Association of Rhinosinusitis With Nasopharyngeal Carcinoma- Case Control

7/26/2019 Association of Rhinosinusitis With Nasopharyngeal Carcinoma- Case Control

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The LaryngoscopeVC 2013 The American Laryngological,Rhinological and Otological Society, Inc.

Association of Rhinosinusitis With Nasopharyngeal Carcinoma:

A Population-Based Study

Shih-Han Hung, MD; Po-Yueh Chen, MD; Herng-Ching Lin, PhD; Jonathan Ting, BS;

Shiu-Dong Chung, MD, PhD

Objectives/Hypothesis:Although it is already known that the inflammation process elevates the risk of developing can-cer, to date the association between rhinosinusitis and nasopharyngeal carcinoma (NPC) remains unknown. This study aimedto evaluate the association between rhinosinusitis and NPC based on a nationwide database.

Study Design: Case-control study.Methods: In total, the cases comprised of 2,242 subjects with NPC and 6,726 randomly selected subjects as controls.

Separate conditional logistic regression analyses were used to calculate the odds ratio (OR) for having been previously diag-nosed with chronic and acute rhinosinusitis between the cases and controls.

Results: Of the total sample, 607subjects (6.77%) had been diagnosed with chronic rhinosinusitis prior to the indexdate: 322 (14.36%) cases with NPC and 285 (4.24%) controls (P


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The purpose of this study was to evaluate the asso-

ciation of acute and chronic rhinosinusitis with NPC

based on a nationwide database.

MATERIALS AND METHODS

Database

Data were retrieved from the Longitudinal Health Insur-ance Database 2000 (LHID2000) released by the Taiwan

National Health Research Institute. Taiwan began a single-

payer National Health Insurance (NHI) program in 1995, and

the program has covered about 98% of the population since its

inauguration. The LHID2000 includes data from all medical

claims of 1 million randomly selected enrollees of all NHI 2000

enrollees. Several studies have demonstrated the high validity

of the data from the NHI program.22,23 Furthermore, hundreds

of studies employing the LHID2000 have been published in

internationally peer reviewed journals.24 Because the database

consists of deidentified secondary data released without condi-

tions to researchers, this study was exempt from a full review

by the institutional review board.

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 depart-

ments 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 hospitali-

zation 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 Insti-

tute 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 rhinosinusi-tis). 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

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.

RESULTSThe 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 (P5.725). Table I presents the

distributions of the samples sociodemographic character-

istics between the cases and controls. It shows that there

was no significant difference between cases and controls

in terms of monthly income, urbanization level, geo-

graphic region, tobacco use, and alcohol abuse/

dependence.

The crude and adjusted OR of prior chronic rhinosi-

nusitis 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 ofNPC 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 (condi-

tioned 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, urbaniza-

tion, 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 haz-

ard 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


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Findings from previous studies lead to a clinical recom-

mendation 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 nitrosaminesthat 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 How-

ever, 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

electrophilic mediators to eradicate pathogens. Although

regarded as an effective host defense mechanism, it inevi-

tably exposes the epithelial and connective tissues to cer-

tain endogenous genotoxic agents. Whereas in most cases

the genotoxic burdens are reduced by the cell repair mech-

anisms and become negligible, in long-term cases inflam-

mation eventually elevates the risk of cancer.20 The

theory is well supported by much of the epidemiological

evidence. Probably the best known example is the associa-tion between colon cancer and ulcerative colitis. In a large

scale study done by Ekbom et al. involving thousands of

patients, investigators reported a 5.7-fold increase in colon

cancer incidence in patients with chronic ulcerative colitis

as compared to those without.28 More interestingly, the

risk of cancer correlated directly with both the severity

and duration of the disease. Later on, the same group

reported that ulcerative colitis does not increase the risk

of other types of cancer.29 This finding is especially impor-

tant because it strongly supports the role localized inflam-

mation plays in cancer development.

TABLE I.Subjects With Nasopharyngeal Carcinoma and ControlsSociodemographic Characteristics (n58,968).

Variables

Nasopharyngeal CarcinomaSubjects, n52,242 Controls, n56,726

PValueNo. % No. %

Gender 1.000

Male 1,478 65.9 4,434 65.9Female 764 34.1 2,292 34.1

Age, yr 1.000

69 244 10.9 732 10.9

Monthly income .280


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The same phenomenon can be observed in the lungs

as well. It is reported that patients with asthma showed

a significant excess risk of developing lung cancer.30

Kallen et al. even reported a reduced risk of most types

of cancers, with the exception of lung cancer and endo-

crine cancer.31 The results from many similar reports

also connect the inflammatory process to the cancers of

the ovary, pancreas, bladder, skin, and esophagus.20

It is possible that NPC shares the common

inflammatory-induced carcinogenic mechanisms related

to the granulocyte secretions. Huang et al. found that the

tissue and serum levels of 8-Oxo-20-deoxyguanosine, an

oxidative stress product, are significantly higher in NPC

patients compared to control patients.32 Recently Zhang

et al. also showed that EBV-infected immortalized naso-

pharyngeal epithelial cells often acquire an enhanced

response to interleukin (IL)26induced signal transducer

and activator of transcription 3 (STAT3) activation to pro-

mote their growth and invasive properties.33 This

enhanced IL-6/STAT3 response was mediated by overex-pression of IL-6 receptor, which implies that besides the

genotoxic burden generated by the granulocyte activity, a

cytokine-receptormediated mechanism might also be

involved in the relation between inflammation and NPC.

Moreover, the IL-6mediated Janus kinase/STAT3 path-

ways were also shown to be involved in the hypermethyl-

ation of several tumor suppressor genes in NPC cells.34

There is even evidence that NPC cells may play a

significant role in maintaining and amplifying the inflam-

mation 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 Evi-

dence from all of these studies provides certain explana-

tions 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 pos-

sibility of surveillance bias. This means that it is possi-

ble the patients with rhinosinusitis visit doctors more

often. In cases with chronic rhinosinusitis, patients weremore 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 II.Crude and Adjusted Odds Ratios of Prior Chronic Rhinosinusitis Between Nasopharyngeal Carcinoma Subjects and Controls (n58968).

Presence of Prior ChronicRhinosinusitis

Total Sample, n58,968Nasopharyngeal Carcinoma

Subjects, n52,242 Controls, n56,726

No. % No. % No. %

Yes 607 6.77 322 14.36 285 4.24

No 8,361 93.23 1,920 85.64 6,441 95.76Crude OR (95% CI) 3.83* (3.23-4.53) 1.00

Adjusted OR (95% CI) 3.79* (3.21-4.48) 1.00

*P


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within 1 year prior to the index date, were excluded.

This was an attempt to reduce the surveillance bias. The

OR of prior chronic rhinosinusitis for subjects with naso-

pharyngeal carcinoma remained significantly higher

than that of controls. The results support our original

hypothesis and reduce the chance that the increased

diagnoses of NPC resulted from accidental findings dur-

ing examinations for rhinosinusitis.

The second limitation is the lack of treatment infor-

mation for the rhinosinusitis group. In this database

study it is difficult to evaluate how well these patients

were treated. Therefore, there may have been some

patients who had been adequately treated for their rhi-

nosinusitis but were still included in the rhinosinusitis

group. This could potentially affect the accuracy of data

interpretation. However, we believe this potential bias

has little effect on our conclusions. If there was a largenumber of treated rhinosinusitis subjects included in the

rhinosinusitis case group, theoretically the results would

be affected toward the null hypothesis. Because the

results of our study reached statistically significant dif-

ferences, we believe this limitation remain fairly

negligible.

Third, the determination of the time period of the

diagnosis of rhinosinusitis before developing NPC is

especially difficult and controversial. In this study, the

cases only included patients who had ever received a

rhinosinusitis diagnosis within 3 years prior to the index

date. This selection was intended to exclude patients

with a very long interval between the diagnosis of rhino-

sinusitis and the development of NPC. However, theduration of time required for a nasal infection/inflamma-

tion to reasonably result in a carcinogenic effect remains

unknown. It is possible that under our duration selection

criteria (interval between the diagnoses of rhinosinusitis

prior to the diagnoses of NPC:


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Association of Rhinosinusitis With Nasopharyngeal Carcinoma- Case Control

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