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Gastroesophageal reflux disease is a risk factor for laryngeal and pharyngeal cancer
THE AMERICAN JOURNAL OF GASTROENTEROLOGY © 2001 by Am. Coll. of Gastroenterology Published by Elsevier Science Inc.
Vol. 96, No. 7, 2001 ISSN 0002-9270/01/$20.00 PII S0002-9270(01)02497-2
Gastroesophageal Reflux Disease Is a Risk Factor for Laryngeal and Pharyngeal Cancer Hashem B. El-Serag, M.D., M.P.H., Edward J. Hepworth, M.D., Patty Lee, M.D., and Amnon Sonnenberg, M.D., M.S. Sections of Gastroenterology and Health Services Research, The Houston Veterans Affairs Medical Center and Baylor College of Medicine, Houston, Texas; and The Albuquerque Veterans Affairs Medical Center and the University of New Mexico, Albuquerque, New Mexico
OBJECTIVE: Gastroesophageal reflux disease (GERD) is a proposed risk factor for developing laryngeal and pharyngeal cancers. No controlled study has examined this association. METHODS: A case-control study was performed using the computerized hospitalization and outpatient databases of the US Department of Veterans Affairs. All patients, who were veterans, had been identified as being hospitalized with laryngeal or pharyngeal during 1991 to 1997. In addition, all persons diagnosed with laryngeal or pharyngeal cancer in 1999 in the outpatient files were identified. From the same patient populations, four nonmatched control subjects were randomly assigned for each case. The medical history for cases and controls was retrospectively searched for GERD diagnoses, tobacco use, and alcohol dependence. Multivariable logistic regression analyses were performed to assess the risk factors for laryngeal and pharyngeal cancers. RESULTS: A total of 8,228 hospitalized patients with laryngeal cancers and 1,912 with pharyngeal cancers were compared to 32,912 and 7,648 hospitalized controls, while 9,292 outpatients with laryngeal cancer and 2,769 outpatients with pharyngeal cancer were compared with 37,168 and 11,076 outpatient controls without cancer. Among hospitalized persons, the prevalence of GERD was higher among patients with laryngeal cancer (8.9 vs 4.0%, p ⬍ 0.0001) and pharyngeal cancer (6.2 vs 3.8%, p ⬍ 0.0001). In a multivariable logistic regression analysis that was controlled for age, gender, ethnicity, smoking, and alcohol, GERD was associated with an adjusted odds ratio (OR) of 2.40 for laryngeal cancer among hospitalized patients (95% CI 2.15–2.69, p ⬍ 0.0001) and an adjusted OR of 2.38 (95% CI 1.87–3.02, p ⬍ 0.0001) for pharyngeal cancer. For outpatients, GERD was associated with an adjusted OR ⫽ 2.31 (95% CI 2.10 –2.53) for laryngeal cancer and adjusted OR ⫽ 1.92 (95% CI 1.72–2.15). CONCLUSIONS: Among US veterans, the risk for laryngeal or pharyngeal cancers is modestly increased in the presence of GERD. This effect seems to be independent of age, gender, smoking, and alcohol intake. (Am J Gastroenterol 2001;96: 2013–2018. © 2001 by Am. Coll. of Gastroenterology)
INTRODUCTION Cancers of the larynx and pharynx continue to be a significant aspect of clinical otolaryngology and oncology. Laryngeal carcinoma constitutes 26% of all head and neck tumors, whereas pharyngeal carcinoma accounts for 8% of these tumors (1). In the United States, laryngeal cancer accounts annually for an estimated 11,100 new cases and 4,300 deaths, whereas 8,600 new cases and 2,100 deaths are expected to occur because of pharyngeal cancer (2). Tobacco and alcohol consumption are well known risk factors for laryngopharyngeal cancers (1, 3, 4). A causal relationship between gastroesophageal reflux disease (GERD) and laryngopharyngeal neoplasms has been suggested (5–11). However, the association between reflux disease and laryngopharyngeal malignancy remains unclear. For example, GERD was diagnosed in a small number of patients with laryngeal or pharyngeal carcinoma who lack the typical risk factors (5– 8). In addition, a high prevalence (36 –58%) of esophageal acid reflux was measured among patients with laryngeal or pharyngeal cancers (9 –11). None of the published studies compared the prevalence of GERD among patients with laryngeal or pharyngeal carcinoma to that of controls free of cancer. Since 1970, the Department of Veteran Affairs (VA) maintains all inpatient records in a computerized database known as the Patient Treatment File (PTF). In 1997, the VA computerized Outpatient Files (OPF) were established. The PTF and OPF offer an opportunity to examine large number of patients over an extended time period. Using the PTF (hospitalized patients) and OPF (outpatients) as data sources, we carried out a case control study among US veterans to examine the risk factors of laryngeal and pharyngeal cancers.
MATERIALS AND METHODS Database The study population was selected from US veterans hospitalized within the nationwide VA hospital system during the 7-yr period of October 1991 through October 1997, and
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from veterans seen in the outpatient department between October 1998 through October 1999. Computerized records from 172 VA hospitals throughout the US are retained in a centralized PTF, which is managed by the VA Central Automation Center at Austin, Texas. The PTF contains the main files, in which discharge diagnoses are recorded for each inpatient hospital visit (average 700,000 – 800,000 annual hospitalizations). Each inpatient record contains one primary and up to nine secondary discharge diagnoses. The much larger OPF were started in 1997 and contain approximately 20 million annual records. Discharge diagnoses, as well as outpatient diagnoses, have been coded according to the 9th revision of the Clinical Modification of International Classification of Diseases (ICD-9-CM) (12). Case and Control Populations The case population consisted of all patients with a diagnosis of laryngeal cancer (ICD-codes 161.0 –161.9) or pharyngeal cancer (ICD-codes 147.0 –147.9, 148.0 –148.9, and 149.0) who were discharged between 1991 and 1997 from the VA hospitals (inpatient population), and all persons identified with these diagnoses in fiscal year 1999 in the OPF (outpatient population). Each patient’s social security number, age, sex, race, and date of admission with a cancer diagnosis were identified and retained for subsequent analyses. The date of a patient’s first appearance in the PTF with a laryngeal or pharyngeal cancer was considered to be the date of cancer diagnosis. After excluding cases with laryngeal and pharyngeal cancers from the file, four nonmatched control patients without these cancers were selected from the identical annual PTF (hospitalized cases and outpatient controls for outpatient cases). A method of random selection without replacement was employed to ensure that no individual control subject was selected more than once. As was done with the case subjects, each control patient’s social security number, age, sex, race, and enrollment date were identified and registered. Each hospitalized case and control subject was followed retrospectively through the annual files using their unique social security numbers and all of their diagnoses encountered as far back as 1981 (1981–1997) were recorded. Outpatient cases and controls identified in 1999 were retrospectively followed through the available outpatient files (1997– 1999). This accumulated medical history was searched for GERD-related diagnoses, such as erosive esophagitis (ICDcode 530.1), peptic esophagitis (ICD-code 530.19), esophageal stricture (ICD-code 530.3), and gastroesophageal reflux (ICD-code 530.81). Other associated risk factors were also evaluated, including alcohol dependence (ICD-codes 303.0 –303.9, 305.0, and V113) and tobacco use (ICD-codes 305.1, 305.11, 305.13, V6549). Statistical Analyses The length of GERD history among hospitalized cases and controls was calculated as the elapsed time between the first diagnosis of GERD and the date of enrollment into the
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study. Any GERD diagnosed within 1 month of the laryngopharyngeal cancer diagnoses was excluded from the analysis to avoid reverse causality. The date of enrollment corresponded with the date of first cancer diagnosis among cases and the initial date of hospitalization during the recruitment period among controls. For the outpatient cases and controls, all GERD diagnoses at or before the time of cancer diagnosis were considered. Chi-square tests were used for univariate comparisons of dichotomous variables, while unpaired t tests were used for univariate comparisons of continuous variables. Separate calculations were performed for hospitalized and outpatient persons. In the multivariate analysis, a logistic regression model was used to assess the occurrence of either laryngeal or pharyngeal cancer using age, gender, ethnicity, GERD, tobacco, smoking, and alcohol as predictor variables. The significance of individual influences was tested by Wald’s 2 tests. Odds ratios and their 95% CIs were presented for each estimate. Interaction terms between sex and tobacco, smoking and GERD, alcohol and GERD, smoking and alcohol were examined while maintaining all the lower order components inside the model. These analyses were performed using SAS (13). To estimate the proportion of cancer cases that is attributable to GERD, the “attributable fraction” was calculated for the whole VA population. The attributable fraction for the entire population, also termed the “attributable risk,” was calculated as p[RR-1]/(1⫹p[RR-1]), where p represents the prevalence of GERD in the VA population, and RR represents the risk ratio (14). The prevalence of GERD among controls was assumed to represent the overall GERD prevalence among veterans. In a case-control study, the risk ratio can be approximated by the adjusted odds ratio (OR).
RESULTS From 1991 through 1997, 8,228 hospitalized patients were diagnosed with laryngeal cancers, while 1,912 hospitalized subjects were diagnosed with pharyngeal cancers. Two groups of 32,912 and 7,648 hospitalized patients without laryngeal or pharyngeal cancers were randomly selected as controls for the two case groups with laryngeal or pharyngeal cancer, respectively. In 1997, 9,292 outpatients cases with laryngeal cancer were compared to 37,168 outpatient controls, and 2,769 outpatient cases with pharyngeal cancer were compared to 11,076 outpatient controls without cancer. The characteristics of the hospitalized case and control groups are presented in Table 1 for laryngeal cancer and in Table 2 for pharyngeal cancer. Compared with their respective controls, case subjects with laryngeal or pharyngeal cancer were on the average slightly older. There were more men (99.5 vs 97.3%) and more Caucasians (73.8 vs 72.8%) among patients with laryngeal cancer than controls. Similar
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GERD as a Risk Factor for Laryngeal and Pharyngeal Cancer
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Table 1. Characteristics of Hospitalized Patients With and Without Laryngeal Cancer Patient Characteristic
With Laryngeal Cancer (N ⫽ 8,228)
Without Laryngeal Cancer (N ⫽ 32,912)
p
Mean age yr (⫾ SD) Men Caucasian Diagnosis of GERD Mean length of GERD yr (⫾ SD) Tobacco use Alcohol dependence
65 ⫾ 9 8,190 (99.5%) 6,070 (73.8%) 731 (8.9%) 4.1 ⫾ 3.0 2,343 (28%) 870 (11%)
60 ⫾ 14 32,008 (97.3%) 23,944 (72.8%) 1,315 (4.0%) 3.4 ⫾ 2.7 3,632 (11%) 1,645 (5%)
⬍0.0001 ⬍0.0001 0.0642 ⬍0.0001 ⬍0.0001 ⬍0.0001 ⬍0.0001
estimates were obtained for pharyngeal cancer (Table 2). Patients with laryngeal or pharyngeal cancer had a higher frequency of GERD than their respective controls. The presence of GERD was associated with an unadjusted OR of 3.44 for laryngeal cancer (95% CI 3.09 –3.67), which means the patients with cancer have a 3.44 increase in the odds of having GERD than the controls without cancer. An OR of 1.66 (95% CI 1.33–2.06) was calculated for GERD and pharyngeal cancer. In both hospitalized case populations, GERD was recorded in the patient files well before the first mention of laryngeal or pharyngeal cancer (Tables 1 and 2). Tobacco use and alcohol dependence diagnoses were documented more frequently among cases with either laryngeal or pharyngeal cancer case than in controls without these cancers. This was the case for both hospitalized and outpatients (Tables 1, 2, and 3). Demographic features similar to those of hospitalized patients were seen for outpatient cases with laryngeal or pharyngeal cancers and their corresponding controls (Table 3). Higher rates of tobacco use and alcohol dependence (more than double) were recorded among outpatient cases and controls (Table 3), however, the relative difference between cases and controls were similar to those observed between hospitalized cases and controls. The results of the multivariable logistic regression for hospitalized patients are displayed in Table 4 for laryngeal cancer and in Table 5 for pharyngeal cancer. All variables with a significant influence in the univariate analyses were entered as predictors into the logistic regression models. Similar to the univariate analyses, all risk factors, with the exception of ethnicity, were found to be highly significant predictors of laryngeal and pharyngeal cancers. The risks included older age, male gender, tobacco use, alcohol de-
pendence, and a prior diagnosis of GERD. The risk for laryngeal and pharyngeal cancer increased by 35 and 28%, respectively, per decade of life. Men were five times as likely as women to develop laryngeal cancer and six times as likely to develop pharyngeal cancer. The regression analyses of both cancer types did not reveal any significant interaction between gender and smoking or GERD and alcohol dependence. After excluding women (2.3% of the total population) from the analysis, a repeat logistic regression yielded results almost identical to those shown for the total population in Tables 4 and 5. The multivariable logistic regression analyses for outpatient laryngeal or pharyngeal cancers are displayed in Table 6. The strength and direction of the estimates are remarkably similar to those of hospitalized cases and controls. For both laryngeal and pharyngeal cancer, a significant interaction was found between GERD and smoking (p ⬍ 0.0001). This was evident in hospitalized and outpatients alike. For example, among outpatients, the adjusted OR associated with GERD without tobacco use was 2.31, whereas the concomitant presence of GERD and tobacco increases the OR to 2.79. There was no interaction between GERD and tobacco in association with outpatient pharyngeal cancer. For laryngeal cancer, the population attributable fraction was calculated to be 5% among hospitalized patients and 14% among outpatients. This means, 5–14% of laryngeal cancer cases occurring among hospitalized veterans could be theoretically eliminated if GERD were absent. In a similar calculation, the population attributable fraction for GERD among patients with pharyngeal cancer was 5% (hospitalized) and 10% (outpatients).
Table 2. Characteristics of Hospitalized Patients With and Without Pharyngeal Cancer
Patient Characteristic
With Pharyngeal Cancer (N ⫽ 8,228)
Without Pharyngeal Cancer (N ⫽ 32,912)
p
Mean age yr (⫾ SD) Men Caucasian Diagnosis of GERD Mean length of GERD yr (⫾ SD) Tobacco use Alcohol dependence
63 ⫾ 10 1,904 (99.6%) 1,354 (70.8%) 118 (6.2%) 3.4 ⫾ 3.0 467 (24%) 304 (16%)
60 ⫾ 15 7,429 (97.1%) 5,603 (73.3%) 292 (3.8%) 3.5 ⫾ 2.9 655 (9%) 534 (7%)
⬍0.0001 ⬍0.0001 0.0340 ⬍0.0001 0.0667 ⬍0.0001 ⬍0.0001
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Table 3. Characteristics and Risk Factors of Outpatient Veterans With Laryngeal or Pharyngeal Cancer and Their Corresponding Controls Without Cancer Laryngeal Cancer
Pharyngeal Cancer
Patient Characteristic
Case (N ⫽ 9,292)
Control (N ⫽ 37,168)
Case (N ⫽ 2,769)
Control (N ⫽ 11,076)
Age mean yr (⫾ SD) Men Caucasian GERD Tobacco use Alcohol dependence
63.3 (10.1) 9,145 (98.4%) 6,403 (68.9%) 2,903 (29.0%) 4,808 (51.7%) 1,217 (13.1%)
56.5 (15.4) 33,709 (90.1%) 16,912 (45.5%) 4,540 (12.2%) 12,845 (34.6%) 3,427 (9.2%)
61.4 (10.5) 2,709 (97.8%) 1,927 (69.6%) 730 (26.4%) 1,546 (55.8%) 453 (16.4%)
56.3 (15.6) 10,054 (90.1%) 5,059 (45.7%) 1,283 (11.6%) 3,821 (34.5%) 1,001 (9.0%)
p ⬍ 0.0001 for all patient characteristics.
DISCUSSION This large case-control study among hospitalized and outpatient United States veterans suggests that GERD is a statistically significant risk factor for the occurrence of laryngeal and pharyngeal cancers. The diagnoses of GERD were twice as frequent among patients as those without laryngopharyngeal cancers. Older age, male gender, tobacco use, and alcohol dependence were other significant risk factors. Even after controlling for the other risk factors in the logistic regression analysis, GERD nearly doubled the risk for laryngeal and pharyngeal cancer. In addition to being confounding, tobacco use also modified the association between GERD and cancer, as evidenced by the statistical interaction between GERD and smoking history. Furthermore, the fraction of laryngopharyngeal cancers attributable to GERD was relatively small ranging between 5% and 14%. Among hospitalized patients, only GERD diagnoses documented at least 1 month before cancer diagnosis were considered in this study. This was done to avoid a possible reporting bias from the overzealous search for risk factors when a cancer is diagnosed, or reverse causality that results if the cancer or its treatment causes GERD (16). However, when all GERD diagnoses were considered including those diagnosed concomitant with the time of identification among outpatient cases and controls, similar OR were obtained to those among hospitalized patients. The mean duration of documented GERD preceding the cancer diagnoses was relatively short (3– 4 yr). However, patients may have experienced reflux symptoms for a longer period before they actually sought medical advice and treatment. The time Table 4. Risk Factors for Laryngeal Cancer Among Hospitalized Patients: Results of Multivariable Logistic Regression Analysis Predictor Variable
Adjusted Odds Ratio
95% CI
Age (per 10 yr increase) Men (vs women) Tobacco use Alcohol dependence Diagnosis of GERD
1.35 5.12 2.60 1.60 2.40
1.32–1.38 3.69–7.11 2.43–2.78 1.36–1.88 2.15–2.69
p ⬍ 0.0001 for all patient characteristics.
when GERD is first registered in the discharge records may reflect the appearance of moderate to high disease severity. It is not possible to determine the grade or type of GERD, because endoscopy or radiology reports are not contained within the database. The proportions of patients with GERD, tobacco use, or alcohol dependence probably were underreported in the hospitalization records, especially in the presence of more acute medical conditions. Such errors were likely to affect cases and controls to a similar degree with little effect on the calculated odds ratios. This was proven by the results from the outpatient files where, although the frequencies of recorded tobacco and alcohol diagnoses was more than double those of hospitalized cases and controls, the calculated OR remained the same. Another type of observation bias could have resulted if a more intense search for specific risks was performed among case subjects than controls (14). However, practitioners unaware of the hypothesis tested recorded the information in the database making it unlikely for this type of bias to occur. Moreover, the well-known increased risks associated with male gender, tobacco use, and alcohol use were confirmed in the current results; these results provide external validity to the study. The ideal retrospective study includes chart review after identification through ICD-9 codes to support the data, however, this could not be performed in a practical way. The number of patients distributed all over the United States, in addition to issues related to patient confidentially, makes it very possible to validate the ICD-9 codes against medical records. The case-control study design is well suited for the exploration of potential risk factors. The large database made it easy to select four times as many controls as case subjects from data files of the same time period. Case and control subjects were subjected to the same type of selection criteria governing their hospitalization (14, 15). Although cases were found to be slightly older than controls, GERD remained a significant predictor even after controlling for the confounding effect of age in the logistic regression models. In a case-control study, matching is defined as selecting controls that are similar to the cases with respect to certain characteristics, such as age, gender, or a variety of other clinical and socioeconomic variables. Matching can be associated with practical and conceptual problems (16, 17).
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GERD as a Risk Factor for Laryngeal and Pharyngeal Cancer
Table 5. Risk Factors for Pharyngeal Cancer Among Hospitalized Veterans: Results of Multivariable Logistic Regression Analysis Predictor Variable
Adjusted Odds Ratio
95% CI
Age (per 10 yr increase) Men (vs women) Tobacco use Alcohol dependence Diagnosis of GERD
1.28 5.58 2.18 2.03 2.38
1.23–1.33 2.74–11.37 1.87–2.54 1.58–2.61 1.87–3.02
p ⬍ 0.0001 for all predictor variables.
It often proves difficult to identify a sufficient number of controls who match cases in more than one characteristic. The statistical analysis changes from a relatively simple logistic regression to conditional logistic regression. The latter type of analysis is more cumbersome to perform and more sensitive to missing data. Therefore, matching should be reserved for confounding variables with a profound effect on the outcome. In the present study, male gender exerted the largest influence by far. However, due to the dominating number of men in the study, the statistical results remained virtually unchanged in a repeat regression analysis restricted to men only. Because of its association with both GERD and cancer, age represents another potential confounder, which is commonly matched. The influence of age on laryngopharyngeal cancer was relatively small and ranged between 23% and 38% per 10-yr increase in age. From previous studies it is known that in the VA population the risk of esophagitis increases by 10% (95% CI 9 –11%) per each 10-yr increase in age (18). Given the 3- to 6-yr age difference between the case and control groups, matching would have had minimal effects on the overall results. Tobacco smoking is the main known risk factor for laryngeal and pharyngeal cancer where it has been associated with a 4- to 7-fold increase in cancer risk (4). Alcohol ingestion is also associated with a 1.9- to 3.3-fold increase in the risk for laryngeal and pharyngeal cancers (19, 20). The calculated OR in the current study are lower than those reported previously. This reflects the relatively high rate of smoking and alcohol dependence among controls in this study. Curious observations, however, have been made regarding these classical risk factors. In the US, the differences in laryngeal cancer observed among consecutive birth cohorts and among the two gender groups seem to coincide
2017
with some, but not all secular trends in the consumption of tobacco or alcohol (21). Furthermore, despite the progressive decline in the number of current tobacco smokers (22), there has been no parallel reduction in the incidence of laryngeal or pharyngeal cancers (23). Data from Japan revealed discrepant patterns between laryngeal cancer and per capita consumption of tobacco and alcohol (24). These observations suggest additional unknown risk factors may be important in the pathogenesis of laryngopharyngeal cancers. GERD is a biologically plausible risk factor for laryngopharyngeal cancers. Several experimental and epidemiological studies have indicated a role for gastroesophageal reflux in chronic laryngitis and pharyngitis (25, 26). However, it remains unknown if a premalignant lesion exists that is analogous with Barrett’s esophagus in GERD or squamous metaplasia in tobacco use. In 1968, Cherry and Margulies reported the presence of laryngeal ulcers in three patients who were known to have GERD, and all ulcers were effectively treated with antacids (27). A malignant transformation from a contact laryngeal ulcer into invasive carcinoma was subsequently reported (5). Ward and Hanson reported a study of 138 patients with laryngeal carcinoma, 19 of whom were nonsmokers and nonalcohol drinkers or only light drinkers, but had moderate to severe GERD symptoms (6). Two other case series reported similar findings in a total of 29 patients with laryngeal cancers (5, 7). Morrison and coworkers reported a 48% prevalence of symptomatic GERD in a group of 21 nonsmoking patients with laryngeal carcinoma as compared to 16% prevalence in a group of 44 smokers with the same type of cancer (8). GERD may have an even greater association with laryngopharyngeal cancer, because reliance on symptoms alone could underestimate the true presence of GERD. Using 24-h pH-metry, abnormal acid reflux was found in 36% of patients with laryngopharyngeal cancer but no reflux symptoms (9). In 1995, Koufman and coworkers reported an increased acid reflux, documented by 24-h pH monitoring, in two-thirds (33 of 50) of their laryngeal cancer patients (25). Similar results were found in pharyngeal cancers (13). Gastroesophageal reflux disease fulfills several Bradford Hill criteria for a causal association with laryngopharyngeal cancers (28). The occurrence of GERD with these cancers is statistically significant, has temporally preceded cancer di-
Table 6. Risk Factors of Laryngeal and Pharyngeal Cancers Among Veterans (Outpatient): Results of the Multivariable Logistic Regression Analysis Laryngeal Cancer Age (per 10 yr) Men (vs women) Caucasian (vs other) Diagnosis of GERD Tobacco use Alcohol dependence
Pharyngeal Cancer
Unadjusted Odds Ratio
Adjusted Odds Ratio
Unadjusted Odds Ratio
Adjusted Odds Ratio
6.38 (5.86–6.95) 1.11 (1.08–1.14) 2.93 (2.77–3.10) 2.03 (1.94–2.13) 1.48 (1.38–1.59)
1.40 (1.37–1.43) 2.95 (2.42–3.59) 0.95 (0.89–1.01) 2.31 (2.10–2.53) 1.45 (1.37–1.54) 1.37 (1.27–1.48)
4.49 (4.01–5.25) 1.08 (1.02–1.14) 2.73 (2.46–3.03) 2.40 (2.21–2.61) 1.96 (1.75–2.22)
1.19 (1.14–1.23) 2.56 (1.87–3.50) 0.97 (0.87–1.09) 1.92 (1.72–2.15) 1.61 (1.50–1.77) 1.50 (1.31–1.71)
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agnoses, is biologically plausible, and is consistent with findings of previous uncontrolled observations. However, the magnitude of risk associated with GERD is relatively small.
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13. 14.
Reprint requests and correspondence: Hashem B. El-Serag, M.D., M.P.H., Houston VA Medical Center (39 A), 2002 Holcombe Boulevard, Houston, TX, 77030. Received July 27, 2000; accepted Dec. 21, 2001
15.
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Vol. 96, No. 7, 2001 ISSN 0002-9270/01/$20.00 PII S0002-9270(01)02497-2
Gastroesophageal Reflux Disease Is a Risk Factor for Laryngeal and Pharyngeal Cancer Hashem B. El-Serag, M.D., M.P.H., Edward J. Hepworth, M.D., Patty Lee, M.D., and Amnon Sonnenberg, M.D., M.S. Sections of Gastroenterology and Health Services Research, The Houston Veterans Affairs Medical Center and Baylor College of Medicine, Houston, Texas; and The Albuquerque Veterans Affairs Medical Center and the University of New Mexico, Albuquerque, New Mexico
OBJECTIVE: Gastroesophageal reflux disease (GERD) is a proposed risk factor for developing laryngeal and pharyngeal cancers. No controlled study has examined this association. METHODS: A case-control study was performed using the computerized hospitalization and outpatient databases of the US Department of Veterans Affairs. All patients, who were veterans, had been identified as being hospitalized with laryngeal or pharyngeal during 1991 to 1997. In addition, all persons diagnosed with laryngeal or pharyngeal cancer in 1999 in the outpatient files were identified. From the same patient populations, four nonmatched control subjects were randomly assigned for each case. The medical history for cases and controls was retrospectively searched for GERD diagnoses, tobacco use, and alcohol dependence. Multivariable logistic regression analyses were performed to assess the risk factors for laryngeal and pharyngeal cancers. RESULTS: A total of 8,228 hospitalized patients with laryngeal cancers and 1,912 with pharyngeal cancers were compared to 32,912 and 7,648 hospitalized controls, while 9,292 outpatients with laryngeal cancer and 2,769 outpatients with pharyngeal cancer were compared with 37,168 and 11,076 outpatient controls without cancer. Among hospitalized persons, the prevalence of GERD was higher among patients with laryngeal cancer (8.9 vs 4.0%, p ⬍ 0.0001) and pharyngeal cancer (6.2 vs 3.8%, p ⬍ 0.0001). In a multivariable logistic regression analysis that was controlled for age, gender, ethnicity, smoking, and alcohol, GERD was associated with an adjusted odds ratio (OR) of 2.40 for laryngeal cancer among hospitalized patients (95% CI 2.15–2.69, p ⬍ 0.0001) and an adjusted OR of 2.38 (95% CI 1.87–3.02, p ⬍ 0.0001) for pharyngeal cancer. For outpatients, GERD was associated with an adjusted OR ⫽ 2.31 (95% CI 2.10 –2.53) for laryngeal cancer and adjusted OR ⫽ 1.92 (95% CI 1.72–2.15). CONCLUSIONS: Among US veterans, the risk for laryngeal or pharyngeal cancers is modestly increased in the presence of GERD. This effect seems to be independent of age, gender, smoking, and alcohol intake. (Am J Gastroenterol 2001;96: 2013–2018. © 2001 by Am. Coll. of Gastroenterology)
INTRODUCTION Cancers of the larynx and pharynx continue to be a significant aspect of clinical otolaryngology and oncology. Laryngeal carcinoma constitutes 26% of all head and neck tumors, whereas pharyngeal carcinoma accounts for 8% of these tumors (1). In the United States, laryngeal cancer accounts annually for an estimated 11,100 new cases and 4,300 deaths, whereas 8,600 new cases and 2,100 deaths are expected to occur because of pharyngeal cancer (2). Tobacco and alcohol consumption are well known risk factors for laryngopharyngeal cancers (1, 3, 4). A causal relationship between gastroesophageal reflux disease (GERD) and laryngopharyngeal neoplasms has been suggested (5–11). However, the association between reflux disease and laryngopharyngeal malignancy remains unclear. For example, GERD was diagnosed in a small number of patients with laryngeal or pharyngeal carcinoma who lack the typical risk factors (5– 8). In addition, a high prevalence (36 –58%) of esophageal acid reflux was measured among patients with laryngeal or pharyngeal cancers (9 –11). None of the published studies compared the prevalence of GERD among patients with laryngeal or pharyngeal carcinoma to that of controls free of cancer. Since 1970, the Department of Veteran Affairs (VA) maintains all inpatient records in a computerized database known as the Patient Treatment File (PTF). In 1997, the VA computerized Outpatient Files (OPF) were established. The PTF and OPF offer an opportunity to examine large number of patients over an extended time period. Using the PTF (hospitalized patients) and OPF (outpatients) as data sources, we carried out a case control study among US veterans to examine the risk factors of laryngeal and pharyngeal cancers.
MATERIALS AND METHODS Database The study population was selected from US veterans hospitalized within the nationwide VA hospital system during the 7-yr period of October 1991 through October 1997, and
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from veterans seen in the outpatient department between October 1998 through October 1999. Computerized records from 172 VA hospitals throughout the US are retained in a centralized PTF, which is managed by the VA Central Automation Center at Austin, Texas. The PTF contains the main files, in which discharge diagnoses are recorded for each inpatient hospital visit (average 700,000 – 800,000 annual hospitalizations). Each inpatient record contains one primary and up to nine secondary discharge diagnoses. The much larger OPF were started in 1997 and contain approximately 20 million annual records. Discharge diagnoses, as well as outpatient diagnoses, have been coded according to the 9th revision of the Clinical Modification of International Classification of Diseases (ICD-9-CM) (12). Case and Control Populations The case population consisted of all patients with a diagnosis of laryngeal cancer (ICD-codes 161.0 –161.9) or pharyngeal cancer (ICD-codes 147.0 –147.9, 148.0 –148.9, and 149.0) who were discharged between 1991 and 1997 from the VA hospitals (inpatient population), and all persons identified with these diagnoses in fiscal year 1999 in the OPF (outpatient population). Each patient’s social security number, age, sex, race, and date of admission with a cancer diagnosis were identified and retained for subsequent analyses. The date of a patient’s first appearance in the PTF with a laryngeal or pharyngeal cancer was considered to be the date of cancer diagnosis. After excluding cases with laryngeal and pharyngeal cancers from the file, four nonmatched control patients without these cancers were selected from the identical annual PTF (hospitalized cases and outpatient controls for outpatient cases). A method of random selection without replacement was employed to ensure that no individual control subject was selected more than once. As was done with the case subjects, each control patient’s social security number, age, sex, race, and enrollment date were identified and registered. Each hospitalized case and control subject was followed retrospectively through the annual files using their unique social security numbers and all of their diagnoses encountered as far back as 1981 (1981–1997) were recorded. Outpatient cases and controls identified in 1999 were retrospectively followed through the available outpatient files (1997– 1999). This accumulated medical history was searched for GERD-related diagnoses, such as erosive esophagitis (ICDcode 530.1), peptic esophagitis (ICD-code 530.19), esophageal stricture (ICD-code 530.3), and gastroesophageal reflux (ICD-code 530.81). Other associated risk factors were also evaluated, including alcohol dependence (ICD-codes 303.0 –303.9, 305.0, and V113) and tobacco use (ICD-codes 305.1, 305.11, 305.13, V6549). Statistical Analyses The length of GERD history among hospitalized cases and controls was calculated as the elapsed time between the first diagnosis of GERD and the date of enrollment into the
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study. Any GERD diagnosed within 1 month of the laryngopharyngeal cancer diagnoses was excluded from the analysis to avoid reverse causality. The date of enrollment corresponded with the date of first cancer diagnosis among cases and the initial date of hospitalization during the recruitment period among controls. For the outpatient cases and controls, all GERD diagnoses at or before the time of cancer diagnosis were considered. Chi-square tests were used for univariate comparisons of dichotomous variables, while unpaired t tests were used for univariate comparisons of continuous variables. Separate calculations were performed for hospitalized and outpatient persons. In the multivariate analysis, a logistic regression model was used to assess the occurrence of either laryngeal or pharyngeal cancer using age, gender, ethnicity, GERD, tobacco, smoking, and alcohol as predictor variables. The significance of individual influences was tested by Wald’s 2 tests. Odds ratios and their 95% CIs were presented for each estimate. Interaction terms between sex and tobacco, smoking and GERD, alcohol and GERD, smoking and alcohol were examined while maintaining all the lower order components inside the model. These analyses were performed using SAS (13). To estimate the proportion of cancer cases that is attributable to GERD, the “attributable fraction” was calculated for the whole VA population. The attributable fraction for the entire population, also termed the “attributable risk,” was calculated as p[RR-1]/(1⫹p[RR-1]), where p represents the prevalence of GERD in the VA population, and RR represents the risk ratio (14). The prevalence of GERD among controls was assumed to represent the overall GERD prevalence among veterans. In a case-control study, the risk ratio can be approximated by the adjusted odds ratio (OR).
RESULTS From 1991 through 1997, 8,228 hospitalized patients were diagnosed with laryngeal cancers, while 1,912 hospitalized subjects were diagnosed with pharyngeal cancers. Two groups of 32,912 and 7,648 hospitalized patients without laryngeal or pharyngeal cancers were randomly selected as controls for the two case groups with laryngeal or pharyngeal cancer, respectively. In 1997, 9,292 outpatients cases with laryngeal cancer were compared to 37,168 outpatient controls, and 2,769 outpatient cases with pharyngeal cancer were compared to 11,076 outpatient controls without cancer. The characteristics of the hospitalized case and control groups are presented in Table 1 for laryngeal cancer and in Table 2 for pharyngeal cancer. Compared with their respective controls, case subjects with laryngeal or pharyngeal cancer were on the average slightly older. There were more men (99.5 vs 97.3%) and more Caucasians (73.8 vs 72.8%) among patients with laryngeal cancer than controls. Similar
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Table 1. Characteristics of Hospitalized Patients With and Without Laryngeal Cancer Patient Characteristic
With Laryngeal Cancer (N ⫽ 8,228)
Without Laryngeal Cancer (N ⫽ 32,912)
p
Mean age yr (⫾ SD) Men Caucasian Diagnosis of GERD Mean length of GERD yr (⫾ SD) Tobacco use Alcohol dependence
65 ⫾ 9 8,190 (99.5%) 6,070 (73.8%) 731 (8.9%) 4.1 ⫾ 3.0 2,343 (28%) 870 (11%)
60 ⫾ 14 32,008 (97.3%) 23,944 (72.8%) 1,315 (4.0%) 3.4 ⫾ 2.7 3,632 (11%) 1,645 (5%)
⬍0.0001 ⬍0.0001 0.0642 ⬍0.0001 ⬍0.0001 ⬍0.0001 ⬍0.0001
estimates were obtained for pharyngeal cancer (Table 2). Patients with laryngeal or pharyngeal cancer had a higher frequency of GERD than their respective controls. The presence of GERD was associated with an unadjusted OR of 3.44 for laryngeal cancer (95% CI 3.09 –3.67), which means the patients with cancer have a 3.44 increase in the odds of having GERD than the controls without cancer. An OR of 1.66 (95% CI 1.33–2.06) was calculated for GERD and pharyngeal cancer. In both hospitalized case populations, GERD was recorded in the patient files well before the first mention of laryngeal or pharyngeal cancer (Tables 1 and 2). Tobacco use and alcohol dependence diagnoses were documented more frequently among cases with either laryngeal or pharyngeal cancer case than in controls without these cancers. This was the case for both hospitalized and outpatients (Tables 1, 2, and 3). Demographic features similar to those of hospitalized patients were seen for outpatient cases with laryngeal or pharyngeal cancers and their corresponding controls (Table 3). Higher rates of tobacco use and alcohol dependence (more than double) were recorded among outpatient cases and controls (Table 3), however, the relative difference between cases and controls were similar to those observed between hospitalized cases and controls. The results of the multivariable logistic regression for hospitalized patients are displayed in Table 4 for laryngeal cancer and in Table 5 for pharyngeal cancer. All variables with a significant influence in the univariate analyses were entered as predictors into the logistic regression models. Similar to the univariate analyses, all risk factors, with the exception of ethnicity, were found to be highly significant predictors of laryngeal and pharyngeal cancers. The risks included older age, male gender, tobacco use, alcohol de-
pendence, and a prior diagnosis of GERD. The risk for laryngeal and pharyngeal cancer increased by 35 and 28%, respectively, per decade of life. Men were five times as likely as women to develop laryngeal cancer and six times as likely to develop pharyngeal cancer. The regression analyses of both cancer types did not reveal any significant interaction between gender and smoking or GERD and alcohol dependence. After excluding women (2.3% of the total population) from the analysis, a repeat logistic regression yielded results almost identical to those shown for the total population in Tables 4 and 5. The multivariable logistic regression analyses for outpatient laryngeal or pharyngeal cancers are displayed in Table 6. The strength and direction of the estimates are remarkably similar to those of hospitalized cases and controls. For both laryngeal and pharyngeal cancer, a significant interaction was found between GERD and smoking (p ⬍ 0.0001). This was evident in hospitalized and outpatients alike. For example, among outpatients, the adjusted OR associated with GERD without tobacco use was 2.31, whereas the concomitant presence of GERD and tobacco increases the OR to 2.79. There was no interaction between GERD and tobacco in association with outpatient pharyngeal cancer. For laryngeal cancer, the population attributable fraction was calculated to be 5% among hospitalized patients and 14% among outpatients. This means, 5–14% of laryngeal cancer cases occurring among hospitalized veterans could be theoretically eliminated if GERD were absent. In a similar calculation, the population attributable fraction for GERD among patients with pharyngeal cancer was 5% (hospitalized) and 10% (outpatients).
Table 2. Characteristics of Hospitalized Patients With and Without Pharyngeal Cancer
Patient Characteristic
With Pharyngeal Cancer (N ⫽ 8,228)
Without Pharyngeal Cancer (N ⫽ 32,912)
p
Mean age yr (⫾ SD) Men Caucasian Diagnosis of GERD Mean length of GERD yr (⫾ SD) Tobacco use Alcohol dependence
63 ⫾ 10 1,904 (99.6%) 1,354 (70.8%) 118 (6.2%) 3.4 ⫾ 3.0 467 (24%) 304 (16%)
60 ⫾ 15 7,429 (97.1%) 5,603 (73.3%) 292 (3.8%) 3.5 ⫾ 2.9 655 (9%) 534 (7%)
⬍0.0001 ⬍0.0001 0.0340 ⬍0.0001 0.0667 ⬍0.0001 ⬍0.0001
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Table 3. Characteristics and Risk Factors of Outpatient Veterans With Laryngeal or Pharyngeal Cancer and Their Corresponding Controls Without Cancer Laryngeal Cancer
Pharyngeal Cancer
Patient Characteristic
Case (N ⫽ 9,292)
Control (N ⫽ 37,168)
Case (N ⫽ 2,769)
Control (N ⫽ 11,076)
Age mean yr (⫾ SD) Men Caucasian GERD Tobacco use Alcohol dependence
63.3 (10.1) 9,145 (98.4%) 6,403 (68.9%) 2,903 (29.0%) 4,808 (51.7%) 1,217 (13.1%)
56.5 (15.4) 33,709 (90.1%) 16,912 (45.5%) 4,540 (12.2%) 12,845 (34.6%) 3,427 (9.2%)
61.4 (10.5) 2,709 (97.8%) 1,927 (69.6%) 730 (26.4%) 1,546 (55.8%) 453 (16.4%)
56.3 (15.6) 10,054 (90.1%) 5,059 (45.7%) 1,283 (11.6%) 3,821 (34.5%) 1,001 (9.0%)
p ⬍ 0.0001 for all patient characteristics.
DISCUSSION This large case-control study among hospitalized and outpatient United States veterans suggests that GERD is a statistically significant risk factor for the occurrence of laryngeal and pharyngeal cancers. The diagnoses of GERD were twice as frequent among patients as those without laryngopharyngeal cancers. Older age, male gender, tobacco use, and alcohol dependence were other significant risk factors. Even after controlling for the other risk factors in the logistic regression analysis, GERD nearly doubled the risk for laryngeal and pharyngeal cancer. In addition to being confounding, tobacco use also modified the association between GERD and cancer, as evidenced by the statistical interaction between GERD and smoking history. Furthermore, the fraction of laryngopharyngeal cancers attributable to GERD was relatively small ranging between 5% and 14%. Among hospitalized patients, only GERD diagnoses documented at least 1 month before cancer diagnosis were considered in this study. This was done to avoid a possible reporting bias from the overzealous search for risk factors when a cancer is diagnosed, or reverse causality that results if the cancer or its treatment causes GERD (16). However, when all GERD diagnoses were considered including those diagnosed concomitant with the time of identification among outpatient cases and controls, similar OR were obtained to those among hospitalized patients. The mean duration of documented GERD preceding the cancer diagnoses was relatively short (3– 4 yr). However, patients may have experienced reflux symptoms for a longer period before they actually sought medical advice and treatment. The time Table 4. Risk Factors for Laryngeal Cancer Among Hospitalized Patients: Results of Multivariable Logistic Regression Analysis Predictor Variable
Adjusted Odds Ratio
95% CI
Age (per 10 yr increase) Men (vs women) Tobacco use Alcohol dependence Diagnosis of GERD
1.35 5.12 2.60 1.60 2.40
1.32–1.38 3.69–7.11 2.43–2.78 1.36–1.88 2.15–2.69
p ⬍ 0.0001 for all patient characteristics.
when GERD is first registered in the discharge records may reflect the appearance of moderate to high disease severity. It is not possible to determine the grade or type of GERD, because endoscopy or radiology reports are not contained within the database. The proportions of patients with GERD, tobacco use, or alcohol dependence probably were underreported in the hospitalization records, especially in the presence of more acute medical conditions. Such errors were likely to affect cases and controls to a similar degree with little effect on the calculated odds ratios. This was proven by the results from the outpatient files where, although the frequencies of recorded tobacco and alcohol diagnoses was more than double those of hospitalized cases and controls, the calculated OR remained the same. Another type of observation bias could have resulted if a more intense search for specific risks was performed among case subjects than controls (14). However, practitioners unaware of the hypothesis tested recorded the information in the database making it unlikely for this type of bias to occur. Moreover, the well-known increased risks associated with male gender, tobacco use, and alcohol use were confirmed in the current results; these results provide external validity to the study. The ideal retrospective study includes chart review after identification through ICD-9 codes to support the data, however, this could not be performed in a practical way. The number of patients distributed all over the United States, in addition to issues related to patient confidentially, makes it very possible to validate the ICD-9 codes against medical records. The case-control study design is well suited for the exploration of potential risk factors. The large database made it easy to select four times as many controls as case subjects from data files of the same time period. Case and control subjects were subjected to the same type of selection criteria governing their hospitalization (14, 15). Although cases were found to be slightly older than controls, GERD remained a significant predictor even after controlling for the confounding effect of age in the logistic regression models. In a case-control study, matching is defined as selecting controls that are similar to the cases with respect to certain characteristics, such as age, gender, or a variety of other clinical and socioeconomic variables. Matching can be associated with practical and conceptual problems (16, 17).
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GERD as a Risk Factor for Laryngeal and Pharyngeal Cancer
Table 5. Risk Factors for Pharyngeal Cancer Among Hospitalized Veterans: Results of Multivariable Logistic Regression Analysis Predictor Variable
Adjusted Odds Ratio
95% CI
Age (per 10 yr increase) Men (vs women) Tobacco use Alcohol dependence Diagnosis of GERD
1.28 5.58 2.18 2.03 2.38
1.23–1.33 2.74–11.37 1.87–2.54 1.58–2.61 1.87–3.02
p ⬍ 0.0001 for all predictor variables.
It often proves difficult to identify a sufficient number of controls who match cases in more than one characteristic. The statistical analysis changes from a relatively simple logistic regression to conditional logistic regression. The latter type of analysis is more cumbersome to perform and more sensitive to missing data. Therefore, matching should be reserved for confounding variables with a profound effect on the outcome. In the present study, male gender exerted the largest influence by far. However, due to the dominating number of men in the study, the statistical results remained virtually unchanged in a repeat regression analysis restricted to men only. Because of its association with both GERD and cancer, age represents another potential confounder, which is commonly matched. The influence of age on laryngopharyngeal cancer was relatively small and ranged between 23% and 38% per 10-yr increase in age. From previous studies it is known that in the VA population the risk of esophagitis increases by 10% (95% CI 9 –11%) per each 10-yr increase in age (18). Given the 3- to 6-yr age difference between the case and control groups, matching would have had minimal effects on the overall results. Tobacco smoking is the main known risk factor for laryngeal and pharyngeal cancer where it has been associated with a 4- to 7-fold increase in cancer risk (4). Alcohol ingestion is also associated with a 1.9- to 3.3-fold increase in the risk for laryngeal and pharyngeal cancers (19, 20). The calculated OR in the current study are lower than those reported previously. This reflects the relatively high rate of smoking and alcohol dependence among controls in this study. Curious observations, however, have been made regarding these classical risk factors. In the US, the differences in laryngeal cancer observed among consecutive birth cohorts and among the two gender groups seem to coincide
2017
with some, but not all secular trends in the consumption of tobacco or alcohol (21). Furthermore, despite the progressive decline in the number of current tobacco smokers (22), there has been no parallel reduction in the incidence of laryngeal or pharyngeal cancers (23). Data from Japan revealed discrepant patterns between laryngeal cancer and per capita consumption of tobacco and alcohol (24). These observations suggest additional unknown risk factors may be important in the pathogenesis of laryngopharyngeal cancers. GERD is a biologically plausible risk factor for laryngopharyngeal cancers. Several experimental and epidemiological studies have indicated a role for gastroesophageal reflux in chronic laryngitis and pharyngitis (25, 26). However, it remains unknown if a premalignant lesion exists that is analogous with Barrett’s esophagus in GERD or squamous metaplasia in tobacco use. In 1968, Cherry and Margulies reported the presence of laryngeal ulcers in three patients who were known to have GERD, and all ulcers were effectively treated with antacids (27). A malignant transformation from a contact laryngeal ulcer into invasive carcinoma was subsequently reported (5). Ward and Hanson reported a study of 138 patients with laryngeal carcinoma, 19 of whom were nonsmokers and nonalcohol drinkers or only light drinkers, but had moderate to severe GERD symptoms (6). Two other case series reported similar findings in a total of 29 patients with laryngeal cancers (5, 7). Morrison and coworkers reported a 48% prevalence of symptomatic GERD in a group of 21 nonsmoking patients with laryngeal carcinoma as compared to 16% prevalence in a group of 44 smokers with the same type of cancer (8). GERD may have an even greater association with laryngopharyngeal cancer, because reliance on symptoms alone could underestimate the true presence of GERD. Using 24-h pH-metry, abnormal acid reflux was found in 36% of patients with laryngopharyngeal cancer but no reflux symptoms (9). In 1995, Koufman and coworkers reported an increased acid reflux, documented by 24-h pH monitoring, in two-thirds (33 of 50) of their laryngeal cancer patients (25). Similar results were found in pharyngeal cancers (13). Gastroesophageal reflux disease fulfills several Bradford Hill criteria for a causal association with laryngopharyngeal cancers (28). The occurrence of GERD with these cancers is statistically significant, has temporally preceded cancer di-
Table 6. Risk Factors of Laryngeal and Pharyngeal Cancers Among Veterans (Outpatient): Results of the Multivariable Logistic Regression Analysis Laryngeal Cancer Age (per 10 yr) Men (vs women) Caucasian (vs other) Diagnosis of GERD Tobacco use Alcohol dependence
Pharyngeal Cancer
Unadjusted Odds Ratio
Adjusted Odds Ratio
Unadjusted Odds Ratio
Adjusted Odds Ratio
6.38 (5.86–6.95) 1.11 (1.08–1.14) 2.93 (2.77–3.10) 2.03 (1.94–2.13) 1.48 (1.38–1.59)
1.40 (1.37–1.43) 2.95 (2.42–3.59) 0.95 (0.89–1.01) 2.31 (2.10–2.53) 1.45 (1.37–1.54) 1.37 (1.27–1.48)
4.49 (4.01–5.25) 1.08 (1.02–1.14) 2.73 (2.46–3.03) 2.40 (2.21–2.61) 1.96 (1.75–2.22)
1.19 (1.14–1.23) 2.56 (1.87–3.50) 0.97 (0.87–1.09) 1.92 (1.72–2.15) 1.61 (1.50–1.77) 1.50 (1.31–1.71)
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agnoses, is biologically plausible, and is consistent with findings of previous uncontrolled observations. However, the magnitude of risk associated with GERD is relatively small.
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13. 14.
Reprint requests and correspondence: Hashem B. El-Serag, M.D., M.P.H., Houston VA Medical Center (39 A), 2002 Holcombe Boulevard, Houston, TX, 77030. Received July 27, 2000; accepted Dec. 21, 2001
15.
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