According to the estimation, there will be 236740 new cases of lung cancer in the USA in 2022, with 130180 deaths. LC is the second most common cancer in both men and women, less than prostate cancer (in males) and breast cancer (in females), and LC is the leading cause of death among cancer patients, with a low 5-year survival rate (1). Metastasis is a characteristic of cancer and is responsible for the greatest number of cancer-related deaths (2). Approximately 20% of cancer patients will develop brain metastases(BMs) (3), and brain metastases from LC account for approximately 45% of the total cases of BMs (4, 5). Approximately 10% of SCLC patients have brain metastases at the time of the initial diagnosis (6). In addition to the brain, the liver and bone are also common metastasis sites of lung cancer (7, 8). Despite the rapid development of multiple therapies, such as targeted therapies and immunotherapy (9), the prognosis of patients with advanced lung cancer remains poor (3). The median survival time of BM patients is approximately 10.6 months (9). It is very important to identify risk and prognostic factors, evaluate individual metastatic risk and make accurate diagnoses to improve the survival outcome. Providing individualized treatment for different patients to maximize personal survival benefits is a research direction (10).

The survival rates for LC patients with different distant organ metastases are not the same. Understanding the epidemiology of the most common distant organ metastasis patterns in different pathological types of LC, as well as their overall survival, will help the process for clinical decisions. A previous study suggested that for SCLC patients with brain metastasis, male sex, older age, liver metastasis, and insurance status were associated with increased death risk (11). For NSCLC patients, age, race, sex, pathology, T stage and N stage were associated with the occurrence of brain metastasis and overall survival (12–14). However, few studies have compared the survival risk among LC patients with different distant metastases and focused on the prediction of distant metastases. The purpose of our study was to describe a detailed landscape of distant organ metastasis status and explore the effects of distant organ metastasis status on overall survival in different pathological types of lung cancer. We also analyzed the risk factors for organ metastasis and prognostic factors in LC patients based on data from the Surveillance, Epidemiology, and End Results (SEER) database (15). Moreover, we tried to construct nomograms predicting the organ metastasis and overall survival of LC patients.

As the second most common tumor, LC is a serious threat to human health. In recent years, with the development of comprehensive cancer treatments, including surgery, radiotherapy, traditional chemotherapy, targeted therapy and immunotherapy, the survival time of LC patients has been prolonged. However, distant metastasis of LC is still an obstacle to treatment and affects the survival of patients. Evaluating the possibility of developing distant metastasis based on clinical characteristics and examining patients at high risk to detect distant organ metastasis earlier could help physicians adjust treatment plans and improve the prognosis of patients.

Previous studies have suggested that SCLC usually metastasizes to the liver, bone, brain and other organs. Genetic changes may affect its metastatic site (17). In addition, the injection of SCLC cells into the middle vein of mice in one study specifically led to the occurrence of liver metastasis rather than lung metastasis (18). This suggests that small cell lung cancer cells may be more likely to metastasize to the liver through the blood, and the potential mechanism of its metastasis remains to be studied. For NSCLC, the AD and LCC pathological types are associated with a higher risk of brain metastasis than SCC (12, 19). Few studies have focused on the survival risk comparison among LC with different distant metastases and the prediction of distant metastases. In our study, our results showed that various pathologic types of LC show a strong correlation with site-specific metastasis patterns. Our results revealed that the most common metastatic organs are bone for SCC and AD, liver for SCLC and brain for LCC. SCLC is the most prone to distant organ metastasis, as well as multiple organ metastases, especially bone+liver metastasis, while SCC is the least prone. This is consistent with the results of a previous study (20). Regarding patient survival, a study focusing on NSCLC showed that adenocarcinoma is the most common variant for NSCLC, and the mortality risk is highest in multiple metastasis and liver metastasis groups (21). Similarly, in our study, the patients with triple metastases (brain-bone-liver) had the worst prognosis, and for nonsquamous carcinoma with single organ metastasis, liver metastases conferred the worst prognosis, which is consistent with the results of another study (22, 23). However, for SCC patients, there was no significant difference between the survival of SCC patients with single liver and single brain metastasis.

Approximately 30-40% of NSCLC patients will have bone metastasis (22, 24). Research has found that bone metastasis of LC is associated with the cytokines TGF-β and PTHrP, which can promote osteolysis (25–27). SCC can produce a large amount of MMP9 via stimulation by collagen I, thus establishing bone metastasis and releasing tumor cell chemokines during osteolysis (28). Our results suggest that SCC patients with bone metastasis alone have the worst prognosis compared with those with brain metastasis and liver metastasis alone. Two previous retrospective studies (29, 30) on esophageal and gallbladder cancer also reached similar conclusions; that is, among patients with single-organ metastasis, patients with bone metastasis had the worst prognosis (compared with patients with liver metastasis and lung metastasis). In addition, in a real-world study on patients with lung squamous cell carcinoma in 2022, the author found that only bone metastasis was found in distant organ metastasis, which was significantly related to the shorter PFS of these patients (31). This suggests that bone metastasis may be the special metastatic site of these tumors. Because few studies have compared the prognosis of different metastatic modes/sites of lung squamous cell carcinoma, the reason for this phenomenon is not clear. Its potential mechanism needs to be elaborated in future research.

We also investigated the risk factors for developing different organ metastases. LC patients of other races (American Indian/Alaska Native race) were more prone to brain and bone metastasis but not liver metastasis. A study exploring the risk factors for BM from esophageal cancer revealed that other races (American Indian/Alaska Native race) were positively associated with the occurrence of brain metastasis (32). All these results suggest that race is an important factor influencing tumor metastasis with unknown mechanisms. A previous study suggested that male sex is associated with a higher risk of brain metastasis in SCLC (33). According to our results, in addition to brain metastasis, male patients are also more likely to develop liver and bone metastasis. The logistic regression analysis showed that the characteristics of the primary tumor, including the location of the primary tumor, pathological type, T stage, N stage, and separate nodules, were closely related to the occurrence of distant metastasis. Compared with the left lower lobe, tumors with a primary focus in the center lung are less prone to organ metastasis, especially tumors with a primary focus in the upper and middle lobes of the center lung. Previous studies have reported that lung adenocarcinoma with a primary focus within the left side has a higher risk of skull metastasis than lung adenocarcinoma with a primary focus within the center side. Peripheral lung cancer was associated with brain metastasis (34), while central lung cancer was associated with bone metastasis (35). However, the research results of Mujoomdar et al. suggested that the risk of brain metastasis of NSCLC was not related to the location of the primary tumor (36). The relationship between the location of the primary lesion and distant metastasis has not been agreed upon. In addition, our results suggest that among various pathological types, patients with SCC are the least likely to have organ metastasis, patients with AD have a higher risk of bone metastasis and brain metastasis, and patients with SCLC have a higher risk of liver metastasis than patients with other pathological types. Patients with higher T stage, N stage and independent tumor nodules have a higher risk of bone, brain and liver metastasis, which is consistent with several previous studies (9, 13). Our nomograms based on these clinical factors showed good performance in predicting the occurrence of bone (AUC=0.724), brain (AUC=0.754) and liver (AUC=0.717) metastasis.

In this study, based on the multivariate Cox analysis, it was suggested that a primary lesion located in the main bronchus was a poor prognostic factor for LC patients, which caught our attention. Similar results were achieved in previous studies focusing on AD and LCC (37–39). The researchers found that the SUV value of tumors located in the center of PET was significantly higher, which may indicate that there was more active tumor metabolism (40). Main bronchial tumors are closely related to a higher risk of lymph node metastasis and organ metastasis (38, 41). In addition, patients with central tumors are more likely to develop obstructive pneumonia, which also leads to poor prognosis (42). These are all possible factors leading to poor prognosis of main bronchial tumors. In the future, more multicenter clinical studies are needed to reveal the potential mechanisms.

Based on the results of the Cox analysis, we established a survival nomogram to predict the survival of LC patients. The nomogram included age, race, sex, pathology type, primary site, whether there was a separate tumor nodule, T stage, N stage and the number of organ metastases. Although several prognostic models were established for patients with LC or NSCLC with brain metastasis in previous studies (13, 14, 43), separate tumor nodules, primary lesion sites and the number of organ metastases were included together as prognostic factors for the first time. Our model gives individual scores according to the clinical characteristics of each patient and predicts the 1-year, 3-year and 5-year survival rates. The model was independently verified in the test set, and the results showed a high concordance index of 0.718 (95% CI, 0.714-0.722) and an AUC score of 0.842. This suggests that our nomogram has a satisfactory predictive ability and shows better performance than the previous prediction models (37, 44, 45). The combination of the separate nodule status, the location of the primary lesion and the number of organ metastases makes this model more comprehensive and personalized to predict the prognosis and survival of different LC patients.

This study has some limitations. Not all the metastasis statuses of LC patients in the SEER database are clearly described. Therefore, the incidence of brain metastasis, liver metastasis and bone metastasis may be inaccurate. The SEER database does not provide detailed information about the follow-up treatment (including chemotherapy, immunotherapy, targeted treatment, etc.) that the patients received, which may contribute to potential bias and may influence the prognosis of patients, and follow up treatment was not included in this study. In addition, previous studies suggested that extrathoracic lymph node metastasis (46–48) was also a key factor affecting the prognosis of LC patients, but this variable is missing for the patients including in this cohort in the SEER database. This will be a key clinical factor for optimizing our predictive model in the following studies. In future research, more clinical data of stage IV LC patients with distant metastasis could be collected prospectively, as well as the therapy and survival time of these patients, so as to verify the results in this study in clinical data and test the accuracy and predictive performance of the model we constructed. What’s more, the molecular mechanisms underlying the preferential metastatic sites of different types of LC need to be elucidated in future studies.

In this study, we described a detailed landscape of distant organ metastasis statuses and their effects on overall survival in different pathological types of lung cancer. We found that the pathology of LC showed a strong correlation with site-specific metastasis patterns. Moreover, we investigated the risk factors for developing distant organ metastases in LC patients using data downloaded from the SEER database and constructed nomograms that predict distant metastasis and OS with good performance. These results are helpful for clinicians to conduct clinical evaluations and develop individualized therapeutic strategies.

The original contributions presented in the study are included in the article/ Supplementary Material . Further inquiries can be directed to the corresponding author.

SEER database is publicly accessible worldwide. The authors signed the SEER database agreement and got the license to access SEER data.

YH: research design, data collection, interpretation and analysis, manuscript drafting. GL: research design, critical manuscript revision. All authors contributed to the article and approved the submitted version.