1.1

Introduction

Barrett’s esophagus (BE) is the presence of metaplastic columnar epithelium in the lower portion of the esophagus, which is normally lined with stratified squamous epithelium. The main cause of the disease is theorized to be reflux esophagitis developed due to chronic acid exposure as a result of symptomatic or asymptomatic gastroesophageal reflux. In addition, the disease is clinically significant as a major risk factor for esophageal adenocarcinoma (EAC).

Barrett’s esophagus is named after Norman Rupert Barrett, a highly regarded and successful thoracic surgeon of his period. Contrary to popular belief, however, Norman Barrett’s contribution to the identification of the disease was quite limited. Barrett wrote of the presence of ulcers in the esophagus and the presence of columnar epithelium around ulcers in an article published in 1950 entitled “Chronic peptic ulcer of the oesophagus and ‘oesophagitis’” . However, there were number of inaccuracies in this article and the history of the disease dates back to much older times .

1.2

Norman Rupert Barrett (1903–1979)

Norman Rupert Barrett was born in North Adelaide, Australia, on May 16, 1903, the son of Alfred Barrett and Catherine Hill Connor . His paternal grandfather was a wealthy malt manufacturer who moved to Australia from England in the 1880s. When Barrett was 10 years old, he moved from Australia to London together with his parents and a younger sister where his brilliant academic career would start. Barrett would return to Australia after 50 years, as a visiting professor at Royal North Shore Hospital Sydney, in 1963.

Barrett received his education at Eton College (1917–1922), then continued in Trinity College, and graduated from Cambridge University in 1925. He completed his medical education at St Thomas Hospital (1925–1928). He continued as resident assistant surgeon for the next 2 years at the same hospital and was elected to fellowship of the Royal College of Surgeons in 1930 and the postgraduate degree M. Chir in 1931. He married Annabel Elizabeth “Betty” Warington Smyth, his school friend, when he was 28. Then he began working at St Thomas as surgical staff, then as a consulting surgeon in 1935 and spent his entire professional career there. Barrett’s first trip to America took place when he became entitled to participate in the Rockefeller Travelling Fellowship (1935–1936) program, a prestigious program at the Mayo Clinic. This program would also have a very important place in Barrett’s career, since he would become interested in the emerging field of thoracic surgery, and he would continue the rest of his professional life as a thoracic surgeon. There was still not a thoracic surgery department when he returned to St Thomas. Therefore, he continued to work as both a consulting general surgeon and a consulting thoracic surgeon at the same time ( Fig. 1.1 ).

Norman Rupert Barrett.

He became a member of the British Thoracic Society, which was known as the Thoracic Society at that time. The Thoracic Society chose him as the first editor of Thorax journal and he served as the editor of the journal until 1971. The first article by Barrett in the literature was a report of two cases and an associated literature review that was titled “Surgical Emphysema During General Anesthesia” in 1944 . He published an article about three cases with spontaneous esophageal perforation and a literature review, his second article, in the first issue of Thorax in 1946 . He also pioneered many advances in the field of thoracic surgery. He successfully operated on a case with esophageal rupture, which had been previously considered fatal, and was the first to report it in the literature . Barrett successfully operated on a case with esophageal diverticulum using a thoracic approach, again the first in the literature . In addition, he wrote scientific articles on subjects such as removal of pulmonary cysts , surgical treatment of bronchial carcinoma , primary tumors of the rib , achalasia , mediastinal fibrosis , and congenital heart disease conditions . His other important contribution to the medical literature was the successful detection of malignant cells in cytological examination of sputum with the “wet film” method in lung cancer patients . However, it was the article titled “Chronic peptic ulcer of the oesophagus and ‘oesophagitis’” in 1950 that made the name Norman Barrett famous in our day . Barrett most likely could not estimate the great influence of his article at that time.

Barrett served as a president of the Thoracic Society as well as president of the Thoracic Surgeons of Great Britain and Ireland. He was a member of the Court of Examiners of the Royal College of Surgeons and he was an examiner at universities of Oxford, Cambridge, Birmingham, London, and Khartoum. He was awarded the Commander of the Most Excellent Order of the British Empire in 1969 . He retired from St Thomas Hospital in 1970 after a long and productive career and passed away in London on January 8, 1979.

1.3

Philip Rowland Allison (1907–1974)

When we look back at the literature and sort through the evidence of how intestinal metaplasia (IM) of the esophagus was identified, we find a particular scientist other than Norman Barrett who played a key role. Dr Philip Rowland Allison (1907–1974) should arguably be more prominent than Barrett in receiving credit for the identification of the disease . Allison was one of the leading cardiothoracic surgeons in England. He worked as a general surgeon and cardiothoracic surgeon for many years in the Leeds General Infirmary. One of his major achievements was the first successful cyanotic congenital heart disease surgery in 1948 in Leeds. In addition to cardiovascular surgery, he was a very successful surgeon in hernia surgery and published several scientific articles on this subject ( Fig. 1.2 ).

Philip Rowland Allison.

Allison was the first person to use the “columnary lined esophagus” phrase, correctly identifying the histological change. Ironically, he was also the first person to use the expression “Barrett’s ulcer” in the literature, when he argued that Barrett had made a mistake in his article in 1950. Allison identified peptic ulcer of esophagus and used the expression “reflux esophagitis” first in the articles titled “Peptic ulcer of the oesophagus” in 1946 and 1948 . In addition, he described in detail and in an accurate manner the function of the cardia, that the esophageal epithelium is not resistant to gastric contents, and that gastric contents passing to the esophagus may cause esophagitis and ulceration in cases in which the cardia function was disabled due to reasons such as sliding hernia. Moreover, he mentioned radiological and histological findings of the disease and identified surgical treatments in a detailed manner in these articles. Allison, who was married and had three children, died in March 6, 1974.

1.4

History of Barrett’s Esophagus

Contrary to popular belief, the historical identification of the disease process started much earlier than in Barrett’s lifetime. Boehm described gastroesophageal reflux first in the literature in 1722 as follows: “acute pain which reached down even to the stomach and which was accompanied by hiccup and a constant flow of serum from the mouth” . Joanne Petro Frank first used the expression “esophagitis” in 1792. Johann Friedrich Hermann Albers, a German physician and pathologist, was the first to propose the concept of esophageal ulcers in history in 1839. Quincke reported histopathological findings of esophageal ulcers with the presentation of three postmortem cases in 1879 . The first scientific account of esophagitis was reported by Morell Mackenzie, a British laryngologist, in 1884 . Mackenzie described acute esophagitis in the Disease of the Gullet section of his book as follows: “acute idiopathic inflammation of the mucous membranes of the esophagus, giving rise to extreme odynophagia, and often to aphagia.”

The probable presence of columnar metaplasia in the esophagus was reported nearly two centuries ago. The presence of gastric mucosal islands in the esophagus was first described by Schmidt from Halle University in Germany in 1805 (about 150 years before Barrett) . Schridde published in 1904 that aberrant columnar epithelial islands were present in the esophagus in autopsy cases . Wilder Tileston, a Harvard pathologist, published the historically important article “Peptic ulcer of the oesophagus” in 1906 . In this article, Tileston wrote that peptic ulcers may develop in the esophagus, that the lack of gastroesophageal junction is necessary for this development, and columnar epithelium, which is normally seen in the stomach, is present around the developed ulcer. In addition, this article is indeed the first in proposing the relationship between gastroesophageal reflux and esophageal ulcer disease, although it did not exactly use the expression gastroesophageal reflux disease (GERD) at that time. Moreover, Tileston described 12 different specific etiologies other than peptic ulcer in this article. A.L. Taylor from University of Leeds reported that macroscopic columnar mucosal islands may present in the distal esophagus and first suggested that this condition is a persistent process in 1927 .

Norman Barrett published the article titled “Chronic peptic ulcer of the oesophagus and ‘oesophagitis’” which started the discussion in 1950 . He proposed in his article as follows: “I believe that reflux oesophagitis is common and that it can give rise to ulceration of the oesophagus and stricture formation… I submit that most of these cases are in truth examples of congenital short esophagus, in which there is neither general inflammation nor stricture formation, but in which a part of the stomach extends upwards into the mediastinum, or even to the neck, and that in this stomach a typical chronic gastric ulcer can form.” . Barrett mentioned chronic peptic ulcer of the esophagus and presence of gastric-type epithelium in this region. However, he believed that this region was not the esophagus but actually a part of the stomach that had slipped into the mediastinum due to congenital short esophagus and not due to hiatal hernia. Bosher and Taylor published an article which was almost a response to this article and identified completely the histopathological features of BE for the first time in literature 1 year later. Authors mentioned aortic arch-level chronic peptic esophageal ulcer disease associated with columnar-lined epithelium and suggested that the epithelium in this region was similar to the gastric epithelium but without parietal cells and contained goblet cells and submucosal glands of the esophagus. Bosher and Taylor disproved Barrett’s theory of the stomach sliding to the mediastinum due to congenital short esophagus with their article. This article is in fact the first article in the literature describing specialized (with goblet cells) IM. One year later Morson and Belcher and 2 years later Allison and Johnstone published articles confirming the presence of columnar epithelium with goblet cells.

The article published by Allison and Johnstone in 1953 has quite an important place in the history of BE. A series of 115 cases with esophageal ulcers and strictures was presented in this article titled “The oesophagus lined with gastric mucous membrane.” They demonstrated the presence of columnar mucosa in the esophagus in 11 cases, presence of reflux esophagitis or hiatal hernia in 7 cases, and presence of EAC in 1 case. Authors pointed out that columnar-lined epithelium was not a rare condition, contrary to common belief. They emphasized that Norman Barrett made a mistake in 1950 and proposed that this condition may occur in the esophagus. The objection to Norman Barrett was published in Thorax journal, of which Barrett was still the editor. The article contained very important details. Authors expressed that: “Patients with the oesophagus lined by gastric mucous membrane are subject to gastric ulcers occurring in that part of the oesophagus lined by gastric mucosa, and it is suggested that, if these become chronic, they might be known as Barrett’s ulcers . Such ulcers may occur alone or in association with reflux ulcers of the oesophagus.” Ironically, although this article was published in objection to Barrett’s article, the disease was referred for the first time in literature with his name and led to coining the term.

The precancerous potential creating the clinical significance of BE would also begin to be mentioned in those years. Before Allison and Johnstone, Carrie published a presentation of 20 cases in 1950 and suggested first that EAC may develop from ectopic gastric epithelium. Subsequently, Morson and Belcher published the first article revealing the relationship between the presence of columnar epithelium in the esophagus (still thought to be ectopic gastric mucosa) and EAC in 1952. They proposed IM with goblet cells to be a predisposing cause for EAC in this article. Allison and Johnstone in 1953 and Thomas and Hay in 1954 mentioned the relationship between EAC and columnar-lined epithelium. There would be many articles confirming this relationship in subsequent years .

Norman Barrett would renounce the idea of congenital short esophagus 7 years after his article but would continue to insist another inaccuracy; “it is probably the result of a failure of the embryonic lining of the gullet to achieve normal maturity” . However, Barrett eventually gave up his insistence and offered in 1960 that “It would have been better if the term had never been introduced, because it has led to wrong thinking” . As it can be seen, Norman Barrett had an important but nonetheless minor contribution on the etiology of the disease, much less so for the correct definition of its histology, and identification of the premalignant potential. It is one of the ironies of Medicine and History that the disease is still known with Norman Barrett’s name to this day.

The eponym of “Barrett’s syndrome” was used by Goldman and Beckman in 1960; and eventually eponym of Barrett’s esophagus was used by Seaman and Wylie in 1966 for the first time in the literature. The continued use of the eponym “Barrett’s esophagus” has over the years led to objections. Bani-Hani mentioned the history of the disease in detail and objected to still referring to the disease with the name of Barrett in an article titled “Columnar-lined esophagus: Time to drop the eponym of ‘Barrett’: Historical review” . They make a compelling argument, however, the disease has become more and more important in the recent decades and a name change at this point will be difficult.

There were many advances in identification of both etiology and histopathological features of the disease in the second half of the 20th century. The disease would be demonstrated to be associated with GERD and hiatal hernia and not to be congenital in publications by Moersch et al. , Hayward , and Adler . Hayward stated that: “It is probably neither ectopic, nor congenital, nor permanent, nor in need of resection but metaplastic and reversible.” Cohen et al. published the most detailed study ever conducted on the issue in 1963. They put an end to whether columnar-lined epithelium belongs to the stomach or the esophagus with this study. They examined this phenomenon with manometric, radiological, endoscopic, and histopathological methods. The region lined by columnar epithelium showed motor activity of the esophagus in manometric examination as well . Naef et al. demonstrated in 1972 that esophagitis findings decreased with Nissen fundoplication, but columnar epithelium did not regress. In subsequent years, it would also be shown that periodic acid suppression decreased esophagitis findings but only led to a partial regression of columnar epithelium; in addition, columnar epithelium did not fully regress even in cases after antireflux surgery, and adenocarcinoma could still develop as well .

Trier , Berenson et al. , and Paull et al. published detailed studies on histopathological features of the disease in those years. Paull et al. examined distal esophageal biopsies taken with manometric examination in detail in a series of 11 patients with BE in 1976. They showed the presence of three different types of columnar epithelium in their cases. The first one was intestinal-type epithelium, which was referred to as specialized (containing intestinal-type goblet cells but not parietal or chief cells) columnar epithelium, and it was present in squamous epithelium junction of the most proximal columnar-lined epithelium. The second one was junctional (cardia-type) epithelium that contained cells secreting mucus and presented in the middle parts. The third one was gastric fundic–type epithelium that contained parietal and chief cells and was located at the most distal end.

The disease was defined thoroughly in the 1980s, and there were many studies on the relationship of the disease with dysplastic changes and EAC . Hayward proposed that the region until 2 cm from the distal of esophagus has cardia-type epithelium, and biopsies taken from this region by the endoscopist may mistakenly lead to a BE diagnosis, thus potentially causing overdiagnosis . Therefore, there was a need for diagnostic criteria. Another problem was the misguided assumption that the disease was always associated with GERD symptoms and thus there was no need to conduct a biopsy in the asymptomatic . Skinner et al. would argue for diagnostic criteria on the issue for the first time and recommended biopsy for asymptomatic patients as well in 1983 . According to them, the 1–2 cm distal portion of the esophagus normally contained cardia-type columnar epithelium, and therefore columnar-lined epithelium was necessary to be ≥3 cm in the distal esophagus in order to be diagnosed as BE. In addition, they showed in this article that dysplasia may develop in asymptomatic patients as well . The 3-m limit would survive for about 10 years, but the study by Spechler et al. showed that it was not very accurate in 1994. Squamocolumnar junction biopsies of 142 white and 114 non-white successive cases without BE on endoscopic examination were taken and examined. There was a presence of IM in 18% of the first group and 14% of the second group. In addition, they showed that endoscopic findings of GERD and GERD symptoms were not reliable diagnostic criteria. Following this study, a new concept came up: the presence of <3 cm IM on esophagus was called “short segment BE.” There would be studies presenting the progressive potential of short segment BE and the relationship of short segment BE with dysplasia and adenocarcinoma in the following years .

Clinical guidelines began to be created in the 1990s. The American College of Gastroenterology guideline was first published in 1998 . Then, different guidelines would be published and would be revised in subsequent years .

In the 2000s, diagnostic histopathological findings (such as the presence of the cardia-type metaplasia, and whether the goblet cells were present or not) as well as surveillance details would be the debated issues as will be described in detail in related sections.

Has Normal Barrett gotten too much credit for this disease? It may appear so when we examine the documented history. However, it does not appear that he himself asked for it and the discussion initiated by him in 1950 still continues today. This in itself deserves significant merit. We have certainly come a long way since the initial proposed argument. It is clear that IM of the esophagus leads to adenocarcinoma. We have identified several risk factors and intense research is being conducted on elucidating the genetics of the disease. In the future, we hope to be able to identify who is going to be at risk depending on genetic factors so that we can influence the lifestyle choices that lead to the disease. We have gotten better than ever at finding early disease and effective surveillance strategies are being evaluated to follow patients cost effectively. There have been several breakthroughs in endoscopic and surgical treatment of BE. However, we are now finding that some of our assumed triumphs, like the duration of complete remission of intestinal metaplasia after ablative therapy, are not as long lasting as we had hoped. The next generation of therapies is sure to focus on noninvasive methods.

The following chapters will take us through the background of the different facets of the disease and provide emerging evidence that we hope will be used to improve clinical practice. At the end of each chapter, a short section has been provided for the authors to expand on where they believe the future research will focus, where the discussion will go.