Rev Clin Esp.

2017;217(7):387---393

Revista Clínica
Española
www.elsevier.es/rce

ORIGINAL ARTICLE

Incidence of cancer in outpatients with chronic

obstructive pulmonary disease夽,夽夽
J.M. Figueira Gonçalves a,∗ , R. Dorta Sánchez a , L.I. Pérez Méndez b,c , L. Pérez Negrín a ,
I. García-Talavera a , A. Pérez Rodríguez a , D. Díaz Pérez a , P. Viña Manrique a ,
C. Guzmán Sáenz a

a
Pneumology and Thoracic Surgery Service, University Hospital Nuestra Sen˜ora de Candelaria, Santa Cruz de Tenerife, Spain
b
Department of Clinical Epidemiology and Biostatistics, Research Unit, University Hospital Nuestra Sen˜ora de Candelaria and
Primary Care Management, Santa Cruz de Tenerife, Spain
c
CIBER de Enfermedades Respiratorias, Instituto de Salud CArlos III, Madrid, Spain

Received 2 February 2017; accepted 14 June 2017

Available online 12 September 2017

KEYWORDS Abstract
Chronic obstructive Introduction: The relationship between chronic obstructive pulmonary disease (COPD) and the
pulmonary disease overall incidence of cancer is poorly understood. The aim of this study was to analyze the
(COPD); incidence of cancer (pulmonary and extrapulmonary sites) in patients with COPD followed up in
Incidence; a specialized outpatient unit, and to assess the relationship to the degree of airflow obstruction.
Cancer Methodology: A prospective observational study was conducted with a cohort of 308 patients
with COPD followed up at pulmonology outpatient clinics from January 2012 to December 2015.
The neoplasms diagnosed during this period were divided into a pulmonary and an extrapul-
monary group.
Results: The overall yearly incidence rates of cancer, lung cancer and extrapulmonary cancer
cases per 1000 patients with COPD were 10.3, 3.4 and 7.3 cases, respectively. The most frequent
cancer types were lung cancer (31%), genitourinary tract cancer (29%) and gastrointestinal
cancer (21%). Mild to moderate stages (grade I---II of the 2009 GOLD classification) and the
increase in the pack-year index (PYI) were related to an increase in the onset of neoplasia,
with an odds ratio (OR) of 2.16 (95% confidence interval [95% CI]: 1.087---4.309; p = .026) and
1.01 (95% CI: 1.002---1.031; p = .023), respectively.

夽 Please cite this article as: Figueira Gonçalves JM, Dorta Sánchez R, Pérez Méndez LI, Pérez Negrín L, García-Talavera I, Pérez Rodríguez

A, et al. Incidencia de cáncer en pacientes ambulatorios con enfermedad pulmonar obstructiva crónica. Rev Clin Esp. 2017;217:387---393.
夽夽 This manuscript won the 2016 Respiratory Disease Prize of the Royal Academy of Medicine of Santa Cruz de Tenerife.
∗ Corresponding author.

E-mail address: juanmarcofigueira@gmail.com (J.M. Figueira Gonçalves).

2254-8874/© 2017 Elsevier España, S.L.U. and Sociedad Española de Medicina Interna (SEMI). All rights reserved.
388 J.M. Figueira Gonçalves et al.

Conclusion: The incidence of extrapulmonary cancer in patients with COPD was twice that of
lung cancer; stages I--II of the 2009 GOLD classification and the PYI were significantly related to
the onset of neoplasia.
© 2017 Elsevier España, S.L.U. and Sociedad Española de Medicina Interna (SEMI). All rights
reserved.

PALABRAS CLAVE Incidencia de cáncer en pacientes ambulatorios con enfermedad pulmonar

Enfermedad obstructiva crónica
pulmonar obstructiva
Resumen
crónica (EPOC);
Introducción: La relación entre la enfermedad pulmonar obstructiva crónica (EPOC) y la inci-
Incidencia;
dencia global de cáncer es poco conocida. El objetivo del estudio fue analizar la incidencia
Cáncer
de cáncer (tanto de localización pulmonar como extrapulmonar) en pacientes con EPOC en
seguimiento en una consulta ambulatoria especializada, así como valorar su relación con el
grado de obstrucción al flujo aéreo.
Metodología: Estudio observacional prospectivo de una cohorte de 308 pacientes con EPOC en
seguimiento en consultas ambulatorias de neumología durante el periodo comprendido entre
enero de 2012 y diciembre de 2015. Las neoplasias diagnosticadas en este periodo se dividieron
en pulmonares y extrapulmonares.
Resultados: Las tasas de incidencia global de cáncer, de cáncer de pulmón (CP) y de cáncer
extrapulmonar fueron de 10,3, 3,4 y 7,3 casos por 1.000 pacientes EPOC-año, respectiva-
mente. Los tumores más frecuentes fueron el CP (31%), los del tracto genitourinario (29%)
y digestivo (21%). Los estadios leve-moderado (grados I-II de la GOLD 2009) y el incremento del
índice paquetes-año (IPA) se relacionaron con un aumento en la aparición de neoplasias con
un odds ratio (OR) de 2,16 (intervalo de confianza al 95% [IC95%] : 1,087-4,309; p = 0,026) y 1,01
(IC95% :1,002-1,031; p = 0,023), respectivamente.
Conclusión: La incidencia de cáncer de localización extrapulmonar en pacientes con EPOC
duplica a la de CP. Los estadios I-II de la GOLD 2009 y el IPA se relacionan de forma significativa
con la aparición de neoplasias.
© 2017 Elsevier España, S.L.U. y Sociedad Española de Medicina Interna (SEMI). Todos los
derechos reservados.

Background Lung cancer and COPD seem to share common envi-

Tobacco use has been defined as the main preventable
cause of premature mortality and constitutes one of the
main health problems in developed countries.1---4 The ingre-
dients of tobacco include ammonia, pyridine, tar, polycyclic
aromatic hydrocarbons and nitrosamines, whose combus-
tion releases more than 4000 hazardous substances, at
least 60 out of which have been demonstrated to be
carcinogenic.5
In addition to being responsible for 90% of lung can-
cers, tobacco smoke has been shown to have a solid
relationship with the development of cancer at other sites,
including the oral cavity, larynx, esophagus, bladder, kid-
neys, pancreas, stomach, colon, rectum and cervix.6---11
Apart from its carcinogenic effects, tobacco smoke has
a role as a risk factor for the development of the main
chronic cardiovascular and respiratory diseases, the latter
of which include disorders such as bronchial asthma, respi-
ratory infections and chronic obstructive pulmonary disease
(COPD).12,13
ronmental exposure factors beyond smoking.14---17 COPD is
known to increase three to fivefold fold the risk of devel-
oping lung cancer.15,18---22 Chronic bronchitis, emphysema
and the degree of bronchial obstruction are independent
risk factors for the onset of lung cancer.18---29 Moreover,
various studies have demonstrated an increase in the devel-
opment of extrapulmonary tumors in patients with COPD
compared with smokers without obstruction.30---35 Although
direct toxicity of tobacco-derived metabolic products may
be responsible for this increase, the underlying inflamma-
tory process in a chronic disease such as COPD could play a
crucial role in the carcinogenic response of various organs,
amplifying mutagenesis and facilitating tumor growth and
subsequent metastatic spread.7,36---39
The incidence rate of lung cancer in patients with COPD
ranges from 1.4 to 16.7 per 1000 person-years.19,22,40 How-
ever, the exact overall incidence rate for cancer, especially
extrapulmonary cancer, is not known. The aim of this
study was to determine incidence rate of both pulmonary
and extrapulmonary cancer in a followed-up, pulmonology
Incidence of cancer in outpatients with chronic obstructive pulmonary disease
outpatient population with COPD and to assess its relation-
ship to the degree of airflow obstruction.
Material and methods
An observational, prospective study was conducted with a
cohort of patients with COPD followed up at outpatient pul-
monology clinics of the University Hospital Nuestra Señora
de Candelaria (HUNSC) between January 1, 2012 and Decem-
ber 31, 2015. The included population represented the
southern and capital area of the island of Tenerife, which
has a reference population of 452,000 inhabitants and 22
health areas.
Inclusion criteria comprised an age over 40 years, active
smokers or ex-smokers with a pack-year index (PYI) ≥10 and
a post-bronchodilator forced expiratory volume in 1 second
(FEV1)/forced vital capacity (FVC) < 70%. Exclusion crite-
ria were the presence of chronic respiratory disease other
than COPD, a previous cancer diagnosis and the presence
of chronic airflow obstruction without exposure to tobacco
smoke or a PYI <10.
Through the computerized medical history, we collected
the following parameters from each patient: age, sex, body
mass index (BMI, i.e. weight in kg/height in m2 ), smok-
ing (active smoker if the patient has smoked at least 1
cigarette in the past 6 months; ex-smoker if the patient
had been a smoker but had ceased for at least a continu-
ous 6-month period; non-smoker if the patient had never
smoked) and the intensity of the smoking by means of the
PYI calculation ([number of daily cigarettes × years of smok-
ing]/20). Likewise, the forced spirometry results FEV1 , FVC
and FEV1 /FVC were recorded and patients stratified accord-
ing to the degree of severity recorded in the 2009 GOLD
guidelines41 and the 2017 GOLD categories.42 According to
the 2009 GOLD guidelines, COPD severity is classified into
the following stages: mild (stage I) FEV1 ≥80%; moderate
(stage II) FEV1 ≥50% and <80%; severe (stage III) FEV1 ≥30%
and <50%; and very severe (stage IV) FEV1 <30%. The 2017
GOLD guidelines added a letter (A, B, C, or D) to stages I--IV,
which provides information on the patient’s symptoms and
risk of exacerbation. Group A and B patients suffer <2 exac-
erbations/year without hospitalization, while the groups C
and D represent patients with 2 or more exacerbations/year,
at least 1 hospitalization or both. Additionally, groups A
and C correspond to patients with a dyspnea score of 0---1
(evaluated with the modified dyspnea scale of the Medical
Research Council [mMRC]) and/or scored <10 in the COPD
Assessment Test (CAT). Groups B and D include patients with
an mMRC ≥2, a CAT score ≥10 or both.
Incident cases of cancer and their date of diagnosis during
the study period were categorized for subsequent analy-
sis into pulmonary and extrapulmonary cancer. Skin cancer
other than melanoma was excluded. Cancer diagnosis was
performed by the specialists from the hospital. Deaths in the
cohort during the study period (January 2012 to December
2015) were counted.
Statistical analysis
An initial descriptive analysis was conducted using
mean ± standard deviation (SD) for the numerical variables
389
1.0
Cumulative probability of cancer-free COPD
0.8
0.6
0.4
0.2
0.0
40 50 60 70 80
Follow-up (Years)
Figure 1 Cumulative probability of being cancer free for
patients with chronic obstructive pulmonary disease. *Age of
the patient with chronic obstructive pulmonary disease at the
time of cancer diagnosis. Dashed line: GOLD III---IV. Continuous
line: GOLD I---II. Log rank test, p = .072. Abbreviations: COPD,
chronic obstructive pulmonary disease; GOLD, Global Initiative
for Chronic Obstructive Lung Disease.
and percentages (%) for the qualitative ones. For point esti-
mates and the 95% confidence intervals (95% CI) of the
cancer incidence rate, we used the follow-up period of
each patient in months as the denominator, divided by the
person-time index until the cancer diagnosis event or the
completion of the follow-up period. We calculated overall as
well as group-specific rates (pulmonary and extrapulmonary
cancer). Bivariate analysis of the cancer incidence according
to patients characteristics as to the computerized medical
history employed Chi-squared, Student’s t, or ANOVA test,
based on the nature of the variable (Table 1). Multivari-
ate analysis was performed using multiple logistic regression
(conditional mode).
For the prospective assessment of the disease-free time
(in years) to cancer diagnosis or the end of follow-up in
December 2015, we employed a survival analysis, expressing
the ‘‘cumulative disease-free percentage’’ as survival. The
event to measure was the diagnosis of cancer (Fig. 1). We
used Cox regression for multivariate adjustment and the log
rank test for comparing the GOLD categories regrouped in
dichotomous format (I-IIvs. III--IV), as these groups better dis-
criminated differences between ‘‘cumulative disease-free
percentages’’.
All hypothesis tests were bilateral, for a significance
level of 5%. The analyses were performed using the sta-
tistical SPSS/PC program (version 21.0 for Windows; SPSS
Inc., Chicago, IL). The study was approved by the Ethics
Committee of the HUNSC.
Results
We included 308 patients with COPD; 33 patients died, and
48 were diagnosed with cancer during the study period. The
incidence rate was therefore 10.3 cases per 1000 COPD cases
per year (95% CI 7.6---13.6 cases). The most frequent tumors
390 J.M. Figueira Gonçalves et al.

Table 1 Clinical and demographic characteristics of the patients with chronic obstructive pulmonary disease.
Variable Overall N = 308 Neoplasia p

No n = 260 Yes n = 48
Age, years (mean ± SD) 70 ± 10 70 ± 10 72 ± 10 .083
Sex .651
Male (%) 81.5 82 79
Female (%) 18.5 18 21
BMI (mean ± SD) 29 ± 6 29 ± 6 29 ± 6 .846
BMI ≥30 (%) 44.5 43.5 50 .402
Smoking .070
Ex-smoker (%) 65 63 77
Active smoker (%) 35 37 23
PYI (mean ± SD) 46.8 ± 21.2 45.8 ± 20.4 52.4 ± 24.1 .047
PYI ≥60 (%) 16 15 21 .275
Pulmonary function
FEV1 (%) 56.34 ± 18.6 55.87 ± 18.9 58.9 ± 16.7 .302
FVC (%) 82.7 ± 21.6 82.2 ± 21.9 84.8 ± 19.7 .448
FEV1 /FVC (%) 52.5 ± 11.4 52.3 ± 11.5 53.6 ± 10.8 .455
FEV1 (L) 1.48 ± 0.59 1.48 ± 0.61 1.46 ± 0.46 .831
FVC (L) 2.80 ± 0.89 2.81 ± 0.91 2.71 ± 0.75 .494
GOLD 2009 .187
I. Mild (%) 11.7 11.9 10.4
II. Moderate (%) 47.1 44.6 60.4
III. Severe (%) 35.1 36.5 27.1
IV. Very severe (%) 6.2 6.9 2.1

A B C D A B C D A B C D
GOLD 2017 .652
I (%) 7.8 3.2 0 0 8 3 0 0 6 4 0 0
II (%) 20 23 1.6 3.6 19 22 1.5 3 27 25 2 6
III (%) 8 17 0.6 9 9 16.5 0.7 10 2 19 0 6
IV (%) 0 3.6 0 2.6 0 4 0 2.6 0 0 0 3
Abbreviations: BMI, body mass index (kg/m2 ); FEV1 , forced expiratory volume in one second; FVC, forced vital capacity; GOLD, Global
Initiative for Chronic Obstructive Lung Disease; PYI, pack-year index; SD, standard deviation.

were lung tumors (31%), genitourinary tract tumors (29%),
gastrointestinal tumors (21%), head/neck tumors (6%) and
miscellaneous (12.5%). In terms of location, the annual inci-
dence rate for lung cancer was 3.4 cases per 1000 COPD
cases per year (95% CI 1.9---5.6 cases). For extrapulmonary
tumors, the rate was 7.3 cases per 1000 COPD cases per
year (95% CI 5---10 cases). These values reflect an incidence
rate of 2.14 (95% CI 1.16---3.94) in favor of malignancies of
extrapulmonary origin (p = .017).
The clinical and demographic characteristics of the series
and the contrasts of the cross-sectional bivariate analysis
are shown in Table 1. Cancer diagnoses were more frequent
in patients with a higher PYI, but we did not detect signifi-
cant differences in the other variables.
In the multivariate logistic regression analysis, we
observed a significant increase in the mean risk of can-
cer in patients with mild to moderate obstruction, grouped
according to the 2009 GOLD classification (grades I and II),
compared to patients with more severe obstructions (grades
III and IV), as well as in those with a higher accumulated
tobacco consumption, when the rest of the variables were
excluded from the equation. The adjusted odds ratio (OR)
is shown in Table 2A. The prospective assessment of cancer
incidence (longitudinal analysis, Cox regression) reinforced
these associations by also showing a significant difference
in the cumulative cancer-free probability: the patient group
with mild to moderate obstruction and the one with a higher
PYI had a higher cancer incidence rate (Fig. 1, Table 2B).
Discussion
In this patient cohort diagnosed with COPD, the incidence
rate of cancer at any site was 10.3 cases per 1000 patients
with COPD per year. The incidence rate for extrapulmonary
malignancies doubled that for primary pulmonary malignan-
cies.
Incidence of cancer in outpatients with chronic obstructive pulmonary disease
Table 2 Factors that increase the risk of cancer in patients with chronic obstructive pulmonary disease.
Variable Odds ratiob
A. Transversal analysis
GOLD 2009a 2.164
Pack-year index 1.016
B. Longitudinal analysis
GOLD 2009a 2.100
Pack-year index 1.016
Abbreviations: CI, confidence interval; GOLD, Global Initiative for Chronic Obstructive Lung Disease.
a Mild to moderate obstruction (I---II) risk category.
b Adjusted odds ratio.
The association between lung cancer and COPD has been
clearly established.15---29 The high prevalence of lung cancer
in COPD suggests that there are common mechanisms in both
diseases. These mechanisms include genetic, epigenetic and
inflammatory factors and the structural lung impairment in
COPD, which promotes the development of malignancies,
beyond the adverse effect of tobacco smoke itself.17,38,40
The incidence rate of lung cancer in patients with COPD
ranges from 1.4 to 16.7 per 1000 person-years,19,22,40 with
our results agreeing with those published in the Lung Health
Study.19 Comparing our series with similar studies in the
Spanish population, our incidence rate was lower than
that described by Torres et al.,22 which could reflect the
increased tobacco consumption (mean PYI of 74.1 ± 39.9)
reported in the former study. The Cancer Prevention Study
II43 showed that smoking a pack of cigarettes per day for
30 years increased the specific mortality due to lung cancer
by 20---40% in men and 14---20% in women, compared with
individuals who had never smoked. The risk virtually dou-
bled if the consumption was maintained for more than 40
years.44 Doll and Peto45 developed a quantitative model for
lung cancer risk, in which the duration of smoking was more
significant than the number of cigarettes smoked, in individ-
uals with a comparable packs-per-year consumption. In this
model, the association between the number of cigarettes
smoked per day and the risk of lung cancer was relatively
linear. However, the duration of tobacco consumption was
related to an exponential increase in the risk of lung cancer.
In line with these data, an association between the PYI and
the development of mutations in various target organs has
been found, which seems to promote not only the develop-
ment of lung cancer but also extrapulmonary tumors in the
bladder, colon and larynx, among others.7 These results are
in accordance with our findings, insofar as the overall inci-
dence of cancer was higher in those patients with COPD who
had a higher PYI.
In our study, there was a notably high incidence of extra-
pulmonary tumors, especially in patients with COPD and mild
to moderate airflow obstruction. Nakayama et al.30 investi-
gated the development of cancer in 127 patients with COPD
compared to patients with no obstruction who smoked. The
patients with COPD had a relative cancer risk of 2.2 (95% CI
1.24---4.27; p = .0069) compared with control subjects. The
most frequent tumors were lung, head and neck and uri-
nary tract tumors. Purdue et al.31 assessed the risk of cancer
in construction workers diagnosed with COPD and found an
391
95% CI Odds ratio p
1.087---4.309 .028
1.002---1.031 .023
1.112---3.963 .022
1.004---1.028 .011
increase of 2.2 (95% CI 1.8---2.7) in the risk of lung cancer and
1.6 (95% CI 1.4---2.0) in the risk of extrapulmonary cancer.
Chiang et al.32 demonstrated that patients with COPD
have a higher risk of developing certain tumors, such as head
and neck, esophageal, lung, breast, prostate, central ner-
vous system, lymphoma and multiple myeloma tumors. In
our cohort, the most frequent extrapulmonary malignancies
were colorectal and prostate cancer. Although their inci-
dence rates in the general population increase from the
age of 50 years of age, which could bias the results given
the mean age of our series, various studies have shown that
these tumors occur more frequently in patients with COPD
than in the general population.32---34 Patients with COPD have
a higher risk of prostate cancer (hazard ratio, 4.9; 95%
CI 1.8---13.5) than patients without bronchial obstruction.34
Although testosterone levels are reduced in COPD patients,
a relation with the development of prostate cancer has
not been established.34,46 A number of factors such as obe-
sity, physical inactivity----circumstances commonly present
in patients with COPD----and the type of diet appear to be
common elements the development of colorectal and lung
cancer.17,47,48 Chun et al.35 found that patients with COPD
had a greater risk of colorectal polyps than patients without
obstruction (OR, 2.1; 95% CI 1.1---3.8; p = .019). The authors
therefore recommended periodic colonoscopies for these
patients to detect premalignant lesions.
In our analysis, the incidence of extrapulmonary cancer
doubled that of lung cancer, with a notable percentage of
patients who developed colorectal, prostate and bladder
cancer. A reasonable explanation, beyond the damage gen-
erated by the carcinogenic substances in tobacco, could be
the presence of low-grade COPD-associated systemic inflam-
mation. A number of key compounds in the pathogenic
process are known to link inflammation with carcinogenesis,
such as integrins, transforming growth factor beta, NF-kappa
beta transcription factor, the signal transducer and acti-
vator of transcription 3, tumor necrosis factor alpha and
cyclooxygenase-2.36---39
It is notable that patients who are more susceptible to
developing cancer were those with milder stages of the
disease. This fact could be due to a survival bias, where
patients with more severe COPD, who could lack the pre-
disposing factors for developing cancer, thereby reach more
advanced phases of the disease.49
This study had some limitations. Firstly, the study pop-
ulation came from a single hospital, and the sample size
392
was limited. Obviously, a larger sample could have revealed
differences undetected in the current analysis. Recruit-
ing a larger, representative sample of patients with COPD
throughout the Canary Islands would undoubtedly be of
interest. Secondly, a potential information bias could have
occurred from obtaining the variables from the patients’
medical history, although the current standardization of
diagnostic criteria minimizes this possibility. Thirdly, we did
not have a control group from the general population or
smokers without obstruction. Therefore, we cannot rule out
some factor that could explain the high number of extra-
pulmonary malignancies in the cohort. Lastly, we should
consider the inherent limitations of a nonpopulational-based
study.
In conclusion, patients with COPD and a mild to moderate
degree of airflow obstruction (grades I and II of the 2009
GOLD guidelines) have a greater risk of developing cancer
at various sites compared with those with a more advanced
obstruction.
Conflict of interests
The authors declare that they have no conflicts of interest.
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