A Brief Introduction to Esophageal Cancer

Abstract: Epidemiological features, etiology, common symptoms and treatment options of esophageal cancer.

Keywords: esophageal cancer, esophagus, esophageal tumor, esophageal squamous cell carcinoma, esophageal adenocarcinoma.

Esophageal cancer is one of the most common malignant tumors in humans. There are about 400,000 new cases worldwide each year, and it ranks sixth among cancer deaths. Esophageal cancer is a malignant tumor originating in the esophagus; in its early stage it often has no obvious symptoms. Only in the intermediate and advanced stages do patients begin to feel a choking sensation on swallowing and a retrosternal foreign-body sensation. The later the disease, the more difficult swallowing becomes; in advanced esophageal cancer, even drinking water is difficult.

In TCM this disease falls under the category of ye ge (dysphagia), but TCM ye ge is not entirely identical to esophageal cancer. Ye ge also includes benign conditions such as Barrett's esophagus, gastroesophageal reflux, achalasia and esophageal ulcer, although most of these benign esophageal diseases are also precancerous lesions of esophageal cancer.

Anatomical features of the esophagus

The esophagus is a flattened muscular tube, the narrowest part of the digestive tract, about 25 cm long. Its upper end connects with the pharynx at the lower border of the 6th cervical vertebra; its lower end reaches approximately the level of the 11th thoracic vertebra and connects with the cardia of the stomach.

The esophagus is divided into cervical, thoracic and abdominal parts.

The cervical part is about 5 cm long, from the beginning of the esophagus to the plane of the jugular notch, attached anteriorly to the posterior wall of the trachea by loose connective tissue. Therefore, as an upper esophageal tumor progresses, it may invade or compress the adjacent trachea, narrowing the airway and causing dyspnea, wheezing or even a sense of suffocation.

The thoracic part is the longest, about 18-20 cm, between the jugular notch and the esophageal hiatus of the diaphragm. When an esophageal tumor involves the thoracic esophagus, the patient feels a retrosternal foreign-body sensation; pain is felt here on swallowing or once the disease reaches an advanced stage.

The abdominal part is the shortest, only 1-2 cm, from the esophageal hiatus to the cardia. The abdominal esophagus connects with the stomach through the cardia; a tumor here causes cardiac obstruction, and the patient cannot swallow and vomits after meals, or eats in the morning and vomits in the evening.

The most important feature of the esophagus is its three physiological narrowings. The first narrowing is at the beginning of the esophagus, at the lower border of the 6th cervical vertebra, about 15 cm from the upper incisors. The second is where the esophagus crosses behind the left main bronchus, about 25 cm from the upper incisors. The third is where the esophagus passes through the esophageal hiatus of the diaphragm, at about the level of the 10th thoracic vertebra, about 40 cm from the upper incisors. These narrowings are predilection sites for foreign-body impaction and esophageal cancer.

Esophageal cancer most often arises in the middle thoracic segment (about 57%), followed by the lower segment (about 29%), and least often in the upper segment (about 23%). In China, esophageal cancer is predominantly squamous cell carcinoma, unlike the West where adenocarcinoma predominates. Its incidence is markedly geographic; rates in high-incidence areas can be 60 times those in low-incidence areas.

The luminal surface of the esophagus has longitudinal folds formed by mucosa and submucosa; when food passes, the lumen expands and the folds disappear. The esophageal mucosal epithelium is non-keratinized stratified squamous epithelium, which abruptly meets the simple columnar epithelium of the gastric cardia; this junction is a predilection site for esophageal cancer.

The submucosa is relatively dense connective tissue containing mucous esophageal glands whose ducts pass through the mucosa to open into the esophageal lumen; their mucus coats the esophageal surface to facilitate the passage of food. Around the esophageal glands there are often dense lymphocytes and plasma cells, even lymphoid nodules, so esophageal cancer readily metastasizes lymphatically.

The muscular layer of the esophagus has an inner circular and an outer longitudinal layer. The upper third is skeletal muscle, the lower third is smooth muscle, and the middle third has both. Skeletal muscle is voluntary, so the initial act of swallowing is under conscious control. But once food enters the middle and lower esophagus, smooth-muscle peristalsis must propel it to the cardia and into the stomach. Esophageal cancer impairs this peristalsis, causing dysphagia.

Classification of esophageal cancer

By histologic type of cancer cells, esophageal cancer is mainly divided into squamous cell carcinoma and adenocarcinoma. Squamous cell carcinoma is most common, accounting for about 80%-90% of all esophageal cancers. Esophageal squamous cell carcinoma is a malignant tumor arising from the esophageal mucosal epithelium.

The esophageal mucosal epithelium is stratified squamous epithelium, a protective epithelium composed of multiple layers of cells whose superficial cells are flat and scale-like, hence also called squamous epithelium; a cancer arising in squamous epithelium is called squamous cell carcinoma.

Depending on whether the superficial cells are keratinized, stratified squamous epithelium is divided into a keratinized type (skin) and a non-keratinized type (mucosa); the esophageal mucosa is non-keratinized stratified epithelium.

The intermediate layer of stratified squamous epithelium consists of polygonal cells; the basal layer has low columnar stem cells capable of division. Stratified squamous epithelium forms a physical barrier through tight intercellular junctions, defending against mechanical friction, microbial invasion and fluid loss. But repeated intake of hard or hot food can damage the esophageal mucosal epithelium; long-term damage leads to carcinogenesis.

Adenocarcinoma is the second most common type of esophageal cancer; it often develops from benign conditions such as Barrett's esophagus, Plummer-Vinson syndrome and gastroesophageal reflux.

In addition, esophageal cancer includes small-cell carcinoma, neuroendocrine carcinoma, adenosquamous carcinoma, adenoacanthoma, adenoid cystic carcinoma, carcinosarcoma, and mucoepidermoid carcinoma of the esophagus. These types are less common but mostly highly malignant with poor prognosis.

Etiology of esophageal cancer

Esophageal cancer results from the combined action of multiple causes. Current medical understanding holds that it is related to certain carcinogens, dietary habits, genetic factors and biological factors. There is a clear family history of esophageal cancer, which is even more evident in high-incidence areas.

High-incidence areas are rural and economically disadvantaged regions with poor nutrition; the diet there generally lacks vitamins, protein and essential fatty acids. Deficiency of these components can cause hyperplasia and dysplasia of the esophageal mucosal epithelium and further lead to carcinogenesis. The Taihang Mountains region in China—especially Linzhou in Henan and Xingtai in Hebei—is a high-incidence area. Because Linzhou has many esophageal cancer cases, its hospitals have accumulated rich clinical experience in treating the disease.

Common carcinogenic factors for esophageal cancer include the following:

1. Long-term smoking and alcohol consumption increase the incidence of both esophageal squamous cell carcinoma and adenocarcinoma; heavy spirits are especially harmful.
2. Human papillomavirus (HPV) infection is associated with esophageal squamous cell carcinoma.
3. Dietary carcinogens associated with the development and progression of esophageal squamous cell carcinoma include:

• Deficiency in trace elements such as molybdenum, iron and zinc in food. Plants grown in such soil are usually low in vitamin C, leading to precancerous lesions such as esophageal mucosal hyperplasia.
• High nitrate levels in drinking water; simmering in soup pots further raises nitrite concentration.
• Fungi in food: Candida geotrichum (mainly in pickled vegetables and air-dried grain), spindle fungi and Aspergillus (grain).
• Eating bread baked weekly or moldy bread (Candida infection).
• Long-term consumption of very hot food, or hard, rough food (such as dried persimmons) that damages the esophageal mucosa; this carcinogenic factor is most common in China.

Natural history of esophageal cancer

Most esophageal cancers pass through a precancerous stage before carcinogenesis. Main precancerous lesions include mild to moderate atypical hyperplasia and Barrett's esophagus. The precancerous stage is reversible, so treatment at this stage can block the development of esophageal cancer. Screening for precancerous lesions in high-incidence areas has positive preventive value.

Once the precancerous stage is missed, esophageal cancer may develop. Initially, carcinoma in situ appears in the esophageal mucosa; this stage is also called stage 0-I. Carcinoma in situ is mainly confined to the mucosa and submucosa and may last for years. If detected at this stage and treated promptly by surgery, more than 90% of patients achieve radical cure.

As esophageal cancer progresses further, it invades the entire muscular layer; this is stage II-III, when patients begin to show clinical symptoms and the tumor advances rapidly. Untreated patients at this stage have a median survival of 9 months; even with various treatments, the 5-year survival is less than 15%.

Further progression leads to invasion and metastasis and serious complications; this is the terminal stage of clinical staging. Untreated or treatment-resistant patients survive only about 3 months.

Common symptoms of advanced esophageal cancer include: 1. Cachexia, dehydration and exhaustion, mainly due to difficulty eating and systemic consumption, accompanied by water-electrolyte disturbances. 2. Tumor penetration of the esophagus invading the mediastinum, trachea, bronchi, hilum, pericardium and great vessels, causing mediastinitis, pneumonia, lung abscess, tracheoesophageal fistula and fatal massive hemorrhage. 3. Systemic widespread metastasis causing corresponding symptoms such as jaundice, ascites, dyspnea from tracheal compression, hoarseness and coma. 4. Tumors at the esophagogastric junction may cause epigastric distending pain, subxiphoid dull pain and anorexia; when the tumor grows large, the patient is completely unable to swallow.

Auxiliary examination of esophageal cancer

Common auxiliary examinations for esophageal cancer include the following:

Imaging:

1. X-ray; CT; 3. MRI; 4. gastroscopy; 5. endoscopic ultrasound; 6. PET/CT.

Histological examination:

Histological examination is the gold standard for diagnosing esophageal cancer. Esophageal cancer is mainly divided into squamous cell carcinoma (well, moderately and poorly differentiated), adenocarcinoma, small-cell undifferentiated carcinoma and carcinosarcoma. Squamous cell carcinoma accounts for over 90%, followed by adenocarcinoma at 5%-10%. The prognosis of esophageal squamous cell carcinoma is better than that of adenocarcinoma; the other types are more malignant.

Tumor markers:

Common tumor markers for esophageal cancer include CEA, SCC, CYFRA21-1, p3-Ab, COX-2, PC-NA, p53, Cyclin D1, VEGF, NF-kappa B, EGFR and Her-1/Neu. Among them, SCC (squamous cell carcinoma antigen) is a diagnostic marker for squamous cell carcinoma with good specificity but low sensitivity. In esophageal squamous cell carcinoma, SCC rises and its positivity rate increases with disease progression. Tumor markers can be used as a reference for evaluating treatment efficacy.

Treatment of esophageal cancer

Common treatment modalities include surgery alone, radiotherapy alone, combined chemoradiotherapy, and surgery combined with chemoradiotherapy. In China, integrated Chinese-Western treatment is also available. The treatment strategy depends on the pre-treatment clinical stage.

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