Marine invertebrates, algae, and microorganisms are prolific producers of novel secondary metabolites. Some of these secondary metabolites have the potential to be developed as chemotherapeutic agents for the treatment of a wide variety of diseases, including cancer. We describe here the mechanism leading to apoptosis of esophageal cancer cell lines in the presence of triprenylated toluquinones and toluhydroquinones originally isolated from the Arminacean nudibranch Leminda millecra. Triprenylated toluquinone–induced and toluhydroquinone-induced cell death is mediated via apoptosis after a cell cycle block. Molecular events include production of reactive oxygen species (ROS), followed by induction and activation of c-Jun (AP1) via c-Jun-NH2-kinase–mediated and extracellular signal-regulated kinase–mediated pathways. Partial resistance to these compounds could be conferred by the ROS scavengers Trolox and butylated hydroxyanisol, a c-Jun-NH2-kinase inhibitor, and inhibition of c-Jun with a dominant negative mutant (TAM67). Interestingly, the levels of ROS produced varied between compounds, but was proportional to the ability of each compound to kill cells. Because cancer cells are often more susceptible to ROS, these compounds present a plausible lead for new antiesophageal cancer treatments and show the potential of the South African marine environment to provide new chemical entities with potential clinical significance. [Mol Cancer Ther 2007;6(9):2535–43]

Footnotes

Grant support: Cancer Association of South Africa, South African National Research Foundation, South African Government Department of Environmental Affairs and Tourism, Rhodes University, and University of Cape Town.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

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Most of the length of the esophagus is lined with squamous cells. If a malignant tumor grows here, it’s called squamous cell cancer. The areas at the bottom of the esophagus and where the esophagus joins the stomach are lined with columnar cells. If a malignant tumor grows here, it’s called adenocarcinomas. Some studies have shown that esophageal adenocarcinoma is the fastest growing cancer in the western world.

Studies show a relationship between frequency of reflux symptoms and risk of adenocarcinoma. The constant acid reflux will irritate the lining of the esophagus, and complications can occur, such as Barrett’s esophagus. Individuals with Barrett’s esophagus are at an increased risk of developing adenocarcinoma. Barrett’s esophagus is a condition in which the lining of the esophagus is replaced by tissue that is similar to that which is normally found in the stomach and intestine. The process of this change is called intestinal metaplasis. Individuals with Barrett’s esophagus are about 40 times more likely to develop esophageal cancer than individuals in the general population.

Symptoms of esophageal cancer

—      Heartburn

—      Difficulty swallowing

—      Inability to swallow solid foods (eventually liquids also)

—      Pain with swallowing

—      Food sticking in esophagus

—      Weight loss

—      Regurgitation of undigested food

—      Vomiting blood or passing old blood with bowel movements

Procedures used to diagnose esophageal cancer

—      Endoscopy

—      Barium x-rays

—      Computed tomography

—      CT scan

Treatment of esophageal cancer

As with any type of cancer, the treatment will depend on the stage the cancer is in at the time of diagnosis, the overall condition of the patient, and whether the cancer has spread to other organs.

If the cancer has not spread to other organs, thus making it potentially curable, surgery can be performed to remove the majority of the esophagus. In some cases, the surgery will also involve removing the stomach, spleen, and lymph nodes inside the chest. Then another part of the lower bowel is pulled up and attached to the remaining section of esophagus. They may receive chemotherapy and radiotherapy treatments after the surgery.

If the cancer has spread to other organs, combined chemotherapy and radiotherapy is the most common treatment. This form of treatment is also used in the cases where the patient can’t have surgery.

Whether preoperative chemotherapy and radiation therapy can improve a patient’s prognosis is still under study by many cancers centers.

Prognosis for those with esophageal cancer

If the cancer is diagnosed in it’s earliest stages, the patient’s chances of living and be cancer free five years after treatment is greatly inproved. Unfortunately, most cases of esophageal cancer is only discovered when the patient comes to their doctor because of swallowing difficulty, which doesn’t happen until later stages of the cancer growth. The prognosis then is very poor.

Esophageal cancer will often recur, despite surgery, chemotherapy and radiation.

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Esophageal mesothelioma cancer occurs in about 11,000 Americans per year. This accounts for less than 1% of all cancers. However, the incidence of esophageal cancer is increasing.

Cancer can develop in any part of the esophagus. It can spread to surrounding lymph nodes, the windpipe, and the large blood vessels in the chest, and other nearby organs. Treatment for esophageal mesothelioma cancer depends on a number of factors, including its exact location, size, extent, and type of cancer cells. It’s also important to consider age and general health to develop a treatment plan to fit each patient’s needs.

Causes of Esophageal Mesothelioma Cancer

Esophageal mesothelioma cancer occurs in the larynx (voice box) and oropharynx that is the part of the throat at the back of the mouth. There is sufficient to suggest that asbestos exposure is a cause of laryngeal cancer. There is insufficient evidence at this time to prove that asbestos is a cause of pharyngeal cancer.

Types of Esophageal Cancer

Squamous cell carcinomas occur in the cells that line the esophagus. Adenocarcinomas occur in the glandular tissue in the lower part of the esophagus and can spread to other parts of the body.

Symptoms of Esophageal Mesothelioma Cancer

Difficulty in swallowing, a feeling of fullness, pressure, or burning as food goes down the esophagus, a feeling of food getting stuck behind the breastbone.

Methods of Diagnosis

Esophagram (also called a barium swallow), is a series of x-rays of the esophagus. To prepare for this test, the patient drinks a barium solution. The barium, which shows up on x-rays, coats the inside of the esophagus for easier viewing. Esophagoscopy is a thin, flexible, lighted instrument (an endoscope) which is passed through the mouth and down the throat to the esophagus to view where the esophagus joins the stomach. Biopsy is a removal of a small amount of tissue through the endoscope to test for the presence of cancer.

Staging

The nature of the tumor is primarily evaluated by a CT scan of the chest. A CT scan reveals if the tumor has travelled into the trachea (windpipe) and large blood vessels or lymph nodes.

Esophageal ultrasound is similar to esophagoscopy, but with the addition of a built-in ultrasound devise.

PET scanning can also be used to evaluate esophageal cancer.

Treatment of Esophageal Mesothelioma Cancer

Treatment for esophageal cancer is contingent upon a number of factors, including its exact location, size, extent, and type of cancer cells. The doctor also considers the patient’s age and general health to develop the best treatment plan.

Surgical resection (removal) of the tumor is the preferred treatment. Recently, surgeons have been using minimally invasive surgical techniques to remove esophageal cancers.

Chemotherapy and radiation are also frequently used, either in conjunction with surgery or independently.

Several additional options are available, including laser treatment, tumor stenting, or photodynamic therapy. For most patients, their ability to eat can be restored satisfactorily using these procedures.

A multidisciplinary team: gastroenterologist, surgeon, oncologist (cancer specialist), radiation oncologist, nurse, dietitian, and social worker join in the facilitation of patient treatment and care.

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The esophagus is the hollow, muscular tube that moves food and liquid from the throat to the stomach. The wall of the esophagus is made up of several layers of tissue, including mucous membrane, muscle, and connective tissue. Esophagealcancer starts at the inside lining of the esophagus and spreads outward through the other layers as it grows.

The two most common forms of esophageal cancer are named for the type of cells that become malignant (cancerous):

—      Squamous cell carcinoma: Cancer that forms in squamous cells, the thin, flat cells lining the esophagus. This cancer is most often found in the upper and middle part of the esophagus, but can occur anywhere along the esophagus. This is also called epidermoid carcinoma.

—      Adenocarcinoma: Cancer that begins in glandular (secretory) cells. Glandular cells in the lining of the esophagus produce and release fluids such as mucus. Adenocarcinomas usually form in the lower part of the esophagus, near the stomach.

Smoking, heavy alcohol use, and Barrett’s esophagus can affect the risk of developing esophageal cancer.

Risk factors include the following:

—      Tobacco use.

—      Heavy alcohol use.

—      Barrett’s esophagus: A condition in which the cells lining the lower part of the esophagus have changed or been replaced with abnormal cells that could lead to cancer of the esophagus. Gastric reflux (the backing up of stomach contents into the lower section of the esophagus) may irritate the esophagus and, over time, cause Barrett’s esophagus.

—      Older age.

—      Being male.

—      Being African-American.

The most common signs of esophageal cancer are painful or difficult swallowing and weight loss.

These and other symptoms may be caused by esophageal cancer or by other conditions. A doctor should be consulted if any of the following problems occur:

—      Painful or difficult swallowing.

—      Weight loss.

—      Pain behind the breastbone.

—      Hoarseness and cough.

—      Indigestion and heartburn.

Tests that examine the esophagus are used to detect (find) and diagnose esophageal cancer.

The following tests and procedures may be used:

—      Chest x-ray: An x-ray of the organs and bones inside the chest. An x-ray is a type of energy beam that can go through the body and onto film, making a picture of areas inside the body.

—      Barium swallow: A series of x-rays of the esophagus and stomach. The patient drinks a liquid that contains barium (a silver-white metallic compound). The liquid coats the esophagus and x-rays are taken. This procedure is also called an upper GI series.

—      Esophagoscopy: A procedure to look inside the esophagus to check for abnormal areas. An esophagoscope (a thin, lighted tube) is inserted through the mouth or nose and down the throat into the esophagus. Tissue samples may be taken for biopsy.

—      Biopsy: The removal of cells or tissues so they can be viewed under a microscope to check for signs of cancer. The biopsy is usually done during an esophagoscopy. Sometimes a biopsy shows changes in the esophagus that are not cancer but may lead to cancer.

Certain factors affect prognosis (chance of recovery) and treatment options.

The prognosis (chance of recovery) and treatment options depend on the following:

—      The stage of the cancer (whether it affects part of the esophagus, involves the whole esophagus, or has spread to other places in the body).

—      The size of the tumor.

—      The patient’s general health.

—      When esophageal cancer is found very early, there is a better chance of recovery. Esophageal cancer is often in an advanced stage when it is diagnosed. At later stages, esophageal cancer can be treated but rarely can be cured. Taking part in one of the clinical trials being done to improve treatment should be considered. Information about ongoing clinical trials is available from the NCI Web site.

Stages of Esophageal Cancer

Key Points:

—      After esophageal cancer has been diagnosed, tests are done to find out if cancer cells have spread within the esophagus or to other parts of the body.

—      The following stages are used for esophageal cancer:

After esophageal cancer has been diagnosed, tests are done to find out if cancer cells have spread within the esophagus or to other parts of the body.

The process used to find out if cancercells have spread within the esophagus or to other parts of the body is called staging. The information gathered from the staging process determines the stage of the disease. It is important to know the stage in order to plan treatment. The following tests and procedures may be used in the staging process:

—      Bronchoscopy: A procedure to look inside the trachea and large airways in the lung for abnormal areas. A bronchoscope (a thin, lighted tube) is inserted through the nose or mouth into the trachea and lungs. Tissue samples may be taken for biopsy.

—      Chest x-ray: An x-ray of the organs and bones inside the chest. An x-ray is a type of energy beam that can go through the body and onto film, making a picture of areas inside the body.

—      Laryngoscopy: A procedure in which the doctor examines the larynx (voice box) with a mirror or with a laryngoscope (a thin, lighted tube).

—      CT scan (CAT scan): A procedure that makes a series of detailed pictures of areas inside the body, taken from different angles. The pictures are made by a computer linked to an x-ray machine. A dye may be injected into a vein or swallowed to help the organs or tissues show up more clearly. This test is also called computed tomography, computerized tomography, or computerized axial tomography.

—      Endoscopic ultrasound (EUS): A procedure in which an endoscope (a thin, lighted tube) is inserted into the body. The endoscope is used to bounce high-energy sound waves (ultrasound) off internal tissues or organs and make echoes. The echoes form a picture of body tissues called a sonogram. This procedure is also called endosonography.

—      Thoracoscopy: A surgical procedure to look at the organs inside the chest to check for abnormal areas. An incision (cut) is made between two ribs and a thoracoscope (a thin, lighted tube) is inserted into the chest. Tissue samples and lymph nodes may be removed for biopsy. In some cases, this procedure may be used to remove portions of the esophagus or lung.

—      Laparoscopy: A surgical procedure to look at the organs inside the abdomen to check for signs of disease. Small incisions (cuts) are made in the wall of the abdomen, and a laparoscope (a thin, lighted tube) is inserted into one of the incisions. Other instruments may be inserted through the same or other incisions to perform procedures such as removing organs or taking tissue samples for biopsy.

—      PET scan (positron emission tomography scan): A procedure to find malignanttumor cells in the body. A small amount of radionuclide glucose (sugar) is injected into a vein. The PET scanner rotates around the body and makes a picture of where glucose is being used in the body. Malignant tumor cells show up brighter in the picture because they are more active and take up more glucose than normal cells. The use of PET for staging esophageal cancer is being studied in clinical trials.

The following stages are used for esophageal cancer:

Stage 0 (Carcinoma in Situ)

In stage 0, cancer is found only in the innermost layer of cells lining the esophagus. Stage 0 is also called carcinoma in situ.

Stage I

In stage I, cancer has spread beyond the innermost layer of cells to the next layer of tissue in the wall of the esophagus.

Stage II

Stage II esophageal cancer is divided into stage IIA and stage IIB, depending on where the cancer has spread.

—      Stage IIA: Cancer has spread to the layer of esophageal muscle or to the outer wall of the esophagus.

—      Stage IIB: Cancer may have spread to any of the first three layers of the esophagus and to nearby lymph nodes.

Stage III

In stage III, cancer has spread to the outer wall of the esophagus and may have spread to tissues or lymph nodes near the esophagus.

Stage IV

Stage IV esophageal cancer is divided into stage IVA and stage IVB, depending on where the cancer has spread.

—      Stage IVA: Cancer has spread to nearby or distant lymph nodes.

—      Stage IVB: Cancer has spread to distant lymph nodes and/or organs in other parts of the body.

Recurrent Esophageal Cancer

Recurrentesophagealcancer is cancer that has recurred (come back) after it has been treated. The cancer may come back in the esophagus or in other parts of the body.

Treatment Option Overview

Key Points:

—      There are different types of treatment for patients with esophageal cancer.

—      Five types of standard treatment are used:

—      Other types of treatment are being tested in clinical trials.

—      Patients have special nutritional needs during treatment for esophageal cancer.

There are different types of treatment for patients with esophageal cancer.

Different types of treatment are available for patients with esophagealcancer. Some treatments are standard (the currently used treatment), and some are being tested in clinical trials. Before starting treatment, patients may want to think about taking part in a clinical trial. A treatment clinical trial is a research study meant to help improve current treatments or obtain information on new treatments for patients with cancer. When clinical trials show that a new treatment is better than the standard treatment, the new treatment may become the standard treatment.

Clinical trials are taking place in many parts of the country. Information about ongoing clinical trials is available from the NCI Web site. Choosing the most appropriate cancer treatment is a decision that ideally involves the patient, family, and health care team.

Five types of standard treatment are used:

Surgery

Surgery is the most common treatment for cancer of the esophagus. Part of the esophagus may be removed in an operation called an esophagectomy. The doctor will connect the remaining healthy part of the esophagus to the stomach so the patient can still swallow. A plastic tube or part of the intestine may be used to make the connection. Lymph nodes near the esophagus may also be removed and viewed under a microscope to see if they contain cancer. If the esophagus is partly blocked by the tumor, an expandable metal stent (tube) may be placed inside the esophagus to help keep it open.

Radiation therapy

Radiation therapy is a cancer treatment that uses high-energy x-rays or other types of radiation to kill cancer cells. There are two types of radiation therapy. External radiation therapy uses a machine outside the body to send radiation toward the cancer. Internal radiation therapy uses a radioactive substance sealed in needles, seeds, wires, or catheters that are placed directly into or near the cancer. The way the radiation therapy is given depends on the type and stage of the cancer being treated.

A plastic tube may be inserted into the esophagus to keep it open during radiation therapy. This is called intraluminal intubation and dilation.

Chemotherapy

Chemotherapy is a cancer treatment that uses drugs to stop the growth of cancer cells, either by killing the cells or by stopping the cells from dividing. When chemotherapy is taken by mouth or injected into a vein or muscle, the drugs enter the bloodstream and can reach cancer cells throughout the body (systemic chemotherapy). When chemotherapy is placed directly into the spinal column, an organ, or a body cavity such as the abdomen, the drugs mainly affect cancer cells in those areas (regional chemotherapy). The way the chemotherapy is given depends on the type and stage of the cancer being treated.

Laser therapy

Laser therapy is a cancer treatment that uses a laser beam (a narrow beam of intense light) to kill cancer cells.

Electrocoagulation

Electrocoagulation is the use of an electric current to kill cancer cells.

Other types of treatment are being tested in clinical trials.

Information about ongoing clinical trials is available from the NCI Web site.

Patients have special nutritional needs during treatment for esophageal cancer.

Many people with esophageal cancer find it hard to eat because they have difficulty swallowing. The esophagus may be narrowed by the tumor or as a side effect of treatment. Some patients may receive nutrients directly into a vein. Others may need a feeding tube (a flexible plastic tube that is passed through the nose or mouth into the stomach) until they are able to eat on their own.

Treatment Options By Stage

Stage 0 Esophageal Cancer (Carcinoma in Situ)

Treatment of stage 0 esophageal cancer (carcinoma in situ) is usually surgery.

Stage I Esophageal Cancer

Treatment of stage I esophageal cancer may include the following:

—      Surgery.

—      Clinical trials of chemotherapy plus radiation therapy, with or without surgery.

—      Clinical trials of new therapies used before or after surgery.

This summary section refers to specific treatments under study in clinical trials, but it may not mention every new treatment being studied. Information about ongoing clinical trials is available from the NCI Web site.

Stage II Esophageal Cancer

Treatment of stage II esophageal cancer may include the following:

—      Surgery.

—      Clinical trials of chemotherapy plus radiation therapy, with or without surgery.

—      Clinical trials of new therapies used before or after surgery.

This summary section refers to specific treatments under study in clinical trials, but it may not mention every new treatment being studied. Information about ongoing clinical trials is available from the NCI Web site.

Stage III Esophageal Cancer

Treatment of stage III esophageal cancer may include the following:

—      Surgery.

—      Clinical trials of chemotherapy plus radiation therapy, with or without surgery.

—      Clinical trials of new therapies used before or after surgery.

This summary section refers to specific treatments under study in clinical trials, but it may not mention every new treatment being studied. Information about ongoing clinical trials is available from the NCI Web site.

Stage IV Esophageal Cancer

Treatment of stage IV esophageal cancer may include the following:

—      External or internal radiation therapy as palliative therapy to relieve symptoms and improve quality of life.

—      Laser surgery or electrocoagulation as palliative therapy to relieve symptoms and improve quality of life.

—      Chemotherapy.

—      Clinical trials of chemotherapy.

This summary section refers to specific treatments under study in clinical trials, but it may not mention every new treatment being studied. Information about ongoing clinical trials is available from the NCI Web site.

Treatment Options for Recurrent Esophageal Cancer

Treatment of recurrentesophagealcancer may include the following:

—      Use of any standard treatments as palliative therapy to relieve symptoms and improve quality of life.

—      Clinical trials of new therapies used before or after surgery.

This summary section refers to specific treatments under study in clinical trials, but it may not mention every new treatment being studied. Information about ongoing

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Esophageal cancer is a malignant (cancerous) tumor of the esophagus, the muscular tube that transports food from the mouth to the stomach.

Alternative Names

Cancer - esophagus

Causes, incidence, and risk factors

Esophageal cancer is relatively uncommon in the United States, and occurs most often in men over 50 years old. It affects less than 5 in 100,000 people. There are two main types of esophageal cancer –squamous cell carcinoma and adenocarcinoma. These two types look different from each other under the microscope.

Squamous cell cancer is associated with smoking and alcohol consumption. The incidence of this disease in the United States has remained mostly the same, while the incidence of adenocarcinoma of the esophagus has risen dramatically.

Barrett’s esophagus, a complication of gastroesophageal reflux disease (GERD), is a risk factor for the development of adenocarcinoma of the esophagus.

Risk factors for adenocarcinoma of the esophagus include male gender, obesity, western diet, and smoking.

Symptoms

—      Difficulty swallowing solids or liquids

—      Regurgitation of food

—      Heartburn

—      Weight loss

—      Vomiting blood

—      Chest pain unrelated to eating

Signs and tests

—      Barium swallow

—      EGD (esophagogastroduodenoscopy) and biopsy

—      Chest MRI or thoracic CT (usually used for helping to determine the stage of the disease)

—      PET scan (sometimes useful for determining the stage of disease, and whether surgery is possible)

—      Evidence of occult (hidden) blood in stool

Treatment

When esophageal cancer is only in the esophagus and has not spread elsewhere, surgery is the treatment of choice. The goal of surgery, in most cases, is to cure the patient. In some circumstances chemotherapy, radiation, or a combination of the two will be used to make surgery easier to perform.

In patients who cannot tolerate surgery, or in situations where the cancer has spread to other organs (metastatic disease), chemotherapy or radiation may be used to help reduce symptoms (this is called palliative therapy). In such circumstances, however, the disease is usually not curable.

Other treatments that may be used to improve a patient’s ability to swallow include endoscopic dilation of the esophagus (sometimes with placement of a stent), or photodynamic therapy. In photodynamic therapy, a special drug is injected into the tumor, which is then exposed to light. The light activates the medicine that attacks the tumor.

 

Support Groups

The stress of illness can often be eased by joining a support group of people who share common experiences and problems. See cancer - support group.

Expectations (prognosis)

Esophageal cancer is a very difficult disease to treat, but it can be cured in patients whose disease is confined to the esophagus. In circumstances in which surgery can be performed, cure rates are in the range of 25%.

In some circumstances in which the cancer is localized to the esophagus and radiation therapy is used instead of surgery, cure is possible but is less likely than with surgery.

For patients whose cancer has spread outside the esophagus, cure is generally not possible and treatment is directed toward relief of symptoms.

Complications

—      Severe weight loss resulting from not eating enough, or difficulty swallowing

—      Spread of the tumor to other areas of the body

Calling your health care provider

Call your health care provider if difficulty swallowing, with no known cause, does not get better; call if other symptoms develop that may point to esophageal cancer.

Prevention

Avoiding smoking and reducing or eliminating alcohol consumption may help reduce the risk of developing squamous cell cancer of the esophagus.

Surveillance EGD (esophagogastroduodenoscopy) and biopsy in people with Barrett’s esophagus may lead to early detection and improved survival. People with symptoms of severe reflux should seek medical attention.

People diagnosed with Barrett’s esophagus should see a gastroenterologist (digestive system specialist) at least every year.

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Although significant advancements have been made in the treatment of esophageal cancer, this aggressive malignancy commonly presents as locally advanced disease with a poor prognosis. Despite improvements in the detection of premalignant pathology, newer preventative strategies, and the development of more effective combination therapies, the overall incidence of esophageal carcinomas has risen. A clear association has been established between the development of esophageal cancer and Helicobacter pylori infection, gastroesophageal reflux disease, smoking, and heavy alcohol use. However, the growing number of newly diagnosed esophageal adenocarcinomas, despite widespread treatments with proton pump inhibitors and the eradication of H. pylori, leaves the medical community searching for more answers. There is a potential link between esophageal adenocarcinoma and obesity. Common presenting symptoms of esophageal cancer are dysphagia, odynophagia, and progressive weight loss. The initial assessment for patients with these symptoms is made with double-contrast barium esophagraphy. Treatment modalities include surgery, chemotherapy, radiation therapy, or a combination of modalities. Prevention strategies include smoking and alcohol cessation. (Am Fam Physician 2006; 73:2187-94.

Epithelial tumors of the esophagus (i.e., squamous cell and adenocarcinoma) are responsible for more than 95 percent of all esophageal carcinomas, with an estimated 14,520 newly diagnosed cases and 13,570 deaths in 2005.1 Nonepithelial cell carcinomas of the esophagus (e.g., metastatic tumors, lymphomas, sarcomas) are rare, and no evidence has suggested an increasing trend.

A large portion of new patients with esophageal cancer will present with advanced disease (i.e., stages III and IV). Of this group, 90 percent will have had vague symptomatology for approximately two to four months.2 There is a need for early detection, aggressive evaluation, and timely referral to an appropriate subspecialist.

Epidemiology

Epidemiologic data have shown considerable variability in determining trends in incidence of gastrointestinal malignancies worldwide, emphasizing that multifactorial etiologies are responsible. A strong association consistently has been demonstrated between Helicobacter pylori infection and gastric cancer.3 The overall worldwide decrease in the incidence of gastric cancer may be attributed to the aggressive treatment of H. pylori, but the overall incidence of esophageal cancer is on the rise.

The rising incidence of esophageal cancer over the past two decades coincides with a change in histologic type and primary tumor location. Adenocarcinoma of the esophagus has slowly replaced squamous cell carcinoma as the most common type of esophageal malignancy in the United States and Western Europe.4 Within the United States, the reported mean incidence of esophageal cancer in patients younger than 80 years is 3.2 per 100,000 persons, with an overall male-to-female ratio of 3:1.5

the major risk factors for esophageal squamous cell carcinoma and adenocarcinoma. Squamous cell carcinoma occurs more commonly in black than white patients and more commonly in men than women, although the prevalence in women has been increasing steadily. Smoking and alcohol ingestion are proven etiologic factors in the development of squamous cell carcinoma, and there is an association between other esophageal irritants such as lye ingestion, rapidly consumed high-starch diets without fruits and vegetables, and radiation therapy.2 There also may be a causal relationship between esophageal tumors and diseases affecting the esophagus and nearby structures such as achalasia, previous head and neck cancer, and Plummer-Vinson syndrome (i.e., esophageal webs associated with iron deficiency anemia).

In contrast to squamous cell carcinoma, it is unclear to what extent, if any, smoking and alcohol contribute to the development of esophageal adenocarcinoma. There is a proven association between adenocarcinoma and Barrett’s esophagus, a condition in which metaplastic columnar epithelium replaces normal stratified squamous mucosa that appears to arise in response to chronic inflammation from gastroesophageal reflux disease (GERD).6,8-10 In the United States, the rapidly growing problem of obesity has been shown to have a causal relationship to GERD, thus increasing the risk of developing esophageal adenocarcinoma.7,11,12 Results from the 1999-2002 National Health and Nutrition Examination Survey indicate that about 65 percent of U.S. adults are overweight or obese.13 This represents a 16 percent increase since 1994, paralleling a rise in the incidence of esophageal adenocarcinoma. Other risk factors for esophageal adenocarcinoma include scleroderma, myotomy-treated achalasia, and Zollinger-Ellison syndrome, each of which has been associated with esophagitis.

Diagnosis

The typical patient with squamous cell carcinoma of the esophagus is male, between 60 and 70 years of age, with a history of cigarette or excessive alcohol use. Adenocarcinoma of the esophagus typically presents in white men between 50 and 60 years of age, usually from the middle or upper socioeconomic class. A history of smoking or alcohol use may not be present, and a hiatal hernia leading to reflux and chronic antacid use often is reported.2

Progressive dysphagia (i.e., difficulty swallowing) or odynophagia (i.e., pain with swallowing) are the most common presenting complaints of patients with esophageal cancer. These symptoms usually have been present for several months before seeking medical treatment and initially present as difficulty or pain when swallowing dry foods or breads. An unintentional loss of 10 percent of normal body weight occurs over a short time (i.e., less than six months). Later signs and symptoms include chest or back pain when swallowing, halitosis, or clubbing. Hoarseness from recurrent laryngeal nerve involvement, Horner syndrome (i.e., miosis, ptosis, absence of sweating on the ipsilateral face and neck), supraclavicular adenopathy, persistent substernal chest pain unrelated to swallowing, a tracheoesophageal fistula, or sudden onset of hiccups are signs indicating possible transmural disease involving the mediastinum or diaphragm.

The diagnostic evaluations of adenocarcinoma and squamous cell carcinoma are essentially identical. Figure 1 is an algorithm for the evaluation of suspicious esophageal symptoms. The first step in diagnosing esophageal cancer is double-contrast barium esophagraphy. The double-contrast technique involves the use of solid preparations (e.g., barium-soaked bread) and liquid barium for a more complete evaluation of dysphagia. An abnormal study would reveal filling defects or esophageal narrowing, and should be followed by endoscopy and cytologic brushings of the involved area. In the presence of suspicious symptoms and normal study results, endoscopy with biopsy and brushings of any questionable areas is indicated. Studies indicate that multiple biopsies of suspicious lesions are required for accurate diagnosis because visible tissue may reveal only inflammation.14-16 An upper gastrointestinal endoscopy also may be used in the initial evaluation of patients suspected of having esophageal pathology.

Work-up of Suspicious Symptoms of Esophageal Cancer