Fig. 2.1
Anatomy and histology in normal and increasing severity of chronic reflux disease. (a) In the normal patient, the esophagus is lined by squamous epithelium (gray) and the stomach is lined by gastric oxyntic mucosa with rugal folds (blue). There is no separation of squamous and oxyntic mucosa. (b): In mild reflux disease, the lower esophageal sphincter is shortened permanently and this is concordant with a dilated distal esophagus that is lined by metaplastic columnar epithelium (shown here as three types—yellow = intestinal metaplasia; green = cardiac mucosa; purple = oxyntocardiac mucosa). Note the partial loss of the acute angle of His and the presence of rugal folds in the dilated distal esophagus. (c): In severe reflux disease, the sphincter damage is greater, the dilated distal esophagus is larger, and there is columnar metaplasia in the distal tubal esophagus. Note the further decrease in the angle of His
The presence of cardiac mucosa, or non-intestinalized columnar mucosa, as a normal phenomena between the normal epithelium of the proximal stomach and squamous esophagus is a false dogma. This falsehood, based on observations made in the 1960s [20], is still accepted by the medical community despite powerful evidence against it, and prevents correct interpretation of histologic changes in reflux [21]. The new histologic definition of the gastroesophageal junction explains why pathology in the endoscopically defined “gastric cardia” such as intestinal metaplasia and adenocarcinoma has an association with GERD and not with distal gastric pathology. Intestinal metaplasia and adenocarcinoma of the gastric cardia are in reality intestinal metaplasia and sometimes adenocarcinoma of the dilated distal esophagus.
Reflux-Induced Damage to Esophageal Squamous Epithelium
Structural Cellular Changes
Exposure of esophageal squamous epithelium to gastric contents causes damage. It is almost certain that acid is the main cause of squamous epithelial damage although suggestion has been made that a combination of acid and bile and/or pepsin is more potent in producing damage than acid alone.
The first change in the squamous epithelium induced by acid is likely to be intraepithelial edema, referred to as “dilated intercellular spaces [22]” and an increase in the rate of loss of surface keratinocytes from the epithelium as a result of direct damage to the surface cells. This results in a more rapid turnover of the squamous cells. Increased surface loss stimulates the proliferative zone cells to increase in number as well as proliferative activity in order to maintain the structural integrity of the epithelium. This is seen morphologically as an increased thickness of the basal cell zone of the epithelium to greater than 30 % of epithelial thickness. This basal cell hyperplasia is associated with elongation of the papillary processes between the rete pegs; these papillary processes become highly vascularized. Staining of the epithelium with Ki67 shows that the proliferative zone has expanded considerably.
Damage to superficial keratinocytes by acid also results in the release of cytokines. These diffuse across the epithelium into the lamina propria where they have many potential effects. One of these is that many of these cytokines are chemo-attractive to eosinophil leukocytes which migrate into the epithelium, usually in small numbers.
With severe damage to the epithelium, superficial erosions may occur in the epithelium and can progress to ulcers that involve the full thickness of the mucosa. Healing associated with these ulcers can induce fibrous strictures in the esophagus.
It is important to note that reflux disease is not associated with an increased incidence of squamous carcinoma of the esophagus. This is fortuitous and implies that gastric contents do not contain molecules that can interact with cell receptors in squamous epithelium and induce mutational changes that result in oncogenic transformation of squamous epithelial cells to squamous dysplasia and carcinoma.
Endoscopic Features
Endoscopic examination of the squamous epithelium is relatively insensitive for the diagnosis of reflux disease. Hyperemia and gross erosions are used as the main diagnostic criteria. The extent of erosions has been used to classify erosive esophagitis into increasing grades of severity (A–D) in the Los Angeles classification [23].
Unfortunately, erosive esophagitis is present in only a minority of patients with symptomatic reflux disease, making it a relatively insensitive endoscopic diagnostic criterion. The presence of erosions is also not specific for reflux disease; erosions may occur in many other esophageal diseases such as infections and pemphigus vulgaris. However, in a patient with clinical reflux disease, the presence of erosions is useful to separate patients into those with and without erosive disease. Patients with erosive esophagitis tend to have more complications and their symptoms are less easily controlled by medical therapy. Patients with clinical reflux disease who have no visible endoscopic abnormality fall into a designation of “non-erosive reflux disease” or NERD.
Biopsy Diagnosis of Reflux Esophagitis
The microscopic changes of squamous epithelial damage represent the presently used criteria for the biopsy diagnosis of reflux disease. A combination of dilated intercellular spaces, basal cell hyperplasia with increased expression of Ki67 by immunoperoxidase staining, increased height of papillary ridges and the presence of intraepithelial eosinophils are histologic features that are associated with reflux esophagitis.
Unfortunately, these morphologic changes in squamous epithelium are of little value in the practical diagnosis of reflux disease. All of these are relatively nonspecific general features of tissue injury rather than specific changes due to reflux. All of these can be seen in esophageal disease other than reflux, notably allergic (eosinophilic) esophagitis [24]. These diagnostic criteria are also not very sensitive; approximately 50 % of patients with symptomatic reflux will not have significant changes on biopsy of their squamous epithelium.
In essence, biopsy of the squamous epithelium has a very low predictive value for the diagnosis of reflux when positive histologic criteria are present. The absence of histologic criteria for reflux also has a very low predictive value for the absence of reflux. Therefore, in and of itself, biopsy of the squamous epithelium is therefore of little value in the evaluation of the patient with reflux disease.
Pathophysiologic Changes
An elegant series of in vitro studies by Tobey et al. [25] has provided excellent evidence of the cellular mechanism involved in acid-induced damage of the squamous epithelium. When the squamous epithelium is exposed to acid in high enough concentration for a sufficient length of time, damage occurs in a highly predictable and progressive manner. The severity and rate of progression of damage is dose-related.
The first visible morphologic change is a separation of the squamous cells due to disruption of the tight junctions between the cells. This is seen electron microscopically as “dilated intercellular spaces” as the earliest morphologic evidence of reflux. With increasing damage, the separation of the squamous cells increases and can easily be recognized by light microscopy in routine sections. The severity of the dilated intercellular spaces correlates with the severity of reflux.
The separation of squamous cells increases the permeability of the epithelium. As reflux-induced damage increases, the normally impervious epithelium becomes increasingly permeable. Luminal molecules of increasing size penetrate the squamous epithelium to an increasing depth [25]. Increased infiltration of luminal molecules into the squamous epithelium has the potential to produce numerous additional effects in the squamous epithelium apart from the morphologic injury.
(a)
Pain: With even mild damage, small molecules like acid (hydrogen ions/protons) can enter the epithelium and stimulate pain-sensitive nerve endings in the epithelium, resulting in “heartburn.” While acid is an extremely powerful pain inducer, other luminal molecules may also enter the damaged squamous epithelium and stimulate nerve endings resulting in discomfort. These other molecules are less effective than acid in causing pain because they are less noxious and larger in size. However, they may be the cause of continuing discomfort in the patients whose symptoms are not completely controlled with acid suppressive drug therapy.
(b)
Eosinophilic esophagitis: The entry of eosinophils into the epithelium is part of the usual pathologic change in reflux disease. This is likely the result of cell damage caused by acid, causing release of chemotactic cytokines by the damaged cells which causes eosinophil migration into the epithelium [24, 26]. However, the absolute number of eosinophils in patients with reflux is usually small.
Eosinophilic esophagitis is considered to be an atopic type I hypersensitivity reaction of esophageal squamous epithelium to ingested allergens. In this condition, the squamous epithelium typically shows severe damage associated with numerous intraepithelial eosinophils. Atopy results from interaction of ingested allergens with sensitized IgE containing mast cells that are usually found in the lamina propria under the squamous epithelium. In normal epithelium, ingestion of allergens does not evoke the atopic response even in the sensitized individual because the allergen does not penetrate the squamous epithelium and is therefore sequestered from the effector mast cell. When the squamous epithelium is damaged by reflux, the allergen can enter and traverse the epithelium and interact with the mast cell. This causes mast cell degranulation and release of histamine and other cytokines that are extremely chemo-attractive to eosinophils, resulting in the massive intraepithelial eosinophil infiltrate that is typical of eosinophilic esophagitis [26].
As expected from this pathophysiology, eosinophilic (atopic) esophagitis can be treated effectively in many patients with acid suppressive drug therapy. PPIs have anti-inflammatory properties in addition to potent acid suppression and are highly effective in reversing the squamous epithelial damage caused by reflux and restoring the impermeable status of the normal esophageal epithelium. The allergen is therefore prevented access to the effector mast cell, preventing the atopic reaction.
(c)
Columnar metaplasia: Entry of large molecules in the gastric juice into the esophageal squamous epithelium because of its increased permeability is the basic reason for columnar metaplasia. These large molecules, when they reach the proliferative and stem cell zone in the deeper part of the epithelium, can interact with cell surface receptors and have the potential to induce alterations in the genetic control mechanisms of the cells.
Cell surface and cytoplasmic receptors usually have complex tertiary structures that require complex complementary molecules for reaction. It is highly unlikely that receptors exist for simple particles like hydrogen ions (protons); acid is not a molecule that is likely to have the capability to cause cell receptor interactions that can result in genetic changes in the cell.
Columnar metaplasia of the esophagus results from the interaction of an unknown molecule in gastric contents that penetrates the damaged squamous epithelium, interacts with the basal region proliferative cells, and causes a switch in the genetic differentiating signal. This switch from the normal signal that dictates squamous differentiation to a new signal that includes BMP-4 (bone morphogenesis protein 4) induces columnar differentiation [27]. The proliferating cell in the deep part of the squamous epithelium, under the BMP-4 signal, differentiates into a columnar epithelium. There is strong evidence that columnar metaplasia occurs early and is actually seen in most patients with chronic reflux disease [28].
Columnar metaplasia first occurs in the most distal esophagus where the damage to the esophagus is highest in reflux disease. This metaplastic columnar epithelium separates the esophageal squamous epithelium from the normal oxyntic mucosa that lines the proximal stomach, creating a histologic squamo-oxyntic gap [1]. The presence of this metaplastic columnar epithelium and the gap is an absolutely specific and an extremely sensitive marker for reflux disease.
With increasing reflux-induced damage of esophageal squamous epithelium, the amount of columnar metaplasia progressively increases and the squamo-oxyntic gap increases in length as the squamo-columnar junction (Z-line) moves cephalad. In the vast majority of patients with chronic reflux disease, a microscopic squamo-columnar gap with endoscopically invisible columnar metaplasia exists [1, 2]. The length of the squamo-oxyntic gap is lowest in autopsy specimens in patients without a history of reflux disease during life [19, 29]. When the disease becomes severe, the squamo-oxyntic gap becomes visible at endoscopy and is recognized as a visible columnar lined esophagus.
In almost all patients with chronic reflux disease, there are two epithelial types in the esophagus: normal squamous epithelium and metaplastic columnar epithelium. The extent (length) of the latter is directly proportional to the severity of cumulative life-long damage to the esophageal squamous epithelium by reflux [30]. The response of these two epithelial types to reflux is different.
As we treat reflux by altering the composition of the offensive agent (gastric contents) with acid suppressive drug therapy, we must be cognizant about how alkalinization of gastric contents impacts both squamous and columnar epithelia in the esophagus. At present, we do not do this; we concentrate on the great benefit produced in controlling squamous epithelial damage and completely ignore changes that result in the columnar epithelium.
One reason for this is that most physicians harbor the notion that columnar metaplasia does not exist until they can recognize it at endoscopy. This is false. The resolution of endoscopes, even with narrow band imaging and magnification, is too low to see the microscopic columnar epithelium that is present in all patients with chronic reflux disease. What the eye does not behold at endoscopy exists in the patient under the microscope [2]. To not recognize this is a fundamental error.
Effect of Acid Suppressive Drug Therapy on Squamous Epithelium
Acid in gastric contents is responsible for most if not all of the reflux-induced damage produced in the squamous epithelium of the esophagus.
It is probably true that if there was no acid in the stomach, reflux would not cause any damage. At lectures, we have been asked whether the use of acid suppressive agents from birth would prevent reflux-induced damage in the esophageal epithelium. The answer to this is probably affirmative.
Populations who have a high prevalence of H. pylori infection have a very low prevalence of reflux disease and GERD-induced adenocarcinoma [31]. This is most likely because the infection causes gastritis with atrophy with achlorhydria early in life and this protects the infected population against reflux disease. Unfortunately, there is a price that is paid in these populations; they have a high incidence of H. pylori induced gastric adenocarcinoma.
It is also not feasible to use acid suppressive drugs from early life to prevent reflux disease because gastric acid also has a vital function. In fact, the present long-term use of proton pump inhibitors for treatment of reflux disease has been reported to have significant side effects. Acid suppression with long-term proton pump inhibitor therapy has been reported to increase infections, notably C. difficile colitis [5], pneumonia; cause malabsorption of minerals like magnesium and calcium (increased risk of decreased bone density and hip fracture [4]); and produce drug interactions.
Suppressing gastric acid secretion is a highly effective method of treating squamous epithelial damage caused by reflux. In adequate dosage, proton pump inhibitors can maintain gastric pH above a pH of 4 for 12–14 h of the day [11]. At this level of alkalinization of gastric contents, the most potent molecule in the offensive agent in the causation of reflux damage of the squamous epithelium is effectively neutralized.
The most reliably reproducible effect of effective acid suppression in patients with reflux disease is healing of erosive esophagitis in over 90 % of patients, usually within a month of initiation of therapy. Continued acid suppression also prevents recurrence of erosive esophagitis, prevents progression of erosions to deeper ulcers, and markedly decreases the incidence of complex strictures of the esophagus. The practical effect of this change has been obvious; deep and intractable ulcers and fibrous strictures of the esophagus have become rare complications of GERD. This is a dramatic change from five decades ago when these complications were common and very difficult to treat.
The second positive effect of alkalinizing gastric contents with proton pump inhibitors is that it controls pain. Heartburn is reduced significantly in most patients because suppression of acid removes the most potent stimulator of pain-sensitive nerve endings. Control of heartburn improves the quality of life for most patients with reflux disease. The availability of proton pump inhibitors for treating reflux disease has in fact, dramatically decreased the misery index of reflux disease in the past five decades.
When investigated carefully however, acid suppression does not completely eradicate pain in many patients with reflux. Approximately 30 % of patients continue to have significant pain and few are completely symptom free even with maximum and long terms proton pump inhibitor therapy.
This can be understood by the fact that proton pump inhibitor therapy does not actually stop or decrease reflux [32, 33]. Patients on PPIs continue to have reflux at the same frequency as before. The squamous epithelium is exposed to all the molecules in the refluxate except acid. In many patients whose symptoms persist despite adequate dosage of acid suppressive drugs, the continuing “weak-acid (pH 4–6)” reflux can still cause pain [34].
Effective control of pain in patients with reflux disease is probably most dependent on restoring the normal impermeable state of the squamous epithelium. It is only when this is achieved that the refluxed material in the lumen of the esophagus is kept completely away from the pain-sensitive nerve endings in the esophagus. The fact that some pain and discomfort frequently occurs despite acid suppression can be explained if the squamous epithelial permeability is not fully reversed. Non-acid molecules in the refluxate can also penetrate the epithelium and stimulate nerve endings to cause pain. While this may be at a lower level than acid-induced pain that was present before treatment was instituted, it is often still a source of significant discomfort. It is interesting that studies of symptomatic patients with “weak-acid reflux” show that successful anti-reflux surgery eradicates their pain [35].
Acid suppressive drug therapy is only directed against the acid in the offensive mixture of reflux disease. It does not address the fact that other molecules in the refluxate may continue to cause both symptoms and pathologic changes in the esophageal epithelium. It also does not correct or improve the damaged lower esophageal sphincter or decrease the number or frequency of reflux events [32, 33].
Study of patients treated with acid suppressive drug therapy will therefore show those elements of reflux disease that are poorly controlled: these include symptoms resulting from exposure of the epithelium to weak-acid reflux, regurgitation, and the progression of pathologic changes in the metaplastic columnar epithelium.
Effect of Acid Suppressive Drug Therapy on Metaplastic Esophageal Columnar Epithelium
Gastroesophageal reflux disease has changed its character over the past six decades. In the 1950s, reflux disease was defined almost entirely by its effects on squamous epithelium. The inability to control pain, ulceration, and strictures were the main problems. Approaches to address these issues sometimes require even esophagectomy. The pharmaceutical industry subsequently stepped up to the plate, developing increasingly potent drugs to control acid secretion, which have proved to be highly successful in controlling pain, ulcers, and strictures.
Columnar metaplasia of the esophagus was common in the 1950s. Examination of detailed descriptions of columnar lined esophagus by Barrett [35, 36] and Allison and Johnstone [37] shows that many patients had extremely long segments of columnar lined esophagus. In fact, evidence suggests that the very long segments of columnar lined esophagus that were common in the 1950s are increasingly rare today. It would be expected that effective acid suppression used early in patients with symptomatic reflux disease would decrease columnar metaplasia of squamous epithelium.
The biggest and most dramatic change in the last six decades has been the explosion in the incidence of intestinal metaplasia and adenocarcinoma within the columnar lined esophagus. In the 1950s, histologic descriptions of the epithelium show that intestinal metaplasia defined by the presence of goblet cells was very uncommon even in very long segments of columnar lined esophagus [35, 37]. Adenocarcinoma was so rare that single cases were reported. The first case was reported in 1952 by Morson and Belcher [38]. Allison and Johnstone’s 1953 paper had the second case [37].
Today, Barrett’s esophagus, defined as intestinal metaplasia in a biopsy taken from visible columnar lined esophagus, is present in an estimated 5–10 % of adults in the population [39]. If symptomatic patients with normal endoscopy are biopsied, intestinal metaplasia is found in up to 25 % of patients in some studies [40]. The increase in the prevalence of intestinal metaplasia in the population from 1950 to 2012 has been astounding.
Similarly, the incidence of esophageal adenocarcinoma has shown an increase not seen for any other human cancer type in human history over such a short period. From the first reported case in 1952, the incidence has increased exponentially. In 1982, Rodger Haggitt declared esophageal adenocarcinoma “an epidemic” [41]. From 1975 to 2003, the incidence of esophageal adenocarcinoma increased six-fold [42]. In 1995, the incidence of adenocarcinoma of the esophagus overtook that of esophageal squamous carcinoma in the USA [42]. Today, I see adenocarcinoma of the esophagus ten times more frequently than squamous carcinoma. Of the 16,000 patients who developed esophageal carcinoma in 2010, it is likely that 90 % (over 14,000) were adenocarcinomas. When adenocarcinoma of the gastroesophageal junctional region and gastric cardia (which are, in reality adenocarcinomas of the distal esophagus [43] and so classified by the AJCC 7th edition [44]) are added to this number, an astonishing 20,000 people in the USA developed adenocarcinoma in 2010. The number is still increasing in an incidence curve that is still upward. A sobering thought is that, with an overall mortality of 85 %, esophageal adenocarcinomas are responsible for the death of nearly 17,000 people every year in the USA alone.
Barrett’s esophagus and esophageal adenocarcinoma are solely the result of gastroesophageal reflux disease. There is no other cause for either of these entities despite some associations with obesity and smoking.
Despite what must be the most dramatic increase in the mortality from a single cancer type in the history of medicine, there has been little or no attempt to address this problem by the medical community at large. The treatment of reflux disease is still aimed at controlling heartburn and healing erosive esophagitis with acid suppressive drugs. While this goal has been met and the medical community declares self-satisfied success at the wonder of their drugs and their ability to control reflux disease and improve quality of life, the number of people dying from cancer that is the complication of reflux disease is increasing exponentially.
As pathologists, we tend to view every disease from a different viewpoint. To us, the criterion of success of treatment of any disease is the mortality rate from that disease. By that criterion, the treatment of reflux disease rivals the worst failures in the history of medicine. From having an occasional death resulting from intractable ulceration or hemorrhage in the 1950s, reflux disease in 2010 is responsible for approximately 17,000 deaths from adenocarcinoma in the USA and many more in Europe.
The goal of a treatment of a disease should be to prevent death at all costs; everything else is secondary. The present treatment algorithms for reflux disease have as their goal the improvement of the quality of life of millions of people who have heartburn caused by reflux. This is an easy goal to achieve but should not be mistaken for an attempt at preventing cancer in the many thousands of patients every year. It is merely the treatment of the squamous manifestations of the disease when the development of cancer is in fact a disease of the columnar metaplastic epithelium.
We need to set a new goal for patients with reflux disease. We need to tell ourselves that our primary goal in this disease is to prevent cancer and death. When we do this, we will stop ignoring the columnar lined esophagus; rather we will focus on it with all the technology that is available.
Metaplastic Esophageal Columnar Epithelial Types
The change in the differentiating genetic signal from the postulated Wnt to BMP-4 in the proliferating cells of the esophageal epithelium results in the transformation of the stratified squamous epithelium to a columnar epithelium composed entirely of undifferentiated mucous cells. These cells line the surface and form a foveolar pit and glands, all composed of morphologically similar mucous cells. This is cardiac epithelium which is defined as an epithelium composed entirely of mucous cells without parietal or goblet cells [45]. Cardiac epithelium has also been called “junctional epithelium” and “mucous-cell only epithelium.”
Cardiac epithelium is subjected to attack by gastric contents as a result of continuing reflux disease. As a result, it has the potential to evolve into two other significant epithelial types within the columnar lined esophagus—oxyntocardiac and intestinal epithelia [46]. These are defined by the presence of parietal cells and goblet cells. Figure 2.1 Many other differentiated cell types can be seen in metaplastic esophageal columnar epithelium—neuroendocrine cells, pancreatic cells, chief cells, Paneth cells, ciliated cells. At present, these cell types have no known significance and are pretty much ignored in the definition of the three basic types of metaplastic epithelia.
The first type of change in cardiac mucosa occurs as a result of development of parietal (oxyntic) cells within its glands (Fig. 2.2). The presence of parietal cells in cardiac mucosa converts the epithelium to oxyntocardiac epithelium. This is defined as a columnar epithelium where the glands contain a mixture of mucous cells and parietal cells. It does not have goblet cells. Like the cardiac metaplasia of squamous epithelium resulted from a genetic switch, oxyntocardiac mucosa is generated in cardiac mucosa by activation of a different differentiating genetic signal—possibly a combination of BMP-4 and the Sonic Hedgehog gene [47]. Sonic hedgehog gene is the usual genetic signal in the gastric oxyntic mucosa and is required for development of parietal cells in gastrointestinal columnar epithelia [48]. Oxyntocardiac epithelium has also been called “gastric fundic-type epithelium” and “mixed mucous and parietal cell epithelium.”
Fig. 2.2
Sequence of epithelial changes in the esophagus caused by reflux disease. In the initial step, squamous epithelium undergoes columnar metaplasia to cardiac mucosa. The cardiac mucosa then evolves in one of two directions: (a) in a strong acid milieu, Sonic Hedgehog gene is activated leading to parietal cells and oxyntocardiac mucosa. This is a stable epithelium that does not progress to cancer. (b) In a weaker acid milieu, CDX2 is activated and intestinal metaplasia results
The second type of change in cardiac epithelium occurs as a result of development of goblet cells which can appear in the surface, foveolar region, or in the glands. This is intestinal metaplastic epithelium (Fig. 2.2). Intestinal epithelium is generated in cardiac mucosa by activation of yet another different differentiating genetic signal—the homeobox gene complex that includes CDX2 [8, 49]. CDX2 is the usual genetic signal in the intestine with CDX2 being dominant for colonic differentiation [50]. Intestinal epithelium in the esophagus has also been called “specialized columnar epithelium” or “Barrett’s Esophagus.”
These three columnar epithelia are the only significant columnar epithelial types that occur in the esophagus. Because the criteria for their definition are simple (based on the presence or absence of three easily recognizable cell type: mucous cells, parietal cells, and goblet cells), their identification in biopsies is easy, precise, and accurate with little inter-observer variation after minimal training.
Together, various combinations of these three columnar epithelial types comprise the entire pathologic metaplastic gap that results from columnar metaplasia of squamous epithelium [1, 40]. Because this process requires two steps (damage to squamous epithelium with increased permeability and a cellular reaction between molecules in gastric contents and esophageal epithelium that produces highly specific changes in differentiating genetic signals), the presence of any or all these epithelia are absolutely specific for reflux disease.
We therefore have a new definition of reflux disease at a cellular level: Reflux disease is the presence of a gap between esophageal squamous epithelium and gastric oxyntic mucosa composed of any combination of cardiac, oxyntocardiac and intestinal epithelia. This is the squamo-oxyntic gap [1]. This definition is 100 % specific for reflux disease; columnar metaplasia does not occur in any other esophageal disease. Having a precisely reproducible definition of reflux disease based on examination of routine biopsy specimens taken at endoscopy has enormous value.
Of the three types of metaplastic columnar epithelium in the esophagus, the only epithelium that is at risk for progression to dysplasia and adenocarcinoma is intestinal epithelium [51]. This defines Barrett esophagus. Patients who have intestinal metaplasia in a biopsy taken from a visible columnar lined esophagus are estimated to have a risk of future cancer of ~0.5 % per year.
Present guidelines for biopsy at endoscopy do not emphasize a complete examination of the epithelium between the Z-line and gastric oxyntic mucosa. Biopsies are not recommended for patients who do not have a visible columnar lined esophagus. This results in early changes of GERD limited to the dilated distal esophagus being ignored [2]. In patients with a visible columnar lined esophagus, biopsies stop at the proximal limit of rugal folds, thereby missing the pathology in the dilated distal esophagus.
The Amount (Length) of the Squamo-Oxyntic Gap
From its normal length of zero cm, the squamo-oxyntic gap progressively increases in length in patients with reflux disease due to increasing amounts of columnar metaplasia of their squamous epithelium. Columnar metaplasia is usually a “permanent” change. Once it has occurred, reversal will not usually occur unless there has been a significant treatment induced alteration such as ablation of the epithelium. Although minor decreases in the presence of goblet cell metaplasia have been reported with therapy, neither acid suppressive drug therapy nor successful anti-reflux surgery reliably reverses columnar metaplasia. As such, the squamo-oxyntic gap changes in only one direction—increase in length.
In autopsy studies of people who have died without symptoms of reflux disease during life, the squamo-oxyntic gap varies from zero to less than 1 cm [19, 29]. If assessed by measured biopsies distal to the endoscopic gastroesophageal junction in patients with heartburn undergoing endoscopy, the gap is usually also less than 1 cm. This gap is limited to the dilated distal esophagus that is often mistaken for proximal stomach by present endoscopic criteria [2]. When a visible columnar epithelium is present, the squamo-oxyntic gap is equal to the length of the endoscopically visible columnar segment (measured by the Prague criteria [52]) plus the endoscopically invisible area within the dilated distal esophagus [1, 17].
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