a School of Public Health, University of California, Berkeley;
b Division of Gastroenterology, Department of Medicine, University of California, San Francisco;
c Gastroenterology Clinical, Outcomes Research, and Epidemiology Group, University of California, San Francisco. USA.
Douglas A Corley, S-357, UCSF, Box 0538, San Francisco, CA 941430538, USA. E-mail: corley{at}itsa.ucsf.edu
Abstract
Background Adenocarcinomas of the oesophagus and proximal stomach are the most rapidly increasing malignancies in some countries; however, there are no comparative studies on global disease incidence, and the relationships between these two malignancies are undefined.
Methods We evaluated the cumulative rates and age-specific incidence rates per 100 000 population for adenocarcinomas of the oesophagus and proximal stomach for all countries in the Cancer Incidence in Five Continents database, and compared them with rates for oesophageal squamous cell carcinoma.
Results Substantial variations in cumulative cancer rates were found between genders, between countries, between different ethnicities within the same country, and within the same ethnicity residing in different countries. Cumulative rates (ages 074 years) for oesophageal adenocarcinoma varied from 0 (e.g. Thailand) to 0.6 (Scotland, males, 95% CI : 0.56, 0.64); for proximal stomach cancer from 0 (Singapore, Malay females, 95% CI : 0.01, 0.11) to 0.52 (The Netherlands, males, 95% CI : 0.49, 0.55); and for oesophageal squamous cell carcinomas from 0 (non-Jews in Israel, females) to 1.84 (Brazil, Porto Alegre, males, 95% CI : 1.42, 2.26). There was a continuous increase in age-specific incidence rates with advancing age for oesophageal/proximal stomach adenocarcinomas, but a decrease in age-specific incidence rates for oesophageal squamous cell carcinoma after age 75 years. The cumulative rate trends for adenocarcinomas of the oesophagus and proximal stomach were often dissimilar, and varied by country, gender, and ethnicity.
Conclusions These results suggest that different risk factors may be associated with adenocarcinomas of the oesophagus versus the proximal stomach; the marked rate variation implies a substantial environmental component to the recent incidence changes.
Keywords Oesophageal cancer, oesophageal adenocarcinoma, gastric cardia adenocarcinoma, cancer incidence, epidemiology
Accepted 15 February 2001
Historically, oesophageal cancer has received considerable attention, however most of this attention has been focused on squamous cell carcinoma of the oesophagus rather than adenocarcinomas of the oesophagus and the proximal stomach/ gastro-oesophageal junction (i.e. the gastric cardia).1 Although all of these malignancies are characterized by a high mortality rate, the overall one-year survival for oesophageal adenocarcinoma is less than 50%.2
In countries where incidence rates of oesophageal and gastric cardia adenocarcinomas have been examined, there has been a sharp increase in cancer incidence over the last few decades, compared with stable or declining rates for oesophageal squamous cell carcinoma.39 Indeed, the incidences of oesophageal and proximal stomach adenocarcinomas have recently risen more rapidly than any other malignancy in some countries; with average annual incidence increases of up to 17% for oesophageal adenocarcinoma.315 The rising incidence of proximal gastric cancer (i.e. in the gastric cardia, just below the stomach' junction with the oesophagus) occurred despite decreases in the overall incidence of distal gastric adenocarcinoma.16
When epidemiological data for adenocarcinomas of the oesophagus and gastric cardia have been examined, they have frequently been considered together rather than as separate entities, precluding an examination of potentially distinct epidemiological patterns between the two anatomical sites. Oesophageal and gastric cardia adenocarcinomas may have different risk factors, and global differences in the distributions of these two cancers are unknown.
The changes in oesophageal and gastric adenocarcinoma incidence rates are largely unexplained, and do not appear related solely to changes in diagnostic criteria.6 The increased incidence of gastric cardia and oesophageal adenocarcinomas in the US occurred despite a decreasing prevalence of some strong risk factors (e.g. smoking).17
The underlying reasons for regional differences in cancer incidence may provide clues to modifying these diseases, for which the most effective approaches are prevention and early detection. National, regional, and ethnic trends may suggest environmental and behavioural risk factors. Well-studied malignancies, such as oesophageal squamous cell carcinomas, can provide comparison data for age-specific incidence and regional trends. Incidence studies to date, however, have been limited primarily to a relatively few developed countries.1416,18 No studies have evaluated detailed global incidence patterns, published works from the international databases do not provide analyses by histological subtypes of oesophageal cancer, and existing studies have not accounted for cancers of unknown histological type.1416,18,19
We thus used the Cancer Incidence in Five Continents database to evaluate geographical variability between oesophageal adenocarcinoma and adenocarcinoma of the gastric cardia, and compare these patterns with rates for oesophageal squamous cell carcinoma; such comparisons may provide insights into potential aetiological factors for these malignancies.
Materials and Methods
The Cancer Incidence in Five Continents, Volume 7 (Ci5vii) database uses national cancer registries for tracking global cancer incidence.20 It contains age-specific, country-specific incidence data for major cancers from 183 populations in 50 countries, raw count data for each cancer, and person-years in the cancer registry population base for the years 19881992. Efforts are made to standardize the reporting techniques, and registries are excluded if they do not meet standards for quality and comparability. Adenocarcinoma was defined using the International Classification of Diseases for Oncology, Second Edition (ICD-O-2) codes 81408560, as outlined in the Cancer Incidence in Five Continents, Volume 7.20 Anatomical sites were defined using ICD-O-2 codes C15.0C15.9 for oesophageal carcinoma, and C16.0 for the gastric cardia (defined as cardio-oesophageal junction, oesophagogastric junction, and gastro-oesophageal junction).20
The Ci5vii database divides gastric cancers into the following sites: cardia, pylorus and antrum, and other/unspecified. The last category includes cancers of the stomach' body and fundus, as well as cancers without a specified site. Gastric cancers in Ci5vii are not separated by histological type; we assumed all cancers were adenocarcinomas.
The Ci5vii database divides cancers into those with a morphological diagnosis (by histology or cytology) and those without morphology. Cancers with no microscopic verification lack microscopic analysis of biopsy tissue; cancers with no morphological verification lack both microscopic and cytological analysis (e.g. cytological brushings).20 The Ci5vii database treats these categories as mutually exclusive (i.e. each patient is only counted once).
Statistical analysis
Analyses were performed using the Ci5vii statistical package (International Agency for Research on Cancer, Lyon, France) and STATA (release 6, STATA corporation, College Station, Texas).20
Age-standardized rates were calculated using the 1970 World Standard Population, for ages 074. The assumption of proportionality was tested using the test for heterogeneity and the test for trend.20,21 There were frequent failures of these tests, thus only cumulative rates and age-specific incidence rates are reported.
Cumulative rates (i.e. lifetime cancer rates) were calculated for ages 074.20 The cumulative rate is the sum of the age-specific incidence rates, is dimensionless, and is frequently expressed as a percentage. It closely approximates the probability that an individual will develop the disease of interest within a certain age range, in the absence of any competing cause of death (i.e. the cumulative risk) when the cumulative risk is <10%.20
Cumulative rates for oesophageal adenocarcinomas and oesophageal squamous cell carcinomas were adjusted for oesophageal cancers without verification of histological type. The reported cumulative rates for microscopically/cytologically verified cancers were added to the estimated cumulative rate of each cancer type among oesophageal cancers of unknown type. The rate for oesophageal cancers of unknown type was calculated as the sum of two cumulative rates from the registry data: oesophageal cancers with no microscopic verification; and oesophageal cancers of unknown morphology. This sum provides the total cumulative rate of oesophageal cancers of unknown histological type. The proportion of adenocarcinomas and squamous cell carcinomas among oesophageal cancers of unknown type were assumed to be the same as among oesophageal cancers of known type. Countries with a proportion of oesophageal cancers of unknown type >0.5 were excluded from all calculations. If the average proportion of cancers of unknown type for an entire country exceeded 0.5, but individual registries within the country had proportions of <0.5, the largest eligible registry for that country was chosen. The variance for the adjusted cumulative rate was calculated using the delta method.22 The cumulative rates of gastric cancers with no microscopic or morphological verification are not reported separately in the database; thus, we report an unadjusted cumulative rate for cardia adenocarcinomas.
Cumulative rate comparisons use two-tailed P-values calculated from the z-statistic for the normal distribution.21
The countries with the lowest, median, and highest cumulative rates of oesophageal adenocarcinoma were used for the unadjusted age-specific incidence graphs. To maximize stability of the incidence estimates, only countries with >80% microscopic/morphological verification of the oesophageal cancer histological types and at least 5 million person-years in their registry population bases were eligible for inclusion.
Results
Exclusion of countries with >50% oesophageal cancers of unknown type provided 39 countries for the primary analysis. Exclusion of countries with >20% oesophageal cancers of unknown type provided 18 countries for calculation of the age-specific rates.
Oesophageal adenocarcinoma
The cumulative rates of oesophageal adenocarcinoma (074 years of age) vary 60-fold between the countries studied, from approximately 0% (e.g. for both genders in Korea, Thailand, and Estonia) to 0.6% [males, Scotland, P < 0.001]) (Tables 14). A Scottish male thus has an approximately 0.6% risk of developing oesophageal adenocarcinoma by age 74, in the absence of competing causes of death. There are also significant differences within small geographical areas, with a twofold difference between The Irish Republic and Scotland (males, 0.29% versus 0.60%, P < 0.001) (Tables 3 and 4
). Rates vary substantially by ethnicity, even within the same country (Tables 3 and 4
). There is a fourfold difference, for example, in cumulative rates between African American males and Caucasian males within the US (0.06% versus 0.27%, P < 0.001), and a threefold difference between the Chinese and Malay male populations within Singapore (0.06% versus 0.02%, P = 0.11).
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Substantial differences in cancer incidence exist between genders, with all countries having an equivalent or higher incidence of oesophageal adenocarcinoma in the male versus female populations (Tables 14). These differences are most marked in the high incidence countries (e.g. US Caucasian males versus females 0.27% versus 0.02%, P < 0.001) (Tables 3 and 4
).
Age-specific incidence rates demonstrate an increased incidence starting at 4555 years of age in high incidence populations, and at approximately 65 years of age in low incidence populations (Figure 1). There is a steady increase in incidence with age in both high and low incidence populations, with no substantial country-specific crossover of age-specific incidence rates with increasing age.
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Differences within ethnic groups based on the country of origin are also sometimes different for gastric cardia adenocarcinoma compared with oesophageal adenocarcinoma. Jews born in America or Europe have a significantly higher cumulative rate of cardia adenocarcinoma compared with Jews born in Israel (0.31% versus 0.09%, P < 0.001), despite similar rates of oesophageal adenocarcinoma (0.05% versus 0.08%, P = 0.7). We were not able to evaluate potential ethnic heterogeneity of these Jewish populations.
Gender differences for cardia adenocarcinoma are similar to oesophageal adenocarcinoma, with equivalent or higher rates for males versus females in all countries studied.
The age-specific incidence trends demonstrate an increased incidence starting at 45 years of age in high incidence populations, and approximately 55 years of age in low incidence populations (Figure 2). Similar to oesophageal adenocarcinoma, there is a steady increase in incidence with age in both high and low incidence populations, with no substantial country-specific crossover of age-specific incidence rates with advancing age.
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Differences in squamous cancer cumulative rates within ethnic groups based on the country of residence are evident between mainland India and the Indian population in Singapore (1.07% versus 0.6%, respectively, P < 0.001).
There are differences in squamous cell cancer incidence between genders, though these are generally less marked than with the adenocarcinoma malignancies (Tables 14). These differences are most pronounced in the high incidence countries, with up to a sixfold higher cumulative rate in males versus females (e.g. Brazil cumulative rates 1.84% versus 0.31%, P < 0.001).
The age-specific incidence trends demonstrate an increased incidence starting at approximately 45 years of age in all populations. Unlike adenocarcinoma, however, squamous cell carcinoma incidence decreases for patients greater than 75 years old (Figure 3). In addition, we observe a substantial country-specific crossover of age-specific incidence rates with increasing age. Scottish women, for example, experience some of the lowest squamous cancer rates prior to age 55, but some of the highest rates after age 65.
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This report confirms individual studies suggesting substantial regional incidence variations for adenocarcinomas of the oesophagus and gastric cardia, and for oesophageal squamous cell carcinoma. Although we could not analyse temporal trends, our results demonstrate that the cumulative rates of oesophageal adenocarcinoma, oesophageal squamous cell carcinoma, and gastric cardia adenocarcinoma vary widely between countries, between ethnic groups within countries, between the same ethnic group in different countries, and between genders. A striking finding is the high rate of oesophageal adenocarcinoma in Scotland, by far the highest cumulative rate in the world. Scotland' high rates are found in both genders, and are significantly different from its neighbouring countries (i.e. England/ Wales, and the Irish Republic). Scotland' high rates are unexplained and, in contrast to oesophageal squamous cell cancer and other gastric cancers, they do not appear related to differences in socioeconomic status.23
One possibility for the international rate differences is different diagnostic site criteria between countries. The Ci5vii uses the oesophageal/cardia classification outlined in the methods section; newer classification nomenclature identifying the gastro-oesophageal junction as a unique site separate from the cardia and oesophagus have been proposed, but not universally adopted.24 The lower oesophagus is immediately adjacent to the proximal stomach/gastric cardia; small differences in site specification could thus lead to substantial differences in the proportions of gastro-oesophageal junction cancers listed as either gastric cardia or oesophageal malignancies.6,25 If this occurred, gastric cardia rates would be relatively lower in countries with higher rates of oesophageal adenocarcinoma, and vice versa; however, this pattern was not seen. Gastric cardia cancer rates were almost identical throughout England/Wales, Scotland, and the Irish Republic, for example, despite substantial differences in oesophageal adenocarcinoma rates; similar rate patterns were also found between blacks and whites in the US. This suggests that the rate variability of cardia/oesophageal junction cancers is not solely related to preferential classification of cardia/oesophageal junction tumours as either cardia or oesophageal malignancies.
Alternatively, if an increased proportion of gastric cancers were specified as gastric cardia cancers, we might observe an increase in the relative rate of gastric cardia cancers. Since a proportion of unspecified location gastric cancers are likely gastric cardia cancers, the reported cumulative rates for cardia cancers would underestimate the true rates, particularly for countries with a high proportion of unspecified cancers. This would be unlikely to completely explain the rate differences seen in this study, however, as there is still marked cardia/ oesophageal adenocarcinoma rate variability between countries with similar proportions of gastric body/fundus/unspecified cancers (data not shown). In addition, there are similar gastric cardia cancer rates between ethnicities within single countries with low rates of unspecified cancers, despite substantial differences in non-cardia gastric cancer rates (e.g. the US, data not shown). This finding of similar cardia cancer rates despite differing non-cardia gastric cancer rates suggests that the cardia cancer rate variability is not solely related to unspecified gastric cancer rate variability. Differences in diagnostic criteria may thus contribute a proportion of the rate variability between countries, however, other studies also suggest that the oesophageal/cardia cancer rate variability is not wholly due to changes in site classification, earlier diagnosis, or improved specificity of histological subtype.6
Other possibilities for the variable incidence rates include differences in underlying risk factors. One possibility is a change in the prevalence of Helicobacter pylori (H. pylori), a bacterium that colonizes the gastric mucosa; colonization is inversely associated with oesophageal and gastric cardia adenocarcinomas.26 The prevalence of virulent H. pylori strains varies widely between countries, from less than 10% in parts of North America to over 80% in Peru.27,28 Gastro-oesophageal reflux is also associated with oesophageal/cardia adenocarcinomas; medications that may decrease lower oesophageal sphincter pressure, thereby potentially increasing reflux, have also been associated with oesophageal adenocarcinoma.2931
Additional hypotheses for the incidence variability are differences in fat intake/composition, micronutrients intake and the prevalence of obesity.32 Obesity is an independent risk factor for oesophageal adenocarcinoma, possibly by increasing gastro-oesophageal reflux.33 An increasing prevalence of obesity is described in some high incidence countries; the proportion of overweight American adults, for example, increased by one-third between 19761980 and 19861991, despite a decreasing average fat intake.34 No regional/ethnic comparisons of micronutrient distribution relative to oesophageal/cardia adenocarcinoma incidence are available, however, oesophageal adenocarcinoma is inversely associated with intakes of vitamins A & C, fibre, and raw fruits.32,35
Smoking is associated with oesophageal adenocarcinoma, and possibly with gastric cardia adenocarcinoma.36 Some high incidence countries experienced a high prevalence of smoking in the decades prior to the increase in cancer incidence.6 The persistence of risk after discontinuation of smoking may thus cause changes in cancer incidence to lag behind changes in the prevalence of smoking.36 Despite a strong association between alcohol consumption and oesophageal squamous cell carcinoma, a consistent relationship has not been found between alcohol consumption and oesophageal/cardia adenocarcinomas.3538
The gender and ethnic differences within countries are largely unexplained. No substantial studies document sufficient variability in the known risk factors between genders and ethnicities to account for the differences in adenocarcinoma incidence. Indeed, some risk factors are distributed inversely to the observed cancer trends (e.g. higher smoking rates among African Americans in the US, yet a lower adenocarcinoma risk in this ethnic group).17 Differences in gastro-oesophageal reflux between groups may partially explain some variability in incidence, but these differences have not been extensively studied.31
Our finding of different rate distributions for gastric cardia and oesophageal adenocarcinomas supports the hypothesis that these cancers may represent biologically different malignancies. Although oesophageal and gastric cardia carcinomas have a similar male:female ratio, median age at diagnosis and survival, studies suggest several epidemiological and molecular differences between the cancers.24,39 Oesophageal adenocarcinomas are strongly associated with gastro-oesophageal reflux and obesity and are inversely associated with H. pylori and antioxidant intake.2931,4042 Gastric cardia cancers, in contrast, are minimally associated with gastro-oesophageal reflux, only modestly associated with obesity, have no association with antioxidant intake, and have an unclear association with H. pylori.29,4144
Inflammation has been proposed as a potential risk factor for carcinogenesis, and it is associated with premalignant changes of the oesophagus; however, studies linking gastric cardia inflammation with H. pylori, gastro-oesophageal reflux, or gastric cancer have been contradictory.43,45,46 Both cancers are thought to have a similar precursor lesion, a change in the cell type lining the distal oesophagus and gastric cardia (a.k.a. intestinal metaplasia).47 Oesophageal intestinal metaplasia, however, stains for cytokeratin 13 (a squamous cell marker) and for an antibody to colonic-type cells (antibody MAbDAS-1). In contrast, gastric cardia intestinal metaplasia does not stain for cytokeratin 13, and gastric cardia cells do not stain for the antibody MAbDAS-1; these patterns suggest that cardia cells are derived from a different cell line than oesophageal metaplastic cells.4851 Finally, data indicate possible genetic mutational differences between gastric cardia and oesophageal adenocarcinomas, although other genetic defects (e.g. p53 gene defects) are similar between the two cancers.5254
Strengths of this study include the use of standardized cancer registry data, cumulative rate data, and adjustment for carcinomas of unknown type. Cumulative rate data provide an intuitive means of comparing lifetime cancer risk. The adjustment for cancers without microscopic/morphological verification permits less biased comparisons of countries with lower rates of histological verification, by decreasing under-reporting of histological subtypes.
Weaknesses of this study include the probable persistence of some variability in reporting techniques between registries, and the inability to test whether cancers without microscopic/ morphological verification have a similar distribution to cancers with verification. A higher proportion of cancers without microscopic/morphological verification occurs at more advanced ages; since there may be a relatively higher incidence of oesophageal adenocarcinoma versus oesophageal squamous cell carcinoma at advanced ages, this adjustment method may still underestimate the incidence of oesophageal adenocarcinoma.20 It still, however, provides a substantially less biased estimate than an unadjusted cumulative rate.
In summary, these results document substantial regional and ethnic differences in the distributions of oesophageal/cardia adenocarcinomas. The regional incidences of oesophageal and cardia adenocarcinomas differ from each other, as well as from oesophageal squamous cell carcinoma despite many similar risk factors for each of these cancers. Further ecologic studies that evaluate variability of the known risk factors between populations may provide additional information on this paradox. A component of the international rate differences may be related to differences in site specification of these cancers, although our results do not support this as the sole or even primary cause of the variability seen. Research on international variability in site specification is needed to evaluate the influence of different diagnostic criteria on these international differences in cancer incidence. More definitive studies of individual patients examining the roles of potential risk factors such as H. pylori, medications that relax the lower oesophageal sphincter, nutrition, etc, will provide firmer data for potential interventions; such large case-control and cohort studies are currently underway. Plausible explanations for the increasing incidence of oesophageal and cardia adenocarcinomas must be able to account for these regional, gender, and ethnic incidence differences, and for the incidence differences between the two cancers.
KEY MESSAGES
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Acknowledgments
This work was funded by the United States National Institutes of Health Mentored Clinical Scientist Development Award (K08).
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