Risk factors for exclusive lung metastasis in colorectal cancer: a comprehensive narrative review

Introduction

Background

As one of the most prevalent tumors all over the world, colorectal cancer (CRC) ranks third in terms of incidence (10.2% of all cancer cases worldwide) and is the second leading cause of cancer-related deaths (9.2% of all cancer-related deaths worldwide) (1). By 2030, according to the study, CRC is expected to impact over 2.2 million people and result in 1.1 million deaths (2).

Metastasis of malignant tumors is a major clinical feature of advanced CRC and a high-risk factor for high mortality rates (3). When they are initially diagnosed with CRC, 20% of the patients already have distant metastases. On the other hand, during the course of the disease, 50–60% of patients with CRC get distant metastases, with lung metastases representing 10–20% of these cases, second only to liver metastases (4). Genetic factors, habits, and lifestyle all influence the risk of having CRC. The prognosis for patients with CRC has significantly improved due to increasing awareness of physical examination, the availability of medicines, and the discovery of early biomarkers (5,6).

The prognosis for patients with metastatic CRC (mCRC) is poorer; the 5-year survival rate is barely 10%, and the median survival duration is only 20–30 months. It is critical to define the risk factors for early death in patients with mCRC (7). Lung metastasis is classified as first metastasis and non-first metastasis by the order of metastasis. Furthermore, based on the presence or absence of extrapulmonary metastases, it is categorized as either exclusive or non-exclusive lung metastasis (ELM) (8).

Rationale and knowledge gap

Although numerous studies have investigated prognostic factors in mCRC, there is a scarcity of literature that synthetically analyzes the risk factors specifically predictive of ELM, which has distinct clinical implications compared to multi-organ or liver-only metastases. Most existing reviews focus on general metastatic patterns or treatment options, leaving a gap in the comprehensive understanding of the determinants that drive metastatic tropism solely to the lungs.

Objective

Therefore, the objective of this comprehensive narrative review is to synthesize and critically evaluate the current evidence on risk factors—encompassing demographic, clinicopathological, molecular, and imaging characteristics—associated with the development of ELMs in CRC. By providing a structured overview of these factors, we aim to inform clinical risk stratification and guide future research directions. Specifically, this review seeks to address the gap in the literature regarding the determinants that drive metastatic tropism solely to the lungs, thereby offering insights that can potentially improve patient outcomes and inform targeted therapeutic strategies (9). We present this article in accordance with the Narrative Review reporting checklist (available at https://jgo.amegroups.com/article/view/10.21037/jgo-2025-762/rc).

Methods

This narrative review was informed by a literature search of PubMed/MEDLINE, Web of Science, and Google Scholar from database inception to April 24, 2024. We focused on English-language human studies published mainly in the last decade (2014–2024), while also considering seminal earlier work. Both original research articles and review articles were included. Reviews were used to provide background, mechanistic insights, and contextual interpretation, but were not the primary source for risk factor synthesis. Titles and abstracts were screened for relevance to CRC lung metastasis (with emphasis on ELM). Eligible full texts were reviewed to extract data on demographic, clinicopathological, molecular, biomarker, and imaging predictors. Studies were excluded if they were non-English, non-human, or did not report on predictors of lung metastasis. The detailed search strategy is summarized in Table 1.

Population characteristics

Age factor

The relationship between age and pulmonary metastasis risk in CRC remains complex, with evidence supporting associations in both younger and older patients.

Some studies link younger age (<65 years) to higher risk, often correlating with more aggressive tumor features like larger size and increased lymph node involvement (10,11). Enhanced detection in younger, healthier patients may also contribute to this observed association.

Conversely, multiple large studies identify advanced age as a significant risk factor (12,13), potentially due to age-related biological changes such as declined immune function, altered lymphatic drainage, and accumulated mutations. Less aggressive diagnostic approaches in older patients with comorbidities might also lead to later metastasis discovery.

These conflicting findings likely arise from variations in study design and population characteristics. Current evidence predominantly supports older age as a risk factor, though the aggressive biology in some younger patients requires attention. Future studies controlling for staging intensity and treatment access are needed to clarify age-specific mechanisms.

Race, regional factors

The risk of pulmonary metastasis from CRC varies significantly across racial, ethnic, and geographic populations, reflecting differences in genetic background, environmental factors, and health systems. Patients of African descent show a higher incidence of lung metastases compared to other groups (14), likely due to variations in tumor biology, barriers in healthcare access, and higher comorbidity rates. A multinational study further reported geographic disparities, with prevalence rates ranging from over 40% in the UK and Spain to around 26% in China (15). These variations may arise from divergent screening practices, lifestyle and environmental influences, and population-specific genetic predispositions. Overall, these disparities emphasize that metastatic risk is shaped by both biological and systemic factors. Future studies should aim to separate genetic from modifiable socioeconomic and healthcare-related influences to better address these inequities.

Marital and insurance status factors

Socioeconomic determinants, particularly insurance and marital status, significantly influence the risk of pulmonary metastasis in CRC, primarily through impacts on healthcare access and social support. Uninsured and unmarried patients demonstrate a higher likelihood of developing lung metastases (12). This association is largely attributed to disparities in the cancer care continuum. Lack of insurance often leads to delayed diagnosis and reduced access to optimal treatment, increasing the risk of metastatic spread. Similarly, marital status serves as a proxy for social support, with unmarried patients potentially experiencing less assistance in navigating healthcare systems and adhering to surveillance protocols.

Thus, these factors likely contribute to metastatic risk indirectly by affecting the timeliness and quality of care. Further research is needed to clarify these relationships and inform strategies for mitigating these disparities.

People with a history of inflammatory lung conditions such as smoking

The lung microenvironment, rich in immune cells, is altered by inflammatory conditions and smoking, fostering a favorable niche for metastatic growth. Chronic inflammation, as seen in chronic obstructive pulmonary disease (COPD), and exposure to cigarette smoke promote tumor progression and pre-metastatic niche formation.

A multivariate analysis of 567 CRC patients confirmed smoking as a significant risk factor for pulmonary metastasis (16). Further studies support that smoking independently increases lung metastasis risk, with current smokers facing the highest risk (17). These findings highlight the need for prospective studies incorporating molecular and histologic assessments to elucidate the underlying mechanisms.

Body mass index (BMI)

While a high-fat, low-fiber diet is an established risk factor for CRC development through mechanisms including bile acid metabolism alteration and chronic inflammation, the role of BMI in pulmonary metastasis remains uncertain. Although BMI is associated with adverse clinicopathological features such as advanced tumor stage and lymph node involvement, current evidence does not support its role as an independent risk factor for pulmonary metastasis from CRC. Further investigation is required to clarify its potential influence on metastatic progression.

Multidisciplinary and surgical perspectives

Beyond general demographic factors, insights from large-scale surgical registries have significantly advanced our understanding of pulmonary metastases from a thoracic perspective. Notably, the Spanish Group for Surgery of Colorectal Lung Metastases (GECMP-CCR-SEPAR) has established a comprehensive prospective registry that elucidates the clinical and demographic profiles of patients undergoing pulmonary metastasectomy. Their findings highlight that specific perioperative characteristics and rigorous patient selection are critical determinants of outcomes, underscoring the necessity of a multidisciplinary approach that integrates thoracic surgical expertise with oncological risk stratification (18,19).

Characterization of the primary lesion

Anatomical location of the primary lesion

The anatomical location of the primary colorectal tumor is a significant determinant of metastatic patterns, particularly for pulmonary metastasis. Rectal cancer (RC) is consistently associated with a higher risk of lung metastasis compared to left colon cancer (LCC) and right colon cancer (RCC), which may even exhibit a protective effect (20). This finding is supported by multiple clinical studies. A Korean retrospective study and a Surveillance, Epidemiology, and End Results (SEER) database analysis (2010–2016) both confirmed that rectal tumors metastasize to the lungs more frequently than colon cancers (14,21). The five-year cumulative incidence of synchronous lung metastasis was 2.8 times higher in RC (16.7% vs. 7.5%), and the rate of metachronous metastasis was 2.63 times greater (9.1% vs. 4.1%) (22). Another study of 1,600 resected CRC patients reported that 43.1% of pulmonary metastases originated from RC, compared to 30.3% from LCC (23).

Anatomic venous drainage provides a key mechanistic explanation: rectal venous flow via the inferior rectal vein connects directly to the systemic circulation (inferior vena cava), bypassing the portal system and facilitating hematogenous spread to the lungs. Further research is needed to identify the molecular mechanisms underlying these site-specific metastatic differences (22).

Size of the primary focus

Primary tumor size is positively correlated with the risk of pulmonary metastasis. Larger tumors (>50 mm) are significantly associated with lymph node metastasis and advanced disease (10). Patients who develop lung metastases have been shown to have significantly larger primary tumors compared to those without metastatic spread (P<0.001) (11).

Pathologic staging, degree of differentiation, TN staging, and histologic type of colorectal tumors

The consensus molecular subtype (CMS) stages

The CMS classification system categorizes CRC into four biologically distinct subtypes, offering insights into metastatic behavior beyond traditional TNM staging. CMS4 (mesenchymal, 23%) demonstrates the strongest association with metastatic spread, including pulmonary metastases. Among primary CRC samples, CMS4 exhibits the highest metastasis rate (25%), and it is the predominant subtype identified in lung metastases (61.4%) (24,25). The propensity of CMS4 tumors to metastasize to the lung is attributed to its molecular profile, which is characterized by epithelial-mesenchymal transition (EMT), TGF-β activation, and stromal infiltration. This creates an immunosuppressive microenvironment conducive to metastatic seeding and outgrowth. The rich immune contexture of the lung may provide a favorable “soil” for these mesenchymal-like “seeds” (25,26). This underscores that molecular subtyping can significantly refine metastatic risk prediction.

The CMS classification substantiates that metastatic organotropism is rooted in molecular subtype. Future studies integrating CMS subtyping with standard clinicopathological criteria could enhance risk stratification, particularly for identifying early-stage patients with high-risk CMS4 biology who may benefit from intensified surveillance or novel therapeutic strategies targeting the EMT and immunosuppressive pathways.

Pathologic typing (gross morphology, histology), degree of differentiation

Histologic grade, tumor type, and TNM stage are critical pathologic factors influencing the risk of pulmonary metastasis. Poorly differentiated (high-grade) tumors demonstrate a strong positive association with lung metastasis development (11). Adenocarcinoma is the most frequent histologic type among CRC with pulmonary metastases, though mucinous adenocarcinoma also presents a notable risk. Pathologic T and N stages serve as independent predictors of metastatic spread. Advanced T stage (particularly T3) and lymph node involvement (N1/N2) are significantly associated with an increased risk of lung metastasis. In one study of 1,600 patients, half of those developing lung metastases within 18 months post-resection had T3-stage primary tumors (11,27).

The link between advanced TNM stage, poor differentiation, and metastasis extends beyond anatomical extent to reflect underlying biological aggression. Larger tumor size (T stage) may allow more time for clonal evolution and pro-metastatic mutation acquisition, while poor differentiation indicates enhanced migratory potential via EMT. Lymph node involvement (N stage) highlights lymphatic access as a critical step toward systemic spread. Integrating these pathological markers with molecular profiling (e.g., CMS subtyping) could improve risk stratification, particularly for intermediate-stage patients (e.g., T3/N0), guiding personalized surveillance and adjuvant therapy.

Medical imaging

Medical imaging features provide valuable predictive information for assessing pulmonary metastasis risk in CRC patients.

Pleural tags and spiculated margins

Specific computed tomography (CT) imaging characteristics show diagnostic value in distinguishing metastatic lesions. The presence of pleural tags and spiculated margins has been identified as independent predictors of pulmonary metastasis. In a study of 120 indeterminate lung lesions, these features significantly favored metastatic origin over primary lung cancer (28).

Radiomics and texture analysis

Radiomic analysis of CT images offers enhanced predictive capability beyond conventional imaging assessment. Texture analysis, which extracts and quantifies subvisual imaging features, has demonstrated strong correlations with tumor biology and behavior. These high-dimensional data can help characterize ambiguous pulmonary nodules and show promise for improving non-invasive metastasis prediction (29).

Metachronous pulmonary nodule

The timing of nodule appearance provides important clinical information. Metachronous pulmonary nodules (developing after initial diagnosis) may represent a more specific indicator of metastatic progression than synchronous nodules. Some evidence suggests they provide better predictive value than nodal (N) staging alone, possibly due to their increased likelihood of representing true metastatic deposits rather than benign lesions (29).

While imaging features provide valuable predictive information, they should be integrated with clinical and molecular data for optimal risk stratification. Future development of standardized radiomic signatures and artificial intelligence-based analysis tools may enhance the precision of metastasis prediction and guide personalized surveillance strategies.

Circulating biomarkers

Liquid biopsy

Liquid biopsy, particularly the detection of circulating tumor DNA (ctDNA), represents a promising approach for dynamic monitoring of metastatic progression in CRC. When integrated with cross-sectional imaging, ctDNA analysis provides a powerful tool for assessing tumor burden and detecting recurrence following primary tumor resection. A longitudinal study demonstrated a clear association between ctDNA dynamics and disease progression in mCRC patients, including those requiring extensive surgical intervention (11). While current evidence supports its utility in monitoring established disease, further clinical validation is needed to establish the role of liquid biopsy in the early detection of pulmonary metastases before they become radiologically apparent.

Carcinoembryonic antigen (CEA) levels

CEA serves as both a diagnostic and prognostic biomarker in CRC, reflecting tumor burden and facilitating tumor-host interactions through cell adhesion and signaling pathways. Elevated preoperative CEA levels consistently predict increased risk of pulmonary metastasis. A previous study identified preoperative CEA ≥5 µg/L as an independent risk factor for lung metastasis in 746 patients undergoing radical surgery (27). Subsequent studies have suggested that higher thresholds (≥10 µg/L) may further stratify metastasis risk. In a large cohort of 1,450 patients with synchronous lung metastases, elevated CEA levels were observed in 84.6–88.1% of cases, with high levels correlating with poorer prognosis (30).

While both ctDNA and CEA provide valuable prognostic information, they offer complementary clinical insights. CEA remains a widely accessible and standardized biomarker for baseline risk assessment, while ctDNA analysis offers greater potential for dynamic monitoring and early detection of micrometastatic disease. The integration of these circulating biomarkers with conventional imaging and clinicopathological factors will enable more precise risk stratification and personalized surveillance strategies.

Peripheral systemic inflammatory markers

Systemic inflammatory markers, including the neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), and lymphocyte-to-monocyte ratio (LMR), reflect the host immune response and have emerged as prognostic indicators in CRC. These hematological parameters represent the balance between pro-tumor inflammatory processes and anti-tumor immune activity.

Elevated pretreatment NLR and PLR, along with decreased LMR, have been independently associated with poorer survival in CRC patients with pulmonary metastases. This correlation is particularly strong in patients with evident neutrophil infiltration in tumor tissues, suggesting that systemic inflammation mirrors the immunosuppressive microenvironment favorable for metastatic progression. A study of 7,207 CRC patients further confirmed significantly elevated peripheral neutrophil counts compared to healthy controls, reinforcing the role of systemic inflammation in cancer pathogenesis (31).

These readily available inflammatory biomarkers offer valuable prognostic information beyond conventional staging. However, standardization of cutoff values and validation in prospective cohorts are needed before routine clinical implementation. Future research should focus on integrating inflammatory markers with molecular profiling to better identify high-risk patients who might benefit from more aggressive treatment or targeted anti-inflammatory therapies.

Tumor vascularization patterns

The blood supply for pulmonary metastases occurs through two distinct mechanisms: angiogenesis (new vessel formation) and vascular co-option (VCO; utilization of existing vessels). While angiogenesis has traditionally been considered essential for tumor growth, emerging evidence indicates that CRC lung metastases frequently utilize VCO, leveraging the lung’s dense vascular network.

Histopathological analysis reveals that VCO is particularly prevalent in CRC lung metastases. A study of 164 lung metastases demonstrated VCO in 98.2% of CRC cases, with 78.9% showing predominant (≥75% of tumor interface) co-option of existing alveolar, interstitial, and perivascular structures. This pattern contrasts with the destructive growth pattern where angiogenesis predominates.

The high frequency of VCO in CRC lung metastases may explain the limited efficacy of anti-angiogenic therapies in some patients. The coexistence of both vascularization patterns within individual metastases suggests dynamic adaptation to the microenvironment. Future research should focus on developing therapeutic strategies that simultaneously target both angiogenesis and VCO pathways, potentially improving treatment response in patients with pulmonary metastases (32,33).

Clinical implications

The identification of specific risk factors for ELM has direct translational value for optimizing clinical decision-making. Regarding surgical management, understanding the biological behavior of the tumor—such as the CMS4 subtype or specific vascularization patterns—can aid in selecting candidates who will benefit most from pulmonary metastasectomy. Patients with favorable prognostic factors (e.g., low preoperative CEA, solitary metastasis) are ideal candidates for curative-intent surgery. Conversely, those with high-risk features may require a more aggressive perioperative systemic therapy approach or closer monitoring to ensure they remain candidates for resection.

In terms of postoperative follow-up, we propose a risk-adapted surveillance strategy. Current guidelines often recommend generic follow-up schedules; however, patients exhibiting high-risk determinants—such as rectal primary location, advanced TNM stage, or elevated inflammatory markers (NLR/PLR)—should warrant intensified surveillance. For these high-risk subgroups, incorporating chest CT scans at shorter intervals (e.g., every 3–6 months) during the first three years may facilitate the detection of pulmonary metastases at an early, oligometastatic stage, thereby significantly improving the chances of curative resection and overall survival.

Strengths and limitations

This review offers a comprehensive synthesis of the multifactorial risks associated with ELM in CRC, integrating evidence from demographics, primary tumor pathology, molecular subtypes, circulating biomarkers, and imaging features. Its principal strength lies in this holistic approach, which provides a unified framework for understanding how diverse factors collectively influence metastatic tropism to the lungs.

The main limitation is inherent to its narrative design. The lack of a systematic methodology may introduce selection bias, and the synthesis of evidence from heterogeneous retrospective studies precludes quantitative data pooling or definitive causal conclusions. The findings highlight associations that require validation in prospective cohorts. Ultimately, translating these identified risk factors into a validated clinical prediction model remains a crucial next step for personalizing patient surveillance.

A summary of the key risk factors is provided in Table 2.

Conclusions

This review has synthesized current evidence on risk factors associated with exclusive pulmonary metastasis in CRC, highlighting the roles of patient demographics (age, socioeconomic status), tumor characteristics (anatomical location, size, molecular subtypes, differentiation grade, TNM stage), circulating biomarkers (CEA, inflammatory indices), and imaging features.

The identification of high-risk patients—particularly those with rectal primary tumors, CMS4 molecular subtype, advanced T/N stage, elevated inflammatory markers, and elevated CEA levels—enables stratified follow-up care. We recommend intensified surveillance using low-dose chest CT for these individuals to facilitate early detection of pulmonary metastases. Future research should focus on developing integrated predictive models that incorporate clinical, pathological, molecular, and imaging biomarkers. Large-scale multicenter prospective studies are needed to validate these risk factors and establish standardized protocols for personalized surveillance and therapeutic interventions aimed at preventing or early treating pulmonary metastases.

Acknowledgments

None.

Footnote

Reporting Checklist: The authors have completed the Narrative Review reporting checklist. Available at https://jgo.amegroups.com/article/view/10.21037/jgo-2025-762/rc.

Peer Review File: Available at https://jgo.amegroups.com/article/view/10.21037/jgo-2025-762/prf

Funding: This study was supported by the Xingliao Talent Program Medical Expert Project (No. YXMJ-LJ-08).

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://jgo.amegroups.com/article/view/10.21037/jgo-2025-762/coif). F.L. is an employee of Merck Co. Inc. 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.

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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