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Esophageal Cancer


Minhhuyen Nguyen

, MD, Fox Chase Cancer Center, Temple University

Last full review/revision Mar 2021| Content last modified Mar 2021

The most common malignant tumor in the proximal two thirds of the esophagus is squamous cell carcinoma; adenocarcinoma is the most common in the distal one third. Symptoms are progressive dysphagia and weight loss. Diagnosis is by endoscopy, followed by CT and endoscopic ultrasound for staging. Treatment varies with stage and generally includes surgery with or without chemotherapy and radiation. Long-term survival is poor except for patients with local disease.

Esophageal cancer accounts for an estimated 18,440 cases and 16,170 deaths in the US annually (1).

General reference

  • 1. Siegel RL, Miller KD, Jemal A: Cancer statistics, 2020. CA Cancer J Clin 70(1):7–30, 2020. doi: 10.3322/caac.21590

Squamous cell carcinoma of the esophagus

Squamous cell carcinoma is the most common esophageal cancer worldwide, but, in the US, adenocarcinoma is about twice as common (1). In the US, it is 4 to 5 times more common among blacks than whites, and 2 to 3 times more common among men than women.

The primary risk factors for esophageal cancer are

  • Alcohol ingestion
  • Tobacco use (in any form)

Other risk factors include achalasia, human papillomavirus infection, lye ingestion (resulting in stricture), sclerotherapy, esophageal webs due toPlummer-Vinson syndrome, and irradiation of the esophagus. Genetic causes are unclear, but 50% of patients with tylosis (hyperkeratosis palmaris et plantaris), an autosomal dominant disorder, have esophageal cancer by age 45, and 95% have it by age 55.

Squamous cell carcinoma of the esophagus reference

  • 1. 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 10(12):e3709, 2018. doi: 10.7759/cureus.3709

Adenocarcinoma of the esophagus

Adenocarcinoma occurs in the distal esophagus. Its incidence is increasing; it accounts for two thirds of esophageal carcinoma in the US. It is 4 times more common among whites than blacks. Alcohol is not an important risk factor, but smoking is contributory. Adenocarcinoma of the distal esophagus is difficult to distinguish from adenocarcinoma of the gastric cardia invading the distal esophagus.

Most adenocarcinomas arise in Barrett esophagus, which results from chronic gastroesophageal reflux disease and reflux esophagitis. In Barrett esophagus, a metaplastic, columnar, glandular, intestine-like mucosa with brush border and goblet cells replaces the normal stratified squamous epithelium of the distal esophagus during the healing phase of acute esophagitis when healing takes place in the continued presence of stomach acid. Obesity is associated with a 16-fold increased risk of esophageal adenocarcinoma, probably because obesity is a contributing factor to reflux.

Other malignant tumors of the esophagus

Less common malignant tumors include spindle cell carcinoma (a poorly differentiated variant of squamous cell carcinoma), verrucous carcinoma (a well-differentiated variant of squamous cell carcinoma), pseudosarcoma, mucoepidermoid carcinoma, adenosquamous carcinoma, cylindroma (adenoid cystic carcinoma), primary oat cell carcinoma, choriocarcinoma, carcinoid tumor, sarcoma, and primary malignant melanoma.

Metastatic cancer constitutes 3% of esophageal cancer. Melanoma and breast cancer are most likely to metastasize to the esophagus; others include cancers of the head and neck, lung, stomach, liver, kidney, prostate, testis, and bone. These tumors usually seed the loose connective tissue stroma around the esophagus, whereas primary esophageal cancers begin in the mucosa or submucosa.

Symptoms and Signs of Esophageal Cancer

Early-stage esophageal cancer tends to be asymptomatic. When the lumen of the esophagus becomes constricted to about < 14 mm, dysphagia commonly occurs. The patient first has difficulty swallowing solid food, then semisolid food, and finally liquid food and saliva; this steady progression suggests a growing malignant process rather than a spasm, benign ring, or peptic stricture. Chest pain may be present, usually radiating to the back.

Weight loss, even when the patient maintains a good appetite, is almost universal. Compression of the recurrent laryngeal nerve may lead to vocal cord paralysis and hoarseness. Nerve compression may cause spinal pain, hiccups, or paralysis of the diaphragm. Malignant pleural effusions or pulmonary metastasis may cause dyspnea. Intraluminal tumor involvement may cause odynophagia, vomiting, hematemesis, melena, iron deficiency anemia, aspiration, and cough. Fistulas between the esophagus and tracheobronchial tree may cause lung abscess and pneumonia. Other findings may include superior vena cava syndrome, malignant ascites, and bone pain.

Lymphatic spread to internal jugular, cervical, supraclavicular, mediastinal, and celiac nodes is common. The tumor usually metastasizes to lung and liver and occasionally to distant sites (eg, bone, heart, brain, adrenal glands, kidneys, peritoneum).

Diagnosis of Esophageal Cancer

  • Endoscopy with biopsy
  • Then CT and endoscopic ultrasonography

There are no screening tests. Patients suspected of having esophageal cancer should have endoscopy with cytology and biopsy. Although barium x-ray may show an obstructive lesion, endoscopy is required for biopsy and tissue diagnosis.

Patients in whom esophageal cancer is identified require CT of the chest and abdomen to determine extent of tumor spread. If CT results are negative for metastasis, endoscopic ultrasonography should be done to determine the depth of the tumor in the esophageal wall and regional lymph node involvement. Findings guide therapy and help determine prognosis.

Basic blood tests, including complete blood count, electrolytes, and liver function, should be done.

Prognosis for Esophageal Cancer

Prognosis depends greatly on stage, but overall is poor (5-year survival: < 5%) because many patients present with advanced disease. Patients with cancer restricted to the mucosa have about an 80% survival rate, which drops to < 50% with submucosal involvement, 20% with extension to the muscularis propria, 7% with extension to adjacent structures, and < 3% with distant metastases.

Treatment of Esophageal Cancer

  • Surgical resection, often combined with chemotherapy and radiation
  • Immunotherapy plus chemotherapy for certain advanced cancers

Esophageal cancer treatment decisions depend on tumor staging, size, location, and the patient’s wishes (many choose to forgo aggressive treatment).

General principles

Patients with stage 0, I, or IIa disease (see table Staging Esophageal Cancer) respond well to surgical resection; preoperative chemotherapy and radiation provide additional benefit. Patients with stages IIb and III have poor survival with surgery alone; response and survival are enhanced by preoperative (neoadjuvant) use of radiation and chemotherapy to reduce tumor volume before surgery. Patients unable or unwilling to undergo surgery may receive some benefit from combined radiation and chemotherapy. Radiation or chemotherapy alone is of little benefit. Patients with stage IV disease require palliation and should not undergo surgery.

Staging Esophageal Cancer*


Tumor (maximum penetration)

Regional Lymph Node Metastasis

Distant Metastasis










T2 or T3




T3 or T4




Any T

Any N


* cTNM classification (clinical staging):

  • Tis = carcinoma in situ; T1 = lamina propria or submucosa; T2 = muscularis propria; T3 = adventitia; T4 = adjacent structures.
  • N0 = none; N1 = present.
  • M0 = none; M1 = present.

After treatment, patients are screened for recurrence by endoscopy and CT of the neck, chest, and abdomen at 6-month intervals for 3 years and annually thereafter.

Patients with Barrett esophagus require intense long-term treatment for gastroesophageal reflux disease and endoscopic surveillance for malignant transformation at 3- to 12-month intervals depending on the degree of metaplasia.


Superficial, early, noninvasive cancers may be treated with endoscopic mucosal resection or endoscopic submucosal dissection (usually by gastroenterologists at tertiary care centers) if the superficial nature of the lesion has been confirmed by endoscopic ultrasound. However, in the large majority of cases, en bloc resection for cure requires removal of the entire tumor, proximal and distal margins of normal tissue, all potentially malignant lymph nodes, and a portion of the proximal stomach sufficient to contain the distal draining lymphatics. The procedure requires gastric pull-up with esophagogastric anastomosis, small-bowel interposition, or colonic interposition. Pyloroplasty (surgical widening of the pylorus) is required to ensure proper gastric drainage because esophagectomy necessarily results in bilateral vagotomy. This extensive surgery may be poorly tolerated by patients > 75 years, particularly those with underlying cardiac or pulmonary disease (ejection fraction < 40%, or forced expiratory volume in 1 second [FEV1] < 1.5 L/minute). Overall, operative mortality is about 5%.

Preoperative chemotherapy combined with radiation therapy can improve survival after surgical resection of thoracic esophageal cancer. Chemotherapy without radiation therapy followed by surgery may also be considered (1).

Complications of surgery include anastomotic leaks, fistulas, and strictures; bilious gastroesophageal reflux; and dumping syndrome. The burning chest pain of bile reflux after distal esophagectomy can be more annoying than the original symptom of dysphagia and may require subsequent Roux-en-Y jejunostomy for bile diversion. An interposed segment of small bowel or colon in the chest has a tenuous blood supply, and torsion, ischemia, or gangrene of the interposed bowel may result.

External beam radiation therapy

Radiation is usually used in combination with chemotherapy for patients who are poor candidates for curative surgery, including those with advanced disease. Radiation is contraindicated in patients with tracheoesophageal fistula because tumor shrinkage enlarges the fistula. Similarly, patients with vascular encasement by tumor may experience massive hemorrhage with tumor shrinkage.

During the early stages of radiation therapy, edema may worsen esophageal obstruction, dysphagia, and odynophagia. This problem may require preradiation dilation and/or placement of a stent. Some patients may require a temporary percutaneous gastrostomy feeding tube. Other adverse effects of radiation therapy include nausea, vomiting, anorexia, fatigue, esophagitis, excess esophageal mucus production, xerostomia, stricture, radiation pneumonitis, radiation pericarditis, myocarditis, and myelitis (spinal cord inflammation).


Tumors are poorly responsive to chemotherapy alone. Response rates (defined as ≥ 50% reduction in all measurable areas of tumor) vary from 10 to 40%, but responses generally are incomplete (minor shrinkage of tumor) and temporary. No drug is notably more effective than another.

Most commonly, cisplatin and 5-fluorouracil are used in combination. However, several other drugs, including mitomycin, doxorubicin, vindesine, bleomycin, and methotrexate, also are active against squamous cell carcinoma.


Immunotherapy plus chemotherapy is now recommended as first-line therapy for advanced esophageal squamous cell cancer regardless of programmed cell death ligand 1 (PD-L1) status. This treatment modality is offered as first-line therapy for advanced esophageal adenocarcinoma with overexpression of PD-L1 (1).


Palliation is directed at reducing esophageal obstruction sufficiently to allow oral intake. Suffering caused by esophageal obstruction can be significant, with salivation and recurrent aspiration. Options include manual dilation procedures (bougienage), orally inserted stents, radiation therapy, laser photocoagulation, and photodynamic therapy. In some cases, cervical esophagostomy with feeding jejunostomy is required.

Relief provided by esophageal dilation rarely lasts more than a few days. Flexible metal mesh stents are more effective at maintaining esophageal patency. Some plastic-coated models can also be used to occlude malignant tracheoesophageal fistulas, and some are available with a valve that prevents reflux when the stent must be placed near the lower esophageal sphincter.

Endoscopic laser therapy can palliate dysphagia by burning a central channel through the tumor and can be repeated if needed. Photodynamic therapy uses an injection of porfimer sodium, a hematoporphyrin derivative that is taken up by tissues and acts as a photosensitizer. When activated by a laser beam directed on the tumor, this substance releases cytotoxic oxygen singlets that destroy tumor cells. Patients receiving this treatment must avoid sun exposure for 6 weeks after treatment because the skin is also sensitized to light.

Treatment reference

  • 1. Wang H, Xuan T, Chen Y, et al: Investigative therapy for advanced esophageal cancer using the option for combined immunotherapy and chemotherapy. Immunotherapy 12(10):697–703, 2020. doi: 10.2217/imt-2020-0063

Key Points

  • Alcohol, tobacco, and human papillomavirus infection are risk factors for squamous cell carcinoma; Barrett esophagus due to chronic reflux (often related to obesity) is a risk factor for adenocarcinoma.
  • Early-stage cancer is typically asymptomatic; initial symptoms are usually progressive dysphagia, which results from significant encroachment on the lumen, and sometimes chest discomfort.
  • Overall, survival is poor (5-year survival: < 5%) because many patients present with advanced disease.
  • Surgery for cure is extensive and often poorly tolerated by older patients and patients with comorbidities.
  • Palliation may involve stenting or endoscopic laser therapy to reduce obstruction and allow oral intake.

Drugs Mentioned In This Article

Drug Name Select Trade
methotrexate OTREXUP
fluorouracil CARAC
mitomycin MITOSOL
bleomycin No US brand name
cisplatin PLATINOL

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