NORD gratefully acknowledges Peter C. Enzinger, MD, Director, Center for Esophageal and Gastric Cancer; Associate Professor of Medicine, Harvard Medical School, for assistance in the preparation of this report.
Esophageal cancer is an uncommon form of cancer (malignancy) that arises in the esophagus. Esophageal cancer is characterized by abnormal, uncontrolled cellular growth that forms in tissues and cells of the esophagus. This cancer can invade surrounding tissues and may spread (metastasize) to distant bodily tissues or organs via the bloodstream, the lymphatic system, or other means. The esophagus is the muscular tube that runs from the back of the throat to the stomach. The esophagus is lined with a mucous membrane, which is a type of tissue that secretes mucus. Mucus provides lubrication and protection. In most people, the esophagus is about 9 inches long (or about 23 centimeters for women and 25 centimeters for men). Esophageal cancer usually begins in the cells that line the wall of the esophagus, eventually forming a tumor. The cancer can then grow to partially block the esophageal tube, making it difficult for food to reach the stomach. More than 95% of people with esophageal cancer have one of two main types – squamous cell carcinoma or adenocarcinoma. The remaining forms are extremely rare instances of lymphoma, melanoma, carcinoid tumors, leiomyosarcoma, or sarcoma occurring in the esophagus. In extremely rare instances, cancer that arises in another areas of the body can spread to the esophagus.
In the early stages esophageal cancer may not be associated with any symptoms (asymptomatic). As the cancer grows, affected individuals may have difficulty swallowing solid foods (dysphagia). This occurs because the tumor has grown enough to partially block the esophageal tube. Initially, this may affect certain foods such as meat, apples or bread, which can “stick” in the throat. Eventually, affected individuals may have difficulty swallowing liquids. Many individuals may experience pain when attempting to swallow (odynophagia). This most often occurs with dry foods, and can often differentiate cancer from more benign causes of swallowing difficulty.
Additional symptoms that can develop include unintended weight loss, indigestion (dyspepsia), chest pain, and heartburn that is unresponsive to medication. The most common symptoms are the combination of difficulty swallowing and unintended weight loss.
Affected individuals may also experience chronic blood loss because of esophageal cancer. This can lead to iron deficiency anemia. Anemia is a condition in which there is a low level of circulating red blood cells. Red blood cells deliver oxygen throughout the body. Anemia is associated with fatigue, pale skin color (pallor), lightheadedness, and other symptoms. Anemia may occur because of unrecognized gastrointestinal bleeding, which if severe can appear as black sticky stools.
Uncommon symptoms that can potentially occur include enlargement of the lymph nodes of the neck (cervical lymphadenopathy), vomiting up blood (hematemesis), coughing up of blood (hemoptysis), and hoarseness. Hoarseness usually occurs because the tumor pushes against (compresses) the nerves of the vocal cords. Compression of other nearby nerves can cause persistent hiccups or spinal pain. If the tumor has grown large enough, pain may affect the back, the area behind the breastbone (retrosternal area), or the upper right area of the abdomen.
Rarely, individuals may develop a fistula, which is an abnormal passageway that connects the esophagus to windpipe (trachea). The windpipe is the tube (airway) that connects the throat to the lungs. It runs from the voice box (larynx) in the throat to the lungs. When there is an abnormal connection between the esophagus and the trachea, it is called a tracheoesophageal fistula (TEF). A TEF may allow food or other foreign particles to reach the lungs (aspiration) and can cause breathing (respiratory) problems and pneumonia.
Esophageal cancer can spread (metastasize) to other areas of the body including in order of frequency: the liver, lungs, bone, and brain. The specific symptoms that develop will depend upon the exact location and extent of the cancer. Esophageal cancer often spreads to the liver and can cause fever and abnormal enlargement of the liver (hepatomegaly). Spread to the lungs can cause a chronic cough, shortness of breath or a collection of fluid within the membrane (pleura) surrounding the lungs (pleural effusion). Spread to the bones can cause bone pain. Headaches, confusion and seizures can be caused by spread to the brain.
The exact underlying cause of esophageal cancer is not fully understood. Many cancers are caused by damage to the DNA (deoxyribonucleic acid; genes) in cells which leads to cancer. However, the exact reason normal cells become cancerous is not known. Most likely, multiple factors including genetic and environmental ones play a role in the development of esophageal cancer in certain people. Current research suggests that abnormalities of DNA which is the carrier of the body’s genetic code, are the underlying basis of cellular malignant transformation.
Esophageal cancer has run in some families in specific geographic areas, but researchers do not know whether this represents a common environmental factor or an inherited predisposition. Familial esophageal cancer is extremely rare. An inherited (or genetic) predisposition to a disorder is when a person has a gene or genes associated with a particular disorder, but who will not develop the disorder unless other factors such as environmental or immunological ones are also present. In esophageal cancer, genetic changes can affect oncogenes or tumor suppressor genes. These gene changes are acquired during life; they are not inherited. They are acquired because of exposure to environmental factors like smoking or they occur randomly for no known reason (spontaneously). These gene changes are altered or incomplete versions of ordinary genes that normally regulate cell growth and division. An altered oncogene promotes out-of-control growth (cancer). Tumor suppressor genes normally limit or stop the growth of cells. When the tumor suppressor genes are altered (mutated), cells can multiply (proliferate) wildly, causing cancer. When the normal gene is present, they appear to prevent cancer from developing.
Certain genes have been identified as being altered (mutated) in people with esophageal cancer than in people without this cancer. This includes the TP53 and the CDKN2A genes in both squamous cell carcinoma and adenocarcinoma. In adenocarcinoma, an additional gene called ERBB2 (also known as the HER2/neu gene) is altered in approximately one in five patients. Several other genes have been noted to be altered in a small percentage of affected individuals with either squamous cell carcinoma or adenocarcinoma of the esophagus. Determining the genetic drivers of each subtype of esophageal cancer can lead to targeted therapies (see Treatment sections below).
There are several risk factors associated with esophageal cancer. A risk factor is anything that increases a person’s risk of developing a condition. Having a risk factor does not mean a person will definitely develop that condition, and people who do not have any risk factors can still develop a condition. The main risk factor for esophageal cancer is smoking, particularly cigar and pipe smoking. Alcohol is also a risk factor for squamous cell carcinoma, but not adenocarcinoma, and that risk is greater in people who smoke and drink. Smoking is predominantly associated with squamous cell carcinoma of the esophagus.
Chronic or long-standing gastroesophageal reflux is associated with an increased risk of developing an adenocarcinoma of the esophagus. Gastroesophageal reflux is when stomach acids and bile flow backward from the stomach into the esophagus. The majority of people who have gastroesophageal reflux will not develop esophageal cancer. Chronic gastroesophageal reflux can cause Barrett esophagus in approximately one of ten people.
Barrett esophagus is a disorder in which chronic backflow of stomach acids and bile into the esophagus damages the tissue of the lower portion of esophagus. The tissue lining the lower portion of the esophagus breaks down because of damage caused by stomach acids and bile. Because of this chronic damage, the affected tissue is slowly replaced by tissue that resembles the lining of the inside of the stomach. The exact reason that esophageal tissue changes into tissue normally found in the stomach is unknown. People with Barrett esophagus have a higher risk of developing adenocarcinoma of the esophagus than the general population. However, only a small percentage of people with Barrett esophagus will eventually develop esophageal cancer.
People who are overweight or obese are at a greater risk of developing adenocarcinoma of the esophagus. Diet is also potentially associated with a decreased or increased risk of esophageal cancer. Some studies have suggested that processed meat is associated with an increased risk, but this remains unproven. A high starch diet, low in fruits and vegetables may increase the risk of squamous cell carcinoma of the esophagus. Studies have also shown that a diet high in fruits and vegetables is associated with a decreased risk. Some studies have shown repeatedly drinking extremely hot liquids may cause chronic damage to the esophagus and increase the risk of squamous cell carcinoma. Extremely hot is defined as 149 degrees Fahrenheit, or 65 degrees Celsius, which is considerably hotter than an average cup of coffee.
Certain disorders are characterized with a higher risk of developing squamous cell carcinoma of the esophagus including achalasia and tylosis. Achalasia is a rare disorder of the esophagus characterized by the impaired ability to push food down toward the stomach (peristalsis), failure of the ring-shaped muscle at the bottom of the esophagus, the lower esophageal sphincter (LES), to relax. It is the contraction and relaxation of the sphincter that moves food through the tube. Tylosis is an extremely rare, genetic disorder that has been identified in two families. The disorder causes overgrowth and hardening of tissue on the soles of the feet and the palms of the hands. People with tylosis also develop small, wart-like growths (papillomas) on the walls of the esophagus.
Another rare disorder that is associated with esophageal cancer is Plummer-Vinson syndrome, or esophageal webs. People with this disorder develop thin strands of membrane that extend out from the walls of the esophagus. These webs may not cause any problems, or can cause narrowing of the esophageal tube. About 1 in 10 people with this disorder eventually develop squamous cell carcinoma in the lower portion of the esophagus.
People who have undergone radiation treatment to the chest or upper abdomen (often for a different form of cancer, typically lymphoma or breast cancer) are at an increased risk of developing esophageal cancer.
The human papillomavirus (HPV), a virus that only infects humans and has more than 150 related types, is also associated with an increased risk of squamous cell carcinoma of the esophagus in East Asia; an association with the West is uncertain. How HPV infection increases the risk of esophageal cancer is not fully understood. HPV usually causes warts to develop in the late teens, but can be seen in early childhood in some instances. Warts may be widespread affecting the hands, feet, face, and trunk and are often highly resistant to treatment (recalcitrant). Mucosal and genital warts may also develop. Some studies have not demonstrated that HPV is not a significant risk factor for esophageal cancer and some researchers state that any association between HPV and esophageal cancer is “inconclusive.”
Approximately 17,000 people are diagnosed with esophageal cancer in the United States each year. Squamous cell carcinoma and adenocarcinoma account for about 95% of people with esophageal cancer. The number of people with squamous cell carcinoma is decreasing in the U.S., but the number of people with adenocarcinoma is increasing. The number of people with esophageal cancer varies greatly throughout the world. It is the seventh most common cancer worldwide. Squamous cell carcinoma of the esophagus is more common in East Asia and the Middle East. Adenocarcinoma is more common in Western Europe, North America, and Australia. Adenocarcinoma occurs more often in the lower portion of the esophagus.
Esophageal cancer affects males more often than females by a ratio of about 3 to 1. Caucasian men develop adenocarcinoma of the esophagus more often than men of other racial backgrounds. Men of African-American descent are more likely to develop squamous cell carcinoma of the esophagus. Most people who develop esophageal cancer are over the age of 55, although the number of younger adults developing esophageal cancer is increasing in the United States.
A diagnosis of esophageal cancer is based upon identification of characteristic symptoms, a detailed patient history, a thorough clinical evaluation and a variety of specialized tests. A diagnosis is usually confirmed by a biopsy, in which a small piece of tissue is taken and studied under a microscope to identify cancerous cells. The tissue sample is studied by a doctor who specializes in examining tissue and cells and determining what disease is present (pathologist).
Clinical Testing and Workup
Doctors may order an upper endoscopy examination. This examination allows doctors to view the upper portion of the digestive tract including the esophagus and the area where the esophagus connects to the stomach (gastroesophageal junction). During this examination, doctors will run a thin, flexible tube (endoscope) down a person’s throat. This tube has a tiny camera attached to it that allows doctors to visually inspect these areas. This examination can reveal abnormal tissue growths, which can include broad, hardened areas of tissue (plaques), small swellings (nodules), or open sores (ulcerations). More advanced disease may appear as a narrowing of the esophageal tube (stricture), ulcerated masses, or large ulcerations. An endoscopy examination also allows doctors to remove a small sample of tissue to be studied by a pathologist to confirm a diagnosis of esophageal cancer, and to determine what subtype of cancer is present.
An endoscopic ultrasonography is performed to provide detailed images of tumors or masses in the esophagus, and their relationship to the layers of tissue that make up the walls of the esophagus. Ultrasounds use high-frequency radio waves to create a picture or image (sonogram) of specific structures like internal organs. The radio waves bounce off of (echo) internal structures within the body and the echoes are recorded to create a sonogram. Endoscopic ultrasonography can be used to determine how far into the esophagus a tumor has grown and whether it has spread to nearby lymph nodes and structures.
Routine x-rays (radiographs) and specialized imaging techniques may be performed to determine the extent of cancer and whether it has spread to other areas of the body. X-rays of the esophagus may be recommended and may involve a barium swallow. Affected individuals swallow barium, which is a chalky, white, metallic element. X-rays cannot pass through barium so the x-ray film will be able to outline structures or tissues in these areas such as within the esophagus. A barium study may be done in individuals who cannot undergo an endoscopy. This is often the first test used because a primary care physician can order this test more quickly than ordering an endoscopic examination.
A specialized imaging technique called computerized tomography (CT) scanning is a specialized imaging technique that is mandatory to stage the cancer. CT scanning uses a computer and x-rays are used to create a film showing cross-sectional images of certain tissue structures. Before the test, patients may be required to drink an oral contrast. An oral contrast is a liquid that helps to produce detailed images of internal structures including within the chest, abdomen, and pelvis. CT scans of the chest and abdomen may be done to determine whether the cancer has spread.
Another advanced imaging technique known as positron emission tomography or PET/CT scan may also be used. This scan gathers information about how much metabolic activity (glucose uptake, measured by PET) a cancer has at the same time as mapping the adjacent body structures (CT). During a PET scan, a radioactive sugar is injected into the body. This sugar will collect in areas of the body where there is a higher demand for energy. Tumors require a lot of energy to keep growing and spreading, and will soak up the radioactive sugar. When the x-ray (scan) is taken, areas that take up the radioactive sugar including esophageal cancer may show up as bright spots on the film. A PET scan is often used to help show whether esophageal cancer has spread to other areas of the body or how well it is responding to treatment. A PET scan can determine whether cancer has spread to the bones. In the past, this required a bone scan, but when a PET scan is used, a bone scan is no longer necessary, but is mandatory if surgery is being considered.
When an individual is diagnosed with esophageal cancer, assessment is also required to determine the extent or “stage” of the disease. Staging is important to help determine how far the disease has spread, characterize the potential disease course, and determine appropriate treatment approaches. Some of the same diagnostic tests described above may be used in staging. The common staging system used for esophageal cancer is called the Tumor Node Metastasis (TNM) Staging System, which is a universal staging system for cancer developed by the American Joint Committee on Cancer/Union for International Cancer Control. This system is based on the extent of the tumor (T), whether and to what extent cancer has spread to the lymph nodes (N), and whether cancer has spread (metastasized) to other areas of the body (M). It is a complex staging system. For more information on this staging system for esophageal cancer, visit the American Cancer Society: https://www.cancer.org/cancer/esophagus-cancer/detection-diagnosis-staging/staging.html
The therapeutic management of individuals with esophageal cancer will require the coordinated efforts of a team of medical professionals such as physicians who specialize in the diagnosis and treatment of diseases of the digestive system (gastroenterologists), physicians who specialize in the diagnosis and treatment of cancer (medical oncologists), physicians who specialize in the diagnosis and treatment of cancer with surgery (surgical oncologists or thoracic surgeons), physicians who specialize in the use of radiation therapy for the treatment of cancer (radiation oncologists), oncology nurses, psychiatrists, nutritionists, and other healthcare specialists.
Psychosocial support for the entire family is essential as well. Several of the organizations listed in the Resources section provide support and information on cancer. Individuals who have esophageal cancer and who still smoke are strongly encouraged to quit smoking. The importance of quitting smoking cannot be overemphasized and is mandatory in patients who wish to be considered for surgery.
Specific therapeutic procedures and interventions may vary, depending upon numerous factors, such as disease stage; tumor size; specific cancer subtype; the presence or absence of certain symptoms; an individual’s age and general health; and/or other elements. Decisions concerning the use of particular drug regimens and/or other treatments should be made by physicians and other members of the health care team in careful consultation with the patient based upon the specifics of his or her case; a thorough discussion of the potential benefits and risks, including possible side effects and long-term effects; patient preference; and other appropriate factors.
In general, esophageal cancer can be treated with surgery, chemotherapy, and radiation therapy, usually in some combination. In very early stages of the disease, some people may be treated with surgery alone. However, most people are diagnosed when esophageal cancer has already spread.
In people in whom cancer is only in the mucosal layer of the esophagus, the tumor can be removed by a surgical procedure called endoscopic mucosal resection. This involves using a thin, flexible tube called an endoscope. This tube is fed down the throat and allows surgeons inject a tumor with saline (saltwater), which allows a small tumor to be sucked out by the endoscope. An endoscope can also be used to cut away (resect) the tumor and any affected tissue. If the cancer is found early enough, sometimes this can be curative. Endoscopic mucosal resection is a minimally-invasively surgical procedure.
If the cancer has spread beyond the mucosal layer, then a procedure called an esophagectomy may be necessary. This surgery involves removing a portion of the esophagus. Sometimes, a small portion of the stomach is removed as well. After the cancer is removed, the remaining portion of the esophagus is reconnected to the stomach (gastric pullup). Sometimes, the stomach must be pulled up to connect to the remaining portion of the esophagus. The exact location, size, and spread of the cancer will determine how much of the esophagus (and whether any of the stomach) needs to be removed. Nearby lymph nodes should also be surgically removed. Surgery for esophageal cancer carries risk including infection, bleeding, and leakage of the affected area, especially where the esophagus is reconnected to the stomach. Trouble swallowing, heartburn, and digestive problems are other potential side effects.
Except for very early stage esophageal cancer, surgery is usually preceded by radiation therapy and chemotherapy. Some people may not be candidates for surgery and will receive chemotherapy and radiation therapy as their first treatment option.
Chemotherapy is the use of certain medications to kill or stop the growth of cancer cells. Cancers cells grow and divide rapidly, which makes them susceptible to chemotherapy medications. Different combinations of medications may be used; this is called a chemotherapy regimen. Radiation therapy uses high-powered x-rays to directly destroy cancer cells. Chemotherapy and radiation therapy are often used in combination (chemoradiotherapy) to treat people with esophageal cancer.
Targeted therapies are being explored as potential treatments for individuals with esophageal cancer. Targeted therapies are drugs and other substances that prevent the growth and spread of cancer by blocking or inhibiting certain specific molecules (often proteins) that are involved in the development of specific cancers. Generally, targeted therapies are less toxic than other treatments for cancer. A few targeted therapies have been approved by the U.S. Food and Drug Administration (FDA) for the treatment of individuals with esophageal cancer.
One type of targeted therapy is called immunotherapy. Immunotherapy is the most recent addition to therapy for cancer. It is designed to enlist the body’s immune system to act against cancer. Most forms of immunotherapy are monoclonal antibodies, which is are manmade (synthetic) version of an immune system protein.
In 2011, the FDA approved trastuzumab (Herceptin®) for the treatment of individuals with HER2-positive gastroesophageal junction cancer. The gastroesophageal junction is the area where the esophagus connects to the stomach. Trastuzumab is an antibody, a specialized protein of the immune system that is targeted specifically for HER2-positive cells. Trastuzumab is used for cancer that has spread (metastasized) to other areas of the body. HER2 is a protein found on the surface of cancer cells that helps cancer cells grow and multiple. Trastuzumab blocks (inhibits) the HER2 protein. Only a small percentage of people with esophageal cancer have a HER2-positive form.
In 2014, the FDA approved ramucirumab (Cyramza®), along with another drug called paclitaxel, for the treatment of advanced gastroesophageal junction adenocarcinoma in individuals who have been previously treated and that treatment failed or the cancer came back. Ramucirumab works by blocking a protein called VEGF, which helps the body make new blood vessels. Tumors require a strong blood supply to grown and spread. By blocking the VEGF protein, ramucirumab essentially cuts off the blood supply from the tumor.
In 2017, the FDA approved pembrolizumab (Keytruda®) for the treatment of advanced or metastatic, gastric or gastroesophageal junction adenocarcinoma whose tumors express PD-L1 as determined by an FDA-approved test. Affected individuals must have disease progression or recurrence despite two other previous therapies. Pembrolizumab is a type of immunotherapy called anti-PD-LI therapy or PD-L1 blockade, which releases the “brakes” on the immune system that some cancers use to try to evade the immune cells. PD-L1 stands for programmed death-ligand 1, which is a protein produced by certain cancerous cells.
In 2019, the FDA approved trifluridine/ tipiracil (Lonsurf®) for adult patients with metastatic gastric or gastroesophageal junction adenocarcinoma previously treated with at least two prior lines of chemotherapy.
Additional and Supportive Therapies
Some affected individuals may be treated with photodynamic therapy. Photodynamic therapy, a procedure in which a drug known as a photosensitizer is used along with a special type light, has been used to treat some individuals with esophageal cancer. During photodynamic therapy, the drug is administered to an affected individual and absorbed by the affected cells. A specific wavelength of light is used to activate the drug which binds with oxygen creating a chemical that destroys the affected cells.
Some affected individuals may be treated with electrocoagulation, in which heat created by an electrical current is used to destroy cancer cells. The electrical current is delivered through an electrode that is placed near the cancerous tissue.
Some affected individuals may have a stent, a tiny wire mesh tube, placed into the throat to keep the esophagus open and allow the passage of food and liquids. Some affected individuals may need a gastrostomy tube, in which a small, thin tube that is inserted into the stomach through a small cut in the abdomen to allow the passage of food and liquid. Sometimes a J tube (jejunostomy tube) is used, typically for patients in which a gastric pullup is planned in order to avoid damage to the stomach before surgery. A jejunostomy tube is a soft, plastic tube inserted through the abdomen and into the middle segment of the small intestine.
Medications and other methods are available for pain management.
Screening is when doctors runs tests to see whether cancer is present, even though there are no symptoms of cancer. Screening for cancer usually depends on whether people have specific risk factors for a particular cancer. In the United States, there are no recommendations for screening individuals in the general population for esophageal cancer. There are established guidelines for follow up (surveillance) and assessment of people with Barrett esophagus because people with this condition are at a greater risk than the general population of developing esophageal adenocarcinoma cancer.
Many several research studies are ongoing to test various targeted therapies for esophageal cancer. More research is necessary to determine all of the specific genetic factors (e.g. altered genes) play a role in the development esophageal cancer and what types of targeted therapies may be possible to treat these tumors.
Information on current clinical trials is posted on the Internet at https://clinicaltrials.gov/. All studies receiving U.S. Government funding, and some supported by private industry, are posted on this government web site.
For information about clinical trials being conducted at the NIH Clinical Center in Bethesda, MD, contact the NIH Patient Recruitment Office:
Toll-free: (800) 411-1222
TTY: (866) 411-1010
Email: [email protected]
Some current clinical trials also are posted on the following page on the NORD website:
For information about clinical trials sponsored by private sources, contact:
For information about clinical trials conducted in Europe, contact:
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Mondaca S, Margolis M, Sanchez-Vega F, et al. Phase II study of trastuzumab with modified docetaxel, cisplatin, and 5 fluorouracil in metastatic HER2-positive gastric cancer. Gastric Cancer. 2018;[Epub ahead of print]. https://www.ncbi.nlm.nih.gov/pubmed/30088161
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