Esophageal cancer

Esophageal cancer (EC) is the eighth most common type of cancer worldwide and affects predominantly male individuals (3:1). The two main forms are esophageal adenocarcinoma and squamous cell carcinoma. Adenocarcinomas are considered the fastest-growing neoplasms in Western countries, while squamous cell carcinoma is still most common in the resource-limited countries. Development of EC is associated with a number of risk factors. Adenocarcinoma, which usually affects the lower third of the esophagus, may be preceded by gastroesophageal reflux disease and associated Barrett esophagus. Other risk factors are smoking and obesity. Major known risk factors for squamous cell carcinoma include carcinogen exposure (e.g., in form of alcohol and tobacco) and a diet high in nitrosamines, but low in fruits and vegetables. Initially, EC is usually asymptomatic, so locally advanced disease is common at time of diagnosis. Weight loss and dyspepsia can precede the primary symptom progressive dysphagia. Late stages may be characterized by cervical adenopathy, hoarseness or persistent cough, and signs of upper gastrointestinal bleeding, such as hematemesis or melena. Esophagogastroduodenoscopy is used for direct visualization and allows biopsy of the lesion for histopathological confirmation. Staging of the tumor includes transesophageal endoscopic ultrasound, CT scans of chest and abdomen, and bronchoscopy. Curative surgical resection may be considered for locally invasive cancers, but in about 60% of patients EC is already unresectable at time of diagnosis. In those cases, treatment options includes chemotherapy, radiation, and palliative stenting. Prognosis is generally poor due to the aggressive nature of EC and oftentimes late diagnosis.

• Sex: ♂ > ♀ (3:1) ^[1]
• Incidence: an estimated 18,440 new cases of esophageal cancer will be diagnosed in 2020 in the United States ^[1]
• Median age of onset: between 60 and 70 years of age
• Adenocarcinoma: most common type of esophageal cancer in the US ^[2]
• Squamous cell carcinoma (SCC): most common type of esophageal cancer worldwide ^[3]

Adenocarcinoma is more common in the US of America.

Epidemiological data refers to the US, unless otherwise specified.

Adenocarcinoma ^[4]

• Exogenous risk factors
  • Smoking (twofold risk)
  • Obesity
• Endogenous risk factors
  • Male sex
  • Older age (50–60 years)
  • Gastroesophageal reflux
  • Barrett esophagus
• Localization: mostly in the lower third of the esophagus

The most important risk factors for esophageal adenocarcinoma are gastroesophageal reflux and associated Barrett esophagus.

Squamous cell carcinoma (SCC) ^[4][5]

• Exogenous risk factors
  • Alcohol consumption
  • Smoking (ninefold risk)
  • Diet low in fruits and vegetables
  • Hot beverages
  • Nitrosamines exposure (e.g., cured meat, fish, bacon) ^[6]
  • Caustic strictures
  • HPV ^[7]
  • Radiotherapy
  • Betel or areca nut chewing
  • Esophageal candidiasis ^[8][9]
• Endogenous risk factors
  • Male sex
  • Older age (60–70 years)
  • African American descent
  • Plummer-Vinson syndrome
  • Achalasia
  • Diverticula (e.g., Zenker's diverticulum)
  • Tylosis
• Localization: mostly in the upper two-thirds of the esophagus

The primary risk factors for squamous cell esophageal cancer are alcohol consumption, smoking, and dietary factors (e.g., diet low in fruits and vegetables).

Early stages ^[10]

• Often asymptomatic
• May manifest with swallowing difficulties or retrosternal discomfort

Advanced stages ^[10]

• General signs
  • Weight loss
  • Dyspepsia
  • Signs of anemia
• Signs of advanced disease
  • Progressive dysphagia (from solids to liquids) with possible odynophagia
  • Retrosternal chest or back pain
  • Cervical adenopathy
  • Hoarseness and/or persistent cough
  • Horner syndrome
• Signs of upper gastrointestinal bleeding
  • Hematemesis
  • Melena

Initially, esophageal cancer is often asymptomatic. It typically becomes symptomatic at advanced stages.

Esophagogastroduodenoscopy

• Best initial and confirmatory test ^[11]
• Direct visualization of the tumor
• Allows biopsy of any suspicious lesions

Barium swallow

• Overview
  • Sensitive, but does not allow confirmation or staging of a malignancy
  • Inferior to endoscopy
• Indications
  • Severe stricture that inhibits endoscopic evaluation
  • Suspected tracheoesophageal fistula
• Findings: asymmetrical and irregular borders of the esophagus with characteristic stenosis and proximal dilatation (apple core lesion)

Staging ^[11]

• Chest and abdominal CT
  • To identify the location and content of the lesion and to exclude distant metastases
  • In case CT scan does not show metastatic disease, a PET scan can be added to increase diagnostic accuracy
• Transesophageal endoscopic ultrasound
  • Used to determine the infiltration depth and register regional lymph node disease
  • Should be combined with FNA to increase sensitivity and specifity for the identification of lymph node disease
• Bronchoscopy: for staging of lesions at or above the carina to rule out airway involvement
• Laparoscopy: in some cases, to increase accuracy of detecting small liver metastases

Siewert classification of adenocarcinoma of the esophagogastric junction

• This classification was proposed by Siewert and is applied in clinical practice.
• Recent guidelines suggest that tumors located ≤ 2 cm below the z-line (i.e., Siewert types I and II) should be treated as esophageal cancer. ^[12]

pTNM staging for esophageal squamous cell carcinoma

pTNM staging for esophageal adenocarcinoma

Adenocarcinoma ^[13]

• Carcinoma arises in context of Barrett esophagus (columnar epithelium with goblet cells) and high-grade dysplasia
• Gland-forming tumors with different possible growth patterns (tubular, papillary, tubulopapillary)
• Mucinous differentiation possible

Squamous cell carcinoma ^[13]

• Breakdown of uniform tissue structure
• Squamous cell carcinoma clusters with circular keratinization
• Lymphocytic infiltration between the carcinoma clusters

Curative

• Indication
  • Locally invasive disease that has not invaded surrounding structures
  • High-grade metaplasia in Barrett syndrome
• Methods
  • Neoadjuvant chemoradiation: as definitive treatment in patients with proven complete response (e.g., during endoscopy)
  • Surgical resection
    • Endoscopic submucosal resection for removal of superficial, epithelial lesions ^[14][15]
    • Subtotal or total esophagectomy with gastric pull-through procedure or colonic interposition

Palliative

• Indication: patients with advanced disease (majority of patients)
• Methods
  • Chemoradiation
  • Stent placement
  • Other endoscopic treatments (e.g., laser therapy)

Cancer-associated complications

• Esophageal stenosis
• Tracheoesophageal fistula → passage of food and fluid into the respiratory tract → ↑ risk of aspiration pneumonia

Treatment-associated complications

• Surgical complications
  • Anastomotic leak or stricture
  • Recurrent laryngeal nerve injury
• Functional gastrointestinal disorders
  • Dysphagia
  • Reflux
  • Dumping syndrome

We list the most important complications. The selection is not exhaustive.

Prognosis is generally poor due to an aggressive course (due to an absent serosa in the esophageal wall) and typically late diagnosis. ^[11][16]

1. Esophagus cancer - Key Statistics for Esophageal Cancer. https://www.cancer.org/cancer/esophagus-cancer/about/key-statistics.html. Updated: March 20, 2020. Accessed: September 16, 2020.
2. Patel N, Benipal B. Incidence of Esophageal Cancer in the United States from 2001-2015: A United States Cancer Statistics Analysis of 50 States. Cureus. 2018 . doi: 10.7759/cureus.3709 . | Open in Read by QxMD
3. Wang Q-L, Xie S-H, Wahlin K, Lagergren J. Global time trends in the incidence of esophageal squamous cell carcinoma. Clinical Epidemiology. 2018; Volume 10 : p.717-728. doi: 10.2147/clep.s166078 . | Open in Read by QxMD
4. Short MW, Burgers KG, Fry VT. Esophageal Cancer.. Am Fam Physician. 2017; 95 (1): p.22-28.
5. Ribeiro U, Posner MC, Safatle-ribeiro AV, Reynolds JC. Risk factors for squamous cell carcinoma of the oesophagus. British Journal of Surgery . 1996; 83 (9): p.1174-85.
6. Straif K, Weiland SK, Bungers M et al. Exposure to high concentrations of nitrosamines and cancer mortality among a cohort of rubber workers. Occupational and Environmental Medicine. 2000; 57 (3): p.180-187. doi: 10.1136/oem.57.3.180 . | Open in Read by QxMD
7. Liyanage SS, Rahman B, Ridda I, et al. The Aetiological Role of Human Papillomavirus in Oesophageal Squamous Cell Carcinoma: A Meta-Analysis. PLoS ONE. 2013; 8 (7): p.e69238. doi: 10.1371/journal.pone.0069238 . | Open in Read by QxMD
8. Domingues-Ferreira M, Grumach AS, Duarte AJDS, De Moraes-Vasconcelos D. Esophageal cancer associated with chronic mucocutaneous candidiasis. Could chronic candidiasis lead to esophageal cancer?. Medical Mycology. 2008; 47 (2): p.201-205. doi: 10.1080/13693780802342545 . | Open in Read by QxMD
9. Delsing CE, Bleeker-Rovers CP, van de Veerdonk FL, et al. Association of esophageal candidiasis and squamous cell carcinoma. Medical Mycology Case Reports. 2012; 1 (1): p.5-8. doi: 10.1016/j.mmcr.2012.02.003 . | Open in Read by QxMD
10. Hemminki K, Li X, Sundquist J, Sundquist K. Cancer risks in Crohn disease patients. Annals of Oncology. 2008; 20 (3): p.574-580. doi: 10.1093/annonc/mdn595 . | Open in Read by QxMD
11. Varghese TK, Hofstetter WL, Rizk NP et al. The society of thoracic surgeons guidelines on the diagnosis and staging of patients with esophageal cancer. The Annals of Thoracic Surgery. 2013; 96 (1): p.346-56. doi: 10.1016/j.athoracsur.2013.02.069 . | Open in Read by QxMD
12. Lin D, Khan U, Goetze TO, et al. Gastroesophageal Junction Adenocarcinoma: Is There an Optimal Management?. American Society of Clinical Oncology educational book. American Society of Clinical Oncology. Annual Meeting. 2019; 39 : p.e88-e95. doi: 10.1200/EDBK_236827 . | Open in Read by QxMD
13. Jain S, Dhingra S. Pathology of esophageal cancer and Barrett’s esophagus. Annals of Cardiothoracic Surgery. 2017; 6 (2): p.99-109. doi: 10.21037/acs.2017.03.06 . | Open in Read by QxMD
14. Pimentel-Nunes P, Dinis-Ribeiro M, Ponchon T et al. Endoscopic submucosal dissection: European Society of Gastrointestinal Endoscopy (ESGE) Guideline. Endoscopy. 2015; 47 (9): p.829-54. doi: 10.1055/s-0034-1392882 . | Open in Read by QxMD
15. Maple JT, Abu Dayyeh BK, Chauhan SS, et al. Endoscopic submucosal dissection: Technology Status Evaluation Report . Gastrointestinal Endoscopy. 2015; 81 (6): p.1311-1325. doi: 10.1016/j.gie.2014.12.010 . | Open in Read by QxMD
16. Berry MF. Esophageal cancer: staging system and guidelines for staging and treatment. Journal of Thoracic Disease. 2014; 6 (Suppl 3): p.S289-97.
17. Survival Rates for Esophageal Cancer. https://www.cancer.org/cancer/esophagus-cancer/detection-diagnosis-staging/survival-rates.html. Updated: March 20, 2020. Accessed: October 8, 2020.