Neosquamous Epithelium Does Not Typically Arise from Barrett's Epithelium

Abstract

Purpose: Neosquamous epithelium (NSE) can arise within Barrett's esophagus as a consequence of medical or surgical acid reduction therapy, as well as after endoscopic ablation. Morphologic studies have suggested that NSE can develop from adjacent squamous epithelium, submucosal gland ducts, or multipotent progenitor cell(s) that can give rise to either squamous or Barrett's epithelium, depending on the luminal environment. The cells responsible for Barrett's epithelium self-renewal are frequently mutated during neoplastic progression. If NSE arises from the same cells that self-renew the Barrett's epithelium, the two tissues should be clonally related and share genetic alterations; if NSE does not originate in the self-renewing Barrett's, NSE and Barrett's esophagus should be genetically independent. Experimental Design: We isolated islands of NSE and the surrounding Barrett's epithelium from 20 patients by microdissection and evaluated each tissue for genetic alterations in exon 2 of CDKN2A or exons 5 to 9 of the TP53 gene. Nine patients had p16 mutations and 11 had TP53 mutations within the Barrett's epithelium. Results: In 1of 20 patients, a focus of NSE had a 146 bp deletion in p16 identical to that found in surrounding Barrett's epithelium. The NSE in the remaining 19 patients was wild-type for p16 or TP53. Conclusion: Our mutational data support the hypothesis that, in most circumstances, NSE originates in cells different from those responsible for self-renewal of Barrett's epithelium. However, in one case, NSE and Barrett's epithelium seem to have arisen from a progenitor cell that was capable of differentiating into either intestinal metaplasia or NSE.The stratified squamous epithelium that normally lines the esophagus is established in the 4th month of embryonic development (1) and usually persists until death. In some individuals, the squamous epithelium is replaced by a specialized intestinal metaplasia in response to chronic gastroesophageal reflux disease, a condition termed Barrett's esophagus (2). Patients with Barrett's esophagus are at a 30-to 40-fold increased risk for the development of esophageal adenocarcinoma, a cancer that has increased rapidly in incidence over the past 30 years (3). The mechanisms of conversion from squamous to intestinal epithelium are not known, but it has been hypothesized that the mucus-producing Barrett's specialized intestinal epithelium provides greater protection against the erosive effects of reflux than squamous epithelium (4).Treatment for Barrett's esophagus consists primarily of surgical and medical interventions to control gastroesophageal reflux. Proton pump inhibitors, used in the United States since the late 1980s, bind irreversibly to the H + /K + ATPase and prevent the production of acid by gastric parietal cells (5, 6). Proton pump inhibitors have become the treatment of choice for reflux and are remarkably effective, capable of reducing acid output by >95% (7). The development of effective acid suppression therapies has led to the observatio...

How Good Is the Neosquamous Epithelium?

“…This it does in the short term by covering the wound with an epithelial barrier that is known to lack the malignant potential of its predecessor [11,16,24,25]. However, in the near and long term, this barrier must be durable in its capacity to protect the esophagus against injury, especially from exposure to noxious contents in gastroesophageal refluxates.…”

“…Ablation of BE combined with acid suppression by proton pump inhibitor therapy has been shown to achieve complete reepithelialization of the wounded areas with neosquamous epithelium (NSE) [11,13,14,15,16]. The more recent availability of radiofrequency ablation has led to a resurgence of interest and enthusiasm for the ablative approach because of its reported efficacy, safety, and ease of performance [17,18,19].…”

Effects of Nissen fundoplication on endoscopic endoluminal radiofrequency ablation of Barrett’s esophagus

“…This new, less invasive therapeutic option is replacing the traditional esophagectomy for treatment of BE with high-grade dysplasia. The neosquamous epithelium that is generated after ablation of BE has been found to be free of oncogenic properties [12]. A recent study demonstrated that total eradication of BE was present in 98% of patients at 2.5 years of follow-up [13].…”

Cyclooxygenase-2 expression in esophageal epithelium before and after photodynamic therapy for Barrett’s esophagus with high-grade dysplasia or intramucosal carcinoma

“…Additional data suggest that both p53 mutation and Ki-67 overexpression are present in columnar epithelium [22] and even in squamous Bars depict median COX-2 immunostain scores in Barrett's HGD/IMC prior to PDT, nondysplastic Barrett's prior to PDT, and neosquamous epithelium following PDT islands following incomplete ablation of BE via argon plasma coagulation or multipolar electrocoagulation [23]. It has also been reported that a focus of neosquamous epithelium had p16 alterations identical to that found in surrounding Barrett's epithelium [24].…”