Diffuse smoking-related lung diseases: insights from a radiologic-pathologic correlation

COPD is depicted by the spirometric evidence of irreversible and usually progressive airflow limitation. The disease comprehends distinct however overlapping obstructive disorders, such as chronic bronchitis, emphysema, and also affecting the distal airways of the lung, with both reductions in the number and the caliber. Bronchiolitis is the earliest lesion in COPD, with narrowing and loss of terminal bronchioles preceding emphysematous changes [3, 8]. Emphysema results from permanent enlargement and wall destruction of the airways distal to the surviving terminal bronchioles, progressing in severe cases to coalescence of destroyed lobules [8, 9]. Centrilobular and panlobular emphysema have clinical significance, often associated with increased dyspnea and poorer functional capacity. Additionally, centrilobular emphysema is related to smoking habits, and panlobular emphysema is associated with low body mass index (BMI). Paraseptal emphysema is more common in men and is frequently of little physiologic significance, except for the development of pneumothorax secondary to the presence of paraseptal bleb/bulla [10]. Visual CT evaluation is considered the clinical gold standard for the assessment and characterization of centrilobular and panlobular emphysema, also demonstrated to be valid regarding the pathologic assessments [10‐14].

Chronic bronchitis consists in the presence of inflammation in the large airways. Clinically, patients present with chronic cough and sputum during at least 3 months per year in two consecutive years [15]. Chronic bronchitis is triggered and sustained by the activation of an abnormal immune response due to long-term cigarette smoking, causing overproduction of mucus from goblet cells, thickening, and fibrosis of the bronchial walls (Fig. 1). The condition promotes a further reduction of the caliber of the airways, predisposing expiratory collapse. Imaging depicts wall thickening of the large airways, and endobronchial mucus plugging may also be depicted (Fig. 2) [15, 16]. Bronchial wall thickening is consistently associated with a decline in FEV1 and with the risk of acute exacerbation and hospitalization [16‐19].

Centrilobular emphysema (CLE) results from an abnormal dilatation of the airspaces distal to the terminal bronchioles. This subtype of emphysema is strongly related to cigarette smoking with higher airway inflammatory cell content and usually with upper lung predominance [10]. CLE originates from the destruction and dilation of bronchioles, with further coalescence of several primary lesions (Fig. 3). On imaging, small well or poorly demarcated regions of low attenuation can be depicted, surrounded by areas of the normal lung [3, 8‐10]. Fleischner Society’s guideline scoring of CLE [20] characterizes emphysema as trace when involving less than 0.5% of a lung region, mild when concerning 0.5–5%, and moderate if more than 5% (Fig. 4). Severe emphysema is classified as confluent (coalescence of centrilobular lucencies) or advanced destructive emphysema (ADE) if the expansion of the entire secondary lobule, distortion of the pulmonary architecture, and splaying or decreased caliber of vessels are present (Fig. 5).

Panlobular emphysema (PLE) like ADE indicates destruction across the lobule. This type of emphysema presents in a younger age group (30–44 years of age). The findings are lower lung predominant in about two-thirds of the individuals (Fig. 6) [3, 8‐10, 20]. It is commonly linked to a mutation in the alpha 1-antitrypsin gene, in which Z allele accounts for approximately 95% of clinically recognized cases, causing unopposed action of neutrophil elastase with consequent destruction of lung parenchyma [21].

Paraseptal emphysema (PSE) is secondary to emphysematous changes of the distal acinus, adjacent to the visceral pleura, including fissures. PSE is also scored as mild (up to 1 cm juxtapleural well-demarcated lucencies) or substantial (cyst-like lucencies or bullae greater than 1 cm adjacent to the pleura) (Fig. 7). Bullae are a risk factor for spontaneous pneumothorax, and they can also be large enough to cause severe compression and reduction of the pulmonary function of the remaining lung (Fig. 8) [20].

AEP is an uncommon condition that occurs most frequently in males between the second and forth decades of life. Approximately two-thirds of patients have smoking habits [22‐25]. Changes in smoking habits are known inducers of the development of AEP: initiation of smoking habit, resumption after interruption, and increased frequency of smoking [26‐28]. The clinical presentation is generally unspecific, letting the disease be frequently misdiagnosed as other most common entities such as community-acquired pneumonia. The clinical symptoms are acute, with duration of the respiratory illness of less than a month, and characterized by moderate fever, cough, dyspnea, pleuritic pain, malaise, myalgia, and night sweats. Acute respiratory failure is frequent and mechanical ventilation is often required [22, 25]. Therefore, the disease is severe, and most patients fulfill diagnostic criteria for acute lung injury (ALI) or acute respiratory distress syndrome (ARDS). The key to diagnosis is evidence of eosinophilia in the bronchoalveolar lavage (BAL), with more than 25% of eosinophils on the cell count. Nevertheless, blood eosinophils are frequently at normal levels at the beginning of the clinical presentation and may rise after a few days. BAL is sterile with no bacterial growth during the disease course [22, 23, 25].

Lung biopsy is usually not needed to meet the diagnosis. It shows alveolar and interstitial eosinophilia and alveolar damage. Additional features include nonnecrotizing perivascular inflammation, eosinophilic abscesses, interstitial lymphocytes, organizing fibrinous exudate in the alveoli, type II pneumocyte hyperplasia, and also involvement of the airway [22, 29].

Imaging findings are predominant in the lower lungs, showing diffuse consolidations, ground-glass opacities (GGO), ill-defined centrilobular nodules, smooth septal thickening, and unilateral or bilateral pleural effusion (Fig. 9). The radiologic differential includes infection, fluid overload, ALI/ARDS, hypersensitivity to drugs, and pulmonary hemorrhage [7, 24, 25, 29, 30].

Treatment with steroids achieves an excellent response, with resolution within days of the immunologic process [22, 23].

PLCH is an unusual respiratory disease found most commonly in young adults between the third and fourth decades of life. It is exceedingly rare in children and occurs in most cases as a part of disseminated LCH secondary to an abnormal immune response. Over 95% of PLCH patients are smokers and it is estimated that the disease affects approximately 3–4% of smokers. PLCH affects both genders equally [31‐33]. Patients usually report fatigue, weight loss, exertional dyspnea, and non-productive cough. Pneumothorax may be the first sign in 15–20% of patients. Although, approximately 20% of patients reported no symptoms at the time of disease detection [33].

Histopathologic findings reveal bronchiole-centered, stellate nodules, containing Langerhans cells, and interspersed with other inflammatory cells (lymphocytes, macrophages, monocytes). Langerhans cells are quite large cells, containing pale cytoplasms and convoluted nucleus, which resemble coffee grains. They are immunoreactive with CD1a and S-100. Along the disease course, cellular nodules evolve from mixed cellular and fibrotic nodules to entirely polymorphic scars associated with enlarged and distorted air spaces [32‐38].

Imaging reveals upper and middle lung predominance of nodules and cysts with variable wall thickness and irregular margins. The disease characteristically spares the costophrenic sulci, extreme apices, and part of the middle lobe and lingula. Imaging findings have a typical progression over time from a predominant nodular pattern to diffusely distributed cysts with bizarre shapes (Fig. 10). The later disease stage is associated with significant emphysematous areas either related to PLCH scars or usual emphysema due to smoking (Fig. 11). GGOs are a frequent imaging finding and may be associated with the presence of other smoke-related diseases, for example, RB and DIP [6, 7, 24, 29, 30, 33, 38]. Smoking cessation is a fundamental key in the treatment process of PLCH. After smoking cessation, symptoms and radiologic alterations may partially regress or stabilize in more than half of the patients (Fig. 12) [34, 39‐46]. However, one third to a half of the patients may show respiratory failure and disease progression, despite smoking cessation (Fig. 13) [47].

PLCH should be differentiated from lymphangioleiomyomatosis (LAM), in which cysts tend to have more regular and rounded shapes and more uniformly distribution through the lung. Other differentials should also be considered, such as pulmonary metastasis, sarcoidosis, Birt-Hogg-Dubé syndrome, and infections (Fig. 14) [32, 35, 48, 49].

RB-ILD and DIP are moderately uncommon diseases related to smoking. On clinical presentation, patients usually complain about insidious dyspnea and cough over the course of weeks to months [5‐7, 50‐54]. The clinical disease course of RB-ILD and DIP tends to be stable in most of the patients. However, the rates of impairment are worse in those with DIP, in which diffusing capacity for carbon monoxide (DLco) may be severely reduced. As a consequence, deaths can occur in patients with DIP, but there are no described related deaths in those with RB-ILD [5, 50, 51]. RB is a classic histological marker of smoking, encountered in the lungs of nearly all active smokers. However, patients with RB are fundamentally asymptomatic, and the disease does not portend any clinical significance. RB and RB-ILD are differentiated by each other by the presence of respiratory symptoms and abnormal pulmonary function tests in the last one [5‐7, 50, 51].

Histopathologic examinations of RB and DIP show an excess number of pigmented or smokers’ macrophages involving the distal airways and peribronchiolar airspaces. However, DIP presents with pigmented macrophages diffusely filling the alveoli, with associated thickening of the septa secondary to the presence of inflammatory cells. On DIP findings, the degree of interstitial fibrosis is usually mild and more severe than in RB. Both entities represent a severity spectrum of the same pathologic event, with an excess number of macrophages filling the distal airways and alveoli secondary to an immune-mediated response due to smoking [5, 24, 29, 51, 55, 56].

On imaging, RB/RB-ILD shows upper lung predominance of the findings, characterized by the evidence of low attenuation centriacinar nodules, GGOs, bronchial wall thickening, few thickened interlobular septa, and also lobular air-trapping, especially depicted on expiratory CT. These findings are generally associated with emphysema (Fig. 15). The radiological findings in DIP are lower lobe predominant and characterized by GGOs and reticular opacities interposed with relatively normal lung zones, forming a mosaic attenuation. Small cystic spaces may be depicted in the areas of GGO, representing dilated alveolar ducts or centrilobular emphysema. The distribution of findings is more often subpleural but may also be random or diffuse (Fig. 16) [6, 7, 24, 29, 30, 54, 56]. Associated findings of RB and emphysema are frequently visualized. The evidence of areas of mild pulmonary fibrosis in DIP, characterized by increased septal lines, traction bronchiectasis, and lung distortion, is associated with disease progression in some individuals, despite smoking cessation and steroids [53].

Some differential diagnoses are important to be considered in association with patient’s complete clinical history, including NSIP, hypersensitivity pneumonitis, and atypical infections, including pneumocystosis (Figs. 17 and 18) [7, 24, 29, 50].