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  • Review Article
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Reflux, Barrett's oesophagus and adenocarcinoma: burning questions

Nature Reviews Cancer volume 3, pages 676–684 (2003)Cite this article

Key Points

  • Oesophageal adenocarcinoma (EA) is commonly preceded by replacement of the normal squamous epithelium by a specialized metaplastic columnar-like epithelium, termed Barrett's oesophagus (BE). Individuals with BE have at at least an order of magnitude increased risk of EA.

  • EA is increasing in incidence in Western countries and in Australia, with an approximate doubling in incidence over a ten-year period. However, potential misclassification of adenocarcinomas of the lower oesophagus and gastric cardia complicate interpretations of time trends in incidence. There is much less information concerning trends in the incidence of BE.

  • Gastro-oesophageal reflux disease (GERD) is a strong risk factor for both the development of BE and EA. Other risk factors include obesity; diets low in fruit, vegetables and fibre; and tobacco.

  • The process by which reflux constituents provoke BE and progression to EA are ill-defined. Acid exposure stimulates the formation of a columnar epithelial phenotype and modifies cell proliferation. The role of bile salts might be potentially modulated by the mildly acidic pH conditions that are stimulated by acid-suppressive medication.

  • The development and progression of BE is characterized by the acquisition of many molecular changes. These molecular changes could be used as biomarkers to refine surveillance programmes in patients with BE.

  • Evidence indicates that oxidative stress and chronic inflammation promote the development and progression of BE. This affords the opportunity for preventative intervention strategies — potentially involving dietary antioxidants and non-steroidal anti-inflammatory drugs.

Abstract

The incidence of oesophageal adenocarcinoma is increasing rapidly in Western populations. Gastro-oesophageal reflux disease is a strong risk factor for both this tumour and the pre-cancerous lesion Barrett's oesophagus, but the underlying disease mechanisms remain unclear. Developing a better understanding of the aetiology and pathogenesis of Barrett's oesophagus, including the induction of DNA damage and genetic alterations, might provide opportunities for improved management of individuals with this disease. This could include a better rationale for screening and surveillance programmes, as well as targeted intervention strategies.

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Figure 1: Key morphological and cytokeratin-expression differences between normal squamous and Barrett's epithelial phenotypes.
Figure 2: The proposed association between reflux exposure and attendant inflammation on the development and progression of Barrett's oesophagus.
Figure 3: Diagramatic representation of reflux in an individual with Barrett's oesophagus.
Figure 4: The proposed mechanistic link between reflux exposure and inflammation on cellular damage.
Figure 5: Molecular events associated with the development of Barrett's oesophagus and oesophageal adenocarcinoma.

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Acknowledgements

The authors would like to thank D. Forman for his critical comments on an earlier version of this manuscript and Yorkshire Cancer Research for financial support for research into oesophageal cancer at the Molecular Epidemiology Unit.

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Authors and Affiliations

  1. Molecular Epidemiology Unit, Epidemiology and Health Services Research, School of Medicine, University of Leeds, Leeds, LS2 9JT, UK

    Christopher P. Wild & Laura J. Hardie

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  1. Christopher P. Wild
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  2. Laura J. Hardie
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Correspondence to Christopher P. Wild.

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DATABASES

Cancer.gov

breast cancer

liver cancer

lung cancer

oesophageal adenocarcinoma

LocusLink

CDKN2A

COX 2

cyclin D1

TP53

FURTHER INFORMATION

Barrett's oesophagus

Barrett's oesophagus

Barrett's oesophagus

Cancer of the oesophagus

Molecular Epidemiology Unit

Glossary

UPPER ENDOSCOPY

A procedure whereby a flexible fibre-optic lens is passed via the mouth to visualize the oesophagus, stomach or small intestine.

GASTRO-OESOPHAGEAL REFLUX DISEASE

(GERD). A consequence of chronic reflux, GERD comprises various possible clinical and histological alterations to the lining of the oesophagus. These include erosive oesophagitis, thickening of the oesophageal lining, strictures and ulceration of the oesophagus. GERD can be accompanied by Barrett's oesophagus.

GASTRO-OESOPHAGEAL REFLUX

The passage of contents of the stomach and sometimes the duodenum back in to the oesophagus. It typically occurs after a meal — the lower oesophageal sphincter usually remains closed, but if it relaxes inappropriately, acid, bile and food particles can reflux into the oesophagus. This can irritate the walls of the oesophagus and induce a secondary peristaltic contraction of smooth muscle, causing the symptoms of discomfort or pain that is known as heartburn.

OESOPHAGITIS

Inflammation of the oesophagus provoked by reflux and motility disturbances.

RECALL BIAS

Differences in recollection across individuals or study groups that are the result of altered perception or circumstance because of disease rather than true experience.

PROTON-PUMP INHIBITORS

A class of drugs that specifically bind to the gastric-acid pump (H+/K+-ATPase) of parietal cells and that inhibit gastric-acid secretion.

BODY-MASS INDEX

A measure of obesity as defined by weight (kg)/ height (m2). Individuals with values of 30 and above are defined as clinically obese.

ANTICHOLINERGICS

Agents that inhibit parasympathetic neural activity by blocking the neurotransmitter acetylcholine.

TH1 RESPONSE

A T-helper-1 cell-mediated immune response is mediated by pro-inflammatory cytokines such as interferon-γ, interleukin-1β and tumour necrosis factor-α. It promotes cellular immune responses against intracellular infections and malignancy.

TH2 RESPONSE

A T-helper-2 response involves production of cytokines such as interleukin-4, which stimulate antibody production. TH2 cytokines promote secretory immune responses of mucosal surfaces to extracellular pathogens and allergic reactions.

ANEUPLOIDY

A chromosome complement that is not a simple multiple of the haploid set.

LOSS OF HETEROZYGOSITY

(LOH). Occurs when loss of a particular segment of the genome can be shown by the analysis of a polymorphic marker in that region. If an individual is somatically heterozygous for this marker, but homozygous in the tumour, then there has been 'loss of heterozygosity' in that region. Recurrent LOH of a region indicates the presence of a classical tumour-suppressor gene, although recurrent regional loss is also seen for other reasons (for example, because of the presence of fragile sites).

ANTI-REFLUX SURGERY

A surgical procedure whereby the upper part of the stomach is wrapped around the lower oesophagus to improve gastro-oesophageal competence and to limit reflux.

META-ANALYSIS

A retrospective analysis of the results from different studies, making certain assumptions, to reach a conclusion that is based on the pooled data.

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Wild, C., Hardie, L. Reflux, Barrett's oesophagus and adenocarcinoma: burning questions. Nat Rev Cancer 3, 676–684 (2003). https://doi.org/10.1038/nrc1166

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