To evaluate annual incidence of low grade dysplasia (LGD) progression to high grade dysplasia (HGD) and/or esophageal adenocarcinoma (EAC) when diagnosis was made by two or more expert pathologists.

Studies evaluating the progression of LGD to HGD or EAC were included. The diagnosis of LGD must be made by consensus of two or more expert gastrointestinal pathologists. Articles were searched in Medline, Pubmed, and Embase. Pooled proportions were calculated using fixed and random effects model. Heterogeneity among studies was assessed using the I² statistic.

Initial search identified 721 reference articles, of which 53 were selected and reviewed. Twelve studies (n = 971) that met the inclusion criteria were included in this analysis. Among the total original LGD diagnoses in the included studies, only 37.49% reached the consensus LGD diagnosis after review by two or more expert pathologists. Total follow up period was 1532 patient-years. In the pooled consensus LGD patients, the annual incidence rate (AIR) of progression to HGD and or EAC was 10.35% (95%CI: 7.56-13.13) and progression to EAC was 5.18% (95%CI: 3.43-6.92). Among the patients down staged from original LGD diagnosis to No-dysplasia Barrett’s esophagus, the AIR of progression to HGD and EAC was 0.65% (95%CI: 0.49-0.80). Among the patients down staged to Indefinite for dysplasia, the AIR of progression to HGD and EAC was 1.42% (95%CI: 1.19-1.65). In patients with consensus HGD diagnosis, the AIR of progression to EAC was 28.63% (95%CI: 13.98-43.27).

When LGD is diagnosed by consensus agreement of two or more expert pathologists, its progression towards malignancy seems to be at least three times the current estimates, however it could be up to 20 times the current estimates. Biopsies of all Barrett’s esophagus patients with LGD should be reviewed by two expert gastroenterology pathologists. Follow-up strict surveillance programs should be in place for these patients.

Barrett’s esophagus (BE), first described in 1950, is a condition in which the normal esophageal squamous epithelium is replaced by columnar epithelium in a process known as metaplasia[1]. The development of esophageal adenocarcinoma (EAC) occurs when BE progresses through dysplasia. Dysplasia in BE is classified as either low grade dysplasia (LGD) or high grade dysplasia (HGD). The populations at risk for developing BE include individuals with chronic gastroesophageal reflux disease (GERD), obesity, male gender, have a smoking history, and are Caucasian[2-4].

The epidemiology of BE varies greatly owing to advancements in knowledge, diagnostic approach, and surveillance strategies. BE is prevalent in 10%-20% of patients with GERD, 2%-7% of general population, and incidence is between 23.1 and 32.7 per 100000[5-11]. The risk of progression to malignancy has been found to be lower in Barret’s esophagus without dysplasia[12-14]. Indefinite for dysplasia (IDBE), indicating no clear evidence of dysplasia, poses an additional diagnostic challenge. Increasing dysplasia levels were associated with increased detection of malignancy in a greater number of patients in shorter time intervals[8].

Further epidemiological analysis has been performed in BE patients assessing the incidence of progression from LGD to HGD and/or progression to EAC. The rate of progression is also variable and has been reported to be between 0.5% to 4% per year[10,11]. This wide range of progression incidence is primarily attributed to inter-observer variability in the assessment amongst the reading pathologists. Although LGD has been clearly defined by its histological features, there is a substantial subjective component involved in making the diagnosis. Recent studies indicate the progression of LGD is grossly underestimated. This may be attributed to the expertise of the reading pathologist, in addition to the number of pathologists assessing the biopsies. Given the concern for the risk of progression, accurate assessment of dysplasia is vital for appropriate risk stratification and surveillance strategies. Large statistical analyses have been conducted on the progression of LGD diagnosed by single pathologists. However, there is no statistical analyses in the form of meta-analysis evaluating LGD progression diagnosed by two or more expert pathologists.

The recognition of BE and prevention of progression to esophageal adenocarcinoma is quickly becoming a national public health concern. EAC incidence has more than quadrupled over the last few decades, and is alarmingly becoming a leader for cancer mortality. The aim of this systematic review and meta-analysis was to evaluate annual incidence of LGD progression (to HGD and/or EAC) when the diagnosis was made by two or more expert pathologists. Primary outcomes are to evaluate the annual incidence rate (AIR) of HGD and EAC in patients with LGD, diagnosed by consensus agreement of two or more expert gastroenterology pathologists. Secondary outcomes are to evaluate the AIR of HGD and EAC in patients down staged to No dysplasia in Barrett’s esophagus (NDBE) and Indefinite for dysplasia in Barrett’s esophagus (IDBE) from the original LGD diagnosis. AIR of EAC from HGD was also evaluated. A sub-group meta-analysis was performed on prospective studies only, evaluating the same variables.

There is a wide variation in the incidence of adenocarcinoma stemming from Barrett’s esophagus in the current literature. Existing endoscopic surveillance studies show anywhere from 1 in 52 to 1 in 441 patient-years of surveillance. The lack of large prospective studies makes it difficult to determine the efficacy and cost-effectiveness of widespread surveillance programs, and thus there is a large discrepancy between surveillance programs[38-41]. Basu et al[32] conducted a retrospective analysis of the Barrett’s epithelium surveillance database to assess the utility of a surveillance program and to determine the natural incidence of dysplasia in this population. The overall prevalence of LGD in the 5-year period was 7.2%, with an annual incidence of 1.4%. None of these patients progressed to HGD. This study disagreed with the previous study by van Sandick et al[42], who concluded an increased progression to HGD from the initial low grade population. The disagreement may be due to study limitations including small sample size and short duration of follow up in the study by Basu et al[32]. Overall, this study concluded that annual endoscopic surveillance showed little reward, but there are variations among regions[43] and surveillance intervals should also be based on the cancer incidence of that specific region.

Another factor affecting surveillance intervals and the true rate of progression to adenocarcinoma is interobserver variability in grading dysplasia. Outcomes in a study by Montgomery et al[33], support that IDBE and LGD should have identical surveillance and follow up as they had similar frequencies of development of adenocarcinoma, but IDBE was slower to progress than LGD by at least 42 mo. Increasing dysplasia was also associated with increased frequency of ulcers found on exam. The study found that approximately 1 of 50 patients with Barrett’s esophagus without dysplasia progressed to HGD at approximately 6 years. Conversely, those with any grade of dysplasia or evidence of ulceration should be followed up in shorter intervals. They further concluded that criteria for the diagnosis of dysplasia are reliable. Patients with Barrett’s esophagus without dysplasia may be followed with endoscopy and biopsies every few years while those with IDBE, any grade of dysplasia, or evidence of ulceration require shorter follow up intervals.

Dysplasia is diagnosed when epithelial atypia also involves the surface epithelium[44]. In cases where the surface epithelium is denuded, uninvolved, or unable to be evaluated, the grading is changed to indeterminate dysplasia or indefinite for dysplasia (IDBE)[45]. Younes et al[35] demonstrated with statistical significance that patients with an initial biopsy diagnosis of either IDBE-Multifocal, LGD, or LGD-Multifocal were more likely to progress to HGD than those with an initial diagnosis of NDBE or IDBE. Unfortunately, there exists a large breadth of interobserver variability, especially in IDBE, where there are no clear guidelines for diagnosis.

Interobsever variability may result in under-diagnosis, such as in the study by Montgomery et al[33] or in over-diagnosis as demonstrated in the study by Curvers et al[36]. In Curvers et al[36] over 75% of cases with previously diagnosed low grade dysplasia were downgraded to NDBE, which were shown to have an incidence rate of 0.49% per patient year. This is in contrast to the study by Montgomery et al[33] in which pathologists rated IDBE despite marked atypia to avoid over-diagnosis. Also, a true diagnosis of low grade dysplasia, which is defined here as one diagnosed by an expert panel of pathologists, carries a 13.4% incidence of progression per patient year. Though low grade dysplasia may be over-diagnosed, those cases which are confirmed by a consensus diagnosis with a panel of expert pathologists should not be underestimated and warrant close follow-up.

Duits et al[28] conducted a large, retrospective cohort which studied the incidence rates of HGD and EAC in patients diagnosed with LGD by an expert panel of pathologists. Seventy-three percent of the initial community cohort of patients were downgraded to a diagnosis of IDBE or NDBD. When the diagnosis of low grade dysplasia was confirmed by an expert panel, the risk of progression to HGD or EAC was 9.1% annually and had a five-year cumulative progression risk of 33.3%, which was much higher than expected. This study again highlights the initial over-diagnosis of low grade dysplasia. Unfortunately, this leads to an underestimation of the risk to malignant progression in cases of low grade dysplasia which have been confirmed by an expert panel.

Skacel et al[34] further evaluated the degree of interobserver variability in the histological diagnosis of LGD and impact on reported risk of progression to HGD or EAC. Biopsy specimens were reviewed individually by three GI pathologists, blind to the previous diagnosis, and found the individual GI pathologists’ diagnosis did not correlate with disease progression. When at least 2 of the pathologists agreed on the histological diagnosis, there was a statistically significant progression (7 out of 17, P = 0.04) When all 3 pathologists agreed, 4 out of the 5 patients progressed (P = 0.012). Of the 8 patients where there was no agreement between pathologists, 0 of these patients progressed

A study by Weston et al[46] showed 5 out of 62 patients initially diagnosed with LGD progressed, but it is unclear if the initial diagnosis was confirmed by an expert panel[46]. In a study by Reid et al[47], it was noted that a consensus diagnosis of low grade dysplasia suggests an increased risk of progression to high grade dysplasia as compared to identifications where pathologists disagree on the diagnosis.

There has been little evaluation of the extent of LGD as a risk factor for the development of EAC, and studies on HGD as a risk factor were conflicting. Previous studies evaluated the extent of HGD as a risk factor for developing adenocarcinoma in Barrett’s esophagus, but they did not evaluate LGD[48,49]. Srivastava et al[37] conducted a study assessing the total numbers of both LGD and HGD crypts, the extent of dysplasia, and total dysplasia correlated with EAC development. In those who progressed to EAC, the number of dysplastic crypts per patient (115.2) including HGD and LGD, were significantly higher than in nonprogressors (56.2, P = 0.01). When the crypts were stratified by dysplasia grade, the patients who developed EAC had a marginally greater mean number of LGD crypts (93.9) as compared with patients that did not progress (41.2, P = 0.07). Per patient, the mean proportion of LGD crypts were also found to be greater in progressors (46.4% vs 26%, P = 0.037), but more significantly than the mean number of crypts. Interestingly, neither the mean number (P = 0.14) nor the mean proportion (P = 0.20) of HGD crypts per patient was significantly associated with development of EAC. The study concluded that the extent of LGD is a significant risk factor for developing esophageal adenocarcinoma, while the extent of HGD was not found to be an independent risk factor. However, the presence of HGD is associated with a greater relative risk for developing adenocarcinoma.

A registry of patients with Barrett’s esophagus has been found to be beneficial with respect to patient management as well as for identifying populations at greater risk in need of alternate surveillance intervals. The utility of a registry is further increased where surveillance is not cost-effective for all[50]. Esophageal adenocarcinoma has increased drastically in Europe, and is predicted to increase even higher in the near future[51-53]. Picardo et al[27] established a Barrett’s registry in 2008 consisting of 1093 patients from the Republic of Ireland. Of the 73 patients with a diagnosis of LGD with endoscopic follow up beyond 1 year, 46 (65%) had histological regression, 8 progressed to HGD, and 6 to EAC. This study showed that the absolute risk of EAC was higher than reported in whole population studies. Incidence was higher in this study as compared to a Danish population study and another study conducted from the Northern Ireland Barrett’s Register[12,54].

The strengths of this meta-analysis include the high quality methodology of statistical analysis, high quality methodology used in individual studies, relatively greater number of studies that met the inclusion criteria, and large total number of patients included in this analysis (n = 971). This is the first meta-analysis to pool the evidence for AIR of malignancy in confirmed LGD patients.

The limitations of this study include: There was a significant level of heterogeneity among studies included in this analysis. Random effects model was used to calculate pooled effects for most of the variables when the heterogeneity was high. We also performed a pooled subgroup analysis after excluding the outliers, with the intention of reducing the heterogeneity. We were unable to perform financial impact analysis due to the lack of data from the individual studies. The local expertise of pathologists/expert pathologists/gastrointestinal pathologists plays a key role in the outcomes. The variability of their expertise is one of the most significant reasons for heterogeneity among studies. A few other important reasons for heterogeneity among studies could be exclusion of prevalent cases of malignancies, and design of individual studies. There were retrospective studies included in this meta-analysis. In order to mitigate this issue, we have performed a sub-group analysis on prospective studies only. Due to the paucity of data available from individual studies, we were not able to analyze the relation between the length of Barrett’s, extent of dysplasia and progression to malignancy

Since the incidence of esophageal adenocarcinoma is rising, it is vital to focus on all possible preventive measures to halt or slow the progression from BE to EAC. Based on the results of this analysis, the incidence of malignancy in confirmed LGD patients is much higher than the current estimates. For these reasons, it is of paramount importance to confirm the diagnosis of patients labelled as LGD. Once a diagnosis of LGD has been confirmed, these patients would benefit from closer follow-up and surveillance. In patients with LGD, most gastroenterology societies recommend surveillance endoscopy with biopsies every 12 mo. However, with more recent evidence suggesting the true rate of transformation is higher, there may be a role for more frequent endoscopic surveillance or sooner procedural intervention. These questions should be answered with further large prospective trials.

Studies with statistically significant positive results tend to be published and cited. Additionally, smaller studies may show larger treatment effects compared to larger studies. This publication and selection bias may affect the summary estimates. The bias can be estimated using Egger bias indicators and the construction of funnel plots, whose shape can be affected by bias. In the present meta-analysis and systematic review, bias calculations both Egger[23] and Begg-Mazumdar[24] bias indicators showed no statistically significant bias. Furthermore, analysis using funnel plots showed no significant publication bias among the studies included in the present analysis.

Overall, when LGD is diagnosed by consensus agreement of two or more expert pathologists, its progression towards malignancy appears to be at least three times the current estimates, and may be up to 20 times the current estimates. Biopsies of all Barrett’s esophagus patients with LGD should be reviewed by two expert gastroenterology pathologists. Follow-up strict surveillance programs should be in place for these patients. Large prospective studies are required to evaluate if confirmed LGD patients should have follow up surveillance more frequently than every year.