Risk of Barrett’s esophagus progression to esophageal adenocarcinoma
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Esophageal adenocarcinoma (EAC) is increasing in prevalence in the United States due to higher rates of gastroesophageal reflux disease (GERD) and obesity.1 Barrett’s esophagus (BE) is intestinal metaplasia caused by chronic damage to the esophageal lining and is a known precursor for EAC. Given that the five-year survival rate for EAC is approximately 50% with localized diseases, 30% with regional diseases, and 6% with distant diseases, surveillance and risk stratification of those with BE is imperative for early detection of pre-cancerous dysplastic transformation and early initiation of preventative treatment.2
The histologic findings of dysplasia in BE can be defined using the Vienna classification which is as follows: (1) no dysplasia or non-dysplastic BE (NDBE), (2) indeterminate dysplasia (IND) when unable to determine if true dysplasia is present versus inflammatory changes, (3) low-grade adenoma or dysplasia (LGD), (4) high-grade adenoma or dysplasia (HGD), carcinoma in situ, suspicion of invasion, or intramucosal carcinoma, and (5) carcinoma. Risk of progression to EAC varies depending on the classification. A cohort based study of 11,028 patients in Denmark with BE found that progression to EAC was greater in those with LGD compared to those with NDBE with 5.1 cases per 1,000 person-years in LGD as opposed to 1.0 case per 1,000 person-years.3 Other large cohort studies have indicated that the annual cancer risk in those without dysplasia is 0.12% to 0.40% as opposed to 1% in those with LGD and greater than 5% for patients with HGD.4 Regrettably, studies have demonstrated significant inter-observer variability in classifying dysplastic BE, especially LGD and IND. Therefore, all guidelines recommend verification of BE dysplasia classification by a second pathologist with expertise in BE prior to management decisions.
There is clear evidence that endoscopic eradication therapies (EET) in the setting of BE with dysplasia can prevent progression to EAC. These techniques include endoscopic mucosal resection (EMR), endoscopic submucosal dissection, radiofrequency ablation (RFA), and cryoablation.5 Accordingly, 2022 practice guidelines from the American College of Gastroenterology (ACG) and 2024 Clinical Practice Guidelines from the American Gastroenterological Association give a strong recommendation for EET with subsequent surveillance in cases of HGD. EET is recommended conditionally in LGD (with endoscopic surveillance an acceptable alternative in the ACG guidelines) and not at all in NDBE.5,6 However, management of IND remains variable and with a lack of consensus, with some guidelines suggesting management similar to NDBE and others recommending surveillance endoscopy every 6 months until findings conform to NDBE or LGD.1,6-8
The study by Elbe et al.9 in this issue of Clinical Endoscopy provides important data on the management of dysplastic BE. This study both validates the importance of secondary pathology review for patients with dysplastic BE, and provides convincing evidence that patients classified as confirmed IND on double-pathologist review should be managed similarly to those with LGD. In this study, 423 patients initially diagnosed with BE with dysplasia from Ersta Hospital in Sweden between 1998 to 2012 were followed for up to 26 years to monitor the progression of their BE to cancer. All patients had their dysplastic specimens re-evaluated by expert pathologists and their diagnoses were updated per the Vienna classification to indeterminate IND, LGD, HGD, and NDBE. The authors noted that 60% of those with an initial diagnosis of BE dysplasia were downgraded to NDBE upon reclassification, 20% to LGD, and 20% as IND. The overall risk of progression from BE to EAC was 8.1% with an annual incidence of 0.87% total, 0.41% in NDBE, 1.43% in IND, and 1.84% in LGD. The risk of progression to cancer in LGD was four times more than those with NDBE. Notably, there was no significant difference in the risk of progression between LGD and IND. This study is strong in terms of sample size as well as follow-up duration, but limited by the lack of data about extraneous variables such as lifestyle factors, obesity, duration of GERD, medication use or other interventions, and BE segment circumference and length.9
This study adds support to data from a recent meta-analysis that the risk of progression to EAC in IND is similar to LGD, and should be managed as such–which per some guidelines would mean consideration of EET.10 However, a decision of whether to proceed with EET for IND must incorporate consideration of the risks of potential overtreatment versus the risks of potential missed opportunity in prevention of EAC. Adverse events from RFA with or without EMR can be as high as 8.8% including strictures, bleeding, and in rare cases, perforation; yet 5-year survival in EAC with localized disease is only 50%.2,6 Further investigation into the long-term benefits and risks of endoscopic interventions for cases of IND is warranted.
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Conflicts of Interest
Dr. Amy Tyberg has consulted for Boston Scientific, Ambu Inc., and Medtronic. The other author has no potential conflicts of interest.
Funding
None.
Author Contributions
Conceptualization: AT; Resources: LK; Supervision: AT; Writing–original draft: LK; Writing–review & editing: all authors.