Impact of endoscopic biopsy surveillance of Barrett's oesophagus on pathological stage and clinical outcome of Barrett's carcinoma

BACKGROUND: The efficacy of endoscopic biopsy surveillance of Barrett's oesophagus in reducing mortality from oesophageal cancer has not been confirmed. AIMS: To investigate the impact of endoscopic biopsy surveillance on pathological stage and clinical outcome of Barrett's carcinoma. METHODS: A clinicopathological comparison was made between patients who initially presented with oesophageal adenocarcinoma (n = 54), and those in whom the cancer had been detected during surveillance of Barrett's oesophagus (n = 16). RESULTS: The surveyed patients were known to have Barrett's oesophagus for a median period of 42 months (range 6-144 months). Prior to the detection of adenocarcinoma or high grade dysplasia, 13 to 16 patients (81%) were previously found to have low grade dysplasia. Surgical pathology showed that surveyed patients had significantly earlier stages than non-surveyed patients (p = 0.0001). Only one surveyed patient (6%) versus 34 non-surveyed patients (63%) had nodal involvement (p = 0.0001). Two year survival was 85.9% for surveyed patients and 43.3% for non-surveyed patients (p = 0.0029). CONCLUSIONS: The temporal course of histological progression in our surveyed patients supports the theory that adenocarcinoma in Barrett's oesophagus develops through stages of increasing severity of dysplasia. Endoscopic biopsy surveillance of Barrett's oesophagus permits detection of malignancy at an early and curable stage, thereby potentially reducing mortality from oesophageal adenocarcinoma.     

Modelling a population with Barrett's oesophagus from oesophageal adenocarcinoma incidence data

Objective. A recent study of adenocarcinoma of the oesophagus (ACO) incidence rates in Denmark showed a steep fall in the over-80 population, interpreted as the result of a decline in the prevalence of Barrett's oesophagus (BO) in this age group, for which three hypotheses were advanced: the specific mortality from ACO and, superimposed, either excess mortality from causes of death unrelated to ACO or a birth cohort effect. The aim of this study was to create models estimating the BO population fitting each of these three hypotheses, in order to select the most plausible hypothesis and to gain insight into the Danish BO population. Material and methods. Models were designed for these three hypotheses, conforming to the generally accepted 0.4–0.5% annual ACO incidence in BO patients. These models employed expectation-maximization (EM) algorithms, Danish life tables and the observed ACO incidence rates. The models enabled the estimation of a BO population for each hypothesis. Results. After testing against set criteria, the most plausible model was found to be that describing a birth cohort effect which predicted a ±5% annual rise in the prevalence of BO and, consequently, in the incidence rate of ACO in Denmark. This prediction was borne out over the subsequent decade. Conclusions. This rising ACO incidence rate is likely to continue into the foreseeable future. The use of EM algorithms enabled a first estimate of the BO population at risk of ACO, although, owing to the limitations imposed by the models, the age- and gender-specific ACO risk for the entire Danish BO population could not as yet be ascertained.     

Intestinal metaplasia at the squamocolumnar junction in patients attending for diagnostic gastroscopy

Background—The incidence of adenocarcinoma of theoesophagus and gastric cardia is increasing rapidly. Barrett'soesophagus is the major risk factor. Intestinal metaplasia at thesquamocolumnar junction in the absence of Barrett's oesophagus iscommon but its relation to adenocarcinoma and gastro-oesophageal refluxdisease is unclear.
Aims—To study the prevalence and clinical,endoscopic, and histological associations of intestinal metaplasia atthe squamocolumnar junction.
Methods—Biopsy specimens were taken from 120 randomly selected patients undergoing routine diagnostic endoscopy.Eight biopsy specimens, taken from above and below the squamocolumnarjunction, gastric fundus, and gastric antrum, were stained withhaematoxylin/eosin, alcian blue/periodic acid-Schiff, and Gimenez, andgraded independently by one pathologist.
Results—Intestinal metaplasia at thesquamocolumnar junction was found in 21 patients (18%). Metaplasia wasassociated with increasing age (p<0.01) and antral intestinalmetaplasia (p=0.04). Logistic regression analysis revealed that age wasthe only independent predictor (p<0.01). There was no association withsymptomatic, endoscopic, or histological markers of gastro-oesophagealreflux disease.
Conclusions—Intestinal metaplasia at thesquamocolumnar junction is a common finding. It is associated withincreasing age but not gastro-oesophageal reflux disease.

Keywords:intestinal metaplasia; Barrett's oesophagus; gastro-oesophageal reflux disease; oesophagus; gastric cardia; adenocarcinoma

     

Correlation of oesophageal acid exposure with Barrett's oesophagus length

BACKGROUND: Gastro-oesophageal reflux disease (GORD) plays a major role in the development of Barrett's oesophagus. However, it has yet to be elucidated what factors determine the length of Barrett's mucosa in each individual patient. AIMS: To determine if there is a correlation between oesophageal acid exposure and the length of Barrett's mucosa. We also compared the extent of oesophageal acid exposure between patients with short segment (SSBE) and long segment (LSBE) Barrett's oesophagus. METHODS: Twenty seven patients with Barrett's oesophagus were recruited prospectively into the study from the outpatient gastroenterology clinic at the Southern Arizona VA Health Care System. Diagnosis of Barrett's oesophagus and its anatomical characteristics were determined during upper endoscopy. Ambulatory 24 hour oesophageal pH monitoring assessed the extent of oesophageal acid exposure. RESULTS: There was a significant correlation between per cent total time pH less than 4 and length of Barrett's mucosa (r=0.6234, p=0.0005). In addition, there was a significant correlation between per cent upright and supine time pH less than 4 and length of Barrett's mucosa (r=0.5847, p=0.0014 and r=0.6265 p=0.0006, respectively). Patients with SSBE had significantly less oesophageal acid exposure than patients with LSBE, in terms of both per cent total time and per cent supine time pH less than 4 (p<0.05). CONCLUSIONS: The length of Barrett's mucosa correlated with the duration of oesophageal acid exposure. Patients with LSBE experienced significantly more oesophageal acid exposure than patients with SSBE. Duration of oesophageal acid exposure appears to be an important contributing factor in determining the length of Barrett's mucosa.     

Eradication of Barrett's mucosa with argon plasma coagulation and acid suppression: immediate and mid term results

Background—Intestinal metaplastic mucosa inBarrett's oesophagus can be replaced by squamous epithelium aftermucosal thermal ablation associated with acid suppression therapy.
Aims—To assess whether restoration of squamousepithelium can be obtained after ablation of Barrett's oesophagususing argon plasma coagulation (APC) associated with proton pumpinhibitor (PPI) therapy.
Methods—Thirty one patients with Barrett'soesophagus received APC. Omeprazole (40 mg/day) was given from thefirst APC application to one month after completion of the treatment,then given symptomatically. Twenty four hour pH-metry was performedduring endotherapy.
Results—Complete re-epithelialisation wasvisualised at endoscopy in 25/31 patients (81%) after a mean number of2.4 APC sessions (range 1-4). Only partial squamousre-epithelialisation was observed in three patients and three othershad no eradication. At histological assessment, eradication ofBarrett's oesophagus was only confirmed in 19/31 patients (61%) dueto the presence of a few residual Barrett's glands under the newsquamous epithelium. Complete eradication was related to a Barrett'soesophagus segment length of less than 4 cm and the absence ofcircumferential extension but not to the normalisation of oesophagealacid exposure under PPI therapy. Seventeen patients with apparentlycomplete endoscopic and histological eradication of Barrett'soesophagus were re-evaluated at one year; eight (47%) disclosedrelapsing islands of Barrett metaplasia despite continuous omeprazoletherapy (10-40 mg/day).
Conclusions—APC combined with 40 mg omeprazoledaily can eradicate Barrett's mucosa with apparent squamousre-epithelialisation in the majority of patients even in the absence ofnormalisation of oesophageal acid exposure. However, one year afterendotherapy for Barrett's oesophagus, relapse is frequent but limitedin extent.

Keywords:Barrett's oesophagus; argon plasma coagulation; omeprazole; gastro-oesophageal reflux; Barrett's adenocarcinoma

     

Endoscopy in Barrett's oesophagus: adherence to standards and neoplasia detection in the community practice versus hospital setting

Objective. Potential process differences between hospital and community‐based endoscopy for Barrett’s oesophagus have not been examined. We aimed at comparing adherence to guidelines and neoplasia detection rates in medical centres (MC) and community practices (CP). Design. Retrospective analysis. Setting. All histologically confirmed Barrett cases seen over a 3‐year period in six MC and 19 CP covering a third of all upper gastrointestinal endoscopies (n = 126 000) performed annually in Berlin, Germany. Main outcome measure. Rate of relevant neoplasia (high‐grade intraepithelial neoplasia or more) in both settings in relation to adherence to standards. Results. Of 1317 Barrett cases, 66% were seen in CP. CP patients had a shorter mean Barrett length (2.6 cm vs. 3.8 cm; P < 0.001) with fewer biopsies taken during an examination (2.5 vs. 4.1 for Barrett length ≤2 cm; P < 0.001). CPs also provided fewer complete esophagogastroduodenoscopy documentation (25.1% vs. 57.8%, P < 0.001). Neoplasias were found more commonly in MCs compared to CPs (9.2% vs. 0.8%; P < 0.001). However, on exclusion of all referred patients with known neoplasia (65%) or those examined for other reasons (27.5%), the detection rate at MCs decreased to 1.3%, not different from the one seen at CPs (0.8%, P = 0.43). Only 13% were found during surveillance, but 57% were diagnosed at an early stage. Conclusions. Referral bias and not better adherence to guidelines could explain the higher neoplasia prevalence in Barrett’s oesophagus at hospital centres. Despite a generally poor adherence to guidelines, most neoplasias found were at an early and potentially curable stage.     

Risk of Barrett's oesophagus,oesophageal adenocarcinoma and reflux oesophagitis and the use of nitrates and asthma medications

Abstract

Objective. To investigate the relationship between use of asthma medication and nitrates and risk of reflux oesophagitis, Barrett's oesophagus and oesophageal adenocarcinoma. Material and methods. Data were collected on use of asthma medication and nitrates at least 1 year before interview from patients with reflux oesophagitis, Barrett's oesophagus and oesophageal adenocarcinoma. Associations between use of asthma medications and nitrates and the risk of reflux oesophagitis, Barrett's oesophagus and oesophageal adenocarcinoma were estimated using multiple logistic regression. Results. Nine hundred and forty-one subjects were recruited: 230 reflux oesophagitis, 224 Barrett's oesophagus, 227 oesophageal adenocarcinoma patients and 260 population controls. Barrett's oesophagus patients were more likely than controls to have had a diagnosis of asthma (odds ratio 2.15, 95% confidence interval 1.15–4.03) and to have used asthma medications (odds ratio 2.13, 95% confidence interval 1.09–4.16). No significant associations were observed between use of asthma medication or nitrates and reflux oesophagitis or oesophageal adenocarcinoma. Conclusions. Gastro-oesophageal reflux symptoms appear to confound the association between asthma medication use and Barrett's oesophagus. However, it is possible that asthma medications may increase the risk of Barrett's oesophagus by other mechanisms.     

Risk factors for Barrett's oesophagus: A population-based approach

Objective. Given its often subclinical course, Barrett's oesophagus (BO) hardly lends itself to epidemiologically stringent evaluations. The objective of this study was to investigate risk factors for incident BO diagnosed in a defined population in southeast Sweden while paying particular attention to epidemiological aspects of the study design. Material andmethods. Consecutive patients (aged 18–79 years) who were endoscoped with new indications at units exclusively responsible for all gastroscopies in defined catchment area populations were invited to take part in the study. Biopsies were taken above and immediately below the gastro-oesophageal junction, and exposure information was collected through self-administered questionnaires. Endoscopy-room-based cross-sectional data from 604 patients were supplemented with exposure data from 160 population controls. Associations, expressed as odds ratios (ORs), were modelled by means of multivariable logistic regression. Results. In the comparison with population controls, reflux symptoms and smoking indicated a 10.7- and 3.3-fold risk, respectively, for BO (95% confidence interval (CI) 3.5–33.4 and 1.1–9.9, respectively). Body mass was unrelated to risk. In the cross-sectional analysis among endoscopy-room patients, reflux symptoms were associated with an OR of 2.0 (95% CI 0.8–5.0). This association was, however, modified by the subjunctional presence of Helicobacter pylori; although the infection was not in itself significantly connected with risk, a combination of reflux symptoms and H. pylori infection was linked to an almost 5-fold risk (95% CI 1.4–16.5) as compared with the absence of both factors. The BO prevalence increased by 5% per year of age (95% CI 1–9%). Conclusions. Reflux is the predominant risk factor for BO, and proximal gastric colonization of H. pylori seems to amplify this risk.     

Barrett's oesophagus: Intestinal metaplasia is not essential for cancer risk

Objective. Barrett's oesophagus is the main identifiable risk factor for oesophageal adenocarcinoma. It has been suggested that only patients with intestinal metaplasia are at risk of cancer, but the British Society of Gastroenterology (BSG) guidelines suggest that glandular mucosa is all that is needed. The aim of this study was to quantify the risk of adenocarcinoma in columnar-lined lower oesophagus, with or without specialized intestinal metaplasia. Material and methods. All patients who had endoscopic biopsies of the lower oesophagus between 1980 and 1994 in a single-centre teaching hospital were included in the study. All histological specimens were re-examined and reported according to whether they contained columnar epithelial-lined lower oesophagus, glandular mucosa, with or without intestinal metaplasia. The primary outcome measure was the development of adenocarcinoma. Results. In total, 712 patients were identified. Of these, 379 (55.1%) were found to have specialized intestinal metaplasia (SIM), and the remaining 309 (44.9%, p=NS) were reported as having glandular mucosa (GM). The median follow-up for patients was 12 years (range 8–20 years). Twenty-eight patients went on to develop adenocarcinoma (4.1%) during the follow-up period – 17 in the SIM group (4.5%) and 11 in the GM group (3.6%, p=NS). The oesophageal malignancy rate was 0.34% per year (SIM 0.37%, GM 0.30%; p=NS). Conclusions. Patients who have glandular mucosa on biopsy without intestinal metaplasia have a similar cancer risk to those with specialized intestinal metaplasia.     

Relative risk of dysplasia for patients with intestinal metaplasia in the distal oesophagus and in the gastric cardia

BACKGROUND—Biopsy specimens obtained from the gastro-oesophageal junction can reveal intestinal metaplasia in patients presenting for routine upper endoscopy. The site of biopsy may play a critical role in determining the dysplasia risk of a patient.
AIMS—To evaluate prospectively the dysplasia risk in patients with intestinal metaplasia of the distal oesophagus or within the gastric cardia.
METHODS—Patients with short segment Barrett's oesophagus (SSBO) and cardia intestinal metaplasia (CIM) were followed prospectively.
RESULTS—177 patients with SSBO were identified (mean age 62 years, range 38-82; 91% whites). Twenty prevalence cases of dysplasia in SSBO were detected: 17 low grade dysplasia (LGD), three high grade dysplasia (HGD). Seventy six patients with CIM were identified (mean age 67 years, range 37-81; 81% whites). A single prevalence case of LGD in CIM was detected. During follow up of 78 SSBO and 34 CIM patients, dysplasia developed in nine (seven LGD, two HGD) with SSBO and in one (LGD) with CIM. There were significant differences between the two groups with respect to age, ethnicity, dysplasia prevalence, and incidence. Time to dysplasia progression was significantly longer in CIM compared with SSBO patients. Of the five patients with SSBO and HGD, one developed adenocarcinoma of the oesophagus on follow up. No HGD or cancers have been detected over this time period in CIM patients.
CONCLUSIONS—The dysplasia risk is significantly greater in SSBO than in CIM patients, indicating two potentially different clinical processes. Future studies should separate SSBO from CIM in order to enhance the understanding of the pathophysiology and malignant potential of each entity.


Keywords: high grade dysplasia; low grade dysplasia; metaplasia; Barrett's oesophagus; gastro-oesophageal reflux disease     

Intramucosal adenocarcinoma arising under squamous re-epithelialisation of Barrett's oesophagus

BACKGROUND: Eradication of Barrett's mucosa by thermal or photoablation combined with high doses of proton pump inhibitors is a potentially attractive strategy in the management of this preneoplastic condition. However, major concerns of this method are the persistence of residual metaplastic glands beneath the new squamous epithelium and the absence of any knowledge of its impact on long term outcome. CASE REPORT: The case of an intramucosal adenocarcinoma diagnosed 18 months after apparently complete squamous re-epithelialisation achieved using argon plasma coagulation and high dose omeprazole (40 mg/daily) is reported in a 68 year old patient presenting initially with a Barrett's oesophagus without dysplasia. Intramucosal adenocarcinoma was located under the new squamous layer and presented as a bulging area covered by the squamous epithelium. It probably originates from residual metaplastic glands after therapy although a pre-existing tumour cannot be definitely excluded. CONCLUSION: This observation might question future application of this experimental endotherapy in non-dysplastic Barrett's oesophagus. It suggests that the residual glands might still be premalignant and that the early diagnosis of neoplastic changes might be compromised by the squamous re-epithelialisation.     

Neuromuscular function of the human lower oesophageal sphincter in reflux disease and Barrett's oesophagus

BACKGROUND: Columnar lined (Barrett's) oesophagus is often considered a sequel to chronic severe reflux disease. Aberrant lower oesophageal sphincter (LOS) motility associated with Barrett's oesophagus includes reduced basal LOS pressures. The aim of this study was to characterise neuromuscular function of the LOS in normal (squamous cell carcinoma (SCC) with uninvolved LOS) and reflux affected (Barrett's) oesophagus in vitro. METHODS: Strips of LOS muscle were prepared at biopsy following oesophagectomy from 16 patients with SCC and seven patients with oesophageal adenocarcinoma and Barrett's oesophagus associated with a history of reflux disease. LOS smooth muscle responses were recorded in response to electrical field stimulation (EFS), potassium chloride (KCl), DMPP, isoprenaline, capsaicin, bethanechol, and tachykinins. RESULTS: Basal LOS tone and LOS relaxations in response to isoprenaline, EFS, and DMPP were not significantly altered in the Barrett's group. After tetrodotoxin pretreatment, responses to KCl and DMPP were significantly reduced in the SCC but not in Barrett's LOS. Maximal contraction in response to bethanechol was significantly decreased in Barrett's LOS while substance P and NK-2 receptor mediated contraction was unaltered. Capsaicin, NK-1, and NK-3 receptor agonists exerted negligible effects on LOS tone. CONCLUSIONS: LOS muscle strips from patients with reflux associated Barrett's oesophagus exhibit a reduction in cholinergic muscle contraction while retaining similar features of basal tone, responses to tachykinins, and inhibitory muscle and neural function. Enteric inhibitory neurones in LOS muscle strips from patients with reflux associated Barrett's oesophagus display resistance to axonal sodium channel blockade. No evidence for functional NK-1 or NK-3 receptors or capsaicin sensitive axon collateral reflexes was observed in the human LOS.     

Cost-effectiveness of Barrett's oesophagus screening and surveillance

Endoscopic screening and surveillance of patients with Barrett's oesophagus to detect oesophageal cancer at earlier stages is contentious. As a consequence, their cost-effectiveness is also debatable. Current health economic evidence shows mixed results for demonstrating their value, mainly due to varied assumptions around progression rates to cancer, quality of life and treatment pathways. No randomized controlled trial exists to definitively support the efficacy of surveillance programs and one is unlikely to be undertaken. Contemporary treatment, cost and epidemiological data to contribute to cost-effectiveness analyses are needed. Risk assessment to stratify patients at low- or high-risk of developing cancer should improve cost-effectiveness outcomes as higher gains will be seen for those at higher risk, and medical resource use will be avoided in those at lower risk. Rapidly changing technologies for imaging, biomarker testing and less-invasive endoscopic treatments also promise to lower health system costs and avoid adverse events in patients.     

Photothermal laser ablation of Barrett's oesophagus: endoscopic and histological evidence of squamous re-epithelialisation

Background—Barrett's oesophagus is acquired bysevere gastro-oesophageal reflux and is a premalignant condition. Acidsuppression or anti-reflux surgery alone do not cause significantregression of the metaplastic mucosa nor reduce the malignantpotential. Recent reports have suggested that the combination ofmucosal ablation with acid suppression may result in squamous regeneration.
Aims—To destroy Barrett's mucosa by thermalablation (in the setting of acid suppression) and so induce squamous regeneration.
Patients—Sixteen patients with non-dysplasticBarrett's oesophagus were recruited from a surveillance programme. Allhad been on a proton pump inhibitor.
Methods—At intervals, non-circumferentialareas of columnar mucosa were ablated using the KTP laser. Acidsuppression was obtained with 40 mg omeprazole daily. Multiple biopsyspecimens were obtained for histological examination from ablated areas.
Results—Ablation of all areas of glandular mucosaresulted in squamous regeneration. The number of treatments requireddepended on the length of the Barrett's segment. In 11 patients therewas evidence of squamous regeneration over remaining Barrett's glands (in some of the post-treatment biopsy specimens) whilst in nine patients squamous metaplasia was seen within Barrett's glands.
Conclusion—Mucosal ablation of Barrett'soesophagus by laser, in the setting of acid suppression, results insquamous regeneration (though some burying of Barrett's glands did occur).

Keywords:Barrett's oesophagus; laser; dysplasia; columnar-lined oesophagus; cancer

     

Mucin gene expression in Barrett's oesophagus: an in situ hybridisation and immunohistochemical study

BACKGROUND AND AIMS: Mucin genes are expressed in a site specific manner throughout the gastrointestinal tract. Little is known about the expression pattern in the oesophagus. In this study we have investigated MUC gene expression in both the normal oesophagus and specialised intestinal metaplasia (Barrett's oesophagus). PATIENTS: Archived paraffin embedded material from eight specimens of normal oesophagus, 18 Barrett's oesophagus, eight gastric metaplasia, six high grade dysplasia, and six cases of adenocarcinoma were examined for expression of the mucin genes MUC1-6. METHODS: Mucin mRNA was detected by in situ hybridisation using [(35)S] dATP labelled oligonucleotide probes. Mucin core protein was detected by immunohistochemistry. RESULTS: Normal oesophagus expressed MUC5B in the submucosal glands and MUC1 and MUC4 in the stratified squamous epithelium. Barrett's oesophagus strongly expressed MUC5AC and MUC3 in the superficial columnar epithelium, MUC2 in the goblet cells, and MUC6 in the glands. In high grade dysplasia and adenocarcinoma there was downregulation of MUC2, MUC3, MUC5AC, and MUC6, but upregulation of MUC1 and MUC4 in half of the specimens examined. CONCLUSIONS: Normal oesophagus and Barrett's oesophagus have a novel pattern of mucin gene expression. Barrett's oesophagus expressed the mucins associated with normal gastric epithelium and normal intestinal epithelium. While most mucin genes were downregulated in severely dysplastic and neoplastic tissues, there was upregulation of the membrane bound mucins MUC1 and MUC4. This may prove useful in detecting early signs of progression to adenocarcinoma of the oesophagus.     

Role of growth factors in oesophageal mucosal healing: A work in progress

Abstract Reflux of gastroduodenal contents into the oesophagus results in dynamic cycles of injury followed by cell proliferation and repair. These processes are receiving increased attention due to the high incidence of gastro-oesophageal reflux disease and the rising incidence of adenocarcinoma of the oesophagus. Repeated cycles of injury and repair may lead to abnormal differentiation followed by abnormal growth. This article summarizes the research performed by our group in the field of oesophageal injury and repair. We initially developed an in vivo perfused rabbit oesophagus model that served to study the effects of various components of the gastroduodenal juice on several parameters of oesophageal injury. We have shown that pepsin causes severe morphological oesophagitis at an acidic pH but is ineffective at an alkaline pH. We have also demonstrated that trypsin causes severe morphological oesophagitis at an alkaline pH but not at an acidic pH. Bile salts were found to disrupt the oesophageal barrier at both pH levels. We have also studied the effects of epidermal growth factor (EGF) and insulin-like growth factor-I (IGF-I) on oesophageal regeneration. We used an ex vivo oesophageal explant model for these experiments. Both EGF and IGF-I cause a dose-dependent increase in oesophageal DNA synthesis, cell proliferation and mucosal growth. These effects are synergistic and can be inhibited by specific tyrphostins. We are currently studying the role of growth factors as therapeutic agents and the role of growth factors in the development of Barrett's oesophagus and adenocarcinoma.     

K-ras codon 12 mutations in Barrett's oesophagus and adenocarcinomas of the oesophagus and oesophagogastric junction

BACKGROUND: Activation of the ras oncogene is commonly found in gastrointestinal tract cancers, but the role of ras in the development and progression of Barrett's oesophagus and associated cancers is uncertain. METHODS: The frequency of K-ras codon 12 point mutations was assessed in 52 paraffin-embedded tissues from 44 patients with oesophageal pathology. The specimens were classified pathologically as follows: adenocarcinoma of the oesophagus or oesophagogastric junction (n = 23), Barrett's high-grade dysplasia (n = 5), low-grade dysplasia (n = 14), intestinal metaplasia (n = 4), normal oesophagus (n = 5) or normal stomach (n = 1). DNA was extracted from three consecutive sections of each paraffin block and mutations at bases 1 and 2 of K-ras codon 12 were identified using a novel restriction endonuclease-mediated selective polymerase chain reaction method. RESULTS: Mutations were found in 7 of 23 (30.4%) adenocarcinomas and in 2 of 5 (40%) high-grade dysplasia specimens. No mutations were found in specimens of low-grade dysplasia, intestinal metaplasia without dysplasia, or normal oesophagus and stomach. There were no significant associations between the presence of mutations and clinicopathologic features in the patients with cancer. One patient who progressed from low-grade to high-grade dysplasia was found to have developed mutant K-ras in the course of this transformation. CONCLUSION: These results suggest that K-ras codon 12 mutations may occur frequently in patients with Barrett's oesophagus with high-grade dysplasia or adenocarcinoma of the oesophagus or oesophagogastric junction. K-ras mutation may be a late event in the Barrett's metaplasia-dysplasia-adenocarcinoma sequence.     

Immunohistochemical analysis of metaplastic non-goblet columnar lined oesophagus shows phenotypic similarities to Barrett's oesophagus: A study in an Asian population

BackgroundBarrett's oesophagus is a premalignant condition, predisposing to oesophageal adenocarcinoma. However, some adenocarcinoma may arise in columnar lined oesophagus without goblet cells. Our aim was to evaluate the biological properties of non-goblet columnar lined oesophagus only and elucidate its relationship with Barrett's oesophagus and associated neoplasia.MethodsEndoscopic biopsies from patients with Barrett's oesophagus (n = 30), non-goblet columnar lined oesophagus (n = 14), Barrett's oesophagus associated high grade dysplasia (n = 6) and adenocarcinoma (n = 4) were selected. Immunostaining for villin, claudin 3 and MUC4 was performed. Statistical analysis was performed and a p value <0.05 was considered significant.ResultsVillin and MUC4 were positive in 42%, 100% each and 50% in non-goblet columnar lined oesophagus, Barrett's oesophagus, high grade dysplasia and adenocarcinoma respectively, while claudin 3 was 100% positive in all the groups. In non-goblet columnar lined oesophagus, six cases that were villin immunopositive, showed positive expression for claudin 3 and/or MUC4 and there was no difference from the high grade dysplasia or adenocarcinoma (p > 0.05).ConclusionOur results indicate that a subset of non-goblet columnar lined oesophagus shows an intestinal phenotype representing an early stage of Barrett's oesophagus. This subset probably harbours the potential to change into adenocarcinoma in the long term.     

When and how to grade Barrett's columnar metaplasia: the Prague system

Barrett's oesophagus (BO), a well-known precursor for oesophageal adenocarcinoma has been generating a great deal of controversy. The initial step in diagnosing BO requires an accurate endoscopic recognition of the columnar lined oesophagus. A reliable diagnosis of BO depends on its effective endoscopic recognition based on the key anatomic landmarks, followed by histological sampling of the columnar-lined epithelium. Precise localisation of the gastrooesophageal junction is pivotal in the endoscopic diagnosis of BO. Multiple ad-hoc grading systems and terminologies of BO have been proposed based on the Z-line appearance, presence or absence of intestinal metaplasia, and the length of Barrett's segment. However, a universally accepted standardised endoscopic grading system of BO is lacking. The Prague C&M criteria, developed by a subgroup of the International Working Group for the Classification of Oesophagitis, are the first explicit, consensus-driven, clinically relevant criteria for the endoscopic recognition and grading of BO that may be useful in both clinical practice and research trials.     

Expression of the p53 homologue p63alpha and DeltaNp63alpha in the neoplastic sequence of Barrett's oesophagus: correlation with morphology and p53 protein

BACKGROUND: While loss of p53 function is a key oncogenic step in human tumorigenesis, mutations of p53 are generally viewed as late events in the metaplasia-dysplasia-adenocarcinoma sequence of Barrett's oesophagus. Recent reports of a series of genes (p63, p73, and others) exhibiting close homology to p53 raise the possibility that abnormalities of these p53 family members may exert their influence earlier in the sequence. AIM: Following recent characterisation of expression of p63 and a major isoform DeltaNp63 by generation of an antiserum that recognises p63 isoforms, but not p53, our aim was a comparative study of expression of p63 protein and p53 protein in a morphologically well defined biopsy series representative of all stages of the metaplasia-dysplasia-carcinoma sequence in Barrett's oesophagus. METHODS: A series of 60 biopsy cases representing normal oesophagus through to invasive adenocarcinoma were stained, using immunohistochemistry, with antibodies to p63 and p53. All biopsies derived from patients with endoscopic and histopathological substantiation of a diagnosis of traditional/classical Barrett's oesophagus. RESULTS: There was exact concordance in p53 and p63 expression in more advanced forms of neoplasia, high grade dysplasia, and invasive adenocarcinoma, while p63, but not p53, was detected in the proliferative compartment of some non-neoplastic oesophageal tissue, in both squamous mucosa and in the non-neoplastic metaplastic glandular epithelium. CONCLUSIONS: In neoplastic Barrett's oesophagus there is upregulation of both p63 and p53 while p63 isoforms may well have an important role in epithelial biology in both non-metaplastic and metaplastic mucosa of the oesophagus. While abnormalities of p53 function represent an indisputable and critical element of neoplastic transformation, other closely linked genes and their proteins have a role in both the physiology and pathophysiology of the oesophageal mucosa.