Exploring the risk factors for the growth of pure ground-glass nodules in a 3-year follow-up period

Introduction

With the widespread use of computed tomography (CT) in lung cancer screening, an increasing number of pure ground-glass nodules (pGGNs) are being detected (1,2). Non-persistent pGGNs are suggestive of benign conditions, such as inflammation or focal hemorrhage, while persistent pGGNs are primarily associated with atypical adenomatous hyperplasia, adenocarcinoma in situ, minimally invasive adenocarcinoma, or invasive adenocarcinoma (3-5). Research has confirmed the indolent natural course of persistent pGGNs; however, debate continues as to the appropriate follow-up period, particularly for those exhibiting short-term growth (6). The average volume doubling time of pGGNs ranges from 769 to 1,005 days, suggesting the need for an extended follow-up period beyond 3 years for pGGNs (7). The American College of Chest Physicians and Fleischner Society guidelines recommend annual CT surveillance for at least 3 years for persistent pGGNs (8,9). However, no further stratified management has been proposed for persistent pGGNs in the initial 3-year follow-up period.

To facilitate the more individualized clinical management of patients with pGGNs, an understanding of the proportion of pGGNs exhibiting growth within the first 3 years and the contributing factors is essential. Rapidly growing pGGNs may indicate a higher risk of malignancy. The rapid growth of pGGNs may be correlated with increased tumor invasiveness, suggesting the potential for transformation into invasive adenocarcinoma. Therefore, this study aimed to assess the proportion of pGGNs exhibiting growth in the initial 3-year follow-up period, and to identify the associated clinical and radiological factors. We present this article in accordance with the STROBE reporting checklist (available at https://qims.amegroups.com/article/view/10.21037/qims-24-2086/rc).

Methods

General data

The study was conducted in accordance with the Declaration of Helsinki (as revised in 2013). The research protocol was approved by the Institutional Ethics Review Committee of Shapingba Hospital Affiliated to Chongqing University (approval No. KY202311), which waived the requirement for informed consent. A total of 93 patients with 138 pGGNs, identified by chest CT from January 2013 to January 2019 at Shapingba Hospital Affiliated to Chongqing University, were included in the study. The inclusion criteria were the persistent presence of pGGNs identified on the initial chest CT scan and subsequent annual follow-up examinations for at least 3 years. The exclusion criteria were non-persistent pGGNs and undergoing surgical treatment within 3 years. The general clinical data of the patients, including their gender, age, and tumor history with a focus on lung cancer, were collected.

Imaging assessment

The CT data were acquired using Siemens Somatom Definition dual-source and AS 64-slice CT scanners (Siemens Healthineers, Munich, Germany). The scanning parameters were as follows: tube voltage: 100–120 kV, tube current at the lesion site: 200–280 mA, slice thickness: 5 mm, and slice-thickness reconstruction: 1 mm. The images were analyzed using lung (window width: 1,200, window level: −600) and mediastinal (window width: 350, window level: 50) windows. Two radiologists, with moderate experience in chest diagnostic research, reviewed all the patient CT images, and documented the maximum diameters of the pGGNs, the CT values, and other radiological features, including the presence of an air bronchogram (yes/no), pleural or fissure retraction (yes/no), shape (round/oval or irregular), and the presence of a bubble sign (yes/no). pGGNs were defined as a hazy area of increased density on lung windows, visible only as blood vessels and bronchial walls on mediastinal windows. The size of pGGNs was defined as the maximum diameter displayed on the lung windows. The CT value and maximum diameter of the pGGNs were each measured once by the two physicians, and the average value for each was calculated; care was taken to avoid blood vessels and bronchi during the measurement of the CT values. pGGN growth was defined as an increase in size ≥2 mm or the appearance of a solid component in the nodule (10). The stability of pGGNs was defined as no increase in size or the appearance of a solid component during the follow-up period. Based on these definitions, the pGGNs were categorized into the following two groups: the growth group and the stable group.

Pathological diagnosis

The pathological diagnosis and histological subtype classification standards for lung cancer established by the World Health Organization in 2015 were followed (11).

Statistical analysis

The statistical analysis was conducted using SPSS 20.0 software (SPSS Inc., Chicago, IL). The continuous data are presented as the median or mean ± standard deviation, while the categorical data are presented as the number. The independent sample t-test or Mann-Whitney U test (for the continuous variables) and the chi-square test or Fisher’s exact test (for the categorical variables) were used to evaluate the statistical differences in the clinical and radiological characteristics between the growth and stable pGGN groups. Variables with a P value <0.05 in the univariate analysis were included as input variables for the logistic regression analysis. The optimal cut-off value for pGGN size, as determined by a receiver operating characteristic curve analysis, was 8.5 mm. To prevent the overestimation of the clinical characteristics of the patients with multiple pGGNs, the univariate analysis of the clinical data focused on the dominant pGGN per patient, which was defined as the largest lesion among all lesions.

Results

Patient general data

A total of 93 patients with 138 pGGNs, confirmed by chest CT, and followed-up for 3 years or more, were included in this study (Figure 1). The median follow-up period was 4 years, and extended to ≥5 years for 42 patients. Three pGGN cases underwent surgical resection after 3 years of follow-up. Tables 1,2 display the clinical characteristics of the 93 patients and the radiological features of the 138 pGGNs, respectively.

Figure 1 Flowchart of the study population. pGGNs, pure ground-glass nodules.

pGGN growth group

During the 3-year follow-up period, 113 of the 138 pGGNs remained stable, while 25 exhibited growth (see Table 3). Figures 2,3 illustrate the dynamic imaging data of one patient with a stable pGGN and another with a rapidly progressing pGGN over the follow-up period, respectively. In the patient-based analysis, pGGN growth in the initial 3-year follow-up period occurred in 23.7% of the patients (22 of 93). In the nodule-based analysis, the growth frequency was 18.1% (25 of 138 pGGNs).

Figure 2 A 56-year-old woman with a persistent pGGN in the right middle lobe, which measured 7.06 mm in the maximum diameter on the initial CT scan (A) and 7.19 mm (B), 7.15 mm (C), and 7.14 mm (D) on the first, second, and third-year follow-up scans, respectively. The pGGN remained stable throughout the 3-year follow-up period. CT, computed tomography; pGGN, pure ground-glass nodule.

Figure 3 A 73-year-old man with a persistent pGGN in the left lower lobe, which measured 1.78 cm in the maximum diameter on the initial CT scan (A) and 2.36 cm (B), 2.62 cm (C), and 2.80 cm (D) on the first, second, and third-year follow-up scans, respectively. The pGGN increased rapidly over the 3-year follow-up period. CT, computed tomography; pGGN, pure ground-glass nodule.

Among the 25 pGGNs that exhibited growth, surgical resection was performed on three after 3 years of follow-up. All the resected pGGNs were diagnosed as stage Ia lung adenocarcinoma (LUAD); pathological assessments revealed invasive LUAD, with one case being predominantly lepidic and the other two being predominantly papillary. None of the three patients diagnosed with invasive LUAD died during the study period.

Risk factors for pGGN growth

Based on the growth of the pGGNs in the 3-year follow-up period, the results of the univariate analysis of the clinical information of the patients are presented in Table 1. Patients with growing pGGNs were older on average than those with stable pGGNs; however, this difference was not statistically significant. Table 2 presents the statistical analysis of the CT findings comparing the stable and growth pGGN groups. The initial maximum diameter of the pGGNs that exhibited growth was significantly larger than that of the stable pGGNs (P<0.001). When categorized based on the optimal cut-off value of 8.5 mm, the pGGNs with larger initial diameters were more likely to grow in the follow-up period (P<0.001). Additionally, the presence of a bubble sign and an irregular shape on CT scans were associated with growth in the 3-year follow-up period. Notably, all 12 pGGNs with an initial diameter <5 mm, followed for ≥5 years, remained stable. Among the 28 pGGNs with an initial diameter <8.5 mm and followed for ≥5 years, 27 remained stable during the initial 3-year period, with one case showing growth in the subsequent 2 years, corresponding to a growth frequency of 3.6% (1/28).

The multivariate analysis identified an initial diameter ≥8.5 mm [odds ratio (OR): 78.367, 95% confidence interval (CI): 14.431–425.557, P<0.001] and an irregular pGGN shape (OR: 12.719, 95% CI: 1.731–93.449, P=0.012) as independent risk factors for 3-year growth (Table 4).

Discussion

The present study identified a maximum diameter ≥8.5 mm and an irregular shape, particularly when accompanied by a bubble sign, as risk factors for PGGN growth in the 3-year follow-up period. The multivariate regression analysis confirmed that a maximum diameter ≥8.5 mm and an irregular shape were independent predictors of growth within 3 years. The current literature indicates that pGGNs typically exhibit slow growth, a low likelihood of distant metastasis, and a generally favorable prognosis (12-14). Accordingly, some researchers advocate a conservative management strategy involving follow-up observation with chest CT for patients with pGGNs (12-14). However, determining the optimal follow-up period for pGGNs remains challenging, especially for those exhibiting rapid growth. Guidelines recommend a minimum surveillance follow-up period of 3 years; however, no detailed stratified management plans have been established for the initial 3-year period.

Previous research has established the diameter of pGGNs as a significant predictor of growth, with a diameter <8 mm identified as the optimal cut-off value for stability within 3 years, which aligns with our findings (15). Concurrently, irregularity in the shape of pGGNs, resulting from varied differentiation of tumor cells at the lesion’s periphery, suggests a higher degree of biological aggressiveness, Consistent with previous studies (16,17). Accordingly, the detection of a pGGN with a diameter ≥8.5 mm that remains after a 3–6-month follow-up period and has an irregular shape strongly indicates the likelihood of progression to the 10 mm threshold within 3 years, a size associated with invasive LUAD (18-20). Although the optimal threshold for distinguishing invasive LUAD from pGGNs remains unclear, several studies have proposed 8.1 and 13.2 mm as potential cut-off values (4,21), likely due to selection bias in retrospective studies. However, there is a consensus that patients with pGGNs who undergo surgical treatment generally have a favorable prognosis (13,14). One study suggested that surgery could be considered for pGGNs that reach 15 mm during the follow-up period (22). These varying cut-off values for diagnosing invasive LUAD do not contradict our findings, as we observed that an initial diameter ≥8.5 mm is a risk factor for growth within 3 years. While such nodules may represent in situ or minimally invasive adenocarcinoma, this size suggests a rapid progression toward invasive LUAD. This indicates that these patients may require closer clinical monitoring and should be prepared for potential surgical intervention.

This study included six patients with a history of lung cancer. Of these six patients, three exhibited growths during the 3-year follow-up, while the remaining three remained stable. A history of lung cancer did not predict the rapid growth of pGGNs, which aligns with Cho et al.’s (15) findings that such a history is associated with stability within 3 years and growth thereafter. This association may reflect the slow, incremental growth of lesions attributed to a clinical history of lung cancer. Conversely, in a follow-up study of indefinite duration, no correlation was observed between a history of lung cancer and the growth of pGGNs (23). Conversely, Lee et al. (24) identified a history of lung cancer as a predictor of pGGN growth. This discrepancy may arise from the lack of pathological diagnoses for the growing pGGNs group and the limited number of patients with a combined history of pGGNs and lung cancer, which hinders the determination of a precise link. Thus, validating this relationship requires larger-scale studies.

In the patient-based analysis, 23.7% of the patients (22 of 93) exhibited rapid pGGN growth in the initial 3-year follow-up period. In the nodule-based analysis, a growth frequency of 18.1% was observed (25 of 138 pGGNs). The growth frequency observed in this study aligns with previous reports (25,26). In our study, all pGGNs measuring <5 mm (12 cases, all with 5-year follow-up periods) remained stable. The American College of Chest Physicians and Fleischner Society recommend against routine chest CT follow-up for such nodules (8,9). Based on our findings, pGGNs <5 mm in size carry a minimal risk of growth, warranting less stringent annual chest CT monitoring. Chest CT monitoring every 2–3 years, or potentially longer, may suffice for pGGNs <5 mm, while for those <8.5 mm, monitoring every 1–2 years may be adequate to minimize radiation exposure. However, studies with larger cohorts are required to establish optimal follow-up intervals.

This study had inherent limitations, including an extended follow-up period and a disproportionately large sample size in the stable group of pGGNs. Additionally, the retrospective design limits the generalizability of the findings, and the sample size of growing pGGNs over the 3-year follow-up was relatively small. Further, not all pGGNs with documented growth underwent surgical resection. For patients with larger nodules (>10 mm), decisions to continue surveillance instead of opting for surgery were often influenced by factors such as advanced age, poor cardiopulmonary function, comorbidities, or economic constraints. Additionally, the methodology did not incorporate state-of-the-art measurement techniques, such as three-dimensional volumetry or mass estimation. Finally, the majority of pGGNs were small in size (with the longest diameter measuring <15 mm). This size bias likely results from a tendency to select larger pGGNs (≥15 mm) for immediate surgical intervention after initial diagnosis rather than for ongoing follow-up (27).

Conclusions

For pGGNs with an initial diameter ≥8.5 mm and an irregular shape, active surgical intervention should be considered the primary clinical management strategy over continued surveillance. For pGGNs with an initial diameter <8.5 mm and a round or oval shape, a chest CT follow-up schedule of once every 1–2 years until the third year, followed by a re-evaluation, may be appropriate. This approach facilitates the individualized and meticulous clinical management of patients with pGGNs by physicians.

Acknowledgments

None.

Footnote

Reporting Checklist: The authors have completed the STROBE reporting checklist. Available at https://qims.amegroups.com/article/view/10.21037/qims-24-2086/rc

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-24-2086/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. The study was conducted in accordance with the Declaration of Helsinki (as revised in 2013). The research protocol was approved by the Institutional Ethics Review Committee of Shapingba Hospital Affiliated to Chongqing University (No. KY202311), which waived the requirement for informed consent.

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/.

References

1. Henschke CI, Yip R, Smith JP, Wolf AS, Flores RM, Liang M, Salvatore MM, Liu Y, Xu DM, Yankelevitz DFInternational Early Lung Cancer Action Program Investigators. CT Screening for Lung Cancer: Part-Solid Nodules in Baseline and Annual Repeat Rounds. AJR Am J Roentgenol 2016;207:1176-84. [Crossref] [PubMed]
2. Hammer MM, Eckel AL, Palazzo LL, Kong CY. Cost-Effectiveness of Treatment Thresholds for Subsolid Pulmonary Nodules in CT Lung Cancer Screening. Radiology 2021;300:586-93. [Crossref] [PubMed]
3. Xie B, Wang R, Fu K, Wang Q, Liu Z, Peng W. The value of predicting the invasiveness and degree of infiltration of pulmonary ground-glass nodules based on computed tomography features and enhanced quantitative analysis. Quant Imaging Med Surg 2024;14:6767-79. [Crossref] [PubMed]
4. Park J, Doo KW, Sung YE, Jung JI, Chang S. Computed Tomography Findings for Predicting Invasiveness of Lung Adenocarcinomas Manifesting as Pure Ground-Glass Nodules. Can Assoc Radiol J 2023;74:137-46. [Crossref] [PubMed]
5. Fang W, Zhang G, Yu Y, Chen H, Liu H. Identification of pathological subtypes of early lung adenocarcinoma based on artificial intelligence parameters and CT signs. Biosci Rep 2022;42:BSR20212416. [Crossref] [PubMed]
6. Kobayashi Y, Fukui T, Ito S, Usami N, Hatooka S, Yatabe Y, Mitsudomi T. How long should small lung lesions of ground-glass opacity be followed? J Thorac Oncol 2013;8:309-14. [Crossref] [PubMed]
7. Lee CT. What do we know about ground-glass opacity nodules in the lung? Transl Lung Cancer Res 2015;4:656-9. [PubMed]
8. Gould MK, Donington J, Lynch WR, Mazzone PJ, Midthun DE, Naidich DP, Wiener RS. Evaluation of individuals with pulmonary nodules: when is it lung cancer? Diagnosis and management of lung cancer, 3rd ed: American College of Chest Physicians evidence-based clinical practice guidelines. Chest 2013;143:e93S-e120S.
9. Naidich DP, Bankier AA, MacMahon H, Schaefer-Prokop CM, Pistolesi M, Goo JM, Macchiarini P, Crapo JD, Herold CJ, Austin JH, Travis WD. Recommendations for the management of subsolid pulmonary nodules detected at CT: a statement from the Fleischner Society. Radiology 2013;266:304-17. [Crossref] [PubMed]
10. Hiramatsu M, Inagaki T, Inagaki T, Matsui Y, Satoh Y, Okumura S, Ishikawa Y, Miyaoka E, Nakagawa K. Pulmonary ground-glass opacity (GGO) lesions-large size and a history of lung cancer are risk factors for growth. J Thorac Oncol 2008;3:1245-50. [Crossref] [PubMed]
11. Travis WD, Brambilla E, Nicholson AG, Yatabe Y, Austin JHM, Beasley MB, Chirieac LR, Dacic S, Duhig E, Flieder DB, Geisinger K, Hirsch FR, Ishikawa Y, Kerr KM, Noguchi M, Pelosi G, Powell CA, Tsao MS, Wistuba I. The 2015 World Health Organization Classification of Lung Tumors: Impact of Genetic, Clinical and Radiologic Advances Since the 2004 Classification. J Thorac Oncol 2015;10:1243-60. [Crossref] [PubMed]
12. Chang B, Hwang JH, Choi YH, Chung MP, Kim H, Kwon OJ, Lee HY, Lee KS, Shim YM, Han J, Um SW. Natural history of pure ground-glass opacity lung nodules detected by low-dose CT scan. Chest 2013;143:172-8. [Crossref] [PubMed]
13. Sun JD, Sugarbaker E, Byrne SC, Gagné A, Leo R, Swanson SJ, Hammer MM. Clinical Outcomes of Resected Pure Ground-Glass, Heterogeneous Ground-Glass, and Part-Solid Pulmonary Nodules. AJR Am J Roentgenol 2024;222:e2330504. [Crossref] [PubMed]
14. Huang KX, Gibney BC. Pure ground-glass opacities (GGO) lung adenocarcinoma: surgical resection is curative. J Thorac Dis 2024;16:3518-21. [Crossref] [PubMed]
15. Cho J, Kim ES, Kim SJ, Lee YJ, Park JS, Cho YJ, Yoon HI, Lee JH, Lee CT. Long-Term Follow-up of Small Pulmonary Ground-Glass Nodules Stable for 3 Years: Implications of the Proper Follow-up Period and Risk Factors for Subsequent Growth. J Thorac Oncol 2016;11:1453-9. [Crossref] [PubMed]
16. He Y, Xiong Z, Tian D, Zhang J, Chen J, Li Z. Natural progression of persistent pure ground-glass nodules 10 mm or smaller: long-term observation and risk factor assessment. Jpn J Radiol 2023;41:605-16. [Crossref] [PubMed]
17. Qi LL, Wu BT, Tang W, Zhou LN, Huang Y, Zhao SJ, Liu L, Li M, Zhang L, Feng SC, Hou DH, Zhou Z, Li XL, Wang YZ, Wu N, Wang JW. Long-term follow-up of persistent pulmonary pure ground-glass nodules with deep learning-assisted nodule segmentation. Eur Radiol 2020;30:744-55. [Crossref] [PubMed]
18. Fu F, Zhang Y, Wang S, Li Y, Wang Z, Hu H, Chen H. Computed tomography density is not associated with pathological tumor invasion for pure ground-glass nodules. J Thorac Cardiovasc Surg 2021;162:451-459.e3. [Crossref] [PubMed]
19. Chu ZG, Li WJ, Fu BJ, Lv FJ. CT Characteristics for Predicting Invasiveness in Pulmonary Pure Ground-Glass Nodules. AJR Am J Roentgenol 2020;215:351-8. [Crossref] [PubMed]
20. Yang HH, Lv YL, Fan XH, Ai ZY, Xu XC, Ye B, Hu DZ. Factors distinguishing invasive from pre-invasive adenocarcinoma presenting as pure ground-glass pulmonary nodules. Radiat Oncol 2020;15:186. [Crossref] [PubMed]
21. Zhan Y, Peng X, Shan F, Feng M, Shi Y, Liu L, Zhang Z. Attenuation and Morphologic Characteristics Distinguishing a Ground-Glass Nodule Measuring 5-10 mm in Diameter as Invasive Lung Adenocarcinoma on Thin-Slice CT. AJR Am J Roentgenol 2019;213:W162-70. [Crossref] [PubMed]
22. Lee HY, Choi YL, Lee KS, Han J, Zo JI, Shim YM, Moon JW. Pure ground-glass opacity neoplastic lung nodules: histopathology, imaging, and management. AJR Am J Roentgenol 2014;202:W224-33. [Crossref] [PubMed]
23. Lee HW, Jin KN, Lee JK, Kim DK, Chung HS, Heo EY, Choi SH. Long-Term Follow-Up of Ground-Glass Nodules After 5 Years of Stability. J Thorac Oncol 2019;14:1370-7. [Crossref] [PubMed]
24. Lee JH, Park CM, Lee SM, Kim H, McAdams HP, Goo JM. Persistent pulmonary subsolid nodules with solid portions of 5 mm or smaller: Their natural course and predictors of interval growth. Eur Radiol 2016;26:1529-37. [Crossref] [PubMed]
25. Sato Y, Fujimoto D, Morimoto T, Uehara K, Nagata K, Sakanoue I, Hamakawa H, Takahashi Y, Imai Y, Tomii K. Natural history and clinical characteristics of multiple pulmonary nodules with ground glass opacity. Respirology 2017;22:1615-21. [Crossref] [PubMed]
26. Yoon HY, Bae JY, Kim Y, Shim SS, Park S, Park SY, Kim SJ, Ryu YJ, Chang JH, Lee JH. Risk factors associated with an increase in the size of ground-glass lung nodules on chest computed tomography. Thorac Cancer 2019;10:1544-51. [Crossref] [PubMed]
27. Cho J, Ko SJ, Kim SJ, Lee YJ, Park JS, Cho YJ, Yoon HI, Cho S, Kim K, Jheon S, Lee JH, Lee CT. Surgical resection of nodular ground-glass opacities without percutaneous needle aspiration or biopsy. BMC Cancer 2014;14:838. [Crossref] [PubMed]