Smoking-Related Interstitial Fibrosis: Evidence of Radiologic Regression with Advancing Age and Smoking Cessation

Figures & data

Figure 1. Map of pathologic slide preparation scheme. Centimeter scale as shown. T, tumour.

Figure 2. Illustrative examples of cancer lobectomy sections showing pre-specified histologic patterns as indicated, including various subtypes of fibrosis patterns. See also Table 3.

Table 1. Clinical data from prospective lung cancer lobectomy cohort.

Parameter	Non SRIF1	SRIF	p-value^2
Subjects, n	12	8
Females/males, n	8/4	4/4	0.65
Mean age, years	67.6	65.8	0.70
Lung Cancer Stage, n (%)^3
1A-1B	6 (50)	3 (37.5)	0.67
2A-2B	5 (41.7)	3 (37.5)	1.0
3A	1 (8.3)	2 (25)	0.54
Known COPD, n (%)^4	2 (16.6)	4 (50)	0.16
Mean FEV1% predicted^5	97	72	0.23
Mean DLCO % predicted^6	77.3	59.2	0.08
Smoking, mean pack-years	30.8	37.4	0.48
current smokers (%)	2 (17)	6 (75)	0.02
ex-smokers (%)	9 (75)	2 (25)	0.06
never smokers (%)	1 (8)	0 (0)	1.0
Cancer histologic subtype
adenocarcinoma	7	8	0.06
squamous cell carcinoma	4	0	0.12
typical carcinoid	1	0	1.0
Tumour size, mean mm	26.3	28	0.27
Location
right upper lobe	2	5	0.06
left upper lobe	2	1	1.0
right middle and lower lobes	3	1	0.62
right lower lobe	1	1	1.0
left lower lobe	4	0	0.12
Follow up, mean months	41.2	50.3	0.2

¹ SRIF, smoking-related interstitial fibrosis.

² P-values represent either two-tailed t-test with unequal variance assumption, or two-tailed Fisher's exact test.

³ Lung cancer staging data are the final post-operative pathological TNM staging (7th edition).

⁴ COPD, chronic obstructive pulmonary disease.

⁵ FEV1, forced expiratory volume in one second.

⁶ DLCO, diffusing capacity of the lung for carbon monoxide.

Figure 3. Examples of radiologic–pathologic correlation in prospective lung cancer cohort subjects with heavy burden of SRIF. A. Right upper lobectomy of subject X with histological evidence of SRIF (insert shows normal lung away from SRIF and cancer). Scale as indicated. B. Corresponding magnified view of high resolution CT thorax of right upper lobe, showing centrilobular emphysema (arrows) and no visible interstitial lung abnormality. C. Right upper lobectomy sample of subject Y with histological evidence of SRIF (insert shows normal lung away from SRIF and cancer). Scale as indicated. D. Corresponding magnified view of high resolution CT thorax of right upper lobe, showing tumour, emphysema and no discernible interstitial lung abnormality.

Table 2. Demographics of comparison cohorts.

	Lobectomies for cancer^1	COPD Transplant^2	A1AT Transplant^3	CPFE^4	IPF^5
Subjects, n	20	20	20	8	10
Females/males	12/8	10/10	10/10	3/5	3/7
Mean age, years	66.9	57	51	72	62
Current smokers	8	0	0	2	0
Former smokers (Mean years cessation)	12	20 (6.4)	15 (9.4)	6	10
Mean duration of cessation, yr yr	12.6	6.4	9.4	16	18
Mean pack-years	33.4	47	25	55	26
Never smokers	1	0	5	0	0
Right lung sample	13	9	8	7	9
Left lung sample	7	8	2	1	1
Bilateral lung samples	0	3	10	0	0
SRIF n (%)^6	8 (40)	7 (35)	4 (20)	2 (25)	1 (10)

¹ Prospective cohort who underwent lobectomy for lung cancer, see Methods.

² COPD, chronic obstructive pulmonary disease. Data relate to lung explant.

³ A1AT, alpha 1-antitrypsin deficiency. Data relate to lung explant.

⁴ CPFE, combined pulmonary fibrosis and emphysema, data relate to video-assisted thoracic surgical (VATS) biopsy.

⁵ IPF, idiopathic pulmonary fibrosis. Data relate to VATS or open surgical biopsy.

⁶ SRIF, smoking-related interstitial fibrosis.

Table 3. Histologic findings among the comparison cohorts.

	n	Interstitial Fibrosis	Fibroblastic Foci	FES^1	Hyaline Fibrosis	PBF^2	PBI^3	PBM^4	RB^5	DIP-Like^6	BL^7	Mucus/GCH^8	Vasc^9	SRIF^10
Lobectomies	20	8	3	8	8	4	11	8	18	5	4	11	19	8
COPD^11	20	11	3	7	3	1	13	6	2	1	14	16	11	7
A1AT^12	20	5	0	5	5	1	20	1	6	6	17	18	14	4
CPFE^13	8	15	4	1	2	2	3	5	2	5	7	7	8	2
IPF^14	10	9	8	2	1	3	4	8	4	3	9	8	10	1

¹ FES, fibroelastotic scarring.

² PBF, peribronchial fibrosis.

³ PBI, peribronchial inflammation.

⁴ PBM, peribronchial metaplasia.

⁵ RB, respiratory bronchiolitis.

⁶ DIP, desquamative interstitial pneumonia.

⁷ BL, bronchiolectasis.

⁸ GCH, goblet cell hyperplasia.

⁹ Vasc, vascular changes (thickening of intima/media).

¹⁰ SRIF, smoking-related interstitial fibrosis.

¹¹ COPD, chronic obstructive pulmonary disease.

¹² A1AT, alpha 1-antitrypsin deficiency.

¹³ CPFE, combined pulmonary fibrosis and emphysema.

¹⁴ IPF, idiopathic pulmonary fibrosis. See methods for description of tissue sources.

Table 4. Relationship of respiratory bronchiolitis to SRIF as a function of background lung histology in the present authors’ cohorts.

Background histology	n	Both SRIF and RB^1	SRIF, no RB
Lung adenocarcinoma	20	8	0
Chronic obstructive pulmonary disease	20	1	6
Alpha 1-antitrypsin deficiency	20	1	3
Combined pulmonary fibrosis and emphysema	8	1	1
Idiopathic pulmonary fibrosis	10	1	0
Total, n (%)	78 (100)	12 (15.4)	10 (12.8)

¹ SRIF, smoking-related interstitial fibrosis. RB, respiratory bronchiolitis.

Figure 4. In all SRIF subjects identified in the current authors’ cohorts, the proportion of cases with and without histologic evidence of respiratory bronchiolitis (RB) are shown, parsed by source tissue lung cancer status. The background histologies of the tissue sources are outlined in Table 4.

Figure 5. Analysis of pooled data of SRIF subjects (authors’ cohorts and other described cohorts in the published literature) with known status regarding radiologic interstitial lung abnormality (ILA), see text. A. Influence of subject age on radiologic ILA. Each dot represents an individual subject. Mean age represented by horizontal line. B. Histogram showing the effect of smoking status on radiologic ILA in the same SRIF subjects as in panel A.

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