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, but without any invasion into normal tissues and without any spread. A malignant tumor is called cancer when these tumor cells gain the propensity to invade tissues and spread locally as well as to distant parts of the body. In this sense, esophageal cancer occurs when cells in the lining of the esophagus grow uncontrollably and form tumors that can invade normal tissues and spread to other 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 a 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 is no risk of spread, as no invasion has occurred. 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?

Esophageal cancer occurs in approximately 13,500 Americans per year, causing about 12,500 deaths. Most patients are diagnosed in their 50s or 60s, with approximately four times as many men diagnosed than women. This being said, there is a dichotomy 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 (with smoking being the stronger), there seems to be a synergistic effect between the two 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 for the development of squamous cell carcinoma of the esophagus are nitrosamines, asbestos fibers, and petroleum products.

This is contrasted with the group of patients at risk for adenocarcinoma, usually of the lower esophagus. Adenocarcinoma was previously a much rarer disease, compared to squamous cell carcinoma. However, it has recently become even more prevalent than squamous cell carcinoma. 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 resembling the stomach. Barrett's esophagus is diagnosed by endoscopy, which is using a fiberoptic camera to look down into the esophagus and to biopsy any suspicious areas.

Adenocarcinoma of the esophagus is thought to develop from Barrett's esophagus from further carcinogenic changes in the abnormal lining. Barrett's esophagus is thought to be caused by the chronic exposure of the lower esophagus to gastric acid. This exposure happens in patients with gastro-esophageal reflux disease (GERD), which causes patients symptoms of heartburn, bloating, loss of appetite, or stomach pains with food or (often) at night while sleeping. Patients with chronic GERD are at risk for developing Barrett's esophagus and hence are at higher risk for developing adenocarcinoma of the esophagus. In addition, other patient attributes that put patients at risk for GERD (obesity, smoking, hiatal hernia) may also place the patient at risk for Barrett's esophagus.

How can I prevent 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.

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. Though much of this is out of the patient's control, decreasing caffeine intake, decreasing alcohol intake, smoking cessation, and preventing obesity can all decrease reflux. 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 symptomatic 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 aforementioned 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 for the general public per se, and there exists no screening test at all 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, to insure that it does not progress to adenocarcinoma.

As above, various medical or surgical procedures can be done to attempt to reverse Barrett's esophagus, but the effect of these is unsubstantiated. Therefore, the best way to insure that Barrett's esophagus causes no problems is repeat evaluations through biopsy via endoscopy. Although Barrett's esophagus, by definition, is when the lining of the esophagus is abnormal, there can be varied levels of how 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 or actually undergo treatment, as these are considered premalignant changes that have a high likelihood of progressing to cancer.

What are signs of esophageal cancer?

Over 90% of patients with esophageal cancer present with problems swallowing, often leading to a significant amount of weight loss prior to the actual diagnosis. Patients often complain of 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. This is obviously uncomfortable for the patient and could even cause pain with swallowing if the normal lining of the esophagus is irritated by the growing tumor. 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, noticed either when the patient vomits or with blackening of the stool (called melena). The trachea (windpipe) is directly in front of the esophagus and it is possible that an esophageal cancer could 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?

Diagnosis

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 entire point of all of the tests done prior to treatment of the esophageal cancer is to determine the extent of disease that is present so that treatment can be adjusted accordingly. This includes documenting the extent of disease both locally, in the tissues surrounding the esophagus, as well as insuring there is no spread distantly, outside the area of the esophagus (called metastases).

The most sensitive test to document local disease is the endoscopy. With the 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 be seen. It may be required to also perform a laryngoscopy (looking at the throat) and a bronchoscopy (looking at the trachea and airways) depending on the location and extent of the esophageal cancer. 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 with over 90% accuracy and the presence of any lymph nodes that are involved with spread of tumor with over 75% accuracy.

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 to insure against spread to the liver or lymph nodes in the area of the stomach. In addition, a barium swallow test is often performed, whereby the patient swallows barium and an x-ray is taken of the chest to determine the source of obstruction. 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 patient.

To obtain a diagnosis of any cancer, tissue or cells must be examined by a pathologist. Therefore, to obtain a diagnosis of esophageal cancer, a biopsy is usually obtained during the endoscopy. Though the extent of disease is usually not obtained, the type of cancer (almost always adenocarcinoma or squamous cell carcinoma) is known after the biopsy.

Staging

After all of these tests are performed, the stage of the cancer is known. The staging of a cancer basically describes how much it is grown before the diagnosis has been made, documenting the extent of disease. This is often 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. Hence, the incidence of distant metastases upon diagnosis is fairly low. It was previously thought that esophageal cancer almost never spread distantly. However, as more and more patients are cured of their local disease with advancements in therapy, this is unfortunately now known not to be the case.

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 "T" stage is as follows:

Tis - carcinoma in situ
T1 - tumor confined to the inner layer of the esophageal wall (submucosa or lamina propria)
T2 - tumor invades into the muscular layer of the wall
T3 - tumor invades into the outer layer of the wall (adventitia)
T4 - tumor invades into other structures or organs.

The "N" stage is as follows for any subsite:

N0 - no spread to lymph nodes
N1 - tumor spread to regional lymph nodes
(lymph nodes outside the chest are considered "M1")

The "M" stage is as follows:

M0 - no tumor spread to other organs
M1 - tumor spread to other organs.

This is also broken down by site of the primary tumor within the esophagus:
Tumors of the lower esophagus:

M1a - cancer spread to the lymph nodes in the abdomen (called celiac nodes).
M1b - cancer has spread to other parts of the body.
Tumors of the upper esophagus:

M1a - cancer spread to the lymph nodes in the neck (called cervical or supraclavicular nodes).
M1b - cancer has spread to other parts of the body.

The overall stage is based on a combination of these T, N, and M parameters:

Stage 0 - Cancer in situ.
Stage I - Cancer in the two inside layers of the esophagus (T1N0M0)
Stage IIA - Cancer in any of the four layers of the esophagus (T2-3N0M0)
Stage IIB - Cancer in any layer of the esophagus, with spread to lymph nodes near the tumor (T1-2N1M0)
Stage III - Cancer is in the outside layer of the esophagus, or through the wall. Cancer is also in the lymph nodes (T3-4N1M0)
Stage IVA - Cancer spread to the lymph nodes of the abdomen or neck (T1-4N0-1M1a)
Stage IVB - Cancer has spread to other parts of the body (T1-4N0-1M1b)

Though complicated, these staging systems help physicians determine the extent of the cancer, and therefore make treatment decisions regarding a patient's cancer.

What are the treatments for esophageal cancer?

The treatment chosen for a patient with esophageal cancer is greatly dependent on two main factors: the extent of the cancer and the general health state of the patient. In order to undergo curative treatment, a patient must be able to tolerate the aggressive therapy required. The reason aggressive therapy is required to cure esophageal cancer is that it usually grows to an advanced stage before causing noticeable symptoms. Therefore, there is often a large amount of tumor present before cancer treatment can even begin. Multi-modality treatment is usually required for cure.

This includes chemotherapy, radiation therapy, and surgery. Most would agree that the addition of surgery to radiation and chemotherapy adds a benefit. However, this surgery (removing the esophagus-an esophagectomy-and exploration of the regional lymph nodes) is a very aggressive procedure that is often not attempted on patients who are not in fairly good health. 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 is a difficult one, mainly from a nutritional standpoint. That being said, surgical resection as at least part of the therapy regimen likely yields the best results.

In esophageal cancer however, 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 potentiate 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 drugs that are used to kill tumor cells. The large advantage in using chemotherapy is that, since it is a medicine, is 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 any chemotherapy.

Different institutions 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. The advantage of this method is that it often results in the decrease in the amount of tumor that needs to be removed and is able to be given in 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. This also results in less toxicity. 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.

Again, however, the extensiveness of an esophagectomy should be stressed. The toxicity associated with the surgery leads many physicians to recommend against surgery. Also many patients either choose not to undergo the procedure or are simply not in the physical shape required to tolerate the 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. 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. However, it obviously spares the patient the extensive surgical procedure.

Another issue that commonly comes up in patients with esophageal cancer is that of palliation of symptoms. 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. Radiation therapy is often used to achieve palliation, with varying success-especially with obstruction, though studies have reported palliation of the obstruction of swallowing in approximately 80% of patients. Actual mechanical stents can also be placed in this scenario or laser removal of tumor can be attempted. These can achieve symptom relief quicker, though they are invasive procedures with their own inherent risks and are also only temporary measures. Hence, these are usually followed by radiation therapy.

Patients being followed for Barrett's esophagus often require treatment for high-grade dysplasia. In addition, there is the rare patient who presents with carcinoma in situ or with an early stage esophageal cancer. The standard of care in these patients is esophagectomy. However, radiation therapy delivered locally by radioactive sources (called brachytherapy), laser ablation, and photodynamic therapy (using light activated drugs to kill the abnormal cells) have also been used in patients who wish to keep their esophagus.

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 physicians involved as well as specialists (nutritionists, speech pathologists, etc.) to maximize chance of cure and function after treatment. Obviously the best treatment for cancer is prevention of ever developing cancer. By far, the best prevention is not smoking or immediate smoking and alcohol cessation.