Trends in reported incidences of gastric cancer by tumour location, from 1975 to 1989 in Japan

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1 IJE vol.33 no.4 International Epidemiological Association 2004; all rights reserved. International Journal of Epidemiology 2004;33: Advance Access publication 11 March 2004 doi: /ije/dyh053 Trends in reported incidences of gastric cancer by tumour location, from 1975 to 1989 in Japan Ying Liu, Satoshi Kaneko and Tomotaka Sobue Accepted 15 October 2003 Background This study was performed to estimate the incidence of gastric cancer by tumour location and to clarify whether the relative and absolute rates of gastric cancer in Japan changed between 1975 and Methods Results The stomach was anatomically divided into the upper, middle, and lower thirds. Age- and sex-specific incidences by tumour location were estimated by multiplying the age- and sex-specific national incidences of gastric cancer by the corresponding proportions of tumour location. We studied cases of gastric cancer from the Gastric Cancer Registry of Japan. Over 15 years, the proportion of tumours in the upper third of the stomach increased in men but did not change much in women. The proportion of tumours in the middle third of the stomach increased among both men and women while the proportion of tumours in the lower third of the stomach decreased among both men and women. The incidence of tumours in the upper third of the stomach showed an increasing trend among elderly men and women but not among young ones. The incidence of tumours in the lower third of the stomach decreased significantly among men and women of most age groups. Conclusions The present study added evidence of disparate trends in the incidence of gastric cancer by tumour location. The separate epidemiological features may indicate different aetiologies as well as changes in the degree of influence of these aetiologies. Keywords Adenocarcinoma, cardia, Japan, adult, age factors, aged, human, incidence, male, female, registries, risk, regression analysis, gastric cancer, tumour location, proportion, incidence The incidence rate of gastric cancer has declined from half a century ago. However, contrary to the general trend of steady decline in the incidence of gastric cancer, many western countries have noticed in recent decades an increase in gastric cancer of the cardia, 1 6 a location associated with a less favourable outcome. Although Japan has the highest national incidence of gastric cancer, evidence of changes in gastric cancer by tumour location is limited, 7 9 and whether there is an absolute increase in incidence or only a relative increase in Cancer Information and Epidemiology Division, Research Institute, National Cancer Center, Tokyo. Correspondence: Ying Liu, Cancer Information and Epidemiology Division, Research Institute, National Cancer Center, Tokyo , Japan. yliu@gan2.res.ncc.go.jp relation to stomach cancer at other sites remains unknown. This study was performed to estimate the incidence of gastric cancer by tumour location and to clarify whether the relative and absolute rates of gastric cancer by tumour location have changed in Japan between 1975 and Methods Cases of gastric cancer We studied cases of gastric cancer from the Gastric Cancer Registry of Japan (GCRJ), a nationwide organization that was founded in 1969 to investigate the diagnosis, treatment, and prognosis of gastric cancer among patients diagnosed since 1963 and admitted to participating hospitals. Hospitals that were selected for inclusion in reports to this cancer registry were 808

2 TRENDS IN GASTRIC CANCER BY TUMOUR LOCATION IN JAPAN 809 mostly large public hospitals with surgical units and with 5-year follow-up rates for 80% of all registered cases. This provision ensures high quality data on staging treatment and prognosis, as well as accuracy in initial evaluation and record keeping. The registration and follow-up forms collected details of address, sex, past history, family history, age at first diagnosis, diagnosis date and methods, TMN stage, tumour location, treatment, histopathological diagnosis, and survival status of each patient provided by a periodic follow-up survey directed at hospitals. Hospital reports made after 1990 are recorded by a new system and are not currently available to the public. Before the registry closed in 1990, a wide variety of hospitals with surgical units throughout Japan participated. The number of reporting facilities varied in any given year, ranging from 174 hospitals in 1975 to 188 in The number of reported cases increased steadily; cases were registered in1989. The registration form was revised in accordance with a major revision of the Japanese Research Society for Gastric Cancer classification in 1974, so cases registered since 1975 have been used in the present study. The estimated annual rates of patients throughout Japan with gastric cancer covered by GCRJ between 1975 and 1989 were calculated by dividing the number of cases in the Registry by the incident number of gastric cancer cases in Japan, estimated from the data of several population-based cancer registries. 10 This estimated annual coverage rate for all gastric cancers was found to be 10 20% for most age groups. 11 Although the rates were not higher due to limited resources, the rates kept relatively stable within the same age group during the observation period. In addition, this registry is the only one that provided coverage throughout all of Japan. We found registered cases 30 years of age and who were initially diagnosed between 1975 and We excluded 4634 of these cases because of incomplete information regarding tumour location and 1897 more cases that involved tumours classified as being other than gastric cancer (e.g. malignant lymphoma) according to the International Classification of Diseases (9th Edn). Thus, cases involving men and women were left for analysis. Of these patients, 95% underwent surgical treatment. Tumour location In this registry, the subsites of gastric carcinoma were classified as cardia, fundus, body, lesser curvature, greater curvature, pylorus, or pyloric antrum, and specified as located in the upper, middle, or lower third of the stomach. Cardia carcinoma has been defined in various ways, 12 and until quite recently in Japan, the upper third of the stomach has been called the cardia based on the guidelines for gastric cancer classification. 13 Because of the difficulty in distinguishing the actual cardia from the upper third of the stomach, we considered both defined areas to be one site for analysis in our study. According to the latest guidelines for gastric cancer classification, 14 the stomach is anatomically delineated into the upper, middle, and lower thirds by dividing the lesser and greater curvatures at two equidistant points and joining these points. Tumours located predominantly in the gastro-oesophageal junction and cardia were determined to be in the upper third of the stomach; those located in the pylorus were considered to be in the lower third of the stomach; and those located in the midbody were determined to be in the middle third of the stomach. If a tumour was located across adjacent regions, the region containing the greater proportion of the tumour was considered to be the tumour s location. If a tumour spanned all three regions, its location was classified as being the entire body of the stomach. Estimation of the incidence of gastric cancer by tumour location Annual proportional frequencies of gastric cancer by tumour location were calculated for each sex and 10-year age group (from years old to those 70 years). Annual age-specific incidence rates of gastric cancer by tumour location were estimated by multiplying the national incidence rates of gastric cancer in the relevant year 15 by the proportional frequencies of gastric cancer by tumour location for each sex and 10-year age group. Statistical analysis The years from 1975 to 1989 were considered as three groups: , , The change over time in the proportion of tumours by location was tested by Mantel- Haenszel 2 analysis. We used a logistic regression model to analyse the percentage of average increase or decrease per year in the incidence rates of gastric cancer by tumour location with 95% CI. By fitting a logistic regression model, time trends stratified by age group were analysed with disease status as a dependent variable and time in years as an independent variable. The results for linear trend analysis were presented by percentage of increase in incidence rate per year (% increase). Statistical analyses were performed with the SAS software package, version 8.2 (SAS Institute, Inc., Cary, NC, USA). Results Table 1 gives the change over time in the proportion of tumours by location among men and women. Compared with those of the first 5 years ( ), the relative frequencies of tumours in the middle third showed a distinctly increasing trend and those of tumours in the lower third and in the entire body of the stomach had a decreasing trend among both men and women. The relative frequencies of tumours in the upper third increased significantly among men but not among women. Changes in the relative frequencies of gastric adenocarcinomas by tumour location according to age groups are presented in Figure 1. The proportion of tumours in the middle third and in the entire body of the stomach decreased with increasing patient age while that of the lower third increased with increasing age; The proportion of tumours in the upper third remained relatively stable with increasing age. Similar tendencies were found in both men and women. For patients 40 years, an increased relative frequency of tumours in the middle third and a decreased relative frequency in the lower third were observed in both sexes over time. The proportion of tumours in the upper third increased in men 50 years and in women 70 years. For patients years old, no marked time transition in the proportion of tumours in any third of the stomach was noted. Age- and sex-specific incidences of gastric cancer are indicated in Figure 2 using log-linear scales according to tumour location. The age-specific incidence of tumours in the upper third of the stomach increased among elderly men and women. That of tumours in the lower third decreased among both men

3 810 INTERNATIONAL JOURNAL OF EPIDEMIOLOGY Table 1 Changes between 1975 and 1989 in the proportion of gastric cancer by tumor location and sex for cases of gastric cancer Time period Tumor location P-value for trend Men N = N = N = Upper third Middle third Lower third Entire stomach Women N = N = N = Upper third Middle third Lower third Entire stomach Values are percentages. P-values are based on Mantel-Haenszel 2 analyses. Figure 1 Changes in the relative frequencies of gastric adenocarcinomas by tumour location, presented by age and diagnosis year

4 TRENDS IN GASTRIC CANCER BY TUMOUR LOCATION IN JAPAN 811 Figure 2 Annual standardized age-specific incidence rates of gastric adenocarcinomas by tumour location from 1975 to 1989 and women in most age groups and that of tumours in the middle third remained stable. Because temporal changes in the age- and sex-specific incidences of gastric cancer according to tumour location occurred slowly, the curves of the trends for incidences were too gentle to be distinguished clearly, so we then calculated the percentage of average annual increase or decrease in the incidence rates by tumour location, with 95% CI (Figure 3). The incidence

5 812 INTERNATIONAL JOURNAL OF EPIDEMIOLOGY Figure 3 Sex-age-group stratified linear trends for gastric cancer by tumour location rates of tumours in the upper third of the stomach of young patients were found to decrease slightly over time; however, statistically significant increases in incidence rates among elderly men ( 50 years) and women ( 70 years) were observed. The incidence rates of tumours in the lower third of the stomach showed significantly decreasing trends among both men and women in most age groups but those of tumours in the middle third showed little change. Men showed more fluctuation than women in the incidence rate over time between age groups. Discussion The low coverage rate of patients throughout Japan by the registry may introduce a selection bias. However, because facilities included in the registry were mostly large public hospitals throughout Japan, it may be reasonable to suppose that the patients of these facilities are representative of the Japanese population, thereby minimizing the influence of any selection bias. Another limitation of the present study is the possibility that severely ill patients may have been excluded from the analysis. Patients who were too sick to undergo a resection operation were more likely to be lost from the reporting process, and the exclusion of 4634 reported cases (2.6%), most of which were without surgical treatment, from analysis because of incomplete information in tumour location may partially explain the high resection rate (95%) compared with that of the Cancer Registry in Osaka prefecture; the latter showed about an 85% operation rate among patients years old with gastric

6 TRENDS IN GASTRIC CANCER BY TUMOUR LOCATION IN JAPAN 813 cancer in In addition, because tumours of the entire stomach and tumours in the upper third of the stomach are considered to be associated with a less optimistic prognosis, 16 the exclusion of the 4363 cases may have falsely decreased the number of cases with tumours in the upper third or entire stomach. However, data from cases diagnosed at autopsy on changes over time by tumour location are not available. Although the limitations described above may exist, and further studies that include autopsy data are needed to confirm our findings, this registry system is the only one covering all of Japan, and with its large sample size, no more precise data are available. To our knowledge, this is the first study from Japan that provided data on the change over time of the incidences of gastric cancer by tumour location, and gave information on age- and sex-specific time trends. The present study has not provided any evidence regarding changes in the incidence rate or proportion of cancer of the gastric cardia, which is a relatively small yet distinct part of the proximal third of the stomach. The present study added evidence of disparate trends in the incidences of proximally localized and other gastric adenocarcinomas, by showing a decreasing incidence of distal gastric cancer and an increasing incidence of proximal gastric adenocarcinoma. The findings of the present study are in agreement with those of two previous Japanese studies, which found a relatively increasing incidence of cardia or proximally localized gastric adenocarcinoma. 7,8 However, these previous Japanese studies were based on the proportional frequency ratio of gastric cancers by tumour location, which does not itself indicate trends of incidence. In addition, information on age-specified time trend, which might be informative for evaluating whether exposure status to relevant environmental factors differed between age groups, is scarce 2 and has not been reported in previous Japanese studies. The findings indicated not only a proportional increase but also an actual increase in the incidence of proximal gastric adenocarcinoma among elderly men and women but not among young people. The findings also indicated an actual decrease in the incidence of distal gastric adenocarcinoma and no change in the incidence of gastric cancer in the middle third of the stomach among men and women of almost all ages. The disparate epidemiological traits of gastric cancer by tumour location may suggest different aetiologies. However, the cause of changes in proportional rate and incidence rate over time is not well understood. An increasingly western lifestyle as well as a decreased incidence of Helicobacter pylori infection 17,18 may contribute to the change over time in the incidence of gastric cancer by tumour location. Infection with H. pylori has been identified as an important risk factor for gastric cancer. 19,20 The effects of H. pylori on tumour development vary by anatomical site. A large amount of evidence suggests that the decreasing prevalence of H. pylori infection, especially with caga+ strains, may be associated with the declining incidence of distal gastric adenocarcinomas. 5,21 23 The decreased infection rate of H. pylori may contribute to the increasing incidence of proximal adenocarcinomas as well. Several recent studies have noted that treating H. pylori infection might increase the risk of peptic oesophagitis and adenocarcinoma of the oesophagus and cardia, 24,25 although the protective effect of H. pylori against cardia tumours remains controversial. 26,27 In addition to H. pylori infection, changes in lifestyle may be responsible for the diverging incidence rates of gastric cancer by tumour location. A study that investigated the incidence of gastric carcinoma in Asian immigrants to the US and their descendants indicated that dietary and other lifestyle differences between the different generations of Japanese-Americans, and between Japanese residents of the US and those of Japan may provide clues regarding the aetiologies of stomach cancers that arise beyond the gastric cardia. 28 Some studies have attempted to interpret the diverging incidence rates by tumour location through an association with dietary antioxidants, 29 fruit and vegetable consumption, 30 cigarette smoking, 31,32 and an increasing prevalence of obesity. 33 Moreover, the Epstein- Barr virus (EBV) has been found to be associated with cardia tumours; when the antrum was used as a referent category, the risk of tumours in the cardia increased five times. 34 Several studies found different rates of gene mutation according to tumour location, suggesting variation in susceptibility and different mechanisms in the pathogenesis of stomach cancer by location. 35,36 Japanese studies noted that familial gastric cancers were frequently located in the cardia and that those appeared to be more aggressive than sporadic gastric cancers. The unique characteristics of familial gastric cancer suggests a genetic component as well as an environmental influence in its aetiology. 37,38 Westernization of lifestyle, the consistently decreasing H. pylori infection rate among young people, and possible changes in gene environment interactions may contribute to the increased incidence of proximal gastric adenocarcinomas. Gastric cancer among young patients was less likely to be found in the proximal part of the stomach and in the antrum than in the gastric body. 39 In the present study, the relative proportion of distal tumours was about half that of tumours in the middle third of the stomach among young patients. However, the relative proportion of distal tumours increased with increasing age and was twice that of tumours in the middle third of the stomach among patients 80 years. This finding suggests that aetiological factors among young patients are different from those among elderly ones. In addition, the moderately decreasing rate over time in the age-specific incidence of proximal tumours among young patients compared with the increasing rate among elderly ones may strengthen this assumption. Two European studies have shown that the early onset of gastric cancers, especially in patients 40 years, is more often associated with genetic changes at preferential chromosomal loci compared with those of older patients, suggesting a difference in genetic predisposition between age groups. 40,41 The effects of rapidly changing environmental factors accumulated over a long time period may be more pronounced among older age groups than younger ones. Remarkable lifestyle changes in Japan from the middle of the 20th century, and their possible interaction with genetic susceptibility, may partially explain why changes in trends are more common among the older age groups than the younger age groups. No previous Japanese studies have differentiated the change over time in the incidence of proximal gastric cancer between men and women. The present study found no remarkable differences in changes over time in the incidence of subsite-specific gastric cancer among men and women.

7 814 INTERNATIONAL JOURNAL OF EPIDEMIOLOGY The similarity of the trends suggests that the aetiological influences did not vary between men and women over the 15-year period. The separate epidemiological features of gastric cancer by tumour location may indicate different aetiologies as well as changes in the degree of influence of these aetiologies. Because little is known about the aetiology of proximal adenocarcinomas, and because not only the relative incidence rate but also the absolute incidence rate seems to be rising, further research into gastric adenocarcinomas by tumour location is urgently needed to clarify the risk factors and mechanisms responsible for the increasing incidence. Acknowledgements Dr Ying Liu is an Awardee of Research Resident Fellowship from the Foundation for Promotion of Cancer Research (Japan) for the 2nd Term Comprehensive 10-Year-Strategy for Cancer Control. KEY MESSAGES The proportions of gastric carcinomas in the upper and middle thirds of the stomach increased while that of lower third decreased, especially among elderly patients. The incidence of tumours in the upper third of the stomach showed an increasing trend among elderly patients but not among young ones, while that in the lower third decreased significantly in most age groups. The disparate trends in the incidence of gastric cancer by tumour location may indicate different aetiologies as well as changes in the degree of influence of these aetiologies. References 1 Blot WJ, Devesa SS, Kneller RW, Fraumeni JF, Jr. Rising incidence of adenocarcinoma of the esophagus and gastric cardia. JAMA 1991; 265: Hansson LE, Sparen P, Nyren O. Increasing incidence of carcinoma of the gastric cardia in Sweden from 1970 to Br J Surg 1993;80: Botterweck AA, Schouten LJ, Volovics A, Dorant E, van Den Brandt PA. 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