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Association between adult otitis media and nasopharyngeal cancer: A nationwide population-based cohort study
Radiotherapy and Oncology 104 (2012) 338–342
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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 b,d, Chang-Ming Chen a, 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 Institute of Clinical Medicine, National Yang-Ming University, Taipei, Taiwan; c Management Office 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 10 000 person-years, respectively (adjusted HR, 11.04; 95% CI, 7.68–5.87; P < 0.0001). The NPC risk for males was significantly higher than that for females (adjusted HR = 3.24; 95% CI, 2.16–4.85). In both female and male patients, the diagnosis of OM was associated with a significantly 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). Stratified by the frequency of OM episodes, more than one episode per year had a significantly greater risk of developing NPC, compared with the comparison cohort (HR = 29.22; 95% CI, 20.19–42.27). 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 findings, further studies are warranted in other areas in which NPC is endemic. Ó 2012 Elsevier Ireland Ltd. All rights reserved. Radiotherapy and Oncology 104 (2012) 338–342
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 orifice 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: [email protected] (C.-H. Kao). 0167-8140/$ - see front matter Ó 2012 Elsevier Ireland Ltd. All rights reserved. http://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 100 000 for men and 3.47 per 100 000 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)
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W.-Y. Huang et al. / Radiotherapy and Oncology 104 (2012) 338–342
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 identification 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 identification 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 defined by the International Classification of Diseases, Ninth Revision, Clinical Modification (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 defined 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 classified 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 100 000 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 Kaplan–Meier method, and the differences between the incidence curves were evaluated by the log-rank test. The Cox’s proportional hazards regression model, adjusted for potential confounding factors, was used to estimate the hazard ratio (HR) and confidence 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 Cox’s 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 significant 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 classified as white-collar. The NPC incidence rate in the OM cohort was 6.41 per 10 000 person-years, and was approximately 11-fold higher than the NPC incidence rate in the comparison cohort (0.58 per 10 000 person-years; Table 2). The NPC cumulative incidence curve showed that the OM cohort had a significantly 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, 7.68–15.87), 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 41–50 >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 demographicspecific NPC incidence was calculated per 10 000 person-years. The cumulative NPC incidence curves for the study cohorts were also
*
t-Test.
Comparison group
Otitis media group
N = 135130 (%)
N = 13513 (%)
47.5 (15.7) 50790 (37.6) 30450 (22.5) 53890 (39.9)
47.5 (15.7) 5079 (37.6) 3045 (22.5) 5389 (39.9)
74120 (54.9) 61010 (45.1)
7412 (54.9) 6101 (45.1)
41119 39396 24003 30610
3950 3872 2522 3169
p-Value
0.99 1.0000
1.0000
0.0012 (30.4) (29.2) (17.8) (22.7)
(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)
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Adult otitis media and nasopharyngeal cancer
Table 2 Incidence of nasopharyngeal cancer and multivariate Cox proportional hazards regression analysis measured hazard ratio for study cohort. Variable
Total Time lag >1 year >2 years >3 years >4 years >5 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 (7.72–15.96)
11.04 (7.68–15.87)
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
(2.09–6.14) (1.66–5.51) (1.69–5.90) (1.73–6.83) (1.02–6.17)
(2.07–6.11) (1.65–5.48) (1.68–5.87) (1.71–6.79) (1.02–6.14)
PYs, person-years; Rate, incidence rate, per 10 000 person-years. a Crude HR. b Model adjusted for age, sex, urbanization level or occupation.
Fig. 1. Cumulative incidence of nasopharyngeal cancer in comparison and otitis media cohort.
Based on the age-specific 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; 41–50 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, 2.16–4.85), 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, 6.00–23.63) and males (HR = 10.78; 95% CI,
7.03–16.55). 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, 8.67–42.99). Compared with white-collar participants, blue-collar status was associated with increased NPC risk (HR, 1.63; 95% CI, 1.08–2.46). Moreover, among the blue-collar participants, OM diagnosis was associated with a 14.12-fold increased risk of NPC (95% CI = 8.11–24.56), 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, 0.06–3.38), compared with higher levels of average OM frequency (average frequency, 0.6–1; HR = 1.40; 95% CI, 0.34–5.73). Nevertheless, an average OM frequency over one event per year was significantly associated with increased risk for NPC (HR = 29.22; 95% CI, 20.19–42.27).
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-specific incidence of nasopharyngeal cancer and multivariate Cox proportional hazards regression analysis measured hazard ratio for study cohort. Variable
Age group 640 41–50 >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)*
Event
PYs
Rate
Event
PYs
Rate
16 18 21
365663 221627 361436
0.44 0.81 0.58
17 18 27
37420 22322 37036
4.54 8.06 7.29
10.45 (5.28–20.68) 9.94 (5.17–19.10) 12.60 (7.12–22.29)
10.55 (5.33–20.88) 9.96 (5.18–19.15) 12.56 (7.10–22.22)
Ref 1.65 (1.03–2.66) 1.26 (0.80–1.98)
15 40
529038 419688
0.28 0.95
18 44
53747 43030
3.35 10.23
11.88 (5.99–23.57) 10.78 (7.03–16.55)
11.91 (6.00–23.63) 10.78 (7.03–16.55)
Ref. 3.24 (2.16–4.85)
21 14 11 9
291254 277793 167999 211665
0.72 0.50 0.65 0.43
17 14 13 18
28355 27806 18131 22486
6.00 5.03 7.17 8.00
8.33 (4.40–15.79) 10.02 (4.77–21.01) 11.07 (4.96–24.70) 18.95 (8.51–42.17)
8.25 (4.35–15.64) 9.92 (4.73–20.81) 11.08 (4.96–24.73) 19.31 (8.67–42.99)
Ref. 0.69 (0.42–1.13) 0.99 (0.59–1.65) 0.75 (0.45–1.26)
26 21 8
497557 323083 128085
0.52 0.65 0.62
26 31 5
49880 34481 12417
5.21 8.99 4.03
9.99 (5.80–17.21) 13.92 (8.00–24.22) 6.49 (2.12–19.83)
9.85 (5.72–16.97) 14.12 (8.11–24.56) 6.53 (2.13–19.96)
Ref. 1.63 (1.08–2.46) 0.99 (0.53–1.82)
PYs, person-years; Rate, incidence rate, per 10 000 person-years. a Comparison group as reference group; crude HR. b 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.
W.-Y. Huang et al. / Radiotherapy and Oncology 104 (2012) 338–342 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. Average OM diagnosis, per year
Event
PYs
Rate
Comparison group <0.6
55 1
948726 37735
0.58 0.27
0.6–1
2
24648
0.81
>1
59
34393
17.15
Model 1 (95% CI)
Model 2 (95% CI)
Ref 0.47 (0.06– 3.38) 1.40 (0.34– 5.73) 29.26 (20.26– 42.25)
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 10 000 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 orifice 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 [4–7]. 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 first 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 10 000 person-years in the OM cohort, representing an approximate 11-fold greater risk, compared with participants with no history of OM. This finding 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 flow 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 significantly 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, 1.02–6.14) 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 significant 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
341
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 carcinogenic pollutants. Inflammation and/or infection in the 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 inflammation 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 inflammation [9,10]. Studies have revealed that chronic infection or inflammation of the ear, paranasal sinus, nose, throat, and lower respiratory tract may double the risk of NPC [11–15]. These findings suggest that persistent inflammation 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 stratified analyses according to age, sex, occupation, and urbanization level. However, there are limitations to our findings. 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 Epstein–Barr 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 Epstein–Barr 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). References [1] Monasta L, Ronfani L, Marchetti F, et al. Burden of disease caused by otitis media: systematic review and global estimates. PLoS One 2012;7:e36226. [2] Chiang TL. Taiwan’s 1995 health care reform. Health Policy 1997;39:225–39. [3] Liu CY, Hung YT, Chuang YL, et al. Incorporating development stratification of Taiwan townships into sampling design of large scale health interview survey. J Health Manag 2006;4:1–22. [4] Dempster JH, Simpson DC. Nasopharyngeal neoplasms and their association with adult onset otitis media with effusion. Clin Otolaryngol Allied Sci 1988;13:363–5. [5] Ho KY, Lee KW, Chai CY, et al. Early recognition of nasopharyngeal cancer in adults with only otitis media with effusion. Otolaryngol Head Neck Surg 2008;37:362–5.
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[6] Robinson PM. Secretory otitis media in the adult. Clin Otolaryngol Allied Sci 1987;12:297–302. [7] Sham JS, Wei WI, Lau SK, et al. Serous otitis media. An opportunity for early recognition of nasopharyngeal carcinoma. Arch Otolaryngol Head Neck Surg 1992;118:794–7. [8] Mantovani A. Cancer: inflaming metastasis. Nature 2009;457:36–7. [9] Coussens LM, Werb Z. Inflammation and cancer. Nature 2002;420:860–7. [10] Grivennikov SI, Greten FR, Karin M. Immunity, inflammation, and cancer. Cell 2010;140:883–99. [11] Chang ET, Adami HO. The enigmatic epidemiology of nasopharyngeal carcinoma. Cancer Epidemiol Biomarkers Prev 2006;15:1765–77. [12] Henderson BE, Louie E, SooHoo Jing J. Risk factors associated with nasopharyngeal carcinoma. N Engl J Med 1976;295:1101–6. [13] Yu MC, Garabrant DH, Huang TB, et al. Occupational and other non-dietary risk factors for nasopharyngeal carcinoma in Guangzhou, China. Int J Cancer 1990;45:1033–9.
[14] Yuan JM, Wang XL, Xiang YB, et al. Non-dietary risk factors for nasopharyngeal carcinoma in Shanghai, China. Int J Cancer 2000;85:364–9. [15] Zhu K, Levine RS, Brann EA, et al. Case-control study evaluating the homogeneity and heterogeneity of risk factors between sinonasal and nasopharyngeal cancers. Int J Cancer 2002;99:119–23. [16] Bartsch H, Ohshima H, Pignatelli B, et al. Endogenously formed N-nitroso compounds and nitrosating agents in human cancer etiology. Pharmacogenetics 1992;2:272–7. [17] Mirvish SS. Role of N-nitroso compounds (NOC) and N-nitrosation in etiology of gastric, esophageal, nasopharyngeal and bladder cancer and contribution to cancer of known exposures to NOC. Cancer Lett 1995;93:17–48. [18] Chien YC, Chen JY, Liu MY, et al. Serologic markers of Epstein-Barr virus infection and nasopharyngeal carcinoma in Taiwanese men. N Engl J Med 2001;345:1877–82.
Contents lists available at SciVerse ScienceDirect
Radiotherapy and Oncology journal homepage: www.thegreenjournal.com
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 b,d, Chang-Ming Chen a, 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 Institute of Clinical Medicine, National Yang-Ming University, Taipei, Taiwan; c Management Office 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 10 000 person-years, respectively (adjusted HR, 11.04; 95% CI, 7.68–5.87; P < 0.0001). The NPC risk for males was significantly higher than that for females (adjusted HR = 3.24; 95% CI, 2.16–4.85). In both female and male patients, the diagnosis of OM was associated with a significantly 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). Stratified by the frequency of OM episodes, more than one episode per year had a significantly greater risk of developing NPC, compared with the comparison cohort (HR = 29.22; 95% CI, 20.19–42.27). 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 findings, further studies are warranted in other areas in which NPC is endemic. Ó 2012 Elsevier Ireland Ltd. All rights reserved. Radiotherapy and Oncology 104 (2012) 338–342
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 orifice 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: [email protected] (C.-H. Kao). 0167-8140/$ - see front matter Ó 2012 Elsevier Ireland Ltd. All rights reserved. http://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 100 000 for men and 3.47 per 100 000 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)
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W.-Y. Huang et al. / Radiotherapy and Oncology 104 (2012) 338–342
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 identification 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 identification 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 defined by the International Classification of Diseases, Ninth Revision, Clinical Modification (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 defined 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 classified 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 100 000 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 Kaplan–Meier method, and the differences between the incidence curves were evaluated by the log-rank test. The Cox’s proportional hazards regression model, adjusted for potential confounding factors, was used to estimate the hazard ratio (HR) and confidence 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 Cox’s 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 significant 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 classified as white-collar. The NPC incidence rate in the OM cohort was 6.41 per 10 000 person-years, and was approximately 11-fold higher than the NPC incidence rate in the comparison cohort (0.58 per 10 000 person-years; Table 2). The NPC cumulative incidence curve showed that the OM cohort had a significantly 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, 7.68–15.87), 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 41–50 >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 demographicspecific NPC incidence was calculated per 10 000 person-years. The cumulative NPC incidence curves for the study cohorts were also
*
t-Test.
Comparison group
Otitis media group
N = 135130 (%)
N = 13513 (%)
47.5 (15.7) 50790 (37.6) 30450 (22.5) 53890 (39.9)
47.5 (15.7) 5079 (37.6) 3045 (22.5) 5389 (39.9)
74120 (54.9) 61010 (45.1)
7412 (54.9) 6101 (45.1)
41119 39396 24003 30610
3950 3872 2522 3169
p-Value
0.99 1.0000
1.0000
0.0012 (30.4) (29.2) (17.8) (22.7)
(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)
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Table 2 Incidence of nasopharyngeal cancer and multivariate Cox proportional hazards regression analysis measured hazard ratio for study cohort. Variable
Total Time lag >1 year >2 years >3 years >4 years >5 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 (7.72–15.96)
11.04 (7.68–15.87)
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
(2.09–6.14) (1.66–5.51) (1.69–5.90) (1.73–6.83) (1.02–6.17)
(2.07–6.11) (1.65–5.48) (1.68–5.87) (1.71–6.79) (1.02–6.14)
PYs, person-years; Rate, incidence rate, per 10 000 person-years. a Crude HR. b Model adjusted for age, sex, urbanization level or occupation.
Fig. 1. Cumulative incidence of nasopharyngeal cancer in comparison and otitis media cohort.
Based on the age-specific 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; 41–50 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, 2.16–4.85), 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, 6.00–23.63) and males (HR = 10.78; 95% CI,
7.03–16.55). 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, 8.67–42.99). Compared with white-collar participants, blue-collar status was associated with increased NPC risk (HR, 1.63; 95% CI, 1.08–2.46). Moreover, among the blue-collar participants, OM diagnosis was associated with a 14.12-fold increased risk of NPC (95% CI = 8.11–24.56), 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, 0.06–3.38), compared with higher levels of average OM frequency (average frequency, 0.6–1; HR = 1.40; 95% CI, 0.34–5.73). Nevertheless, an average OM frequency over one event per year was significantly associated with increased risk for NPC (HR = 29.22; 95% CI, 20.19–42.27).
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-specific incidence of nasopharyngeal cancer and multivariate Cox proportional hazards regression analysis measured hazard ratio for study cohort. Variable
Age group 640 41–50 >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)*
Event
PYs
Rate
Event
PYs
Rate
16 18 21
365663 221627 361436
0.44 0.81 0.58
17 18 27
37420 22322 37036
4.54 8.06 7.29
10.45 (5.28–20.68) 9.94 (5.17–19.10) 12.60 (7.12–22.29)
10.55 (5.33–20.88) 9.96 (5.18–19.15) 12.56 (7.10–22.22)
Ref 1.65 (1.03–2.66) 1.26 (0.80–1.98)
15 40
529038 419688
0.28 0.95
18 44
53747 43030
3.35 10.23
11.88 (5.99–23.57) 10.78 (7.03–16.55)
11.91 (6.00–23.63) 10.78 (7.03–16.55)
Ref. 3.24 (2.16–4.85)
21 14 11 9
291254 277793 167999 211665
0.72 0.50 0.65 0.43
17 14 13 18
28355 27806 18131 22486
6.00 5.03 7.17 8.00
8.33 (4.40–15.79) 10.02 (4.77–21.01) 11.07 (4.96–24.70) 18.95 (8.51–42.17)
8.25 (4.35–15.64) 9.92 (4.73–20.81) 11.08 (4.96–24.73) 19.31 (8.67–42.99)
Ref. 0.69 (0.42–1.13) 0.99 (0.59–1.65) 0.75 (0.45–1.26)
26 21 8
497557 323083 128085
0.52 0.65 0.62
26 31 5
49880 34481 12417
5.21 8.99 4.03
9.99 (5.80–17.21) 13.92 (8.00–24.22) 6.49 (2.12–19.83)
9.85 (5.72–16.97) 14.12 (8.11–24.56) 6.53 (2.13–19.96)
Ref. 1.63 (1.08–2.46) 0.99 (0.53–1.82)
PYs, person-years; Rate, incidence rate, per 10 000 person-years. a Comparison group as reference group; crude HR. b 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.
W.-Y. Huang et al. / Radiotherapy and Oncology 104 (2012) 338–342 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. Average OM diagnosis, per year
Event
PYs
Rate
Comparison group <0.6
55 1
948726 37735
0.58 0.27
0.6–1
2
24648
0.81
>1
59
34393
17.15
Model 1 (95% CI)
Model 2 (95% CI)
Ref 0.47 (0.06– 3.38) 1.40 (0.34– 5.73) 29.26 (20.26– 42.25)
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 10 000 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 orifice 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 [4–7]. 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 first 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 10 000 person-years in the OM cohort, representing an approximate 11-fold greater risk, compared with participants with no history of OM. This finding 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 flow 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 significantly 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, 1.02–6.14) 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 significant 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
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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 carcinogenic pollutants. Inflammation and/or infection in the 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 inflammation 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 inflammation [9,10]. Studies have revealed that chronic infection or inflammation of the ear, paranasal sinus, nose, throat, and lower respiratory tract may double the risk of NPC [11–15]. These findings suggest that persistent inflammation 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 stratified analyses according to age, sex, occupation, and urbanization level. However, there are limitations to our findings. 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 Epstein–Barr 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 Epstein–Barr 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). References [1] Monasta L, Ronfani L, Marchetti F, et al. Burden of disease caused by otitis media: systematic review and global estimates. PLoS One 2012;7:e36226. [2] Chiang TL. Taiwan’s 1995 health care reform. Health Policy 1997;39:225–39. [3] Liu CY, Hung YT, Chuang YL, et al. Incorporating development stratification of Taiwan townships into sampling design of large scale health interview survey. J Health Manag 2006;4:1–22. [4] Dempster JH, Simpson DC. Nasopharyngeal neoplasms and their association with adult onset otitis media with effusion. Clin Otolaryngol Allied Sci 1988;13:363–5. [5] Ho KY, Lee KW, Chai CY, et al. Early recognition of nasopharyngeal cancer in adults with only otitis media with effusion. Otolaryngol Head Neck Surg 2008;37:362–5.
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[6] Robinson PM. Secretory otitis media in the adult. Clin Otolaryngol Allied Sci 1987;12:297–302. [7] Sham JS, Wei WI, Lau SK, et al. Serous otitis media. An opportunity for early recognition of nasopharyngeal carcinoma. Arch Otolaryngol Head Neck Surg 1992;118:794–7. [8] Mantovani A. Cancer: inflaming metastasis. Nature 2009;457:36–7. [9] Coussens LM, Werb Z. Inflammation and cancer. Nature 2002;420:860–7. [10] Grivennikov SI, Greten FR, Karin M. Immunity, inflammation, and cancer. Cell 2010;140:883–99. [11] Chang ET, Adami HO. The enigmatic epidemiology of nasopharyngeal carcinoma. Cancer Epidemiol Biomarkers Prev 2006;15:1765–77. [12] Henderson BE, Louie E, SooHoo Jing J. Risk factors associated with nasopharyngeal carcinoma. N Engl J Med 1976;295:1101–6. [13] Yu MC, Garabrant DH, Huang TB, et al. Occupational and other non-dietary risk factors for nasopharyngeal carcinoma in Guangzhou, China. Int J Cancer 1990;45:1033–9.
[14] Yuan JM, Wang XL, Xiang YB, et al. Non-dietary risk factors for nasopharyngeal carcinoma in Shanghai, China. Int J Cancer 2000;85:364–9. [15] Zhu K, Levine RS, Brann EA, et al. Case-control study evaluating the homogeneity and heterogeneity of risk factors between sinonasal and nasopharyngeal cancers. Int J Cancer 2002;99:119–23. [16] Bartsch H, Ohshima H, Pignatelli B, et al. Endogenously formed N-nitroso compounds and nitrosating agents in human cancer etiology. Pharmacogenetics 1992;2:272–7. [17] Mirvish SS. Role of N-nitroso compounds (NOC) and N-nitrosation in etiology of gastric, esophageal, nasopharyngeal and bladder cancer and contribution to cancer of known exposures to NOC. Cancer Lett 1995;93:17–48. [18] Chien YC, Chen JY, Liu MY, et al. Serologic markers of Epstein-Barr virus infection and nasopharyngeal carcinoma in Taiwanese men. N Engl J Med 2001;345:1877–82.