Esophageal Cancer

Esophageal cancer is 1 of the most common causes of cancer-related deaths worldwide. Nearly all esophageal cancers are either adenocarcinoma (commonly affecting the distal esophagus Esophagus The esophagus is a muscular tube-shaped organ of around 25 centimeters in length that connects the pharynx to the stomach. The organ extends from approximately the 6th cervical vertebra to the 11th thoracic vertebra and can be divided grossly into 3 parts: the cervical part, the thoracic part, and the abdominal part. Esophagus) or squamous cell carcinoma Squamous cell carcinoma Cutaneous squamous cell carcinoma (cSCC) is caused by malignant proliferation of atypical keratinocytes. This condition is the 2nd most common skin malignancy and usually affects sun-exposed areas of fair-skinned patients. The cancer presents as a firm, erythematous, keratotic plaque or papule. Squamous Cell Carcinoma (affecting the proximal two-thirds of the esophagus Esophagus The esophagus is a muscular tube-shaped organ of around 25 centimeters in length that connects the pharynx to the stomach. The organ extends from approximately the 6th cervical vertebra to the 11th thoracic vertebra and can be divided grossly into 3 parts: the cervical part, the thoracic part, and the abdominal part. Esophagus). Major risk factors for adenocarcinoma include smoking, obesity Obesity Obesity is a condition associated with excess body weight, specifically with the deposition of excessive adipose tissue. Obesity is considered a global epidemic. Major influences come from the western diet and sedentary lifestyles, but the exact mechanisms likely include a mixture of genetic and environmental factors. Obesity, and Barrett’s esophagus Esophagus The esophagus is a muscular tube-shaped organ of around 25 centimeters in length that connects the pharynx to the stomach. The organ extends from approximately the 6th cervical vertebra to the 11th thoracic vertebra and can be divided grossly into 3 parts: the cervical part, the thoracic part, and the abdominal part. Esophagus. For squamous cell carcinoma Squamous cell carcinoma Cutaneous squamous cell carcinoma (cSCC) is caused by malignant proliferation of atypical keratinocytes. This condition is the 2nd most common skin malignancy and usually affects sun-exposed areas of fair-skinned patients. The cancer presents as a firm, erythematous, keratotic plaque or papule. Squamous Cell Carcinoma, risk factors include smoking, alcohol consumption, and certain dietary factors. Early-stage cancer is often asymptomatic, with dysphagia Dysphagia Dysphagia is the subjective sensation of difficulty swallowing. Symptoms can range from a complete inability to swallow, to the sensation of solids or liquids becoming "stuck." Dysphagia is classified as either oropharyngeal or esophageal, with esophageal dysphagia having 2 sub-types: functional and mechanical. Dysphagia and weight loss presenting as the disease progresses. Diagnosis is by endoscopic biopsy or image-guided biopsy of the metastatic site. Management depends on the disease stage. Options include surgical resection, chemotherapy, and radiation. For unresectable esophageal cancers, palliative measures are provided for symptom relief and to prolong survival.

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Editorial responsibility: Stanley Oiseth, Lindsay Jones, Evelin Maza

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Epidemiology and Etiology

Epidemiology

  • 8th-most common cancer worldwide and 6th-most common cause of cancer-related deaths
  • Risk increases with age, especially during the 6th to 7th decades of life
  • Males > females
  • Majority of cases fall under 2 types:
    • Adenocarcinoma (AC)
      • Most common form in the United States
      • Higher incidence in Caucasians
    • Squamous cell carcinoma (SCC)
      • Most common form worldwide
      • 90% of esophageal cancers occur in the “esophageal cancer belt” (northern Iran, northern China, Central Asia, and southern Russia)
      • Incidence decreasing in the United States
      • Higher incidence in African Americans and Asians

Etiology

  • Risk factors for adenocarcinoma:
    • Barrett’s esophagus Esophagus The esophagus is a muscular tube-shaped organ of around 25 centimeters in length that connects the pharynx to the stomach. The organ extends from approximately the 6th cervical vertebra to the 11th thoracic vertebra and can be divided grossly into 3 parts: the cervical part, the thoracic part, and the abdominal part. Esophagus secondary to gastroesophageal reflux disease Gastroesophageal Reflux Disease Gastroesophageal reflux disease (GERD) occurs when the stomach acid frequently flows back into the esophagus. This backwash (acid reflux) can irritate the lining of the esophagus, causing symptoms such as retrosternal burning pain (heartburn). Gastroesophageal Reflux Disease ( GERD GERD Gastroesophageal reflux disease (GERD) occurs when the stomach acid frequently flows back into the esophagus. This backwash (acid reflux) can irritate the lining of the esophagus, causing symptoms such as retrosternal burning pain (heartburn). Gastroesophageal Reflux Disease)
    • Obesity
    • Smoking
  • Risk factors for squamous cell carcinoma Squamous cell carcinoma Cutaneous squamous cell carcinoma (cSCC) is caused by malignant proliferation of atypical keratinocytes. This condition is the 2nd most common skin malignancy and usually affects sun-exposed areas of fair-skinned patients. The cancer presents as a firm, erythematous, keratotic plaque or papule. Squamous Cell Carcinoma (SCC):
    • Smoking
    • Alcohol intake
    • Diet low in vegetables and fruits
    • Achalasia Achalasia Achalasia is a primary esophageal motility disorder that develops from the degeneration of the myenteric plexus. This condition results in impaired lower esophageal sphincter relaxation and absence of normal esophageal peristalsis. Patients typically present with dysphagia to solids and liquids along with regurgitation. Achalasia
    • Caustic injuries
    • Human papillomavirus Human papillomavirus Human papillomavirus (HPV) is a nonenveloped, circular, double-stranded DNA virus belonging to the Papillomaviridae family. Humans are the only reservoir, and transmission occurs through close skin-to-skin or sexual contact. Human papillomaviruses infect basal epithelial cells and can affect cell-regulatory proteins to result in cell proliferation. Papillomaviridae: HPV infection
    • Atrophic gastritis Gastritis Gastritis refers to inflammation of the gastric mucosa. Gastritis may occur suddenly (acute gastritis) or slowly over time (chronic gastritis). Gastritis may be asymptomatic or with symptoms, including burning abdominal pain (which either worsens or improves with eating), dyspepsia, nausea, and vomiting. Gastritis
    • Tylosis (Howel-Evans syndrome): autosomal dominant Autosomal dominant Autosomal inheritance, both dominant and recessive, refers to the transmission of genes from the 22 autosomal chromosomes. Autosomal dominant diseases are expressed when only 1 copy of the dominant allele is inherited. Autosomal Recessive and Autosomal Dominant Inheritance disease with hyperkeratosis of palm and sole 
    • Plummer-Vinson syndrome
    • Poor oral hygiene
    • Nitrosamine exposure (e.g., cured meats)
    • Drinking scalding-hot liquids
    • Areca nut or betel quid chewing
Table: Epidemiology of and risk factors for esophageal cancer
Adenocarcinoma Squamous cell carcinoma
Sex Male Male
Race Caucasians African Americans, Asians
Major risk factors Barrett’s esophagus Esophagus The esophagus is a muscular tube-shaped organ of around 25 centimeters in length that connects the pharynx to the stomach. The organ extends from approximately the 6th cervical vertebra to the 11th thoracic vertebra and can be divided grossly into 3 parts: the cervical part, the thoracic part, and the abdominal part. Esophagus, smoking, obesity Obesity Obesity is a condition associated with excess body weight, specifically with the deposition of excessive adipose tissue. Obesity is considered a global epidemic. Major influences come from the western diet and sedentary lifestyles, but the exact mechanisms likely include a mixture of genetic and environmental factors. Obesity Smoking, alcohol consumption, low vegetable and fruit intake, drinking hot liquids, caustic strictures, achalasia

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Clinical Presentation and Complications

Clinical presentation

  • Asymptomatic in early stages 
  • Signs and symptoms:
    • Progressive dysphagia Dysphagia Dysphagia is the subjective sensation of difficulty swallowing. Symptoms can range from a complete inability to swallow, to the sensation of solids or liquids becoming "stuck." Dysphagia is classified as either oropharyngeal or esophageal, with esophageal dysphagia having 2 sub-types: functional and mechanical. Dysphagia (from solids to liquids):
      • Due to obstruction by the tumor
      • Noted when esophageal lumen is < 13 mm
    • Weight loss (from dysphagia Dysphagia Dysphagia is the subjective sensation of difficulty swallowing. Symptoms can range from a complete inability to swallow, to the sensation of solids or liquids becoming "stuck." Dysphagia is classified as either oropharyngeal or esophageal, with esophageal dysphagia having 2 sub-types: functional and mechanical. Dysphagia and tumor-related anorexia)
    • Odynophagia in 20% of patients
Table: Esophageal cancers—differences in presentation
Adenocarcinoma Squamous cell carcinoma
Location (major distinguishing factor) Distal ⅓ of esophagus Esophagus The esophagus is a muscular tube-shaped organ of around 25 centimeters in length that connects the pharynx to the stomach. The organ extends from approximately the 6th cervical vertebra to the 11th thoracic vertebra and can be divided grossly into 3 parts: the cervical part, the thoracic part, and the abdominal part. Esophagus Esophagogastric junction (EGJ) Proximal two-thirds of esophagus Esophagus The esophagus is a muscular tube-shaped organ of around 25 centimeters in length that connects the pharynx to the stomach. The organ extends from approximately the 6th cervical vertebra to the 11th thoracic vertebra and can be divided grossly into 3 parts: the cervical part, the thoracic part, and the abdominal part. Esophagus
Early lesions
  • Mucosal irregularities, ulcer, or nodule
  • Detected due to surveillance of Barrett’s esophagus Esophagus The esophagus is a muscular tube-shaped organ of around 25 centimeters in length that connects the pharynx to the stomach. The organ extends from approximately the 6th cervical vertebra to the 11th thoracic vertebra and can be divided grossly into 3 parts: the cervical part, the thoracic part, and the abdominal part. Esophagus
  • Subtle, may appear normal
  • Friable tissue, erythema, erosions, plaques, nodules
Advanced lesions Ulcerated or exophytic mass with obstruction Infiltrating or ulcerated mass, may be circumferential

Complications

  • Iron-deficiency anemia Anemia Anemia is a condition in which individuals have low Hb levels, which can arise from various causes. Anemia is accompanied by a reduced number of RBCs and may manifest with fatigue, shortness of breath, pallor, and weakness. Subtypes are classified by the size of RBCs, chronicity, and etiology. Anemia: Overview secondary to chronic gastrointestinal bleeding Gastrointestinal bleeding Gastrointestinal bleeding (GIB) is a symptom of multiple diseases within the gastrointestinal (GI) tract. Gastrointestinal bleeding is designated as upper or lower based on the etiology's location to the ligament of Treitz. Depending on the location of the bleeding, the patient may present with hematemesis (vomiting blood), melena (black, tarry stool), or hematochezia (fresh blood in stools). Gastrointestinal Bleeding
  • Local tumor spread:
    • Cough ( trachea Trachea The trachea is a tubular structure that forms part of the lower respiratory tract. The trachea is continuous superiorly with the larynx and inferiorly becomes the bronchial tree within the lungs. The trachea consists of a support frame of semicircular, or C-shaped, rings made out of hyaline cartilage and reinforced by collagenous connective tissue. Trachea)
    • Hoarseness and vocal paralysis (recurrent laryngeal nerve)
    • Tracheoesophageal fistulas (direct invasion through the esophageal wall and main stem bronchus)
  • Metastasis:
    • Compressive symptoms from lymph node metastasis (aortic, liver Liver The liver is the largest gland in the human body. The liver is found in the superior right quadrant of the abdomen and weighs approximately 1.5 kilograms. Its main functions are detoxification, metabolism, nutrient storage (e.g., iron and vitamins), synthesis of coagulation factors, formation of bile, filtration, and storage of blood. Liver, lung, mediastinal)
    • SCC: usually intrathoracic
    • AC: usually intraabdominal

Diagnosis

Diagnosis

  • Initial work-up of dysphagia Dysphagia Dysphagia is the subjective sensation of difficulty swallowing. Symptoms can range from a complete inability to swallow, to the sensation of solids or liquids becoming "stuck." Dysphagia is classified as either oropharyngeal or esophageal, with esophageal dysphagia having 2 sub-types: functional and mechanical. Dysphagia
    • Barium swallow study: asymmetric narrowing or intraluminal masses 
  • Upper endoscopy: 
    • Allows for direct visualization and biopsy of lesions
    • Early lesions: superficial plaques, nodules, ulceration, mucosal irregularities
    • Advanced lesions: strictures, masses, obstruction
  • Endoscopic biopsy with brush cytology or image-guided biopsy (for metastatic site):
    • Adenocarcinoma: 
      • Mucin-producing intestinal-type mucosa
      • Adjacent Barrett’s mucosa and high-grade dysplasia
    • SCC: 
      • Keratin pearls: clusters of neoplastic cells with circular keratinization
      • Individual cell keratinization and intercellular bridges

Evaluation for regional disease and metastasis

  • Endoscopic ultrasound (EUS):
    • Most accurate for locoregional staging Staging Cancer is the 2nd leading cause of death in the US after cardiovascular disease. Many malignancies are treatable or curable, but some may recur. Thus, all malignancies must be assigned a grade and stage in order to guide management and determine prognosis. Grading, Staging, and Metastasis
    • Visualizes local disease and tumor depth
    • Detects regional nodal involvement 
    • Allows for fine needle aspiration biopsy of lymph nodes
  • Bronchoscopy:
    • Indicated for thoracic esophageal tumor at or above the carina
    • Helps assess airway invasion
  • Laryngoscopy:
    • Indicated for cervical SCC
    • Determines presence of concomitant SCC of the head and neck
  • Chest and abdominal computed tomography (CT) and/or positron emission tomography (PET)
    • For detection of metastasis
    • Integrated fluorodeoxyglucose (FDG)-PET/CT available for occult metastasis

Staging

Tumor, node, metastasis (TNM) staging Staging Cancer is the 2nd leading cause of death in the US after cardiovascular disease. Many malignancies are treatable or curable, but some may recur. Thus, all malignancies must be assigned a grade and stage in order to guide management and determine prognosis. Grading, Staging, and Metastasis:

  • T: extent of tumor in the esophageal wall 
    • T1: mucosa (innermost layer) and submucosa
    • T2: muscularis propria
    • T3: adventitia (outermost layer)
    • T4: involves adjacent structures of the esophagus Esophagus The esophagus is a muscular tube-shaped organ of around 25 centimeters in length that connects the pharynx to the stomach. The organ extends from approximately the 6th cervical vertebra to the 11th thoracic vertebra and can be divided grossly into 3 parts: the cervical part, the thoracic part, and the abdominal part. Esophagus
  • N: regional lymph nodes involved
  • M: presence of distant metastasis
Esophageal cancer staging

Locoregional esophageal cancer staging Staging Cancer is the 2nd leading cause of death in the US after cardiovascular disease. Many malignancies are treatable or curable, but some may recur. Thus, all malignancies must be assigned a grade and stage in order to guide management and determine prognosis. Grading, Staging, and Metastasis: The cancer is seen as the lesion penetrating the esophageal wall. Illustration depicts the staging Staging Cancer is the 2nd leading cause of death in the US after cardiovascular disease. Many malignancies are treatable or curable, but some may recur. Thus, all malignancies must be assigned a grade and stage in order to guide management and determine prognosis. Grading, Staging, and Metastasis from T1 (mucosa and submucosa) to advanced disease, involving adjacent structures in T4 and the lymph nodes (N).

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Management and Prognosis

Curative treatment options

  • Endoscopic mucosal resection: 
    • For early cancer (limited to mucosa) or high-grade dysplasia (HGD) in Barrett’s esophagus Esophagus The esophagus is a muscular tube-shaped organ of around 25 centimeters in length that connects the pharynx to the stomach. The organ extends from approximately the 6th cervical vertebra to the 11th thoracic vertebra and can be divided grossly into 3 parts: the cervical part, the thoracic part, and the abdominal part. Esophagus
    • Lesion with diameter ≤ 2 cm
    • < ⅓ of the circumference of the esophageal wall involved
  • Surgery:
    • Esophagectomy:
      • Lesion penetrating up to the submucosa (T1 with no regional lymph nodes, no metastasis)
      • In some centers, lesions penetrating up to muscularis propria (T2) can be resected.
    • Esophagectomy following neoadjuvant chemotherapy or followed by chemoradiotherapy:
      • For locally advanced tumors (T3) with or without nodal disease
      • Selected patients with T4 disease
    • Contraindication to surgery: 
      • Metastasis to other organs or extraregional lymph node spread
  • Chemoradiation:
    • Use of radiation therapy and chemotherapy 
    • For downstaging the tumor for later resection or as definitive treatment
    • 2–3 drug cytotoxic regimen used due to higher response rate

Palliative options

  • For advanced esophageal cancer (metastatic disease)
  • Goals:
    • Symptom palliation and comfort
    • Prolong survival 
  • Chemoradiation 
  • Assess for positive HER2 (human epidermal growth factor 2) status of adenocarcinoma: add trastuzumab, a monoclonal antibody targeting the HER2 receptor
  • Endoscopic procedures:
    • Dilation
    • Stenting
    • Laser ablation

Prognosis

  • Depends on the stage of disease
  • 50%80% of patients on presentation have locally advanced or metastatic esophageal cancer.
  • Low survival rate noted in patients with lymph node or distant metastasis 
  • Overexpression of HER2 receptor: associated with aggressive cancer growth and poor survival

Differential Diagnosis

  • Barrett’s esophagus Esophagus The esophagus is a muscular tube-shaped organ of around 25 centimeters in length that connects the pharynx to the stomach. The organ extends from approximately the 6th cervical vertebra to the 11th thoracic vertebra and can be divided grossly into 3 parts: the cervical part, the thoracic part, and the abdominal part. Esophagus: results from chronic gastroesophageal reflux disease Gastroesophageal Reflux Disease Gastroesophageal reflux disease (GERD) occurs when the stomach acid frequently flows back into the esophagus. This backwash (acid reflux) can irritate the lining of the esophagus, causing symptoms such as retrosternal burning pain (heartburn). Gastroesophageal Reflux Disease ( GERD GERD Gastroesophageal reflux disease (GERD) occurs when the stomach acid frequently flows back into the esophagus. This backwash (acid reflux) can irritate the lining of the esophagus, causing symptoms such as retrosternal burning pain (heartburn). Gastroesophageal Reflux Disease) leading to replacement of esophageal squamous epithelium Epithelium The epithelium is a complex of specialized cellular organizations arranged into sheets and lining cavities and covering the surfaces of the body. The cells exhibit polarity, having an apical and a basal pole. Structures important for the epithelial integrity and function involve the basement membrane, the semipermeable sheet on which the cells rest, and interdigitations, as well as cellular junctions. Surface Epithelium by gastric columnar epithelium Epithelium The epithelium is a complex of specialized cellular organizations arranged into sheets and lining cavities and covering the surfaces of the body. The cells exhibit polarity, having an apical and a basal pole. Structures important for the epithelial integrity and function involve the basement membrane, the semipermeable sheet on which the cells rest, and interdigitations, as well as cellular junctions. Surface Epithelium. Barrett’s esophagus Esophagus The esophagus is a muscular tube-shaped organ of around 25 centimeters in length that connects the pharynx to the stomach. The organ extends from approximately the 6th cervical vertebra to the 11th thoracic vertebra and can be divided grossly into 3 parts: the cervical part, the thoracic part, and the abdominal part. Esophagus is a risk factor for esophageal adenocarcinoma. Surveillance is recommended to detect dysplasia or adenocarcinoma early enough to provide treatment.
  • Esophageal stricture: narrowing of the esophagus Esophagus The esophagus is a muscular tube-shaped organ of around 25 centimeters in length that connects the pharynx to the stomach. The organ extends from approximately the 6th cervical vertebra to the 11th thoracic vertebra and can be divided grossly into 3 parts: the cervical part, the thoracic part, and the abdominal part. Esophagus that can result from GERD GERD Gastroesophageal reflux disease (GERD) occurs when the stomach acid frequently flows back into the esophagus. This backwash (acid reflux) can irritate the lining of the esophagus, causing symptoms such as retrosternal burning pain (heartburn). Gastroesophageal Reflux Disease, malignancies, and caustic ingestion Caustic Ingestion Caustic agents are acidic or alkaline substances that damage tissues severely if ingested. Alkali ingestion typically damages the esophagus via liquefactive necrosis, whereas acids cause more severe gastric injury leading to coagulative necrosis. Caustic Ingestion (Cleaning Products). The condition presents with dysphagia Dysphagia Dysphagia is the subjective sensation of difficulty swallowing. Symptoms can range from a complete inability to swallow, to the sensation of solids or liquids becoming "stuck." Dysphagia is classified as either oropharyngeal or esophageal, with esophageal dysphagia having 2 sub-types: functional and mechanical. Dysphagia to solids, progressing to liquids. Barium swallow study shows a narrowed luminal diameter. Upper endoscopy allows for biopsy and dilation when necessary.
  • Esophageal spasm: presents with dysphagia Dysphagia Dysphagia is the subjective sensation of difficulty swallowing. Symptoms can range from a complete inability to swallow, to the sensation of solids or liquids becoming "stuck." Dysphagia is classified as either oropharyngeal or esophageal, with esophageal dysphagia having 2 sub-types: functional and mechanical. Dysphagia to solids and liquids but is associated with sudden onset of chest pain Chest Pain Chest pain is one of the most common and challenging complaints that may present in an inpatient and outpatient setting. The differential diagnosis of chest pain is large and includes cardiac, gastrointestinal, pulmonary, musculoskeletal, and psychiatric etiologies. Chest Pain that is not exertion-related. There are 2 types of esophageal spasm: distal esophageal spasm and hypercontractile esophagus Esophagus The esophagus is a muscular tube-shaped organ of around 25 centimeters in length that connects the pharynx to the stomach. The organ extends from approximately the 6th cervical vertebra to the 11th thoracic vertebra and can be divided grossly into 3 parts: the cervical part, the thoracic part, and the abdominal part. Esophagus. Manometry shows characteristic esophageal contractions with normal relaxation of the esophagogastric junction. 
  • Achalasia Achalasia Achalasia is a primary esophageal motility disorder that develops from the degeneration of the myenteric plexus. This condition results in impaired lower esophageal sphincter relaxation and absence of normal esophageal peristalsis. Patients typically present with dysphagia to solids and liquids along with regurgitation. Achalasia: an esophageal motility disorder that develops from degeneration of the myenteric plexus. There is impaired lower esophageal sphincter relaxation and absence of normal esophageal peristalsis. Patients present with dysphagia Dysphagia Dysphagia is the subjective sensation of difficulty swallowing. Symptoms can range from a complete inability to swallow, to the sensation of solids or liquids becoming "stuck." Dysphagia is classified as either oropharyngeal or esophageal, with esophageal dysphagia having 2 sub-types: functional and mechanical. Dysphagia to solids and liquids along with regurgitation. Diagnosis is established by high-resolution manometry. 
  • Esophageal ring and web: thin structures that produce partial occlusion of the esophageal lumen. Plummer-Vinson syndrome consists of iron-deficiency anemia Anemia Anemia is a condition in which individuals have low Hb levels, which can arise from various causes. Anemia is accompanied by a reduced number of RBCs and may manifest with fatigue, shortness of breath, pallor, and weakness. Subtypes are classified by the size of RBCs, chronicity, and etiology. Anemia: Overview, dysphagia Dysphagia Dysphagia is the subjective sensation of difficulty swallowing. Symptoms can range from a complete inability to swallow, to the sensation of solids or liquids becoming "stuck." Dysphagia is classified as either oropharyngeal or esophageal, with esophageal dysphagia having 2 sub-types: functional and mechanical. Dysphagia, and a cervical esophageal web. Schatzki’s ring is the most common type of esophageal ring. Patients present with dysphagia Dysphagia Dysphagia is the subjective sensation of difficulty swallowing. Symptoms can range from a complete inability to swallow, to the sensation of solids or liquids becoming "stuck." Dysphagia is classified as either oropharyngeal or esophageal, with esophageal dysphagia having 2 sub-types: functional and mechanical. Dysphagia to solids. Diagnosis is by barium swallow study and upper endoscopy.

References

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  3. Jain, S., Dhingra, S. (2017). Pathology of esophageal cancer and Barrett’s esophagus. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5387146/
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  7. Saltzman, J., Howell, D., Goldberg, R., Savarese, D. (2018). Clinical manifestations, diagnosis, and staging of esophageal cancer. UpToDate. Retrieved 14 Oct 2020, from https://www.uptodate.com/contents/clinical-manifestations-diagnosis-and-staging-of-esophageal-cancer
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