Adenocarcinoma develops in Barrett's esophagus by a multistep process in which specialized metaplasia progresses to dysplasia, then to early adenocarcinoma, and eventually to invasive disease (Figure 20-1). A variety of epithelial biomarker studies have been performed in Barrett's esophagus to identify key cellular and molecular markers that may provide valuable data on the risk of disease progression and cancer development. Markers of cancer risk, including changes in DNA content, have been identified, but these abnormalities have yet to be validated in multicenter studies with routine follow-up. Therefore, none of these potential bio-markers have yet been incorporated into routine patient care. Once and if such markers are validated, their use in clinical practice will have the potential to permit stratification of patients by risk and to enable a more individualized and perhaps more selective approach to endoscopic surveillance. Furthermore, an increased understanding of the genetic and cellular mechanisms leading to cancer development might allow earlier diagnosis and provide an opportunity to eliminate high-risk lesions before adenocarcinoma develops.


Detection of dysplasia relies on extensive tissue sampling at endoscopy with random biopsies. Other techniques using cytology brushings of the esophageal mucosa have been tried but have been shown not to be as sensitive or specific as histologic sampling (Wang et al, 1997). Tissue biopsies, however, can be problematic because they have poor predictive values for indefinite and low-grade dysplasia and yield inconsistent results for high-grade dysplasia between different pathologists (Reid et al, 1988; Montgomery et al, 2001). Even with extensive biopsy regimens, it may be impossible to differentiate between high-grade dysplasia and invasive adenocarcinoma (Clark et al, 1996). Therefore, dysplasia alone is not an ideal marker for selecting patients at high risk for adenocarci-noma (Ertan and Younes, 2000). Alternatives need to be found to either supplement the histologic findings or to take the place of biopsies for risk stratification.


Abnormal DNA content as determined by DNA ploidy analysis has been extensively evaluated in single-institution studies in patients with Barrett's esophagus. Aneuploidy is an important chromosomal change that occurs during carcinogenesis and can predict histologic progression (Barrett et al, 1999; Reid et al, 2001). The prevalence of aneuploid cell populations increases with histologic progression from Barrett's metaplasia to low-grade dysplasia to high-grade dysplasia and finally cancer (Haggitt, 1994). Aneuploidy can be detected in more than 90% to 95% of esophageal adenocarcinomas. Furthermore, an aneuploid fraction greater than 6% can be used to distinguish between low-grade and high-grade dysplasia. Flow cytometric abnormalities in endoscopic biopsy specimens can therefore identify patients with a higher risk of progression to high-grade dyspla-sia or adenocarcinoma before histologic evidence of such is detected (Robaszkiewicz et al, 1991). In 322 patients with Barrett's epithelium, the relative risk of cancer development was significantly greater in patients with tetraploid or aneuploid DNA content than in patients without such abnormalities (Reid et al, 2000b). Flow cytometric results have also been combined with histologic determination of dysplasia in an attempt to improve predictive ability by defining low-risk and high-risk patient subsets (Reid et al, 2000b). Within aneuploid populations are subpopulations of cells with p53 mutations, which are more frequently found in highgrade dysplasia and cancer.

Molecular Alterations

Loss of heterozygosity at 17p is a mechanism of p53 inactivation that enables this tumor-suppressor gene to function as an oncogene. A single-

center study (Reid et al, 2001) showed that in patients with Barrett's esophagus, allelic loss at chromosome 17p (site of p53) identified patients at increased risk for progression to adenocarcinoma. In 269 Barrett's patients with 17p loss of heterozygosity, the 3-year cumulative incidence of cancer was 38%, versus 3.3% in patients with two 17p alleles (Reid et al, 2001). Wu et al (1998) determined the prevalence of 17p and 18q chromosomal losses in Barrett's mucosa and in the dysplasia-to-adenocarcinoma sequence. 17p allelic loss occurred in 14% of cases of Barrett's mucosa, 42% of low-grade dysplasias, 79% of high-grade dysplasias, and 75% of adenocarcinomas; allelic loss of 18q was found in 32%, 42%, 73%, and 69%, respectively. Esophageal adenocarcinomas with allelic loss of both 17p and 18q were associated with worse survival than cancers with no or one allelic loss (P = .002) (Wu et al, 1998).

p53 mutations can be detected in dysplastic Barrett's epithelium before invasive cancer develops and are associated with an increased risk for progression to high-grade dysplasia as well as esophageal adenocarcinoma (Reid et al, 2001). While these mutations develop in diploid cell populations, the same p53 mutations are also found in aneuploid cell populations in high-grade dysplasia, in esophageal cancer, and in multiple aneuploid cell populations within cancer (Neshat et al, 1994). These data suggest that p53 may be a predictor of progression in Barrett's epithelium and may be useful for risk assessment (Ortiz-Hidalgo et al, 1998; Reid et al, 2001). Recent studies have shown that p53 protein accumulation, as determined by immunohistochemistry, can be detected in low-grade dysplasia as well as high-grade dysplasia within Barrett's epithelium, although the degree of expression is greatest with high-grade dysplasia (Ertan and Younes, 2000). Frequent overexpression of the p53 protein has also been reported in Barrett's adenocarcinomas (Neshat et al, 1994). While detection of p53 expression is suggestive of mutation, false-positive staining does occur, as shown by comparison with gene sequencing. p53 positivity has the potential to be combined with a panel of other biomarkers for use in risk assessment.

Chromosome p16 allelic loss has been detected in metaplastic Barrett's epithelium, providing cells with the ability to undergo clonal expansion and creating a field defect in which other abnormalities can arise that can lead to esophageal adenocarcinoma (Wong et al, 2001). Other genetic alterations may hold promise in risk-stratifying patients. In this regard, an increase in the frequency of chromosome 7q33-q35 loss between low-grade dysplasia and high-grade dysplasia, as determined by comparative genomic hybridization, suggests that this marker may be useful as a diagnostic tool (Riegman et al, 2002). Of note, microsatellite instability due to defective DNA mismatch repair is rare in Barrett's esophagus and esophageal adenocarcinoma (Wu et al, 1998; Kulke et al, 2001).

Proliferative Activity

Intestinalized epithelium in long-segment Barrett's esophagus shows increased proliferative activity and a statistically significant increase in the mean crypt proliferative index and mean crypt proliferation zone (Gillen et al, 1994; Hong et al, 1995). Intestinalized epithelium in the distal esophagus and gastroesophageal junction shows similar increases in pro-liferative activity, suggesting a similar process with an increased risk of carcinogenesis (Gulizia et al, 1999). Acid exposure increases proliferation and decreases apoptosis, implicating acid exposure in the metaplasia-dysplasia-adenocarcinoma sequence in Barrett's esophagus (Souza et al, 2002).


Recently, expression of the cyclooxygenase-2 (COX-2) enzyme has been detected in Barrett's esophagus and esophageal adenocarcinoma (Wilson et al, 1998; Zimmerman et al, 1999; Shirvani et al, 2000). In one report, the level of COX-2 expression was 3 times higher in Barrett's esophagus than in normal control samples, and after therapy with a selective COX-2 inhibitor, the levels of COX-2 and prostaglandin E2 were significantly decreased (Kaur et al, 2002). The constitutive COX-1 and inducible COX-2 isoforms regulate the synthesis of prostaglandins from arachidonic acid. COX-2 is induced by cytokines, growth factors, and tumor promoters, and studies indicate that COX-2 can protect cells from apoptosis, stimulate angiogenesis, and influence tumor cell invasiveness and metastatic potential (reviewed in Sinicrope et al, 2004). The synthesis of prostaglandins and other mediators of inflammation may be involved in the progression to neoplasia via mucosal injury. COX-2 is a target of nonsteroidal anti-inflammatory drugs (NSAIDs), including selective COX-2 inhibitors, which displayed chemopreventive effects in an animal model of Barrett's esophagus (Buttar et al, 2002b).

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