Natural History of Pulmonary Subsolid Nodules: A Prospective Multicenter Study Ryutaro Kakinuma, MD, PhD, Masayuki Noguchi, MD, PhD, Kazuto Ashizawa,

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Natural History of Pulmonary Subsolid Nodules: A Prospective Multicenter Study Ryutaro Kakinuma, MD, PhD, Masayuki Noguchi, MD, PhD, Kazuto Ashizawa, MD, PhD, Keiko Kuriyama, MD, PhD, Akiko Miyagi Maeshima, MD, PhD, Naoya Koizumi, MD, PhD, Tetsuro Kondo, MD, PhD, Haruhisa Matsuguma, MD, PhD, Norihisa Nitta, MD, PhD, Hironobu Ohmatsu, MD, PhD, Jiro Okami, MD, PhD, Hiroshi Suehisa, MD, PhD, Taiki Yamaji, MD, PhD, Ken Kodama, MD, PhD, Kiyoshi Mori, MD, PhD, Kouzo Yamada, MD, PhD, Yoshihiro Matsuno, MD, PhD, Sadayuki Murayama, MD, PhD, Kiyoshi Murata, MD, PhD Journal of Thoracic Oncology Volume 11, Issue 7, Pages 1012-1028 (July 2016) DOI: 10.1016/j.jtho.2016.04.006 Copyright © 2016 International Association for the Study of Lung Cancer Terms and Conditions

Figure 1 Classification 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). Journal of Thoracic Oncology 2016 11, 1012-1028DOI: (10.1016/j.jtho.2016.04.006) Copyright © 2016 International Association for the Study of Lung Cancer Terms and Conditions

Figure 2 Growth 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 (*). Journal of Thoracic Oncology 2016 11, 1012-1028DOI: (10.1016/j.jtho.2016.04.006) Copyright © 2016 International Association for the Study of Lung Cancer Terms and Conditions

Figure 3 Time 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. Journal of Thoracic Oncology 2016 11, 1012-1028DOI: (10.1016/j.jtho.2016.04.006) Copyright © 2016 International Association for the Study of Lung Cancer Terms and Conditions

Figure 4 Follow-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. Journal of Thoracic Oncology 2016 11, 1012-1028DOI: (10.1016/j.jtho.2016.04.006) Copyright © 2016 International Association for the Study of Lung Cancer Terms and Conditions