Nonmodifiable risk factors

Race and ethnicity are nonmodifiable risk factors for gastric cancer. Although environmental factors likely play a role, they alone cannot explain the high incidence of disease in East Asia; particularly because this increased incidence persists in immigrants and their offspring from East Asia to the West. Age is also important, with more than 90% of cases occurring after the age of 45 years. Family history also contributes to risk, with studies from both the West and East showing a first-degree relative with gastric cancer increases a person’s risk 2- to 4-fold. Gender also plays a role, with men having a 2- to 5-fold increased risk of gastric cancer. Higher estrogen levels seem to protect women from the disease. Increased rates of gastric cancer in women on estrogen-blocking therapies (tamoxifen) and after menopause demonstrate this effect. In fact, women seem to develop gastric cancer at a similar rate to men but with a 10 to 15 year lag.

Although gastric cancer is usually sporadic, about 10% of cases seem linked to genetic syndromes. The most common syndrome is hereditary diffuse gastric cancer (HDGC), recently defined by the International Gastric Cancer Linkage Consortium. HDGC is characterized by autosomal dominant inheritance, with about a 60% to 80% increase in the risk of gastric cancer and a 40% to 50% increase in breast cancer. About 40% of HDGC is due to mutations in E-cadherin (CDH1). Mutations in CTNNA1 have also recently been found in a subset of patients with the condition. Other cancer syndromes have been associated with increased risk of gastric cancer, including Lynch syndrome (DNA mismatch repair gene mutation), familial adenomatous polyposis (APC gene mutation), Peutz-Jeghers syndrome (STK11 gene mutation), juvenile-polyposis syndrome (SMAD4 or BMPR1A mutation), hereditary breast and ovarian cancer syndrome (BRCA 1 or BRCA 2 mutation), and Li-Fraumeni syndrome (p53 mutation). However, gastric cancer still remains very uncommon in these syndromes, with rates of occurrence less than 5%.

Modifiable risk factors

The most clear modifiable risk factor for gastric cancer is Helicobacter pylori infection. Although gastric cancer develops in only about 1% of infected humans, more than 90% of those with gastric cancer have been infected with H pylori . Other modifiable risk factors are less influential. Cigarette use seems to increase the risk of both cardia and noncardia cancer. Obesity (body mass index [BMI] >30) seems to increase the risk of noncardia cancer. A high salt diet also seems to increase the risk, whereas diets high in fruit and vegetables seem to be protective.

Serology screening

H pylori serology is the least invasive test for gastric cancer but is limited by a very low sensitivity and an inability to detect premalignant lesions. Furthermore, the test may become negative as gastric atrophy progresses, causing false-negative results in those most at risk for the condition.

Alternatively, pepsinogen testing has been studied as part of mass screening protocols. A precursor to pepsin, pepsinogen comes in subtypes I and II. Subtype I is secreted from the chief stomach cells. Subtype II is secreted from all gastric cells. Reductions in levels of subtype I and in the ratio of subtype I and II suggest increasing gastric atrophy. A subtype I cutoff of less than 70 ng/L and pepsinogen I to II ratio less than 3.0 were 77% sensitive and 73% specific for gastric cancer. A case control study also demonstrated a reduction in odds ratio (OR) of death from gastric cancer at 1 and 2 years in subjects screened with pepsinogen levels. However, the test was not found to be effective enough for it to be adopted into currently implemented mass screening programs.

Gastric imaging

Although a barium upper gastrointestinal series only has a sensitivity of 60% to 80%, 2 case control studies from Japan showed a 40% to 60% decline in gastric cancer mortality. As such, barium imaging remains part of the mass screening programs of both Korea and Japan.

Endoscopy is the gold standard for gastric cancer screening because it has the highest detection rate (sensitivity of 78%–84%) and allows for biopsies to confirm the diagnosis. In areas of high incidence, endoscopy is the mainstay of screening. In countries such as the United States, where gastric cancer is less prevalent and the cost of endoscopy is higher, endoscopic screening is unlikely to be cost-effective.

Studies suggest that narrow-band imaging and digital-based image enhancement technologies, such as computed virtual chromoendoscopy, increase the diagnostic yield and accuracy of gastric neoplasia detection. However, imaging criteria are inconsistent and validation studies have yet to be performed. These techniques cannot be recommended currently.

Clinical risk factors for Barrett esophagus progression

Although GERD is the strongest risk factor, 15% to 45% of BE develops in patients with no symptoms of GERD. Furthermore, although GERD occurs in 15% to 20% of the Western population, only 10% to 15% of those patients have BE. Although BE is clearly a precursor, it only progresses to EAC at a rate of 0.12% to 0.60% per year. As such, other risk factors are looked for to determine who should be screened for BE ( Box 1 ).

Men with BE develop EAC at more than twice the yearly rate of women, 0.28% to 0.13%, respectively. Other clinical factors include increasing age, central obesity, and active smoking; essentially the same as risk factors for developing BE.

Endoscopic risk factors for Barrett esophagus progression

Evidence of esophagitis or anatomic risk factors for worse reflux (ie, hiatal hernia) has been associated with increased progression from BE to EAC. Furthermore, most investigations into BE segment length suggest the increasing area of disease increases the risk for EAC. Finally, mucosal nodularity, ulcers, and strictures noted on endoscopy have been associated with increased risk of EAC. However, these probably indicate present high-grade dysplasia or EAC instead of risk of future development.

Histologic risk factors for Barrett esophagus progression

Rates of progression increase to about 1% per year for patients with BE that includes low-grade dysplasia and about 7% per year for patients with BE that includes high-grade dysplasia. The use of histology, however, is limited. First, biopsies of BE may miss dysplastic areas, leading to sampling error. Second, interpathologist and intrapathologist agreement in rating dysplasia is poor, leading to interpretative error.

Biomarkers are being developed to improve the accuracy of histologic assessment of BE. P53, a tumor suppression gene, is the most promising and immunostaining is currently recommended by the British Society of Gastroenterology guidelines. Reid and colleagues have promoted the use of aneuploidy and tetraploidy, evidence of genetic instability, as a marker of potential tumor progression. Kastelein and colleagues demonstrated that both p53 overexpression (adjusted relative risk 5.6, 95% CI 3.1–10.3) and p53 loss of expression (adjusted relative risk 14.0, 95% CI 5.3–37.2) were associated with an increased risk of developing high-grade dysplasia or EAC. Other complex combinations of tumor markers are in development but require significant testing before they can be clinically used.

Direct visualization

There are obvious benefits to endoscopic screening, such as direct visualization and the ability to take biopsies for histologic analysis. However, there are also significant limitations, such as that the physical process of the technique is unappealing to patients, it requires an endoscopy suite, and the side effects of sedation. Cost is another limitation, directly because of the need for staffing, equipment, and so forth; and indirectly due to the patients’ time off work and decreased productivity.

Capsule endoscopy is a noninvasive way to detect BE. However, the technique has low sensitivity, requires endoscopy to confirm diagnosis and obtain biopsies, and is not cost-effective compared with standard endoscopy. Recently, a tethered capsule endomicroscope, which uses optical frequency domain imaging to provide cross-sectional architectural images of esophageal mucosa, allows identification of BE and dysplasia. Although this is reusable (overcoming some cost-effectiveness issues of capsule endoscopy), its accuracy is unproven and it is unclear patients would find swallowing a tethered pill more appetizing than a sedated endoscopic procedure.

Instead of standard endoscopy, ultrathin transnasal endoscopy (TNE) offers an endoscopy approach that avoids issues with sedation and can be performed outside an endoscopic suite. The procedure does seem to be effective. A meta-analysis of 5 studies (439 subjects) comparing TNE with standard endoscopy in the same subjects showed the pooled sensitivity and specificity of TNE in detecting BE was 91% and 96%, respectively. However, even when a mobile unit brought TNE to patients’ neighborhoods, only 48% were willing to undergo the procedure. Furthermore, the technique has not gained widespread acceptance among physicians.

Tissue sampling

Cytosponge is an abrasive sponge encapsulated in gelatin to form a pill attached to a tether. The patient swallows it, the gelatin capsule dissolves, and the sponge is pulled back up through the esophagus, capturing mucosa for analysis. The cytosponge does have good sensitivity and specificity at 73.3% and 93.8%, respectively, with a BE segment with circumferential length greater than or equal to 1 cm; and 90.0% and 93.5%, respectively, with a BE segment with circumferential length greater than 2 cm. Furthermore, cost-effectiveness analysis demonstrated benefit in men older than 50 years with GERD, with a potential reduction of EAC by 19%. However, patient tolerability still seems to be an issue; only 18% of subjects offered the test were willing to proceed in the initial studies.

Unfortunately, tests with blood, urine, or stool to detect those at risk for EAC have not been developed. A promising noninvasive test, however, involves electronic nose technology, in which a device uses reactable compounds to detect different volatile organic compounds in breath samples. In a study of 85 subjects undergoing surveillance for dysplastic BE (43 with biopsy proven active BE and 42 without), the test had 86% specificity and 90% sensitivity. More encouraging, the test had 98% acceptance rate in recruitment. This technology could represent an acceptable, easily used, cost-effective mechanism to screen large populations for BE or EAC.