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Published in: Journal of Gastroenterology 5/2018

Open Access 01-05-2018 | Original Article—Alimentary Tract

The tumor-stromal ratio as a strong prognosticator for advanced gastric cancer patients: proposal of a new TSNM staging system

Authors: Chunwei Peng, Jiuyang Liu, Guifang Yang, Yan Li

Published in: Journal of Gastroenterology | Issue 5/2018

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Abstract

Background

Insufficient attention is paid to the underlying tumor microenvironment (TME) evolution, that resulting in tumor heterogeneity and driving differences in cancer aggressiveness and treatment outcomes. The morphological evaluation of the proportion of the stroma at the most invasive part of primary tumor (tumor-stromal ratio, TSR) in cancer is gaining momentum as evidence strengthens for the clinical relevance.

Methods

Tissue samples from the most invasive part of the primary gastric cancer (GC) of 494 patients were analyzed for their TSR, and a new TSNM (tumor-stromal node metastasis) staging system based on patho-biological behaviors was established and assessed.

Results

TSR is a new and strong independent prognostic factor for GC patients. The likelihood of tumor invasion is increased significantly for patients in the stromal-high subgroup compared to those in the stromal-low subgroup (P = 0.011). The discrimination ability of TSR was not less than the TNM staging system and was better in patients with stages I and II GC. We integrated the TSR parameter into the TNM staging system and proposed a new TSNM staging system creatively. There were three new subgroups (IC, IIC, IIID). There were four major groups and 10 subgroups in the TSNM system. The difference in overall survival (OS) was statistically significant among all TSNM system (P < 0.005 for all). Deep analyses revealed well predictive performance of the TSNM (P < 0.001).

Conclusions

This study confirms the TSR as a TME prognostic factor for GC. TSR is a candidate TME parameter that could easily be implemented in routine pathology diagnostics, and the TSNM staging system has been established to optimize risk stratification for GC. The value of the TSNM staging system should be validated in further prospective study.
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Literature
1.
go back to reference Chen W, Zheng R, Baade PD, et al. Cancer statistics in China, 2015. CA Cancer J Clin. 2016;66:115–32.CrossRefPubMed Chen W, Zheng R, Baade PD, et al. Cancer statistics in China, 2015. CA Cancer J Clin. 2016;66:115–32.CrossRefPubMed
3.
go back to reference Bang YJ, Kim YW, Yang HK, et al. Adjuvant capecitabine and oxaliplatin for gastric cancer after D2 gastrectomy (CLASSIC): a phase 3 open-label, randomised controlled trial. Lancet. 2012;379:315–21.CrossRefPubMed Bang YJ, Kim YW, Yang HK, et al. Adjuvant capecitabine and oxaliplatin for gastric cancer after D2 gastrectomy (CLASSIC): a phase 3 open-label, randomised controlled trial. Lancet. 2012;379:315–21.CrossRefPubMed
4.
go back to reference Mlecnik B, Tosolini M, Kirilovsky A, et al. Histopathologic-based prognostic factors of colorectal cancers are associated with the state of the local immune reaction. J Clin Oncol. 2011;29:610–8.CrossRefPubMed Mlecnik B, Tosolini M, Kirilovsky A, et al. Histopathologic-based prognostic factors of colorectal cancers are associated with the state of the local immune reaction. J Clin Oncol. 2011;29:610–8.CrossRefPubMed
5.
go back to reference Peng CW, Wang LW, Zeng WJ, et al. Evaluation of the staging systems for gastric cancer. J Surg Oncol. 2013;108:93–105.CrossRefPubMed Peng CW, Wang LW, Zeng WJ, et al. Evaluation of the staging systems for gastric cancer. J Surg Oncol. 2013;108:93–105.CrossRefPubMed
6.
go back to reference Cristescu R, Lee J, Nebozhyn M, et al. Molecular analysis of gastric cancer identifies subtypes associated with distinct clinical outcomes. Nat Med. 2015;21:U217–449.CrossRef Cristescu R, Lee J, Nebozhyn M, et al. Molecular analysis of gastric cancer identifies subtypes associated with distinct clinical outcomes. Nat Med. 2015;21:U217–449.CrossRef
7.
go back to reference Jeng KS, Chang CF, Jeng WJ, et al. Heterogeneity of hepatocellular carcinoma contributes to cancer progression. Crit Rev Oncol Hematol. 2015;94:337–47.CrossRefPubMed Jeng KS, Chang CF, Jeng WJ, et al. Heterogeneity of hepatocellular carcinoma contributes to cancer progression. Crit Rev Oncol Hematol. 2015;94:337–47.CrossRefPubMed
10.
11.
go back to reference Salgado R, Denkert C, Demaria S, et al. The evaluation of tumor-infiltrating lymphocytes (TILs) in breast cancer: recommendations by an International TILs Working Group 2014. Ann Oncol. 2015;26:259–71.CrossRefPubMed Salgado R, Denkert C, Demaria S, et al. The evaluation of tumor-infiltrating lymphocytes (TILs) in breast cancer: recommendations by an International TILs Working Group 2014. Ann Oncol. 2015;26:259–71.CrossRefPubMed
13.
go back to reference Cirri P, Chiarugi P. Cancer-associated-fibroblasts and tumour cells: a diabolic liaison driving cancer progression. Cancer Metastasis Rev. 2012;31:195–208.CrossRefPubMed Cirri P, Chiarugi P. Cancer-associated-fibroblasts and tumour cells: a diabolic liaison driving cancer progression. Cancer Metastasis Rev. 2012;31:195–208.CrossRefPubMed
15.
go back to reference Buchert M, Burns CJ, Ernst M. Targeting JAK kinase in solid tumors: emerging opportunities and challenges. Oncogene. 2016;35:939–51.CrossRefPubMed Buchert M, Burns CJ, Ernst M. Targeting JAK kinase in solid tumors: emerging opportunities and challenges. Oncogene. 2016;35:939–51.CrossRefPubMed
16.
go back to reference Barcellos-Hoff MH, Lyden D, Wang TC. The evolution of the cancer niche during multistage carcinogenesis. Nat Rev Cancer. 2013;13:511–8.CrossRefPubMed Barcellos-Hoff MH, Lyden D, Wang TC. The evolution of the cancer niche during multistage carcinogenesis. Nat Rev Cancer. 2013;13:511–8.CrossRefPubMed
17.
go back to reference Peng CW, Wang LW, Fang M, et al. Combined features based on MT1-MMP expression, CD11b+ immunocytes density and LNR predict clinical outcomes of gastric cancer. J Transl Med. 2013;11:153.CrossRefPubMedPubMedCentral Peng CW, Wang LW, Fang M, et al. Combined features based on MT1-MMP expression, CD11b+ immunocytes density and LNR predict clinical outcomes of gastric cancer. J Transl Med. 2013;11:153.CrossRefPubMedPubMedCentral
18.
go back to reference Peng CW, Liu X-L, Chen C, et al. Patterns of cancer invasion revealed by QDs-based quantitative multiplexed imaging of tumor microenvironment. Biomaterials. 2011;32:2907–17.CrossRefPubMed Peng CW, Liu X-L, Chen C, et al. Patterns of cancer invasion revealed by QDs-based quantitative multiplexed imaging of tumor microenvironment. Biomaterials. 2011;32:2907–17.CrossRefPubMed
19.
go back to reference Huijbers A, Tollenaar RA, Pelt GWV, 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, Pelt GWV, 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
20.
go back to reference Mesker WE, Junggeburt JM, Szuhai K, 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, 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
21.
go back to reference Liu J, Liu J, Li J, et al. Tumor-stroma ratio is an independent predictor for survival in early cervical carcinoma. Gynecol Oncol. 2014;132:81–6.CrossRefPubMed Liu J, Liu J, Li J, et al. Tumor-stroma ratio is an independent predictor for survival in early cervical carcinoma. Gynecol Oncol. 2014;132:81–6.CrossRefPubMed
22.
go back to reference Wang K, Ma W, Wang J, et al. Tumor-stroma ratio is an independent predictor for survival in esophageal squamous cell carcinoma. J Thorac Oncol. 2012;7:1457–61.CrossRefPubMed Wang K, Ma W, Wang J, et al. Tumor-stroma ratio is an independent predictor for survival in esophageal squamous cell carcinoma. J Thorac Oncol. 2012;7:1457–61.CrossRefPubMed
23.
go back to reference Moorman AM, Vink R, Heijmans HJ, et al. The prognostic value of tumour-stroma ratio in triple-negative breast cancer. Eur J Surg Oncol. 2012;38:307–13.CrossRefPubMed Moorman AM, Vink R, Heijmans HJ, et al. The prognostic value of tumour-stroma ratio in triple-negative breast cancer. Eur J Surg Oncol. 2012;38:307–13.CrossRefPubMed
24.
go back to reference Marchet A, Mocellin S, Ambrosi A, et al. The ratio between metastatic and examined lymph nodes (N ratio) is an independent prognostic factor in gastric cancer regardless of the type of lymphadenectomy: results from an Italian multicentric study in 1853 patients. Ann Surg. 2007;245:543–52.CrossRefPubMedPubMedCentral Marchet A, Mocellin S, Ambrosi A, et al. The ratio between metastatic and examined lymph nodes (N ratio) is an independent prognostic factor in gastric cancer regardless of the type of lymphadenectomy: results from an Italian multicentric study in 1853 patients. Ann Surg. 2007;245:543–52.CrossRefPubMedPubMedCentral
25.
go back to reference Association JGC. Japanese classification of gastric carcinoma: 3rd English edition. Gastric Cancer. 2011;14:101–12.CrossRef Association JGC. Japanese classification of gastric carcinoma: 3rd English edition. Gastric Cancer. 2011;14:101–12.CrossRef
27.
28.
go back to reference Calon A, Lonardo E, Berenguer-Llergo A, et al. Stromal gene expression defines poor-prognosis subtypes in colorectal cancer. Nat Genet. 2015;47:U62–320.CrossRef Calon A, Lonardo E, Berenguer-Llergo A, et al. Stromal gene expression defines poor-prognosis subtypes in colorectal cancer. Nat Genet. 2015;47:U62–320.CrossRef
29.
go back to reference Peng CW, Liu XL, Liu X, et al. Co-evolution of cancer microenvironment reveals distinctive patterns of gastric cancer invasion: laboratory evidence and clinical significance. J Transl Med. 2010;8:101.CrossRefPubMedPubMedCentral Peng CW, Liu XL, Liu X, et al. Co-evolution of cancer microenvironment reveals distinctive patterns of gastric cancer invasion: laboratory evidence and clinical significance. J Transl Med. 2010;8:101.CrossRefPubMedPubMedCentral
30.
31.
go back to reference Kouniavsky G, Khaikin M, Zvibel I, et al. Stromal extracellular matrix reduces chemotherapy-induced apoptosis in colon cancer cell lines. Clin Exp Metastasis. 2002;19:55–60.CrossRefPubMed Kouniavsky G, Khaikin M, Zvibel I, et al. Stromal extracellular matrix reduces chemotherapy-induced apoptosis in colon cancer cell lines. Clin Exp Metastasis. 2002;19:55–60.CrossRefPubMed
32.
go back to reference Liotta LA, Rao CN, Barsky SH. Tumor invasion and the extracellular matrix. Lab Invest. 1983;49:636–49.PubMed Liotta LA, Rao CN, Barsky SH. Tumor invasion and the extracellular matrix. Lab Invest. 1983;49:636–49.PubMed
33.
go back to reference Catalano V, Turdo A, Di Franco S, et al. Tumor and its microenvironment: a synergistic interplay. Semin Cancer Biol. 2013;23:522–32.CrossRefPubMed Catalano V, Turdo A, Di Franco S, et al. Tumor and its microenvironment: a synergistic interplay. Semin Cancer Biol. 2013;23:522–32.CrossRefPubMed
34.
go back to reference Lorusso G, Ruegg C. The tumor microenvironment and its contribution to tumor evolution toward metastasis. Histochem Cell Biol. 2008;130:1091–103.CrossRefPubMed Lorusso G, Ruegg C. The tumor microenvironment and its contribution to tumor evolution toward metastasis. Histochem Cell Biol. 2008;130:1091–103.CrossRefPubMed
35.
go back to reference de Kruijf EM, van Nes JG, van de Velde CJ, et al. Tumor-stroma ratio in the primary tumor is a prognostic factor in early breast cancer patients, especially in triple-negative carcinoma patients. Breast Cancer Res Treat. 2011;125:687–96.CrossRefPubMed de Kruijf EM, van Nes JG, van de Velde CJ, et al. Tumor-stroma ratio in the primary tumor is a prognostic factor in early breast cancer patients, especially in triple-negative carcinoma patients. Breast Cancer Res Treat. 2011;125:687–96.CrossRefPubMed
36.
go back to reference Mesker WE, Liefers GJ, Junggeburt JM, 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, 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
37.
go back to reference Ueno H, Konishi T, Ishikawa Y, et al. Histologic categorization of fibrotic cancer stroma in the primary tumor is an independent prognostic index in resectable colorectal liver metastasis. Am J Surg Pathol. 2014;38(10):1380–6.CrossRefPubMed Ueno H, Konishi T, Ishikawa Y, et al. Histologic categorization of fibrotic cancer stroma in the primary tumor is an independent prognostic index in resectable colorectal liver metastasis. Am J Surg Pathol. 2014;38(10):1380–6.CrossRefPubMed
38.
go back to reference Ueno H, Shinto E, Shimazaki H, et al. Histologic categorization of desmoplastic reaction: its relevance to the colorectal cancer microenvironment and prognosis. Ann Surg Oncol. 2015;22(5):1504–12.CrossRefPubMed Ueno H, Shinto E, Shimazaki H, et al. Histologic categorization of desmoplastic reaction: its relevance to the colorectal cancer microenvironment and prognosis. Ann Surg Oncol. 2015;22(5):1504–12.CrossRefPubMed
Metadata
Title
The tumor-stromal ratio as a strong prognosticator for advanced gastric cancer patients: proposal of a new TSNM staging system
Authors
Chunwei Peng
Jiuyang Liu
Guifang Yang
Yan Li
Publication date
01-05-2018
Publisher
Springer Japan
Published in
Journal of Gastroenterology / Issue 5/2018
Print ISSN: 0944-1174
Electronic ISSN: 1435-5922
DOI
https://doi.org/10.1007/s00535-017-1379-1

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