American Indian (AI) and Alaska Native (AN) people are disproportionately affected by gastric cancer when compared with their non-Hispanic white (NHW) counterparts (1,2), a pattern that has been observed among indigenous peoples globally (3). In contrast to the relatively consistent rates observed across NHW people nationally, gastric cancer incidence among AIAN people also varies regionally from a low of 6.1/100,000 in the Eastern United States to a high of 24.5/100,000 in Alaska (4). Gastric cancer is the fifth leading cause of cancer death among AN people, and only a fifth of AN patients are diagnosed at the local stage when there may be some chance of a cure (5). This is a leading health disparity for AN people, with both incidence and mortality rates over 3 times than those observed among NHW people (6). Similarly, high rates are observed in Asia (7) and among other indigenous populations across the circumpolar North (8,9). Risk factors for gastric cancer that are shared among these populations include chronic Helicobacter pylori infection, tobacco use, and high intake of salted and smoked foods (10–12).
Despite sharing a high burden of gastric cancer with other circumpolar and Asian populations, there are unique pathologic and molecular genetic features of gastric cancer among AN people. A recent examination of gastric cancer tumors showed that compared with their NHW counterparts, a higher proportion of AN patients with gastric cancer were diagnosed with noncardia and diffuse subtype cancers, including signet-ring cell carcinomas (SRCC) (5). Diffuse-type gastric adenocarcinomas tend to be highly metastatic, have worse prognosis, and are more difficult to identify using endoscopy (13). This has implications not only for prognosis and survival but also for the design and implementation of screening programs like those in Japan and South Korea, where cancer is predominately intestinal-type (14). These pathologic and molecular differences highlight the need to specifically evaluate the gastric cancer within this population.
Our group recently convened a symposium of international experts, community members, and Tribal health leaders to identify the best strategies to reduce the burden of gastric cancer among AN people (15). Recommendations offered by the symposium included the creation of a gastric cancer screening program for particularly high-risk patients (e.g., first degree relatives of patients with gastric cancer and patients with gastric intestinal metaplasia) and the development of risk stratification tools specific to AN people. There was agreement that more research is needed to understand the basic epidemiology and molecular genetics of this malignancy and the prevalence and transmission of H. pylori in AN communities.
Despite the high risk of gastric cancer among AN people and the important differences in clinical and pathologic features, there have been no recent population-based studies of this malignancy in this population (16). We describe the epidemiology of gastric cancer among AN people living in Alaska from 1990 to 2017.
Approximately 144,274 AI/AN people resided in Alaska in 2015 (17) (individuals reporting AI/AN identity alone or in combination with another racial identity), comprising 19.5% of the Alaskan population. Almost 90% of AI/AN people living in Alaska identify as AN (18); therefore, hereafter, we will refer to all AI/AN people residing in Alaska as “Alaska Native (AN) people.” Healthcare for AN people residing in Alaska is provided by 32 regional Tribal Health Organizations and the Alaska Native Tribal Health Consortium, which provides statewide specialty care services. The Alaska Native Medical Center (ANMC) is the sole tribally managed tertiary healthcare facility in the state, located in Anchorage. Most patients with gastric cancer receive their treatment at ANMC.
Cancer data were collected by the Alaska Native Tumor Registry (ANTR). This population-based central cancer registry records information on AN people who meet eligibility requirements for Indian Health Service benefits, who have been diagnosed with cancer in Alaska since 1969 and who reside in Alaska at the time of diagnosis. The ANTR has been collecting cancer information according to National Cancer Institute's Surveillance, Epidemiology, and End Results Program (SEER) standards since its inception in 1969 and has been a full member of the SEER Program since 1999. According to ANTR standard case-finding practices, cases were ascertained through a variety of sources, including (i) hospital discharge diagnoses for tribal and nontribal health facilities in Alaska; (ii) tumor registry and pathology files of the ANMC and other in-state healthcare facilities; (iii) linkage to the Alaska Cancer Registry and the Washington State Cancer Registry, which assures that all cases of cancer in AN in Alaska are captured, irrespective of where they receive their care; and (iv) death certificates (<1% cases were registered solely on the basis of information from a death certificate). For the purpose of this study, we report on cancers diagnosed from 1990 through 2017. Data for AN people are compared with those of US Whites (USWs), using data from the SEER 9 database (19).
We evaluated incident gastric cancers, excluding cases of leukemia, lymphoma, mesothelioma, and Kaposi sarcoma using the International Classification for Diseases for Oncology, third edition (ICD-O-3) (20), site codes C160-169; we excluded histology codes 9050–9055, 9140, and 9590–9989. For analysis of tumor location, we define proximal cancers as those occurring in the cardia (16.0) and the fundus (16.1); distal as those cancers occurring in the body (16.2), gastric antrum (16.3), pylorus (16.4), lesser curvature (16.5), and greater curvature (16.6); and overlapping/unknown as those in the overlapping lesion (16.8) and stomach not otherwise specified (16.9). For analysis of specific histologic types, we defined broad histologic categories after the Lauren criteria (21) as diffuse (ICD-O-3 histology codes 8490, 8145, and 8142), intestinal (ICD-O-3 histology codes 8010, 8140, 8211, and 8144), and other. We also gave information for select subtypes of interest, including SRCC (ICD-O-3 histology code 8490), diffuse-type carcinoma (ICD-O-3 histology code 8145), intestinal-type adenocarcinoma (ICD-O-3 histology code 8144), and adenocarcinoma (ICD-O-3 histology codes 8140). The proportion of cancers in the histologic subtypes of interest were evaluated for people younger than 40 years, 40–59 years, and older than 60 years. Cancer stage is given for cases diagnosed from 2004 to 2017 using the derived SEER summary stage 2000 variable.
This study was Institutional Review Board exempt because the ANTR collects these data for the purposes of public health surveillance and is available publicly through the SEER program. The authors received tribal approval for publication of this article from the Alaska Native Tribal Health Consortium.
Differences in demographic and clinical characteristics between AN and USW patients with gastric cancer were assessed using the χ2 test for categorical variables. When a significant association was found for a characteristic, pairwise comparisons with a Bonferroni correction for each level of the categorical variable were performed for further evaluation. Within the SEER public use data set, all patients aged older than 85 years at diagnosis are assigned an age of 85 years to protect patient privacy. The average annual age-adjusted incidence rates and 95% confidence intervals (CIs) per 100,000 persons were calculated overall and by sex for the entire study period and for the 3-year period (1990–1993, 1994–1996, 1997–1999, 2000–2002, 2003–2005, 2006–2008, 2009–2011, 2012–2014, and 2015–2017). The average annual age-adjusted mortality rates and 95% CIs per 100,000 persons were calculated overall and by sex for the entire study period. Age-adjusted rates were directly adjusted using the 2000 US population as the standard (22). Denominators for rate calculations were derived from population estimates from the US Bureau of the Census and National Center for Health Statistics for AN people (bridged estimates). Rate ratios (RRs) and 95% CIs were compared between race and sex strata using the direct method (23) and between age groups using Poisson regression. Trends in incidence and mortality rates over time were evaluated separately for AN people and USW people using Poisson regression. All statistical tests were 2-sided and were assessed at an alpha level of P < 0.05 or with a Bonferroni correction for pairwise comparisons. Statistics were generated using standard modules of SAS (version 9.4; SAS Institute, Cary, NC). As per the ANTR standard procedure, incidence rates and case counts are not given where cell sizes were <5 to protect individuals' privacy.
A total of 415 AN people and 41,167 USW people were diagnosed with gastric cancer from 1990 to 2017 (Table 1). The age distribution was significantly different between AN and USW patients (P < 0.001), with a greater proportion of AN people diagnosed younger than 40 years (11% among AN vs 3% among USW, P < 0.0001) and 40–59 years (AN: 37% and USW: 20%, P < 0.0001). Most of the cancer cases were among men in both populations (AN: 63% and USW: 64%, P = 0.98). The distribution of cancer site/location was different between AN people and USW people (P < 0.0001). A greater proportion of AN cancers were distal (AN: 54% and USW: 34%, P < 0.0001) and specifically on the lesser (AN: 21% and USW: 7%, P < 0.0001) and greater (AN: 9% and USW: 4%, P < 0.0001) curvature of the stomach and the pylorus (AN: 7% and USW: 2%, P < 0.0001). A smaller proportion of AN people compared with USW people were diagnosed with proximal gastric cancer (AN: 24% vs USW: 40%, P < 0.0001) and specifically at the cardia (AN: 19% and USW: 36%, P < 0.0001).
Table 1. -
Characteristics of AN gastric cancer cases (Alaska Native Tumor Registry), compared with USWs (SEER 9 registries), 1990–2017
||AN people (n = 415), n (%)
||USW people (n = 41,167), n (%)
|Site/location (ICD code)
| Proximal stomach
| Cardia, NOS (16.0)
| Fundus (16.1)
| Distal stomach
| Body (16.2)
| Antrum (16.3)
| Pylorus (16.4)
| Lesser curvature (16.5)
| Greater curvature (16.6)
| Overlapping lesion of stomach (16.8)
| Stomach, NOS (16.9)
||n = 241
||n = 20,822
AN, Alaska Native; ICD, International Classification for Diseases; NOS, not otherwise specified; SEER, Surveillance, Epidemiology, and End Results Program; USW, US white.
aSignificance levels were corrected using the Bonferroni correction. Significant values are in bold.
bSignificance was first compared for the overall category and then analyzed by subgroup.
A significant difference in the overall distribution of pathologic types existed between AN people and USW people (P = 0.006; Table 1); however, there were no significant differences in the number of AN people and USW people with diffuse or intestinal groupings in the post hoc pairwise comparisons. Looking at specific subtypes within the diffuse grouping, we found that there was a greater proportion of AN cases that were SRCC (75/415 [18%]) compared with USW (5,930/41,167 [14%], P = 0.034); however, after adjusting the significance level using the Bonferroni correction, this was no longer significant. We evaluated the subtypes within the intestinal grouping and found that AN people were more likely to have intestinal-type (43/415 [10%]) compared with USW people (2,011/41,167 [5%], P < 0.0001), whereas there was no difference between the populations for adenocarcinoma (AN: 221/415 [53%] and USW: 2,272/41,167 [55%], P = 0.43).
We also found that stage distribution differed between AN people and USW people, with a greater proportion of AN people being diagnosed at a distant stage (AN: 48% and USW: 35%, P < 0.0001; Table 1). More AN people younger than 40 years diagnosed with cancer at a distant stage (91%, 14/23) than who were older than 40 years (47%, 101/217); however, this difference was not statistically significant (P = 0.19).
Overall distribution of pathologic groupings differed by age group for both AN people (P < 0.003) and USW people (P < 0.0001; data not shown). Both USW individuals and AN individuals younger than 40 years and between 40 and 59 years were more likely than those 60 years and older to have diffuse cancer, and within the diffuse category, more likely to have SRCC (P = 0.01 or less for all).
The age-adjusted incidence rate over the study period was 20.8 per 100,000 persons among AN people. The age-adjusted rate of gastric cancer in the AN population was significantly/higher than the USW population overall (20.8 vs 6.7 per 100,000 persons, RR: 3.1 [2.8–3.4], P < 0.0001) and for both men (28.5 vs 9.6, RR: 3.0 [2.6–3.4], P < 0.0001) and women (14.3 vs 4.4, RR: 3.2 [2.7–3.8], P < 0.0001). The difference in rates varied by age group, with the most pronounced difference in people <40 years (AN: 2.1 vs USW: 0.34, RR: 6.2 [4.6–8.3], P < 0.0001), followed by 40 and 59 years of age (23.2 vs 5.3, RR: 5.3 [3.6–5.1], P < 0.0001) and in people 60 years and older (77.1 vs 30.2, RR: 3.0 [2.2–2.9], P < 0.0001). The incidence rate in the AN population ranged from a high of 27.2 per 100,000 persons in the 2000–2002 period to a low of 15.4 per 100,000 persons in the 2015–2017 period; however, no significant trend was found over the 28-year period, either overall (P = 0.16) or when stratified by sex (men: P = 1.0 and women: P = 0.08; Figure 1). By contrast, we observed a decreasing trend in the incidence rate among USW people, both overall and in both men and women (P < 0.001). Incidence varied between Alaska's tribal health regions, with the highest rate found in the North Slope (40.9/100,000 people, CI 27.8–57.7) and the lowest in the Southeast (11.9/100,000 people, CI 8.3–16.4; Figure 2). In addition, incidence was significantly different by sex in the AN population, with 28.5 cases per 100,000 men and 14.3 cases per 100,000 women (RR: 2.0, 95% CI 1.6–2.5, P < 0.0001) (see Supplementary Table 1, Supplementary Digital Content 1, http://links.lww.com/CTG/A640). Similarly, age-adjusted mortality rates were significantly higher among AN people compared with USW people (13.7 vs 3.6 per 100,000 persons, RR: 3.7 [3.3–4.2], P < 0.0001) and for both men (18.7 vs 5.0, RR: 3.8 [3.2–4.4], P < 0.0001) and women (9.3 vs 2.6, RR: 3.6 [2.9–4.4], P < 0.0001). Given the small numbers of deaths from gastric cancer, it was not possible to model the trend in mortality for the AN population.
This study compared the epidemiology of gastric cancer among AN people and USW people from 1990 to 2017. Our data show that AN people not only have a higher rate of gastric cancer than USW people but are also more likely to be diagnosed when younger and have more advanced disease at diagnosis. Although there has been a downward trend in the incidence of gastric cancer among the USW population, this was not seen in AN people. Similar to other populations, AN women have a lower incidence of gastric cancer than AN men; however, even this lower risk group had a higher rate of gastric cancer than USW men.
Our data agree with previous publications that have found that AIAN people have a higher rate of gastric cancer, are diagnosed at a younger age, and have a higher proportion of SRCC than NHW people (2,5,24). By contrast, our data differ from previous reports in that we saw AN people were significantly more likely than USW people to be diagnosed when their cancer was at the distant stage, (24) and we did not observe any trend to suggest a decreasing incidence over time (2). This difference is likely due to the fact that this study was based in Alaska and the AIAN population studied here is 90% AN, whereas other studies that encompasses nationwide data reflect the larger American Indian population. AN people represent a distinct population with specific cancer trends (25) and unique health access issues (15) that are easily lost in nationwide data; therefore, focused analysis is very important to understand unique trends and problems within the AN population.
A larger proportion of gastric cancers were diagnosed among AN people <40 years old relative to their USW counterparts, reflecting a higher rate of cancer in this age group. Clinicians do not typically consider gastric cancer in people <40 years old because only 3% of gastric cancers occurred in this age group in the USW population. However, it is important that clinicians add this to their differential when treating AN people because 11% of cancers within this population occur in this young age group. We also found a higher percentage of AN people younger than 40 years had distant cancer at diagnosis than those older than 40 years; however, we were unable to show a significant difference between these groups, likely due to the small sample size. Although we cannot determine whether young patients have more advanced cancers because of a delay in diagnosis or differing pathologies, our findings support the importance of improving the awareness of clinicians regarding the high number of gastric cancers that occur in young AN patients to ensure early diagnosis and treatment.
SRCC are a particularly aggressive tumor type, usually diagnosed at a more advanced stage and with a shorter 5-year survival than other adenocarcinomas (26,27). Among both AN people and USW people, we found that SRCC tumors were more common among those aged <40 years and 40–59 years, relative to those older than 60 years; this finding is in agreement with previous studies from other non-Native populations (28–30). Very little is known about risk factors specific to SRCC. Mutations in the e-cadherin gene, CDH-1, have been linked to an increased risk of SRCC; however, only a small proportion of patients with SRCC have a mutation in this gene (31). Some isolated populations, such as the Maori of New Zealand, have been found to have a higher rate of CDH-1 mutations (32); however, this does not seem to be true in the AN population (33).
The higher rates of gastric cancer and the higher proportion of noncardia cancers observed among AN people relative to USW people may reflect the high prevalence of H. pylori infection among AN people (34). Previous studies have demonstrated that up to 70% of AN people in some rural villages have been exposed to H. pylori (35,36). We observed higher gastric cancer rates in more rural Tribal Health Regions to the north and west of Alaska, compared with regions in the south and interior, which contain larger urban centers. This pattern mirrors the known distribution of H. pylori infection (35). Unfortunately, studies conducted in Alaska have found that many rural AN people become reinfected with H. pylori after treatment, likely due to crowded living conditions and limited access to clean water (37). This, along with high antibiotic resistance rates (38), makes the widespread elimination of H. pylori in the AN population very difficult. Further research is needed to determine effective strategies to control H. pylori infection among AN people and the potential impact of H. pylori eradication on gastric cancer prevention.
This study has several strengths and limitations that should be considered in the interpretation of the results. The primary limitation of this study was the small case count, which limited our statistical power to identify trends and test differences between groups. In particular, our estimation rates for Tribal Health Regions are based on small case counts and therefore should be interpreted with caution. However, the small size of the AN population does not diminish the importance of this work because it highlights an important cancer disparity. Analysis of additional variables, including tumor size and American Joint Committee on Cancer stage, was not possible because data for these variables were incomplete for a large percentage of cases. A key strength of this work was our use of high-quality, population-based data from the ANTR. The ANTR has followed SEER guidelines and standards for data collection since its inception in 1974 and has been a full SEER-member registry since 1999; therefore, we are confident that these data represent the highest quality cancer surveillance data available.
This study highlights the continued health disparity of gastric cancer in the AN population. This detailed information informs our understanding of past gastric cancer trends among AN people and provides baseline data for future prevention and control efforts. We anticipate that these results will be of interest to those who are interested in the global epidemiology of gastrointestinal malignancies and clinicians working within the tribal health system and among other high-risk populations. The data presented here emphasize the importance of continued implementation of practices to prevent gastric cancer, including screening and treatment of H. pylori infection in high-risk individuals, use of diagnostic tests such as esophogastroduodenoscopy, and clinician education to increase their awareness around the possibility of gastric cancer in young AN people.
CONFLICTS OF INTEREST
Guarantor of the article: Leisha D. Nolen, MD, PhD.
Specific author contributions: L.D.N. and S.N.: concept formation, data analysis, and article preparation. S.S.: data analysis. K.M.: data collection. S.M.V.: concept review.
Financial support: Baseline CDC funding supported the work of L.D.N. and S.S. S.N., K.M., and the Alaska Native Tumor Registry were supported by the National Cancer Institute (NCI) Surveillance, Epidemiology and End Results Program, NCI contract number HHSN26120130010I, Task Order HHSN26100005.
Potential competing interests: None to report. The findings and conclusions in this article are those of the authors and do not necessarily represent the official positions of the Centers for Disease Control and Prevention.
WHAT IS KNOWN
- ✓ Alaska Native (AN) people have a disproportionally high rate of gastric cancer than the US white (USW) population.
WHAT IS NEW HERE
- ✓ AN people develop gastric cancer at a younger age than the USW population.
- ✓ AN people are more often diagnosed with gastric cancer at a distant stage than the USW population.
- ✓ Although the rates of gastric cancer are decreasing in the USW population, no significant change has been seen in the AN population.
- ✓ Clinicians may consider gastric cancer in AN people at a younger age than the general population.
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