Correlation of ultrastructural aberrations with dysplasia and flow cytometric abnormalities in Barrett's epithelium

Abstract

Barrett's esophagus develops as a complication of chronic gastroesophageal reflux and predisposes patients to the development of dysplasia and adenocarcinoma of the esophagus. Because light microscopy of dysplasia in Barrett's esophagus shows diminished or absent mucus, we used transmission electron microscopy to compare cytoplasmic organelles required for mucus production in dysplastic and nondysplastic esophageal columnar epithelium. These observations of the rough endoplasmic reticulum, Golgi apparatus, and secretory granules were correlated with histologic interpretations and flow cytometric measurements of abnormalities of DNA content. Ultrastructural abnormalities included depletion and alteration of organelles required for mucus biosynthesis. These abnormalities often were accompanied by cells with markedly distended rough endoplasmic reticulum and massive accumulation of cytoplasmic glycogen aggregates. All 9 patients who had Barrett's dysplasia with or without early adenocarcinoma had ultrastructural abnormalities, as did 3 of 8 patients whose biopsy histology was indefinite for dysplasia. Abnormalities measured by flow cytometry correlated well with the presence of these ultrastructural aberrations. All 9 patients with Barrett's dysplasia with or without early adenocarcinoma had abnormalities observed by electron microscopy and aneuploidy or increased G2/tetraploid fractions measured by flow cytometry. Two of the 3 patients whose biopsies were indefinite for dysplasia and who had ultrastructural abnormalities also had aneuploidy or increased G2/tetraploid fractions. Neither ultrastructural nor flow cytometric abnormalities were found in the remaining 5 patients whose biopsies were indefinite for dysplasia, in 19 of 22 patients with Barrett's specialized metaplasia, or in any of the 7 patients with gastroesophageal reflux disease without Barrett's specialized metaplasia. Two of the 22 patients with Barrett's specialized metaplasia had distended rough endoplasmic reticulum in rare cells, and one other had an aneuploid cell population. We conclude that neoplastic progression in Barrett's esophagus is associated with abnormalities of cytoplasmic organelles required for mucus production. With few exceptions, these ultrastructural aberrations correspond to the presence of dysplasia or of aneuploidy or increased G2/tetraploid fractions. Electron microscopy and flow cytometery detect abnormalities associated with the development of dysplasia and cancer in Barrett's esophagus that may be biologically significant.