All About Esophageal Cancer
Ryan P. Smith, MD and Eric T. Shinohara, MD
Updated by: Elizabeth Prechtel Dunphy MSN, CRNP, AOCN
The Abramson Cancer Center of the University of Pennsylvania
Last Modified: April 1, 2015
What is the esophagus?
The esophagus is a muscular tube, which connects the mouth to the stomach. The wall of the esophagus is composed of a series of muscles that are responsible for peristalsis, or the muscular motion that moves food down the throat into the stomach. The esophagus is lined with two layers of tissue known as the mucosa and submucosa, which are where most cancers of the esophagus develop. The esophagus is a long tube, with an average length of 25 cm. The throat (or pharynx) is continuous with the esophagus, and although the two are indistinguishable, the esophagus is thought to start a few centimeters below the thyroid cartilage (Adam's apple). The esophagus travels down through the chest, between the lungs. It then passes through a hole in the diaphragm to connect with the stomach. There is a ring of muscle, also known as the lower esophageal sphincter, between the stomach and esophagus, which prevents food and stomach acid from going back up into the esophagus.
What is esophageal cancer?
The definition of a tumor is a mass of quickly and abnormally growing cells. Tumors can be either benign or malignant. Benign tumors have uncontrolled cell growth that do not invade into normal tissues or spread. A malignant tumor is called cancer when these tumor cells have the ability to invade tissues and spread locally and/or to distant parts of the body. Cancers are described by the types of cells from which they arise. The vast majority of esophageal cancers develop from the inner lining (mucosa) of the esophagus and not from the muscle or cartilage cells that make up the rest of the esophagus. The lining of the esophagus is somewhat unique as it changes as it goes from the throat to the stomach. In the upper (proximal) esophagus, the lining of the esophagus resembles the lining of the throat, made up of squamous cells. Hence, when cancers develop in this region, they are usually squamous cell carcinomas. In the lower (distal) esophagus, the more common type of cancer is called adenocarcinoma, which is what the cancer is called when it develops from an area of the lining that contains glands.
In addition to invasive cancers, patients are sometimes diagnosed with precancerous lesions, called carcinoma-in-situ. These precancerous lesions can be seen prior to the development of either squamous cell carcinoma or adenocarcinoma. Carcinoma-in-situ occurs when the lining of the esophagus undergoes changes similar to cancerous changes without any invasion into the deeper tissues. Hence, while the cells themselves have cancer-like qualities, there has been no spread or invasion by the cancer cells. Another type of lesion that is considered to be a precursor to cancer itself is called Barrett's esophagus, which is explained in depth below.
Am I at risk for esophageal cancer?
The American Cancer Society estimates that there will be 16,980 new diagnoses and 15,590 deaths in 2015 related to esophageal cancer. Most patients are diagnosed in their 50s or 60s, with approximately four times as many men diagnosed than women. This being said, there are two different groups of patients who develop esophageal cancer. In the past, the vast majority (85%) of the esophageal cancers diagnosed were squamous cell cancers that occurred in the upper esophagus. Risk factors for this type of cancer include smoking and alcohol use. Although both are thought to be independent risk factors (meaning they can cause cancer on their own, with smoking’s risk being the higher), there seems to be a synergistic effect, when both are combined, for the development of esophageal cancer. In other words, people that both smoke and drink heavily are at an exceptionally high risk to develop esophageal cancer when compared to non-smokers and non-drinkers. Other potential carcinogens that are related to the development of squamous cell carcinoma of the esophagus include nitrosamines, asbestos fibers, and petroleum products.
However, in recent years the number of adenocarcinomas have been on the rise, and these are now the most common type of esophageal cancer seen. In contrast with squamous cell carcinomas of the esophagus, adenocarcinomas of the esophagus tend to involve the lower part of the esophagus. Adenocarcinoma is thought to almost always arise in the setting of Barrett's esophagus, which is a condition in which the normal lining of the esophagus is replaced by lining normally found in the stomach. Barrett's esophagus is diagnosed by endoscopy, which is a procedure that uses a fiberoptic camera to look down into the esophagus. A gastroenterologist usually performs this test and if any suspicious lesions are seen, they can be biopsied during the endoscopy. Adenocarcinoma of the esophagus is thought to develop from Barrett's esophagus due to further carcinogenic changes in the abnormal lining.
Other pre-existing esophageal conditions may also increase the risk of developing squamous cell carcinoma of the esophagus. Conditions like achalasia, which is a condition where there is ineffective peristalsis (movement) in the esophagus, as well as caustic esophageal injury, from lye ingestion, can increase the risk of esophageal cancer. Some experts believe a history of bulimia, which chronically exposes the esophagus to stomach contents, may also be a risk factor.
Barrett's esophagus is thought to be caused by chronic irritation due to stomach acid. This happens due to a defect in the lower esophageal sphincter, which separates the stomach from the esophagus. This sphincter is located at approximately the level of the diaphragm. When the sphincter is dysfunctional, acid can reflux, or pass from the stomach into the esophagus. This condition is commonly known as gastroesophageal reflux disease or GERD. This can result in heartburn, bloating, loss of appetite, and stomach pain. Additionally, some people complain of chronic cough from the reflux due to irritation of the voice box from the acid reflux. Patients with chronic GERD are at risk for developing Barrett's esophagus and hence are at higher risk for developing adenocarcinoma of the esophagus. It is not clear if GERD outside the setting of Barrett's esophagus increases the risk of esophageal cancer, though it appears a long or severe history of reflux may increase the risk of esophageal cancer. There are several conditions, which can cause or worsen GERD, including a condition known as a hiatal hernia, where portions of the stomach herniate or improperly move through the diaphragm into the chest, causing sphincter dysfunction and resulting reflux. Additionally, obesity, smoking, and certain foods such as coffee and chocolate may potentially worsen reflux.
How can I prevent esophageal cancer?
There is not a clear link between a family medical history of esophageal cancer and an individual's risk of developing esophageal cancer. Smoking is by far the strongest risk factor associated with the development of squamous cell cancer of the esophagus, with alcohol likely playing a supporting role. Therefore, smoking cessation and decreasing alcohol intake are by far the best methods of decreasing the risk of developing squamous cell carcinoma of the esophagus. There are several dietary factors, which have been linked with squamous cell carcinoma of the esophagus, predominantly foods containing N-nitroso compounds, as seen in pickled, dried or smoked foods. These food types should be avoided.
Adenocarcinomas of the esophagus tend to be more common in Caucasian males. As it is thought that the majority of adenocarcinomas develop from Barrett's esophagus, the best prevention of adenocarcinoma would be decreasing the risk of chronic GERD, the cause of Barrett's esophagus in the first place. Smoking, particularly in the setting of Barrett's esophagus, may increase the risk of developing adenocarcinomas of the esophagus. As previously mentioned, obesity may also increase the risk of developing adenocarcinoma of the esophagus. Additionally, decreasing caffeine intake may decrease the risk of adenocarcinoma of the esophagus. Decreasing alcohol intake may also reduce the risk of esophageal adenocarcinoma, but this is controversial. Certain genetic conditions that cause increased acid secretion, such as Zollinger-Ellison syndrome, may increase the risk of adenocarcinomas of the esophagus. Although pharmaceutical agents for the prevention of acid secretion (histamine blockers, proton pump inhibitors) can be effective for the prevention of GERD symptoms, there is no proof that they decrease the incidence of Barrett's esophagus. In fact, many think that it increases the risk, as it decreases the pressure of the sphincter between the esophagus and the stomach, making it easier for acid to reach the esophagus. More research into this is required before the answer is known. Once Barrett's esophagus has developed, there is also little evidence that medical treatments (histamine blockers and proton pump inhibitors) prevent the development of cancer. Some believe that proton pump inhibitors may cause Barrett's esophagus to regress and hence not develop into cancer. Again, this is mainly unproven. Surgical manipulation of the esophageal sphincter, making it more difficult for acid to reach the esophagus, may lead to regression, though again, this is unproven. The most important recommendation for someone with Barrett's esophagus is persistent surveillance, which will be discussed below under screening.
What screening tests are available?
There are no mass screening recommendations and no specific screening test that exists for squamous cell carcinoma of the esophagus. This makes it even more important to reduce the risk factors for squamous cell cancer-mainly smoking and heavy alcohol use. However, screening and surveillance is very important in patients with Barrett's esophagus (BE), to insure that it does not progress to adenocarcinoma.
The "gold standard" for diagnosis of BE is endoscopy and biopsy. Cost and the invasiveness of the procedure have fueled efforts to find an alternative diagnostic method. A screening test for Barrett's called Cytosponge has been tested in the UK. Cytosponge is a gelatin capsule attached to a string that when swallowed releases a mesh that collects esophageal cells. The cells collected using the Cytosponge were stained for trefoil factor 3, a biomarker for intestinal metaplasia (microscopic changes in the tissue) associated with BE. This has been shown to be an effective screening tool and research continues.
It has been estimated that there is approximately a 0.2%-2% risk annually of someone with Barrett's esophagus developing esophageal cancer, or a 10% lifetime risk. As above, various medical or surgical procedures can be done to attempt to reverse Barrett's esophagus, but the effect of these is uncertain. Therefore, the best way to insure that Barrett's esophagus causes no problems is repeat evaluations through biopsy via endoscopy. The primary goal of endoscopy is to detect dysplasia early. Although Barrett's esophagus, by definition, is when the lining of the esophagus is abnormal, there can be varied levels of "abnormal". This is graded in terms of dysplasia, which is a term that refers to how likely the Barrett's esophagus is to progress to cancer. In patients without dysplasia, but just simple replacement of normal esophageal lining with stomach lining, endoscopy is recommended every two to three years. In patients with mild or low-grade dysplasia, at least two endoscopies should be done six months apart, then yearly if those are OK. Patients with Barrett's esophagus with high grade dysplasia should be followed by endoscopy every 3 months, as these are considered premalignant changes that have a high likelihood of progressing to cancer. Areas of dysplasia can be treated during endoscopy. Ablative techniques exist, such as with a laser. Photodynamic therapy can be used to treat high-grade lesions using a compound to sensitize tumors to a specific wavelength of light, followed by light exposure to the tumor. Endoscopic resection of an involved portion of mucosa can also be used. What are signs of esophageal cancer?
Over 90% of people with esophageal cancer present with problems swallowing, often leading to a significant amount of weight loss prior to the actual diagnosis. Patients also report a sensation that food "gets stuck" somewhere in the chest, where the growing of the cancer precludes the passage of food. Problems usually start with food, though eventually even liquids could "get stuck" if the cancer progresses and continues to grow into the hollow tube that the esophagus is. This is similar to a bathroom drain being clogged-if something is in the pipe preventing water from draining, it backs up and is not allowed to pass. People with esophageal cancer often have pain with swallowing as well. Though these are the most common symptoms, others could exist, especially if the tumor grows through the esophageal wall or into other organs. Chest pain can occur in patients who have esophageal spasm, again from irritation from the tumor. A larger tumor can erode the wall to the point where it causes bleeding. This can cause patients to cough up blood, or vomit blood. Additionally, if the blood is swallowed, one may notice blood in the stool or black tarry stools also known as melena. The trachea (windpipe) is located directly in front of the esophagus, and it is possible for an esophageal cancer to erode the entire way through the esophageal wall and into the trachea, creating what is called a tracheoesophageal (respiratory) fistula. This causes cough, an irritating sensation with breathing (especially with deep breaths), and hoarseness.
How is esophageal cancer diagnosed and staged?
Work up of an esophageal cancer usually starts after the patient presents with symptoms. In the case of esophageal cancer, this usually means problems with swallowing. The first step is to establish the diagnosis of esophageal cancer. Initial tests sometimes include a barium swallow, where the person swallows barium to permit visualization of the contours of the esophagus on x-rays. Generally, the esophagus is smooth, and if there is a defect in the smooth contour of the esophagus, this may suggest a cancer. An endoscopy is commonly done when people first present with symptoms. Using endoscopy, the area of concern in the esophagus can be viewed directly with the fiber-optic camera, and the location of the abnormality, the presence or absence of bleeding, and the amount of obstruction can all be seen. Endoscopy also allows a biopsy to be performed. Once a biopsy is performed, the pathologist can determine if there is esophageal cancer, and whether it is adenocarcinoma or squamous cell carcinoma.
Once the diagnosis has been established, it is important to determine how much cancer is present in the esophagus, as well as whether it has spread to any other parts of the body (metastasis). This is known as cancer staging and plays an important role in selecting the optimal treatment for the cancer. If your doctor suspects that the tumor may have grown into the trachea, a bronchoscopy may be ordered, which allows the airways to be visualized. The standard of care today would also include performing an ultrasound during the endoscopy, called an endoscopic ultrasound examination (EUS). This allows for the prediction of how much of the esophageal wall is involved by tumor and the presence of enlarged lymph nodes that are involved with spread of tumor. A CT ("CAT") scan is also usually done to determine the amount of disease in the chest, though it is seemingly less accurate than the EUS. The CT scan should include imaging through the upper abdomen so that the liver and lymph nodes in the area of the stomach can be visualized. Other, more routine tests done before treatment include blood screening tests, to insure that overall blood counts are within normal limits, and that a patient's liver, kidneys, and overall health are normal. Other tests may also be included, as symptoms require. Granted, that is a lot of tests, though all are important to offer the best individual treatment for every person.
After all of these tests are performed, the stage of the cancer is determined. The staging of a cancer describes how much cancer has grown within the esophagus as well as whether it has spread. This is extremely important in terms of what treatment is offered to each individual patient. Before the staging systems are introduced, first some background on how cancers grow and spread, and therefore advance in stage.
Cancers cause problems because they spread and can disrupt the functioning of normal organs. One way esophageal cancer can spread is by local extension to invade through the normal structures in the chest and into adjacent structures. These include the trachea, the diaphragm, and even into the large veins and arteries emanating from the heart. All cancers can spread via local extension, and it is very common for esophageal cancer to spread quite extensively locally before diagnosis is obtained. This is what causes the many symptoms of esophageal cancer, including difficulties with swallowing, cough, bleeding, and subsequent fatigue and weight loss due to malnutrition.
Esophageal cancer can also spread by accessing the lymphatic system. The lymphatic circulation is a complete circulation system in the body (somewhat like the blood circulatory system) that drains into various lymph nodes. When cancer cells access this lymphatic circulation, they can travel to lymph nodes and start new sites of cancer. This is called lymphatic spread. Within the wall of the esophagus, there is an extensive network of lymphatic channels, hence a large proportion of patients present with lymph nodes already involved with cancer.
The first lymph nodes that cancer cells spread to are the lymph nodes found just along the side of the esophagus (peri-esophageal lymph nodes. Cancer can then spread into the middle of the chest (mediastinal lymph nodes) and into the areas of the neck above the collar bone (supraclavicular lymph nodes) or into the abdomen (peri-gastric and celiac lymph nodes), depending where the primary esophageal cancer is located.
Esophageal cancers can also spread through the bloodstream. Cancer cells gain access to distant organs via the bloodstream and the tumors that arise from cells' travel to other organs are called metastases. Cancers of the esophagus generally spread locally or to lymph nodes before spreading distantly through the bloodstream.
The staging system used in esophageal cancer is designed to describe the extent of disease within the esophagus, in the surrounding lymph nodes, and distantly. The staging system used to describe esophageal tumors is the "TNM system", as described by the American Joint Committee on Cancer. The TNM systems are used to describe many types of cancers. They have three components: T-describing the extent of the "primary" tumor (the tumor in the esophagus itself); N-describing the spread to the lymph nodes; M-describing the spread to other organs (i.e.-metastases). The staging system for esophageal cancer is complex. The most recent 7th edition (2010), TNM staging system provides a separate staging for squamous cell carcinoma and adenocarcinoma of the esophagus.
The "T" stage is as follows:
- Tis- High grade dysplasia (formerly carcinoma in situ).
- T1-tumor confined to the inner layer of the esophageal wall (submucosa , T1a or lamina propria, T1b).
- T2-tumor invades into the muscular layer of the wall (muscularis propria).
- T3-tumor invades into the outer layer of the wall (adventitia).
- T4-tumor invades into adjacent structures.
- T4a - resectable tumor invading pleura, pericardium, or diaphragm
- T4b - unresectable tumor invading other adjacent structures, such as aorta, vertebral body, trachea, etc.
The "N" stage is as follows for any subsite:
- Nx- Lymph nodes cannot be assessed.
- N0-no spread to lymph nodes.
- N1-tumor spread to 1-2 regional lymph nodes.
- N2- tumor spread to 3-6 regional nodes.
- N3- tumor spread to seven or more regional nodes.
The "M" stage is as follows:
- M0-no tumor spread to other organs
- M1-tumor spread to other organs
The overall stage is based on a combination of these T, N, and M parameters:
The following stages are the same for squamous cell & adenocarcinoma:
- IIIA - T1-2 N2, T3 N1, T4a N0, M0
- IIIB - T3 N2 M0
- IIIC - T4a N1-2 M0, T4b, N3 M0
- IV – any T, any M, the presence of any metastases (M1)
What are the treatments for esophageal cancer?
The treatment chosen for a person with esophageal cancer is greatly dependent on two main factors: the extent of the cancer and the general health state of the person. In people who have very early stage disease where it has not spread to lymph nodes or deep into the esophagus, surgery alone may be appropriate. Certain very early tumors, limited to the submucosa (the superficial layer of the esophagus), may be treated with endoscopic resection. However there are no head to head trials comparing surgical resection with endoscopic resection. More commonly, people present with advanced stage disease because symptoms often develop only after the tumor has grown to a large size or has spread. Therefore, there is often a large amount of tumor present before cancer treatment can even begin. There are a number of different modalities that can be used to treat esophageal cancer including surgery, radiation, and chemotherapy. However, in people who can tolerate it, combined modality treatment with surgery, radiation and chemotherapy is preferred.
Surgery, including removing the esophagus (called an esophagectomy) is a very aggressive procedure that is often not attempted on patients who are not in fairly good health. There are several different surgical procedures to remove the esophagus, however, generally the esophagus is removed either using an incision through the ribs and abdomen or the neck and abdomen. When the esophagus is removed, the stomach is pulled up into the chest to keep the passageway for food intact. Not only is there a risk of infection and bleeding from the surgery itself, but the recovery period after surgery can be difficult. Additionally, there is the risk of a leak forming at the new connection that is formed between the stomach and the remaining portion of the esophagus (known as an anastamosis), which can then require further surgery and potentially lead to very serious complications. In advanced esophageal cancer, there is still a high failure rate with surgery alone. These failures occur both locally (in the region of the primary tumor or regional lymph nodes) or distantly (from metastatic spread of cancer through the bloodstream). Many studies have looked into adding chemotherapy and radiation therapy to esophagectomy to attempt to add to the cure rate. Though the results of these studies are somewhat mixed, it is thought that both radiation and chemotherapy add a benefit. Therefore, radiation therapy (for local tumor control) and chemotherapy (for distant control as well as to improve the effectiveness of radiation therapy) is almost always recommended either before or after the surgery.
Radiation therapy makes the use of high energy x-rays to kill cancer cells. It does this by damaging the DNA in tumor cells. Normal cells in our body can repair radiation damage much quicker than tumor cells, so while tumor cells are killed by radiation, many normal cells are not. This is the basis for the use of radiation therapy in cancer treatment. Radiation is delivered using large machines that produce the high energy x-rays. After radiation oncologists set up the radiation fields ("radiation fields" are the areas of the body that will be treated by radiation), treatment is begun. Radiation is given 5 days a week for approximately 5-7 weeks at a radiation treatment center. The treatment takes just a few minutes each day and is completely painless. It is designed to kill tumor cells in the area that is at risk to contain cancer cells, whether it is in the esophagus or the regional lymph nodes. Typical side effects mainly include a sore throat, skin irritation (resembling a sunburn), and fatigue.
Chemotherapy is defined as medications that are used to kill tumor cells. The large advantage in using chemotherapy is that it travels throughout the entire body. Hence, if some tumor cells have spread outside of what surgery or radiation can treat, they can potentially be killed by chemotherapy. The additional important benefit from chemotherapy in the treatment of esophageal cancer is that it works with radiation, resulting in more killing of cancer cells. Similar to radiation, some normal cells are damaged during treatment, resulting in side effects. The exact side effects depend on which type of chemotherapy is used, though fatigue, some nausea, and a decrease in blood counts can result from commonly used chemotherapy agents.
There is some debate as to the optimal order in which to deliver these treatments to the esophagus. Different institutions may vary the order in which they use these three modalities in the attempt to cure esophageal cancer. Many will use radiation therapy combined with chemotherapy pre-operatively (prior to surgery). Combination platinum based chemotherapy (using several medications including one from the platinum family) is used; combinations include 5-FU and cisplatin (or oxaliplatin), carboplatin and paclitaxel, and cisplatin and etoposide. The advantage of using chemo and radiation together is that it often results in the decrease in the amount of tumor that needs to be removed and is able to be given to a patient who has not already had to undergo an extensive procedure. This allows for easier tolerance of the radiation and chemotherapy and also decreases the size of the radiation field required which reduces this toxicity from surgery. However, the toxicity from combining radiation with chemotherapy is worse than either alone. It is very important for the people to maintain their nutrition such that they can heal well in anticipation of surgery, which usually takes place around 4-8 weeks after chemoradiation. Surgery after chemotherapy and radiation appears to improve the local control further. However, some centers recommend post-operative treatment. The main advantage of this method is that surgery can be performed in an unirradiated field, allowing for a better surgical technique. Since the surgical removal of the entire tumor is the crucial step in therapy, this consideration often trumps any other.
In some cases, the person is too sick to undergo surgery, or may choose not to undergo surgery. In these cases, a combined, concurrent use of chemotherapy with radiation therapy is usually employed. This method has been proven better than radiation alone, and some think it can reach cure rates comparable to surgery, however this is still being studied. The combined use of radiation therapy and chemotherapy has toxicities as well-mainly irritation of the esophagus making it extremely painful and hence difficult to swallow towards the end of treatment. Some people are too sick to tolerate combined treatment and are treated with radiation or chemotherapy alone.
Advanced esophageal cancer is treated with chemotherapy using single agents or a combination of agents, including paclitaxel, carboplatin, cisplatin, 5FU, irinotecan, epirubicin, capecitabine, and docetaxel. Target therapies are also being used in patients with advanced or metastatic esophageal cancer. Two of those agents are Herceptin (targets/blocks Her2neu receptor) and ramucirumab (which blocks vascular endothelial growth factor (VGEF) receptor).
Other investigational agents that are being evaluated in clinical trials are targeting endothelial growth factor receptor (EGFR) and MET/hepatocyte growth factor receptors.
Alternatively, people can be treated with techniques to help alleviate the symptoms in the event that they are too sick to undergo radiation or chemotherapy. Advanced esophageal cancer that is incurable often leaves the patient with difficulty swallowing or unable to swallow at all. Chest pain and bleeding are other common symptoms that can require palliation (treatment to relieve symptoms, not necessarily treat the cancer). Radiation therapy is often used to achieve palliation, with varying success-especially with obstruction, though studies have reported improvement in swallowing in approximately 80% of patients. Actual mechanical stents can be placed in this scenario, a “balloon” used to temporarily open the esophagus or laser removal of tumor can be attempted. These can achieve symptom relief quicker, though they have their risks and are only temporary measures. Hence, these are usually followed by radiation therapy.
As different treatments may be effective in treating a patient's cancer, the more well-informed the better. Regardless of the treatment chosen, it is very important to work with the oncology physicians involved as well as specialists (gastroenterologist, nutritionist, speech pathologist, etc.) to maximize chance of cure and function after treatment.
For patients who have completed therapy, the National Comprehensive Cancer Network (NCCN) recommends follow up every 3 months for the first two years and then every 6 months for years 3-5. Labs and imaging studies are performed as clinically indicated. After treatment, talk with your oncology team about receiving a survivorship care plan, which can help you manage the transition to survivorship and learn about long-term concerns and life after cancer. You can create a care plan on OncoLink.
NCI General Cancer Information About Esophageal Cancer
Esophageal Cancer Awareness Association: Offers help and advice to patients, caregivers, survivors, family members affected by the disease.
Esophageal Cancer Action Network (ECAN): provides information and support for patients andcaregivers and public awareness.
ACOR Esophageal Cancer Group: email support group for esophageal cancer patients and families.
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