The Columnar Lined Esophagus: aspects on the assessment of dysplasia and on the relationship with the esophageal submucosal glands

Abstract: Columnar metaplasia, where columnar epithelium replaces the normal squamous epithelium in esophagus, is considered to be a precancerous condition in which the development of adenocarcinoma can be followed through various grades of dysplasia. The interpretation of these histological changes is subjective and suffers from considerable inter-observer variation among pathologists. In study I, we devised and tested two clinically applicable methods for immunohistochemical assessment of p53 and Ki67 as surrogate dysplasia markers. Using these methods, the inter-observer agreement improved substantially from mean k value 0.24 for H&E evaluation to 0.71 and 0.52 for p53 and Ki67 evaluations, respectively. There was a correlation between severity of dysplasia, p53 over-expression and shift of the proliferation zone towards the mucosal surface. We conclude that our methods are reproducible and associated with less inter-observer variation than morphologic dysplasia grading, and that p53 and Ki67 are useful supplementary prognostic markers. The origin of columnar metaplasia in esophagus is debated. The submucosal glands have been proposed as a stem cell source, but studies of the human esophageal glands are rare. In studies II – IV, we conducted comparative and descriptive analyses of the distribution and morphology of the submucosal glands in patients with columnar metaplasia in esophagus. We have shown that there is an accumulation of submucosal glands beneath the transformation-zones between squamous and columnar mucosa, and that the submucosal glands in the columnar lined part of esophagus are hyperplastic. There are overlapping immunophenotypes between the submucosal gland unit, the columnar metaplasia and the transformation-zones for the markers CK17, CK4 and lysozyme. We propose that the submucosal glands are the esophageal counterparts of skin adnexa as a source of re-epithelialization, and conclude that in esophagus both neosquamous islands and columnar metaplasia originate in the submucosal gland unit.