Nonneoplastic Lung Diseases: Chronic Inflammation, Chronic Obstructive Pulmonary Disease, and Pulmonary Fibrosis

Lung cancer risk has been reported
to be increased among persons with a history of tuberculosis,
pulmonary fibrosis as in silicosis, or chronic bronchitis
and emphysema. An increased risk of lung cancer following
the diagnosis of tuberculosis has been reported in cohort and
case-control studies. For example, in a population-based casecontrol
study of lung cancer that was conducted in Shanghai,
Zheng et al. 130 reported that the age-, sex-, and smokingadjusted
odds ratio or RR of lung cancer was increased by 50%
(95% CI, 1.2 to 1.8) among all survivors of tuberculosis, and
by 100% among those diagnosed with tuberculosis within the
previous 20 years. Among men, prior infection was reported
by 26% of the cases and by 20% of the controls. The RR of
lung cancer was higher for adenocarcinoma than for squamous
or oat-cell carcinoma, and the locations of the granulomatous
fibrotic lesions were highly correlated with that of the lung
cancers. Based on the estimation of RR and the proportion of
the population in Shanghai exposed to pulmonary tuberculosis,
9% of lung cancer cases were attributed to prior infection.
In a case-control study by Hinds et al., 131 the RR of lung cancer
in never-smoking women in Hawaii with prior tuberculosis
was increased significantly (OR 8.2; 95% CI, 1.3 to 54.4).
The IARC has classified silica as a “probable” lung carcinogen
(2A). Inhalation of silica causes both lung fibrosis and cancer in
rats, but fibrosis in the absence of cancer has been observed in
mice. For workers exposed to crystalline silica, with clinical indication
of pneumoconiosis, as reported in 12 cohort and 3 casecontrol
studies, the combined RR of lung cancer was 1.33 (95%
CI, 1.12 to 1.45). 132 In a metaanalysis of lung cancer mortality
among patients with silicosis, Smith et al.133 reported a pooled
estimated RR of 2.2 (95% CI, 2.1 to 2.4). RRs have been elevated
in workers with increased exposure to silica dust that is incurred in
mining and quarrying, and in the granite, ceramics and glass, and
foundry industries. In underground mining, exposure to silicon
dioxide or crystalline silica may be confounded by exposure to
radon and its -particle progeny, diesel fumes, asbestos, and other
occupational carcinogens, and/or to tobacco smoke. Increased risk
appears to vary with the severity of pulmonary fibrosis or with
clinical signs of obstructive lung disease that accompanies chronic
silicosis. The excess risk of lung cancer reported in previous studies
has persisted after adjusting for smoking or has not been associated
with excess risks for other smoking-related cancers, as in the
upper digestive or urinary tract organs. 134
Cigarette smoking may result in COPD and/or emphysema,
and/or lung cancer. In the early 1960s, Passey135 hypothesized
that it was the irritating properties of tobacco smoke,
resulting in chronic bronchitis and inflammatory destruction of
lung tissue, which was of pathogenic significance in the causal
pathway of lung cancer, rather than any direct action by volatile
and particulate carcinogens in tobacco smoke. The experiments
of Kuschner,136 however, suggested an alternative explanation;
namely that bronchial and bronchiolar inflammation,
accompanied by reactive proliferation, squamous metaplasia,
and dysplasia in basal epithelial cells, provided a cocarcinogenic
mechanism for neoplastic cell transformation upon exposure
to polycyclic aromatic hydrocarbons. Continued smoking in
association with COPD, when accompanied by moderate or
marked cytological atypia in exfoliated cells in the sputum, was
significantly predictive of lung cancer in the Colorado Cancer
Center Sputum Screening Cohort Study. 137
Although cigarette smoking is the predominant cause of
COPD, with an estimated attributable (etiologic) risk fraction
exceeding 80% in smoking affected individuals, perhaps
only 10% to 15% of current smokers will eventually develop
clinically significant sequellae of productive cough, exertional
dyspnea, and cardiovascular disease. 138,139 There are at least
10 cohort studies indicating that chronic obstructive airway
disease is an independent predictor of lung cancer risk, and
numerous studies reporting an increased risk of lung cancer
among adults with asthma (Table 1.6). 140–149
Chronic cigarette smoking retards mucociliary clearance
of foreign particulates and respiratory tract secretions,
evokes an inflammatory response accompanied by fibrosis
and thickening in the membranous and respiratory bronchioles,
and causes mucus gland hypertrophy, hyperplasia, and
dysplasia in the proximal airways. 150 The manifestations of
COPD signal the extent of bronchopulmonary structural and
functional damage arising from the interaction of sustained
exposure to toxic products of tobacco combustion and host
susceptibility. In this context, COPD is both a biomarker
of both exposure dose level and tissue susceptibility. A more
controversial issue would be that of how COPD impacts
the development of lung cancer. A conceptual model is proposed
that incorporates the potential cocarcinogenic effects
of chronic obstructive inflammatory disease in the causal
pathway of cigarette smoke and lung cancer. The molecular
events in the natural history of lung cancer comprise multiple
genetic mutations that are determinants of neo plastic
transformation and tumor progression, and the elaboration
of autocrine growth factors that influence the clonal behavior
and morphologic features of neoplastic cells. Chronic inflammation
in the proximal and distal bronchial airways is
an important cause of obstructive symptoms and provides
the dynamic setting for oxidative stress and the formation
of free radicals that accompany the reparative proliferative
response. Increased proliferation kinetics and the interaction
of hydroxyl radicals with DNA augment the likelihood of
DNA structural and transcriptional errors.