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Tumor deposits improve staging in colon cancer: what are the next steps?

2021; Elsevier BV; Volume: 32; Issue: 10 Linguagem: Inglês

10.1016/j.annonc.2021.08.1751

1569-8041

Nelleke P.M. Brouwer, Irıs D. Nagtegaal,

Gastric Cancer Management and Outcomes

Traditionally, lymph node metastases (LNM) play a crucial part in the staging of colon cancer patients according to the TNM (tumor–node–metastasis) system, which is based on the prevailing hypothesis that metastatic disease is the direct result of lymphatic spread.1Dukes C.E. The classification of cancer of the rectum.J Pathol Bacteriol. 1932; 35: 323-332Crossref Google Scholar In recent years, however, studies have shown that other types of locoregional spread, such as tumor deposits (TD), add very relevant prognostic information.2Lord A.C. D'Souza N. Pucher P.H. et al.Significance of extranodal tumour deposits in colorectal cancer: a systematic review and meta-analysis.Eur J Cancer. 2017; 82: 92-102Abstract Full Text Full Text PDF PubMed Scopus (48) Google Scholar,3Nagtegaal I.D. Knijn N. Hugen N. et al.Tumor deposits in colorectal cancer: improving the value of modern staging – a systematic review and meta-analysis.J Clin Oncol. 2017; 35: 1119-1127Crossref PubMed Scopus (104) Google Scholar TD are aggregates of tumor cells in the fat surrounding the bowel, found in 20%-25% of colon cancer patients.3Nagtegaal I.D. Knijn N. Hugen N. et al.Tumor deposits in colorectal cancer: improving the value of modern staging – a systematic review and meta-analysis.J Clin Oncol. 2017; 35: 1119-1127Crossref PubMed Scopus (104) Google Scholar In the absence of LNM, TD result in an N1c classification, but TD are ignored in the presence of LNM. Despite the fact that TD were already described 90 years ago and are highly prevalent, several issues surrounding TD are still unsolved.4Gabriel W.B. Dukes C. Bussey H.J.R. Lymphatic spread in cancer of the rectum.Br J Surg. 1935; 23: 395-413Crossref Scopus (278) Google Scholar Firstly, the evidence regarding the prognostic impact of TD has been mostly based on retrospective studies or prospective cohorts with suboptimal pathological reporting.3Nagtegaal I.D. Knijn N. Hugen N. et al.Tumor deposits in colorectal cancer: improving the value of modern staging – a systematic review and meta-analysis.J Clin Oncol. 2017; 35: 1119-1127Crossref PubMed Scopus (104) Google Scholar,5Delattre J.F. Cohen R. Henriques J. et al.Prognostic value of tumor deposits for disease-free survival in patients with stage III colon cancer: a post hoc analysis of the IDEA France phase III trial (PRODIGE-GERCOR).J Clin Oncol. 2020; 38: 1702-1710Crossref PubMed Scopus (18) Google Scholar Secondly, although TD have been incorporated into TNM since the 5th edition, their definition has changed constantly. They were considered LNM (or not) and stratified according to size, contour, or presence of other histological structures.6International Union against CancerTNM Classification of Malignant Tumours. 5th ed. John Wiley & Sons, New York, NY1997Google Scholar, 7International Union Against CancerTNM Classification of Malignant Tumours. 6th ed. John Wiley & Sons, Hoboken, NJ2002Google Scholar, 8International Union Against CancerTNM Classification of Malignant Tumours. 7th ed. Wiley-Blackwell, Hoboken, NJ2010Google Scholar Currently, there is still no clear definition of TD, which has led to high interobserver variation.9Rock J.B. Washington M.K. Adsay N.V. et al.Debating deposits: an interobserver variability study of lymph nodes and pericolonic tumor deposits in colonic adenocarcinoma.Arch Pathol Lab Med. 2014; 138: 636-642Crossref PubMed Scopus (43) Google Scholar Lastly, the origin and development of TD are poorly understood and it is unclear how TD differ biologically from other types of locoregional spread such as LNM.In this issue of Annals of Oncology, Cohen and colleagues10Cohen R. Shi Q. Meyers J. et al.Combining tumor deposits with the number of lymph node metastases to improve the prognostic accuracy in stage III colon cancer: a post hoc analysis of the CALGB/SWOG 80702 phase III study (Alliance).Ann Oncol. 2021; 32: 1267-1275Abstract Full Text Full Text PDF Scopus (11) Google Scholar evaluate the prognostic value of TD for disease-free survival (DFS) and overall survival, as well as the impact of combining the number of TD and the number of LNM in patients with stage III colon cancer, using a post hoc analysis of the CALGB/SWOG 80702 phase III trial. The current study has validated the earlier findings from the post hoc analysis of the IDEA France study5Delattre J.F. Cohen R. Henriques J. et al.Prognostic value of tumor deposits for disease-free survival in patients with stage III colon cancer: a post hoc analysis of the IDEA France phase III trial (PRODIGE-GERCOR).J Clin Oncol. 2020; 38: 1702-1710Crossref PubMed Scopus (18) Google Scholar by showing that TD are an independent prognostic factor with a linear relationship between the number of TD and survival, and that prognostic accuracy is improved when TD and LNM count are combined. There are now several epidemiological studies, two prospective cohorts from large clinical trials, and an elaborate meta-analysis that provide evidence for the prognostic value of TD, even in the presence of LNM.3Nagtegaal I.D. Knijn N. Hugen N. et al.Tumor deposits in colorectal cancer: improving the value of modern staging – a systematic review and meta-analysis.J Clin Oncol. 2017; 35: 1119-1127Crossref PubMed Scopus (104) Google Scholar,5Delattre J.F. Cohen R. Henriques J. et al.Prognostic value of tumor deposits for disease-free survival in patients with stage III colon cancer: a post hoc analysis of the IDEA France phase III trial (PRODIGE-GERCOR).J Clin Oncol. 2020; 38: 1702-1710Crossref PubMed Scopus (18) Google Scholar,10Cohen R. Shi Q. Meyers J. et al.Combining tumor deposits with the number of lymph node metastases to improve the prognostic accuracy in stage III colon cancer: a post hoc analysis of the CALGB/SWOG 80702 phase III study (Alliance).Ann Oncol. 2021; 32: 1267-1275Abstract Full Text Full Text PDF Scopus (11) Google Scholar, 11Peacock O. Limvorapitak T. Hu C.-Y. et al.Improving the AJCC/TNM staging classification for colorectal cancer: the prognostic impact of tumor deposits.J Clin Oncol. 2020; 38: 4012Crossref Google Scholar, 12Wang S. Guan X. Ma M. et al.Reconsidering the prognostic significance of tumour deposit count in the TNM staging system for colorectal cancer.Sci Rep. 2020; 10: 89Crossref PubMed Scopus (20) Google Scholar It can be concluded that ignoring TD in the presence of LNM is suboptimal,13Lord A. Brown G. Abulafi M. et al.Histopathological diagnosis of tumour deposits in colorectal cancer: a Delphi consensus study.Histopathology. 2021; 79: 168-175Crossref PubMed Scopus (10) Google Scholar and that the current nodal classification in the TNM system for colon cancer is in urgent need of change. The evidence indicates that the number of TD should be combined with the number of LNM to improve the accuracy of staging in colon cancer.Still, there are important issues to be solved. The definition and origin of TD have been subject to debate. In the current edition of the TNM classification, the most complex definition so far has been introduced, aiming on excluding any lesion with identifiable structures pointing towards LNM, extramural venous invasion or perineural invasion.14International Union Against CancerBrierley J.D. Gospodarowicz M.K. Wittekind C.H. TNM Classification of Malignant Tumours. 8th ed. Wiley-Blackwell, Hoboken, NJ2017Google Scholar From a scientific point of view, the distinction of the different origins of TD is indeed very interesting, but from a practical perspective this seems less relevant.13Lord A. Brown G. Abulafi M. et al.Histopathological diagnosis of tumour deposits in colorectal cancer: a Delphi consensus study.Histopathology. 2021; 79: 168-175Crossref PubMed Scopus (10) Google Scholar It is widely believed that TD constitute a group of different entities which have grown out of different histological structures (Figure 1A).13Lord A. Brown G. Abulafi M. et al.Histopathological diagnosis of tumour deposits in colorectal cancer: a Delphi consensus study.Histopathology. 2021; 79: 168-175Crossref PubMed Scopus (10) Google Scholar Comprehensive histological studies demonstrate, however, the association of individual TD with multiple histological structures (Figure 1B and C).15Goldstein N.S. Turner J.R. Pericolonic tumor deposits in patients with T3N+MO colon adenocarcinomas: markers of reduced disease free survival and intra-abdominal metastases and their implications for TNM classification.Cancer. 2000; 88: 2228Crossref PubMed Scopus (135) Google Scholar This makes tracing back TD to a single origin impossible.In order to improve the definition of TD and thereby the staging of colon cancer, a more fundamental biological understanding of TD in the context of locoregional spread is necessary. Is it the origin that determines their behavior or is it the fact that TD show the capacity to grow outside of histological boundaries that results in the poor outcome of patients with TD? A more detailed look at the different stages of LNM supports the hypothesis that the disruption of boundaries by tumor cells has prognostic impact. In general, any form of LNM is associated with a decreased prognosis. Single tumor cells or micrometastases, however, are less detrimental than macrometastases.16Sloothaak D.A. Sahami S. van der Zaag-Loonen H.J. et al.The prognostic value of micrometastases and isolated tumour cells in histologically negative lymph nodes of patients with colorectal cancer: a systematic review and meta-analysis.Eur J Surg Oncol. 2014; 40: 263-269Abstract Full Text Full Text PDF PubMed Scopus (63) Google Scholar Extranodal extension (i.e. crossing of the lymph node capsule) is associated with the poorest outcome, with a 66.4% 5-year DFS compared with 80.1% for LN without extranodal growth in colorectal cancer.17Kim C.W. Kim J. Yeom S.S. et al.Extranodal extension status is a powerful prognostic factor in stage III colorectal cancer.Oncotarget. 2017; 8: 61393-61403Crossref PubMed Scopus (13) Google Scholar If a TD originates from LNM, it most likely represents the next stage of disruption after extranodal extension.This breakdown of boundaries reflects the early steps in epithelial carcinogenesis in which tumor cells undergo epithelial-to-mesenchymal transition (EMT) necessary for the acquisition of migratory and invasive abilities.18Cao H. Xu E. Liu H. Wan L. Lai M. Epithelial-mesenchymal transition in colorectal cancer metastasis: a system review.Pathol Res Pract. 2015; 211: 557-569Crossref PubMed Scopus (259) Google Scholar Recent studies have shown that single tumor cells or small groups of tumor cells at the invasive border of the primary tumor (tumor buds) show an EMT-like state that enables them to migrate.19De Smedt L. Palmans S. Andel D. et al.Expression profiling of budding cells in colorectal cancer reveals an EMT-like phenotype and molecular subtype switching.Br J Cancer. 2017; 116: 58-65Crossref PubMed Scopus (86) Google Scholar Once they arrive at a different anatomical niche (e.g. a lymph node), the tumor cells need to undergo the reverse process [mesenchymal-to-epithelial transition (MET)], to re-instate cell division and rebuild a cohesive tumor structure. In LNM without extranodal extension, tumor cells then continue to grow in an epithelial-like manner, whereas tumor cells in TD present a behavior that is similar to that of tumor buds, as they migrate over and through histological boundaries. It is very well possible that this re-acquisition of mesenchymal-like characteristics by tumor cells in TD illustrates a more profound phenotypic plasticity. This could provide an explanation for the poor prognosis of TD, as the ability to repeatedly and rapidly undergo the process of both EMT and MET is needed for tumor cells to spread and grow out at secondary sites.18Cao H. Xu E. Liu H. Wan L. Lai M. Epithelial-mesenchymal transition in colorectal cancer metastasis: a system review.Pathol Res Pract. 2015; 211: 557-569Crossref PubMed Scopus (259) Google ScholarIn summary, it can be concluded that TD have an independent prognostic impact beyond LNM. The current staging can be improved by combining TD and LNM count. Still, the current definition of TD is complex and subjective, and the focus on their origin is not justified by literature and not supported by experts in the field.13Lord A. Brown G. Abulafi M. et al.Histopathological diagnosis of tumour deposits in colorectal cancer: a Delphi consensus study.Histopathology. 2021; 79: 168-175Crossref PubMed Scopus (10) Google Scholar Insights in the mechanisms behind the poor outcome associated with TD is necessary to improve definitions and staging. This is an essential step to facilitate treatment decisions in stage III colon cancer. Traditionally, lymph node metastases (LNM) play a crucial part in the staging of colon cancer patients according to the TNM (tumor–node–metastasis) system, which is based on the prevailing hypothesis that metastatic disease is the direct result of lymphatic spread.1Dukes C.E. The classification of cancer of the rectum.J Pathol Bacteriol. 1932; 35: 323-332Crossref Google Scholar In recent years, however, studies have shown that other types of locoregional spread, such as tumor deposits (TD), add very relevant prognostic information.2Lord A.C. D'Souza N. Pucher P.H. et al.Significance of extranodal tumour deposits in colorectal cancer: a systematic review and meta-analysis.Eur J Cancer. 2017; 82: 92-102Abstract Full Text Full Text PDF PubMed Scopus (48) Google Scholar,3Nagtegaal I.D. Knijn N. Hugen N. et al.Tumor deposits in colorectal cancer: improving the value of modern staging – a systematic review and meta-analysis.J Clin Oncol. 2017; 35: 1119-1127Crossref PubMed Scopus (104) Google Scholar TD are aggregates of tumor cells in the fat surrounding the bowel, found in 20%-25% of colon cancer patients.3Nagtegaal I.D. Knijn N. Hugen N. et al.Tumor deposits in colorectal cancer: improving the value of modern staging – a systematic review and meta-analysis.J Clin Oncol. 2017; 35: 1119-1127Crossref PubMed Scopus (104) Google Scholar In the absence of LNM, TD result in an N1c classification, but TD are ignored in the presence of LNM. Despite the fact that TD were already described 90 years ago and are highly prevalent, several issues surrounding TD are still unsolved.4Gabriel W.B. Dukes C. Bussey H.J.R. Lymphatic spread in cancer of the rectum.Br J Surg. 1935; 23: 395-413Crossref Scopus (278) Google Scholar Firstly, the evidence regarding the prognostic impact of TD has been mostly based on retrospective studies or prospective cohorts with suboptimal pathological reporting.3Nagtegaal I.D. Knijn N. Hugen N. et al.Tumor deposits in colorectal cancer: improving the value of modern staging – a systematic review and meta-analysis.J Clin Oncol. 2017; 35: 1119-1127Crossref PubMed Scopus (104) Google Scholar,5Delattre J.F. Cohen R. Henriques J. et al.Prognostic value of tumor deposits for disease-free survival in patients with stage III colon cancer: a post hoc analysis of the IDEA France phase III trial (PRODIGE-GERCOR).J Clin Oncol. 2020; 38: 1702-1710Crossref PubMed Scopus (18) Google Scholar Secondly, although TD have been incorporated into TNM since the 5th edition, their definition has changed constantly. They were considered LNM (or not) and stratified according to size, contour, or presence of other histological structures.6International Union against CancerTNM Classification of Malignant Tumours. 5th ed. John Wiley & Sons, New York, NY1997Google Scholar, 7International Union Against CancerTNM Classification of Malignant Tumours. 6th ed. John Wiley & Sons, Hoboken, NJ2002Google Scholar, 8International Union Against CancerTNM Classification of Malignant Tumours. 7th ed. Wiley-Blackwell, Hoboken, NJ2010Google Scholar Currently, there is still no clear definition of TD, which has led to high interobserver variation.9Rock J.B. Washington M.K. Adsay N.V. et al.Debating deposits: an interobserver variability study of lymph nodes and pericolonic tumor deposits in colonic adenocarcinoma.Arch Pathol Lab Med. 2014; 138: 636-642Crossref PubMed Scopus (43) Google Scholar Lastly, the origin and development of TD are poorly understood and it is unclear how TD differ biologically from other types of locoregional spread such as LNM. In this issue of Annals of Oncology, Cohen and colleagues10Cohen R. Shi Q. Meyers J. et al.Combining tumor deposits with the number of lymph node metastases to improve the prognostic accuracy in stage III colon cancer: a post hoc analysis of the CALGB/SWOG 80702 phase III study (Alliance).Ann Oncol. 2021; 32: 1267-1275Abstract Full Text Full Text PDF Scopus (11) Google Scholar evaluate the prognostic value of TD for disease-free survival (DFS) and overall survival, as well as the impact of combining the number of TD and the number of LNM in patients with stage III colon cancer, using a post hoc analysis of the CALGB/SWOG 80702 phase III trial. The current study has validated the earlier findings from the post hoc analysis of the IDEA France study5Delattre J.F. Cohen R. Henriques J. et al.Prognostic value of tumor deposits for disease-free survival in patients with stage III colon cancer: a post hoc analysis of the IDEA France phase III trial (PRODIGE-GERCOR).J Clin Oncol. 2020; 38: 1702-1710Crossref PubMed Scopus (18) Google Scholar by showing that TD are an independent prognostic factor with a linear relationship between the number of TD and survival, and that prognostic accuracy is improved when TD and LNM count are combined. There are now several epidemiological studies, two prospective cohorts from large clinical trials, and an elaborate meta-analysis that provide evidence for the prognostic value of TD, even in the presence of LNM.3Nagtegaal I.D. Knijn N. Hugen N. et al.Tumor deposits in colorectal cancer: improving the value of modern staging – a systematic review and meta-analysis.J Clin Oncol. 2017; 35: 1119-1127Crossref PubMed Scopus (104) Google Scholar,5Delattre J.F. Cohen R. Henriques J. et al.Prognostic value of tumor deposits for disease-free survival in patients with stage III colon cancer: a post hoc analysis of the IDEA France phase III trial (PRODIGE-GERCOR).J Clin Oncol. 2020; 38: 1702-1710Crossref PubMed Scopus (18) Google Scholar,10Cohen R. Shi Q. Meyers J. et al.Combining tumor deposits with the number of lymph node metastases to improve the prognostic accuracy in stage III colon cancer: a post hoc analysis of the CALGB/SWOG 80702 phase III study (Alliance).Ann Oncol. 2021; 32: 1267-1275Abstract Full Text Full Text PDF Scopus (11) Google Scholar, 11Peacock O. Limvorapitak T. Hu C.-Y. et al.Improving the AJCC/TNM staging classification for colorectal cancer: the prognostic impact of tumor deposits.J Clin Oncol. 2020; 38: 4012Crossref Google Scholar, 12Wang S. Guan X. Ma M. et al.Reconsidering the prognostic significance of tumour deposit count in the TNM staging system for colorectal cancer.Sci Rep. 2020; 10: 89Crossref PubMed Scopus (20) Google Scholar It can be concluded that ignoring TD in the presence of LNM is suboptimal,13Lord A. Brown G. Abulafi M. et al.Histopathological diagnosis of tumour deposits in colorectal cancer: a Delphi consensus study.Histopathology. 2021; 79: 168-175Crossref PubMed Scopus (10) Google Scholar and that the current nodal classification in the TNM system for colon cancer is in urgent need of change. The evidence indicates that the number of TD should be combined with the number of LNM to improve the accuracy of staging in colon cancer. Still, there are important issues to be solved. The definition and origin of TD have been subject to debate. In the current edition of the TNM classification, the most complex definition so far has been introduced, aiming on excluding any lesion with identifiable structures pointing towards LNM, extramural venous invasion or perineural invasion.14International Union Against CancerBrierley J.D. Gospodarowicz M.K. Wittekind C.H. TNM Classification of Malignant Tumours. 8th ed. Wiley-Blackwell, Hoboken, NJ2017Google Scholar From a scientific point of view, the distinction of the different origins of TD is indeed very interesting, but from a practical perspective this seems less relevant.13Lord A. Brown G. Abulafi M. et al.Histopathological diagnosis of tumour deposits in colorectal cancer: a Delphi consensus study.Histopathology. 2021; 79: 168-175Crossref PubMed Scopus (10) Google Scholar It is widely believed that TD constitute a group of different entities which have grown out of different histological structures (Figure 1A).13Lord A. Brown G. Abulafi M. et al.Histopathological diagnosis of tumour deposits in colorectal cancer: a Delphi consensus study.Histopathology. 2021; 79: 168-175Crossref PubMed Scopus (10) Google Scholar Comprehensive histological studies demonstrate, however, the association of individual TD with multiple histological structures (Figure 1B and C).15Goldstein N.S. Turner J.R. Pericolonic tumor deposits in patients with T3N+MO colon adenocarcinomas: markers of reduced disease free survival and intra-abdominal metastases and their implications for TNM classification.Cancer. 2000; 88: 2228Crossref PubMed Scopus (135) Google Scholar This makes tracing back TD to a single origin impossible. In order to improve the definition of TD and thereby the staging of colon cancer, a more fundamental biological understanding of TD in the context of locoregional spread is necessary. Is it the origin that determines their behavior or is it the fact that TD show the capacity to grow outside of histological boundaries that results in the poor outcome of patients with TD? A more detailed look at the different stages of LNM supports the hypothesis that the disruption of boundaries by tumor cells has prognostic impact. In general, any form of LNM is associated with a decreased prognosis. Single tumor cells or micrometastases, however, are less detrimental than macrometastases.16Sloothaak D.A. Sahami S. van der Zaag-Loonen H.J. et al.The prognostic value of micrometastases and isolated tumour cells in histologically negative lymph nodes of patients with colorectal cancer: a systematic review and meta-analysis.Eur J Surg Oncol. 2014; 40: 263-269Abstract Full Text Full Text PDF PubMed Scopus (63) Google Scholar Extranodal extension (i.e. crossing of the lymph node capsule) is associated with the poorest outcome, with a 66.4% 5-year DFS compared with 80.1% for LN without extranodal growth in colorectal cancer.17Kim C.W. Kim J. Yeom S.S. et al.Extranodal extension status is a powerful prognostic factor in stage III colorectal cancer.Oncotarget. 2017; 8: 61393-61403Crossref PubMed Scopus (13) Google Scholar If a TD originates from LNM, it most likely represents the next stage of disruption after extranodal extension. This breakdown of boundaries reflects the early steps in epithelial carcinogenesis in which tumor cells undergo epithelial-to-mesenchymal transition (EMT) necessary for the acquisition of migratory and invasive abilities.18Cao H. Xu E. Liu H. Wan L. Lai M. Epithelial-mesenchymal transition in colorectal cancer metastasis: a system review.Pathol Res Pract. 2015; 211: 557-569Crossref PubMed Scopus (259) Google Scholar Recent studies have shown that single tumor cells or small groups of tumor cells at the invasive border of the primary tumor (tumor buds) show an EMT-like state that enables them to migrate.19De Smedt L. Palmans S. Andel D. et al.Expression profiling of budding cells in colorectal cancer reveals an EMT-like phenotype and molecular subtype switching.Br J Cancer. 2017; 116: 58-65Crossref PubMed Scopus (86) Google Scholar Once they arrive at a different anatomical niche (e.g. a lymph node), the tumor cells need to undergo the reverse process [mesenchymal-to-epithelial transition (MET)], to re-instate cell division and rebuild a cohesive tumor structure. In LNM without extranodal extension, tumor cells then continue to grow in an epithelial-like manner, whereas tumor cells in TD present a behavior that is similar to that of tumor buds, as they migrate over and through histological boundaries. It is very well possible that this re-acquisition of mesenchymal-like characteristics by tumor cells in TD illustrates a more profound phenotypic plasticity. This could provide an explanation for the poor prognosis of TD, as the ability to repeatedly and rapidly undergo the process of both EMT and MET is needed for tumor cells to spread and grow out at secondary sites.18Cao H. Xu E. Liu H. Wan L. Lai M. Epithelial-mesenchymal transition in colorectal cancer metastasis: a system review.Pathol Res Pract. 2015; 211: 557-569Crossref PubMed Scopus (259) Google Scholar In summary, it can be concluded that TD have an independent prognostic impact beyond LNM. The current staging can be improved by combining TD and LNM count. Still, the current definition of TD is complex and subjective, and the focus on their origin is not justified by literature and not supported by experts in the field.13Lord A. Brown G. Abulafi M. et al.Histopathological diagnosis of tumour deposits in colorectal cancer: a Delphi consensus study.Histopathology. 2021; 79: 168-175Crossref PubMed Scopus (10) Google Scholar Insights in the mechanisms behind the poor outcome associated with TD is necessary to improve definitions and staging. This is an essential step to facilitate treatment decisions in stage III colon cancer. None declared.