Nonneoplastic Esophagus

Tanya A. Rege

Amy E. Noffsinger

▪ ESOPHAGEAL DEVELOPMENT

The esophagus develops from the cranial part of the primitive foregut, becoming recognizable at the 2.5-mm stage of development (approximately the 3rd gestational week) as an annular constriction located between the stomach and pharynx (Fig. 2.1) (1). It elongates and grows in a cephalad direction, becoming increasingly tubular. Early, the cephalad parts of both the esophagus and trachea lie within a single common tube. Lateral ridges of proliferating epithelium develop in the uppermost segment, dividing the lumen into anterior and posterior compartments. Primitive mesenchyme grows into the forming septum, eventually separating the esophagus and trachea. As soon as the esophagus and trachea divide, the esophagus lies dorsally, and the trachea and lung buds lie ventrally (Figs. 2.1 and 2.2).

The earliest identifiable esophagus consists of two to three layers of pseudostratified columnar cells (Fig. 2.3). The cell layers thicken and then vacuolate (Fig 2.4). Eventually the vacuoles disappear. Abnormalities in the vacuolation process account for the formation of some esophageal cysts. Mucinsecreting cells replace the ciliated cells (2). Glycogenated, nonkeratinized, stratified squamous cells then replace the mucinous epithelium. Squamous cells first appear in the midesophagus and extend both proximally and distally to line the remainder of the esophagus by the fifth gestational month. Submucosal glands appear following the development of the squamous epithelium; they fully mature after birth (2). The implication of these developmental changes is that residual nests of embryonic types of esophageal epithelium may persist in the adult esophagus giving rise to some congenital abnormalities.

▪ GROSS ANATOMIC FEATURES

The esophagus begins in the pharynx at the cricopharyngeus muscle and ends at the gastroesophageal junction (GEJ) to the left of midline opposite the 10th or 11th thoracic vertebrae. In adults, the esophagus usually measures 25 to 40 cm in length. For the endoscopist, the esophagus starts 15 cm from the incisor teeth and ends with the appearance of gastric folds at the GEJ or Z line (Fig. 2.5). The esophagus follows the course of the vertebral column, maintaining close proximity with the trachea, left mainstem bronchus, aortic arch, descending aorta, and left atrium (Fig. 2.6). It is customarily divided into thirds. The normal esophagus has constrictions (Fig. 2.7) at its cricoid origin, along its left side at the aortic arch, at the crossing of the left mainstem bronchus, at the fifth thoracic vertebra and left atrium, and where it passes through the diaphragm. These constrictions become clinically significant when food or pills lodge in them, making them susceptible to ulceration. The esophagus enters the abdomen, passing through the esophageal hiatus formed by the diaphragmatic muscles. Its intra-abdominal portion measures approximately 1.5 cm in length. The right side of the GEJ appears smooth, whereas the left side forms a sharp angle known as the incisura or angle of His.

Sphincters that maintain esophageal closure under resting conditions lie at the proximal and distal ends. The esophagus is mobile between the upper sphincter and its passage through the diaphragm, allowing it to be displaced by mediastinal or pulmonary diseases. Lower esophageal sphincter (LES) pressure involves a balance between neurogenic and tonic contraction of the musculature and various neural and possibly endocrine and paracrine influences that inhibit contraction resulting in relaxation. The LES keeps the esophageal lumen closed, preventing reflux during rest and regulating food passage into the stomach. The most distal portion of the LES defines the GEJ. The esophageal mucosa has a smooth, featureless, glistening, pink-tan appearance. The squamocolumnar junction (SCJ) appears as a serrated line known as the Z line (Fig. 2.5). Grossly, the Z line consists of small projections of red glandular epithelium measuring up to 5 mm in length and

3 mm in width extending through the pink-white squamous epithelium.

FIG. 2.1 Embryogenesis of the gut. A: Embryo at the end of first month shows a primitive gastrointestinal tract divided into the foregut, midgut, and hindgut. B: A 5-mm embryo. Note the development of primary intestinal loop.

FIG. 2.2 Septation events. A: The embryonic foregut begins as a single tube from which the tracheobronchial diverticulum develops. B: The more proximal portion of the foregut divides into the posterior esophagus and the anterior tracheal tree. C: Septation results from ingrowth of epithelium and mesenchyme in the area of constriction. D: This ingrowth eventually forms a complete septum between the trachea and the esophagus.

FIG. 2.3 Section through developing fetus at approximately 12 weeks of age by dates. A: Hematoxylin and eosin-stained section demonstrating fetus in the amniotic sac with the forming heart (H) and gastrointestinal tract. The section indicated in the box represents the separated trachea and esophagus. B: Higher magnification of the area outlined in the box in (A). It is stained with an antibody to cytokeratin. Two distinct lumens representing the esophagus and the trachea are present (arrows). Immature mesenchyme surrounds the two lumina.

FIG. 2.4 Cross section of fetal esophagus at 60-mm stage. A: The mucosal lining consists of pseudostratified cells. L represents the central lumen; N represents developing neural tissue. Epithelial vacuoles (V) are beginning to form. B: Higher magnification of the pseudostratified epithelium. The epithelium appears clear due to intracytoplasmic glycogen accumulations. The underlying tissues consist of immature mesenchyme. Two intraepithelial vacuoles (V) are present.

Four arterial groups regionally supply the esophagus: (a) the thyroidal arterial trunk and branches of the subclavian artery that supply the upper esophagus, (b) bronchial arteries and esophageal arch arteries from the upper descending aorta that supply the upper and midesophagus, (c) intercostal arteries and periesophageal arteries from the lower thoracic aorta that supply the distal esophagus, and (d) branches from the inferior phrenic, left gastric, and short gastric artery that supply the diaphragmatic part of the esophagus. The arteries run within the muscularis propria, giving rise to branches that course through the submucosal plexus (3). Extensive anastomoses among these arterial supplies account for the rarity of esophageal ischemic injury or infarction.

FIG. 2.5 Esophagogastric Z line. A: A double-contrast esophagogram demonstrates a white zigzag line (arrows) representing the Z line. B: The Z line lies where the pinkish-gray squamous mucosa of the esophagus meets the velvety brown glandular gastric mucosa.

FIG. 2.6 The esophagus commences as an inferior extension of the pharynx. Superiorly it is related to the larynx and thyroid gland. Its middle region courses with the trachea, bronchi, and aortic arch, whereas the lower third descends with the aorta and passes through the esophageal diaphragmatic hiatus.

Venous drainage also demonstrates a regional distribution. Esophageal veins form a well-developed submucosal plexus that drains into the thyroid, azygos, hemizygous, and left gastric veins, thereby providing links between the systemic and portal venous circulations. The lower esophagus drains into the systemic circulation through branches of the azygos and left inferior phrenic veins. The lower segment also drains into the portal system through the left gastric vein and into the splenic vein through the short gastric veins. The azygos veins ascend on either side of the thoracic segment and drain the midesophagus. The anterior and posterior hypopharyngeal plexus, the superior laryngeal and internal jugular veins, and the inferior thyroidal vein and intercostal veins drain the proximal esophagus. These eventually drain into the superior vena cava.

Seven lymph node groups drain the esophagus (Fig. 2.8). The nodes adjacent to the esophagus include paratracheal, parabronchial, paraesophageal, pericardial, and posterior mediastinal lymph nodes. The superior and inferior deep cervical lymph nodes lie further away. In general, the cervical esophagus drains into the internal jugular and upper tracheal lymph nodes. The thoracic esophagus drains into the superior, middle, and lower mediastinal lymph nodes. It also drains into the bronchial and posterior mediastinal paraesophageal lymph nodes and then to the thoracic duct. The distal esophagus drains into the pericardial lymph nodes at the GEJ. The infradiaphragmatic portion drains to the left gastric and perigastric nodes (4). The two sets of intramural lymphatics lie in the submucosa and in the muscularis propria. The rich mucosal lymphatic plexus connects with a less extensive submucosal one and communicates with longitudinally oriented channels in the muscularis propria. Because of this arrangement, esophageal cancers tend to display early and extensive intramucosal and submucosal intralymphatic spread (see Chapter 3).

FIG. 2.7 Normal double-contrast esophagogram showing indentation from aorta (arrow), left mainstem bronchus (arrowhead) and indentation of spinal disc spaces (open arrows).

Parasympathetic and sympathetic nerves innervate the esophageal mucosa, glands, blood vessels, and musculature. Adrenergic, cholinergic, and peptidergic nerves richly supply the esophageal smooth muscle and serve several neurotransmitter functions, particularly in the LES (5,6,7). LES function is regulated in part by neural nitric oxide synthetase (8). Nitric oxide is a major mediator of LES relaxation. It also initiates the release of and enhances the effect of other transmitters. Intramuscular interstitial cells of Cajal also play an important role in nitric oxide-dependent neurotransmission in the LES (9).

FIG. 2.8 Lymph nodes draining the esophagus. See text for further description.

▪ MUCOSAL DEFENSES

Preepithelial, epithelial, and submucosal (postepithelial) defenses protect the esophagus from injury. Preepithelial defenses include the coordinated actions of the LES and the esophageal muscles to minimize reflux of gastric contents and promote clearance of refluxed material. Microridges on squamous cells hold mucus on their surfaces, providing a protective coat (10). The esophageal epithelium is also protected by a luminal mucus-bicarbonate barrier and hydrophobic surfactants that derive from submucosal and salivary gland secretions. Other salivary components, including mucin, nonmucin proteins, epidermal growth factor (EGF), prostaglandin E2, and carbonic anhydrase also significantly enhance the preepithelial barrier.

FIG. 2.9 Diagram of the normal protective mechanisms for the esophageal mucosa. See text for further description.

Epithelial defenses include the glycocalyx, permeability properties of the cell plasma membrane, cell junctions, and ion transport processes that regulate intracellular pH (11). The multiple layers of squamous cells functionally resist damage from the passage of substances over the epithelial surface (Fig. 2.9). Submucosal defenses mainly involve regulation of blood supply via responses of nerves, mast cells, and the blood vessels themselves.

▪ HISTOLOGIC FEATURES

The Squamous Mucosa

Most of the esophagus is lined by squamous epithelium. The normal SCJ lies at the level of the diaphragm. The squamous mucosa contains three components: Squamous epithelium, lamina propria, and a thick muscularis mucosae (Figs. 2.10 and 2.11). The squamous epithelium consists of nonkeratinizing stratified squamous epithelium (Figs. 2.10, 2.11 and 2.12). The basal zone consists of several layers of cuboidal basophilic cells with dark nuclei arranged in an orderly fashion along the basement membrane. Its upper limit is defined as the level where the nuclei are separated by a distance equal to their diameter. It rarely contains mitoses unless some form of injury (esophagitis) is present. The basal layer gives rise to daughter cells that progressively differentiate as they move toward the surface and desquamate. Epithelial cell renewal takes an average of 7 days (12). The basal layer normally occupies the lower 10% to 15% of the epithelium,
being one to four cells thick. However, most individuals without evidence of gastroesophageal reflux (GER) show basal cell hyperplasia greater than 15% in the distal 3 cm of the esophagus (13). Above the basal cell layer the glycogenated cells progressively flatten as they approach the surface (Fig. 2.13). Periodic acid-Schiff (PAS) stains, which detect intracellular glycogen, facilitate their identification (Fig. 2.14). As one approaches the luminal surface, cell polarity changes from a vertical to a horizontal orientation. This change is accompanied by conversion from a round to an elliptical cell shape. The esophageal mucosa may contain rare keratohyaline granules even though granular and keratinizing layers are usually absent; this finding suggests previous injury.

FIG. 2.10 Low-power view of the normal esophagus showing the mucosa (M), submucosa (SM), and muscularis propria (MP).

FIG. 2.11 Histology of the normal esophagus. The following layers of the esophageal stratified squamous epithelium can be identified: basal layer of oval cells, intermediate layers of cuboidal cells, and outer layers of squamous cells with flattened nuclei. The papillary lamina propria (P) invaginates halfway into the epithelium carrying small blood vessels and inflammatory cells. Smooth muscle fibers of the muscularis mucosae (MM) are seen at the bottom of the photograph.

FIG. 2.12 Measurement of the height of esophageal papillae. The distance between the basal lamina of the squamous epithelium and the basal lamina at the top of the papillae is one half the full thickness of the epithelium.

Endocrine cells lie scattered among the basal cells; they are not present in the mucous glands or ducts. Melanocytes may also be present (Fig. 2.15) (14). Occasional CD3+
intraepithelial lymphocytes populate the lower and middle squamous cell layers (15). As these lymphocytes interdigitate between the epithelial cells, their nuclei become convoluted, a feature that has led to their designation as “squiggle cells.” Antigen-presenting S100+ Langerhans cells lie in a suprabasal location (Fig. 2.16) (15).

FIG. 2.13 Photograph of squamous mucosa stained with hematoxylin and eosin demonstrating the esophageal squamous lining. The star indicates the center of a papilla. It is surrounded by small basal cells with high nuclear-to-cytoplasmic ratios. The cells progressively enlarge, acquiring intracytoplasmic glycogen, and then eventually flatten out toward the surface. Normally, a small number of intraepithelial lymphocytes are present (arrows).

FIG. 2.14 A: The glycogenated superficial keratinocytes are demarcated from the basal epithelial layers by a periodic acid-Schiff (PAS) stain. The submucosal glands are also PAS positive. A lymphoid follicle (LF) is present. B: PAS-stained example of the gastroesophageal junction. Note the presence of the strongly PAS-positive glands both in the superficial portions as well as in the submucosa of the esophagus. The basal layer of the distal esophagus is thicker than elsewhere and is present in this photograph as a pale band underneath the pink-staining glycogenated epithelium superficial to it.

Papillae, projections of lamina propria, extend into the squamous epithelium at regular intervals creating an irregular lower border of the squamous epithelium. These papillae normally do not extend upward through more than 50% to 60% of the epithelial height. One measures the height of the papillae from the basal lamina of the surrounding squamous epithelium to the basal lamina at the top of the papilla. Papillary height is generally expressed as a percentage of the total epithelial thickness. The papillae and lamina propria contain blood vessels, lymphatics, fibrovascular tissue, elastic tissue, and occasional inflammatory cells. The lamina propria rests on a two-layer, relatively thick muscularis mucosae. The mucosa is maintained in part by EGF, a mitogenic polypeptide that helps maintain tissue integrity and cell maturation. The epidermal growth factor receptor (EGFR) possesses tyrosine kinase activity (16) and binds EGF. This may make the esophageal mucosa vulnerable to the anti-EGFR therapies used to treat multiple types of cancer.

FIG. 2.15 Melanocytes in the esophagus.

FIG. 2.16 An antibody to anti-S100 protein identifies the dendritic Langerhans cells scattered in the normal esophageal mucosa. Submucosal nerves and ganglia are also positive (diaminobenzidine—methylene blue).

Normal Histology at the Gastroesophageal Junction

The normal histology of the GEJ is a contentious topic. Traditional teaching suggests that the normal Z line is a junction between the esophageal squamous epithelium and the cardiac epithelium of the most proximal part of the stomach (17). The controversy centers on whether the distal esophageal mucosa normally contains cardiac-type mucosa and whether cardiac mucosa can contain parietal cells. Currently, most authors agree that the extent of the cardiac epithelium is shorter than had been previously suggested. If cardiac epithelium is present at all, it rarely extends more than a few millimeters below the Z line or a few millimeters into the esophagus. Some view the cardia as a normal structure that is present at birth (18,19), whereas others argue that cardiac mucosa develops as a metaplastic response to gastroesophageal reflux disease (GERD) (20,21,22,23). Thus, it remains unclear whether there is a tiny band of cardiac mucosa that is a normal structure and whether it lines the esophagus, the proximal stomach, or both.

The histologic definition of cardia-type mucosa is also controversial. Some experts feel that the presence of any parietal cells precludes a histologic diagnosis of cardiac epithelium (24), while others contend that cardiac glands can contain occasional parietal cells provided that other architectural features typical of cardiac mucosa are present (25). Some recommend terms such as oxyntocardiac or cardio-oxyntic or transitional mucosa to describe a cardiac mucosa with occasional parietal cells (24). The histologic controversies are complicated by the fact that there are no uniformly accepted criteria by which the GEJ can be recognized grossly. Thus, it is difficult to establish whether the Z line normally lies precisely at or slightly proximal to the GEJ (26). Furthermore, the upper gastrointestinal (GI) tract easily undergoes metaplastic changes as a result of injury, making precise characterization of this region difficult.

When cardiac mucosa or cardio-oxyntic mucosa overlies submucosal esophageal glands or squamous epitheliallined ducts, one can be certain that the tissue in question originated in the esophagus and not in the proximal stomach. In the absence of this landmark, the location is less clear and it is perhaps best referred to as the area of the GEJ. Variability in the extent of the cardiac mucosa likely reflects the presence of underlying disorders such as GERD or Helicobacter pylori gastritis (22) and suggests that the area of the GEJ is a dynamic structure that may change over time.

In our view, cardiac mucosa consists of a surface mucussecreting columnar epithelium similar to gastric foveolar epithelium. This epithelium dips down to form foveolae into which branched or compound tubular glands open. In the proximal end of the cardiac mucosa the glands branch freely and show a distinctly lobular architecture (Fig. 2.17). Distally the glands are less branched and the lobular arrangement becomes less evident. The glands contain mucin-producing cells and may contain parietal cells or even rare chief cells. Abundant endocrine cells are also present.

Lamina Propria

The lamina propria constitutes the nonepithelial portion of the mucosa above the muscularis mucosae. It consists of loose areolar connective tissue containing blood vessels, nerves, inflammatory cells, and mucus-secreting glands. Lymphocytes (mostly immunoglobulin-producing B cells), plasma cells, and, occasionally, lymphoid follicles are present.

Muscularis Mucosae

The muscularis mucosa begins at the cricoid cartilage and becomes thicker distally. Proximally it consists of isolated or irregularly arranged muscle bundles rather than being arranged in a continuous sheet. In the middle and lower esophagus, the muscularis mucosae forms a continuum of longitudinal and transverse fibers that may appear thicker than elsewhere in the GI tract (Fig. 2.11), especially at the GEJ. The muscularis mucosae may appear so thick as to be mistaken for the muscularis propria in biopsy specimens.

Submucosa

The submucosa is a wide zone that lies below the muscularis mucosae. It consists of loose connective tissue containing blood vessels, nerves, poorly formed submucosal ganglia, lymphatics, and submucosal glands (Fig. 2.17). The submucosa contains an extensive ramifying lymphatic plexus lying in a loose connective tissue network accounting for early and extensive submucosal spread of esophageal carcinomas. It also contains a rich vascular supply.

There are two types of submucosal glands in the esophagus: simple tubular mucous glands called superficial or mucosal mucous glands, and deep or submucosal glands. The former lie in the lamina propria, confined to narrow zones at the distal and proximal ends of the esophagus. They produce neutral mucins and to that produced by the glands of the gastric cardia. In contrast, deep or submucosal glands lie in the submucosa, along the length of the esophagus. These glands produce acidic mucins and drain their secretions via ducts lined by columnar epithelium surrounded by myoepithelial cells (27). From two to four lobules drain into a common duct lined by stratified columnar epithelium that passes obliquely through the muscularis mucosae into the lumen. Loose connective tissue often surrounds these ducts. They vary in position and number from patient to patient. The glands may be surrounded by lymphocytes.

Muscularis Propria

The muscularis propria consists of well-developed circular and longitudinal layers. In its upper part, the muscle fibers assume an oblique orientation and are striated in
nature. The striated muscle gradually changes to smooth muscle in the middle third of the esophagus. The LES is not a clearly defined anatomic structure but consists of thickened smooth muscle fibers that extend approximately 2 cm above and 3 cm below the diaphragmatic esophageal hiatus.

FIG. 2.17 Submucosal glands. A: Mucous glands are located in the submucosa and empty their secretions into the esophageal lumen via ducts that penetrate the muscularis mucosae. B: High power view of the mucin producing glands. C: Periodic acid-Schiff (PAS)-stained esophagus. Note the PAS-positive acini in the submucosal glands.

Adventitia

The esophagus does not have a serosa as exists elsewhere in the GI tract. Rather, the external part is called the adventitia. It consists of loose connective tissue with longitudinally directed blood and lymph vessels and nerves; it gradually
merges into the loose connective tissue in the mediastinum. Numerous elastic fibers at the GEJ attach the esophagus to the diaphragm.

FIG. 2.18 Normal esophagus. A: Normal superficial squamous epithelial cells without keratinization. (Unless otherwise specified, all figures are taken from brushing material and stained with Papanicolaou.) B: Normal intermediate squamous epithelial cells.

▪ CYTOLOGY OF THE NORMAL ESOPHAGUS

Esophageal cells normally exfoliate from the esophageal mucosa. These include nonkeratinized superficial squamous cells, intermediate cells, and, rarely, parabasal cells (Fig. 2.18). Some squamous cells seen in esophageal cytology specimens derive from the oropharynx. Benign epithelial pearls may occasionally be found. The presence of large numbers of the latter suggests an inflammatory or erosive lesion. Metaplastic squamous cells may exfoliate from the subepithelial mucous glands and their ducts. Benign columnar gastric-type cells (Fig. 2.19) derive from the distal esophagus or from islands of gastric mucosa associated with inlet patches or Barrett esophagus (BE). Foreign material, particularly plant cells, may be present, especially if the esophageal lumen is obstructed. One may also find cells of respiratory origin, such as dust-containing macrophages and ciliated bronchial cells. These usually represent cells that are swallowed, although esophagobronchial or esophagotracheal fistulae or the presence of congenital abnormalities containing bronchial mucosa may account for these cells as well.

FIG. 2.19 Normal cells from the esophageal-gastric junction.

▪ HETEROTOPIAS

Cervical Inlet Patch

Inlet patches affect 1% to 21% of the population (28,29,30,31,32,33), with the highest incidence occurring during the first year of life. A subsequent decline in incidence suggests that some lesions regress with age. Two pathogenic mechanisms have been advanced to explain inlet patches. As noted earlier, columnar epithelium lines the fetal esophagus and remnants of columnar or ciliated epithelium may persist leading to the formation of inlet patches. Alternatively, inlet patches may represent metaplastic replacement of the squamous mucosa in adults with GERD. Those favoring an association with GERD cite similar mucin and cytokeratin patterns in both inlet patches and Barrett esophagus (34). Inlet patches lie in the subcricoid and upper sphincteric region, usually within 3 cm of the upper esophageal sphincter. Most lesions remain asymptomatic. Acid or pepsin secretion by the ectopic gastric mucosa may produce peptic symptoms, ulcers, webs, strictures, esophagotracheal fistulae, or perforations (35,36,37). Rarely, adenocarcinomas may develop in a preexisting inlet patch (38).

Inlet patches appear as velvety, ovoid, pink-red mucosal areas with distinct borders that vary in diameter from a few millimeters to complete esophageal encirclement. Histologically, they consist of cardiac, antral, and/or oxyntic glands covered by foveolar epithelium (Fig. 2.20). In patients with gastric H. pylori (HP) infections, the heterotopic epithelium may become colonized by the bacteria. Intestinal or pancreatic metaplasia may develop (29,30,32). Large amounts of lymphoid tissue accompany smaller lesions, as compared to larger ones, suggesting that the lymphocytes play a role in lesional regression. An intense inflammatory reaction may surround the lesion, especially following peptic ulceration.

FIG. 2.20 Inlet patch. A: Low magnification of an upper esophageal “polyp” containing lobular nests of gastric epithelium. B: Higher magnification showing the gastric epithelium.

Heterotopic Gastric Mucosa away from Inlet Patches

Ectopic gastric mucosa also occurs in the mid- or distal esophagus, usually in congenital malformations, including duplications or diverticula. It may also develop following atresia repair (39). Since it often contains oxyntic mucosa, it may present with peptic ulceration.

Heterotopic Pancreas

Heterotopic pancreas usually affects the distal esophagus. It may associate with trisomy 18, trisomy 13, esophageal atresia, and esophageal duplication. Complications include fat necrosis, bleeding, ulcers, diverticulum formation, cystic degeneration, inflammation, and, rarely, malignancy. Heterotopic pancreas usually presents as a submucosal mass and contains normal-appearing pancreatic acini and ducts (Figs. 2.21 and 2.22) usually without islets, although any pancreatic tissue component may be present. Injury due to heterotopic pancreas likely involves failure of the pancreatic ducts to empty into the esophageal lumen. Eventually the obstructed ducts dilate and rupture, releasing proteolytic enzymes into surrounding tissues. Inflammation and necrosis follow. Heterotopic pancreas differs from pancreatic metaplasia, which is discussed in a later section. The latter is usually a focal change consisting only of pancreatic acini that blend into cardiac or oxyntic mucosa. Pancreatic ducts are never present in pancreatic metaplasia.

Other Heterotopic Tissues

Ectopic esophageal sebaceous glands present grossly as multiple small, yellowish, mucosal plaques, typically lying in the mid- or distal esophagus. Mature sebaceous glands underlie the squamous mucosa (Fig. 2.23). The lesion represents
a developmental abnormality without any clinical significance (40). Patches of ciliated columnar cells may lie within the esophagus. These represent residual fetal remnants and are particularly common in premature infants. They are rarely seen in adults unless they are found in inlet patches, duplications, and/or bronchogenic cysts. Heterotopic thyroid tissue may be present in the esophagus either alone or in tracheobronchial hamartomas. In addition, the esophagus may occasionally contain heterotopic salivary glandular tissue (Fig. 2.24).

FIG. 2.21 Heterotopic pancreas at gastroesophageal junction presenting as a submucosal mass (arrows).

FIG. 2.22 Histologic appearance of the lesion illustrated in Figure 2.21 demonstrating the presence of pancreatic acini and ducts.

▪ DEVELOPMENTAL CONGENITAL ANOMALIES

Congenital Esophageal Atresia, Fistula, and Stenosis (Tracheoesophageal Fistula)

Demography and Pathophysiology

Esophageal atresia affects 1 in 3,500 live births (41,42). Atresia with a common tracheoesophageal fistula occurs in 1 of every 800 to 1,500 live births. Esophageal stenosis affects only 1 in every 25,000 live births (43). Atresia is more common in males than in females. Premature babies and monozygotic twins have a higher risk of atresia than other infants. Occasionally esophageal atresia affects siblings (44). Risk factors include prenatal exposure to lead (45), drugs, and physical agents; maternal diabetes; and maternal age (42,46). Genetic factors include Down syndrome, trisomy 18, and various other chromosomal alterations (47). Severe etiologic insults occur in the first trimester when major organogenesis occurs, often resulting in many associated abnormalities (48).

FIG. 2.23 Ectopic sebaceous glands underlying the esophageal squamous epithelium.

FIG. 2.24 Ectopic salivary gland tissue within esophageal submucosal glands.

In esophageal agenesis the proximal primitive foregut develops primarily into a trachea rather than an esophagus (49). Esophageal atresia results from failure of the primitive foregut to recanalize; tracheoesophageal fistula results from failure of the lung bud to separate completely from the foregut. The fistulas that develop vary depending on the amount of epithelium left behind to maintain foregut epithelial continuity. The distal esophageal segment may contain respiratory elements representing a transition zone between the upper foregut, which differentiates into the trachea, and the lower part, which differentiates into the lower esophageal segment (49).

Studies in animal models and in patients with syndromic forms of esophageal atresia indicate the importance of altered genes in the development of this anomaly. The syndromes and the associated genes involved are summarized in Table 2.1. There are also a number of other genes that are important for normal tracheoesophageal development (Table 2.2); abnormalities in these may also account for some cases of tracheoesophageal malformations (50).

Clinical Features

Esophageal atresia may be detected prenatally by finding a small or absent gastric bubble and maternal polyhydramnios or by the presence of a fluid-filled, blind-ending esophagus
(Fig. 2.25). At birth, the presence of a single umbilical artery may alert clinicians to the possibility of esophageal atresia. Infants typically present in the first few hours or days of life with regurgitation, excessive drooling, choking, aspiration, cyanosis, and respiratory distress. Inability to pass a nasogastric tube into the stomach confirms the diagnosis. Air in the stomach and small bowel indicates the presence of a distal tracheoesophageal fistula. Most patients with esophageal stenosis present with dysphagia and regurgitation upon the introduction of solid food.

TABLE 2.1 GENETIC SYNDROMES AND GENES ASSOCIATED WITH ESOPHAGEAL ATRESIA AND TRACHEOESOPHAGEAL FISTULA

		Gene	Locus
Single Gene Disorders
	Feingold syndrome	MYCN	2p24.1
	CHARGE syndrome	CHD7	8q12
	AEG syndrome	SOX2	3q26.3-q27
	Pallister-Hall syndrome	GLI3	7p13
	Opitz G syndrome	MID1	Xp22
	Fanconi anemia	FANCA	16p24.3
	VACTERL syndrome	FANCC	9q22.3
		FANCD1	13q12.3
		FANCD2	3p25.3
		FANCG	9p13
		FANCB	Xp22.31
		PTEN	10q23.31
Chromosomal Abnormalities
	Trisomy 13		Chromosome 13
	Trisomy 18		Chromosome 18
	Trisomy 21		Chromosome 21
	DiGeorge syndrome	TBX1	22q11.2
	13q Deletion	ZIC2	13q22-qter
	17q Deletion	RARα	17q21.3-q24.2
		NOG
		TBX4
16q24 Deletion		FOXF1	16q24.1

Approximately 50% of infants with esophageal atresia have associated congenital anomalies involving the cardiovascular, GI, neurologic, genitourinary, or orthopedic systems (51,52). Some of the more complex associations are described briefly. The VATER syndrome links vertebral defects, anal atresia, tracheoesophageal fistula, and renal dysplasia (53). The VATER association is defined by finding at least three of the VATER anomalies. A subset of infants with the VATER syndrome have other defects including diaphragmatic, genital, cardiovascular, and neural tube defects; oral clefts; bladder exstrophy; small intestinal atresias; and omphalocele. A variant syndrome, the VACTERL anomaly, combines the VATER syndrome with radial or other limb defects (54). It affects approximately 1.6 of 10,000 live births (55). Defective development of the neural tube and preaxial mesoderm may result in the full spectrum of changes (55). Patients with VACTERL are most likely to be male, have a higher perinatal mortality rate, and have lower mean birth weights than control populations (56). Mothers of infants with VACTERL often exhibit a higher frequency of fetal loss in previous pregnancies than a control population. Patients with a familial form of X-linked VACTERL, X-linked VACTERL-H, develop hydrocephalus due to aqueductal stenosis.

TABLE 2.2 GENES NECESSARY FOR NORMAL TRACHEOESOPHAGEAL DEVELOPMENT

Gene	Human Chromosomal Location
Foxf1	16q24
Gli2	2q14
Gli3	7p13
Hoxc4	12q13.3
RARα	17q21
RARβ	3p24
Shh	7q36
Tbx4	17q21-q22

FIG. 2.25 Radiograph of esophageal atresia.

Esophageal atresia also associates with the CHARGE syndrome (coloboma, heart disease, atresia choanae, growth and developmental retardation, genital hyperplasia, and ear anomalies) (57). The oculodigitoesophageoduodenal syndrome, also known as Feingold syndrome, is a dominantly inherited combination of hand and foot anomalies, microcephaly, esophageal/duodenal atresia, short palpebral fissures, and learning disabilities. The abnormality maps to chromosome 2p23-p24 (58). The Bartsocas-Papas syndrome consists of
bilateral renal agenesis, esophageal atresia, hypoplastic diaphragm, unilateral renal agenesis, agenesis of the penile shaft, or anal atresia (59).

FIG. 2.26 Esophageal atresias and stenoses. A: In type I atresia, a segment of the esophagus is represented by only a thin, noncanalized cord with resultant formation of an upper blind pouch connecting with the pharynx and a lower pouch leading to the stomach. Most commonly, the atresia is located at or near the tracheal bifurcation. B: Rare type II atresia. The proximal and distal portions of the esophagus are completely separate. The upper part connects with the trachea. C: Type III is the most common anomaly. The lower pouch communicates with the trachea or mainstem bronchus. D: In type IV, both the upper and lower pouches connect to the trachea. E: Esophageal stenosis near tracheal bifurcation. Tracheoesophageal fistula is also illustrated. F: Simple esophageal stenosis.

Pathologic Features

Six types of esophageal atresia and stenosis are recognized (Figs. 2.26 and 2.27). In esophageal atresia, hypertrophic esophageal and tracheal muscles intimately blend with one another and the muscle layer contains an extramyenteric plexus. This is a manifestation of incomplete tracheal-esophageal separation. Striated muscle is present in the upper esophagus but not in the lower. Accompanying congenital esophageal neural abnormalities contribute to esophageal dysmotility (60).

Several types of stenosis exist. The stenotic segment varies from 2 to 20 cm in length and is usually located in the mid- or distal esophagus. In the first type of stenosis, segmental narrowing and loss of esophageal mural elasticity produces a localized area of muscular hypertrophy. In rare cases, the muscular hypertrophy involves the entire esophagus. The muscular hypertrophy may result from inflammatory damage to the myenteric plexus, with loss of the muscle-relaxing nitric oxide-producing nerves (61), and may coexist with hypertrophic pyloric stenosis. In a second form of stenosis, cartilaginous tracheobronchial remnants and respiratory epithelium lie within the esophageal wall, as a result of
sequestration of a tracheobronchial anlage during the period of cranial elongation before embryologic separation of the esophagus and trachea. In a third form, a membranous diaphragm or web arising from the esophageal wall, containing fibromuscular tissue with a small central perforation, obstructs the lumen. These anomalies are treated surgically but when the lesions are repaired, patients often suffer residual esophageal dysmotility due to underlying neural abnormalities in the remaining esophagus. The abnormal motility often leads to GERD with all of its complications (62). Restenosis commonly occurs, leading to aspiration and respiratory infections.

FIG. 2.27 Tracheoesophageal fistula. Thoracic and upper abdominal organs viewed from the posterior surface in a neonate born with esophageal atresia. The upper esophagus terminates blindly in a blunted esophageal pouch (arrow) and distal esophageal communication with the trachea at the carina (arrowhead).

Congenital Bronchoesophageal Fistulas

Bronchopulmonary malformations occur less commonly than tracheoesophageal abnormalities and result from imperfect separation of pulmonary and esophageal anlagen or from an accessory esophageal lung bud. If the communication between the pulmonary tissue and the esophagus is lost, the pulmonary tissue appears as a sequestration. Extralobar sequestrations remain anatomically separate from the lung and have their own pleura. They usually lie adjacent to the esophagus, with which they may communicate. Rarely, intralobar sequestrations communicate with the esophagus presenting as bronchoesophageal fistulas (63). Patients usually present in infancy with a mediastinal mass. Tracheobronchial chondroepithelial hamartomas represent an uncommon related lesion (64), which also results from the abnormal separation of the esophagus and trachea. They contain tracheobronchial lining epithelium, cartilage, and sometimes ectopic thyroid tissue or heterotopic pancreas. These lesions are extremely rare and usually lie in the distal esophagus (64).

FIG. 2.28 Duplication cyst. A: Radiograph of a large intramural defect in proximal esophagus. B: Gross picture showing the presence of a bulging submucosal sausage-shaped mass from a different patient cyst (arrows).

Duplications

Esophageal duplications account for only 10% to 20% of all GI duplications. They affect approximately 1 of 8,000 persons (65). Duplications develop while columnar, ciliated columnar, or squamous epithelium lines the fetal esophagus and occur in three major forms: cysts, diverticula (discussed in a later section), and tubular malformations. Cysts account for 80% of duplications. Duplications often present in infancy and childhood with dysphagia, nausea, vomiting, weight loss, pain, bleeding, anorexia, dyspnea, wheezing or recurrent coughing, and pneumonitis.

Duplication cysts are single, fluid-filled cysts (65) that lie posteriorly in a periesophageal location, develop within the esophageal wall (Fig. 2.28), or present as pedunculated intraluminal lesions (66). They average up to 5 cm in diameter. Duplication cysts typically demonstrate continuity of the esophageal muscularis propria with the muscle layer
of the cyst wall. It may be difficult to distinguish between esophageal duplication cysts and other intrathoracic cysts lined by respiratory columnar (Fig. 2.29), cuboidal enteric, stratified squamous, or gastric epithelium. Tubular duplications usually lie within the esophageal wall paralleling the true esophageal lumen. Unlike duplication cysts, tubular duplications communicate with the true lumen at either or both ends of the tube. Duplications usually have a duplicated muscularis propria.

FIG. 2.29 Duplication cyst. A: An intramural cyst with epithelial lining lies within the muscularis propria. B: The lining is a ciliated respiratory epithelium.

Bronchogenic Cysts

Bronchogenic cysts lie anteriorly, representing defective tracheoesophageal separation and aberrant bronchial budding from the foregut. They occur in the mediastinum, within the lung, or in the abdomen. Histologically, they contain cartilage, smooth muscle cells, and seromucinous minor salivary glands and are usually lined by ciliated, mucus-secreting, respiratory epithelium. Other bronchogenic cysts are lined by respiratory squamous epithelium but lack cartilage.

Esophageal Rings and Webs

The distal esophagus contains two rings that demarcate the proximal and distal borders of the esophageal vestibule (67). They occur alone or together. The muscular ring lies at its proximal border and corresponds to the upper end of the LES. It is a broad, 4- to 5-mm symmetric band of hypertrophic muscle covered by squamous epithelium that constricts the tubular esophageal lumen at its junction with the vestibule. The mucosal ring or Schatzki ring affects 6% to 14% of individuals and always associates with a hiatal hernia. Mucosal rings are thin, 2-mm transverse mucosal folds that protrude into the esophageal lumen. They usually lie at the SCJ with squamous epithelium covering the upper surface and columnar epithelium lining the lower. The core of the ring contains connective tissue, fibers of the muscularis mucosae, and blood vessels. The muscularis propria contributes little to its formation. Mucosal rings may progress to strictures due to coexisting inflammation (67). Mucosal webs and rings are compared in Table 2.3.

The incidence of esophageal webs ranges from 0.7% to 16%. Congenital esophageal webs are characterized by one or more thin horizontal membranes covered by stratified squamous epithelium arising in the upper and midesophagus. Unlike rings, webs rarely encircle the lumen, but instead protrude from the anterior wall, extending laterally. Webs rarely exceed 2 mm in thickness. Postinflammatory esophageal webs complicate many forms of esophagitis. As a result, they tend to be multiple and distributed throughout the esophagus. Histologically, webs consist of a thin layer of variably inflamed connective tissue covered on both sides by stratified squamous epithelium. Gastric mucosa may line the undersurface of distal webs. The epithelium covering esophageal webs may undergo neoplastic transformation.

The association of cervical webs, dysphagia, and iron deficiency anemia is known as the Plummer Vinson syndrome or Patterson Kelly syndrome (68). It develops in middle-aged
women with iron deficiency anemia, glossitis, splenomegaly, and oropharyngeal and esophageal inflammation. Not all patients with the syndrome have webs. Instead, they have nonpropulsive esophageal peristalsis (69) resulting from the iron deficiency, explaining symptom reversal following iron replacement therapy in patients without webs (69). The patients often have other abnormalities, some of which have autoimmune etiologies including autoimmune gastritis, ulcerative colitis, thyroid disease, Sjögren syndrome, and celiac disease (70). Shelflike mucosal webs arise from the anterior wall of the proximal esophagus, occasionally extending laterally or becoming circumferential. They are sometimes multiple. Most lie within 2 to 3 cm of the postcricoid area.

TABLE 2.3 COMPARISON OF RINGS AND WEBS

Type	Prevalence	Pathology	Pathogenesis
Postcricoid web	Association with iron deficiency anemia	Thin mucous membrane	Autoimmune Iron deficiency
Low esophageal mucosal ring	10% autopsies	Consists of center of loose areolar tissue covered on each side by thinned squamous epithelium	Associated with hiatus hernia Congenital Secondary to esophagitis
Low esophageal muscular ring	4% autopsies	Hypertrophy; muscle layer; mucosa thinned	Exaggeration of normal anatomy
Ringlike peptic stricture	Rare, complicates Barrett esophagus	Fibrous, inflamed tissue	Peptic esophagitis

Esophageal Intramural Pseudodiverticulosis

Esophageal intramural pseudodiverticulosis (EIP) is a rare condition, affecting 0.15% of patients undergoing barium swallow exams (71). The pseudodiverticula result from submucosal duct obstruction caused by inflammation, mucin, or squamous debris. Males are slightly more commonly affected than females, and over half are in their seventh or eighth decade of life (72). The disease has several known associations but since many are common, the relationships may be fortuitous rather than etiologic. Possible predisposing factors include alcohol abuse, GERD, and diabetes mellitus. The etiology of the disorder is not well understood, but chronic inflammation due to GER or Candida infection might be a causative factor (73). Strictures are present in approximately 75% of patients, and 50% have persistent Candida esophagitis (74). Patients present with dysphagia and acute bolus obstruction. These symptoms probably result from coexisting esophagitis or strictures rather than the pseudodiverticula themselves.

Multiple cystically dilated submucosal glandular ducts produce innumerable 1- to 3-mm flask-shaped diverticula with pinpoint mouths lying evenly distributed in a linear fashion along the esophageal wall (Fig. 2.30). These are most numerous proximally. The dilated ducts are lined by stratified squamous epithelium, which may appear hyperplastic (Fig. 2.31). The lumen may contain desquamated squamous cells or inflammatory cells. Organisms, including bacteria, fungi, and parasites, can secondarily colonize the cysts. Nonspecific acute or chronic inflammation often surrounds the acini and the ducts. The inflammation may lead to subsequent submucosal fibrosis or stricture formation.

Diverticula

Esophageal diverticula are saccular outpouchings that contain all, or part, of the esophageal wall. One can classify them by their location (pharyngoesophageal, thoracic, or epiphrenic), their pathogenesis (congenital, traction, or pulsion), or their status as true or false, or congenital or acquired (Fig. 2.32). The most important feature distinguishing congenital versus acquired diverticula is the absence of an intact muscularis propria in acquired diverticula. Zenker (hypopharyngeal) diverticulum represents the most common (up to 70%) esophageal diverticulum. Twenty-one percent of diverticula
originate in the midesophagus; 8.5% originate in the supradiaphragmatic region. Histologically, squamous epithelium lines all acquired esophageal diverticula unless they develop in an area of BE. Congenital diverticula contain all of the components of the esophageal wall, including the muscularis propria, and may be lined by columnar, ciliated, or squamous epithelium.

FIG. 2.30 Esophageal intramural pseudodiverticulosis. Doublecontrast esophagram demonstrates numerous irregular thin outpouchings from the esophageal lumen, some of which have flaskshaped bases. These represent ectatic submucosal glands.

FIG. 2.31 Diffuse esophageal intramural pseudodiverticulosis. A: Low-power magnification demonstrating the presence of a cystically dilated duct, which passes between lobules of the submucosal glands. Some of the ducts have also undergone squamous metaplasia. B: Higher magnification of one of the ducts showing the presence of inspissated secretions and flattened cuboidal lining epithelium. A mild inflammatory infiltrate surrounds the duct.

FIG. 2.32 Comparison of congenital versus acquired diverticula. A: False or acquired diverticula tend to demonstrate epithelial or mucosal outpouchings through the muscularis propria. In some instances, the submucosa follows the mucosa. B: In contrast, congenital or true diverticula represent herniations of the entire wall of the gastrointestinal tract, including the muscularis propria.

Zenker Diverticulum (Pharyngoesophageal Diverticulum)

Patients with Zenker diverticula are generally in their seventh or eighth decades of life. There is a 2:1 male preponderance. The diverticulum originates in the proximal esophagus (Fig. 2.33) from mucosal outpouchings at points of weakness in the esophageal wall at its junction with the pharynx. Most develop posteriorly or posterolaterally between the inferior constrictor muscle and fibers of the cricopharyngeus muscle through a triangular zone of sparse musculature termed the Killian triangle. These pulsion diverticula result from uncoordinated muscular contractions during swallowing. As the diverticulum enlarges, it protrudes between the posterior wall of the esophagus and the vertebrae leading to anterior displacement of the proximal esophagus, sometimes causing esophageal compression.

Patients typically present with dysphagia, halitosis, and regurgitation of food consumed several days previously. Aspiration and secondary pneumonitis may occur. Bacterial colonization of the diverticulum results in diverticulitis. Perforation leads to mediastinitis. Zenker diverticulum and cervical esophageal webs or hiatal hernias sometimes coexist. Squamous epithelium lines Zenker diverticula (Fig. 2.34). The muscle may appear attenuated and the wall is variably inflamed, sometimes with prominent lymphoid follicles. Ulcers may occur. There is a 0.31% to 0.7% incidence of squamous cell carcinoma secondary to long-standing inflammation (75).

FIG. 2.33 Zenker diverticulum. Lateral view demonstrates the diverticulum as a large saclike structure containing barium.

FIG. 2.34 Histologic appearance of Zenker diverticulum. Herniation of the mucosa, submucosa, and part of the muscularis propria into the paraesophageal tissues. The resulting diverticulum consists of muscular wall, submucosa, and a hyperplastic squamous epithelium.

Midesophageal Diverticula

Diverticula arising at the level of the tracheal bifurcation are less common than those in the cervical esophagus. Midesophageal diverticula almost always represent incidentally discovered lesions, unless there is coexisting diverticulitis. They are single or multiple (Fig. 2.35), and usually develop in association with mediastinal inflammation that causes traction on the esophageal wall, pulling it outward. Other diverticula result from motility disturbances, including achalasia or diffuse esophageal spasm. These wide-mouthed diverticula (Fig. 2.36) consist of a variably inflamed squamous mucosa and submucosa with an attenuated muscularis propria.

Epiphrenic Diverticula

Epiphrenic diverticula are rare, developing in middle age, supporting an acquired etiology. They are almost always of the pulsion type, resulting from increased intraesophageal pressure that pushes the mucosa outward in areas of muscular weakness. They frequently coexist with other disorders including hiatal hernia, diaphragmatic eventration, and carcinoma and/or motility disturbances (76). The presence of hypertrophic muscle distal to the diverticula supports the concept that functional or anatomic obstruction is important in their pathogenesis. Patients present with substernal pain, dysphagia, and weight loss. Complications include aspiration pneumonia and lung abscesses, diverticulitis, esophageal obstruction, perforation, mediastinitis, or hemorrhage. Epiphrenic diverticula develop in the distal 10 cm of the esophagus. They appear globular and wide mouthed and, in contrast to midesophageal lesions, may become quite large. The diverticula contain a squamous mucosa and submucosa but no muscularis propria (Fig. 2.37). Chronic inflammation is often present. Carcinomas may develop within epiphrenic diverticula for the same reason they do in other diverticula (i.e., stasis of luminal contents).

FIG. 2.35 Esophageal diverticulum. Mucosal view of two esophageal traction diverticula (arrows).

▪ PANCREATIC METAPLASIA

Pancreatic metaplasia develops in patients with BE (77), carditis, and inlet patches. The mean patient age is 52 years with a range of 18 to 89 years. It occurs in 24% to 60% of patients with biopsy specimens from the SCJ (77,78,79). The metaplastic glands often lie in the deeper aspects of the mucosa and vary in size from 0.1 to 0.5 mm in greatest diameter (77). They form small clusters of compactly packed cells that either blend imperceptibly into the adjacent metaplastic or native gastric glands or form distinct nodules that can stand out prominently within the mucosa (Fig. 2.38). The pyramidal pancreatic acinar-type cells have abundant apical and midcellular eosinophilic coarse granular cytoplasm and appear basophilic in the basal areas. The basally located nuclei are small, round, and uniform with occasional conspicuous but small nucleoli. The acinar cells are positive for pancreatic lipase and amylase. Mucous cells may intermingle with the pancreatic acinar cells within individual lobules. Endocrine cells may also be present. The foci of pancreatic metaplasia lack pancreatic ducts, periductal smooth muscle fibers, and islet cells.

FIG. 2.36 Esophageal diverticulum. A: Unopened esophagus and stomach with the dissected-out heart (H). A large saccular dilation (D) extends from the midesophageal region and lies next to the heart on the photography table. B: Opened specimen demonstrating the presence of a large diverticulum containing necrotic debris. This diverticulum was attached to the pericardium.

FIG. 2.37 Esophageal diverticulum. A: Midsagittal section of the diverticulum showing a lining of tan squamous mucosa; the outer coat is thinned. B: Histologic section of (A).

FIG. 2.38 Pancreatic metaplasia of the esophagus. A: Low magnification of pancreatic metaplasia forming a nodule. B: High magnification of pancreatic acinar-type cells.

▪ MUCOSAL LACERATIONS, ULCERATIONS, AND PERFORATIONS

Esophageal perforation occurs in many settings (Fig. 2.39) (Table 2.4). A retrospective study of esophageal perforations in a large hospital found 26 instances in a 10-year time frame. Only 6 of these were spontaneous, while 19 were due to instrumentation with the largest number due to pneumatic dilation in cases of achalasia (80). Perforations due to foreign bodies occur in areas of physiologic narrowing. Spontaneous transmural perforations qualify for a diagnosis of Boerhaave syndrome. Spontaneous intramural tears qualify for a diagnosis of a Mallory-Weiss tear. When the esophagus perforates, free air enters the mediastinum and spreads to adjacent structures causing palpable cervical emphysema, mediastinal crackling sounds, and pneumothorax. Over time, secondary infections may cause mediastinal abscesses, pyopneumothorax, and pleural-pulmonary suppurations.

Mallory-Weiss Syndrome

The term Mallory-Weiss syndrome refers to cases of painless GI bleeding resulting from esophageal or gastroesophageal mucosal lacerations (Fig. 2.39), usually following severe vomiting. Sometimes, vomiting precipitates tears of preexisting ulcers. Less traumatic events, even snoring, can produce partial esophageal tears, usually above the cardia (81). Most patients are males with a history of alcohol and/or salicylate abuse or hiatal hernias. Rarely lacerations develop in children (82), even neonates. Risk factors for bleeding include portal hypertension or a coagulopathy. These tears account for 5% to 10% of cases of upper GI hemorrhage (83). Single or multiple lacerations lie along the long axis of the distal esophagus crossing the GEJ or lying in the gastric fundus. Over 75% of lacerations are limited to the stomach; they average 1.5 cm in length. The lacerations vary in depth, often only affecting the mucosa; they rarely extend into the muscularis propria. Submucosal hematomas may form and dissect for a distance beyond the tear. Histologic changes reflect the temporal relationship to the tear. If acute, there may be little in the way of acute inflammation. Over time, acute and then chronic inflammatory cells infiltrate the area around the tear. Previous lacerations may associate with scarring. Bleeding from Mallory-Weiss tears usually stops spontaneously; less than 5% of patients rebleed.

FIG. 2.39 Esophageal lacerations and perforations. A: Mallory-Weiss tear. This tear straddles the gastroesophageal junction. Deeper ulceration is present as well. This laceration occurred through an area of preexisting esophagitis. B: Boerhaave syndrome with spontaneous transmural rupture.

Boerhaave Syndrome

The typical patient with Boerhaave syndrome is a middleaged male, and frequently an alcohol abuser. The disorder may also affect children, including neonates (84). Severe vomiting followed by constant excruciating chest pain are the classic clinical signs. Hematemesis occurs at times. The clinical and radiologic findings point to an intrathoracic catastrophe. The nonspecific symptomatology often delays the correct diagnosis. The mortality rate is approximately 31%. The sudden development of a pressure gradient between an internal portion of a viscus and its external supporting tissues represents the common pathogenic denominator in
cases of GI rupture (85). The antecedent background varies; the viscus may become overdistended by food, drink, gas, or any combination thereof. Other antecedent events include abdominal blows, straining at stool, parturition, seizures, asthma, prolonged hiccups, and neurologic diseases.

TABLE 2.4 CAUSES OF ESOPHAGEAL PERFORATION

Esophagitis regardless of cause
Penetrating wounds
Iatrogenic trauma
	Pneumatic dilation
	Intubation
		Intraoperative
		Endoscopic
Foreign bodies
Blast injury
Postemetic (Mallory-Weiss syndrome)
Blunt trauma (auto accidents, etc.)
Esophageal diverticula
Esophageal cancer
Corrosive injury
Sclerotherapy
Mucosal ablative therapies

Characteristically, the rent is linear and longitudinal and occurs most commonly in a left lateral posterior location, 1 to 3 cm above the GEJ (Fig. 2.39). The tears measure 1 to 20 cm in length with an average length of 2 cm; the mucosal part of the tear is usually longer than the muscular part. Immediate surgical repair must occur if the patient is to survive. Persistent reflux often follows repair of the rupture (85).

▪ ESOPHAGITIS

General Comments

Esophagitis has many causes (Table 2.5), the most common being GER, infections, and drug induced injury. Esophageal biopsies are taken to determine the etiology of the esophagitis, to assess the consequences of the inflammation, to follow the course of the underlying disease, and to gauge therapeutic responses. Irrespective of its cause, most cases of esophagitis share common histologic features. Therefore, determining a specific etiology may be difficult unless one detects specific diagnostic features such as the presence of viral inclusions. Additionally, multiple etiologies may be present in any given patient.

Esophageal inflammation can be acute, chronic, or mixed. Mild esophageal injury results in reversible mucosal changes and transient inflammation. Changes associated with acute damage include the presence of balloon cells and inflammatory cells (particularly mononuclear cells) and eosinophils. Basal cell hyperplasia and papillary elongation develop and vascular lakes form. In severe esophagitis, ulcers, erosions, or neutrophils may be seen. Chronic damage leads to submucosal fibrosis or strictures. Patients with long-standing reflux esophagitis may develop BE.

TABLE 2.5 CAUSES OF ESOPHAGITIS

Gastroesophageal reflux
Uremia
Ingested material
	Drugs
	Corrosive agents
	Food
Graft vs. host disease
Infections
Radiation
Smoking
Systemic disorders
Behçet syndrome
Crohn disease
Epidermolysis bullosa
Pemphigus
Sarcoid
Scleroderma
Trauma
Intubation
Vascular disease
Motility disorders
Repaired tracheoesophageal fistula
Sclerotherapy

Multinucleated epithelial giant cell changes develop in esophagitis of varying etiologies, representing a nonspecific reparative response. The mucosa contains multinucleated (mean three nuclei per cell, range two to nine) squamous epithelial cells (Fig. 2.40). They are often confined to the basal
zone, but sometimes they involve both the basal and superficial epithelium. The nuclei contain single or multiple eosinophilic nucleoli with a perinuclear halo but no inclusions, hyperchromicity, or atypical mitoses (86). Multinucleated cells can also be seen in viral infections, but the use of immunostains or genetic tests allows one to separate nonspecific giant cell changes from virally induced changes.

FIG. 2.40 Multinucleated squamous epithelial giant cells. Several squamous epithelial cells with multiple nuclei are identified in the basal epithelium and should not be mistaken for viral inclusions (immunohistochemical staining for HSV types I and II was negative).

Cytologic material obtained from patients with esophagitis may show a nonspecific acute and chronic inflammatory infiltrate with mixtures of neutrophils, eosinophils, lymphocytes, plasma cells, histiocytes, and erythrocytes. Epithelial cells, when present, usually appear degenerative.

Reflux Esophagitis

The term gastroesophageal reflux (GER) refers to the retrograde flow of gastric and sometimes duodenal contents into the esophagus. The term gastroesophageal reflux disease is a symptomatic condition or histopathologic alteration resulting from episodes of GER. Reflux esophagitis describes a subset of GERD patients with histopathologic changes in the esophageal mucosa.

Demography/Epidemiology

GERD affects patients of all ages, even children and small infants, but is most common among patients over age 65 (87). GERD affects from 3% to 4% of the population, and its incidence has increased in the past few decades. The annual cost of managing the disease in the United States is estimated at 9 billion dollars (88). GERD is equally present among men and women, but there is a male predominance of esophagitis and BE. GERD affects whites more frequently than it does members of other races. There is also geographic variability in the prevalence of GERD with very low rates in Africa and Asia and high rates in North America and Europe (89). However, GERD is increasing in frequency in Asians. Ethnic and geographic demographic differences suggest that both genetic factors and environmental factors play a role in predisposition to GERD (90).

Conditions predisposing to GERD include smoking, decreased physical activity, increased intra-abdominal or intragastric pressure, including pregnancy, ascites, body mass index and obesity; and delayed gastric emptying. Postmenopausal estrogen therapy has been associated with GERD symptoms (91,92). Motility disorders including diabetes, alcoholic neuropathies, achalasia, and scleroderma also predispose to GERD. Patients with hiatal hernias and strictures are especially prone to develop GERD. It also follows surgical procedures. Erosive esophagitis is particularly common in acid hypersecretors such as those with the Zollinger-Ellison syndrome (93). GER in infants and children complicates congenital esophageal or gastric abnormalities. GER also associates with cystic fibrosis (94).

Pathophysiology

GERD is a multifactorial disorder (Table 2.6). Most patients have a lower mean LES resting pressure than is seen in patients without GERD. This allows acid to reflux into the esophagus, leading to the development of esophagitis. The inflammation further impairs LES pressure, increasing acid exposure in the esophagus (95). Patients also have inadequate or slowed clearance of refluxed material and delayed gastric emptying and/or increased gastric volume. The nature and amount of refluxed material and the length of time it remains in contact with the esophageal mucosa as well as the number of reflux episodes determine whether GERD develops (96). GERD results from reflux of both acid and alkaline secretions (Fig. 2.41). Acid alone causes relatively few changes, but when combined with pepsin or bile acids, more severe damage results (97). Pepsin requires an acid pH
to exert its full damaging effects (98). Patient age, nutritional status, and other less well-understood factors also influence the mucosal capacity to withstand injury and to repair itself following injury. Reflux esophagitis may also be enhanced by the genesis of free radicals during reflux. These free radicals damage cell membranes, thereby altering the mucosal barrier. Lipid peroxidation increases with the increasing grade of esophagitis; it is highest in patients with BE (99).

TABLE 2.6 CAUSES OF, OR PREDISPOSITION TO, GASTRIC REFLUX

Loss of lower esophageal sphincter (LES) pressure gradient
Loss of esophageal closure pressure
Abnormal LES sphincter position
Hiatus hernia
Certain foods, drinks
Smoking
Pyloric stenosis
Smooth muscle medications
Atropine
β-Adrenergics
Aminophylline
Nitrates
Calcium channel antagonists
Smooth muscle relaxants
Iatrogenic destruction of the LES
Surgical resection
Myotomy
Balloon dilation
Gastroplasty
Gastrostomy feeding
Nasogastric intubation
Pregnancy
Esophageal dysmotility syndromes (inefficient mucosal clearing)
	Collagen vascular diseases
	Intestinal pseudoobstruction syndromes
	Autoimmune neuropathies
	Diabetes
Zollinger-Ellison syndrome
Decreased esophageal mucosal resistance
Infections
Prior chemotherapy
Intubation (nasogastric)
Increased gastric pressure
Abnormally distended stomach
Refluxed duodenal contents
Esophageal and gastric structural abnormalities

FIG. 2.41 Bile reflux esophagitis. Surface of the esophageal mucosa demonstrating the presence of bile crystals overlying the squamous epithelium.

Relationship of Reflux Esophagitis to Helicobacter pylori Infections

Studies addressing the relationship of HP infection to GERD often reach conflicting conclusions. This results from the fact that the interplay of HP infections and GERD is complex and complicated by the common use of proton pump inhibitor (PPI) therapy in these patients. At the heart of the debate is the link between gastric acid secretion, HP infection, and GERD. In patients with gastric ulcer and corpus gastritis, the impact of HP infection varies substantially producing wide variation in patterns of acid secretion. In many patients gastric acid is suppressed and is no longer produced in the amount necessary to induce GERD. Bacterial eradication in some of these individuals results in a substantial recovery of acid secretion with sufficient acid to increase the aggressiveness of refluxed gastric juice to the esophageal mucosa (100). The result is an increase in prevalence of histologic esophagitis and increased reactive oxygen species at the GE junction in patients with H. pylori gastritis before and after anti-HP treatment (101). In contrast, duodenal ulcer patients typically have antrum-predominant HP gastritis and a well-preserved acid-secreting mucosa. In these patients, HP infections may make the acid-secretory mechanism hyperresponsive to stimulation, increasing acid production. In this patient group, HP infections can increase the aggressiveness of the gastric juice to the esophageal mucosa.

Current epidemiologic trends indicate an inverse relationship in the Western world between the rising incidence of GERD and the decreasing incidence of HP infections (102). The lower prevalence of HP in GERD patients, the increase of GERD following HP eradication, and the association with certain gastritis patterns (atrophic corpus gastritis) have led to the widespread opinion that HP exerts a protective effect on the esophagus and may prevent the development of GERD and its complications (102). However, as noted, the data and their interpretations are conflicting, keeping this subject one of continuing interest.

Clinical Features

Transient mild reflux affects most individuals including children and adults. It is especially common in preterm infants (103). The degree of reflux must be severe for individuals to become symptomatic. Fifty percent of symptomatic patients have complications including esophagitis, strictures, and BE. Adults present with diverse symptoms including heartburn, regurgitation, bitter-tasting fluid in the mouth, dysphagia, odynophagia, nausea, vomiting, hiccups, anginalike chest pain, and hoarseness. The regurgitation can cause a spectrum of conditions, including asthma, chronic cough, chronic laryngitis or pharyngitis, subglottic stenosis, and dental disease. Some patients present with bleeding from esophageal ulcers. Complications peak between ages 50 and 70 years (104). The severest complication is carcinoma developing in the setting of BE.

The clinical course and prognosis of infants and children with GER differ depending on the age at onset. Some children present with symptoms of asthma. GERD may also cause obstructive apnea in infants. Severe dental caries are common. The most frequent complication of recurrent GER in children is failure to thrive as the result of caloric deprivation, vomiting, recurrent bronchitis, or pneumonia caused by repeated episodes of pulmonary aspiration. Some children require gastroesophageal fundoplication and/or pyloroplasty to alleviate the symptoms.

The majority of patients with GERD symptoms are treated with PPI therapy, often prior to being seen by a gastroenterologist (105). As many as 38% of patients receiving PPI treatment have residual symptoms (106). As a result, many of the patients undergoing endoscopy and biopsy for GERD symptoms are those that are refractory to PPI therapy rather than patients with untreated GER. Such patients may have additional disorders superimposed on GERD. The differential diagnosis of esophageal disorders that may be associated with refractory symptoms in patients treated with PPIs is summarized in Table 2.7.

TABLE 2.7 DISORDERS ASSOCIATED WITH RESIDUAL SYMPTOMS IN PATIENTS TREATED WITH PPIS

Esophageal Disorders
	Reflux Related
		Incorrect medication dose timing
		Medication noncompliance
		Residual pathologic acid secretion
		Rapid PPI metabolism
		Hypersecretory state
		Anatomic abnormalities
		Defective LES function
		Hypersensitivity of esophagus to small amounts of refluxed material
	Non-Reflux Related
		Achalasia
		Esophageal spasm
		Scleroderma
		Eosinophilic esophagitis
		Pill esophagitis
		Infectious esophagitis
Nonesophageal Disorders
	Gallbladder disease
	Cardiovascular disease
	Musculoskeletal disorders
	Malignancy (GI and non-GI)

Gross and Endoscopic Features

The gross appearance of the esophagus varies with disease severity. Approximately one third of patients with chronic GERD symptoms are endoscopically normal (107). Lowgrade esophagitis is only evident histopathologically. Areas of patchy erythema and red streaks are the first endoscopic abnormalities. Later, erosions and ulcers develop; these predominate distally and taper off proximally. The esophagus appears friable, diffusely reddened, and hemorrhagic (Fig. 2.42); it bleeds easily. As the disease progresses, the ulcers become confluent, even circumferential. Strictures or BE characterize severe chronic disease. Prolonged reflux may result in esophageal shortening. Inflammatory polyps may be present. The distinction between the squamous and the columnar epithelium becomes less clear.

Several endoscopic classifications have been developed to evaluate the esophageal mucosa. The three most common are the Savary-Miller, MUSE (metaplasia, ulcer, stricture, erosion), and “Los Angeles” classifications (108,109,110) (Table 2.8). Although all of the classifications show high reproducibility among experienced endoscopists, the Los Angeles and MUSE systems are the most reproducible classification among endoscopists of all levels of experience (110). Using either the Los Angeles or the Savary-Miller classifications, there is poor correlation between endoscopic grade and histologic findings (111).

Histologic Features

Biopsies are performed to confirm the diagnosis of GERD; to document complications, including esophagitis, BE, dysplasia or tumor development; and to rule out the presence of coexisting infections. Since esophagitis tends to be a patchy process, it is easy to miss diagnostic changes on a single biopsy. The current wisdom is that biopsies should be taken in the area just distal to the Z line to detect carditis (see below), just proximal to the Z line to detect esophagitis, and 3 cm proximal to the Z line to detect the hyperplastic changes that are more predictive of the presence of GERD than more distally derived biopsies.

FIG. 2.42 Reflux esophagitis. Area of the Z line is destroyed. Acute hemorrhagic ulcerative reflux esophagitis demonstrating multiple areas of ulceration and erythema.

Repetitive episodes of tissue injury and healing produce histologic features that reflect disease activity at the time of examination, superimposed on changes from previous injurious episodes. Esophagitis can heal completely or it may progress on to a number of the complications discussed later. Biopsies from patients with heartburn commonly show only basal cell hyperplasia without inflammation. The basal hyperplasia can progress to frank esophagitis. There are four stages of reflux esophagitis: (a) acute (necrosis, inflammation, and granulation tissue formation); (b) repair (basal cell hyperplasia and elongation of the papillae); (c) chronic (fibrosis and formation of BE); and (d) complications (dysplasia and adenocarcinoma).

Various histologic features should be assessed when examining the biopsy for GERD (Table 2.9). No single feature described below represents an absolute criterion for the presence of GERD, but each is helpful in establishing the diagnosis. In the absence of a known drug history or the presence of specific microorganisms, biopsies, particularly
distal biopsies showing esophagitis, are most likely to be due to GERD.

TABLE 2.8 ENDOSCOPIC CLASSIFICATION OF GERD

Savary-Miller Classification
Grade 1:	One or more supravestibular reddish spots with or without exudates
Grade 2:	Erosive and exudative lesions in the distal esophagus that may be confluent, but not circumferential
Grade 3:	Circumferential erosions in the distal esophagus covered by hemorrhagic and pseudomembranous exudates
Grade 4:	Presence of chronic complications such as deep ulcers, stenosis, or scarring with Barrett metaplasia
Los Angeles Classification
Grade A:	One or more mucosal breaks ≤5 mm in length
Grade B:	At least one mucosal break > 5 mm long, but not continuous between the tops of adjacent mucosal folds
Grade C:	At least one mucosal break that is continuous between adjacent mucosal folds, but not circumferential (<75% of periphery)
Grade D:	Mucosal breaks that involve at least three quarters of the luminal circumference
MUSE Classification
Grade	Metaplasia	Ulcer	Stricture	Erosions
0	M0 Absent	U0 Absent	S0 Absent	E0 Absent
1	M1 One fold	U1 One	S1 >9mm	E1 One
2	M2 Circumferential	U2 Two or more	S2 ≤9mm	D2 Confluent
Note: Ulcers, strictures, Barrett metaplasia, and other findings are reported as an adjunct to each grade.

Epithelial Hyperplasia

The normal basal cell layer is only one to four cells high; it should not constitute more than 15% of the epithelial thickness. In the setting of GERD, the basal zone increases from 10% to more than 50%; papillary height can increase to more than 50% to 75% of the total epithelial thickness (112). This change affects patients with an endoscopically normal mucosa as well as those with endoscopic evidence of esophagitis. Regenerative changes are characterized by nuclear enlargement, hyperchromasia, and mitoses that remain limited to the basal layer (Fig. 2.43). Prominent nucleoli may be present. EGFR expression is enhanced in the hyperplastic cells (113).

Although recognition of the basal layer of the squamous epithelium is not difficult, determination of its uppermost limit often is. One definition that may be helpful (114) is that the upper limit of the basal zone is that point where the majority of epithelial cell nuclei are separated by a distance less than the diameter of one nucleus (115). In addition, accurate assessment of the thickness of the basal layer requires evaluating well-oriented specimens. The basal height should not be assessed near vascular papillae. It may be helpful to divide the epithelial thickness into thirds. When the lower third is divided in half, the basal cells should be confined to its lower half. In less optimally oriented specimens, basal zone thickness can be evaluated if one sees at least three to four papillae arranged in parallel to one another and not cut tangentially. In tangentially cut sections, a helpful feature is an increase in the number of papillae, which can be evaluated in an en face section. In this setting one may see overlapping capillaries. Since the biopsies may be small or have minimal or no lamina propria or they may be inappropriately oriented and therefore difficult to evaluate for basal hyperplasia and papillary elongation, we recommend that the biopsies be examined at three levels to increase their diagnostic accuracy.

TABLE 2.9 HISTOLOGIC FEATURES OF REFLUX ESOPHAGITIS

Basal zone hyperplasia

Elongated papillae

Dilated intercellular spaces

Intraepithelial eosinophils

Intraepithelial neutrophils

Intraepithelial lymphocytes

Venular dilation (vascular lakes)

Balloon cells

Erosions or ulcers

If marked squamous epithelial hyperplasia develops, the elongated epithelial pegs extend into the underlying lamina propria, in a process known as acanthosis (Fig. 2.44). Extensive acanthosis, also termed pseudoepitheliomatous hyperplasia, can simulate dysplasia or invasive carcinoma. The epithelium may appear markedly regenerative with cytoplasmic basophilia, an increased nuclear-to-cytoplasmic ratio, glycogen depletion, and increased mitotic activity. However, the reactive cells more or less maintain their polarity and abnormal mitoses are absent. The individual cell keratinization seen in high-grade dysplasia is absent. The cell nuclei may have prominent nucleoli but the nuclei appear relatively uniform in size and one may see some evidence of squamous cell maturation in the more superficial cell layers. The boundary between the epithelium and the underlying stroma appears smooth, unless extensive inflammation occurs.

The stroma underlying the epithelium may appear inflamed, but one should not see desmoplasia.

FIG. 2.43 Esophagitis. A: Esophagitis with basal cell hyperplasia and a bandlike inflammatory infiltrate in the lamina propria. B: The mucosal vessels are dilated and congested. This histology corresponds to the hyperemia seen endoscopically in esophagitis. Numerous intraepithelial inflammatory cells are present. The epithelium appears poorly glycogenated.

The sensitivity of hyperplasia as a diagnostic feature of GERD is only 60% to 70% (116). Basal cell hyperplasia is a reversible change that disappears with treatment. Hyperplasia also complicates other forms of esophagitis so that it is not specific for GERD.

FIG. 2.44 Esophagitis. A: Acanthosis and immaturity of the squamous epithelium is present. Note the long prolongations of the epithelium into the underlying lamina propria. The lymphatics appear dilated and lymphocytes infiltrate the epithelium. B: Higher magnification of (A) demonstrating the elongated acanthotic, glycogen-depleted squamous epithelial prolongations. The flattened cells between the epithelial ridges represent compressed endothelium in the papillae. Chronic inflammation underlies the hyperplastic process.

Papillary Height

Papillary elongation is most often defined as papillae extending more than two thirds of the distance to the epithelial surface (Fig. 2.45). The degree of papillary elongation correlates with severity of reflux (117), but is not a specific
feature of GERD. Evaluation of papillary height, like basal layer thickness, requires a well-oriented biopsy in which the entire thickness of the epithelium is visible.

FIG. 2.45 Papillary elongation. Papillae can extend more than two thirds of the epithelial thickness in reflux esophagitis.

Dilated Intercellular Spaces

Dilated intercellular spaces occur in patients with both erosive and nonerosive GERD (118,119,120). In light microscopic studies, dilated intercellular spaces are defined as an increase in the distance between squamous epithelial cells. This distance varies from greater than 0.47 to 2.4 µm depending on the study (118,119,120,121,122). Dilated intercellular spaces are seen predominantly in the basal layer, and are thought to occur as a result of stretching and detachment of desmosomes (119) (Fig. 2.46). The prevalence of dilated intercellular spaces in biopsies from patients with GERD ranges from 67% to 94% depending on whether or not clinical symptoms, endoscopically identifiable lesions, or pH monitoring abnormalities are present (123).

FIG. 2.46 Dilated intercellular spaces. Intercellular bridges are visible due to dilatation of intercellular spaces. Occasional eosinophils are also present.

Inflammation

Intraepithelial Lymphocytes. Small numbers of lymphocytes populate both the normal mucosa and the lamina propria so that their presence does not aid in making a diagnosis of esophagitis. However, they are very conspicuous in patients with GERD (124). Biopsies with esophagitis average greater than six lymphocytes per high-power field (hpf) (125). Intraepithelial lymphocytes contain scant to invisible cytoplasm. The nuclear shape often curves to fit between the squamous cells (Fig. 2.47). These cells exhibit a T-lymphocyte phenotype (125). They are part of the inflammatory response in GERD but are not an independent marker of reflux esophagitis (124). A small percentage of the lymphocytes are intraepithelial S100+ antigen-presenting cells. Occasionally, the mononuclear cell infiltration becomes severe enough to cause a focal lymphoid hyperplasia mimicking a lymphoma.

Neutrophils. The presence of isolated neutrophils, either in the squamous epithelium or in the lamina propria, serves as evidence for acute esophagitis of many etiologies, and are most commonly observed in erosive GERD (126) (Fig. 2.48). Neutrophils are present in the epithelium of 10% to 40% of patients with reflux esophagitis, making them a relatively insensitive marker (127,128,129). They tend not to appear until the inflammation becomes severe and the epithelium ulcerated. They generally decrease in number the further one goes away from the erosion or ulcer. When numerous neutrophils are identified in an esophageal biopsy, the possibility of other ulcerating conditions including infection and pill-mediated injury should be considered.

Eosinophils. The normal number of eosinophils present in the esophagus is still somewhat controversial. However, many feel that eosinophils are normally absent (129,130). Some, however have found a modest number (usually less than five per high power field) may be seen (127) (Fig. 2.49). It is likely that these differences arise from differing definitions of normal controls versus GERD. Influx of eosinophils into the epithelium occurs early in the course of reflux esophagitis and may be seen in the absence of basal cell hyperplasia. Other causes for mucosal eosinophilia include the entities listed in Table 2.10. One can easily appreciate eosinophils in small endoscopic biopsies, even when the biopsies are not well oriented. They affect up to 60% of adults with severe disease but the intraepithelial eosinophils may be focal in nature, necessitating a search for them on serial sections; their presence does not correlate with disease severity (124,131). Eosinophils are not a sensitive marker for GERD, since they are only found in 40% to 50% of individuals with GERD (123,128,131). Significant esophageal eosinophilia (>15 intraepithelial eosinophils per hpf) may sometimes be seen in patients with GERD, but should prompt the pathologist to
consider the diagnosis of eosinophilic esophagitis (EoE) as discussed in a later section.

FIG. 2.47 Intraepithelial lymphocytes in reflux esophagitis. A: Increased numbers of lymphocytes insinuate themselves between the epithelium. B: Lymphocyte common antigen-immunostained sample demonstrating the presence of numerous intraepithelial lymphocytes (brown).

Balloon Cells

Balloon cells often develop in the midzone of the epithelium clustering around vascular papillae (132). These occur in approximately two thirds of cases of GERD (Fig. 2.50). The cytoplasm of the enlarged, globoid cells appears swollen; cells contain irregular pyknotic nuclei or demonstrate karyorrhexis. The presence of balloon cells does not establish a diagnosis of GERD, since they develop in any damaged mucosa, irrespective of its cause. Nonetheless, in the absence of other more characteristic features, the presence of balloon cells may be the only clue to suggest that some form of injury has occurred.

FIG. 2.48 Erosive reflux esophagitis. The squamous mucosa adjacent to an erosion shows a mixed active inflammatory infiltrate composed of neutrophils and eosinophils. Dilated intercellular spaces and papillary elongation are also present.

FIG. 2.49 Eosinophilia in reflux esophagitis. Eosinophils infiltrate the epithelium. Other features of reflux esophagitis (e.g., papillary elongation, balloon cells, dilated intercellular spaces, and neutrophilic inflammation) are also present.

TABLE 2.10 EOSINOPHIL-ASSOCIATED ESOPHAGEAL DISORDERS

Primary eosinophilic disorders
	Eosinophilic esophagitis
Secondary eosinophilic disorders
	Eosinophilic gastroenteritis
	Hypereosinophilic syndrome
Secondary noneosinophilic disorders
	Infection
	Pill esophagitis
	Gastroesophageal reflux disease
	Tumors
	Vasculitis
	Connective tissue disorders

Vascular Changes

Papillary capillary ectasia (sometimes called vascular lakes) (Fig. 2.51) and hemorrhage represent an early but nonspecific histologic sign of GERD. These lakes correspond to the red streaks seen endoscopically. Capillary ectasia develops in up to 83% of patients with reflux, contrasting with its presence in only 10% of control patients (133). This change is often present in the absence of any inflammation. Dilated and congested venules are seen high up at the top of the lengthened papillae. This may be accompanied by mucosal red cell extravasation. This change develops in many other forms of esophagitis.

Erosions, Ulcers, and Fistulas in Gastroesophageal Reflux Disease

The mucosal changes of reflux esophagitis range from the changes already described to acute esophagitis, erosions, superficial ulcers (Figs. 2.52, 2.53 and 2.54), and extension of the inflammatory process, leading to fistula formation. The depth of the process distinguishes an esophageal erosion from an ulcer. Erosions are superficial lesions that remain confined to the lamina propria and muscularis mucosae sparing all but the most superficial layers of the submucosa. The necrosis, hemorrhage, and inflammation associated with ulcers extend deeper into the underlying submucosa or muscularis propria. The epithelium close to erosions or ulcers often contains neutrophils, eosinophils, and many lymphocytes. The erosions or ulcers (Fig. 2.53) often contain granulation tissue, an inflammatory exudate, and fibrinoid necrosis in the ulcer base. Lymphoplasmacytic infiltrates, often forming lymphoid aggregates, tend to cluster around erosions and ulcers. Epithelium at the ulcer margin is usually attenuated. Marked basal cell hyperplasia may occupy the entire mucosal thickness and there may be marked acanthosis. These changes may be accompanied by occasional bizarre epithelial or stromal cells.

FIG. 2.50 Ballooning degeneration. A: Beginning hydropic degeneration of squamous epithelial cells is evidenced by vacuolization of the cytoplasm. B: The epithelium has become paler than usual. The underlying lamina propria appears hemorrhagic and the epithelium separates from the underlying lamina propria.

FIG. 2.51 Patients with esophagitis often develop vascular lakes and extravasated red cells. These begin at the area of the papillae and extend outward.

FIG. 2.52 Complications of reflux esophagitis. (LES, lower esophageal sphincter.)

Erosions or ulcers may be isolated or confluent; they commonly coexist with one another. The damaged mucosa present in reflux esophagitis becomes prone to secondary infections. For this reason, both ulcers and adjacent tissues need to be carefully examined for the presence of coexisting fungal or viral infections.

Esophageal peptic ulcers develop in the setting of reflux esophagitis; they resemble peptic ulcers occurring elsewhere. These may erode through the muscular layers, resulting in perforation. Peptic ulcers appear large, oval, and well circumscribed with elevated borders and deep necrotic centers. As these heal, strictures develop. This occurs in about 10% of patients with severe reflux esophagitis. Fibrosis is usually present and may extend into the submucosa or beyond, sometimes extending into the periesophageal tissues. Although peptic strictures nearly always involve the distal esophagus, they occasionally develop more proximally. Proximal strictures average 2 to 4 cm in length. Extensive strictures may complicate severe reflux esophagitis as well as nasogastric intubation in patients with reflux esophagitis or Zollinger-Ellison syndrome.

Differential Diagnosis

The differential diagnosis includes that of the esophagitis itself, as well as the distinction of associated reactive epithelial changes from a neoplastic process. The histologic features discussed in the preceding sections suggest the diagnosis of reflux esophagitis, but, as indicated, none is specific for this entity, since they represent a common pattern of response to diverse forms of injury. Entities to be considered in the differential diagnosis include those listed in Table 2.5.

Reactive changes in biopsies from patients with GERD may appear so atypical (Fig. 2.55) that the differential diagnosis includes both invasive and noninvasive neoplasia. When the basal cell hyperplasia occupies the full thickness of the mucosa and it is very reactive in appearance, it may mimic squamous cell dysplasia. The mucosa in reactive lesions remains architecturally uniform and orderly with relatively regular and uniform papillae. In contrast, dysplastic lesions tend to appear more disorderly (irregularly irregular) and lengthened papillae are generally not present, but if they are present, they are irregular in their configurations. Hyperplastic squamous epithelial cells may appear atypical, but they are uniformly atypical, resembling one another. The enlarged nuclei of hyperplastic cells have generally smooth nuclear membranes, prominent nucleoli, and open chromatin with little or no nuclear overlapping. The cells maintain their normal polarity and abnormal mitoses are absent.

Fragments or irregular nests of very regenerative-appearing squamous cells, areas of pseudoepitheliomatous hyperplasia, bizarre mesenchymal cells in ulcer bases, or enlarged reactive endothelial cells in the granulation tissue or ulcer bases can simulate an invasive carcinoma. Routine histologic examination and immunohistochemical stains using antibodies directed against endothelial cells and cytokeratin can distinguish between some reparative reactions and malignancy. The bizarre stromal cells are usually distributed singly or in groups of two to three cells, usually in obvious granulation tissue. The nuclei are normal or almost normal in size and are nonoverlapping. If the atypia remains confined to cells that mark with endothelial cell antibodies, one can be certain that the tissue is inflammatory in nature. The presence of isolated cytokeratin positive cells strongly

suggests the presence of an invasive cancer, especially if the cytokeratin positive cells demonstrate significant nuclear atypia and lie within a desmoplastic stroma. However, care must be taken in interpreting the immunostains since some of the mesenchymal cells occasionally stain with antibodies to cytokeratin. Additionally, isolated benign epithelial cells can drop into a severely inflamed stroma. In some cases with significant atypia and severe inflammation a definitive diagnosis may need to be deferred until the inflammation subsides.

FIG. 2.53 Gross appearance of reflux esophagitis. A: This photograph demonstrates the presence of both stress gastritis and reflux esophagitis. The gastric folds extend over the brown discolored, more distal portions of the stomach and end in a hemorrhagic zone. The Z line has been destroyed. The overlying mucosa appears ulcerated, hemorrhagic, and eroded. B: Multiple linear continuous and noncontinuous erosions and ulcers are present. Histologically, the most distal lesion just above the Z line in the center of the esophageal mucosa demonstrated Barrett mucosa. The remaining erosive lesions appear more tan in the surrounding mucosa. The epithelium in the distal portion of the esophagus is also whiter than normal due to the presence of hyperkeratosis. C: Severe Barrett esophagus arising in the setting of reflux esophagitis. One can see the termination of the gastric folds and then the presence of more proximal red epithelium extending up into the esophagus. Just above the gastroesophageal junction are two linear ulcers lying in the longitudinal axis of the esophagus. Several more proximal erosions are seen. The more proximal portion of the mucosa demonstrates ridges and valleys. The tops of the ridges are associated with white epithelium consistent with areas of hyperkeratosis. D: Areas of hyperkeratosis and ulcerations. In this particular patient, the area of the Z line is maintained and there is no evidence of Barrett esophagus.

FIG. 2.54 Esophageal ulcer. The ulcer bed is filled with granulation tissue. Reactive hyperplasia is seen in the adjacent squamous mucosa.

FIG. 2.55 In this example of severe reflux esophagitis, the epithelium is acanthotic and shows significant inflammatory atypia that mimics an invasive squamous cell carcinoma. However, the individual cells contain abundant cytoplasm, the nuclei are not overlapping, and there are no abnormal mitotic figures. There is also intercellular edema.

Carditis

As noted earlier, there is debate about the cardia, where it is located, and whether it represents a normal structure or a metaplastic process that occurs in response to GER. There is also debate as to whether cardiac mucosa contains parietal cells. We view the cardiac mucosa as one that contains lobular mucin-secreting glands, with or without parietal cells. Regardless of how one views the cardia, the diagnosis of carditis is usually straightforward. Carditis, as the name implies, is an inflammation of cardiac-type epithelium, whether it be in the distal esophagus or proximal stomach. This inflammation is usually chronic in nature consisting of lymphocytes and plasma cells. In active carditis, neutrophils are present.

The main question is whether carditis is an indication of GERD, HP gastritis, both or neither. Many studies show that both GERD and HP may be associated with inflammation of cardiac epithelium. However, many studies also demonstrate that carditis is a common finding in all cardia biopsies, and can be seen in patients without evidence of either GERD or HP infection (25,134,135). Distinguishing the etiology requires evaluation of the carditis in the context of coexisting changes that may be present in either the esophagus or the stomach. Determining the etiology of the carditis is difficult if only a single biopsy is examined. In patients with multiple biopsies, one is often able to determine the etiology of the carditis by examining the histologic changes in the squamous epithelium and/or the gastric epithelium. If there are classic features of GERD in the esophageal squamous biopsies, then the carditis is most likely part of GERD. In this setting, the carditis occurs in the absence of similar changes in the stomach. Carditis in this setting is characterized by the presence of lymphocytic, eosinophilic, or plasma cell infiltrates in the lamina propria (Fig. 2.56). Frequently there is foveolar hyperplasia and reactive changes. In GERD patients, the inflammation tends to decrease with increasing distance from the SCJ. Pancreatic acinar metaplasia is also common (Fig. 2.57). Since HP infection is associated with chronic active gastritis, the presence of prominent lamina propria lymphoplasmacytosis and associated neutrophilic infiltrates, particularly affecting the necks of the cardiac glands, should prompt a search for the organism, especially if no coexisting gastric biopsy was taken for evaluation (Fig. 2.58).

Infectious Esophagitis

General Comments

Infectious esophagitis is a major cause of morbidity, due to increased numbers of individuals with altered immune defenses as a result of organ transplantation, aggressive
cancer treatments, an aging population, increased use of steroids and other immunosuppressive agents, and HIV/AIDS. Various clinical settings predispose patients to infectious esophagitis. These include general debilitation, advanced age, immunodeficiency states, chronic alcoholism, diabetes, and motility disorders. Certain malignancies, especially hematologic malignancies, increase the risk of infections. GERD or an anatomic abnormality also predispose patients to infectious esophagitis.

FIG. 2.56 Carditis. In both figures (A, B) cardiac mucosa is present that is heavily inflamed. The example in (A) has a villiform surface and the lobular appearance of the glands is less evident than in (B). In (B) the surface is flatter and the glands are more obviously lobular.

FIG. 2.57 Pancreatic acinar metaplasia in an esophageal biopsy showing carditis.

Esophageal endoscopy with brushings and biopsies is the procedure of choice in the diagnostic workup of patients with suspected infections. Because different infections localize to different areas, ulcer bases as well as ulcer edges and intervening areas should be biopsied (Fig. 2.59). Candida, cytomegalovirus (CMV), and herpes infections are the commonest causes of infectious esophagitis in the Western world. The presence of bacteria within esophageal specimens does not always imply the presence of an infection. The bacterial biota of the normal esophagus resembles that of the oropharynx (136). Organisms are swallowed or carried into the esophagus by the endoscope. One commonly encounters round or small oval-shaped bacteria lying in pairs or tetrads in the esophageal lumen. Bacteria may be present in both the normal esophagus or in an esophagus affected by esophagitis due to other causes (Fig. 2.60). Bacteria lying free on mucosal surfaces or in the esophageal lumen are unlikely to be pathogenic. In contrast, bacteria invading the underlying tissues are usually pathogenic.

Bacterial Esophagitis

Bacterial esophagitis is defined as the presence of histopathologically demonstrable bacterial invasion of the esophageal mucosa or deeper layers without concomitant fungal, viral, or neoplastic disease. Esophageal bacterial infections are unusual and
generally occur in profoundly granulocytopenic patients or they represent an extension of infection from adjacent structures. Bacterial esophagitis often occurs subsequent to mucosal damage due to GERD, radiation, chemotherapy, or nasogastric intubation. These processes allow bacteria access to the lamina propria, submucosa, or even the vasculature. The commonest causes of bacterial esophagitis include Staphylococcus aureus, Staphylococcus epidermidis, and streptococcus strains. Rare bacterial esophagitis results from Klebsiella or Lactobacillus acidophilus infections. Bacterial esophagitis may also complicate diphtheria (in which case, pseudomembranes form over the upper esophageal mucosa) anthrax (137), syphilis, brucellosis, or bacillary angiomatosis (138). Often, several bacterial species are present.

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