Esophageal Cancer Pathophysiology and Symptoms
The two most common forms of esophageal carcinoma are squamous cell carcinoma (SCC) and adenocarcinoma (AC). Less than 1% to 2% of all esophageal cancers are sarcomas or small cell carcinomas. Regardless of the specific cell type, all forms are difficult to treat due to the late onset of symptoms and its aggressive nature.
The esophagus is a 23-25cm muscular mucosal tube running from the pharynx to the stomach. It is divided into three sections: upper, middle, and lower. The mucosa of the esophagus is made up of squamous cells. The esophagus has several properties that cause its versions of cancer to be unique from those of other gastrointestinal malignancies. The esophagus has no serous membrane, thereby reducing its resistance against spread of cancer cells. Furthermore, the esophagus has a vast network of lymphatics allowing for early tissue invasion and metastatic disease. A majority of the lymphatic fluid from the upper two-thirds of the esophagus tends to flow upward, and the lymph from the lower third of the esophagus flows relatively downward, but all the lymphatic channels of the esophagus communicate. Therefore, lymphatic fluid from any portion of the esophagus may spread in either direction.
The esophagus contains two sphincters to control the contents of the stomach and oral cavity. The upper sphincter is under conscious control when breathing, eating, belching and vomiting, thereby protecting the airway. The lower sphincter is not under voluntary control, but controlled by the vagus nerve, which prevents the reflux of acids and stomach content from returning to the esophagus.
Squamous cell carcinoma (SCC) is the most common type of esophageal cancer worldwide, although the incidence rate is decreasing in the United States. SCC develops in the flat squamous cells that line the esophagus, thus the name. This type of esophageal cancer is typically found in the upper and middle third of the esophagus. Most studies have shown that alcohol is the primary risk factor in the development of SCC. Smoking in combination with alcohol consumption may have a bolstering effect and increase the risk of developing SCC. Alcohol can damage the cellular DNA by decreasing metabolic activity within the cell and therefore reduceing its detoxification function. Alcohol is a solvent; hence, the hazardous carcinogens within tobacco are able to penetrate the esophageal epithelium easier. Other irritants to the esophageal mucosa include consumption of extremely hot liquids, chewing tobacco and environmental toxins.
Other carcinogens, such as nitrosamines found in certain salted vegetables, pickled foods, and preserved meats and fish have also been implicated in SCC of the esophagus. Pathogenesis appears to be linked to inflammation of the squamous epithelium that leads to dysplastic changes.
There are very few genetic factors that have been identified as being important in the development of esophageal SCC. One exception is tylosis. Tylosis is a rare autosomal dominant genetic disorder characterized by thickening of the palms and soles, oral patches and webbing within the esophagus. This is the only genetic syndrome known to predispose a person to SCC of the esophagus. The risk of developing esophageal SCC in patients with tylosis is 95% by age 70. The genetic cause of this link is not well known.
There are several ongoing studies as to the correlations between the human papilloma virus (HPV) and the development of SCC. Already known to be causative in the development of cervical and nasopharyngeal cancers, HPV is believed to result in loss of function of the tumor suppressor genes.
Adenocarcinoma (AC) is the most common type of esophageal cancer in the United States and appears to be on the rise. AC usually occurs in the middle or lower third of the esophagus. Chronic gastroesophageal reflux disease (GERD) is the most common cause of AC, with severe, long-standing reflux symptoms increasing the risk of cancer. Untreated GERD washes the lower section of the esophagus in gastric acids and bile into the gastrointestinal junction. GERD is associated with the development of Barrett’s esophagus.
Barrett’s esophagus is characterized by the esophageal changes in the normal lining of squamous cells to goblet cells. Goblet cells are the normal lining cells in the intestines and produce mucus. This mucus then covers the epithelial cells causing an intestinal metaplasia at the gastrointestinal junction. This appears to be an adaptation to protecting the lower esophagus from further harm or erosion. This “protective” metaplasia may become dysplastic and ultimately malignant. Patients with Barrett’s esophagus have a significant increase in the development of AC.
There are several other conditions that increase the risk of AC by causing the same reflux or other chronic anatomic irritations to the lining of the esophagus. Achalasia is a chronic, congenital stiffness of the esophageal wall causing a lack in the involuntary reflex after swallowing. Obesity, medications, and hiatal hernia may play a role in the development of AC by mechanically and chemically causing reflux of stomach acids.
Symptoms
Symptomatology in esophageal cancer is greatly dependent on local invasion as well as the spread to regional and distant organs within the body. Esophageal cancer is notoriously aggressive in nature, spreading by a variety of pathways specifically through the lymphatic and blood systems. Lymphatic pathways allow rapid dissemination into the adjacent structures of the neck and thorax including the thyroid gland, trachea, larynx, lung, pericardium, aorta and diaphragm. Esophageal cancer spreads in order of decreasing frequency to the liver, lungs, bones, adrenal glands, kidney and brain.
AC and SCC have similar presentations:
Dysphagia initially with solids, eventually progressing to include liquids
Weight loss due to lack of nutrient absorption and increased cellular activity
Reflux symptoms including heartburn an indigestion
Fatigue
Abdominal pain and bloating, especially in the epigastrium
Nausea and vomiting
Chronic cough due to aspiration or tumor irritation
Lymphadenopathy due to metastasis
Hiccups due to phrenic nerve involvement
Bleeding due to erosion of tumor or fistula
Bone pain with metastatic disease
Hoarseness due to invasion of the laryngeal nerve
Hepatomegaly due to hepatic metastasis
Esophageal carcinoma survival rates are dependent on an early index of suspicion to patients with behaviors and symptoms that put patients at an increased risk. Patients with heavy alcohol use, smoking, and GERD should be quickly evaluated when presenting with early complaints. Further research into the pathogenesis of esophageal cancers may help in identifying these patients sooner.
References:
Masab, Muhammad. (2018). Esophageal Cancer. Medscape. Retrieved from https://emedicine.medscape.com/article/277930-overview.
Napier, Kyle et. al. (2014). Esophageal cancer: A Review of epidemiology, pathogenesis, staging workup and treatment modalities. World Journal of Gastrointestinal Oncology, 6 (5), 112-120. Retrieved from https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4021327/.
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