Endoscopic therapy in early adenocarcinomas (Barrett's cancer) of the esophagus

The incidence of early esophageal adenocarcinoma has been increasing significantly in recent decades. Prognosis depends greatly on the choice of treatment. Early cancers can be treated by endoscopic resection, whereas advanced carcinomas have to be sent for surgery. Esophageal resection is associated with high perioperative mortality (1–5%) even in specialized centers. Early diagnosis enables curative endoscopic treatment option. Patients with gastrointestinal symptoms and a familial risk for esophageal cancer should undergo upper gastrointestinal endoscopy. High‐definition endoscopes have been developed with technical add‐on that helps endoscopists to find fine irregularities in the esophageal mucosa, but interpreting the findings remains challenging. In this review we discussed novel and old diagnostic procedures and their values, as well as our own recommendations and those of the authors discussed for the diagnosis and treatment of early Barrett's carcinoma. Endoscopic resection is the therapy of choice in early esophageal adenocarcinoma. It is mandatory to perform a subsequent ablation of all residual Barrett's mucosa to avoid metachronous lesions.     

Australian clinical practice guidelines for the diagnosis and management of Barrett's esophagus and early esophageal adenocarcinoma

Barrett's esophagus (BE), a common condition, is the only known precursor to esophageal adenocarcinoma (EAC). There is uncertainty about the best way to manage BE as most people with BE never develop EAC and most patients diagnosed with EAC have no preceding diagnosis of BE. Moreover, there have been recent advances in knowledge and practice about the management of BE and early EAC. To aid clinical decision making in this rapidly moving field, Cancer Council Australia convened an expert working party to identify pertinent clinical questions. The questions covered a wide range of topics including endoscopic and histological definitions of BE and early EAC; prevalence, incidence, natural history, and risk factors for BE; and methods for managing BE and early EAC. The latter considered modification of lifestyle factors; screening and surveillance strategies; and medical, endoscopic, and surgical interventions. To answer each question, the working party systematically reviewed the literature and developed a set of recommendations through consensus. Evidence underpinning each recommendation was rated according to quality and applicability.     

Eosinophilic infiltration of the esophagus following endoscopic ablation of Barrett's neoplasia

To assess the incidence of esophageal intra‐epithelial eosinophilic infiltration following endoscopic ablation of Barrett's esophagus (BE), a retrospective study of consecutive cases of endoscopic ablation of BE with dysplasia or cancer using radiofrequency ablation (RFA) and spray cryotherapy at two centers in the United States was performed. Post‐ablation eosinophilia was defined as ≥5 eosinophils per high power field during post‐treatment surveillance. Twenty of 122 patients (16%) undergoing ablation developed esophageal eosinophilia after ablation, including 8/77 (10%) treated with RFA and 12/44 (27%) treated with cryotherapy. No patient had clinical or endoscopic findings of or risk factors for eosinophilic esophagitis. Esophageal eosinophilia persisted in 30% over a median of 20.2 months. On multivariate analysis, post‐ablation eosinophilia was independently associated with increasing BE segment length (adjusted odds ratio 1.46 for every 2‐cm increase, 95% confidence interval 1.24–1.71) and cryotherapy as the ablation modality (adjusted odds ratio 5.23, 95% confidence interval 1.67–16.39). Esophageal eosinophilic infiltration after endoscopic ablation with RFA and cryotherapy is common and is associated with the BE segment length and treatment modality. The clinical significance of post‐ablation eosinophilia is unclear.     

Chinese National Consensus on diagnosis and management of Barrett's esophagus (BE): revised edition, June 2011, Chongqing, China

To standardize the diagnosis and management of Barrett's esophagus (BE) in China, the Chinese Society of Gastroenterology convened the Second National Conference on BE in June 2011 in Chongqing, China. After intense discussion among experts in this field and an extensive review of the literature, a revised consensus on the diagnosis and management of BE was generated.     

Advances in endoscopic diagnosis and treatment of Barrett's esophagus

Barrett's esophagus (BE) is defined as abnormal specialized columnar metaplasia with intestinalization in place of the normal squamous esophageal epithelium. Gastroesophageal reflux disease is a known risk factor for BE; nonetheless BE is also detected in asymptomatic individuals. Other risk factors for BE include smoking, male gender, age over 50 and obesity. Patients diagnosed with BE (without dysplasia) are recommended to undergo endoscopic surveillance every 3-5 years. Advances in imaging techniques (such as narrow band imaging, autofluorescence imaging and confocal laser endomicroscopy) have the potential to improve the detection of dysplasia and early cancer, thus making surveillance a more cost-effective endeavor. Patients with high grade dysplasia (HGD) and early cancer have a high rate of progression to invasive adenocarcinoma and traditionally these patients were treated with esophagectomy. The rapid advancement of endoscopic therapeutic techniques along with a low risk of complications have made endoscopic therapy an acceptable alternative to an esophagectomy in patients with HGD and early cancer. Several endoscopic treatment techniques such as endoscopic mucosal resection, multipolar electrocoagulation, photodynamic therapy, argon plasma coagulation, cryotherapy, and radiofrequency ablation have been studied for endoscopic treatment.     

Management of cancer risk in Barrett's esophagus

The importance of Barrett's esophagus (BE) lies in its potential to give rise to esophageal adenocarcinoma (EAC), postulated to be through a series of progressive degrees of dysplasia; from intestinal metaplasia to low-grade dysplasia, high-grade dysplasia, and subsequently, to cancer. The management strategies for the detection and treatment of dysplasia and early esophageal cancer on a background of BE have changed significantly in the last few decades, with the emergence of newer and less invasive non-operative alternatives. This review aims to outline BE and its relation to EAC, the rationale and cost-effectiveness of both screening and surveillance programs, methods of diagnosing and identifying dysplasia and early cancer in Barrett's, and approaches to individualizing their endoscopic and surgical management based on best-available staging techniques.     

Histopathological diagnosis of adenocarcinoma in Barrett's esophagus

The present review describes the histological markers of Barrett's esophagus (BE) that make it possible to distinguish between Barrett's carcinoma (BC) and gastric carcinoma. With regard to high‐grade dysplasia, the indications for endoscopic resection (ER) or major surgery for management of BC cannot be decided on the basis of biopsy histology, and the choice between them should be made according to BC invasion depth. Therefore, we recommend that the term ‘well‐differentiated tubular adenocarcinoma’ be used rather than ‘high‐grade dysplasia’ (intraepithelial neoplasia). High‐grade dysplasia is regarded as BC in Japan and other countries such as Germany. Such lesions should not be treated by endoscopic ablation but by ER, because components of invasive carcinoma are frequently present in the mucosa and submucosa, and knowledge obtained from ER samples is needed for additional therapy. Further studies on the relationship between the incidence of nodal metastasis and mucosal depth in mucosal BC are needed to decide the indications for ER. Suchstudies should involve subserial microscopic examination of slices 2–3 mm thick. To resolve the issue of regression of high‐grade dysplasia, international experts in gastroenterological pathology need to conduct histopathological reviews of the first and last samples taken from such cases, as there are large differences between North American, European, and Japanese pathologists in the criteria used for histological diagnosis of dysplasia and adenocarcinoma without clear invasion, and both interobserver and intraobserver variations have been reported. Future studies will need to focus on which carcinomas are curable by ER.     

Cytokeratin and CDX-2 expression in Barrett's esophagus

Objective. Barrett's esophagus (BE) is a premalignant condition of the distal esophagus. For diagnostic purposes it is important to find biomarkers that can specifically identify BE, for instance to differentiate BE epithelial cells from gastric cardia epithelial cells in brush cytology specimens. The objective of this study was to determine the specificity of CDX-2 and a set of cytokeratins (CKs) as specific markers for BE as compared with normal squamous esophageal and gastric cardia tissue. Material andmethods. Immunohistochemistry (IHC) with specific antibodies against CDX-2, and a set of CKs was performed on fresh frozen consecutive tissue sections of normal squamous, gastric cardia and non-dysplastic BE of 80 patients. Results. IHC results showed CK8, CK18 and CK20 expression in both BE and gastric cardia, while CK7 was seen in all BE but also in 26% of gastric cardia biopsies. CK10/13 was only expressed in normal squamous epithelium. CDX-2 nuclear staining was found in 87.5% of the BE biopsies, whereas normal squamous esophagus and cardia biopsies were negative. Conclusions. CDX-2 in combination with a set of CKs can be used as biomarkers to distinguish between BE and normal squamous esophagus. In order to distinguish BE from cardia tissue, a combination of CDX-2 and CK7 is most informative.     

Dysplasia detection rate of confirmatory EGD in nondysplastic Barrett's esophagus

Current guidelines for endoscopic surveillance of Barrett's esophagus (BE) recommend that patients with newly diagnosed BE undergo confirmatory esophagogastroduodenoscopy (EGD) to exclude the presence of dysplasia. The extent to which confirmatory endoscopy alters management and detects missed dysplasia in newly diagnosed BE has not been reported. The frequency with which confirmatory endoscopy changed surveillance management in patients with newly diagnosed BE was assessed. A two center cohort analysis was conducted on patients newly diagnosed with BE. The rate of dysplasia on confirmatory endoscopy for patients who had nondysplastic BE was obtained. Demographic and endoscopic variables were assessed for association with dysplasia detection using Firth logistic regression model. Out of the 146 patients newly diagnosed with BE and initially determined to be without dysplasia, 12 had dysplasia on the confirmatory second EGD (8.2%). Eleven of 12 cases with dysplasia on confirmatory endoscopy had long‐segment BE (LSBE). Among all the LSBE cases in our cohort, 11 had newly diagnosed dysplasia on confirmatory EGD, 29.7% (11/37). The average number of biopsies obtained from the 11 LSBE cases with dysplasia was comparable with the rest of the LSBE cases without dysplasia (6.73 and 5.42, respectively, P‐value 0.205). The rate of dysplasia detection in short‐segment BE (SSBE) was much lower, 0.95% (1 out of 105). There were no cases of high‐grade dysplasia (HGD) or cancer detected in any SSBE case. HGD was detected on confirmatory EGD in two cases, both were LSBE. Segment length was the only statistically significant factor to predict the presence of dysplasia on confirmatory endoscopy (odds ratio 9.158, P. 0.008). Confirmatory EGD in newly diagnosed LSBE had significant rate of dysplasia detection (29.7%) in this cohort. Among patients with SSBE, there was a low rate of dysplasia detection with confirmatory EGD, less than 1% of cases. No additional cases of HGD or esophageal carcinoma in SSBE cases were detected. This suggests that the yield of confirmatory EGD is greater in patients with LSBE.     

How to diagnose and manage patients with Barrett's esophagus in China

In order to prevent the development of Barrett's esophagus (BE)-related esophageal cancer in China and facilitate the communication of research results among different centers, we propose using standardized diagnostic criteria and taking a conservative approach to diagnose and manage BE patients. BE patients without dysplasia need to be treated medically. For low-grade dysplasia, an annual endoscopy with biopsies is recommended, along with medical therapy. For high-grade dysplasia and intramucosal carcinoma, an endoscopic or surgical intervention is suggested. All BE patients should be followed up closely.     

p27 and Barrett's esophagus: a review*.

The rising prevalence of Barrett's esophagus and Barrett's associated adenocarcinoma in the Western world has stimulated increasing interest in this disease. This has resulted in a plethora of articles concerning its molecular biology, but the tumor suppressor gene, p27, has received little attention. In this article, we review the literature concerning the role of p27 in Barrett's esophagus and its malignant transformation, and we evaluate its possible role as an important clinical biomarker, as well as potential chemopreventive clinical agents aimed at substituting its antitumoral activity.     

Critical reappraisal of current surveillance strategies for Barrett's esophagus: analysis of a large German Barrett's database

Endoscopic surveillance is recommended for patients with Barrett's esophagus (BE). Based on a large database, gathered from predominantly community‐based practices in Germany, we aimed to investigate the time‐course of malignant progression and apply these findings to current clinical practice. Data of 1438 patients with BE from a large German BE database were analyzed. Patients with at least one follow‐up endoscopy/biopsy were included. Detection of ‘malignant Barrett’ (either high‐grade intra‐epithelial neoplasia or invasive adenocarcinoma) was considered as study end‐point. Of 1438 patients with BE, 57 patients had low‐grade intra‐epithelial neoplasia (LG‐IN) on initial biopsy and 1381 exhibited non‐neoplastic BE. ‘Malignant Barrett’ was detected in 28 cases (1.9%) during a median follow‐up period of 24 months (1–255), accounting for an incidence of 0.95% per patient year of follow‐up. The frequency of ‘malignant Barrett’ was significantly higher (P < 0.001, χ²‐test) in the LG‐IN group (n = 11, 19.3%) compared with the non‐neoplastic BE group (n = 17, 1.2%). In the non‐neoplastic BE group, ‘malignant Barrett’ was predominantly found during re‐endoscopy within the first year of follow‐up (12 of 17; 70.6%), in contrast to the LG‐IN group, in which ‘malignant Barrett’ was observed predominantly after a time exceeding 12 months (8 of 11, 72.7%; P = 0.05, Fisher's exact test). Initial endoscopic evaluations seem to play the most crucial role in managing BE. After 1 year of follow‐up, endoscopic surveillance should be focused on patients with LG‐IN. In patients with repeatedly proven non‐neoplastic BE, elongation of the follow‐up intervals to the upper limit of current guidelines, that is, 5 years, might be justified.     

Human papillomavirus and the risk of Barrett's esophagus

Human papillomavirus (HPV) is strongly associated with squamous esophageal cancer. The potential role of HPV in Barrett's esophagus (BE) has been examined but remains unclear. The aim of the study was to determine the prevalence of HPV in esophageal and gastric tissues obtained from patients with and without BE. We designed a cross‐sectional study was conducted with prospective enrollment of eligible patients scheduled for esophagogastroduodenoscopy (EGD). All participants had biopsies of endoscopic BE, squamous‐lined esophagus, and stomach. Immunohistochemistry (IHC) on formalin‐fixed and paraffin‐embedded tissue was conducted using monoclonal antibodies. Polymerase chain reaction (PCR) for HPV was performed on DNA extracted from esophageal biopsies snapped frozen within 30 minutes after endoscopic capture. The Roche HPV Linear Array Assay with PGMY primers that has high sensitivity for detecting 37 types of HPV was used. A total of 127 subjects were included: 39 with definitive BE had IHC done on samples from non‐dysplastic BE, squamous esophagus, gastric cardia, and gastric body; and 88 control patients without BE had IHC done on squamous esophageal samples, gastric cardia, and gastric body. HPV was not detected in any of the samples in either group. For confirmation, HPV DNA PCR was performed on randomly selected samples from 66 patients (both esophagus and BE from 13 patients with BE, and 53 esophagus from patients without BE); no sample had HPV DNA detected via PCR in the presence of adequate quality control. HPV infection does not play a role in the formation of non‐dysplastic Barrett's esophagus in men in the United States.     

Lower esophageal palisade vessels and the definition of Barrett's esophagus

SUMMARY. The designated area of the columnar‐lined esophagus (CLE) is anatomically defined by the distal limit of the lower esophageal palisade vessels (LEPV) and the term ‘Barrett's esophagus’ is equally used along with the name CLE in Japan. The aim of this study was to investigate the actual prevalence of CLE based on the Japanese criteria and to evaluate the criteria per se. A total of 42 esophagi consecutively resected at this institute were included. All subjects underwent a surgical resection for squamous cell carcinoma of the esophagus. The position of the LEPV, squamocolumnar junction, the prevalence of CLE and intestinal metaplasia were investigated both pre‐ and postoperatively. Preoperative endoscopy revealed CLE based on the Japanese criteria in half of all patients. In the resected specimens the distal limit of LEPV was lower than the squamocolumnar junction in 95.2%. In other words, almost all cases had CLE (equivalent to Barrett's mucosa in Japanese criteria). However, most of the CLE areas were very short and their average maximum length was only about 5 mm. In addition, no intestinal metaplasia was observed in any of the CLE cases. Almost all individuals might therefore be diagnosed to have CLE or Barrett's mucosa based on precise endoscopic observations in Japan. The CLE located in a small area, e.g. less than 5 mm, defined according to the LEPV criteria without any other factor concerning typical Barrett's esophagus such as signs of gastroesophageal reflux should therefore be excluded from consideration as a high‐risk mucosa.     

Fluorescence spectroscopy incorporated in an Optical Biopsy System for the detection of early neoplasia in Barrett's esophagus

Endoscopic surveillance is recommended for patients with Barrett's esophagus (BE) to detect high‐grade intraepithelial neoplasia (HGIN) or early cancer (EC). Early neoplasia is difficult to detect with white light endoscopy and random biopsies are associated with sampling error. Fluorescence spectroscopy has been studied to distinguish non‐dysplastic Barrett's epithelium (NDBE) from early neoplasia. The Optical Biopsy System (OBS) uses an optical fiber integrated in a regular biopsy forceps. This allows real‐time spectroscopy and ensures spot‐on correlation between the spectral signature and corresponding physical biopsy. The OBS may provide an easy‐to‐use endoscopic tool during BE surveillance. We aimed to develop a tissue‐differentiating algorithm and correlate the discriminating properties of the OBS with the constructed algorithm to the endoscopist's assessment of the Barrett's esophagus. In BE patients undergoing endoscopy, areas suspicious for neoplasia and endoscopically non‐suspicious areas were investigated with the OBS, followed by a correlating physical biopsy with the optical biopsy forceps. Spectra were correlated to histology and an algorithm was constructed to discriminate between HGIN/EC and NDBE using smoothed linear dicriminant analysis. The constructed classifier was internally cross‐validated and correlated to the endoscopist's assessment of the BE segment. A total of 47 patients were included (39 males, age 66 years): 35 BE patients were referred with early neoplasia and 12 patients with NDBE. A total of 245 areas were investigated with following histology: 43 HGIN/EC, 66 low‐grade intraepithelial neoplasia, 108 NDBE, 28 gastric or squamous mucosa. Areas with low‐grade intraepithelial neoplasia and gastric/squamous mucosa were excluded. The area under the receiver operating characteristic curve of the constructed classifier was 0.78. Sensitivity and specificity for the discrimination between NDBE and HGIN/EC of OBS alone were 81% and 58% respectively. When OBS was combined with the endoscopist's assesssment, sensitivity was 91% and specificity 50%. If this protocol would have guided the decision to obtain biopsies, half of the biopsies would have been avoided, yet 4/43 areas containing HGIN/EC (9%) would have been inadvertently classified as unsuspicious. In this study, the OBS was used to construct an algorithm to discriminate neoplastic from non‐neoplastic BE. Moreover, the feasibility of OBS with the constructed algorithm as an adjunctive tool to the endoscopist's assessment during endoscopic BE surveillance was demonstrated. These results should be validated in future studies. In addition, other probe‐based spectroscopy techniques may be integrated in this optical biopsy forceps system.     

Original article: Quality of life after esophagectomy and endoscopic therapy for Barrett's esophagus with dysplasia

Esophagectomy (EG) and endoscopic therapy (ET) can eradicate Barrett's esophagus with early neoplasia. Their relative effect on quality of life is unknown. The 36‐item Short Form Health Survey (SF‐36) and Gastrointestinal Quality of Life Index (GIQLI) questionnaires were sent to all patients who underwent either EG or ET at our institution over the last 9 years. Groups were stratified by age and American Society of Anesthesia (ASA) class. Surveys were sent to 77 patients and completed by 14 EG (50%) and by 28 ET patients (57%). The average time between treatment and survey was 4 years in the ET group and 5 years in the EG group. There were no significant differences in SF‐36 scores between EG and ET patients except for superior physical functioning among EG patients 65 and older QOL scores among EG and ET groups were not significantly different than sex age‐matched controls. GIQLI scores were similar between ET and EG patients of all ages (P= 0.60). GIQLI scores were higher among younger ET patients than young EG patients (P= 0.049). GIQLI scores also tended to be higher among ASA 1 and 2 ET patients than ASA 1 and 2 EG patients, but this did not reach statistical significance (P= 0.09). EG and ET for early Barrett's neoplasia appear to have similar impact on QOL 1 year or more after treatment compared with age‐matched controls. Negative QOL impact appears to be greater for younger patients undergoing EG than for ET.