Swollen lymph node metastasis in gastric cancer: A forgotten prognostic signal in need of clinical action

Abstract

Gastric cancer (GC) remains a leading cause of cancer mortality. While the extent of nodal involvement is a well-known prognostic factor, the specific entity of swollen lymph node metastasis (SLNM), bulky nodal tumor deposits detectable radiologically or pathologically, has received little attention in staging. Recent data from a study by Cui et al demonstrated that SLNM is an independent predictor of very poor survival in GC. Through robust data and rigorous propensity-matched analyses, SLNM emerged not merely as an anatomical finding but as an independent predictor of poor prognosis, even among patients undergoing curative resection. As precision oncology advances, the findings by Cui et al urge a fundamental rethinking of how SLNM is incorporated into clinical decision-making for GC management. In this editorial, we critically examine the prognostic significance of SLNM, challenge its omission from traditional staging frameworks, and advocate for its formal integration into preoperative risk stratification and treatment planning. Recognizing SLNM at diagnosis could unlock intensified neoadjuvant therapy strategies and optimize outcomes for a historically high-risk patient subgroup.

Key Words: Gastric cancer; Lymph node metastasis; Neoadjuvant chemotherapy; Precision oncology; Prognosis; Staging; Swollen lymph node

Core Tip: Swollen lymph node metastasis (SLNM), defined by bulky nodal tumor deposits (> 3 cm on imaging or multiple > 1.5 cm nodes) in gastric cancer, confers a dramatically worse outcome. In a large recent cohort, SLNM was independently associated with approximately 50% higher mortality risk. This editorial emphasizes SLNM’s under-recognized prognostic value. Formally incorporating SLNM into gastric cancer staging and treatment algorithms (for example, prioritizing neoadjuvant chemotherapy) may improve risk stratification. Recognizing SLNM as a biomarker can enhance precision oncology approaches by identifying patients for intensified multimodal therapy.

INTRODUCTION

Gastric cancer (GC) ranks as the fifth most common malignancy and the fourth leading cause of cancer-related mortality worldwide[1,2]. Most patients present with advanced locoregional disease. The presence and extent of lymph node metastasis (LNM) are key determinants of outcome. Standard TNM staging counts the number of involved nodes (N category) without explicitly considering nodal size or burden beyond the number[3]. Clinicians often note that grossly swollen lymph nodes, especially those exceeding 3 cm, signal a poor prognosis and surgical difficulty. These bulky nodal metastases, especially around the celiac axis, pose surgical challenges and may indicate highly aggressive tumor biology.

Historically, Western centers have regarded GC with extensive bulky nodal disease as effectively incurable, offering only palliative chemotherapy. In Asia, by contrast, clinicians have treated such cases with intensive multimodal therapy. Yet formal recognition of swollen LNM (SLNM) as a prognostic biomarker has been lacking in staging guidelines.

In 2025, Cui et al[4] define radiologic SLNM as the presence of a single lymph node measuring ≥ 3 cm or at least two lymph nodes each ≥ 1.5 cm in diameter on preoperative computed tomography. This criterion identifies patients with substantial nodal tumor burden. The definition of SLNM varies across studies, with some using a threshold of ≥ 3 cm for a single lymph node and others using ≥ 1.5 cm for multiple nodes. For instance, Cui et al[4] and Cheong et al[5] apply different criteria, creating inconsistencies in identifying and categorizing patients.

This lack of standardization poses significant challenges. First, it undermines the comparability of study results, which is essential for developing reliable evidence-based guidelines. Variations in thresholds can lead to differences in reported incidence, treatment decisions, and outcome evaluations. This is particularly problematic in meta-analyses or multi-center studies, where data heterogeneity reduces statistical power and generalizability.

To improve research quality and clinical practice, a unified and universally accepted definition of SLNM is crucial. Consensus guidelines, ideally developed through expert panels and supported by clinical outcome data, would ensure consistency across studies, facilitate better treatment stratification, and ultimately enhance patient care.

Cui et al[4] analyzed 507 GC patients with pathologically confirmed LNM (all stage II/III by AJCC TNM) and classified them by SLNM status. Remarkably, 27.4% had SLNM, and these patients had dramatically lower 5-year overall survival than those without bulky nodes (13.6% vs 35.8%) and remained at higher risk even after propensity score matching (13.4% vs 21.2%, HR = 1.318, P = 0.031). In multivariate analysis, SLNM found to be an independent adverse prognostic factor (hazard ratio approximately 1.32). These results reinforce smaller prior observations that large nodal metastases (> 2 cm) predict poor outcomes in GC[5].

In 2008, Cheong et al's study[5] demonstrated that a metastatic lymph node size ≥ 2 cm independently predicted poorer outcomes in gastric cancer (HR approximately 1.76). Since then, newer retrospective analyses have reinforced and extended this finding. For instance, a 2023 single-center study involving 163 stage II/III patients found that the largest metastatic lymph node, identified histopathologically, had a cut-off of ≥ 1.05 cm to predict worse survival, with those above this size exhibiting approximately 3.5-fold greater mortality risk[6]. This suggests that even moderately enlarged nodes carry significant prognostic weight.

To improve research quality and clinical practice, a unified and universally accepted definition of SLNM is crucial. Consensus guidelines, ideally developed through expert panels and supported by clinical outcome data, would ensure consistency across studies, facilitate better treatment stratification, and ultimately enhance patient care.

While analyses like those by Cui et al[4] and Cheong et al[5] provide important insights into the prognostic relevance of SLNM, they carry notable limitations. Cui et al’s study[4], for instance, was single-institutional, raising concerns about selection bias, incomplete control of confounders, and limited external generalizability. Similarly, definitions of SLNM varied across studies, ranging from a ≥ 3 cm single node to multiple nodes ≥ 1.5 cm, introducing heterogeneity that complicates cross-study comparisons and evidence synthesis. Furthermore, imaging criteria were not uniformly applied or validated, and pathologic assessments lacked centralized review. These factors collectively weaken the strength of current recommendations. To establish SLNM as a reliable prognostic and therapeutic biomarker, prospective, multi-center studies with standardized definitions, imaging protocols, and outcome measures are urgently needed.

PROGNOSTIC IMPLICATIONS

Given this data, SLNM should no longer be overlooked. It reflects a high tumor burden and likely aggressive pathological features, such as T4 primaries, N3 stage, lymphovascular invasion, and poor differentiation. Indeed, SLNM was associated with more frequent T4 tumors and N3 nodal stage, and only 13.6% of SLNM patients survived 5 years. In comparison, the non-SLNM group had a median survival roughly double that of SLNM patients. Notably, SLNM affected survival independent of the numeric N-stage: Even within the same N category, patients with bulky nodes did worse. Thus, SLNM adds prognostic granularity beyond current staging. Biologically, this may parallel with extranodal tumor deposits, which in GC indicate highly invasive disease and also worsen survival[7].

SLNM cuts across TNM categories, meaning even patients staged as “lower risk” by node count may still have poor outcomes if bulky nodes are present. This limitation of numeric N-staging calls for refinement. One proposal is to adopt an “S” suffix (e.g., N2-S or N3-S), where the “S” denotes swollen or bulky nodes exceeding a defined size threshold (e.g., ≥ 3 cm), which could be recorded via imaging or pathology. This would maintain consistency within the TNM system while enhancing prognostic granularity. Alternatively, SLNM could function as a separate parameter outside the core TNM system, akin to the way tumor deposits (N1c) are treated in colorectal cancer. In a similar fashion, the presence of bulky nodal metastases (SLNM) could define an N3c or N1b-SLNM category, recognizing these as biologically and prognostically distinct entities. In this model, SLNM would not alter the N category per se but would be flagged independently, similar to perineural invasion or lymphovascular invasion, which still affects treatment planning and risk stratification.

Operationally, radiology reports could standardize identification of SLNM using size criteria (e.g., ≥ 3 cm single node or ≥ 1.5 cm in multiple nodes) and location (e.g., celiac or para-aortic regions), while pathology could annotate resected nodes meeting these definitions. These would serve as staging modifiers to guide therapeutic escalation. Inclusion of such categories in AJCC or UICC staging manuals would enable more personalized risk stratification, promote research standardization, and facilitate real-world adoption. Given that SLNM confers an adverse prognosis even within the same numeric N stage, its incorporation into staging warrants careful consideration.

Ultimately, whether SLNM is best integrated as a modifier within N staging or as an independent variable depends on future prospective validation. Until then, clinical guidelines could recommend that SLNM be reported explicitly and consistently, and multidisciplinary teams should factor SLNM status into therapeutic decision-making, regardless of formal TNM designation.

Therapeutic implications

Recognizing SLNM has immediate therapeutic implications. Bulky nodal involvement traditionally identifies borderline resectable disease that may benefit from intensive preoperative chemotherapy.

Neoadjuvant therapy and surgical outcomes in SLNM

A Japanese trial showed that a cocktail of cisplatin/S-1 followed by extended surgery (including para-aortic nodes) yielded surprisingly good survival (3-year OS approximately 58%) in patients with extensive nodal metastasis[8]. A meta-analysis of three Japanese trials (JCOG0001, 0405, 1002) showed that neoadjuvant chemotherapy followed by gastrectomy improved survival even in bulky nodal cases[9]. An integrated analysis of these JCOG trials further demonstrated that bulky nodal disease (particularly near the celiac trunk) responded well to neoadjuvant chemotherapy, while para-aortic lymph node dissection conferred minimal additional survival benefit in patients with a favorable pathological response.

Lymph node ratio and surgical implications

A separate study of 1884 patients revealed that a high lymph node ratio (LNR; ≥ 0.4) significantly predicted worse 5-year survival. Notably, the LNR offered more prognostic precision than traditional pN staging, underscoring the importance of both the number and burden of metastatic nodes[3].

Among patients with oligo-recurrent GC, lymph node metastasectomy combined with chemotherapy was associated with prolonged survival (mean OS post-surgery: Approximately 102 months), reinforcing the value of aggressive surgical management for limited nodal recurrences[10].

SLNM as a trigger for neoadjuvant therapy

Cui et al’s study[4] supports this multimodal approach: Patients with SLNM who received neoadjuvant chemotherapy experienced significantly improved survival outcomes compared to those who did not. Accordingly, current Chinese and Japanese guidelines conditionally recommend preoperative chemotherapy for advanced GC with bulky nodes. For example, in China’s RESOLVE trial[11], perioperative SOX chemotherapy (oxaliplatin/S-1) improved 3-year disease-free survival compared to adjuvant therapy in locally advanced GC. These data suggest that SLNM on staging scans should prompt preoperative chemotherapy to increase resectability and improve outcomes.

Integration of SLNM with targeted and immunotherapies

While SLNM is not itself a molecular biomarker, its presence may identify patients who would benefit from more aggressive multimodal systemic therapy. For instance, microsatellite instability-high GCs respond robustly to PD-1 checkpoint inhibitors[12]; if such tumors also show bulky nodal involvement, they may be ideal candidates for immunotherapy.

In 2025, a study by Du and Ye[13] involving 133 patients demonstrated that combining PD-1 inhibitors with chemotherapy significantly improved 2-year survival (90.3% vs 62.9%) and pathological complete response rates (37.1% vs 4.2%) in patients with LNM. Similarly in 2024, a case report by Wang et al[14] described a patient with advanced GC and rare axillary LNM who responded to combination immunotherapy for nearly two years. This patient’s tumor was PD-L1+, EBV+, had high TMB, and dense CD8+ TIL infiltration—factors suggesting that bulky or atypical nodal disease may be a clinical flag for immunologically responsive tumors.

Toward a precision oncology paradigm

In essence, SLNM status could be used in conjunction with molecular profiling to refine treatment decisions. This precision oncology paradigm would blend anatomical biomarkers (e.g., lymph node size or burden) with molecular features (e.g., HER2 status, MSI, EBV, TMB) to guide tailored therapies. Surgical and radiology teams should clearly document SLNM in operative and imaging reports, while multidisciplinary tumor boards should consider escalated or personalized treatment strategies for patients with SLNM.

CLINICAL APPLICATIONS

How should practitioners use the concept of SLNM in daily practice? First, SLNM should be reported explicitly on preoperative imaging and pathology. Radiologists and surgeons can be vigilant for celiac and perigastric nodes meeting SLNM criteria. Pathologists should note when resected nodes contain gross tumor deposits measuring above a threshold. In operative planning, the presence of SLNM may shift the balance toward neoadjuvant chemotherapy rather than upfront surgery. After curative (D2) gastrectomy, SLNM-positive patients merit very close follow-up and possibly intensified adjuvant therapy.

Table 1 highlights that SLNM conveys a far worse prognosis[4]. Importantly, SLNM cut across TNM categories, meaning even some patients staged as “lower” disease by node count have poor outcomes if bulky nodes are present. Accordingly, staging manuals (such as the AJCC TNM) should consider an “S” qualifier for swollen nodes, or risk scores could be updated. Some Japanese guidelines already list SLNM as an indication for neoadjuvant chemotherapy. International consensus is needed so that, say, the presence of SLNM would automatically upstage a patient or trigger multimodal therapy.

Table 1 Impact of swollen lymph node metastasis on survival outcomes in gastric cancer: Summary of prognostic significance from Cui et al[4].

Parameter	SLNM present (n = 139)	SLNM absent (n = 368)	P value
Proportion of LN+ patients (%)	27.4	72.6	-
5-year OS (%)	13.6	35.8	< 0.001
5-year OS (%; matched cohorts, n = 133 per group)	13.4	21.2	0.006
Hazard ratio for mortality (vs no SLNM)	1.32	1.00 as a reference	0.031
Associated tumor stage	T4 primary, N3 nodal stage	Variable	-
Recommended management	Neoadjuvant chemotherapy + D2 gastrectomy + adjuvant therapy	Standard D2 gastrectomy + adjuvant therapy	-

P values from log-rank test or Cox proportional hazards model as reported by Cui et al[4]. SLNM: Swollen lymph node metastasis; OS: Overall survival.

Furthermore, SLNM should be incorporated into risk stratification models and trials. Prognostic nomograms for GC can include SLNM as a variable to refine predictions[7]. Clinical trials should stratify or adjust for SLNM status, just as trials for stage II/III might stratify by ypT/N or other factors. The prefix ypT/N in cancer staging signifies the pathologic stage assessed after neoadjuvant therapy, where “y” indicates that staging follows preoperative treatment (e.g., chemotherapy or radiation), “p” denotes that it is based on pathological examination of the surgical specimen, “T” refers to the size and extent of the primary tumor, and “N” describes the extent of regional lymph node involvement. Finally, novel loco-regional therapies (e.g., targeted radiotherapy or intra-arterial chemoembolization to bulky nodes) could be explored for SLNM cases that are borderline resectable.

Future directions

The identification of SLNM opens several avenues for research. Biologically, why do some GC tumors produce massive nodal metastases while others remain microscopic? Studies should compare the genomic and microenvironmental profiles of SLNM-positive and SLNM-negative tumors. Although SLNM is clinically associated with poor prognosis in GC, its underlying biological mechanisms remain unclear. Preliminary data suggest that tumors with SLNM may exhibit distinct molecular features, including overexpression of oncogenic pathways such as MET, FGFR2, and VEGFA, as well as transcriptional signatures linked to EMT and angiogenesis[15-17].

Immunologically, these tumors often show an immunosuppressive microenvironment characterized by low CD8+ T-cell infiltration, increased regulatory T cells, and PD-L1 expression, which may contribute to immune evasion[18]. These features suggest that SLNM may represent a biologically aggressive subtype of GC that could benefit from targeted or immunotherapy approaches, highlighting the need for molecular profiling and prospective studies to validate these associations.

Advances in liquid biopsy may allow detection of SLNM-driven disease through ctDNA assays or circulating tumor cells, enabling monitoring of minimal residual disease after resection. For instance, enlarged metastatic nodes may reflect an immunosuppressive niche; profiling immune cell subsets in SLNM may inform the use of checkpoint inhibitors or immunomodulatory agents.

On the clinical trials front, prospective studies are needed to confirm that tailoring therapy by SLNM improves outcomes. A randomized trial could test neoadjuvant vs upfront surgery specifically in patients with SLNM to validate the survival advantage. The MATTERHORN trial[19], a phase III study of durvalumab plus neoadjuvant FLOT chemotherapy in resectable gastric and gastroesophageal junction cancer, exemplifies the kind of stratified trial design now emerging. This trial adjusted for clinical lymph node status, PD-L1 expression, and geographic region using a stratified log-rank test, offering a template for how future SLNM-focused trials might incorporate anatomical and molecular risk factors into precision therapy frameworks. Additionally, translational trials could evaluate adding targeted agents to standard regimens in SLNM-positive patients (for example, combining anti-HER2 or anti-angiogenic drugs with chemotherapy). The concept of SLNM might also extend to other cancers. Indeed, “bulky nodal disease” is a concern in esophageal and colon cancers as well.

CONCLUSION

In summary, SLNM in GC, long observed by surgeons, has been resurrected as a powerful prognostic biomarker by Cui et al’s analysis[4]. Patients with SLNM have markedly worse survival, yet may derive particular benefit from intensive therapy, including neoadjuvant chemotherapy. We urge the oncology community to translate this finding into practice: SLNM should be systematically recorded and considered in staging, and clinical guidelines should reflect its implications. By incorporating SLNM into multidisciplinary decision-making, we can improve personalized care for high-risk GC patients. Recognizing this forgotten signal may help salvage outcomes through tailored, precision oncology approaches.