Lung Adenocarcinomas Manifesting as Radiological Part-Solid Nodules Define a Special Clinical Subtype

ORIGINAL ARTICLE

Lung Adenocarcinomas Manifesting as Radiological Part-Solid Nodules Define a Special Clinical Subtype Ting Ye, MD, PhD,a,b Lin Deng, MD,c Shengping Wang, MD, PhD,b,d Jiaqing Xiang, MD, PhD,a,b Yawei Zhang, MD, PhD,a,b Hong Hu, MD,a,b Yihua Sun, MD, PhD,a,b Yuan Li, MD, PhD,b,e Lei Shen, MD,b,e Li Xie, MD,f Wenchao Gu, MD,g Yue Zhao, MD,a,b Fangqiu Fu, MD,a,b Weijun Peng, MD, PhD,b,d Haiquan Chen, MD, PhDa,b,h,i,* a

Department of Thoracic Surgery, Shanghai Cancer Center, Fudan University, Shanghai, People’s Republic of China Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, People’s Republic of China Department of Radiology, Shanghai Proton and Heavy Ion Center, Shanghai, People’s Republic of China d Department of Radiology, Shanghai Cancer Center, Fudan University, Shanghai, People’s Republic of China e Department of Pathology, Shanghai Cancer Center, Fudan University, Shanghai, People’s Republic of China f Clinical Research Center, Shanghai Jiao Tong University School of Medicine, Shanghai, People’s Republic of China g Department of Diagnostic Radiology and Nuclear Medicine, Gunma University Graduate School of Medicine, Maebashi, Japan h School of Life Sciences, Fudan University, Shanghai, People’s Republic of China i Institutes of Biomedical Sciences, Fudan University, Shanghai, China b c

Received 3 August 2018; revised 10 December 2018; accepted 14 December 2018 Available online - 16 January 2019

ABSTRACT Introduction: The clinicopathologic features and prognostic predictors of radiological part-solid lung adenocarcinomas were unclear. Methods: We retrospectively compared the clinicopathologic features and survival times of part-solid tumors with those of pure ground glass nodules (pGGNs) and pure solid tumors treated with surgery at Fudan University Shanghai Cancer Center and evaluated the prognostic implications of consolidation-to-tumor ratio (CTR), solid component size, and tumor size for part-solid lung adenocarcinomas. Results: A total of 911 patients and 988 pulmonary nodules (including 329 part-solid nodules [PSNs], 501 pGGNs, and 158 pure solid nodules) were analyzed. More female patients (p ¼ 0.015) and nonsmokers (p ¼ 0.003) were seen with PSNs than with pure solid nodules. The prevalence of lymphatic metastasis was lower in patients with PSNs than in those with pure solid tumors (2.2% versus 27% [p ¼ .000]). The 5-year lung cancer–specific (LCS) recurrencefree survival and LCS overall survival of patients with PSNs were worse than those of patients with pGGNs (p < 0.001 and p ¼ .042, respectively) but better than those of patients with pure solid tumors ([p < 0.001 and p < 0.0001, respectively]). CTR (OR ¼ 12.90; 95% confidence interval [CI]: 1.85–90.04), solid component size (OR ¼ 1.45; 95% CI: 1.28–1.64), and tumor size (OR ¼ 1.23; 95% CI: 1.15–1.31)

could predict pathologic invasive adenocarcinoma for patients with PSNs. None of them could predict the prognosis. Patients receiving sublobar resection had prognoses comparable to those of patients receiving lobectomy (p ¼ .178 for 5-year LCS recurrence-free survival and p ¼ .319 for 5-year LCS overall survival). The prognostic differences between patients with systemic lymph node dissection and those without systemic lymph node dissection were statistically insignificant. Conclusions: Part-solid lung adenocarcinoma showed clinicopathologic features different from those of pure solid tumor. CTR, solid component size, and tumor size could not predict the prognosis. Part-solid lung adenocarcinomas define one special clinical subtype.

*Corresponding author. Dr. Ye, Dr. Deng, and Dr. Wang contributed equally to this work. Disclosure: The authors declare no conflict of interest. Address for correspondence: Dr. Haiquan Chen, MD, 270 Dong’an Road, Shanghai, People’s Republic of China. E-mail: [email protected] ª 2019 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved. ISSN: 1556-0864 https://doi.org/10.1016/j.jtho.2018.12.030

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 2019 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved. Keywords: Part-solid nodule; Lung adenocarcinoma; Prognosis; Solid component size; Tumor size

Introduction With the wide application of thoracic computed tomography (CT) scans, an increase in the detection of incidental pulmonary nodules, especially subsolid nodules, is being encountered.1–4 According to guidelines from the Fleischner Society in 2017, subsolid nodules are categorized as either pure ground glass nodules (pGGNs) having only a ground glass opacity (GGO) component or part-solid nodules (PSNs) having both GGO and solid components on thin-section CT (TS-CT). Persistent PSNs with solid components 6 mm or larger should be considered highly suspicious.5 There have been some controversies regarding lung cancers manifesting as PSNs. In 2017, a systemic review indicated that lung cancers manifesting as PSNs had different surgical outcomes depending on the different percentages of solid component in relation to the entire nodule size and that both disease-free survival (DFS) and overall survival (OS) were higher in patients with solid component percentages lower than 80% than in patients with solid component percentages of 80% or higher. The authors suggested a clear definition of the upper limit of the solid component of PSNs.6 In 2017, Matsunaga et al. divided part-solid lung cancers into ground glass–predominant and consolidation-predominant tumors, with a cutoff value 0.5 for the consolidation-to-tumor (CTR) ratio. They found that PSNs with a CTR of 0.5 or higher had a higher prevalence of lymphatic invasion and worse 5-year recurrence-free survival (RFS) than those with a CTR less than 0.5.7 However, they did not provide the data for 5-year OS in their article. Currently, our Japanese colleagues use CTR to classify PSNs and determine surgical strategy in their clinical practice. Several Japanese Clinical Oncology Group trials were designed depending on the different CTR values.8–10 But application of CTR for PSNs is not well accepted globally. In the eighth edition of the TNM classification of lung cancer, the International Association for the Study of Lung Cancer (IASLC) used the size of the solid part to classify clinical T stage for part-solid tumors (for cT1mi, 0 < solid part  5 mm; for cT1a, 6  solid part  10 mm; for cT1b,11 mm  solid part  20 mm; and for cT1c, 21 mm  solid part  30 mm ).11 However, in 2016, Hattori et al. found that CTR value, maximum tumor size, and solid component size could not predict the OS in radiological part-solid lung cancer.12 In 2017, they indicated that tumor size

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significantly affected survival outcome only in pure solid lung cancer, but neither maximum tumor size nor solid component size could predict the long-term survival in part-solid lung cancer when they evaluated the prognostic impact of several clinicopathologic variables in the clinical T classification based on solid component size according to the eighth edition of the classification of NSCLC.13 Therefore, how to clinically define and classify the part-solid tumors requires further investigations. Thus, in this study we compared the clinicopathologic features and long-term survival of patients with radiological PSNs with those of patients with pGGNs and pure solid nodules in a large, homogeneous cohort of patients undergoing an operation at a single institution. We aimed to find the prognostic predictors to classify lung adenocarcinomas manifesting as PSNs.

Material and Methods Patient Cohort We retrospectively reviewed the medical records of patients with small pulmonary nodules who underwent surgical resection at Fudan University Shanghai Cancer Center (FUSCC) between January 2008 and December 2014. The inclusion criteria were a pathologic diagnosis of lung adenocarcinoma and clinical stage IA disease (according to the TNM eighth edition). The exclusion criteria were a having received a diagnosis of benign or atypical adenoid hyperplasia lesion, having synchronous subsolid and pure solid nodules, not having received a TS-CT scan in our institution, or not having complete radiological information. Analyses for lung cancer– specific (LCS) recurrence and LCS survival were performed on all eligible patients who underwent an operation. This study was approved by the institutional review board of FUSCC. Informed consent was waived because it was a retrospective study.

Radiological and Histologic Evaluation Whole lung CT scans were performed with a helical technique using a 64- or 40-slice multidetector scanner (Siemens Somatom Sensation, Berlin, Germany). The scanning parameters were as follows: pitch, 1.2; section thickness and interval, 5.0 and 5.0 mm, respectively; reconstruction section width and interval, 1.0 and 1.0 mm, respectively; field of view, 375 mm; voltage, 120 kV; and electric charge, 270 mAs. Two radiologists (L. D. and S. P. W.) with more than 6 years of experience in chest radiology and without any clinical information evaluated these CT images on lung window settings (window width, 1600 HU; window level, –600 HU; and width and interval, 1.0 and 1.0 mm, respectively). The maximum diameter on the single largest axial dimension was measured on a lung window, and an edge-enhancing (sharp) filter was

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recorded for the size of solid component and whole nodule. Subsolid and pure solid nodules were distinguished depending on the presence of GGO. In the subsolid nodules, pGGN was defined as a nodule without a solid component and PSN was defined as a lung lesion with both a GGO and solid component.5 CTR was defined as the ratio of the maximum size of solid component to the maximum tumor size on the TS-CT scan in the axial plane (for pGGNs, CTR ¼ 0; for part-solid tumors, 0 < CTR < 1; and for pure solid tumors, CTR ¼ 1) (Fig. 1). When the solid part was irregular or multiple, multiple-plane reconstruction was used and only the largest diameter was analyzed. Interobserver and intraobserver agreements were analyzed for the first 110 radiological measurements to quantify the reproducibility and accuracy between the two radiologists in this study. For differentiating between subsolid and pure solid lung nodules, the interobserver agreement (k) value was 0.703 (95% confidence interval [CI]: 0.565–0.821) and the intraobserver agreement (k) values were 0.867 (95% CI: 0.761–0.956) and 0.783 (95% CI: 0.619–0.913). Each radiologist interpreted the first 110 lung nodules in two different sessions that were separated by 4 weeks. They resolved differences of opinion through discussion. In view of the favorable levels of interobserver and intraobserver agreements, the two radiologists preformed the rest of the radiological measurements separately. Postoperative pathologic diagnosis was made according to the IASLC/American Thoracic Society/ European Respiratory Society classification as adenocarcinoma in situ, minimally invasive adenocarcinoma,

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and invasive adenocarcinoma (IAD), which was further divided into lepidic predominant, acinar predominant, papillary predominant, micropapillary predominant, solid predominant, and invasive mucinous adenocarcinoma. The predominant pattern was defined as the pattern with the largest percentage (not necessarily 50% or higher).14

Follow-up Protocol Patients were followed up every 3 months after the operation for the first 2 years and underwent chest CT scans and abdominal ultrasonography every 3 to 6 months. The follow-up frequency was changed to every 6 months for the third year and once per year for subsequent years. CT or magnetic resonance imaging scans of the brain and bone scintigraphy were performed every 6 months for patients with IAD in the first 3 years. Positron emission tomography–CT scan was optional and performed if necessary. LCS-RFS was defined as time from initial resection to date of first lung cancer–related recurrence. Diagnosis of recurrence was confirmed by biopsy if possible, and imaging (i.e., positron emission tomography–CT scan or brain magnetic resonance imaging) was performed to support the clinical diagnosis and the decision to initiate treatment. In cases in which a new tumor developed in the lung or pleura and a biopsy specimen was available, the histologic profile was reviewed to determine whether the new tumor was a metachronous primary tumor, recurrence, or metastasis (especially for the pure solid lesion). Genetic information, including common

Figure 1. Definition of pure ground glass nodules (GGNs), part-soid nodules and pure solid nodules and description of radiological measurements for consolidation-to-tumor ratio (CTR), the solid component size (red line), and tumor size (black line).

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oncogenic mutations, was evaluated if necessary. The date of recurrence was defined as the time of pathologic or radiological confirmation. LCS-OS was defined as the time from initial resection to death resulting from lung cancer. Non-cancer–related deaths or deaths related to other malignancies were censored at date of death.

Statistics Baseline characteristics were reported as number (percentage) for categorical variables. Categorical variables were compared by using the Pearson chi-square test or Fisher exact test, when appropriate. Continuous variables were compared by using the paired t test. Estimation of survival curves of LCS-RFS and LCS-OS were generated by the Kaplan-Meier method; the logrank test was used to compare survival curves. Logistic regression modeling was used as the method for identifying risk factors for pathologic diagnosis of IAD. All p values were two sided with a significance level of 0.05. All statistical analysis were performed by using SPSS software (version 19.0, (IBM Corporation, Armonk, NY) and PRISM software (version 7.0, GraphPad Software, La Jolla, CA).

Results In all, 1212 patients with 1339 lung nodules underwent surgical resection in FUSCC; benign disease was diagnosed in 75 patients and 85 nodules, atypical adenoid hyperplasia was diagnosed in 46 patients and 62 nodules, 17 patients had 38 synchronous subsolid and pure solid nodules, and 163 patients did not a receive TS-CT scan or have complete radiological information. In total, 911 patients and 988 pulmonary nodules were analyzed in this study. This study included 329 PSNs, 501 pGGNs, and 158 pure solid nodules. Females accounted for 71.1% of those seen for the 329 PSNs versus for 60.5% of those seen for the 158 part-solid nodules (p ¼ 0.015). Also, nonsmokers accounted for 83.5% of those seen for PSNs versus for 75.2% of those seen for pure solid nodules (versus [p ¼ .003]). Patients with PSNs were older than those with pGGNs (58.89 ± 9.71 versus 53.64 ± 10.86 y [p ¼ .000]) but younger than those with pure solid nodules (58.89 ± 9.71 versus 60.54 ± 10.52 y [p ¼ .102]). PSNs were more common in bilateral upper lobes than pure solid nodules were (68.1% versus 49.9% [p ¼ .009]). The mean tumor diameter of the PSNs was larger than that of the pGGNs (20.51 ± 7.18 versus 10.22 ± 3.84 mm [p ¼ .000]) but similar to that of pure solid nodules (20.51 ± 7.18 versus 19.54 ± 5.58 mm [p ¼ .066]). The percentage of IAD in patients with PSNs was higher than that in patients with pGGNs (83.0% versus 10.8% [p ¼ .000]) but lower than that in patients with

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pure solid nodules (83.0% versus 96.2% [p ¼ .000]). The percentage of lepidic predominant adenocarcinomas was higher in patients with PSNs than the percentage in patients with pure solid tumors (38.8% versus 13.3% [p ¼ .000]) whereas the percentage of solid/micropapillary predominant adenocarcinomas was lower in patients with PSNs than the percentage in patients with pure solid tumors (1.5% versus 3.4% [p ¼ .000]). Seven patients with PSNs (2.2%) had lymphatic metastasis (N1/ 2), whereas 41 patients with pure solid nodules (27%) had lymphatic metastasis (N1/2). No patients with pGGNs had lymphatic metastasis. Detailed clinicopathologic characteristics of patients are described in Table 1. Among the 329 PSNs, there were 185 nodules with a CTR less than 0.5 (0 ＜ CTR  0.5) and 144 nodules with CTR larger than 0.5 (0.5＜CTR＜1). The differences in patient characteristics, including age, sex, and smoking status, between the two groups were statistically insignificant. The differences in mean tumor size, distribution of nodules, and prevalence of IAD between the two groups were statistically insignificant. There were two cases with lymph node metastasis (1.2%) in patients with PSNs with a CTR less than 0.5 (0 ＜CTR  0.5), whereas there were five cases with lymph node metastasis (3.5%) in patients with PSNs with a CTR higher than 0.5 (0.5＜CTR＜1) (Table 2). The mean follow-up period was 42.22 plus or minus 14.70 months. Of the 911 patients enrolled, five (0.55%) were lost during follow-up period, 81 (8.89%) experienced recurrence, and 36 (3.9%) died. The 5-year LCS-RFS rate was 88.30% (95% CI: 85.31%–90.71%). The 5-year LCS-OS rate was 94.87% (95% CI: 92.39%–96.56%). For patients with PSNs, the 5-year LCS-RFS rate was worse than that of patients with pGGNs (91.74% [95% CI: 87.15%–94.74%] versus 99.43% [95% CI: 98.25%–99.82%]) (p < 0.001) but better than that of patients with pure solid tumors (91.74% [95% CI: 87.15%–94.74%] versus 58.08% [95% CI: 49.33%–65.77%]) (p < 0.001). Similarly, the 5-year LCS-OS rate of patients with PSNs was worse than that of patients with pGGNs (98.13% [95% CI: 95.52%–99.23%] versus 100% [p ¼ .042]) but better than that of patients with pure solid tumors (98.13% [95% CI: 95.52%–99.23%] versus 80.27% [95% CI: 72.27%–86.19%]) (p < 0.0001) (Fig. 2). In this study, one patient with pGGNs, 20 patients with PSNs, and 60 patients with pure solid nodules experienced tumor recurrence. The recurrence sites are illustrated in Supplementary Table 1. No deaths occurred among the patients with pGGNs, whereas six patients with PSNs and 30 patients with pure solid tumors died during the follow-up period. There were no significant differences in 5-year LCSRFS or LCS-OS between PSNs with CTR less than 0.5 (0

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＜CTR  0.5) or those with a CTR higher than 0.5 (0.5 ＜ CTR ＜1) (5-year LCS-RFS of p ¼ .062 and 5-year of LCSOS [p ¼ .556]). Also, there were no statistical differences in the 5-year LCS-RFS or 5-year LCS-OS between patients with PSNs with a CTR less than 0.8 (0＜CTR0.8) and patients with PSNs with a CTR higher than 0.8 (0.8 ＜ CTR ＜1) (5-year LCS-RFS of p ¼ .410 and 5-year LCS-OS of p ¼ .616, respectively) (Fig. 3). In addition, there were no significant differences in 5year LCS-RFS or LCS-OS among patients with the different categories of solid component sizes (0 < solid component size  10 mm, 10 < solid component size  20 mm, and 20 < solid component size  30 mm ) (5-year LCS-RFS of p ¼ 0.198 and 5-year LCS-OS of p ¼ 0.768) (Fig. 4). When we defined CTR and solid component size as continuous variables, neither of them could predict the 5year LCS-RFS or 5-year LCS-OS (Table 3).

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Moreover, we compared the impact of clinical T stage on the prognosis between patients with partsolid lung adenocarcinoma and patients with pure solid lung adenocarcinoma based on the eighth edition of the IASLC TNM classification of lung cancer. We found that patients with part-solid tumors had better 5-year LCS-RFS and LCS-OS than did patients with pure solid tumors according to similar clinical T stage (cT1b and cT1c). Tumor size could predict the 5-year LCS-RFS and LCS-OS for patients with pure solid tumors, but solid component size could not predict the prognosis for patients with part-solid tumors (see Fig. 4). Furthermore, we evaluated risk factors related to the postoperatively pathologic diagnosis of IAD for patients with PSNs. When logistic regression analysis was used, higher CTR value (OR ¼ 12.90, 95%

Table 1. Baseline Clinicopathologic Characteristics of Objects in This Study Characteristic Mean age, y (± SD) Sex Male Female Smoking status Smoker Nonsmoker Tumor size, mm Location RUL RML RLL LUL LLL Surgery Wedge resection Segmentectomy Lobectomy Pathologic type AIS/MIA IAD Lepidic predominant Solid/micropapillary predominant Acinar/papillary predominant Mucinous adenocarcinoma Lepidic componentc Solid/micropapillary componentc Acinar/papillary componentc Mucinous componentc Pathologic N status N0 N1/2 a

All (N ¼ 988)

PSN (n ¼ 329)

Pure GGN (n ¼ 501)

Pure Solid Nodule (n¼158)

56.49 ± 10.83

58.89 ± 9.71

53.64 ± 10.86

60.54 ± 10.52

277 (30.4) 634 (69.6)

91 (28.9) 224 (71.1)

124 (28.2) 315 (71.8)

62 (39.5) 95 (60.5)

153 (16.8) 758 (83.2) 15.14 ± 7.38

52 (16.5) 263 (83.5) 20.51 ± 7.18

62 (14.1) 377 (85.9) 10.22 ± 3.84

39 (24.8) 118 (75.2) 19.54 ± 5.58

364 (36.8) 67 (6.8) 181 (18.3) 266 (26.9) 110 (11.2)

126 (38.3) 21 (6.4) 48(14.6) 98 (29.8) 36 (10.9)

197 (39.3) 29 (5.8) 93 (18.6) 130 (25.9) 52 (10.4 )

41 17 40 38 22

456 (46.2) 97 (9.8) 435 (44.0)

72 (21.9) 33 (10.0) 224 (68.1)

370 (73.8) 58 (11.6) 73 (14.6)

14 (8.9) 6 (3.8) 138 (87.3)

509 (51.5) 479 (48.5) 154 (32.6) 21 (4.5) 290 (61.4) 7 (1.5) 216 (45.1) 67 (14.0) 356 (74.3) 10 (2.1)

56 (17.0) 273 (83.0)a 104 (38.8) 4 (1.5) 157 (58.6) 3 (1.1) 148 (55.2) 15 (5.6) 197 (73.5) 3 (1.1)

447(89.2) 54 (10.8) 30 (55.5) 1 (1.9) 22 (40.7) 1 (1.9) 36 (66.7) 1 (1.8) 31 (57.4) 1 (1.8)

6(3.8) 152 (96.2)b 20 (13.3) 16 (3.4) 111 (74.0) 3 (2.0) 32 (21.3) 51 (34) 128 (85.3) 6 (3.4)

904 (94.9) 48 (5.1)

305 (97.8) 7 (2.2)

488 (100) 0 (0)

111 (73) 41 (27)

p Value 0.000 0.015

0.003

0.000 0.009

(25.9) (10.7) (25.3) (24) (14.1) 0.000

0.000

0.000 0.000 0.000 0.753 0.000 0.000 0.005 0.052 0.000

Of 273 PSNs, 268 had the confirmed subtypes of IADs. Of 152 pure solid nodules, 150 had the confirmed subtypes of IADs. c Any amount of subtypes present. PSN, part-solid nodule; GGN, ground glass nodule; RUL, right upper lobe; RML, right middle lobe; RLL, right lower lobe; LUL, left upper lobe; LLL, left lower lobe; AIS, adenocarcinoma in situ; MIA, minimally invasive adenocarcinoma; IAD, invasive adenocarcinoma. b

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CI: 1.85–90.04, p ¼ 0.010), larger solid component size (OR ¼ 1.45, 95% CI: 1.28–1.64, p ¼ 0.000), and larger tumor size (OR ¼ 1.23, 95% CI: 1.14–1.31, p ¼ 0.000) remained independently associated with invasive lung adenocarcinoma (see Supplementary Table 2). For the 329 part-solid lung adenocarcinomas, 224 lobectomies, 33 segmentectomies, and 72 wedge resections were performed. Patients receiving segmentectomy or wedge resection had a 5-year LCS-RFS comparable to that of patients receiving lobectomy. Also, 5-year LCS-OS was similar among patients who underwent the three different operations (Supplementary Fig. 1). In addition, of the patients with part-solid IAD, 16 did not undergo systemic lymph node dissection (sLND) whereas 251 did undergo sLND. There was no recurrence or death among the 16 patients. The differences in the 5-year LCS-RFS and 5-year LCS-OS between patients with sLND and those without sLND were statistically insignificant (p ¼ 0.231for 5-year LCSRFS and p ¼ .501 5-year LCS-OS ) (Supplementary Fig. 2).

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Discussion One of the most important questions regarding lung adenocarcinomas manifesting as PSNs is how to define or classify them. In other words, according to the results in this study, is it reasonable that part-solid lung adenocarcinomas could be clinically regarded as one subtype when we are deciding on treatment strategies because CTR value, solid component, and tumor size could not predict the prognosis for them? Currently, size of the solid component is applied to the category T stage for part-solid lung cancers according to the eighth edition of the TNM classification of lung cancer because the solid component is regarded as the invasive part.11 In 2018, Yamanashi et al.15 found that the prognoses of part-solid and pure-solid tumors of clinical T1a-c NSCLCs based on the eighth edition of the TNM classification of lung cancer after propensity score–matched analysis were similar. As a result, they supported justification of the T component categories in the eighth edition of the TNM classification for part-solid tumors.15 However, they did not evaluate the influences of different solid component sizes on prognosis of partsolid tumors. If the part-solid tumors with different

Table 2. Comparison of Clinicopathologic Features between PSNs with CTR Greater than Zero but Less than 0.5 and CTR Greater than 0.5 but Less than 1 Feature Age, y Sex Male Female Smoking status Smoker Nonsmoker Tumor size, mm Location RUL RML RLL LUL LLL Surgery Wedge resection Segmentectomy Lobectomy Pathology AIS/MIA IAD Pathologic N status N0 N1/2 a

All (N ¼ 329)

0＜CTR0.5 (n ¼ 185)

0.5＜CTR＜1 (n ¼ 144)

58.89 ± 9.71

59.54 ± 9.49

58.05 ± 9.96

88 (27.9) 227 (72.1)

50 (28.9) 123 (71.1)

38 (26.8) 104 (73.2)

52 (16.5) 263 (83.5) 20.52 ± 7.18

26 (15.0) 147 (85.0) 20.65 ± 7.00

26 (18.3) 116 (81.7) 20.35 ± 7.44

126 (38.3) 21 (6.4) 48 (14.6) 98 (29.8) 36 (10.9)

66 10 31 56 22

60 11 17 42 14

72 (21.9) 33 (10.0) 224 (68.1)

47 (25.4) 22 (11.9) 116 (62.7)

25 (17.4) 11 (7.6) 108 (75.0)

56 (17.0)a 273 (83.0)

37 (20.0)b 148 (80.0)

19 (13.2)c 125 (86.8)

305 (97.8) 7 (2.2)

166 (98.8) 2 (1.2)

139 (96.5) 5 (3.5)

p Value 0.169 0.972

0.566

(35.7) (5.4) (16.7) (30.3) (11.9)

0.295 0.536

(41.7) (7.6) (11.8) (29.2) (9.7) 0.059

0.164

0.136

Included 19 AISs and 37 MIAs. Included 12 AISs and 25 MIAs. c Included 7 AISs and 12 MIAs. PSN, part-solid nodule; CTR, consolidation-to-tumor ratio; RUL, right upper lobe; RML, right middle lobe; RLL, right lower lobe; LUL, left upper lobe; LLL, left lower lobe; AIS, adenocarcinoma in situ; MIA, minimally invasive adenocarcinoma; IAD, invasive adenocarcinoma. b

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Figure 2. Comparisons of survival times between patients with part-solid nodules (PSNs) and patients with pure ground glass nodules (pGGNs) and pure solid tumors.

solid component sizes had similar prognoses, Yamanashi et al.15 could not have reached their conclusions. Moreover, Hattori et al. suggested that the impact of tumor

size be applied exclusively to radiological pure solid lung cancer and recommended that radiological part-solid lung cancer be described as c-T1a.12 Similarly, our

Figure 3. Comparison of survival times between patients with part-solid nodules (PSNs) with different cutoff values of 0.5 and 0.8. CTR, consolidation-to-tumor ratio.

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Figure 4. Impact of clinical T stage on the prognosis between part-solid lung adenocarcinoma and pure solid lung adenocarcinoma based on the eighth edition of the International Associaton for the Study of Lung Cancer TNM classification of lung cancer.

results indicated that tumor size and solid component size might be valuable for selection of extent of surgery (sublobar or lobar resection) because they could predict the pathologic invasive adenocarcinoma for PSNs. However, they promised similar favorable prognoses despite the different sizes or percentages of the “invasive” solid component. Accordingly, it might be reasonable that part-solid lung adenocarcinomas be regarded as one special subtype when evaluating their long-term survivals. Presence of the feature GGO on a TS-CT scan always suggests favorable surgical outcomes for early-stage lung adenocarcinoma.16,17 In 2015, Cho et al. showed that the 5-year OS rate was 98.6% for patients with pure GGO adenocarcinoma versus 95.5% for patients

with mixed GGO adenocarcinoma.16 In 2017, Hattori et al. indicated that clinical stage IA radiological invasive NSCLC with a GGO component had a 5-year OS rate of 95.3%; in their study, GGO predominant tumor had a 5-year OS rate of 95.3% and solid predominant tumor had a 5-year OS rate of 96.8%.17 Similarly, for patients with part-solid lung adenocarcinoma in this study, the 5-year LCS-RFS rate was 91.74% (95% CI: 87.10%–94.74%) and the 5-year LCS-OS rate was 98.13% (95% CI: 95.52%–99.23%). The favorable prognosis of part-solid tumors might be one reason why radiological CTR and solid component size could not be the prognostic predictors despite the fact that larger CTR, larger solid component size, and larger tumor size were independently associated with

Table 3. Multivariate Analysis for Prognosis of Part-Solid Lung Adenocarcinomas in This Study (Cox Regression Model) 5-y Recurrence-Free Survival

5-y Overall Survival

Feature

HR (95% CI)

p Value

HR (95% CI)

p Value

Age Sex Male Female Smoking status Nonsmoker Smoker CTR valuea Solid component size, mma Tumor size, mma Pathology IAD AIS/MIA

0.99 (0.95–1.04)

0.728

1.005 (0.919–1.099)

0.911

3.06 (1.04–8.94) 1.0

0.041

1.764 (0.185–16.817) 1.0

0.622

0.414 (0.139–2.256) 1.0 0.004 (0.000–20.034) 1.424 (0.97–2.093) 0.828(0.657-1.043)

0.414

0.555 (0.029–10.513) 1.0 0.54 (0.004–71.36) 0.517 (0.000–6943123.23) 0.993(0.682-1.446)

0.695

a

26.09 (0.13-5238.47) 1.0

0.202 0.071 0.108 0.962

25.72 (0.001-855626.85) 1.0

0.806 0.937 0.972 0.979

Calculated as the continuous variable. HR, hazard ratio; CI, confidence interval; CTR, consolidation-to-tumor ratio; IAD, invasive adenocarcinoma; AIS, adenocarcinoma in situ; MIA, minimally invasive adenocarcinoma.

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postoperative IAD. Our findings seem to be inconsistent with the results of several previous studies. In 2013, Matsuguma et al. indicated that proportion of GGO was a significant prognostic factor for DFS along with solid area diameter for clinical stage I NSCLC.18 In 2015, Saji et al. found that solid component size could predict pathologic high-grade malignancy and prognosis more precisely than whole tumor size for primary lung adenocarcinoma could.19 However, both of these studies included pure solid and pGGNs as well. Considering that solid tumors had an obviously worse prognosis than part-solid tumors did, the conclusions could be statistically different. Contrarily, the results of the study by Hattori et al.12 and our study showed that CTR value, maximum tumor size, and solid component size could not predict OS when we focused on analyzing radiological part-solid lung adenocarcinoma. It could be postulated that part-solid IAD had the much less invasive instinct than pure solid IAD did, and though PSNs had numerous subgroups with different percentages of solid components, the prognoses were similar and favorable. Another question was whether sublobar resection was enough for part-solid lung adenocarcinomas considering the favorable prognosis. In 2014, Tsutani et al. demonstrated that segmentectomy and wedge resection could provide 3-year RFS comparable to that provided by lobectomy for GGO predominant adenocarcinoma (96.1% and 98.7% versus 96.4% [p ¼ 0.44]) and segmentectomy provided 3-year DFS similar to that provided by lobectomy for solid predominant adenocarcinoma (84.8% versus 84.4% [p ¼ 0.69]).20,21 In 2015, Yoshida et al. evaluated wedge or segmental resection for subsolid cT1N0M0 lung carcinoma with a GGO ratio of 0.5 or higher, and they found no recurrence with a median follow-up period of 88 months.22 In addition, Cho et al. showed that patients with mixed GGO adenocarcinoma receiving wedge resection had a 5-year OS rate of 95.5%.16 Also, our results showed that patients with part-solid adenocarcinoma treated with wedge resection or segmentectomy had 5-year LCS-RFS and OS rates similar to those of patients receiving lobectomy. This indicated that sublobar resection could be enough for part-solid lung adenocarcinomas when it is appropriately selected. Moreover, because the prevalence of lymph node metastasis was very low for part-solid lung adenocarcinoma, could sLND still be necessary? In 2015, when evaluating 876 patients with clinical stage I NSCLCs, Haruki et al. showed that there were no cases with hilar and mediastinal nodal involvement in GGO predominant tumors.23 In 2017, Floves et al. evaluated sLND for pure solid and subsolid nodules detected by CT screening and found that for 203 patients with a subsolid nodule (151

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9

patients with sLND and 52 without sLND), the survival rate was 100%. For the 404 patients with a pure solid nodule (311 with and 93 without sLND), the rate was 87% versus 94%. They advocated that performing sLND is not mandatory when screen-diagnosed NSCLC manifests as a subsolid nodule.24 In this study, in which 16 patients did not receive sLND and 251 patients did receive sLND, the 5-year LCS-RFS and 5-year OS values were similar. As a result, we thought that it was not obligatory to perform sLND for part-solid lung adenocarcinoma. Limitations of this study are that the sample size of 329 part-solid tumors analyzed might be small, though a total of 988 lung nodules were included in this study. In addition, the mean follow-up period of 42 months was relatively short regarding the favorable prognosis of part-solid tumor. Therefore, a larger number of patients with a longer follow-up period might be required to identify the prognostic implications of CTR value, solid component size, and tumor size for 5-year LCS-RFS and 5-year LCS-OS in the future. Moreover, selection bias should be pointed out, especially when analyzing the impact of sublobar resection on patients’ survival. We routinely select wedge and segmental resections for patients with adenocarcinoma in situ or minimally invasive adenocarcinoma according to intraoperative pathologic diagnosis25 or for those with insufficient cardiopulmonary function, whereas we choose lobectomy for patients with invasive adenocarcinma. Therefore, the long-term survival of the patients in the Japanese Clinical Oncology Group 0802 trial was expected.9 Strengths of this study were that comprehensive radiological and histologic assessments were performed and detailed analysis of postoperative recurrence and death were documented. In addition, we evaluated LCS recurrence and death in this study. Considering the favorable prognosis of part-solid adenocarcinomas, recurrence and death related to other malignancies should be carefully distinguished. Moreover, we first evaluated the CTR value, solid component size, and tumor size as continuous variables, whereas most of previous studies evaluated the prognostic implications of these three parameters as categorical variables. In conclusion, lung adenocarcinomas manifesting as PSNs had significantly different clinicopathologic characteristics and rare prevalence of lymph node metastases compared with pure solid lung adenocarcinomas. Considering that CTR value, solid component size, and tumor size could not predict the favorable prognosis, part-solid lung adenocarcinomas might be clinically regarded as one special subtype when being treated. Sublobar resection might be suitable for this cohort when appropriately selected.

10 Ye et al

Acknowledgments This study was supported by the National Natural Science Foundation of China (grant 81572253), Shanghai Shen Kang Hospital Development Center City Hospital Emerging Cutting-edge Technology Joint Research Project (grant SHDC12017102) and Shanghai Municipal Health Commission Key Discipline Project (2017ZZ02025).

Supplementary Data Note: To access the supplementary material accompanying this article, visit the online version of the Journal of Thoracic Oncology at www.jto.org and at https://doi. org/10.1016/j.jtho.2018.12.030.

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