Studies of the pathophysiology of Barrett's oesophagus

Barrett’s oesophagus is a common condition in which the normal stratified squamous oesophageal epithelium is replaced by metaplastic reflux-induced glandular (“columnar”) mucosa (Jankowski, Barr, Wang et al. 2010;Playford 2005). Over the last three decades, the incidences of oesophageal adenocarcinoma (OA) and Barrett’s oesophagus have risen to the point that OA is now common in the United Kingdom, with Scotland having one of the highest rates in the world (Jankowski, Provenzale, & Moayyedi 2002). Unfortunately most cancers present at an advanced stage with five year survival less than 30% (Holmes and Vaughan 2007). Barrett’s oesophagus is associated with malignant progression via a recognised metaplasia-dysplasia-carcinoma sequence (Jankowski, Wright, Meltzer et al. 1999). The premalignant nature of Barrett’s oesophagus has powered intense clinical interest in the hope of eventually having an impact on the earlier diagnosis and treatment of dysplasia, and ultimately the prognosis of oesophageal adenocarcinoma. Despite years of research interest, Barrett’s oesophagus remains an enigmatic condition. The exact incidence is unknown, and it is recognised that not all patients with Barrett’s oesophagus will progress to adenocarcinoma. Current strategies aim to ascertain the presence of dysplasia, the current gold standard marker of malignant progression. However although Barrett’s mucosa is visible at endoscopy, the presence of dysplasia is difficult to diagnose as these areas tend to be focal and inconspicuous to the naked eye. Current systematic biopsy regimes are recommended, but can be fraught with sampling errors. Furthermore, the molecular mechanisms underlying Barrett’s metaplasia and progression to dysplasia remain unclear. Molecular risk biomarkers have been sought with modest success, and at present dysplasia remains the most reliable clinical marker. However dysplasia itself is not without limitations: focal dysplasia can be difficult to ascertain, with many biopsies sometimes necessary to detect it reliably (Abela, Going, Mackenzie et al. 2008). Inter-observer variability may cause over or under diagnosis, especially regarding LGD (Flejou 2005). Moreover, although patients with HGD are at elevated risk of progression to OA, few studies provide reliable data on rates of progression from HGD to OA, with estimates varying between 16-59% at five years (Reid, Blount, Feng et al. 2000;Schnell, Sontag, Chejfec et al. 2001;Shaheen and Richter 2009;Spechler SJ 2011). There is a real need, therefore, to be able to identify and treat those patients at greatest risk of malignant transformation, and reassure those at low risk. Without an improved molecular understanding of Barrett's metaplasia and progression to neoplasia, clinically useful prognostic biomarkers (allowing appropriate targeting of surveillance and therapy) will be delayed. The current challenges associated with Barrett’s oesophagus are 1) to accurately determine the rate of malignant progression of Barrett’s oesophagus and identify clinical risk factors, 2) to improve the endoscopic detection of dysplasia and early neoplasia allowing earlier diagnosis and treatment and, 3) to understand the molecular mechanisms involved in the initiation of Barrett’s metaplasia, and the pathways involved in disease progression. In an attempt to improve the care of patients with Barrett’s oesophagus within the West of Scotland, my thesis will address each of the main challenges associated with this puzzling condition at clinical, endoscopic and molecular levels. The hypotheses of my thesis are threefold - a) Patients with Barrett's oesophagus in the West of Scotland have high rates of progression to high grade dysplasia and oesophageal adenocarcinoma. b) The WavSTAT optical biopsy system will be able to correctly identify non-dysplastic and dysplastic Barrett's oesophagus. c) The Wnt signalling pathway is upregulated in Barrett's oesophagus and dysplasia. The aims of my thesis are as follows: 1)To present a general overview of the Barrett’s literature highlighting current clinical challenges. 2)To examine the incidence of dysplasia and oesophageal adenocarcinoma in the West of Scotland by analysing a cohort of patients undergoing surveillance endoscopy 3)To review the current endoscopic imaging adjuncts for the diagnosis of Barrett’s oesophagus and dysplasia, and assess the role of optical biopsy forceps in determining the presence of dysplasia. 4)To evaluate the role of Wnt signalling in Barrett’s oesophagus, from metaplasia to carcinoma in a mouse model, with complementary human studies. Chapter 1. introduces the reader to Barrett’s oesophagus and highlights current areas of clinical challenge and debate. A universal definition of Barrett’s oesophagus does not exist and Chapter 2 explores the need for the presence of intestinal metaplasia in the diagnosis of Barrett’s oesophagus. Chapters 3 and 4 present original data from a West of Scotland Barrett’s oesophagus database, specifically analysing rates of dysplasia and adenocarcinoma and cause of death. This study suggests patients with Barrett’s oesophagus in the West of Scotland are at high risk of disease progression with almost 10% of patients dying from oesophageal adenocarcinoma. The results highlight the importance of a comprehensive surveillance in our “high risk” population - an ideal niche for future chemopreventative and molecular studies. In an attempt to improve the diagnosis of dysplasia in our West of Scotland population, Chapter 5 reviews current endoscopic imaging adjuncts used in research and clinical practice while Chapter 6 presents original data from a pilot study assessing the use of innovative optical biopsy forceps in the endoscopic diagnosis of dysplasia. While this technology is in its infancy and further changes in the algorithm are required, the optical forceps could be a promising tool for ongoing surveillance in high risk Barrett’s patients. Chapter 7 summarises the role of biomarkers in Barrett’s oesophagus, reviewing the literature and highlighting the lack of clinically useful markers of disease progression to date. The Wnt signalling pathway plays an important role in normal oesophageal (and intestinal) development, yet when aberrantly activated leads to carcinogenesis. To date, very little is known about the role of Wnt signalling in Barrett’s oesophagus. Chapter 8 presents the results of a mouse model of upregulated Wnt signalling and the interesting finding of dysplasia within the oesophageal mucosa. Chapter 9 therefore translates these results to the human population by assessing the role of Wnt signalling in Barrett’s metaplasia and dysplasia by immunohistochemical analysis of a panel of markers. The results suggest Wnt signalling is upregulated in Barrett’s dysplasia, particularly in high grade, and this may have a future role as a biomarker. Chapter 10 summarises the main findings of the thesis, and presents future directions.