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Natural History of Pulmonary Subsolid Nodules: A Prospective Multicenter Study

Open ArchivePublished:April 15, 2016DOI:https://doi.org/10.1016/j.jtho.2016.04.006

      Abstract

      Introduction

      The purpose of this study was to evaluate the natural course of the progression of pulmonary subsolid nodules (SSNs).

      Materials and Methods

      Eight facilities participated in this study. A total of 795 patients with 1229 SSNs were assessed for the frequency of invasive adenocarcinomas. SSNs were classified into three categories: pure ground-glass nodules (PGGNs), heterogeneous GGNs (HGGNs) (solid component detected only in lung windows), and part-solid nodules.

      Results

      The mean prospective follow-up period was 4.3 ± 2.5 years. SSNs were classified at baseline as follows: 1046 PGGNs, 81 HGGNs, and 102 part-solid nodules. Among the 1046 PGGNs, 13 (1.2%) developed into HGGNs and 56 (5.4%) developed into part-solid nodules. Among the 81 HGGNs, 16 (19.8%) developed into part-solid nodules. Thus, the SSNs at the final follow-up were classified as follows: 977 PGGNs, 78 HGGNs, and 174 part-solid nodules. Of the 977 PGGNs, 35 were resected (nine minimally invasive adenocarcinomas [MIAs], 21 adenocarcinomas in situ [AIS], and five atypical adenomatous hyperplasias). Of the 78 HGGNs, seven were resected (five MIAs and two AIS). Of the 174 part-solid nodules, 49 were resected (12 invasive adenocarcinomas, 26 MIAs, 10 AIS, and one adenomatous hyperplasia). For the PGGNs, the mean period until their development into part-solid nodules was 3.8 ± 2.0 years, whereas the mean period for the HGGNs was 2.1 ± 2.3 years (p = 0.0004).

      Conclusion

      This study revealed the frequencies and periods of development from PGGNs and HGGNs into part-solid nodules. Invasive adenocarcinomas were diagnosed only among the part-solid nodules, corresponding to 1% of all 1229 SSNs.

      Keywords

      Introduction

      With the introduction of computed tomography (CT) screening for lung cancer,
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      pulmonary subsolid nodules (SSNs) have emerged as a possible indicator of lung cancer.
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      SSNs are classified into pure ground-glass nodules (PGGNs) and part-solid GGNs. PGGNs are focal nodular areas of increased lung attenuation, including both well and poorly defined lesions through which normal parenchymal structures, including airways and vessels, can be visualized; part-solid GGNs include a combination of ground-glass and solid components, the latter obscuring the underlying lung architecture.
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      Although some SSNs are transient,
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      persistent SSNs have a high likelihood of being malignant.
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      Focal ground-glass opacity detected by low-dose helical CT.
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      CT screening for lung cancer: frequency and significance of part-solid and nonsolid nodules.
      However, the natural history of SSNs has not yet been clarified thoroughly.
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      Recommendations for the management of subsolid pulmonary nodules detected at CT: a statement from the Fleischner Society.
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      International Association for the Study of Lung Cancer/American Thoracic Society/European Respiratory Society international multidisciplinary classification of lung adenocarcinoma.
      Regarding the causes of SSNs, transient SSNs have been mainly caused by inflammation,
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      Transient part-solid nodules detected at screening thin-section CT for lung cancer: comparison with persistent part-solid nodules.
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      whereas most of the persistent SSNs have been preinvasive or invasive adenocarcinomas.
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      Persistent pulmonary nodular ground-glass opacity at thin-section CT: histopathologic comparisons.
      Although various algorithms have been developed to address these lesions,
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      Recommendations for the management of subsolid pulmonary nodules detected at CT: a statement from the Fleischner Society.
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      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.

      National Comprehensive Cancer Network NCCN Clinical Practice Guidelines in Oncology: Lung Cancer Screening, version 1.2016. http://www.nccn.org/professionals/physician_gls/pdf/lung_screening.pdf. Accessed March 7, 2016.

      American College of Radiology Lung CT Screening Reporting and Data System (Lung-RADS™). http://www.acr.org/Quality-Safety/Resources/LungRADS. Accessed March 7, 2016.

      • Baldwin D.R.
      • Callister M.E.J.
      On behalf of the members of the Guideline Development Group
      The British Thoracic Society guidelines on the investigation and management of pulmonary nodules.

      The Japanese Society of CT Screening. Guidelines for the management of pulmonary nodules detected by low-dose CT lung cancer screening, version 3. http://www.jscts.org/index.php?page=guideline_index. Accessed March 7, 2016.

      to our knowledge, these algorithms have not been based on prospective follow-up results for SSNs.
      Thus, the purpose of this prospective multicenter study was to evaluate the natural course of the progression of pulmonary SSNs.

      Materials and Methods

      Ethics Statement

      This study was conducted with the approval of the institutional review boards of each of the eight participating institutions. Informed consent was obtained from the patients.

      Participating Institutions

      The eight institutions that participated in this study were as follows: Kanagawa Cancer Center, National Cancer Center Hospital East, National Cancer Center Research Center for Cancer Prevention and Screening, Niigata Cancer Center, Osaka Medical Center for Cancer and Cardiovascular Diseases, Shiga University of Medical Science, Shikoku Cancer Center, and Tochigi Cancer Center.

      Nodule-Related Entry Criteria

      The inclusion criteria for SSNs were as follows. First, the persistence of the SSNs for 3 months was confirmed after the initial CT examination. Second, the included GGNs had a long axial diameter of 3 cm or less.
      • Hansell D.M.
      • Bankier A.A.
      • MacMahon H.
      • et al.
      Fleischner Society: glossary of terms for thoracic imaging.
      Third, the included part-solid nodules had a long axial diameter of 3 cm or less and a solid component with a long axial diameter of 5 mm or less when viewed using a mediastinal window. Finally, each SSN had been evaluated using thin-section CT images with a section thickness of 1.25 mm or less.

      Numbers of Patients and SSNs

      A total of 845 patients with 1325 SSNs agreed to participate in this study between April 2009 and December 28, 2011. However, 57 SSNs in 50 patients were excluded because of the following reasons: availability of thick-section CT images only (31 nodules in 26 patients [21 with one nodule and five with two nodules]), resection within 2 months after the first CT scan (seven nodules in five patients [three with one nodule and two with two nodules]), a decrease in maximal diameter of 2 mm or more (six nodules in six patients), a maximal diameter of the solid component larger than 5 mm (five nodules in five patients), fluctuation in maximal diameter (three nodules in three patients, with fluctuating defined as an increase in diameter after a decrease in diameter or vice versa, as a result of which an increase in maximal diameter of 2 mm or more from the baseline CT could not be determined), a diameter of an SSN larger than 3 cm (two nodules in two patients), disappearance after persistence for at least 3 months (two nodules in two patients), and hospital transfer (one nodule in one patient). In addition, 30 other SSNs in patients with multiple SSNs were excluded because of the following reasons: availability of thick-section CT images only (20 nodules in 20 patients), diameter of solid component larger than 5 mm (five nodules in four patients [three with one nodule and one with two nodules), and diagnosis of inflammation on the basis of the conclusions of a radiology panel (five nodules in one patient). Thus, 795 patients with 1238 SSNs were eligible for an assessment of the frequency of growth.
      After the exclusion of nine resected nodules (two non–lung cancer nodules reviewed by the pathology panel and seven nodules not reviewed by the pathology panel because those pathological specimens were not sent to the study secretariat by the last review session), the frequency of invasive adenocarcinomas was assessed in 795 patients with 1229 SSNs.
      The final evaluation of the presence or absence of progression of SSNs was performed as of December 27, 2013. Information regarding patient sex, age, smoking status, past history of lung cancer, reasons for SSN detection, and number of SSNs per patient was collected.
      The flow diagram is shown in a figure (see Fig., Supplementary Data 1).

      Protocol for CT scanning

      The section thickness was prescribed as 1.25 mm or less. Other parameters (i.e., tube voltage, tube current, pitch factor, field of view, and reconstruction kernel) were based on the protocols of each institution (see Table, Supplementary Data 2). The interval for the CT scans was, in principle, 1 year, although the intervals varied for some follow-up CT examinations depending on the situation at each institution or the patient’s availability.

      Classification of SSNs

      In this study, the SSNs were classified into three groups on the basis of their texture (Fig. 1): pure GGNs (PGGNs), heterogeneous GGNs (HGGNs), and part-solid nodules.
      Figure thumbnail gr1
      Figure 1Classification of subsolid nodules. (A) The first group of pure ground-glass nodules (GGNs), referred to here as pure GGNs, consisted of homogeneous opacities when viewed using the lung window. (B) A solid component in the mediastinal window was not observed. (C and D) The second group consisted of heterogeneous GGNs, or GGNs with a solid component (black arrow) in only the lung window but not in the mediastinal window. (E and F) The third group of part-solid nodules consisted of GGNs with a solid component both in the lung window (black arrow) and in the mediastinal window (white arrow).

      Surgery

      The criteria for surgery were not prescribed by the study protocol. Decisions regarding resection were made according to the protocols of each institution.

      Follow-up Report

      Follow-up reports on the patients treated at each institution were submitted to the study secretariat. The follow-up reports contained anonymized patient identification numbers, dates of the CT examinations, slice thickness, slice interval, maximal diameter and perpendicular diameters of each SSN, presence or absence of a solid component in lung windows (if present, the maximal diameter and perpendicular diameter of the solid component were included), and presence or absence of a solid component in mediastinal windows (if present, the maximal diameter and perpendicular diameter of the solid component were included) for each CT examination. A single doctor at each institution who had more than 10 years of experience reading chest CT images measured the diameters of the SSNs and solid components. Growth of an SSN or solid component was defined as an increase in the maximal diameter of 2 mm or more. The appearance of a solid component in a PGGN or a HGGN when viewed using a mediastinal window was also defined as growth. For patients who underwent resection, the date of surgery, surgical procedure, pathological diagnosis, and pathological stage were also included in the report.

      Central Review by Radiology Panel

      The radiology panel consisted of three board-certified radiologists (K. A., 25 years of experience in reading chest CT scans as of March 2012; K. K., 27 years of experience in reading chest CT scans; and S. M., 31 years of experience in reading chest CT scans). The radiology panel reviewed the CT images of patients in which an increase in the size of an SSN, a change from PGGN to HGGN, a change from PGGN to part-solid nodule, a change from HGGN to part-solid nodule, or an increase in the size of a solid component had been noted by the participating institution where the images had originated. The CT images had been anonymized at each facility and sent to the study secretariat. The three radiologists gathered together at the Research Center for Cancer Prevention and Screening and reviewed these CT images simultaneously on the monitor of an Apple iMac using the OsiriX MD (Pixmeo SARL, Bernex, Switzerland). The lung windows were set at a window width of 1500 Hounsfield units (HU) and a window level –500 HU. Mediastinal windows for the measurement of solid components were set at a window width of 350 HU and a window level of 40 HU. Assessments of the consistency of the SSNs were based on the consensus of the three radiologists. The measurement of the diameter of an SSN in a lung window or the measurement of the diameter of a solid component in a mediastinal window was performed by a single radiologist during all the review sessions and confirmed by the consensus of the three radiologists. For measurements of solid components, the CT image was magnified by an appropriate power to enable the measurement of the solid component in a mediastinal window. The radiologists were not informed whether the patient had undergone a resection or whether a pathological diagnosis was present or absent.

      Central Review by Pathology Panel

      The pathology panel consisted of three board-certified pathologists (A.M.M., 17 years of experience as of March 2012; Y.M., 29 years of experience; and M.N, 33 years of experience). Pathological specimens (stained using hematoxylin-eosin stain and elastica van Gieson stain) were sent to the study secretariat. The three pathologists gathered together at the National Cancer Center Hospital and reviewed these specimens using a multi-headed microscope simultaneously without information regarding the CT findings. Lung adenocarcinomas were classified on the basis of the 2015 World Health Organization (WHO) classification of tumors of the lung, pleura, thymus, and heart
      ; that is, they were classified as preinvasive lesions (atypical adenomatous hyperplasia [AAH] or adenocarcinoma in situ [AIS]), minimally invasive adenocarcinoma (MIA), invasive adenocarcinoma, or variants of invasive adenocarcinoma. If an invasive focus was detected in a pathological specimen, the maximal diameter of the invasive focus was measured by a single pathologist during all the review sessions and confirmed by the consensus of the three pathologists.

      CT-Pathological Correlation of Solid Components on CT Images in MIAs among Part-Solid Nodules

      The maximal diameters of the solid components in mediastinal windows on CT images of MIAs were correlated with the maximal diameters of invasive foci in pathological specimens of the MIAs.

      VDT of Resected SSNs

      The volume-doubling times (VDTs) of the resected SSNs that showed growth, i.e., an increase of 2 mm or more in the maximal diameter of the SSN or an increase of 2 mm or more in the maximal diameter of the solid components, were calculated using a modified Schwartz equation
      • Hasegawa M.
      • Sone S.
      • Takashima S.
      • et al.
      Growth rate of small lung cancers detected on mass CT screening.
      : VDT = (t × log2)/[log (Vt/V0)], where Vt and V0 are respectively the volumes of an SSN or a solid component at last thin-section CT scan and baseline thin-section CT scan, t is the interval between the two CT scans, and V =π/6 × ab2 (where a is the maximal diameter of an SSN or a solid component and b is perpendicular dimension of an SSN or a solid component).

      Statistical Analyses

      The mean and median age, maximum diameter of the SSN, maximum diameter of the solid component, maximum diameter of the invasive foci, follow-up period, and VDT were calculated. Multiple comparisons of the mean diameters of the solid components of the AIS, MIAs, and invasive adenocarcinomas (three groups), and of the mean follow-up periods of the SSNs (three or four groups) were evaluated using the Kruskal-Wallis test followed by the Wilcoxon signed rank test with Bonferroni correction. Other comparisons were evaluated using the Mann-Whitney U test. Univariate analyses for factors affecting the time until SSN growth of 2 mm or more in maximal diameter, the appearance of a solid component in a PGGN or HGGN, and solid component growth of 2 mm or more in maximal diameter were analyzed using the Kaplan-Meier method. Differences between curves were determined using the log-rank test. A multivariate analysis of several variables was performed using the Cox proportional hazards regression model. An evaluation of the cutoff value for the maximal diameter of a solid component in the mediastinal window for differentiating AIS and MIA from invasive adenocarcinoma was performed using a receiver operating characteristic analysis. All the statistical evaluations were performed using JMP version 11 (SAS Institute Inc., Cary, NC). A p value less than 0.05 was considered statistically significant for the Mann-Whitney U test. When the Bonferroni correction was used, a p value less than 0.0167 was considered statistically significant for comparisons of three groups and a p value less than 0.0083 was considered statistically significant for comparisons of four groups.

      Results

      Characteristics of the Patients

      Table 1 shows the characteristics of the patients. The 795 patients consisted of 454 women and 341 men (mean age 62 ± 9.4 years, median age 62 years, and interquartile range [IQR] 56–69 years). Among the 795 patients, 588 patients with SSNs were detected using CT screening for lung cancer, and the other 207 patients with SSNs were detected using nonscreening CT examinations. The reasons for the nonscreening CT examinations were as follows: chest radiograph abnormality was detected incidentally during a follow-up for another disease (meaning that the SSN was not visible on the chest radiograph, but another abnormal shadow was pointed out on the chest radiograph) (n = 133 patients); workup after chest radiography screening for lung cancer (meaning that the SSN was not visible on the chest radiograph, but another abnormal shadow was pointed out on the chest radiograph) (n = 45 patients); and symptoms leading to a suspicion of pulmonary disease (n = 29 patients). A total of 1238 SSNs that were eligible for an assessment of the frequency of growth were classified into three subgroups: 1053 PGGNs, 81 HGGNs, and 104 part-solid nodules; the mean diameter of the SSNs was 7.8 ± 3.4 mm (median 7.0 mm, IQR 5.5–9.0 mm). The median number of SSNs per patient was 1 (IQR 1–2). No new SSNs developed in any of the patients in this study cohort during the observation period of this study.
      Table 1Characteristics of the Patients (N = 795)
      Characteristicn%
      Sex
       Female45457.1
       Male34142.9
      Reason for detection
       CT screening58874.0
       Incidental13316.7
       Chest radiograph screening455.7
       Symptomatic293.6
      Smoking status
       Never smoked47459.6
       Ex-smoker25932.6
       Smoker587.3
       Unknown40.5
      History of lung cancer
       Absent72991.7
       Present648.1
       Unknown20.3
      No. SSNs
       Solitary54969.1
       Multiple24630.9
      Eligible for assessment of frequency of growth (No. nodules = 1238)
       Consistency
      PGGN105385.1
      HGGN816.5
      Part-solid1048.4
      Assessment of invasive adenocarcinoma frequency (No. nodules = 1229)
       Initial consistency
      PGGN104685.1
      HGGN816.6
      Part-solid1028.3
      CT, computed tomography; SSN, subsolid nodule; PGGN, pure ground-glass nodule; HGGN, heterogeneous ground-glass nodule.

      SSN Growth

      The time until SSN growth of 2 mm or more in maximal diameter, the time until the appearance of a solid component, and the time until solid component growth of 2 mm or more in maximal diameter are shown according to the SSN consistency in Figure 2. For the PGGNs and HGGNs, the curves for a solid component growth of 2 mm or more did not show any growth during the first 2 years of the follow-up period (Fig. 2C) whereas the curve for a solid component growth of 2 mm or more for part-solid nodules showed growth at 6 months after the start of the follow-up period.
      Figure thumbnail gr2
      Figure 2Growth curves of subsolid nodules (SSNs). The red, green, and blue curves indicate the accumulated percentages of growth of pure ground-glass nodules (PGGNs), heterogeneous ground-glass nodules (HGGNs), and part-solid nodules, respectively. Each pair of colored lines on the right side of each graph shows the results of a log-rank test (i.e., the red and green lines indicate PGGNs versus HGGNs, whereas the red and blue lines indicate PGGNs versus part-solid nodules and the green and blue lines indicate HGGNs versus part-solid nodules, respectively). (A) Time until SSN growth of 2 mm or more according to SSN consistency. The 2-year and 5-year estimated probabilities of nodule growth were 2% and 14% for PGGNs, 12% and 24% for HGGNs, and 17% and 48% for part-solid nodules, respectively. Each pair of growth curves except for that for HGGNs and part-solid nodules showed a statistically significant difference after Bonferroni correction (*). (B) Time until the appearance of a solid component according to SSN consistency. The 2-year and 5-year estimated probabilities of the appearance of a solid component were 1% and 6% for PGGNs and 16% and 22% for HGGNs; the pair of growth curves showed a statistically significant difference. (C) Time until solid component growth of 2 mm or more according to SSN consistency. The 2-year and 5-year estimated probabilities of solid component growth were 0% and 2% for PGGNs, 0% and 5% for HGGNs, and 9% and 22% for part-solid nodules, respectively. Each pair of growth curves except for that for PGGNs and HGGNs showed a statistically significant difference after Bonferroni correction (*).
      Univariate and multivariate analyses for variables affecting the time until SSN growth are shown in Tables 2 and 3. Multivariate analyses were performed according to each consistency and each type of growth: the main factor for predicting growth was the initial maximal diameter of the SSN. The time until PGGN growth according to the initial maximal diameter and sex is shown in Figure 3 (see Fig., Supplementary Data 3). Univariate analyses indicated that SSN growth events detected using nonscreening CT scans occurred more often than SSN growth events detected using screening CT scans (Table 2); however, the multivariate analysis did not show any significant difference between screening CT–detected SSNs and nonscreening CT–detected SSNs (Table 3).
      Table 2Univariate Analyses Based on SSN Consistency and Each Growth Type
      ConsistencyVariableSSN Growth ≥2 mmAppearance of Solid ComponentSolid Component Growth ≥2 mm
      Estimated Probabilityp ValueEstimated Probabilityp ValueEstimated Probabilityp Value
      2 y5y2y5y2y5y
      PGGNSex0.00040.08340.3033
      N§ = 635 Male2800.060.250.030.130.000.05
       Female3550.020.150.020.060.000.02
      Age0.00110.08150.0258
       >603450.040.250.020.110.000.05
       ≤602870.020.140.020.070.000.01
      Initial diameter, mm<0.0001<0.0001<0.0001
       >101280.130.540.100.200.000.07
       ≤105070.010.110.000.070.000.02
      Smoking status<0.00010.00980.0664
       Smoker
      Includes current smokers and ex-smokers.
      2570.060.270.030.150.000.05
       Never Smoked3780.010.140.020.050.000.02
      History of lung cancer0.03390.42890.0105
       Present460.020.300.050.130.000.04
       Absent5890.030.190.020.090.000.03
      No. SSNs0.21940.20870.6743
       Solitary4320.030.200.020.090.000.04
       Multiple2030.050.200.030.110.000.01
      Reason for detection0.19410.07640.0848
       CT screening4920.030.200.020.080.000.03
       Other1430.050.200.030.140.000.03
      HGGNSex0.37020.80750.3355
      N§ = 70 Male210.240.360.100.260.000.00
       Female490.070.160.150.190.000.03
      Age0.32390.52820.2233
       >60440.100.250.140.240.000.04
       ≤60260.160.200.120.180.000.00
      Initial diameter, mm0.0090.07690.3877
       >10290.230.380.230.400.000.00
       ≤10410.050.120.080.110.000.03
      Smoking status0.09390.29390.3951
       Smoker
      Includes current smokers and ex-smokers.
      190.260.390.170.330.000.00
       Never smoked510.060.160.120.170.000.03
      History of lung cancer0.01270.23640.8231
       Present70.330.500.171.000.000.00
       Absent630.100.190.130.190.000.03
      No. SSNs0.08150.04760.4186
       Solitary570.130.190.110.150.000.03
       Multiple130.080.330.250.420.000.00
      Reason for detection0.28720.99210.081
       CT screening370.120.160.110.200.000.00
       Other330.130.320.160.240.000.05
      Part-solid noduleSex0.38510.9823
      N§ = 84 Male380.210.560.030.20
       Female460.170.160.140.29
      Age0.13820.013
       >60560.230.620.120.31
       ≤60280.120.320.040.13
      Initial diameter, mm<0.00010.0017
       >10360.330.870.160.38
       ≤10480.100.300.040.17
      Smoking status0.57730.6425
       Smoker
      Includes current smokers and ex-smokers.
      410.190.590.030.17
       Never Smoked430.190.420.160.31
      History of lung cancer0.00010.3645
       Present110.181.000.100.41
       Absent730.190.400.090.23
      No. SSNs0.57560.8226
       Solitary570.230.530.060.25
       Multiple270.120.440.150.25
      Reason for detection0.02070.0126
       CT screening560.180.360.080.21
       Other280.210.790.120.33
      SSN, subsolid nodule; N§, number of patients; PGGN, pure ground-glass nodule; HGGN, heterogeneous ground-glass nodule; CT, computed tomography.
      a Includes current smokers and ex-smokers.
      Table 3Multivariate Analyses Based on SSN Consistency and Each Growth Type
      ConsistencyType of GrowthVariableHR95% CIp Value
      PGGNSSN growth ≥2 mmSex1.710.99–2.970.0536
      Age1.520.98–2.400.0646
      Initial diameter6.173.98–9.57<0.0001
      Smoking status1.550.91–2.670.1084
      History of lung cancer1.140.53–2.350.7358
      Number of SSN1.030.67–1.570.8832
      Reason for detection1.030.59–1.870.9254
      Final model
       Initial diameter7.064.67–10.72<0.0001
       Sex2.391.58–3.65<0.0001
      Appearance of solid componentSex1.180.57–2.470.6592
      Age1.240.65–2.190.4750
      Initial diameter4.142.28–7.48<0.0001
      Smoking status1.760.84–3.660.132
      History of lung cancer0.730.23–1.900.538
      Number of SSN1.170.65–2.060.5893
      Reason for detection0.700.36–1.420.3109
      Final model
       Initial diameter4.562.60–7.94<0.0001
       Smoking status1.981.14–3.490.0151
      Solid component growth ≥2 mmSex0.940.27–3.530.9205
      Age2.40.81–8.760.1159
      Initial diameter5.692.01–16.110.0013
      Smoking status2.240.60–8.250.2277
      History of lung cancer1.380.28–7.180.6888
      Number of SSN0.710.24–1.900.5027
      Reason for detection0.680.19–3.110.5928
      Final model
       Initial diameter7.232.84–19.00<0.0001
      HGGN
      Note: Solid component growth of 2 mm or more was not analyzed because of number of events was only 2.
      SSN growth ≥2 mmSex0.880.19–3.830.8614
      Age1.990.62–7.530.2557
      Initial diameter2.770.84–10.440.0952
      Smoking status3.020.81–12.380.1016
      History of lung cancer3.20.63–13.320.1467
      Number of SSN2.450.64–9.440.1841
      Reason for detection0.620.18–2.130.4439
      Final model
       Initial diameter3.521.33–10.310.0114
      Appearance of solid componentSex0.320.05–1.790.1984
      Age1.630.50–6.500.4287
      Initial diameter2.770.76–11.290.1220
      Smoking status3.920.75–18.550.1024
      History of lung cancer2.910.40–14.260.2550
      Number of SSN2.30.60–8.500.2138
      Reason for detection1.270.37–4.540.7061
      Part-solid noduleSSN growth ≥2 mmSex1.710.99–2.970.0536
      Age1.520.98–2.400.0646
      Initial diameter6.173.98–9.57<0.0001
      Smoking status1.550.91–2.670.1084
      History of lung cancer1.140.53–2.350.7358
      Number of SSN1.030.67–1.570.8832
      Reason for detection1.030.59–1.870.9254
      Final model
       Initial diameter7.064.67–10.72<0.0001
      Solid component growth ≥2 mmSex0.940.27–3.530.9205
      Age2.40.81–8.760.1159
      Initial diameter5.692.01–16.110.0013
      Smoking status2.240.60–8.250.2277
      History of lung cancer1.380.28–7.180.6888
      Number of SSN0.710.24–1.900.5027
      Reason for detection0.680.19–3.110.5928
      Final model
       Initial diameter7.232.84–19.00<0.0001
      HR, hazard ratio; CI, confidence interval; PGGN, pure ground-glass nodule; SSN, subsolid nodule; HGGN, heterogeneous ground-glass nodule.
      a Note: Solid component growth of 2 mm or more was not analyzed because of number of events was only 2.
      Figure thumbnail gr3
      Figure 3Time until pure ground-glass nodule (PGGN) growth according to the initial maximal diameter and sex. The red, green, blue, and orange curves indicate the accumulated percentages of growth of PGGNs with a maximal diameter larger than 10 mm in male patients, PGGNs with a maximal diameter larger than 10 mm in female patients, PGGNs with a maximal diameter of 10 mm or less in male patients, and PGGNs with a maximal diameter 10 mm or less in female patients, respectively. Each pair of colored lines on the right side of the graph shows the results of a log-rank test. Each pair except for that for PGGNs with a maximal diameter 10 mm or less in male patients and PGGNs with a maximal diameter 10 mm or less in female patients showed a statistically significant difference. However, all curves showed growth within 1 year. D, initial maximal diameter, N, number of patients.

      Frequency and Period of Progression into Part-Solid Nodules from PGGNs and HGGNs

      After the exclusion of nine resected nodules (two non–lung cancer nodules [an alveolar collapse and a nodular lymphoid hyperplasia] and seven lesions that were not reviewed by the pathology panel), the remaining 1229 pulmonary SSNs among which the frequency of invasive adenocarcinoma had been assessed were classified at baseline as follows: 1046 PGGNs, 81 HGGNs, and 102 part-solid nodules (Table 1). The mean prospective follow-up period was 4.3 ± 2.5 years (median 3.5 years, IQR 2.4–6.0 years). Among the 1046 PGGNs, 13 developed into HGGNs and 56 (5.4% [56 of 1046]) developed into part-solid nodules. Among the 81 HGGNs, 16 (19.8% [16 of 81]) developed into part-solid nodules. Thus, the 1229 SSNs were classified at the time of the final follow-up as follows: 977 PGGNs (79.5% [977 of 1229]), 78 HGGNs (6.3% [78 of 1229]), and 174 part-solid nodules (14.2% [174 of 1229]). For the 56 PGGNs, the mean period until development into a part-solid nodule was 3.8 ± 2.0 years (median 3.4 years, IQR 2.0–5.2); for the 16 HGGNs, the mean period until development into a part-solid nodule was 2.1 ± 2.3 years (median 1.0 year, IQR 0.7–3.4 years) (p = 0.0004).

      Histopathological Features of the Resected SSNs and Frequency of Invasive Adenocarcinomas

      Of the 977 PGGNs, the 35 resected PGGNs consisted of nine MIAs, 21 AIS, and five AAHs; of the 78 HGGNs, the seven resected HGGNs consisted of five MIAs and two AIS; and of the 174 part-solid nodules, the 49 part-solid nodules consisted of 12 invasive adenocarcinomas (nine lepidic, two acinar, and one solid), 26 MIAs, 10 AIS, and one AAH. In total, among the 1229 SSNs, 12 invasive adenocarcinomas (1.0%), 40 MIAs (3.3%), 33 AIS (2.7%), and six AAHs (0.5%) were resected as of December 27, 2013, after a mean prospective follow-up period of 4.3 years.

      Surgical Procedures for Resected Lung Cancer Cases and Outcomes

      The total number of patients with resected SSNs was 80; 71 patients had single resected SSNs and nine patients had multiple resected SSNs (two with three SSNs and seven with two SSNs). The surgical procedures were as follows: segmentectomy in 22 patients, wedge resection in 33 patients, and lobectomy in 25 patients. All the tumor resections were confirmed pathologically to be complete. All the patients were stage I (78 stage IA and two stage IB). The mean follow-up period after resection was 3.0 ± 1.1 years (median 3.0 years, IQR 2.0–3.9 years). As of March 31, 2015, no recurrences had occurred in any of the patients who had undergone resection.

      Solid Components in Part-Solid Nodules

      The relationship between the diameters of the solid components on thin-section CT images in mediastinal windows and the pathological diagnoses was analyzed (see Table, Supplementary Data 4). The mean diameters of the solid components in the 10 AIS, 26 MIAs, and 12 invasive adenocarcinomas were 2.5 ± 1.3 mm (median 2.8 mm, IQR 1.2–3.7 mm), 3.3 ± 2.0 mm (median 3.0 mm, IQR 1.9–4.7 mm), and 5.5 ± 2.7 mm (median 4.8 mm, IQR 3.7–7.2 mm), respectively; each comparison between groups except for the comparison of AIS and MIA was statistically significant (AIS versus invasive adenocarcinomas, p = 0.0045; MIA versus invasive adenocarcinomas, p = 0.0087; AIS versus MIA, p = 0.48). The mean follow-up periods for the 10 AIS, 26 MIAs, and 12 invasive adenocarcinomas from baseline CT examination until surgery were 4.2 ± 2.5 years (median 5.2 years, IQR 1.7–6.2 years), 3.3 ± 2.6 years (median 2.6 year, IQR 1.0–4.9 years), and 3.3 ± 1.6 years (median 3.3 years, IQR 2.0–4.4 years), respectively; none of the comparisons between groups were statistically significant (see Table, Supplementary Data 5).
      The mean diameters of part-solid nodules in 10 AIS, 26 MIAs, and 12 invasive adenocarcinomas were 16.6 ± 7.3 mm (median 16.2 mm, IQR 9.6–24.0 mm), 15.6 ± 4.5 mm (median 15.0 mm, IQR 13.0–18.4 mm), and 14.8 ± 4.5 mm (median 13.9 mm, IQR 12.3–17.7 mm), respectively; none of the comparisons between groups were statistically significant.

      Period Until an Increase in the Diameter of the Solid Component in Part-Solid Nodules to 3.3 mm or More on First-Time CT Examinations during Follow-up

      On the basis of an receiver operating characteristic analysis for differentiating AIS and MIA from invasive adenocarcinomas, the cutoff value of the maximal diameter of a solid component was 3.3 mm, yielding a sensitivity of 61% and a specificity of 91% (see Fig., Supplementary Data 6). During the follow-up of the SSNs, 20 part-solid nodules developed from PGGNs (36% [20 of 56], group A), five part-solid nodules developed from HGGNs (31% [five of 16], group B), and 22 part-solid nodules with solid components 3 mm or less in maximal diameter at the first thin-section CT scan (24% [22 of 93], group C) developed from part-solid nodules with a solid component 3.3 mm or larger in maximal diameter when viewed using a mediastinal window. The minimum periods for the development of part-solid nodules with a solid component 3.3 mm or larger in maximal diameter were 1.8 years for group A, 2.5 years for group B, and 6 months for group C, respectively (Fig. 4).
      Figure thumbnail gr4
      Figure 4Follow-up periods until an increase in the diameter of the solid component in the part-solid nodules 3.3 mm or larger in maximal diameter. The mean period for the development of part-solid nodules with a solid component 3.3 mm or larger in maximal diameter was 4.2 ± 1.7 years for 20 part-solid nodules developed from pure ground-glass nodules (PGGNs), 4.2 ± 1.2 years for five part-solid nodules developed from heterogeneous ground-glass nodules (HGGNs), and 2.4 ± 1.3 years for 22 part-solid nodules with solid components 3 mm or smaller in maximal diameter at the first thin-section computed tomography scan, respectively.

      CT-Pathological Correlation of Solid Components on CT Images in 26 MIAs Resected among the 174 Part-Solid Nodules

      Among 18 MIAs (69% [18 of 26]), if the diameter of an invasive focus <1 mm (n = 2) was assumed to be 0.9 mm in diameter, all the diameters of the solid components (mean 4.0 ± 2.0 mm, median 3.5 mm, IQR 2.8–5.0 mm) on CT images viewed using a mediastinal window were larger than the diameters of the invasive foci in the 18 MIAs (mean 1.5 ± 1.0 mm, median 1.0 mm, IQR 1.0–2.0 mm). The difference between the mean diameter of the solid components viewed using a mediastinal window and the mean diameter of the invasive foci in the 18 MIAs was statistically significant (p < 0.0001). In three of the 18 MIAs, the maximal diameters of the solid components viewed using a mediastinal window were larger than 5 mm (5.3 mm, 7.2 mm, and 9.1 mm, with corresponding invasive foci of 2 mm, <1 mm, and 3 mm in maximal diameter, respectively). In the remaining eight MIAs (31% [8 of 26]), all the maximal diameters of the invasive foci (mean 3.1 ± 1.3 mm, median 3.5 mm, IQR 2.0–4.4 mm) were larger than the maximal diameters of the solid components viewed using a mediastinal window (mean 2.0 ± 1.3 mm, median 1.9 mm, IQR 0.8–3.0 mm). The difference between the mean diameter of invasive foci and the mean diameter of the solid components in the eight MIAs was not statistically significant (p = 0.0645); the difference between the diameter of an invasive focus and the diameter of a solid component in the eight MIAs each ranged from 0.1 mm to 2 mm (mean 1.2 ± 0.6 mm, median 1.2 mm, IQR 0.6–1.7 mm).

      VDT of the Resected Adenocarcinomas

      Among the resected SSNs, the VDTs of the resected SSNs and the VDTs of the solid components in the resected part-solid nodules were calculated only for lesions showing growth; growth was regarded as an increase of 2 mm or more in the maximal diameter of an SSN or a solid component (Table 4). For the SSNs in nine invasive adenocarcinomas, in 23 MIAs, and in 18 AIS, the mean VDT was longer than 400 days; the mean VDTs of the SSNs for any pair of histological types were not statistically significant. For the solid components in eight invasive adenocarcinomas, in nine MIAs, and in three AIS, the mean VDT was less than 400 days; the mean VDTs of the solid components between any pair of histological types were not statistically significant. However, the mean VDT of the solid components in each histological type was significantly shorter than the mean VDT of the SSNs for each histological type (invasive adenocarcinoma, p = 0.005; MIA, p < 0.0001; AIS, p = 0.0067).
      Table 4VDTs of the Resected Adenocarcinomas Exhibiting Growth
      CharacteristicHistopathological DiagnosisNo. Resected SSNsWith Growth, n (%)
      With growth increase of 2 mm or more in maximal diameter of subsolid nodules or solid components.
      VDTp Value
      Mean ± SDMedian0.22420.26880.82330.14870.60820.19560.0005<0.00010.0067
      SSNsInvasive Ad129 (75)671 ± 342631
      MIA4023 (58)1199 ± 1013802
      AIS3318 (55)953 ± 787811
      SCsInvasive Ad128 (67)127 ± 59106
      MIA269 (35)209 ± 113223
      AIS103 (30)105 ± 18100
      Note: Pairwise comparisons performed between the variables indicated by the black squares.
      VDT, volume-doubling time; SD, standard deviation; SSN, subsolid nodule; Ad, adenocarcinoma; MIA, minimally invasive carcinoma; AIS, ademocarcinoma in situ; SC, solid component.
      a With growth increase of 2 mm or more in maximal diameter of subsolid nodules or solid components.

      Discussion

      This study prospectively evaluated the natural course of the progression of pulmonary SSNs. The mean follow-up period was 4.3 years. As of December 27, 2013, 91 (7.4%) of the 1229 SSNs were resected and 12 (13.2%) of the 91 resected SSNs were invasive adenocarcinomas. The mean maximal diameter of the solid component in the mediastinal window was 3.3 mm for MIAs and 5.5 mm for invasive adenocarcinomas; this difference in the mean diameter of the solid component was statistically significant. If the growth of the solid component has not exceeded 3.3 mm, an option for the management of SSNs on the basis of the results of the present study is as follows: a follow-up examination may be performed every 6 months in cases with a part-solid nodule and every 1 or 2 years in cases with a PGGN or an HGGN.
      As of September 30, 2015, two articles based on prospective follow-up studies had reported the natural history of SSNs detected using CT screening for lung cancer. One of these articles was from the NELSON study,
      • Scholten E.T.
      • de Jong P.A.
      • de Hoop B.
      • et al.
      Towards a close computed tomography monitoring approach for screen detected subsolid pulmonary nodules?.
      and the other was from the I-ELCAP study.
      • Yankelevitz D.F.
      • Yip R.
      • Smith J.P.
      • et al.
      CT screening for lung cancer: nonsolid nodules in baseline and annual repeat rounds.
      In the NELSON study, the percentage of invasive adenocarcinomas was 18.8% among 101 SSNs, whereas in the I-ELCAP, the percentage was 2.7% among 2392 cases with a nonsolid nodule (a synonym of PGGN) at the baseline screenings and 1.9% among 485 cases with a new nonsolid nodule at the annual repeat screenings. However, neither report differentiated MIAs from invasive adenocarcinomas, although MIA is a newly defined concept with an expected 100% disease-specific survival rate if completely resected.
      • Travis W.D.
      • Brambilla E.
      • Noguchi M.
      • et al.
      International Association for the Study of Lung Cancer/American Thoracic Society/European Respiratory Society international multidisciplinary classification of lung adenocarcinoma.
      In our study, if we combined the numbers of MIAs (n = 40) and invasive adenocarcinomas (n = 12), the percentage of MIA plus invasive adenocarcinomas was 4.2% among 1229 SSNs. The frequency of the development of a solid component in a PGGN was 29% (20 of 69 cases) in the NELSON study
      • Scholten E.T.
      • de Jong P.A.
      • de Hoop B.
      • et al.
      Towards a close computed tomography monitoring approach for screen detected subsolid pulmonary nodules?.
      and 1.1% (19 of 1764 cases with persistent nonsolid nodules detected at baseline screenings) and 1.8% (three of 163 cases with persistent nonsolid nodules detected at annual repeat screenings) in the I-ELCAP,
      • Lee S.M.
      • Park C.M.
      • Goo J.M.
      • et al.
      Transient part-solid nodules detected at screening thin-section CT for lung cancer: comparison with persistent part-solid nodules.
      whereas the frequency was 5.4% among 1046 PGGNs and 19.8% among 81 HGGNs in our study. In the NELSON study, 65% (46 of 68) of the part-solid nodules were not resected after a median follow-up time of 95 months,
      • Scholten E.T.
      • de Jong P.A.
      • de Hoop B.
      • et al.
      Towards a close computed tomography monitoring approach for screen detected subsolid pulmonary nodules?.
      whereas in our study, 71.8% (125 of 174) of the part-solid nodules were not resected after a median follow-up period of 3.5 years; moreover, among the 49 resected part-solid nodules, 75.5% (37 of 49) of the part-solid nodules were preinvasive lesions or MIAs; therefore, the appearance of solid components might not always be an appropriate parameter for a “prompt” resection from the standpoint of avoiding overdiagnosis.
      • Naidich D.P.
      • Bankier A.A.
      • MacMahon H.
      • et al.
      Recommendations for the management of subsolid pulmonary nodules detected at CT: a statement from the Fleischner Society.
      SSNs were classified into three categories in this study: PGGNs, HGGNs, and part-solid nodules. From another point of view, an HGGN may be a part-solid nodule with a solid component of 0 mm in the mediastinal window. From the standpoint of the appearance of a solid component, the frequency of the development of a solid component in an HGGN was greater than that of the development of a solid component in a PGGN, and this difference was statistically significant (Fig. 2B). In contrast, from the standpoint of solid component growth of 2 mm or more, the difference between HGGNs and PGGNs was not statistically significant (Fig. 2C); moreover, solid component growth of 2 mm or more never occurred within 2 years of the start of the follow-up period for either the HGGNs or the PGGNs examined in this study cohort. Further study is warranted to determine whether this intermediate nodule category is appropriate.
      Risk factors for SSN growth based on multivariate analyses have been reported by several studies. Regarding SSN (PGGN and part-solid nodule) growth, one study showed that a larger size (more than 10 mm) and a history of lung cancer were risk factors for SSN growth,
      • Hiramatsu M.
      • Inagaki T.
      • Inagaki T.
      • et al.
      Pulmonary ground-glass opacity (GGO) lesions-large size and a history of lung cancer are risk factors for growth.
      whereas another study showed that smoking history and the initial lesion diameter were robustly associated with SSN growth.
      • Kobayashi Y.
      • Sakao Y.
      • Deshpande G.A.
      • et al.
      The association between baseline clinical-radiological characteristics and growth of pulmonary nodules with ground-glass opacity.
      Regarding PGGN growth, one study disclosed that a large nodule size (>10 mm) and a history of lung cancer were significant predictors of growth in nonsolid nodules,
      • Matsuguma H.
      • Mori K.
      • Nakahara R.
      • et al.
      Characteristics of subsolid pulmonary nodules showing growth during follow-up with CT scanning.
      whereas another study reported that the nodule diameter was the only significant predictor for the interval growth of PGGNs.
      • Lee J.H.
      • Park C.M.
      • Lee S.M.
      • et al.
      Persistent pulmonary subsolid nodules with solid portions of 5 mm or smaller: their natural course and predictors of interval growth.
      Regarding part-solid nodules, one study demonstrated that a history of lung cancer and the part-solid GGN diameter were independent predictors of the interval growth of part-solid GGNs,
      • Lee J.H.
      • Park C.M.
      • Lee S.M.
      • et al.
      Persistent pulmonary subsolid nodules with solid portions of 5 mm or smaller: their natural course and predictors of interval growth.
      whereas another study did not report any significant predictors of the growth of part-solid nodules.
      • Matsuguma H.
      • Mori K.
      • Nakahara R.
      • et al.
      Characteristics of subsolid pulmonary nodules showing growth during follow-up with CT scanning.
      In our study, the main factor for predicting growth was the initial maximal diameter of the SSN; however, a history of lung cancer was not a risk factor for SSN growth.
      The CT window that should be used to measure the size of a solid component and the measurement method have been controversial. In 2013, the Fleischner Society proposed that the solid component in a part-solid nodule be evaluated using a narrow and/or mediastinal window and that the size of the solid component be based on the average of the long and short axial dimensions.
      • Naidich D.P.
      • Bankier A.A.
      • MacMahon H.
      • et al.
      Recommendations for the management of subsolid pulmonary nodules detected at CT: a statement from the Fleischner Society.
      As of September 30, 2015, however, most of the published articles related to part-solid nodules had used the maximal diameters of the SSN and solid component as viewed using a lung window
      • Lee J.H.
      • Park C.M.
      • Lee S.M.
      • et al.
      Persistent pulmonary subsolid nodules with solid portions of 5 mm or smaller: their natural course and predictors of interval growth.
      • Zhang Y.
      • Qiang J.W.
      • Ye J.D.
      • et al.
      High resolution CT in differentiating minimally invasive component in early lung adenocarcinoma.
      • Wilshire C.L.
      • Louie B.E.
      • Manning K.A.
      • et al.
      Radiologic evaluation of small lepidic adenocarcinomas to guide decision making in surgical resection.
      • Lee K.H.
      • Goo J.M.
      • Park S.J.
      • et al.
      Correlation between the size of the solid component on thin-section CT and the invasive component on pathology in small lung adenocarcinomas manifesting as groud-glass nodules.
      or the maximal diameter of the SSN as viewed using a lung window and the maximal diameter of the solid component as viewed using a mediastinal window.
      • Lee S.M.
      • Goo J.M.
      • Lee K.H.
      • et al.
      CT findings of minimally invasive adenocarcinoma (MIA) of the lung and comparison of solid portion measurement methods at CT in 52 patients.
      Our study started in 2009, and the parameters for assessing the growth of an SSN and a solid component were defined as the maximal diameter of the SSN as viewed using a lung window and the maximal diameter of the solid component as viewed using a mediastinal window. Although the Fleischner Society recommended that measurements of solid components be based on the average of the long and short dimensions and that 5 mm be used as a threshold for dividing a follow-up group (solid component ≤5 mm) and a workup group (solid component >5 mm), our study showed that the cutoff value for differentiating AIS plus MIAs from invasive adenocarcinoma was a maximal diameter of 3.3 mm as viewed using a mediastinal window. One previous study reported that a maximal diameter of a solid component of 3 mm or less as viewed using a lung window may be a safe and useful radiologic measurement for predicting preinvasive and MIA lesions preoperatively with a high specificity.
      • Lee S.M.
      • Goo J.M.
      • Lee K.H.
      • et al.
      CT findings of minimally invasive adenocarcinoma (MIA) of the lung and comparison of solid portion measurement methods at CT in 52 patients.
      Another study showed that patients with radiologic AIS (no solid component in lung windows) or MIA (largest axial diameter of a solid component ≤5 mm in lung windows) who underwent sublobar resections had no recurrences and 100% disease-free and overall survival outcomes at 5 years.
      • Wilshire C.L.
      • Louie B.E.
      • Manning K.A.
      • et al.
      Radiologic evaluation of small lepidic adenocarcinomas to guide decision making in surgical resection.
      One study pointed out that an average of the long and short axial dimensions of the solid component in a mediastinal window may not always be the most appropriate parameter for assessing the progression of a part-solid nodule.
      • Kakinuma R.
      • Muramatsu Y.
      • Kusumoto M.
      • et al.
      Solitary pure ground-glass nodules 5 mm or smaller: frequency of growth.
      Regarding the dimensions of the solid component, further study is warranted to determine how the size of the solid component can best be measured.
      • Travis W.D.
      • Brambilla E.
      • Noguchi M.
      • et al.
      International Association for the Study of Lung Cancer/American Thoracic Society/European Respiratory Society international multidisciplinary classification of lung adenocarcinoma.
      The solid components in mediastinal windows are not equal to the invasive foci in pathological specimens.
      • Saito H.
      • Kameda Y.
      • Masui K.
      • et al.
      Correlations between thin-section CT findings, histopathological and clinical findings of small pulmonary adenocarcinomas.
      The size of the solid component can be expected to be larger on the CT image than the size of the actual invasive component because the histopathological components of small adenocarcinomas of the lung can include alveolar collapse, inflammatory cells, and miscellaneous changes, as well as invasive adenocarcinoma.
      • Austin J.H.M.
      • Grag K.
      • Aberle D.
      • et al.
      Radiologic implications of the 2011 classification of adenocarcinoma of the lung.
      In our study, approximately 70% of the MIAs (18 of 26) resected among the part-solid nodules exhibited a mean maximal diameter of the solid components in the mediastinal window that was larger than the mean maximal diameter of invasive foci on pathological specimens, whereas 30% of the MIAs (eight of 26) exhibited the opposite results. In contrast, one study reported that, compared with the invasive component observed pathologically, the size of the solid portion in the mediastinal window as evaluated by one of two observers was significantly smaller.
      • Lee S.M.
      • Goo J.M.
      • Lee K.H.
      • et al.
      CT findings of minimally invasive adenocarcinoma (MIA) of the lung and comparison of solid portion measurement methods at CT in 52 patients.
      In our study, 12% of the MIAs (three of 26) resected among the part-solid nodules showed that the maximal diameter of the solid components in the mediastinal window was larger than 5 mm despite a maximal diameter of the invasive foci of less than 5 mm. One study also reported that MIAs with solid components larger than 5 mm in the mediastinal window accounted for between 7.7% and 9.6%.
      • Lee S.M.
      • Goo J.M.
      • Lee K.H.
      • et al.
      CT findings of minimally invasive adenocarcinoma (MIA) of the lung and comparison of solid portion measurement methods at CT in 52 patients.
      Further study is warranted regarding the relationship between the maximal diameter of solid components as viewed using a mediastinal window and the maximal diameter of invasive foci in pathological specimens.
      The VDTs of the subtypes of adenocarcinoma based on the International Association for the Study of Lung Cancer, American Thoracic Society, and European Respiratory Society classification of adenocarcinoma of the lung
      • Travis W.D.
      • Brambilla E.
      • Noguchi M.
      • et al.
      International Association for the Study of Lung Cancer/American Thoracic Society/European Respiratory Society international multidisciplinary classification of lung adenocarcinoma.
      have been reported in one previous study
      • Song Y.S.
      • Park C.M.
      • Park S.J.
      • et al.
      Volume and mass doubling times of persistent pulmonary subsolid nodules detected in patients without known malignancy.
      : for 16 AIS, the median VDT was 1240.3 days; for 3 MIAs, the median VDT was 1328.3 days; and for seven invasive adenocarcinomas, the median VDT was 941.5 days. These median VDTs were longer than the median VDTs in the respective subtypes of adenocarcinoma in our study. Regarding the VDTs of the solid components that exhibited growth in our study, the mean VDTs of the solid components were less than 400 days for each of the adenocarcinoma subtypes, whereas the mean VDTs of the SSNs were more than 400 days. To the best of our knowledge, only one previous study has reported the VDTs of solid components
      • Kakinuma R.
      • Ohmatsu H.
      • Kaneko M.
      • et al.
      Progression of focal pure ground-glass opacity detected by low-dose helical computed tomography screening for lung cancer.
      ; the VDTs of solid components as viewed using a mediastinal window may enable the differentiation of aggressive part-solid nodules from indolent part-solid nodules.
      On the basis of prospective follow-up of CT screening-detected SSNs, one study
      • Scholten E.T.
      • de Jong P.A.
      • de Hoop B.
      • et al.
      Towards a close computed tomography monitoring approach for screen detected subsolid pulmonary nodules?.
      reported that long-term CT follow-up may be a safe option for monitoring changes in persistent SSNs and recommended that invasive intervention be considered only for SSNs that show 30% or more growth in mass,
      • de Hoop B.
      • Gietema H.
      • van der Vorst S.
      • et al.
      Pulmonary ground-glass nodules: increase in mass as an early indicator of growth.
      have a newly appeared solid component, or exhibit the growth of a solid component; another study also reported that nonsolid nodules of any size can be safely monitored using CT at 12-month intervals to assess their transition to part-solid lesions.
      • Yankelevitz D.F.
      • Yip R.
      • Smith J.P.
      • et al.
      CT screening for lung cancer: nonsolid nodules in baseline and annual repeat rounds.
      Prospective study of the natural history of PGGNs detected not only by using CT screening but also at follow-up CT after lung cancer resection suggested that some PGGNs will never progress to clinical disease and would be included in the category of PGGNs with an overdiagnosis bias.
      • Kodama K.
      • Higashiyama M.
      • Yokouchi H.
      • et al.
      Natural history of pure ground-glass opacity after long-term follow-up of more than 2 years.
      Retrospective studies of the natural history of SSNs have reported the following findings: more than 2 years of follow-up are necessary to detect the growth of PGGNs
      • Takahashi S.
      • Tanaka N.
      • Okimoto T.
      • et al.
      Long term follow-up for small pure ground-glass nodules: implications of determining an optimum follow-up period and high-resolution CT findings to predict the growth of nodules.
      ; approximately 90% of the screening-detected PGGNs in patients with no history of malignancy did not grow after a median follow-up period of 59 months
      • Chang B.
      • Hwang J.H.
      • Choi Y.H.
      • et al.
      Natural history of pure ground-glass opacity lung nodules detected by low-dose scan.
      ; the tendency to grow was clear within the first 3 years, and therefore, SSNs should be followed for at least 3 years
      • Kobayashi Y.
      • Fukui T.
      • Ito S.
      • et al.
      How long should small lung lesions of ground-glass opacity be followed?.
      ; and 26% of SSNs had increased in size, with a mean VDT of 1041 days after median follow-up of 45 months.
      • Lee S.W.
      • Leem C.S.
      • Kim T.J.
      • et al.
      The long-term course of opacities detected on thin-section computed tomography.
      The interim suggestion for the follow-up of SSNs on the basis of the results of the present study is as follows: every 6 months for a part-solid nodule and every year for a PGGN or HGGN; moreover, to avoid overdiagnosis and overtreatment,
      • Naidich D.P.
      • Bankier A.A.
      • MacMahon H.
      • et al.
      Recommendations for the management of subsolid pulmonary nodules detected at CT: a statement from the Fleischner Society.
      • Heuvelmans M.A.
      • Oudkerk M.
      Management of subsolid pulmonary nodules in CT lung cancer screening.
      if the development of a solid component has not exceeded 3.3 mm, a follow-up every 2 years for a PGGN or an HGGN may be possible on the basis of the minimum period for development of the solid component of 3.3 mm or more (as shown in Fig. 4). Regarding part-solid nodules, although a follow-up every 6 months may be initially appropriate, the follow-up period can be subsequently lengthened to, for example, every year; one of the options for deciding on a follow-up strategy may be to make decisions on the basis of the VDTs of the solid components. Although segmentation software for measurement of the volume, mass, and diameter of SSNs has been proposed,
      • Scholten E.T.
      • Jacobs C.
      • van Ginneken B.
      • et al.
      Detection and quantification of the solid component in pulmonary subusolid nodules by semiautomatic segmentation.
      this software was not yet available worldwide as of September 30, 2015. Therefore, for the time being, simple parameters, such as the maximal diameter of solid components as viewed using a mediastinal window,
      • Naidich D.P.
      • Bankier A.A.
      • MacMahon H.
      • et al.
      Recommendations for the management of subsolid pulmonary nodules detected at CT: a statement from the Fleischner Society.
      should be used for daily clinical practice.
      This study had several limitations. First, SSNs that showed a decrease in size (n = 6) or a fluctuation in size (n = 2) were excluded for the assessment of growth, although invasive adenocarcinoma exhibiting a decrease in the size of GGNs has been reported.
      • Kaneda H.
      • Nakano T.
      • Taniguchi Y.
      • et al.
      A decrease in the size of ground glass nodules may indicate the optimal timing for curative surgery.
      This may have affected the results; however, none of the nodules had shown any changes requiring resection as of December 27, 2013. Second, among the resected cases, the pathology panel did not review seven lesions that were not presented in time for the last pathological review. This may have affected the results for the assessment of the frequency of invasive adenocarcinomas. Third, the protocol for CT scanning was not prescribed in detail, only that the section thickness should be equal to or less than 1.25 mm; consequently, the field of view and kernel for the reconstruction of the CT image were based on the protocols of each institution, which also might have affected the results of this study. Fourth, the radiology panel did not review the CT images for SSNs that did not show growth because of their tight work schedules and the large work burdens involved at each participating institution for anonymizing the personal information in the CT data. However, the definition of growth, (i.e., a 2-mm or greater increase in the maximal diameter of an SSN [ground-glass component] and a 2-mm or more increase in the maximal diameter of a solid component) was thought to be adequate for avoiding interreader variability because the 2-mm criterion exceeded the upper limit of the 95% confidence interval for the limits of agreement.
      • Kakinuma R.
      • Ashizawa K.
      • Kuriyama K.
      • et al.
      Measurement of focal ground-glass opacity diameters on CT images: interobserver agreement in regard to identifying increase in the size of ground-glass opacities.
      • Revel M.P.
      • Bissery A.
      • Bienvenu M.
      • et al.
      Are two-dimensional CT measurements of small noncalcified pulmonary nodules reliable?.
      Fifth, interreader variability of potential SSNs was not evaluated because of the large volume of CT data. Regarding the evaluation of potential SSNs, moderate interreader variability was reported.
      • Penn A.
      • Ma M.
      • Chou B.B.
      • et al.
      Inter-reader variability when applying the 2013 Fleischner guidelines for potential solitary subsolid lung nodules.
      This may be a weakness of the present study. Sixth, the correlation between molecular biomarkers and the spectrum of the CT patterns of lung adenocarcinomas
      • Aoki T.
      • Hanamiya M.
      • Uramoto H.
      • et al.
      Adenocarcinomas with predominant ground-glass opacity: correlation of morphology and molecular biomarkers.
      was not examined. A molecular-CT correlation was beyond the scope of this study. Future study is warranted. Finally, pathological or cytological diagnoses of SSNs other than the resected lesions were not obtained; this also might have affected the results of this study.
      In conclusion, our prospective multicenter study revealed the frequencies and periods of development from PGGNs and HGGNs into part-solid nodules. Invasive adenocarcinomas were diagnosed only among the resected part-solid nodules in this study. The findings of this study could contribute to the development of guidelines for the follow-up of pulmonary SSNs.

      Acknowledgments

      This research was supported in part by a grant-in-aid from the Ministry of Health, Labour and Welfare, Tokyo, Japan (21-5-1), a grant-in-aid from the Third-term Comprehensive Cancer Control Strategy sponsored by the Ministry of Health, Labour and Welfare, Tokyo, Japan (16-016, 19-1, 22-019), the National Cancer Center Research and Development Fund, Tokyo, Japan (23-A-25, 23-A-48, 27-A-5), and a grant-in-aid from the Japan Agency for Medical Research and Development (AMED) for the Health and Labor Sciences Research Expenses for Commission (the Practical Research for Innovative Cancer Control: 15ck0106096h0002). All sponsors had no involvement in the study design; in the collection, analysis, and interpretation of data; in the writing of the report; or in the decision to submit the article for publication. The authors belonging to the participating institutions thank the multidisciplinary team at each institution for supporting each researcher in this study.

      Supplementary Data

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      • Erratum
        Journal of Thoracic OncologyVol. 11Issue 9
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          Erratum to: Kakinuma R, et al. Natural History of Pulmonary Subsolid Nodules: A Prospective Multicenter Study. J Thorac Oncol. 2016;11(7):1012-1028.
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