Objectives
We proposed a modification of the ACR Lung Imaging Reporting and Data System (Lung-RADS) to clarify the characteristics of subsolid nodules with categories 1–11, and to compare the diagnostic accuracy with Lung-RADS and National Lung Screening Trial criteria in an Asian population with high prevalence of adenocarcinoma.
Methods
We analyzed a retrospective cohort of 1978 consecutive healthy subjects (72.8% nonsmoker) who underwent low-dose computed tomography from August 2013 to October 2014 (1084 men, 894 women). Lung-RADS categories 2 and 3 were modified to include subcategories of 2A/2B/2C and 3A/3B/3C, respectively. Clinical information and nodule characteristics were recorded. Receiver operating characteristic curves were used to compare diagnostic accuracy at different cutoffs.
Results
Thirty-two subjects (30 nonsmokers) had pathology-proven adenocarcinoma spectrum lesions in the follow-up period (1.6 ± 0.5 years). Modified Lung-RADS, using modified Lung-RADS category 2C as cutoff, had an area under the curve (AUC) of 0.973 in predicting adenocarcinoma spectrum lesions (sensitivity of 100%, specificity of 89.3%), which was significantly higher than that of Lung-RADS (AUC = 0.815, P < .001) and National Lung Screening Trial (AUC = 0.906, P < .001). Furthermore, modified Lung-RADS showed an AUC of 0.992 in predicting invasive adenocarcinoma (sensitivity of 95%, specificity of 97.8%) when category 3B was used as cutoff.
Conclusions
Modified Lung-RADS may substantially improve sensitivity while maintaining specificity for detection of adenocarcinoma spectrum lesions in an Asian population. Compared to Lung-RADS, it has enhanced ability to differentiate invasive from indolent adenocarcinoma by more refined subclassification of subsolid nodules using two cutoff values of category 2C and 3B. The effect of using modified Lung-RADS in clinical practice must be carefully studied in prospective large cohort studies.
Introduction
The National Lung Screening Trial (NLST) demonstrated that annual lung screening of high-risk population with low-dose computed tomography (LDCT) results in a 20% reduction in lung cancer-specific mortality compared to screening with chest radiography . However, a major concern is the high false-positive rate of NLST by setting the cutoff threshold of positive scan at 4 mm for noncalcified lung nodule . In an effort to reduce false-positive rate and standardize reporting of lung cancer screening examinations, the American College of Radiology (ACR) in 2014 released the Lung Imaging Reporting and Data System (Lung-RADS) . Recent studies have demonstrated that Lung-RADS, compared to NLST criteria, substantially reduces the false-positive result rate with a small corresponding decrease in sensitivity .
In general, cancer cases that are falsely classified as negative by Lung-RADS and classified as positive screen based on NLST criteria are speculated to represent less aggressive lesions, such as minimally invasive adenocarcinoma (MIA) or adenocarcinoma in situ (AIS) . However, Lung-RADS was designed to be used in the United States where screening programs target high-risk smokers, and the diagnostic performance of Lung-RADS in populations with high prevalence of nonsmoking associated lung cancer, such as in China, Taiwan, Korea, and Japan, is unclear . Lung cancer is the leading cause of death among all cancer types in Taiwan, accounting for 19.7% of cancer mortality in 2012. In Taiwan, more than 95% of women with lung cancer are nonsmokers, and the majority of these patients have adenocarcinomas (about 83%) . More than half of women with lung cancer are diagnosed at advanced stages.
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Materials and Methods
Study Cohort
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LDCT Image Acquisition and Interpretation
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Retrospective Reclassification of Scans According to the Definition of NLST, Lung-RADS, and Modified Lung-RADS Criteria
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TABLE 1
Summary of Lung-RADS Classification and Modified Lung-RADS Classification
Lung-RADS Baseline Screening Category Modified Lung-RADS Category Modified Lung-RADS Categories in Numbers 1 No nodules 1A (no nodules) 1 Nodules with calcification 1B (nodules with calcification) 2 2 Solid: <6 mm 2A (Solid: <6 mm) 3 Part solid: <6 mm 2B (Part solid: <6 mm) 4 GGN: <20 mm 2C (GGN: <20 mm) 5 3 Solid: ≥6 to <8 mm 3A (Solid: ≥6 to <8 mm) 6 Part solid: ≥6 mm with solid component <6 mm 3B (Part solid: ≥6 mm with solid component <6 mm) 7 GGN: ≥20 mm 3C (GGN: ≥20 mm) 8 4A Solid: ≥8 mm to <15 mm 4A(Correspond to Lung-RADS 4A) 9 Part solid: ≥8 mm with solid component ≥6 and <8 mm 4B Solid: ≥15 mm 4B(Correspond to Lung-RADS 4B) 10 Part solid: Solid component ≥8 mm 4X Category 3 or 4 nodules with additional features; imaging findings that increase suspicion of malignancy 4X (Correspond to Lung-RADS 4X) 11
ACR, American College of Radiology; GGN, ground-glass nodule; Lung-RADS, the ACR Lung Imaging Reporting and Data System; modified Lung-RADS, a modified 11-category scheme classification system from the Lung-RADS.
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Statistical Analysis
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Results
Demographics and Clinical Characteristics
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TABLE 2
Clinical Characteristics of the Total Screened Population at the Baseline
Characteristics Mean, Median, Range/n (%) Ethnic group Asian (%) 100% Gender Male, n (%) 1084 (54.80%) Female, n (%) 894 (45.20%) Age (y) 56.56, 57, 40–80 BMI (kg/m 2 ) 24.33 ± 3.54 (13–42) Family history of lung cancer 20.40% Family history of other cancer 31.40% COPD 3.40% TB 2.80% NLST criteria 149 (7.50%) Smoking status Nonsmoker 1440 (72.80%) Smoker 211 (10.70%) Quit 327 (16.50%) Pack-years of smoking Smoker 23.18 ± 19.95, 20, 1–120 Quit 6.60 ± 13.12, 6.6, 0–120 Lung-RADS 1 1559 (78.81%) 2 345 (17.44%) 3 21 (1.06%) 4 53 (2.60%) Lung-RADS Negative (1–2) 1904 (96.30%) Positive (3–4) 74 (3.70%) Lung adenocarcinoma spectrum type AAH 3 (9.37%) AIS 3 (9.37%) MIA 6 (18.75%) Invasive adenocarcinoma 20 (62.50%) Lung cancer stage Stage 0 6 (18.75%) Stage I 23 (71.87%) Stage II 2 (6.25%) Stage III 0 (0%) Stage IV 1 (3.10%) Eligible risk factor for 32 subjects with lung adenocarcinoma spectrum Eligible for NLST criteria 1 (3.10%) Smoking-related (not eligible for NLST criteria) 1 (3.10%) Nonsmoking related 30 (93.80%)
AAH, atypical adenomatous hyperplasia; ACR, American College of Radiology; AIS, adenocarcinoma in situ; BMI, body mass index; COPD, chronic obstructive pulmonary disease; Lung-RADS, The ACR Lung Imaging Reporting and Data System; MIA, minimally invasive adenocarcinoma; NLST, National Lung Screening Trial; TB, tuberculosis.
Data are presented as mean ± SD, median, or range/n (%).
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TABLE 3
Comparison Between Lung-RADS Classification and Modified Lung-RADS Classification in Baseline Screening of 1978 Subjects Enrolled in This Study
Lung-RADS Modified Lung-RADS Cancer Diagnosed, n (%) All Classifications, n (%) Percentage of ADE and MIA Stage Distribution 1 1A (1) 0 (0%) 1301 (65.70%) 0 N/A 1B (2) 0 (0%) 258 (13.04%) 0 N/A 2 2A (3) 0 (0%) 173 (8.76%) 0 N/A 2B (4) 0 (0%) 6 (0.30%) 0 N/A 2C (5) 11 (6.60%) 166 (8.39%) 45.40% (5/11) Stage I (5); stage 0 (6) 3 3A (6) 0 (0%) 13 (0.65%) 0 N/A 3B (7) 2 (28.50%) 7 (0.35%) 100% (2/2) Stage I (2) 3C (8) 0 (0%) 1 (0.05%) 0 N/A 4A 4A (9) 3 (13.60%) 22 (1.10%) 100% (3/3) Stage I (3) 4B 4B (10) 7 (35.00%) 20 (1.01%) 100% (7/7) Stage I (7) 4X 4X (11) 9 (81.80%) 11 (0.55%) 100% (9/9) Stage I (6); stage II (2); stage IV (1)
ACR, American College of Radiology; ADE, invasive adenocarcinoma; Lung-RADS, The ACR Lung Imaging Reporting and Data System; MIA, minimally invasive adenocarcinoma; N/A, not applicable.
Cancer diagnosed: lung adenocarcinoma spectrum lesions.
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Predictive Ability for Lung Adenocarcinoma Spectrum Lesions
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TABLE 4
Comparison of Diagnostic Accuracy for Lung Adenocarcinoma Spectrum Lesions at Different Size Criteria Definition and Cutoff Values
Positive Scan Definition Cutoff Value AUC Sensitivity (95% CI) Specificity (95% CI) DA (%) PPV (95% CI) NPV (95% CI) LR+ LR− Lung-RADS Positive scan results † 0.815 (0.797, 0.831) ‡ 65.6 (46.8, 81.4) 97.2 (96.5, 98.0) 96.76 28.4 (18.5, 40.1) 99.4 (99.0, 99.7) 24.100 0.350 Modified Lung-RADS Category 2C \* 0.973 (0.965, 0.980) ‡ 100.0 (89.1, 100.0) 89.3 (87.9, 90.6) 89.48 13.3 (9.3, 18.3) 100.0 (99.8, 100.0) 9.360 0 Size criteria 4 mm 4 mm 0.875 (0.860, 0.890) ‡ 100.0 (89.1, 100.0) 75.0 (73.1, 77.0) 75.36 6.2 (4.3, 8.6) 100.0 (99.7, 100.0) 4.010 0 Size criteria 6 mm 6 mm 0.919 (0.907, 0.931) ‡ 93.7 (79.2, 99.2) 90.1 (88.7, 91.4) 90.15 13.5 (9.3, 18.7) 99.9 (99.6, 100.0) 9.500 0.069 Size criteria 8 mm 8 mm 0.914 (0.900, 0.926) ‡ 87.50 (71.0, 96.5) 95.2 (94.2, 96.1) 95.07 23.1 (16.0, 31.7) 99.8 (99.4, 99.9) 18.310 0.130 NLST criteria 4 mm, noncalcified 0.906 (0.892, 0.919) ‡ 96.8 (83.8, 99.9) 84.3 (82.6, 85.9) 84.52 9.2 (6.4, 12.8) 99.9 (99.7, 100.0) 6.180 0.037
ACR, American College of Radiology; AUC, area under the curve; AAH, atypical adenomatous hyperplasia; AIS, adenocarcinoma in situ; CI, confidence interval; DA, diagnostic accuracy; LR+, positive likelihood ratio; LR−, negative likelihood ratio; Lung-RADS, the ACR Lung Imaging Reporting and Data System; MIA, minimal invasive adenocarcinoma; NLST, National Lung Screening Trial; NPV, negative predictive value; PPV, positive predictive value.
Lung adenocarcinoma spectrum classification, including AAH, AIS, MIA, and invasive adenocarcinoma.
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Predictive Ability for Invasive Lung Adenocarcinoma
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TABLE 5
Comparison of Diagnostic Accuracy for Invasive Adenocarcinoma at Different Optimal Cutoff Values Comparing the Predictive Ability of NLST, Lung-RADS, and Modified Lung-RADS Criteria
Positive Scan Definition Cutoff Value AUC Sensitivity (95% CI) Specificity (95% CI) DA (%) PPV (95% CI) NPV (95% CI) LR+ LR− NLST criteria 4 mm, Noncalcified 0.973 (0.965, 0.980) ‡ 95.0 (75.1, 99.9) 83.8 (82.1, 85.4) 83.92 5.7 (3.4, 8.7) 99.9 (99.7, 100.0) 5.870 0.060 Modified Lung-RADS Category 3B \* 0.992 (0.987, 0.995) ‡ 95.0 (75.1, 99.9) 97.8 (97.1, 98.4) 97.82 31.1 (19.9, 44.3) 99.9 (99.7, 100.0) 33.820 0.051 Lung-RADS Positive scan † 0.961 (0.951, 0.969) ‡ 95.0 (75.1, 99.9) 97.1 (96.4, 97.9) 97.16 25.7 (16.2, 37.2) 99.9 (99.7, 100.0) 33.820 0.051
ACR, American College of Radiology; AUC, area under the curve; CI, confidence interval; DA, diagnostic accuracy; LR+, positive likelihood ratio; LR−, negative likelihood ratio; Lung-RADS, the ACR Lung Imaging Reporting and Data System; modified Lung-RADS, a modified 11-category scheme classification system from the Lung-RADS proposed in this study; NLST, National Lung Screening Trial; NPV, negative predictive value; PPV, positive predictive value.
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Discussion
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Supplementary Data
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Table S1
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