Esophageal cancer

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Hadeel Maksoud M.D.[2]

Esophageal cancer is malignancy of the esophagus. There are two sub-types, squamous cell carcinoma and adenocarcinoma. Esophageal tumors usually lead to dysphagia, odynophagia, weight loss, and hematemesis and are diagnosed by carrying out a biopsy. Esophageal cancer must be differentiated from gastroesophageal reflux disease (GERD), Barrett’s esophagus, esophageal achalasia, gastritis, gastric ulcer, and stomach cancer. Common risk factors in the development of esophageal cancer are smoking, alcohol, gastroesophageal reflux disease, and Barrett’s esophagus. Small and localized tumors are treated with surgery, and advanced tumors are treated with chemotherapy, radiotherapy or a combination of both. Prognosis is fairly poor but depends on the extent of the disease and other medical problems.

Esophageal cancer may be classified into squamous cell carcinoma or adenocarcinoma based on histology.

The pathophysiology of esophageal cancer depends on the histological sub-type, whether squamous cell carcinoma or adenocarcinoma.

Esophageal cancer must be differentiated from gastroesophageal reflux disease (GERD), Barrett’s esophagus, esophageal achalasia, gastritis, gastric ulcer, and stomach cancer.

Esophageal cancer is the 6th leading cause of death from cancer and the 8th most common cancer in the world. The prevalence of esophageal cancer worldwide is about 3.5 per 100,000. In the United States, about 17,000 new cases are diagnosed every year, and 4.2 per 100,000 Americans has esophageal cancer. Esophageal cancer is mostly present in the “Asian belt” region which include China, Japan, India and Iran.

Common risk factors in the development of esophageal cancer are tobacco smoking, alcohol, gastroesophageal reflux disease, and Barrett’s esophagus.

Screening for esophageal cancer has not yet been established. Screening may be effective in reducing the incidence of esophageal adenocarcinoma, especially in Barrett’s esophagus, but it is left at the physician’s discretion.

The incidence of esophageal dysplasia turning malignant is very low, especially outside the United States. Complications of esophageal cancer include dysphagia, anemia, and tracheoesophageal fistula. This finding has caused some uncertainty as to the usefulness of screening. Esophageal cancer is associated with a 5 year survival rate of 20%.

Esophageal cancer is best diagnosed using an endoscope to visualize the esophageal lesion, followed by a biopsy to confirm the diagnosis. Endoscopic biopsy is done in a single visit at the hospital.

According to the American Joint Committee on Cancer, there are 4 stages of esophageal cancer based on the tumor spread.

Patient history in esophageal cancer includes pain in the throat or chest, regurgitation of food and hoarseness of voice. Symptoms of esophageal cancer include dysphagia, odynophagia, weight loss, and hematemesis. It should be noted that superficial esophageal cancer may have an insidious onset, so screening for Barrett’s esophagus is important in this case to diagnose cancer earlier.

Physical examination of patients with esophageal cancer is usually unremarkable, unless the disease has metastasized, in which case cervical lymphadenopathy and jaundice may be seen.

There are no diagnostic lab findings since diagnosis is based mainly on biopsy and esophageal endoscopy. However, routine tests are done to rule out anemia and metastases to the liver.

CT scans may be used for staging of esophageal cancer. Findings on a CT scan suggestive of esophageal cancer include eccentric or circumferential wall thickening, or peri-esophageal soft tissue and fat stranding.

MRIs can be useful when used with positron emission tomography (PET) for staging esophageal cancer since it has greater soft tissue contrast than CT scans.

Other imaging studies for esophageal cancer include positive emission tomography scanning with 18-fluorodeoxyglucose (FDG-PET). FDG-PET is a noninvasive staging modality that is more sensitive than CT or EUS for the detection of distant metastases.

Laparoscopy, thoracoscopy and bronchoscopy can be used in addition to EUS and CT in locally advanced esophageal cancer to accurately diagnose and stage lymph node metastasis.

The predominant therapy for esophageal cancer is surgical. Chemotherapy is used to treat advanced esophageal cancer. Chemotherapy can be used alone as monotherapy or in combination with radiotherapy or surgery. Chemotherapy may be used as adjuvant therapy to shrink a tumor before being surgically resected or as neoadjuvant therapy after surgery to kill any cancerous cells that may have been left, and finally, in advanced tumors to shrink them or to relieve symptoms.

The predominant therapy for esophageal cancer is surgical resection by esophagectomy. The disease must be localized in order for it to be operable. Adjunctive chemotherapy and radiation may be required in more advanced cases of esophageal cancer, and to shrink down a localized tumor so that it may become operable.

Effective measures for the primary prevention of esophageal cancer include the treatment of gastroesophageal reflux disease and Barrett’s esophagus, weight loss, avoidance of tobacco and alcohol, and a diet rich in fruits and vegetables.

Secondary prevention may be effective in reducing the incidence of esophageal cancer, if treated early at the dysplasia stage with monoclonal antibody therapy. Presently, there is no particular program in place to reduce the incidence of esophageal cancer.

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]Associate Editor(s)-in-Chief: Hadeel Maksoud M.D.[2]

Esophageal cancer may be classified into squamous cell carcinoma or adenocarcinoma based on histology.

Esophageal cancers are typically carcinomas, which arise from the epithelium, or surface lining of the esophagus. Most esophageal cancers fall into one of two classes according to their histology. ^[1]

• Squamous cell carcinoma
  • Esophageal squamous cell carcinoma are similar to head and neck cancer in their appearance and are associated with smoking and alcohol consumption.
• Adenocarcinoma
  • Esophageal adenocarcinomas make up more than 70% of esophageal cancers.
  • They are often associated with a history of gastroesophageal reflux disease and Barrett’s esophagus.

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor(s)-in-Chief: Hadeel Maksoud M.D.[2]

The pathophysiology of esophageal cancer depends on the histological subtype, whether squamous cell carcinoma or adenocarcinoma.

• The esophagus is lined by nonkeratinized stratified squamous epithelium.
• This lining is maintained as long as there are no risk factors that can lead to a metaplastic change.

• The risk factors for esophageal squamous cell carcinoma include smoking and alcohol.^[1][2]
• When alcohol and tobacco are combined they have a synergistic effect and the risk for esophageal squamous cell carcinoma is higher.
• Alcohol is able to dissolve fat soluble compounds, like that of the esophageal epithelium.
• Tobacco carcinogens such as aromatic amines, nitrosamines and polycyclic hydrocarbons are, therefore, able to penetrate the esophageal epithelium deeper when in the presence of alcohol.
• Alcohol is also able to decrease the metabolic activities of epithelial cells by damaging DNA.
• When the cellular DNA is damaged, the cell cannot undergo detoxification and protect itself from oxidative damage.
• Oxidation leads to inflammation of the squamous epithelium.
• Continuous irritation of the epithelium leads to dysplasia and in situ malignant transformation.

• The risk factors for esophageal adenocarcinoma include gastroesophageal reflux disease and obesity.^{[3][4][5][6][7]}
• The chronic reflux of gastric acid and bile at the gastroesophageal junction leads to the irritation of squamous epithelium lining the esophagus.
• Chronic irritation leads to metaplasia of esophagus.
• The lining of the esophagus changes from non-keratinized stratified squamous epithelium to columnar epithelium.
• This condition is called Barrett’s esophagus .
• The progression of Barrett’s esophagus to adenocarcinoma is associated with changes in genetic and protein structure, as well as gene expression.
• These mutations include:
  • Chromosomal losses (4q, 5q, 9p, and 18q)^[8]
  • Chromosomal gains (8q, 17q, and 20q)
  • Gene amplifications (7, 8, and 17q)
  • PT53 genes and P16 genes
  • Variants in ADH and/or ALDH2 genes^[9]
  • Possibly Cyclin D1 (CCND1) G870A polymorphism
• In addition, obesity is implicated in the development of esophageal adenocarcinoma.^[10]
• Patients with central obesity tend to have hypertrophied adipocytes and inflammatory cells within their fat deposits.
• This creates a microenvironment within the adipocyte that promotes tumor development through the release of adipokines and cytokines.
• Adipocytes potentiate tumor expansion by supplying energy to support the tumor’s growth.

Squamous cell carcinoma or adenocarcinoma of the esophagus may appear as:^[11]

• Flat and irregular plaque
• Polypoid lesion
• Ulcerating, fungating mass.
  • Location:
    • Squamous cell carcinoma is usually found in the mid-third of the esophagus.
    • Adenocarcinoma is usually found in the lower third of the esophagus near the gastric opening.

• Found in both types:^[12]
  • Poikilocytosis
  • Anisocytosis
  • Staining variation
  • Mitotic activity

• Atypical squamous cells invade the basement membrane
  • Cytology of squamous cells:
    • Eccentric nucleus
    • High mitotic activity
    • Eosinophilic cytoplasm
    • Squamous whorls or keratin pearls

• Atypical adenomatous cells show:^[13]
  • Invading cell clusters or glands
  • Cribriforming
  • Desmoplasia
  • Invasion into submucosa

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]Associate Editor(s)-in-Chief: Parminder Dhingra, M.D. [2]Hadeel Maksoud M.D.[3]

Esophageal cancer must be differentiated from gastroesophageal reflux disease (GERD), Barrett’s esophagus, esophageal achalasia, gastritis, gastric ulcer, and stomach cancer.

• Esophageal adenocarcinoma must be differentiated from other causes of dysphagia, odynophagia and food regurgitation such as GERD, esophageal stricture, reflux esophagitis, systemic sclerosis, esophageal spasm, pseudoachalasia, stroke, esophageal candidiasis and Chagas disease.^{[1][2][3][4][5][6][7][8][9][10][11]}

Disease	Signs and Symptoms				Barium esophagogram	Endoscopy	Other imaging and laboratory findings	Gold Standard
	Dysphagia	Weight loss	Heartburn	Other findings
Esophageal carcinoma	Gradual progressive dysphasia to solid and liquid	+	±	Lymphadenopathy Cachexia	Irregular stricture Pre-stricture dilatation	Esophageal obstruction Staging of disease {{#ev:youtube|5ucSlgqGAno}}	CT and PET scan for staging of the disease	Biopsy
Plummer-Vinson syndrome	Gradual non-progressive dysphagia to solids	±	–	Glossitis Koilonychia Weakness Pale color of the skin Cold intolerance Reduced resistance to infection Altered behavior Craving for for unusual items (such as ice or cold vegetables)	Thin projections on the anterior esophageal wall Multiple upper esophageal constrictions	Direct visualization of esophageal webs Superior to esophagogram {{#ev:youtube|HFfsTgsB6Pg}}	Videofluoroscopy shows mucosal and submucosal foldings Iron deficiency anemia	Triad of Iron deficiency anemia Esophageal webs Glossitis
Esophageal stricture	Sudden onset and gradual progressive dysphasia to solids	±	±	Odynophagia Cough Chest pain	Sacculations Fixed transverse folds Esophageal intramural pseudodiverticula	Mucosal edema Circumferential thickening in GERD Pale mucosa with white exudate in lymphocytic esophagitis Swelling and hemorrhagic congestion in caustic ingestion {{#ev:youtube|vax5E-jMnQ}}	Manometry may show dysmotility CT scan for staging malignant strictures	Barium esophagogram
Diffuse esophageal spasm	Sudden non-progressive dysphagia to solid and liquid	+	+	Chest pain	Nonperistaltic and nonpropulsive contractions Corkscrew or rosary bead esophagus	Inconclusive {{#ev:youtube|2ipA34iMA3c}}	Manometry shows high-amplitude esophageal contractions CT scan may show hypertrophy of esophageal muscles	Manometry
Achalasia	Gradual non-progressive dysphagia to solid and liquid	±	–	Dyspnea Regurgitation of undigested food Chest pain Cough	“Bird’s beak” or “rat tail” appearance Dilated esophageal body Air fluid level (absent peristalsis) Absence of an intragastric air bubble	Dilated esophagus Residual food fragments Normal mucosa {{#ev:youtube|ydLcskQzEjM}}	Residual pressure of LES > 10 mmHg Incomplete relaxation of the LES Increased resting tone of LES Aperistalsis	History of dysphagia with positive endoscopy and manometry
Systemic sclerosis	Gradual progressive dysphasia to solid and liquid	±	+	Muscle and joint pain Raynaud’s phenomenon Skin changes	Dysmotility Patulous esophagus	Mucosal damage Peptic stricture (advanced cases)	Positive serology for Antinuclear antibodies Rheumatoid factor Creatine kinase ESR	Skin biopsy
Zenker’s diverticulum	Gradual dysphasia to solid	±	–	Food regurgitation Halitosis Cough Hoarseness	Thin projections on esophageal wall over Killian’s triangle	Outpouching of posterior pharyngeal wall Exclude the presence of SCC {{#ev:youtube|FdEruFsNdVA}}	CT & MRI shows out-pouching over the posterior esophagus in the Killian’s triangle	Barium esophagography
Stroke (Cerebral hemorrhage)	Sudden progressive dysphasia to solid and liquid	+	±	Dysarthria Limb weakness Fatigue	Pooling of contrast in the pharynx Aspiration of barium contrast into the airway	Reduced opening of upper esophageal sphincter Reduced larynx elevation	CT without contrast shows acute hemorrhage as a hyperattenuating clot	CT without contrast
Motor disorders (Myasthenia gravis)	Gradual progressive dysphasia to solid and liquid	±		Ptosis Diplopia Fatigue	Stasis in pharynx and pooling in pharyngeal recesses	Velopharyngeal insufficiency Delayed swallowing function	CT may show anterior mediastinal mass (thymoma) Positive tensilon test	Anti–acetylcholine receptor antibody test
GERD	Sudden onset gradual progressive dysphasia to solid	±	+	Cough Hoarseness Retrosternal burning chest pain	Free acid reflux Esophagitis with scarring Strictures Barrett’s oesophagus	Erythema, erosions and ulceration Barrett’s esophagus	Esophageal manometry may show decreased tone of LES	24 hour esophageal pH monitoring
Esophageal web	Gradual progressive dysphasia to solid and/or liquid	–	±	Findings of the underlying cause such as iron deficiency anemia or bullous pemphigoid	Symmetrical narrowing of the esophagus	Smooth membrane not encircling the whole lumen	Videofluoroscopy shows mucosal and submucosal foldings	Barium esophagogram

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1];Associate Editor(s)-in-Chief: Hadeel Maksoud M.D.[2]

Esophageal cancer is the 6th leading cause of death from cancer and the 8th most common cancer in the world. The prevalence of esophageal cancer worldwide is about 3.5 per 100,000. In the United States, about 17000 new cases are diagnosed every year and 4.2 per 100,000 Americans has esophageal cancer. Esophageal cancer is mostly present in the “Asian belt” region which includes, China, Japan, India and Iran.

• The incidence of esophageal cancer is approximately 3.5 per 100,000 individuals worldwide.^[1]
• The incidence of invasive esophageal cancer was 4.2 per 100,000 individuals in the United States.
• The American Cancer Society estimates that by the end of 2017, there will be 16,960 new cases of esophageal cancer in the United States .

• In 2014, the prevalence of esophageal cancer was estimated to be 7.25 cases per 100,000 individuals in the United States.^[1]

• Between 2010 – 2014, the incidence of esophageal cancer in the United States was approximately 4.2 per 100,000 individuals with a case-fatality rate/mortality rate of 4.1 per 100,000 individuals.^[1]
• Mortality rates from esophageal cancer are higher in blacks and white females than white males.^[2]

• The incidence of esophageal cancer increases with age; the median age at diagnosis is 67 years.^[3][4]
• The age-adjusted incidence of invasive esophageal cancer worldwide by age category is:
  • Under 65 years: 1.8 per 100,000
  • 65 and over: 22.5 per 100,000

• Esophageal adenocarcinoma usually affects individuals of the Caucasian race, whilst Black individuals are more likely to develop esophagus squamous cell carcinoma. ^[5]
• More Black individuals are diagnosed with esophageal cancer then Caucasian individuals overall.^[6]
• In the United States, 68.5% of Caucasian subjects with esophageal cancer had adenocarcinoma, whereas 80% of black individuals affected with esophageal cancer had squamous cell carcinoma.

• Men are more commonly affected by esophageal cancer than women. The male to female ratio is approximately 4 to 1.^[3]

• The majority of esophageal cancer cases are reported in in the area of the “Asian belt” which includes China, Japan, India, Iran, Turkey, among other Middle Eastern countries.^[7]
• In China, the incidence rate of esophageal cancer is 16.7 per 100 000 population.^[8]

• Worldwide, the predominant type of esophageal cancer is squamous cell carcinoma.^[1]
• However, the rate of adenocarcinoma outnumbers squamous cell carcinoma in developed countries like the United States and some European countries.
• Squamous cell carcinoma is predominant in developing countries.

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]Associate Editor(s)-in-Chief: Hadeel Maksoud M.D.[2]

Common risk factors in the development of esophageal cancer are tobacco smoking, alcohol, gastroesophageal reflux disease, and Barrett’s esophagus.

• There are a number of risk factors for esophageal cancer.
• Some subtypes of cancer are linked to particular risk factors:^{[1][2][3][4][5]}

• Risk appears to be less in patients using aspirin or related drugs (NSAIDs).
• The role of helicobacter pylori in progression to esophageal adenocarcinoma is still uncertain, but, on the basis of population data, it may carry a protective effect. It is postulated that helicobacter pylori prevents chronic gastritis, which is a risk factor for reflux, which in turn is a risk factor for esophageal adenocarcinoma.
• Diets high in cruciferous (cabbage, broccoli, cauliflower) and green and yellow vegetables and fruits are associated with a decreased risk of esophageal cancer.

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]Associate Editor(s)-in-Chief: ;Hadeel Maksoud M.D.[2]

The incidence of esophageal dysplasia turning malignant is very low, especially outside the United States. Complications of esophageal cancer include dysphagia, anemia, and tracheoesophageal fistula. This finding has caused some uncertainty as to the usefulness of screening. Esophageal cancer is associated with a 5 year survival rate of 20%.

• The symptoms of esophageal cancer typically develop insidiously and starts with symptoms such as dysphagia, chest pain and weight loss.^[1]
• If left untreated, patients with esophageal cancer may progress to develop vomiting, aspiration pneumonia and hematemesis.
• Depending on the degree of invasion both squamous cell carcinoma or adenocarcinoma can cause rupture of the esophagus, which can manifest as hematemesis, melena and severe chest pain.
• Ultimately, esophageal cancer can metastasize and be fatal.

Complications can occur as a result of esophageal cancer or because of radiotherapeutic treatment.

• Anemia
• Weight loss
• Dysphagia
• Cachexia
• Aspiration pneumonia
• Metastases

• Tracheoesophageal fistula
• Postradiotherapy esophageal strictures, may lead to recurrent dysphagia.^[2]

Prognosis is generally poor, and the 5-year survival rate of patients with esophageal cancer is approximately 20% for both squamous cell carcinoma and adenocarcinoma of the esophagus.^[3]

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