; 152 (90.5%) patients were men, and 49 (29.2%) were positive for TB. At a median follow-up time of 35 months, 33 patients (19.6%) showed progression. Progression was observed in 32.7% of the patients positive for TB and in only 14.3% of those who were negative (p = 0.006). TB was significantly associated with the endoscopic tumor pattern (TP) (papillary/solid) and lymphovascular invasion (LVI). Univariate analysis showed that TB, carcinoma in situ (CIS), TP, LVI, sub-staging, and BCG induction predict progression. The multivariate analysis showed that TB (p = 0.032, hazard ratio 2.1), CIS, TP, and lack of BCG induction were significant for progression. Conclusions: TB is a new and significant pathological variable for predicting progression in HGT1 tumors and can be easily introduced in clinical practice. Its inclusion in the TNM system should be carefully considered, as it may aid early cystectomy decisions.

1.
Ferlay
J
,
Steliarova-foucher
E
,
Lortet-tieulent
J
,
Rosso
S
.
Cancer incidence and mortality patterns in Europe : estimates for 40 countries in 2012
.
Eur J Cancer
.
2013
;
49
:
1374
403
.
2.
Van Den Bosch
S
,
Witjes
JA
.
Long-term cancer-specific survival in patients with high-risk, non-muscle-invasive bladder cancer and tumour progression: a systematic review
.
Eur Urol
.
2011
;
160
:
493
500
.
3.
Xylinas
E
,
Kent
M
,
Kluth
L
,
Pycha
A
,
Comploj
E
,
Svatek
RS
,
Accuracy of the EORTC risk tables and of the CUETO scoring model to predict outcomes in non-muscle-invasive urothelial carcinoma of the bladder
.
Br J Cancer
.
2013
;
109
:
1460
6
.
4.
Babjuk
M.
,
Böhle
A.
,
Burger
M.
,
Compérat
E.
,
Kaasinen
E.
,
Palou
J.
,
EAU guidelines on non-muscle-invasive bladder cancer (Ta, T1 and CIS) 2016
.
Eur Assoc Urol
.
2017
;
71
:
447
61
.
5.
Hautmann
RE
,
Volkmer
BG
,
Gust
K
.
Quantification of the survival benefit of early versus deferred cystectomy in high-risk non-muscle invasive bladder cancer (T1 G3)
.
World J Urol
.
2009
;
27
:
347
51
.
6.
Aziz
A
,
May
M
,
Burger
M
,
Palisaar
RJ
,
Trinh
QD
,
Fritsche
HM
,
Prediction of 90-day mortality after radical cystectomy for bladder cancer in a prospective European multicenter cohort
.
Eur Urol
.
2014
;
66
:
156
63
.
7.
Raj
GV
,
Herr
H
,
Serio
AM
,
Donat
SM
,
Bochner
BH
,
Vickers
AJ
,
Treatment paradigm shift may improve survival of patients with high risk superficial bladder cancer
.
J Urol
.
2007
;
177
:
1283
6
.
8.
Orsola
A
,
Werner
L
,
De Torres
I
,
Martin-Doyle
W
,
Raventos
CX
,
Lozano
F
,
Reexamining treatment of high-grade T1 bladder cancer according to depth of lamina propria invasion: a prospective trial of 200 patients
.
Br J Cancer
.
2015
;
112
:
468
74
.
9.
Orsola
A
,
Cecchini
L
,
Raventós
CX
,
Trilla
E
,
Planas
J
,
Landolfi
S
,
Risk factors for positive findings in patients with high-grade T1 bladder cancer treated with transurethral resection of bladder tumour (TUR) and bacille Calmette-Guérin therapy and the decision for a repeat TUR
.
BJU Int
.
2010
;
105
(
2
):
202
7
.
10.
Hase
K
,
Shatney
C
,
Johnson
D
,
Trollope
M
,
Vierra
M
.
Prognostic value of tumor “budding” in patients with colorectal cancer
.
Dis Colon Rectum
.
1993
;
36
:
627
35
.
11.
Grigore
A
,
Jolly
M
,
Jia
D
,
Farach-Carson
M
,
Levine
H
.
Tumor budding: the name is EMT. Partial EMT
.
J Clin Med
.
2016
;
5
:
51
.
12.
Watanabe
T
,
Muro
K
,
Ajioka
Y
,
Hashiguchi
Y
,
Ito
Y
,
Saito
Y
,
Japanese society for cancer of the colon and rectum (JSCCR) guidelines 2016 for the treatment of colorectal cancer
.
Int J Clin Oncol
.
2018
;
23
:
1
34
.
13.
Fukumoto
K
,
Kikuchi
E
,
Mikami
S
,
Ogihara
K
,
Matsumoto
K
,
Miyajima
A
,
Tumor budding, a novel prognostic indicator for predicting stage progression in T1 bladder cancers
.
Cancer Sci
.
2016
;
107
:
1338
44
.
14.
Lorenzo Soriano
L
,
Ordaz Jurado
G
,
Pontones Moreno
JL
,
Villarroya Castillo
S
,
Hernández Girón
S
,
Sáez Moreno
I
,
Tumor budding: prognostic value in muscle-invasive bladder cancer
.
Urology
.
2019
;
130
:
93
8
.
15.
Cottrell
L
,
Nairn
ER
,
Hair
M
.
Consistency of microstaging pT1 bladder transitional cell carcinoma
.
J Clin Pathol
.
2007
;
60
:
735
6
.
16.
Dawson
H
,
Assarzadegan
N
,
Riddell
R
,
Kirsch
R
,
Blank
A
,
Zlobec
I
,
Tumor budding is a strong predictor of disease-free survival in stage II colorectal cancer: validation study based on the International tumor budding consensus conference (ITBCC) recommendations
.
J Clin Oncol
.
2017
;
35
.
17.
Kadota
K
,
Yeh
YC
,
Villena-Vargas
J
,
Cherkassky
L
,
Drill
EN
,
Sima
CS
,
Tumor budding correlates with the protumor immune microenvironment and is an independent prognostic factor for recurrence of stage i lung adenocarcinoma
.
Chest
.
2015
;
148
:
711
21
.
18.
Salhia
B
,
Trippel
M
,
Pfaltz
K
,
Cihoric
N
,
Grogg
A
,
Lädrach
C
,
High tumor budding stratifies breast cancer with metastatic properties
.
Breast Cancer Res Treat
.
2015
;
150
:
363
71
.
19.
O’Connor
K
,
Li-Chang
HH
,
Kalloger
SE
,
Peixoto
RD
,
Webber
DL
,
Owen
DA
,
Tumor budding is an independent adverse prognostic factor in pancreatic ductal adenocarcinoma
.
Am J Surg Pathol
.
2015
;
39
:
472
8
.
20.
Angadi
PV
,
Patil
PV
,
Hallikeri
K
,
Mallapur
MD
,
Hallikerimath
S
,
Kale
AD
.
Tumor budding is an independent prognostic factor for prediction of lymph node metastasis in oral squamous cell carcinoma
.
Int J Surg Pathol
.
2015
;
23
:
102
10
.
21.
Kalluri
R
.
EMT: when epithelial cells decide to become mesenchymal-like cells
.
J Clin Invest
.
2009
;
119
:
1417
9
.
22.
Prall
F
.
Tumour budding in colorectal carcinoma
.
Histopathology
.
2007
;
50
:
151
62
.
23.
Sylvester
RJ
,
Van Der Meijden
APM
,
Oosterlinck
W
,
Witjes
JA
,
Bouffioux
C
,
Denis
L
,
Predicting recurrence and progression in individual patients with stage Ta T1 bladder cancer using EORTC risk tables: a combined analysis of 2596 patients from seven EORTC trials
.
Eur Urol
.
2006
;
49
:
466
5
.
24.
Soukup
V
,
Čapoun
O
,
Cohen
D
,
Hernández
V
,
Burger
M
,
Compérat
E
,
Risk stratification tools and prognostic models in non–muscle-invasive bladder cancer: a critical assessment from the European association of urology non-muscle-invasive bladder cancer guidelines panel
.
Eur Urol Focus
.
2018
;
6
:
479
89
.
25.
Divrik
RT
,
Ahin
AF
,
Yildirim
Ü
,
Altok
M
,
Zorlu
F
.
Impact of routine second transurethral resection on the long-term outcome of patients with newly diagnosed pT1 urothelial carcinoma with respect to recurrence, progression rate, and disease-specific survival: a prospective randomised clinical trial
.
Eur Urol
.
2010
;
58
:
185
90
.
26.
Huguet
J
,
Gaya
JM
,
Sabaté
S
,
Palou
J
,
Villavicencio
H
.
Radical cystectomy in patients with non-muscle invasive bladder cancer who fail BCG therapy
.
Actas Urol Esp
.
2010
;
34
:
63
70
.
27.
Rieger
G
,
Koelzer
VH
,
Dawson
HE
,
Berger
MD
,
Hädrich
M
,
Inderbitzin
D
,
Comprehensive assessment of tumour budding by cytokeratin staining in colorectal cancer
.
Histopathology
.
2017
;
70
:
1044
51
.
28.
Ferlay
J
,
Soerjomataram
I
,
Ervik
M
,
Dikshit
R
,
Eser
S
,
Mathers
C
,
Cancer incidence and mortality worldwide: sources, methods and major patterns in GLOBOCAN 2012
.
Int J Cancer
.
2015 Mar 1
;
136
(
5
):
E359
86
.
29.
Koelzer
VH
,
Zlobec
I
,
Lugli
A
.
Tumor budding in colorectal cancer: ready for diagnostic practice?
Hum Pathol
.
2016
;
47
:
4
19
.
30.
Brieu
N
,
Gavriel
CG
,
Nearchou
IP
,
Harrison
DJ
,
Schmidt
G
,
Caie
PD
.
Automated tumour budding quantification by machine learning augments TNM staging in muscle-invasive bladder cancer prognosis
.
Sci Rep
.
2019
;
9
:
5174
.
Copyright / Drug Dosage / Disclaimer
Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher.
Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.
Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.
You do not currently have access to this content.