The continuing tale of cytokeratins in Barrett’s mucosa: As you like it

Barrett’s adenocarcinoma (BA) has seen a rapid increase in incidence throughout the Western world. The diagnosis of BA is often at an advanced stage and is generally associated with a poor prognosis and a mean survival of less than one year. Adenocarcinomas however do not arise de novo but follow an established sequence from Barrett’s metaplasia (BM) through dysplasia to neoplasia. EVorts to intervene in the pathogenesis of oesophageal adenocarcinomas have so far been disappointing. Reduction of gastro-oesophageal reflux disease has led to minimal regression of BM and has yet to be shown to have any impact on cancer prevention. Surveillance programmes for patients with BM have had variable results and have raised important questions about their cost eVectiveness and of better risk stratification of patients with BM. The prevalence of BM in the general population is approximately 1–3%, with only 0.5–1% of patients with BM converting to neoplasia each year. 2 The reliable diagnoses of intestinal metaplasia and dysplasia have also been diYcult to validate in each patient, mostly related to sampling errors due to the variable anatomy of the lower oesophagus and their patchy distribution within a segment of BM. Our understanding of the molecular biology of BM has yielded many phenotypic and genetic changes within the epithelium that are associated with diVerent stages along the metaplasia-dysplasia-neoplasia sequence. It has been suggested that some of these changes, such as cytokeratin subsets, might aid in the diagnosis and management of patients with BM and is the focus of the paper by Couvelard et al in this issue of Gut (See page 761). Cytokeratins are highly conserved polypeptides that heterodimerise and form the building blocks for the intermediate filaments as part of the cell cytoskeleton. Intermediate filaments are anchored to desmosomes in the cell membrane and are of particular interest in epithelial systems in maintaining cell morphology, polarity, and intercellular adhesion. Cytokeratins are expressed in 20 distinct forms in epithelial cells but are absent from mesenchymal tissue where vimentin is used in the assembly of intermediate filaments. There are variable patterns of expression of cytokeratins in epithelial cells depending on the type, location, and differentiation of epithelium. Some cytokeratins have a broad range of expression in columnar epithelium, such as CK8 and CK19, while others such as CK7 and CK20 show highly restricted expression. CK20 is commonly used as a marker of intestinal diVerentiation. It is expressed on the surface and crypt epithelium of the normal colon and small intestine. In the stomach, expression is limited to the surface foveolar epithelium, with no gastric gland or pit staining. CK7 has been proposed as a marker of ductal diVerentiation. It is expressed in ductal breast carcinomas but not in the normal epithelium of the gastrointestinal tract. Cytokeratins are very stable proteins and are conserved in most epithelial cancers, even in the presence of gross phenotypic and genetic alterations. For this reason, detection of cytokeratin subsets such as CK7 and CK20 have become very useful in diagnosing the origins of occult or poorly diVerentiated cancers and are part of current clinical practice. DiVerential patterns of cytokeratin expression have been demonstrated in the oesophagus and proposed as useful clinical markers. A phenotypic map of cytokeratin expression validates our current histopathological categorisation of the gastro-oesophageal junction (fig 1). However, a unique pattern of CK7 and CK20 immunohistochemical