Our study demonstrated subsite-specific differences in gastric cancer incidence over time. Based on data for the entire 32 year study period, ASRs for gastric corpus cancer rose among whites and blacks, whereas all other race- and subsite-specific ASRs declined. Data from the most recent 9 years indicated a significant increase in gastric corpus cancer rates for whites and for non-Hispanic whites aged 25–39 and 40–59 years. However, the recent age-specific trends among blacks as well as among other races were not statistically significant. Although subsite-specific rates for younger age groups are based on small numbers with large variance, these patterns extend previous observations of age-specific differences in the US for non-cardia gastric cancer incidence overall.3
Rates of gastric cancer are higher in Hispanic than US non-Hispanic whites,10
which may contribute to some of the long-and short-term trends we observed for whites overall. The population fraction of Hispanic origin has increased from 6.4% in 198011
to 14.6% in 2006,12
and Hispanics are somewhat younger than the US population overall.12
However, there are no obvious demographic shifts to account for the long-term increases in gastric corpus cancer among non-Hispanic whites or blacks.
infection is the primary risk factor for non-cardia gastric cancer.2
The prevalence of H pylori
seropositivity increases with age in the USA, which may reflect decreasing risk of childhood exposure for successive birth cohorts.13–17
Thus, infection trends would seemingly favour decreasing (not increasing) rates of gastric corpus cancer. Assuming the corpus-specific increases are not artefactual, the role of cofactors for rising risk should be considered.
Histamine-2-receptor antagonists and proton pump inhibitors, the most common treatments to reduce gastric acid production, first entered the US market in 1976 and 1989, respectively.18
Acid inhibitor treatment affects the pattern of H pylori
colonisation within the stomach and leads to development of a corpus-predominant atrophic gastritis, a precursor lesion for cancer.19,20
Oxidative stress, a putative mechanism of gastric carcinogenesis, significantly increases in the corpus mucosa of H pylori
-infected subjects after long-term acid suppression.21
Although it has been suggested that the long-term effects of these medications may increase the risk of gastric cancer, results of most formal studies have been inconclusive.22,23
The disappearance of H pylori
infection may have been accompanied by compensatory changes in the gastric microbiota and emergence of other infectious agents, some of which may be carcinogenic. In particular, Epstein–Barr virus (EBV) has been found in ~9% of non-cardia gastric cancer cases worldwide.24
The mechanism by which EBV may contribute to gastric carcinogenesis is uncertain, but several lines of evidence support its aetiological role: (1) monoclonality of viral episomes in the tumour25
; (2) distinct clinical features of EBV-carrying gastric carcinomas as compared with EBV-negative tumours26
; (3) characteristic molecular markers, including specific chromosomal aberrations, a transcription pattern resembling but not identical to nasopharyngeal carcinomas, and expression of the EBV BARF1
; and (4) EBV reactivation preceding clinical presentation of gastric precancerous or cancerous lesions, as indicated by elevated antibodies to viral capsid and nuclear antigens.28,29
EBV-positive tumours are preferentially located in the corpus and other non-antral portions of the stomach,24,30
which may have particular relevance for the shifting subsite distribution we detected.
Tobacco smoking has been reported to have a causal role in the development of gastric cancer.31
Based on a meta-analysis including 18 cohort studies, smoking is significantly associated with both cardia and non-cardia cancers.32
In addition, smoking may contribute to the persistence of H pylori
and to increased risk of its eradication failure.33,34
However, smoking has been declining among US adults in recent decades,35
so this factor would not explain the increases we observed.
Another hypothesis to consider is the carcinogenic effects of obesity, which is increasing markedly in the USA.36
A meta-analysis of 10 observational studies found no statistically significant association with non-cardia gastric cancer (OR 1.26: 95% CI 0.89 to 1.78).37
However, the possibility of a specific association with gastric corpus cancer has not been investigated.
Finally, the incidence trends we observed might be related to changes in diet. Epidemiological studies have associated high salt or salted food consumption with risk of non-cardia gastric cancer.38
Indeed, US salt consumption may have risen over the last 30 years. Per capita sales of food-grade salt rose ~55% between 1983 and 1998.39
Also, reported sodium intake increased between the National Health and Nutrition Examination Surveys (NHANES) of 1971–1974 and NHANES of 1999–2000.40,41
However, a meta-analysis of 24 h urine sodium excretion studies (an indirect, but objective measure of salt intake) did not support an increase over the past several decades.42
Also, low consumption of fresh fruits and vegetables may increase the risk of non-cardia gastric cancer.43
Trends in food availability data indicate that the US population had increasing access to fruits and vegetables between 1970 and 2005.44
However, survey data from NHANES, the Behavioural Risk Factor Surveillance System, the National Health Interview Survey, the National Cancer Institute’s 5 A Day for Better Health Program and the US Department of Agriculture consistently indicate that reported fruit and vegetable consumption have changed little over the last two45–51
or even three decades.40,52–55
While diet differs by race/ethnicity and socioeconomic status,50,53
these differentials have been stable over time and would not explain the trends we observed.
Notably, long- and short-term trends among blacks apparently differ, with a rise in corpus cancer that plateaued prior to the most recent period of analysis. Trends for the period 1999–2007 in SEER9 are consistent with those based on NPCR +SEER combined, indicating that the difference may be associated with time period rather than geographic area.
The increases in corpus cancer affected a broad range of ages among whites and blacks. Interestingly, antral cancer also increased among whites aged 25–39 years. Since corpus and antrum cancers together represent approximately half of all non-cardia cases, the increasing trend in these two subsites is consistent with previous observations that non-cardia gastric cancer overall has increased in young whites.3
Furthermore, we did not observe an increase in gastric corpus cancer in other races (mainly of Asian descent). This group has higher age-specific prevalence of H pylori
infection, indicating that decreases in childhood acquisition may have been achieved more recently than among whites and blacks.56
The marked impact of declining age-specific prevalence of this primary gastric cancer risk factor could potentially obscure countervailing cofactor trends apparent among lower incidence groups.
The strengths of this study are the quality and time span of the underlying data. SEER and NPCR combined capture nearly all gastric cancer cases occurring in the USA. However, our analysis may have been limited by incomplete and/or uncertain designation of anatomical subsite. Although the specialised literature tends to distinguish gastric pathology for the proximal (eg, cardia), middle (eg, corpus) and distal (eg, antrum) portions of the stomach, 27% of the non-cardia cases in NPCR+SEER were assigned to the lesser and greater curvatures by the WHO classification. Moreover, gastric cancer with unspecified subsite declined from 29% in 1976 (for SEER) to 19% in 2007 (for NPCR +SEER), so some of the increase in corpus cancers probably reflects redistribution from the unspecified category. Under the assumption that this shift affected all specific subsites equally, the observed trends were not substantially modified, although the increase among non-Hispanic whites aged 25–39 years was no longer statistically significant. In addition, corpus cancer increased in some race and age groups but not in others cared for by the same health providers. Thus, temporal trends in clinical practice would not be a likely explanation for the shift.
We are not aware of other changes in routine pathological practices or the introduction of screening programmes that may have affected our findings. Nevertheless, given the small proportion of all gastric cancer represented by corpus cancer and the large drop in cases with an unspecified subsite, we cannot dismiss artefact due to biased re-classification as a contributor to the increased rates of corpus cancer.
Other limitations of this study are common to all registry-based analyses, including the retrospective review and lack of risk factor data. Furthermore, non-standardised pathological classification precluded analyses by histological subtype, which could have been additionally informative. Finally, we were unable to assess sex differences due to small samples sizes.
In conclusion, our analysis indicates that gastric corpus cancer may be epidemiologically distinct from other non-cardia carcinomas. The increasing incidence of cancers at this anatomical subsite warrants examination in other populations and studies addressing the potential causes.