T4bN0 colon cancer shows worse survival than T1–2N1 disease: a multicenter real-world study in China

Introduction

Background

The American Joint Committee on Cancer (AJCC) tumor-node-metastasis (TNM) staging system remains the cornerstone for prognostication and treatment selection in colon cancer (1). Traditionally, stage II disease—defined by tumor penetration without nodal involvement—has been considered to have a more favorable prognosis than stage III disease, which involves regional lymph node metastasis (2). However, accumulating evidence suggests that this paradigm may not fully apply to deeply invasive node-negative tumors, particularly those staged as T4bN0 (3-9).

Rationale and knowledge gap

Multiple registry-based and retrospective studies have reported inferior survival in T4bN0 colon cancer compared with early node-positive subgroups such as T1–2N1, despite the former being classified as stage II under the AJCC 8th edition (2,3,8,10). These observations highlight a mismatch between anatomic stage and biological risk, raising concern that the depth of local invasion may carry prognostic implications comparable to, or even exceeding, limited nodal involvement. Biologically, deeply invasive tumors may reflect a more aggressive phenotype associated with epithelial-mesenchymal transition, occult residual disease, and higher metastatic potential (5,11,12).

In this context, the AJCC Colon Cancer Expert Panel has recently proposed, at American Society of Clinical Oncology (ASCO) 2025, reassignment of T4N0 tumors within the forthcoming AJCC Version 9 framework (13). This proposal aims to better align staging with emerging biological and clinical evidence. However, real-world validation remains limited, particularly in multicenter Asian cohorts. In addition, whether the adverse prognostic signal applies uniformly across T4aN0 and T4bN0 disease, or is driven primarily by T4bN0, remains unclear. Another unresolved question is whether systemic biomarkers such as carcinoembryonic antigen (CEA) further refine risk stratification within these stage groups.

Objective

To address these gaps, we conducted a multicenter retrospective study in a Chinese population restricted to colon cancer cases. We aimed to: (I) compare survival across stage IIB (T4aN0), stage IIC (T4bN0), and stage IIIA (T1–2N1) disease under the AJCC 8th edition framework; (II) characterize the clinicopathological aggressiveness of T4 subgroups; and (III) explore whether preoperative CEA identifies a subgroup with a more unfavorable survival pattern. These findings may help refine risk-adapted staging and postoperative management strategies for biologically high-risk colon cancer. We present this article in accordance with the STROBE reporting checklist (available at https://tcr.amegroups.com/article/view/10.21037/tcr-2026-0545/rc).

Methods

Study design and cohort selection

We conducted a multicenter retrospective cohort study to evaluate the outcomes of T4N0 colon cancer under the AJCC 8th edition framework. Consecutive patients treated between 2014 and 2024 were identified from three academic centers in Yunnan, China: The First Affiliated Hospital of Kunming Medical University, Honghe Prefecture Tumor Hospital, and Yunnan Cancer Hospital. The study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments. The study was approved by the institutional review boards of all participating centers [The First Affiliated Hospital of Kunming Medical University (No. 2024-L-124), The Third People’s Hospital of Honghe Prefecture (No. 2024-KYXM-29), and the Yunnan Cancer Hospital (No. KYLX2024-146)], and the requirement for informed consent was waived because of the retrospective nature of the study.

Eligible patients had histologically confirmed colon adenocarcinoma staged as IIB (T4aN0), IIC (T4bN0), or IIIA (T1–2N1) according to the AJCC 8th edition and had undergone curative-intent surgery. To reduce treatment heterogeneity related to rectal cancer management, all rectal cancer cases were excluded from the revised analysis. Patients with hereditary colorectal cancer syndromes, synchronous or metachronous malignancies, receipt of neoadjuvant therapy, or incomplete pathology or follow-up data were also excluded.

Data collection

Clinicopathological data were extracted from institutional electronic medical records and harmonized across centers. Variables collected included age, sex, body mass index (BMI), primary tumor location, histologic subtype, tumor differentiation, pathologic T and N categories, lymph-node yield, perineural invasion, vascular invasion, bowel obstruction, preoperative CEA, adjuvant chemotherapy, and follow-up outcomes.

Outcome definitions and follow-up

Progression-free survival (PFS) was defined as the time from surgery to documented recurrence, progression, or death, whichever occurred first. Overall survival (OS) was defined as the time from surgery to death from any cause. Patients without an event were censored at the last available follow-up.

Follow-up was performed according to institutional routine clinical practice. Survival status and recurrence information were obtained from outpatient records, inpatient records, and follow-up documentation from the participating centers.

Statistical analysis

Categorical variables were compared using the chi-square test or Fisher’s exact test, as appropriate. Continuous variables were summarized as medians with interquartile ranges (IQRs) and compared using the Kruskal-Wallis test.

Survival curves for PFS and OS were estimated using the Kaplan-Meier method and compared using the log-rank test. Prespecified comparisons included overall comparison among stage IIB, stage IIC, and stage IIIA; pairwise comparisons between stage IIC and stage IIIA, stage IIB and stage IIIA, and stage IIB and stage IIC; and regrouped comparisons between T4N0 and T1–2N1 disease.

Multivariable Cox proportional hazards models were used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) for PFS and OS. Covariates included stage group, sex, age, preoperative CEA, adjuvant chemotherapy, perineural invasion, vascular invasion, bowel obstruction, and tumor sidedness. Additional regrouped Cox models were fitted to compare T4N0 versus T1–2N1 disease. CEA-stratified analyses were performed exploratorily. Formal stage-by-CEA interaction testing was conducted by adding a multiplicative interaction term between stage subgroup and preoperative CEA status to the Cox proportional hazards model.

All statistical analyses were performed using SPSS version 26.0 and R version 4.3.0. A two-sided P value <0.05 was considered statistically significant.

Results

Clinicopathological characteristics

A total of 391 patients with colon cancer were included in the final analysis, including 254 with AJCC 8th edition stage IIB (T4aN0), 56 with stage IIC (T4bN0), and 81 with stage IIIA (T1–2N1) disease. Baseline clinicopathological characteristics are summarized in Table 1. Age, sex, BMI, adjuvant chemotherapy exposure, and primary tumor sidedness were generally balanced across the three groups.

By contrast, T4N0 tumors showed a less favorable pathological profile than stage IIIA disease. Compared with stage IIIA, T4N0 tumors were associated with poorer differentiation, more frequent perineural invasion, and more frequent elevation of preoperative CEA. These adverse features were particularly evident in the T4bN0 subgroup. Overall, these findings suggest that deeply invasive node-negative colon cancer carries a heavier burden of adverse clinicopathological characteristics than early node-positive disease.

Survival disparities under AJCC 8th edition framework

Kaplan-Meier analysis showed a borderline difference in OS among stage IIB, stage IIC, and stage IIIA disease (log-rank P=0.07) (Figure 1A), whereas the corresponding difference in PFS was statistically significant (log-rank P=0.03) (Figure 1B).

Figure 1 Kaplan-Meier curves for OS and PFS among patients with stage IIB (T4aN0), stage IIC (T4bN0), and stage IIIA (T1–2N1) colon cancer after exclusion of all rectal cancer cases. (A) OS across the three stage groups. (B) PFS across the three stage groups. (C) OS for stage IIC versus stage IIIA. (D) PFS for stage IIC versus stage IIIA. (E) OS for stage IIB versus stage IIIA. (F) PFS for stage IIB versus stage IIIA. (G) OS for stage IIB versus stage IIC. (H) PFS for stage IIB versus stage IIC. OS, overall survival; PFS, progression-free survival.

In pairwise comparisons, patients with stage IIC (T4bN0) had significantly worse OS than those with stage IIIA (T1–2N1) disease (log-rank P=0.02) (Figure 1C). A similar pattern was observed for PFS, with stage IIC showing significantly poorer outcome than stage IIIA (log-rank P=0.008) (Figure 1D). In contrast, no statistically significant differences were observed between stage IIB (T4aN0) and stage IIIA for either PFS (log-rank P=0.26) or OS (log-rank P=0.057) (Figure 1E,1F). Direct comparison between stage IIB and stage IIC further showed significantly worse PFS in stage IIC (log-rank P=0.03), whereas the OS difference did not reach statistical significance (log-rank P=0.38) (Figure 1G,1H). Taken together, these results indicate that the adverse prognostic signal within T4N0 colon cancer is driven primarily by the T4bN0 subgroup.

Multivariable survival analysis

Multivariable Cox proportional hazards models for PFS and OS under the AJCC 8th edition framework are presented in Table 2. For PFS, stage IIC remained independently associated with poorer outcome compared with stage IIIA, whereas stage IIB did not. For OS, stage IIC showed an adverse direction of effect relative to stage IIIA, although the association was attenuated after adjustment. Across models, bowel obstruction was consistently associated with worse PFS and OS, while elevated CEA was independently associated with poorer OS. Right-sided tumor location was associated with better PFS.

Exploratory analyses stratified by CEA

CEA-stratified Kaplan-Meier analyses suggested that the adverse survival pattern of stage IIC relative to stage IIIA was more pronounced in patients with elevated preoperative CEA (Figure 2). In patients with elevated CEA, stage IIC showed worse OS than stage IIIA, whereas this difference was less evident in the normal-CEA subgroup. A similar directional pattern was observed for PFS. However, formal stage-by-CEA interaction testing did not reach statistical significance (Table 3). Therefore, the CEA findings should be interpreted as exploratory and hypothesis-generating rather than definitive evidence of interaction.

Figure 2 Kaplan-Meier curves for OS and PFS comparing stage IIC (T4bN0) and stage IIIA (T1–2N1) colon cancer after stratification by preoperative CEA level. (A) OS in patients with elevated CEA (>5 ng/mL). (B) OS in patients with normal CEA (≤5 ng/mL). (C) PFS in patients with elevated CEA (>5 ng/mL). (D) PFS in patients with normal CEA (≤5 ng/mL). CEA-stratified analyses suggested a stronger adverse survival pattern for stage IIC disease in the elevated-CEA subgroup; however, formal stage-by-CEA interaction testing was not statistically significant. CEA, carcinoembryonic antigen; OS, overall survival; PFS, progression-free survival.

Survival under regrouping of T4N0 versus T1–2N1

To evaluate the prognostic direction of the proposed stage reassignment framework, we regrouped stage IIB and stage IIC tumors as T4N0 and compared them with stage IIIA (T1–2N1) disease. In this analysis, regrouped T4N0 disease was associated with significantly worse OS than T1–2N1 disease (log-rank P=0.04) (Figure 3A), whereas the difference in PFS did not reach statistical significance (log-rank P=0.11) (Figure 3B). Multivariable Cox models for this regrouped comparison are presented in Table 4. These findings suggest that the adverse prognostic signal of T4N0 colon cancer is most strongly supported by OS and is largely driven by the unfavorable behavior of T4bN0 tumors.

Figure 3 Kaplan-Meier curves comparing regrouped T4N0 disease [stage IIB (T4aN0) plus stage IIC (T4bN0)] versus T1–2N1 disease (stage IIIA) in the colon-only cohort. (A) OS. (B) PFS. This regrouping analysis was performed to evaluate the prognostic direction of the proposed stage reassignment framework for T4N0 colon cancer. OS, overall survival; PFS, progression-free survival.

Discussion

Key findings

In this multicenter colon-only cohort, the adverse prognostic signal within T4N0 disease was not uniform but appeared to be driven primarily by T4bN0. Patients with stage IIC (T4bN0) colon cancer had significantly worse progression-free survival and overall survival than those with stage IIIA (T1–2N1) disease, whereas stage IIB (T4aN0) did not consistently differ from stage IIIA. In addition, T4N0 tumors carried a heavier burden of adverse clinicopathological features, including poorer differentiation, more frequent perineural invasion, and more frequent elevation of preoperative CEA. Together, these findings suggest that deeply invasive node-negative colon cancer, particularly T4bN0 disease, may carry biological risk comparable to or greater than that of early node-positive tumors.

Strengths and limitations

There are several strengths in this study. First, it was conducted across multiple centers in a real-world clinical setting. Second, by restricting the analysis to colon cancer and excluding rectal cancer, we reduced an important source of treatment heterogeneity related to neoadjuvant strategies and local treatment pathways. Third, we distinguished between T4aN0 and T4bN0 rather than treating T4N0 as a homogeneous category, which allowed a more nuanced interpretation of the survival paradox.

Several limitations should also be acknowledged. The study was retrospective in nature. The sample size of the T4bN0 subgroup was relatively modest, which may have reduced statistical power in adjusted and interaction analyses. Molecular data were unavailable, precluding evaluation of biomarkers such as MSI, RAS/BRAF status, and consensus molecular subtype. In addition, the analysis did not include more advanced stage III subgroups, and the cohort was derived from three centers in China, which may limit generalizability to other populations. Future prospective studies incorporating molecular profiling are warranted to further refine risk stratification in T4N0 colon cancer.

Comparison with similar research

Our findings are directionally consistent with previous registry-based and retrospective studies reporting a survival paradox between stage IIB/IIC and stage IIIA colon cancer (6-9,14). However, the present study adds an important nuance: in our colon-only cohort, the adverse prognostic signal was driven mainly by T4bN0 rather than being uniformly present across all T4N0 tumors. This distinction is clinically relevant because it suggests that the biological and prognostic heterogeneity within T4N0 disease should be acknowledged when considering stage reassignment strategies.

Explanations of findings

The inferior survival of T4bN0 colon cancer compared to T1–2N1 disease reflects its intrinsically aggressive biology. T4b tumors directly invade adjacent organs or structures, indicating a more advanced local phenotype and increasing the likelihood of occult residual disease despite apparently curative resection (5,15,16). Such tumors may require more extensive surgery and may be associated with more challenging postoperative management (17). In our cohort, T4N0 tumors—particularly T4bN0—were also enriched for adverse pathological features such as poorer differentiation, more frequent perineural invasion, and more frequent CEA elevation (18). These findings support the biological plausibility that some deeply invasive node-negative tumors may behave more aggressively than limited node-positive disease.

CEA has been associated with tumor burden and prognosis in colorectal cancer in prior studies (19-21). In the present study, CEA-stratified analyses suggested a more unfavorable survival pattern among patients with elevated preoperative CEA, particularly in the T4bN0 subgroup. However, because formal stage-by-CEA interaction testing was not statistically significant, CEA is better interpreted here as a clinically relevant risk-stratification variable rather than a definitively established effect modifier. Even so, the observed pattern suggests that preoperative CEA may help identify a subgroup warranting closer postoperative attention.

Implications and actions needed

Clinically, these data suggest that the AJCC 8th edition framework may underestimate postoperative risk in a subset of T4N0 colon cancer, especially T4bN0 disease. Our regrouped analysis of T4N0 versus T1–2N1 further supports this interpretation, with the adverse signal being most clearly reflected in overall survival. While our findings do not by themselves mandate immediate treatment reclassification, they support reconsideration of current staging paradigms and justify further prospective evaluation of risk-adapted postoperative strategies, including closer surveillance and refinement of adjuvant treatment decision-making for selected patients.

Conclusions

In conclusion, T4N0 colon cancer is biologically and prognostically heterogeneous, and the adverse signal within this category appears to be driven primarily by T4bN0. In this multicenter colon-only cohort, T4bN0 showed worse survival than T1–2N1 disease, whereas T4aN0 did not consistently differ from stage IIIA. These findings support reconsideration of current staging paradigms and warrant further prospective validation of risk-adapted postoperative strategies for T4N0 colon cancer.

Acknowledgments

The authors thank the clinical and data management teams at the participating centers for their support in case identification and follow-up.

Footnote

Reporting Checklist: The authors have completed the STROBE reporting checklist. Available at https://tcr.amegroups.com/article/view/10.21037/tcr-2026-0545/rc

Data Sharing Statement: Available at https://tcr.amegroups.com/article/view/10.21037/tcr-2026-0545/dss

Peer Review File: Available at https://tcr.amegroups.com/article/view/10.21037/tcr-2026-0545/prf

Funding: This work was supported by the 535Talent Project of First Affiliated Hospital of Kunming Medical University (No. 2022535D07); National Natural Science Foundation of China (No. 82160533); The Yunnan Revitalization Talent Support Program (Nos. RLQB20200004 and RLMY20220013); and Education Teaching Research Project of The First Affiliated Hospital of Kunming Medical University (No. 2024-JY-19).

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://tcr.amegroups.com/article/view/10.21037/tcr-2026-0545/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. The study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments. The study was approved by the Ethics Committee of The First Affiliated Hospital of Kunming Medical University (No. 2024-L-124), the Ethics Committee of The Third People’s Hospital of Honghe Prefecture (No. 2024-KYXM-29), and the Ethics Committee of Yunnan Cancer Hospital (No. KYLX2024-146). Individual consent for this retrospective analysis was waived.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

References

1. Amin MB, Greene FL, Edge SB, et al. The Eighth Edition AJCC Cancer Staging Manual: Continuing to build a bridge from a population-based to a more "personalized" approach to cancer staging. CA Cancer J Clin 2017;67:93-9.
2. O'Connell JB, Maggard MA, Ko CY. Colon cancer survival rates with the new American Joint Committee on Cancer sixth edition staging. J Natl Cancer Inst 2004;96:1420-5.
3. Zheng P, Xu G, Qin Z, et al. The Causes Behind the Survival Paradox in Non-Metastatic Colorectal Cancer Patients and its Impact on the Treatment Regimen: A Retrospective Cohort Study. Surgery 2024;176:310-8. [Crossref] [PubMed]
4. Lim JH, Huh JW, Lee WY, et al. Comparison of Long-Term Survival Outcomes of T4a and T4b Colorectal Cancer. Front Oncol 2021;11:780684. [Crossref] [PubMed]
5. Kim MJ, Jeong SY, Choi SJ, et al. Survival paradox between stage IIB/C (T4N0) and stage IIIA (T1-2N1) colon cancer. Ann Surg Oncol 2015;22:505-12. [Crossref] [PubMed]
6. Daprà V, Gandini A, Schietroma F, et al. Prognostic impact and clinical management of pT4N0 colon cancer: data from a large, multicenter, international, real-world dataset. ESMO Open 2025;10:105496. [Crossref] [PubMed]
7. Chu QD, Li T, Hsieh MC, et al. Survival paradox between stage IIB/C and stage IIIA colon cancer: is it time to revise the American Joint Committee on Cancer TNM system?. Surg Endosc 2024;38:2857-70. [Crossref] [PubMed]
8. Liao YT, Huang J, Hung JS, et al. Staging Paradox and recurrence pattern among stage IIB, IIC, and IIIA Colon cancers: a retrospective cohort study. Int J Colorectal Dis 2024;39:161. [Crossref] [PubMed]
9. Yu C, Shi Z, Zhou G, et al. Revisiting the survival paradox between stage IIB/C and IIIA colon cancer. Sci Rep 2024;14:22133. [Crossref] [PubMed]
10. Weiser MR. AJCC 8th Edition: Colorectal Cancer. Ann Surg Oncol 2018;25:1454-5.
11. Baratti D, Riva CG, Guaglio M, et al. Clinical and Pathological Risk Factors for Peritoneal Metastases in a Surgical Series of T4 Colorectal Cancers. Cancers (Basel) 2025;17:1103. [Crossref] [PubMed]
12. Nie F, Sun X, Sun J, et al. Epithelial-mesenchymal transition in colorectal cancer metastasis and progression: molecular mechanisms and therapeutic strategies. Cell Death Discov 2025;11:336. [Crossref] [PubMed]
13. Shi Q, Chang GJ, Pederson LD, et al. Proposed changes to the pathologic staging for colon cancer (CC): AJCC Colon Cancer Expert Panel (AJCCCCEP). J Clin Oncol 2025;43:3520.
14. Li H, Fu G, Wei W, et al. Re-Evaluation of the Survival Paradox Between Stage IIB/IIC and Stage IIIA Colon Cancer. Front Oncol 2020;10:595107. [Crossref] [PubMed]
15. Lu D, Dong C, Wang K, et al. Updates of CSCO guidelines for colorectal cancer version 2025. Chin J Cancer Res 2025;37:297-302. [Crossref] [PubMed]
16. Lee J, Park HM, Lee SY, et al. Oncologic outcomes of multivisceral resection for locally advanced colorectal cancer: a single-center retrospective cohort study. BMC Surg 2025;26:63. [Crossref] [PubMed]
17. Filip B, Grigoras A, Gavrilescu M, et al. Multivisceral Resection for Locally Advanced Colon Cancer: Clinical and Treatment Characteristics Based on Final Pathological Evaluation. A Retrospective Study. Chirurgia (Bucur) 2025;120:396-402.
18. Kumamoto T, Yamaguchi S, Nakagawa R, et al. Prognostic risk factors for pT4 colon cancer: A retrospective cohort study. Oncol Lett 2023;25:29. [Crossref] [PubMed]
19. Gramkow MH, Mosgaard CS, Schou JV, et al. The prognostic role of circulating CA19-9 and CEA in patients with colorectal cancer. Cancer Treat Res Commun 2025;43:100907. [Crossref] [PubMed]
20. Xie H, Wei L, Wang Q, et al. Grading carcinoembryonic antigen levels can enhance the effectiveness of prognostic stratification in patients with colorectal cancer: a single-centre retrospective study. BMJ Open 2024;14:e084219. [Crossref] [PubMed]
21. Tang F, Huang CW, Tang ZH, et al. Prognostic role of serum carcinoembryonic antigen in patients receiving liver resection for colorectal cancer liver metastasis: A meta-analysis. World J Gastrointest Surg 2023;15:2890-906. [Crossref] [PubMed]