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201343 College of American Pathologists

Research Article

Smoking-Related Interstitial Lung Disease

Teri J. Franks, MD; Jeffrey R. Galvin, MD

 Context.Emphysema, respiratory bronchiolitis, desquamative interstitial pneumonia, pulmonary Langerhans

cell histiocytosis, small-airway injury including submucosal and adventitial fibrosis, increased bronchus-associated
lymphoid tissue, and small artery/arteriolar wall thickening are recognized histologic findings in cigarette smokers.
It has only recently been acknowledged that the range of
lung injury from cigarette smoke is wider than generally
accepted, in particular, there is increasing recognition that
fibrosis of alveolar walls occurs in smokers.
Objectives.To review the literature that describes the
range of histologic findings in cigarette smokers and that

links cigarette smoke exposure to the development of

alveolar wall fibrosis.
Data Sources.Relevant peer-reviewed literature indexed in PubMed (National Library of Medicine) form the
basis of this review.
Conclusions.Smokers demonstrate a wide range of
lung injury at biopsy that defies simple placement within
single categories, and the current categories do not
adequately take into account the importance of alveolar
wall and airway fibrosis.
(Arch Pathol Lab Med. doi: 10.5858/arpa.2013-0384-RA)

It has only recently been acknowledged that the range of

lung injury from cigarette smoke is wider than generally
accepted,12 in particular, there is increasing recognition that
fibrosis of alveolar walls occurs in smokers. As a result,
lesions called combined pulmonary fibrosis and emphysema,13
respiratory bronchiolitisinterstitial lung disease with fibrosis,14
airspace enlargement with fibrosis,15 and clinically occult
smoking-related interstitial fibrosis16 have been added to our
lexicon of smoking-related lung injury, again as separate
entities. That alveolar wall fibrosis occurs in smokers should
not be a surprise. There is long-standing evidence that
fibrosis of alveolar walls is related to cigarette smoke
exposure. This has been documented in animal1720 and
human10,2124 studies. Collectively, these studies demonstrate not only that cigarette smoke causes alveolar wall
fibrosis as evidenced by increased elastic and collagen
content, but also that fibrosis increases with time and
intensity of exposure. From the study of Auerbach et al10 in
1963, to the article by Katzenstein et al16 in 2010, there are at
least 5 decades of studies providing evidence that links
cigarette smoke exposure to the development of alveolar
wall fibrosis.
The clinical significance of fibrosis in dyspneic cigarette
smokers is controversial. However, there is consistent
evidence that smokers who have emphysema and fibrosis
can be extremely dyspneic and may present with normal
flow rates on spirometry, normal total lung capacity, and
strikingly low diffusion capacity.25,26 Destruction of lung
parenchyma by emphysema reduces elastic recoil of the
lung, resulting in reduced flow rates, air trapping, and
increased total lung capacity. The opposite occurs with lung
fibrosis, which increases elastic recoil of the lung, resulting
in increased flow rates and reduced total lung capacity.
When emphysema and fibrosis occur together, total lung
capacity and flow rates tend to normalize. Both emphysema
and fibrosis, however, reduce diffusing capacity, and in
combination, the reduction in diffusing capacity is additive.

uman lung tissue responds to injury with a combination of destruction, remodeling, and repair that is
manifest by airspace enlargement and laying down of
collagen and elastin.1,2 The process of remodeling and repair
has been well documented as a response to the inflammation and destruction from cigarette smoke that involves all
compartments of the respiratory system from the conducting airways to the alveolar walls.3 The inflammation,
destruction, remodeling, and repair from inhaled cigarette
smoke are reflected radiologically and histologically as a
variety of airway and parenchymal alterations. These
alterations have been described over decades as separate
diseases, including emphysema,4 respiratory bronchiolitis,3
respiratory bronchiolitisinterstitial lung disease,5 desquamative interstitial pneumonia,6 and pulmonary Langerhans
cell histiocytosis.7 Small-airway injury, including submucosal and adventitial fibrosis, remodeling evidenced by
distortion, and increased bronchus-associated lymphoid
tissue,8,9 along with thickening of walls of small arteries
and arterioles,911 are well-recognized histologic findings in
cigarette smokers.
Accepted for publication January 16, 2014.
From Pulmonary and Mediastinal Pathology, The Joint Pathology
Center, Silver Spring, Maryland (Dr Franks); and the Departments of
Diagnostic Radiology and Nuclear Medicine, Chest Imaging Section,
and Internal Medicine, Pulmonary/Critical Care Medicine, University of Maryland School of Medicine, Baltimore, Maryland, and
Chest Imaging, American Institute for Radiologic Pathology, Silver
Spring, Maryland (Dr Galvin).
The authors have no relevant financial interest in the products or
companies described in this article.
The views expressed in this article are those of the authors and do
not necessarily reflect the official policy or position of the
Department of Defense or the US Government.
Reprints: Teri J. Franks, MD, The Joint Pathology Center, Defense
Health Agency National Capital Region Medical Directorate,
Department of Defense, 606 Stephen Sitter Ave, Silver Spring, MD
20910 (e-mail: teri.j.franks.civ@mail.mil).
Arch Pathol Lab Med

Smoking-Related Interstitial Lung DiseaseFranks & Galvin 1

Smoking-related lung injury. Axial chest computed tomography slices of the right lung acquired at the level of the (a) upper lobe and (b) lower lobe
demonstrate widespread, geographic areas of ground glass (asterisks) involving more than 70% of both lungs. Well-defined, small (, 1 cm) cystic
spaces (arrowheads) are best identified throughout the areas of ground glass. They are most numerous in the upper lobes following the normal
distribution associated with emphysema. The corresponding open lung biopsy shows a constellation of findings including (c) emphysema, varying
alveolar wall fibrosis, and stellate scars consistent with fibrotic lesions of pulmonary Langerhans cell histiocytosis (PLCH); (d) respiratory bronchiolitis
(smokers macrophages) and small-airway injury evidenced by subtle submucosal and adventitial fibrosis; and (e) small-airway injury including
marked fibrosis with airway distortion, and thickening of the walls of arterioles (arrowhead). The stellate shape of PLCH lesions (f) may be obscured
by surrounding fibrosis; however, (g) even in the absence of obvious Langerhans cells, the typical polymorphous mixture of lymphocytes, plasma
cells, and eosinophils (arrowheads) is diagnostic (hematoxylin-eosin, original magnifications 312.5 [c and f], 3100 [d], 340 [e], and 3600 [g]).

2 Arch Pathol Lab Med

Smoking-Related Interstitial Lung DiseaseFranks & Galvin

Consequently, patients are dyspneic out of proportion to

their spirometric findings. This constellation of dyspnea,
normal spirometry findings, and low diffusing capacity often
prompts the clinical decision to subject dyspneic smokers to
open lung biopsy. The presence of normal spirometry
findings in dyspneic cigarette smokers has led to an
erroneous assumption that the fibrosis commonly found
on biopsy in these patients is clinically insignificant.14,16,27 In
our experience, a substantial percentage of cigarette
smokers who undergo open lung biopsy because of dyspnea
demonstrate normal flow rates and markedly reduced
diffusion capacity. Some meet the criteria for usual
interstitial pneumonia both on chest computed tomography
(CT) and lung biopsy, a finding also reported by Katzenstein
et al,16 which is not unexpected as smoking is considered to
be a risk factor for idiopathic pulmonary fibrosis.28,29 Many,
however, demonstrate a combination of emphysema and
fibrosis similar to that described by Yousem14 and Katzenstein et al.16 Progression of disease in smokers with this type
of fibrosis appears to be slower than in patients with
idiopathic pulmonary fibrosis.14,16 Chest CT often shows
evidence of both emphysema and fibrosis even when the
spirometry findings are normal (Figure, a and b). However,
chest CT, including high-resolution studies, may be
insensitive in diffuse fibrosis and the only hint is provided
by the presence of emphysematous spaces that are
unusually well demarcated because of the surrounding
fibrotic lung.
As described and referenced in the preceding paragraphs,
the histologic appearance of lung injury secondary to
cigarette smoke is a constellation of findings that includes
smokers macrophages within airspaces, which may be
airway centered (respiratory bronchiolitis) or diffuse (desquamative interstitial pneumonia) in distribution; emphysema; small-airway injury evidenced by submucosal and
adventitial fibrosis, remodeling that results in distortion, and
increased bronchus-associated lymphoid tissue; thickening
of walls of small arteries and arterioles; stellate cellular and/
or fibrotic lesions of pulmonary Langerhans cell histiocytosis; and alveolar wall fibrosis (Figure, c through g).
Currently, we attempt to package this array of findings into
separate categories for diagnosis.30 However, Hansell and
Nicholson12 emphasize the frequent coexistence of smoking-related lung diseases, and in practice, open lung
biopsies from smokers more often than not display a
combination of histologic findings that cross the boundaries
of our established diagnostic categories. The terms smokingrelated interstitial lung disease and smoking-related interstitial
pneumonia are used in an attempt to bring together
coexisting histologic findings into a single diagnosis.30
Although useful as umbrella terms, the terms are incomplete descriptions in that they suggest the injury from
smoking is entirely interstitial, and they ignore the
importance of smokers macrophages in the pathogenesis
of cigarette smokeinduced lung injury.31 The presence of
constrictive historical categories has to some degree
impeded progress in our understanding of smoking-related
lung injury. The recent expansion in descriptive language
highlights the need for reassessment of the range of injury
related to cigarette smoke that includes all compartments of
the respiratory system from the conducting airways to the
alveolar walls. Rigorous multidisciplinary investigation8,26,32
will be required to fully understand the nature and clinical
implication of the multiple interrelated components of
smoking-related lung injury. In the meantime, smokingArch Pathol Lab Med

related alveolar wall fibrosis is a well-supported concept and

a clinically important form of lung injury.
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