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The LaryngoscopeVC 2013 The American Laryngological,Rhinological and Otological Society, Inc.
Association of Rhinosinusitis With Nasopharyngeal Carcinoma:
A Population-Based Study
Shih-Han Hung, MD; Po-Yueh Chen, MD; Herng-Ching Lin, PhD; Jonathan Ting, BS;
Shiu-Dong Chung, MD, PhD
Objectives/Hypothesis:Although it is already known that the inflammation process elevates the risk of developing can-cer, to date the association between rhinosinusitis and nasopharyngeal carcinoma (NPC) remains unknown. This study aimedto evaluate the association between rhinosinusitis and NPC based on a nationwide database.
Study Design: Case-control study.Methods: In total, the cases comprised of 2,242 subjects with NPC and 6,726 randomly selected subjects as controls.
Separate conditional logistic regression analyses were used to calculate the odds ratio (OR) for having been previously diag-nosed with chronic and acute rhinosinusitis between the cases and controls.
Results: Of the total sample, 607subjects (6.77%) had been diagnosed with chronic rhinosinusitis prior to the indexdate: 322 (14.36%) cases with NPC and 285 (4.24%) controls (P
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The purpose of this study was to evaluate the asso-
ciation of acute and chronic rhinosinusitis with NPC
based on a nationwide database.
MATERIALS AND METHODS
Database
Data were retrieved from the Longitudinal Health Insur-ance Database 2000 (LHID2000) released by the Taiwan
National Health Research Institute. Taiwan began a single-
payer National Health Insurance (NHI) program in 1995, and
the program has covered about 98% of the population since its
inauguration. The LHID2000 includes data from all medical
claims of 1 million randomly selected enrollees of all NHI 2000
enrollees. Several studies have demonstrated the high validity
of the data from the NHI program.22,23 Furthermore, hundreds
of studies employing the LHID2000 have been published in
internationally peer reviewed journals.24 Because the database
consists of deidentified secondary data released without condi-
tions to researchers, this study was exempt from a full review
by the institutional review board.
Study Sample
This study was designed as a case-control study. For the
selection of cases, we identified 2,356 subjects who had received
a first-time diagnosis of NPC (International Classification of
Diseases, 9th Revision, Clinical Modification [ICD-9-CM] code
147) in an ambulatory care visit (including outpatient depart-
ments of hospitals and clinics) or during hospitalization
between the dates of January 1, 2002 to December 31, 2011.
One hundred fourteen subjects younger than 18 years old were
excluded to limit the study sample to the adult population. In
total, 2,242 subjects with NPC were considered cases in this
study. We assigned the first ambulatory care visit or hospitali-
zation date for a nasopharyngeal carcinoma diagnosis as their
index date.
Likewise, we selected the controls from the LHID2000.First we excluded all of the subjects who had ever received a
diagnosis of NPC since the initiation of the NHI program in
1995. We then randomly selected 6,726 controls (three controls
per case) to match the cases in terms of gender, age group (18
29, 3039, 4049, 5059, 6069, and >69 years), and index year
through an SAS PROC SURVEYSELECT program (SAS Insti-
tute Inc., Cary, NC). For the controls, the year of index date
was simply a matched year in which controls had a medical
visit. In addition, we further assigned the first utilization of
medical care occurring in the index year as the index date.
Exposure Assessment
This study identified rhinosinusitis cases by ICD-9-CM
codes 461 (acute rhinosinusitis) and 473 (chronic rhinosinusi-tis). Furthermore, this study only included rhinosinusitis cases
who had received a rhinosinusitis diagnosis within 3 years prior
to the index date.
Statistical Analysis
SAS System for Windows version 8.2 (SAS Institute Inc.)
was used for the statistical analyses in this study. Pearson v2
tests were used to examine the differences between cases and
controls on sociodemographic characteristics (monthly income,
urbanization, and geographic location). Conditional logistic
regression analyses (conditioned on sex, age group, and index
year) were also used to calculate the odds ratio (OR) for having
been previously diagnosed with rhinosinusitis between cases
and controls. We adjusted for tobacco use and alcohol abuse/
dependence in the regression models. The conventional P.05
was used to assess statistical significance.
RESULTSThe mean sample age was 50.5 years (standard
deviation [SD], 14.7 years); 50.6 years for the cases and
50.4 years the controls (P5.725). Table I presents the
distributions of the samples sociodemographic character-
istics between the cases and controls. It shows that there
was no significant difference between cases and controls
in terms of monthly income, urbanization level, geo-
graphic region, tobacco use, and alcohol abuse/
dependence.
The crude and adjusted OR of prior chronic rhinosi-
nusitis is shown in Table II. Of the total sample, 607
subjects (6.77%) had received chronic rhinosinusitis
prior to their index date: 322 (14.36%) subjects with
NPC and 285 (4.24%) controls. The mean periods of time
between the occurrence of rhinosinusitis and onset ofNPC were 1,091 (SD, 964) days, and 702 (SD, 888) and
1,123 (SD, 961) days for subjects who respectively had
chronic and acute rhinosinusitis (not shown in the
tables). Conditional logistic regression analysis (condi-
tioned on sex, age group, and index year) revealed that
the OR of prior chronic rhinosinusitis for subjects with
NPC was 3.83 (95% confidence interval [CI], 3.23-4.53)
that of controls. After adjusting for income, urbaniza-
tion, geographic location, tobacco use, and alcohol abuse/
dependence, the OR of prior chronic rhinosinusitis for
those with NPC was 3.79 (95% CI, 3.21-4.48) that of
controls.
Table III presents the crude and adjusted OR haz-
ard ratios of acute rhinosinusitis. A total of 1,199(53.48%) cases and 2,938 (42.19%) controls had acute
rhinosinusitis prior to the index date (P
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Findings from previous studies lead to a clinical recom-
mendation that avoiding certain exposures might lead to
a decreased incidence of NPC. The carcinogenic effects
of some of these known environmental risk factors were
understood based on previous knowledge. For instance,
EBV and human papillomavirus were already known for
their molecular level carcinogenic mechanisms.26 The
risk factor of consuming salt-cured food is believed to be
mediated through the releases of volatile nitrosaminesthat are carried by the blood steam and distributed over
the nasopharyngeal mucosa.5 Even the carcinogenic
effects behind the use of Chinese medicinal herbs were
considered to contribute, either by reactivating EBV or
through a direct effect on EBV-transformed cells.27 How-
ever, none of these pathogenic theories were focused on
the more common phenomenon: inflammation.
The theories connecting the inflammatory process
and carcinogenesis have been proposed for more than a
decade. During the inflammatory process, granulocytes
secrete chemically reactive oxidants, radicals, and
electrophilic mediators to eradicate pathogens. Although
regarded as an effective host defense mechanism, it inevi-
tably exposes the epithelial and connective tissues to cer-
tain endogenous genotoxic agents. Whereas in most cases
the genotoxic burdens are reduced by the cell repair mech-
anisms and become negligible, in long-term cases inflam-
mation eventually elevates the risk of cancer.20 The
theory is well supported by much of the epidemiological
evidence. Probably the best known example is the associa-tion between colon cancer and ulcerative colitis. In a large
scale study done by Ekbom et al. involving thousands of
patients, investigators reported a 5.7-fold increase in colon
cancer incidence in patients with chronic ulcerative colitis
as compared to those without.28 More interestingly, the
risk of cancer correlated directly with both the severity
and duration of the disease. Later on, the same group
reported that ulcerative colitis does not increase the risk
of other types of cancer.29 This finding is especially impor-
tant because it strongly supports the role localized inflam-
mation plays in cancer development.
TABLE I.Subjects With Nasopharyngeal Carcinoma and ControlsSociodemographic Characteristics (n58,968).
Variables
Nasopharyngeal CarcinomaSubjects, n52,242 Controls, n56,726
PValueNo. % No. %
Gender 1.000
Male 1,478 65.9 4,434 65.9Female 764 34.1 2,292 34.1
Age, yr 1.000
69 244 10.9 732 10.9
Monthly income .280
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The same phenomenon can be observed in the lungs
as well. It is reported that patients with asthma showed
a significant excess risk of developing lung cancer.30
Kallen et al. even reported a reduced risk of most types
of cancers, with the exception of lung cancer and endo-
crine cancer.31 The results from many similar reports
also connect the inflammatory process to the cancers of
the ovary, pancreas, bladder, skin, and esophagus.20
It is possible that NPC shares the common
inflammatory-induced carcinogenic mechanisms related
to the granulocyte secretions. Huang et al. found that the
tissue and serum levels of 8-Oxo-20-deoxyguanosine, an
oxidative stress product, are significantly higher in NPC
patients compared to control patients.32 Recently Zhang
et al. also showed that EBV-infected immortalized naso-
pharyngeal epithelial cells often acquire an enhanced
response to interleukin (IL)26induced signal transducer
and activator of transcription 3 (STAT3) activation to pro-
mote their growth and invasive properties.33 This
enhanced IL-6/STAT3 response was mediated by overex-pression of IL-6 receptor, which implies that besides the
genotoxic burden generated by the granulocyte activity, a
cytokine-receptormediated mechanism might also be
involved in the relation between inflammation and NPC.
Moreover, the IL-6mediated Janus kinase/STAT3 path-
ways were also shown to be involved in the hypermethyl-
ation of several tumor suppressor genes in NPC cells.34
There is even evidence that NPC cells may play a
significant role in maintaining and amplifying the inflam-
mation process, which recruit and activate additional
immune cells in the nasopharyngeal path and promote
tumor progression.35
IL-6 is known to be an important proinflammatory
cytokine and to be expressed during the rhinosinusitis
process.36,37 It has already been shown that oxidative
stress and antioxidant enzyme activity significantly
increases during acute rhinosinusitis.38,39 In a recent
study, researchers found that the genes involved in
nitric oxide and reactive oxygen species regulation in
patients with chronic rhinosinusitis are altered.40 Evi-
dence from all of these studies provides certain explana-
tions to our findings that patients with rhinosinusitis
are more likely to develop nasopharyngeal carcinoma.
The major limitation of this study, like much of the
health insurance database analysis research, is the pos-
sibility of surveillance bias. This means that it is possi-
ble the patients with rhinosinusitis visit doctors more
often. In cases with chronic rhinosinusitis, patients weremore likely to receive examinations such as computed
tomography or nasal endoscopy. Therefore, it is possible
that NPC patients with underlying rhinosinusitis have a
higher chance of it being detected, whereas those in the
control group might remain symptomless and undetected
for a certain period of time. In the last part of our study,
we conducted a sensitivity analysis in which subjects
who were newly diagnosed with chronic rhinosinusitis,
TABLE II.Crude and Adjusted Odds Ratios of Prior Chronic Rhinosinusitis Between Nasopharyngeal Carcinoma Subjects and Controls (n58968).
Presence of Prior ChronicRhinosinusitis
Total Sample, n58,968Nasopharyngeal Carcinoma
Subjects, n52,242 Controls, n56,726
No. % No. % No. %
Yes 607 6.77 322 14.36 285 4.24
No 8,361 93.23 1,920 85.64 6,441 95.76Crude OR (95% CI) 3.83* (3.23-4.53) 1.00
Adjusted OR (95% CI) 3.79* (3.21-4.48) 1.00
*P
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within 1 year prior to the index date, were excluded.
This was an attempt to reduce the surveillance bias. The
OR of prior chronic rhinosinusitis for subjects with naso-
pharyngeal carcinoma remained significantly higher
than that of controls. The results support our original
hypothesis and reduce the chance that the increased
diagnoses of NPC resulted from accidental findings dur-
ing examinations for rhinosinusitis.
The second limitation is the lack of treatment infor-
mation for the rhinosinusitis group. In this database
study it is difficult to evaluate how well these patients
were treated. Therefore, there may have been some
patients who had been adequately treated for their rhi-
nosinusitis but were still included in the rhinosinusitis
group. This could potentially affect the accuracy of data
interpretation. However, we believe this potential bias
has little effect on our conclusions. If there was a largenumber of treated rhinosinusitis subjects included in the
rhinosinusitis case group, theoretically the results would
be affected toward the null hypothesis. Because the
results of our study reached statistically significant dif-
ferences, we believe this limitation remain fairly
negligible.
Third, the determination of the time period of the
diagnosis of rhinosinusitis before developing NPC is
especially difficult and controversial. In this study, the
cases only included patients who had ever received a
rhinosinusitis diagnosis within 3 years prior to the index
date. This selection was intended to exclude patients
with a very long interval between the diagnosis of rhino-
sinusitis and the development of NPC. However, theduration of time required for a nasal infection/inflamma-
tion to reasonably result in a carcinogenic effect remains
unknown. It is possible that under our duration selection
criteria (interval between the diagnoses of rhinosinusitis
prior to the diagnoses of NPC:
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