The esophagus is a muscular tube that is lined with stratified squamous epithelium. Its average length is about 11 cm in newborn and about 25 cm in adults. The upper boundary of the esophagus consists of cricopharyngeal muscle that forms the upper esophageal sphincter at the level of the sixth cervical vertebra. The esophagus enters the stomach at an oblique angle (angle of His) several centimeters below the diaphragm.

Endoscopists measure esophageal landmarks as the number of centimeters from the incisors. The upper esophageal sphincter is located 15 to 18 cm from the incisors. The gastroesophageal junction is classically described as being approximately 40 cm (range 37-42 cm) from the incisors, but this location varies considerably according to the individual’s height and whether a hiatal hernia is present (Fig. 9-1). In the latter instance, the gastroesophageal junction is located, on average, 36 cm from the incisors; however, in a short person with a hiatal hernia, it may be located as little as 30 cm from the incisors.

The endoscopic determination of the location of the gastroesophageal junction is based on visualizing the zigzag ora serrata, known more popularly as the Z-line; this is the interface between the pearly, gray-white squamous epithelium of the esophagus and the pink-orange columnar epithelium of the stomach (Fig. 9-2). It straddles the region of the lower esophageal sphincter (LES), which appears endoscopically as an indented or contracted part of the distal esophagus. There may not be a strict correlation between the location of the LES zone and the histologic esophagogastric (squamocolumnar) mucosal
junction. This is reflected in the endoscopic appearance of the Z-line. Gastric mucosa may thus normally extend into the esophagus in this irregular (Z-line) fashion. Endoscopically the junction of tubular esophagus with the saccular stomach is defined by the upper border of convergence of the gastric folds, as neither the squamocolumnar junction nor the lower sphincter defined by manometry is considered reliable or accurate.

The blood supply to the esophagus is from the inferior thyroid artery in the upper segment; bronchial arteries, direct aortic branches, accessory branch of subclavian artery, and sometimes branches from the intercostal arteries in the midsegment; and the left gastric artery and the left phrenic artery in the distal segment. The venous drainage arises from intercommunicating plexuses that are both superficial and deep to the muscle coats. The upper third of the esophagus drains through the inferior thyroid veins into the superior vena cava. The middle third of the esophagus drains into the azygous system, and the lower third into gastric veins and ultimately into the portal vein.

The innervation of the esophagus is from both the vagus nerve and the sympathetic nervous system. Most of the esophageal musculature is supplied from the vagus nerve. Its fibers anastomose with short postganglionic fibers in the myenteric (Auerbach’s) plexuses. The sympathetic fibers to the esophagus are derived from cervical and thoracic sympathetic ganglia. As is true throughout the gastrointestinal (GI) tract, regulatory peptides interact with neural and muscle elements in the control of normal function.¹

The mucosal and submucosal lymphatics communicate with longitudinal lymphatic channels in the muscle coats. The upper third of the esophagus drains into the cervical nodes, the middle third into the paraesophageal and paratracheal nodes of the mediastinum, and the lower third into the para-aortic nodes, nodes in the celiac axis, or both.

Mucosa. The mucosal lining consists of stratified squamous epithelium of the nonkeratinized type (Fig. 9-3). Occasionally, keratohyalin particles are present, although a well-developed granular cell layer is absent, which differentiates it from the squamous
epithelium of skin. With electron microscopy the cell layers have been characterized as basal, prickle, and functional, the last referring to the flattened surface cells.² The epithelium is generally 15 cell layer thick (350-450 µm). In clinical practice, one need to only distinguish between the basal and overlying nonbasal cells. The basal cell zone is one to four cells thick and does not exceed 15% of the thickness of the squamous layer except in the most distal centimeters of the esophagus.³, ⁴ The cells above the basal zone contain flattened nuclei and a glycogen-rich cytoplasm. The cells at the surface are elongated, with a very narrow margin of cytoplasm surrounding pyknotic-appearing nuclei. Basal cells are distinguished from nonbasal cells by the fact that the former do not contain glycogen. In clinical practice, using conventionally stained sections, basal cells appear juxtaposed. One rule of thumb used to define the upper margin of the basal layer is to determine where nuclei are separated by a distance of at least one nuclear diameter.⁵ Sometimes the tongues of columnar mucosa of the gastric type normally extend several centimeters on either side of the apparent LES zone. In addition, glands similar to those of the gastric cardia, with mucous glands and scattered fundic gland elements, commonly extend up into the lamina propria of the esophagus for a short distance.

Mitoses can be observed in the parabasal cell layer and are associated with increased proliferative activity. No mitoses are detected in the basal cell layer, and presumably the cells move higher up once they enter mitotic cycle. The exact time for cells to move from basal zone to surface for shedding is believed to be <10 days, while in mice and rats this is between 4 and 7 days.

Melanocytes have also been described in some esophagi.⁶ Melanocytes are believed to occur in between 4% and 8% of esophagi. The latter are likely relevant to the rare primary malignant melanomas of the esophagus (see Chapter 12), in which melanosis may surround the neoplasms.⁷ The number of melanocytes seems to be increased in many esophageal resections (27%-34%) performed for squamous cell carcinoma for yet unclear reasons. Pseudomelanosis of the esophagus has been reported, but the cause is still unknown.⁸

Endocrine cells can be observed in the esophageal epithelium as well. The incidence is reported to be about 28%. Mostly these cells are found in the basal cell layer of squamous epithelium. There is an ongoing discussion whether these cells contribute to the regulation of esophageal sphincters. Langerhans cells are also present in the esophageal squamous epithelium that can be highlighted with S100 and CD1a immunostains. Their function is likely to be antigen presentation similar to their role in skin, and their
number seems to increase in esophagitis. Merkel cells are also found in the esophageal mucosa.⁹ Compared to fetuses their numbers are slightly increased in adults (1.2/cm vs. 2.2/cm). The numbers of Merkel cells vary markedly among individuals (Fig. 9-4). Immunohistochemically Merkel cells are positive for CK20. Merkel cells with their long dendritic processes can be identified from the 13th week of gestation onward. They are associated with light touch and in the skin can discriminate shape and textures, but it is unclear if they can do this in the esophagus.

Lymphocytes may be scattered throughout the squamous cell layer, interspersed between epithelial cells. Their nuclei may be compressed (squiggle cells) or lobulated and thus may be mistaken for neutrophils (Fig. 9-5A). Some tiny cell fragments in the epithelium may defy identification of their origin. Immunocytochemical studies show that these are mostly T lymphocytes¹⁰ and are CD8 immunoreactive. Intraepithelial mast cells and B cells can also be found.¹¹

The basal cell zone is invaginated by extensions of the lamina propria termed dermal papillae (see Fig. 9-3B). They generally do not extend more than two-thirds of the thickness of the epithelium, except in the distal 2 to 3 cm of the esophagus.³, ⁴ These papillae contain narrow capillaries; sometimes they are engorged with erythrocytes.

The lamina propria consists of connective tissue, which contains scattered plasma cells and occasional lymphoid nodules (see Fig. 9-3B). Sparsely distributed mucous glands are present in the lamina propria of the distal esophagus. These have been termed esophageal cardiac glands. Near the gastroesophageal junction, these glands may contain oxyntic mucosa glands, such as parietal cells.¹²

The muscularis mucosae become progressively thicker in the distal part of the esophagus. In biopsy specimens, the unwary morphologist may make the frightening mistake of confusing the thick muscularis mucosae for the muscularis propria (Fig. 9-5). The muscularis mucosa is particularly thick in cases of Barrett’s associated distal esophageal or GE junction cancers and can form multiple layers (duplication of muscularis mucosa).¹³, ¹⁴

Submucosa and muscularis propria. The submucosa consists of loose connective tissue containing blood vessels, nerve fibers, scattered lymphocytes, and small lymphoid follicles. Ganglion cells of Meissner’s submucosal plexus are very sparse in the esophagus. Submucosal esophageal mucous glands are distributed throughout the esophagus (Fig. 9-3B). Ducts from these glands penetrate the muscularis mucosae and end in the epithelium. The ducts are covered with a cuboidal epithelium and then by a stratified epithelium in their terminal parts (Fig. 9-5).¹⁵ Focal cystic dilatation of these ducts and glands and surrounding lymphoid collections may be seen in some autopsy specimens of “normal” esophagi.¹⁶

The muscle coats that lie outside the submucosa consist of striated muscle in the upper one-quarter to one-third of the esophagus and of smooth muscle in the lower two-thirds of the esophagus. Much of the striated muscle portion (except for the upper esophageal sphincter) is actually a blend of striated and smooth muscles.¹⁷ Individual muscle fibers are arranged in a spiral fashion, with inner horizontally curved bands and outer bands with a more longitudinal orientation.¹⁵, ¹⁷ The ganglion cells of the myenteric plexus (Auerbach’s) are more dense in the distal esophagus. The number of cells of Cajal is related to the plexus density. In achalasia cells of Cajal are more sparse.¹⁸ Thus, it is proposed in the esophagus also that cells of Cajal are necessary for a neural-controlled motor function.¹⁹, ²⁰

The LES consists of a thickened zone of inner circular fibers in a spiral or oval arrangement. Some of these fibers blend with inner oblique muscle fibers of the stomach.²¹, ²² The esophagus lacks a serosa, except in the distal few centimeters.

The data on age-dependent esophageal changes are very limited. It is known that the smooth musculature does not change with age, but in the elderly the number of ganglia in the Auerbach’s plexus is reduced.²³ With age the esophageal lumen is believed to become wider, and the wall consistency and sensitivity to stretching are said to decrease.²⁴

Esophageal atresia along with tracheoesophageal fistula is the most frequent esophageal anomaly (1:3,000-5,000 births), although isolated esophageal atresia is quite rare.³³ It is unclear whether this results from lack of proper separation of foregut into respiratory and intestinal tracts by the growth of tracheoesophageal septum or improper recanalization of the esophagus following esophageal epithelial proliferation.²⁵ The use of teratogenic substances during pregnancy has been implicated in the development of esophageal atresia. Frequently additional anomalies involving other organ systems are also present (Table 9-1; Fig. 9-8).

Esophageal atresia occurs in five different forms (Table 9-2).³⁴, ³⁵ Unfortunately, the terminology in the literature is not consistent and many different classification schemes are in use resulting in some confusion (A-E, Type I-V, Type 1-5, Type I-IIIc). The most common variant is type C (Table 9-2) with a proximal blind esophageal pouch and a fistula between the trachea and the distal esophagus. The fistula often enters the trachea close to the carina. The second most common anomaly is type A—pure esophageal atresia without tracheoesophageal fistula.

The clinical presentation depends on the type of atresia and the presence of a tracheoesophageal fistula. Lack of swallowing and absorption of the amniotic fluid due to esophageal atresia result in polyhydramnios during pregnancy, which may be the first sign of the problem. When the proximal esophagus ends as a blind loop, drooling of saliva or recurrent vomiting in the neonatal period is the most common presentation. In the presence of a tracheoesophageal fistula the child is at risk of aspiration pneumonia and repeated respiratory infections. In addition, entry of air through tracheoesophageal fistula into the GI tract distal to the atretic segment results in overinflation seen on imaging. In contrast, cases that have no connection with the respiratory tract show absence of gas shadow on imaging. The diagnosis of so-called H-fistula can be very difficult, and some cases are
recognized for the first time during adulthood due to recurrent respiratory infections.³⁶

The diagnosis is established using imaging studies with contrast (Fig. 9-9), although the exact type of fistula may not be established till the surgical correction is undertaken. The overall mortality of these patients has improved over the years, and the prognosis is largely dependent on the presence of other associated anomalies that occurs in up to 50% of affected individuals (see Table 9-1). Tracheomalacia with attendant tracheal collapse and respiratory complications is an additional source of morbidity. Early delivery, low birth weight, and wide distance between the atretic segments are believed to represent unfavorable factors. Sequelae following surgical correction include, for example, secondary stenosis, secondary fistula, dehiscence of sutures, stridor, and hiatal hernia.

Congenital bronchoesophageal fistulas are rare (<10%), and most lesions encountered in practice are acquired.³⁷ Esophageal atresia as discussed above is associated in some cases. Often the fistula is
connected to the right main bronchus.³⁸ The fistulous tract may be lined by a squamous, respiratory, or a transitional-type epithelium.³⁹ Grossly several types of bronchoesophageal fistulas can be identified:

1. Short-segment fistulas between esophagus and a lobar or segmental bronchus

2. Fistula that is connected to a lung cyst

3. Fistula with a sequestration of lung that has aortic blood supply

4. Esophageal diverticulum with penetration into lung (acquired)

In adults it could be difficult to differentiate congenital from an acquired fistula. Congenital fistulas are believed to be identified on the basis of the following criteria: (a) lack of inflammatory reaction in the surrounding connective tissue at the point of resection, (b) lack of adhesion between fistula and adjacent lymph nodes, (c) lack of esophageal muscosa containing muscularis mucosae, and (d) lack of focal vascular inflammatory changes.

Acquired benign broncho- or tracheoesophageal fistulas are mostly secondary to either inflammatory causes, for example, tuberculosis, or are posttraumatic.⁴⁰ Acquired fistulas may also form secondary to infiltration by esophageal squamous cell carcinomas. Sometimes the etiology of the fistula remains unclear.

Duplication and congenital cysts. These represent a variety of confusing lesions, for which a wide variety of names have been used in the past, some of which include dorsal enteric cysts, enterogenous cysts, neurenteric cysts, giant diverticula, and persistent neurenteric canal. A simple classification would be to divide them into duplications, congenital enteric/esophageal cysts, and neurenteric cysts/remnants.

Duplications of the GI tract conceptually represent an extra copy or a replica of a GI segment that is often imperfect. General duplications have an organization similar to the gut with muscular wall, neural plexus, and a lining epithelium (either embryonic
or mature type typical for that site). These need not communicate with the lumen. The esophageal duplications can become cystic, and it then becomes difficult to differentiate them from other congenital cysts (see later), and currently there are no reliable criteria to differentiate between these. Most would agree that an esophageal duplication should be contiguous with esophagus and have smooth muscle layers (Figs. 9-10 and 9-11). Most often these cysts are not connected to the esophageal lumen and are partially intramural or attached to the wall. Those that are connected to the esophageal lumen could be considered as esophageal diverticula.⁴¹, ⁴², ⁴³ The lesions may become cystic or remain tubular. Histologically duplications show all the layers of the esophageal wall that include mucosa, muscularis mucosae, submucosa, and muscularis propria.⁴⁴ The lining epithelium could be nonkeratinizing squamous epithelium, pseudostratified ciliated respiratory epithelium, or simple flat cuboidal to columnar epithelium. Rarely gastric fundic-type mucosa may be present, and some cases fail to show any lining epithelium at all. Many of the cysts defy classification and show a variety of lining epithelium and a fibrous wall. Depending on the appearance and the lining epithelium, a variety of names are in use. Some that are lined by gastric⁴⁵ or small bowel-type epithelium⁴⁶ have also been described that are referred to as gastroenteric cysts, while others are simply referred to as congenital esophageal cysts. The congenital cysts have a predilection for the lower third of the esophagus and rarely involve the upper esophagus.⁴⁷

These duplications and other cysts are usually asymptomatic and detected incidentally. However, they may result in a mass effect causing symptoms of obstruction or compression of adjacent structures like respiratory tract or heart. Rarely adenocarcinoma or squamous cell carcinoma can arise in these cysts.⁴⁸, ⁴⁹ Definitive treatment of duplications and congenital cysts is surgical resection.

Neurenteric cysts/remnants. These include a variety of lesions including diverticula, fistulas, cysts, and fibrous cords that originate from the dorsal midline of the GI tract. They are often associated with abnormalities of the vertebral column, spinal cord, or both. Many of the abnormalities are not compatible with life and only detected at autopsy. They can occur at any level but are most common at the cervicothoracic and lumbosacral areas. The walls of these structures are composed of the normal layers of the GI tract, and neuroglial tissues or less likely leptomeningeal tissues may be found in and around the lesions that are close to or involve the vertebra and spinal cord. The lining epithelium is variable and may be similar to the gut at that site or could be a mixture of different types.

Bronchogenic cysts. Bronchogenic cysts are often seen anteriorly and are often attached to a bronchus rather than esophagus. The lining epithelium is most often pseudostratified ciliated columnar and less commonly squamous, gastric, or intestinal type. The wall contains bronchial-type mucus glands and cartilage and lacks esophagus-like muscularis mucosae and muscularis propria.⁴⁴ Despite these differences differentiation from an esophageal duplication can be sometimes very difficult.

Other cysts. These are the cysts that cannot be assigned to other specific categories.⁴⁴ The lining epithelium is variable, and the wall does not contain the GI wall structures or cartilage.

Pathogenesis and Clinical Features For decades it has been known that heterotopic gastric tissue can occur anywhere between the mouth and the anus.⁵⁰ Interest in this condition has been rejuvenated because endoscopists have rediscovered it.⁵⁰, ⁵¹, ⁵² These tissue nests are easily missed at endoscopy because they are usually located in the proximal esophagus, within or just below the upper esophageal sphincter (Fig. 9-12), hence the colloquial term inlet patch.⁵² So-called inlet patches can be observed in more than 10% of all upper GI endoscopies. The prevalence at endoscopy of about 4% may be an underestimate because of difficulty in endoscopically visualizing the mucosa within or just below the upper esophageal sphincter.⁵¹ By contrast, the prevalence of 21% in an autopsy study of children is likely an overestimate because some of the subjects had other congenital anomalies, and there was an inverse relation with age up to 14 years. Perhaps some of these congenital nests are overgrown by squamous epithelium later in life.⁵³

It should be stressed that despite a flurry of reports detailing complications of these nests, they are overwhelmingly incidental and do not require surveillance of any kind. Because they are capable of secreting
acid, it is not surprising that they are rarely associated with burning sensations in the neck or with ulceration or cause strictures with resultant dysphagia.⁵⁴, ⁵⁵, ⁵⁶, ⁵⁷ Adenocarcinoma may arise in these ectopic patches but is rare.⁵⁸ Some carcinomas have been described as arising from heterotopic gastric patches further downstream in the esophagus.⁵⁸, ⁵⁹ When inlet patches are encountered, there is no indication for biopsy. However, it is difficult for many endoscopists to resist the urge to biopsy the first few they encounter.