Documenti di Didattica
Documenti di Professioni
Documenti di Cultura
INTRODUCTION
Nasopharyngeal carcinoma (NPC) accounts for
80,000 incident cases and 50,000 deaths worldwide
annually.1 It is unique because of its high prevalence in
the Chinese populations. The male-to-female ratio for an
NPC diagnosis is approximately 2 to 3:1. The incidence
of NPC in the Chinese population is known to be significantly higher as compared to the incidence in the United
States and Japanese populations. Furthermore, secondgeneration Chinese immigrants to the United States are
seven times more likely to develop NPC as compared to
1515
The purpose of this study was to evaluate the association of acute and chronic rhinosinusitis with NPC
based on a nationwide database.
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.
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 departments 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 hospitalization 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 Institute 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 rhinosinusitis). 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
1516
RESULTS
The 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 (P 5.725). Table I presents the
distributions of the samples sociodemographic characteristics between the cases and controls. It shows that there
was no significant difference between cases and controls
in terms of monthly income, urbanization level, geographic region, tobacco use, and alcohol abuse/
dependence.
The crude and adjusted OR of prior chronic rhinosinusitis 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 of
NPC 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 (conditioned 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, urbanization, 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 hazard 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 < 0.001). Furthermore, the OR of prior acute rhinosinusitis for subjects with NPC was 1.57 (95% CI, 1.43-1.73) that of
controls after adjusting for income, urbanization, geographic location, tobacco use, and alcohol abuse/alcohol
dependence.
Table IV shows a sensitivity analysis. After excluding subjects who were newly diagnosed with chronic rhinosinusitis within 1 year prior to the index date, the
adjusted OR of prior chronic rhinosinusitis for subjects
with NPC was 3.90 (95% CI, 3.26-4.68) that of controls.
DISCUSSION
In this study we were able to demonstrate that
patients with rhinosinusitis were more likely to have
NPC, and our findings strongly support that rhinosinusitis should be considered as a possible risk factor. In
endemic populations, the risk factors appear to be an
interaction of several factors including EBV infection,
genetic predispositions, and environmental factors such
as the high intake of preserved foods and smoking. It is
also very interesting to note that the exposure to a common agent early in life seems to act as a critical factor.25
Hung et al.: Sinusitis and Nasopharyngeal Carcinoma
TABLE I.
Subjects With Nasopharyngeal Carcinoma and ControlsSociodemographic Characteristics (n 5 8,968).
Nasopharyngeal Carcinoma
Subjects, n 5 2,242
Variables
Controls, n 5 6,726
No.
No.
1,478
764
65.9
34.1
4,434
2,292
65.9
34.1
<30
3039
171
317
7.6
14.1
513
951
7.6
14.1
4049
579
25.8
1,737
25.8
5059
6069
586
345
26.1
15.4
1,758
1,035
26.1
15.4
>69
244
10.9
732
10.9
819
36.5
2,343
34.8
Gender
Male
Female
1.000
Age, yr
Monthly income
<NT$15,841
NT$15,841 NT$25,000
P Value
1.000
.280
805
35.9
2,523
37.5
618
27.6
1,860
27.7
643
28.7
1,937
28.8
2
3
662
384
29.5
17.1
1,930
1,176
28.7
16.4
302
13.5
900
13.4
251
11.2
783
11.6
Northern
1,006
44.9
3,132
46.6
Central
Southern
499
691
22.3
30.8
1,539
1,923
22.9
28.5
Eastern
46
2.1
132
2.0
28
1.3
87
1.3
.871
69
3.1
219
3.2
.678
NT$25,001
Urbanization level
5
Geographical region
Alcohol abuse/alcohol
dependence syndrome
Tobacco use disorder
.312
.234
Findings from previous studies lead to a clinical recommendation 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 nitrosamines
that 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 However, 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
Laryngoscope 124: July 2014
1517
TABLE II.
Crude and Adjusted Odds Ratios of Prior Chronic Rhinosinusitis Between Nasopharyngeal Carcinoma Subjects and Controls (n 5 8968).
Total Sample, n 5 8,968
Presence of Prior Chronic
Rhinosinusitis
Yes
No
Crude OR (95% CI)
No.
607
6.77
8,361
93.23
Nasopharyngeal Carcinoma
Subjects, n 5 2,242
No.
322
14.36
1,920
85.64
3.83* (3.23-4.53)
3.79* (3.21-4.48)
Controls, n 5 6,726
No.
285
4.24
6,441
95.76
1.00
1.00
*P <.001.
Conditional logistic regression conditioned on subjects age and sex, adjusted for monthly income, geographic region, urbanization level, alcohol
abuse/alcohol dependence syndrome, and tobacco use disorder.
CI 5 confidence interval; OR 5 odds ratio.
significant role in maintaining and amplifying the inflammation 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 Evidence from all of these studies provides certain explanations 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 possibility of surveillance bias. This means that it is possible the patients with rhinosinusitis visit doctors more
often. In cases with chronic rhinosinusitis, patients were
more 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 III.
Crude and Adjusted Odds Ratios of Prior Acute Rhinosinusitis Between Nasopharyngeal Carcinoma Subjects and Controls (n 5 8968).
Total Sample, n 5 8,968
Presence of Prior Acute
Rhinosinusitis
No.
Yes
No
4,037
4,931
45.02
54.98
Nasopharyngeal Carcinoma
Subjects, n 5 2,242
No.
1,199
1,043
53.48
46.52
Controls, n 5 6,726
No.
2,838
3,888
42.19
57.81
1.60 (1.45-1.76)*
1.00
1.57 (1.43-1.73)*
1.00
*P <.001.
Conditional logistic regression conditioned on subjects age and sex, adjusted for monthly income, geographic region, urbanization level, alcohol
abuse/alcohol dependence syndrome, and tobacco use disorder.
CI 5 confidence interval; OR 5 odds ratio.
1518
TABLE IV.
Sensitivity Analysis.
Excluding Subjects Who Received a Chronic Rhinosinusitis Diagnosis Within 1 Year Prior to the Index Date
Nasopharyngeal Carcinoma
Subjects, n 5 2,197
No.
Controls, n 5 6,679
No.
Yes
277
12.61
238
3.56
No
1,920
87.39
6,441
96.44
3.94 (3.28-4.72)*
3.90 (3.26-4.68)*
1.00
1.00
*P <.001.
Conditional logistic regression conditioned on subjects age and sex, adjusted for monthly income, geographic region, urbanization level, alcohol
abuse/alcohol dependence syndrome, and tobacco use disorder.
CI 5 confidence interval; OR 5 odds ratio.
CONCLUSION
This study demonstrated an association between
rhinosinusitis and NPC. We recommend physicians to be
more aggressive when dealing with rhinosinusitis, as
this common and frequently overlooked condition may
potentially contribute to more problems than what are
conventionally expected. In addition, although the true
relationship between rhinosinusitis and NPC requires
further investigation, we recommend that patients found
to have rhinosinusitis, either acute or chronic, to seek
aggressive management to reduce both the tissue burden
and the risk of subsequently developing NPC.
BIBLIOGRAPHY
1. Ferlay J, Shin HR, Bray F, Forman D, Mathers C, Parkin DM. Estimates
of worldwide burden of cancer in 2008: GLOBOCAN 2008. Int J Cancer
2010;127:28932917.
2. Gleeson MJ, Browning G, Burton Martin J, et al. Scott-Browns Otolaryngology. Boca Raton, FL: CRC Press, 2008.
3. Taiwan Cancer Registry Database 2009. Available at: http://cph.ntu.edu.
tw/main.php?Page5N2#. Accessed on December 12, 2013.
4. Jia WH, Qin HD. Non-viral environmental risk factors for nasopharyngeal
carcinoma: a systematic review. Semin Cancer Biol 2012;22:117126.
5. Yuan JM, Wang XL, Xiang YB, Gao YT, Ross RK, Yu MC. Preserved foods
in relation to risk of nasopharyngeal carcinoma in Shanghai, China. Int
J Cancer 2000;85:358363.
6. Farrow DC, Vaughan TL, Berwick M, Lynch CF, Swanson GM, Lyon JL.
Diet and nasopharyngeal cancer in a low-risk population. Int J Cancer
1998;78:675679.
7. Liebowitz D. Nasopharyngeal carcinoma: the Epstein-Barr virus association. Semin Oncol 1994;21:376381.
8. Hildesheim A, West S, DeVeyra E, et al. Herbal medicine use, EpsteinBarr virus, and risk of nasopharyngeal carcinoma. Cancer Res 1992;52:
30483051.
9. Gallicchio L, Matanoski G, Tao XG, et al. Adulthood consumption of preserved and nonpreserved vegetables and the risk of nasopharyngeal carcinoma: a systematic review. Int J Cancer 2006;119:11251135.
1519
10. Hsu WL, Chen JY, Chien YC, et al. Independent effect of EBV and cigarette smoking on nasopharyngeal carcinoma: a 20-year follow-up study
on 9,622 males without family history in Taiwan. Cancer Epidemiol Biomarkers Prev 2009;18:12181226.
11. Ung A, Chen CJ, Levine PH, et al. Familial and sporadic cases of nasopharyngeal carcinoma in Taiwan. Anticancer Res 1999;19:661665.
12. Polesel J, Franceschi S, Talamini R, et al. Tobacco smoking, alcohol drinking, and the risk of different histological types of nasopharyngeal cancer
in a low-risk population. Oral Oncol 2011;47:541545.
13. Chen L, Gallicchio L, Boyd-Lindsley K, et al. Alcohol consumption and the
risk of nasopharyngeal carcinoma: a systematic review. Nutr Cancer
2009;61:115.
14. Cheng YJ, Hildesheim A, Hsu MM, et al. Cigarette smoking, alcohol consumption and risk of nasopharyngeal carcinoma in Taiwan. Cancer
Causes Control 1999;10:201207.
15. Feng BJ, Khyatti M, Ben-Ayoub W, et al. Cannabis, tobacco and domestic
fumes intake are associated with nasopharyngeal carcinoma in North
Africa. Br J Cancer 2009;101:12071212.
16. Anon JB. Upper respiratory infections. Am J Med 2010;123:S16S25.
17. Scadding GK, Durham SR, Mirakian R, et al. BSACI guidelines for the
management of rhinosinusitis and nasal polyposis. Clin Exp Allergy
2008;38:260275.
18. Rosenfeld RM, Andes D, Bhattacharyya N, et al. Clinical practice guideline: adult sinusitis. Otolaryngol Head Neck Surg 2007;137:S1S31.
19. Yuan JM, Wang XL, Xiang YB, Gao YT, Ross RK, Yu MC. Non-dietary
risk factors for nasopharyngeal carcinoma in Shanghai, China. Int J
Cancer 2000;85:364369.
20. Fitzpatrick FA. Inflammation, carcinogenesis and cancer. Int Immunopharmacol 2001;1:16511667.
21. De Marzo AM, Platz EA, Sutcliffe S, et al. Inflammation in prostate carcinogenesis. Nat Rev Cancer 2007;7:256269.
22. Kang JH, Chen YH, Lin HC. Comorbidity profiles among patients with
ankylosing spondylitis: a nationwide population-based study. Ann
Rheum Dis 2010;69:11651168.
23. Cheng CL, Kao YH, Lin SJ, Lee CH, Lai ML. Validation of the National
Health Insurance Research Database with ischemic stroke cases in Taiwan. Pharmacoepidemiol Drug Saf 2011;20:236242.
24. Chen YC, Yeh HY, Wu JC, Haschler I, Chen TJ, Wetter T. Taiwans
National Health Insurance Research Database: administrative health
care database as study object in bibliometrics. Scientometrics 2011;86:
365380.
25. Chang ET, Adami HO. The enigmatic epidemiology of nasopharyngeal carcinoma. Cancer Epidemiol Biomarkers Prev 2006;15:17651777.
1520
Copyright of Laryngoscope is the property of Wiley-Blackwell and its content may not be
copied or emailed to multiple sites or posted to a listserv without the copyright holder's
express written permission. However, users may print, download, or email articles for
individual use.