Understanding metastatic patterns in gastric cancer: Insights from lymph node distribution and pathology

Abstract

Gastric cancer (GC) represents a significant global health burden due to its high morbidity and mortality. Specific behaviors of GC sub-types, distinct dissemination patterns, and associated risk-factors remain poorly understood. This editorial highlights several key prognostic factors, including pathological staging and vascular invasion, that impact GC. It examines a recent study’s investigation of differential metastatic lymph nodes distribution and survival in upper and lower GC sub-types, focusing on histological characterization, pathophysiology, usage of neoadjuvant chemotherapy, and additional predictive determinants. We assess the statistical robustness and clinical applicability of the findings, underscoring the importance of treating GC as a heterogeneous disease and emphasizing how tailored surgical approaches informed by lymph node distribution can optimize tumor detection while minimizing unnecessary interventions. The study’s large cohort, multi-center design, and strict inclusion criteria strengthen its validity in guiding surgical planning and risk-stratification. However, integrating genetic and molecular data is critical for refining models and broadening applicability. Additionally, recurrence-metrics and infection-related factors, such as Helicobacter pylori and Epstein-Barr virus, absent in the original study, remain vital for directing future research. By bridging metastatic patterns with prospective methodologies and inclusion of diverse populations, this editorial provides a framework for advancing early detection and personalized GC care.

Key Words: Gastric cancer; Lymph node metastasis patterns; Upper vs lower gastric cancer; Prognostic factors; Survival outcomes

Core Tip: Gastric cancer (GC) remains a leading cause of cancer-related mortality worldwide, underscoring the need for improved detection and management strategies. This editorial emphasizes the importance of personalized approaches to GC management by examining distinct metastatic lymph node distributions and prognostic factors in upper and lower GC. Future research can incorporate critical variables such as genomic and molecular characterization, infection-related factors like Helicobacter pylori and Epstein-Barr virus, and recurrence metrics. Incorporating these factors into patient predictive models offers promising opportunities to enhance understanding of GC and inform tailored, patient-centered treatment modalities across diverse populations.

INTRODUCTION

Gastric cancer (GC) remains a significant global health concern, ranking as the fifth most common malignancy and the fourth leading cause of cancer-related deaths globally[1,2]. Despite significant advances in prevention and early detection, as indicated by a global decline in GC incidence, the rates of upper GC have been steadily rising. This challenge is compounded by late-stage diagnosis, where tumors are typically more refractory to currently available treatments[1,2]. Additionally, the asymptomatic presentation of patients with low to moderate grade GC in conjunction with the need for invasive procedures, such as endoscopies, for biopsy and diagnosis, further impedes early diagnosis[1,2]. This trend highlights the importance of understanding the distinct biological behaviors and clinicopathological features of GC tumors, specifically stratified by location within the abdomen.

A recent multicenter retrospective study by Yuan et al[3] titled “Metastatic lymph node distribution and pathology correlations in upper and lower gastric cancer patients: A multicenter retrospective study” delves into this issue with the aim of investigating the distribution patterns of metastatic lymph nodes in upper vs lower GC, as well as analyzing associated prognostic factors and survival outcomes. By examining these differences, the authors hope to inform a more tailored surgical approach for accurate detection of GCs.

The aforementioned study conducted a retrospective review of 1806 patients who underwent radical GC resection surgery between 2005 and 2020 across four hospital systems. Of these patients, 817 had upper GC (45.2%), while 989 had lower GC (54.8%). Inclusion criteria ensured that participants had not received prior gastric surgery or neoadjuvant therapy, had no metastases, and had undergone R0 radical gastrectomy with at least 16 Lymph nodes resected.

PATTERNS OF LYMPH NODE METASTASIS IN GC

Comparative analysis showed that upper GC patients had more aggressive disease than those with lower GC. Specifically, upper GC was linked to larger tumor diameters (> 4cm), more advanced tumor invasion (> pT staging), poorer or undifferentiated histology, greater lymph node involvement (> pN stage), and increased vascular invasion. Furthermore, the study identified distinct patterns of lymph node metastasis between upper and lower GC. In upper GC-particularly Siewert types II and III-the highest rates of metastasis were seen in lymph node groups 1, 2, 3, and 7. In contrast, lower GC showed a predilection for metastasis to groups 3-8. Understanding these trends is crucial for proper surgical planning and could lead to more tailored lymphadenectomy and biopsy, mitigating unnecessary procedures, and reducing hospital resource strain whilst ensuring comprehensive removal of metastatic nodes and maintenance of higher quality of life for patients.

PROGNOSTIC FACTORS THAT INFLUENCE SURVIVAL OUTCOMES

Through univariate analysis followed by multivariate logistic regression, independent risk factors for lymph node metastasis were identified. Yuan et al[3] discovered that certain pathological types-especially signet ring cell carcinoma-along with histological grades from moderately differentiated to undifferentiated, advanced pT stage (T2-T4), higher pTNM stage (II or III), and the presence of vascular invasion were all significant risk factors[3]. Additionally, through multivariate Cox regression analysis, they identified that age over 60 years, pathological type, advanced pT and pN staging, higher pTNM stages, vascular invasion, and absence of adjuvant chemotherapy were independent prognostic factors affecting overall survival. These findings underscore the multifaceted nature of GC prognosis. By correlating these prognostic factors with lymph node metastasis and survival metrics, the authors further emphasize the need for personalized treatment strategies that could improve diagnosis, staging accuracy, and patient outcomes.

One of the most significant strengths of this study is its large sample size and multicenter design, which enhances the generalizability of its findings, reducing single-site bias, and allowing for a more robust statistical analysis, thereby increasing the reliability of the conclusions drawn. By including over a thousand patients from four different hospitals, this study minimizes potential biases associated with single-center studies and increases the diversity of its patient population. However, while the study’s extensive cohort offers a representative sample of the Chinese population affected by GC, questions arise regarding its applicability on a global scale.

GENETIC AND EPIDEMIOLOGICAL CONTRIBUTIONS TO GC

Genetic factors play a critical role in the heterogeneous presentation and recurrence rates of GC, with some classification systems now based solely on genetic and epidemiological factors[2,4,5]. High-risk factors like previous infections with Helicobacter pylori (H. pylori) and Epstein-Barr virus (EBV) have been strongly linked to GC via specific gene alterations, including mutations in PIK3CA (80% of EBV-positive cases), ARID1A (54%), and BCOR (23%), as well as amplifications involved in JAK2 and PD-L1/PD-L2 genes (15%)[4-6]. EBV-related GC, which represents approximately 9% of all GC diagnoses, is an important factor to consider in research design, as is H. pylori, the leading cause of GC[1,5,7]. Similarly, genetic predispositions, such as variations in the CDH1, RHOA, and CLDN18 genes, play a crucial role in GC development and progression and may influence tumor behavior and metastasis patterns.

Beyond genetic predispositions, the epidemiology of infections like H. pylori and EBV plays a pivotal role in shaping the disease burden across populations, influencing both the differential likelihood of developing GC and the prognosis of affected patients. The global prevalence of H. pylori and EBV infections varies significantly across regions. In 2017, Hooi et al[7] conducted a meta-analysis that reported the highest prevalence of H. pylori in Africa (70.1%, 95%CI: 62.6-77.7) and the lowest in Oceania (24%, 95%CI: 18.5-30.4)[8]. Another meta-analysis by Zamani et al[8] reported an overall global prevalence (44.3%, 95%CI: 40.9-47.7), with developing countries reporting greater incidences (50.8%, 95%CI: 46.8-54.7) compared to developed countries (34.7%, 95%CI: 30.2-39.3). Similarly, EBV infection, while globally prevalent in over 90% of adults, exhibits regional variability in disease burden[9]. For example, EBV-associated nasopharyngeal carcinoma and gastric carcinoma are more common in East Asia, where specific strains like Trans Eurasian strains are linked to malignancy[10,11]. The incidence is highest in high and middle-high social demographic indices, peaking in adults aged 50-70. In contrast, EBV-associated endemic Burkitt lymphoma is more frequent in sub-Saharan Africa due to the interaction of EBV with malaria, wherein infection occurs earlier in life with higher rates in young children[12,13]. These geographic and demographic variations in H. pylori and EBV prevalence underscore the importance of considering regional differences when generalizing study findings and tailoring GC prevention and treatment strategies.

LIMITATIONS AND FUTURE DIRECTIONS

By not incorporating genetics analyses, the authors miss an opportunity to deepen the understanding of the mechanisms driving tumor behavior and metastasis, which could differ across populations. Of course, given the retrospective nature of this study, the authors may be excused provided a lack of access to genetic sequencing data. Future research should integrate these infection-related variables alongside genetic markers and established risk factors to better understand their combined impact on GC development and metastasis, while also facilitating the development of more comprehensive prognosis models for GC[4,14]. Incorporating advanced molecular profiling, such as comprehensive genomic profiling (multiplexed next-generation sequencing) or epigenetic analyses, into future research would identify key driver mutations that direct tumor behavior and metastatic patterns. For example, mutations in CLDN18, or amplification of PD-L1, may correlate with specific metastatic patterns or responses to targeted therapies. Similarly, the integration of epigenetic data, such as DNA-methylation and mircoRNA expression profiles, could provide deeper insight into tumor progression and resistance mechanisms. Prospective studies that combine molecular, pathological, and clinical data will better facilitate the development of more precise prognostic models and personalized perioperative management strategies, ultimately improving outcomes in patients with GC.

Furthermore, expanding this research to include multicenter studies across diverse geographic regions would enhance the external validity of these findings. Such studies would be essential to account for variations and confounding variables in environmental exposures, healthcare systems, geographic-specific infections, and genetic predispositions that influence GC outcomes. For example, differences in the prevalence of routine endoscopic screenings, established lymphadenectomy resection protocols, and access to adjuvant therapies may impact survival outcomes and overall metastatic patterns. By conducting larger multicenter studies and sampling genetically and geographically diverse populations, methodologies can be standardized, refining treatment algorithms and ensuring applicability in a global context.

This study also excelled in its comprehensive presentation of findings, encompassing general trends in GC, population distribution, independent risk factors for lymph node metastasis and prognosis, as well as variations in prognostic outcomes and lymph node metastasis patterns based on the tumor's original location. This breadth of data presents a robust foundation for understanding GC progression and supports targeted approaches in clinical practice. These findings, particularly the detailed, multifaceted analysis of lymph node metastasis distribution and frequency based on tumor type and location, offer valuable insights that can directly aid surgeons in tailoring lymph node dissection protocols to specific GC presentations. This approach enhances risk stratification, supports personalized patient management, and improves survival outcomes. Additionally, by identifying a plethora of independent risk factors, the study lays a foundation for future research focused on mitigating these risks through preventive interventions, which could enable earlier diagnosis and more targeted treatment. This, in turn, paves the way for developing efficient screening protocols that facilitate quicker, more accurate prognoses and optimized patient care. Yet, the retrospective design and absence of propensity score matching introduce limitations that temper the strength of the conclusions. Unmeasured confounding variables and unmatched examined confounding variables could influence the observed associations. By accounting for baseline variations in patient characteristics, propensity score matching would strengthen causal relationships, improving the validity of conclusions drawn from the data.

Another area of concern is the absence of detailed information regarding adjuvant chemotherapy regimens. While the study acknowledges that the lack of such data limits the depth of analysis regarding treatment impacts on prognosis, without detailed specifics on which patient populations received therapy, the chemotherapy type, dosages, and durations, it is difficult to assess the true influence of adjuvant therapy on survival outcomes.

For instance, response rates to adjuvant chemotherapy can vary significantly between populations. Fluoropyrimidine monotherapy or combination therapy has demonstrated efficacy predominantly in Asian populations, whereas these regimens show no significant survival benefit in non-Asian cohorts. In contrast, 5-fluorouracil-based chemotherapy has consistently provided survival advantages across diverse populations when compared to surgery alone[1,15,16]. Without further exploration of these factors, the study's findings are limited in its ability to deliver nuanced guidance and recommendations for treatment protocols.

In order to provide stronger and more actionable recommendations, future studies should move beyond a broad comparison of adjuvant chemotherapy vs no chemotherapy, a standard that is already well-established in Asian populations, and instead, investigate the relative effectiveness of various chemotherapy regimens across large and diverse populations[1,15,16].

A lack of nuanced recommendations regarding the efficacy of specific adjuvant chemotherapy regimens risks promoting a one-size-fits-all approach, which could lead to the overuse of certain chemotherapy regimens in populations less likely to benefit, particularly non-Asian cohorts. Such broad generalizations expose patients to unnecessary toxicity, financial burdens, and diminished quality of life without significant survival advantages compared to traditional surgery alone. It is imperative to stray away from vague conclusions that may inadvertently encourage overtreatment. Instead, a more personalized approach to adjuvant therapy should be prioritized, tailoring treatment decisions to individual patient profiles, tumor biology, and population-specific response patterns. To achieve this, future studies must prospectively validate findings in diverse populations and explicitly investigate regimen-specific outcomes, ensuring that recommendations are evidence-based, equitable, and ethically sound.

Finally, the lack of report of disease-free survival metrics or recurrence-free survival reduces the depth of prognostic insights, as overall survival alone does not capture recurrence risk, an important factor for patient management. While overall survival is a critical endpoint, understanding recurrence patterns is key for comprehensive patient care. This limitation reduces the study’s ability to fully assess recurrence risk, which is a critical factor influencing long-term clinical management and treatment planning. DFS metrics could provide clinicians with actionable insights, such as the identification of high-risk periods for relapse or tailoring surveillance strategies. Future studies that include disease-free survival metrics would enhance the prognostic insights garnered from this study and could inform strategies for monitoring and managing recurrence.

CONCLUSION

The strengths of this study lie in its large, multi-center design, robust data analysis, and practical clinical implications within a Chinese context. The inclusion of a substantial patient population of 1806 individuals, combined with a 15-year span of data collection, further enhances the validity and reliability of its findings, providing a comprehensive and longitudinal perspective on GC trends and outcomes. However, the limitations, including its retrospective design, lack of associated genetic and infection data, and potential reduced applicability to global populations, highlight areas that require further investigation. Future studies can incorporate these independent factors and further investigate their applicability in more racially diverse populations while incorporating important prognostic factors like genetics and infection from high-risk pathologies like H. pylori or EBV. By doing so, more refined guidance and therapeutic approaches can be curated to incorporate targeted therapies which have shown favorable results in the literature[4]. Prospective studies with standardized methodologies may also offer strength to the evidence base.

Overall, Yuan et al’s study makes a valuable contribution to understanding GC and provides a plethora of clinically useful information, which has the potential to lead to better surgical planning, and patient outcomes[3]. By highlighting the differential distribution of metastatic lymph nodes between upper and lower GCs, and identifying key pathological and prognostic factors, the study presents crucial insights that can inform personalized and more effective treatment strategies. While the importance of lymph node involvement in GC prognosis is well-established, this study uniquely provides a site-specific distribution map for metastatic lymph nodes, which offers a novel approach to guiding tailored lymphadenectomy during surgery. Yuan et al[3] identified that patients with upper GC exhibit higher rates of lymph node metastasis in groups 1, 2, 3, and 7, while lower GC showed a greater predilection for involvement in groups 3 through 8.

This site-specific approach enables a more nuanced understanding of lymphatic spread, directing surgical management through enabling surgeons with a more tailored approach to lymphadenectomy rather than pursuing a radical or super-extended approach. This would ensure comprehensive removal of high-risk lymph nodes while minimizing unnecessary dissection, reducing post-operative complications and preserving quality of life. Furthermore, this study builds upon previously established conclusions regarding lymph node involvement but does so in the specific context of site-based lymph node metastasis and overall patient prognosis. The identification of adverse prognostic factors, such as advanced pT staging (T2-T4), high pTNM staging (II or III), signet ring cell carcinoma, and vascular invasion underscore the importance of incorporating these variables into pre-operative risk stratification models. Incorporating these findings into routine clinical workflows would not only optimize surgical and adjuvant treatment strategies, but would also lay the foundation for more precise, personalized approaches to GC management and treatment, ultimately improving survival outcomes and quality of life for patients. These findings provide hope for improving early detection, advancing minimally invasive treatments, and enhancing patient outcomes in GC care.