1.I believe such a case.

2.Such a case is not due to reflux of duodenal cotent. I think it is due to alchol and smoking.

3.It is difficult to define. From my impression, immunostin (COX2,p53 etc ) will be suitable tool to differentiate between Barrett's OAD and non-Barrett's OAD.

Thanks Naoki

For classic oesophageal adenocarcinoma, the main risk factors are GORD, obesity, male gender, smoking, but not alcohol.

Based on Lagergren (NEJM 1999), reflux symptoms are very strong factor for OAD regardless of the presence of Barrett's. So if those symptoms are really come from acid reflux, some patients may develop acid induced OAD without passing Barrett's stage.

Thank you Mohammad for a very interesting discussion topic

As you mentioned, many patients develop OAD without showing any evidence for Barrett's oesophagus. In my experience the number of dysphasia related to Barrett are very low. This means that not every patient with Barrett oesophagus is at similar high risk for dysplasia. I agree, it is time to narrow the surveillance to those Barrett truly at high risk and identify those patient with non Barrett presentation faster in earlier stage.

Thanks Kamran

As we do not know exact mechanism of non-Barrett's OAD, early recognition and prevention is challenging.

I wonder whether the cases you are referring to underwent resection and carefully examined by expert GI pathologist - endoscopic surveillance and biopsies are often inaccurate for diagnosis of Barrett's esophagus. Agree with immunostains and that is what we do.

I believe the existence of non-Barrett's OAD but it is a very small proportion of esophageal adenocarcinoma.

In our epidemiological datas (Finistere Registry of Digestive Tumors), adenocarcinomas of the lower third of the esophagus are much rarer than those of Barrett mucosa.

In my opinion the risk factors are likely to be rather different than Barrett's OAD with exposure to toxic substances (tobacco, alcohol, nitrosamines...), why not on heterotopic glandular areas or submucosal glands.

Screening is therefore impossible in my opinion because it is uncommon and there is no identified risk factors.

For discusion I recomended this study:

Das, D. et al. Management of Barrett's esophagus in the UK: overtreated and underbiopsied but improved by the introduction of a national randomized trial. Am. J. Gastroenterol. 103, 1079–1089 (2008).

Some theories discuss the possibility that Barrett's esophagus in most patients is a form of mucosal defense, and successful adaptation to the ongoing hostile environment associated with chronic GERB

1 Specialized intestinal metaplasia is a well-differentiated epithelium criptal architecture, in which stem cells proliferate bases in different specialized cells facing the lumen of the crypt.

Such architecture is considered as a tumor inhibiting mutant cells that do not arise from stem cells fail to accumulate in large numbers but are discarded in the lumen of the crypt.

2.Cylindrical epithelium secretes bicarbonate anions in quantities that exceed several times the possibility of secretion of squamous epithelium

3.Specialized intestinal metaplasia cells secrete a thick mucus barrier that is not found in squamous epithelium.

Recent ultrastructural studies in favor of this theory that just destroying mucose barriers created conditions for chromosomal instability in Barrett's esophagus.

4.Barrett's esophagus has claudin18 + intercellular connections (tight junctions), this protein prevents the penetration of HCl - the squamous epithelium lacking this protein.

5.With Barrett's esophagus is the overexpression of genes involved in the defense and restoration of mucosal cells Barrett's esophagus maintain intra-cellular pH in the normal range and the protracted / repeated reflux episodes

Incidence of esophageal adenocarcinoma (AE) is increasing more rapidly than any other cancer in the Western countries and some parts of Asia, despite the efforts of early diagnostic and treatment (IPP ect.)

Current practice of controlling the incidence of the disease based on endoscopic diagnosis of patients with symptomatic GERD and histologic conditioned monitoring and treatment of patients with Barrett's esophagus has many flaws and no apparent effect on the incidence

Obvious is the need to develop new strategies of prevention, monitoring and treatment to reduce morbidity and mortality

Except HCl, reflux of gastric contents consist of a number of potentially carcinogenic compounds such as bile salts, pancreatic enzymes, food ingredients (metabolites, additives, ect.). All of these compounds can cause acute and chronic inflammation of the lining of the esophagus, which leads to oxidative stress.

** Cooper, BT, Chapman, W., Neumann, CS & Gearty, JC Continuous treatment of Barrett's esophagus patients with proton pump inhibitors up to 13 years: observations on regression and cancer incidence. Aliment Pharmacol. Ther. 23, 727-733 (2006).

Feagins, L. A. et al. Acid has antiproliferative effects in nonneoplastic Barrett's epithelial cells. Am. J. Gastroenterol. 102, 10-20 (2007)

Jenkins, G. J. et al. The acid was Deoxycholic acid has a non-linear dose response for DNA damage and possibly NF-kappaB activation in oesophageal cells, with a mechanism of action involving ROS. Mutagenesis 23, 399-405, 2008

According to everything we know aboat AE there are four main risk factors of developing adenocarcinoma:

gastroesofagealna reflux disease (GERD)

visceral adiposity

cigarette smoking

diet without fresh fruit and vegetables

genetic predisposition

Visceral adiposity except that promotes long-term GERD, supported by a state of "low-level" systemic inflammation characterized by elevated proinflammatory cytokines, receptors and hormones, such as: interleukin-6 (IL-6), tumor necrosis factor-α (TNF) and TNF receptor 2, CRP and leptin

Smoking causes systemic inflammation and local inflammation, epithelial esophagus (swallowing various products of cigarette smoke)

State of chronic systemic and localized inflammation and oxidative stress leads to DNA damage, cell proliferation, leukocyte telomere shortening, which increases the risk of developing clones with different changes in the genome, extended chromosomal instability and adenocarcinoma

Chronic inflammation plays a central role in the development of esophageal adenocarcinoma

**von Zglinicki, T. Oxidative stress shortens telomeres. Trends Biochem. Sci. 27, 339-344 (2002).

None of the currently available interventions, whether it is based on changing lifestyles chemoprevention or medical treatment so far, in randomized studies did not show efficacy in reducing the incidence and / or mortality of AE.

The focus of future research should be directed at finding new strategies to prevent and treat this disease.

Develop and evaluate effective diagnostic test to assist in the risk assessment and risk stratification.

Biomarkers that are now of interest, for example, the status of Helicobacter pylori infection, leukocyte telomere length, the level of the reactants of inflammation and related proteines,.citokines and hormones.

Develop and evaluate the most effective interventional procedures for each of the risk groups

modification of lifestyle / education

chemoprevention

surveillance protocols

Develop and evaluate a variety of medical, endoscopic and surgical intervention in the treatment of individuals at high risk (eg photodynamic th / ablation)

Adenocarcinoma of the esophagus (ACE) not associated with adjacent Barrett’s epithelium is occasionally observed by endoscopist and pathologists. This phenomenon has led to the theory that ACE can arise in the absence of BE. What is not known about these cases is what type of epithelium previously occupied the mucosal surface occupied by the ACE at the time of index endoscopic observation or surgery. If such cases are treated with chemoradiation rather than surgery there is a near certainty that as the cancer shrinks or disappears in response to the chemoradiation dysplastic Barrett’s epithelium will appear in the surface area formally occupied by the ACE (see Barthel, et al. Does Barrett’s esophagus respond to chemoradiation therapy for adenocarcinoma of the esophagus? Gastrointestinal endoscopy 2010; 71:235-40). It is reasonable to conclude that the BE was there initially and gave rise to the cancer which simply overgrew the original area of BE. Barrett’s epithelium appears to be relatively resistant to chemoradiation therapies effective against ACE. The persistent BE following chemoradiation appears to be quite dangerous and capable of quickly re-establishing treatment resistant ACE. Recognition of this phenomenon led the NCCN to recommend beginning in 2010 that endoscopic surveillance of the esophagus be carried out following treatment of EAC with definitive chemoradiation therapy. If one accepts that carcinogenesis is a phenomenon of dysregulated cell system evolution rather than specific metabolic pathways and that cell system evolution is described by the mathematical principles governing aperiodic behavior in deterministic nonlinear dynamical systems then the likelihood that heterogeneous precancerous transitional states such as BE did not exist initially becomes infinitesimally small (see Heng, et al Genetic and Epigenetic Heterogeneity in cancer: A Genome- Centric Perspective. J Cell Physiol 2009; 220:538-47).

I’m very happy to see the question has attracted many valuable comments from experts. The recent opinions by Ziad, Julien, Brkic and James indicate that almost all of us believe the existence of non-Barrett’s OAD, which may be defined in different ways.

To continue the discussion and attract more ideas from scholars we need to reach an agreement on the definition of “non-Barrett’s OAD” first. I propose the following definition and everybody may want to revise it or may suggest a completely different definition:

A. Non-Barrett’s OAD is a histologically proven adenocarcinoma located at the distal oesophagus in a patient without any evidence of current or past Barrett’s oesophagus.

A1. As the therapeutic modalities (i.e. EMR, Ablation, all types of chemotherapy, chemoradiation) may change the histological characteristics of background mucosa, the definition can be applied to only treatment- naïve subjects.

A2. Definition of Barrett’s Oesophagus here is based on the endoscopic appearance of mucosal changes at the distal oesophagus followed by histological confirmation of specialised columnar metaplasia (presence of goblet cells is necessary by American but not by British definition of Barrett’s).

This is a very thought provoking question. I thank Mohammad for posting it and for proposing a definition of non-Barrett OAD.

However, there is a problem with the proposed definition in that the definition element specified as ‘without any past evidence of BE’ relies on inherently imprecise measurements. The proposed definition consists of three elements: 1) OAD is histologically proven, 2) the patient is without any present evidence of BE (at the time of diagnosis), and 3) the patient is without any past evidence of BE. As observers, from our position in the present, the first two elements of the definition can be measured on a binary scale with extreme precision for any observed OAD. Unfortunately, the precision of the third element is entirely dependent upon prior sporadic continuous scale time interval measurements that lack useful levels of precision. Therefore, only two of the three elements of the non-Barrett’s OAD definition can be measured with the near absolute precision required to permit an accurate prediction that the presently observed OAD with no associated BE did not arise from BE. Non-Barrett’s OAD as defined appears to lead to a situation of predictive hopelessness – we simply cannot know (predict) given the precision of the measurements we can make or otherwise have access to. These considerations are independent of any future treatment of the observed OAD and of how evolutionary transitional states such as BE are defined. This is why it is important to look beyond system definitions for clues concerning system behavior.

It seems that it is necessary to bring consensus on the diagnosis of BE. I think that the presence of goblet cells is necessary for the diagnosis Likely that at least some cases of the non BE ACE recruited due to inconsistent diagnostic criteria for BE

Also, the assessment of the degree of dysplasia is subjective methods with large variations in interpretation among pathologists. It has been shown that treatment of dysplasia as determined by the entry surrogate, or an “end point” of the development of esophageal adenocarcinoma does not reduce the incidence nor mortality of this disease. I have a feeling that we need to find more subtle diagnostic marker (higher specificity and sensitivity than a degree of dysplasia) as well as bring new standards of histologic interpretation.

I agree with Dr. Barthel´s comment on the difficulty of diagnosing non-BE adenocarcinoma. In my opinion a clear diagnosis of non-BE adenocarcinoma has several drawbacks. First, sometimes it is difficult to distinguish between esophageal adenocarcinoma and adenocarcinoma from the gastric cardia, therefore two different entities may be mixed. Second, Barrett´s epithelium may disappear during the development of the carcinomatous tissue. If you don´t find it in the surgical specimen does not automatically mean it was not there. Finally, many of esophageal adenocarcinomas on BE are prevalent cancers, diagnosed before the beginning of the surveillance program.

On the other hand, we must acknowledge that some kind of metaplasia from esquamous to a glandular tissue is needed before the development of an esophageal adenocarcinoma. It may not be necessary to harbor a BE as we define it, but a gastric metaplasia or a IM of the gastric junction.