The prognostic role of tumor budding and tumor-stroma ratio in pulmonary metastasis of colorectal carcinoma

Topias Karjula; Niko Kemi; Anne Niskakangas; Olli Mustonen; Iiris Puro; Vesa Matti Pohjanen; Teijo Kuopio; Hanna Elomaa; Maarit Ahtiainen; Jukka Pekka Mecklin; Toni T. Seppälä; Erkki Ville Wirta; Eero Sihvo; Juha P. Väyrynen; Fredrik Yannopoulos; Olli Helminen

doi:10.1016/j.ejso.2023.02.009

The prognostic role of tumor budding and tumor-stroma ratio in pulmonary metastasis of colorectal carcinoma

Topias Karjula, Niko Kemi, Anne Niskakangas, Olli Mustonen, Iiris Puro, Vesa Matti Pohjanen, Teijo Kuopio, Hanna Elomaa, Maarit Ahtiainen, Jukka Pekka Mecklin, Toni T. Seppälä, Erkki Ville Wirta, Eero Sihvo, Juha P. Väyrynen, Fredrik Yannopoulos, Olli Helminen

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Abstract

Objective: To evaluate the prognostic value of tumor budding and tumor-stroma ratio (TSR) in resected pulmonary metastases of colorectal carcinoma (CRC). Methods: In total, 106 pulmonary metastasectomies were performed to 74 patients in two study hospitals during 2000–2020. All relevant clinical data were retrospectively collected. Tumor budding based on the International Tumor Budding Consensus Conference recommendations and TSR in the first resected pulmonary metastases and primary tumors were evaluated from diagnostic hematoxylin-eosin-stained histopathological slides. Results: 60 patients (85.7%) had low tumor budding (≤5 buds/field) and 10 patients (14.3%) had high tumor budding (>5 buds/field) in their first pulmonary metastases of CRC. 5-year overall survival rates of pulmonary metastasectomy in low and high total tumor budding were 28.3% and 37.3% (p = 0.387), respectively. 19 patients (27.1%) had low TSR and 51 patients (72.9%) had high TSR. The 5-year overall survival rates were 32.9% in low and 28.6% in high TSR of first pulmonary metastases (p = 0.746). Tumor budding and TSR did not provide prognostic value in Cox multivariate analysis. Tumor budding and TSR in resected pulmonary metastases were not associated with those of the primary tumor. Conclusion: Tumor budding and TSR in the resected pulmonary metastases of CRC showed no statistically significant prognostic value, however, additional well-powered confirmatory studies are needed.

Original language	English
Pages (from-to)	1298-1306
Number of pages	9
Journal	European Journal of Surgical Oncology
Volume	49
Issue number	7
DOIs	https://doi.org/10.1016/j.ejso.2023.02.009
Publication status	Published - 2023
Publication type	A1 Journal article-refereed

Funding

This study was funded by Instrumentarium Science Foundation (O.H), Mary and Georg C. Ehrnrooth Foundation (O.H) and Finnish State Research Funding (O.H, J-P.M), Cancer Foundation Finland (J.P.V), J&A Erkko Foundation (J-P.M). The funding sources had no involvement in the study design, collection of data, analysis and interpretation of the data, in writing the report or submitting decision of the article. Tumor budding has been suggested to represent EMT of malignant tumor cells and the invasive metastatic capacity of the tumor. In the primary CRC tumors, tumor budding has been linked to the lowered expression of cell adhesion molecules, such as E-cadherin [23,24], supporting the linkage between tumor budding and EMT. The prognostic value of tumor budding in primary CRC tumors has been proven in early to metastatic stages of the disease [7,25]. As cancer cells migrate to the peripheral tissues and form metastatic nodules, they are proposed to regain their epithelial characteristics via mesenchymal-epithelial transition (MET) [26,27]. Cancer cells in the metastases express higher levels of cell adhesion molecules compared to the primary tumors [28], however there is also contradictory reports [29]. There is limited research on the prognostic effect of tumor budding in CRC metastases. Several studies have suggested tumor budding in CRC liver metastases having prognostic value in univariate models [11,12,30]. In our study, tumor budding in pulmonary metastases of CRC did not show a survival effect. With the predefined cut-off of 5 buds in a two-tiered classification, TTB and PTB showed no prognostic effect on 5-year overall survival. However, in this analysis, only up to 10 patients had high tumor. In the ROC curve analysis, the areas under curves in TTB, PTB and ITB were 0.647, 0.623 and 0.561, respectively. Using the cut-offs picked from the ROC-curve, TTB and PTB did not provide prognostic value. Also, the reproducibility weakened as the kappa-values with the ROC cut-off values were only 0.21 and 0.362 in TTB and PTB, respectively. Whereas the kappa-values with a cut-off of 5 were 0.696 and 0.697 in TTB and PTB, respectively. The use of median cut-offs also provided no additional prognostic value in the pulmonary metastases.This study was funded by Instrumentarium Science Foundation (O.H), Mary and Georg C. Ehrnrooth Foundation (O.H) and Finnish State Research Funding (O.H, J-P.M), Cancer Foundation Finland (J.P.V), J&A Erkko Foundation (J-P.M). The funding sources had no involvement in the study design, collection of data, analysis and interpretation of the data, in writing the report or submitting decision of the article.

Keywords

Colorectal cancer
Pulmonary metastases
Tumor budding
Tumor-stroma ratio

Publication forum classification

Publication forum level 1

ASJC Scopus subject areas

Surgery
Oncology

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1016/j.ejso.2023.02.009Licence: CC BY

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https://urn.fi/URN:NBN:fi:tuni-202306276926Licence: CC BY

Cite this

Karjula, T., Kemi, N., Niskakangas, A., Mustonen, O., Puro, I., Pohjanen, V. M., Kuopio, T., Elomaa, H., Ahtiainen, M., Mecklin, J. P., Seppälä, T. T., Wirta, E. V., Sihvo, E., Väyrynen, J. P., Yannopoulos, F., & Helminen, O. (2023). The prognostic role of tumor budding and tumor-stroma ratio in pulmonary metastasis of colorectal carcinoma. European Journal of Surgical Oncology, 49(7), 1298-1306. https://doi.org/10.1016/j.ejso.2023.02.009

@article{accb60a4f8964839ba9b45066b79e826,

title = "The prognostic role of tumor budding and tumor-stroma ratio in pulmonary metastasis of colorectal carcinoma",

abstract = "Objective: To evaluate the prognostic value of tumor budding and tumor-stroma ratio (TSR) in resected pulmonary metastases of colorectal carcinoma (CRC). Methods: In total, 106 pulmonary metastasectomies were performed to 74 patients in two study hospitals during 2000–2020. All relevant clinical data were retrospectively collected. Tumor budding based on the International Tumor Budding Consensus Conference recommendations and TSR in the first resected pulmonary metastases and primary tumors were evaluated from diagnostic hematoxylin-eosin-stained histopathological slides. Results: 60 patients (85.7%) had low tumor budding (≤5 buds/field) and 10 patients (14.3%) had high tumor budding (>5 buds/field) in their first pulmonary metastases of CRC. 5-year overall survival rates of pulmonary metastasectomy in low and high total tumor budding were 28.3% and 37.3% (p = 0.387), respectively. 19 patients (27.1%) had low TSR and 51 patients (72.9%) had high TSR. The 5-year overall survival rates were 32.9% in low and 28.6% in high TSR of first pulmonary metastases (p = 0.746). Tumor budding and TSR did not provide prognostic value in Cox multivariate analysis. Tumor budding and TSR in resected pulmonary metastases were not associated with those of the primary tumor. Conclusion: Tumor budding and TSR in the resected pulmonary metastases of CRC showed no statistically significant prognostic value, however, additional well-powered confirmatory studies are needed.",

keywords = "Colorectal cancer, Pulmonary metastases, Tumor budding, Tumor-stroma ratio",

author = "Topias Karjula and Niko Kemi and Anne Niskakangas and Olli Mustonen and Iiris Puro and Pohjanen, {Vesa Matti} and Teijo Kuopio and Hanna Elomaa and Maarit Ahtiainen and Mecklin, {Jukka Pekka} and Sepp{\"a}l{\"a}, {Toni T.} and Wirta, {Erkki Ville} and Eero Sihvo and V{\"a}yrynen, {Juha P.} and Fredrik Yannopoulos and Olli Helminen",

note = "Funding Information: This study was funded by Instrumentarium Science Foundation (O.H), Mary and Georg C. Ehrnrooth Foundation (O.H) and Finnish State Research Funding (O.H, J-P.M), Cancer Foundation Finland (J.P.V), J&A Erkko Foundation (J-P.M). The funding sources had no involvement in the study design, collection of data, analysis and interpretation of the data, in writing the report or submitting decision of the article. Funding Information: Tumor budding has been suggested to represent EMT of malignant tumor cells and the invasive metastatic capacity of the tumor. In the primary CRC tumors, tumor budding has been linked to the lowered expression of cell adhesion molecules, such as E-cadherin [23,24], supporting the linkage between tumor budding and EMT. The prognostic value of tumor budding in primary CRC tumors has been proven in early to metastatic stages of the disease [7,25]. As cancer cells migrate to the peripheral tissues and form metastatic nodules, they are proposed to regain their epithelial characteristics via mesenchymal-epithelial transition (MET) [26,27]. Cancer cells in the metastases express higher levels of cell adhesion molecules compared to the primary tumors [28], however there is also contradictory reports [29]. There is limited research on the prognostic effect of tumor budding in CRC metastases. Several studies have suggested tumor budding in CRC liver metastases having prognostic value in univariate models [11,12,30]. In our study, tumor budding in pulmonary metastases of CRC did not show a survival effect. With the predefined cut-off of 5 buds in a two-tiered classification, TTB and PTB showed no prognostic effect on 5-year overall survival. However, in this analysis, only up to 10 patients had high tumor. In the ROC curve analysis, the areas under curves in TTB, PTB and ITB were 0.647, 0.623 and 0.561, respectively. Using the cut-offs picked from the ROC-curve, TTB and PTB did not provide prognostic value. Also, the reproducibility weakened as the kappa-values with the ROC cut-off values were only 0.21 and 0.362 in TTB and PTB, respectively. Whereas the kappa-values with a cut-off of 5 were 0.696 and 0.697 in TTB and PTB, respectively. The use of median cut-offs also provided no additional prognostic value in the pulmonary metastases.This study was funded by Instrumentarium Science Foundation (O.H), Mary and Georg C. Ehrnrooth Foundation (O.H) and Finnish State Research Funding (O.H, J-P.M), Cancer Foundation Finland (J.P.V), J&A Erkko Foundation (J-P.M). The funding sources had no involvement in the study design, collection of data, analysis and interpretation of the data, in writing the report or submitting decision of the article. Publisher Copyright: {\textcopyright} 2023 The Authors",

year = "2023",

doi = "10.1016/j.ejso.2023.02.009",

language = "English",

volume = "49",

pages = "1298--1306",

number = "7",

}

Karjula, T, Kemi, N, Niskakangas, A, Mustonen, O, Puro, I, Pohjanen, VM, Kuopio, T, Elomaa, H, Ahtiainen, M, Mecklin, JP, Seppälä, TT , Wirta, EV, Sihvo, E, Väyrynen, JP, Yannopoulos, F & Helminen, O 2023, 'The prognostic role of tumor budding and tumor-stroma ratio in pulmonary metastasis of colorectal carcinoma', European Journal of Surgical Oncology, vol. 49, no. 7, pp. 1298-1306. https://doi.org/10.1016/j.ejso.2023.02.009

TY - JOUR

T1 - The prognostic role of tumor budding and tumor-stroma ratio in pulmonary metastasis of colorectal carcinoma

AU - Karjula, Topias

AU - Kemi, Niko

AU - Niskakangas, Anne

AU - Mustonen, Olli

AU - Puro, Iiris

AU - Pohjanen, Vesa Matti

AU - Kuopio, Teijo

AU - Elomaa, Hanna

AU - Ahtiainen, Maarit

AU - Mecklin, Jukka Pekka

AU - Seppälä, Toni T.

AU - Wirta, Erkki Ville

AU - Sihvo, Eero

AU - Väyrynen, Juha P.

AU - Yannopoulos, Fredrik

AU - Helminen, Olli

N1 - Funding Information: This study was funded by Instrumentarium Science Foundation (O.H), Mary and Georg C. Ehrnrooth Foundation (O.H) and Finnish State Research Funding (O.H, J-P.M), Cancer Foundation Finland (J.P.V), J&A Erkko Foundation (J-P.M). The funding sources had no involvement in the study design, collection of data, analysis and interpretation of the data, in writing the report or submitting decision of the article. Funding Information: Tumor budding has been suggested to represent EMT of malignant tumor cells and the invasive metastatic capacity of the tumor. In the primary CRC tumors, tumor budding has been linked to the lowered expression of cell adhesion molecules, such as E-cadherin [23,24], supporting the linkage between tumor budding and EMT. The prognostic value of tumor budding in primary CRC tumors has been proven in early to metastatic stages of the disease [7,25]. As cancer cells migrate to the peripheral tissues and form metastatic nodules, they are proposed to regain their epithelial characteristics via mesenchymal-epithelial transition (MET) [26,27]. Cancer cells in the metastases express higher levels of cell adhesion molecules compared to the primary tumors [28], however there is also contradictory reports [29]. There is limited research on the prognostic effect of tumor budding in CRC metastases. Several studies have suggested tumor budding in CRC liver metastases having prognostic value in univariate models [11,12,30]. In our study, tumor budding in pulmonary metastases of CRC did not show a survival effect. With the predefined cut-off of 5 buds in a two-tiered classification, TTB and PTB showed no prognostic effect on 5-year overall survival. However, in this analysis, only up to 10 patients had high tumor. In the ROC curve analysis, the areas under curves in TTB, PTB and ITB were 0.647, 0.623 and 0.561, respectively. Using the cut-offs picked from the ROC-curve, TTB and PTB did not provide prognostic value. Also, the reproducibility weakened as the kappa-values with the ROC cut-off values were only 0.21 and 0.362 in TTB and PTB, respectively. Whereas the kappa-values with a cut-off of 5 were 0.696 and 0.697 in TTB and PTB, respectively. The use of median cut-offs also provided no additional prognostic value in the pulmonary metastases.This study was funded by Instrumentarium Science Foundation (O.H), Mary and Georg C. Ehrnrooth Foundation (O.H) and Finnish State Research Funding (O.H, J-P.M), Cancer Foundation Finland (J.P.V), J&A Erkko Foundation (J-P.M). The funding sources had no involvement in the study design, collection of data, analysis and interpretation of the data, in writing the report or submitting decision of the article. Publisher Copyright: © 2023 The Authors

PY - 2023

Y1 - 2023

N2 - Objective: To evaluate the prognostic value of tumor budding and tumor-stroma ratio (TSR) in resected pulmonary metastases of colorectal carcinoma (CRC). Methods: In total, 106 pulmonary metastasectomies were performed to 74 patients in two study hospitals during 2000–2020. All relevant clinical data were retrospectively collected. Tumor budding based on the International Tumor Budding Consensus Conference recommendations and TSR in the first resected pulmonary metastases and primary tumors were evaluated from diagnostic hematoxylin-eosin-stained histopathological slides. Results: 60 patients (85.7%) had low tumor budding (≤5 buds/field) and 10 patients (14.3%) had high tumor budding (>5 buds/field) in their first pulmonary metastases of CRC. 5-year overall survival rates of pulmonary metastasectomy in low and high total tumor budding were 28.3% and 37.3% (p = 0.387), respectively. 19 patients (27.1%) had low TSR and 51 patients (72.9%) had high TSR. The 5-year overall survival rates were 32.9% in low and 28.6% in high TSR of first pulmonary metastases (p = 0.746). Tumor budding and TSR did not provide prognostic value in Cox multivariate analysis. Tumor budding and TSR in resected pulmonary metastases were not associated with those of the primary tumor. Conclusion: Tumor budding and TSR in the resected pulmonary metastases of CRC showed no statistically significant prognostic value, however, additional well-powered confirmatory studies are needed.

AB - Objective: To evaluate the prognostic value of tumor budding and tumor-stroma ratio (TSR) in resected pulmonary metastases of colorectal carcinoma (CRC). Methods: In total, 106 pulmonary metastasectomies were performed to 74 patients in two study hospitals during 2000–2020. All relevant clinical data were retrospectively collected. Tumor budding based on the International Tumor Budding Consensus Conference recommendations and TSR in the first resected pulmonary metastases and primary tumors were evaluated from diagnostic hematoxylin-eosin-stained histopathological slides. Results: 60 patients (85.7%) had low tumor budding (≤5 buds/field) and 10 patients (14.3%) had high tumor budding (>5 buds/field) in their first pulmonary metastases of CRC. 5-year overall survival rates of pulmonary metastasectomy in low and high total tumor budding were 28.3% and 37.3% (p = 0.387), respectively. 19 patients (27.1%) had low TSR and 51 patients (72.9%) had high TSR. The 5-year overall survival rates were 32.9% in low and 28.6% in high TSR of first pulmonary metastases (p = 0.746). Tumor budding and TSR did not provide prognostic value in Cox multivariate analysis. Tumor budding and TSR in resected pulmonary metastases were not associated with those of the primary tumor. Conclusion: Tumor budding and TSR in the resected pulmonary metastases of CRC showed no statistically significant prognostic value, however, additional well-powered confirmatory studies are needed.

KW - Colorectal cancer

KW - Pulmonary metastases

KW - Tumor budding

KW - Tumor-stroma ratio

U2 - 10.1016/j.ejso.2023.02.009

DO - 10.1016/j.ejso.2023.02.009

M3 - Article

C2 - 36841693

AN - SCOPUS:85149036545

SN - 0748-7983

VL - 49

SP - 1298

EP - 1306

JO - European Journal of Surgical Oncology

JF - European Journal of Surgical Oncology

IS - 7

ER -

The prognostic role of tumor budding and tumor-stroma ratio in pulmonary metastasis of colorectal carcinoma

Abstract

Funding

Keywords

Publication forum classification

ASJC Scopus subject areas

UN SDGs

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