ORIGINAL ARTICLE
Subsequent risk of nasopharyngeal carcinoma among patients with allergic rhinitis:
A nationwide population-based cohort study
Kuen-Tze Lin, MD,1 Wen-Yen Huang, MD,1,2 Che-Chen Lin, MSc,3 Yee-Min Jen, MD, PhD,1 Chun-Shu Lin, MD,1 Cheng-Hsiang Lo, MD,1
Chia-Hung Kao, MD4,5*
1
Department of Radiation Oncology, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan, 2Institute of Clinical Medicine, National Yang-Ming University,
Taipei, Taiwan, 3Management Office for Health Data, China Medical University Hospital, Taichung, Taiwan, 4Department of Nuclear Medicine and PET Center, China Medical
University Hospital, Taichung, Taiwan, 5Graduate Institute of Clinical Medicine Science and School of Medicine, College of Medicine, China Medical University, Taichung, Taiwan.
Accepted 10 January 2014
Published online 9 April 2014 in Wiley Online Library (wileyonlinelibrary.com). DOI 10.1002/hed.23617
ABSTRACT: Background. The purpose of this study was to examine the
risk of nasopharyngeal carcinoma (NPC) after a diagnosis of allergic
rhinitis.
Methods. We identified 67,532 patients with allergic rhinitis (allergic rhinitis cohort) and a 135,064 control cohort with the same mean age and
sex ratio by using a Taiwan Longitudinal Health Insurance Database
(LHID) sample from 2000 to 2005.
Results. After adjusting for the possible confounding factors of the study,
the allergic rhinitis cohort had a 2.33-fold higher risk of developing NPC
than did the comparison cohort. The frequency of allergic rhinitis visits
was correlated with the risk of subsequent NPC. Patients with 4 or more
allergic rhinitis visits per year were significantly associated with increasingly developing NPC risk.
Conclusion. Patients with allergic rhinitis might be associated with subsequent NPC in Taiwan. Those who had repeated visits for allergic rhinitis had even higher risk for NPC. Physicians should be aware of the link
C 2014 Wiley Periodicals,
when assessing patients with allergic rhinitis. V
Inc. Head Neck 37: 413–417, 2015
INTRODUCTION
the world but common in Southern China, Hong Kong,
and Taiwan.8,9 Based on the 2009 cancer registry annual
report released by the Taiwan Department of Health, the
incidence of NPC was 9.99 per 100,000 for men and 2.98
per 100,000 for women. Thus, in Taiwan, NPC is the
11th most common cause of cancer-related death for men
and the 16th for women.
Because allergic rhinitis is such a common condition,
any association between allergic rhinitis and an increased
risk of NPC is a public health concern in Taiwan. Previous studies have shown that the risk of NPC is higher in
patients with chronic local infection/inflammation of the
aerodigestive tract in the head and neck, such as sinusitis,
otitis media, and tonsillitis.10–13 However, the association
between allergic rhinitis and subsequent NPC is less
known and even less studied.
Taiwan initiated its National Health Insurance (NHI)
program in 1996, and 97% of the hospitals and clinics
throughout Taiwan were under contract with the system
by the end of 1996. By 1998, the NHI provided health
care for nearly 99% of the population of Taiwan.14 The
NHI has made the Taiwan National Health Insurance
Research Database (NHIRD) available to researchers in
Taiwan, and this database has been extensively used in
epidemiologic studies.11,15,16
In this research, we conducted a large nationwide retrospective cohort study to examine the risk of NPC after
diagnosis of allergic rhinitis.
Allergic rhinitis is the most common chronic disorder of
the respiratory tract and includes symptoms of sneezing,
rhinorrhea, nasal obstruction, nasal itching, postnasal drip,
and cough.1,2 The economic burden of allergic rhinitis
and its complications are considerable.3,4 Allergic rhinitis
is also associated with a lower quality of life.5,6 The prevalence of allergic rhinitis varies worldwide. The prevalence of allergic rhinitis is extremely high (24.2% to
43.0%) and continues to increase in Taiwan,1,7,8 which is
an island country with a population of approximately 23
million, the majority of whom are ethnic Chinese.7
Nasopharyngeal cancer (NPC) is a malignant tumor of
the nasopharynx, the narrow tubular passage behind the
nasal cavity. The incidence of NPC demonstrates a
marked geographic variation. It is rare in most parts of
*Corresponding author: C.-H. Kao, Graduate Institute of Clinical Medicine Science and School of Medicine, College of Medicine, China Medical University,
No. 2, Yuh-Der Road, Taichung 404, Taiwan.
E-mail: d10040@mail.cmuh.org.tw
Contract grant sponsor: This study was supported in part by the study projects
of DMR-103-012, DMR-103-018; Taiwan Ministry of Health and Welfare Clinical Trial and Research Center for Excellence (DOH102-TD-B-111-004), Taiwan
Ministry of Health and Welfare Cancer Research Center for Excellence
(MOHW103-TD-B-111-03); and International Research-Intensive Centers of
Excellence in Taiwan (I-RiCE; NSC101-2911-I-002-303). The role of study
sponsors in the study was in the collection of data from the Taiwan National
Health Insurance Research Database (NHIRD).
KEY WORDS: nasopharyngeal carcinoma, allergic rhinitis, cohort
study, National Health Insurance, National Health Insurance Research
Database
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LIN ET AL.
TABLE 1. Baseline demographic status and comorbidity compared
between the comparison and allergic rhinitis cohorts.
No. (%) by cohort†
Variables
Age, y (SD)*
<40 y
40–49 y
50 y
Sex
Female
Male
Comorbidity
Without any
comorbidity
Hypertension
Diabetes
CAD
Asthma
Atopic dermatitis
Comparison
cohort
(n 5 135,064)
Allergic
rhinitis cohort
(n 5 67,532)
42.9 (16.1)
67,586 (50.0)
26,716 (19.8)
40,762 (30.2)
42.9 (16.0)
33,793 (50.0)
13,358 (19.8)
20,381 (30.2)
.998
1.0000
74,824 (55.4)
60,240 (44.6)
37,412 (55.4)
30,120 (44.6)
1.0000
105,934 (78.4)
44,077 (65.3)
<.0001
22,664 (16.8)
8483 (6.3)
9792 (7.2)
2652 (2.0)
1225 (0.9)
14,774 (21.9)
4795 (7.1)
8167 (12.1)
8622 (12.8)
1225 (1.8)
<.0001
<.0001
<.0001
<.0001
<.0001
p value
nitis (ICD-9-CM 477) from 2000 to 2005. The index date
was set on a half year of allergic rhinitis diagnosis. The
comparison cohort consisted of persons without any allergic rhinitis diagnosis in the LHID randomly 2-fold frequency-matched according to sex, age (per 5 years), and
year of index date. This study excluded patients with cancer occurrence before the index date, and aged <20 years.
The follow-up period was terminated upon developing
NPC (ICD-9-CM 147; based on data obtained from the
catastrophic illness registry file), withdrawal from the
insurance program, or December 31, 2010.
We considered demographic characteristics and NPCassociated comorbidities as confounding factors in this
study.
Based on inpatient and outpatient files, the comorbidities included hypertension (ICD-9-CM 401-405), diabetes
(ICD-9-CM 250), coronary artery disease (CAD; ICD-9CM 410-414), atopic dermatitis (ICD-9-CM 691), and
asthma (ICD-9-CM 493).
Statistical analysis
The Taiwan government instituted the Taiwan NHI program, a single-payer and universal insurance plan, in
1996. By 1998, the program covered nearly 99% of the
citizens of Taiwan. The NHIRD, which contains the
annual registration files and original claims data for reimbursement, is managed by the National Health Research
Institute (NHRI). To protect patient privacy, all personal
identification information is encrypted before the data are
released for research.
We used the Longitudinal Health Insurance Database
(LHID), which is a sub-dataset of the NHIRD. The almost
23.75 million insured people in the period of 1996 to
2000 were used as the database pool. The NHRI assigned
a random number for each person by Knuth and Park and
Miller’s method. The NHRI random sampled 1 million
insured people into the LHID. According to the NHRI
report, there was no statistically significant difference
between LHID and NHIRD in age, sex, annual birth rate,
and health costs. The NHRI created a scrambled, anonymous identification number to combine each person’s
information, including sex, birth date, and registry of
medical services.
In this study, we collected disease histories from inpatient, out-patient, and catastrophic illness registry files.
The disease diagnoses were based on the International
Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM).
To describe the structure of the allergic rhinitis and
comparison cohorts, we showed the mean and SD for
continuous variables and the count and percentage for category variables. The t test for continuous variables and
the chi-square test for category variables were used to
examine the differences between the 2 cohorts. The
results demonstrate a cumulative NPC incidence and
demographic-specific and comorbidity-specific NPC incidence for the allergic rhinitis and comparison cohorts.
Compared to the comparison cohort, the Cox proportional
hazards regression model with adjusted potential confounding factors was applied to the estimate hazard ratio
(HR) and the confidence interval (CI) for the allergic rhinitis cohort. The average number of allergic rhinitis visits
was measured as the total frequency of allergic rhinitis
visits during the follow-up time divided by the follow-up
duration (years). The allergic rhinitis cohort was divided
into 3 sub-cohorts based on allergic rhinitis visits: <2
times per year, 2 to 4 times per year, and 4 times per
years. We used 2 methods to assess the relationship
between increasing allergic rhinitis visits and developing
NPC risk. In the first method, we estimated the HR for
each frequency level of average allergic rhinitis visits,
and treated allergic rhinitis visits as continuous variables
to test the trend by using the Cox proportional hazards
regression. In the second method, we calculated the number of allergic rhinitis visits in each follow-up year and
treated this value as a time-dependent covariate in the
Cox proportional hazards regression model to estimate
the association between the frequencies of allergic rhinitis
visits and developing NPC risk.
We used SAS 9.3 software (SAS Institute, Cary, NC)
to manage and analyze the data. The significance level
was set at < .05 for 2-sided testing of the p value.
Study population
RESULTS
We conducted a population-based retrospective cohort
study to clarify the relationship between allergic rhinitis
and developing NPC risk. We established an allergic rhinitis cohort of patients with newly diagnosed allergic rhi-
We established a 67,532 allergic rhinitis patient cohort
and a 135,064 individual comparison cohort with the
same mean age (42.9 years) and sex ratio (55.4% female;
Table 1). The proportion of comorbidity in the allergic
Abbreviation: CAD, coronary artery disease.
* Used the t test.
†
Except as otherwise stated.
MATERIALS AND METHODS
Data source
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ALLERGIC
RHINITIS AND
NPC
TABLE 2. Incidence of subsequent nasopharyngeal cancer and multivariate Cox proportional hazards regression analysis measured hazard
ratio for the study cohort.
Comparison cohort
Variables
Total
Age group
<40
40–49
50
Sex
Female
Male
Comorbidity
Without any comorbidity*
Hypertension
No
Yes
Diabetes
No
Yes
CAD
No
Yes
Asthma
No
Yes
Atopic dermatitis
No
Yes
Allergic rhinitis cohort
Event
PYs
Rate
Event
PYs
52
985,482
0.53
58
509,851
18
16
18
502,132
201,718
281,632
0.36
0.79
0.64
20
17
21
13
39
552,795
432,687
0.24
0.90
38
787,444
41
11
Rate
Crude HR (95% CI)
Adjusted HR (95% CI)
1.14
2.16 (1.49–3.14)
2.33 (1.59–3.40)
259,536
102,768
147,547
0.77
1.65
1.42
2.16 (1.14–4.08)
2.09 (1.06–4.14)
2.24 (1.19–4.20)
2.15 (1.13–4.10)
2.15 (1.06–4.34)
2.57 (1.35–4.88)
20
38
284,217
225,634
0.70
1.68
3.01 (1.50–6.05)
1.87 (1.20–2.93)
3.02 (1.47–6.22)
2.06 (1.31–3.25)
0.48
37
337,754
1.10
2.28 (1.45–3.58)
2.43 (1.54–3.82)
832,719
152,763
0.49
0.72
46
12
403,275
106,576
1.14
1.13
2.32 (1.52–3.54)
1.58 (0.70–3.58)
2.43 (1.58–3.74)
1.74 (0.76–4.00)
51
1
929,870
55,612
0.55
0.18
52
6
475,880
33,971
1.09
1.77
2.00 (1.36–2.94)
9.98 (1.2–82.94)
2.13 (1.44–3.16)
10.47 (1.25–87.57)
47
5
921,221
64,261
0.51
0.78
53
5
451,409
58,442
1.17
0.86
2.31 (1.56–3.42)
1.12 (0.32–3.86)
2.43 (1.63–3.63)
1.22 (0.35–4.25)
52
0
968,930
16,552
0.54
0
53
5
446,108
63,743
1.19
0.78
2.22 (1.51–3.26)
–
2.26 (1.53–3.32)
–
52
0
977,502
7980
0.53
0
56
2
501,473
8377
1.12
2.39
2.11 (1.44–3.07)
–
2.26 (1.54–3.32)
–
Abbreviations: HR, hazard ratio; CI, confidence interval; PY, person-years; Rate, incidence rate per 10,000 person-years; CAD, coronary artery disease.
Model adjusted for age, sex, hypertension, diabetes, CAD, asthma, and atopic dermatitis.
* Model adjusted for age and sex.
rhinitis cohort was substantially greater than that in the
comparison cohort.
The NPC incidence in the allergic rhinitis cohort was
1.14 per 10,000 person-years. In the comparison cohort,
the NPC incidence was 0.53 per 10,000 person-years
(Table 2). The NPC incidence in the allergic rhinitis
cohort was nearly 2.16-fold higher than that in the comparison cohort. After adjusting for the possible confounding factors of the study, the allergic rhinitis cohort had a
2.33-fold higher risk of developing NPC than did the
comparison cohort (HR 5 2.33; 95% CI 5 1.59–3.40).
Compared to the comparison cohort, the patients with
allergic rhinitis had a similar risk of developing NPC in
each age group. In the female population, the patients
with allergic rhinitis had a nearly 3-fold higher risk of
developing NPC compared with the comparison persons
(HR 5 3.02; 95% CI 5 1.47–6.22); in the male population, the patients with allergic rhinitis had only a 2-fold
higher risk of developing NPC than did the comparison
cohort (HR 5 2.06; 95% CI 5 1.31–3.25).
Table 2 also shows the comorbidity-specific developing
NPC incidence and estimated HR for both study cohorts.
Compared to the comparison cohort, the allergic rhinitis
cohort was significantly associated with a higher risk of
developing NPC when both cohorts were without each
comorbidity. Especially of the study population without
any comorbidity, the patients with allergic rhinitis still had
a 2.43-fold higher risk of developing NPC risk than did
the comparison person (HR 5 2.43; 95% CI 5 1.54–3.82).
Table 3 shows the relationship between allergic rhinitis
visit frequencies and developing NPC risk. There was no
difference between the NPC risk in comparison persons
and patients with <2 times the average allergic rhinitis
visits per year. However, patients with 2 to 4 times or 4
times the average allergic rhinitis visits per year were significantly associated with increasingly developing NPC
risk (HR 5 5.25 and 14.80, respectively). These results
also show that the increasing average frequencies of allergic rhinitis visits might be associated with increased NPC
risk (p value for trend < .0001). Moreover, after timedependent modifiers, an increase in allergic rhinitis visit
frequency was associated with an 11% increase in the
risk of developing NPC (HR 5 1.11; 95% CI 5 1.08–
1.14).
We also used sensitivity analysis to validate the association between allergic rhinitis occurrence and developing
NPC risk in the study population with different follow-up
durations (Table 4). These results suggest that the allergic
rhinitis cohort was associated with a significantly higher
risk of developing NPC compared to the comparison
cohort, despite the study population having at least a
3-year follow-up duration. When the follow-up time was
1 year, the allergic rhinitis cohort had a dramatically
increased risk of NPC compared with the comparison
cohort (HR 5 15.77; 95% CI 5 6.38–38.97). The risk in
the allergic rhinitis cohort was not significant when
follow-up time was >4 years (HR 5 1.58; 95% CI 5
0.89–2.82).
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LIN ET AL.
TABLE 3. Incidence of nasopharyngeal cancer and multivariate Cox proportional hazards regression analysis measured hazard ratios for the study cohort
by average frequencies of allergic rhinitis visit.
Average frequency of allergic
rhinitis visit, per year
Comparison cohort
<2
2–4
4
Event
PYs
Rate
Crude HR (95% CI)
Adjusted HR (95% CI)
52
18
16
24
985,482
412,450
64,306
33,094
0.53
0.44
2.49
7.25
Ref
0.83 (0.49–1.42)
4.72 (2.70–8.27)
13.72 (8.46–22.25)
p for trend < .0001
1.11 (1.09–1.14)
Ref
0.91 (0.53–1.56)
5.25 (2.98–9.24)
14.80 (9.00–24.33)
p for trend < .0001
1.11 (1.08–1.14)
Increased allergic rhinitis visit*
Abbreviations: PY, person-years; Rate, incidence rate per 10,000 person-years HR, hazard ratio; CI, confidence interval.
Model adjusted for age, sex, hypertension, diabetes, coronary artery disease, asthma, and atopic dermatitis.
* Time-dependent model.
DISCUSSION
analysis, NPC showed an elevated risk (standardized incidence ratio 5 1.31; 95% CI 5 1.04–1.63). However, this
study did not include comorbidity data or a sensitivity
test to adjust for possible confounding factors.
Although the association between allergic rhinitis and
NPC is apparent, the mechanism underlying this association is a focus of ongoing research. A possible explanation is that chronic repeated airway stimulation and
inflammation, reduced mucociliary clearance, and epithelial cell changes after the deposition of allergens in the
nasopharynx may promote a malignant change after a certain induction time.24,25
The large sample size of this study enhances the statistical power of our results. The participants represented a
wide range of demographic characteristics. Therefore, we
could have conducted stratified analyses based on age,
sex, and comorbidities. The strengths of this study include
its use of population-based data, which are highly representative of the general population. Nearly all of the participants had a complete follow-up because of the
widespread coverage of the nationwide database, which
records outpatient diagnoses and hospitalizations.
There are inherent limitations to the data presented in
this study, and the results should be interpreted with caution. First, the NHIRD does not contain detailed information regarding status of Epstein–Barr virus infection,
smoking habits, alcohol consumption, dietary factors, or
family history of NPC, all of which may be risk factors
of NPC. We only include comorbidities that are available
in the Taiwan LHID. Therefore, we selected the 3 most
common systemic diseases and the 2 common immune-
To the best of our knowledge, no other large-scale
cohort studies have focused on the correlation between
allergic rhinitis and NPC. In this study, the allergic rhinitis
cohort exhibited a link to the subsequent NPC. We found a
2.33-fold increased risk of NPC among the allergic rhinitis
participants after controlling for other critical covariates.
Some may argue that patients with allergic rhinitis and
NPC represent overlapping symptoms and that these
increased risks are likely to be attributed to diagnostic confusion or misclassification. Therefore, we applied a sensitivity analysis. The frequency of allergic rhinitis visits, which
refers to allergic rhinitis severity, is correlated strongly with
the risk of subsequent NPC. These findings confirm the
result that patients with allergic rhinitis increase the risk of
subsequent development of NPC in Taiwan.
Previous studies have investigated the correlation
between allergy and subsequent cancer risk. Their results
are discrepant and insufficiently strong to draw firm conclusions.17–22 Koh et al20 examined the data from a
population-based cohort of 63,257 Singaporean Chinese, in
which 954 cohort participants who had rhinitis or sinusitis
developed lung cancer. This indicated a 59% increase in
risk compared with those without rhinitis or sinusitis.
Hwang et al23 conducted a retrospective cohort study to
investigate whether the diagnoses of allergic rhinitis,
asthma, and atopic dermatitis are associated with an
increased overall cancer risk. They found that the overall
cancer risks in patients with allergic rhinitis do not significantly increase at a standardized incidence ratio of 1.02
(95% CI 5 0.98–1.05). In a further cancer site-specific
TABLE 4. Cox proportional hazards model estimated developing nasopharyngeal cancer incidence in study cohorts by follow-up year and hazard
ratio of developing nasopharyngeal cancer for study cohorts.
Comparison cohort
Allergic rhinitis cohort
Variables
Event
PYs
Rate
Event
PYs
Time lag
1
>1
>2
>3
>4
8
44
36
33
27
1078
984,404
981,627
977,489
971,795
74.18
0.45
0.37
0.34
0.28
14
44
34
29
22
162
509,688
509,146
508,114
506,611
Rate
860.09
0.86
0.67
0.57
0.43
Abbreviations: PY, person-years; Rate, incidence rate per 10,000 person-years HR, hazard ratio; CI, confidence interval.
Model adjusted for age, sex, hypertension, diabetes, coronary artery disease, asthma and atopic dermatitis.
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HEAD & NECK—DOI 10.1002/HED
MARCH 2015
Crude HR(95% CI)
Adjusted HR(95% CI)
11.11 (4.66–26.50)
1.93 (1.27–2.93)
1.81 (1.13–2.89)
1.68 (1.02–2.77)
1.55 (0.88–2.72)
15.77 (6.38–38.97)
2.09 (1.36–3.19)
1.89 (1.17–3.06)
1.74 (1.04–2.90)
1.58 (0.89–2.82)
ALLERGIC
associated diseases as the comorbidities. Second, the evidence derived from a retrospective cohort study generally
has a lower statistical quality than that from randomized
trials. This is because of potential biases related to adjustments for confounding variables. Despite our meticulous
study design and control measures for confounding factors, a bias resulting from unknown confounders may
have affected our results. Third, all data in the NHIRD
are anonymous. Thus, relevant clinical variables, including imaging results, pathology findings, and serum laboratory data, were unavailable for our study patient cases.
However, the data regarding allergic rhinitis or NPC diagnoses are reliable. Fourth, the follow-up was too short for
a causal association. Fifth, we cannot exclude the possibility of a screening effect because the risk is much
higher when the time lag is shorter than 1 year.
In conclusion, patients with allergic rhinitis might be
associated with subsequent NPC in Taiwan. Those who
had repeated visits for allergic rhinitis had even higher
risk for NPC. Physician should be aware of the link when
assessing patients with allergic rhinitis.
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