Diagnosis of Barrett’s Esophagus

5.1

Introduction

In 1950, Norman Barrett wrote the paper entitled “Chronic peptic ulcer of the oesophagus and ‘oesophagitis’” where he described a case in which a portion of the stomach was noted to be within the chest . It was later determined by Allison and Johnstone in a detailed description of seven cases that what Barrett had described was actually a columnar-lined esophageal segment. They also noted an association with esophageal reflux disease . Since that time there have been dramatic changes in the understanding of this condition, which it seems will forever bear Norman Barrett’s eponym.

Barrett’s esophagus is an acquired condition present in 10–15% of patients with chronic gastroesophageal reflux disease (GERD). It is currently defined as a condition in which normal stratified squamous epithelium is replaced with columnar epithelium with intestinal type mucosa in the distal esophagus . While Barrett’s esophagus is asymptomatic, its clinical importance is that it is one of the only known risk factors for esophageal adenocarcinoma. Esophageal adenocarcinoma is the cancer with the most rapidly increasing incidence in the Western world . Barrett’s is thought to progress in stages from intestinal metaplasia to low-grade dysplasia (LGD), high-grade dysplasia (HGD), and then finally to invasive adenocarcinoma.

In the United States, the diagnosis of Barrett’s esophagus first begins with the endoscopic visualization of proximally displaced squamous epithelial lining of the distal esophagus followed by biopsy specimens obtained from the true tubular esophagus showing specialized intestinal metaplasia. Biopsies are obtained not only to enable a diagnosis of Barrett’s but also to identify dysplasia and early cancers at a stage when curative treatment may be possible. A clear diagnosis is very important for patients as, once diagnosed, they will likely be placed into routine endoscopic surveillance based on current society guidelines and there will be personal fears and concerns about their risk for esophageal cancer in the future. A diagnosis of Barrett’s may also have implications for health and life insurance in the United States .

5.2

Histopathologic Diagnosis of Barrett’s

Barrett’s esophagus (BE) is well established as a complication of GERD . Reflux of various substances such as acid and bile from the stomach, along with other factors such as increased transient lower esophageal sphincter relaxations (TRLES) and decreased esophageal motility allow for a prolonged exposure of the esophagus to refluxate from the stomach. This causes chronic inflammation and subsequent repair of the esophageal mucosa. The repair process in some individuals results in the replacement of normal esophageal epithelium with intestinal metaplasia. These changes may be the result of a number of genetic alterations and changes in cellular molecular pathways. It has been proposed that loss of p63 expression in squamous mucosa is involved . Other studies have suggested overexpression of CDX2 and BMP4 to play a role in the pathogenesis of Barrett’s . Loss of TGFβ signaling as seen in knockout mice may lead to altered cell differentiation and intestinal metaplasia .

For many years, there has been disagreement on what defines Barrett’s esophagus histologically. In the United States, the definition of Barrett’s esophagus as per the American Gastroenterological Association (AGA) is “the condition in which any extent of metaplastic columnar epithelium that predisposes to cancer development replaces the stratified squamous epithelium that normally lines the distal esophagus” . Thus, the presence of goblet cells is required for a diagnosis of Barrett’s esophagus in the United States and many other countries ( Fig. 5.1 ). The British Society of Gastroenterology requires the presence of endoscopically visible features of Barrett’s esophagus with metaplastic columnar epithelium on esophageal biopsies . It does not necessarily require the detection of intestinal metaplasia in the affected segment. The Japanese do not require the presence of intestinal type epithelium either, but do require the presence of endoscopically evident palisading vessels to delineate the gastroesophageal junction .

There is much debate about whether intestinal metaplasia must be present for the diagnosis of BE or if only the presence of columnar mucosa is enough. Although most esophageal adenocarcinomas occur in the presence of intestinal metaplasia, esophageal adenocarcinomas may also occur in the presence of other types of mucosa such as cardia type in the absence of intestinal metaplasia . Some studies have suggested that columnar cell epithelium may have analogous immunohistochemical profiles to intestinal metaplasia based on similar intestinal markers such as CDX-1, cytokeratins, mucin, and similar chromosomal instability . But much of what is known about cancer risk in Barrett’s esophagus is based on an association with intestinal metaplasia either primarily or exclusively. For the past several decades, most studies on Barrett’s esophagus have used specialized intestinal metaplasia as an entry criterion.

More recently in 2015, experts conducted an international, multidisciplinary, systematic search and evidence-based review of BE (BOB CAT) and established an international agreement for a definition of BE. The definition states “BE is defined by the presence of columnar mucosa in the esophagus and it should be stated whether intestinal metaplasia (IM) is present above the gastroesophageal junction” . This definition works to combine endoscopic and pathological diagnosis of various worldwide GI societies. It recognizes that intestinal metaplasia may not always be sampled on biopsies and there are cases where EA is not always preceded by intestinal metaplasia (see sections later). There are likely to be future modifications of this working definition.

5.2.1

Definition of Intestinal Metaplasia

Barrett’s esophagus is composed of columnar epithelium and may contain goblet cells, enterocytes, Paneth cells, and some cells with combined gastric and intestinal features. There may also be multilayered epithelium, which has characteristics of both squamous and columnar features . Goblet cells are specialized columnar epithelial cells normally found in the intestinal lining that function to produce gel-forming mucins. When these cells are identified in the stomach or esophagus, they represent intestinal metaplasia . Goblet cells are identified both with hematoxylin–eosin stain and ancillary stains like Alcian blue/periodic acid Schiff stain. On hematoxylin–eosin stains, Goblet cells are dispersed on a background of nongoblet neutral mucin-containing cells similar to those of the gastric mucosa. Goblet cells contain acid mucin that imparts blue discoloration to the mucin vacuole, which compresses the nucleus and laterally displaces the membranes of adjacent cells. The Alcian blue/periodic acid Schiff stain facilitates identification of goblet cells. This stain colors the neutral mucin of gastric foveolar epithelium red, while the acidic mucin of goblet cells is blue ( Fig. 5.1 ). However, a variety of goblet cell mimics may also show Alcian blue positivity, thereby representing diagnostic pit falls when these stains are utilized. For example, injured, hyperplastic foveolar type epithelial cells, columnar cells that contain blue-tinged mucin, columnar cells lining ducts that drain mucosal and submucosal glands, submucosal mucinous glands, and multilayered epithelium cells may also stain positive for Alcian blue stains (Alcian blue-positive goblet cell mimics). None of these goblet cell mimics have been shown to confer as a high risk of malignant progression and should not be considered to represent specialized epithelium .

Columnar metaplasia of the distal esophagus is difficult to distinguish from the proximal gastric cardia histologically. Cardiac epithelium, which has traditionally been considered the normal lining of the most proximal portion of the stomach (the gastric cardia), is almost exclusively composed of mucus secreting gastric foveolar type cells without goblet cells. Observations suggest that cardiac epithelium found in the esophagus might not be a normal type of epithelium but rather an abnormal, metaplastic epithelium acquired as a consequence of GERD . Although lacking the goblet cells of specialized intestinal metaplasia, cardiac epithelium nevertheless expresses molecular markers of intestinal differentiation (eg, villin and CDX2) . Cardiac epithelium can be considered “intestinalized” even without goblet cells. Furthermore, cardiac epithelium exhibits genetic abnormalities similar to those found in specialized intestinal metaplasia. Thus, cardiac epithelium might be predisposed to malignancy despite its lack of goblet cells . In one series of 141 patients with small esophageal adenocarcinoma removed primarily by endoscopic mucosa resection, more than 70% of the lesions were adjacent to cardiac/fundic-type mucosa rather than intestinal metaplasia. Intestinal metaplasia was actually not found in 56.6% of biopsy specimens . Indeed, even in specialized intestinal metaplasia, the highly differentiated goblet cell seems an unlikely candidate to be the malignant cell of origin. Examples of low-grade, high-grade and indefinite for dysplasia are shown in ( Figs. 5.2–5.4 ).

5.3