Radiotherapy and Oncology 104 (2012) 338342

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Otitis and nasopharyngeal carcinoma

Association between adult otitis media and nasopharyngeal cancer: A

nationwide population-based cohort study
Wen-Yen Huang a,b, Che-Chen Lin c, Yee-Min Jen a, Kuen-Tze Lin a, Muh-Hwa Yang
Ying-Nan Chang e, Fung-Chang Sung c,f, Chia-Hung Kao g,h,
a

Department of Radiation Oncology, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan;

b,d,

Chang-Ming Chen a,

Institute of Clinical Medicine,

National Yang-Ming University, Taipei, Taiwan; c Management Ofce for Health Data, China Medical University Hospital, Taichung, Taiwan; d Division of Hematology-Oncology,
Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan; e Department of Otolaryngology-Head & Neck Surgery, Tri-Service General Hospital,
National Defense Medical Center, Taipei, Taiwan; f Departments of Public Health, China Medical University, Taichung, Taiwan; g Graduate Institute of Clinical Medicine Science and
School of Medicine, College of Medicine, China Medical University, Taichung, Taiwan; h Department of Nuclear Medicine and PET Center, China Medical University Hospital,
Taichung, Taiwan

a r t i c l e

i n f o

Article history:
Received 17 August 2012
Accepted 26 August 2012
Available online 14 September 2012
Keywords:
Otitis media
Nasopharyngeal cancer
Cohort study

a b s t r a c t
Purpose: To determine whether the diagnosis of otitis media (OM) in adults is associated with an
increased risk for the subsequent development of nasopharyngeal cancer (NPC) using a nationwide population-based retrospective study.
Methods and materials: We selected 13,513 adult patients that had been previously diagnosed with OM
between 2000 and 2005 from the Taiwan Longitudinal Health Insurance Database 2000 as the study
cohort, and randomly extracted the data of 135,130 participants matched by sex, age, and baseline year
for the comparison cohort. The follow-up period was terminated upon developing NPC, withdrawal from
the national health insurance system, or the end of 2009. Cumulative incidences and hazard ratios (HRs)
of NPC development were determined.
Results: The subsequent NPC incidence rates in the OM and comparison cohorts were 6.41 and 0.58 per
10000 person-years, respectively (adjusted HR, 11.04; 95% CI, 7.685.87; P < 0.0001). The NPC risk for
males was signicantly higher than that for females (adjusted HR = 3.24; 95% CI, 2.164.85). In both
female and male patients, the diagnosis of OM was associated with a signicantly increased risk for
NPC (adjusted HR, 11.91 vs. 10.78, respectively). Among the OM cohort, 62 participants were subsequently diagnosed with NPC, with 71% of them occurring within 1 year following the diagnosis of OM.
However, even after 5-year follow-up, the OM cohort still displayed a higher risk for NPC (adjusted
HR = 2.50). Stratied by the frequency of OM episodes, more than one episode per year had a signicantly
greater risk of developing NPC, compared with the comparison cohort (HR = 29.22; 95% CI, 20.1942.27).
Conclusion: We found that adult OM is a warning sign for the development of NPC in Taiwan, with
approximately an 11-fold higher risk for adult OM patients. We recommend that OM patients undergo
follow-up examinations for at least 5 years. To extrapolate our ndings, further studies are warranted
in other areas in which NPC is endemic.
2012 Elsevier Ireland Ltd. All rights reserved. Radiotherapy and Oncology 104 (2012) 338342

Otitis media (OM) is a common global health care problem, and

the overall burden from OM and its sequelae is considerable. The
incidence rate is estimated to be 10.85% for acute OM and 4.76%
for chronic suppurative OM [1]. OM primarily occurs in childhood,
and the incidence markedly declines with age, presumably a result
of the maturation of the immune system and the anatomy of the
middle ear, the Eustachian tube, and the nasopharynx.
Nasopharyngeal cancer (NPC) arises in the nasopharynx, in
which the orice of the Eustachian tube is located. Obliteration
Corresponding author at: Department of Nuclear Medicine and PET Center,
China Medical University Hospital, No. 2, Yuh-Der Road, Taichung 404, Taiwan.
E-mail address: d10040@mail.cmuh.org.tw (C.-H. Kao).
0167-8140/$ - see front matter 2012 Elsevier Ireland Ltd. All rights reserved.
ttp://dx.doi.org/10.1016/j.radonc.2012.08.015

of the opening of the Eustachian tube by the tumor or adenoid tissue may lead to OM with effusion. Thus, much emphasis is placed
on the exclusion of NPC in adult patients with OM. However, it remains unclear whether adult OM is an indicator of subsequent
NPC, and whether OM patients should undergo subsequent regular
medical examinations as a high-risk group.
NPC shows a distinct geographical and racial distribution. It is
rare in most parts of world, but common in southern China, Hong
Kong, and Taiwan. According to the 2008 cancer report released by
the Taiwan Department of Health, the incidence of NPC was 9.99
per 100000 for men and 3.47 per 100000 for women. It is the ninth
most common cause of cancer-related death for men and the 14th
for women in Taiwan. The Taiwan National Health Insurance (NHI)

W.-Y. Huang et al. / Radiotherapy and Oncology 104 (2012) 338342

program was initiated in 1996, with 97% of the hospitals and clinics throughout Taiwan under contract with the system by the end
of 1996 [2]. By 1998, the health care of almost 99% of the population of Taiwan was covered by the NHI. The NHI patient records
provide a unique opportunity to examine our hypothesis that a
diagnosis of OM in adults is associated with an increased risk for
subsequent development of NPC using a nationwide populationbased cohort study.
Patients and methods
Data source
The Taiwan National Health Research Institute established and
managed the National Health Insurance Research Database (NHIRD)
which includes the reimbursement claim data for the Taiwan NHI
program. All personal identication information is encrypted before
being released to the public to protect patient privacy.
Our research used the Longitudinal Health Insurance Database
(LHID), a subset of the NHIRD. LHID is composed of historical claim
data for one million claimants randomly sampled from the total insured population between 1996 and 2000. Anonymous identication numbers are used to link each claimants demographic
information, including sex, birth date, occupation, residential area,
and registry of medical services. The disease diagnosis that was
used in our study was dened by the International Classication
of Diseases, Ninth Revision, Clinical Modication (ICD-9-CM) from
outpatient data, inpatient data, and the registry of catastrophic illness. Our study was approved by the Ethics Review Board of the
China Medical University (CMU-REC-101-012).
Study population
Our study used a population-based retrospective approach. The
OM cohort included participants that were initially diagnosed with
OM (ICD-9-CM 381.0-381.4 and ICD-9-CM 382) between 2000 and
2005, and the baseline was set as the date of the initial OM diagnosis. Ten comparison cohort participants were randomly selected for
each OM cohort participant. Comparison cohort participants were
matched by sex, age, and baseline year. The event of the study
was dened as subsequent NPC based on the diagnosis code,
ICD-9-CM 147, from the registry of catastrophic illness. We excluded patients with a history of cancer before the baseline year,
and those who were aged 20 years or under during the baseline
year. The follow-up period was terminated upon developing NPC,
withdrawal from the insurance system, or the end of 2009.
The demographic data included sex, age, occupation, and residence area. Occupation was classied into three groups: White collar, blue collar, and others. The urbanization of Taiwan cities
grouped into seven levels that were based on the following indices:
(1) Population density (people/km2); (2) the population ratio of
different educational levels; (3) the population ratio of elderly persons; (4) the population ratio of agriculture workers and the number of physicians per 100000 people [3]. The subjects in levels 5, 6
and 7 were small so that these levels were combined into level 4.
Level 1 was considered to represent the highest degree of urbanization and level 4 represented the lowest.

evaluated by the KaplanMeier method, and the differences between the incidence curves were evaluated by the log-rank test.
The Coxs proportional hazards regression model, adjusted for potential confounding factors, was used to estimate the hazard ratio
(HR) and condence interval (CI) for the OM cohort and the comparison cohort. The average OM frequency was calculated as the
total number of OM diagnoses during the follow-up period divided
by the follow-up duration in years. The average OM frequency was
separated into 3 groups by percentile (33rd percentile and 66th
percentile). To measure the association between the average OM
frequency and the risk of NPC, we estimated the risk in every level
of average OM frequency, and the OM frequency was considered a
continuous variable to evaluate the trends using the Coxs proportional hazards regression model.
Data management and analysis were performed using SAS version 9.1 software (SAS Institute, Cary, NC, USA), and the cumulative
incidence curve was plotted using R software (R Foundation for
Statistical Computing, Vienna, Austria). P values for the two-tailed
tests that were less than .05 were considered to represent signicant differences among the data sets.
Results
Our study evaluated 13,513 OM participants and 135,130 comparison cohort participants between 2000 and 2005 (Table 1). The
average age (47.5 y) and sex ratio were identical between the two
cohorts. In both cohorts, approximately 30% of the participants
lived in the highest urbanization level, and approximately 50%
were classied as white-collar.
The NPC incidence rate in the OM cohort was 6.41 per 10000
person-years, and was approximately 11-fold higher than the
NPC incidence rate in the comparison cohort (0.58 per 10000 person-years; Table 2). The NPC cumulative incidence curve showed
that the OM cohort had a signicantly higher risk for NPC than
the comparison cohort (P value for log-rank test <0.0001; Fig. 1).
After adjusting for potential confounders, the HR of subsequent
NPC in the OM cohort was 11.04 (95% CI, 7.6815.87), compared
with the comparison cohort. We also applied sensitivity analysis
to measure the NPC risk in the study population throughout the
follow-up duration. While 71% of the NPC events occurred in the
OM cohort within 1 year of OM diagnosis, approximately 10% of
the NPC events in the comparison cohort occurred within the same
period. These results suggest that the OM cohort displayed a significantly increased risk of NPC, compared with the comparison
cohort.
Table 1
Baseline demographic status and comorbidity compared between Comparison and
otitis media cohorts.
Variable

Age, years (SD)*

640
4150
>50
Sex
Female
Male
Urbanization level
1
2
3
4
Occupation
White collar
Blue collar
Others

Statistical analysis
We used the chi-square test for category variables and the t-test
for continuous variables to assess the difference in baseline demographic characteristics between the OM cohort and the comparison
cohort participants. The total NPC incidence and the demographicspecic NPC incidence was calculated per 10000 person-years. The
cumulative NPC incidence curves for the study cohorts were also

340

339

t-Test.

Adult otitis media and nasopharyngeal cancer

Comparison group

Otitis media group

N = 135130 (%)

N = 13513 (%)

47.5 (15.7)

47.5 (15.7)

50790 (37.6)
30450 (22.5)
53890 (39.9)

5079 (37.6)
3045 (22.5)
5389 (39.9)

74120 (54.9)
61010 (45.1)

7412 (54.9)
6101 (45.1)

p-Value

0.99
1.0000

1.0000

0.0012
41119
39396
24003
30610

(30.4)
(29.2)
(17.8)
(22.7)

3950
3872
2522
3169

(29.2)
(28.7)
(18.7)
(23.5)
0.0005

70160 (51.9)
46206 (34.2)
18764 (13.9)

6918 (51.2)
4827 (35.7)
1768 (13.1)

Table 2
Incidence of nasopharyngeal cancer and multivariate Cox proportional hazards regression analysis measured hazard ratio for study cohort.
Variable

Total
Time
>1
>2
>3
>4
>5

lag
year
years
years
years
years

Comparison group

Otitis media group

HR (95% CI)a

aHR (95% CI)b

Event

PYs

Rate

Event

PYs

Rate

55

948726

0.58

62

96778

6.41

11.10 (7.7215.96)

11.04 (7.6815.87)

49
45
40
31
23

947824
945119
940786
935001
859021

0.52
0.48
0.43
0.33
0.27

18
14
13
11
6

96730
96579
96308
95813
88225

1.86
1.45
1.35
1.15
0.68

3.58
3.03
3.15
3.43
2.51

3.56
3.01
3.14
3.41
2.50

(2.096.14)
(1.665.51)
(1.695.90)
(1.736.83)
(1.026.17)

(2.076.11)
(1.655.48)
(1.685.87)
(1.716.79)
(1.026.14)

PYs, person-years; Rate, incidence rate, per 10000 person-years.

a
b

Crude HR.
Model adjusted for age, sex, urbanization level or occupation.

7.0316.55). Although the level of urbanization was not

statistically associated with NPC risk, the OM cohort displayed a
19.31-fold higher risk of developing NPC in level 4 of urbanization, compared with the comparison cohort (HR, 19.31; 95% CI,
8.6742.99). Compared with white-collar participants, blue-collar
status was associated with increased NPC risk (HR, 1.63; 95% CI,
1.082.46). Moreover, among the blue-collar participants, OM
diagnosis was associated with a 14.12-fold increased risk of NPC
(95% CI = 8.1124.56), relative to participants without OM.
Table 4 shows the relationships between the average frequencies of OM diagnosis and the risk of developing NPC. The results
revealed that the NPC risk increased with increasing frequency of
OM diagnosis (P value for trend <0.0001). A lower level of average
OM diagnosis frequency was not associated with increased risk for
NPC (average frequency <0.6; HR = 0.47; 95% CI, 0.063.38), compared with higher levels of average OM frequency (average
frequency, 0.61; HR = 1.40; 95% CI, 0.345.73). Nevertheless, an
average OM frequency over one event per year was signicantly
associated with increased risk for NPC (HR = 29.22; 95% CI,
20.1942.27).

Fig. 1. Cumulative incidence of nasopharyngeal cancer in comparison and otitis

media cohort.

Based on the age-specic HR for subsequent NPC, the OM cohort

displayed an approximate 10-fold increase in the risk of NPC
relative to the comparison cohort participants within the
same age group (<40 years, HR = 10.45; 4150 years, HR = 9.94;
>50 years, HR = 12.56; Table 3). The NPC risk for males was 3.24fold higher than that for females (95% CI, 2.164.85), and OM
diagnosis in the study cohort was associated with increased risk
for NPC relative to the comparison cohort for females
(HR = 11.91; 95% CI, 6.0023.63) and males (HR = 10.78; 95% CI,

Discussion
OM primarily occurs in childhood. Medical studies of OM have
overwhelmingly focused on the epidemiology, the etiology, the
immunology, and the management of OM in children. The most

Table 3
Demographic-specic incidence of nasopharyngeal cancer and multivariate Cox proportional hazards regression analysis measured hazard ratio for study cohort.
Variable

Age group
640
4150
>50
Sex
Female
Male
Urbanization level
1
2
3
4
Occupation
White collar
Blue collar
Others

Comparison group

Otitis media group

HR (95% CI)a

aHR (95% CI)b

aHR (95% CI)*

4.54
8.06
7.29

10.45 (5.2820.68)
9.94 (5.1719.10)
12.60 (7.1222.29)

10.55 (5.3320.88)
9.96 (5.1819.15)
12.56 (7.1022.22)

Ref
1.65 (1.032.66)
1.26 (0.801.98)

53747
43030

3.35
10.23

11.88 (5.9923.57)
10.78 (7.0316.55)

11.91 (6.0023.63)
10.78 (7.0316.55)

Ref.
3.24 (2.164.85)

17
14
13
18

28355
27806
18131
22486

6.00
5.03
7.17
8.00

8.33 (4.4015.79)
10.02 (4.7721.01)
11.07 (4.9624.70)
18.95 (8.5142.17)

8.25 (4.3515.64)
9.92 (4.7320.81)
11.08 (4.9624.73)
19.31 (8.6742.99)

Ref.
0.69 (0.421.13)
0.99 (0.591.65)
0.75 (0.451.26)

26
31
5

49880
34481
12417

5.21
8.99
4.03

9.99 (5.8017.21)
13.92 (8.0024.22)
6.49 (2.1219.83)

9.85 (5.7216.97)
14.12 (8.1124.56)
6.53 (2.1319.96)

Ref.
1.63 (1.082.46)
0.99 (0.531.82)

Event

PYs

Rate

Event

PYs

16
18
21

365663
221627
361436

0.44
0.81
0.58

17
18
27

37420
22322
37036

15
40

529038
419688

0.28
0.95

18
44

21
14
11
9

291254
277793
167999
211665

0.72
0.50
0.65
0.43

26
21
8

497557
323083
128085

0.52
0.65
0.62

Rate

PYs, person-years; Rate, incidence rate, per 10000 person-years.

Comparison group as reference group; crude HR.
Comparison group as reference group; model adjusted for age, sex, urbanization level or occupation.
Age 640, female, urbanization level = 1 and white collar as reference group; model adjusted for age, sex, urbanization level or occupation.

a
b
*

W.-Y. Huang et al. / Radiotherapy and Oncology 104 (2012) 338342

Table 4
Incidence of nasopharyngeal cancer and multivariate Cox proportional hazards
regression analysis measured hazard ratio for study cohort by average frequencies of
otitis media diagnosis.

in our OM cohort. We speculate that adult OM may share a

common etiology with NPC. Nasopharyngeal epithelium is exposed
to environmental factors, such as bacteria, fungi, viruses, and

341

carcinogenic pollutants. Inammation and/or infection in the

Average OM
diagnosis, per year
Comparison group
<0.6

Event
55

PYs

Rate

948726
37735

0.58
0.27

0.61

24648

0.81

>1

59

34393

17.15

Model 1
(95% CI)
Ref
0.47 (0.06
3.38)
1.40 (0.34
5.73)
29.26
(20.26
42.25)

Model 2
(95% CI)
Ref
0.47 (0.06
3.40)
1.39 (0.34
5.69)
29.22
(20.19
42.27)

PYs, person-years; Rate, incidence rate, per 10000 person-years.

p-Value for trend <0.0001.
Model 1: crude hazard ratio.
Model 2: adjusted for age, sex, urbanization level and occupation.

important factor in the pathogenesis of OM is the dysfunction of

the Eustachian tube. Descent of the soft-palate muscle sling relative to the Eustachian tube orice in adolescents improves the patency of the Eustachian tube, resulting in a declining incidence of
OM with age. Thus, adult OM is relatively uncommon, and theoretically raises concerns that the diagnosis of NPC in OM patients may
have an anatomical correlation. However, evidence of the association between adult OM and subsequent NPC has primarily come
from small-scale case series studies with a diverse range of results
[47]. A study conducted in Hong Kong showed that adult-onset
OM provided a good opportunity for early recognition and, perhaps
better control, of NPC [7]. A study in Taiwan by Ho et al. [5] reported that the incidence of NPC among adults that were diagnosed as OM with effusion was 5.7% in 87 patients, and
concluded that they should be subjected to medical examination
and biopsy of the nasopharynx to exclude NPC. However, other
studies have challenged the routine examination of adult patients
with OM because of a low frequency of NPC diagnosis [4,6]. To our
knowledge, our study is the rst to investigate the epidemiologic
association between adult OM and the subsequent development
of NPC using a nationwide population-based dataset. During the
5-year follow-up period, the incidence rate of NPC was 6.41 per
10000 person-years in the OM cohort, representing an approximate 11-fold greater risk, compared with participants with no history of OM. This nding supports our hypothesis that the risk of
NPC is increased following a diagnosis of OM in adults. Such evidence also supports regular medical examinations of adult OM patients for early detection of NPC during the 5 years following OM
diagnosis. However, such conclusions may be limited to adult
OM patients in Taiwan.
The underlying mechanisms of subsequent NPC in patients with
adult OM remain unclear. One possible explanation is mechanical
obliteration. Tumors may directly invade, compress the Eustachian
tube, or impair the function of muscles controlling the Eustachian
tube, particularly the tensor veli palatini. These effects may inhibit
air ow through the Eustachian tube, thereby creating a negative
pressure in the middle ear followed by an effusion. Thus, it is possible that OM is an early clinical manifestation of NPC. However,
the signicantly increased risk for NPC that was observed among
the OM cohort even 5 years after the initial diagnosis of OM in
our study (adjusted HR = 2.50; 95% CI, 1.026.14) may indicate a
multifactorial etiology. Among the OM cohort, although the majority of subsequent NPC events occurred within 2 years following the
diagnosis of OM, a signicant number of events did occur between
3 and 5 years. These data imply that, although some patients may
have suffered from delayed diagnosis of NPC, other pathogenic
mechanisms may also have contributed to the incidence of NPC

342

nasopharynx can extend to the middle ear through the Eustachian

tube, which may contribute to the development of both OM and
NPC. Recently, chronic infection and inammation have gained
prominence as potentially important factors for tumor development, and are regarded as the seventh hallmark of cancer [8], with
up to 20% of cancer cases linked to chronic inammation [9,10].
Studies have revealed that chronic infection or inammation of
the ear, paranasal sinus, nose, throat, and lower respiratory tract
may double the risk of NPC [1115]. These ndings suggest that
persistent inammation and infection of the respiratory tract
may render the nasopharyngeal mucosa more susceptible to carcinogenesis. Moreover, bacterial growth within the nasopharynx
may reduce nitrates to nitrites, contributing to the formation of
carcinogenic N-nitroso compounds [16] that increase the risk of
NPC [17]. Therefore, further studies of the underlying mechanisms
of NPC are warranted.
The large samples size that was obtained from our nationwide
population-based dataset strengthens the statistical power of our
examination of associations between adult OM and subsequent
NPC. In addition, the participants in our study displayed a wide
range of demographic characteristics, which allowed us to perform
stratied analyses according to age, sex, occupation, and urbanization level. However, there are limitations to our ndings. First, the
dataset did not contain information regarding health-related factors, such as smoking, diet, and family history of NPC. Therefore,
we were unable to adjust for the relevant effects of such factors
on the risk for NPC. Second, the status of EpsteinBarr virus infection and its serologic markers, though well-known predictors of
NPC [18], were not routinely checked in the general population
in Taiwan during our study period. Therefore, the associations of
EpsteinBarr virus infection with adult OM and NPC could not be
surveyed.
In summary, the risk of developing NPC in adults in Taiwan was
approximately 11 times higher among participants that had been
previously been diagnosed with OM, compared to control participants. Thus, physicians should be aware of the statistical link to
NPC when assessing OM in adults, and we recommend follow-up
examinations for at least 5 years, based on the results of our study.
Further studies of associations of OM and NPC in other countries
are warranted, especially in areas in which NPC is endemic.
Acknowledgments
The study was supported in part by the study projects of DMR101-061, DMR-100-076, and TSGH-C102-151 and Taiwan Department of Health Clinical Trial and Research Center and for Excellence (DOH101-TD-B-111-004), and Taiwan Department of
Health Cancer Research Center for Excellence (DOH101-TD-C111-005).
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