Natural History of Pure Ground-Glass Opacity Lung Nodules Detected by Low-Dose CT Scan
Boksoon Chang, MD; Jung Hye Hwang, MD; Yoon-Ho Choi, MD; Man Pyo Chung, MD, PhD; Hojoong Kim, MD, PhD, FCCP; O Jung Kwon, MD, PhD; Ho Yun Lee, MD; Kyung Soo Lee, MD, PhD; Young Mog Shim, MD, PhD; Joungho Han, MD, PhD; and Sang-Won Um, MD, PhD
CHEST / 143 / 1 / JANUARY 2013
Background: Although focal ground-glass opacity (GGO) lung nodules are generally reported to grow slowly, their natural course is unclear. The purpose of this study was to elucidate the natural course of screening-detected pure GGO lung nodules in patients with no history of malignancy.
Methods: We retrospectively reviewed the database of subjects who had undergone screenings involving low-dose CT scans. We included patients with pure GGO lung nodules who were followed for . 2 years after the initial screening.
Results: Between June 1997 and September 2006, 122 pure GGO nodules were found in 89 patients. The median nodule size was 5.5 mm (range, 3-20 mm) in the largest diameter on initial low-dose CT scan. The median follow-up period per patient was 59 months. On a per-person basis, the frequency of growth was 13.5% (12 of 89 patients). On a per-nodule basis, the frequency of growth was 9.8% (12 of 122 nodules). Nodule growth was signifi cantly associated with initial size
and new development of an internal solid portion. The median volume doubling time was 769 days for growing pure GGO nodules. A total of 11 growing nodules were surgically validated, and all lesions were confi rmed as primary lung cancer.
Conclusions: About 90% of the screening-detected pure GGO lung nodules did not grow during long-term follow-up in subjects with no history of malignancy and most growing nodules had an indolent clinical course. A strategy of long-term follow-up and selective surgery for growing nodules should be considered for pure GGO lung nodules. CHEST 2013; 143(1):172–178
Abbreviations: GGO 5 ground-glass opacity; HU 5 Hounsfi eld unit; LDCT 5 low-dose CT; TDR 5 tumor shadow disappearance rate
The advent of low-dose CT (LDCT) scanning has altered the landscape of lung cancer screening. The National Lung Cancer Screening Trial in the United States showed that screening with LDCT scanning reduces mortality from lung cancer. 1 With the increased use of LDCT scan screening for lung cancer since the 1990s, very faint and smaller lesions termed ground-glass opacities (GGOs) have been encountered more frequently . GGOs are characterized as lesions of homogenous density and with hazy increase in density in the lung fi eld that does not obscure the bronchovascular structure. 2-4 GGOs are found in 0.2% to 0.5% of screened populations,5 and they pose a diagnostic challenge to clinicians, as GGOs can result in a variety of differential diagnoses of benign and malignant diseases. If the GGO is due to inflammation or bleeding, it typically disappears during an initial 3-month follow-up. However, persis- tent focal GGOs correspond to focal fibrosis, atypical adenomatous hyperplasia, bronchoalveolar carcinoma, and invasive adenocarcinoma.6-9 The frequency of malignancy was higher for mixed GGO nodules than for pure GGO nodules among patients who under- went LDCT scan screening.10
Although GGOs are generally reported to grow slowly, their natural history is still unclear due to short clinical experience with them.11-13 Also, suspi- cion exists that some focal GGOs are the result of an overdiagnosis bias.13 The purpose of this study was to elucidate the natural history of screening-detected pure GGO nodules during a long-term follow-up of . 2 years in patients with no history of lung cancer or other malignancy.
Materials and Methods
We retrospectively reviewed the database for subjects who had undergone screening LDCT scans at the Center for Health Promotion, Samsung Medical Center (Seoul, South Korea), between June 1997 and September 2006. We included patients with persistent, pure GGO lung nodules, who were followed for . 2 years after the initial LDCT scans. The exclusion criteria were transient GGO lung nodules, diffuse GGO lung lesions and a suspicion of interstitial lung disease, fibrotic changes or bronchiolitis, a confirmed solid or mixed GGO nodule on thin- section chest CT scan, a history of previous primary lung can- cer or any other malignancy, resection of GGO lung nodules within 2 years, and failure to undergo thin-section chest CT scans (, 2.5 mm) at the initial LDCT scan or during the follow-up period. This study was approved by the Institutional Review Board of Samsung Medical Center (No. 2009-05-013). The requirement for informed consent was waived, given the retrospective nature of the study.
CT Screening and Serial Follow-up
CT scans were obtained with a 64-detector row scanner (LightSpeed VCT XT; General Electric Company) using the unenhanced helical technique (40 mA; 120 kVp; beam width,
10-20 mm; beam pitch, 1.375-1.5) at the end inspiration during one breath hold. Image data were reconstructed with a 1-mm sec- tion thickness using a high-spatial-frequency algorithm. CT scans performed in the 1990s were obtained with a single-detector scanner (HiSpeed Advantage scanner; General Electric Company) with a pitch of 1.7 and 5-mm-thick reconstructions at 4-mm inter- vals. If the GGO nodule displayed an internal solid portion or diameter . 10 mm, intervention (transthoracic needle aspira- tion/biopsy or video-assisted thoracoscopic surgery) was consid- ered for persistent GGO nodules if patient consent was provided. However, if the GGO nodule was , 10 mm in diameter and did not possess a solid portion, thin-section CT scans were obtained within a short-term follow-up period of 3 months, again after 6 months, and annually thereafter.
Radiologic Definition of GGO Nodules
Both mediastinal (width, 400 Hounsfield units [HU]; level, 20 HU) and lung (width, 1,500 HU; level, 2700 HU) window images were viewed. The characteristics of the GGO nodules were evaluated on thin-section chest CT scans (section thick- ness , 2.5 mm). All radiologic images were evaluated by two specialists (H. Y. L. and S.-W. U.). The definitions of pure GGO and mixed GGO nodules were based on the tumor shadow disap- pearance rate (TDR): solid (TDR 5 1), mixed (0 , TDR , 1), and pure GGOs (TDR 5 0).14 For enrolled patients, all available chest CT scans were evaluated and the changes in size and char- acteristics were recorded. An increased GGO nodule size was defined as an increase of > 2 mm from the size on initial screening LDCT scan. A GGO nodule decrease was defined as a decrease of > 2 mm from the size on initial screening LDCT scan. Other conditions were defined as unchanged. For analysis on a per- patient basis, the growth group was defined as patients with detection of increased size in one or more nodules. The non- growth group was defined as patients with lack of nodule growth or decreased nodule size. The volume doubling time was calcu- lated based on the sizes of the GGO nodules on the initial LDCT scan and the final chest CT scan. The volume doubling time was calculated according to a modified method of the Schwartz formula.11,15,16 We evaluated the association between the size change and the morphologic characteristics of the nod- ules. Nodules were considered peripherally distributed if they were located in the lateral two-thirds of the lung parenchyma on transverse CT scans.
Surgery and Histopathologic Findings
During follow-up, surgical resection was considered for growing pure GGO nodules (diameter increase . 2 mm) and GGO nodules with new development of an internal solid portion. Data regarding the type of surgery, maximum tumor dimensions on surgical specimens, and pathologic staging were evaluated. The histologic classification of adenocarcinoma followed the International Association for the Study of Lung Cancer/American Thoracic Society/European Respiratory Society classification of lung adenocarcinoma.17
The data are presented as the number (%) or median (range) unless otherwise stated. The duration of nodule follow-up was defined from the date of the initial LDCT scan to the date of the final chest CT scan. Follow-up was completed by March 31, 2010. The Pearson x2 test and Fisher exact test were used for categorical data, and an independent sample t test or the Mann-Whitney U test were used for numerical data. P values , 0.05 were consid- ered statistically significant. All statistical tests were performed with Predictive Analytics Software, version 17.0 (SPSS, Inc).
Characteristics of the Study Patients
During the study period, 40,006 LDCT scans were performed at the Samsung Medical Center on
19,919 subjects (82.8% male patients) with a median age of 49 years. Among patients who had undergone one or more LDCT scans, 857 displayed GGO lung lesions on the initial scans. Among these 857 patients, 491 were followed for . 2 years using serial LDCT scans or routine chest CT scans. However, 402 patients were excluded from the study; Figure 1 summarizes the reasons for exclusion. Therefore, 89 subjects in total were enrolled in the study (Fig 1).
The characteristics of the 89 study patients and CT scan findings of the 122 pure GGO nodules identi- fied are summarized in Tables 1 and 2. Of the patients, 73 were men (82%) and 16 were women (18%); median age was 53 years. The median nodule size was 5.5 mm (range, 3-20 mm) in the largest diameter at the initial LDCT scan.
Size Changes in GGO Lung Nodules During the Follow-up Period
The nodule size increased in 12 of the 89 patients during the median follow-up period of 59 months (range, 25-140 months) (Fig 1). Two patients who possessed a single nodule that increased in size and a second nodule whose size did not change, respec- tively, were included in the increased-size group (Table 1). On a per-person basis, the frequency of growth was 13.5% (12 of 89). On a per-nodule basis, the frequency of growth was 9.8% (12 of 122).
Clinical and Radiologic Factors Associated With Growth of GGO Nodules
When the clinical characteristics of the growth and nongrowth groups were compared, age, sex, and smoking history did not differ significantly between the two groups (Table 3).
Table 4 summarizes the radiologic findings for GGO nodules according to the changes in nodule size. The initial nodule size dif- fered significantly between the nongrowth and growth groups (P 5 .048). When the initial nodule sizes were categorized into four size groups (, 5 mm, 5-7 mm, 8-9 mm, and > 10 mm in the largest dimension), a significant trend for nodule growth was observed in relation to the increased size (P 5 .003). Furthermore, new development of an internal solid portion during follow-up was significantly associated with GGO nod- ule growth (P 5 .009). The median volume doubling time of the 12 growing GGO nodules was 769 days (range, 330-3031 days). Figure 2 displays the growth patterns of 12 individual GGO nodules.
Surgery and Histopathologic Findings
Eleven of the 12 patients who displayed increased nodule size or new solid portion underwent surgical resection, and all 11 patients were diagnosed with primary lung cancer. One patient with a growing nodule refused the operation. The surgical method, pathologic staging, and histologic diagnoses are sum- marized in Table 5. All the study patients had patho- logic stage T1aN0 lung cancer, except for one patient whose cancer was confirmed as stage T2aN2. This patient had 5-mm pure GGO nodule at the initial LDCT scan, but it had become a 14-mm mixed GGO nodule by 68-month follow-up. The preoperative clinical staging was T2aN0, but the surgical spec- imen revealed microscopic metastasis in a right, lower, paratracheal lymph node. As of May 2011, the median postoperative follow-up period was 51 months (range, 10-75 months) and all patients survived.
Focal GGO lung nodules are generally thought to grow slowly. However, long-term follow-up data for screening-detected pure GGO lung nodules have not been sufficient until now. Previous studies of the natural history of GGO lung nodules have had limitations, including a short follow-up period, a small number of patients, heterogeneous populations that included patients with a history of malignancy, pop- ulations that included both pure and mixed GGO nodules, and populations that included only patients who had undergone surgical resection.18-24 In these studies, some GGO nodules did not grow during the follow-up period and mean follow-up periods ranged from 7 to 41.6 months.18-21,23,24 Two studies evaluated the natural history of GGO nodules in patients with a history of primary lung cancer and healthy subjects who underwent LDCT screening.18,20 The propor- tions of pure GGO nodule growth in these studies were 13% and 58%, respectively. Based on these studies, a history of lung cancer appears to be a risk factor for GGO growth.18 Furthermore, the GGO lung nodules in patients with extrapulmonary malig- nancies tended to display a high malignancy rate.25
Therefore, studies should be performed in subjects with no previous history of malignancy to elucidate the natural history of screening-detected pure GGO nodules. Thus, previous studies may have overesti- mated the proportion of pure GGO lung-nodule growth following screening.18,20 In the present study, growth was observed in 12 of 122 pure GGOs (9.8%) without a history of previous malignancy during a median CT scan follow-up period of 59 months. One strength of this study was the long-term follow-up evaluation of a relatively large number of patients without a history of lung cancer.
We observed a median volume doubling time of 769 days for growing, pure GGO nodules. Our results were similar to the doubling times of 831 days for pure GGO nodules and 457 days for mixed GGO nodules reported by Hasegawa et al.11 In our study, five patients with mixed GGO nodules were excluded from the analysis. The frequency of GGO growth was 60% in these patients. The volume doubling time for grow- ing, mixed GGO nodules was 488 days (range, 376-4,338 days), and all growing lesions were confirmed as minimally invasive or invasive adenocarcinoma. The frequency and rate of growth were higher for mixed GGO nodules than for pure GGO nodules in the pre- sent study. These findings are consistent with those of previous studies, which have reported a different clinical course and frequency of malignancy in pure and mixed GGO nodules.7,10,21-23
For growing, pure GGO nodules, the volume dou- bling time exceeded 400 days in 11 of 12 pure GGO nodules (91.7%) in our series and the clinical course of most growing GGO nodules could be considered as relatively indolent. Moreover, surgically resected GGO nodules were adenocarcinoma in situ or mini- mally invasive adenocarcinoma in eight of 11 patients (72.7%). Of patients with GGO nodules who under- went surgery, 27.3% had invasive adenocarcinoma and
9.1% had microscopic mediastinal nodal metastasis. However, a portion of pure GGO lung nodules could develop into invasive adenocarcinoma. Stepwise evolu- tion of a focal, pure GGO lung nodule into an inva- sive lung adenocarcinoma during long-term follow-up has been reported.26,27 Therefore, screening-detected pure GGO lung nodules may include heterogeneous populations of both clinically indolent and invasive tumors. It is necessary to develop a prediction model for invasive lung cancer development using epide- miologic data and biologic markers to identify the optimal target population.
The present study found that initial size and new development of a solid portion were significantly associated with nodule growth in patients with pure GGO nodules, which is consistent with a previous report.18 Among patients with pure GGO nodules, nodule growth was observed in 7.7% of patients with an initial nodule size < 5 mm, in 5.7% of patients with nodule size 5-7 mm, in 20.0% of patients with nodule size 8-9 mm, and in 42.9% of patients with a nodule size ≥ 10 mm. Although recent guidelines recommend no further follow-up for pure GGO lung nodules < 5 mm,13 we observed growth of a 4-mm pure GGO nodule. The follow-up duration should be extended to 5 or 10 years, considering the long vol- ume doubling time. The results of our study support recent guidelines recommending that pure GGO nodules > 10 mm should be considered for surgical resection,13 as they have a high risk for growth.
This study had several limitations. First, it was per- formed retrospectively, meaning that the follow-up CT scan protocol and duration were heteroge- neous. Thin-section chest CT scans (section thick- ness < 2.5 mm) were performed as an initial evaluation in five patients, but all GGO nodules were confirmed by thin-section chest CT scans in the initial LDCT scan or at follow-up evaluations. Second, all study patients did not undergo tissue confirmation; therefore, we could not calculate the prevalence of primary lung can- cer in this patient cohort. Third, the size change and volume doubling time of GGO nodules may be diffi- cult to evaluate accurately based on a two-dimensional size measurement. GGO nodule volumetry could not be applied because of the limitation of screening LDCT scan in this study.
In conclusion, about 90% of the screening-detected pure GGO lung nodules did not grow during long- term follow-up in subjects with no history of malig- nancy and most of growing nodules had an indolent clinical course. Nodule growth is important in dif- ferentiating those that are malignant from those that should be followed for future growth. A strategy of long-term follow-up and selective surgery for growing nodules should be considered for screening-detected pure GGO lung nodules.
Authors contributions: Dr Um had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.
Dr Chang: contributed to data acquisition and analysis and writing and revision of the manuscript and served as principal author.
Dr Hwang: contributed to data acquisition, analysis, and review of the manuscript.
Dr Choi: contributed to data acquisition and review of the manuscript.
Dr Chung: contributed to data acquisition and review of the manuscript.
Dr Kim: contributed to data acquisition and review of the manuscript.
Dr Kwon: contributed to data acquisition and review of the manuscript.
Dr H. Y. Lee: contributed to data analysis and review of the manuscript.
Dr K. S. Lee: contributed to data acquisition and review of the manuscript.
Dr Shim: contributed to data acquisition and review of the manuscript.
Dr Han: contributed to data analysis and review of the manuscript. Dr Um: contributed to conception and design of the study, data analysis, and writing and revision of the manuscript. Financial/nonfinancial disclosures: The authors have reported to CHEST that no potential conflicts of interest exist with any companies/organizations whose products or services may be dis- cussed in this article.
Role of sponsors: The sponsor had no role in the design of the study, the collection and analysis of the data, or in the preparation of the manuscript.
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Manuscript received October 1, 2011; revision accepted June 6, 2012.
Affi liations : From the Division of Pulmonary and Critical Care Medicine (Drs Chang, Chung, Kim, Kwon, and Um), Department of Medicine; Center for Health Promotion (Drs Hwang and Choi); Department of Radiology and Center for Imaging Science (Drs H. Y. Lee and K. S. Lee); Department of Thoracic Surgery (Dr Shim); and Department of Pathology (Dr Han), Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, South Korea. Drs Chang and Hwang contributed equally to this work.
Funding/Support : This study was supported by the Samsung Medical Center Clinical Research Development Program [Grant CRS-110-19-1].
Correspondence to: Sang-Won Um, MD, PhD, Division of Pulmonary and Critical Care Medicine, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, 50 Irwon-Dong, Kangnam-Gu, Seoul, 135-710, South Korea; e-mail: firstname.lastname@example.org
© 2013 American College of Chest Physicians. Reproduction of this article is prohibited without written permission from the American College of Chest Physicians. See online for more details. DOI: 10.1378/chest.11-2501
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