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Volume: Barrett's Esophagus
Chapter: Diagnosis

What is the cause and significance of intestinal metaplasia distal to the Z-line?

H.D. Appelman (Ann Arbor)

The Z-line is the endoscopic equivalent of the histologic squamocolumnar junction. In normal people, it marks the junction between the most proximal gastric columnar mucosa and the most distal esophageal squamous mucosa. We have been taught for years that the mucosa on the gastric side is cardiac mucosa and that cardiac mucosa is a normal part of the gastric microscopic anatomy, although there is now some debate as to whether it is really normal or whether it is a metaplastic response to injury such as reflux [1, 2]. This cardiac mucosa has been largely ignored until recently, but now it is a hot topic for analysis, discussion and debate. Virtually all biopsies from the cardia are inflamed, generally with a superficial layer of plasma cells. This is carditis. Activity with neutrophils in the epithelium, mainly in the gland necks, is occasionally present, and when it is, H. pylori is often on the surface, so that this active chronic carditis with H. pylori is identical to the H. pylori gastritis in the antrum [3]. However, most cases of carditis have no activity, the plasmacytosis is mild, and there is nothing about the histologic findings or the clinical stories to suggest a cause. Cardiac and Barrett's mucosae are similar. Barrett's mucosa commonly has mucus glands that appear identical to those in the cardia, except there are far fewer of them.

The similarities between Barrett's and cardiac mucosae became more complicated by the discovery that biopsies taken from the gastric side of the Z-line, in other words from the most proximal cardiac mucosa, have intestinal metaplasia (IM) marked by goblet cells in a large number of people. In other words, IM, perhaps comparable to that in Barrett's mucosa, occurs in the cardia, and it is not rare [4-24]. Thus, all mucosa from the cardioesophageal junction area that has goblet cells is not Barrett's mucosa, and it is difficult at times to determine if a biopsy comes from a Barrett's mucosa with mucus glands or from an intestinalized gastric cardia. There are two other considerations. First what causes goblet cells to appear in cardiac mucosa? Does their appearance have anything to do with the ubiquitous carditis mentioned above? Second, we know that goblet cell rich mucosae in both the esophagus, namely Barrett's, and in the gastric body and antrum, namely atrophic gastritis, have powerful cancer associations. Do goblet cells in the cardia have similar cancer implications?

The types of intestinal metaplasia distal to the Z-line

Goblet cells are headline grabbing, mature, intestinal-type mucus containing cells that are, in reality, only a small part of two different types of IM. In one type the goblet cells are mixed exclusively with other intestinal cells, including absorptive and Paneth cells. This is referred to as complete IM. In the second type, the goblet cells are mixed with mucuscontaining columnar cells that resemble gastric pit cells, although they may have mucins that are different than those in the stomach. This is incomplete IM, and it is the characteristic type found in Barrett's mucosa, where it is also referred to as the "specialized columnar epithelium" (SCE). This same SCE term is used in many studies to refer to goblet cells in cardiac mucosa, although few studies actually offer any details about the specific histologic characteristics of the goblet cell containing cardiac mucosa. This lack of characterization of the type of IM in the cardia is a potential problem, since complete and incomplete IMs have different cancer associations, especially in the stomach. The complete form has little cancer association, while for the incomplete form the association is stronger, especially for that subtype of incomplete IM in which the columnar cells contain sulfated mucins [25]. In the two studies which cardiac IM was separated into its two types, one from Finland and the other from the Netherlands, complete IM in the cardia was about 1.5 to 2 times as common as incomplete IM [19,24]. If these findings apply to all the other reports of IM in the cardia, then the potential carcinoma-associated IM may account for only bout 40% of cardiac IM.

For the rest of this discussion, the abbreviation IM is synonymous with goblet cellcontaining columnar mucosa regardless of type. The abbreviation SCE, for specialized columnar mucosa, is synonymous with incomplete IM.

What is the cause of intestinal metaplasia immediately distal to the Z-line?

The many studies of cardiac goblet cells, although they seem to be comparable, actually have differences in patient selection and in biopsy sites, so that the data are not comparable (Table I). In some studies biopsies were only taken when the squamocolumnar junction and the gastroesophageal junction (GEJ) coincided. In other studies, the biopsies were taken from the squamocolumnar junction even when it was in the lower 3 cm of the esophagus, as long as there were no endoscopic findings to suggest Barrett's mucosa. [23] One study even compared two types of biopsies: in one type, the biopsies contained cardiac mucosa immediately adjacent to the squamous, while the second type, the biopsies were taken a few millimeters distally [11]. The results were that the cardiac mucosa adjacent to the squamous was more likely to be inflamed and to contain goblet cells than the mucosa a few millimeters away. This suggested that the more proximal in the stomach the biopsies are

Table I. Cardiac goblet cells in patients without endoscopic Barrett's mucosa: percent positive, location of biopsy and sex.

taken, the more likely goblet cells are present. This also implies that the mucosa immediately adjacent to the squamous is different than that only a few millimeters away. Supporting this view of the cardia as a very small mucosa is an autopsy study of the GEJ, in which the segments of cardia that contained goblet cells were likely to be tiny, usually less than 3 millimeters below the squamocolumnar junction [17]. These two studies have relevance regarding other studies in which the biopsies, said to be of cardia, actually were taken as far as 2 cm distal to the squamocolumnar junction, in which case some of the biopsies were not from the cardia at all.

Perhaps either because of or in spite of these sampling issues, the studies report that the two most important potential causes of cardiac goblet cells include gastroesophageal reflux and H. pylori infection. With H. pylori, cardiac IM becomes the most proximal manifestation of the H. pylori-associated multifocal atrophic gastritis. Of course, there may be other causes, that are currently unknown or unsuspected. All of the following studies need to be reevaluated in light of the fact that the biopsies they analyzed may have been taken too far from the squamocolumnar junction to actually have cardiac mucosa.

The data implicating reflux largely emanate from clinical studies performed at the University of Southern California School of Medicine [1, 2, 16]. In these studies biopsies of the GEJ were correlated with esophageal motility and pH measurements. The findings were that cardiac mucosa was invariably inflamed and the presence of not only the inflammation but the cardiac epithelium itself correlated with deficient lower esophageal sphincter function and increased acid exposure in the lower esophagus. Furthermore, the prevalence of goblet cells, presumably SCE, although the type of IM was not specifically stated, increased as the acid exposure increased and was related to esophagitis as defined by the presence of endoscopic, not histologic, erosions. This was supported by a Finnish study covering biopsies from the cardia in over 1,000 patients. Ten percent of these patients had cardiac incomplete IM, which was associated with increasing age, carditis and endoscopic erosive esophagitis, but not H. pylori. In contrast, 12% of the patients had IM, which was associated with multifocal atrophic gastritis and H. pylori in the rest of the stomach [24]. However, even in a single institution, studies performed at different times may yield different results. An Australian study published in 1997 concluded that cardiac IM was associated with histologic esophagitis and cardiac inflammation, but not with H. pylori at the junction [14]. An abstract published in 2000 from the same group found that cardiac IM was not associated with reflux but was associated with increasing age and H. pylori [15].

There is other data suggesting that reflux is not important, while H. pylori may be. In a study from the Midwestern United States, patients without reflux symptoms were much more likely to have cardiac IM than were refluxers, and in this population, IM was associated with H. pylori and IM in the gastric antrum [7]. Gastric atrophy and IM are commonly sequellae of H. pylori gastritis, and the cardia is frequently involved with that infection [3]. A Germany study found that IM in columnar mucosa immediately below the normal squamocolumnar junction in over 300 consecutive patients who had upper endoscopy was associated with gastric H. pylori and gastric IM but not with reflux symptoms [9]. A study from a large military hospital in the US found that IM just distal to the squamocolumnar junction was associated with H. pylori at the junction, but not with heartburn or endoscopic esophagitis [10]. A study from the southwestern United States found that IM in the proximal stomach, 1-2 cm below the endoscopic GEJ, was related to more distal gastric atrophy and IM, but not to H. pylori [6]. However, in this study the biopsies were taken from sites more distal to the junction than in other studies. Since cardiac mucosa may be limited to no more than a few millimeters distal to the junction, it is likely that some of their biopsies actually came from proximal body mucosa rather than from cardiac mucosa. In a study from the United Kingdom, 18% of 194 patients had IM at the GEJ that was not associated with either reflux symptoms or endoscopic inflammation of the distal esophagus [4]. This is similar to an Austrian study in which IM at the squamocolumnar junction was not associated with anything, including reflux symptoms, squamous hyperplasia in the distal esophagus, carditis and H. pylori [18]. However, a study of 150 patients of all types from the Midwest United States who had upper endoscopy found that cardiac IM was related to microscopic cardiac inflammation, the cause of which might be H. pylori in some cases but in others, the cause was not obvious, although reflux was suspected [8].

It is obvious from this discussion that the studies of IM in cardiac mucosa are not comparable in terms of either patients or of biopsy sites. As a result, this ever increasing literature has done little to inform us as to whether the cause of goblet cells in this site is H. pylori, reflux, some other stimuli or combinations of all three.

What is the significance of intestinal metaplasia immediately distal to the Z-line?

Regardless of the cause of goblet cells in the cardia, do these goblet cells have any meaning? Why should we care if they are present? It is an established fact that IM in the esophagus as Barrett's mucosa and in the stomach as a component of atrophic gastritis is the soil in which adenocarcinomas evolve. The discovery of cardiac goblet cells and the rapidly increasing number of cardiac adenocarcinomas fueled the concept that cardiac IM was the precursor of these cancers. In fact, virtually every paper dealing with IM at the cardia begins with some statement about the alarming increase in carcinomas of either the cardia or the GEJ. Although an assumption of a link between cardiac IM and carcinoma seems reasonable, there is little data to support it. Some studies have found that carcinomas centered at the GEJ are often accompanied by Barrett's mucosa, but this seems to indicate that some carcinomas at the very end of the esophagus also involving the proximal most stomach are really Barrett's cancers [26, 27]. The ideal cardiac carcinomas to study in order to determine the milieu in which they arose are those that are tiny, and unfortunately there is little data. One study from Italy evaluated the mucosa next to low stage cardiac carcinomas, including what the authors referred to as in situ carcinomas, really the same as high-grade dysplasia [21]. They reported finding goblet cells in the adjacent mucosa at the GEJ and cardia in 11 of 16 low stage cardiac carcinomas and high-grade dysplasias. However, they defined cardiac carcinomas as those centered not only in the proximal 12 cm of the stomach, an area which may or may be limited to the cardia, but those also located at the GEJ which may include some carcinomas arising in short segment Barrett's mucosa. Also they did not specify whether the IM was the cancer-associated incomplete type, and only 1 of the 3 high-grade dysplasias had adjacent goblet cells. If goblet cells were important in cardiac carcinogenesis, we would expect all 3 small high-grade dysplasias to have adjacent goblet cells.

Since cardiac IM occurs within millimeters of the distal esophagus where the same IM is diagnostic of Barrett's mucosa, is it possible that cardiac IM and Barrett's mucosa are really the same thing? This becomes a problem because of the difficulties in defining all the anatomic landmarks during endoscopy [22]. Is a biopsy taken from the squamocolumnar junction that seems to be at the endoscopically defined anatomic GEJ really from the cardia, a region of the proximal stomach, or from the distal esophagus? The separation of these 2 mucosal sites is not always easy. In fact, in some studies, the presence of cardiac IM is given the name of "short segment Barrett's esophagus" [14]. The data relating Barrett's mucosa to cardiac IM is limited but what data is available suggests that cardiac IM is more closely allied to short segment Barrett's rather than to the long segment disease [20].

There is a follow-up study from the southwest United States in which 28 patients with cardiac IM, 9 of whom also had Barrett's mucosa, were followed for a mean of 2.5 years [12]. One patient who did not have Barrett's developed low-grade dysplasia that was not found in 2 subsequent sets of biopsies. This is a small short-term follow-up study but it suggests that the likelihood of a neoplastic complication occurring in an intestinalized cardia is very low.

Some epidemiologic data cast doubt on the carcinogenic importance of cardiac IM. Since cardiac carcinoma is a tumor with a strong male predominance, if IM at the cardia is an important cancer precursor, we would expect that the IM would also be heavily male weighted. Here, the studies vary greatly (Table I). The strongest male predominance for cardiac IM is found in a Japanese study, yet cardiac carcinoma is rare in Japan, and apparently the incidence is not increasing [13]. In studies from the west, the M:F for cardiac IM varies from 7:1 in a US study to 0.4:1 in Portugal [5,7]. In US studies alone, the M:F varies from a high of 7:1 to a low of 1.9:1 [6-8, 10, 11, 16, 17, 23]. Thus, there is no clear support for the same male dominance of cardiac IM that is so prevalent in cardiac carcinoma.

The use of simple arithmetic should give us a picture of the significance of goblet cells in the cardia, but we don't know enough to develop simple equations. Are we correct if we assume that all cardiac cancers develop only in those cardias that have goblet cells, or is it possible that there is another precursor mucosal abnormality? We do not know! Cancers in the adjacent stomach have a strong link to IM that in turn has a strong link to H. pylori infection, but that organism has not been linked to cardiac carcinoma, although it has been linked to cardiac goblet cells in some studies. Here is a statistical model, based upon whatever data is available in order to determine the likelihood of a carcinoma occurring in the gastric cardia that has IM:
1) in the United States it is virtually impossible to obtain prevalence numbers for cardiac carcinomas, because they are included among all other generic gastric carcinomas. The latest data from the SEER Cancer Review covering the period from 1973 through 1997 from the National Cancer Institute, indicates that the incidence rate for all invasive gastric carcinomas in 1997 was 6.7 per 100,000 population, adjusted for the 1970 US population which was 203 million [28]. This means that in 1997, there were about 14,000 new cases of gastric carcinoma in the US;
2) since cardiac carcinoma seems to account for possibly 60% of all gastric carcinomas, then about 8,400 of these cancers were cardiac;
3) according to the latest cumulative data, cardiac IM is present in about 20% of adults subjected to upper endoscopy, but we don't really know if this population is a microcosm of all adults. Furthermore, the Dutch and Finnish studies quoted above that separated cardiac IM into complete and incomplete types found that the complete or low cancer risk type was about one and 1/2 times as common as the high risk or incomplete type of IM. This then means that only about 8% of adults have the cancer-associated cardiac IM or specialized columnar epithelium;
4) for the year 1997 it was estimated that there were about 275 million people in the US, possibly half of whom, or 135 million people, were adults. If the endoscoped adults are representative of the general adult population, then about 8% of those 135 million people, or 10.8 million have cardiac specialized columnar epithelium;
5) these 10.8 million people only developed 8,400 cardiac cancers a year, a rate of 1 cardiac carcinoma in 1,286 people with cardiac incomplete IM, clear evidence that the risk of cardiac cancer is very low for people with cardiac IM.

Of course, much of the data in this calculation is based on supposition. The number of cardiac cancers may be greater or smaller, and the number of adults with cardiac goblet cells may be much smaller or much larger, there may be other precursors of cardiac carcinoma that do not include IM, so the risk may be much higher or much lower than 1 in 1,286.


In spite of a large number of published studies, it is apparent that we don't know either the cause or the importance of goblet cells immediately below the Z-line. Part of our ignorance stems from the data itself which is based upon studies that:
-vary in the sites of the biopsies, all of which are assumed by the authors to be cardia,
-vary in geographic location and in the frequency H. pylori infection,
-use study populations that may not be comparable,
-mostly fail to separate the high cancer risk type of IM from the low cancer risk types, but group them together.

In order to determine if these goblet cells have any meaning, we need to know:
-what is the true definition of the cardia so that there can also be a clear definition of cardiac carcinoma,
-the prevalence of this rigidly defined cardiac carcinoma that is separate from all other gastric carcinomas,
-whether goblet cells at the cardia indicate that there is a high cancer risk for the cardia, meaning that long-term follow-up studies of large numbers of subjects with cardiac goblet cells separated into high- and low-risk IM types is necessary,
-the size of the population at risk to develop cardiac carcinoma, assuming that incomplete IM defines that population. At the moment, it appears that goblet cells in the cardia are so common that, perhaps they are not a manifestation of a disease, but are nothing more than a variant of normal.


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Publication date: August 2003 OESO©2015