Analysis of risk and prognostic factors for pulmonary metastasis in gastric cancer: a study based on the Surveillance, Epidemiology, and End Results database

Introduction

Gastric cancer (GC) is one of the most prevalent malignant tumors worldwide. Despite a decline in incidence rates, it remains a leading cause of cancer-related mortality due to its high metastatic potential. Distant metastasis often indicates a poor prognosis. According to the World Health Organization, GC is the fifth most common cancer globally (1). The 2022 global cancer statistics reveal that there are over 960,000 new cases of GC each year, accounting for 4.9% of all new cancer cases, with nearly 660,000 deaths, representing 6.8% of all cancer deaths (2). Although advancements have been made in early screening and targeted therapies, the prognosis for advanced GC patients remains bleak, with an overall survival (OS) rate of less than 20% over 5 years, particularly for those with distant metastases (3,4).

The lungs, as the primary filter for systemic venous return, are a common site for tumor metastasis (5). Although the incidence of lung metastases from GC is relatively low, ranging from 0.5% to 0.96%, their impact on prognosis is significant (6,7). Kong et al. reported that advanced GC patients with lung metastases have a median survival of only 4 months (6). Additionally, pulmonary metastases often coexist with liver or bone metastases, posing challenges to therapeutic decision-making. However, for patients with isolated pulmonary metastases, surgical resection may markedly improve outcomes. Studies have demonstrated that postoperative survival rates are relatively high, with a 4-year survival rate of 75% and a median survival time of 19.7 months (7,8).

Research on the risk factors and survival impact of pulmonary metastases in GC remains relatively limited, primarily focusing on small case series and retrospective studies. This study utilizes the Surveillance, Epidemiology, and End Results (SEER) database, which encompasses a substantial dataset of validated cancer cases, offering detailed information on incidence, treatment modalities, and survival outcomes. The SEER database serves as an ideal foundation for large-scale epidemiological investigations. Accordingly, this study aims to identify the risk factors for pulmonary metastases in GC and evaluate their impact on patient prognosis, providing robust evidence to inform clinical decision-making and enhance individualized treatment strategies. We present this article in accordance with the STROBE reporting checklist (available at https://tcr.amegroups.com/article/view/10.21037/tcr-24-2019/rc).

Methods

Data source

This study is a retrospective cohort analysis based on the SEER database, funded by the National Cancer Institute. Data were extracted from the “Incidence-SEER Research Data, 17 Registries, Nov 2023 Sub (2000–2021)” dataset, which provides extensive information on cancer, including demographic characteristics, tumor pathology, treatment modalities, and survival outcomes. The SEER database began recording detailed information on distant organ metastases, including pulmonary metastases, in 2010. Therefore, cases diagnosed between 2010 and 2021 were selected for this study. Case selection was performed using SEER*Stat software version 8.4.4. The inclusion criteria were as follows: (I) pathologically confirmed GC identified using primary site coding (ICD-O-3/WHO 2008); (II) complete information on distant metastases, including pulmonary, hepatic, cerebral, and osseous metastases; and (III) comprehensive survival data, including survival status and survival time. Exclusion criteria included: (I) incomplete or ambiguous metastasis data that prevented determination of pulmonary metastasis status; (II) missing or conflicting survival data, such as undefined survival time or cause of death; and (III) logical inconsistencies or unclear diagnostic information, such as discrepancies between diagnosis and death dates. Excluding incomplete or inconsistent records was critical for maintaining data integrity and ensuring reliable analyses. Missing metastasis data could result in misclassification of metastasis status, impairing the accuracy of risk assessments. Similarly, incomplete survival data could bias estimates of OS and cancer-specific survival (CSS). By rigorously selecting cases with complete and reliable data, this study ensured the scientific robustness and credibility of its findings. The study was conducted in accordance with the Declaration of Helsinki (as revised in 2013).

Outcome variables

We collected data on patient demographics, including gender, age, race, histological type, grade, tumor T-stage, lymph node N-stage, surgical status of the primary tumor and lymph nodes, chemotherapy status, tumor size, months of survival, cause-specific death, survival status, marital status, the location of the primary tumor, and metastasis to the lungs, liver, brain, and bones. The interval between GC diagnosis and death from any cause was defined as OS, while the interval between diagnosis and death specifically from GC was defined as CSS. Since we obtained authorization from the SEER website, no additional ethical approval was required.

Statistical analysis

Descriptive statistical methods were employed to summarize the demographic and tumor characteristics of the included patients. Chi-squared tests were used to compare patients with and without lung metastases. Logistic regression analysis identified risk factors for liver metastasis in GC patients. We constructed receiver operating characteristic (ROC) curves and calculated the area under the curve (AUC) to assess the diagnostic efficacy of various predictors for lung metastasis. Kaplan-Meier methods were used to estimate and compare survival functions for patients with and without lung metastasis, and Cox proportional hazards regression analysis identified variables associated with prognosis in lung metastasis. All statistical analyses were conducted using R version 4.3.1, with a significance level set at α=0.05.

Results

General data

This study included a total of 48,474 patients with confirmed GC, comprising 28,496 males (58.8%) and 19,978 females (41.2%). The majority of patients (72.2%, n=34,977) were aged 60 years or older, and 70.1% (n=33,981) identified as White. Additionally, 2,694 patients (5.6%) were diagnosed with pulmonary metastases.

Characteristics of patients with or without lung metastasis

The results of this study demonstrate that several factors, including gender, race, histological type, tumor differentiation, T stage, N stage, surgical status, regional lymph node dissection, chemotherapy status, tumor size, marital status, metastasis to other sites (such as the liver, brain, or bones), and the primary tumor location, were significantly associated with the incidence of pulmonary metastasis (P<0.05). In contrast, age was not significantly correlated with the occurrence of lung metastasis. These findings highlight the complex interplay of clinical and pathological factors in the development of lung metastasis in GC patients (P>0.05) (Table 1).

Univariate and multivariate logistic regression analysis of lung metastasis in GC

The results of the univariate analysis indicated that factors such as gender, race, histological type, T stage, N stage, surgical status, lymph node dissection, chemotherapy, tumor size, and the presence of liver, brain, and bone metastases, as well as the location of the primary tumor, were all significant independent risk factors for lung metastasis (P<0.05). In contrast, age and marital status did not exhibit a significant association with lung metastasis (P>0.05) (Table 2).

All factors identified as significant in the univariate analysis were included in the multivariate logistic regression model. The results demonstrated that the risk of lung metastasis was significantly increased in patients with squamous cell carcinoma (SCC) compared to those with adenocarcinoma [adjusted odds ratio (aOR) 1.575, 95% confidence interval (CI): 1.152–2.120], while patients with other histological types exhibited a significantly reduced risk of lung metastasis (aOR 0.269, 95% CI: 0.214–0.333). Regarding T staging, patients classified as T4 had a significantly higher risk of lung metastasis compared to those classified as T1 (aOR 1.487, 95% CI: 1.130–1.954). The N staging results indicated that patients with N1 had a significantly higher risk of lung metastasis compared to N0 patients (aOR 1.825, 95% CI: 1.385–2.391), and patients with unknown N stage also displayed a significantly increased risk of lung metastasis (aOR 1.503, 95% CI: 1.280–1.771). Patients who underwent surgery had a significantly lower risk of lung metastasis compared to those who did not (aOR 0.198, 95% CI: 0.145–0.265). Furthermore, the risk of lung metastasis was significantly reduced in patients who underwent dissection of four or more lymph nodes (aOR 0.489, 95% CI: 0.330–0.725). Conversely, patients receiving chemotherapy had a significantly increased risk of lung metastasis (aOR 1.123, 95% CI: 1.026–1.228). When comparing patients with liver metastasis to those without, the risk of lung metastasis was significantly elevated in the former group (aOR 3.888, 95% CI: 3.568–4.238). Similarly, the presence of brain metastasis (aOR 4.434, 95% CI: 3.480–5.631) and bone metastasis (aOR 2.883, 95% CI: 2.568–3.234) was associated with a significant increase in lung metastasis risk. Compared to patients with tumors located in the upper stomach, those with tumors in the middle (aOR 0.712, 95% CI: 0.632–0.802) and lower stomach (aOR 0.716, 95% CI: 0.611–0.836) exhibited a significantly reduced risk of lung metastasis. Notably, gender, age, race, tumor size, and marital status were not identified as significant predictors of lung metastasis (Table 2).

Diagnostic efficacy comparison of risk factors for lung metastasis in GC

We constructed ROC curves to evaluate the diagnostic ability of various risk factors for lung metastasis in GC patients (Figure 1). By comparing the AUC values for different risk factors, we found that the AUC for sex was 0.538 (95% CI: 0.529–0.547, P<0.001), while the AUC for age was 0.505 (95% CI: 0.496–0.514, P=0.27). The AUC for race was 0.531 (95% CI: 0.523–0.540, P=0.002), and the AUC for histological type was 0.598 (95% CI: 0.592–0.604, P<0.001). The AUC for T stage was 0.540 (95% CI: 0.533–0.546, P=0.13), and for N stage, it was 0.554 (95% CI: 0.548–0.561, P<0.001). The AUC for surgical status was 0.691 (95% CI: 0.687–0.696, P<0.001), while the AUC for lymph node dissection was 0.625 (95% CI: 0.621–0.629, P<0.001). The AUC for chemotherapy was 0.538 (95% CI: 0.529–0.548, P<0.001), and for tumor size, it was 0.553 (95% CI: 0.543–0.563, P<0.001). In contrast, the AUC for marital status was 0.522 (95% CI: 0.513–0.532, P=0.77). The combined AUC for liver metastasis was 0.705 (95% CI: 0.696–0.715, P<0.001), while for brain metastasis, it was 0.523 (95% CI: 0.519–0.527, P<0.001), and for bone metastasis, it was 0.580 (95% CI: 0.573–0.588, P<0.001). The AUC for the location of the primary tumor was 0.601 (95% CI: 0.590–0.611, P=0.47). These results suggest that liver metastasis is the most effective diagnostic factor for predicting lung metastasis.

Figure 1 ROC curve predicting the risk factors for pulmonary metastasis in gastric cancer. ROC, receiver operating characteristic; AUC, area under the curve; DX, diagnosis; Mets, metastasis.

Survival analysis

The median OS for patients with pulmonary metastases was found to be 2.0 months, in stark contrast to 14 months for those without pulmonary metastases (P<0.001; Figure 2). The 1-, 3-, and 5-year OS rates for patients with lung metastases were 15.03%, 3.92%, and 2.02%, respectively. In comparison, the 1-, 3-, and 5-year OS rates for patients without lung metastases were 52.59%, 34.61%, and 28.78%. Furthermore, the median CSS for patients with pulmonary metastases was 3.0 months, whereas the median CSS for patients without lung metastases was 20 months (P<0.001). The 1-, 3-, and 5-year CSS rates for patients with lung metastases were 17.95%, 5.19%, and 3.49%, respectively, compared to 58.07%, 41.87%, and 37.79% for those without lung metastases.

Figure 2 Kaplan-Meier curves for overall survival and cancer-specific survival in gastric cancer patients with and without pulmonary metastasis.

Prognostic factors affecting outcomes in GC patients with pulmonary metastases

Univariate Cox regression analysis revealed that factors such as age over 60 years, Black race, the presence of other epithelial tumors, tumor size exceeding 5 cm, being divorced or separated, being widowed, being single (never married), liver metastasis, bone metastasis, and primary site located in the lower stomach or others were all significant predictors of poor OS. Conversely, histologic type classified as others, undergoing surgical intervention, removal of four or more lymph nodes, and receiving chemotherapy were significant predictors of better OS (Table 3).

All significant factors identified in the univariate analysis were included in a multivariate Cox regression model for further investigation. The multivariate analysis indicated that patients with other epithelial tumors had a significantly increased risk of mortality, with a hazard ratio (HR) of 1.194 (95% CI: 1.019–1.399). Conversely, patients who underwent surgical intervention exhibited a decreased risk of mortality, with an HR of 0.632 (95% CI: 0.473–0.843). Additionally, patients receiving chemotherapy demonstrated a significantly reduced risk of mortality, with an HR of 0.322 (95% CI: 0.295–0.351). Single patients (never married) faced an increased risk of mortality, with an HR of 1.142 (95% CI: 1.020–1.278). Liver metastasis and bone metastasis were associated with increased mortality risk, with HR of 1.240 (95% CI: 1.144–1.344) and 1.183 (95% CI: 1.071–1.307), respectively. Finally, patients with primary tumors located in the lower stomach also had an elevated risk of mortality, with an HR of 1.289 (95% CI: 1.110–1.496) (Table 3).

Univariate Cox regression analysis for CSS revealed that several factors significantly predicted poorer CSS. These factors include being over 60 years of age, being of Black race, having the presence of other epithelial tumors, having tumors larger than 5 cm, being divorced or separated, being widowed or single (never married), having liver metastases, and having the primary tumor located in the lower stomach or other regions. Conversely, histologic type classified as others, undergoing surgical intervention, removal of four or more lymph nodes, and receiving chemotherapy were significant predictors of better CSS (Table 4).

All factors identified as significant in the univariate analysis were incorporated into a multivariate Cox regression model for further examination. The results of the multivariate analysis indicated that patients with other epithelial tumors faced an increased risk of mortality, with a HR of 1.191 (95% CI: 1.006–1.409). In contrast, patients who underwent surgical intervention demonstrated a reduced risk of mortality, with an HR of 0.659 (95% CI: 0.486–0.894). Additionally, those receiving chemotherapy exhibited a significantly lower risk of mortality, with an HR of 0.336 (95% CI: 0.307–0.369). Single (never married) showed an increased risk of mortality, with an HR of 1.159 (95% CI: 1.030–1.305). Furthermore, liver metastasis was associated with an elevated risk of mortality, with an HR of 1.275 (95% CI: 1.171–1.388). Lastly, patients with primary tumors located in the lower stomach also had an increased risk of mortality, with an HR of 1.203 (95% CI: 1.026–1.410) (Table 4).

Discussion

Due to the relative rarity of pulmonary metastases in GC patients, the associated risk factors and prognostic variables remain unclear. This study, based on the SEER database, analyzed 48,474 diagnosed cases of GC, systematically investigating the relevant risk factors for pulmonary metastasis and their prognostic implications. The findings reveal several significant risk factors, providing guidance for clinical practice. The results indicate that patients with SCC, those at T4 stage, N1 stage patients, individuals receiving chemotherapy, and patients with liver, brain, or bone metastases are at a higher risk for pulmonary metastasis. Conversely, patients who undergo surgical intervention, have more than four lymph nodes cleared, and have tumors located in the middle to lower parts of the stomach exhibit a lower risk of pulmonary metastasis. This study establishes liver metastasis as the most predictive factor for pulmonary metastasis, underscoring its importance in diagnosis and treatment. Additionally, the OS and CSS of patients with pulmonary metastasis are significantly lower compared to those without. Patients who undergo surgery for the primary tumor and receive chemotherapy demonstrate improved survival outcomes. In our cohort, 5.56% of patients experienced pulmonary metastasis. Literature indicates that GC is more commonly associated with liver metastasis, with an incidence ranging from 9% to 16.92% (9-12), while the occurrence of brain metastases is less than 1% (0.2–0.7%) (13-15), and bone metastases occur in only 0.9% to 3.8% of cases (16-18).

This study demonstrated that patients with SCC had a significantly higher risk of pulmonary metastasis compared to those with adenocarcinoma (aOR 1.575, 95% CI: 1.152–2.120). Patients with T4-stage tumors also had an increased risk of pulmonary metastasis (aOR 1.487, 95% CI: 1.130–1.954), indicating that tumor invasion into adjacent organs heightens the likelihood of hematogenous and lymphatic spread. These findings align with existing literature, underscoring that highly invasive tumors tend to disseminate via these pathways, increasing the risk of distant metastases (19). Surgical intervention was associated with a significantly lower risk of pulmonary metastasis (aOR 0.198, 95% CI: 0.145–0.265). Furthermore, extensive lymph node dissection (≥4 nodes) further reduced the risk (aOR 0.489, 95% CI: 0.330–0.725). Previous studies suggest that primary tumor resection and thorough lymph node dissection can lower the risk of distant metastases, including cerebral and hepatic metastases (12,20,21). Surgery, particularly when combined with comprehensive lymph node dissection, plays a critical role in curbing the dissemination of cancer cells through the hematogenous or lymphatic routes (22,23). These findings highlight the necessity of aggressive surgical management, especially in high-risk patients, to reduce the likelihood of distant metastases and improve prognosis. Interestingly, chemotherapy was associated with an increased risk of pulmonary metastasis (aOR 1.123, 95% CI: 1.026–1.228). This result is consistent with studies, such as that by An et al., which reported a similar association between chemotherapy and hepatic metastasis risk (aOR 1.335, 95% CI: 1.129–1.578) (21). The higher metastatic risk may reflect the advanced disease stage typically observed in patients receiving chemotherapy. Advanced disease is inherently associated with a greater likelihood of distant metastases. The presence of liver, brain, and bone metastases significantly increased the risk of pulmonary metastasis. Rehman et al. reported that pulmonary metastases significantly heightened the risk of cerebral metastasis (aOR 3.943, 95% CI: 3.101–5.013) (20). Consistently, this study found that brain metastases were strongly associated with pulmonary metastases (aOR 4.434, 95% CI: 3.480–5.631). Liver metastasis emerged as a key predictor of pulmonary metastasis, with an AUC of 0.705 (95% CI: 0.696–0.715, P<0.001). The findings of Pearson et al. suggest that liver metastases may alter tumor biology, accelerating metastatic spread to other sites (24). This study corroborates the direct association between liver and pulmonary metastases, emphasizing the need for thorough pulmonary evaluation in GC patients with liver metastases. Notably, this research identifies liver metastases as the strongest predictor of pulmonary metastasis, supporting a potential “liver-lung-brain” metastatic progression pathway. Patients with tumors originating in the lower stomach had a lower risk of pulmonary metastasis, consistent with findings by Qiu et al., who reported a higher metastatic risk for upper GC (12). However, survival outcomes for upper GC remain controversial in the literature. Yang et al. observed higher survival rates in upper GC patients (25), while Pinto-de-Sousa et al. reported the opposite (26). These discrepancies may reflect variations in patient characteristics, treatment regimens, and follow-up durations across studies, necessitating further high-quality research to clarify these differences. Jin et al. indicated that marital status has a protective effect on GC patients, as married individuals have higher survival rates compared to unmarried, divorced, or widowed patients (27). Spouses of married patients are more likely to encourage them to pursue surgical treatment (28). In our study, single (never married) patients exhibited worse OS and CSS (HR 1.142, 95% CI: 1.020–1.278; HR 1.159, 95% CI: 1.030–1.305). The study by Zheng et al. demonstrated through multivariate Cox regression analysis that liver metastasis significantly reduces OS in patients with GC (HR 1.440, 95% CI: 1.179–1.760, P<0.001). Additionally, CSS was also adversely affected (HR 1.524, 95% CI: 1.217–1.909, P<0.001) (29). Our findings further corroborate the association between liver metastasis and poor prognosis in terms of OS (HR 1.240, 95% CI: 1.144–1.344, P<0.001) and CSS (HR 1.275, 95% CI: 1.171–1.388, P<0.001), consistent with the results of previous studies. Patients with bone metastases exhibited poorer OS, consistent with findings by Chen et al., who reported a median OS of 4 months for bone metastasis patients compared to 30 months for those without (30). However, bone metastases in this study did not significantly impact CSS. Zhang and Ma noted that T staging is an independent factor associated with survival in GC patients (31,32), Although T4 stage patients are more prone to pulmonary metastasis, T staging is not a significant predictor of OS or CSS. The median OS for patients with pulmonary metastasis is 2 months, while it is 14 months for those without pulmonary metastasis (P<0.001), further confirming that pulmonary metastasis significantly reduces survival rates, consistent with findings by Zheng and Kong (6,29). The studies by Lin et al. and Qiu et al. highlighted that brain, bone, and liver metastases significantly impact the survival outcomes of patients with GC (11,12). The novelty of this study lies in identifying liver metastasis as not only a significant factor impacting survival rates but also an independent predictor of pulmonary metastasis—an association that has not been systematically explored or thoroughly discussed in the existing literature. Surgery remains the only potential curative treatment for GC and forms the cornerstone of its management (22,33). Patients who undergo surgical intervention demonstrate a significantly reduced risk of pulmonary metastasis and better OS and CSS outcomes (34). Although our findings indicate that the risk of pulmonary metastasis is heightened in patients receiving chemotherapy, those patients ultimately exhibit better OS and CSS.

While this study identified various clinicopathological factors associated with pulmonary metastases in GC patients, certain limitations must be acknowledged. As a retrospective analysis based on the SEER database, selection and omission biases may have affected the assessment of clinicopathological characteristics. Additionally, the SEER database lacks detailed information on treatment regimens, such as chemotherapy protocols and surgical approaches, which are crucial for understanding patient survival outcomes. The absence of these treatment details could potentially influence the study’s findings. Moreover, the database does not include genotypic or molecular biological data, limiting the ability to investigate and elucidate the mechanisms underlying pulmonary metastases in GC. Therefore, while the SEER database provides extensive clinical and pathological data, its lack of treatment and molecular biology information poses challenges to the comprehensiveness and accuracy of the research.

This study highlights that pulmonary metastases in GC are closely associated with multiple clinicopathological factors, with liver metastases markedly increasing the risk of pulmonary involvement. These findings underscore the importance of early identification of pulmonary metastases, particularly in patients with liver metastases. Future research should focus on exploring the role of molecular biomarkers in predicting pulmonary metastases, optimizing multidisciplinary treatment approaches, and advancing precision medicine strategies. Emphasis should be placed on early diagnosis and intervention to improve survival rates, enhance quality of life, and refine prognostic outcomes for GC patients. Such efforts could provide more personalized and effective treatment options, especially for high-risk patients prone to pulmonary metastases.

Conclusions

Overall, the incidence of pulmonary metastases in GC patients was found to be 5.56%, and pulmonary metastases significantly reduced both OS and CSS. Factors such as other epithelial tumor histology, single (never-married) status, liver metastases, bone metastases, and primary tumors located in the lower stomach were strongly associated with poor prognosis. Surgical intervention and chemotherapy remain the primary strategies for improving outcomes.

Acknowledgments

The authors extend their gratitude to the SEER database for providing the data utilized in this study.

Footnote

Reporting Checklist: The authors have completed the STROBE reporting checklist. Available at https://tcr.amegroups.com/article/view/10.21037/tcr-24-2019/rc

Peer Review File: Available at https://tcr.amegroups.com/article/view/10.21037/tcr-24-2019/prf

Funding: None.

Conflicts of Interest: Both authors have completed the ICMJE uniform disclosure form (available at https://tcr.amegroups.com/article/view/10.21037/tcr-24-2019/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 (as revised in 2013).

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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