Radiologic features of precancerous areas of the lungs in chronic obstructive pulmonary disease

Figures & data

Figure 1 CT and 3D CT images of placement of a 2 cm diameter sphere in a lung.

Notes: A 2 cm diameter sphere appears within a red circle in the lung on transverse (A), sagittal (B), and coronal (C) planes. The placements of these three circles are finely adjusted in a synchronized manner to minimize the involvement of vessels and airways. The enhanced images of the sphere are shown in each inset. The location of the sphere (red circle) is visualized (D).
Abbreviations: 3D, three dimensional; CT, computed tomography; R, right; L, left.

Table 1 Baseline characteristics of the study population

Participants (n)	435
Gender, female, n (%)	36 (8.3)
Age, years	72.7±8.0
Pack-years of smoking	56.3±29.9
Current smokers, n (%)	46 (11.0)
BMI, kg/m^2	22.4±3.3
FEV1/FVC (%)	51.9±12.1
%FEV1 (%)	61.6±21.6
COPD grades 1/2/3/4, n (%)	93/201/109/32 (21.4/46.2/25.1/7.3)

Note: Data are presented as n, mean ± standard deviation, or n (%).

Abbreviations: BMI, body mass index; COPD, chronic obstructive pulmonary disease; FEV₁, forced expiratory volume in 1 second; FVC, forced vital capacity; %FEV₁, percent predicted forced expiratory volume in 1 second.

Figure 2 Flow chart of the study profile over 3 years of follow-up.

Table 2 Comparison of baseline characteristics between patients according to lung cancer development

	COPD patients who did not develop lung cancer	COPD patients who developed lung cancer	P-value
Patients, n	414	21
Gender, female, n (%)	34 (8.2)	2 (9.5)	0.83
Age, years	72.6±8.1	73.4±7.2	0.65
Pack-years of smoking	55.8±29.9	64.4±29.6	0.16
Current smokers, n (%)	45 (11.4)	1 (4.8)	0.62
Extra-pulmonary cancer, n (%)	77 (19.4)	5 (23.8)	0.62
BMI, kg/m^2	22.4±3.3	22.8±4.0	0.69
FEV1/FVC (%)	51.8±12.1	54.4±11.3	0.35
FEV1, L	1.6±0.6	1.7±0.5	0.71
%FEV1 (%)	61.4±21.6	66.2±22.0	0.25
COPD grades 1/2/3/4, n (%)	86/193/104/31 (20.8/46.6/25.1/7.5)	7/8/5/1 (33.3/38.1/23.8/4.8)	0.57
Inhaled drugs
ICS, n (%)	135 (33.1)	7 (33.3)	0.98
LABA, n (%)	181 (44.9)	10 (47.6)	0.81
LAMA, n (%)	246 (60.4)	12 (57.1)	0.76

Notes: Data are presented as n, mean ± standard deviation, or n (%). P-values from chi-square test (for categorical variables) or t-test (for continuous variables).

Abbreviations: BMI, body mass index; COPD, chronic obstructive pulmonary disease; FEV₁, forced expiratory volume in 1 second; FVC, forced vital capacity; %FEV₁, percent predicted forced expiratory volume in 1 second; ICS, inhaled corticosteroids; LABA, long-acting beta agonist; LAMA, long-acting muscarinic antagonist.

Table 3 Emphysema as a predictor of lung cancer in COPD patients

	OR (95% CI)	P-value
Emphysema
Present vs none	5.4 (1.4–35.7)	0.012
Mild vs none	4.6 (0.9–33.3)	0.063
Moderate/severe vs none	6.1 (1.4–42.7)	0.015
Moderate/severe vs mild	1.3 (0.4–4.9)	0.63

Note: Analyses used multivariate logistic analysis adjusted by gender, age, and pack-years.

Abbreviations: COPD, chronic obstructive pulmonary disease; OR, odds ratio; CI, confidence interval.

Figure 3 (A) Frequency of emphysema at enrollment between the COPD patients who developed lung cancer and those who did not. (B) LAA% at enrollment between COPD patients who developed lung cancer afterward and those who did not. Median, 25th and 75th percentile values are displayed. P-values from chi-square tests (A) or Mann–Whitney U tests (B).

Abbreviations: COPD, chronic obstructive pulmonary disease; LAA, low attenuation area.

Table 4 Association of interstitial lung abnormality as a predictor of lung cancer in COPD patients

	OR (95% CI)	P-value
Interstitial lung abnormality
Present vs none	17.7 (5.1–72.5)	<0.0001
With emphysema vs others	32.2 (8.9–138.2)	<0.0001

Note: Analyses used multivariate logistic analysis adjusted by gender, age, and pack-years.

Abbreviations: COPD, chronic obstructive pulmonary disease; OR, odds ratio; CI, confidence interval.

Figure 4 Frequency of interstitial abnormalities at enrollment between COPD patients who developed lung cancer and those who did not.

Note: P-values from chi-square test.
Abbreviation: COPD, chronic obstructive pulmonary disease.

Table 5 Comparison of lung densities between the whole lung and the precancerous sphere

Patient ID	Pathology of lung cancer	Interstitial lung abnormalities	LAA% of whole lung	Median whole lung density (HU)	Sphere density (HU)	Difference between the two densities (HU)
1	Unknown	None	40.0	−932.5	−944.0	11.5
2	Adeno	None	5.9	−898.0	−885.2	−12.8
3	Adeno	None	22.1	−902.0	−880.8	−21.2
4	Adeno	None	5.3	−858.8	−832.7	−26.1
5	Adeno	None	14.9	−896.2	−764.4	−131.8
6	Unknown	Present	26.7	−902.1	−769.1	−133.0
7	Small cell	Present	34.0	−930.9	−674.2	−256.7
8	Small cell	Present	10.7	−823.2	−664.5	−158.8
9	Squamous	Present	16.1	−868.1	−702.4	−165.7
10	Unknown	Present	11.4	−843.9	−698.5	−145.4
11	Squamous	Present	13.8	−904.4	−803.8	−100.5
12	Unknown	Present	27.6	−907.3	−905.1	−2.2
13	Adeno	Present	19.7	−899.9	−910.9	11.0
14	Squamous	Present	17.7	−906.9	−901.4	−5.5

Abbreviations: LAA, low attenuation area; HU, Hounsfield unit; Adeno, adenocarcinoma; Small cell, small cell carcinoma; Squamous; squamous carcinoma.

Figure 5 Chest CT scans before and after the appearance of a malignant lesion and the histogram of lung density distribution in a patient who had emphysema, but no interstitial abnormalities.

Notes: (A) A transverse CT image at enrollment with superimposed LAA (<−95 HU: green). The red circle indicates the precancerous sphere. (B) The location of the sphere is visualized on 3D CT image (red circle). (C) Histogram of CT density distribution of the entire lungs. The area under the curve of the histogram is total lung volume. The median of whole lung density is indicated as a dotted line. The solid line indicates the local lung density of precancerous sphere. (D) A transverse CT image when a suspicious lesion (arrow) was detected at the same level of A.

Abbreviations: CT, computed tomography; LAA, low attenuation area; HU, Hounsfield unit; 3D, three dimensional; A, anterior; R, right; L, left; P, posterior.

Figure 6 Chest CT scans before and after the appearance of a malignant lesion and the histogram of lung density distribution in a patient who had emphysema and interstitial abnormalities.

Notes: (A) A transverse CT image at enrollment with superimposed LAA (<−950 HU: green). The red circle indicates the precancerous sphere. (B) The location of the sphere (red circle) is visualized on 3D CT image. (C) The histogram of CT density distribution of the entire lungs. The area under the curve of the histogram is total lung volume. The median of lung attenuation is indicated as a dotted line. LAA (−950 HU) is shown as a shaded area. The solid line indicates the local lung density of the precancerous sphere. (D) Transverse CT image when a suspicious lesion (arrow) was detected at the same level of A.
Abbreviations: CT, computed tomography; LAA, low attenuation area; HU, Hounsfield unit; 3D, three dimensional; R, right; L, left.

Figure S1 The histograms of the lung density of all 14 individuals.

Notes: There are five individuals without interstitial lung abnormalities (ID 1–5) and nine individuals with interstitial lung abnormalities (ID 6–14). The area under the curve of the histogram is total lung volume. The median of lung attenuation is indicated as a dotted line. The solid line indicates the local lung density of the precancerous sphere.

Abbreviation: HU, Hounsfield unit.

Table S1 Comparison of baseline characteristics between patients with 3-year follow-up and those who dropped out

	Patients with 3-year follow-up	Patients who dropped out	P-value
Patients, n	253	182
Gender, female, n (%)	17 (6.7)	19 (10.4)	0.16
Age, years	71.8±7.6	74.0±8.4	0.0046
Pack-years of smoking	56.9±30.8	55.3±28.7	0.60
BMI, kg/m^2	22.9±3.0	21.7±3.6	0.00020
FEV1/FVC (%)	52.7±12.0	50.8±12.1	0.11
%FEV	63.7±20.7	58.7±22.6	0.018

Notes: Data are presented as n, mean ± SD, or n (%). P-values from chi-square test (for categorical variables) or t-test (for continuous variables).

Abbreviations: BMI, body mass index; FEV₁, forced expiratory volume in 1 second; FVC, forced vital capacity; %FEV₁, percent predicted forced expiratory volume in 1 second; SD, standard deviation.

Table S2 Comparison of baseline characteristics according to pathology of lung cancer

	Adenocarcinoma	Squamous cell carcinoma	Small cell carcinoma	Undiagnosed
Patients, n	9	4	3	5
Gender, female, n (%)	1 (11.1)	0 (0)	1 (33.3)	0 (0)
Age, years	70.8±8.4	76.5±6.2	72.0±7.5	76.6±4.6
Smoking index, pack-years	61.6±20.0	65.9±28.5	48.2±14.0	78.1±49.2
Current smokers, n (%)	0 (0)	1 (25.0)	0 (0)	0 (0)
Previous history of extra-pulmonary cancer, n (%)	1 (11.1)	1 (25.0)	1 (33.3)	2 (40.0)
%FEV1	73.9±19.4	49.1±19.4	64.8±25.7	66.9±25.1
COPD grades 1/2/3/4, n	4/3/2/0	0/3/0/1	1/1/1/0	2/1/2/0
Blood examination
Leukocytes, ×10^9/L	7.3±1.6	6.8±2.1	9.2±0.3	6.4±0.7
CRP, mg/dL	0.4±0.3	0.6±0.8	0.5±0.5	0.1±0.1
SAA/μg/mL	12.0±11.1	16.3±12.4	33.4±23.8	75.6±129.1
CEA/ng/mL	28.3±57.6	4.1±0.8	4.4±0.4	5.3±3.5
Pro-GRP/pg/mL	45.5±9.9	51.8±19.2	73.4±7.3	102.7±32.7
CYFRA/ng/mL	2.2±1.4	2.5±2.0	3.2±2.3	3.9±2.8
Clinical stage of NSCLC
I/II/III/IV/unknown, n	6/0/2/1/0	1/1/1/1/0		3/0/0/0/2
Clinical stage of SCLC LD/ED			1/2
Location of primary mass
Upper/middle/lower lobes, n	6/0/3	1/0/3	0/1/2	1/2/2
Diagnosis and annual follow-up
Chest CT/other extra causes, n	8/1	4/0	1/2	4/1
Treatment
Operation/radiation/chemotherapy + radiation/chemotherapy/best supportive care, n	5/0/1/2/1	0/1/0/2/1	0/0/0/3/0	0/1/0/0/4

Note: Data are presented as n, mean ± SD, or n (%).

Abbreviations: %FEV₁, percent predicted forced expiratory volume in 1 second; COPD, chronic obstructive pulmonary disease; CRP, C-reactive protein; SAA, serum amyloid A; CEA, carcinoembryonic antigen; pro-GRP, pro-gastrin-releasing peptide; CYFRA, cytokeratin-19 fragments; NSCLC, non-small cell lung cancer; SCLC, small cell lung cancer; LD, limited disease; ED, extensive disease; CT, computed tomography; SD, standard deviation.

Table S3 Emphysema and interstitial lung abnormalities as an independent risk factor for future lung cancer in COPD patients

	OR (95% CI)	P-value
Emphysema
Present vs none	4.2 (1.0–29.0)	0.049
Interstitial lung abnormality
Present vs none	15.6 (4.4–65.4)	<0.0001

Note: Multivariate logistic analysis adjusted by gender, age, and pack-years.

Abbreviations: COPD, chronic obstructive pulmonary disease; OR, odds ratio; CI, confidence interval.