Esophageal Cancer: Pathophysiology, Aetiology and Risk Factors

These are the risk factors for the two main types of esophageal cancer.

- Gastroesophageal reflux disease (GERD) is the most common predisposing factor for adenocarcinoma of the esophagus.

o As a consequence of the irritation caused by the reflux of acid and bile, 10-15% of patients who undergo endoscopy for evaluation of GERD symptoms are found to have Barrett epithelium.

o 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.

o Adenocarcinoma may develop in these patients, representing the last event of a sequence that starts with the development of GERD and progresses to (Barrett) metaplasia, low-grade dysplasia, high-grade dysplasia, and adenocarcinoma.

o 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.

o The progression of Barrett metaplasia to adenocarcinoma is associated with several changes in gene structure, gene expression, and protein structure. The oncosuppressor gene TP53 and various oncogenes, particularly erb -b2, have been studied as potential markers. Casson and colleagues identified mutations in the TP53 gene in patients with Barrett epithelium associated with adenocarcinoma.8 In addition, alterations in p16 genes and cell cycle abnormalities or aneuploidy appear to be some of the most important and well-characterized molecular changes. However, the exact sequence of events in the progression of Barrett esophagus to adenocarcinoma is not known. Probably multiple molecular pathways interact and are involved.

o 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 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. The end result is local spread and invasion into surrounding tissue, with early metastatic disease developing in most patients.

- Plummer-Vinson syndrome—the triad of dysphagia, iron deficiency anemia, and esophageal webs

- 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.

- Tylosis with esophageal cancer: A genetic disorder characterized by thickening (hyperkeratosis) of the palms and soles, white patches in the mouth (oral leukoplakia), and a very high risk of esophageal cancer. This is the only genetic syndrome known to predispose to squamous cell carcinoma of the esophagus. The risk of developing esophageal cancer is 95% by age 70. The syndrome is inherited in an autosomal dominant manner. The gene has been mapped to chromosome 17q25 but has not been identified. The syndrome is also called nonepidermolytic palmoplantar keratoderma.

- In a high-risk country such as China, deficiencies in vitamin or microelement levels may play a role in causation. Riboflavin deficiency in China may contribute to a high incidence of esophageal cancer.

- Heavy drinking: People who have more than 3 alcoholic drinks each day are more likely than people who don't drink to develop squamous cell carcinoma of the esophagus. Heavy drinkers who smoke are at a much higher risk than heavy drinkers who don't smoke. In other words, these two factors act together to increase the risk even more.

Esophageal Cancer (Investigation)

Esophageal Cancer (Investigation)

Imaging studies

Barium swallow

Barium is swallowed. It coats the walls of the esophagus. When x-rays are taken, the barium outlines the esophagus clearly. This test can be done by itself, or as a part of a series of x-rays that includes the stomach and part of the intestine, called an upper gastrointestinal (GI) series. A barium swallow test can show any irregularities in the normally smooth surface of the esophageal wall.

A barium swallow test is often the first test done to see what is causing a problem with swallowing. Even small, early cancer can be seen using this test. Tumors grow out from the lining of the esophagus. These masses stick out into the lumen (the open area of the tube). They cause the barium to coat that area of the esophagus unevenly. In the barium x-ray, early cancers can look like small round bumps. They also can appear as a flat, raised area called a plaque. Advanced cancers look like large irregular areas and cause a narrowing of the width of the esophagus. A barium swallow test cannot be used to determine how far a cancer may have spread outside of the esophagus.

A barium swallow test can also be used to diagnose one of the more serious complications of esophageal cancer called a tracheoesophageal fistula. This occurs when the tumor destroys the tissue between the esophagus and the trachea and creates a hole connecting them. With this connection, anything that is swallowed can pass from the esophagus into the windpipe and lungs. This leads to frequent coughing and gagging. This problem can be helped with surgery or an endoscopy procedure.

Computed tomography (CAT or CT) scan

CT scans are not usually used to make the initial diagnosis of esophageal cancer, but they can help see how far it has spread. CT scans often can show where the cancer is in the esophagus. These scans can also show the nearby organs and lymph nodes, as well as distant areas of cancer spread. The CT scan can help to determine whether surgery is a good treatment option.

Before any pictures are taken, you may be asked to drink 1 to 2 pints of oral contrast. This helps outline the esophagus and intestines so that certain areas are not mistaken for tumors. You may also receive an IV (intravenous) line through which a different kind of contrast dye (IV contrast) is injected. This helps better outline structures in your body.

CT scans can also be used to guide a biopsy needle precisely into a suspected area of cancer spread. This procedure is called a CT-guided needle biopsy. The patient lies on the CT scanning table while a radiologist advances a biopsy needle toward the location of the mass. CT scans are repeated until the doctors can see that the needle is in the mass. A fine-needle biopsy sample (tiny fragment of tissue) or a core needle biopsy sample (a thin cylinder of tissue about one-half inch long and less than 1/8-inch in diameter) is removed and examined under a microscope.

Magnetic resonance imagings (MRI) scan

Not often needed for Esophageal cancer

Positron emission tomography (PET) scan

In this test, radioactive glucose (sugar) is injected into the vein. Because cancers use sugar much faster than normal tissues, the radioactivity will tend to concentrate in the cancer. A scanner is used to spot the radioactive deposits. This test is useful for finding areas of cancer spread. It can help find small collections of cancer cells that may not be seen on other tests.

The uptake of the radioactive glucose ("brightness") may be measured. Studies are being done to see if the degree of uptake or brightness can be used as to tell how fast the tumor is growing. Studies are also looking to see whether changes in the brightness on a PET scan can be used to see whether treatment, such as chemotherapy, is working. Some machines combine a PET scan with a CT scan. This allows any abnormal areas seen on the PET scan to be precisely located on the CT scan. This type of scan may be used to look for areas of cancer spread if nothing is found on other imaging tests.

Endoscopy

Upper endoscopy

An endoscope is a flexible, very narrow tube with a video camera and light on the end. During an upper endoscopy procedure, the patient is sedated and then the endoscope is placed through the mouth and into the esophagus and stomach.

Endoscopy is an important test for diagnosing esophageal cancer. The doctor can see the cancer through the scope and biopsy. If the esophageal cancer is blocking the lumen of the esophagus, then certain instruments can be used to help enlarge the opening to help food and liquid pass. Upper endoscopy can give the surgeon information for follow-up surgery, including the size and spread of the tumor and whether the tumor can be completely removed.

Endoscopic ultrasound

Ultrasound tests use sound waves to take pictures of parts of the body. For an endoscopic ultrasound, the probe that gives off the sound waves is at the end of an endoscope. This allows the probe to get very close to the cancer.

This test is very useful in finding the size of an esophageal cancer and how far it has grown into nearby tissues.

Endoscopic ultrasound can help determine how much of the tissue next to the esophagus (including nearby lymph nodes) is affected by the cancer. This helps surgeons decide which tumors can be surgically removed and which cannot.

Bronchoscopy

This procedure uses an endoscope to look into the trachea and tubes leading from the trachea into the bronchi. Check for metastasis. The patient is sedated for this procedure.

Thoracoscopy and laparoscopy

These procedures allow the doctor to see lymph nodes and other organs near the esophagus inside the chest (by thoracoscopy) or the abdomen (by laparoscopy) through a hollow lighted tube. The surgeon can operate instruments through the tube and remove lymph node samples and take biopsies to see if the cancer has spread. This information is often important in deciding whether or not a person is likely to benefit from surgery. These procedures are done in an operating room and under general anesthesia (the patient is in a deep sleep).

Biopsy

Confirm cancer and staged the cancer

References:

http://www.cancer.org/Cancer/EsophagusCancer/DetailedGuide/esophagus-cancer-diagnosis

http://www.cancer.gov/cancertopics/wyntk/esophagus/page7