Introduction
Background
Cancer of the esophagus remains a devastating disease because it is usually not detected until it has progressed to an advanced incurable stage. Modern imaging techniques, including barium esophagraphy, contrast-enhanced computed tomography (CT), magnetic resonance imaging (MRI), endoscopic ultrasonography (EUS), and positron-emission tomography (PET), are powerful tools in the detection, diagnosis, and staging of this malignancy. Early detection remains the elusive but essential goal of research. Only surgical resection at a very early stage has been shown to improve survival rates in patients with this disease.
Pathophysiology
The most common types of esophageal carcinoma are squamous cell carcinoma and adenocarcinoma.
Squamous cell carcinoma
The normal esophagus is lined by stratified squamous nonkeratinizing epithelium. Squamous cell carcinoma arises from this epithelial layer in apparent response to chronic toxic irritation. Alcohol, tobacco, and certain nitrogen compounds have been identified as carcinogenic irritants.
Alcohol and tobacco use are the principal modifiable risk factors for esophageal squamous cell carcinoma. According to the American Cancer Society, the combination of long-term alcohol ingestion and tobacco use is the most substantial risk factor. Nitrosamines and other nitrosyl compounds are found in pickled vegetables, smoked meats, and the water supply of certain geographic regions where the incidence of esophageal squamous cell carcinoma is high. In regions in which the soil is deficient in molybdenum and zinc, plants are impaired in their ability to metabolize nitrites to ammonia. This impairment permits potentially toxic nitrogen compounds to accumulate within plants that enter the human food supply.
Anecdotal associations have been made between esophageal squamous cell carcinoma and chronic consumption of hot liquids, betel nuts, asbestos, air pollution, and diets high in spice content. Conversely, consumption of a diet high in fruits and vegetables has a protective effect.
Certain medical conditions predispose patients to the development of esophageal squamous cell carcinoma. These include achalasia, lye strictures, head and neck tumors, celiac disease, Plummer-Vinson syndrome, tylosis, and prior exposure to radiation. Squamous cell carcinoma may arise in the setting of achalasia, typically after a period of 20 or more years, and it is believed to result from long-standing irritation by retained material. Of patients with strictures caused by lye ingestion, 3% develop squamous carcinomas after 20-40 years. The association of head and neck tumors with squamous cell carcinoma of the esophagus is explained best by the common risk factors of alcohol and tobacco use.
Plummer-Vinson syndrome consists of dysphagia, iron-deficiency anemia, and esophageal webs. Patients with this syndrome have an increased incidence of postcricoid squamous cell carcinoma. Squamous cell carcinoma of the esophagus occurs in almost all patients with tylosis, a rare autosomal dominant disorder characterized by esophageal papillomas and hyperkeratosis of the palms and soles.
Infection with human papillomavirus, particularly subtypes 16 and 18, has been implicated in the pathogenesis of esophageal squamous cell carcinoma.
Adenocarcinoma
Adenocarcinoma, which is most common in the mid and distal esophagus, arises from abnormal esophageal mucosa in a well-characterized sequence. In reaction to chronic gastroesophageal reflux, metaplasia of the normal stratified squamous epithelium of the distal esophagus occurs, resulting in a specialized intestinal glandular epithelium containing goblet cells called Barrett epithelium. Further genetic alterations in this epithelium lead to dysplasia, which may progress from low-grade to high-grade dysplasia and, ultimately, to adenocarcinoma.
Gastroesophageal reflux disease (GERD) is the most important factor in the development of Barrett epithelium. Of patients with GERD, 10% develop Barrett epithelium. Of patients with Barrett epithelium, 1% develop esophageal adenocarcinoma, a risk that is 30-40 times higher than in the population without Barrett epithelium. Therefore, patients with Barrett epithelium are advised to undergo periodic surveillance esophageal endoscopy with biopsy.
Although alcohol use has not been strongly linked to the development of esophageal adenocarcinoma, smoking has been identified as a risk factor. Scleroderma and other motor disorders of the esophagus that predispose patients to GERD increase risk accordingly. Obesity, certain medications and environmental exposures, and diet and nutritional habits have been implicated as additional risk factors.
Frequency
United States
Cancer of the esophagus accounts for 7% of gastrointestinal tract cancers in the United States. In 2000, approximately 12,300 new cases of esophageal carcinoma occurred in the United States, and 12,100 deaths resulted from the disease. In the past, squamous cell carcinoma accounted for more than 95% of cases of esophageal cancer. However, by the early 1990s, adenocarcinoma had become the most common cancerous cell type among white Americans, accounting for approximately one half of esophageal malignancies in the United States and Europe. Squamous cell cancers still predominate among African American patients.
International
Worldwide, certain geographic regions have a high incidence of esophageal squamous cell carcinoma. In particular, a band of high incidence extends from the region of the Caspian Sea eastward through Central Asia to northern China.
Mortality/Morbidity
Only early surgical resection improves survival rates in patients with this disease. Of patients with esophageal cancer, 50% present with metastatic disease and most patients with apparent local disease develop metastases despite potentially curative local therapy. An improved 5-year survival rate of approximately 30% is believed to be the result of standardized oncologic practice and attention to complete resection at surgery. The primary cause of death in patients who are treated surgically is local recurrence, compared to other gastrointestinal tract tumors in which metastatic disease is usually the cause.
Prognosis depends on depth of tumor penetration through the esophageal wall and the presence of lymph node metastases. The TNM system is used to classify the extent of disease.
Table 1. TNM Classification of Esophageal Carcinoma
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Table
| Grade | Description | |
|---|---|---|
| Tumor Tx | Tumor not assessed | |
| T0 | No evidence of primary tumor | |
| Tis | Carcinoma in situ | |
| T1 | Carcinoma invading the lamina propria or submucosa | |
| T2 | Carcinoma invading the muscularis propria | |
| T3 | Carcinoma invading the adventitia | |
| T4 | Carcinoma invading local structures | |
| Node Nx | Nodes not assessed | |
| N0 | No evidence of lymph node involvement | |
| N1 | Evidence of lymph node involvement | |
| Metastases Mx | Metastases not assessed | |
| M0 | No evidence of metastatic disease | |
| M1* | Evidence of metastatic disease |
| Grade | Description | |
|---|---|---|
| Tumor Tx | Tumor not assessed | |
| T0 | No evidence of primary tumor | |
| Tis | Carcinoma in situ | |
| T1 | Carcinoma invading the lamina propria or submucosa | |
| T2 | Carcinoma invading the muscularis propria | |
| T3 | Carcinoma invading the adventitia | |
| T4 | Carcinoma invading local structures | |
| Node Nx | Nodes not assessed | |
| N0 | No evidence of lymph node involvement | |
| N1 | Evidence of lymph node involvement | |
| Metastases Mx | Metastases not assessed | |
| M0 | No evidence of metastatic disease | |
| M1* | Evidence of metastatic disease |
*Metastatic disease from a primary lesion in the lower esophagus is classified as M1a if celiac nodes are involved. M1b designates metastatic disease beyond locoregional and celiac lymph nodes. For a primary lesion in the mid esophagus, the M1a status is not applicable; metastatic disease beyond locoregional lymph nodes is designated M1b. For a primary lesion in the upper esophagus, involvement of cervical lymph nodes is designated M1a; metastatic disease beyond locoregional and cervical lymph nodes is designated M1b.
Staging groups are formed on the basis of the TNM classifications and are used to guide therapy and predict the prognosis and survival.
Table 2. Staging of Esophageal Carcinoma
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Table
| Stage | TNM | 5-Year Survival Rate |
|---|---|---|
| 0 | Tis, NO, MO | 75% |
| I | T1, NO, MO | 50% |
| IIA | T2, NO, MO or T3, NO, MO | 40% |
| IIB | T1, N1, MO or T2, N1, MO | 20% |
| III | T3, N1, MO or T4, any N, MO | 15% |
| IVA | Any T, any N, M1a | <1% |
| IVB | Any T, any N, M1b | <1% |
| Stage | TNM | 5-Year Survival Rate |
|---|---|---|
| 0 | Tis, NO, MO | 75% |
| I | T1, NO, MO | 50% |
| IIA | T2, NO, MO or T3, NO, MO | 40% |
| IIB | T1, N1, MO or T2, N1, MO | 20% |
| III | T3, N1, MO or T4, any N, MO | 15% |
| IVA | Any T, any N, M1a | <1% |
| IVB | Any T, any N, M1b | <1% |
Race
African Americans are 3 times more likely than whites to develop cancer of the esophagus. Although squamous cell carcinoma is relatively more common in African Americans, adenocarcinoma is more common in white Americans.
Sex
Males are 3 times more likely to develop esophageal carcinoma than females.
Age
Incidence of both squamous cell carcinoma and adenocarcinoma increases with age.
Anatomy
The esophagus is a muscular tube extending from the pharynx to the stomach. Histologically, the esophageal wall contains 4 major layers:
- Mucosa or a mucous membrane composed of the lining epithelium; the lamina propria, a layer of loose connective tissue enriched with capillaries and lymphatics; and the muscularis mucosae, a thin double layer of smooth muscle
- Submucosa, a loose connective tissue layer also rich in capillaries and lymphatics
- Muscularis externa (propria), consisting of 2 layers of muscle, the inner layer deployed circumferentially, and the outer layer arranged longitudinally
- Loose adventitia (unlike other areas of the gastrointestinal tract, which have a true serosa)
Because the esophagus lacks a serosal covering, esophageal carcinoma encounters few anatomic barriers to local invasion.
The cervical esophagus is that portion extending from the inferior aspect of the cricoid cartilage to the thoracic inlet. Caudal to the thoracic inlet, the thoracic esophagus is divided into thirds: The upper third extends from the thoracic inlet to the carina, and the middle and lower thirds are defined as the cranial and caudal halves of the remaining esophagus from the carina to the gastroesophageal junction.
The esophagus is drained by a rich network of lymphatics; therefore, precisely determining the particular draining lymph node chain for a given segment is often difficult. Jump lymph-node metastases occur when a node close to the involved esophageal segment is not diseased, but a more distant node is diseased.
For the cervical esophagus, cervical and supraclavicular lymph nodes are considered local, and mediastinal and upper abdominal lymph nodes are considered distant. For the upper and mid thoracic esophagus, mediastinal lymph nodes are considered local, and involved cervical, supraclavicular, and abdominal lymph nodes are considered distant. For the lower esophagus, mediastinal and perigastric lymph nodes are considered local, whereas involved cervical, supraclavicular, and celiac lymph nodes are considered distant.
Presentation
At the time of diagnosis, weight loss and dysphagia are the most common symptoms. Dysphagia usually occurs late in the course of the disease when the esophageal lumen has been narrowed by 50-75%. Less commonly, presenting symptoms may be related to local invasion or metastases.
Examples of signs and symptoms include stridor, cough, and aspiration pneumonia as the result of erosion into the tracheobronchial tree; hemoptysis or hematemesis resulting from invasion of a mediastinal vessel; left vocal cord paralysis resulting from recurrent laryngeal nerve involvement by tumor or lymph node metastasis; malignant pleural effusion; and diaphragmatic paralysis. Jaundice and bone pain are systemic manifestations of organ metastases.
Preferred Examination
Barium esophagraphy is a useful initial examination in the evaluation of a patient with esophageal complaints because it allows the assessment of esophageal morphology and motility. Esophageal endoscopy permits direct inspection and biopsy of the esophageal mucosa for histologic diagnosis. For the purpose of staging esophageal carcinoma, EUS, contrast-enhanced CT, and PET each offer unique information.
Limitations of Techniques
Barium esophagraphy has optimal sensitivity for the detection of lesions when a double-contrast technique is used. Such technique requires that the patient be able to stand upright, which may not be possible with patients who are debilitated. For bulkier obstructive lesions, an air-contrast technique may not be possible, and a detailed mucosal examination may not be achieved distal to the obstruction.
A notable limitation of CT in diagnosis involves the characterization of lymph nodes. With CT scans, size criteria are used to determine possible metastatic involvement; however, lymph nodes may be enlarged because of infectious or inflammatory etiologies. Conversely, subcentimeter lymph nodes may harbor metastatic tumor.
Ultrasonographic examinations are highly operator dependent. Limitations of EUS with the standard Olympus diagnostic echo-endoscope (13 mm in diameter) include an inability to pass the malignant stricture with the transducer. This limitation results in an incomplete examination, which occurred in 40% of patients reported by Massari et al. However, the use of a dedicated 8-mm-diameter esophagoprobe for EUS allows complete examination in most patients.
With PET, the resolution and cost remain the primary limitations. Subcentimeter foci of tumor metabolism may not be detected.
Differential Diagnoses
Esophageal Varices
Esophagitis, Infectious
Esophagus, Foreign Body
Hiatal Hernia
Schatzki Ring
Other Problems to Be Considered
The differential diagnosis of esophageal carcinoma depends on the morphologic appearance of the lesion. Esophageal strictures, filling defects, fold thickening, and dilatation are abnormal patterns to be considered.
Abnormal narrowing of the esophagus may result from extrinsic compression resulting from vascular structures such as aortic aneurysm, aberrant vascular anatomy (aberrant subclavian artery or vascular ring), and left atrial enlargement. Lymph node enlargement, whether reactive or neoplastic, may cause impressions on the esophageal contour. Primary mediastinal tumors may secondarily invade and narrow the esophagus. Esophageal strictures may be inflammatory or infectious in etiology. Inflammatory causes include epidermolysis, pemphigoid, strictures arising in the setting of GERD, caustic ingestion, or esophageal intubation. Severe infectious esophagitis may lead to stricture formation.
Filling defects within the esophagus may be caused by benign and malignant neoplasms and foreign bodies. Benign neoplasms that may cause an esophageal filling defect include leiomyoma, fibrovascular polyp, duplication cyst, papilloma, fibroma, and hemangioma. Malignant neoplasms include squamous cell carcinoma, adenocarcinoma, carcinosarcoma, small cell carcinoma, lymphoma, and metastases. Esophageal foreign bodies should also be considered in the differential diagnosis.
Thickened esophageal folds may be caused by esophagitis, lymphoma, varicoid carcinoma, or esophageal varices.
A dilated debris-filled esophagus may result from achalasia, scleroderma, Chagas disease, diabetic or alcoholic neuropathy, or bulbar palsy. Alternatively, an obstructing mass lesion or stricture may cause this appearance.
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Further Reading
Keywords
esophageal carcinoma, squamous cell carcinoma of the esophagus, adenocarcinoma of the esophagus
