TUMOR BUDDING IN COLORECTAL CANCER
CLINICAL APPROACH
Prof. A. Lugli, MD
Division of Clinical Pathology
University of Bern
Symposium de Gastroentérologie – Aurigen
Lausanne, April 10th 2014
CONTENT
BIOLOGY OF TUMOR BUDDING
PROGNOSTIC AND PREDICTIVE IMPACT
SURGICAL PATHOLOGY OF TUMOR BUDDING
CONCLUSION
THE IMPORTANCE OF
TUMOR MICROENVIRONMENT
Hanahan and Weinberg, Cell 2011
THE TUMOR MICROENVIRONMENT
Hanahan and Weinberg. Cell 2011
TUMOR BUDS
Definition
Single tumor cells or cluster up to
5 tumor cells at the invasive
margin
EMT like cells
Transformation to a motile and
invasive phenotype
Low proliferation
Potentially malignant stem cells
TUMOR BUDS
Phenotype
MUC1
p16
b-Cat
E-Cad
TUMOR BUDS
Low proliferation
Dawson et al, Histopathology 2014
TUMOR BUDS
Stem cell character ?
Hostettler et al, WJG 2010
TUMOR BUDS‘ CREED
CRC‘s special force
Detachment
Stroma migration
Loss of E-Cadherin
MMP-2, MMP-9
Activated wnt
Angiogenesis & vessel
affinity
Nuclear b-Catenin
VEGF, CXC3&4
Low proliferation
Stem cell like
Loss of Ki-67
CD133, ABCG5
Zlobec & Lugli, Oncotarget 2010
Zlobec & Lugli. Oncotarget 2010
CONTENT
BIOLOGY OF TUMOR BUDDING
PROGNOSTIC AND PREDICTIVE IMPACT
SURGICAL PATHOLOGY OF TUMOR BUDDING
CONCLUSION
TUMOR BUDDING AND PROGNOSIS
A marker of tumor progression
Lymph node metastasis
Ueno et al. Gastroenterology 2004
Kazama et al. Br J Cancer 2006
Distant metastasis
Nakamura et al. DCR 2008
Prall et al. Histopathology 2005
Lymphovascular invasion
Lugli et al. Br J Cancer 2009
Ishikawa et al. Cancer 2008
Local recurrence
Tanaka et al. DCR 2003
Guzinska-Ustimowicz. AntiC Research 2005
TUMOR BUDDING AND PROGNOSIS
Independent of the applied scoring system
Authors
Journal
Sample Size
CRC Stage
Prognostic factor
Cancer 1989
112
I - IV
Yes
Hase et al.
Dis C&R 1993
663
I - IV
Yes
Ueno et al.
Histopathology 2002
638
I - IV
Yes
Ueno et al.
Cancer
437
I - IV
Yes
Jass et al.
J Clin Pathol 2003
80
I - IV
Yes
Okuyama et al.
J Surg Oncol 2003
83
II / III
Yes
Okuyama et al.
Dis C&R 2003
196
II / III
Yes
Park et al.
Dis C&R 2005
174
I - IV
Yes
Prall et al.
Histopathology 2005
186
I / II
Yes
Hörkkö et al.
Eur J Cancer 2006
466
I - IV
Yes
Shinto et al.
Dis C&R 2006
136
II / III
Yes
Masaki et al.
J Gastro & Hepatol 2006
76
I
Yes
Choi et al.
Int J Colorectal Dis 2007
244
III
Yes
Konazawa et al.
Colorect Diss 2008
159
I - IV
Yes
Nakamura et al.
Dis C&R 2008
200
II
Yes
Anticancer Res 2008
149
I - IV
Yes
Wang et al.
Am J Surg Pathol 2009
126
II
Yes
Lugli et al.
Br J Cancer 2010
470
I - IV
Yes
Dis C&R 2010
477
III
No
Morodomi et al.
Ohtsuki et al.
Sy et al.
TUMOR BUDDING AND PROGNOSIS
UICC Classification
Prognostic Factor
Tumor-related
Host-related
Environment related
Essential
T category
N category
M category
Venous/lymphatic invasion
Obstruction
Quality of surgery
Quality of TME (rectal cancer)
Additional
Grade, tumor budding, border
configuration, perineural invasion,
medullary type, CEA, perforation
Thrombocytosis
Diabetes mellitus
Number of lymph nodes in
resection specimen
New and promising
MSI
LOH 18q status
P53
DNA ploidy
TGFbeta1 type II
Thymidylate synthase polymorphism
VEGF expression
20q copy number, Karyotype
Proliferation rate, Metalloproteinase
expression, Gene expression profiles
Compton C. Prognostic Factors in colorectal cancer edited by Gospodarowicz, O’Sullivan and Sobin, 3 rd edition, 2006
TUMOR BUDDING AND PROGNOSIS
WHO Classification
PREDICTIVE VALUE OF TUMOR BUDDING
Anti-EGFR therapy
Zlobec et al, WJG 2010
CONTENT
BIOLOGY OF TUMOR BUDDING
PROGNOSTIC AND PREDICTIVE IMPACT
SURGICAL PATHOLOGY OF TUMOR BUDDING
CONCLUSION
TUMOR BUDDING
Scoring system
10 HPF Method
Horcic et al, Hum Pathol 2011
TUMOR BUDDING
10 HPF Method
Horcic et al, Hum Pathol 2011
TUMOR BUDDING
Validation of the 10 HPF Method
Karamitopoulou et al, Mod Pathol 2012
ITB AND PTB
pT1 CRC
Ueno et al, Gastroenterology 2004
PERITUMORAL BUDDING (PTB)
Resections – Stage II CRC
n = 128
T3N0M0
Wang et al, Am J Surg Pathol 2009
INTRATUMORAL BUDDING (ITB)
2 independent cohorts: n=289 and 222
Concept:
Intratumoural Budding (ITB) + Peritumoural Budding PTB) = Overall
Tumour Budding (OTB)
Lugli et al, Human Pathol 2011
INTRATUMORAL BUDDING (ITB)
1 HPF Method
Zlobec et al, BJC 2013
INTRATUMORAL BUDDING (ITB)
Preoperative biopsies
CONTENT
BIOLOGY OF TUMOR BUDDING
PROGNOSTIC AND PREDICTIVE IMPACT
SURGICAL PATHOLOGY OF TUMOR BUDDING
CONCLUSION
POINTS TO CONSIDER
Tumor budding is an independent adverese prognostic factor
ITB has to be distinguished from PTB
A standardized scoring system is important, but not mandatory
The fields of action may include stage II CRC, pT1 CRC and
preoperative biopsies
THANK YOU FOR YOUR ATTENTION !