DEFINITION

Esophageal cancer has long been considered one of the deadliest malignancies, and considerable controversy has surrounded its management. The most common histologic types are squamous cell carcinoma (SCC) and adenocarcinoma (AC), which together constitute more than 90% of esophageal malignancies. Rarely, melanoma, sarcoma, small cell carcinoma, or lymphoma may arise in the esophagus. Although SCC is more evenly distributed throughout the length of the esophagus, AC is predominantly a disease of the distal esophagus and gastroesophageal junction, and is rarely found in the cervical esophagus.

PREVALENCE AND RISK FACTORS

Cancers arising from the esophagus and gastroesophageal junction are relatively uncommon in the United States; there were approximately 14,520 new cases and 13,570 deaths in 2005. Worldwide, however, esophageal cancer is the eighth most common malignancy and the sixth most common cause of cancer-related death. The epidemiology of esophageal cancer changed dramatically during the latter half of the 20th century. Although 40 years ago SCC accounted for more than 90% of all esophageal tumors in the United States, diagnoses of esophageal AC have significantly increased and now represent 80% of cases. However, SCC remains the most common worldwide. The mean age at diagnosis is 67 years, and men are affected more frequently than women, particularly among patients with AC.

There are considerable geographic and racial variations in the incidence of this cancer, which is mostly explained by varying exposure to risk factors, although genetic susceptibility may play a partial role. Many of the causative and risk factors for AC and SCC have been well established (Box 1).

PATHOPHYSIOLOGY AND NATURAL HISTORY

Smoking and heavy alcohol intake are important risk factors for the development of SCC. Smoking has a synergistic effect with heavy alcohol consumption, and heavy exposure to both increases the risk of SCC by a factor of more than 100. This is further complicated by the increased risk of other aerodigestive tract cancers in a person who smokes and drinks alcohol.

Dietary and environmental factors, and certain esophageal disorders (e.g., achalasia, diverticuli) that cause chronic irritation and inflammation of the esophageal mucosa may also increase the incidence of SCC. Plummer-Vinson syndrome—the triad of dysphagia, iron deficiency anemia, and esophageal webs—has been associated with this cancer, although it is becoming increasingly rare in the developed world as overall nutrition improves. There are few genetic factors that have been identified as being important in the development of esophageal SCC. One exception is tylosis, a rare autosomal dominant syndrome associated with hyperkeratosis of the palms and soles and a high rate of esophageal SCC. Infectious agents have also been implicated in the pathogenesis of esophageal SCC. Human papillomavirus has received the most attention. It is believed that the infection results in loss of function of the tumor suppressor genes p53 and Rb. The importance of this mechanism is not well established.

The risk factors for AC of the esophagus are different. Chronic gastroesophageal reflux is the most important, with severe, long-standing reflux symptoms increasing the risk of cancer by a factor of 40. Chronic gastroesophageal reflux disease is associated with Barrett’s metaplasia (Barrett’s esophagus), a condition in which an abnormal columnar epithelium replaces the stratified squamous epithelium that normally lines the distal esophagus. Most esophageal ACs are believed to arise from Barrett’s esophagus. Although this mucosal change appears to be a favorable adaptation to chronic reflux—columnar epithelium appears to be more resistant to reflux-induced injury than the native squamous cells—this specialized intestinal metaplasia may become dysplastic and ultimately malignant, with genetic alterations that activate proto-oncogenes, disable tumor suppressor genes, or both. Factors that increase the risk for gastroesophageal reflux, such as obesity or medications that lower the lower esophageal sphincter tone, may result in an increased risk for esophageal AC.

An infectious etiology for this disease has not been identified and, unlike AC of the gastric cardia, the role of Helicobacter pylori colonization is unknown. The genetic and molecular changes underlying the development of esophageal AC also remain poorly understood, although allelic losses at chromosomes 4q, 5q, 9p, 9q, and 18q and abnormalities of p53, Rb, cyclin D1, and c-myc have been implicated.

The esophagus itself has several unique properties that distinguish the behavior of cancer in this organ from those of other gastrointestinal malignancies. In contrast to the rest of the gastrointestinal tract, the esophagus has no serosa, thus reducing the resistance against local spread of invasive cancer cells. Furthermore, the esophagus has an extensive network of lymphatics, allowing for early regional tumor advancement (Fig. 1). The end result is local spread and invasion into surrounding tissue, with early metastatic disease developing in most patients.

Figure 1 Anatomic and histologic properties of the esophagus.

The esophagus has no serosa and has an extensive network of lymphatics, thus reducing the resistance against local spread of invasive cancer cells and allowing early regional tumor advancement.

SIGNS AND SYMPTOMS

The clinical presentation of patients with esophageal cancer can be attributed to the direct effects of the local tumor, regional or distant complications of the disease, or paraneoplastic syndromes (Box 2). AC and SCC have similar clinical manifestations, which reflect the extent of local esophageal involvement. Dysphagia, the most common manifesting symptom, usually develops in response to dense solid food, and progresses gradually to interfere with the intake of softer foods and, finally, liquids. This can sometimes be accompanied by vomiting or regurgitation of saliva or food uncontaminated by gastric secretions, particularly in patients with advanced local disease. Pain is frequent and can occur in the absence of dysphagia. It can be related to swallowing itself (odynophagia) or to the local extension of the tumor into adjacent structures, such as the pleura, mediastinum, or vertebral bodies. Weight loss is common and correlates with dysphagia, dietary changes, and tumor-related anorexia. Weight loss is noted in more than 70% of patients and, if present, carries a worse prognosis. Other manifesting signs and symptoms reflect complications from disease spread, such as cough or fever from a respiratory tract fistula, upper or lower gastrointestinal bleeding, hoarseness from recurrent laryngeal nerve involvement, and hiccups from phrenic nerve involvement.

Symptoms related to distant metastasis in the lungs, bone, liver, and central nervous system, particularly in the case of AC, can also be found at the initial clinical presentation. Hypercalcemia is the most common paraneoplastic syndrome. In the absence of bone metastases, it is most common in patients with SCC and is believed to be caused by the production of a parathyroid hormone–related protein. The physical examination is often unremarkable, but should be directed toward finding evidence of metastatic disease, including supraclavicular lymphadenopathy, hepatosplenomegaly, and pleural effusion.

DIAGNOSIS

Dysphagia is an alarming symptom, and mandates the need for an immediate evaluation to define its exact cause and initiate appropriate therapy. Dysphagia in older adults should not be attributed to normal aging. Aging alone causes mild esophageal motility abnormalities, but these are rarely symptomatic. Evaluation of dysphagia starts with a barium swallow examination or an upper endoscopy. Endoscopy will allow the direct visualization of any tumor mass and histologic confirmation with a biopsy or brush cytology. Combining these techniques yields an overall diagnostic accuracy of 98%.

After establishing a diagnosis of esophageal cancer, adequate staging is required, because staging is the most important step in choosing appropriate therapy. More than 50% of patients have unresectable or metastatic disease at the time of presentation. For the others, survival is closely related to the stage of the disease.

The staging evaluation allows patients to be assigned a clinical stage according to the American Joint Committee on Cancer tumor-node-metastasis (TNM) classification (Box 3; Fig. 2). Informed recommendations about therapy and appropriate information regarding prognosis depends on this clinical staging, an assessment that can, however, only approximate the true disease stage

Box 3 American Joint Commission on Cancer (AJCC) Staging for Esophageal Cancer

TNM Definitions

Primary Tumor (T)

TX: Primary tumor cannot be assessed

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