Skip to main content
Top
Published in: Diagnostic Pathology 1/2018

Open Access 01-12-2018 | Research

Does heterogeneity matter in the estimation of tumour budding and tumour stroma ratio in colon cancer?

Authors: Ann C. Eriksen, Johnnie B. Andersen, Jan Lindebjerg, René dePont Christensen, Torben F. Hansen, Sanne Kjær-Frifeldt, Flemming B. Sørensen

Published in: Diagnostic Pathology | Issue 1/2018

Login to get access

Abstract

Background

Tumour budding (TB) and Tumour Stroma Ratio (TSR) may be rewarding in the treatment stratification of patients with stage II colon cancer. However, lack of standardization may exclude these parameters from being used in a clinical setting. The purpose of this methodologic study was to compare stereology with semi-quantitative estimations of TSR, to investigate the intra-tumoural heterogeneity of TB and TSR, and to assess the intra- and inter-observer agreement.

Methods

Three paraffin embedded tumour blocks, one of them representing the deepest invasive front, were selected from each of 43 patients treated for stage II colon cancer. TSR was estimated in H&E sections semi-quantitatively using conventional microscopy, and stereologically on scanned slides, using the newCAST stereology platform. TB was scored across 10 high power fields at the invasive front in cytokeratin AE1/AE3 stained sections.

Results

Subjective, semi-quantitative estimates of TSR significantly correlated to the stereological estimates, with the best correlation found for sections with the deepest invasive tumour penetration (σ = 0.621, p < 0.001). Inter-observer agreement was moderate to substantial for both TB (Κappa = 0.46–0.73) and TSR (Κappa = 0.70–0.75).
The Intraclass correlation coefficient (ICC) for TSR varied from 0.322 based on stereological hotspot estimation to 0.648 for the semi-quantitative evaluation. For TB, ICC varied from 0.646 based on continuous data to 0.698 based on categorical data (cut-off: 10 buds). Thus, the intra-tumoural heterogeneity for both TB and the semi-quantitative estimation of TSR was low.

Conclusion

We recommend using only one tissue section representing the deepest invasive tumour area for estimation of TSR. For TB we recommend using one tissue section; however due to low representation of high-budding tumours, results must be considered with caution.
Appendix
Available only for authorised users
Literature
2.
go back to reference Morris M, Platell C, de Boer B, McCaul K, Iacopetta B. Population-based study of prognostic factors in stage II colonic cancer. Br J Surg. 2006;93:866–71.CrossRefPubMed Morris M, Platell C, de Boer B, McCaul K, Iacopetta B. Population-based study of prognostic factors in stage II colonic cancer. Br J Surg. 2006;93:866–71.CrossRefPubMed
3.
go back to reference Mesker WE, Junggeburt JM, Szuhai K, de Heer P, Morreau H, Tanke HJ, et al. The carcinoma-stromal ratio of colon carcinoma is an independent factor for survival compared to lymph node status and tumor stage. Cell Oncol. 2007;29:387–98.PubMedPubMedCentral Mesker WE, Junggeburt JM, Szuhai K, de Heer P, Morreau H, Tanke HJ, et al. The carcinoma-stromal ratio of colon carcinoma is an independent factor for survival compared to lymph node status and tumor stage. Cell Oncol. 2007;29:387–98.PubMedPubMedCentral
4.
go back to reference Huijbers A, Tollenaar RA, v Pelt GW, Zeestraten EC, Dutton S, McConkey CC, et al. The proportion of tumor-stroma as a strong prognosticator for stage II and III colon cancer patients: validation in the VICTOR trial. Ann Oncol. 2013;24:179–85.CrossRefPubMed Huijbers A, Tollenaar RA, v Pelt GW, Zeestraten EC, Dutton S, McConkey CC, et al. The proportion of tumor-stroma as a strong prognosticator for stage II and III colon cancer patients: validation in the VICTOR trial. Ann Oncol. 2013;24:179–85.CrossRefPubMed
5.
go back to reference Park JH, Richards CH, McMillan DC, Horgan PG, Roxburgh CS. The relationship between tumour stroma percentage, the tumour microenvironment and survival in patients with primary operable colorectal cancer. Ann Oncol. 2014;25:644–51.CrossRefPubMedPubMedCentral Park JH, Richards CH, McMillan DC, Horgan PG, Roxburgh CS. The relationship between tumour stroma percentage, the tumour microenvironment and survival in patients with primary operable colorectal cancer. Ann Oncol. 2014;25:644–51.CrossRefPubMedPubMedCentral
6.
go back to reference West NP, Dattani M, McShane P, Hutchins G, Grabsch J, Mueller W, et al. The proportion of tumour cells is an independent predictor for survival in colorectal cancer patients. Br J Cancer. 2010;102:1519–23.CrossRefPubMedPubMedCentral West NP, Dattani M, McShane P, Hutchins G, Grabsch J, Mueller W, et al. The proportion of tumour cells is an independent predictor for survival in colorectal cancer patients. Br J Cancer. 2010;102:1519–23.CrossRefPubMedPubMedCentral
7.
go back to reference Hynes SO, Coleman HG, Kelly PJ, Irwin S, O'Neill RF, Gray RT, et al. Back to the future: routine morphological assessment of the tumour microenvironment is prognostic in stage II/III colon cancer in a large population-based study. Histopathology. 2017;71:12–26.CrossRefPubMed Hynes SO, Coleman HG, Kelly PJ, Irwin S, O'Neill RF, Gray RT, et al. Back to the future: routine morphological assessment of the tumour microenvironment is prognostic in stage II/III colon cancer in a large population-based study. Histopathology. 2017;71:12–26.CrossRefPubMed
8.
go back to reference Hutchins GGA, Treanor D, Wright A, Handley K, Magill L, Tinkler-Hundal E, et al. Intra-tumoural stromal morphometry predicts disease recurrence but not response to 5-fluorouracil - results from the QUASAR trial of colorectal cancer. Histopathology. 2017; https://doi.org/10.1111/his.13326. Hutchins GGA, Treanor D, Wright A, Handley K, Magill L, Tinkler-Hundal E, et al. Intra-tumoural stromal morphometry predicts disease recurrence but not response to 5-fluorouracil - results from the QUASAR trial of colorectal cancer. Histopathology. 2017; https://​doi.​org/​10.​1111/​his.​13326.
9.
go back to reference Ueno H, Murphy J, Jass JR, Mochizuki H, Tumour TIC. budding' as an index to estimate the potential of aggressiveness in rectal cancer. Histopathology. 2002;40:127–32.CrossRefPubMed Ueno H, Murphy J, Jass JR, Mochizuki H, Tumour TIC. budding' as an index to estimate the potential of aggressiveness in rectal cancer. Histopathology. 2002;40:127–32.CrossRefPubMed
10.
go back to reference 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.CrossRefPubMed 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.CrossRefPubMed
11.
go back to reference Wang LM, Kevans D, Mulcahy H, O'Sullivan J, Fennelly D, Hyland J, et al. Tumor budding is a strong and reproducible prognostic marker in T3N0 colorectal cancer. Am J Surg Pathol. 2009;33:134–41.CrossRefPubMed Wang LM, Kevans D, Mulcahy H, O'Sullivan J, Fennelly D, Hyland J, et al. Tumor budding is a strong and reproducible prognostic marker in T3N0 colorectal cancer. Am J Surg Pathol. 2009;33:134–41.CrossRefPubMed
12.
go back to reference Horcic M, Koelzer VH, Karamitopoulou E, Terracciano L, Puppa G, Zlobec I, et al. Tumor budding score based on 10 high-power fields is a promising basis for a standardized prognostic scoring system in stage II colorectal cancer. Hum Pathol. 2013;44:697–705.CrossRefPubMed Horcic M, Koelzer VH, Karamitopoulou E, Terracciano L, Puppa G, Zlobec I, et al. Tumor budding score based on 10 high-power fields is a promising basis for a standardized prognostic scoring system in stage II colorectal cancer. Hum Pathol. 2013;44:697–705.CrossRefPubMed
13.
go back to reference Tanaka M, Hashiguchi Y, Ueno H, Hase K, Mochizuki H. Tumor budding at the invasive margin can predict patients at high risk of recurrence after curative surgery for stage II, T3 colon cancer. Dis Colon Rectum. 2003;46:1054–9.CrossRefPubMed Tanaka M, Hashiguchi Y, Ueno H, Hase K, Mochizuki H. Tumor budding at the invasive margin can predict patients at high risk of recurrence after curative surgery for stage II, T3 colon cancer. Dis Colon Rectum. 2003;46:1054–9.CrossRefPubMed
14.
go back to reference Nakamura T, Mitomi H, Kanazawa H, Ohkura Y, Watanabe M. Tumor budding as an index to identify high-risk patients with stage II colon cancer. Dis Colon Rectum. 2008;51:568–72.CrossRefPubMed Nakamura T, Mitomi H, Kanazawa H, Ohkura Y, Watanabe M. Tumor budding as an index to identify high-risk patients with stage II colon cancer. Dis Colon Rectum. 2008;51:568–72.CrossRefPubMed
15.
go back to reference Lai YH, Wu LC, Li PS, Wu WH, Yang SB, Xia P, et al. Tumour budding is a reproducible index for risk stratification of patients with stage II colon cancer. Color Dis. 2014;16:259–64.CrossRef Lai YH, Wu LC, Li PS, Wu WH, Yang SB, Xia P, et al. Tumour budding is a reproducible index for risk stratification of patients with stage II colon cancer. Color Dis. 2014;16:259–64.CrossRef
16.
go back to reference Lugli A, Kirsch R, Ajioka Y, Bosman F, Cathomas G, Dawson H, et al. Recommendations for reporting tumor budding in colorectal cancer based on the international tumor budding consensus conference (ITBCC) 2016. Mod Pathol. 2017;30:1299–311.CrossRefPubMed Lugli A, Kirsch R, Ajioka Y, Bosman F, Cathomas G, Dawson H, et al. Recommendations for reporting tumor budding in colorectal cancer based on the international tumor budding consensus conference (ITBCC) 2016. Mod Pathol. 2017;30:1299–311.CrossRefPubMed
17.
go back to reference Koelzer VH, Zlobec I, Berger MD, Cathomas G, Dawson H, Dirschmid K, et al. Tumor budding in colorectal cancer revisited: results of a multicenter interobserver study. Virchows Arch. 2015;466:485–93.CrossRefPubMed Koelzer VH, Zlobec I, Berger MD, Cathomas G, Dawson H, Dirschmid K, et al. Tumor budding in colorectal cancer revisited: results of a multicenter interobserver study. Virchows Arch. 2015;466:485–93.CrossRefPubMed
18.
go back to reference Karamitopoulou E, Zlobec I, Kolzer V, Kondi-Pafiti A, Patsouris ES, Gennatas K, et al. Proposal for a 10-high-power-fields scoring method for the assessment of tumor budding in colorectal cancer. Mod Pathol. 2013;26:295–301.CrossRefPubMed Karamitopoulou E, Zlobec I, Kolzer V, Kondi-Pafiti A, Patsouris ES, Gennatas K, et al. Proposal for a 10-high-power-fields scoring method for the assessment of tumor budding in colorectal cancer. Mod Pathol. 2013;26:295–301.CrossRefPubMed
19.
go back to reference Jass JR. Classification of colorectal cancer based on correlation of clinical, morphological and molecular features. Histopathology. 2007;50:113–30.CrossRefPubMed Jass JR. Classification of colorectal cancer based on correlation of clinical, morphological and molecular features. Histopathology. 2007;50:113–30.CrossRefPubMed
20.
go back to reference Rehemtulla A. Overcoming intratumor heterogeneity of polygenic cancer drug resistance with improved biomarker integration. Neoplasia. 2012;14:1278–89.CrossRefPubMedPubMedCentral Rehemtulla A. Overcoming intratumor heterogeneity of polygenic cancer drug resistance with improved biomarker integration. Neoplasia. 2012;14:1278–89.CrossRefPubMedPubMedCentral
21.
go back to reference McGraw KO. Forming inferences about some intraclass correlation coefficient. Psychol Methods. 1996;1:30–46.CrossRef McGraw KO. Forming inferences about some intraclass correlation coefficient. Psychol Methods. 1996;1:30–46.CrossRef
22.
go back to reference Svanholm H, Starklint H, Gundersen HJ, Fabricius J, Barlebo H, Olsen S. Reproducibility of histomorphologic diagnoses with special reference to the kappa statistic. APMIS. 1989;97:689–98.CrossRefPubMed Svanholm H, Starklint H, Gundersen HJ, Fabricius J, Barlebo H, Olsen S. Reproducibility of histomorphologic diagnoses with special reference to the kappa statistic. APMIS. 1989;97:689–98.CrossRefPubMed
23.
go back to reference Landis JR, Koch GG. The measurement of observer agreement for categorical data. Biometrics. 1977;33:159–74.CrossRefPubMed Landis JR, Koch GG. The measurement of observer agreement for categorical data. Biometrics. 1977;33:159–74.CrossRefPubMed
24.
go back to reference Mesker WE, Liefers GJ, Junggeburt JM, van Pelt GW, Alberici P, Kuppen PJ, et al. Presence of a high amount of stroma and downregulation of SMAD4 predict for worse survival for stage I-II colon cancer patients. Cell Oncol. 2009;31:169–78.PubMedPubMedCentral Mesker WE, Liefers GJ, Junggeburt JM, van Pelt GW, Alberici P, Kuppen PJ, et al. Presence of a high amount of stroma and downregulation of SMAD4 predict for worse survival for stage I-II colon cancer patients. Cell Oncol. 2009;31:169–78.PubMedPubMedCentral
25.
go back to reference Courrech Staal EF, Smit VT, van Velthuysen ML, Spitzer-Naaykens JM, Wouters MW, Mesker WE, et al. Reproducibility and validation of tumour stroma ratio scoring on oesophageal adenocarcinoma biopsies. Eur J Cancer. 2011;47:375–82.CrossRefPubMed Courrech Staal EF, Smit VT, van Velthuysen ML, Spitzer-Naaykens JM, Wouters MW, Mesker WE, et al. Reproducibility and validation of tumour stroma ratio scoring on oesophageal adenocarcinoma biopsies. Eur J Cancer. 2011;47:375–82.CrossRefPubMed
26.
go back to reference De Smedt L, Palmans S, Sagaert X. Tumour budding in colorectal cancer: what do we know and what can we do? Virchows Arch. 2016;468:397–408.CrossRefPubMed De Smedt L, Palmans S, Sagaert X. Tumour budding in colorectal cancer: what do we know and what can we do? Virchows Arch. 2016;468:397–408.CrossRefPubMed
27.
go back to reference Koelzer VH, Assarzadegan N, Dawson H, Mitrovic B, Grin A, Messenger DE, et al. Cytokeratin-based assessment of tumour budding in colorectal cancer: analysis in stage II patients and prospective diagnostic experience. The journal of pathology. Clin Res. 2017;3:171–8. Koelzer VH, Assarzadegan N, Dawson H, Mitrovic B, Grin A, Messenger DE, et al. Cytokeratin-based assessment of tumour budding in colorectal cancer: analysis in stage II patients and prospective diagnostic experience. The journal of pathology. Clin Res. 2017;3:171–8.
28.
go back to reference Puppa G, Senore C, Sheahan K, Vieth M, Lugli A, Zlobec I, et al. Diagnostic reproducibility of tumour budding in colorectal cancer: a multicentre, multinational study using virtual microscopy. Histopathology. 2012;61:562–75.CrossRefPubMed Puppa G, Senore C, Sheahan K, Vieth M, Lugli A, Zlobec I, et al. Diagnostic reproducibility of tumour budding in colorectal cancer: a multicentre, multinational study using virtual microscopy. Histopathology. 2012;61:562–75.CrossRefPubMed
Metadata
Title
Does heterogeneity matter in the estimation of tumour budding and tumour stroma ratio in colon cancer?
Authors
Ann C. Eriksen
Johnnie B. Andersen
Jan Lindebjerg
René dePont Christensen
Torben F. Hansen
Sanne Kjær-Frifeldt
Flemming B. Sørensen
Publication date
01-12-2018
Publisher
BioMed Central
Published in
Diagnostic Pathology / Issue 1/2018
Electronic ISSN: 1746-1596
DOI
https://doi.org/10.1186/s13000-018-0697-9

Other articles of this Issue 1/2018

Diagnostic Pathology 1/2018 Go to the issue