Abstract
Background/Aim: Lymphovascular invasion is a well-established poor prognostic factor following limited resection in lung cancer patients. Therefore, predicting the presence of lymphovascular invasion based on clinical factors may facilitate the selection of the most appropriate surgical procedure. The aim of the present study was to identify preoperative predictive factors associated with pathological lymphovascular invasion.
Patients and Methods: A total of 248 primary lung cancer patients with cN0, computed tomography findings of ≤2.0 cm overall diameter, were included in this retrospective study. The presence of lymphovascular invasion was evaluated on a pathological basis, using resection specimens for factors of lymphatic and vascular invasions. Positive results for one or both factors were defined as positive for lymphovascular invasion. The diagnosis of lymphatic invasion was examined using immunostaining for D2-40. The presence of vascular invasion was evaluated using the elastic van Gieson staining method.
Results: Univariate analysis indicated that the presence of a smoking history, a consolidation tumor ratio (CTR) >0.5, an elevated CYFRA, and a tumor in the hilar location were significant predictive factors for lymphovascular invasion. In multivariate analysis, the CTR >0.5, elevation of CYFRA, and tumor hilar location were independent predictive factors for lymphovascular invasion. A statistically significant correlation between tumor location and lymphovascular invasion was also observed in both the adenocarcinoma and squamous cell carcinoma subgroups.
Conclusion: Central lesions tended to exhibit higher frequency of lymphovascular invasion. Therefore, the expansion of limited resection for centrally located tumor lesions in small-sized NSCLC should be carefully considered.
Introduction
Vascular and lymphatic invasion are known as indicators of malignancy in primary lung cancer and have been identified as poor prognostic factors following surgical intervention in patients with early-stage lung cancer (1, 2). In particular, vascular invasion has been documented as a poor prognostic factor after wedge resection in patients with small-sized lung cancer (3). Sublobar resection is a feasible option for low-risk pathological stage I non-small cell lung cancer (NSCLC). In contrast, lobectomy offers a prognostic benefit for high-risk NSCLC cases with lymphovascular invasion (4). Prediction of lymphovascular invasion using clinical factors may facilitate the selection of the most appropriate surgical approach.
The present study aimed to investigate the predictive value of preoperative clinical factors for identifying patients with small-sized lung cancer who are at risk of pathological lymphovascular invasion.
Patients and Methods
A total of 565 patients underwent definitive pulmonary resection for primary non-small cell lung cancer at our institute from 2021 to 2024. Of these, 248 patients with cN0, CT findings of ≤2.0 cm overall diameter, and no preoperative treatment were included in the study. The presence of lymphovascular invasion was evaluated on a pathological basis, using resection specimens for factors of lymphatic (ly) and vascular (v) invasions. Positive results for one or both factors were defined as positive for lymphovascular invasion. Tumor localization in this study was defined as follows: a tumor was classified as peripheral if its location was in the outer one-third of the CT horizontal section, and as central otherwise. Prior to undergoing surgical procedures, all patients provided written informed consent for the application of their examination data in the context of clinical studies. The present study was approved by the local institutional ethical committee (approval no. 2505019, approval date: 21 May 2025).
The clinical and pathological stages were determined based on the eighth edition of the TNM classification of malignant tumors (5). The histological type was determined based on the World Health Organization classification (6). The diagnosis of factor ly was based on a pathological examination using immunostaining for D2-40 to clarify the location of the lymphatic ducts. The presence of factor v was evaluated using the elastic van Gieson staining method. The invasion of the tumor above the elastic layer of the vessels was determined.
Statistical analysis. Categorical variables are presented as counts and percentages, while continuous data as median (range). Median values were utilized as cut-off points for age categorization. The cut-off values for tumor markers were determined according to the institutional standards. Univariate analyses were conducted using logistic regression methods. Variables witη a p-value <0.05 in the univariate analysis were included in the multivariate model. Hazard ratios were calculated to estimate the relative risks for pathological lymphovascular invasion. To assess potential differences in clinical-pathological factors according to tumor location, appropriate statistical tests were used, including the Student’s t-test, Mann-Whitney U test, and chi-squared test. A p-value of <0.05 was considered statistically significant. All statistical analyses were performed using JMP 10 software (SAS Institute, Cary, NC, USA).
Results
As demonstrated in Table I, adenocarcinoma was the most prevalent histological type in the patient cohort of this study. Lymphovascular invasion was observed in twenty patients. Univariate analysis indicated that the presence of a smoking history, a consolidation tumor ratio (CTR) >0.5, an elevated CYFRA, and a tumor in the hilar location are significant predictive factors for lymphovascular invasion (Table II).
Patients characteristics in this study.
Univariate and multivariate analyses of predictive factors for lymphovascular invasion.
According to the multivariate analysis, a CTR >0.5, elevation of CYFRA, and tumor hilar location were independent predictive factors for lymphovascular invasion (Table II). As illustrated in Table III, peripheral tumors demonstrated lower CYFRA levels and were significantly associated with reduced frequencies of lymphatic and vascular invasion, compared to hilar tumors.
Clinical and pathological features according to the tumor location.
We further classified patients with small-sized lung cancer according to histological type, adenocarcinoma or squamous cell carcinoma, and examined the correlation between tumor location and lymphovascular invasion in both categories. As demonstrated in Table IV, there was a statistically significant correlation between tumor location and lymphovascular invasion in both histological types.
Correlation between tumor location and lymphovascular invasion according to histological type.
Discussion
This study investigated the predictive value of preoperative clinical factors for identifying patients with small-sized NSCLC who are at risk of pathological lymphovascular invasion. The results demonstrated that CTR, blood CYFRA level, and tumor location are significantly predictive factors for lymphovascular invasion in patients with small-sized NSCLC. The CTR has been reported to be a significant predictor of invasive disease, including lymphatic and vascular invasion (7). Given that similar findings have been observed in previous studies, the patient population and methodology used in this study are considered appropriate. A comprehensive review of the literature failed to identify any reports indicating that blood CYFRA levels serve as a predictive factor for lymphovascular invasion in cases of small-sized lung cancer. However, there is evidence suggesting that elevated CYFRA levels may be associated with lymph node metastasis (8). Additionally, preoperative CYFRA levels are considered a significant predictive factor for invasive lung cancer.
Previous studies on both adenocarcinomas and squamous cell primary lung cancers have reported differences in the clinicopathological features between peripherally and centrally located tumors (9, 10). Grbić and colleagues have demonstrated that lymphovascular invasion was much more frequently observed in centrally located lung adenocarcinoma compared to peripherally located tumors (11). However, their study included many advanced cases. Notwithstanding, this is the first study to elucidate the correlation between tumor location and lymphovascular invasion in cases of small-sized NSCLC cancer.
A previous study has reported comparable prognoses between segmentectomy and lobectomy in patients with early-stage non-small cell lung cancer (NSCLC), regardless of the presence of lymphovascular invasion (12). However, this report did not provide detailed information regarding tumor location. Segmentectomy is widely accepted for treating small peripheral lung tumors. In contrast, the present study demonstrated an association between hilar tumor location and lymphovascular invasion. However, the oncological implications of lymphovascular invasion remain to be fully elucidated. These findings raise concerns regarding the appropriateness of expanding limited surgical approaches, such as segmentectomy, to small-sized hilar NSCLC.
No significant differences in clinical and pathological features were observed based on the tumor location. However, centrally located lesions demonstrated a higher malignant potential, irrespective of histological type. It has been hypothesized that the expression levels of transforming growth factor-β (TGF-β) and α-smooth muscle actin in stromal fibroblasts may have prognostic significance in patients with clinical stage I–IIIA non-small cell lung cancer (NSCLC) following curative resection (13). Notably, airway epithelial cells, primarily located in the central airways, are a major source of TGF-β. Previous studies have demonstrated that TGF-β secreted by epithelial cells stimulates fibroblasts in the central regions of the lungs (14), potentially contributing to increased malignant behavior of centrally located tumors. Furthermore, it has been reported that immune cell expression within the tumor microenvironment differs between the central and peripheral lung cancer tissues (15), suggesting that tumor location influences tumor microenvironment. These variations may influence tumor aggressiveness and malignancy grade.
Hypoxia-inducible factor-1α (HIF-1α) is expressed in hypoxic environments and correlates with tumor malignant potential and prognosis (16). A previous study has reported an association between HIF-1α expression and the T factor in NSCLC (17). Based on these findings, it is hypothesized that the effects of hypoxia within the tumor are minimal in small-sized NSCLC. However, partial oxygen tension has been shown to progressively decline from 159 torr in the central airway to 100 torr in the alveoli, 40 torr in interstitial fluid, and 15 torr in peripheral cells (18). Oxidative stress, which has been linked to malignant potential, including lymphovascular invasion, in resected lung cancer specimens, may also play a role in this context (19). Given that the microenvironment differs between the central and peripheral lung tissues, and it is possible that variations in oxidative stress affect tumor aggressiveness.
Study limitations. First, it is a retrospective study and minor data gaps were identified. Data collection from a larger number of patients, in conjunction with further analyses, is currently ongoing. Second, we were not able to analyze tumor microenvironment at the molecular level according to tumor location. Finally, although positron emission tomography (PET) imaging data has been reported to significantly correlate with lymphovascular invasion in lung adenocarcinoma patients (20), PET scans were not performed in all patients in this study. Future studies should incorporate PET imaging data and perform detailed analyses in conjunction with conventional clinicopathological factors.
Conclusion
CTR, blood CYFRA level, and tumor location are independent predictive factors for lymphovascular invasion in patients with small-sized NSCLC. Notably, this is the first report to demonstrate a significant correlation between centrally located lesions and pathological lymphovascular invasion, a known indicator of malignant potential. These findings suggest that the expansion of limited surgical approaches to central lesions should be considered cautiously. Further molecular biological investigations are warranted to elucidate the differences in the tumor microenvironment between central and peripheral lung cancer tissues.
Footnotes
Authors’ Contributions
Takuma Tsukioka designed the study, analyzed the data, prepared the tables, and wrote the original draft. Satoshi Okada, Kazuya Kishimoto, and Hiroyuki Kochi collected the clinical data. Ryu Nakajima and Kyukwang Chung critically reviewed the manuscript. All Authors read and approved the final manuscript.
Conflicts of Interest
The Authors have no conflicts of interest to declare regarding this study.
Artificial Intelligence (AI) Disclosure
No artificial intelligence (AI) tools, including large language models or machine learning software, were used in the preparation, analysis, or presentation of this manuscript.
- Received August 12, 2025.
- Revision received September 19, 2025.
- Accepted October 1, 2025.
- Copyright © 2025 The Author(s). Published by the International Institute of Anticancer Research.
This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY-NC-ND) 4.0 international license (https://creativecommons.org/licenses/by-nc-nd/4.0).
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