Jean-François François Delattre

MD Ayse Selcen

Oguz Erdogan

Romain Cohen

Qian Shi

Jean François

Jean- François F Emile

Julien Taieb

Josep Tabernero

Thierry André

Jeffrey A Meyerhardt

Iris D Nagtegaal

Professor Magali Svrcek
email: magali.svrcek@aphp.fr

A comprehensive overview of tumour deposits in colorectal cancer: Towards a next TNM classification

Keywords: Tumour deposit, colorectal cancer, histoprognostic factor, TNM classification, lymph node metastasis, extra-mural vascular invasion, perineural invasion

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INTRODUCTION

Colorectal cancer (CRC) is currently the third most common cancer worldwide and the second leading cause of cancer deaths, with more than 1,800,000 new cases and nearly 900,000 deaths each year, worldwide [START_REF] Bray | Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries[END_REF]. Its management is based on the TNM staging system, developed in the 1950s, which has been constantly evolving throughout the history of scientific advances [START_REF]Manual for Staging of Cancer[END_REF][START_REF]Manual for Staging of Cancer[END_REF][START_REF]Manual for Staging of Cancer[END_REF][START_REF]Manual for Staging of Cancer[END_REF][START_REF]Pathologic TNM Staging of colorectal carcinoma[END_REF]. The latest 8th edition of the TNM classification has been published in 2017 [START_REF] Weiser | AJCC 8th Edition: Colorectal Cancer[END_REF]. Yet, it is essential to identify new histological markers to further improve the classification and to define more relevant subgroups of patients. In CRC, several markers of interest are thought to bear a prognostic impact, including vascular emboli (particularly extramural i.e., located beyond the muscularis, within the colonic subserosa or perirectal fat), perineural invasion, and tumour deposits (TDs).

TDs are defined as tumour foci in the pericolic or perirectal fat, distant from the tumour invasion front, in the lymphatic drainage territory of the tumour, without recognizable residual lymph node tissue [START_REF] Weiser | AJCC 8th Edition: Colorectal Cancer[END_REF]. TDs, observed in approximately 20% of CRCs, have been shown to be associated with poor prognosis in several cohort studies [START_REF] Nagtegaal | Tumor Deposits in Colorectal Cancer: Improving the Value of Modern Staging-A Systematic Review and Meta-Analysis[END_REF]. Thus, they constitute a prognostic marker of interest and have therefore been included in the 7th edition TNM classification (TNM7) node status of CRC as a pN1c subcategory [START_REF]Pathologic TNM Staging of colorectal carcinoma[END_REF]. In pN1c subcategory, TDs are considered only in the absence of lymph node (LN) metastasis (LNM). Consequently, in the presence of LNM, TDs have no impact on tumour staging. There has been constant debate in the medical community over this specific modality of integration of TDs into TNM7. Firstly, among pathologists, for whom such a consideration does not accurately reflect the physiological and prognostic reality of this marker [START_REF] Nagtegaal | Tumor Deposits in Colorectal Cancer: Improving the Value of Modern Staging-A Systematic Review and Meta-Analysis[END_REF][START_REF] Lord | Histopathological Diagnosis of Tumour Deposits in Colorectal Cancer: A Delphi Consensus Study[END_REF]. Secondly, among oncologists, for whom this modification has a concrete therapeutic implication, with a potential indication for adjuvant chemotherapy [START_REF] André | Oxaliplatin, fluorouracil, and leucovorin as adjuvant treatment for colon cancer[END_REF][START_REF] Kuebler | Oxaliplatin combined with weekly bolus fluorouracil and leucovorin as surgical adjuvant chemotherapy for stage II and III colon cancer: results from NSABP C-07[END_REF][START_REF] Quirke | Evidence-based medicine: the time has come to set standards for staging[END_REF]. Moreover, new data on the modalities of adjuvant chemotherapy in colon cancer (CC) have further complicated the debate. The results from the international collaboration IDEA (International Duration Evaluation of Adjuvant Chemotherapy) have shown that the type and duration of adjuvant chemotherapy can be personalized in stage III CC (i.e., with LNM) according to histological criteria, particularly the number of LNM [START_REF] André | Three Versus 6 Months of Oxaliplatin-Based Adjuvant Chemotherapy for Patients With Stage III Colon Cancer: Disease-Free Survival Results From a Randomized, Open-Label, International Duration Evaluation of Adjuvant (IDEA) France, Phase III Trial[END_REF][START_REF] André | Effect of duration of adjuvant chemotherapy for patients with stage III colon cancer (IDEA collaboration): final results from a prospective, pooled analysis of six randomised, phase 3 trials[END_REF][START_REF] Grothey | Duration of Adjuvant Chemotherapy for Stage III Colon Cancer[END_REF]. In the IDEA study, the 3-year disease-free survival (DFS) was 83% in patients with pT1-3 and pN1 tumors (i.e., low-risk stage III) versus 64% in those with pT4 and/or pN2 CCs (i.e., high-risk stage III). Importantly, for patients with low-risk tumors, the evidence from this non-inferiority phase III study supports a shortened duration of oxaliplatin-based adjuvant therapy. Thus, it is now widely accepted that the duration of adjuvant chemotherapy in stage III CC should be based on a consideration of pT and pN criteria to best guide the choice of treatment [START_REF] Argilés | Localised colon cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up[END_REF] In this context, overlooking TDs in the presence of LNM in patients with stage III CC could represent an important prognostic underestimation. In addition, accumulate evidence for the recent meta-analysis, randomized trials, the Surveillance, Epidemiology, and End Results (SEER) database, and the National Cancer DataBase (NCDB) data to support an update of the current pN classification of the AJCC staging system by TDs count [START_REF] Simon | N1c colon cancer and the use of adjuvant chemotherapy: a current audit of the National Cancer Database[END_REF][START_REF] Wang | Reconsidering the prognostic significance of tumour deposit count in the TNM staging system for colorectal cancer[END_REF][START_REF] Li | Tumor deposits counted as positive lymph nodes in TNM staging for advanced colorectal cancer: a retrospective multicenter study[END_REF][START_REF] Pricolo | Tumor Deposits in Stage III Colon Cancer[END_REF][START_REF] Delattre | 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)[END_REF][START_REF] Mirkin | Prognostic Significance of Tumor Deposits in Stage III Colon Cancer[END_REF][START_REF] Wong-Chong | Impact of Tumor Deposits on Oncologic Outcomes in Stage III Colon Cancer[END_REF][START_REF] Peacock | Improving the AJCC/TNM staging classification for colorectal cancer: The prognostic impact of tumor deposits[END_REF][START_REF] Landau | Histopathological Predictors of Recurrence in Stage III Colon Cancer: Reappraisal of Tumor Deposits and Tumor Budding Using AJCC8 Criteria[END_REF][START_REF] Song | Can the tumor deposits be counted as metastatic lymph nodes in the UICC TNM staging system for colorectal cancer?[END_REF].

Therefore, given prognostic importance, biological complexity, and scientific interest of TDs, we discuss the different implications of the variations between their definitions, summarize evidence about their prognostic value, and suggest the potential scenarios to update the current version of the AJCC/TNM staging system.

The definition(s) of TDs

TDs have been initially described in 1935 as "deposits of carcinoma cells at a distance from the primary growth although the lymphatic glands themselves have been free" [START_REF] Gabriel | Lymphatic spread in cancer of the rectum[END_REF]. This definition has changed in CC over time. TDs were first introduced in the AJCC/TNM5 staging in 1997, in which tumour nodules of > 3 mm in diameter without histological evidence of a residual LN were classified as regional LNM, while those of < 3 mm were classified in the T category as a discontinuous extension [START_REF]Manual for Staging of Cancer[END_REF]. In 2002, the AJCC/TNM6 staging system defined TDs according to criterion on their contours, with TDs being defined as positive LNs when they have the firm and smooth contour of LN, while irregular TDs remained in the T category [START_REF]Manual for Staging of Cancer[END_REF]. This variation in TDs definition yields the effect of stage migration over time, with CC being considered as stage I, II, or III depending on the chosen AJCC/TNM version [START_REF]Manual for Staging of Cancer[END_REF][START_REF]Manual for Staging of Cancer[END_REF][START_REF] Weiser | AJCC 8th Edition: Colorectal Cancer[END_REF]. Another issue is the high inter-observer variability in the diagnosis of TDs partly due to the subjective nature in their definition. For these different reasons, the definition of TDs in CRC has been updated in the AJCC/TNM7 classification [START_REF]Pathologic TNM Staging of colorectal carcinoma[END_REF].

In this revised staging system, TDs were considered as a specific entity and defined as nodules in the pericolic or perirectal fat tissue, distant from the tumour invasion front, without histological evidence of residual LNs in the lymphatic drainage area of the primary tumour.

These were no longer classified in the pT category (i.e., tumour extension), but instead in the category pN (i.e., LN). Even so, the presence of TDs was still considered only in the absence of LNM and classified the tumour as pN1c (irrespective of the number of TDs). Importantly, patients with pN1c CC are less likely to receive adjuvant therapy (52% versus 74% of patients with LN-positive tumors; p < 0.0001) as shown in an analysis of the National Cancer DataBase (NCDB) [START_REF] Mirkin | Prognostic Significance of Tumor Deposits in Stage III Colon Cancer[END_REF]. This separate category for TDs in TNM7 was mainly intended to highlight the population of patients with only TDs to better appreciate their inherent prognosis. However, this important change in TNM7 did not solve all issues and new modifications have been introduced in the most recent TNM8 classification [START_REF] Weiser | AJCC 8th Edition: Colorectal Cancer[END_REF].

Although the way TDs were considered in the AJCC/TNM8 staging system has not been revised, their definition has been changed from tumour nodules with histological aspects of venous emboli, lymphatic emboli, or perineural invasion to venous emboli, lymphatic emboli, or perineural invasion, respectively. The TNM8 has thus potentially downstaged tumors of some patients from stage III pN1c (TNM7) to stage II pN0. Hence, changes in the definition of TDs may affect therapeutic decisions for adjuvant treatment. The evolution of the diagnostic criteria for TDs through the various AJCC/TNM classifications is summarized in Fig. 1.

Origin of TDs and their association with other histoprognostic factors

To date, the pathogenesis of TDs remains unclear. Early studies of tumor nodules found on pathological analysis, and identified as non-nodes, classified them into four different subtypes: (i) without identifiable underlying origin, (ii) with vascular invasion, (iii) with perinervous invasion and (iv) diffuse [START_REF] Ueno | Clinical significance of extrabowel skipped cancer infiltration in rectal cancer[END_REF]. In the study by Goldstein and Turner [START_REF] Goldstein | 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[END_REF], tumour nodules were found to have three distinct origins by cross-section analysis: peri-nervous, perivascular, and intravascular. In total, 10% of patients had only one origin (7% peri-nerve, 3% perivascular), 53% two origins, and 37% all three components. Similarly, Ratto et al. [START_REF] Ratto | Mesorectal microfoci adversely affect the prognosis of patients with rectal cancer[END_REF],

in their study of 77 surgical specimens from rectal cancer patients found that TDs had the endovascular (12%), endolymphatic (16%), peri-nervous (20%), and "isolated" (14%; tumour foci with no origin found) origin. Most cases had a single component (59% versus 32%, 6%, and 3% with two, three, and four components, respectively). Yet another study found that venous invasion, lymphatic invasion, peri-nerve invasion, and continuous growth were responsible for TDs in 26%, 4%, 9%, and 12% of cases, respectively [START_REF] Shimada | Clinical impact of mesorectal extranodal cancer tissue in rectal cancer: detailed pathological assessment using whole-mount sections[END_REF]. In 49% of cases, no morphologically distinct structures were identified in association with the deposits. The current hypothesis is that TDs might result from an invasion of a certain structure, followed by its subsequent destruction. TDs would therefore reflect the different possible invasion routes of the tumour along the lymphatic, venous, or nervous axes. However, these axes usually run parallel, explaining the presence of multiple structures in the larger TD. This varied origin is to be linked with the frequently found association between TDs and other pejorative histological biomarkers such as LNM, vascular emboli, and perineural invasion.

Firstly, the occurrence of TDs seems to be more frequently associated with the LN involvement [START_REF] Ueno | Clinical significance of extrabowel skipped cancer infiltration in rectal cancer[END_REF][START_REF] Yabata | Effect of tumor deposits on overall survival in colorectal cancer patients with regional lymph node metastases[END_REF][START_REF] Basnet | Tumor deposit is an independent prognostic indicator in patients who underwent radical resection for colorectal cancer[END_REF]. In 1997, Ueno et al. [START_REF] Ueno | Clinical significance of extrabowel skipped cancer infiltration in rectal cancer[END_REF] observed that LN invasion is more frequent in the presence of TDs (19% versus 58%, p<0.001). Similarly in 2014, Yabata et al. [START_REF] Yabata | Effect of tumor deposits on overall survival in colorectal cancer patients with regional lymph node metastases[END_REF] found that invasion of LN was increased when TDs were present in tumours (70% versus 32%; p<0.001). In the meta-analysis of Nagtegaal et al. [START_REF] Nagtegaal | Tumor Deposits in Colorectal Cancer: Improving the Value of Modern Staging-A Systematic Review and Meta-Analysis[END_REF], TDs were found in 8.7% of patients without LNM and 41.6% of patients with LN involvement (HR 4.2, p=0.002). In another study in patients who underwent radical resection for CRC [START_REF] Basnet | Tumor deposit is an independent prognostic indicator in patients who underwent radical resection for colorectal cancer[END_REF], the presence of TDs was associated with LN status (p<0.001).

The presence of TDs also appears to be correlated with the existence of extramural vascular emboli. In the meta-analysis of 2,805 patients from nine studies [START_REF] Nagtegaal | Tumor Deposits in Colorectal Cancer: Improving the Value of Modern Staging-A Systematic Review and Meta-Analysis[END_REF], TDs were present in 20.9% of patients without vascular emboli and in 31.6% (HR 2.6) of these with extramural vascular emboli. Other more recent studies have confirmed the observed trend, with the proportions of tumours presenting extramural vascular emboli ranging from 20.9 to 60.8% in the absence of TDs and from 31.6 to 95.0% in the presence of TDs [START_REF] Yabata | Effect of tumor deposits on overall survival in colorectal cancer patients with regional lymph node metastases[END_REF][START_REF] Basnet | Tumor deposit is an independent prognostic indicator in patients who underwent radical resection for colorectal cancer[END_REF][START_REF] Bouquot | Prognostic value and characteristics of N1c colorectal cancer[END_REF]. In addition, there also appears to be an association between TDs and the presence of peri-neural invasion, however still not as clearly demonstrated compared to other histological factors of poor prognosis [START_REF] Prabhudesai | Impact of microscopic extranodal tumor deposits on the outcome of patients with rectal cancer[END_REF][START_REF] Puppa | Pathological assessment of pericolonic tumor deposits in advanced colonic carcinoma: relevance to prognosis and tumor staging[END_REF].

The association of TDs with other histopathological factors of poor prognosis, not only underlies the questions raised about their pathophysiological origin, but also questions their intrinsic prognostic value.

Prognostic impact of TDs

TDs as a qualitative variable

There is growing body of evidence concerning the negative prognostic impact of the TDs presence in patients with CC. The meta-analysis by Nagtegaal et al. [START_REF] Nagtegaal | Tumor Deposits in Colorectal Cancer: Improving the Value of Modern Staging-A Systematic Review and Meta-Analysis[END_REF] summarizes published data on TDs prior to 2017. The average prevalence of TDs for all included studies was 22.0% (range, 4.9% to 41.8%). Survival data from five studies (n = 1246), showed that TDs were associated with poorer DFS (HR = 2.0; 95% CI 1.4-2.8) and overall survival (OS; HR = 2.2; 95% CI 1.7-2.8). However, the parameters included in the prognostic models varied between studies, which may hamper the robustness of this meta-analysis. Patients with pN1c CC (approximately 3-5% of all stage III tumours) experienced similar outcomes than those with pN1a/b tumors; the 3-year DFS was ranging from 60% to 80% [START_REF] Pricolo | Tumor Deposits in Stage III Colon Cancer[END_REF][START_REF] Delattre | 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)[END_REF][START_REF] Wong-Chong | Impact of Tumor Deposits on Oncologic Outcomes in Stage III Colon Cancer[END_REF].

Several cohort studies confirmed the association between poor survival and the presence of TDs in patients with LN-positive CCs [START_REF] Nagtegaal | Tumor Deposits in Colorectal Cancer: Improving the Value of Modern Staging-A Systematic Review and Meta-Analysis[END_REF]. In Wong-Chong study [START_REF] Wong-Chong | Impact of Tumor Deposits on Oncologic Outcomes in Stage III Colon Cancer[END_REF], patients whose tumours had both LNM and TDs (18.4% of the entire population) had significantly worse 5-year OS than those with LN-positive and TD-negative tumors or with pN1c tumors (46.0% versus 63.4% or 61.9%). The negative prognostic impact of the presence of TDs was observed regardless of the pN substage (≤ 3 positive LN, or ≥4 LNM) [START_REF] Mirkin | Prognostic Significance of Tumor Deposits in Stage III Colon Cancer[END_REF]. Unfortunately, the NCDB data do not provide any information on local recurrence or metastatic disease and therefore DFS could not be estimated. Similar results were reported from analyses of the Surveillance, Epidemiology and End Results (SEER) database [START_REF] Peacock | Improving the AJCC/TNM staging classification for colorectal cancer: The prognostic impact of tumor deposits[END_REF]. Overall, these studies suggest that the presence of TDs should be considered despite the pN substage and should not be restricted to the pN1c population. However, several limitations preclude to draw any definitive conclusion, notably the retrospective nature of these studies that are based on cohort or registries with no control on the therapeutic management.

Taking advantage of two recent adjuvant therapy trials with fluoropyrimidine and oxaliplatin in stage III disease, (IDEA France [START_REF] Delattre | 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)[END_REF] and CALGB/SWOG 80702 [START_REF] Cohen | 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)[END_REF]) both comparing 3 months to 6 months of therapy, we have recently conducted two distinct post-hoc analyses [START_REF] Delattre | 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)[END_REF][START_REF] Cohen | 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)[END_REF] focused on prognostic value of TDs. All pathological reports from patients enrolled on those two trials were reviewed for the presence and number of TDs. In the analysis by Delattre et al. [START_REF] Delattre | 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)[END_REF], a low frequency of TDs was reported (184 out of 1942 patients; 9.5%), probably because of a lack of standardization of pathological reports. The pN1a/b and pN1c groups had similar 3-year DFS (78.8%, 95% CI 76.6-80.9 and 80.7%, 95% CI 67.0-89.1, respectively). The negative prognostic impact of the presence of TDs was observed regardless of pN substage. In multivariate analysis, TDs were associated with a higher risk of recurrence or death (HR = 1.4; p=0.0201). In the second study (CALGB/SWOG 80702) [START_REF] Cohen | 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)[END_REF], the incidence of TDs was 26%. Again, the presence of TDs was associated with worse survival outcomes (DFS and OS) for pN1a/b and pN2 groups. Data from these two post-hoc analyses in the adjuvant setting further reinforced the necessity for consideration of TDs in the AJCC/TNM staging system for LN-positive CCs that represent most TDs-positive tumours (i.e., pN1c tumours account for only 15.4% to 29.9% of all TDs-positive cases).

Regarding rectal cancer, the impact of TDs remains even more complex, as the pathological analysis often occur after multimodality treatment, including chemotherapy and radiotherapy. Therefore, it has been suggested that the pN1c category cannot be used because it is unclear whether the TDs are true "TDs" or these are just residual tumour cells present in the mesorectum [START_REF] Song | Is the N1c category of the new American Joint Committee on cancer staging system applicable to patients with rectal cancer who receive preoperative chemoradiotherapy?[END_REF]. Moreover, the prognostic value of the TDs in this setting remains controversial, while one studies have found a predictive role of poor response for TDs in case of preoperative multimodal treatment [START_REF] Gopal | Tumor deposits in rectal adenocarcinoma after neoadjuvant chemoradiation are associated with poor prognosis[END_REF], other have shown no prognostic impact [START_REF] Song | Is the N1c category of the new American Joint Committee on cancer staging system applicable to patients with rectal cancer who receive preoperative chemoradiotherapy?[END_REF]. New data suggested the prognostic importance of TDs in rectal cancer [START_REF] Wei | The clinicopathologic relevance and prognostic value of tumor deposits and the applicability of N1c category in rectal cancer with preoperative radiotherapy[END_REF][START_REF] Zheng | Prognostic value of tumor deposits in locally advanced rectal cancer: a retrospective study with propensity score matching[END_REF][START_REF] Zhang | Tumor deposits: markers of poor prognosis in patients with locally advanced rectal cancer following neoadjuvant chemoradiotherapy[END_REF][START_REF] Wang | Poor prognostic and staging value of tumor deposit in locally advanced rectal cancer with neoadjuvant chemoradiotherapy[END_REF].

TDs as a quantitative variable

The number of TDs may provide additional prognostic information for patients with stage III CCs. Goldstein et al., [START_REF] Goldstein | 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[END_REF] studied 418 patients with pT3 LN-positive colon adenocarcinomas, 18% of which had TDs. Overall, 31, 15, and 35 patients had 1, 2, or more than 3 TDs, respectively. The 5-year DFS was 35%, 24%, and 2% (p < 0.01) in these groups. Both the presence and number of TDs were associated with the risk of recurrence, independently of the LN status. Another publication by Jin et al. [START_REF] Jin | The impact of tumor deposits on colonic adenocarcinoma AJCC TNM staging and outcome[END_REF], reported a shorter survival for the pN1c group with a number of TDs greater than three (16.5 months versus 32.5 months, p=0.025). These results were confirmed in an analysis of the NCDB database [START_REF] Pricolo | Tumor Deposits in Stage III Colon Cancer[END_REF]. In this study, pN1c patients with ≥ 3 TDs experienced worse survival than those with 1 or 2 TDs (the 5-year OS was 51.4% versus 60.6%) but had similar survival to that of patients with pN2 tumours (48.9%) or those with 1 to 3 LNM and TDs (currently staged as pN1a/b; 50.7%). Shi et al. [START_REF] Shi | The Role of Tumor Deposits in Predicting the Efficacy of Chemotherapy in Stage III Colon Cancer[END_REF] analysed 29 017 stage III CC patients with the known number of TDs from the SEER database. The 5-year cancer-specific survival rates of patients with no TDs, 1-2 TDs, and ≥ 3 TDs were 76.3%, 68.9%, and 53.6%, respectively (p < 0.0001). These results are in line with those from several cohort studies [START_REF] Song | Can the tumor deposits be counted as metastatic lymph nodes in the UICC TNM staging system for colorectal cancer?[END_REF][START_REF] Chen | Questioning the staging of tumor deposits of colorectal cancer in the eighth edition of the TNM classification: validation by prognosis[END_REF] and the CALGB/SWOG 80702 phase III trial [START_REF] Cohen | 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)[END_REF].

In the latter, an increased number of TDs was associated with a significant increase of the HR for DFS and OS: the higher the count of TDs the worse the survival prognostic [START_REF] Cohen | 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)[END_REF]. Table 1 summarizes the main studies assessing TDs in cancer patients in the last 4 years.

Possible scenarios for the integration of TDs in the AJCC/TNM classification

The presence and number of TDs have a negative prognostic impact for patients with CC, regardless of the pN substage. This histological feature, however, is considered currently only in the absence of LNM in the AJCC/TNM7 and AJCC/TNM8 classifications. Therefore, a modification of the current pN category in the AJCC/TNM staging system seems warranted, with several conceivable scenarios (Table 2):

1/ Combining the number of TDs with the number of LNM

In this scenario, TDs are considered as a quantitative parameter and one TD is considered as one LNM: pN1 CCs (less than four LNM or the presence of TDs without positive LN) would be restaged as pN2 if the combined number of TDs and LNM would be four or more [START_REF] Song | Can the tumor deposits be counted as metastatic lymph nodes in the UICC TNM staging system for colorectal cancer?[END_REF]. This scenario, which is supported by the prognostic impact of TD as a quantitative parameter, was explored in the post-hoc analyses of the IDEA France and CALGB/SWOG 80702 studies [START_REF] Delattre | 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)[END_REF][START_REF] Cohen | 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)[END_REF]. In the first study, 35 patients initially classified as pN1 (2.4%) were reclassified as pN2 by adding TDs to the count of LNM. These patients experienced worse DFS than patients whose number of TDs and LNM remained inferior to four (the 3-year DFS: 60.7% versus 79.3%; p=0.015) and similar prognosis compared to those initially classified as pN2 [START_REF] Delattre | 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)[END_REF]. These results were confirmed in the CALGB/SWOG 80720 trial for both DFS and OS [START_REF] Cohen | 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)[END_REF]. Overall, 104 of 1470 (7.1%) patients initially considered as pN1 were restaged as pN2.

These restaged patients experienced significantly worse DFS compared to those who remained pN1 (the 3-year DFSe: 65.4% versus 80.5%, p=0.0003) and OS (the 5-year OS: 69.1% versus 87.9%, p=0.0001). Survival outcomes were not significantly different between patients restaged as pN2 and those initially staged as pN2 (the 3-year DFS: 65.4% versus 62.3%, respectively, p=0.4895). These results demonstrate that scenario #1 may impact a significant proportion of patients (from 2.4% to 7.1%) and would significantly improve the considers only the presence or absence of TDs, even though the number of TDs has been shown to provide additional prognostic accuracy.

4/ Including TDs in the pM category

Another proposed scenario is to include TDs in the M category as in-transit melanoma metastases. TDs without lymphocytes and associated with veins and/or nerves would be classified in the M1a category, whereas cases with distant (visceral) metastases in the M1b category [START_REF] Puppa | Tumor deposits are encountered in advanced colorectal cancer and other adenocarcinomas: an expanded classification with implications for colorectal cancer staging system including a unifying concept of in-transit metastases[END_REF].

This scenario is also with limitations. It ignores the number of TDs and its potential impact on the prognostic accuracy and therapeutic decisions is unclear since it would induce a stage migration of all TD-positive CCs from stage III to stage IV.

Conclusions

The presence and number of TDs are the major independent prognostic factors for patients with stage III CC. These represent a decisive source of prognostic information and can no longer be ignored either in pathology reports or in evaluation of patients' prognosis. It is crucial that pathologists use a standardized report requesting the presence or absence and the number of TDs. Nonetheless, many questions about their definition and origin and the best way to consider them in the AJCC/TNM staging system remain unanswered. Further studies evaluating the prognostic accuracy of different scenarios for the new TNM classification are warranted.

Figure 1 .

 1 Figure 1. The changes in the diagnostic criteria for TDs according to different editions of the

Fig. 1 TNM5

 1 Fig. 1

  Epidemiology and End Results, FUSCC: Fudan University Shanghai Cancer Center, NCDB: National Cancer Data Base, EMVI: extramural vascular invasion; LNM: lymph node metastases, PNI: perineural growth, LVI: lymphatic invasion, TD: tumor deposit, DFS: disease-free survival,

	Liu [50] Delattre [19] Post-hoc/Multicenter Retrospective/FUSCC	All III	3137 1932	14.8 9.5	Location, PNI		OS: HR 3.2 (2.6-4.0) Poorer prognosis in	Reclassification has been Reclassification has been	NA NA
							T, N, PNI,	the presence of TD	proposed proposed
							EMVI		irrespective of N
	Peacock [22] Retrospective/SEER Mirkin [20] Retrospective/NCDB Landau [23] Retrospective	histological	I/III III II/III	74494 6424 256	6 2.5 21	Stage, LNM Grade, PNI. NA Stage,	CSS: patients with TD for worse in stage 5-year OS: 40.2% (TD, LNM) vs all groups (N0, N1a/b, DFS: HR: 2.2 (1.2-55.4% (LNM alone) N2) 68.1% (TD alone) vs	Reclassification has been NA proposed No impact of size,	NA Less ACT in pN1c patients; NA p=0.003
	review/Monocentric Retrospective/SEER Retrospective/SEER Retrospective/SEER Retrospective/SEER Bouquot [32] Case control/bicentric Pei [46] Liu [51] Bai [52] Bai [52]	III III/IV III III III pN1c	14906 25868 6384 10504 10802 1122	13.1 18.6 13.1 15 15.5 18.3	EMVI PNI NA T, N, TNM, Location Grade NA T, Stage, Location PNI T, EMVI, Location,	4.0); worse 5-year OS: in 73.5 (TD+) % vs N1a/b patients with TD CSS: worse in N1c 54.4% (TD-); p<0.001 patients compared 5-year OS: with N0/1a but better 74.5% (TD+) vs than in N2 patients CSS: worse in N1/2 patients with TD 56.8% (TD-); p<0.001 No effect of TD on pN1c between pN1a/b and No difference	Less N1c with new Reclassification has been definition proposed NA Reclassification has been proposed Increased number of TD is associated with poor outcome NA	NA NA NA Less ACT in patients with TD, p<0.001) 39% without TD (36% vs NA
										pN1a/b
	Simon [53]	Retrospective/NCDB		pN1c	5684	1.59	NA			1-year OS: no-ACT	NA	ACT
	Wong-	Retrospective/Multicenter/NCDB	III	74577	6.8	NA			5-year vs ACT: 96.2% vs OS: 46%	NA	Less ACT in administered in
	Chong [21]									(TD+LNM) vs 63.4% 80%,	pN1c patients; 55% of N1c
										(LNM 3-year OS: no-ACT alone) vs	p<0.001 patients
										61.9% (TD alone) vs ACT: 67.4% vs
	Zheng [39]	Retrospective/SEER		III	4623	19.3	NA			OS: HR 1.6 (1.5-1.8) 72.9%,	NA	NA
										OS TD+LNM worse 5-year OS: no-ACT
										outcome vs ACT: 48.5% vs
	Cohen [35]	Post-hoc/Multicenter		III	2028	26	T,	LNM,	DFS: HR 1.6 (1.3-33.8%; p<0.001	Increased number of TD	NA
	Pricolo [18] SEER: Surveillance, OS: Retrospective/NCDB overall survival,	III CSS:	42901 cause-specific 3.9	LVI, PNI NA	2.0) OS: HR 1.6 (1.2-2.0) OS: 41.5% (TD+LNM) vs 59.8% survival, ACT:	is associated with poor outcome Increased number of TD is poorer outcome. adjuvant	NA chemotherapy
										(LNM	alone)	vs	Reclassification has been
										58.2% (TD alone)	proposed

prognosis accuracy of the AJCC/TNM classification. Still, although these two IDEA post-hoc studies lack an area under the curve analysis to evaluate properly the prognostic discrimination of this modified pN classification, they demonstrate the superiority of this system over the current AJCC/TNM staging system.

2/ Creating a pN2c substage

Other authors proposed to create new categories in the AJCC/TNM classification, which would consider the number of TDs while maintaining a pN1c group. In this modified pN system, tumors with both LNM and TDs, whatever their number, would be restaged as pN2c.

Only patients with one or two TDs and no positive LN would remain in the pN1c group. This is supported by data provided by Pricolo et al. [START_REF] Pricolo | Tumor Deposits in Stage III Colon Cancer[END_REF] showing that pN1c CC patients with more than two TDs have worse survival outcomes than those with only one or two TDs.

The disadvantage of this strategy is that the number of TDs and LNM is ignored when tumours harbour these two pathological features.

3/ Integrating the presence of TDs within the pN subgroups

Several authors evaluated staging systems with TDs as a qualitative parameter. Analysing patients data from the SEER database, Peacock et al. [START_REF] Peacock | Improving the AJCC/TNM staging classification for colorectal cancer: The prognostic impact of tumor deposits[END_REF] proposed an AJCC reclassification which would incorporate the presence of TDs into each nodal status: pN1c tumours would be integrated to the pN1b substage, TDs-positive pN1a/b tumours would be restaged as pN2a, pN2a TDs-positive tumours would be restaged as pN2b, and a new "pN3" category would be created for pN2b TDs-positive tumours. A similar modified TNM classification was developed by Pei et al. [START_REF] Pei | A Modified Pathological N Stage Including Status of Tumor Deposits in Colorectal Cancer With Nodal Metastasis[END_REF] with superior model-fitting compared with pN stage.

Nonetheless, the complexity of such a system might hamper its implementation into daily clinical practice. Besides, the retrospective nature of these two mentioned analyses, which are based on one single dataset, do not permit firm conclusions to be drawn. Finally, this scenario ACKNOWLEDGEMENTS: Editorial support was provided by Magdalena Benetkiewicz, PhD.

ROLE OF FUNDING SOURCE:

This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

DECLARATION OF COMPETING INTEREST:

TA reports consulting/advisory role and/or honoraria from Amgen, Astellas Pharma, AstraZeneca, Bristol-Myers Squibb, Chugai, Clovis, Gritstone Oncology, GlaxoSmithKline,