Esophageal cancer

Esophageal cancer (EC) is the eighth most common type of cancer worldwide and affects men more than women (3:1 ratio). The two main forms are esophageal adenocarcinoma and squamous cell carcinoma. Esophageal adenocarcinomas are among the neoplasms with the fastest increasing incidence in northern and western Europe and North America, while squamous cell carcinoma is the most common form worldwide. Adenocarcinoma, which usually affects the lower third of the esophagus, may be preceded by gastroesophageal reflux disease and Barrett esophagus. Other risk factors include smoking and obesity. Risk factors for squamous cell carcinoma include carcinogen exposure (e.g., in the form of alcohol and tobacco) and a diet high in nitrosamines but low in fruits and vegetables. Locally advanced disease is common at the time of diagnosis because EC is typically asymptomatic early in the disease course. Symptomatic patients may experience weight loss, dyspepsia, progressive dysphagia, cervical adenopathy, hoarseness or persistent cough, and signs of upper gastrointestinal bleeding, such as hematemesis, melena, or anemia. Esophagogastroduodenoscopy (EGD) is used to directly visualize the lesion and obtain a biopsy sample for histopathological confirmation. Staging of the tumor involves CT scan of the chest and abdomen, a PET scan, and often transesophageal endoscopic ultrasound (EUS). Curative surgical resection may be considered for locally invasive cancers, but EC is unresectable in approximately 60% of patients at the time of diagnosis. For patients with unresectable disease, treatment options include chemotherapy, radiation, and palliative stenting. Prognosis is generally poor because of the aggressive nature of EC and oftentimes late diagnosis.

• Sex: ♂ > ♀ (3:1) ^[1]
• Incidence: an estimated 20,640 new cases of esophageal cancer will be diagnosed in 2022 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 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).

Siewert classification of adenocarcinoma of the esophagogastric junction ^[10]

• Based on the location of the tumor in relation to the Z line
• Siewert type I and II tumors are managed as esophageal cancer. ^[11]

Early stages ^[4]

• Often asymptomatic
• May manifest with dysphagia or retrosternal discomfort

Advanced stages ^[4]

• General signs
  • Unintentional weight loss
  • Dyspepsia
  • Signs of anemia
• Signs of advanced disease
  • Progressive structural 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 (EGD) with biopsy is the best initial and confirmatory test in patients with suspected esophageal cancer. ^[12][13]

EGD ^[14]

• Indications
  • Red flags for dysphagia
  • Patients with both clinical features and risk factors for EC
• Uses
  • Direct visualization of the tumor
  • Biopsy of any suspicious lesions

Barium swallow ^[12]

• Indications
  • Severe esophageal strictures
  • Suspected tracheoesophageal fistula
  • Tumors near the Z line: to differentiate between gastroesophageal junction and gastric tumors
• Findings
  • Characteristic stenosis and proximal dilatation (apple core lesion)
  • Asymmetrical and irregular esophagal borders

Staging investigations ^[12]

Consider the following studies in consultation with a multidisciplinary team.

• Routine studies ^[15]
  • CT chest and abdomen with IV contrast
  • FDG-PET/CT skull base to mid-thigh
  • Transesophageal EUS with fine-needle aspiration biopsy
• Additional studies
  • Bronchoscopy: for lesions at or above the tracheal carina to rule out airway involvement
  • Laparoscopy: to increase staging accuracy in adenocarcinoma of the gastroesophageal junction

Laboratory studies ^[4]

• CBC: iron deficiency anemia may indicate occult GI bleeding
• Liver chemistries
  • ↑ Transaminases may indicate liver metastases
  • ↑ ALP may indicate bone metastases
• Serum creatinine: to determine pretreatment renal function ^[13]

Once the diagnosis is confirmed, EC should be staged to determine management. The American Joint Committee for Cancer (AJCC) TNM classification is currently the standard staging system used in clinical practice.

AJCC staging (8th Edition, 2017) ^[16]

• Use a staging calculator based on the type of EC:
  • Adenocarcinoma
  • Squamous cell carcinoma

Adenocarcinoma ^[17]

• 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 ^[17]

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

General principles

• Multidisciplinary cancer care should be utilized if available.
• The treatment approach should be guided by shared decision-making and the patient's performance status.
• Treatment goals ^[4]
  • Curative for patients with:
    • High-grade metaplasia in Barrett esophagus
    • Localized lesions that have not infiltrated surrounding structures
  • Palliative for patients with unresectable locally advanced or metastatic cancer
• See “Principles of cancer care.”

Surgical resection ^[18]

• Endoscopic submucosal resection for mucosal lesions ^[19]
• Subtotal or total esophagectomy
  • Indications: localized or resectable locally advanced disease
  • Options include: gastric pull-through procedure, colonic interposition

Chemoradiotherapy ^[18][20]

• Neoadjuvant chemoradiotherapy
  • Indications: locally advanced disease
  • Common regimen: fluorouracil, leucovorin, oxaliplatin, and docetaxel (FLOT) ^[18]
• Chemoradiotherapy with or without targeted therapies
  • Indication: unresectable or metastatic disease
  • Common regimens
    • Cisplatin and fluorouracil ^[20]
    • Oxaliplatin and capecitabine ^[20]
    • Adenocarcinomas overexpressing ERBB2: trastuzumab ^[20]
    • Tumors overexpressing PD-L1: pembrolizumab or nivolumab ^[21][22]
    • Recurrence after chemoradiotherapy and surgical resection: nivolumab ^[23]

Other interventional therapy ^[13]

• Endoscopic placement of self-expanding metal stents for palliation of dysphagia and fistulae
• Gastrojejunostomy (GJ) tube for specialized nutrition support ^[24]

Cancer-associated complications

• Esophageal stenosis
• Tracheoesophageal fistula → passage of food and fluid into the respiratory tract → ↑ risk of aspiration pneumonia
• Metastasis, e.g.: ^[13]
  • Squamous cell carcinoma → lungs and thorax
  • Adenocarcinoma → liver, peritoneum, bones ^[13]

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. ^[12][25]
• The Surveillance, Epidemiology, and End Results (SEER) database tracks survival rates for patients with EC in the United States.