Primary Motility  Disorders of the  Esophagus
 The Esophageal
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Volume: Barrett's Esophagus
Chapter: Diagnosis

What is the value of Villin expression and heterogeneity of enterocytic differentiation in Barrett's esophagus?

G. Triadafilopoulos (Stanford)

Villin is a cytoskeletal actin-binding protein (Mr 95 kDa) that is universally expressed in small intestinal microvilli and serves as an early marker of intestinal differentiation [1]. Combined electron microscopic and immunoblotting studies have shown that Villin expression correlates well with appearance of microvilli in intestinal cells (Figure 1, left panel). Therefore, Villin could serve as a useful marker of intestinal differentiation in the premalignant Barrett's mucosa, characterized by specialized intestinal metaplasia (IM).

Villin as a marker of differentiation in Barrett's esophagus

In a study of 23 Barrett's esophagus patients, Villin expression was noted in the Barrett's biopsies in all but 7 patients. Densitometric analysis of the Villin bands from these patients showed variable Villin expression when compared with expression in the duodenum of the same patients. Villin expression ranged from 0 to 67% of duodenal expression (Figure 2). Ultrastructural studies revealed that Villin expression correlates very well with formation of microvilli on the surface of the metaplastic epithelium (Figure 1, middle and right panels). Detailed mapping studies evaluating Villin expression in different areas of the Barrett's epithelial surface have revealed focal molecular heterogeneity (Figure 3). Two possible scenarios can be envisioned that could account for Villin expression in Barrett's esophagus. First, a phenotype that more resembles colonic rather than small intestinal

Figure 1. Ultrastructural evaluation of Barrett's epithelium. Electron microscopy of Villin-positive (middle panel) and Villin-negative (right panel) Barrett's esophagus is compared with normal duodenum (left panel) from the same patient (from [1]).

Figure 2. Relative Villin expression in Barrett's esophagus. Villin expression was evaluated by immuno-blotting of detergent lysate of duodenal and Barrett's esophagus biopsies in 23 consecutive patients with Barrett's esophagus. Villin expression is given as a percent compared with expression in the normal duodenum for each patient (from [1]).

Figure 3. Mapping study of a patient with Barrett's intestinal metaplasia. Four quadrant biopsies from the entire length of Barrett's esophagus were evaluated by histology and immuno-blotting. Villin expression was subjectively graded as 0 (not detectable), +1 (detectable but less than 30% of duodenal expression) or +2 (30% or more of duodenal expression). Although the entire length of Barrett's esophagus segment showed intestinal metaplasia, Villin expression was highly variable (0 to +2) and focally heterogeneous (from [1]).

differentiation may be possible in Barrett's esophagus, and/or, second, Villin expression occurs in cells that are more differentiated. The latter scenario appears to be more likely, since Villin expression exhibits a dynamic response to acid exposure. In the ex vivo organ culture model of Barrett's esophagus, prolonged acid exposure (24 hours) enhances Villin expression, an effect that is correlated with ultra-structural maturation of the Barrett's esophagus brush border [2].


Barrett's esophagus could be viewed as representing a spectrum of differentiated cells. Assuming maturity of Villin-expressing highly differentiated cells, it is possible that such cells are less likely to progress to dysplasia and adenocarcinoma. However, unless a direct prospective evaluation of Villin expression in Barrett's esophagus as it progresses to dysplasia and cancer is performed, the significance of Villin expression in Barrett's esophagus remains to be determined.


1. Kumble S, Fajardo L, Omary MB, Triadafilopoulos G. Multifocal heterogeneity in Villin and Ep-CAM expression in Barrett's esophagus. Int J Cancer 1996;66:48-54.

2. Fitzgerald RC, Omary MB, Triadafilopoulos G. Dynamic effects of acid on Barrett's esophagus: an ex vivo proliferation and differentiation model. J Clin Invest 1996;98:2120-2128.

Publication date: August 2003 OESO©2015