Background The causes of adenocarcinomas of the esophagus andgastric cardia are poorly understood. We conducted an epidemiologicinvestigation of the possible association between gastroesophagealreflux and these tumors.
Methods We performed a nationwide, population-based, case–controlstudy in Sweden. Case ascertainment was rapid, and all caseswere classified uniformly. Information on the subjects' historyof gastroesophageal reflux was collected in personal interviews.The odds ratios were calculated by logistic regression, withmultivariate adjustment for potentially confounding variables.
Results Of the patients interviewed, the 189 with esophagealadenocarcinoma and the 262 with adenocarcinoma of the cardiaconstituted 85 percent of the 529 patients in Sweden who wereeligible for the study during the period from 1995 through 1997.For comparison, we interviewed 820 control subjects from thegeneral population and 167 patients with esophageal squamous-cellcarcinoma. Among persons with recurrent symptoms of reflux,as compared with persons without such symptoms, the odds ratioswere 7.7 (95 percent confidence interval, 5.3 to 11.4) for esophagealadenocarcinoma and 2.0 (95 percent confidence interval, 1.4to 2.9) for adenocarcinoma of the cardia. The more frequent,more severe, and longer-lasting the symptoms of reflux, thegreater the risk. Among persons with long-standing and severesymptoms of reflux, the odds ratios were 43.5 (95 percent confidenceinterval, 18.3 to 103.5) for esophageal adenocarcinoma and 4.4(95 percent confidence interval, 1.7 to 11.0) for adenocarcinomaof the cardia. The risk of esophageal squamous-cell carcinomawas not associated with reflux (odds ratio, 1.1; 95 percentconfidence interval, 0.7 to 1.9).
Conclusions There is a strong and probably causal relation betweengastroesophageal reflux and esophageal adenocarcinoma. The relationbetween reflux and adenocarcinoma of the gastric cardia is relativelyweak.
The incidence of adenocarcinomas of the esophagus and gastriccardia has risen rapidly in the United States and western Europe,including Sweden, in recent decades.1,2,3,4 The increase hasbeen more pronounced for adenocarcinoma of the esophagus thanfor adenocarcinoma of the gastric cardia.1,2,3,4,5 Only a few,moderately strong, risk factors have been identified, and thereasons for the rising incidence are unknown.6
There are reasons to suspect that gastroesophageal reflux playsan important part in the development of esophageal adenocarcinoma.Chronic reflux is the main cause of Barrett's esophagus,7 acolumnar-cell metaplasia that replaces the native squamous-cellepithelium of the esophageal mucosa.8 The specialized epitheliumof Barrett's esophagus has been linked to a substantially increasedrisk of esophageal adenocarcinoma.8 Recent studies have shownthat adenocarcinoma of the gastric cardia may arise in a similarmetaplasia adjacent to the squamocolumnar border.9
There is a paucity of epidemiologic data on the associationbetween gastroesophageal reflux and the risk of adenocarcinomaof the esophagus or gastric cardia. A previous study based onthe medical records of 196 patients with adenocarcinoma of theesophagus or cardia (mainly the latter) and 196 controls foundan odds ratio of 2.1 (95 percent confidence interval, 1.2 to3.6) for adenocarcinoma among patients whose records indicatedthat they had reflux disease.10 It is uncertain, however, howwell medical records capture the occurrence of reflux.
We conducted a large-scale case–control study to identifyrisk factors for adenocarcinomas of the esophagus and gastriccardia. The aim of this investigation was to estimate the magnitudeof the contribution of symptoms of reflux to the risk of thesecancers.
Methods
Study Design
The study encompassed the whole population of Sweden youngerthan 80 years, born in Sweden, and living there during the periodfrom December 1, 1994, through December 31, 1997. All newlydiagnosed cases of adenocarcinoma of the esophagus or gastriccardia and half the newly diagnosed cases of esophageal squamous-cellcarcinoma (those in patients born on even-numbered days) wereeligible. A comprehensive organization for the rapid ascertainmentof cases, involving contact persons at all 195 departments ofgeneral surgery, thoracic surgery, otorhinolaryngology, oncology,and pathology in Sweden, as well as continuous collaborationwith the six regional tumor registries, ensured that every potentialcase patient throughout the country was identified soon afterdiagnosis. The control subjects were selected randomly fromamong the persons matched for age (within 10 years) and sexin the entire Swedish population, through the use of the populationregister, which is computerized and is updated continuously.The numbers of controls selected in each stratum defined bysex and age group were adjusted to approximate the age and sexdistribution among the patients with esophageal adenocarcinoma.
Classification of Cases
To reduce misclassification of the tumor site or histologictype, uniform routines for the documentation of the tumors wereintroduced at all participating sites. All patients were examinedendoscopically. The distances between the gastroesophageal junction(defined as the point where the proximal longitudinal mucosalfolds begin in the stomach) and the upper and lower bordersof the tumor were measured. It was usually possible to passthe endoscope beyond obstructing tumors after dilatation, butin 22 patients in which this was impossible or the gastroesophagealjunction could not be identified, the borders of the tumor weremeasured as distances to the incisor teeth, and endoscopy wassupplemented with radiologic imaging. Serial biopsy specimenswere obtained every 2 cm from the proximal stomach, the gastroesophagealjunction, and the esophagus until normal squamous-cell epitheliumwas reached. Additional specimens were obtained proximal, distal,and lateral to the tumor. Surgeons and pathologists gave standardized,detailed descriptions of the location of the cancer in the 424patients in whom resection was performed. Biopsy samples, surgicalspecimens, or both from 97 percent of the patients were reviewedby a single pathologist. Ambiguous cases were classified bya panel of investigators, who used all information available.For a case to be classified as a cancer of the gastric cardia,the tumor had to have its center within 2 cm proximal, or 3cm distal, to the gastroesophageal junction. Barrett's esophaguswas defined as columnar-cell metaplasia of the specialized type,with goblet cells and villiform surface configuration of themucosa resembling the features of the intestines. Five patientswith junctional or fundus metaplasia recorded more than 3 cmproximal to the gastroesophageal junction were also classifiedas having Barrett's esophagus. In seven patients in whom Barrett'sesophagus was detected adjacent to an adenocarcinoma locatedin the gastric cardia, the tumors were classified as esophageal.Squamous-cell carcinomas were classified as esophageal evenif the location was the gastric cardia.
Data on Symptoms of Reflux
All patients and controls underwent computer-aided personalinterviews conducted by specially trained professional interviewersfrom Statistics Sweden (a government agency), mostly withina few weeks after diagnosis. We were unable to blind the interviewersto the case or control status of the subjects, but they wereunaware of the study hypotheses and were trained to treat thecase patients and controls strictly the same. The total numberof questions varied between 169 and 553, depending on the numberof "question loops" entered (some questions could be skippedif a respondent answered "no" to an earlier question), and theaverage length of the interview was 80 minutes (range, 50 to180). Questions were asked about recurrent heartburn and regurgitation,which are the cardinal symptoms of gastroesophageal reflux.11To avoid reverse causality — that is, to avoid collectingdata on reflux caused by adenocarcinoma — we disregardedsymptoms that had occurred less than five years before the interview.Information was collected about several potential confoundingfactors. In multivariate analyses, we adjusted for age (in five-yeargroups), sex, body-mass index (in quartiles), tobacco smoking(assessed as of two years before the interview and with therespondents classified as nonsmokers, former smokers, or currentsmokers), alcohol ingestion (total amount of all types of alcoholicbeverages consumed, with the respondents categorized in fourgroups), socioeconomic status (reflected by the number of yearsof formal education, with the respondents categorized in threegroups), dietary intake of fruit and vegetables (three groups),energy intake (estimated by the amounts of seven kinds of disheseaten at each meal with the respondents categorized in threegroups), whether the respondent worked in a stooped posture(hours per week, in three categories), physical activity atwork (three categories), and extent of physical activities duringleisure time (four categories).
Informed consent, both written and oral, was obtained from eachsubject before the interview, and the study was approved byall regional ethics committees in Sweden.
Statistical Analysis
Logistic regression was used in both univariate and multivariatemodeling. Model parameters were estimated by the maximum-likelihoodmethod.12 From these estimates, odds ratios with 95 percentconfidence intervals were computed. In multivariate modeling,adjustments were made for the 11 potential confounders. We alsoperformed an analysis showing the association between gastroesophagealreflux and the risk of cancer after the successive inclusionof potentially confounding variables. Furthermore, we analyzedthe relation between reflux and its potential predictors bymeans of logistic regression.
Results
Altogether, 618 patients with cancer of the esophagus or gastriccardia and 820 control subjects were interviewed. The participationrates, characteristics of the respondents, and reasons for nonparticipationare shown in Table 1. The 451 cases of adenocarcinoma of theesophagus or gastric cardia together constituted 85 percentof all eligible cases of adenocarcinoma in Sweden during thestudy period. The participation rate among both controls andpatients with esophageal squamous-cell carcinoma was 73 percent.
Table 1. Characteristics of the Subjects Interviewed.
Esophageal Adenocarcinoma
The risk of esophageal adenocarcinoma was almost eight timesas high among persons in whom heartburn, regurgitation, or bothoccurred at least once a week as among persons without thesesymptoms (Table 2). Symptoms of reflux at night were associatedwith a risk nearly 11 times as high. The estimates changed marginallyas suspected confounders were added successively to the model(Table 3). The frequency of symptoms of reflux was stronglylinked to the risk: the more frequent the symptoms, the higherthe risk (Table 4). To evaluate further the effect of the severityof the symptoms, the symptoms were graded with scores for heartburnonly (1 point), regurgitation only (1), heartburn and regurgitationcombined (1.5), nightly symptoms (yes=2 and no=0), and frequencyof symptoms (once a week=0, 2 to 6 times a week=1, 7 to 15 timesa week=2, and more than 15 times a week=3). Persons with a scoreof 4.5 or higher had a risk of esophageal adenocarcinoma 20times as high as did those without symptoms of reflux (Table 4).The risk of esophageal adenocarcinoma also increased withan increasing duration of symptoms. Among persons with bothlong-standing symptoms (duration, more than 20 years) and severesymptoms (reflux-symptom score, 4.5 or higher), the adjustedodds ratio for esophageal adenocarcinoma was 43.5 (95 percentconfidence interval, 18.3 to 103.5), as compared with asymptomaticpersons. Stratified analyses revealed no important variationin relative risk among age groups.
Table 2. Symptoms of Reflux Five Years or More before the Interview and the Risk of Esophageal Adenocarcinoma, Adenocarcinoma of the Gastric Cardia, and Esophageal Squamous-Cell Carcinoma.
Table 3. Association of Symptoms of Reflux with Disease after the Successive Inclusion of Potential Confounding Variables in the Multivariate Analysis.
Table 4. Frequency, Severity, and Duration of Symptoms of Reflux Five Years or More before the Interview.
In 118 (62 percent) of the 189 patients with esophageal adenocarcinoma,Barrett's esophagus was detected. The strength of the associationwith symptoms of reflux was virtually identical for patientswith esophageal adenocarcinomas who had Barrett's esophagusand those who did not (data not shown). We compared the riskof esophageal adenocarcinoma among persons who used medicationfor symptoms of reflux at least five years before the interviewwith that among symptomatic persons who did not use such medication.The odds ratio was 3.0 (95 percent confidence interval, 2.0to 4.6) without adjustment for the severity of symptoms and2.9 (95 percent confidence interval, 1.9 to 4.6) with this adjustment.Among the 14 patients with esophageal adenocarcinoma and the6 control subjects who had been surgically treated for reflux,the risk estimates were similar to those for the total groupof patients with symptoms of reflux (data not shown).
Adenocarcinoma of the Gastric Cardia
Reflux symptoms were associated with the risk of adenocarcinomaof the gastric cardia, but not as strongly as with the riskof esophageal adenocarcinoma (Table 2). The risk among personswith symptoms of reflux was approximately two times as highas among those without such symptoms. We found no indicationof confounding by the factors we evaluated (Table 3). The riskestimates increased with increases in the frequency of symptoms,the symptom score, and the duration of symptoms, but not asmarkedly as for esophageal adenocarcinoma. Only among personswith symptoms that were most severe or of the longest durationdid the odds ratios approach 3 (Table 4). Persons who reportedboth long-standing and severe reflux symptoms had an adjustedodds ratio of 4.4 (95 percent confidence interval, 1.7 to 11.0).The relative risk was similar in all age groups.
Esophageal Squamous-Cell Carcinoma
Esophageal squamous-cell carcinoma was not associated with symptomsof reflux (Table 2), irrespective of the frequency, severity,or duration of the symptoms (Table 4). The odds ratio was 1.1(95 percent confidence interval, 0.7 to 1.9) for persons withsymptoms of reflux at least once a week, as compared with personswho had no such symptoms (Table 2).
Predictors of Gastroesophageal Reflux
The associations of age, sex, body-mass index, tobacco smoking,and alcohol use with symptoms of reflux are presented in Table 5.None of these factors were strongly associated with the presenceof symptoms. We also analyzed the effects of the remaining suspectedconfounding factors but found no important associations withreflux (data not shown). The results were similar when we restrictedthe analysis to the control subjects (data not shown).
Table 5. Association between Potential Predictors of Reflux and the Occurrence of Symptoms.
Discussion
Our main finding is the strong association between symptomsof gastroesophageal reflux and the risk of esophageal adenocarcinoma,regardless of the presence of Barrett's esophagus. An association,although weaker, was also found for adenocarcinoma of the cardia,but not for esophageal squamous-cell carcinoma.
The strengths of the study include the population-based design,the uniform classification of tumors, and the complete and rapidcase ascertainment, which enabled us to conduct personal interviewswith all subjects. To avoid the problem of reverse causality,we restricted our analysis to symptoms that had begun at leastfive years before the interview. Patients with an esophagealtumor may be more inclined to remember previous esophageal symptoms(including reflux) than are other subjects. But because thepatients were unaware of the histologic subtype of their tumorsand of the possible differences in the pattern of risk amongthe subtypes, the effects of any recall bias should be similarfor squamous-cell carcinoma and adenocarcinoma. For this reason,the totally negative finding with regard to squamous-cell carcinomashould allay concern about recall bias. Moreover, the cleardose–response relation points to a biologic effect ratherthan to bias.
We adjusted for tobacco smoking, body-mass index,13,14,15 andother possible confounders. None of them had a serious influenceon the risk estimates. The effect of gastroesophageal refluxon the risk of esophageal adenocarcinoma thus appears to beindependent of other variables. Moreover, associations of themagnitude found here are not plausibly explained by confounding.A nonparticipation rate of 27 percent among controls could haveintroduced bias. However, nonparticipation by patients and controlsis unlikely to be linked to reflux.
Symptoms of reflux are considered to be fairly accurate, butnot perfect, indicators of gastroesophageal reflux disease.11,16,17,18,19The misclassification should be random, hence leading to underestimationrather than exaggeration of the association with the risk ofcancer.20
Some misclassification of tumors according to site was unavoidablein some cases as a result of anatomy that had become derangedby the tumor. To evaluate the contribution of misclassificationto the moderate association we found between reflux and riskof adenocarcinoma of the gastric cardia, we reanalyzed our dataafter applying more conservative criteria for cancer near thegastroesophageal junction (69 tumors were located within 10mm of the gastroesophageal junction in endoscopic, surgical,and histopathologic measures). The point estimates were unchanged,indicating the robustness of our findings. The differentialassociation with the symptoms of reflux implies that adenocarcinomasof the esophagus and of the gastric cardia are different diseases,contrary to recent suggestions.15
Multiple comparisons involving three groups of patients andone control group inflated the risk of a type I error. However,the strength and consistency of the observed association andthe clear dose dependency make an effect of chance unlikely.
As compared with the only previous epidemiologic study of gastroesophagealreflux and esophageal adenocarcinoma or adenocarcinoma of thegastric cardia,10 we found a considerably stronger association.Our more extensive data on symptoms of reflux and our abilityto distinguish accurately between adenocarcinomas of the esophagusand those of the gastric cardia may explain the discrepancy.
Barrett's esophagus appears to be a common, but not necessary,step in the evolution of esophageal adenocarcinoma.21 Most suchtumors arise in Barrett's metaplasia,22 a finding confirmedin our study. The risk of adenocarcinoma among patients withBarrett's esophagus has been estimated to be 30 to 60 timesthat in the general population.23,24,25,26 Because the riskamong subjects in our study with the most severe and long-standingsymptoms of reflux was of the same magnitude, and because theassociation was equally strong among patients with esophagealadenocarcinoma with Barrett's esophagus and those without it,we hypothesize that gastroesophageal reflux, rather than Barrett'sesophagus, may be the crucial factor. Admittedly, the prevalenceof Barrett's esophagus may have been underestimated as a resultof tumor overgrowth or sampling error. However, in view of oursystematic efforts to identify this condition, it is remarkablethat there was no important difference in the strength of theassociation between patients who had Barrett's esophagus andthose who did not.
The mechanisms by which gastroesophageal reflux could causecancer in the absence of Barrett's esophagus are unclear. Thesubmucosal glands or ectopic gastric epithelium may constitutethe starting point. Chronic irritation and inflammation arecarcinogenic in several tissues,27,28 and animal studies haveimplicated reflux of bile as a key factor in esophageal carcinogenesis.29,30
We found no indication that treatment of reflux reduced therisk of esophageal cancer. In fact, patients who received medicaltreatment had a higher risk than those who did not. Althoughwe adjusted our data for the severity of symptoms, residualconfounding by the severity of reflux may have affected ourestimates. Moreover, the subjects in our survey had almost invariablyreceived sporadic short-term courses of medical treatment. Theeffect of long-term treatment is unknown. It seems implausiblethat medical treatment itself increases the risk of esophagealcancer, but patients with symptoms of reflux were sometimestreated with anticholinergic drugs, which promote gastroesophagealreflux. The analysis of the risk of esophageal adenocarcinomaamong surgically treated patients was hampered by small numbers,but no dramatic protective effect was found.
The possible clinical implications to be drawn from our datainclude the advisability of prophylactic treatment and endoscopicsurveillance of patients with symptomatic reflux. Medical orsurgical treatment does not seem to prevent cancer in patientswith overt Barrett's esophagus, but therapy may be effectiveif administered before the development of irreversible precancerouschanges. Our data do not, however, support this supposition.Furthermore, the advent of increasingly potent inhibitors ofacid production in the past 20 years does not seem to have affectedthe rising incidence of esophageal adenocarcinoma. For thisreason, pleas for more active treatment to prevent esophagealadenocarcinoma are based on speculation only.
The possible benefits of endoscopic surveillance should exceedthe costs and inconvenience for patients and health care systems.In view of the relatively high number of esophageal adenocarcinomasdetected early23,24,25,26,31,32,33 and the advantage in survivalassociated with an early diagnosis,34 many clinicians considerendoscopic surveillance to be justified in patients with Barrett'sesophagus.35,36 Reflux without Barrett's esophagus, however,is much more common. Symptoms severe enough to be associatedwith a risk of esophageal adenocarcinoma eight times as highas normal were reported by 9 percent of our control subjects.If endoscopic surveillance were restricted to men older than40 who had symptoms of reflux that were so severe as to entaila risk 20 times as high as normal, a Swedish physician wouldneed to follow more than 1400 such patients for one year toencounter a single case of esophageal adenocarcinoma; such apolicy would surely overtax the available health care resources.Until the group at a sufficiently high risk to justify endoscopicsurveillance is better delineated, it seems unwise to make dramaticchanges in current practice.
There are no firm data to substantiate the idea that gastroesophagealreflux is becoming more common. Hence, the role of reflux asa cause of the rapid increase in the incidence of adenocarcinomaof the esophagus and cardia is uncertain.
In conclusion, our study identified symptomatic reflux as astrong risk factor for esophageal adenocarcinoma and a relativelyweak risk factor for adenocarcinoma of the gastric cardia. Thestrength of the association, the dose dependency, and the biologicplausibility suggest causality. The proportion of cases of esophagealadenocarcinoma in the population that are attributable to reflux(the etiologic fraction37) was estimated to be 53 percent inour study, and among the persons who had symptoms of refluxthis proportion20 was 87 percent. It is uncertain whether therisk can be reduced by medical or surgical means, and the needfor endoscopic surveillance is debatable. Moreover, it may benecessary to reappraise the critical role of Barrett's esophagusin the carcinogenic pathway.
Funded by a grant (R01 CA57947-03) from the National CancerInstitute, by the Swedish Cancer Society, and by Dalarna ResearchInstitute.
We are indebted to Leila Nyrén for invaluable coordinationof the fieldwork, to Wolfgang Kraaz for expert guidance in pathologyduring the planning of the study and during the fieldwork, toDr. Lars Backman and Dr. Lars Granström of the Departmentof Surgery at Danderyd Hospital, and to all 227 doctors whoacted as contact persons at the participating departments orprovided invaluable advice during the planning of this study.
Source Information
From the Department of Medical Epidemiology, Karolinska Institute, Stockholm (J.L., R.B., O.N.); the Department of Surgery, Karolinska Institute and Danderyd Hospital, Stockholm (J.L.); the Department of Statistics, Uppsala University, Uppsala (R.B.); and the Department of Pathology, Falu Hospital, Falun (A.L.) — all in Sweden.
Address reprint requests to Dr. Lagergren at the Department of Medical Epidemiology, Karolinska Institute, Box 281, S-171 77 Stockholm, Sweden, or at jesper.lagergren{at}mep.ki.se.
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