Esophageal Cancer

The authors break down the genetic, medical, and lifestyle-related risk factors for adenocarcinoma and squamous cell carcinoma of the esophagus and discuss screening, diagnosis, staging, and treatment for these malignancies.

By Jonathan Woods, MD, and Girish Mishra, MD

What are the different types of esophageal cancer and how are they different?

The two types of esophageal cancer are adenocarcinoma and squamous cell carcinoma. In the United States, there are about 6,000 new cases of each type of esophageal cancer annually. Squamous cell is three times more likely to occur in males than females and six times more likely in African-Americans than whites. Adenocarcinoma is seven times more likely in males and four times more likely in whites. Adenocarcinoma is most commonly linked to Barrett's esophagus, whereas squamous cell is most commonly associated with alcohol and tobacco use.
 

What causes squamous cell esophageal cancer?

Alcohol and tobacco are risk factors for the development of squamous cell carcinoma of the esophagus. The likelihood of developing cancer is related to the amount of tobacco and alcohol used. The type of alcohol is also important; hard liquor is more closely associated with the development of cancer than wine or beer. Several dietary factors have been implicated. N-nitroso compounds, found in processed and preserved foods such as hot dogs and other meats, are known carcinogens that act as DNA-alkylating agents, which produce mutagenesis. Toxin-producing fungi convert nitrates to nitroso compounds and have been identified in food sources in high-risk endemic areas. Chewing of betel nuts, common in Asia, has also been linked with squamous cell carcinoma.
 

What other diseases have been associated with squamous cell carcinoma?

Achalasia has been associated with a 16-fold increase in the risk of squamous cell carcinoma. Achalasia is an esophageal motility disorder that causes dysphagia due to incomplete relaxation of the lower esophageal sphincter. Plummer-Vinson syndrome, characterized by esophageal webs, angular stomatitis, koilonychia, and anemia, has also been linked to squamous cell. About 95% of patients with tylosis, an autosomal-dominant disorder marked by hyperkeratosis of the palms and soles, develop squamous cell carcinoma by the age of 65. Squamous cell esophageal cancer has also been linked with the human papilloma virus, concomitant head and neck cancers, and partial gastrectomy.
 

What are the causes of adenocarcinoma?

Unlike squamous cell carcinoma, adenocarcinoma has not been associated with alcohol use. However, smokers are 2.4 times more likely than nonsmokers to develop adenocarcinoma. Most cases arise from Barrett's metaplasia. Obesity has also been linked to esophageal adenocarcinoma. Having a body mass index greater than 30 kg/m² is associated with a 16-fold increase in adenocarcinoma.
 

What are the genetic factors linked to the development of esophageal cancer?

Several genetic alterations have been linked to the development of squamous cell carcinoma. Alterations in oncogenes, tumor suppressor genes, and DNA mismatch repair genes have all been implicated as causative factors. In 50% of cases, the cyclin-D1 cell cycle regulatory protein is overexpressed. This has been associated with a poor prognosis. Also, p53 mutation is present in more than 70% of cases of adenocarcinoma.
 

What is the link between gastroesophageal reflux disease (GERD) and adenocarcinoma?

A case control study published in the New England Journal of Medicine in 1999 examined the link between GERD and adenocarcinoma. Using logistic regression, they found that having recurrent symptoms of reflux was associated with an odds ratio of 7.7 for development of adenocarcinoma of the esophagus. Having long-standing symptoms or symptoms classified as severe yielded an odds ratio of 43.5 for development of adenocarcinoma.
 

What is Barrett's esophagus?

Barrett's esophagus is marked by the replacement of the normal squamous epithelium of the esophagus by columnar epithelium. This change is caused by damage from long-standing reflux disease. Barrett's esophagus is found in 5% to 15% of patients presenting for elective esophagoduodenoscopy. The annual incidence of adenocarcinoma in patients with Barrett's esophagus is 0.5% to 0.8%. This is a 60- to 80-fold increase over the general population.
 

Should patients with Barrett's esophagus be screened for esophageal cancer?

Given the strong association of Barrett's esophagus with adenocarcinoma, the following guidelines for cancer screening in these patients have been established. For patients with no dysplasia on two separate endoscopies, screening endoscopy should be performed every two or three years. Low-grade dysplasia is defined as some atypical changes but not involving most of the cells and with a normal growth pattern to the cells. These patients require endoscopy every six months to one year. High-grade dysplasia involves atypical changes in many cells with atypical growth patterns. These patients may have carcinoma in situ confined to the basement membrane and not involving the lamina propria. They should be considered for surgical intervention or, if unfit for surgery, referred to centers that perform photodynamic therapy, which uses a photosensitizing agent with low-power endoscopic laser exposure to destroy the tumor. Atypical cells that extend beyond the lamina propria would be classified as invasive adenocarcinoma and require surgical intervention.
 

What is the typical presentation in patients with esophageal cancer?

Both adenocarcinoma and squamous cell carcinoma have a similar presentation. One of the most common symptoms is progressive solid food dysphagia with weight loss caused by obstruction of the esophagus by the tumor. Approximately 90% of patients with esophageal carcinoma will experience dysphagia, indicating that more than 50% of the lumen is compromised. Regurgitation of saliva or solid food unchanged by gastric secretions is common in advanced disease. Chronic gastrointestinal bleeding producing iron deficiency anemia is also common, but patients rarely experience melena or acute upper gastrointestinal bleeding. Intractable coughing or frequent pneumonias can be a presenting sign if the patient has developed a tracheoesophageal fistula. These patients usually have less than four weeks to live. Hoarseness can also be a presenting sign if there is involvement of the recurrent laryngeal nerve.
 

What physical examination and laboratory findings are typical of esophageal cancer?

The physical exam does not provide many clues that are helpful in diagnosing esophageal cancer. Regional palpable nodes are rarely found. Virchow's node, or left supraclavicular adenopathy, may be present. With liver metastasis, hepatomegaly will be present. Laboratory abnormalities in esophageal cancer include anemia, hypercalcemia, and hypoalbuminemia. However, none of these findings is specific for esophageal cancer.
 

What is the pathology of squamous cell carcinoma?

Squamous cell carcinoma is more common in the mid-portion of the esophagus. It usually arises from small polypoid plaques. Squamous cell invades the submucosa early in its course. Local lymph node invasion is also a common early finding because the lymphatics in the esophagus are located in the lamina propria. In the rest of the gastrointestinal tract, they are located beneath the muscularis mucosa. Distant metastases to bone, liver, and lung are found in nearly 30% of patients.
 

What is the pathology of adenocarcinoma?

Adenocarcinoma is more common at the gastroesophageal junction. When it is associated with Barrett's esophagus, it may arise as an ulcer, a nodule, or with no endoscopic abnormality. As is the case with squamous cell, regional lymph node invasion is an early finding. Invasion of the celiac and perihepatic nodes is more common with adenocarcinoma because of its proximity to the gastroesophageal junction.
 

How is the diagnosis of esophageal cancer made?

Barium studies may suggest the presence of esophageal cancer. They are helpful for showing the degree of stenosis, the presence of stricture, and fistula formation. Usually, however, the diagnosis is made by endoscopy. The presence on endoscopy of a large mucosal mass is usually diagnostic of esophageal cancer. Biopsies are then used to confirm the diagnosis. Taking more biopsies increases the likelihood of making the diagnosis. In one study, the percentage of correct diagnoses with one biopsy was 93%. With four biopsies, the percentage increased to 95%, and with seven biopsies, to 98%.
 

How is esophageal cancer staged?

The stage of esophageal cancer is strongly associated with its outcome. Staging usually begins with a computed tomography (CT) scan to evaluate for distant metastases. If there is no evidence of metastatic disease, an endoscopic ultrasound is used to evaluate the extent of invasion of the esophageal mass. Endoscopic ultrasonography involves using an ultrasound transducer to provide images of the mass and its involvement with the layers of the esophageal wall. Computed tomography may underestimate the tumor stage in approximately 40% of patients; it has an accuracy rate of 55% to 63% in detecting regional disease. Endoscopic ultrasonography is the modality of choice for evaluating the depth of tumor penetration, but it also incorrectly predicts tumor depth in 15% to 20% of patients and nodal status in 25% to 30% of patients. Positron emission tomography appears to be more sensitive than CT for distant metastases. However, it is not as useful in evaluating the primary site or regional lymph nodes.
 

What is the staging system for esophageal cancer?

Esophageal cancer is staged based on the TNM system. T represents the depth of local tumor invasion. This starts with T1 lesions, which are localized to the mucosa or the lamina propria. T2 involves the muscularis propria but does not break through it. T3 invades the adventitia. T4 lesions demonstrate tumor invasion into the mediastinal structures such as the aorta or bronchi. The N represents involvement of regional lymph nodes. N0 disease has no regional lymph node involvement, whereas N1 disease does have lymph node involvement. Similarly, the M represents distant metastasis, with M0 for no distant metastasis and M1 for distant organ involvement.
 

What is the treatment for localized esophageal cancer?

Treatment of esophageal cancer is stage-dependent. Surgery alone had originally been the mainstay of treatment for early-stage lesions. This has an operative mortality risk of 3% to 10%. However, in one study, only 5% to 20% of patients treated with surgery alone were alive after five years. This has led to the use of adjuvant therapies. Appropriate treatment for nonmetastatic esophageal cancer is a subject of intense debate. Conflicting data exist from randomized trials. An Intergroup study published in 1998 randomly assigned patients with potentially resectable tumors to either immediate surgery or neoadjuvant therapy. Median and two-year survival rates were similar in the two groups. However, a Medical Research Council study of 802 patients with resectable esophageal cancer showed a modest benefit with neoadjuvant chemotherapy. Median survival was 405 days in the immediate surgery group, compared to 512 days in those who received cisplatin and 5-FU prior to surgery. Multiagent chemotherapy combined with radiation therapy provides both local tumor effect and prevention of micrometastatic disease. Endoscopic mucosal resection can also be used for localized disease in patients too ill to undergo surgery. This involves snare removal of the tumor and can be curative in certain patients.
 

What treatment options are available for advanced disease?

Surgery is curative for stage 0 (carcinoma in situ) and stage I (T1, N0, and M0) cancers. Patients with dysphagia are best managed with surgery or chemotherapy and radiation with or without subsequent surgery (usually stage II and III with T1-T3, N0-N1, and M0) or palliation (stage III with T4 and stage IV with metastatic cancer). The main goal for chemotherapy in patients with metastatic disease is to palliate symptoms and improve survival. Multiple regimens have been used, but no one agent or combination has been established as the gold standard of therapy. Platinum-based agents along with 5-FU are most commonly used for patients with good performance status. Patients with poorer status are usually treated with a single agent such as cisplatin.
 

What other palliative measures are available?

Malignant dysphagia is a common problem in patients with advanced disease. This can be treated with chemotherapy and radiation; however, they can take several weeks to produce a change in symptoms. Photodynamic therapy causes local tumor destruction by damaging the microvasculature and reducing the blood supply. Endoscopic laser therapy can also be used to destroy the tumor locally and attempt to restore luminal patency. Functional success occurs in about 70% to 80% of patients. Stents can also be placed in the esophagus at the site of the tumor in an attempt to alleviate dysphagia. Esophageal stents produce palliation of symptoms in up to 95% of patients with few complications. They have also been the treatment of choice for managing tracheoesophageal fistulas.

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