Re: clonal expansion and loss of heterozygosity at chromosomes 9p and 17p in premalignant esophageal (Barrett's) tissue.

The Journal recently published an article by Galipeau et al. (1) about loss of heterozygosity (LOH) at chromosomes 9p and 17p and clonal heterogeneity in Barrett’s esophagus. The article described a high prevalence of LOH at 9p and 17p in endoscopic biopsy specimens and found that LOH at 9p was more common than LOH at 17p in diploid samples. The biopsy samples contained a mosaic of patterns of LOH and ploidy, indicating that a high degree of clonal heterogeneity exists in Barrett’s esophagus. One important issue was not addressed by the article by Galipeau et al., however, because the samples that were investigated were not clearly histopathologically classified. Dysplasia often arises in the intestinal metaplasia of Barrett’s esophagus as multiple foci. Moreover, when high-grade dysplasia is present, it is often mixed with areas of low-grade dysplasia and intestinal metaplasia without dysplasia. However, these precursor lesions are not endoscopically distinguishable within the segment of Barrett’s esophagus. In addition, one cannot exclude the possibility that several patients may have already developed a microinvasive carcinoma, since it is found in 45%– 75% of resection specimens of patients undergoing esophagectomy for highgrade dysplasia (2–4). Since histopathologic evaluation was not performed on every sample actually investigated by Galipeau et al. (1), the endoscopic specimens could presumably have presented the whole spectrum of the metaplasia– dysplasia–adenocarcinoma sequence. Thus, the clonal heterogeneity observed as a mosaic of clones and subclones with different patterns of LOH is not surprising, and it is possibly a reflection of the inclusion of several types of lesions, including intestinal metaplasia, lowand high-grade dysplasia, or even carcinoma. We recently published a study dealing with genetic alterations in Barrett’s esophagus (5). Applying exclusively morphologically linked techniques, such as microdissection and comparative genomic hybridization or in situ hybridization, we were able to correlate molecular genetic findings to specific steps of the metaplasia–dysplasia–adenocarcinoma sequence in Barrett’s esophagus. Of interest, we found genetic loss at chromosome 9p to be more prevalent than DNA loss at 17p in premalignant Barrett’s esophagus, and both become steadily more frequent along the metaplasia– dysplasia–adenocarcinoma sequence (5). Moreover, a high degree of heterogeneity of c-erbB2 gene amplification and overexpression was clearly evident in high-grade dysplasia and adenocarcinoma by fluorescence in situ hybridization and immunohistochemistry (5–7). Since the histopathology of the specific steps of the metaplasia–dysplasia– adenocarcinoma sequence has a fundamental impact on our understanding of the development of Barrett’s adenocarcinoma, the scientific value of molecular genetic data is especially high when it is obtained as a result of the direct correlation between molecular genetic and histopathologic findings in the same biopsy specimen. Thus, although the flow cytometric method used by Galipeau et al. (1) has its advantages and the findings of the study are potentially important, an accurate histopathologic evaluation of each sample analyzed would greatly add to the value of the findings in terms of the understanding of the molecular biology of the metaplasia– dysplasia–adenocarcinoma sequence in Barrett’s esophagus.