Esophagus

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Embryology of esophagus

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· notocord induces formation of foregut from endoderm

· at day 21 (end of week 3), lateral walls of foregut develop septa that fuse and divide foregut into esophagus and trachea

· at week 4, myenteric plexus develops

· at weeks 5-6, septation of walls ends; initial lining is stratified columnar epithelium, which proliferations and almost occludes the lumen

· at weeks 6-7, submucosal plexus develops, circular muscular layer develops

· at weeks 6-7, epithelial vacuolization appears, vacuoles coalesce to form a single esophageal lumen

· at week 8, ciliated cells appear and extend to almost entire columnar epithelium

· at week 9, longitudinal muscle layer develops; interstitial cells of Cajal appear

· at week 10, a single layer of columnar cells covers entire esophagus

· at month 4, submucosal glands appear due to downward growth of columnar cells, extend distally to cardiac mucosa

· at month 5, stratified squamous epithelium initially appears in mid esophagus, and replaces ciliated epithelium cephalad and caudally; proximal esophagus may retain ciliated epithelium at birth

· at month 5, upper esophagus has both striated and smooth muscle

Drawings: 4 weeks-relation of gut to yolk sac

References: GI Motility online

Normal anatomy of esophagus

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Also called gullet

Muscular tubular structure 25 cm long in adults; connects pharynx and stomach; has cervical, thoracic and abdominal segments

Main purpose is to propel food from pharynx to stomach via peristalsis; secretes mucin for lubrication, but has no other significant secretory or absorptive functions

Extends from cricopharyngeus muscle in pharynx (level of C6) to lower esophageal sphinchter at gastroesophageal junction (T11/T12); diagram

Regions (diagram):

· cervical (lower border of cricoid cartilage to suprasternal notch / thoracic inlet, 3 cm long, begins 15 cm from incisors); contains striated muscle

· upper thoracic (suprasternal notch to tracheal bifurcation, 6 cm long, begins 18 cm from incisors); has striated and smooth muscle

· mid-thoracic (tracheal bifurcation to diaphragmatic hiatus, 8 cm long, begins 24 cm from incisors); has striated and smooth muscle

· lower thoracic and abdominal (8 cm long [AJCC says 3 cm-this appears to be an error], begins 32 cm from incisors); extends past diaphragm to its junction with stomach; has smooth muscle only

Usual points of narrowing (possible sites of food / pill lodging): cricoid cartilage (due to cricopharyngeus muscle), aortic arch, anterior crossing of left main bronchus and left atrium, where it passes through diaphragm

Gastroesophageal junction: traditionally defined as macroscopic point of flaring of tubular esophagus or proximal limit of gastric rugal folds (diagram; gross image); endoscopic definition is Z (“zigzag”) line at irregular boundary of squamous and columnar mucosa in distal esophagus, which is usually 2-3 cm proximal to macroscopic GE junction (Z line; micro image); proposed definition is proximal limit of gastric oxyntic (fundic) mucosa (micro image), defined by histology (Hum Path 2006;37:40)

The distal 1-2 cm of esophagus is often composed of cardiac or cardiac-oxyntic type of mucosa; whether this is normal or due to reflux esophagitis is debatable

Esophageal sphincters: two areas of high pressure at rest; upper esophageal sphincter at cricopharyngeus (diagram) and inferior pharyngeal constrictor muscles and lower esophageal sphincter at 2-4 cm proximal to esophagogastric junction at level of diaphragm (composed of intrinsic esophageal muscles, sling fibers of proximal stomach and crural diaphragm, diagram)

Vagotomy does NOT affect tone of lower esophageal sphincter; tone is affected by gastrin, acetylcholine, serotonin

Arterial blood supply: cervical region-inferior thyroid artery; upper thoracic-bronchial and intercostal arteries; lower thoracic-aortic branches; abdominal-left gastric and inferior phrenic arteries; infarction is rare due to numerous anastomoses; diagram

Venous drainage: extensive submucosal venous plexus communicates with periesophageal veins; flows into inferior thyroid (upper 1/3), azygous (middle 1/3) and gastric veins (lower 1/3);

azygous vein empties into superior vena cava and gastric veins into portal system; this connection between caval and portal venous systems explains esophageal varices due to portal hypertension; diagram

Normal anatomy of esophagus (continued)

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Nerves: left and right vagus nerves run lateral to esophagus, form plexi along anterior and posterior surfaces, then reunite to form anterior and posterior vagal trunks to stomach; parasympathetic and sympathetic innervation

Lymphatic drainage: freely anastomosing networks in submucosa, muscularis propria and occasionally lamina propria; facilitate lengthwise tumor dissemination; upper third drains into paratracheal and internal jugular nodes, middle third to mediastinal nodes, lower third to nodes around aorta and celiac axis; diagram

Adjacent structures: cervical esophagus lies in posterior mediastinum, posterior to trachea and thyroid gland; is bounded by left and right recurrent laryngeal nerves and carotid sheaths; distal esophagus is posterior to left atrium and bounded by azygous veins; passes through opening in diaphragm called the hiatus; diagram

Incisura / angle of His: left side of esophagus forms sharp angle where it joins the stomach

Gross images: transverse section at level of aortic arch

Normal histology of esophagus

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Layers (similar to GI tract): mucosa, submucosa, muscularis propria, adventitia

Mucosa: epithelium, lamina propria and muscularis mucosae

epithelium: nonkeratinized stratified squamous epithelium with melanocytes, endocrine cells, Langerhans cells, Merkel cells, T cells with convoluted nuclei (“squiggle cells”); basal zone has basophilic proliferative cells with minimal cytoplasm, usually 3-4 cells thick, 15% or less of epithelial thickness except distally; suprabasal zone (with prickle and functional [anucleated] cell layers) has glycogen-rich squamous cells that flatten and mature as they approach lumen / surface

lamina propria: fibrovascular connective tissue between epithelium and muscularis mucosae; folds into slender papillae that project into epithelium, usually less than 2/3 of epithelial thickness; may contain gastric cardia-like mucus glands lined by foveolar-like cells with neutral mucin (PASD positive, Alcian Blue at pH 2.5 negative), particularly in distal esophagus, and scattered inflammatory cells

muscularis mucosae: smooth muscle bundles oriented longitudinally; begins at cricoid cartilage and becomes thickened distally, where it may resemble muscularis propria (important to remember for accurate AJCC staging of adenocarcinoma in this region)

Submucosa: loose connective tissue with vessels, lymphatics, occasional white blood cells and lymphoid follicles, Meissner’s plexus (sparse ganglia) and nerves, submucosal glands lined by mucinous cells that produce acid mucin (continuation of minor salivary glands of oropharynx) that drain through cuboidal or squamous lined ducts; glands are PASD+, Alcian Blue+ at pH 2.5 (indicates acidic mucin) and also produce bicarbonate; ducts are positive for CK7, CK8/18, CK14, CK19

Muscularis propria: inner circular and outer longitudinal layers; proximally includes skeletal muscle from cricopharyngeus and inferior pharyngeal constrictor muscles (thus, skeletal muscle disorders cause esophageal dysfunction); contains Auerbach (myenteric) plexus

Note: longitudinal muscle originates as two bands from cricoid cartilage that incompletely digitate and leave bare a V shaped region (area of Laimer) that exposes the underlying circular muscle and creates area of weakness where Zenker’s diverticulum (a pharyngeal diverticulum due to outpouching of posterior pharyngeal wall, just above upper esophageal sphincter) may occur;

longitudinal muscle distally is continuous with longitudinal muscle of stomach; esophageal circular muscle continues as middle circular and inner oblique muscles of stomach

Adventitia: loose connective tissue; no consistent serosa, so tumors and infections spread readily; majority of esophagus is surrounded by fascia

Drawing: various layers

Normal histology of esophagus (continued)

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Micro images: transverse section #1; #2; #3; #4; full thickness #1; #2; #3; #4; #5; #6; #7-esophageal fold (trichrome); #8-upper third

squamous epithelium - #1-thin basal zone, prickle cell zone has glycogen rich-flattened cells which occupy most of epithelium, functional zone consists of a few flattened cells on surface without nuclei #2; #3; #4; #5-with intraepithelial lymphocytes (normal finding); #6-with lymphocytes and squiggle cell (center)

mucosa and submucosa - mucosa and submucosa; muscularis mucosae-thin layer; muscularis mucosae-thick layer; submucosal glands and ducts #1; #2; #3 (just above GE junction); #4-Alcian blue; submucous gland with squamous metaplasia

muscularis propria - smooth muscle-middle third

Virtual slides: normal esophagus #1; #2

Biopsy of esophagus

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For tumors, 5-6 biopsies recommended, including edge of ulcers, base of ulcer, other non-necrotic areas

Cytology samples may pick up additional cancers missed by biopsies

Limit a cassette to 3-4 biopsy fragments so they will be properly embedded

Recommend embedding on edge and cutting perpendicular to mucosa, although difficult to do with small biopsies

Immediate fixation is particularly important for lymphoid lesions

Common stains are Alcian Blue pH 2.5 (detects acidic mucin), mucicarmine (detects acidic mucin), PAS with and without diastase (detects acidic and neutral mucin)

Congenital anomalies of esophagus

Atresia of esophagus

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Definition: esophageal segment is usually a thin, noncanalized cord with a proximal blind pouch connected to pharynx and a distal pouch leading to stomach

Present in 1 per 2500 live births, etiology unknown but not genetic (recurrence risk in siblings is only 1%)

Discovered shortly after birth due to immediate regurgitation after feeding

Usually near tracheal bifurcation; fistula present in >80% (see topic below) connecting the upper or lower pouch with the trachea or a bronchus; also associated with congenital heart disease, neurologic disease, GI or GU malformations in 50%; also single umbilical artery

Most common is a blind upper segment, fistula between blind lower segment and trachea

Diagrams: common types of atresia; classification of Esophageal Atresia/TracheoEsophageal Fistula (EA/TEF) #1; #2

Diagnosis: inability to pass a nasogastric tube

Case reports: due to diverticulum of Kommerell (very rare, Pediatr Cardiol 2007;28:303)

Treatment: surgery (diagram, early since incompatible with life) is usually successful, but complications are GERD, esophagitis (J Pediatr Surg 2007;42:370) and tracheomalacia

References: Orphanet J Rare Dis 2007 May 11;2:24 (review), Chest 2004;126:915 (complications), eMedicine #1 (includes classification systems), #2

Ectopic gastric tissue in esophagus

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Also called gastric heterotopia, cervical inlet patch

Most common form of heterotopia

Usually in postcricoid region (may be difficult to examine endoscopically, South Med J 2006;99:865), found in 1-4% endoscopically (J Gastroenterol Hepatol 2004;19:891, Int J Clin Pract 2007 May 29 [Epub ahead of print])

May be due to rests of gastric precursor cells that remain after original esophageal mucosa is replaced by stratified squamous epithelium

May cause dysphagia or heartburn

Associated with H. pylori (29-77%, Am J Gastroenterol 2003;98:1266), esophagitis and Barrett’s esophagus (20%, Archives 2004;128:444); Barrett’s has similar mucin profile (Hum Path 1988;19:1301) and keratin expression (AJSP 2005;29:437)

Classified based on symptoms and morphologic changes (Am J Gastroenterol 2004;99:543)

Complications: ulceration, bleeding, stricture or perforation from acid secretion; rarely adenocarcinoma

Endoscopy: circular, red-orange flat area referred to as “inlet patch”

Endoscopy images: salmon colored patch

Case reports: with hypopharyngeal squamous cell carcinoma (Auris Nasus Larynx 2007;34:135), with adenocarcinoma (Am J Clin Oncol 2004;27:644, Dig Dis Sci 1998;43:901)

Gross: resembles gastric mucosa with sharp border from normal squamous epithelium; deep pink and velvety

Micro: usually cardiac-fundic glands with parietal and chief cells, often extensive inflammation causing reactive changes; may ulcerate

Micro images: mucosal biopsy shows antral type mucosa and a small fragment of squamous epithelium; various images

Ectopic pancreatic tissue in esophagus

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Also called pancreatic heterotopia

At gastroesophageal junction in 16% of pediatric/young adult patients

May be congenital and independent of Barrett’s esophagus (AJSP 1996;20:1507)

Usually no clinical significance, but may exhibit pathologic changes of pancreatic tissue including ductal carcinoma (Archives 1994;118:568), other malignancy (Ann Thorac Surg 2000;69:259) or pancreatitis (Surg Laparosc Endosc Percutan Tech 2005;15:345, Dig Dis Sci 1995;40:2373)

Micro: benign appearing pancreatic ducts and acini

Cytology: clusters of benign appearing ducts and small acini mixed with inflammatory cells (Diagn Cytopathol 2004;31:175)

Micro images: esophageal squamous mucosa overlying pancreatic type parenchyma, immunostaining for trypsin, lipase and amylase

Positive stains: trypsin, chymotrypsin, amylase, lipase (AJSP 1995;19:1172)

References: Archives 2000;124:1165

Ectopic sebaceous glands

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Approximately 2% of adult autopsies

May be multiple (Am J Gastroenterol 1994;89:1884); occurs at any level of esophagus

Case reports: 53 year old woman with > 100 minute polyps of mid-lower esophagus (Dig Dis Sci 1995;40:287), 50 year old man with reflux esophagitis (The Internet Journal of Gastroenterology 2007;5(2)), 69 year old woman with multiple esophageal nodules

Micro: sebaceous glands in lamina propria; may be metaplastic submucosal gland ducts

Micro images: ectopic sebaceous glands in lamina propria surrounded by lymphocytes; squamous epithelium with sebaceous glands #1; #2; #3; cuboidal/squamoid cells with foamy lipid filled cells

Fistula (congenital) of esophagus

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Associated with atresia; also tracheomalacia, Auerbach plexus abnormalities, cardiovascular abnormalities

May be due to abnormality during foregut separation phase or fixation during elongation of trachea (Texas Medical Center)

Gross’s classification:

Type A: no connection with trachea (i.e. atresia but no fistula, 8%)

Type B: upper segment connects with trachea (1%)

Type C: lower segment connects with trachea (87%)

Type D: both segments connect with trachea (1%)
Type E: both segments join to connect with trachea (H type-4%)

Tracheobronchial remnants often persist in lower esophageal segment as dilated epithelial clusters of seromucous glands and cartilage (Archives 2003;127:1523)

Treatment: surgical repair, possibly through thoracoscopy (Ann Surg 2005;242:422)

Drawings: various types of fistulas #1; #2 (has different Type designations since Netter’s drawings were before Gross’s publication)

Gross images: blind sac of esophagus above (left) and continuation of esophagus from carina inferiorly #1 (right); #2; #3; apparent perforation of membranous portion of trachea into esophagus

Micro images: tracheobronchial remnants - fig 1: GERD with cardiac-type metaplasia; fig 2-3: plates of mature cartilage and acini of minor salivary glands; fig 4: branchial cleft-like cysts

References: Orphanet J Rare Dis 2007 May 11;2:24-review, Chest 2004;126:915 (complications), eMedicine #1 (includes classification systems), #2, Am Fam Physician 1999;59:910

Paterson-Brown-Kelly or Plummer-Vinson syndrome of esophagus

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Also called sideropenic dysphagia

Very rare; decreased incidence may be due to better diets (J Gastroenterol Hepatol 1994;9:654)

Occurs mostly in Scandinavia and Great Britain

Usually women ages 30+ years

Pathogenesis not known, may be due to iron and nutritional deficiencies, genetic predisposition, and autoimmune factors.

Upper esophageal web, iron deficiency anemia and dysphagia; also glossitis, cheilitis (scaling and fissures at corners of mouth due to riboflavin deficiency), nail changes; at risk for postcricoid squamous cell carcinoma

Endoscopic images: upper esophageal web

Case reports: patients requiring balloon dilation for webs (Turk J Gastroenterol 2005;16:224), post-cricoid carcinoma leading to diagnosis of syndrome (Am J Otolaryngol 2007;28:22), with stomach cancer (rare, World J Gastroenterol 2005;11:7048)

Treatment: iron supplements, mechanical dilation, monitor for upper GI carcinoma

Micro: thin layer of squamous mucosa and submucosa

References: Orphanet J Rare Dis 2006 Sep 15;1:36, eMedicine

Rings of esophagus

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Definition: concentric, smooth, thin (3-5 mm) protrusions of normal esophageal tissue (with mucosa, submucosa and muscularis propria) into the lumen

Usually in distal esophagus

May be congenital, or a scar from drinking caustic liquids

Type A: lower muscular ring; rare; thickened circular smooth muscle with overlying squamous mucosa; usually 1.5 cm proximal to squamocolumnar junction, usually asymptomatic (Am J Gastroenterol 2000;95:43)

Type B: lower mucosal ring / Schatzki’s ring; 5% of normal esophagi; upper surface is lined by stratified squamous epithelium, undersurface is lined by columnar-type epithelium; ring contains connective tissue and fibers of muscularis mucosae; located at squamocolumnar junction at proximal margin of hiatal hernia; associated with meat impaction (“steakhouse syndrome”, Surg Endosc 1989;3:195), “swallow syncope” (Dysphagia 2005;20:273), and a reduced incidence of Barrett’s esophagus (Dig Dis Sci 2004;49:770)

Initially described as a constant, symmetrical, diaphragm-like narrowing at the GE junction associated with a small sliding hiatus hernia (Amer J Roentgenol 1953;70:911)

Type C: rare; refers to indentation on radiographic studies caused by diaphragmatic crura; usually asymptomatic

Diagrams: Types A, B and C rings; B is border of hiatal hernia (HH), V is vestibule; Netter drawings of A and B rings

Case reports: 16 year old boy with dysphagia and Schatzki’s ring (J Postgrad Med 1987;33:99), 54 year old man with dysphagia (Dis Chest 1968;54:465)

Treatment: dilation, possibly anti-reflux medical therapy or surgery (Ann Thorac Surg 1984;37:103)

Micro images: Schatzki’s ring-various images; hypertrophied squamous mucosa, hyperplasia of gastric glandular elements and increased submucosal fibrous connective tissue (fig 2)

References: eMedicine #1, #2 (Schatzki’s ring), GI motility online, Wikipedia

Stenosis of esophagus-congenital

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Fibrous thickening of esophageal wall, particularly the submucosa, with atrophy of muscularis propria; thin and ulcerated lining epithelium

Incidence of 1 per 25-50,000 live births

Congenital cases defined as intrinsic alteration of esophageal wall due to ectopic tracheobronchial tissue, membranous diaphragm, muscular hypertrophy or diffuse fibrosis of submucosa (Pediatr Surg Int 2001;17:188)

Associated with esophageal atresia or other congenital malformations in 17-33%

May occur in adults (AJR Am J Roentgenol 2001;176:1179)

Case reports: 1 month old boy (J Pediatr Surg 2006;41:E5), due to tracheobronchial remnants with cartilage (Arch Pediatr 2006;13:1043), due to membranous diaphragm with tracheoesophageal fistula (J Pediatr Surg 2005;40:e11)

Treatment: dilation and resection plus anastomosis (J Pediatr Surg 2002;37:1024)

Acquired cases due to severe esophageal injury with scarring (reflux, radiation, scleroderma, caustic injury); associated with progressive dysphagia, may cause total obstruction

Webs of esophagus

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Uncommon, ledge like, semi circumferential protrusions of mucosa into lumen

In upper esophagus are called webs, are covered by squamous mucosa and have vascularized fibrous tissue core; associated with Paterson-Kelly syndrome above

In lower esophagus are called Schatzki’s rings (just above squamocolumnar junction), have gastric epithelium on their undersurface

Rarely protrude more than 5 mm into lumen

More common in women over 40 years

Etiology uncertain, but may be associated with gastric heterotopia (South Med J 1997;90:554