33  The Syndrome of Combined Pulmonary Fibrosis and Emphysema	571

Fig. 33.7  Chest HRCT showing thick-walled large cysts (male, ex-­ smoker). In this example, large subpleural cysts are relatively isolated, with little reticulation in the area surrounding the cysts. Septa are visible inside the right lower lobe cyst

Pathology

Due to emphysematous changes, frequent comorbidities, and severity of gas exchange impairment, very few patients with CPFE at imaging are subjected to lung biopsy by video-­ assisted thoracoscopic surgery. Therefore, only limited and likely skewed data are available regarding lung pathology in patients with CPFE, consisting of small series of autopsy cases or explants [158, 166, 167]. Patterns of brosis observed in patients with CPFE are histologically heterogeneous [168, 169].

Histopathologic ndings are dominated by the UIP pattern (Fig. 33.8), and commonly by overlapping patterns of smoking-related ILD and pulmonary brosis, including respiratory bronchiolitis-associated ILD, desquamative interstitial pneumonitis, and Langerhans cell histiocytosis (Table 33.3) [8, 24, 154–156, 170]. Due to the presence of emphysema, and to the frequent overlap of smoking-related

a

b

c

Fig. 33.8  Lung pathology in a patient with the CPFE syndrome. (a) emphysema adjacent to interstitial brosis (upper right lobe); (b) densebrosis with subpleural pathological honeycombing (lower right lobe,

low magni cation); (c) broblastic focus in an area of dense brosis, at the center of the slide (lower right lobe, high magni cation). (Courtesy of Pr Françoise Thivolet-Béjui, Lyon (France))

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abnormalities, classifying subtypes of pulmonary brosis may be challenging in the setting of CPFE [8, 167].

In an autopsy series of 22 cases including 15 (68%) with a UIP pattern at HRCT—and 19 with lung cancer—a pathological pattern of UIP was observed in all cases [158]. Honeycombing coexisting with emphysema was present in half of the patients. Interestingly, thick-walled large cysts at imaging corresponded pathologically to thick-walled cystic lesions lined by bronchiolar epithelium, located in the centriacinar/centrilobular region, involving one or more acini, with emphysematous changes and enlargement of membranous and respiratory bronchioles, dense collagen brosis of the walls, and occasional broblastic foci, surrounded by honeycombing and normal alveoli. Thick-walled large cysts were not observed in IPF without emphysema [158]. Non-­ prominent bronchiolocentric brosis was occasionally present.

Histopathology of lung specimens in patients with emphysema has demonstrated thickened interstitium in addi-

tion to enlargement of alveolar spaces [171]. Excess of collagen and elastin deposition was present in the interstitium at electron microscopy, especially in septal walls of diseased areas [171]. Clinically occult interstitial brosis is surprisingly common in lobectomy specimens in smokers [172]. These abnormalities have been described with various terminologies with likely overlapping features [173]: “smoking-­ related interstitial brosis” (Figs. 33.9 and 33.10) [174], “clinically occult interstitial brosis” [172], “airspace enlargement with brosis” [175], “ brosis superimposed on emphysema” [173], “respiratory bronchiolitis-associated ILD” [176], “respiratory bronchiolitis-associated ILD withbrosis” [170], and unclassi able smoking-related interstitial brosis [172]. Such histopathological changes may only rarely be associated with physiological or radiological features of an ILD [173]. For the pathologist, the further presence of tobacco-laden alveolar macrophages is helpful as an indicator that the brosis is likely related to smoking and “superimposed on emphysema” [173]. Collectively, these

Fig. 33.9  Smoking-related interstitial brosis. Severe interstitial brosis involving deep parenchyma in a centrilobular distribution associated with emphysema. Very little infammation is present. (From Katzenstein AL et al., gure 2, panel B, [172] with permission)

33  The Syndrome of Combined Pulmonary Fibrosis and Emphysema	573

Fig. 33.10  Chest HRCT in a patient with smoking-related interstitialbrosis at histopathology. Upper panel: upper lobes demonstrating centrilobular emphysema. Lower panel: combination of brotic interstitial lung disease with ground-glass attenuation, suggestive of desquamative interstitial pneumonia, admixed with cystic changes distant to the pleura and with thickened walls, suggestive of smoking-related interstitial brosis

observations suggest that remodeling of the alveolar interstitium takes place in patients with predominant emphysema, even in the absence of ILD changes at imaging, further suggesting that emphysema with mild brosis of alveolar walls only at the histopathologic level on the one hand, and overt CPFE syndrome on the other hand, may be part of a continuum of smoking-related lung disease.

Indeed, SRIF is a distinctive pattern of brosis observed in CPFE and linked to cigarette smoking. Described by A. L. Katzenstein [113, 167, 172, 174], SRIF is characterized by densely eosinophilic collagen deposited in expanded alveolar septa with preservation of lung architecture and little or no infammation. It overlaps with previous descriptions of airspace enlargement with brosis [175, 177, 178], respiratory bronchiolitis-associated ILD with brosis [170], respiratory bronchiolitis with brosis [179], and desquamative interstitial pneumonitis [174]. SRIF may be frequently combined with paraseptal emphysema, likely accounting for the “thick-walled cystic lesions” observed on HRCT that are unique to CPFE and distinct from the honeycomb cysts of UIP [65, 113, 158].

Extensive vascular changes (intimal thickening, medial hypertrophy, and occasionally plexiform lesions) are more frequent in CPFE than in IPF or emphysema alone [166], and may involve emphysematous, brotic, and relatively preserved parenchyma. Malignancy, especially squamous cell carcinomas, is also not uncommon in CPFE [105].

Diagnosis

CPFE syndrome is de ned by the combined presence of emphysema (generally predominating in the upper lobes) and pulmonary brosis (mostly in the lower lobes). Lack of consensus on criteria for CPFE has limited our ability to compare cohorts and draw consistent conclusions about the features, outcomes, and optimal management of these patients [180]. The role of multidisciplinary discussion has not been formally studied in CPFE but is likely as important as in IPF [163].

The following diagnostic criteria used in the seminal description of the CPFE syndrome and later series [8, 25, 26] comprised: (1) “conspicuous” emphysema (centrilobular and/or paraseptal) de ned as well-demarcated areas of low attenuation delimitated by a very thin wall (≤1 mm) or no wall; and (2) bibasilar reticular abnormalities with basal and subpleural predominance, traction bronchiectasis and/or honeycombing, and with minimal ground-glass opacities on HRCT scan. Although not based on semi-quanti cation of emphysema, this rather simple approach for diagnosing emphysema (e.g. noticeable without quanti cation of imaging features) has revealed to select patient populations with very reproducible physiology [8, 25, 26].

However, such criteria do not specify what extent of emphysema and brosis at imaging is needed to classify an individual has having CPFE rather than isolated IPF (or emphysema with no signi cant ILD), which hampers reproducibility and research. Several studies have therefore de ned CPFE as IPF (according to international criteria for the diagnosis of IPF at the time) with associated emphysema at imaging, using various thresholds or de nitions for emphysema, including emphysema being notable or at least equivalent in extent to the brosis (“moderate emphysema”) [132]; or IPF with emphysema score ≥4/24 and brosis score ≥4/24, with scores based on estimates of the percentage of low attenuation areas (or of areas with reticulation/honeycombing) at three anatomic levels in both lungs (with emphysema andbrosis considered signi cant when present in over half of the total lung elds) [148]; or IPF with >10% of the lung affected with emphysematous changes [21]; or IPF with total emphysema score ≥10% [13], a thresholds that corresponds to GOLD stage II or worse in patients with isolated chronic obstructive pulmonary disease; or brotic ILD combined with emphysema using a speci c threshold of emphysema

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extent of >5% [131, 142], >10% [13, 21, 181–183], >15% [130], >20% [184], or >25% [167] of total lung volume. >5%, 10%, 15%, 20% or 25% of total lung volume.

An ongoing international taskforce proposes a common terminology, and provisional de nition and classi cation criteria (Table 33.4). CPFE is de ned as the combination of emphysema and any subtype of brosing ILD. Emphysema

Table 33.4  Proposed research defnition of CPFE (to serve research purposes) and classi cation criteria of CPFE clinical syndrome (intended to have clinical relevance)

Research defnition of	Coexistence of both pulmonary brosis
CPFE	and emphysema
	Patients must have both criteria on
	HRCT:
	•  Emphysema of any subtype at HRCT
	de ned as well-demarcated areas of
	low attenuation delimitated by a very
	thin wall (≤1 mm) or no walla, b, c and
	involving at least 5% of total lung
	volumed
	•  Lung brosis of any subtypee
Classifcation criteria of	Patients must have CPFE (see above)
CPFE clinical syndrome	and one or more of the following:
These additional criteria	• Emphysema extent ≥15% of total
serve research purposes,	lung volumed, f
and may be considered	•  Relatively preserved lung volumes and
depending on the	airfow with very or disproportionately
objective of the study	decreased DLco, especially in patients
	with limited extent of HRCT
	abnormalities, and in the absence of
	pulmonary hypertension
	•  Precapillary pulmonary hypertension
	considered not related to the sole
	presence of emphysema
	(FEV1 > 60%), brosis (FVC > 70%),
	or the etiological context (e.g.
	absence of connective tissue disease).

CPFE combined pulmonary brosis and emphysema, DLco diffusion capacity for carbon monoxide, FEV1 forced expiratory volume in 1 s, FVC forced vital capacity, HRCT high resolution computed tomography, ILD interstitial lung disease

a Emphysema generally predominates in the upper lobes but may be present in other areas of the lung or may be admixed with brosis b Emphysema may be replaced by thick-walled large cysts greater than 2.5 cm in diameter (“CPFE, thick-walled large cysts variant”) c Surgical lung biopsy is not required if the HRCT pattern is diagnostic, however, CPFE is suggested if lung biopsies show emphysema and any pattern of pulmonary brosis; emphysema can then be quanti ed on HRCT

d Emphysema extent is assessed visually by an experienced radiologist. Emphysema extent <5% is unlikely to impact physiology or outcome, and is more open to interobserver disagreement

e Signs of brosis on HRCT in a patient with ILD include architectural distortion, traction bronchiectasis, honeycombing and volume loss. Caution must be exerted for the identi cation of honeycombing in patients with associated emphysema. Ground-glass attenuation may be present. Interstitial lung abnormalities [165] are not suf cient to support the diagnosis of CPFE

f Emphysema extent greater than 15% is associated with relatively stable FVC over time. Several studies have used a 10% threshold, however association with outcome and FVC has not been demonstrated

predominates in the upper lobes but may be present in the lower zones or be admixed with brosis. When reporting CPFE in the individual patient, it is useful to describe the radiologic and, if available, the histopathologic pattern, as well as the etiological context. As an example, a case with UIP on HRCT and emphysema in a smoker may be described as smoking-related “CPFE—radiologic UIP.”A case with brotic NSIP on biopsy and emphysema may be described as idiopathic “CPFE—histologic NSIP.” A case of UIP pattern and emphysema on HRCT in a non-smoker with rheumatoid arthritis may be described as “rheumatoid arthritis-­associated CPFE—radiologic UIP.” Thresholds of emphysema extent are proposed. The research defnition for CPFE was developed to enable future research and uses a threshold of 5% emphysema extent; and the provisional classi cation criteria of the CPFE clinical syndrome was developed to delineate a scenario which may serve clinicians managing patients with CPFE, and use a threshold of 15% emphysema extent on HRCT.

One limitation of these criteria is that they require the assessment of emphysema extent on HRCT. In the future, diagnostic criteria for CPFE may be re ned, and the assessment of whether emphysema is clinically signi cant in a patient with brotic ILD, e.g. whether criteria are met to consider CPFE clinical syndrome, may be supported by physiologic criteria. Indeed, pulmonary function tests may actually contribute to the diagnosis of CPFE when demonstrating a typical functional pro le, with preserved physiology and decreased DLco, especially in patients with mild imaging abnormalities. When present, thick-walled large cysts may contribute to the recognition of the syndrome. Similarly, precapillary PH in a patient with suspected CPFE may be considered as an additional clue to the diagnosis, as it is its most frequent complication present in about half of the patients. Conversely, CPFE may be diagnosed at an early stage as a result of screening for lung cancer [138, 185, 186], as described for IPF.

CPFE Is a Syndrome

CPFE is considered a syndrome based on distinct clinical features (clinical utility), and pathogenetic considerations and to facilitate further potentially crucial pathogenetic research (pathogenic utility). The main clinical arguments in favor of CPFE being a syndrome include differences in outcome between patients with CPFE and those with isolated IPF (e.g. greater mortality and greater risk of PH for a given extent of brotic ILD), increased risk of lung cancer as compared to isolated IPF, implications for monitoring of disease progression which cannot be reliably based on FVC, and implications for clinical research (FVC is not a reliable endpoint in patients with IPF combined with emphysema). Pathogenic arguments in favor of CPFE being a syndrome