Prevalence and incidence of Barrett’s esophagus

BE primarily affects older adults in the developed world. The prevalence in living adults is difficult to ascertain, because individuals with Barrett’s are often asymptomatic and do not seek care. One of the earliest estimates of the prevalence of BE was via an autopsy study. Cameron and colleagues estimated a prevalence of long-segment BE (LSBE) of 376 cases per 100,000, or roughly 0.4% of the population, and suggested that only a small minority of cases were detected clinically. Population-based studies have provided estimates of the prevalence of BE in the general public. A Swedish study by Ronkainen and colleagues estimated the prevalence of BE by performing upper endoscopy on 1000 randomly selected adults. These investigators found BE in 16 (1.6%) of the individuals, with 5 subjects (0.5%) in their study showing long-segment disease.

Tertiary care center endoscopy studies have also attempted to estimate the prevalence of BE. Rex and colleagues performed upper endoscopy in 961 individuals presenting for routine screening colonoscopy. These investigators found an overall prevalence of BE of 6.8%, or 65 of 961 individuals, of whom 12 (1.2%) had LSBE. In patients who reported heartburn, the prevalence was slightly higher at 8.3%, but most of the patients (54%) who were found to have BE reported no reflux symptoms. These estimates may be higher than the prevalence in the general population, because this tertiary center population of volunteers may have had more GERD than a random sample of the adult population. Zagari and colleagues analyzed 1033 patients originally identified as part of a large multicenter cross-sectional study on gallstone disease. Of these patients, 1.3% (13) had histologically confirmed BE, whereas 0.2% (2) had LSBE. These estimates suggest that the prevalence of BE is between 0.5% and 2% of unselected individuals. In individuals with reflux symptoms, prevalence estimates are more variable ( Table 1 ), ranging from 5% to 15%.

Given that the use of endoscopy depends on the patient’s socioeconomic status, access to care, and other nonmedical factors, the incidence of BE has historically been difficult to ascertain. However, the incidence of endoscopically detected BE seems to have increased dramatically over the past 30 years, a finding that is partially attributable to the increasing frequency of endoscopy during the same period. However, data from the United Kingdom and the Netherlands suggest that incidence rates of BE have increased even after controlling for increasing endoscopy rates. These estimates place the increase in BE incidence at near 65% between 1997 and 2002 and 159% between 1993 and 2005. Alarmingly, the greatest proportional increase in BE diagnosis was in individuals less than 60 years of age, which is in agreement with other work from Europe.

Age, sex, and ethnic variations in Barrett’s esophagus

Men, especially white men, have a strong predilection for the development of BE, with a male/female ratio of 2:1 to 3:1 in most studies ( Table 2 ). Age at diagnosis can vary widely, because many individuals are asymptomatic and undergo diagnostic endoscopy for other reasons. BE on average is diagnosed in the sixth to seventh decade of life, but may develop earlier. In addition to the greater overall prevalence of BE in men, there is evidence that men develop the disease earlier than women. From a British endoscopy center, Van Blankenstein and colleagues reviewed endoscopy records and histology reports of individuals who received upper endoscopy at a single center. Men on average developed BE about 20 years earlier than women in that study. The overall ratio of BE cases was 2:1 favoring men, but in younger adults the ratio of men to women approached 4:1. A similar trend to early development of BE in men was seen in follow-up studies from Europe. White people in general are disproportionately affected compared with other races. In a large cross-sectional study, Ford and colleagues, in a sample from the United Kingdom, found that white people had significantly higher prevalence of BE compared with Asians or Afro-Caribbean people. In that population, LSBE was found in 2.9% of white people, compared with 0.31% of Asians and 0.2% of Afro-Caribbean people.

Studies assessing BE prevalence in Latin Americans also show that BE is considerably less prevalent in Latin Americans compared with white people. In a large study by Abrams and colleagues, the prevalence of BE was significantly lower among those of Latin American background than among white people (1.7% vs 6.1%). Other studies have corroborated variations in BE prevalence among ethnic groups living in the same country, possibly suggesting an effect of as-yet unrecognized polygenetic factors across different ethnicities.

Multiple environmental factors are strongly associated with BE. These factors, such as obesity, GERD, and hiatal hernias, are more common in developed countries. However, genetic factors are likely also at play. Work from twin studies suggests that symptoms of GERD, even when adjusted for obesity and other clinical factors, are more concordant in monozygotic twins than in dizygotic twins.

Selected risk factors for Barrett’s esophagus development

Cigarette smoking

Most studies have found an association between cigarette smoking and an increased risk of developing BE. A pooled analysis of 5 case-control studies found a consistent increase in risk of BE over several pack-year cut points, with ORs ranging from 1.44 to 1.99 ( Fig. 1 ). However, there was significant heterogeneity between studies, and exclusion of a single study yielded pooled ORs with a higher magnitude across all exposure groups, ranging from 1.75 to 2.89, with an average OR of 2.09. To explore a possible synergistic effect between GERD and tobacco use in the genesis of BE, these investigators conducted additional modeling to assess the concurrent effects of smoking and GERD. The OR of Barrett’s increased significantly when both GERD and smoking were present, compared with when smokers did not have GERD.

Forrest plots summarizing the association between smoking and the risk of BE, using population controls. Smoking exposure is grouped by categories. Large unfilled diamonds represent the pooled estimates across all studies within that category. The width of the diamonds represents the 95% CIs. Black squares indicate the point estimate for each individual study. FINBAR, Factors Influencing the Barrett’s/Adenocarcinoma Relationship; KPNC, Kaiser Permanente Northern California; UNC, University of North Carolina.

( Adapted from Cook MB, Shaheen NJ, Anderson LA, et al. Cigarette smoking increases risk of Barrett’s esophagus: an analysis of the Barrett’s and Esophageal Adenocarcinoma Consortium. Gastroenterology 2012;142:749; with permission.)

However, not all studies have identified smoking as a risk factor for BE. Thrift and colleagues studied 258 patients with BE in a case-control study from Houston, Texas. These patients were compared with 2 control groups: one group was composed of patients receiving elective esophagogastroduodenoscopy for any indication, and the other was composed of primary care patients undergoing screening colonoscopy. These researchers found no association between smoking and BE in either group, even when stratified by pack-year exposures, length of time smoking, or number of cigarettes per day. In a prospective study design, Steevens and colleagues found ORs of 1.33 in former smokers and 0.93 in current smokers compared with controls. In conclusion, smoking seems to increase risk of BE, but there is wide variability in risk estimates. Further study may clarify the precise role of tobacco in BE pathogenesis.

Prevalence and incidence of esophageal adenocarcinoma

EAC was once a rare form of esophageal malignancy. Surgical series in the early twentieth century showed that EAC made up only 0.8% to 3.7% of all esophageal malignancies. However, by 1990, EAC overtook squamous cell carcinoma of the esophagus, and is now the more common of the two in developed nations. EAC continues to increase in incidence ( Figs. 2 and 3 ). In 2014, there are expected to be 18,170 new esophageal cancers diagnosed in the United States. About 15,000 individuals will die from esophageal cancer in 2014, and more than half of these will be from EAC.

Incidence and incidence-based mortality from EAC, 1975 to 2009. Produced from SEER 9 data.

( From Hur C, Miller M, Kong CY, et al. Trends in esophageal adenocarcinoma incidence and mortality. Cancer 2013;119(6):1152; with permission.)

Incidence and incidence-based mortality by stage, for ( A ) local, ( B ) regional, and ( C ) distant spread of disease. Produced from SEER 9 data.

( From Hur C, Miller M, Kong CY, et al. Trends in esophageal adenocarcinoma incidence and mortality. Cancer 2013;119(6):1154; with permission.)

Age, sex, and ethnic variations

Esophageal cancer in general affects men in a 4:1 ratio compared with women. With EAC, incidence is highest in white men, with a male/female ratio in white people that approaches 8:1 (See Table 3 ). The reported incidence of EAC has risen dramatically over the past 30 to 40 years. By some estimates the incidence has increased from 300% to 500% over this time, or by a 10% annual increase in men, and between 5% and 7% annually in women. In the United States from 1975 to 2006, the incidence of EAC increased 7-fold, an increase greater than that of any other major malignancy. Among women, rates of EAC increased from 0.17 per 100,000 in 1975 to 1979 to 0.74 per 100,000 from 2000 to 2004. With EAC similar increases have been seen in the Latin American population of the United States Fewer analyses have been done on African American men or women, often because of significantly lower numbers of reported cases of disease, yielding unstable estimates of risk. In the last quarter of the twentieth century, men more than 65 years of age saw the greatest increase in incidence of EAC (about 600%). Similar increases have been seen in European and some Asian populations as well. More recent data suggest that, when separated by stage of disease at diagnosis, incidences of localized EAC have slowed, whereas distant and regional cases have continued a rapid increase (see Fig. 3 ).

Multiple studies assessing Surveillance, Epidemiology, and End Results (SEER) data have suggested a ratio of EAC cases in white people to African Americans of approximately 5:1. These results parallel data on the prevalence of both erosive esophagitis and BE in white people versus African Americans, in which rates are significantly higher in white people. The increased incidence in EAC among white people is counterintuitive, in that African Americans, white people, and Asians report a similar prevalence of heartburn. Similarly, across multiple races, women in general often have fewer complications of GERD, whereas men are more likely to have erosive disease, BE, or EAC.

The greatest gender disparity in EAC cases is seen in white people, with an 8:1 ratio. In African Americans, a 3:1 ratio is seen, and, in Latin Americans, there is a 7:1 predominance of men compared with women. Other work has placed male/female ratios for Latin Americans even higher than those of white people in some age groups.

Recent research suggests that age-related incidence rates show similar patterns in different ethnic groups, and that older individuals are disproportionately affected. Nordenstedt and colleagues, in an analysis of SEER data, showed that incidence of EAC peaks in the 70-year-old and older category in white people, African Americans, and Latin Americans. The reasons for the great gender disparity in EAC incidence are not known. A greater proportion of abdominal fat, or possibly unknown influences of estrogen or testosterone on disease activity and severity, are possible explanations.

In the immediate future, the incidence of EAC is expected to continue its increase. Kong and colleagues conducted an analysis of 3 models assessing projections of EAC incidence, progression, and mortality. According to recent predictions, the incidence of EAC is expected to increase until at least 2030 in men. At that point, the estimates place the incidence of EAC at 8.4 to 10.1 per 100,000 person-years.

Selected risk factors for esophageal adenocarcinoma

Obesity

Obesity is a risk factor for development of EAC, and some authorities have suggested that obesity is the central driver of BE and EAC rates in the developed world. However, the initial increase in EAC incidence predated the obesity epidemic, and thus obesity does not fully explain observed EAC incidence trends. The risk of EAC in patients in the highest categories of BMI has consistently been shown to be 3-fold to 7-fold higher than in those with normal body weight. This relationship has been reliably shown in other population-based studies as well, and, remarkably, occurs whether or not reflux is present. Other studies have suggested a linear risk increase with increasing BMI ( Fig. 4 ). A pooled analysis of 10 case-control studies assessed the relationship between BMI and EAC. Compared with the referent group (BMI<25), increasing BMI was associated with increased risk at cut points of 30 to 34.9 (OR, 2.39), 35.0 to 39.9 (OR, 2.79), and greater than 40.0 (OR, 4.76). Prospective studies have shown similar trends. In a prospective cohort study design, Abnet and colleagues compared individuals with BMIs of 18.5 to 25 (normal body weight) with those with obesity (BMI >30.0) and found that the risk of EAC was increased by more than a factor of 2 (hazard ratio [HR], 2.1). The risk of EAC increased further in those with BMIs greater than 35 (HR, 2.64).

Restricted cubic regression splines depicting the relationship between BMI and adenocarcinomas of the esophagus and esophageal junction.

( From Hoyo C, Cook MB, Kamangar F, et al. Body mass index in relation to esophageal and oesophagogastric junction adenocarcinomas: a pooled analysis from the international BEACON consortium. Int J Epidemiol 2012;41:1706–18; with permission.)

As in BE, the obesity risk in EAC may lie primarily in patients with truncal obesity. In a prospective cohort study, Steffen and colleagues found a rate ratio (RR) for EAC of 2.6 compared with those in the highest quartile of waist circumference versus those in the lower quartile. This finding has been corroborated in other recent studies.

Dysplasia in Barrett’s esophagus

Dysplasia in BE is a histologic diagnosis suggesting that epithelial cells have acquired genetic or epigenetic alterations that predispose them to the development of malignancy. When identified in a patient with BE, dysplasia predicts a higher risk of EAC, but several issues have limited its utility. For example, sampling error during surveillance endoscopy is an obstacle that has hindered the effectiveness of dysplasia as an accurate marker of cancer risk. Because dysplasia is not readily distinguished endoscopically from typical BE, an area of dysplastic epithelium can easily be missed. Thus, even with extensive sampling, by the time histology shows dysplasia, cancer may be present. Surgical series have shown that cancer was often present at referral for esophagectomy when the referral was for endoscopically diagnosed high-grade dysplasia (HGD). Because of sampling error, guidelines recommend use of the Seattle biopsy protocol, an aggressive biopsy technique that seeks to minimize sampling error and improve reliability of cancer and dysplasia detection. Studies have shown that strict adherence to the Seattle protocol improves detection of HGD and cancer. After implementing the strict guidelines, a hospital system in the United Kingdom improved detection of HGD or cancer by more than 4-fold. Despite the benefits of aggressive biopsy protocol, in practice adherence is suboptimal. In a 2009 study by Abrams and colleagues of a national pathology database, these biopsy guidelines were followed in slightly more than half (51.2%) of more than 2200 BE surveillance cases. Furthermore, nonadherence was associated with a significant reduction in dysplasia detection (summary OR, 0.53).

Another issue is the rate of progression. Rates of EAC development in low-grade dysplasia (LGD) were once thought to be as high as 7% to 8% or more per year, or higher. More recent estimates place the annual risk of progression in BE with LGD closer to 0.5% to 3%, with some newer estimates even lower. However, these estimates are heterogeneous ( Table 4 ). Numerous issues confound the accurate interpretation of the presence and severity of dysplasia in BE. Even among experienced pathologists, the extent of interobserver agreement when diagnosing LGD can be less than 50%. Other work has shown difficulty in reproducing the diagnosis of BE, in part because inflammation can cause cytologic atypia in the bases of crypts that mimics dysplasia. Regression of LGD, or the failure to detect dysplastic changes on subsequent endoscopies, also occurs in half or more of patients with LGD. Because of uncertainties regarding LGD-associated cancer risk, there remains debate over the optimal management strategy in these patients. Incidence of EAC or HGD is estimated at 1.1% to 6% annually but some estimates are as high as 13.4% per year. With HGD, interobserver agreement is better but is still less than 90%. Given the high cumulative incidence of progression from HGD to EAC, current guidelines recommend endoscopic intervention for such patients.

Factors that increase risk for dysplasia progression

The strongest predictor of progression to HGD or EAC is baseline LGD. Sikkema and colleagues followed 713 patients with BE with or without LGD for a mean of 4 years, and found that the strongest predictor of incident EAC was the presence of LGD (with OR, 9.6). In longitudinal studies, progression rates are significantly higher in those with LGD, but estimates of increased risk vary widely (see Table 2 ). Most studies following both patients with nondysplastic BE (NDBE) and patients with LGD have found increased risk in the 4-fold to 9-fold range if LGD is present but estimates have ranged from 2-fold to 27-fold increases in progression rates.

When patients’ slides are reviewed by an expert panel of pathologists, the risk of cancer progression increases because of many patients with LGD being downstaged to NDBE. Curvers and colleagues found an annual progression rate of 9.4% in those with LGD confirmed by expert review, compared with an annual risk of 0.53% in those who were downstaged to NDBE after review. This finding was corroborated by Duits and colleagues in 2014. These investigators found that approximately 75% of patients deemed to have LGD by community pathologists were subsequently downgraded to nondysplastic reads by expert pathologists. Among the quarter of patients who had their LGD readings confirmed, progression rates were extremely high: 9.1% of these patients progressed to either HGD or EAC on an annual basis.

Duration of BE is also a risk factor for disease progression. Sikkema and colleagues found that the cumulative incidence of HGD or EAC was 9.6% over 4 years in patients with BE duration greater than 10 years. In those with BE duration less than 10 years, the cumulative incidence was 3.1%. Incidence was 13.3% in those with esophagitis compared with 3.0% in those without.

Among patients with HGD, the risk of cancer is substantially higher. Reid and colleagues reported a cancer risk of 59% over 5 years (or 11.8% annually) in patients with HGD at index endoscopy, compared with 1.5% annual cancer risk in patients with LGD. A meta-analysis published in 2008 yielded a crude incidence rate of 5.6% across 4 studies, with point estimates of annual incidence rates ranging from 2.3% per year to 10.3% per year. Endoscopic therapy is highly effective for the eradication of BE and associated dysplasia, and is now considered the preferred management strategy for patients with HGD.

In summary, LGD represents a marker of increased risk of progression to cancer in patients with BE. However, the magnitude of risk increase is unclear, because reported progression rates to EAC in LGD have been widely variable. This variability is caused in part by the poor reproducibility of this diagnosis. Patients with HGD are at very high risk of progression to cancer, prompting recommendations for therapeutic intervention when it is found. More robust data on progression risk may help better tailor surveillance strategies to each patient in the future.

Barrett’s esophagus segment length

Other risk factors have been identified that increase the risk of developing EAC in the setting of BE. Several studies have found that the risk of EAC is greater in longer segments of BE compared with shorter segments. A study by Weston and colleagues found that the risk increased by a factor of 6 in longer segments. Sikkema and colleagues, in a prospective study design, found that for every additional centimeter of BE the cumulative risk of HGD or EAC increased by 11% over 4 years. The relationship between segment length and increased risk of EAC is not always linear, but the preponderance of evidence suggests that greater surface area of columnar-lined mucosa correlates with increased cancer risk.

Extent of dysplasia

Studies have attempted to determine whether greater extent of dysplasia within a Barrett’s segment confers increased risk of neoplastic progression. Studies have had conflicting results as to whether or not more extensive LGD or HGD increases the risk of subsequent EAC. A study by Srivastava and colleagues suggested that, when looking at crypts showing dysplasia (as a criteria for LGD diagnosis), increased fractions of dysplastic crypts correlated with increased EAC risk. Buttar and colleagues also found a 4-fold higher risk of cancer progression in patients with extensive HGD compared with those with unifocal HGD. However, this result could not be duplicated in a follow-up study. Intuitively, it seems that the presence of greater numbers of dysplastic crypts would confer an increased risk of future cancer. However, in part because of sampling error limitations of endoscopic surveillance, the utility of focal versus multifocal dysplasia as a risk stratification tool is unclear.

Molecular/biological markers for progression from Barrett’s esophagus to dysplasia/cancer

Numerous studies have attempted to assess the utility of molecular biomarkers to predict progression and assist with risk stratification. If low-risk patients can be accurately identified, then little or no follow-up may be warranted. Alternatively, chemopreventive or endoscopic interventions could be targeted to high-risk patients. However, to date none of the candidate biomarkers has been prospectively validated.

P53 may have the most promise of any of the biomarkers for predicting neoplastic progression in patients with Barrett’s. Kastelein and colleagues studied the effect of aberrant p53 expression in a nested case-control study and found striking results. P53 overexpression assessed by immunohistochemistry was associated with significantly increased risk of progression to either HGD or EAC (RR, 5.6; 95% CI, 3.1, 10.3). Among patients with loss of p53 expression, the risk of progression was even higher (RR, 14.0; 95% CI, 5.3, 37.2). LGD alone was far less predictive of progression (RR, 2.4; 95% CI, 0.9, 6.0), and the positive predictive value of progression was 15% with LGD alone compared with 33% in patients with both LGD and aberrant p53 expression. P53 has been found to increase the risk of progression in other studies as well. In a prospective cohort study, Reid and colleagues found that loss of heterozygosity of the chromosome harboring p53 was associated with a 7-fold increase in progression risk.

In a prospective study design, Reid and colleagues analyzed abnormalities in genetic content by flow cytometry and found that, among patients with HGD, incidence of esophageal cancer varied from 58% over 3 years in patients with baseline cytologic abnormalities, to 7.7% in those without baseline cytometric changes. In such lower risk patients, a less invasive management strategy might be warranted. Bird-Lieberman and colleagues performed a retrospective, nested case-control study from a large cohort of patients in Northern Ireland. In that study, LGD, abnormal DNA ploidy, and Aspergillus oryzae lectin (AOL) were all risk factors for progression. Expert LGD contributed significantly, but AOL (OR, 3.7) and ploidy (OR, 2.8) were also independent predictors of advancement to EAC.

Another retrospective study found that, among 322 patients with BE, aneuploidy and/or tetraploidy, when assessed by flow cytometry, was associated with an RR of 11.7 for neoplastic progression to cancer.

Fluorescence in situ hybridization (FISH) is a method by which a tissue sample can be tested for a panel of genetic abnormalities. A prospective study by Davelaar and colleagues tested a protocol comparing p53 staining by immunohistochemistry and FISH on brush cytology specimens. They found that p53 abnormalities detected by immunohistochemistry (OR, 17; 95% CI, 3.2, 96) and FISH (OR, 7.3; 95% CI, 1.3, 41) were both independent predictors of progression. In addition, when both p53 and FISH were used, detection of LGD, HGD, and EAC was 100% accurate, both p53 and FISH improved the risk stratification capability of p53 alone, and because flow cytometry requires frozen sections of tissue (something rarely done in clinical practice) the potential for clinical use of FISH may be greater.

Despite the significant advances in biomarker development, significant barriers remain. Of all the biomarkers currently identified, the greatest potential for clinical application may lie with assays using p53. P53 can easily be tested, and in multiple studies has been documented to improve the reproducibility of the diagnosis of dysplasia and to predict neoplastic progression. Because of the imperfect nature of dysplasia alone as a predictor of neoplastic progressions, work on molecular biomarkers continues at a rapid pace. However, to date, no biomarkers are approved for diagnosis or risk stratification, and the most recent guidelines from the American Gastroenterological Association recommend against use of molecular biomarkers for risk stratification. Recent British Society of Gastroenterology guidelines propose that p53 immunostaining should be considered, in addition to routine clinical diagnosis, for BE diagnosis. However, pathology societies have yet to develop guidelines for the interpretation and reporting of p53 staining by immunohistochemistry in BE.