Cottin et al. defined the following criteria as CPFE: a) presence of emphysema on CT scan, defined as well-demarcated areas of decreased attenuation in comparison with contiguous normal lung and marginated by a very thin (<1 mm) or no wall and/or multiple bullae (>1 cm) with upper zone predominance and b) presence of a diffuse parenchymal lung disease with significant pulmonary fibrosis on CT scan, defined as reticular opacities with peripheral and basal predominance, honeycombing, architectural distortion, and/or traction bronchiectasis or bronchiolectasis. Focal ground-glass opacities and/or areas of alveolar condensation may be associated but should not be prominent [6]. And although chest X-ray is generally useful to evaluate the volume loss of the lung due to interstitial pneumonia, the lung volume is tend to be preserved by complicated with emphysema in CPFE.

The type of emphysema in CPFE was centrilobular emphysema, paraseptal emphysema, and bullae, whose prevalence was 97 %, 93 %, and 54 %, respectively [8]. Above all, paraseptal emphysema (low-attenuation areas in subpleural zone) has been described in almost all reports about CPFE, and Portillo et al. suggest that paraseptal emphysema is a typical feature of CPFE [9]. However, discrimination of the emphysema type in CPFE was very difficult because of the modification of the HRCT appearance by fibrosis [10]. And thick-walled large cysts (TWLCs), which are defined as cysts 2 cm or more in diameter and delimitated by a wall 1 mm or more thick in an area of the lung where reticulation is present, are also considered as one of the characteristic feature of CPFE [11, 12].

Matsuoka et al. evaluated the differences in 5-year morphological changes among the patients with CPFE, emphysema alone, and fibrosis alone [13]. The authors revealed that the mean change of the percentage of low attenuation area was higher in CPFE (7.4 ± 3.8 %) than in emphysema alone (4.5 ± 3.3 %). And the mean change of the percentage of destructed lung area was higher in CPFE (12.9 ± 5.8 %) than in emphysema alone (4.9 ± 2.8 %) and fibrosis alone (7.1 ± 5.7 %). So they concluded that the morphological progression of the patients with CPFE were different from the patients with emphysema alone or fibrosis alone.

Airspace enlargement with fibrosis (AEF) has been identified pathologically as a smoking-related change [14]. Watanabe et al. revealed that HRCT features of AEF were multiple thin-walled cysts (MTWCs) and/or reticular opacities. And the authors suggested the possibility that these changes had been confused with/interpreted as honeycombing and/or emphysema in the past [15].

The biggest problem in diagnostic criteria using CT findings is that there are no definitive criteria in the extent of emphysema or fibrosis. So this disease entity may include various phenotype because the diagnosis is arbitrary dependent on the physicians. Under such circumstances, some studies defined CPFE as the coexistence of “significant” emphysema that was the total percentage of low-attenuation area due to emphysema calculated from six lung fields (upper, middle, lower) on chest HRCT that is more than 5–25 % [16–20].

Although the pathological features have not yet been fully studied, there were several reports of pathological consideration associated with CPFE, which were presented as the characteristic lung lesions in smokers (Fig. 17.2).

In 2006, Yousem et al. reported respiratory bronchiolitis-associated interstitial lung disease with fibrosis, which was associated with a respiratory bronchiolitis having extensive paucicellular lamellar eosinophilic collagenous thickening of alveolar septa in a patchy, particularly subpleural distribution [21].

In 2008, Kawabata et al. examined the pathological findings of 587 smokers in lobectomy specimens for lung cancer and reported that AEF was an important smoking-related change in the lung [14] (Fig. 17.2). Macroscopically, AEF showed various sized thin-walled cysts (thinner than that of honeycombing) which was seen slightly apart from pleura in the basal areas of the lower lobe. And microscopically, AEF was characterized as (a) fibrous (frequently hyalinized) interstitium with structural remodeling, (b) emphysematous change, (c) frequent bronchiolocentric location, and (d) absence of fibroblast foci. The incidence of AEF was 6.5 % in mild smokers and 17.7 % in moderate smokers with lower lobe predominance, thus appeared to correlate with the smoking history.

In 2010, Katzenstein et al. also examined 20 smokers in lobectomy specimens excised for neoplasms and reported clinically occult interstitial fibrosis in smokers [22]. This lesion was characterized by varying degrees of alveolar septal thickening by collagen deposition along with emphysema and respiratory bronchiolitis. The fibrosis occurred both in subpleural and in deeper parenchyma and surrounded enlarged airspaces of emphysema, but it also involved non-emphysematous parenchyma. And the authors termed them smoking-related interstitial fibrosis.

In the study of an autopsy series of 22 CPFE patients, Inomata et al. described that thick-cystic lesions involving one or more acini with dense wall fibrosis and occasional fibroblastic foci surrounded by honeycombing and normal alveoli were confirmed as TWCL. And emphysematous destruction and enlargement of membranous and respiratory bronchioles with fibrosis were observed in the TWCLs. The prevalence of both radiological and pathological TWCLs was 72.7 % in CPFE patients, but nothing in patients with IPF or emphysema alone (p = 0.001). So the authors suggested that TWCLs would be considered the one of the feature in CPFE [12].

Various findings in the pathological features of CPFE have been reported as described above; however, Wright et al. concluded that smoking commonly produces a degree of fibrosis in the walls of the respiratory bronchioles (RB) and that this fibrosis might extend around the enlarged airspaces of centrilobular emphysema which is formed from damaged RB [23]. And the fibrosis can also extend in the interstitium away from the RB, typically toward the pleura.

Cottin et al. demonstrated the physiological consequences of the coexistence of emphysema and fibrosis, which resulted in preserved lung volumes but a markedly decreased diffusing capacity [6]. More specifically, forced vital capacity (FVC), forced expiratory volume in the first second (FEV1), and total lung capacity (TLC) are usually within nearly normal ranges, unlike diffusing capacity for carbon monoxide (DLCO), which is significantly reduced. And almost all of the other reports have confirmed these physiological findings [6, 8, 11, 16, 17, 29–31, 34, 37, 59, 61, 62] (Table 17.2).