Distinct metastatic patterns and survival outcomes in intestinal- versus diffuse-type gastric cancer: a SEER-based propensity score-matched analysis

Introduction

Gastric cancer (GC) is the fifth most common malignancy and the fourth leading cause of cancer-related mortality worldwide (1). According to the Lauren classification, GC is broadly categorized into intestinal- and diffuse-type tumors, which differ substantially in epidemiology, histopathology, and biological behavior (2). Intestinal-type GC is more frequently associated with environmental and dietary risk factors, typically occurs in older patients, and often exhibits glandular structures. In contrast, diffuse-type GC is characterized by poorly cohesive tumor cells, younger age at onset, and more aggressive clinical behavior (3,4). Despite advances in diagnosis and treatment, a considerable proportion of patients present with distant metastases at initial diagnosis. Approximately 34% of patients with GC present with metastatic disease at diagnosis, and liver involvement is observed in 4–14% of cases (5). Prognosis in metastatic GC remains poor, with median overall survival (OS) generally ranging from 1 to 2 years despite systemic treatment (6,7).

Increasing evidence suggests that Lauren classification is associated with distinct patterns of distant metastasis (8). Intestinal-type GC more commonly metastasizes to the liver, whereas diffuse-type GC demonstrates a greater tendency for peritoneal, bone, and ovarian dissemination (9). In addition, the metastatic site is an important determinant of survival outcomes in patients with metastatic GC. Previous studies have found that patients with isolated liver metastasis may experience relatively more favorable survival outcomes than those with bone or brain metastases, which are generally associated with poorer prognosis (10).

Previous studies have provided important insights into the metastatic patterns and survival differences. However, most population-based analyses have focused primarily on metastatic distribution or OS, while relatively few studies have systematically investigated metastatic patterns, metastatic-site-specific survival, and treatment-associated survival outcomes within different Lauren subtypes (11). In addition, some studies are insufficient in methodological approaches, such as the lack of propensity score matching (PSM), to control for baseline imbalances between the subtypes, potentially leading to biased estimates (12,13). Therefore, further investigation is needed to better characterize the prognostic heterogeneity associated with metastatic patterns across Lauren subtypes.

In the present study, we utilized data from the Surveillance, Epidemiology, and End Results (SEER) database to investigate metastatic patterns and survival outcomes in patients with intestinal- and diffuse-type metastatic GC. PSM was applied to reduce baseline imbalances between groups. We further explored the association between treatment modalities and survival outcomes within each histological subtype. Our findings may contribute to improved prognostic stratification and provide additional insights into subtype-specific metastatic behavior in metastatic GC. We present this article in accordance with the STROBE reporting checklist (available at https://jgo.amegroups.com/article/view/10.21037/jgo-2026-0323/rc).

Methods

Data acquisition

Data were obtained from the SEER database utilizing the SEER 17 Registries between 2000–2019 (November 2021 submission). The SEER program covers approximately 26.5% of the United States population and represents one of the largest population-based cancer registries worldwide. This study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments.

Cohort selection

In this retrospective study, patients with metastatic GC were identified from the SEER database using SEER*Stat software version 9.0.4. Histological subtypes were classified according to the International Classification of Diseases for Oncology, Third Edition (ICD-O-3). Tumors with ICD-O-3 codes 8145, 8142, 8490, and 8010 were categorized as diffuse-type GC, whereas codes 8211, 8140, 8144 were classified as intestinal-type GC (14).

The criteria for inclusion were as follows: (I) diagnosis between 2010 and 2015; (II) primary tumor located in the stomach; (III) staging according to the 7th edition of the American Joint Committee on Cancer (AJCC) staging system; (IV) evidence of distant metastasis at diagnosis, including liver, bone, brain, or lung sites; and (V) complete survival information available. The exclusion criteria included: (I) unknown survival time; (II) survival time less than one month after diagnosis; (III) unknown metastatic status; and (IV) T0 stage disease.

Study variables

The following clinicopathological variables were extracted from the SEER database: age at diagnosis (20–39, 40–59, and ≥60 years), sex (male or female), race (White, Black, and other), T stage (T1–3, T4, and TX), N stage (N0–3 and NX), number of examined lymph nodes, primary tumor site, metastatic sites (liver, bone, brain, and lung), and treatment modalities. Age was categorized into 20–39, 40–59, and ≥60 years to reflect young, middle-aged, and older patient populations and to facilitate clinically meaningful comparisons across age groups. Metastatic sites were categorized according to the organ-specific metastasis information available in the SEER database. Patients presenting with involvement of more than one metastatic organ were classified as having multiple-site metastases because previous studies have demonstrated that metastatic burden is associated with survival outcomes.

Treatment modalities were categorized as “combined surgery and chemo-/radio-therapy”, “surgery alone”, “chemo-/radio-therapy alone”, and “no/unknown treatment”. Treatment modalities were grouped according to the major treatment categories recorded in the SEER database to reflect the intensity of therapeutic intervention received by patients and to facilitate comparisons of survival outcomes across commonly encountered treatment strategies.

Histological subtype was classified as intestinal-type or diffuse-type GC. Based on ICD-O-3 topography codes, the primary site was further categorized into cardia, fundus, body, antrum, pylorus, lesser curvature, greater curvature, and other locations, including overlapping lesions and unspecified gastric sites.

Study outcome

OS and gastric cancer-specific survival (GCSS) were the primary outcomes. OS was calculated from the date of diagnosis to death from any cause or last follow-up. GCSS was defined as the interval from diagnosis to death specifically attributable to GC.

Statistical analysis

Baseline clinicopathological characteristics between diffuse-type and intestinal-type GC were compared using the chi-square test. Survival curves for OS and GCSS were estimated using the Kaplan-Meier method and compared using the log-rank test. Multivariate Cox proportional hazards regression models were constructed to identify independent prognostic factors for OS and GCSS, with hazard ratios (HRs) and 95% confidence intervals (CIs) calculated accordingly.

To reduce baseline imbalances between groups, 1:1 PSM was performed using a caliper width of 0.02, as recommended in previous methodological studies to improve matching precision and reduce residual bias (15). Covariate balance before and after PSM was evaluated using absolute standardized differences (ASDs), with an ASD <0.1 considered indicative of adequate balance. Variables included in the PSM model were sex, race, tumor differentiation, metastatic sites, primary tumor site, treatment modalities, N stage, and T stage.

All statistical analyses were conducted using SPSS version 27.0 (IBM SPSS, Chicago IL, USA). PSM was performed using the sklearn library in Python. A two-tailed P value of less than 0.05 was deemed statistically significant.

Results

Patient characteristics

A total of 4,696 patients diagnosed with metastatic GC between 2010 and 2015 were identified from the SEER database (Figure S1). Among them, 938 patients (21%) were classified as diffuse-type GC, whereas 3,758 patients (79%) were classified as intestinal-type GC. Before PSM, significant differences were observed between the two groups in several baseline characteristics, including race, N stage, metastatic sites, and primary tumor location (P<0.05, Table 1). To reduce baseline imbalances, 1:1 PSM was performed, resulting in 934 matched pairs. After PSM, baseline characteristics between the diffuse-type and intestinal-type groups were generally well balanced, with all ASDs below 0.1, indicating adequate covariate balance (Figure 1).

Figure 1 Assessment of covariate balance before and after propensity score matching. The plot displays the mean ASD for baseline clinical and pathological covariates between the diffuse- and intestinal-type cohorts. The red dashed line represents the standard acceptable threshold for optimal balance (ASD <0.1). The blue bars (ASD before) and orange bars (ASD after) indicate the degree of difference before and after 1:1 propensity score matching, respectively. ASD, absolute standardized difference.

Correlation between Lauren classification and metastatic patterns

In the overall unadjusted cohort, 3,694 patients (78.7%) presented with single-site metastasis, whereas 1,002 patients (21.3%) had multiple-site metastases. Liver-only metastasis was the most common metastatic pattern, accounting for 2,616 cases (55.7%), followed by bone-only metastasis (n=563, 11.9%), lung-only metastasis (n=447, 9.5%), and brain-only metastasis (n=68, 1.4%) (Table 1). Overall, the distribution of metastatic sites differed significantly between the two Lauren subtypes (P<0.001, Table 1). Specifically, the incidence of liver-only metastasis was substantially lower in diffuse-type GC than in intestinal-type GC (37.2% vs. 60.3%). Conversely, diffuse-type GC exhibited a notably higher frequency of bone-only metastasis (27.1% vs. 8.2%) and lung-only metastasis (15.5% vs. 8.0%). Brain-only metastasis and multiple-site metastasis accounted for 2.1% and 18.1% in the diffuse-type GC group, and 1.3% and 22.1% in the intestinal-type GC group, respectively (Figure 2).

Figure 2 Distribution of metastatic patterns in diffuse- and intestinal-type metastatic gastric cancer. The proportions of patients with liver-only, bone-only, brain-only, lung-only, and multiple-site metastases were compared between Lauren subtypes. AJCC, American Joint Committee on Cancer; ASD, absolute standardized difference; N, node; T, tumor.

Effect of Lauren classification on survival outcomes in GC

Kaplan-Meier survival curves for OS and GCSS according to Lauren classification are presented in Figure 3. Before PSM, patients with intestinal-type GC demonstrated significantly longer OS and GCSS than those with diffuse-type GC (median OS: 6 vs. 4 months; median GCSS: 31 vs. 20 months; all P<0.05, Figure 3A,3B). Similar findings were observed after PSM (median OS: 5 vs. 4 months; median GCSS: 8 vs. 6 months; all P<0.001, Figure 3C,3D).

Figure 3 Survival outcomes stratified by Lauren classification before and after PSM. (A,B) Kaplan-Meier curves of OS (A) and GCSS (B) between intestinal- and diffuse-type GC before PSM. (C,D) Kaplan-Meier curves of OS (C) and GCSS (D) between intestinal- and diffuse-type GC after PSM. GC, gastric cancer; GCSS, gastric cancer-specific survival; OS, overall survival; PSM, propensity score matching.

Multivariate Cox regression analysis demonstrated that diffuse-type GC was independently associated with worse OS (HR =1.158, 95% CI: 1.071–1.254, P<0.001) and GCSS (HR =1.193, 95% CI: 1.088–1.307, P<0.001), using intestinal-type GC as the reference category (Table 2). These associations remained significant after PSM (OS: HR =1.159, 95% CI: 1.051–1.278, P=0.003; GCSS: HR =1.159, 95% CI: 1.036–1.297, P=0.01; Table 3). Among the metastatic sites analyzed, bone metastasis showed the strongest association with reduced OS (HR =0.769, 95% CI: 0.681–0.869, P<0.001) and GCSS (HR =0.830, 95% CI: 0.719–0.957, P<0.001) among the metastatic sites examined (Table 3).

Impact of metastatic sites on survival outcomes in diffuse- and intestinal-type GC

In diffuse-type GC, significant differences in OS were observed among patients with different metastatic sites before PSM (P<0.05, Figure 4A). Kaplan-Meier analyses showed that patients with liver or lung metastases tended to have longer survival than those with bone, brain, or multiple-site metastases. A similar trend was observed for GCSS, although the difference did not reach statistical significance (P>0.05, Figure 4B). After PSM, differences in OS remained statistically significant (P<0.05, Figure 4C), whereas no significant difference was observed for GCSS (P>0.05, Figure 4D).

Figure 4 Survival outcomes according to distinct metastatic sites in patients with diffuse-type metastatic gastric cancer, before and after PSM. Kaplan-Meier survival analyses comparing outcomes among patients with liver-only, bone-only, brain-only, lung-only, and multiple-site metastases. (A,B) Kaplan-Meier curves for OS (A) and GCSS (B) by metastatic site before PSM. (C,D) Kaplan-Meier curves for OS (C) and GCSS (D) by metastatic site after PSM. GCSS, gastric cancer-specific survival; OS, overall survival; PSM, propensity score matching.

In intestinal-type GC, survival outcomes varied according to metastatic site. Before PSM, significant differences were observed in both OS and GCSS across metastatic sites (all P<0.05, Figure 5A,5B). Kaplan-Meier analyses showed that patients with liver metastasis tended to have longer survival than those with brain, lung, or multiple-site metastases, while survival outcomes were generally comparable between patients with liver and bone metastases. Similar patterns were observed for GCSS. After PSM, the OS patterns remained generally consistent for both OS and GCSS analyses (all P<0.05, Figure 5C,5D).

Figure 5 Survival outcomes according to distinct metastatic sites in patients with intestinal-type metastatic gastric cancer, before and after propensity score matching. Kaplan-Meier survival analyses comparing outcomes among patients with liver-only, bone-only, brain-only, lung-only, and multiple-site metastases. (A,B) Kaplan-Meier curves for OS (A) and GCSS (B) by metastatic site before PSM. (C,D) Kaplan-Meier curves for OS (C) and GCSS (D) by metastatic site after PSM. GCSS, gastric cancer-specific survival; OS, overall survival; PSM, propensity score matching.

Impact of treatment modalities on survival in diffuse- and intestinal-type GC

We further evaluated the association between treatment modalities and survival outcomes in diffuse- and intestinal-type GC. Significant differences in OS and GCSS were observed among different treatment modality groups in both Lauren subtypes (all P<0.001, Figures S2,S3). Overall, patients who received combined surgery and chemo-/radio-therapy demonstrated the longest survival, followed by those who received chemo-/radio-therapy alone, surgery alone, and no/unknown treatment. Similar survival patterns were observed after PSM.

Discussion

Key findings

In this study, we systematically evaluated the prognostic impact of Lauren classification in metastatic GC and its association with metastatic patterns and survival outcomes using a large population-based cohort from the SEER database. After adjustment using PSM, distinct differences in metastatic patterns were observed between Lauren subtypes. Intestinal-type GC was more frequently associated with liver metastasis, whereas diffuse-type GC demonstrated a higher propensity for bone metastasis. Kaplan-Meier analyses demonstrated survival differences according to metastatic site, with patients presenting with liver metastasis showing relatively longer survival than those with bone, brain, lung, or multiple-site metastases. Furthermore, diffuse-type GC emerged as an independent adverse prognostic factor. In addition, patients receiving combined surgery and chemo-/radio-therapy demonstrated longer survival than those receiving other treatment modalities.

Strengths and limitations

This study has several strengths. First, it included a relatively large population-based cohort of patients with metastatic GC, allowing evaluation of both metastatic patterns and survival outcomes according to Lauren classification. Second, PSM was performed to reduce baseline imbalances and facilitate more robust comparisons between intestinal- and diffuse-type GC. Third, both OS and GC-specific survival were assessed, providing complementary prognostic information.

Nevertheless, several limitations should be acknowledged. First, the retrospective design of this SEER-based study inevitably introduced potential selection bias and unmeasured confounding. Although PSM was applied to reduce baseline imbalances, residual confounding may still exist because several clinically important variables are not available in the SEER database, including ECOG performance status, comorbidities, nutritional status, detailed systemic treatment regimens, and molecular characteristics. These unmeasured factors may have influenced both treatment allocation and survival outcomes. In addition, matching for variables such as metastatic sites and treatment modalities could potentially introduce overadjustment bias. We attempted to mitigate this issue by presenting both pre- and post-PSM results. Second, information regarding peritoneal metastases, one of the most common metastatic patterns in GC (16), was not available in the SEER database, which could affect the assessment of metastatic patterns. Third, although primary tumor location was included in the multivariable models, further stratified analyses according to anatomical subsite were not performed. Given the relatively small sample sizes in some location-specific subgroups, such analyses may have been underpowered and yielded unstable estimates. In addition, as the SEER database reflects the United States population, the applicability of our findings to regions with high GC incidence, such as East Asia, may be limited (17,18). Furthermore, the study cohort consisted of patients diagnosed between 2010 and 2015, before the widespread adoption of immune checkpoint inhibitors and several advances in systemic treatment strategies for metastatic GC. Therefore, the survival outcomes reported here may not fully reflect contemporary clinical practice. Nevertheless, this timeframe allows for a relatively homogeneous evaluation of metastatic patterns and survival outcomes in the pre-immunotherapy era, providing valuable baseline epidemiological insights.

Comparison with similar research and explanations of findings

Previous studies have reported that metastatic patterns of GC vary according to Lauren classification, indicating distinct biological behaviors between intestinal- and diffuse-type tumors (19). A nationwide cohort study by Koemans et al. identified that intestinal-type GC was more likely to develop liver metastases (57% vs. 21%), whereas diffuse-type GC exhibited a higher propensity for bone metastases (9% vs. 6%) (20). Consistent with the findings of previous studies, intestinal-type GC is more likely to develop liver metastases, whereas diffuse-type GC shows a higher propensity for bone metastases. Several factors might explain these differences. Intestinal-type GC typically exhibits glandular structures and a more cohesive growth pattern (21). Tumor cells may invade surrounding tissues and migrate via lymphatic and blood vessels, owing to the rich vascular supply of the gastric wall, which facilitates local lymph node involvement and vascular invasion (22). Through the portal venous system, these cells are readily transported to the liver, where they may form distant metastatic foci (5,23). Moreover, the unique immune-suppressive microenvironment of the liver further promotes the survival and growth of tumor cells (24,25). In contrast, diffuse-type has been reported to exhibit a greater propensity for bone marrow involvement, particularly in tumors with signet ring cell features (26,27). Genomic evidence also supports this clinical observation. For instance, Oh et al. reported that GC with bone metastases harbored more frequent mutations in TP53, KDR, APC, KDM5A, and RHOA (28). Notably, activation of the PI3K/AKT/mTOR pathway in bone-metastatic GC promotes tumor cell survival, proliferation, metabolic adaptation, and interaction with the bone microenvironment, thereby enhancing the propensity for skeletal colonization and progression (29-31). These biological differences may partially explain the distinct metastatic patterns observed between intestinal- and diffuse-type GC.

Survival analysis indicated that the Lauren classification was an independent prognostic factor in metastatic GC, with intestinal-type GC patients exhibiting significantly longer OS and GCSS than diffuse-type GC patients. This finding is consistent with previous SEER-based analyses, which also reported inferior survival outcomes in diffuse-type GC (32), and the association remained significant after adjustment for baseline characteristics in our cohort. Importantly, multivariate Cox regression further confirmed diffuse-type GC as an independent adverse prognostic factor, in line with a recent SEER-based analysis of early-onset GC (33). This prognostic discrepancy may be partly explained by the slower disease progression and greater chemosensitivity of intestinal-type tumors, whereas diffuse-type GC is often characterized by scattered infiltration and mucinous components, which make treatment more challenging (34,35). In particular, the relatively longer survival observed among patients with liver metastasis in the Kaplan-Meier analyses should be interpreted cautiously, as this finding may partly reflect differences in underlying disease burden. Patients with isolated liver metastasis may have lower metastatic burden and less extensive systemic disease compared with those presenting with bone, brain, or multiple-site metastases. Furthermore, the SEER database does not provide information regarding the number of metastatic lesions or detailed measures of tumor burden, which may further confound survival comparisons across metastatic sites. In addition, more established treatment approaches are available for patients with liver metastasis (5,36), which may partly contribute to the survival differences observed across metastatic sites. We also found that patients with bone metastasis tended to demonstrate relatively poor survival outcomes. In the cases of GC, bone metastasis not only introduces primary alterations caused by the cancer itself but can also result in skeletal-related complications, such as pathological fractures, inadequate response to chemotherapy, pain, and compression of the spinal cord or nerve roots. These issues substantially affect patients’ quality of life and decrease their survival rates (11,37). These findings suggest that bone involvement may serve as a marker of poorer prognosis in metastatic GC. It should also be noted that peritoneal metastasis, a common metastatic pattern of diffuse-type GC (16), could not be evaluated in the SEER database. The absence of peritoneal metastasis data may have resulted in an incomplete characterization of metastatic patterns and potentially biased comparisons between Lauren subtypes. Future studies based on multi-center clinical registries or prospective cohorts that specifically capture peritoneal metastatic disease are warranted to provide a more comprehensive evaluation of subtype-specific metastatic patterns in GC.

Furthermore, while surgical interventions are not typically advised for metastatic GC (38,39), previous studies have reported favorable outcomes in selected patients receiving gastrectomy combined with chemotherapy (12,40). In our cohort, patients receiving combined surgery and chemo-/radio-therapy demonstrated longer survival than those receiving other treatment modalities. Similarly, Hu et al. found that the median OS for patients who underwent gastrectomy combined with chemotherapy was 14.2 months, compared with 7.0 months for those receiving chemotherapy alone and 3.9 months for those undergoing surgery alone (41). However, these findings should be interpreted cautiously, as patients selected for multimodal treatment were likely to have better performance status, lower disease burden, and fewer comorbidities, factors that are not captured in the SEER database. Therefore, the observed survival advantage may partly reflect treatment selection bias rather than a direct therapeutic effect. In recent years, the therapeutic landscape of metastatic GC has evolved with the incorporation of targeted therapies and immune checkpoint inhibitors into systemic treatment strategies (42-44). However, because the SEER database does not provide detailed information regarding treatment regimens or molecular biomarkers such as human epidermal growth factor receptor 2 (HER2), microsatellite instability (MSI), and programmed death-ligand 1 (PD-L1) status, we were unable to evaluate potential interactions between Lauren classification, tumor biology, and contemporary systemic therapies. Future studies incorporating molecular profiling and detailed treatment data are warranted to further clarify these relationships.

Implications and actions needed

Our findings provide clinically relevant insights into the relationship between Lauren classification, metastatic patterns, and survival outcomes in metastatic GC. The observed heterogeneity in metastatic behavior between intestinal- and diffuse-type GC suggests that Lauren classification may contribute to improved risk stratification and support future investigations into subtype-specific surveillance and therapeutic strategies.

From a research perspective, future studies should incorporate more comprehensive clinical information, including performance status, comorbidities, detailed treatment regimens, and molecular biomarkers such as HER2, MSI, and PD-L1 status. In addition, multicenter registries and prospective cohorts with detailed documentation of peritoneal metastases are needed to provide a more complete characterization of metastatic patterns. Further validation in ethnically diverse populations and contemporary treatment-era cohorts will also be important to determine the generalizability and clinical applicability of these findings.

Conclusions

In conclusion, Lauren classification was associated with distinct metastatic patterns and survival outcomes in patients with metastatic GC. Intestinal-type GC was more frequently associated with liver metastasis, whereas diffuse-type GC demonstrated a higher propensity for bone metastasis. Differences in survival were observed across Lauren subtypes and metastatic sites. In addition, combined surgery and chemo-/radio-therapy was associated with longer survival compared with other treatment modalities.

Acknowledgments

None.

Footnote

Reporting Checklist: The authors have completed the STROBE reporting checklist. Available at https://jgo.amegroups.com/article/view/10.21037/jgo-2026-0323/rc

Peer Review File: Available at https://jgo.amegroups.com/article/view/10.21037/jgo-2026-0323/prf

Funding: None.

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://jgo.amegroups.com/article/view/10.21037/jgo-2026-0323/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. This study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments.

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/.

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