CORRESPONDENCE

RESPONSE: Re: Clonal Expansion and Loss of Heterozygosity at Chromosomes 9p and 17p in Premalignant Esophageal (Barrett's) Tissue

Brian J. Reid

Correspondence to: Brian J. Reid, M.D., Ph.D., Divisions of Human Biology and Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, WA 98109 (e-mail: bjr{at}fhcrc.org).

We appreciate the comments of Walch et al. concerning the differences between our respective studies. Both groups used objective methods (comparative genomic hybridization [CGH] versus fluorescent loss of heterozygosity analysis) to assess somatic genetic abnormalities in Barrett's esophagus. Both groups provided similar data that progression is associated with nonlinear evolution of neoplastic cell lineages leading to clonal heterogeneity in Barrett's epithelium.

Walch et al. applied "exclusively morphologically linked techniques" to correlate their findings to specific histologic grades. However, routine histologic interpretation of dysplasia in Barrett's esophagus is subjective, and numerous studies have found that the results are not generally reproducible. For example, in our study of observer variation, there was only 48% agreement on all grades of a dysplasia classification system, and another study reported 63% agreement (1,2). Objective, reproducible methods are essential for independent validation of results by other investigators. We and others (3,4) have prospectively validated objective flow cytometric biomarkers that have high interlaboratory reproducibility. Furthermore, flow sorting purifies neoplastic clones that can arise independent of morphologic changes (5). It is unlikely that clonal heterogeneity can be attributed simply to histologic heterogeneity because extensive clonal heterogeneity has been documented independent of histologic findings (5), which is consistent with the observations of Walch et al. that the same histologic grade can have multiple, different chromosomal abnormalities in different patients.

Other reasons exist to re-evaluate assumptions underlying the proposed linear model for disease progression in Barrett's esophagus from metaplasia to low-grade dysplasia to high-grade dysplasia to adenocarcinoma. Clinical studies (3,6) have found that these intermediate events can regress, progress, or remain stable. This variable behavior may be due to diagnostic inconsistency in histologic interpretation, exposures to risk and protective factors, or biological properties of the clones themselves. We have observed some clones that appear to progress slowly or not at all, whereas others progress (5). Walch et al. described copy number changes in lower grade histologic lesions that were not present in higher grade lesions from the same patient, which is not predicted by a linear model. However, DNA copy number changes detected by CGH or other techniques can be caused by a number of mechanisms and, in isolation, may not be stable clonal markers that can be used to follow the evolution of neoplastic cell lineages. Nevertheless, our two respective studies and other studies indicate that genetic instability leads to clonal heterogeneity that can arise early and that clonal evolution drives neoplastic progression (3,5). Thus, rigid adherence to an assumed linear histologic pathway may limit interpretation of results.

Although the surgical literature contains numerous reports of patients found to have cancer in surgical resections after an endoscopic diagnosis of high-grade dysplasia, the weaknesses of this literature have been well described (6,7). None of these studies used the systematic, intensive biopsy protocols repeated at closely timed intervals recommended for the surveillance of high-grade dysplasia, which consistently detect cancers when they are small and early (7). In our study, a mean of 2.7 endoscopies (range, 1–16) and 78.4 histologic biopsy specimens (range, 9–490) were evaluated in the 61 patients without detection of cancer, making it highly unlikely that undetected cancers contributed substantially to our results (7).

REFERENCES

1 Reid BJ, Haggitt RC, Rubin CE, Roth G, Surawicz CM, Van Belle G, et al. Observer variation in the diagnosis of dysplasia in Barrett's esophagus. Hum Pathol 1988;19:166–78.[Medline]

2 van Sandick JW, Baak JP, van Lanschot JJ, Polkowski W, ten Kate FJ, Obertop H, et al. Computerized quantitative pathology for the grading of dysplasia in surveillance biopsies of Barrett's oesophagus. J Pathol 2000;190:177–83.[Medline]

3 Reid BJ, Levine DS, Longton G, Blount PL, Rabinovitch PS. Predictors of progression in Barrett's esophagus: baseline histology and flow cytometry identify low and high risk patient subsets. Am J Gastroenterol 2000;95: 1669–76.[Medline]

4 Bergers E, Montironi R, van Diest PJ, Prete E, Baak JP. Interlaboratory reproducibility of semiautomated cell cycle analysis of flow cytometry DNA-histograms obtained from fresh material of 1,295 breast cancer cases. Hum Pathol 1996;27:553–60.[Medline]

5 Barrett MT, Sanchez CA, Prevo LJ, Wong DJ, Galipeau PC, Paulson TG, et al. Evolution of neoplastic cell lineages in Barrett oesophagus. Nat Genet 1999;22:106–9.[Medline]

6 Wright TA. High-grade dysplasia in Barrett's oesophagus. Br J Surg 1997;84:760–6.[Medline]

7 Levine DS. Management of dysplasia in the columnar-lined esophagus. Gastroenterol Clin North Am 1997;26:613–34.[Medline]



             
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