The value of relative CT attenuation in predicting invasiveness in patients with T1-stage lung adenocarcinoma

Introduction

Lung cancer remains the leading cause of cancer incidence and mortality worldwide (1), with early diagnosis and surgical resection being critical for improving cure rates. Lung adenocarcinoma (LUAD), the most common subtype of lung cancer, relies on postoperative histopathological examination as the gold standard for assessing tumor invasiveness. However, due to the lagging nature of pathological diagnosis, preoperative prediction of invasiveness in malignant pulmonary nodules has become central to clinical decision-making, including surgical approach selection and lymph node dissection strategy. Multiple studies (2,3) have demonstrated that computed tomography (CT) attenuation values serve as independent predictors of pathological invasiveness in early-stage LUAD, particularly for ground-glass opacity (GGO)-predominant adenocarcinomas.

Emphysema, characterized by abnormal dilation of distal airspaces (respiratory bronchioles, alveolar ducts, alveolar sacs, and alveoli), loss of lung elasticity, and destruction of alveolar walls, exhibits a strong correlation with CT attenuation values. This pathological condition leads to reduced lung tissue density, manifesting on CT images as increased low-attenuation regions and lower CT values. In theory, relative CT attenuation values—defined as the normalized difference between nodule CT values and surrounding lung parenchyma—may mitigate fluctuations in CT measurements caused by variable scanning protocols, patient positioning, or emphysema severity, thereby enhancing the accuracy of tumor assessment (4,5). However, traditional relative CT calculations based on two-dimensional (2D) slice-level differences or ratios between nodule and adjacent lung tissue fail to account for the three-dimensional (3D) characteristics of nodules, limiting their clinical utility (6,7). Previous research has shown that 3D relative CT parameters (e.g., relative maximum CT difference, relative mean CT difference, relative maximum CT ratio) derived from the mean CT attenuation of the nodule-bearing lung lobe demonstrate high predictive performance for invasiveness in T1-stage LUAD [area under the curve (AUC) range: 0.830–0.850], but their superiority in emphysematous populations remains unclear. Clinically, emphysema often induces atypical morphological features in pulmonary nodules (e.g., ill-defined margins, atypical boundary and spiculation signs, pleural depression signs, etc.), potentially leading to diagnostic bias in invasiveness prediction (8,9). This study aims to investigate whether 3D relative CT parameters can reduce the confounding effects of emphysema and identify specific populations where these parameters outperform traditional absolute CT values, thereby optimizing imaging biomarkers for clinical risk stratification. We present this article in accordance with the STARD reporting checklist (available at https://qims.amegroups.com/article/view/10.21037/qims-2025-1261/rc).

Methods

General information

This was a multicenter retrospective cohort study. Patients with pathologically confirmed T1-stage LUAD who underwent surgical resection at Zhengzhou People’s Hospital, The First Affiliated Hospital of Zhengzhou University, and the National Cancer Center/Cancer Hospital, Chinese Academy of Medical Sciences were included. A total of 1,092 patients with 1,259 pulmonary nodules met the inclusion criteria, including 889 cases from Zhengzhou People’s Hospital (July 2016–November 2023), 267 cases from The First Affiliated Hospital of Zhengzhou University (June–December 2023), and 103 cases from the National Cancer Center/Cancer Hospital, Chinese Academy of Medical Sciences (May–June 2024). CT imaging was performed using the following systems: Siemens Somatom Definition, Somatom Force, Philips Brilliance 16, IQon Spectral CT, and United Imaging NeuViz 16Classic.

The study used anonymized data without risk of harm, disclosure of personally identifiable information, or commercial conflicts of interest and was conducted in accordance with the ethical principles of the Declaration of Helsinki and its subsequent amendments. The Institutional Review Board (IRB) of Zhengzhou People’s Hospital approved this study (No. 2025070204). The other two centers were informed and agreed with the study. Due to the retrospective nature of the study, individual patient consent was waived in accordance with international ethical guidelines. The study flowchart is shown in Figure 1.

Figure 1 Flowchart for exploring the advantages and disadvantages of relative CT values versus absolute CT values of pulmonary nodules in predicting the aggressiveness of T1 stage lung adenocarcinoma. Hospital 1, Zhengzhou People’s Hospital; Hospital 2, The First Affiliated Hospital of Zhengzhou University; Hospital 3, the National Cancer Center/Cancer Hospital, Chinese Academy of Medical Sciences. 3D, three-dimensional; AAH, atypical adenomatous hyperplasia; AIS, adenocarcinoma in situ; CT, computed tomography; HU, Hounsfield unit; IAC, invasive adenocarcinoma; MIA, minimally invasive carcinoma.

Inclusion criteria

The 3D diameter of the pulmonary nodule, as quantified by artificial intelligence (AI) on CT lung window images, is ≤3 cm. Postoperative pathological confirmation of atypical adenomatous hyperplasia (AAH), adenocarcinoma in situ (AIS), minimally invasive adenocarcinoma (MIA), or invasive adenocarcinoma (IAC). No patients received any form of preoperative neoadjuvant therapy. Thin-section chest CT images (slice thickness ≤1.5 mm) were obtained within 1 month prior to surgery. All relevant parameters were precisely identified and quantified by the AI software (Shukun Technology).

Exclusion criteria

Missing key scanning sequences in preoperative CT images. Presence of artifacts or other pulmonary lesions that may compromise the accuracy of AI-quantified parameters. Postoperative pathological diagnosis of other types of lung cancer in addition to the primary lesion. Significant errors identified upon manual review of AI-quantified analysis data.

Grouping

• Non-invasive group: postoperative pathological confirmation of AAH, AIS, and MIA;
• Invasive group: postoperative pathological confirmation of IAC.

For each group, relative CT values (including relative maximum CT value, mean CT value, and median CT value) were calculated and further categorized into relative difference (relative CT value 1) and relative ratio (relative CT value 2). For example, the relative mean CT value 1 was defined as the relative mean difference, calculated as follows: relative mean CT value 1 = (mean CT value of the lung lobe) – (mean CT value of the lung lobe containing the pulmonary nodule). The relative mean CT value 2 was defined as the relative mean ratio, calculated as follows: relative mean CT value 2 = (mean CT value of lung lobe)/(mean CT value of the lung lobe containing the pulmonary nodule). Subgroup analysis was conducted based on the different mean CT values of the lung lobes where the pulmonary nodules were located. The subgroups were divided into four categories: >−750, −750 to −800, −800 to −850, and ≤−850 HU.

Statistical methods

Statistical analysis and data visualization were performed using R 4.2.1. Measurement data are expressed as mean ± standard deviation. We addressed the issue of missing data by employing a deletion approach. Independent sample t-test was used to compare the clinical characteristics between the two groups. Chi-square test was used to compare the differences in group characteristics of categorical variables. We drew the ROC curve, complete and calculate its AUC, 95% confidence interval (CI). Subgroup analysis was conducted by grouping with the mean CT value of the lung lobe where the pulmonary nodule is located. P<0.05 indicates a statistically significant difference.

Results

Comparison of characteristics between non-invasive and invasive groups

A total of 1,259 pulmonary nodules were included in this study, with 828 nodules in the non-invasive group, accounting for 65.77%, and 431 nodules in the invasive group, accounting for 34.23%. Among the non-invasive group, the mean age was 54.08 years, while in the invasive group, the mean age was 60.48 years. There was a statistically significant difference in the mean age between the two groups (t=10.92, P<0.001). In terms of CT characteristics, the maximum CT value, mean CT value, median CT value, as well as their relative CT differences and ratios were analyzed, and statistically significant differences were observed between the two groups (P<0.05). Regarding the distribution of nodules across lung lobes, in the non-invasive group, there were 276 nodules in the right upper lobe, 62 in the right middle lobe, 154 in the right lower lobe, 219 in the left upper lobe, and 117 in the left lower lobe. In the invasive group, there were 142 nodules in the right upper lobe, 29 in the right middle lobe, 81 in the right lower lobe, 103 in the left upper lobe, and 76 in the left lower lobe. The consolidation-tumor ratio (CTR) was defined as the proportion of solid-component volume to total nodule volume, determined by an artificial-intelligence threshold-segmentation algorithm with a fixed attenuation threshold of −350 HU on non-contrast thin-section CT. No statistically significant difference was observed in the distribution of nodules across lung lobes between the two groups. Detailed information is presented in Table 1.

Subgroup analysis

In this study, pulmonary nodules were categorized into four groups based on the mean CT value of the lung lobe where the nodule was located: >−750, −750 to −800, −800 to −850, and ≤−850 HU. The predictive performance of absolute and relative CT values was compared between the invasive and non-invasive groups. Specifically, there were 306 cases with a mean nodule CT value >−750 HU, 435 cases between −750 and −800 HU, 471 cases between −800 and −850 HU, and 47 cases ≤−850 HU. The minimum mean lung CT value included in the analysis was −880 HU.

When the mean nodule CT value of the lung lobe where the pulmonary nodule was located was >−750 HU, the general characteristics of the non-invasive and invasive groups were shown in Table 2. Among the 306 participants, 178 (58.2%) were in the non-invasive group and 128 (41.8%) were in the invasive group. Participants in the invasive group were older (mean age 60.27±8.36 vs. 55.49±11.37 years; P<0.001). No significant difference was observed in the mean CT value of the lung lobe with the pulmonary nodule (P=0.744). The invasive group had higher CTR (0.69±0.32 vs. 0.27±0.27; P<0.001), larger maximum 3D diameter (17.63±5.55 vs. 10.23±4.14 mm; P<0.001), and higher CT values (maximum, mean, and median; all P<0.001). No significant difference was found in the minimum CT value (P=0.091). The invasive group also had higher relative maximum, mean, and median CT values (all P<0.001), but no differences were observed in relative minimum CT values (P=0.244 and P=0.418) or sex distribution (P=0.888). No significant differences were found in lobe distribution (P=0.724). The invasive group had lower relative maximum, mean, and median CT values (all P<0.001). The AUC for the mean CT value was 0.835, the AUC for the relative mean CT difference was 0.824, and the AUC for the relative mean CT ratio was 0.811 (Figure 2A). For the median CT value, the AUC was 0.839, the AUC for the relative median CT difference was 0.829, and the AUC for the relative median CT ratio was 0.815 (Figure 2B). For the maximum CT value, the AUC was 0.832, the AUC for the relative maximum CT difference was 0.811, and the AUC for the relative maximum CT ratio was 0.809 (Figure 2C). DeLong’s test results showed no statistically significant differences between relative and absolute CT values. The ROC curves are shown in Figure 2.

Figure 2 When the mean CT value of the lung lobe where the pulmonary nodule is located is >−750 HU, the ROC curve of relative CT value and absolute CT value in predicting the invasiveness of T1-stage lung adenocarcinoma. AUC, area under the curve; CT, computed tomography; FPR, false positive rate; HU, Hounsfield unit; ROC, receiver operating characteristic; TPR, true positive rate.

When the mean CT value of the lung lobe containing the pulmonary nodule was in the range of −750 to −800 HU, the detailed characteristics of the two groups are shown in Table 3. In this study, a total of 471 participants were included, with 337 (71.55%) in the non-invasive group and 134 (28.45%) in the invasive group. Significant differences were observed between the two groups in the following parameters: age, consolidation-to-tumor ratio (CTR), maximum 3D diameter, maximum CT value, mean CT value, median CT value, relative maximum CT value 1, relative mean CT value 1, relative median CT value 1, relative maximum CT value 2, relative mean CT value 2, relative median CT value 2, and sex distribution (all P<0.05). Conversely, no significant differences were found between the groups in the mean CT value of the lung lobe with the pulmonary nodule (Avg CT V of L L w PN), minimum CT value, relative minimum CT value 1, relative minimum CT value 2, or lobe distribution (all P>0.05). The AUC for the mean CT value was 0.840. The AUC for the relative mean CT difference and the AUC for the relative mean CT ratio were both 0.840 (Figure 3A). For the median CT value, the AUC was 0.825, the AUC for the relative median CT difference was 0.826, and the AUC for the relative median CT ratio was 0.825 (Figure 3B). For the maximum CT value, the AUC was 0.876, the AUC for the relative maximum CT difference was 0.876, and the AUC for the relative maximum CT ratio was 0.876 (Figure 3C). DeLong’s test results showed no statistically significant differences between the relative and absolute CT values in terms of predictive performance. The ROC curves are shown in Figure 3.

Figure 3 When the mean CT value of the lung lobe containing the pulmonary nodule is ≤−750 HU but >−800 HU, the ROC curves of relative CT value and absolute CT value in predicting the invasiveness of T1-stage lung adenocarcinoma. AUC, area under the curve; CT, computed tomography; FPR, false positive rate; HU, Hounsfield unit; ROC, receiver operating characteristic; TPR, true positive rate.

When the mean CT value of the lung lobe containing the pulmonary nodule ranges from −800 to −850 HU, the detailed characteristics of the two groups are presented in Table 4. In this study, a total of 435 participants were included, of whom 276 (63.45%) were in the non-invasive group and 159 (36.55%) were in the invasive group. Significant differences were observed between the two groups in terms of age, consolidation-to-tumor ratio (CTR), maximum 3D diameter, maximum CT value, mean CT value, median CT value, relative maximum CT value 1, relative mean CT value 1, relative median CT value 1, relative maximum CT value 2, relative mean CT value 2, relative median CT value 2, and sex distribution (all P<0.05). However, no significant differences were found between the groups in the Avg CT V of L L w PN, minimum CT value, relative minimum CT value 1, relative minimum CT value 2, or lobe distribution (all P>0.05). The AUC of the mean CT value was 0.850, the AUC of the relative mean CT difference was 0.852, and the AUC of the relative mean CT ratio was 0.852 (Figure 4A). The AUC of the median CT value was 0.831, the AUC of the relative median CT difference was 0.834, and the AUC of the relative median CT ratio was 0.834 (Figure 4B). The AUC of the maximum CT value was 0.843, the AUC of the relative maximum CT difference was 0.845, and the AUC of the relative maximum CT ratio was 0.844 (Figure 4C). DeLong’s test results showed no statistical difference between relative CT values and absolute CT values. The ROC curves are shown in Figure 4.

Figure 4 When the mean CT value of the lung lobe containing the pulmonary nodule is ≤−800 HU but >−850 HU, the ROC curves of relative CT values and absolute CT values in predicting the invasiveness of T1-stage lung adenocarcinoma. AUC, area under the curve; CT, computed tomography; FPR, false positive rate; HU, Hounsfield unit; ROC, receiver operating characteristic; TPR, true positive rate.

When the mean CT value of the lung lobe containing the pulmonary nodule was no more than −850 HU, the detailed characteristics of the non-invasive and invasive groups were shown in Table 5. Among the 47 participants, 37 (78.7%) were in the non-invasive group and 10 (21.3%) were in the invasive group. The AUC of the mean CT value was 0.886, the AUC of the relative mean CT difference was 0.884, and the AUC of the relative mean CT ratio was 0.880 (Figure 5A). The AUC of the median CT value was 0.859, the AUC of the relative median CT difference was 0.865, and the AUC of the relative median CT ratio was 0.862 (Figure 5B). The AUC of the maximum CT value was 0.897, the AUC of the relative maximum CT difference was 0.899, and the AUC of the relative maximum CT ratio was 0.896 (Figure 5C). DeLong’s test results showed no statistical difference between relative CT values and absolute CT values. The ROC curves are shown in Figure 5.

Figure 5 When the mean CT value of the lung lobe containing the pulmonary nodule is ≤−850 HU, the ROC curves of relative CT values and absolute CT values in predicting the invasiveness of T1-stage lung adenocarcinoma. AUC, area under the curve; CT, computed tomography; FPR, false positive rate; HU, Hounsfield unit; ROC, receiver operating characteristic; TPR, true positive rate.

Discussion

In clinical practice, when considering malignant pulmonary nodules, the prediction of their aggressiveness is particularly important for surgical planning. At present, the prediction factors mainly focus on imaging features. Characteristics such as the size of nodules, morphology (such as lobulation, spiculation), growth mode (such as doubling time) and tumor heterogeneity are considered to be related to their aggressiveness. Relevant research shows that larger nodules and nodules with lobulated or spiculated edges are more likely to have higher aggressiveness (10-13).

The CT value is a numerical value used to represent tissue density in computed tomography. Different types of tissues and lesions usually have specific CT value ranges. By observing and comparing the CT value differences between lesion tissues and surrounding normal tissues, doctors can judge the nature, size, location and other information of lesions, thereby providing a basis for formulating treatment plans. CT value is also an important indicator for evaluating the aggressiveness of lung cancer. Our team (14,15) has previously explored the application of solid component volume and its proportion based on threshold segmentation method in the evaluation of LUAD aggressiveness and achieved promising results. The mean CT value has been confirmed by most studies to be an independent predictor of LUAD aggressiveness (3,16-18). However, most current studies predominantly rely on the absolute CT values of pulmonary nodules themselves for analysis. Previous research has demonstrated that relative CT values, calculated based on the mean CT value of the lung lobe where the nodule is located, can reliably predict the aggressiveness of T1 stage LUAD. The focus of the present study is to investigate and compare the predictive performance of relative CT values versus absolute CT values in terms of LUAD aggressiveness among patient populations with varying mean lung CT values.

Emphysema refers to the pathological state in which the airway elasticity at the distal part of the terminal bronchiole (including respiratory bronchioles, alveolar ducts, alveolar sacs and alveoli) is reduced, resulting in excessive expansion, inflation, increased lung volume or accompanied by the destruction of airway walls.

There is a close relationship between emphysema and CT value. Emphysema causes damage to the lung tissue structure, over-expansion and rupture of alveoli, resulting in a decrease in lung tissue density. On CT images, it is manifested as an increase in low-density areas and a decrease in CT value. The CT value range of normal lung tissue is about −800 to −700 HU. However, due to the increase in air content in emphysema areas, the CT value is significantly reduced. In theory, by measuring the CT value, the severity of emphysema can be quantitatively evaluated (19,20). For example, when there is emphysema around pulmonary nodules, it will inevitably cause atypical morphological features of pulmonary nodules. When predicting according to common invasive prediction factors, there will often be deviations. Therefore, for such populations, a more accurate indicator is more needed to evaluate the degree of infiltration.

Zhang et al. (4) found in their research that relative CT differences/ratios, derived by comparing the mean CT value of pulmonary nodules with that of the adjacent normal lung tissue, showed certain advantages in predicting the aggressiveness of part-solid nodules in emphysema patients. However, the results of our current study indicate no significant differences in the predictive performance of relative CT values and absolute CT values regarding the aggressiveness of LUAD. The discrepancy in conclusions between the two studies may stem from the different approaches used to assess the severity of emphysema. In our study, we evaluated the degree of emphysema based on the mean CT value of the lung lobe where the nodule was located, whereas Zhang et al. (4) examined a population with a mean lung CT value of approximately −907.8±27.5 HU. The lowest mean CT value of the lung lobes containing nodules in our study was −880 HU, which might also be related to the relatively small number of patients with more severe emphysema included in our study. Additionally, according to the 2020 Global Initiative for Chronic Obstructive Lung Disease (GOLD) guidelines (21), there is no definitive “threshold” for the radiological diagnosis of emphysema, as the diagnosis primarily relies on pulmonary function tests, particularly a post-bronchodilator FEV₁/FVC ratio of less than 0.7. Further research is still needed to identify the population in which relative CT values may offer advantages in predicting the aggressiveness of LUAD.

The limitations of this study should be acknowledged as follows: First, selection bias may exist due to the retrospective nature of the analysis, which could affect the generalizability of the findings. Second, variations in CT equipment and image acquisition protocols across different centers may compromise the accuracy and comparability of the data. Third, the imaging diagnostic threshold for emphysema remains ill-defined, and differences among its subtypes were not adequately considered. For instance, centrilobular emphysema presents as focal hypodense areas with decreased CT values, predominantly in the upper lung zones; panlobular emphysema manifests as extensive, uniform hypodensities with markedly reduced CT values, typically in the lower lungs; and paraseptal emphysema appears as subpleural hypodense areas with decreased CT values but limited extent. Additionally, evaluating emphysema severity based on the entire lung lobe containing pulmonary nodules has inherent limitations, partly due to inconsistencies between the location of nodules and the distribution of emphysema. Furthermore, the negative findings may be associated with the distribution of the CTR among enrolled cases. Specifically, included cases with excessive solid components, when compared to the low-grade group, already exhibited substantial differences in CT values. It is plausible that the impact of emphysema has been mitigated—regardless of whether relative or absolute CT values were utilized—and this will be further refined in subsequent studies. This relationship warrants deeper investigation in future work.

Conclusions

In summary, although the relative CT differences and ratios, calculated based on the mean CT value of the lung lobe where the pulmonary nodule is located, can provide a stable prediction of the invasiveness of T1 stage LUAD, they do not offer a significant advantage over absolute CT values. Therefore, we continue to recommend the use of absolute CT values of the pulmonary nodule (including mean CT value, median CT value, and maximum CT value) as the primary indicators for assessing the invasiveness of T1 stage LUAD. Which alternative features may be employed to determine invasiveness in patients with significant emphysema, where such emphysema interferes with the morphological assessment of pulmonary nodules? Given the scarcity of existing research in this domain, we further advocate for prospective multicenter studies to validate these alternative indicators.

Acknowledgments

We would like to express our sincere appreciation and gratitude to these who helped to coordinate the study.

Footnote

Reporting Checklist: The authors have completed the STARD reporting checklist. Available at https://qims.amegroups.com/article/view/10.21037/qims-2025-1261/rc

Data Sharing Statement: Available at https://qims.amegroups.com/article/view/10.21037/qims-2025-1261/dss

Funding: None.

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://qims.amegroups.com/article/view/10.21037/qims-2025-1261/coif). L.Z. is an employee of Shukun (Beijing) Technology Co., which provided data analysis and interpretation for this research. But the company had no role in the study design, data collection, analysis, or manuscript preparation. The other 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 conducted in accordance with the ethical principles of the Declaration of Helsinki and its subsequent amendments. The Institutional Review Board (IRB) of Zhengzhou People’s Hospital approved this study (No. 2025070204). The other two centers were informed and agreed with the study. Due to the retrospective nature of the study, individual patient consent was waived in accordance with international ethical guidelines.

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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