Independent prognostic value of tumor deposits in stage III colorectal cancer: a large-scale systematic review and meta-analysis

Introduction

Colorectal cancer (CRC) ranks as the third most common malignancy and the second leading cause of cancer-related death globally, posing a significant public health threat to human health (1). Global epidemiological data indicate that the age-standardized incidence rate of CRC ranges from 58 to 89 per 100,000 individuals, with stage III patients accounting for 30–40% of all cases (2). Despite the adoption of curative surgery combined with adjuvant chemotherapy as the first-line treatment for stage III CRC, the 5-year recurrence rate remains at 20–40%. Moreover, substantial heterogeneity in survival outcomes exists among patients with the same tumor-node-metastasis (TNM) stage, suggesting that the current staging system centered on lymph node metastasis (LNM) count has room for optimization. There is an urgent need to identify more precise prognostic indicators to guide individualized treatment.

Tumor deposits (TDs) are a distinct pathological entity in CRC, first described in 1935 as discrete nodules of tumor cells discontinuous from the primary tumor in the pericolonic or perirectal adipose tissue. According to the 7th edition of the American Joint Committee on Cancer (AJCC) TNM staging system, TDs are formally defined as isolated tumor foci identified in the pericolonic, perirectal, or adjacent mesenteric adipose tissue, lacking histologically recognizable residual lymph node architecture, vascular, or neural components (3,4). Since this edition, the prognostic value of TDs has been initially recognized—TDs-positive patients without positive lymph nodes are classified as N1c stage, categorized under stage III CRC, and recommended for adjuvant chemotherapy (5,6). However, the prognostic significance of TDs in lymph node-positive (LN+) stage III CRC patients remains unclear, particularly lacking quantitative evidence, which has become a key point of contention in current staging systems and clinical practice.

Existing studies have confirmed that the incidence of TDs in stage III CRC patients ranges from 10% to 30%, and their presence is closely associated with adverse patient outcomes (7,8). Nevertheless, the 8th edition of the AJCC TNM staging system still relies solely on the number of positive lymph nodes for N staging, failing to fully integrate TDs as a crucial prognostic factor (9). For patients with both TDs and LNM, there is a lack of targeted staging strategies. Additionally, fundamental controversies persist regarding whether TDs and LNM have equivalent prognostic value and whether they exert a synergistic effect (10-12). Some studies advocate counting TDs as positive lymph nodes for staging purposes (13,14), while others, through pathological morphological and molecular characterization, have confirmed that TDs exhibit unique biological behaviors with prognostic significance independent of LNM (15-17). Furthermore, inconsistencies remain regarding whether the impact of TDs on prognosis varies across different N subgroups (N1 and N2) and whether differential risk weighting is warranted.

This study aims to systematically evaluate the prognostic value of TDs in stage III CRC patients (including N1 and N2 subgroups) through a systematic review and meta-analysis, clarify the interactive effects of TDs and LNM on survival outcomes, and provide evidence-based medicine to optimize the CRC TNM staging system and guide the development of individualized treatment strategies, with 5-year overall survival (OS) and 5-year disease-free survival (DFS) as the primary outcomes. We present this article in accordance with the PRISMA reporting checklist (available at https://jgo.amegroups.com/article/view/10.21037/jgo-2026-0313/rc) (18).

Methods

This study was registered in PROSPERO (ID: CRD420261288077) and conducted in strict adherence to Cochrane Handbook for Systematic Reviews of Interventions (19). As a secondary analysis of anonymized published data, ethical approval and informed consent were waived.

Literature search strategy

A comprehensive search was performed across PubMed, ScienceDirect, Web of Science, Cochrane Library, and Embase databases for studies published from database inception to December 31, 2025. A combination of MeSH terms and free-text words was used, including “colorectal cancer”, “rectal cancer”, “colon cancer”, “tumor deposits”, “tumour deposits”, and “nodular deposits”. Search strategies were tailored to the specific features of each database. Additionally, reference lists of included studies and recent publications in high-impact journals in the field were manually searched to avoid missing potentially eligible studies. The initial database search had no language restrictions, but only English full-text studies were included for accurate data extraction and quality assessment.

Inclusion and exclusion criteria

Two independent researchers (J.L., H.Q.) screened the literature according to predefined inclusion and exclusion criteria, following the PRISMA statement guidelines: initial screening based on titles and abstracts to exclude clearly ineligible studies; full-text review of potentially eligible studies for final confirmation. Disagreements between the two researchers were resolved through discussion, with involvement of a third independent researcher for arbitration if necessary.

Inclusion criteria: (I) pathologically confirmed stage III colorectal adenocarcinoma (per AJCC 6th edition or later staging criteria); (II) pathological diagnosis of TDs conforms to the AJCC/TNM staging system (6th edition and later). (III) studies reporting TDs status; (IV) prospective or retrospective study design; (V) studies including OS or DFS as outcome measures.

Exclusion criteria: (I) patients with stage I, II, IV, or recurrent CRC; (II) patients not undergoing curative surgery; (III) studies not reporting 5-year OS or 5-year DFS; (IV) studies not reporting TD+LN+, TD−LN+, or TD+LN− subgroups; (V) duplicate publications and low-quality studies; (VI) conference abstracts, case reports, reviews, systematic reviews, meta-analyses, and basic experimental studies; (VII) studies with incomplete data, missing data, or no extractable data.

Data extraction and quality assessment

Two independent researchers (J.L., H.Q.) extracted data using a pre-designed data extraction form, including: (I) basic study information (first author, year of publication, country, year of data inclusion, study design, study population, and follow-up duration); (II) quality assessment indicators; (III) outcome measures (number of events (deaths/recurrences) and total number of patients for 5-year OS and 5-year DFS, or survival curves and related statistics convertible to the above data). For studies with unclear or missing data, corresponding authors were contacted via email for supplementary information. If no response was received after multiple attempts, the study was considered to have missing data, and the reason for exclusion was documented.

The Newcastle-Ottawa Scale (NOS) was used to assess the quality of retrospective cohort studies (RCSs) (20), encompassing three dimensions: selection of cases (4 points), comparability between groups (2 points), and assessment of outcomes (3 points), with a maximum score of 9. Studies with a score ≥6 were considered high-quality. For randomized controlled trials (RCTs), the Jadad scoring scale was employed (21), evaluating four dimensions: random sequence generation, allocation concealment, blinding, and withdrawal/loss to follow-up, with a maximum score of 5. Studies with a score ≥3 were deemed high-quality. Quality assessment was performed independently by two researchers, with disagreements resolved through discussion or arbitration by a third researcher.

Statistical analysis

Statistical analyses were conducted using the “meta” packages in R software (version 4.4.1). Dichotomous outcomes (5-year OS, 5-year DFS) were synthesized using relative risk (RR) with 95% confidence intervals (CI) as the effect size, given that RR is more intuitive for clinical interpretation than hazard ratio in this setting. Heterogeneity among studies was assessed using the Q test (significance level α=0.10) and I² statistic: I²<40% indicated low heterogeneity, and a fixed-effects model was used for data synthesis; I²≥40% suggested moderate to high heterogeneity, and a random-effects model using the DerSimonian-Laird method was employed. Subgroup analyses (stratified by N1/N2 subgroups, tumor location, and study region) were performed to explore potential sources of heterogeneity (22). Sensitivity analysis was conducted by sequentially excluding individual studies to test the robustness of the pooled results. Publication bias was evaluated through visual inspection of funnel plots combined with Egger’s weighted linear regression test (23). All statistical tests were two-tailed, with P<0.05 considered statistically significant. If publication bias was detected, the Trim-and-fill method was used for correction, and the corrected effect size was reported.

Results

Literature search and inclusion

A total of 1,252 relevant studies were retrieved through systematic searches across PubMed (n=412), Science Direct (n=127), Web of Science (n=624), Cochrane Library (n=35), and Embase (n=54) databases, supplemented by manual searches (n=3). After removing duplicate studies (n=382) using Endnote software, 133 studies were excluded due to incomplete or inadequate data, 700 studies were excluded after initial screening based on titles and abstracts, and 7 studies were excluded due to unobtainable full texts. Full-text assessment of the remaining 33 studies resulted in the exclusion of 15 studies, ultimately leading to the inclusion of 18 high-quality studies involving 236,867 stage III CRC patients. The flowchart of literature screening is shown in Figure 1.

Figure 1 The flowchart of literature screening.

Included studies were from eight countries, consisting of 2 RCTs (24,25), 16 RCSs (3,7,12-14,26-36). Only one study (28) did not report the TD+LN− subgroup, while the remaining 17 studies (3,7,12-14,24-27,29-36) reported data for TDs positivity but lymph node negativity (TD+LN−), TDs positivity and lymph node positivity (TD+LN+), and TDs negativity but lymph node positivity (TD−LN+) subgroups. Five studies (13,14,24,27,28) reported both OS and DFS, while the remaining studies reported a single outcome measure. The basic characteristics and quality assessment results of the included studies are summarized in Table 1.

TD+LN− vs. TD+LN+ comparisons and subgroup analyses

Fourteen studies (3,12-14,24,26,27,29-34,36) (I²=67.2%, P<0.001) analyzed using a random-effects model showed that TD+LN− patients had significantly better OS compared to TD+LN+ patients (RR =0.72, 95% CI: 0.67–0.77, Z=−9.78, P<0.001) (Figure 2A). Seven studies (7,12,13,24,25,27,35) (I²=39.9%, P=0.13) analyzed using a fixed-effects model demonstrated that TD+LN− patients had significantly better DFS than TD+LN+ patients (RR =0.83, 95% CI: 0.71–0.96, Z=−2.54, P=0.01) (Figure 2B).

Figure 2 Forest plots of data on 5-year OS and DFS in patients with TD+LN− vs. TD+LN+ and its subgroup analysis. (A) OS in TD+LN− vs. TD+LN+; (C) OS in TD+LN− vs. TD+LN1; (E) OS in TD+LN− vs. TD+LN2; (B) DFS in TD+LN− vs. TD+LN+; (D) DFS in TD+LN− vs. TD+LN1; (F) DFS in TD+LN− vs. TD+LN2. CI, confidence interval; DFS, disease-free survival; LN, lymph node; OS, overall survival; TD, tumor deposit.

In LN1 subgroup analyses, nine OS studies (3,12,13,24,27,30-32,34) (I²=0%, P=0.57) and four DFS studies (13,24,25,27) (I²=0%, P=0.91) were analyzed using fixed-effects models. TD+LN− patients exhibited significantly better OS (RR =0.81, 95% CI: 0.78–0.84, Z=−10.27, P<0.001) (Figure 2C) and DFS (RR =0.75, 95% CI: 0.61–0.92, Z=−2.73, P=0.006) (Figure 2D) compared to TD+LN1 patients.

In LN2 subgroup analyses, nine OS studies (3,12,13,24,27,30-32,34) (I²=67.6%, P=0.002) analyzed using a random-effects model showed that TD+LN− patients had significantly better OS than TD+LN2 patients (RR =0.63, 95% CI: 0.52–0.75, Z=−4.96, P<0.001) (Figure 2E). Four DFS studies (13,24,25,27) (I²=38.4%, P=0.18) analyzed using a fixed-effects model demonstrated that TD+LN− patients had significantly better DFS compared to TD+LN2 patients (RR =0.67, 95% CI: 0.54–0.83, Z=−3.74, P<0.001) (Figure 2F).

TD+LN− vs. TD−LN+ comparisons and subgroup analyses

Fourteen studies (3,12-14,24,26,27,29-34,36) (I²=76.6%, P<0.001) analyzed using a random-effects model revealed that TD+LN− patients had significantly poorer OS than TD−LN+ patients (RR =1.21, 95% CI: 1.06–1.38, Z=2.74, P=0.006) (Figure 3A). Seven studies (7,13,14,24,25,27,35) (I²=56.7%, P=0.03) analyzed using a random-effects model showed that TD+LN− patients had significantly inferior DFS compared to TD−LN+ patients (RR =1.30, 95% CI: 1.04–1.62, Z=2.31, P=0.02) (Figure 3B).

Figure 3 Forest plots of data on 5-year OS and DFS in patients with TD+LN− vs. TD−LN+ and its subgroup analysis. (A) OS in TD+LN− vs. TD−LN+; (C) OS in TD+LN− vs. TD−LN1; (E) OS in TD+LN− vs. TD−LN2; (B) DFS in TD+LN− vs. TD−LN+; (D) DFS in TD+LN− vs. TD−LN1; (F) DFS in TD+LN− vs. TD−LN2. CI, confidence interval; DFS, disease-free survival; LN, lymph node; OS, overall survival; TD, tumor deposit.

In LN1 subgroup analyses, nine OS studies (3,12,13,24,27,30-32,34) (I²=68.5%, P=0.001) analyzed using a random-effects model demonstrated that TD+LN− patients had significantly poorer OS than TD-LN1 patients (RR =1.39, 95% CI: 1.18–1.64, Z=3.98, P<0.001) (Figure 3C). Five DFS studies (7,13,24,25,27) (I²=40.3%, P=0.15) analyzed using a fixed-effects model showed that TD+LN− patients had significantly worse DFS compared to TD-LN1 patients (RR =1.44, 95% CI: 1.20–1.73, Z=3.99, P<0.001) (Figure 3D).

In LN2 subgroup analyses, 9 OS studies (3,12,13,24,27,30-32,34) (I²=80%, P<0.001) and 5 DFS studies (7,13,24,25,27) (I²=57.0%, P=0.054) were analyzed using random-effects models. No statistically significant differences were observed in OS (RR =0.89, 95% CI: 0.70–1.13, Z=−0.98, P=0.33) (Figure 3E) or DFS (RR =0.90, 95% CI: 0.66–1.23, Z=−0.66, P=0.51) (Figure 3F) between the two groups.

TD+LN+ vs. TD−LN+ comparisons and subgroup analyses

Fifteen studies (3,12-14,24,26-34,36) (I²=75.3%, P<0.001) analyzed using a random-effects model showed that TD+LN+ patients had significantly poorer OS compared to TD−LN+ patients (RR =1.58, 95% CI: 1.50–1.65, Z=19.49, P<0.001) (Figure 4A). Eight studies (7,13,14,24,25,27,28,35) (I²=35.9%, P=0.14) analyzed using a fixed-effects model demonstrated that TD+LN+ patients had significantly inferior DFS than TD-LN+ patients (RR =1.64, 95% CI: 1.52–1.75, Z=13.78, P<0.001) (Figure 4B).

Figure 4 Forest plots of data on 5-year OS and DFS in patients with TD+LN+ vs. TD−LN+ and its subgroup analysis. (A) OS in TD+LN+ vs. TD−LN+; (C) OS in TD+LN1 vs. TD−LN1; (E) OS in TD+LN2 vs. TD−LN2; (B) DFS in TD+LN+ vs. TD−LN+; (D) DFS in TD+LN1 vs. TD−LN1; (F) DFS in TD+LN2 vs. TD−LN2. CI, confidence interval; DFS, disease-free survival; LN, lymph node; OS, overall survival; TD, tumor deposit.

In LN1 subgroup analyses, nine OS studies (3,12,13,24,27,30-32,34) (I²=43.6%, P=0.08) analyzed using a random-effects model revealed that TD+LN1 patients had significantly poorer OS compared to TD-LN1 patients (RR =1.63, 95% CI: 1.56–1.71, Z=20.35, P<0.001) (Figure 4C). Four DFS studies (13,24,25,27) (I²=9.5%, P=0.35) analyzed using a fixed-effects model showed that TD+LN1 patients had significantly worse DFS than TD-LN1 patients (RR =1.79, 95% CI: 1.59–2.02, Z=9.57, P<0.001) (Figure 4D).

In LN2 subgroup analyses, nine OS studies (3,12,13,24,27,30-32,34) (I²=0, P=0.52) and four DFS studies (13,24,25,27) (I²=0, P=0.89) were analyzed using fixed-effects models. TD+LN2 patients had significantly poorer OS (RR =1.32, 95% CI: 1.30–1.34, Z=34.86, P<0.001) (Figure 4E) and DFS (RR =1.30, 95% CI: 1.15–1.47, Z=4.22, P<0.001) (Figure 4F) compared to TD-LN2 patients.

Sensitivity analysis and publication bias

Sensitivity analysis for TD+LN− vs. TD+LN+ (sequential individual study exclusion) showed no significant fluctuations in RR and 95% CI across comparisons and subgroups, confirming the meta-analysis results’ robustness. Publication bias assessment via funnel plot visualization and Egger’s weighted linear regression revealed no significant asymmetry for OS (P=0.84) or DFS (P=0.63) analyses of TD+LN− vs. TD+LN+, indicating minimal publication bias and high result reliability (Figure 5).

Figure 5 Egger’s publication bias and sensitivity analysis plot in (A) OS with TD+LN− vs. TD+LN+ and (B) DFS with TD+LN− vs. TD+LN+. CI, confidence interval; DFS, disease-free survival; LN, lymph node; OS, overall survival; TD, tumor deposit.

Discussion

Historically, TDs were considered a special form of LNM, but current evidence generally supports their independent biological nature. The 2025 TNM 9th edition revision consensus further clarifies that TDs are discrete tumor nodules discontinuous from the primary tumor in the pericolorectal adipose tissue, which can originate from lymph node, vascular, or neural structures but must be distinguished from simple vascular or neural invasion (37). Despite long-standing controversies regarding the origin of TDs, their crucial prognostic value in stage III CRC is undeniable. However, the current TNM staging system only classifies TDs-positive, lymph node-negative status as N1c, severely underestimating the core role of TDs in tumor staging and prognostic assessment (38-40).

Based on data from 18 high-quality studies involving 236,867 stage III CRC patients, this study systematically validated the independent prognostic value of TDs through three core comparisons (TD+LN− vs. TD+LN+, TD+LN− vs. TD−LN+, TD+LN+ vs. TD−LN+) and subgroup analyses stratified by LN1 and LN2, clarifying the regulatory role of the combined effects of TDs and LNM on patient survival outcomes. These findings are expected to provide evidence-based medicine for the precise staging and individualized treatment of CRC.

The presence of TDs is independently associated with worse prognosis in stage III CRC patients, with its prognostic impact significantly dependent on lymph node status—this core conclusion is consistent with several landmark studies in recent years (11,40-42). In the core comparison of TD+LN+ vs. TD−LN+, this study found that TD+LN+ patients had a 58% increased risk of 5-year OS and a 64% increased risk of 5-year DFS compared to TD−LN+ patients, with this adverse effect consistently observed in both LN1 and LN2 subgroups (LN1 subgroup OS: RR =1.63; LN2 subgroup OS: RR =1.32). This is highly consistent with the conclusions of a 2023 study by Wang et al. (42) based on 38,446 patients from the Surveillance, Epidemiology and End Results (SEER) database—the proposed “coN” staging system confirmed that TDs-positive patients had a significantly increased risk of cancer-specific death (HR =1.37, 95% CI: 1.31–1.44) and exhibited a synergistic adverse effect with LNM, essentially reflecting the additive effect of two independent dissemination patterns on the malignant phenotype of the tumor. Notably, the prognostic impact of TDs was significantly stronger in the LN1 subgroup than in the LN2 subgroup (DFS: RR =1.79 vs. RR=1.30), suggesting that TDs play a more dominant prognostic role in the setting of low LNM burden. This finding is consistent with the conclusions of a 2023 systematic review by Ueno et al. (39): TDs can effectively distinguish high-risk populations among N1 stage patients, while in N2 stage patients, LNM burden becomes the dominant prognostic factor, and the additional impact of TDs is partially masked. The underlying mechanism for this phenomenon may be related to the “threshold effect” of tumor burden—when the LNM burden reaches a certain level (e.g., N2 stage), its impact on prognosis becomes predominant, and the independent effect of TDs is attenuated. Furthermore, the comparison of TD+LN− vs. TD−LN+ showed that TD+LN− (N1c stage) patients had significantly poorer OS and DFS compared to TD−LN1 patients but no significant difference from TD−LN2 patients. This result clarifies the prognostic position of N1c stage as intermediate between N1 and N2, confirming the core conclusion from a meta-analysis by Nagtegaal et al. (43) that “N1c stage patients have a significantly higher survival risk than traditional N1 stage patients”. It also explains why the current practice of simply classifying N1c stage into N1 stage leads to the underestimation of prognostic heterogeneity.

The precise stratification value of TDs count has emerged as a research hotspot in recent years, providing important supplementary insights to the results of this study. Historically, most studies have focused on the presence or absence of TDs, but a study by Wang et al. (42) based on the SEER database first identified the optimal cutoff value for TDs count as 4, with 5-year OS rates of 69.4%, 60.5%, and 42.6% for TD0 [0], TD1 [1–3], and TD2 [≥4] patients, respectively, showing a significant gradient downward trend. Lundström et al. (41) further validated through Swedish national cancer registry data that patients with ≥5 TDs had a 5-year OS rate of only 49%, significantly lower than the 79% observed in patients without TDs, with this association independent of LNM status. Although this study did not directly analyze TDs count, subgroup results indirectly corroborated the prognostic effect related to TDs count—the survival difference between TD+ and TD− patients in the LN2 subgroup (OS: RR =1.32; DFS: RR =1.30) was attenuated compared to the LN1 subgroup (OS: RR =1.63; DFS: RR =1.79), suggesting that the impact of TDs count may be partially masked in the setting of high LNM burden. A study by Zheng et al. (44) further confirmed that among low-risk stage III patients (T1-3N1), those with ≥3 TDs had a significantly higher cancer-specific mortality rate (HR =3.445) compared to those with 1–2 TDs, while this difference was attenuated in high-risk patients, highlighting the prognostic refinement value of TDs count in low-risk populations. Additionally, a study by Liu et al. (45) found that combined analysis of TDs and the lymph node ratio (LNR) significantly improved prognostic predictive performance—TDs-positive patients with high LNR (≥0.4) had a 4.09-fold higher risk of CRC-specific death (95% CI: 3.54–4.72) compared to TDs-negative patients with low LNR, with particularly poor prognosis in right-sided CRC. This suggests that combined assessment of TDs count and LNM burden can further optimize risk stratification, providing a more comprehensive dimension for precise clinical risk assessment. We believe that TDs count should serve as a key supplementary indicator for risk stratification in stage III CRC, particularly in low-risk populations, enabling effective identification of high-recurrence-risk patients who may be underestimated by traditional staging.

The prognostic value of TDs is also associated with tumor location and treatment modality. In rectal cancer patients receiving neoadjuvant chemoradiotherapy (nCRT), the prognostic impact of TDs may be attenuated—a phenomenon validated in several studies. nCRT can reduce the biological activity of TDs by inhibiting local tumor invasiveness, inducing tumor cell degeneration and fibrosis, thereby weakening their adverse impact on survival outcomes (14). For example, a study of 91 cT3/cT4 rectal cancer patients showed that despite 3-year DFS being significantly lower in patients with MRI-detected TDs (ymrTDs) after nCRT compared to negative patients (44.83% vs. 82.73%, P<0.001), the adverse prognostic effect of TDs was significantly attenuated compared to rectal cancer patients not receiving nCRT (46). Moreover, the degree of TDs regression was closely associated with DFS (3-year DFS of 69.23% in patients with good regression vs. 33.33% in those with poor regression). In contrast, in colon cancer patients, whose treatment modality primarily consists of surgery combined with adjuvant chemotherapy, the lack of local radical chemoradiotherapy to inhibit tumor invasiveness results in a more pronounced adverse effect of TDs (26). This is consistent with the observed trend of site-specific heterogeneity in this study and aligns with the pathological findings by Jiang et al. (47)—the incidence of TDs in colon cancer (28.3%) was significantly higher than in rectal cancer (19.7%), and TDs were associated with poorer pathological differentiation and vascular invasion. This site-specific difference suggests that the assessment of TDs prognostic value should take into account tumor location and treatment modality, and future staging system optimization should consider incorporating site stratification factors.

The 8th edition of the AJCC TNM staging system only classifies TD+LN- as N1c stage and fails to incorporate TDs status into the staging stratification of LN+ patients, leading to inadequate prognostic assessment—this limitation is fully demonstrated in this study. TD+LN1 patients in this study had significantly poorer 5-year OS and DFS compared to TD−LN1 patients, with prognosis comparable to some TD−LN2 patients. However, the current staging system does not reflect the characteristics of this high-risk population, which may lead to inappropriate treatment strategy selection—for example, classifying TD+LN1 patients into the same risk group as TD-LN1 patients and administering the same adjuvant chemotherapy regimen may result in insufficient treatment intensity for TD+LN1 patients. A 2023 review by Ueno et al. (39) noted that the definition and classification of TDs in the TNM staging system have undergone 5 revisions but remain controversial. In particular, the 8th edition of the TNM staging system excludes TDs containing vascular/neural structures, leading to the underdiagnosis of approximately 30% of high-risk patients and further exacerbating the disconnect between staging and prognosis. Furthermore, the independent biological nature of TDs and LNM is overlooked. Goldstein et al. (48) confirmed through pathological morphological and molecular characterization that TDs and lymph node metastases differ inherently in their origin, invasion patterns, and molecular expression profiles. The practice of simply counting TDs as positive lymph nodes (as proposed in some studies) can lead to staging inaccuracies—in this study, TD+LN1 patients had significantly better prognosis than TD−LN2 patients, and classifying TDs as equivalent to positive lymph nodes would incorrectly categorize them as N2 stage, inconsistent with actual prognosis. This result negates the view that “TDs are equivalent to positive lymph nodes” from a prognostic perspective. A study by Lino-Silva et al. (49) also supports this conclusion, proposing the addition of a new “pN” subgroup in the TNM staging system to independently reflect the prognostic value of TDs rather than simply incorporating them into lymph node counting.

Based on the findings of this study and the latest literature evidence, the optimization of the TNM staging system should focus on two core directions: repositioning N1c stage and adding TDs subgroups in LN+ patients. The “coN” staging system proposed by Wang et al. (42) serves as a paradigm—this system integrates TDs status and LNM, classifying stage III colon cancer into five subgroups (coN1a–coN2c). Compared to the traditional N staging system, it has a smaller Akaike’s information criterion (AIC) value (197,097.581 vs. 197,358.006), a larger C-index (0.611 vs. 0.601), and significantly higher area under the curve (AUC) values for 3-, 5-, and 7-year survival, with external validation in domestic multicenter cohorts. The results of this study support further refinement of the subgroup staging schema: classifying N1 stage into N1a (TD−LN1) and N1b (TD+LN1), N2 stage into N2a (TD−LN2) and N2b (TD+LN2), and clearly positioning N1c stage as a transitional stage between N1 and N2, forming a continuous prognostic gradient of “N1a→N1b→N1c→N2a→N2b”. This schema aligns with the “counting method” staging concept proposed by Sassun et al. (40), which integrated TDs into colon cancer staging. Using institutional and National Cancer Database cohorts, they developed and validated the formula— “RLN⁺ = LN⁺ + + 4 ×log_½(TD + 1)”. This real positive lymph node (RLN+) index combines positive lymph node and TD counts. The Sassun-Mayo N/TNM staging outperformed conventional AJCC staging in OS stratification, supporting its clinical utility for refined colon cancer prognostic assessment.

Despite its large sample size, this meta-analysis has limitations: most included studies are retrospective (only two RCTs), inevitably introducing selection bias. Additionally, incomplete reporting of confounding factors (e.g., adjuvant chemotherapy regimens, tumor differentiation, microsatellite instability status) in some studies may affect result accuracy. Fine-grained TDs stratification (count, size, distribution, origin) was not performed, precluding determination of optimal assessment criteria. Moderate-to-high heterogeneity was observed in certain analyses (e.g., TD+LN− vs. TD−LN+ OS, I²=76.6%), and while corrected via random-effects models, specific sources, like tumor location (colon vs. rectal cancer), neoadjuvant therapy, TDs pathological diagnostic criteria, study design (retrospective vs. prospective), and geographic differences, were not fully elucidated. And meta-regression was not performed due to the limited number of included studies and incomplete reporting of confounding variables. Future studies should address these gaps by: (I) conducting large-sample, multicenter prospective cohorts to validate TDs count/size/origin prognostic value and define optimal pathological criteria; (II) exploring core TDs formation pathways, identifying specific molecular markers (e.g., SFRP2, MXRA5), and developing targeted therapies for high-risk TD+LN+ populations; (III) performing clinical trials to evaluate intensive therapies/immunotherapies in high-risk TD+ patients under modified staging; (IV) establishing integrated prognostic models and user-friendly tools (e.g., nomograms) for precise stage III CRC risk stratification; (V) standardizing TDs diagnosis with unified pathological criteria to enhance staging reproducibility.

Conclusions

This large-sample meta-analysis confirms that TDs are independently associated with worse prognosis in patients with stage III CRC. Combined TDs and LNM exert a synergistic adverse effect: TD+LN+ patients have significantly poorer long-term survival than TD−LN+ patients, with these consistent results across LN1/LN2 subgroups. N1c stage (TD+LN−) patients exhibit intermediate prognostic risk between TD−LN1 and TD−LN2, which is inadequately reflected in the current TNM staging system.

The current TNM staging system underutilizes the prognostic value of TDs. We recommend future revisions incorporate TDs status as a core indicator for stage III CRC, add N1/N2 subgroups (e.g., N1a/N1b, N2a/N2b), and reposition N1c stage. Clinically, emphasis should be placed on TDs pathological detection and reporting; patients should be stratified by TDs status (presence/absence, count, subtype) to develop intensive therapies for high-risk TD+LN+ patients and optimize adjuvant chemotherapy for N1c stage patients. Future prospective, molecular mechanism, and clinical translational studies are needed to further clarify TDs’ clinical value, enhance CRC prognostic precision, and ultimately improve long-term outcomes.

Acknowledgments

None.

Footnote

Reporting Checklist: The authors have completed the PRISMA reporting checklist. Available at https://jgo.amegroups.com/article/view/10.21037/jgo-2026-0313/rc

Peer Review File: Available at https://jgo.amegroups.com/article/view/10.21037/jgo-2026-0313/prf

Funding: This study was supported by the Key Research and Development Program of Guangxi (No. AB23026079).

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://jgo.amegroups.com/article/view/10.21037/jgo-2026-0313/coif). The authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

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