Risk of Extraesophageal Malignancy in Patients with Adenocarcinoma Arising in Barrett's Esophagus

Objectives : It has been suggested that the presence of Barrett's mucosa is a marker for potential malignancy in other organs. Our objective was to study subjects with adenocarcinoma of the esophagus arising in Barrett's epithelium. Methods : We reviewed the medical records of patients with esophageal adenocarcinoma, with esophageal squamous cell carcinoma, and with no esophageal pathology and recorded the occurrence of extrae-sophageal malignancies and the heavy use of tobacco and alcohol. Results : The prevalence of extraesophageal malignancies was not higher in patients with esophageal adenocarcinoma (15%) than in patients in either control group (14% each). Patients with either type of cancer of the esophagus had higher rates of tobacco and alcohol use than normal controls (tobacco: p = 0.02 and/7 < 0.01 for adenocarcinoma and squamous cell carcinoma, respectively, vs. normal controls; alcohol:/; < 0.01 for each esophageal malignancy vs . normal controls). The rate of tobacco and alcohol use was higher in patients with esophageal squamous cell carcinoma than in those with adenocarcinoma, but only the difference in alcohol consumption was statistically significant ( p < 0.01). Conclusion : Patients with adenocarcinoma of the esophagus are not at higher risk for development of extraesophageal malignancy. This observation applies to both those with and without underlying Barrett's epithelium. Alcohol and tobacco use appear to be related to the malignant transformation of esophageal epithelium.     

Life expectancy and cancer risk in patients with Barrett's esophagus: a prospective controlled investigation.

BACKGROUND: It has been suggested that patients with Barrett's esophagus have a substantially increased risk of esophageal and possibly extra-esophageal cancers. We compared the incidence of cancer and the survival rates of patients with Barrett's esophagus with those observed in patients with achalasia, with Schatzki's ring, and in the general population. PATIENTS AND METHODS: From 1980 through 1994, 60 consecutive patients with newly diagnosed long-segment Barrett's esophagus without dysplasia were seen in a single gastroenterology consultation office and followed until the Fall of 1999. Cancer incidence and survival rates were compared with age- and sex-matched patients with symptomatic Schatzki's ring (n = 60) and achalasia (n = 60). Survival data were also compared with those of the German population. RESULTS: During a mean (+/-SD) observation period of 10 +/- 5 years, 2 patients with Barrett's esophagus (3%; 95% confidence interval [CI]: 0% to 11%) developed esophageal cancer, and 9 (15%; 95% CI: 7% to 27%) developed extra-esophageal cancers. These data differed only slightly from those of patients with Schatzki's ring (esophageal cancer: n = 1, 2%; 95% CI: 0% to 9%; extra-esophageal cancers: n = 9, 15%; 95% CI: 7%-27%) and achalasia (no esophageal cancers, extra-esophageal cancers: n = 3, 5%; 95% CI: 1% to 4%). Estimated 10-year survival was similar in patients with Barrett's esophagus (83%), patients with symptomatic Schatzki's ring (80%), patients with achalasia (87%), and in the general population (82%). CONCLUSIONS: The cancer risk in patients with Barrett's esophagus has been overestimated. If patients with nondysplastic epithelium are followed, the risk of esophageal cancer is about 1 per 300 patient-years.     

Have patients with esophagitis got an increased risk of adenocarcinoma？ Results from a population-based study

AIM: To examine an increased risk of esophageal adenocarcinoma is restricted to patients who develop Barrett's esophagus or whether esophagitis per is a risk factor for adenocarcinoma. METHODS: A population-based cohort of patients with histological evidence of esophagitis without Barrett's esophagus was constructed using electronic pathology reports relating to all esophageal biopsies in Northern Ireland between 1993 and 1996. Person-years of follow-up and incident cases of esophageal cancer were calculated by linking the cohort to death files and the Northern Ireland Cancer Registry records. Standardized incidence ratios (SIR) were calculated for esophageal cancers (adenocarcinoma, squamous cell carcinoma (SCC), and historically unspecified cancers). RESULTS: A total of 2 013 patients in the cohort provided 13 559 patient-years of follow-up (mean follow-up 6.7 years). None of the patients developed adenocarcinoma. Three patients developed SCC, and six developed histologically unspecified cancers. The SIR for all esophageal cancers and for SCC were 2.73 (95%CI 1.25-5.19) and 2.93 (95%CI 0.61-8.59), respectively. In a sensitivity analysis in which all unspecified esophageal cancers were treated as adenocarcinomas, the SIR for adenocarcinoma was 2.64 (0.97-5.75). CONCLUSION: The risk of adenocarcinoma is not elevated in patients with histological evidence of esophagitis without Barrett's esophagus; however, these patients may have a moderately increased risk of SCC. Further studies are required to confirm these findings, which suggest that Barrett's esophagus, not esophagitis, is the key precursor lesion in the development of adenocarcinoma.     

Prospective evaluation of multilayered epithelium in Barrett's esophagus

OBJECTIVE: We recently identified a distinctive type of multilayered epithelium in two patients with Barrett's esophagus, which shows morphological characteristics of both squamous and columnar epithelium. This study was performed to prospectively evaluate the prevalence of multilayered epithelium in patients with Barrett's esophagus. METHODS: Mucosal biopsies were obtained from the squamocolumnar junction (Z-line) of 58 patients with endoscopic evidence of esophageal columnar epithelium and from the gastroesophageal junction in 21 patients without endoscopic evidence of esophageal columnar epithelium. Specimens were evaluated for the presence of multilayered epithelium and goblet cells. RESULTS: Twenty-four of 58 (41%) of the patients with endoscopic evidence of esophageal columnar epithelium had multilayered epithelium compared with only one of 21 patients (5%) in the control group (p = 0.005). Of the 58 patients in the study group, 43 had goblet cell metaplasia and 15 did not (p < 0.001). Only patients with goblet cell metaplasia had multilayered epithelium. Shorter lengths of columnar epithelium were noted in the 24 patients with goblet cells and multilayered epithelium compared with the 19 patients with goblet cells and no multilayered epithelium (p < 0.05). CONCLUSIONS: Multilayered epithelium is strongly associated with goblet cell metaplasia in patients with endoscopic evidence of esophageal columnar epithelium. These data support the hypothesis that multilayered epithelium may represent a transitional stage in the development of Barrett's esophagus.     

Chemoprevention for Barrett''s Esophagus Trial. Design and outcome measures

Barrett's esophagus is a premalignant condition in which normal squamous epithelium of the esophagus is replaced by metaplastic columnar epithelium. It is a known risk factor for the development of esophageal adenocarcinoma. With the incidence of esophageal adenocarcinoma rising, it is reasonable to study Barrett's esophagus as a potential target for therapy that may prevent, delay and/or reverse ongoing tumorigenic processes. Epidemiologic and animal studies support the use of nonsteroidal anti-inflammatory drugs (NSAIDs) in the chemoprevention of several cancers, including esophageal cancer. Cyclo-oxygenase-2 (COX-2) inhibitors are a new class of NSAIDs that inhibit prostaglandin synthesis by selectively blocking the COX-2 enzyme. The COX-2 enzyme has been reported to be over-expressed in premalignant and malignant states, including in Barrett's esophagus and esophageal adenocarcinoma. The Chemoprevention for Barrett's Esophagus Trial (CBET) is a phase IIb, multicenter, randomized, double-masked, placebo-controlled study of the selective COX-2 inhibitor, celecoxib, in patients with Barrett's dysplasia. The sample size is 200 patients with high or low grade Barrett's dysplasia. Celecoxib is administered orally, 200 mg twice per day; the dosing schedule for placebo is the same. Randomization is stratified by dysplasia grade and by clinic. Endoscopy with biopsies is performed at specified time intervals according to the highest grade of dysplasia determined at randomization. The primary outcome measure is the change from baseline to 1 year in the proportion of biopsies exhibiting dysplasia. Secondary outcomes include change from baseline in the maximal grade, extent and surface area of dysplasia. Tertiary outcomes will include measurements of various relevant biomarkers.     

Current status of ablative therapies in esophageal disorders

Endoscopic ablative therapies for esophageal diseases have been used for palliation of inoperable esophageal cancer, but their use in eradication of early esophageal cancer and Barrett’s esophagus (with and without dysplasia) has been reported in recent publications. Pharmacologic and surgical treatment of reflux symptoms in patients with Barrett’s esophagus has not consistently reversed the metaplastic epithelium. This has led investigators to try different modalities of local injury to the columnar mucosa in an acid-reduced environment. Endoscopic reversal of Barrett’s esophagus (visual replacement of columnar mucosa by squamous mucosa) is more readily achievable than complete histologic reversal. Preliminary data show that endoscopic reversal of Barrett’s esophagus can be achieved, but intestinal metaplasia underlying the new squamous mucosa is reported in almost all series. Incidence of adenocarcinoma in patients with Barrett’s without dysplasia is probably so low that endoscopic ablation as a therapy cannot be advocated outside of study protocols. Endoscopic therapy as a definitive treatment for patients with high-grade dysplasia (HGD) and/or early adenocarcinoma holds promise, especially in older patients with comorbid illnesses. Future long-term randomized studies are needed to determine whether ablative therapies can provide an alternative approach for patients with HGD and early cancer. Advanced cancers that are not resectable for cure can be effectively treated by endoscopic therapy for palliation of dysphagia.     

Biomarkers in Barrett’s esophagus and esophageal adenocarcinoma:Predictors of progression and prognosis

Barrett’s esophagus is a well-known premalignant lesion of the lower esophagus that is characterized by intestinal metaplasia of the squamous epithelium. It is clinically important due to the increased risk (0.5% per annum) of progression to esophageal adenocarcinoma (EA), which has a poor outcome unless diagnosed early. The current clinical management of Barrett’s esophagus is hampered by the lack of accurate predictors of progression. In addition, when patients develop EA, the current staging modalities are limited in stratifying patients into different prognostic groups in order to guide the optimal therapy for an individual patient. Biomarkers have the potential to improve radically the clinical management of patients with Barrett’s esophagus and EA but have not yet entered mainstream clinical practice. This is in contrast to other cancers like breast and prostate for which biomarkers are utilized routinely to inform clinical decisions. This review aims to highlight the most promising predictive and prognostic biomarkers in Barrett’s esophagus and EA and to discuss what is required to move the field forward towards clinical application.     

Dysplasia in Barrett's esophagus: limitations of current management strategies

Dysplasia is a very imperfect biomarker for malignancy in Barrett's esophagus. Invasive cancer has been found in 30-40% of esophagi resected because preoperative endoscopic examinations had shown high-grade dysplasia. Reports on the natural history of this disorder are sometimes contradictory, but suggest that 10-30% of patients with high-grade dysplasia in Barrett's esophagus will develop a demonstrable malignancy within 5 yr of the initial diagnosis. Proposed management strategies for high-grade dysplasia include esophagectomy, endoscopic ablative therapies, endoscopic mucosal resection (EMR), and intensive endoscopic surveillance. Endoscopic ablative therapies and EMR may not be effective if neoplastic cells have invaded the submucosa or disseminated through mucosal lymphatic channels, and a number of studies suggest that the endoscopic therapies usually leave metaplastic or neoplastic epithelium with malignant potential behind. Limited data suggest that intensive endoscopic surveillance might be a reasonable approach for elderly or infirm patients, but some patients managed in this fashion have developed incurable esophageal cancers. The fundamental question of what is the appropriate length of follow-up for studies on dysplasia treatments has not been resolved. Although 5 yr might be considered the absolute minimum duration for a meaningful follow-up on dysplasia therapy, the follow-up duration in most studies is substantially less than 5 yr. Specific recommendations for management based on these considerations are proposed at the end of this report.     

Restoration of the normal squamous lining in Barrett's esophagus by argon beam plasma coagulation

Objective: Barrett's esophagus is associated with significantly increased risk of development of esophageal adenocarcinoma. Replacing columnar epithelium with the normal squamous lining in this condition offers the possibility of decreasing the risk of degeneration to invasive adenocarcinoma. This study aimed to establish the feasibility of argon beam plasma coagulation (ABPC), in conjunction with control of gastroesophageal reflux, to restore the squamous lining.
Methods: Thirty patients with Barrett's esophagus (four low-grade dysplasia, three high-grade) were recruited from our surveillance program, and underwent endoscopic ABPC.
Results: Twenty-seven patients completed treatment, with macroscopic replacement of their columnar lining by squamous epithelium, histologically confirmed in all 27, and followed up for a median of 9 months (range, 6–18 months). Two patterns of squamous replacement were identified: 70% of patients showed squamous epithelium with no persistent intestinal metaplasia, and in 30% the new squamous epithelium covered areas of underlying intestinal metaplasia. One patient has withdrawn from the study. Two esophageal perforations, with one death, occurred early in the study.
Conclusion: ABPC, in conjunction with control of gastroesophageal reflux, allows squamous regrowth in both benign and dysplastic Barrett's esophagus. Despite the theoretical safety advantages of ABPC over techniques such as laser, esophageal perforation may occur with this technique. It is too soon to recommend ABPC for dysplastic or nondysplastic Barrett's because follow-up is too short to show a decreased incidence of and mortality from adenocarcinoma.     

Acid suppression and reepithelialization after ablation of Barrett's esophagus

The role of acid reflux in the development of esophageal columnar epithelium was first described in the early 1970s in the canine esophageal reflux model. In the presence of acid reflux, columnar epithelium developed at the site of induced esophageal mucosal injury. When reflux was suppressed, most epithelium reverted back to squamous mucosa. Similar findings in human patients with Barrett's esophagus (BE) who were treated with laser ablation were first described in 1993. While acid suppression with antireflux surgery or proton pump inhibitors (PPIs) has proven insufficient to completely reverse BE, ablation of the lesion followed by acid suppression may be a promising option. Although at least one report disputes the importance of complete acid suppression following mucosal ablation of BE, most investigators use full-dose PPI therapy following ablation, in the belief that full acid suppression provides an environment that allows the esophageal progenitor cell to develop squamous mucosa. This article provides a review of the literature to date regarding ablative therapies and acid suppression for patients with BE.     

Molecular targets for treatment of Barrett''s esophagus

SUMMARY. Esophageal cancer is one of the most deadly forms of gastrointestinal cancer with a mortality rate exceeding 90%. The major risk factors for esophageal adenocarcinoma are gastroesophageal reflux disease (GERD) and its sequela, Barrett's esophagus. GERD commonly leads to esophagitis. In a minority of patients however, ongoing GERD leads to replacement of esophageal squamous mucosa with metaplastic, intestinal-type Barrett's mucosa. In the setting of continued peptic injury, Barrett's mucosa can give rise to esophageal adenocarcinoma. Despite the widespread use of potent acid suppressive therapies for patients with GERD, the incidence of esophageal adenocarcinoma, among white men in the USA, the UK and Europe has continued to rise. Cancers in Barrett's esophagus arise through a sequence of genetic events that endow the cells with six essential physiologic hallmarks of cancer as described by Hanahan and Weinberg in 2000. These cancer hallmarks include the ability to proliferate without exogenous stimulation, to resist growth-inhibitory signals, to avoid triggering the programmed death mechanism (apoptosis), to resist cell senescence, to develop new vascular supplies (angiogenesis), and to invade and metastasize. While the acquisition of these essential attributes is not specific to the neoplastic progression of Barrett's esophagus, this review will focus on the genetic alterations that occur in Barrett's cells that contribute to the acquisition of each of the hallmarks. Moreover, potential diagnostic and therapeutic strategies for Barrett's patients aimed at each of these cancer hallmarks will be reviewed.     

Squamous cell carcinoma in Barrett's esophagus: field effect versus metastasis

Barrett's esophagus (BE) is a premalignant condition with an increased risk of developing esophageal adenocarcinoma (EAC). Risk factors for EAC overlap with those for esophageal squamous cell carcinoma (ESCC), but ESCC is surprisingly rare in BE. We report two cases of ESCC directly surrounded by BE. Both patients had a previous medical history of cancers, i.e., head and neck squamous cell carcinomas, and were using alcohol and smoking tobacco. Using immunohistochemistry for p63, CK5, CK7, and CDX2, it was confirmed that these carcinomas were pure squamous cell carcinomas, and not EACs or esophageal adenosquamous carcinomas arising from BE. Using TP53 mutation and loss of heterozygosity analysis, we established that the ESCCs in BE were not metastases of the previously diagnosed head and neck squamous cell carcinomas but de novo primary ESCCs. This study shows the strength of molecular analysis as an adjunct to the histopathologic diagnosis for distinguishing between metastases of prior cancers and primary cancers. Furthermore, these cases imply that presence of BE is not protective with regards to developing ESCC in the lower one third of the esophagus. We suggest that their ESCCs arose from islets of squamous epithelium in BE.     

Esophageal cancer: epidemiology, pathogenesis and prevention

Esophageal cancer is highly aggressive and is a common cancer both worldwide and in the US. In the past two decades, the incidence and mortality of esophageal cancer in the US have both increased, where as the incidence and mortality of other cancers have decreased. Although esophageal squamous cell carcinoma and esophageal adenocarcinoma differ in their histology and epidemiologic distribution, some of their risk factors (e.g. dietary deficiencies and tobacco) and underlying mechanisms of carcinogenesis are the same. Intensive research into risk factors combined with the ability to identify precursor lesions (e.g.squamous dysplasia in esophageal squamous cell carcinoma and Barrett's esophagus in esophageal adenocarcinoma) has paved the way for studies of chemoprevention for esophageal cancer, some of which have shown promising results.     

Chirurgische Therapiestrategien beim ?sophagus- und Magenkarzinom

This review summarizes surgical strategies for esophageal and gastric cancers. In addition to well-established standardized procedures, more recently developed limited resections for early cancers and multimodality treatments for locally advanced T3/4 tumors are discussed. Esophageal squamous cell cancer and adenocarcinoma (Barrett’s cancer) are discussed individually because of their different pathogenesis, tumor biology, and applied treatment strategies. Because Barrett’s cancer is usually located in the distal esophagus, it should be distinguished from true cancer of the gastric cardia and gastric cancers invading the distal esophagus. Based on the classification of Siewert, esophageal adenocarcinoma is therefore discussed in context with adenocarcinomas of the esophagogastric junction. For the recent developments in surgical strategies for gastric cancer, our Asian, especially Japanese and South Korean, colleagues deserve particular merit. Modern techniques developed in those countries and not yet established in the West are extensively discussed along with our common standard procedures. It is still true for all these different tumors that surgical resection is an elementary part of curative treatment strategies; however, treatment is becoming more and more differentiated and interdisciplinary and therefore requires further specialization for our patients’ sake.     

Cyclooxygenase-2 Expression in Barrett's Esophagus

Barrett's epithelium is a recognized premalignant condition for esophageal adenocarcinoma. Nonsteroidal antiinflammatory drugs (NSAIDs) decrease the relative risk of colon cancer in humans and the esophageal tumor load in carcinogen-treated mice. Previous studies provided conflicting results for COX-2 activity in Barrett's mucosa. Pinch mucosal biopsies were collected from Barrett's and adjacent normal esophageal mucosa from 17 patients with Barrett's esophagus. Low-grade dysplasia was found in seven patients. COX-2 protein was undetectable in normal esophageal mucosa. COX-1 protein expression did not vary between normal and Barrett's epithelium. Increased COX-2 protein was detected in Barrett's epithelium in seven patients (41%) but did not differ with or without dysplasia (43% vs 40%). In conclusion, COX-2 protein is increased in 41% of patients with Barrett's epithelium compared to normal esophageal mucosa but did not differ with or without dysplasia. COX-2 induction may be an early event in the development of Barrett's esophagus.     

Early esophageal cancer in patients with a history of gastrectomy for gastric cancer

To detect early esophageal cancer effectively, it is important to select high-risk groups. Because we often see early esophageal cancer after gastrectomy for gastric cancer, we investigated 11 early esophageal cancers treated endoscopically in 7 patients who had undergone gastrectomy for gastric cancer. Their average age was 70.8 ± 5.2 years. Median interval between previous gastrectomy and the diagnosis of esophageal cancer was 10 years. Endoscopic examination revealed mild bile reflux into the remnant stomach and esophagitis, but there was no case of Barrett's esophagus. Histological types were all squamous cell carcinoma. Although it has been reported that cancer development is most frequent in the lower esophagus after gastrectomy, we noticed that the majority of these were located in the middle thoracic esophagus (6/11, 55%), similar to general esophageal cancer. As all cases were detected by a regular checkup, it is important to follow up patients after gastrectomy for gastric cancer.     

Effect of Up to 3 Years of High-dose Lansoprazole on Barrett's Esophagus

Objective: Barrett's esophagus is a metaplastic condition resulting from gastroesophageal reflux disease. Previous medical and surgical therapies have failed to predictably eradicate Barrett's. The objective of this study was to assess the impact of long-term, high-dose lansoprazole, a proton pump inhibitor, on Barrett's esophagus. Methods: Patients with Barrett's esophagus at least 3 cm long and with specialized columnar epithelium were treated with 60 mg of lansoprazole each morning. Every 6 months, patients had standardized symptomatic, laboratory, and endoscopic assessment. The length of Barrett's esophagus was measured, photo-documented, and biopsied. Resutts: Twenty-seven patients with Barrett's esophagus have been treated an average of 2.9 yr. Symptoms improved (70%, 19 patients), and erosive esophagttis healed (100%, 13 patients), but there was no significant reduction in the length of Barrett's epithelium (mean length at baseline 5.7 cm, final visit 5.3 cm). However, by the final visit, 20 of 26 patients (77%) had squamous islands: two unchanged in size, six with increased surface area, and 12 newly developed on therapy. Initially, mean fasting gastrin levels rose significantly but then plateaued after 1 month of therapy. Of 10 patients with gastrin levels for 18 months or longer, only one had a level ≥400 pg/ml. Conctusions: Lansoprazole 60 mg for up to 3 yr was safe and effective in controlling symptoms and esophagitis. The impact on the extent of Barrett's esophagus over this time interval was manifested by the extension and development of squamous islands.     

Photodynamic therapy for Barrett''s esophagus: a review

Barrett's esophagus is the major risk factor for the development of esophageal adenocarcinoma, which is increasing in incidence faster than any other cancer in the Western world. Barrett's esophagus has previously been considered an irreversible lesion that required life-long surveillance to detect malignant transformation. However, endoscopic ablative techniques to destroy the abnormal mucosa and allow squamous regeneration have now been developed. Photodynamic therapy (PDT) is a non-thermal technique where the interaction of a photosensitizer in the tissues and light of a known wavelength results in tissue destruction. It appears to be an effective tool for ablating dysplasia and superficial cancers in Barrett's esophagus. The status of PDT for this disease is reviewed.