Letter to the Editor: Beyond ypN status: Lymph node regression grade refines risk stratification in rectal cancer

Abstract

Risk stratification after neoadjuvant chemoradiotherapy for locally advanced rectal cancer remains suboptimal, largely due to the limited prognostic reliability of tumor regression grade (TRG) when lymph node status is not fully integrated. In the study by Shi et al published in this issue of the World Journal of Gastroenterology, lymph node regression grade (LRG) is proposed as a clinically relevant biomarker reflecting treatment response at the nodal level and a refined six-tier LRG system is validated. The internal coherence of the results is noteworthy: TRG retains prognostic value only in ypN0 patients, whereas LRG emerges as a key determinant of survival in patients with residual nodal disease, precisely where TRG loses relevance. The proposed LRG system also holds potential clinical value for refining postoperative risk stratification and guiding adjuvant chemotherapy decisions beyond conventional post-treatment pathological tumor-node-metastasis staging. Nonetheless, interpretation is tempered by histopathological challenges in distinguishing LRG0 from LRG1, the retrospective single-center design and limited sample size in higher LRG subgroups. Despite these constraints, the study represents a well-founded contribution that shifts prognostic focus from the primary tumor to lymph node biology, positioning LRG as a meaningful complement to TRG and tumor-node-metastasis staging.

Key Words: Lymph node regression; Neoadjuvant chemoradiotherapy; Pathologic nodal status; Rectal cancer; Risk stratification; Total mesorectal excision; Tumor regression grade

Core Tip: Lymph node regression grade offers independent and clinically meaningful prognostic information after neoadjuvant chemoradiotherapy for rectal cancer that is not adequately captured by assessment of primary tumor regression alone. Evaluating nodal treatment response can enhance postoperative risk stratification beyond conventional pathological staging, particularly in patients with residual nodal disease, a subgroup in which therapeutic decision-making remains especially complex. Routine incorporation of lymph node response into standardized pathological reporting may support more precise, individualized adjuvant treatment strategies. However, harmonized histopathological criteria and robust prospective validation are required before widespread clinical implementation.

TO THE EDITOR

We read with great interest the recently published retrospective study by Shi et al[1], which evaluates the prognostic significance of a refined six-tier lymph node regression grade (LRG) system in patients with locally advanced rectal cancer treated with long-course neoadjuvant chemoradiotherapy (nCRT) followed by total mesorectal excision. The authors address a clinically relevant and unresolved challenge: The limited prognostic reliability of tumor regression grade (TRG) when lymph node status is not fully integrated into post-treatment risk stratification.

Despite substantial therapeutic advances, including total neoadjuvant therapy and organ-preservation strategies, pathological staging after nCRT remains the cornerstone of adjuvant treatment decision-making. However, conventional post-treatment pathological tumor-node-metastasis (ypTNM) staging does not fully reflect the biological heterogeneity induced by treatment. In this context, the study provides a structured and biologically grounded approach to refining postoperative prognostic assessment by incorporating nodal regression as an independent determinant of outcome.

CONDITIONAL PROGNOSTIC VALUE OF TRG IN THE CONTEXT OF NODAL STATUS

TRG, particularly according to Mandard or comparable systems, has long been used as a surrogate marker of response to nCRT[2]. Several meta-analyses have shown that favorable TRG correlates with improved disease-free survival (DFS) and overall survival (OS)[3,4]. However, growing evidence indicates that the prognostic contribution of TRG is attenuated once nodal status is accounted for, as post-treatment pathological lymph node status (ypN) remains one of the most powerful predictors of recurrence and mortality after nCRT[5,6].

The present study reinforces this concept. In the overall cohort, TRG was not significantly associated with OS or DFS, and its prognostic relevance was confined to ypN0 patients, in whom it independently predicted recurrence-free survival. This finding is biologically coherent: In the absence of residual nodal disease, primary tumor response may adequately reflect tumor radiosensitivity and systemic control. Conversely, in ypN+ patients, residual nodal metastases likely represent treatment-resistant clonal populations with enhanced metastatic potential, thereby diminishing or overriding the prognostic impact of primary tumor regression.

This observation aligns with prior analyses showing that nodal status after nCRT exerts a stronger prognostic impact than T-stage downstaging[7]. It also reinforces the notion that TRG, while informative, should not be interpreted in isolation from nodal response but rather within an integrated pathological framework.

LRG: A BIOLOGICALLY GROUNDED REFINEMENT

The most innovative aspect of the study is the systematic evaluation of lymph node regression using a six-tier LRG system (LRG0-5). This grading system classifies lymph nodes according to the estimated percentage of cross-sectional area occupied by residual viable tumor cells after neoadjuvant treatment: LRG0 indicates a normal lymph node without prior metastasis; LRG1 corresponds to complete nodal response without residual tumor; LRG2 denotes rare residual cancer cells (< 10%); LRG3 indicates 10%-50% residual tumor; LRG4 reflects 50%-90% residual tumor; and LRG5 represents minimal regression with > 90% residual tumor burden. By using the worst observed nodal score to standardize classification, the authors aimed to capture the most biologically aggressive residual nodal component and minimize potential underestimation of residual disease burden.

Among patients with residual nodal disease (ypN+), LRG also emerged as an independent predictor of OS (hazard ratio = 1.533; 95% confidence interval: 1.223-1.922; P = 0.0002) and DFS (hazard ratio = 1.278; 95% confidence interval: 1.061-1.539; P = 0.010) in multivariate Cox models adjusted for age, sex, post-nCRT CEA, post-treatment pathological tumor stage, and ypN stage. Importantly, LRG retained prognostic significance even when categories were consolidated (e.g., LRG0-1 vs LRG2-5), particularly for OS, further reinforcing the presence of a consistent dose-response relationship between nodal regression and survival.

These findings are consistent with the broader concept that lymph node response may serve as a surrogate for systemic tumor sensitivity to chemoradiation. Persistent viable tumor in lymph nodes may reflect biological resistance and retained micrometastatic competence, features not fully captured by primary tumor regression alone. Prior work has highlighted the heterogeneity of nodal response and its potential independent prognostic value, although few studies have implemented a structured, multi-tier grading system comparable to that used in the present analysis[6,8]. Similar observations have been reported in other gastrointestinal malignancies, where metabolic activity of metastatic lymph nodes assessed by fluorodeoxyglucose positron emission tomography/computed tomography independently predicted survival and relapse patterns, highlighting the biological relevance of nodal disease beyond primary tumor characteristics[9].

An additional noteworthy finding is the interaction between poor nodal regression (LRG 2-5) and low tumor location. In this subgroup, shorter distance to the anal verge independently predicted worse OS. This observation raises the hypothesis that distal tumors with poor nodal response may represent a distinct and biologically aggressive clinical phenotype, potentially influenced by anatomical constraints or surgical complexity. Future research should explore whether this subgroup correlates with recognized molecular subtypes of rectal cancer or specific genomic alterations associated with radio resistance and metastatic potential. Such investigations may provide mechanistic insights into the observed interaction and support biologically informed risk stratification.

CLINICAL IMPLICATIONS: TOWARD REFINED ADJUVANT DECISION-MAKING

Integrating LRG into postoperative assessment could have meaningful and immediate therapeutic implications. Current guidelines for adjuvant chemotherapy after nCRT and total mesorectal excision rely largely on ypTNM staging, although the benefit in ypN+ patients remains inconsistent and still debated[10,11]. By incorporating the quality of nodal treatment response, clinicians may better distinguish between biologically favorable and unfavorable subsets within ypN+ disease.

Patients with good primary tumor regression but poor nodal regression may represent a high-risk subgroup that could benefit from intensified systemic therapy, including oxaliplatin-based regimens or participation in clinical trials. Conversely, favorable LRG despite limited nodal involvement could support a more individualized treatment de-escalation approach, potentially reducing overtreatment and treatment-related toxicity.

Such stratification aligns with the ongoing shift toward biologically driven, risk-adapted management in rectal cancer, as illustrated by recent trials evaluating total neoadjuvant therapy and response-adapted strategies (e.g., RAPIDO and PRODIGE 23)[12,13]. However, unlike preoperative predictive markers, LRG is inherently postoperative, which limits its clinical utility to adjuvant treatment tailoring, rather than informing neoadjuvant intensification or organ-preservation strategies such as watch-and-wait.

LIMITATIONS AND FUTURE DIRECTIONS

Several limitations warrant careful interpretation. First, the histopathological distinction between LRG0 (uninvolved node) and LRG1 (complete nodal response) may be challenging due to treatment-induced fibrosis and potential obscuration of prior micrometastases. Clearer morphological definitions, standardized pathological criteria, and formal interobserver reproducibility studies are needed to ensure consistency.

Recent pathology consensus guidelines support the separate assessment and reporting of treatment-related changes within resected lymph nodes after neoadjuvant therapy, including the proportion of residual viable tumor, necrosis, and regression bed[14,15]. However, these recommendations explicitly acknowledge that the incremental prognostic value of nodal regression patterns beyond conventional ypN classification remains unproven and requires prospective validation. This methodological gap underscores the relevance of the present work while simultaneously highlighting the need for multicenter confirmation before lymph node regression grading can be incorporated into routine postoperative risk stratification.

Second, the retrospective, single-center design introduces potential selection bias and limits external validity. Although the median follow-up of 31 months is acceptable, longer follow-up would be desirable to confirm the robustness of survival estimates, particularly for 5-year outcomes.

Third, the absence of complete baseline clinical TNM data in some patients restricts precise evaluation of true nodal downstaging. Future prospective, multicenter studies integrating molecular markers, circumferential resection margin status, and vascular invasion are likely to provide a more comprehensive and biologically informative risk model.

Finally, future validation efforts should be directed toward integrative prognostic frameworks that use pathological nodal status (ypN) as the central anchor, explicitly incorporate LRG together with quantitative or continuous measures of nodal response (e.g., percentage of residual viable tumor)[14,15], and add systemic biomarkers of minimal residual disease (such as circulating tumor DNA) to capture recurrence risk not explained by conventional pathology and to identify discordant or biologically heterogeneous risk phenotypes[16].

CONCLUSION

Taken together, this study represents a clinically relevant and conceptually robust step forward in refining prognostic stratification after nCRT for rectal cancer. By demonstrating that TRG retains prognostic value primarily in ypN0 disease, while LRG independently predicts outcomes in patients with residual nodal involvement, the authors reframe postoperative risk assessment by shifting attention from primary tumor response alone toward the biological behavior of nodal disease.

If prospectively validated and supported by standardized histopathological criteria, LRG could meaningfully complement conventional ypTNM staging and TRG, enabling a more biologically coherent and clinically informative postoperative risk framework. Such integration may help refine adjuvant treatment selection, particularly within the heterogeneous ypN+ population, where therapeutic decision-making remains most challenging.

Ultimately, incorporating nodal response into routine pathological evaluation would align with the broader movement toward biologically driven, risk-adapted management in rectal cancer, providing a pragmatic step toward more individualized postoperative care.