Primary Motility  Disorders of the  Esophagus
 The Esophageal
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 Barrett's
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OESO©2015
 
Volume: Barrett's Esophagus
Chapter: Short Barrett's esophagus
 

Should long and short segment Barrett's esophagus be differentiated by the length of intestinal metaplasia rather than of glandular mucosa?

P. Chandrasoma (Los Angeles)

The presently accepted definition of Barrett's esophagus is that it is a change in the esophageal epithelium of any length that can be recognized at endoscopy and is confirmed to have intestinal metaplasia (IM) by biopsy [1]. This definition has evolved over time. Barrett's esophagus was originally defined by the presence of any columnar lining in the lower esophagus exceeding 3 cm. In 1976, Paull et al. [2], classified Barrett's esophagus into three histologic types: junctional (= cardiac), fundic (= oxynto-cardiac) and specialized (= intestinal). When evidence emerged that adenocarcinoma developed only in the intestinal type of Barrett's esophagus [3], the definition changed to require IM as a criterion.

Until recently, the definition of Barrett's esophagus that was universally accepted required IM in an endoscopically visualized length of columnar epithelium exceeding 3 cm. This entity, which is called long segment Barrett's esophagus (LSBE) is the only one that is universally accepted to be associated with adenocarcinoma and therefore requiring surveillance. Recently, it has become recognized that short segment Barrett's esophagus (SSBE), which is defined as IM occurring in columnar epithelium < 3 cm in length, can also be complicated by dysplasia and adenocarcinoma. However, the risk of adenocarcinoma in this group is not universally accepted and there is no agreement regarding surveillance in this group [1].

It is likely that the definitions of Barrett's esophagus will evolve further with the new information regarding histologic normalcy [4, 5]. Assimilation of new suggestions that cardiac mucosa is an abnormal reflux-induced epithelium that is a precursor of Barrett's esophagus and that the gastroesophageal junction (GEJ) is best defined by the proximal limit of oxyntic mucosa may lead to new concepts. In particular, the occurrence of cardiac mucosa and IM in the proximal stomach ("intestinal metaplasia of the gastric cardia") need re-evaluation in terms of these new findings.

In evaluating the evolution of the definition of Barrett's esophagus, we appear to be very appropriately changing the definition to better characterize the risk of adenocarcinoma. However, these very logical efforts do not appear to be successful in curbing the increasing incidence of reflux-induced adenocarcinoma, which has become the most rapidly increasing cancer type in the United States [6].

Mutational gastroesophageal reflux disease

The mutational sequence in gastroesophageal reflux disease (GERD) is unusual in that it does not affect the native epithelium of the esophagus. There is no increased incidence of squamous carcinoma. The mutational sequence begins only after there has been a transformation of the squamous epithelium to cardiac mucosa. This transformation most likely represents a reversible genetic switch rather than an irreversible mutation. The switch results in an alteration of the direction of differentiation of the pluripotential foregut epithelial cell from squamous to glandular, resulting in a conversion from squamous to cardiac mucosa. This conversion is related to acid exposure and can result from relatively low levels of acid exposure. The length of squamous epithelium that transforms into cardiac mucosa is directly proportional to the severity of acid exposure [7].

When transformation into cardiac mucosa has occurred, the stage is set for mutational GERD. Mutagens in gastric refluxate act on the cells in cardiac mucosa to cause increased proliferative activity and produce genetic alterations that ultimately result in adenocarcinoma. It is very likely that multiple genetic hits are necessary. The exact mutagenic sequence involved in this carcinogenesis is not yet characterized. The mutagenic agents involved are likely to be independent of acid in the refluxate based on the evidence that the incidence of adenocarcinoma has not decreased with increasing effectiveness of acid suppression therapy over the past two decades.

The risk of developing IM in cardiac mucosa is directly proportional to the amount of cardiac mucosa present [7]. When the length of cardiac mucosa exceeds 3 cm, IM is almost invariably present. IM first occurs at the junction between cardiac mucosa and the squamous epithelium and then progresses caudad to involve increasing amounts of cardiac mucosa within the abnormal columnar epithelial segment. Even when extensive IM is present, there is usually cardiac mucosa and oxynto-cardiac mucosa in the distal esophagus adjacent to gastric oxyntic mucosa.

The best way of evaluating the mutagenic process is by identifying the exact genetic alterations that are involved. As molecular biology advances, there is an expectation that this will become a reality. However, at present we can only recognize morphologic changes in the reflux-adenoarcinoma sequence, which are: transformation of squamous epithelium to cardiac mucosa, IM of cardiac mucosa, low-grade dysplasia, high-grade dysplasia, and adenocarcinoma. This sequence recognizes that IM is at a further stage of carcinogenesis than cardiac mucosa. It would therefore be logical to believe that the risk of carcinoma is directly proportional to the amount of IM that is present in the esophagus, rather than the amount of all abnormal glandular mucosa which includes cardiac mucosa and oxyntocardiac mucosa.

When there is an abnormal reflux-induced glandular mucosa between the gastric oxyntic mucosa and squamous epithelium, a grading system can be developed based on the types and extent of mucosal types present that will stratify patients according to their risk of adenocarcinoma (Table I). The grading system recognizes the elements of increasing risk -increasing amounts of cardiac mucosa, increasing amounts of intestinal metaplasia, and increasing dysplasia. Though exact risk levels are not known for each grade, recognition of the level of risk can help plan prevention protocols.

Table I. Grading system for reflux disease based on the risk of adenocarcinoma.

This grading system is based on systematic measured four-quadrant biopsies taken at 1-2 cm intervals from the proximal limit of the rugal folds to the squamocolumnar junction. When there is no endoscopic abnormality (i.e. the proximal limit of the rugal folds are at the squamocolumnar junction), biopsies should attempt to capture the mucosal junction by both retrograde and antegrade biopsies of the squamocolumnar junction.

It has been our experience that antireflux surgery reverses the reflux-adenocarcinoma sequence in the following ways: a) decreases inflammation and proliferative activity in cardiac mucosa, decreasing risk of mutation, b) converts cardiac mucosa to oxynto-cardiac mucosa, c) reverses short segments of IM, and d) promotes squamous overgrowth and thereby decreases exposure of glandular epithelium to mutagen exposure. This suggests that antireflux surgery maybe prophylactic against carcinogenesis if used in patients at the lower grades of risk.

Approximately 56-65% of the general population will not have cardiac mucosa in biopsies and will be Grade 0, which we call "compensated reflux". These patients need no treatment aimed at preventing carcinoma, and can be confidently managed by acid suppression to control symptoms. The number of patients in the lower grades who will have a lower risk will be larger than the numbers in the higher grades. This would explain why reflux-induced adenocarcinoma occurs as frequently in patients with short segments of IM as those with long segments.

References

1. Sampliner RE, The Practice Parameters Committee of the American College of Gastroenterology. Practice guidelines on the diagnosis, surveillance and therapy of Barrett's esophagus. Am J Gastroenterol 1998;93:1028-1032.

2. Paull A, Trier JS, Dalton MD, Camp RC, Loeb P, Goyal RK. The histologic spectrum of Barrett's esophagus. N Engl J Med 1976;295:476-480.

3. Haggitt RC, Tryzelaar J, Ellis FH, Colcher H. Adenocarcinoma complicating columnar epithelium lined (Barrett's) esophagus. Am J Clin Pathol 1978;70:1-5.

4. Chandrasoma PT, Der R, Ma Y, Dalton P, Taira M. Histology of the gastroesophageal junction; an autopsy study. Am J Surg Pathol 2000;24:402-409.

5. Kilgore SP, Ormsby AH, Gramlich TL, Rice TW, Richter JE, Falk GW, Goldblum JR. The gastric cardia: fact or fiction? Am J Gastroenterol 2000;95:921-924.

6. Blot WJ, Devesa SS, Kneller RW, Fraumeni JF. Rising incidence of adenocarcinoma of the esophagus and gastric cardia. JAMA 1991;265:1287-1289.

7. Chandrasoma PT, Lokuhetty DM, DeMeester TR, Bremner CG, Peters JH, Oberg S, Groshen S. Definition of histopathologic changes in gastroesophageal reflux disease. Am J Surg Pathol 2000;24:344-351.


Publication date: August 2003 OESO©2015