Clonal Transitions and Phenotypic Evolution in Barrett's Esophagus.

BACKGROUND & AIMS: Barrett's esophagus (BE) is a risk factor for esophageal adenocarcinoma but our understanding of how it evolves is poorly understood. We investigated BE gland phenotype distribution, the clonal nature of phenotypic change, and how phenotypic diversity plays a role in progression. METHODS: Using immunohistochemistry and histology, we analyzed the distribution and the diversity of gland phenotype between and within biopsy specimens from patients with nondysplastic BE and those who had progressed to dysplasia or had developed postesophagectomy BE. Clonal relationships were determined by the presence of shared mutations between distinct gland types using laser capture microdissection sequencing of the mitochondrial genome. RESULTS: We identified 5 different gland phenotypes in a cohort of 51 nondysplastic patients where biopsy specimens were taken at the same anatomic site (1.0-2.0 cm superior to the gastroesophageal junction. Here, we observed the same number of glands with 1 and 2 phenotypes, but 3 phenotypes were rare. We showed a common ancestor between parietal cell-containing, mature gastric (oxyntocardiac) and goblet cell-containing, intestinal (specialized) gland phenotypes. Similarly, we have shown a clonal relationship between cardiac-type glands and specialized and mature intestinal glands. Using the Shannon diversity index as a marker of gland diversity, we observed significantly increased phenotypic diversity in patients with BE adjacent to dysplasia and predysplasia compared to nondysplastic BE and postesophagectomy BE, suggesting that diversity develops over time. CONCLUSIONS: We showed that the range of BE phenotypes represents an evolutionary process and that changes in gland diversity may play a role in progression. Furthermore, we showed a common ancestry between gastric and intestinal-type glands in BE.

Chyle Leak Following Radical En Bloc Esophagectomy with Two-Field Nodal Dissection: Predisposing Factors, Management, and Outcomes.

BACKGROUND: Chyle leak is an uncommon complication following esophagectomy, accounting for significant morbidity and mortality; however, the optimal treatment for the chylothorax is still controversial. OBJECTIVE: The aim of this study was to evaluate the incidence, management, and outcomes of chyle leaks within a specialist esophagogastric cancer center. METHODS: Consecutive patients undergoing esophagectomy for esophageal cancers (adenocarcinoma or squamous cell carcinoma) between 1997 and 2017 at the Northern Oesophagogastric Unit were included from a contemporaneously maintained database. Primary outcome was overall survival, while secondary outcomes were overall complications, anastomotic leaks, and pulmonary complications. RESULTS: During the study period, 992 patients underwent esophagectomy for esophageal cancers, and 5% (n = 50) of them developed chyle leaks. There was no significant difference in survival in patients who developed a chyle leak compared with those who did not (median: 40 vs. 45 months; p = 0.60). Patients developing chyle leaks had a significantly longer length of stay in critical care (median: 4 vs. 2 days; p = 0.002), but no difference in total length of hospital stay. CONCLUSION: Chyle leak remains a complication following esophagectomy, with limited understanding on its pathophysiology in postoperative recovery. However, these data indicate chyle leak does not have a long-term impact on patients and does not affect long-term survival.

Columnar Metaplasia in the Esophageal Remnant After Esophagectomy: A Common Occurrence and a Valuable Insight Into the Development of Barrett Esophagus.

OBJECTIVE: This study aimed to establish the incidence of postesophagectomy columnar metaplasia and dysplasia, and the timescale over which it develops. It also aimed to assess if this epithelium is molecularly similar to sporadic Barrett esophagus, thereby confirming suitability as a research model. BACKGROUND: Metaplasia in the esophageal remnant after esophagectomy is well described, but incidence and the potential for dysplasia are uncertain, and the clinical relevance unclear. Although proposed as a model for Barrett esophagus, no large studies have examined the molecular phenotype of postesophagectomy metaplasia. METHODS: Patients underwent prospective endoscopic evaluation having previously undergone esophagectomy. The macroscopic appearance of the esophageal remnant was noted and biopsies taken. Specimens were stained using hematoxylin and eosin and by immunohistochemistry for cytokeratins 7 and 20, and Chromogranin A-proteins which have a well described expression pattern in sporadic Barrett esophagus. RESULTS: Of the 126 eligible patients, 45 (36%) had evidence of metaplasia. There were no cases of dysplasia. Nonintestinalized columnar epithelium occurred earlier than specialized intestinal metaplasia (median 4.8 vs 8.1 yr; P = 0.025). Thirty-seven samples underwent immunohistochemical analysis. A classic cytokeratin 7/20 staining pattern was present in 23 cases (62%), within the prevalence range reported for sporadic Barrett. CONCLUSIONS: Columnar metaplasia is common following esophagectomy, but the absence of dysplasia in this large cohort is reassuring. Presence of specialized intestinal metaplasia is associated with increased time from surgery, suggesting this represents later disease. Immunohistochemistry staining is similar to sporadic Barrett, suggesting that this group of patients represent an accurate human model for the development of Barrett.

Trefoil Factor Expression in a Human Model of the Early Stages of Barrett's Esophagus.

BACKGROUND: Trefoil proteins are believed to have an important role in mucosal protection and repair in the gastrointestinal tract. They are well recognized in Barrett's esophagus and considered a potential biomarker for the condition. Metaplasia occurring in the esophageal remnant after esophagectomy is a human model for the early stages of development of Barrett's esophagus. AIMS: To assess expression of trefoil proteins in post-esophagectomy columnar epithelium and to use trefoils as a molecular tool to understand regenerative mucosa in the esophagus. METHODS: Patients with columnar metaplasia in the esophageal remnant were recruited from a large esophago-gastric cancer center. Trefoil factor expression was determined using immunohistochemical techniques. RESULTS: Samples were obtained from 37 patients. TFF1 and TFF2 were expressed by all samples in a similar pattern to that described in studies of sporadic Barrett's esophagus. TFF3 was less widely expressed and was significantly associated with time elapsed between surgery and endoscopy. Median time from surgery to endoscopy was 8.1 years for patients with TFF3 expression versus 3.4 years for those without (p = 0.004). CONCLUSIONS: Widespread expression of trefoils in this environment suggests that these proteins have an important role in development of Barrett's metaplasia. TFF3 expression may be absent in the early stages of metaplasia and may represent more established columnar epithelium. Biopsy samples from post-esophagectomy patients provide a valuable resource to study the early stages of Barrett's esophagus.

Barrett's adenocarcinoma 52 years after subtotal esophagectomy for pediatric peptic stricture.

Barrett's esophagus results from the long-term effects of both acid and bile reflux. After subtotal esophagectomy and reconstruction with a gastric tube, many patients experience profound reflux. Development of Barrett's epithelium in the esophageal remnant has been reported. Here we report the case of a man who was diagnosed with adenocarcinoma in his esophageal remnant on a background of Barrett's change 52 years after undergoing one of the first esophageal resections for benign disease as a child.