Comparison of metastasis and treatment patterns among different histopathologic types of lung cancer: analysis of 6 years of nationwide lung cancer cohort data in Korea

Introduction

Lung cancer, characterized by distinct histologic types, exhibits varying patterns of metastasis, both intrathoracic and extrathoracic. These patterns and their histology-specific predilections may differ according to the pathologic subtype. Understanding the metastasis pattern of each histologic type is crucial for predicting patient outcomes and determining the need for further diagnostic studies. The most common histologic type of lung cancer is adenocarcinoma, followed by squamous cell carcinoma (SqCC) and small cell lung cancer (SCLC). A smaller proportion of cases are large cell neuroendocrine and sarcomatoid cancers, which also contribute to the histopathologic diversity of lung cancer populations (1-4). It is important to know the clinical features unique to each pathologic type, in order to provide more personalized treatment of lung cancer.

The treatment paradigm for stage IV lung cancer has undergone a significant transformation, shifting from a traditionally palliative intent to a more aggressive and curative stance when compared to decades ago. This shift is particularly pronounced in select patient populations, where local control modalities, predominantly thoracic radiotherapy, and metastasis-directed therapy, have been integrated into the comprehensive management plan (5-13). Such interventions are most commonly employed in the context of oligometastatic disease, where local ablative therapies, including curative intent radiotherapy or surgical resection of metastases, have been increasingly adopted (12,14-16). Personalized management of stage IV lung cancer requires a deeper understanding of metastatic patterns and the potential benefits of localized treatments in each histologic type.

This study aims to find patterns of both intrathoracic and extrathoracic metastases in various histologic types of lung cancer using a nationwide Korean national lung cancer database comprised of newly diagnosed lung cancer patients from 2014 to 2019. We present this article in accordance with the STROBE reporting checklist (available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-24-770/rc).

Methods

Data acquirement

Dataset from patients diagnosed as lung cancer from year 2014 to 2019 were screened for eligibility.

The study is based on the Korean Association of Lung Cancer Registry (KALC-R) database, the second nationwide survey, a multi-center cancer registry. The patients with lung cancer were randomly selected from 13 certified regional cancer centers and 38 hospitals in Korea from which a significant number of registrations were made. The KALC-R encompasses around 80 variables including demographic specifics. The dataset includes patient age, gender, body mass index (BMI), clinical symptoms, tobacco use history, performance status, histological cancer type, and clinical stage as defined by the tumor-node-metastasis (TNM) classification. Additionally, initial therapeutic approaches and molecular diagnostic outcomes, specifically mutations in the epidermal growth factor receptor (EGFR) and anaplastic lymphoma kinase (ALK) translocations, were systematically recorded. Variables such as BMI, symptoms, and smoking status were documented during the patient’s initial clinical assessment at the time of diagnosis (17,18). Patients were monitored for a minimum duration of 36 months, with follow-up concluding upon the occurrence of death or the end of the observation period, whichever came first. This study was exempt from consent from study participants and was waived by the Institutional Review Board (No. 2023-1473-0001) due to the deidentified nature of the database. The study was conducted in accordance with the Declaration of Helsinki (as revised in 2013).

Histopathologic types, categorization

Patient histopathological reports were examined and classified according to the WHO 2015 guidelines for lung cancer classification. The categorization was as follows: (I) SqCC; (II) adenocarcinoma; (III) adenosquamous carcinoma; (IV) non-SCLC (NSCLC), not otherwise specified (NOS); (V) large cell neuroendocrine carcinoma (LCNEC); (VI) SCLC; (VII) sarcomatoid carcinoma; and (VIII) carcinoid tumor, based on pathological subtyping documented at diagnosis following World Health Organization’s classification of lung tumors for detailed criteria and definitions (19). For the adenocarcinoma group, subgroup analyses were performed.

TNM stage

The database consisted of clinical information of patients diagnosed with lung cancer from 2014 to 2019. The databases from 2014 to 2017 adhered to the 7^th edition of the TNM classification, whereas those from 2018 to 2019 followed the 8^th edition. Data originally categorized under the 7^th edition were converted to align with the 8^th edition TNM classification. As the study focuses on metastases pattern of lung cancer patients, only those with an M stage indicative of stage IV were included in this study.

Definition of overall survival (OS)

OS was defined as duration between date of diagnosis to date of death or censored. Also, survival rates at 6-, 12-, and 24-month points after diagnosis were also assessed.

Radiotherapy-related information

Whether patients underwent radiotherapy to intrathoracic lesion or extrathoracic lesion were described. We also looked at whether radiotherapy was performed to the specific extrathoracic organ which was metastasized at the time of diagnosis (bone, extrathoracic lymph node, brain, adrenal gland, and liver).

Statistical analysis

Data are expressed as mean ± standard deviation for continuous variables or as frequency (%) for categorical variables. Student’s t-test or analysis of variance (ANOVA) was used to compare continuous variables and Chi-square test or Fisher’s exact test was used to compare categorical variables. Cox proportional hazards models were used to investigate mortality risk factors. All parameters evaluated in the univariate analysis were entered into the multivariate models (backward elimination method). Survival analysis was performed using Kaplan-Meier analysis and log-rank test. Logistic regression was used to compare each possible combination of different extrathoracic metastatic lesions. All P values <0.05 were considered statistically significant. All statistical analyses were performed using SAS ver. 9.4.

Results

Clinical characteristics

The cohort comprised a total of 7,562 patients with stage IV lung cancer, distributed among various histological subtypes, with adenocarcinoma being the most common, accounting for 3,722 patients (49.2%), followed by SqCC with 1,312 patients (17.3%), SCLC with 1,337 patients (17.7%), NSCLC NOS with 449 patients (5.9%), LCNEC with 52 patients (0.7%), sarcomatoid with 66 patients (0.9%), and carcinoid with 28 patients (0.4%).

Baseline clinical characteristics of stage IV lung cancer patients are shown in Table 1. Among all patients, 72.1% were male. SqCC was the type with the highest proportion of male (88.8%), followed by SCLC (87.1%). LCNEC showed the highest proportion of current smoker (51.9%) followed by SCLC (51.7%). Performance status, as assessed by the Eastern Cooperative Oncology Group (ECOG) scale, revealed significant differences (P<0.001) among the histopathologic types, with SCLC, sarcomatoid, carcinoid, and adenosquamous patients more likely to have an ECOG status of 2 or more.

TNM factors among the different histologic types are compared (Table 2). Clinical staging of the T stage showed that SqCC and SCLC are the types with the highest proportion of patients with T4 stage. Among the total patients, proportion of N0, N1, N2, and N3 were 13.2%, 6.3%, 24.4%, and 52.0%, respectively. Histologic types with the highest proportion of N3 were SCLC (61.0%), followed by LCNEC (57.7%).

Regarding M status, patients categorized as M1a, M1b, M1c, and M1 not specified account 27.3%, 56.3%, 15.7%, and 0.6%, respectively among total patients. SqCC was the type with the highest proportion of M1a disease (34.8%). LCNEC type was the type with the highest proportion of M1b disease (73.1%). Adenosquamous type (42.9%) was the type with the highest proportion of M1c disease, followed by carcinoid type (21.4%).

For intrathoracic metastatic lesion, malignant pleural effusion showed the highest proportion (28.5%), followed by contralateral lung metastases (23.3%), pleural nodule (14.6%), and malignant pericardial effusion (3.7%) in total patients. Adenocarcinoma was the type with the highest proportion of malignant pleural effusion (31.0%), and contralateral lung metastases (28.6%). Regarding extrathoracic metastatic lesion, bone was the most frequently metastasized organ (42.3%), followed by brain (25.6%), liver (18.8%), and adrenal gland (14.2%) among all patients. Among SqCC patients, bone was the most frequently metastasized organ, followed by brain, respectively. This pattern of order was seen across all histologic types, except for the carcinoid type.

Regarding the number of metastasized extrathoracic organs, adenosquamous had the highest proportion of patients with 3 or more metastasized organs (21.4%) followed by sarcomatoid type (21.2%). Also, sarcomatoid type had the highest proportion of patients with 2 or more distant metastatic sites (regardless of metastasized organs) (40.9%), followed by LCNEC (34.6%).

Comparison of treatment-related parameters

Treatment-related parameters including median and mean survival duration of the patients were also compared (Table 3). Among 7,562 patients, 7,366 patients (97.4%) had eligible survival data. Median survival duration was 8.0 months among overall patients. Median OS was the longest in adenocarcinoma (12.9 months), followed by LCNEC (7.6 months), SCLC (6.4 months), and carcinoid (6.2 months). Sarcomatoid type showed the shortest median OS of 3.3 months. Adenocarcinoma also had the longest mean OS of 20.2 months among the various histologic types. Regarding survival rate, adenocarcinoma showed the highest 6-, 12- and 24-month survival rates (0.700, 0.519, and 0.326 respectively).

Targetable mutations at diagnosis were also analyzed. In total patients, EGFR mutation was positive in 19.4%, while ALK immunohistochemistry (IHC) and ALK fluorescence in situ hybridization (FISH) were prevalent in 3.1% and 2.5%, respectively. In adenocarcinoma, EGFR mutation was prevalent in 36.1%, and ALK mutation were positive in 5.2% by IHC and 4.3% by FISH.

Treatment modalities and the prevalence of targetable mutations varied significantly across different pathological subtypes. Adenocarcinoma patients had the highest proportion undergoing systemic therapy at 70.7%, with the most common first-line regimens being cytotoxic chemotherapy (37.2%) and targeted therapy (30.6%). This subtype also showed the highest frequency of targetable EGFR and ALK mutations, identified in 36.1% and 4.3% of patients respectively. In contrast, the sarcomatoid subtype had a notably lower performance of systemic therapy (40.9%). For the first-line systemic therapy regimen, cytotoxic chemotherapy was the most common regimen across all subtypes. In the second-line setting, cytotoxic chemotherapy also showed highest proportion across the subtypes.

Regarding radiotherapy, 9.4% of the patients underwent radiotherapy to intrathoracic lesion, while 29.4% of the patients underwent radiotherapy to extrathoracic metastatic lesion among overall patients.

Among overall patients, 29.3% of the patients with bone metastases at diagnosis underwent radiotherapy to bone metastatic lesion, while 55.8% of the patients with brain metastases at diagnosis underwent radiotherapy to the lesions. Adenosquamous type was the pathologic type with highest proportion of radiotherapy performed to bone metastatic lesion (44.4%), followed by adenocarcinoma (36.3%). Regarding brain metastatic lesion at diagnosis, patients with adenocarcinoma had the highest proportion undergoing radiotherapy to the lesions (59.1%), followed by SCLC (58.8%), and NSCLC NOS (58.1%).

Comparison of OS by presence of metastatic lesion within each histologic type

Patients were stratified based on: (I) the presence of intrathoracic metastases; (II) the presence of extrathoracic metastases; and (III) whether they had only intrathoracic or extrathoracic metastases, or both, and OS were compared (Table 4). Patients with extrathoracic metastases exhibited significantly shorter OS compared to those without, across SqCC, adenocarcinoma, and SCLC groups. Similar trend was seen in other histologic types, but no statistical significance was present.

However, no significant differences were observed between groups stratified by intrathoracic metastases within each histopathologic subgroup. Statistical significance was noted only in the overall patient population.

When concurrently comparing the three groups, a statistically significant difference in OS was observed among the SqCC, adenocarcinoma, and SCLC groups. The median OS was highest for patients with intrathoracic metastases only, followed by those with extrathoracic metastases only, and lowest for patients with both, across all histopathologic subgroups except the carcinoid group.

Comparison of OS between groups stratified by specific extrathoracic metastatic site

Stratified analysis of OS in stage IV lung cancer based on extrathoracic metastatic sites was also performed. Specifically, metastases in the liver and bones were associated with a decrease in survival times across histologic types. In SqCC, group with liver metastases showed a median OS of 3.3 months [95% confidence interval (CI): 2.85–4.3] compared to 6.0 months in the absence of liver metastases (95% CI: 5.5–6.6) (P<0.001). In SCLC, patients with bone metastases showed median OS of 5.2 months (95% CI: 4.55–5.8), in comparison to 7.5 months (95% CI: 6.85–8.2) in patients with no bone metastases. In adenocarcinoma while other extrathoracic metastases showed significant reduction in OS, brain metastases did not significantly affect OS (Table 5).

Combination of different metastases

The overlap of different extrathoracic metastatic lesions was also analyzed (Table 6, Figure 1). In SqCC, bone metastases are significantly associated with liver and adrenal gland metastases, with odds ratios (ORs) of 1.74 and 2.03, respectively. Concurrent metastases to the brain and adrenal glands were also observed (OR =1.62). In adenocarcinoma, significant associations between various metastatic sites were identified, with the strongest correlation observed between bone and liver (OR =3.93), followed by liver and adrenal gland (OR =2.85). In SCLC, concurrent metastases to bone and liver were associated with an OR of 2.87, demonstrating statistical significance. In the sarcomatoid subtype, bone metastases were significantly associated with liver and adrenal gland involvement.

Figure 1 Combination of different metastatic sites by each histologic type. Only statistically significant combinations are shown with ORs and 95% CIs. Cell color explanation: light orange: OR, not available; light blue: OR ≤1; light green: 1< OR ≤2; darker green: 2< OR ≤3; darker blue: OR >3. NSCLC, non-small cell lung cancer; NOS, not otherwise specified; SCLC, small cell lung cancer; OR, odds ratio; CI, confidence interval.

Association between distant metastases and T, N factors

Association between T stages with different extrahepatic metastases was analyzed. There were significant negative association between T1 and T2 with liver metastases in adenocarcinoma (OR =0.66 and 0.74, respectively). Association between N stages with different extrahepatic metastases was also analyzed. In adenocarcinoma, there were significant negative association of N0 stage with brain, bone, and liver (OR =0.64, 0.47, and 0.30, respectively), and N3 stage showed a significant positive association with metastases to the brain, bone, and liver (OR =1.26, 1.80, and 2.15, respectively). In SCLC, significant negative association was found between bone metastases and N0 or bone metastases and N1 (OR =0.33 and 0.54, respectively).

Comparison of survival between patients who received radiotherapy to extrathoracic metastatic site and patients who did not

Survival between patients who received radiotherapy for extrathoracic metastatic sites identified at diagnosis and those who did not was compared. A statistically significant difference was observed in adenocarcinoma and SCLC, with increased OS for patients undergoing radiotherapy (P<0.001 and P<0.001, respectively). Although there was a trend towards better survival in squamous, adenosquamous, large cell, and sarcomatoid cancers, no statistical significance was found (Table 7).

Survival analysis in total patients

In the multivariate analysis of OS, several prognostic factors were identified. Patients with two or more extrathoracic metastases had significantly worse OS [hazard ratio (HR) =1.66; 95% CI: 1.37–2.01; P<0.001]. An ECOG score of 2 or higher was associated with decreased OS (HR =1.64; 95% CI: 1.47–1.82; P<0.001). Advanced N stage (N3 vs. N0) was also correlated with decreased OS (HR =1.73; 95% CI: 1.53–1.96; P<0.001). The presence of bone metastases (HR =1.24; 95% CI: 1.11–1.39; P<0.001) and, separately, liver metastases (HR =1.31; 95% CI: 1.16–1.49; P<0.001) were each associated with decreased OS.

Patients who received radiotherapy to lung lesions demonstrated better OS (HR =0.68; 95% CI: 0.60–0.78; P<0.001) compared to those who did not. Similarly, radiotherapy to extrathoracic metastatic lesions was associated with significantly better OS (HR =0.85; 95% CI: 0.77–0.92; P<0.001). Histologic type was also an independent predictor for OS, with adenocarcinoma showing an HR of 0.65 (95% CI: 0.58–0.73; P<0.001) compared to squamous cell lung cancer (Table 8).

Adenocarcinoma subgroup with valid EGFR/ALK mutation profiles

Baseline characteristics

Among 3,454 patients with adenocarcinoma and valid data for EGFR and ALK mutations, a significant proportion (45.8%) had either EGFR or ALK mutations. Patients with mutations were younger (mean age 65.5 vs. 68.1 years, P<0.001) and had a higher proportion of females (56.7% vs. 26.5%, P<0.001). They also had a higher average BMI (23.3 vs. 22.9 kg/m², P=0.001). The mutation-positive group had a higher percentage of never smokers (62.6% vs. 34.1%, P<0.001) and were more likely to have a better performance status (ECOG 0–1). No significant difference was observed in the distribution of N stage between the groups, while T stage showed higher incidences of early-stage (T1 and T2) tumors in the mutation-positive group. Among intrathoracic metastases, pleural nodules showed significantly higher proportion in the mutant group (P=0.007). Bone and brain metastases were also significantly higher in the mutant group (P=0.006 and P<0.001, respectively) (Table S1).

Treatment-related parameters

Patients with EGFR or ALK mutations showed a significantly higher median OS of 24.5 months compared to 8.0 months for those without the mutations (P<0.001). The mutant group had a higher rate of survival at 6, 12, and 24 months. Additionally, they showed a higher proportion of completion for treatment modalities, including surgery, radiotherapy, and systemic therapy (P=0.02, P<0.001, and P<0.001, respectively). Proportion of patients who were administered RT to lung lesions and extrathoracic metastatic sites were significantly higher in the mutation-positive patients (P=0.014 and P<0.001, respectively) (Table S2).

Comparison of median OS in adenocarcinoma patients stratified by the presence of extrathoracic metastases

Univariate analysis of OS was conducted based on the presence of metastases in each organ (brain, bone, adrenal, and liver). In the wild-type patients, the presence of brain metastases did not significantly impact OS (P=0.304), but bone, liver, and adrenal metastases were associated with decreased survival (P<0.001 for all three comparisons). When compared to the wildtype group, EGFR or ALK positive patients showed a more favorable median OS across all sites. In the mutant group, presence of brain, bone, liver, and adrenal lesions were associated with decreased median OS (P<0.001 for all comparisons). In overall adenocarcinoma patients, no significant difference in OS was seen between the groups with or without brain metastases, while other metastases were associated with significantly worse OS (Table S3).

Survival analysis in adenocarcinoma group

In the multivariate analysis for OS in adenocarcinoma patients, several parameters showed significant associations. Males had a higher risk of mortality (HR =1.35; 95% CI: 1.13–1.61; P=0.001) compared to females. Age at diagnosis (HR =1.02; 95% CI: 1.01–1.03; P<0.001) and BMI (HR =0.96; 95% CI: 0.94–0.98; P<0.001) were also significant. The presence of extrathoracic metastases was significantly associated with survival, with the highest risk observed in patients with two or more sites (HR =1.67; 95% CI: 1.25–2.23; P=0.001). EGFR mutations (HR =0.50; 95% CI: 0.43–0.57; P<0.001) and ALK mutations (HR =0.48; 95% CI: 0.39–0.60; P<0.001) were significant factors.

While liver metastases (HR =1.42; 95% CI: 1.16–1.74; P=0.001) and bone metastases (HR =1.34; 95% CI: 1.13–1.60; P=0.001) were significantly associated with worse survival, brain metastases did not show a significant association (P=0.077). Receiving radiotherapy to lung lesions (HR =0.80; 95% CI: 0.64–0.99; P=0.042) or extrathoracic metastatic lesions (HR=0.82; 95% CI: 0.71–0.94; P=0.005) was associated with improved survival. The presence of intrathoracic metastases was also significantly associated with worse survival (HR =1.26; 95% CI: 1.10–1.49; P=0.002).

ECOG status (P<0.001), T stage (T1–2 vs. T3–4, P=0.002), and N stage (N0 vs. N3, P<0.001) also showed significant associations with survival (Table S4).

Discussion

Present study has undergone exploratory analyses of metastases pattern of lung cancer patients enrolled in KCCR from 2014 to 2019.

It was notable that patients diagnosed as SCLC, large neuroendocrine, and sarcomatoid type cancer showed higher proportion of extrathoracic metastasis. In previous studies, it was known that SCLC, sarcomatoid types show invasive and proliferative nature (20,21). When compared to previous studies with similar design, prevalence of bone metastases and brain metastases seem to be lower. The study from Samsung Medical Center in Korea, showed prevalence of 58.3% and 44.3% for bone and brain metastases, respectively (22). This could be due to smaller denominator in this study, which make the proportion larger, but order of frequency and predilection of distant metastatic lesion for each histopathologic type seems to be similar.

The impact of intrathoracic and extrathoracic metastases on the prognosis of stage IV cancer was evaluated across different histologic types. The presence of extrathoracic metastases regardless of sites was associated with decreased OS for all histologic types, with statistical significance observed in major types such as adenocarcinoma, SCLC, and SqCC. A comparison among three groups (patients with only intrathoracic metastases, those with only extrathoracic metastases, and those with both) revealed that patients with both types of metastases exhibited the shortest OS across all histologic types. Moreover, patients with only extrathoracic metastases demonstrated worse survival than those with only intrathoracic metastases.

Recent changes in the TNM 9^th edition include a revision of the M stage. M1c is now subdivided into M1c1 (multiple metastases in a single extrathoracic organ system) and M1c2 (multiple metastases in multiple extrathoracic organ systems) (23). In the multivariate analysis for OS, it was shown that as the number of extrathoracic metastases increases, the HR for mortality increases incrementally, with statistical significance. Although the number of metastasized extrathoracic organs was not included in the multivariate analysis, our findings support the need for a more detailed assessment of metastatic burden in the context of TNM staging.

Notably, this study found that undergoing radiotherapy for both lung lesions and extrathoracic metastases resulted in better outcomes. This significant improvement in OS was observed in the multivariate analysis for the overall patient group and the adenocarcinoma subgroup. Although there were limitations, such as variations in disease burdens between the groups who received radiotherapy and those who did not, it remains clinically significant that more intensive localized treatment results in more favorable outcomes. The potential survival benefit of radiotherapy to extrathoracic metastases was particularly pronounced in adenocarcinoma and SCLC subtypes. In NSCLC, local consolidation treatment to oligometastatic disease was associated with better PFS and OS (24-26). In extensive-stage SCLC, consolidative thoracic radiotherapy can be administered both before and during maintenance immunotherapy (26). The ongoing RAPTOR/NRG LU007 trial (NCT04402788) will evaluate the efficacy and safety of radiotherapy for ES-SCLC patients following immunotherapy (27). In our analysis, brain lesions were the most likely to receive radiotherapy across all subtypes. For most subtypes, except adenosquamous carcinoma, more than 50% of patients underwent radiotherapy for brain metastases found at diagnosis. Conversely, a lower percentage of patients received radiotherapy for bone metastases. Adenocarcinoma and adenosquamous carcinoma had the highest percentages of patients undergoing radiotherapy. We assume that this is because brain metastases can induce neurologic symptoms, making early management more beneficial. Conversely, asymptomatic bone metastases are less likely to undergo radiotherapy. Nevertheless, the decision to undergo localized radiotherapy requires a case-by-case approach and should be discussed within a multidisciplinary team.

The finding that patients with SCLC demonstrated significantly better survival with brain metastases compared to those without requires careful interpretation. This result may be partially explained by the fact that the entire study population consists of patients with metastatic lesions, whether intrathoracic or extrathoracic. It appears that among various metastatic sites, the presence of brain metastases may be linked to relatively better outcomes, potentially due to the more accessible nature of local treatment options, such as radiotherapy or metastasectomy. However, this finding should not be generalized to draw the conclusion that brain metastases are associated with better prognosis, as this is contrary to historical findings (28).

In the interpretation of the combination of different extrathoracic metastatic sites in our study, the association of bone metastases with metastases to the liver and adrenal glands, exhibiting relatively higher ORs across different histologic types, is notable. Despite the absence of a precise cause-and-effect relationship, this potential relationship is worth discussion. The observation of distant bone metastases may indicate a higher likelihood of metastatic spread to other organs, which warrants more cautious attention from physicians. This strong association was also observed in a previous study by Wang et al., where the OR between bone metastases and liver metastases exceeded 4.99 (29). Indeed, in our study, patients with bone metastases showed worse OS compared to patients without, and even worse than those with brain metastases. This pattern aligns with findings from other studies, which have demonstrated that brain metastases are not associated with a worse prognosis to the same extent as bone or liver metastases. This may be due to adenocarcinoma patients having the highest rates of brain metastases while simultaneously exhibiting the best prognosis. In addition, we hypothesize that brain metastases are more easily detected because magnetic resonance imaging (MRI) is the standard modality for this organ, rather than computed tomography (CT), which is typically used to identify abnormalities in the liver. Therefore, it can be inferred that by the time liver metastases are detected by abdominal CT or positron emission tomography (PET) scans, or bone metastases being detected by bone scan, the tumor volume tends to be larger.

Metastasis patterns varied with the presence of targetable mutations in the adenocarcinoma subgroup. Patients with EGFR or ALK mutations had a significantly higher incidence of pleural nodules, indicating a tendency for more peripheral lesions. Additionally, these patients showed a significantly higher prevalence of bone and brain metastases when compared to patients without driver mutations. A higher percentage of brain metastases in the EGFR-mutated group has been reported in previous studies (30,31) supporting the consistency of our study with historical data.

Based on the findings of our study, a more tailored approach to managing metastatic lung cancer is recommended, emphasizing treatment strategies and comprehensive evaluation of metastatic patterns. Radiotherapy demonstrated significant clinical benefits for patients with extrathoracic metastases, particularly those with brain involvement. In recent studies, a combined approach involving local ablative therapies and systemic treatments, such as targeted therapy and immunotherapy, has shown improved outcomes in advanced NSCLC (16,32,33), particularly in oligometastatic cases. Our findings indirectly support this strategy, suggesting that integrating radiotherapy into the treatment plan could provide substantial benefits for eligible patients. The study also underscores the importance of identifying metastatic sites with a more focused approach. Bone and liver metastases were frequently associated with metastases in other organs, potentially serving as sentinel lesions, highlighting the need for thorough evaluations to detect additional sites. Furthermore, in the adenocarcinoma subgroup with EGFR/ALK mutations, higher prevalences of pleural nodules, brain metastases, and bone metastases were observed, suggesting that more focused surveillance for metastatic lesions could be particularly beneficial in these cases.

Our study has several limitations. Firstly, our data do not provide detailed genetic alterations beyond EGFR and ALK. Most patients were diagnosed during a period when comprehensive mutation workups were not yet common. Secondly, few patients received immunotherapy, as its widespread use had not yet begun. Consequently, a detailed analysis of how metastasis patterns affected the efficacy of immunotherapy-containing regimens was not possible. Lastly, as the study period [2014–2019] includes patients diagnosed in different years and national reimbursement policies for systemic therapy varied over time, a detailed comparison of treatment regimens between histopathologic types or survival analyses based on these regimens was not feasible.

Conclusions

Present study shows notable differences in metastatic patterns among lung cancer histologic types. Understanding these patterns is important for tailoring diagnostic and treatment strategies, ultimately supporting personalized management of lung cancer.

Acknowledgments

We thank statistician Seulki Kim for her statistical analyses. The data used for this study were provided by the Korean Association for Lung Cancer & Ministry of Health and Welfare, Korea Central Cancer Registry.

Footnote

Reporting Checklist: The authors have completed the STROBE reporting checklist. Available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-24-770/rc

Data Sharing Statement: Available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-24-770/dss

Peer Review File: Available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-24-770/prf

Funding: None.

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-24-770/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 exempt from consent from study participants and was waived by the Institutional Review Board (No. 2023-1473-0001) due to the deidentified nature of the database. 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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