Causes and Risk Factors for Esophageal Cancer

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The exact cause of esophageal cancer is unknown, but genetics appears to play a role. Several risk factors for the disease have also been identified. These vary depending on the type of cancer, with acid reflux (GERD), Barrett's esophagus, and obesity linked with adenocarcinoma, and the combination of smoking and excess alcohol intake associated with the majority of squamous cell carcinomas. There are also tremendous geographical variations in the incidence of these cancers, and different risk factors appear to be more important in different regions of the world.

Since the disease is often diagnosed in the later, less treatable stages, having an awareness of the risk factors, as well as being familiar with the symptoms of esophageal cancer, is important to detect the disease as early as possible. For reasons unknown, the incidence of adenocarcinoma of the esophagus has recently shown a dramatic increase in developed countries.

Genetics

Like many cancers, genetics likely factor into the development of esophageal cancer, and clusters of cancer within families have been noted in some regions of the world. Genetics probably play a greater role in squamous cell carcinoma than adenocarcinoma, especially with regard to certain gene abnormalities that have been tied to the disease. One genetic syndrome, tylosis, is associated with a very high risk of esophageal squamous cell carcinoma. The syndrome is characterized by thickening of the skin on the palms and soles due to defective vitamin A metabolism.

Genetics alone isn't responsible for esophageal cancer, but they may add to the risk posed by other risk factors for the disease.

Understanding Risk

A risk factor for a disease refers to something that is associated with an increased chance of developing the disease but doesn't mean that it causes the disease. Esophageal cancer begins when DNA damage (gene mutations) occur in normal esophageal cells so that the cells grow in an out of control fashion. Having a risk factor does not mean that you will develop esophageal cancer, and people without any risk factors can and do develop the disease at times.

Some of the risk factors for esophageal cancer are things that cause irritation and damage to the lining of the esophagus, and we are learning that chronic inflammation can lead to changes in tissue that eventually lead to cancer. Some risk factors, such as tobacco, contain carcinogens (cancer-causing substances) that can directly damage DNA. 

Squamous Cell Carcinoma

Squamous cell cancers begin in the surface cells (squamous cells) that line the esophagus. These cancers are more common in the upper part of the esophagus and are the most common type worldwide.

Risk factors for this type of esophageal cancer include:

Age 

Most squamous cell carcinomas occur in people between ages 45 and 70, and these cancers are uncommon in young people. 

Sex

While cancer of the esophagus is more common in men than in women overall, the reverse is true for squamous cell carcinoma in the United States.

Race

In the United States, squamous cell carcinomas are much more common in blacks than in whites, while the opposite is true for adenocarcinomas.

Geography

The incidence of both types of esophageal cancer varies significantly around the world. The highest incidence of squamous cell carcinoma of the esophagus is in what's been coined the "Asian Esophageal Cancer Belt." This region includes areas such as Turkey, Iran, Kazakhstan, and central and northern China. The incidence is also very high in southeastern Africa.

Smoking

Squamous cell carcinomas of the esophagus are roughly five times more common in people who smoke. Smoking is not, however, a risk factor for esophageal cancer in all parts of the world. For example, in China, it appears that smoking plays only a small role; dietary factors appear more important.

Heavy Alcohol Use

Like smoking, alcohol intake is a significant risk factor for squamous cell carcinoma of the esophagus in some parts of the world but not others. Heavy alcohol intake is associated with a 1.8- to 7.4-fold increase in risk. Low to moderate alcohol intake, according to a 2018 study, is actually associated with a lower risk of developing the disease than for those who abstain.

Smoking Plus Heavy Alcohol Use

The combination of smoking and drinking is the most significant risk factor for squamous cell carcinoma and is thought to account for around 90 percent of cases worldwide. The risk is higher than would be expected if you were to add up the risk of smoking plus heavy drinking alone (instead of being additive, the risk is multiplied).

Environmental Exposures

Exposure to some chemicals—tetrachloroethylene used in dry cleaning, for example—may increase the risk of esophageal cancer.

Drinking Lye (Drain Cleaner)

Lye is found in household drain cleaners and is a corrosive agent. Each year many children accidentally ingest these products. Esophageal cancer may occur many years after an accidental ingestion.

Achalasia

Achalasia is a condition in which the muscular band around the lower part of the esophagus (the lower esophageal sphincter) doesn't relax properly to allow food to leave the esophagus and enter the stomach. This results in food remaining in and stretching the lower esophagus. Achalasia is associated with a high risk of esophageal cancer, with cancer often occurring 15 to 20 years after the diagnosis.

Radiation Therapy to the Chest and Upper Abdomen

Radiation therapy to the chest for conditions such as breast cancer or Hodgkin's disease may increase risk. While women who have had radiation after a mastectomy have an elevated risk, this does not appear to be the case for women who have radiation to remaining breast tissue after a lumpectomy.

History of Head and Neck or Lung Cancer

A personal history of cancer is associated with a higher risk of esophageal cancer, particularly squamous cell carcinomas of the head, neck, and lungs.

Drinking Hot Beverages

Drinking very hot beverages (much warmer than a typical cup of coffee) has long been thought to carry an increased risk. A 2018 study supported this belief, though drinking tea at high temperatures was a risk only when combined with excessive alcohol intake or smoking.

Speaking of beverages, you may have heard that soda can cause esophageal cancer by way of related heartburn. This possible connection was debunked by a study from the National Cancer Institute and subsequent studies that not only found no increased risk of squamous cell carcinoma or adenocarcinoma but potentially just the opposite.

Diet

Diet—especially a diet low in fruits and vegetables, and high in red and/or processed meat—is associated with a higher risk of both types of esophageal cancer, but the link is stronger with squamous cell carcinoma. With meats, the method of cooking also appears to be important, and cooking or grilling at high temperatures is associated with greater risk. Betel and areca nuts have also been associated with the development of esophageal cancer.

In China, foods high in nitrates may double the risk. The risk is also higher for those who have vitamin and mineral deficiencies (especially folate, vitamin C, and molybdenum) in developing countries.

Human Papillomavirus Infection (HPV)

Human papillomavirus (HPV), the virus that causes cervical as well as some other cancers, may possibly be related to the development of squamous cell carcinoma. While researchers are uncertain if the virus is causative, it has been found in up to a third of esophageal cancers in Asia and parts of Africa. Thus far, HPV does not appear to be linked with esophageal cancer in the United States.

Adenocarcinoma 

Adenocarcinomas occur most often in the lower third of the esophagus and begin in glandular cells. Ordinarily, the lower third of the esophagus is lined with squamous cells, but chronic damage (such as chronic acid reflux) results in the transformation of these cells so that they appear more like the cells that line the stomach and intestines. Over time, these cells may become precancerous cells and then cancer cells. Adenocarcinomas have now surpassed squamous cell carcinomas in the United States, the United Kingdom, Australia, and Western Europe.

Risk factors for this type of esophageal cancer include:

Age 

Like squamous cell cancers, adenocarcinomas are most common in people between ages 50 and 70.

Sex

In the United States, adenocarcinomas are eight times more common in men than in women.

Race

Unlike squamous cell cancers, adenocarcinomas of the esophagus are much more common (by a factor of 5) in whites than in blacks.

Geography

The incidence of adenocarcinoma of the esophagus is highest in Western Europe, North America (particularly the United States), and Australia.

Gastroesophageal Reflux Disease (GERD)

Acid reflux, or gastroesophageal reflux disease (GERD), is a significant risk factor for esophageal adenocarcinoma, with roughly 30 percent of these cancers thought to be linked to the condition. It's thought that between 0.5 percent and 1 percent of people with GERD will develop esophageal cancer.

Barrett's Esophagus

Barrett's esophagus is a condition in which the normal cells of the lower esophagus (squamous cells) are replaced with glandular cells like those present in the stomach and intestines. It is usually found in people who have longstanding chronic acid reflux and occurs in 6 percent to 14 percent of people with chronic GERD. Though estimates vary, roughly 1 in 100 to 1 in 200 people with Barrett's esophagus will develop esophageal cancer each year. Like adenocarcinoma, Barrett's esophagus is increasing in the United States.

Some studies (but not all) have shown a reduction in the risk of esophageal adenocarcinoma in people who have Barrett's esophagus who have taken non-steroidal anti-inflammatory drugs (such as Advil, ibuprofen, proton pump inhibitors (such as Prilosec, omeprazole), or statin drugs (such as Lipitor, atorvastatin).

Hiatal Hernia

A hiatal hernia is a weakening of the diaphragm that allows the stomach to extend into the chest from the abdomen and often causes symptoms of heartburn. Having a hiatal hernia may increase risk by a factor of 2 to 6.

Overweight/Obesity

Being overweight or obese increases the risk of adenocarcinoma of the esophagus. According to a 2015 review, people who are overweight (body mass index of 25 to 29) are about 50 percent more likely to develop cancer, while those who are obese (body mass index of 30 or higher) are roughly twice as likely to develop esophageal cancer. Having type 2 diabetes may also increase risk, but it's uncertain whether this is related to diabetes itself or co-occurring obesity.

Smoking

Smoking is linked to the development of adenocarcinoma of the esophagus, but less so than squamous cell cancers. Smoking raises the risk of adenocarcinoma by a factor of 2.7.

Medications

Some medications are associated with either an increased or decreased risk of adenocarcinoma of the esophagus. The use of bisphosphonates (used for osteoporosis) may increase risk, as may the use of estrogen-only hormone replacement therapy. In contrast, the use of aspirin is associated with a decreased risk. 

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