Cancer Letters 382 (2016) 240–244

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Cancer Letters
j o u r n a l h o m e p a g e : w w w. e l s e v i e r. c o m / l o c a t e / c a n l e t

Mini-review

COPD, emphysema and the onset of lung cancer. A systematic review

Cecilia Mouronte-Roibás a, Virginia Leiro-Fernández a, Alberto Fernández-Villar a,
Maribel Botana-Rial a, Cristina Ramos-Hernández a, Alberto Ruano-Ravina b,c,*
a
Pulmonary Department, Hospital Álvaro Cunqueiro, EOXI Vigo; NeumoVigoI+i Research Group, Vigo Biomedical Research Institute (IBIV), Galicia, Spain
b Preventive Medicine and Public Health, School of Medicine, University of Santiago de Compostela, San Francisco st s/n Santiago de Compostela, La Coruña, Spain
c CIBER de Epidemiología y Salud Pública (CIBERESP), Spain

A R T I C L E I N F O A B S T R A C T

Article history: Chronic Obstructive Pulmonary Disease (COPD) and emphysema have been described as possible risk
Received 18 July 2016 factors for lung cancer. We aim to assess the relationship between COPD, emphysema and the onset of
Received in revised form 25 August 2016 lung cancer. We have developed a systematic review of the published literature in order to systemati-
Accepted 1 September 2016
cally analyze the scientific evidence available on this association, applying predefined inclusion and exclusion
criteria. 11 Studies were included. Both COPD and emphysema seem to increase the risk of developing
Keywords:
lung cancer, being this risk higher for smokers with heavier tobacco consumption. These results em-
COPD
phasize the need for physicians to perform spirometries in current and former smokers and lung image
Emphysema
Lung cancer tests when needed in order to identify COPD and emphysema and thus select patients at higher risk of
developing lung cancer.
© 2016 Elsevier Ireland Ltd. All rights reserved.

Introduction
Lung cancer is the first cause of cancer mortality in the World,
representing up to 13% of all cancer deaths with more than 1,400,000
annual deaths [1,2]. On the other hand, Chronic Obstructive Pul-
monary Disease (COPD) is the fourth cause of death in the World
with a trend towards being the third one by 2020, with a current
prevalence around 10% [3]. Tobacco consumption is the main risk
factor for lung cancer, given that more than 85% of all lung cancer
cases occur among current or former smokers [4]. Tobacco is also
the main cause of COPD.
COPD and lung cancer share common features: their high mor-
tality and their common risk factors such as smoking, some genetic
background, environmental exposures and underlying common in-
flammatory processes [5,6]. Some studies have demonstrated that
COPD is a risk factor for lung cancer development, independent of
smoking exposure, with a four to six-fold greater risk of develop-
ing lung cancer when compared to matched smokers with normal
lung function [7]. This risk seems to increase with progressive de-
clines in FEV1, independent of smoking history [8]. Besides, COPD
has proved to worsen lung cancer prognosis due to higher mor-
bidity and mortality [9].
Pulmonary emphysema is a pathological lesion defined as the
enlargement of airspaces distal to the terminal bronchioles accom-
panied by destruction of their walls [10,11]. Along with chronic
The study was performed in Vigo Complex University Hospital, EOXI Vigo.
* Corresponding author. Fax: +34881872282.
E-mail address: alberto.ruano@usc.es (A. Ruano-Ravina).
bronchitis, emphysema has been recognized as one of the COPD phe-
notypes, although it may be present in other phenotypes and even
in smokers without COPD criteria [3]. There are mixed conclu-
sions in available studies exploring the relationship between lung
cancer and emphysema. Some studies report a significant risk of
lung cancer when emphysema is detected visually on chest CT
[12,13]. In contrast, other case–control studies found no associa-
tion between both entities [14].
Taking into account the importance of a potential relationship
between COPD, emphysema and the onset of lung cancer, we have
developed a systematic review of the published literature in order
to systematically analyze the scientific evidence available on this
association.
Methods
Literature search
We performed a literature search in Pubmed (Medline). To retrieve informa-
tion we used a predefined search strategy employing a combination of MeSH terms
(“Lung Neoplasms” [Mesh] AND “Pulmonary Disease, Chronic Obstructive” [Mesh]).
The search period comprised between 01/01/2000 and 30/05/2016. We retrieved
papers published in English and Spanish.
Inclusion and exclusion criteria
We used the following inclusion and exclusion criteria to include papers in the
systematic review: (a) regarding the study design we included: cohort studies, case
control studies, systematic reviews or meta-analysis; (b) regarding the sample size
we included studies with at least 500 individuals; (c) regarding COPD diagnosis we
included: patients older than 35 years, with a cumulated tobacco consumption higher
than 10 pack/years and with an obstructive spirometry; (d) regarding emphysema
diagnosis we included studies with either qualitative or quantitative evaluations of

http://dx.doi.org/10.1016/j.canlet.2016.09.002
0304-3835/© 2016 Elsevier Ireland Ltd. All rights reserved.
 C. Mouronte-Roibás et al. / Cancer Letters 382 (2016) 240–244 241

computed tomography imaging; (e) regarding lung cancer diagnosis, only studies COPD patients. These results are discrepant on the role of airflow
with anatomopathological diagnosis were included. obstruction on the risk of lung cancer, although De Torres et al. [21]
showed that the risk of lung cancer decreased with the increase in
Synthesis of information and management of search results
airflow obstruction, with a HR for GOLD 1 patients of 3.05 (95% CI
The search results were checked by one reviewer and if there were doubts re- 1.41–6.59), 2.06 (95% CI 1.01–4.18) for GOLD 2 patients and 1.67 (95%
garding the inclusion or exclusion of some papers, this was solved by consensus of CI 0.81–3.44) for GOLD 3 patients, respectively. The meta-analysis
all authors. The references of the included papers were manually reviewed and those included 7368 patients, 2809 showing emphysema in the com-
papers that might be included were also obtained and reviewed.
puted tomography and 870 lung cancer patients [11]. The risk of
We retrieved the same information for each of the included papers (following
the PRISMA guidelines, www.prisma-statement.org) using a standardized proce- lung cancer was 2.11 (95% CI 1.10–4.04) for emphysema patients.
dure consisting of a predefined table with common fields for each paper. We have Different studies have analyzed the different risk of lung cancer
presented information from each study in an evidence table and a global qualita- in patients with COPD considering the different amounts of tobacco
tive conclusion has been reached. It has been impossible to perform a meta-
smoked. Abal Arca et al. observed that the percentage of smokers
analysis due to the important heterogeneity of the included studies.
in the COPD subgroup was considerably higher than in the non-
COPD subgroup (96.6% vs 74.4%) [16] in a sample of 996 lung cancer
Results
patients. COPD patients had smoked 67 pack/years compared with
59 pack-years in the non-COPD group. De Torres et al. compared
We obtained 713 registries in the bibliographic search and we
the characteristics of lung cancer patients with non lung cancer pa-
selected 43 to be full-text read. 11 fulfilled the sample size crite-
tients in a sample of 2507 COPD patients [21]. The percentage of
rion, with sample sizes ranging from 624 to 72,653 patients. These
smokers was higher for COPD patients with lung cancer and also
papers comprised one meta-analysis, 8 cohort studies and 2 case–
the number of pack-years (74.1 vs 66.9). Other investigation by the
control studies. Most of them were performed in the USA and Spain,
same group [20] observed that the risk of lung cancer in COPD pa-
with Chinese and Japanese studies. The most frequent exclusion cri-
tients was higher if they had smoked more than 60 pack-years with
teria were not fulfilling COPD definition (spirometry with FEV1/
a HR of 2.7 (95% CI 1.7–4.3). For emphysema, lung cancer preva-
FVC < 70, cumulated tobacco consumption >10 pack/years and age
lence was higher in patients with heavier tobacco consumption (0.6%
>35 years); lung cancer diagnosis without pathologic confirma-
for those with less than 30 pack-years, 1.6% for 30–60 pack-years
tion or emphysema ascertained from a baseline low-dose CT image.
and 2.8% for those who smoked more than 60 pack-years) [15]. Li
Fig. 1 shows the flowchart of the search results.
et al. observed in a case–control study [10] that lung cancer risk
COPD prevalence in patients with lung cancer ranges from 28.4
in emphysema patients was higher when patients smoked more than
to 39.8% [15,16] in studies specifically designed to assess the rela-
40 pack-years (OR 4.46 95% CI 3.07–6.49 vs OR 2.84 95% CI 1.51–
tionship between COPD and lung cancer. This percentage is higher
5.32). Only one study has analyzed the risk of lung cancer in never-
when the study includes selected populations to be screened for lung
smokers with emphysema [15], with an OR of 6.3 (95% CI 2.4–16.9).
cancer (66%) since these patients are older and have smoked more
Regarding histological types of lung cancer, 98% of lung cancers
pack-years [17]. Emphysema is present in 47–76% [15,18] of lung
in COPD patients are non-small cell lung cancers [18]. A descrip-
cancer patients and increases with a higher tobacco consumption.
tion of lung cancer histological types in COPD patients can be found
Lung cancer prevalence is a 6% for patients with GOLD grade 1 or 2
in Table 1.
[19] and increases to a 9% when more severe patients are included
[20,21]. Table 1 shows the characteristics of all the papers included.
De Torres et al. analyzed the risk of lung cancer in COPD pa- Discussion
tients showing an incidence of lung cancer of 16.7 per 1000 person-
years [21]. Sanchez-Salcedo et al. [17] observed a Hazard Ratio (HR) To our knowledge, this is the first systematic review focused ex-
of 4.52 (95% CI 2.5–8.18) for COPD patients compared with non- clusively on the relationship between COPD or emphysema and lung

Fig. 1. Flowchart showing inclusion and exclusion flow.

 242
Table 1
Description of the included studies.

Author Publication Design Sample Emphysema (%) FEV1 (%)* Current Former Never Lung cancer + COPD/ Histologic distribution (%)
year size smokers (%) smokers (%) smokers (%) emphysema (%)

Abal Arca et al. [16] 2009 Cohort 996 NS 62 ± 19 35.9 50.7 13.4 39.8 Squamous 48.2
Adenocarcinoma 21.9
SCLC 22.5
Other 7.3

C. Mouronte-Roibás et al. / Cancer Letters 382 (2016) 240–244

De Torres et al. [21] 2011 Cohort 2,507 NS 55 ± 21 30 70 0 – Adenocarcinoma 21.86
Squamous 25.58
SCLC 6.98
Other 3.26
Smith et al. [11] 2012 Meta-analysis 7,368 38.1 NS NS NS NS NS NS
Li et al. [10] 2012 Case–control 1,015 Cases 77.99 NS Cases 45.31 Cases 54.69 0 76 Adenocarcinoma 45.84
Controls 60 Controls 39.33 Controls 60.67 Squamous 28.14
Large cell 2.3
SCLC 12.57
Hohberger et al. [18] 2013 Cohort 624 87.3 NS NS NS NS 47.3 NSCLC 98
SCLC 2
de Torres et al. [19] 2013 Case–control 666 NS Cases 85 ± 13.2 Cases 37 Cases 63 0 6 Adenocarcinoma 65 y 46
Controls 85.1 ± 12.5 Controls 42 Controls 58 Squamous 25 y 37
Sekine et al. [22] 2014 Cohort 72,653 20.1 NS 36.8 63.2 0 28.4 NS
Sanchez-Salcedo 2015 Cohort 2,989 24 NS P-IELCAP 64 P-IELCAP 36 0 66/60 (COPD/emphysema) Adenocarcinoma 55
et al. [17] Controls 65 Controls 35 Squamous 22
Large cell 12
SCLC 8
Other 3
de Torres et al. [20] 2015 Cohort 2,125 P-IELCAP 45 P-IELCAP 79 (66–91) P-IELCAP 34 P-IELCAP 66 0 – NS
PLuSS 62 PLuSS 71 (58–83) PLuSS 33 PLuSS 67
Henschke et al. [15] 2015 Cohort 62,124 Current smokers 28.5 NS 37.69 42.4 19.91 Current smokers 76.58 NS
Former smokers 20.6 Former smokers NS
Never smokers 1.6 Never smokers 9.61
Sanchez-Salcedo 2015 Cohort 6,699 P-IELCAP 24 P-IELCAP 96 ± 18 P-IELCAP 64 P-IELCAP 36 0 P-IELCAP 1.66 NS
et al. [23] PLuSS 43 PLuSS 82 ± 19 PLuSS 65 PLuSS 35 PLuSS 2.56

NS, not specified; FEV1, forced expiratory volume in one second; P-IELCAP, Pamplona International Early Lung Cancer Detection Program; PLuSS, Pittsburg Lung Screening Study; COPD, chronic obstructive pulmonary disease;
SCLC, small-cell lung cancer; NSCLC, non-small-cell lung cancer.
* Mean ± SD.
 C. Mouronte-Roibás et al. / Cancer Letters 382 (2016) 240–244
cancer. We have found that COPD is a common comorbid disease
in lung cancer [24,25], affecting 28.4–39.8% of lung cancer pa-
tients in the studies included in this systematic review [15,16]. This
is a narrow range that implies a low variability between the avail-
able studies. In addition, the development of emphysema is
associated with lung cancer, affecting 47–76% of lung cancer pa-
tients [15,18].
Prevalence is higher for emphysema than COPD in lung cancer
patients due to different possible factors. First of all, there are no
reference values to classify the presence or absence of emphyse-
ma and therefore this condition might be more frequent than COPD.
When assessed quantitatively, densitometry might be too sensi-
tive to distinguish clinically meaningful emphysema with respect
to lung cancer risk; while when ascertained visually, it is also pos-
sible that radiographic abnormalities suggestive of lung cancer may
bias the assessment of emphysema. On the other hand, COPD is
known to be underdiagnosed, as its evaluation needs of a spirom-
etry, while emphysema can be diagnosed in the same CT used to
assess the existence of lung cancer. The risk of developing lung cancer
is even higher for patients with a heavier smoking history [7]. 96.6%
of lung cancer patients with COPD are smokers [16], with increas-
ing risk with higher amounts of tobacco smoked [10,15,20,21].
Epidemiological studies of smokers show that FEV1 or COPD is
strongly associated with an increased risk of lung cancer [26], al-
though in this systematic review only two studies assessed
specifically this topic [20,21]. De Torres et al. [21] paradoxically ob-
served that the risk of lung cancer decreased with the increase in
airflow obstruction. The explanation for this finding might be that
other studies assessing the incidence of lung cancer in COPD did
not take into account the possible stages for COPD.
Smoking exposure is found in a high percentage of patients di-
agnosed with either COPD or lung cancer. Thus, the coexistence of
both diseases could also reflect a shared smoking exposure. Young
et al. [7] found a prevalence of COPD of 50% in their study includ-
ing lung cancer patients. Given those results, they proposed that
20% of smokers might get COPD and 10% of smokers might get lung
cancer, then if 50% of the latter have pre-existing COPD, 25% of COPD-
smoking patients might develop lung cancer. The importance of
smoking and COPD in lung cancer appearance is also evident in the
fact that while approximately 85% of lung cancers appear in smokers
[4], 95% of lung cancer patients presenting also with COPD are
smokers [16].
An association between persistent chronic inflammation and
cancer has long been suggested. It seems that complex inflamma-
tory processes involving many types of immune cells can cause tissue
damage and remodeling, resulting in the development of COPD and
ulterior lung cancer [27,28]. In that sense, over the past decade, there
has been a great deal of interest in the identification of biomarkers,
at least in COPD [29,30]. Some studies have even observed a reduced
lung cancer risk in patients using inhaled corticosteroids [31]. The
chance of getting lung cancer due to COPD might be therefore re-
inforced if a chronic inflammatory pathway is present along with
the action of carcinogenic tobacco compounds.
Considering the available studies in this systematic review, it is
not possible to establish a relationship between the existence of
COPD or emphysema and a particular histological type of lung cancer.
Analogous to the results of general series, there has been a change
in the most prevalent histological type over the last decade, with
a shift from squamous, that represented up to 48% of lung cancers
[16], to adenocarcinoma, representing nowadays around 50% of all
lung cancers diagnosed [10,17,19]. Nevertheless, it is intriguing why
practically all lung cancers diagnosed in COPD patients are NSCLC,
while tobacco consumption is tightly associated with SCLC. In fact,
very few SCLC are diagnosed in never smokers [32]. COPD pres-
ence (chronic inflammation) along with tobacco consumption could
cause molecular changes leading to NSCLC instead of SCLC.
243
We found different methodological problems in the literature
search. Some studies did not differentiate between COPD and em-
physema, others did not explain how emphysema was ascertained
(in a qualitative or quantitative/semi-quantitative manner), and
others made COPD diagnosis based on patient reports, or on reg-
istries not including a spirometric evaluation [33].
This review has some advantages. It is a systematic review, so
the risk of missing relevant results is scarce due to the exhaustive
search strategy. Having used MeSH terms complemented with
manual search of the references confers a low probability of losing
relevant information. We have obtained the same information from
all the included studies and the search results were indepen-
dently reviewed by the authors.
This review has also some limitations due to the heteroge-
neous methodology of the included studies, which did not allow
performing a meta-analysis. Furthermore, some studies included
thousands of patients while others only some hundreds. Due to our
strict inclusion criteria, we only included 11 papers. Some of them
are part of the multicenter cohorts PLuSS (Pittsburg Lung Screen-
ing Study) and P-IELCAP (Pamplona International Early Lung Cancer
Detection Program) [17,19–21,23]. Thus, our observations may not
be valid for patients living in other geographical areas different from
The United States, China, Japan or Spain. We are not sure that our
findings are applicable to other different populations. Also, there
are no data available on differences between men and women re-
ferring to the relationship between COPD or emphysema and lung
cancer.
In conclusion, both COPD and emphysema seem to increase the
risk of developing lung cancer, being this risk higher for smokers
with heavier tobacco consumption. These entities probably share
some underlying pathophysiologic mechanisms. The growing in-
terest in investigating the relationship between COPD and lung
cancer onset is reflected in the fact that all the papers included in
our review have been published from 2010 onwards. To have a better
picture on the association between COPD and lung cancer we need
well-designed case–control or cohort studies. Our results also em-
phasize the need for physicians to perform spirometries in current
and former smokers and lung image tests when needed in order
to identify COPD and emphysema and thus select patients at higher
risk of developing lung cancer.
Authors’ contributions
Literature search: Cecilia Mouronte-Roibás, Virginia Leiro-
Fernández. Data Collection: Cecilia Mouronte-Roibás, Virginia Leiro-
Fernández, Alberto Fernández-Villar, Maribel Botana-Rial, Cristina
Ramos-Hernández. Study Design: Cecilia Mouronte-Roibás, Virgin-
ia Leiro-Fernández, Alberto Fernández-Villar, Alberto Ruano-
Ravina. Analysis of data: Cecilia Mouronte-Roibás, Virginia Leiro-
Fernández, Alberto Fernández-Villar, Alberto Ruano-Ravina.
Manuscript preparation: Cecilia Mouronte-Roibás, Alberto Ruano-
Ravina. Review of the manuscript: Virginia Leiro-Fernández, Maribel
Botana-Rial, Alberto Fernández-Villar, Alberto Ruano-Ravina.
This paper is part of the work conducting to the PhD degree of
Cecilia Mouronte-Roibás.
Conflict of interest
None declared.
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