Medical History, Medication Use, and Risk of Nasopharyngeal Carcinoma

Abstract

Because persistent inflammation may render the nasopharyngeal mucosa susceptible to carcinogenesis, chronic ear-nose-throat (ENT) disease and its treatment might influence the risk of nasopharyngeal carcinoma (NPC). Existing evidence is, however, inconclusive and often based on methodologically suboptimal epidemiologic studies. In a population-based case-control study in southern China, we enrolled 2,532 persons with NPC and 2,597 controls, aged 20–74 years, from 2010 to 2014. Odds ratios were estimated for associations between NPC risk and history of ENT and related medications. Any history of chronic ENT disease was associated with a 34% increased risk of NPC. Similarly, use of nasal drops or aspirin was associated with approximately doubled risk of NPC. However, in secondary analyses restricted to chronic ENT diseases and related medication use at least 5 years prior to diagnosis/interview, most results were statistically nonsignificant, except a history of uncured ENT diseases, untreated nasal polyps, and earlier age at first diagnosis of ENT disease and first or most recent aspirin use. Overall, these findings suggest that ENT disease and related medication use are most likely early indications rather than causes of NPC, although the possibility of a modestly increased NPC risk associated with these diseases and related medications cannot be excluded.

Nasopharyngeal carcinoma (NPC) has a remarkable geographical and racial/ethnic distribution, and it is endemic in parts of southern China. Numerous studies have suggested that NPC develops through interactions among genetic and environmental factors and Epstein-Barr virus (EBV) infection. The etiologic role of EBV in NPC is supported by molecular analyses, as well as by serological studies (1, 2). Assumed environmental risk factors for NPC include salted fish consumption, smoking, and poor oral health (3, 4), while genetic studies have consistently shown that certain human leukocyte antigens influence NPC risk (5).

Inflammation has been proposed as one of the hallmarks of cancer (6), and persistent inflammation and infection of the respiratory tract in particular may render the nasopharyngeal mucosa more susceptible to carcinogenesis. Individual history of ear-nose-throat (ENT) disease, including sinusitis and otitis media, has been shown to increase NPC risk (7–11). Modern medicines, such as aspirin and nasal drops, as well as traditional herbal medicines, such as balms and essential oils, are commonly used in southern China to relieve symptoms of headache and nasal obstruction. Nasal balms or oils may increase NPC risk (12), whereas an inverse association between aspirin use and NPC risk has been reported (13). However, published studies of the use of these medications were either small in size or hospital-based, and observed associations may be due to reverse causality, recall bias, or confounding by underlying ENT disease.

To fill the existing knowledge gap regarding the possible relationship of medical history and medication use with NPC risk, we conducted a large, population-based case-control study in southern China, where NPC is endemic. This study enabled a more rigorous investigation of the potential independent etiologic roles of ENT-related medical history and medication use in NPC development.

METHODS

Study population

The NPC Genes, Environment, and EBV study (NPCGEE) is a collaborative population-based case-control study of NPC based in the Zhaoqing area of Guangdong Province and in the Wuzhou and Guiping/Pingnan areas of Guangxi Autonomous Region. These areas encompass 13 cities/counties (Deqing, Fengkai, Gaoyao, Huaiji, Sihui, Zhaoqing, Guangning, Wuzhou, Cenxi, Cangwu, Tengxian, Pingnan, and Guiping) in southern China, with a total population of approximately 8 million.

Recruitment of cases and controls was described previously (14). In brief, cases were aged 20–74 years at diagnosis between March 2010 and December 2013, living in the described geographic area, and without a prior history of malignant disease or congenital or acquired immunodeficiency. All cases were histopathologically confirmed by pathology reports. We established a rapid case-ascertainment system including 10 hospitals and 2 cancer research institutions that directly notified study investigators of newly diagnosed NPC cases. In the Zhaoqing area, 1,528 eligible cases were identified between March 2010 and August 2013; in the Wuzhou area, 792 eligible cases were identified between April 2010 and September 2013; in the Guiping/Pingnan area, 727 eligible cases were identified between July 2010 and December 2013. The number of cases identified in each region was close to the expected number of incident NPC cases based on historical incidence rates. Of eligible patients who were contacted by study staff, 1,306 (85% of 1,528 cases) in the Zhaoqing area, 689 (87% of 792 cases) in the Wuzhou area, and 559 (77% of 727 cases) in the Guiping/Pingnan area were enrolled in the study.

Controls were randomly selected every 6–12 months between November 2010 and November 2014 from continuously updated total population registries covering the Zhaoqing, Wuzhou, and Guiping/Pingnan populations, with frequency matching to the 5-year-age and sex distribution of the cases according to geographic region. Eligible controls were required to be residents of the study area without a prior history of malignant disease or congenital or acquired immune deficiency. Controls who had worked outside of the study area for 10 years or more, as identified with the help of the local government in each town or community, were not considered part of the study base, because they were highly unlikely to return to the study area if they were diagnosed with NPC; therefore, they were replaced. Of 3,932 potential controls selected from the total population registries, 730 (19%) could not be linked to an identifiable person because of invalid contact information. Of the 3,202 who were identified, 138 (4%) had emigrated out of the study area, 90 (3%) were deceased or incapacitated, and 326 (10%) refused to participate. Of the 2,648 (83% of 3,202) enrolled controls, 2,133 (81%) were initial selections from the population registry, and the other 515 (19%) were replacements.

This study was approved by the institutional review boards of Sun Yat-sen University Cancer Center, the Institute for Viral Disease Control and Prevention of the Chinese Center for Disease Control and Prevention, Guangxi Medical University, and Harvard T.H. Chan School of Public Health, as well as the Regional Research Ethics Vetting Board in Stockholm, Sweden. All subjects granted written or oral informed consent to participate.

Data collection

Trained interviewers used a structured electronic questionnaire to conduct audiotaped face-to-face or telephone interviews with study participants. Although blinding to case-control status was not feasible, in an effort to reduce information bias, we required all interviewers, who were unaware of the study hypotheses, to interview an approximately equal number of cases and controls. The questionnaire covered demographic characteristics, residential history, occupational history, medical history of chronic ENT disease, medication use, family medical history, dietary habits, cigarette smoking, alcohol and tea drinking, and use of Chinese herbal medicine, among other topics. Questionnaire data were automatically flagged for logic errors and missing values, and errors were corrected by making comparisons against audio recordings or by contacting participants again.

Five chronic ENT diseases were investigated: chronic sinusitis, chronic pharyngitis, chronic otitis media, nasal polyps, and septal abnormalities. For each disease, questions addressed whether the subject had ever been diagnosed (yes or no), age at diagnosis, number of times of diagnosed, age at most recent occurrence, any use of medications or surgical treatment, and whether the disease had been cured (i.e., was no longer symptomatic). Persistent, chronic ENT disease was classified based on having an interval of 3 months or less between multiple episodes (15).

Medications assessed were nasal drops (use for at least 3 months in 1 year), aspirin (use for at least 3 months in 1 year), balm or peppermint (any use), flower oil (any use), and qufeng oil (any use). Qufeng oil, a traditional Chinese medicine, consists mainly of methyl salicylate, peppermint oil, and camphor oil, and is used topically on the skin to treat arthralgia. For nasal drops and aspirin, additional questions included reasons for use (free text), ages at initiation and cessation of use, frequency of use (times per day, week, or month), and duration of use (years).

After data cleaning, 1 case and 17 controls had misplaced data, and 6 controls outside the eligible range at interview were excluded. We further excluded 1 case with missing data on medical history and medication use and 20 cases and 28 controls with poor-quality questionnaire data as determined by the interviewers. After excluding these 73 subjects, 2,532 cases and 2,597 controls were included in the present analysis.

Statistical analysis

We used multivariate unconditional logistic regression models to estimate odds ratios and corresponding 95% confidence intervals for risk of NPC associated with history of chronic ENT diseases and medication use. In secondary analyses, to reduce the potential for reverse causality, chronic ENT diseases and use of related medications within the 5 years prior to diagnosis (for cases) or interview (for controls) were excluded. Based on prior knowledge and analyses in this study population (3, 4), potential confounders included in the multivariate models were age (in 5-year groups), sex, residential area (Zhaoqing, Wuzhou, or Guiping/Pingnan), educational level (in years: ≤6, 7–9, 10–12, or >12), current housing type (concrete building, clay brick cottage, or boat), current occupation (unemployed, farmer, blue-collar, white-collar, or other/unknown), cigarette smoking (current, former, or never), first-degree family history of NPC (yes, no, or unknown), alcohol drinking (never, ever), tea drinking (never, ever), salt-preserved fish consumption in adulthood (energy-adjusted intake categories: 1 = lowest intake (none) to 4 = highest intake), and herbal medicine use (never, yearly, monthly, or weekly or more).

Crude differences between NPC cases and controls were compared using the χ² test for categorical variables and Student’s t test for continuous variables. Where continuous variables were classified into categories, the median value was used as the cutpoint. Data analyses were performed with SAS, version 9.4 (SAS Institute, Inc., Cary, North Carolina). All statistical tests were 2-sided, and a P value of <0.05 was considered statistically significant.

RESULTS

Descriptive characteristics

Table 1 shows the distribution of demographic and other characteristics among the 2,532 NPC cases and 2,597 population-based controls. Because we began interviewing controls about 1 year later than cases, cases were slightly younger than controls. Cases were less educated and more likely to live in cottages, have blue-collar jobs, have a first-degree family history of NPC, have consumed more salt-preserved fish in adulthood, and have used herbal medicines at least weekly, compared with controls.

Table 1.

Characteristics of Nasopharyngeal Carcinoma Cases and Controls Enrolled in a Population-Based Case-Control Study in Southern China, 2010–2014

Characteristic	Case Group (n = 2,532)		Control Group (n = 2,597)		P Value
	No.	%	No.	%
Residential area					0.3
Zhaoqing	1,286	50.8	1,321	50.9
Wuzhou	688	27.2	665	25.6
Guiping/Pingnan	558	22.0	611	23.5
Sex					0.97
Male	1,860	73.5	1,909	73.5
Female	672	26.5	688	26.5
Age at diagnosis/interview, years
Overalla	48.54 (10.70)		49.75 (10.90)		<0.001b
20–34	232	9.2	207	8.1	0.07
35–39	277	11.0	246	9.5
40–44	418	16.5	399	15.4
45–49	492	19.4	491	18.9
50–54	333	13.2	347	13.4
55–59	353	13.9	382	14.7
60–74	427	16.9	525	20.2
Educational level, years					0.004
≤6	1,005	39.7	932	35.9
7–9	1,013	40.0	1,040	40.1
10–12	407	16.1	484	18.6
>12	107	4.2	141	5.4
Current housing type					<0.001
Building (concrete structure)	1,820	71.9	2,019	77.7
Cottage (clay brick structure)	702	27.7	575	22.1
Boat	10	0.4	2	0.1
Missing	0	0	1	0.04
Current occupation					<0.001
Unemployed	78	3.1	96	3.7
Farmer	855	33.8	984	37.9
Blue-collar	1,023	40.4	900	34.7
White-collar	350	13.8	416	16.0
Other/unknown	226	8.9	201	7.7
Cigarette smoking					0.12
Current smoker	1,121	44.3	1,213	46.7
Former smoker	182	7.2	152	5.9
Never smoker	1,228	48.5	1,230	47.4
Missing	1	0.04	2	0.1
First-degree family history of NPC					<0.001
No	2,208	87.2	2,483	95.6
Yes	272	10.7	70	2.7
Unknown	46	1.8	43	1.7
Missing	6	0.2	1	0.04
Alcohol drinking					0.11
Never	1,735	68.5	1,815	69.9
Ever	791	31.2	766	29.5
Missing	6	0.2	16	0.6
Tea drinking					<0.001
Never	1,618	63.8	1,513	58.3
Ever	911	36.0	1,081	41.6
Missing	3	0.1	3	0.1
Salt-preserved fish consumption in adult diet, categoryc					<0.001
1	846	33.4	797	30.7
2	489	19.3	583	22.5
3	488	19.3	582	22.4
4	678	26.8	596	23.0
Missing	31	1.2	39	1.5
Herbal medicine use					0.03
Nonusers	355	14.0	419	16.1
Yearly	965	38.1	974	37.5
Monthly	905	35.7	942	36.3
Weekly or more often	269	10.6	220	8.5
Missing	38	1.5	42	1.6

Abbreviation: NPC, nasopharyngeal carcinoma.

^a Values are expressed as mean (standard deviation).

^bP value was determined by a 2-sided t test. Other P values were determined by a χ² test.

^c Energy-adjusted intake categories: 1 = lowest intake (none) to 4 = highest intake.

ENT diseases

Table 2 presents adjusted odds ratios for the association between chronic ENT disease and risk of NPC. Any history of chronic ENT disease was associated with a 34% (95% confidence interval (CI): 12, 59) higher risk of NPC. Having been treated for chronic ENT disease was associated with a similar magnitude of increase in NPC risk. Having been cured of chronic ENT disease was, however, not significantly associated with NPC risk, whereas uncured ENT disease conferred an increased risk (odds ratio (OR) = 1.53, 95% CI: 1.25, 1.89). After exclusion of individuals first diagnosed with ENT disease within the past 5 years, however, odds ratios were attenuated toward (or even past) the null, and none remained statistically significant, except a history of uncured ENT disease (OR = 1.28, 95% CI: 1.00, 1.64) and initial diagnosis of ENT disease at a young age (OR = 1.35, 95% CI: 1.04, 1.76).

Table 2.

Odds Ratios for Nasopharyngeal Carcinoma Associated With Chronic Ear-Nose-Throat Diseases in Southern China, 2010–2014

Variable	Any History of Chronic ENT Disease				ENT Disease Diagnosed More Than 5 Years Before Interview
	No. of Cases (n = 2,532)	No. of Controls (n = 2,597)	ORa	95% CIa	No. of Cases (n = 2,413)	No. of Controls (n = 2,533)	ORa	95% CIa
Chronic ENT diseases
No	2,161	2,304	1.00	Referent	2,161	2,304	1.00	Referent
Yes	371	293	1.34	1.12, 1.59	240	223	1.16	0.94, 1.42
Untreated	61	52	1.29	0.87, 1.92	36	42	0.96	0.60, 1.54
Some diseases treated	310	241	1.35	1.12, 1.63	216	187	1.23	0.99, 1.53
Uncured	260	183	1.53	1.25, 1.89	167	141	1.28	1.00, 1.64
Some diseases cured	111	110	1.01	0.76, 1.35	85	88	1.02	0.73, 1.40
Missing	0	0			12	6
Age at first diagnosis, years
1–30	181	140	1.39	1.09, 1.77	151	118	1.35	1.04, 1.76
31–74	178	147	1.26	1.00, 1.60	89	105	0.94	0.69, 1.27
Unknown	12	6			12	6

Abbreviations: CI, confidence interval; ENT, ear-nose-throat; OR, odds ratio.

^a Adjusted for sex, age (5-year categories), residential area (Zhaoqing, Wuzhou, or Guiping/Pingnan), educational level (in years: ≤6, 7–9, 10–12, or >12), current housing type (building, cottage, or boat), current occupation (unemployed, farmer, blue-collar, white-collar, or other/unknown), cigarette smoking (current smoker, former smoker, or never smoker), first-degree family history of nasopharyngeal carcinoma (yes, no, or unknown), alcohol drinking (never, ever), tea drinking (never, ever), salt-preserved fish consumption in adulthood (energy-adjusted intake categories: 1 = lowest intake (none) to 4 = highest intake), and herbal medicine use.

Focusing on each chronic ENT disease separately, we found that a history of chronic sinusitis was associated with a 1.3-fold increased risk of NPC, as was treated chronic sinusitis. While cured chronic sinusitis was not significantly associated with NPC risk, uncured chronic sinusitis was positively associated with a close to 50% increased risk of NPC. After restriction of the analysis to those first diagnosed at least 5 years earlier, the associations were generally attenuated and were statistically nonsignificant (Web Table 1, available at https://academic.oup.com/aje).

Chronic otitis media was associated with an almost doubled risk of NPC, and the results were similar for treated and uncured chronic otitis media (Web Table 2). Older age at first diagnosis, older age at the most recent occurrence, and persistent chronic otitis media were associated with increased risk of NPC. When we excluded individuals who were first diagnosed within the past 5 years, nearly all estimates were attenuated, and only older age at the most recent diagnosis of chronic otitis media (i.e., having had a more recent occurrence) remained significant (OR = 2.05, 95% CI: 1.06, 3.97).

A history of nasal polyps was not significantly associated with NPC risk, but untreated and uncured nasal polyps were associated with significantly greater risk (Web Table 3). When we excluded individuals who were first diagnosed with nasal polyps within the past 5 years, all associations were attenuated and most were statistically nonsignificant, except for untreated nasal polyps (OR = 3.26, 95% CI: 1.14, 9.34).

No associations were found between NPC risk and chronic pharyngitis and septal abnormalities, in the primary or secondary analyses (Web Tables 4 and 5).

Medications

Table 3 shows the adjusted odds ratios for associations between use of nasal drops and risk of NPC. Any history of use of nasal drops was associated with an almost doubled risk of NPC. Use of nasal drops for nasal obstruction demonstrated a significantly increased risk for NPC (OR = 2.82), whereas use of nasal drops for allergic rhinitis did not (OR = 1.23). Older age at initiation and more recent use of nasal drops were more strongly associated with NPC risk than earlier and more distant past use. Shorter duration of nasal drops use (1–6 years), was more strongly associated with NPC risk than longer duration of use (7–40 years), but more frequent use (at least daily) was more strongly associated with risk than less frequent use. However, when individuals who started to use nasal drops within the past 5 years were excluded from the analysis, associations with nasal drops use were weakened, and all were statistically nonsignificant.

Table 3.

Odds Ratios for Nasopharyngeal Carcinoma Associated With Nasal Drops Use in Southern China, 2010–2014

Variable	Any History of Nasal Drops				First Use of Nasal Drops More Than 5 Years Before Interview
	No. of Cases (n = 2,532)	No. of Controls (n = 2,597)	ORa	95% CIa	No. of Cases (n = 2,497)	No. of Controls (n = 2,590)	ORa	95% CIa
History of nasal drops use (at least 3 months in 1 year)
No	2,458	2,558	1.00	Referent	2,458	2,558	1.00	Referent
Yes	74	39	1.98	1.31, 3.01	39	32	1.25	0.75, 2.07
Reason for use of nasal drops
Nasal obstruction	51	20	2.82	1.63, 4.88	25	15	1.80	0.90, 3.59
Allergic rhinitis	13	10	1.23	0.50, 3.00	12	9	1.39	0.54, 3.55
Other	10	9	1.06	0.41, 2.73	2	8	0.24	0.05, 1.15
Age at first use of nasal drops, years
1–34	32	20	1.69	0.92, 3.09	20	17	1.30	0.64, 2.65
35–64	42	19	2.28	1.29, 4.02	19	15	1.20	0.58, 2.44
Age at most recent use of nasal drops, years
1–42	32	19	1.68	0.92, 3.07	21	16	1.34	0.67, 2.68
43–74	42	20	2.29	1.30, 4.05	18	16	1.16	0.56, 2.41
Duration of nasal drops use, years
1–6	52	21	2.55	1.51, 4.31	21	16	1.31	0.67, 2.57
7–40	22	18	1.23	0.61, 2.48	18	16	1.17	0.55, 2.51
No. of uses of nasal drops
≥1/day	39	15	2.51	1.35, 4.65	21	13	1.48	0.72, 3.06
≥1/week	15	12	1.38	0.60, 3.17	7	11	0.70	0.25, 2.02
≥1/month	19	12	1.84	0.83, 3.92	11	8	1.54	0.57, 4.16
Missing	1	0			0	0

Abbreviations: CI, confidence interval; OR, odds ratio.

^a Adjusted for sex, age (5-year categories), residential area (Zhaoqing, Wuzhou, or Guiping/Pingnan), educational level (in years: ≤6, 7–9, 10–12, or >12), current housing type (building, cottage, or boat), current occupation (unemployed, farmer, blue-collar, white-collar, or other/unknown), cigarette smoking (current smoker, former smoker, or never smoker), first-degree family history of nasopharyngeal carcinoma (yes, no, or unknown), alcohol drinking (never, ever), tea drinking (never, ever), salt-preserved fish consumption in adulthood (energy-adjusted intake categories: 1 = lowest intake (none) to 4 = highest intake), and herbal medicine use.

As shown in Table 4, aspirin use was also associated with an almost doubled risk of NPC. The major reasons for use of aspirin were arthritis and myocardial infarction, neither of which was significantly associated with NPC risk, whereas unspecified “other” reasons for use were associated with significantly greater risk (OR = 2.01). Relative risks did not vary appreciably by age at initiating aspirin, but more distant past use was more strongly associated with NPC risk than more recent use (for last use before age 50 years, OR = 2.58, 95% CI: 1.86, 3.58). Shorter duration of aspirin use (1–5 years) was more strongly associated with NPC risk than longer duration (6–51 years), but more frequent use (at least daily) was associated with greater risk than less frequent use. After restriction of the analysis to those who started using aspirin at least 5 years earlier, aspirin use overall was not significantly associated with NPC risk, but earlier age at initiation and most recent use remained significantly associated with greater NPC risk, although odds ratios were attenuated toward the null (for both, OR = 1.68).

Table 4.

Odds Ratios for Nasopharyngeal Carcinoma Associated With Aspirin Use in Southern China, 2010–2014

Variable	Aspirin Use				First Use of Aspirin More Than 5 Years Before Interview
	No. of Cases (n = 2,532)	No. of Controls (n = 2,597)	ORa	95% CIa	No. of Cases (n = 2,390)	No. of Controls (n = 2,551)	ORa	95% CIa
History of aspirin use (at least 3 months in 1 year)
No	2,291	2,468	1.00	Referent	2,291	2,468	1.00	Referent
Yes	241	129	1.91	1.52, 2.41	99	83	1.21	0.89, 1.66
Reason for use of aspirin
Arthritis	16	15	1.37	0.66, 2.87	11	9	1.39	0.56, 3.46
Myocardial infarction	0	2			0	2
Other	225	112	2.01	1.57, 2.57	88	72	1.22	0.88, 1.71
Age at first use of aspirin, years
1–40	130	63	2.05	1.49, 2.83	72	43	1.68	1.13, 2.52
41–74	111	66	1.77	1.28, 2.46	27	40	0.69	0.41, 1.17
Age at most recent use of aspirin, years
16–49	147	55	2.58	1.86, 3.58	63	35	1.68	1.08, 2.60
50–74	94	74	1.38	0.99, 1.92	36	48	0.85	0.53, 1.34
Duration of aspirin use, years
1–5	158	64	2.43	1.79, 3.31	33	35	0.87	0.53, 1.45
6–51	83	65	1.38	0.98, 1.95	66	48	1.48	0.99, 2.20
No. of uses of aspirin
≥1/day	89	34	2.54	1.67, 3.85	23	18	1.28	0.66, 2.48
≥1/week	35	20	1.67	0.94, 2.96	12	9	1.09	0.43, 2.74
≥1/month	116	73	1.72	1.26, 2.35	63	54	1.24	0.84, 1.82
Missing	1	2			1	2

Abbreviations: CI, confidence interval; OR, odds ratio.

^a Adjusted for sex, age (5-year categories), residential area (Zhaoqing, Wuzhou, or Guiping/Pingnan), educational level (in years: ≤6, 7–9, 10–12, or >12), current housing type (building, cottage, or boat), current occupation (unemployed, farmer, blue-collar, white-collar, or other/unknown), cigarette smoking (current smoker, former smoker, or never smoker), first-degree family history of nasopharyngeal carcinoma (yes, no, or unknown), alcohol drinking (never, ever), tea drinking (never, ever), salt-preserved fish consumption in adulthood (energy-adjusted intake categories: 1 = lowest intake (none) to 4 = highest intake), and herbal medicine use.

Web Table 6 shows estimated associations with use of balm or peppermint and use of flower or qufeng oil. Both were associated with a significantly elevated risk of NPC (OR = 2.63, 95% CI: 2.00, 3.46, and OR = 2.50, 95% CI: 1.97, 3.18, respectively). Use of both types of herbal medicines was associated with a further increased risk of NPC (OR = 2.95). Because age at first use of these medications was not assessed, individuals who initiated use within the past 5 years could not be excluded from the analysis.

DISCUSSION

This population-based case-control study, conducted in the NPC-endemic region of southern China, is one of the largest to investigate ENT-related medical history and medication use in the etiology of NPC. A recent history of chronic ENT disease, especially chronic sinusitis and otitis media, was associated with an increased risk of NPC, whereas chronic pharyngitis, nasal polyps, and septal abnormalities had no association with NPC. We also found that having been treated for (but not cured of) chronic ENT disease, chronic sinusitis, or chronic otitis media, or having uncured ENT disease, chronic sinusitis, chronic otitis media, or nasal polyps, was associated with an increased NPC risk. Our results are generally consistent with those from previous studies, including case-control studies in Thailand, Taiwan, the United States, Guangzhou, and Shanghai, China, which reported relative risks from 1.8 to 3.8 in association with a history of overall and specific chronic ENT diseases (7–11, 16, 17).

However, after exclusion of individuals first diagnosed with ENT disease within the past 5 years, we found that these associations were substantially weakened and statistically nonsignificant, and only the associations with early age at first diagnosis of ENT disease and untreated nasal polyps remained significant, suggesting an influence of reverse causality or recall bias. The positive associations with treated and uncured ENT disease could be due to greater severity of preclinical disease within 5 years before NPC diagnosis. Nonspecific symptoms of NPC include epistaxis, unilateral nasal obstruction, and auditory complaints due to cranial nerve palsies (18). These symptoms are shared by benign ENT diseases, which should be included in the differential diagnosis for NPC. Although our results are perhaps most likely explained by recall bias or especially reverse causality, where ENT disease is a preclinical symptom of NPC, we could not preclude the possibility of a modest excess risk of NPC associated with ENT disease. A biologically plausible explanation for our findings and those from previous studies, including some that excluded ENT disease within 5 or 10 years of NPC diagnosis (9, 11, 16, 17), is a carcinogenic effect of chronic inflammation. This theory is well supported by epidemiologic evidence on other cancers, as exemplified by the likely association between inflammatory bowel disease and colorectal cancer (19), between Helicobacter pylori infection and gastric cancer (20), and many others (21, 22). However, research on potential inflammatory mechanisms of NPC development remains sparse.

With reference to medications for ENT disease, most nasal drops act primarily via vasoconstriction to relieve symptoms of nasal obstruction but not to reduce inflammation. Our study found that a history of nasal drops use within the past 5 years was associated with increased risk of NPC. When individuals who started to use nasal drops within the past 5 years were excluded from the analysis, the association became weaker and statistically nonsignificant. This finding, which may be due to confounding by indication, probably reflects the inflamed condition of the upper respiratory tract before NPC diagnosis.

After restriction of the analysis to those who started using aspirin at least 5 years earlier, aspirin use overall was not significantly associated with NPC risk, but earlier age at initiation and more distant past use were significantly associated with greater NPC risk. Aspirin use has been shown to be associated with reduced risk of several common malignancies (23–25). Results of epidemiologic studies analyzing aspirin use and head and neck cancers have been inconsistent (26–28). Thus far, only one small, hospital-based case-control study found a reduced risk of NPC in association with regular aspirin use (13).

Although reverse causality must again be considered as a potential explanation for our finding of a positive association between aspirin use and NPC, this result might alternatively be due to the unique involvement of EBV infection, especially EBV reactivation, in the etiology of NPC (29). Given that aspirin can induce EBV activation and lytic cycle replication in EBV-positive cells (30, 31), aspirin might increase NPC risk by reactivating EBV. However, another EBV-associated malignancy, Hodgkin lymphoma, has been shown in some studies to be inversely associated with aspirin use (32, 33). This may be due to the distinctive role of EBV in the pathogenesis of malignancies from epithelial or lymphatic origin. Thus, the potential effect, if any, of aspirin use on NPC development, and whether it might interact with EBV infection, remains uncertain. Given that aspirin use for unspecified reasons other than arthritis and myocardial infarction was most strongly associated with NPC risk, the observed association could have been due to aspirin use for relieving pain, which is a preclinical symptom of NPC.

Consistent with the results of a study conducted 4 decades ago in Taiwan, we found that use of balm or peppermint and flower or qufeng oil was associated with increased NPC risk (12), perhaps due to alleviation of potential premonitory symptoms of NPC. However, because we did not collect information about age at first use of these products, we could not conduct a secondary analysis to examine whether the observed positive associations were due to confounding by indication.

Our study has some weaknesses. First, all information was retrospective and self-reported. Because NPC cases may overestimate or be more likely than controls to recall their history of chronic ENT diseases and related medication use, especially close to the time of NPC diagnosis, we conducted secondary analyses restricted to chronic ENT diseases and related medication use at least 5 years prior to diagnosis/interview. In general, the magnitude of the associations was attenuated, suggesting an influence of reverse causality and/or recall bias. Second, the lack of blinding of interviewers to case-control status could also have contributed to some amount of information bias. Third, invalid contact information for potential controls might have resulted in some underrepresentation of younger, urban, residentially mobile controls. However, we adjusted for age and socioeconomic factors in the multivariate analysis, and the overall control participation rate was relatively high. Although health-care utilization among enrolled controls might have been lower than in the source population (34), resulting in underascertainment of ENT diseases among controls and overestimation of associations with NPC risk, the attenuation of associations after restriction to diagnoses at least 5 years ago indicates that any such bias was modest.

In conclusion, our results indicate that positive association between ENT diseases and NPC risk detected in our study and others is probably due to bias, especially reverse causation resulting from preclinical ENT disease within 5 years of NPC diagnosis. In light of the lack of an association between more distant past ENT disease and NPC risk, our findings call into question any potential role of chronic ENT inflammation in the etiology of NPC. Similarly, the observed associations between the medication use related to ENT diseases and NPC risk might well be due to confounding by indication. However, we could not exclude the possibility of a modest excess NPC risk in association with ENT diseases and their related medication use. Future studies, with particular attention to these pitfalls, are needed to clarify whether there exists a weak association between chronic ENT diseases and/or related medication use, and NPC risk.

Abbreviations

CI

confidence interval

EBV

Epstein-Barr virus

ENT

ear-nose-throat

NPC

nasopharyngeal carcinoma

OR

odds ratio