Maria O'Donovan

British Society of Gastroenterology guidelines on the diagnosis and management of Barrett's oesophagus

These guidelines provide a practical and evidence-based resource for the management of patients with Barretts oesophagus and related early neoplasia. The Appraisal of Guidelines for Research and Evaluation (AGREE II) instrument was followed to provide a methodological strategy for the guideline development. A systematic review of the literature was performed for English language articles published up until December 2012 in order to address controversial issues in Barretts oesophagus including definition, screening and diagnosis, surveillance, pathological grading for dysplasia, management of dysplasia, and early cancer including training requirements. The rigour and quality of the studies was evaluated using the SIGN checklist system. Recommendations on each topic were scored by each author using a five-tier system (A+, strong agreement, to D+, strongly disagree). Statements that failed to reach substantial agreement among authors, defined as >80% agreement (A or A+), were revisited and modified until substantial agreement (>80%) was reached. In formulating these guidelines, we took into consideration benefits and risks for the population and national health system, as well as patient perspectives. For the first time, we have suggested stratification of patients according to their estimated cancer risk based on clinical and histopathological criteria. In order to improve communication between clinicians, we recommend the use of minimum datasets for reporting endoscopic and pathological findings. We advocate endoscopic therapy for high-grade dysplasia and early cancer, which should be performed in high-volume centres. We hope that these guidelines will standardise and improve management for patients with Barretts oesophagus and related neoplasia.

Molecular imaging using fluorescent lectins permits rapid endoscopic identification of dysplasia in Barrett's esophagus

Barretts esophagus is an example of a pre-invasive state, for which current endoscopic surveillance methods to detect dysplasia are time consuming and inadequate. The prognosis of cancer arising in Barretts esophagus is improved by early detection at the stage of mucosal carcinoma or high-grade dysplasia. Molecular imaging methods could revolutionize the detection of dysplasia, provided they permit a wide field of view and highlight abnormalities in real time. We show here that cell-surface glycans are altered in the progression from Barretts esophagus to adenocarcinoma and lead to specific changes in lectin binding patterns. We chose wheat germ agglutinin as a candidate lectin with clinical potential. The binding of wheat germ agglutinin to human tissue was determined to be specific, and we validated this specific binding by successful endoscopic visualization of high-grade dysplastic lesions, which were not detectable by conventional endoscopy, with a high signal-to-background ratio of over 5.

Ordering of mutations in preinvasive disease stages of esophageal carcinogenesis

Cancer genome sequencing studies have identified numerous driver genes, but the relative timing of mutations in carcinogenesis remains unclear. The gradual progression from premalignant Barretts esophagus to esophageal adenocarcinoma (EAC) provides an ideal model to study the ordering of somatic mutations. We identified recurrently mutated genes and assessed clonal structure using whole-genome sequencing and amplicon resequencing of 112 EACs. We next screened a cohort of 109 biopsies from 2 key transition points in the development of malignancy: benign metaplastic never-dysplastic Barretts esophagus (NDBE; n = 66) and high-grade dysplasia (HGD; n = 43). Unexpectedly, the majority of recurrently mutated genes in EAC were also mutated in NDBE. Only TP53 and SMAD4 mutations occurred in a stage-specific manner, confined to HGD and EAC, respectively. Finally, we applied this knowledge to identify high-risk Barretts esophagus in a new non-endoscopic test. In conclusion, mutations in EAC driver genes generally occur exceptionally early in disease development with profound implications for diagnostic and therapeutic strategies.

Hereditary diffuse gastric cancer: updated clinical guidelines with an emphasis on germline CDH1 mutation carriers

Germline CDH1 mutations confer a high lifetime risk of developing diffuse gastric (DGC) and lobular breast cancer (LBC). A multidisciplinary workshop was organised to discuss genetic testing, surgery, surveillance strategies, pathology reporting and the patients perspective on multiple aspects, including diet post gastrectomy. The updated guidelines include revised CDH1 testing criteria (taking into account first-degree and second-degree relatives): (1) families with two or more patients with gastric cancer at any age, one confirmed DGC; (2) individuals with DGC before the age of 40 and (3) families with diagnoses of both DGC and LBC (one diagnosis before the age of 50). Additionally, CDH1 testing could be considered in patients with bilateral or familial LBC before the age of 50, patients with DGC and cleft lip/palate, and those with precursor lesions for signet ring cell carcinoma. Given the high mortality associated with invasive disease, prophylactic total gastrectomy at a centre of expertise is advised for individuals with pathogenic CDH1 mutations. Breast cancer surveillance with annual breast MRI starting at age 30 for women with a CDH1 mutation is recommended. Standardised endoscopic surveillance in experienced centres is recommended for those opting not to have gastrectomy at the current time, those with CDH1 variants of uncertain significance and those that fulfil hereditary DGC criteria without germline CDH1 mutations. Expert histopathological confirmation of (early) signet ring cell carcinoma is recommended. The impact of gastrectomy and mastectomy should not be underestimated; these can have severe consequences on a psychological, physiological and metabolic level. Nutritional problems should be carefully monitored.

Elastic scattering spectroscopy accurately detects high grade dysplasia and cancer in Barrett's oesophagus

Background and aims: Endoscopic surveillance of Barrett’s oesophagus currently relies on multiple random biopsies. This approach is time consuming, has a poor diagnostic yield, and significant interobserver variability. Elastic scattering spectroscopy is a real time in vivo optical technique which detects changes in the physical properties of cells. The aim of this study was to assess the potential for elastic scattering to detect high grade dysplasia or cancer within Barrett’s oesophagus. Methods: Elastic scattering spectroscopy measurements collected in vivo were matched with histological specimens taken from identical sites within Barrett’s oesophagus. All biopsies were reviewed by three gastrointestinal pathologists and defined as either “low risk” (non-dysplastic or low grade dysplasia) or “high risk” (high grade dysplasia or cancer). Two different statistical approaches (leave one out and block validation) were used to validate the model. Results: A total of 181 matched biopsy sites from 81 patients, where histopathological consensus was reached, were analysed. There was good pathologist agreement in differentiating high grade dysplasia and cancer from other pathology (kappa = 0.72). Elastic scattering spectroscopy detected high risk sites with 92% sensitivity and 60% specificity and differentiated high risk sites from inflammation with a sensitivity and specificity of 79%. If used to target biopsies during endoscopy, the number of low risk biopsies taken would decrease by 60% with minimal loss of accuracy. A negative spectroscopy result would exclude high grade dysplasia or cancer with an accuracy of >99.5%. Conclusions: These preliminary results show that elastic scattering spectroscopy has the potential to target conventional biopsies in Barrett’s surveillance saving significant endoscopist and pathologist time with consequent financial savings. This technique now requires validation in prospective studies.

Whole-genome sequencing provides new insights into the clonal architecture of Barrett's esophagus and esophageal adenocarcinoma.

The molecular genetic relationship between esophageal adenocarcinoma (EAC) and its precursor lesion, Barretts esophagus, is poorly understood. Using whole-genome sequencing on 23 paired Barretts esophagus and EAC samples, together with one in-depth Barretts esophagus case study sampled over time and space, we have provided the following new insights: (i) Barretts esophagus is polyclonal and highly mutated even in the absence of dysplasia; (ii) when cancer develops, copy number increases and heterogeneity persists such that the spectrum of mutations often shows surprisingly little overlap between EAC and adjacent Barretts esophagus; and (iii) despite differences in specific coding mutations, the mutational context suggests a common causative insult underlying these two conditions. From a clinical perspective, the histopathological assessment of dysplasia appears to be a poor reflection of the molecular disarray within the Barretts epithelium, and a molecular Cytosponge technique overcomes sampling bias and has the capacity to reflect the entire clonal architecture.

Non-endoscopic screening biomarkers for Barrett’s oesophagus: from microarray analysis to the clinic

Background and aims: Barrett’s oesophagus predisposes to oesophageal adenocarcinoma but the majority of patients are undiagnosed. A novel non-endoscopic cytological screening device, called a capsule sponge, makes population-based screening for the disease a feasible option. However, due to the mixed cell population retrieved by the capsule sponge, biomarkers specific for Barrett’s oesophagus are required. Methods: Three publically available microarray datasets were used to identify putative biomarkers present in Barrett’s oesophagus but absent from normal oesophagus and gastric mucosa. Validation was performed by qPCR (n = 10 each of normal oesophagus, Barrett’s oesophagus, gastric mucosa) and immunohistochemistry (normal oesophagus, n = 20; Barrett’s oesophagus, n = 21; gastric mucosa, n = 24; duodenum, n = 18). The biomarker was then prospectively evaluated on capsule sponge specimens from 47 patients with Barrett’s oesophagus and 99 healthy controls. Results: 2/14 genes identified, dopa decarboxylase (DDC) and Trefoil factor 3 (TFF3), were confirmed by qPCR to be upregulated in Barrett’s oesophagus compared to normal oesophagus (p<0.01) and gastric mucosa (p<0.01 and p<0.05, respectively). Immunohistochemistry confirmed that DDC protein expression was restricted to Barrett’s oesophagus but was confined to <1% of the cells within the crypt compartment. TFF3 protein was expressed to high levels at the luminal surface of Barrett’s oesophagus compared to absent expression in normal oesophagus and gastric mucosa (p<0.001). Using the capsule sponge 36/46 patients with Barrett’s oesophagus (one inadequate sample) and 6/96 controls were positive for TFF3 giving a sensitivity of 78% and a specificity of 94%. Conclusions: TFF3 is a promising marker for Barrett’s oesophagus screening since it is expressed at the luminal surface of Barrett’s oesophagus but not in adjacent tissue types and may be applied to a non-endoscopic screening device.

Mutational signatures in esophageal adenocarcinoma define etiologically distinct subgroups with therapeutic relevance

Esophageal adenocarcinoma (EAC) has a poor outcome, and targeted therapy trials have thus far been disappointing owing to a lack of robust stratification methods. Whole-genome sequencing (WGS) analysis of 129 cases demonstrated that this is a heterogeneous cancer dominated by copy number alterations with frequent large-scale rearrangements. Co-amplification of receptor tyrosine kinases (RTKs) and/or downstream mitogenic activation is almost ubiquitous; thus tailored combination RTK inhibitor (RTKi) therapy might be required, as we demonstrate in vitro. However, mutational signatures showed three distinct molecular subtypes with potential therapeutic relevance, which we verified in an independent cohort (n = 87): (i) enrichment for BRCA signature with prevalent defects in the homologous recombination pathway; (ii) dominant T>G mutational pattern associated with a high mutational load and neoantigen burden; and (iii) C>A/T mutational pattern with evidence of an aging imprint. These subtypes could be ascertained using a clinically applicable sequencing strategy (low coverage) as a basis for therapy selection.

Evaluation of a Minimally Invasive Cell Sampling Device Coupled with Assessment of Trefoil Factor 3 Expression for Diagnosing Barrett's Esophagus: A Multi-Center Case-Control Study

Background Barretts esophagus (BE) is a commonly undiagnosed condition that predisposes to esophageal adenocarcinoma. Routine endoscopic screening for BE is not recommended because of the burden this would impose on the health care system. The objective of this study was to determine whether a novel approach using a minimally invasive cell sampling device, the Cytosponge, coupled with immunohistochemical staining for the biomarker Trefoil Factor 3 (TFF3), could be used to identify patients who warrant endoscopy to diagnose BE. Methods and Findings A case–control study was performed across 11 UK hospitals between July 2011 and December 2013. In total, 1,110 individuals comprising 463 controls with dyspepsia and reflux symptoms and 647 BE cases swallowed a Cytosponge prior to endoscopy. The primary outcome measures were to evaluate the safety, acceptability, and accuracy of the Cytosponge-TFF3 test compared with endoscopy and biopsy. In all, 1,042 (93.9%) patients successfully swallowed the Cytosponge, and no serious adverse events were attributed to the device. The Cytosponge was rated favorably, using a visual analogue scale, compared with endoscopy (p < 0.001), and patients who were not sedated for endoscopy were more likely to rate the Cytosponge higher than endoscopy (Mann-Whitney test, p < 0.001). The overall sensitivity of the test was 79.9% (95% CI 76.4%–83.0%), increasing to 87.2% (95% CI 83.0%–90.6%) for patients with ≥3 cm of circumferential BE, known to confer a higher cancer risk. The sensitivity increased to 89.7% (95% CI 82.3%–94.8%) in 107 patients who swallowed the device twice during the study course. There was no loss of sensitivity in patients with dysplasia. The specificity for diagnosing BE was 92.4% (95% CI 89.5%–94.7%). The case–control design of the study means that the results are not generalizable to a primary care population. Another limitation is that the acceptability data were limited to a single measure. Conclusions The Cytosponge-TFF3 test is safe and acceptable, and has accuracy comparable to other screening tests. This test may be a simple and inexpensive approach to identify patients with reflux symptoms who warrant endoscopy to diagnose BE.

Randomized crossover study comparing efficacy of transnasal endoscopy with that of standard endoscopy to detect Barrett's esophagus

BACKGROUND Unsedated transnasal endoscopy (TNE) may be safer and less expensive than standard endoscopy (SE) for detecting Barretts esophagus (BE). Emerging technologies require robust evaluation before routine use. OBJECTIVE To evaluate the sensitivity, specificity, and acceptability of TNE in diagnosing BE compared with those of SE. DESIGN Prospective, randomized, crossover study. SETTING Single, tertiary-care referral center. PATIENTS This study enrolled consecutive patients with BE or those referred for diagnostic assessment. INTERVENTION All patients underwent TNE followed by SE or the reverse. Spielberger State-Trait Anxiety Inventory short-form questionnaires, a visual analogue scale, and a single question addressing preference for endoscopy type were administered. MAIN OUTCOME MEASUREMENTS Diagnostic accuracy and tolerability of TNE were compared with those of SE. RESULTS Of 95 patients randomized, 82 completed the study. We correctly diagnosed 48 of 49 BE cases by TNE for endoscopic findings of columnar lined esophagus compared with the criterion standard, SE, giving a sensitivity and specificity of 0.98 and 1.00, respectively. The BE median length was 3 cm (interquartile range [IQR] 1-5 cm) with SE and 3 cm (IQR 2-4 cm) with TNE, giving high correlations between the two modalities (R(2) = 0.97; P < .001). The sensitivity and specificity for detecting intestinal metaplasia by TNE compared with those by SE was 0.91 and 1.00, respectively. The mean (± standard deviation) post-endoscopy Spielberger State-Trait Anxiety Inventory short-form score for TNE (30.0 ± 1.10 standard error of the mean [SEM]) was lower than that for SE (30.7 ± 1.29 SEM), (P = .054). The visual analogue scale scores were no different (P = .07). The majority of patients (59%) expressed a preference for TNE. LIMITATIONS This is a small study, with limited generalizability, a high prevalence of patients with BE, differential drop-out between the two procedures, and use of sedation. CONCLUSION TNE is an accurate and well-tolerated method for diagnosing BE compared with SE. TNE warrants further evaluation as a screening tool for BE.