path 767 to 774
Esophageal Obstruction
 Esophageal dysmotility interferes with normal coordinated wave of peristaltic contractions
o High-amplitude esophageal contractions in which outer longitudinal layer of smooth muscle contracts
before inner circular layer results in nutcracker esophagus; can cause periodic short-lived esophageal
obstruction
o Diffuse esophageal spasm – can result in functional obstruction; because it increases esophageal wall
stress, it can cause small diverticulae to form (more accurately described as pseudodiverticulae because
they lack true muscularis); diverticulae uncommon because of dense and continuous esophageal
musculature
 Zenker diverticulum (pharyngoesophageal diverticulum) – located immediately above upper
esophageal sphincter; may reach several cm in size and accumulate significant amounts of food,
producing mass and symptoms including regurgitation
 Traction diverticulum occurs near midpoint of esophagus
 Epiphrenic diverticulum immediately above lower esophageal sphincter
 Passage of food can be impeded by esophageal stenosis; generally caused by fibrous thickening of submucosa
and associated with atrophy of muscularis propria as well as secondary epithelial damage
o Most often due to inflammation and scarring that may be caused by chronic gastroesophageal reflux,
irradiation, or caustic injury
o Dysphagia associated with stenosis usually progressive, first affecting ability to eat solids and only later
interfering with ingestion of liquids
o Because obstruction develops slowly, patients may subconsciously modify their diet to favor soft foods
and liquids and be unaware of their condition until obstruction nearly complete
 Esophageal mucosal webs – uncommon ledge-like protrusions of mucosa that may cause obstruction; most
frequently occur in women over 40
o Often associated with gastroesophageal reflux, chronic graft-versus-host disease, or blistering skin
diseases
o Upper esophageal webs accompanied by iron-deficiency anemia, glossitis, and cheilosis part of
Paterson-Brown-Kelly or Plummer-Vinson syndrome
o Most common in upper esophagus, where they are generally semicircumferential, eccentric lesions that
protrude less than 5 mm and have thickness of 2-4 mm
o Microscopically composed of fibrovascular CT and overlying epithelium
o Main symptom is dysphagia associated with incompletely chewed food
 Esophageal rings (Schatzki rings) similar to webs, but are circumferential and thicker
o Include mucosa, submucosa, and in some cases, hypertrophic muscularis propria
o When present in distal esophagus, above gastroesophageal junction, they are A rings; covered by
squamous mucosa
o Those located at squamocolumnar junction of lower esophagus are B rings and may have gastric cardiatype mucosa on their undersurface
 Achalasia – characterized by triad of incomplete LES relaxation, increased LES tone, and aperistalsis of
esophagus
o Increased tone of lower esophageal sphincter (LES) as result of impaired smooth muscle relaxation;
release of NO and vasoactive intestinal polypeptide form inhibitory neurons, along with interruption of
normal cholinergic signaling, allows LES to relax during swallowing
o Primary achalasia caused by failure of distal esophageal inhibitory neurons and is by definition idiopathic
 Degenerative changes in neural innervation, either intrinsic to esophagus or within
extraesophageal vagus nerve or dorsal motor nucleus of vagus may also occur
o Secondary achalasia may arise in Chagas disease, in which Trypanosoma cruzi infection causes
destruction of myenteric plexus, failure of peristalsis, and esophageal dilatation
 Duodenal, colonic, and ureteric myenteric plexi can also be affected in Chagas disease
o Achalasia-like disease may be caused by diabetic autonomic neuropathy; infiltrative disorders such as
malignancy, amyloidosis, or sarcoidosis; and lesions of dorsal motor nuclei, particularly polio or surgical
ablation
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Treatment options for achalasia include laparascopic myotomy and pneumatic balloon dilation
Botulinum neurotoxin (Botox) injection to inhibit LES cholinergic neurons can also be effective
Esophagitis
 Mallory-Weiss tears – longitudinal tears in esophagus near gastroesophageal junction; most often associated
with severe retching or vomiting secondary to acute alcohol intoxication
o Normally, reflex relaxation of gastroesophageal musculature precedes antiperistaltic contractile wave
associated with vomiting; relaxation fails during prolonged vomiting, with result that refluxing gastric
content overwhelm gastric inlet and cause esophageal wall to stretch and tear
o Roughly linear lacerations of Mallory-Weiss syndrome longitudinally oriented and range in length from
mm-several cm
o Tears usually cross gastroesophageal junction but may also be located in proximal gastric mucosa
o Up to 10% of upper GI bleeding (often presents as hematemesis) due to superficial esophageal
lacerations such as those associated with Mallory-Weiss syndrome
o Don’t generally require surgical intervention, and healing tends to be rapid and complete
 Boerhaave syndrome – characterized by distal esophageal rupture and mediastinitis; occurs rarely and is
catastrophic
 Stratified squamous mucosa of esophagus may be damaged by alcohol, corrosive acids or alkalis, excessively hot
fluids, and heavy smoking
o Esophagus may also be injured when medicinal pills lodge and dissolve in esophagus rather than passing
into stomach intact (pill-induced esophagitis)
o Esophagitis due to chemical injury generally only causes self-limited pain, particularly dysphagia
o Hemorrhage, stricture, or perforation may occur in severe cases
o Iatrogenic esophageal injury may be caused by cytotoxic chemotherapy, radiation therapy, or graftversus-host disease
 Infections may occur in otherwise healthy individuals but are most frequent in those who are debilitated or
immunosuppressed as a result of disease or therapy
o Esophageal infection by Herpes simplex viruses, cytomegalovirus (CMV), or fungal organisms common
o Among fungi, candidiasis is most common, although mucormycosis and aspergillosis may occur
 Esophagus may be involved by desquamative skin diseases bullous pemphigoid and epidermolysis and rarely
Crohn disease
 Dense infiltrates of neutrophils present in most cases but may be absent following injury induced by chemicals
(lye, acids, or detergent), which may result in outright necrosis of esophageal wall
o Pill-induced esophagitis frequently occurs at site of strictures that impede passage of luminal contents;
ulceration accompanied by superficial necrosis with granulation tissue and eventual fibrosis
o Esophageal irradiation includes intimal proliferation and luminal narrowing of submucosal and mural
blood vessels; mucosal damage is in part often secondary to radiation-induced vascular injury
 Infection by fungi or bacteria can either cause damage or complicate preexisting ulcer
o Nonpathogenic oral bacteria frequently found in ulcer beds, while pathogenic organisms (account for
about 10% of infectious esophagitis) may invade lamina propria and cause necrosis of overlying mucosa)
o Candidiasis in most advanced form characterized by adherent gray-white pseudomembranes composed
of densely matted fungal hyphae and inflammatory cells covering esophageal mucosa
 Herpes viruses typically cause punched-out ulcers; biopsy specimens demonstrate nuclear viral inclusions within
rim of degenerating epithelial cells at margin of ulcer
 CMV causes shallower ulcerations and characteristic nuclear and cytoplasmic inclusions within capillary
endothelium and stromal cells
 Immunohistochemical stains for virus-specific antigens sensitive and specific ancillary diagnostic tool
 Histologic features of esophageal graft-versus-host disease include basal epithelial cell apoptosis, mucosal
atrophy, and submucosal fibrosis without significant acute inflammatory infiltrates
 Reflux esophagitis – stratified squamous epithelium of esophagus resistant to abrasion from foods but sensitive
to acid; submucosal glands (most abundant in proximal and distal esophagus) contribute to mucosal protection
by secreting mucin and HCO3-; constant lower esophageal sphincter tone prevents reflux of acidic gastric
contents, which are under positive pressure and would otherwise enter esophagus
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Reflux of gastric contents into lower esophagus is most frequent cause of esophagitis and most common
outpatient GI diagnosis in U.S.; associated clinical condition is gastro-esophageal reflux disease (GERD)
o Reflux of gastric juices central to development of mucosal injury in GERD; in severe cases, reflux of bile
from duodenum may exacerbate damage
o Conditions that decrease lower esophageal sphincter tone or increase abdominal pressure contribute to
GERD (alcohol and tobacco use, obesity, CNS depressants, pregnancy, hiatal hernia, delayed gastric
emptying, and increased gastric volume); in many cases, no definitive cause identified
o Simple hyperemia (redness on endoscopy) may be only alteration
o In mild GERD, mucosal histology often unremarkable; with more significant disease, eosinophils
recruited into squamous mucosa followed by neutrophils, which are usually associated with more
severe injury
o Basal zone hyperplasia exceeding 20% of total epithelial thickness and elongation of lamina propria
papillae, such that they extend into upper third of epithelium, may be present
o Most common clinical symptoms are dysphagia, heartburn, and, less frequently, noticeable
regurgitation of sour-tasting gastric contents
o Rarely, chronic GERD punctuated by attacks of severe chest pain that may be mistaken for heart disease
o Treatment with proton pump inhibitors or H2 histamine receptor antagonists (reduce gastric acidity)
typically provides symptomatic relief
 Severity of symptoms not closely related to degree of histologic damage, but histologic damage
tends to increase with disease duration
o Complications of reflux esophagitis include esophageal ulceration, hematemesis, melena (black tarry
feces), stricture development, and Barrett esophagus
 Hiatal hernia characterized by separation of diaphragmatic crura and protrusion of stomach into thorax through
resulting gap; can be congenital or acquired
o Symptomatic in fewer than 10% of adults, and generally associated with other causes of LES
incompetence; symptoms including heartburn and regurgitation of gastric juices similar to GERD
 Eosinophilic esophagitis – symptoms include food impaction and dysphagia in adults and feeding intolerance or
GERD-like symptoms in children
o Cardinal histologic feature is large numbers of intraepithelial eosinophils, particularly superficially
o Clinical characteristics, particularly failure of high-dose proton pump inhibitor treatment and absence of
acid reflux, necessary for diagnosis
o Majority of patients are atopic (prone to allergies) and many have atopic dermatitis, allergic rhinitis,
asthma, or modest peripheral eosinophilia
o Treatments include dietary restrictions to prevent exposure to food allergens (such as cow’s milk and
soy products) or topical or systemic corticosteroids
Barrett Esophagus
 Complication of chronic GERD characterized by intestinal metaplasia within esophageal squamous mucosa
 Most common in white males and typically presents between 40-60 years of age
 Greatest concern is that it confers increased risk of esophageal adenocarcinoma
 Barrett epithelium more similar to adenocarcinoma than normal esophageal epithelium (pre-malignant
condition); epithelial dysplasia (pre-invasive lesion) detected in 0.2-2.0% of patients each year
o Epithelial dysplasia associated with prolonged symptoms and increased patient age
 Vast majority of esophageal adenocarcinomas associated with Barrett esophagus, but most individuals with
Barrett esophagus don’t develop esophageal tumors
 Recognized as one or several tongues or patches of red, velvety mucosa extending upward from
gastroesophageal junction
o Metaplastic mucosa alternates with residual smooth, pale squamous (esophageal) mucosa and
interfaces with light-brown columnar (gastric) mucosa distally
 Can be classified as long segment (3 cm or more of esophagus involved) or short segment (less than 3 cm)
 Diagnosis requires both endoscopic evidence of abnormal mucosa above gastroesophageal junction and
histologically documented intestinal metaplasia
o Goblet cells (have distinct mucosal vacuoles) define intestinal metaplasia and are necessary for diagnosis
of Barrett esophagus
o Intestinal metaplasia correlates with neoplastic risk
 Foveolar mucus cells (don’t have distinct mucous vacuoles) insufficient for diagnosis
 Requirement for endoscopic abnormality helps prevent misdiagnosis if metaplastic goblet cells in cardia
included in biopsy
 When dysplasia present, it is classified as low grade or high grade
o Increased epithelial proliferation, often with atypical mitoses, nuclear hyperchromasia, and
stratification, irregularly clumped chromatin, increased nuclear-to-cytoplasmic ratio, and failure of
epithelial cells to mature as they migrate to esophageal surface present in both grades of dysplasia
o Gland architecture frequently abnormal and characterized by budding, irregular shapes, and cellular
crowding
o High-grade dysplasia exhibits more severe cytologic and architectural changes
o Intramucosal carcinoma characterized by invasion of neoplastic epithelial cells into lamina propria
 Treatment options include surgical resection (esophagectomy), photodynamic therapy, laser ablation, and
endoscopic mucosectomy
o Multifocal high-grade dysplasia (which carries significant risk of progression to intramucosal or invasive
carcinoma) treated similarly to intramucosal carcinoma
 Diseases that impede portal blood flow cause portal hypertension and can lead to development of esophageal
varices (important cause of esophageal bleeding)
o Portal hypertension results in development of collateral channels at sites where portal and caval
systems communicate; collateral veins allow some drainage to occur, but lead to development of
congested subepithelial and submucosal venous plexus within distal esophagus
o Varices develop in 90% of cirrhotic patients
o Worldwide, hepatic schistosomiasis is second most common cause of varices
o Varices can be detected by venogram and appear as tortuous dilated veins lying primarily within
submuscosa of distal esophagus and proximal stomach
 Venous channels directly beneath esophageal epithelium may also become massively dilated
o Varices may not be grossly obvious after surgical removal because they collapse in absence of blood
flow and, when not ruptured, overlying mucosa is intact
o Variceal rupture results in hemorrhage into lumen or esophageal wall, in which case overlying mucosa
appears ulcerated and necrotic
o If past rupture occurred, venous thrombosis, inflammation, and evidence of prior therapy may present
o Varices often asymptomatic, but they may rupture, causing massive hematemesis
 Inflammatory erosion of thinned overlying mucosa, increased tension in progressively dilated
veins, and increased vascular hydrostatic pressure associated with vomiting contribute to
chances of rupture
o Hemorrhage due to variceal rupture is medical emergency treated by sclerotherapy by endoscopic
injection of thrombotic agents; endoscopic balloon tamponade; or endoscopic rubber band ligation
 Despite interventions, as many as half of patients die from first bleeding episode either as direct
consequence of hemorrhage or following hepatic coma triggered by hypovolemic shock
 Among those who survive, additional instances of hemorrhage occur in over 50% in a year
 Each episode has similar rate of mortality
o Over half of deaths among individuals with advanced cirrhosis result from variceal rupture
Esophageal Tumors
 Majority of esophageal cancers are adenocarcinoma or squamous cell carcinoma
 Adenocarcinoma of esophagus typically arises in background of Barrett esophagus and long-standing GERD
o Risk greater in those with documented dysplasia and further increased by tobacco use, obesity, and
prior radiation therapy
o Risk reduced by diets rich in fresh fruits and vegetables
o Some H. pylori serotypes associated with decreased risk of adenocarcinoma by causing gastric atrophy
and reducing acid reflux
o Occurs most frequently in Caucasians and shows strong gender bias for men; highest in developed
Western countries; in countries where esophageal adenocarcinoma more common, incidence increased
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markedly since 1970 (more rapidly than almost any other cancer); no accounts for half of all esophageal
cancers in U.S. (versus 5% in 1970)
o Progression of Barrett esophagus to adenocarcinoma occurs over extended period through stepwise
acquisition of genetic and epigenetic changes; epithelial clones identified in nondysplastic Barrett
metaplasia persist and accumulate mutations during progression to dysplasia and invasive carcinoma
o Chromosomal abnormalities and mutation or overexpression of p53 present at early stages of
esophageal adenocarcinoma
 Additional genetic changes include amplification of c-ERB-B2, cyclin D1 and cyclin E genes;
mutation of retinoblastoma tumor suppressor gene; and allelic loss of cyclin-dependent kinase
inhibitor p16/INK4a
 In other instances p16/INK4a epigenetically silenced by hypermethylation
 Increased epithelial expression of TNF-dependent and NF-κB-dependent genes suggests
inflammation may contribute to neoplastic progression
o Esophageal adenocarcinoma usually occurs in distal third of esophagus and may invade adjacent gastric
cardia; initially appear as flat or raised patches in otherwise intact mucosa; large masses may develop
 Tumors may infiltrate diffusely or ulcerate and invade deeply
 Microscopically, Barrett esophagus frequently present adjacent to tumor
 Tumors most commonly produce mucin and form glands, often with intestinal-type morphology
 Less frequently tumors composed of diffusely infiltrative signet-ring cells (similar to those seen
in diffuse gastric cancers) or, in rare cases, small poorly differentiated cells (similar to small-cell
carcinoma of lung)
o Esophageal adenocarcinoma may be discovered in evaluation of GERD or surveillance of Barrett
esophagus, but more commonly present with pain or difficulty swallowing, progressive weight loss,
hematemesis, chest pain, or vomiting
 By time symptoms appear, tumor has usually spread to submucosal lymphatic vessels
 Overall 5-year survival less than 25% because of advanced stage at diagnosis
 5-year survival about 80% in few patients with adenocarcinoma limited to mucosa or submucosa
Squamous cell carcinoma – in U.S., occurs in adults over age 45 and affects males 4x more frequently than
females; risk factors include alcohol and tobacco use, poverty, caustic esophageal injury, achalasia, tylosis,
Plummer-Vinson syndrome, and frequent consumption of very hot beverages
o Nearly 6x more common in African-Americans than Caucasians
o Previous radiation therapy to mediastinum predisposes individuals to esophageal carcinoma (typically
10 or more years after exposure)
o More common in rural and underdeveloped countries
o Majority of cases in U.S. and Europe at least partially attributable to use of alcohol and tobacco, which
synergize to increase risk
o Nutritional deficiencies as well as polycyclic hydrocarbons, nitrosamines, and other mutagenic
compounds, such as those found in fungus-contaminated foods implicated; HPV infection implicated
o Loss of several tumor suppressor genes (including p53 and p16/INK4a) involved
o Half of squamous cell carcinomas occur in middle third of esophagus
o Begins as in situ lesion (called squamous dysplasia, intraepithelial neoplasia, or carcinoma in situ); early
lesions appear as small, gray-white, plaque-like thickenings
 Over months to years, they grow into tumor masses that may be polypoid or exophytic and
protrude into and obstruct lumen
 Other tumors are either ulcerated or diffusely infiltrative lesions that spread within esophageal
wall and cause thickening, rigidity, and luminal narrowing; may invade surrounding structures
including respiratory tree (causing pneumonia), aorta (causing catastrophic exsanguination), or
mediastinum and pericardium
o Most squamous cell carcinomas moderately to well-differentiated; less common histologic variants
include verrucous squamous cell carcinoma, spindle cell carcinoma, and basaloid squamous cell
carcinoma
o Symptomatic tumors generally very large at diagnosis and have already invaded esophageal wall
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Rich submucosal lymphatic network promotes circumferential and longitudinal spread, and
intramural tumor nodules may be present several centimeters away from principal mass
 Cancers in upper third of esophagus favor cervical lymph node metastasis; those in middle third
favor mediastinal, paratracheal, and tracheobronchial nodes; and those in lower third spread to
gastric and celiac nodes
o Onset of esophageal squamous cell carcinoma insidious and ultimately produces dysphagia,
odynophagia (pain on swallowing), and obstruction
 Patients subconsciously adjust to progressively increasing obstruction by altering diet from solid
to liquid foods
o Extreme weight loss and debilitation result from both impaired nutrition and effects of tumor itself
o Hemorrhage and sepsis may accompany tumor ulceration
o Occasionally, first symptoms caused by aspiration of food via tracheoesophageal fistula
o Increased prevalence of endoscopic screening led to earlier detection of esophageal squamous cell
carcinoma; 5-year survival rates are 75% in individuals with superficial esophageal carcinoma but much
lower in patients with more advanced tumors
o Lymph node metastases, which are common, associated with overall 5-year survival at 9%
Other malignancies of esophagus include unusual forms of adenocarcinoma, undifferentiated carcinoma,
carcinoid tumor, melanoma, lymphoma, and sarcoma
Benign tumors of esophagus generally mesenchymal in origin and arise within esophageal wall
o Tumors of smooth muscle origin (leiomyomas) most common
o Fibromas, lipomas, hemangiomas, neurofibromas, and lymphangiomas also occur
o Some benign tumors take form of mucosal polyps; usually composed of fibrous and vascular tissue
(fibrovascular polyps) or adipose tissue (pedunculated lipomas)
Squamous papillomas sessile lesions with central core of CT and hyperplastic papilliform squamous mucosa
o Uncommonly, papillomas associated with HPV infection (then called condylomas)
In rare instaces, mass of inflamed granulation tissue, growing either as inflammatory polyp or infiltrative mass in
wall of esophagus may resemble malignant lesion (inflammatory pseudotumors)