The Changing Epidemiology of Gastric Cancer
Douglas Morgan, MD, MPH
Associate Professor, Division of Gastroenterology, Vanderbilt University, Nashville, TN
November is Stomach Cancer Awareness Month. We have chosen to focus several articles on gastric cancer. In this two-part feature, Douglas Morgan, MD, MPH, takes a panoramic look at the changing epidemiology of gastric cancer in the Americas. Pelayo Correa, MD, gives an overview of intestinal metaplasia and its relationship to gastric cancer.
Gastric Cancer in the Americas
In global terms, with nearly one million incident cases annually, gastric cancer is the second leading cause of cancer mortality and the leading cause of infection-associated cancer mortality.1, 2 It is projected to rise from 14th into the top 10 in all-cause mortality in the near term, primarily due to growing and aging populations in the high-incidence areas. Gastric cancer demonstrates marked geographic variability, both regionally and within countries. The high incidence areas include eastern Asia (China, Japan, Korea), western Latin America, and parts of Europe and the Middle East. The gender burden is relatively consistent (2:1, males to females), wherein estrogen may play a protective role.3
H. pylori as a biomarker for the changing western microbiome
Helicobacter pylori (H. pylori) is the most common chronic bacterial infection, colonizing about one half of the world, with important roles as pathogen and human microbiome component.4 The biologic costs from chronic colonization and inflammation include an increased risk for noncardia gastric adenocarcinoma, leading the World Health Organization to classify H. pylori as a class I carcinogen. In contrast, recent observations suggest that as an important part of the human microbiome, H. pylori may be a beneficial commensal early in life. Its absence serves as a biomarker of the dramatic changes in the human microbiome in western societies in the last 50 years. Studies indicate that H. pylori infection is inversely related to the atopic diseases such as childhood asthma, atopic dermatitis and eosinophilic esophagitis. By modulation of immune responses, H. pylori and components of the human microbiome may be beneficial early in life and in transition to pathogen in the adult years.
Racial differences in North America
In the U.S., the overall gastric cancer incidence and mortality rates are modest, but are comparable to those of esophageal cancer. In 2012, 21,320 incident cases (males, 13,020; females, 8,300) and 10,540 deaths related to gastric cancer are expected, compared with esophageal cancer (17,460 new cases, 15,070 deaths), respectively.5 Significantly higher rates are observed among African Americans and Asian Americans (see figure). The overall decline in gastric cancer incidence over the past 50 years parallels the decrease in prevalent H. pylori infection, although large racial differences certainly persist in adults: 28 percent in whites versus 54 percent in African Americans and 63 percent in Mexican Americans.6 Interestingly, a rising incidence of gastric cancer has been observed among young white males in the U.S. over the past several decades.7
H. pylori in Latin America
At national and international scientific meetings in Latin America, there is considerable interest in H. pylori, dyspepsia and gastric cancer, as they reflect the daily patient care reality. H. pylori is highly prevalent in adults in most regions. In a recent large H. pylori eradication trial in the community setting in six countries (Mexico, Honduras, Nicaragua, Costa Rica, Colombia, Chile), the overall prevalence was 79 percent, with a cytotoxin-associated gene A prevalence of 84 percent in the study group.8 Interestingly, chronic dyspepsia, as assessed with the Rome III criteria and questionnaire, is also highly prevalent (26 percent) in the community setting. This is echoed among specialists, as the care of dyspeptic patients is commonplace in Latin America and among Hispanic immigrants in the U.S.
The altitude enigma in Latin America
Gastric cancer has a wide geographic variability within Latin America. In general terms, higher rates are observed in western Latin America along the Pacific coast, contrasting with lower rates in the Caribbean, Amazonia and Atlantic coastal regions. Country-wide standardized annual incidence rates range from 23 to 31 in males. The highest mortality rates are noted in the mountainous regions, which follow the Pacific from Mexico to Chile, and include the Sierra Madre in Mexico, the Cordillera de Centroamérica in Central America and the Andes in South America. This is amply demonstrated in Colombia, where there is a clear correlation between gastric cancer mortality and altitude. Altitude is likely a surrogate for clustering of host genetic risk factors, H. pylori virulent strains, diet and environmental factors.
Gastric cancer is a leading cause of cancer mortality in many regions in the Americas; its burden will increase due to the growing and aging populations. The marked geographic variability offers the opportunity for accelerated scientific discovery and focused prevention programs.
Dr. Morgan is a member of ACG’s international committee.
1. Ferlay J, et al. Estimates of worldwide burden of cancer in 2008: Globocan 2008. Int J Cancer 2010; 127(12): 2893.
2. de Martel C, et al. Global burden of cancers attributable to infections in 2008: a review and synthetic analysis. Lancet Oncol 2012; 13(6):607.
3. Camargo M, et al. Sex hormones, hormonal interventions and gastric cancer risk: A Meta-Analysis. Cancer Epidemiol Biomarkers Prev 2012; 21(1): 20.
4. Cho I, et al. The human microbiome: at the interface of health and disease. Nat Rev Genet 2012; 13(4): 260.
5. Siegal R, et al. Cancer Statistics 2012. CA Cancer J Clin 2012; 62:10.
6. McQuilan GM, et al. Racial and ethnic differences in the seroprevalence of 6 infectious diseases in the U.S.: Data from NHANES III, 1988-1994. Am J Public Health. 2004; 94:1952.
7. Anderson WF, et al. Age-specific trends in incidence of noncardia gastric cancer in US adults. JAMA 2010; 303(17):1723.
8. Greenberg ER, et al. A randomised trial of empiric 14-day triple, five-day concomitant, and ten-day sequential therapies for Helicobacter pylori in seven Latin American sites. Lancet. 2011 Aug 6; 378(9790):507.
Gastric Intestinal Metaplasia and Risk Stratification
Pelayo Correa, MD
Professor of Medicine; Anne Potter Wilson Chair in Medicine; Professor of Pathology, Microbiology and Immunology, Vanderbilt University School of Medicine, Nashville, TN
Gastric cancer incidence in the Americas is characterized by marked contrasts. In the Andean region, it is directly proportional to the altitude above sea level: the so-called altitude enigma. The disease carries a very poor prognosis, with five-year survival rates below 20 percent, mostly driven by late diagnosis because the disease is asymptomatic in the early phases. Early diagnosis campaigns in Japan result in five-year survival rates above 90 percent. The clinical disease is preceded by a series of well-characterized changes in the gastric mucosa: the so-called precancerous cascade consisting of subsequent lesions of atrophy (gland loss), intestinal metaplasia (first “complete” and later “incomplete”) and dysplasia. These changes take place over several decades, providing an ample window of opportunity for prevention. Given the contrasting incidence rates, prevention strategies should focus on populations at high cancer risk. Intestinal metaplasia represents the best marker of cancer risk. It is frequently mentioned by pathologists in their reports on gastric biopsies. An algorithm for the management of patients with intestinal metaplasia has been proposed, calling for endoscopic surveillance of patients in whom the metaplasia is extensive and/or of the incomplete type.1-3
In general, the prevalence of precancerous lesions and their risk of progression to gastric adenocarcinoma correlate with the background incidence of gastric cancer in the population. This applies both to racial and ethnic groups, as well as specific geographic regions. The rate of progression is modest in affluent western countries, but may be elevated in higher incidence regions. In a study conducted with the large histo-pathology registry in the Netherlands from 1991 to 2004, the rates of progression to adenocarcinoma over a five-year period were 0.1 percent, 0.25 percent, 0.6 percent and 6 percent, respectively for chronic atrophic gastritis, intestinal metaplasia, low-grade dysplasia and high-grade dysplasia. Notably, in the Colombia cohorts followed by Correa, et al., the dynamic flow of progression and regression between these precancerous lesions is observed. In addition, the challenges of gastric mucosal sampling are highlighted.4
In the higher risk patient, gastric biopsies for topographic mapping to rule out precancerous and advanced lesions are indicated. This may further delineate cancer risk and the need for surveillance. In practical terms, the optimal approach is two to four biopsies from the corpus, incisura and antrum, with greater and lesser curve sampling of the antrum and corpus. Irregular areas of the mucosa should also be biopsied to rule out dysplasia, early gastric cancer or other pathology. Higher risk extensive intestinal metaplasia is defined by the presence of intestinal metaplasia in at least two areas of the stomach (antrum, incisura, corpus), whereas limited intestinal metaplasia is confined to one site.5
The specific histo-pathologic subtypes of intestinal metaplasia may also help define risk and the need for surveillance. Complete intestinal metaplasia is defined by the presence of small intestinal type mucosa with goblet cells, a brush border and eosinophilic enterocytes. In patients with complete intestinal metaplasia limited to one biopsy site, the risk for progression is modest. Incomplete intestinal metaplasia is defined by the presence of epithelium with multiple mucus vacuoles and absence of a brush border with higher cancer risk.4
In summary, with respect to the histo-pathologic diagnosis, extensive intestinal metaplasia based upon gastric biopsy mapping and/or incomplete intestinal metaplasia with the presence of colonic epithelium may warrant endoscopic surveillance with gastric mapping. The interval may range from two to three years depending upon the severity of the lesions. New guidelines support this approach, in parallel with prospective studies. In addition, Helicobacter pylori eradication is indicated in general.1
Lastly, we comment that the evolution of novel imaging technologies for detection of precancerous lesions and neoplasia detection may aid in early detection. Examples include chromoendoscopy, narrow-band imaging and autofluorescence imaging. These technologies are now being used throughout the gastrointestinal tract, primarily being driven by programs in Japan for the detection of early gastric cancer. Similarly, the need for better approaches to the treatment of early gastric cancer has led to the development of advanced endoscopic resection techniques, such as endoscopic mucosal resection and endoscopic submucosal dissection, also now in common use beyond the stomach. The use of advanced imaging modalities is limited to specialized centers in Latin America to date.
1. Correa P, Piazuelo MB, Wilson KT. Pathology of gastric intestinal metaplasia: clinical implications. Am J Gastroenterol 2010 Mar;105(3):493.
2. Dinis-Ribeiro M, et al. Management of precancerous conditions and lesions in the stomach (MAPS). Endoscopy 2012; 44:74.
3. de Vries AC, Haringsma J, de Vries RA, Ter Borg F, van Grieken NCT, Meijer GA, van Dekken H, Kuipers EJ. Biopsy strategies for endoscopic surveillance of pre-malignant gastric lesions. Helicobacter 2010 Aug;15(4):259.
4. Mera R, et al. Long term follow up of patients treated for Helicobacter pylori infection. Gut 2005 Nov; 54(11):1536.
5. Whiting JL, Sigurdsson A, Rowlands DC, Hallissey MT, Fielding JWL. The long term results of endoscopic surveillance of premalignant gastric lesions. Gut 2002 Mar;50(3):378.