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Esophageal cancer is malignancy of the esophagus. There are various subtypes, primarily adenocarcinoma (approx. 50-80% of all Esophageal cancer) and squamous cell cancer. Squamous cell cancer arises from the cells that line the upper part of the esophagus. Adenocarcinoma arises from glandular cells that are present at the junction of the esophagus and stomach. Esophageal tumors usually lead to dysphagia (difficulty swallowing), pain and other symptoms, and are diagnosed with biopsy. Small and localized tumors are treated surgically with curative intent. Larger tumors tend not to be operable and hence are treated with Palliative care; their growth can still be delayed with chemotherapy, radiotherapy or a combination of the two. In some cases chemo- and radiotherapy can render these larger tumors operable. Prognosis depends on the extent of the disease and other medical problems, but is fairly poor.

Classification

Esophageal cancers are typically carcinomas which arise from the epithelium, or surface lining, of the esophagus. Most esophageal cancers fall into one of two classes: squamous cell carcinomas, which are similar to head and neck cancer in their appearance and association with tobacco and alcohol consumption, and adenocarcinomas, which are often associated with a history of gastroesophageal reflux disease and Barrett's esophagus.

Signs and symptoms

Dysphagia and Odynophagia are the most common symptoms of esophageal cancer. Dysphagia (difficulty swallowing) is the first symptom in most patients. Odynophagia (painful swallowing) may be present. Fluids and soft foods are usually tolerated, while hard or bulky substances (such as bread or meat) cause much more difficulty. Substantial weight loss is characteristic as a result of poor nutrition and the active cancer. Pain, often of a burning nature, may be severe and worsened by swallowing, and can be spasmodic in character. An early sign may be an unusually husky or raspy voice.

The presence of the tumor may disrupt normal peristalsis (the organised swallowing reflex), leading to nausea and vomiting, regurgitation of food, coughing and an increased risk of aspiration pneumonia. The tumor surface may be fragile and bleed, causing hematemesis (vomiting up blood). Compression of local structures occurs in advanced disease, leading to such problems as upper airway obstruction and superior vena cava syndrome. Fistulas may develop between the esophagus and the trachea, increasing the pneumonia risk; this condition is usually heralded by cough, fever or aspiration.

If the disease has spread elsewhere, this may lead to symptoms related to this: liver metastasis could cause jaundice and ascites, lung metastasis could cause shortness of breath, pleural effusions, etc.

Causes

Increased risk

There are a number of risk factors for esophageal cancer. Some subtypes of cancer are linked to particular risk factors:
  • Age. Most patients are over 60, and the median in US patients is 67.
  • Sex. It is more common in men.
  • Heredity. It is more likely in people who have close relatives with cancer.
  • Tobacco smoking and heavy alcohol use increase the risk, and together appear to increase the risk more than either individually.
  • Gastroesophageal reflux disease (GERD) and its resultant Barrett's esophagus increase esophageal cancer risk due to the chronic irritation of the mucosal lining (adenocarcinoma is more common in this condition, while all other risk factors predispose more for squamous cell carcinoma).
  • Human papillomavirus (HPV)
  • Corrosive injury to esophagus by swallowing strong alkalines (lye) or acids.
  • Particular dietary substances, such as nitrosamine.
  • A medical history of other head and neck cancers increases the chance of developing a second cancer in the head and neck area, including esophageal cancer.
  • Plummer-Vinson syndrome (anemia and esophageal webbing)
  • Tylosis and Howel-Evans syndrome (hereditary thickening of the skin of the palms and soles).
  • Radiation therapy for other conditions in the mediastinum.
  • Celiac disease predisposes towards squamous cell carcinoma.
  • Obesity increases the risk of adenocarcinoma fourfold. It is suspected that increased risk of reflux may be behind this association.
  • Drinking large quantities of hot beverages, especially hot brewed teas
  • Alcohol consumption in individuals predisposed to alcohol flush reaction
  • Achalasia


Decreased risk

  • Risk appears to be less in patients using aspirin or related drugs (NSAIDs).
  • The role of Helicobacter pylori in progression to esophageal adenocarcinoma is still uncertain, but, on the basis of population data, it may carry a protective effect. It is postulated that H. pylori prevents chronic gastritis, which is a risk factor for reflux, which in turn is a risk factor for esophageal adenocarcinoma.
  • According to the National Cancer Institute, "diets high in cruciferous (cabbage, broccoli, cauliflower) and green and yellow vegetables and fruits are associated with a decreased risk of esophageal cancer."
  • Moderate coffee consumption is associated with a decreased risk.
  • According to one Italian study of "diet surveys completed by 5,500 Italians"—a study which has raised debates questioning its claims among cancer researchers cited in news reports about it—eating pizza more than once a week appears "to be a favorable indicator of risk for digestive tract neoplasms in this population."


Diagnosis



Clinical evaluation

Although an occlusive tumor may be suspected on a barium swallow or barium meal, the diagnosis is best made with esophagogastroduodenoscopy (EGD, endoscopy); this involves the passing of a flexible tube down the esophagus and visualising the wall. Biopsies taken of suspicious lesions are then examined histologically for signs of malignancy.

Additional testing is usually performed to estimate the tumor stage. Computed tomography (CT) of the chest, abdomen and pelvis, can evaluate whether the cancer has spread to adjacent tissues or distant organs (especially liver and lymph nodes). The sensitivity of CT scan is limited by its ability to detect masses (e.g. enlarged lymph nodes or involved organs) generally larger than 1 cm. FDG-PET (positron emission tomography) scan is also being used to estimate whether enlarged masses are metabolically active, indicating faster-growing cells that might be expected in cancer. Esophageal endoscopic ultrasound (EUS) can provide staging information regarding the level of tumor invasion, and possible spread to regional lymph nodes.

The location of the tumor is generally measured by the distance from the teeth. The esophagus (25 cm or 10 inches long) is commonly divided into three parts for purposes of determining the location. Adenocarcinomas tend to occur distally and squamous cell carcinomas proximally, but the converse may also be the case.

Histopathology

Most tumors of the esophagus are malignant, only about 0.5% are benign. A very small proportion (under 10%) is leiomyoma (smooth muscle tumor) or gastrointestinal stromal tumor (GIST). Malignant tumors are generally adenocarcinomas, squamous cell carcinomas, and occasionally small-cell carcinomas. The latter share many properties with small-cell lung cancer, and are relatively sensitive to chemotherapy compared to the other types.

Management

General approaches

Esophageal cancer affecting the lower esophageus.
Insets show the tumor in more detail both before and after placement of a stent.
The treatment is determined by the cellular type of cancer (adenocarcinoma or squamous cell carcinoma vs other types), the stage of the disease, the general condition of the patient and other diseases present. On the whole, adequate nutrition needs to be assured, and adequate dental care is vital.

If the patient cannot swallow at all, a stent may be inserted to keep the esophagus patent; stents may also assist in occluding fistulas. A nasogastric tube may be necessary to continue feeding while treatment for the tumor is given, and some patients require a gastrostomy (feeding hole in the skin that gives direct access to the stomach). The latter two are especially important if the patient tends to aspirate food or saliva into the airways, predisposing for aspiration pneumonia.

Tumor treatments

Surgery is possible if the disease is localised, which is the case in 20–30% of all patients. If the tumor is larger but localised, chemotherapy and/or radiotherapy may occasionally shrink the tumor to the extent that it becomes "operable"; however, this combination of treatments (referred to as neoadjuvant chemoradiation) is still somewhat controversial in most medical circles. Esophagectomy is the removal of a segment of the esophagus; as this shortens the length of the remaining esophagus, some other segment of the digestive tract (typically the stomach or part of the colon) is pulled up to the chest cavity and interposed. If the tumor is unresectable or the patient is not fit for surgery, palliative esophageal stenting can allow the patient to tolerate soft diet.

Endoscopic Therapy for Localized Disease There is accumulating data that endoscopic therapy is a safe, less invasive, and effective therapy for very early esophageal cancer. The candidates for endoscopic therapy are Stage 1 patients with tumors invading into the lamina propria (T1 mucosal) or submucosa (T1 submucosal) that do not have regional or distant metastasis. Patients with carcinoma in-situ or high-grade dysplasia can also be treated with endoscopic therapy. Submucosa cancers with increased risk of nodal metastases may not be as amenable to curative therapy.

The two forms of endoscopic therapy that have been used for Stage 0 and I disease are endoscopic mucosal resection (EMR) and mucosal ablation using photodynamic therapy , Nd-YAG laser, or argon plasma coagulation.

EMR Endoscopic Mucosal Resection has been advocated for early cancers (that is, those that are superficial and confined to the mucosa only) and has been shown to be a less invasive, safe, and highly effective nonsurgical therapy for early squamous cell esophageal cancer. Preliminary reports also suggest its safety and efficacy for early adenocarcinoma arising in Barrett’s esophagus. The prognosis after treatment with endoscopic mucosal resection is comparable to surgical resection. This technique can be attempted in patients, without evidence of nodal or distant metastases, with differentiated tumors that are slightly raised and less than 2 cm in diameter, or in differentiated tumors that are ulcerated and less than 1 cm in diameter. The most commonly employed modalities of endoscopic mucosal resection include strip biopsy, double-snare polypectomy, resection with combined use of highly concentrated saline and epinephrine, and resection using a cap.

The strip biopsy method for endoscopic mucosal resection of esophageal cancer is performed with a double-channel endoscope equipped with grasping forceps and snare. After marking the lesion border with an electric coagulator, saline is injected into the submucosa below the lesion to separate the lesion from the muscle layer and to force its protrusion. The grasping forceps are passed through the snare loop. The mucosa surrounding the lesion is grasped, lifted, and strangulated and resected by electrocautery.The endoscopic double-snare polypectomy method is indicated for protruding lesions. Using a double-channel scope, the lesion is grasped and lifted by the first snare and strangulated with the second snare for complete resection.

Endoscopic resection with injection of concentrated saline and epinephrine is carried out using a double-channel scope. The lesion borders are marked with a coagulator. Highly concentrated saline and epinephrine are injected (15–20 ml) into the submucosal layer to swell the area containing the lesion and elucidate the markings. The mucosa outside the demarcated border is excised using a high-frequency scalpel to the depth of the submucosal layer. The resected mucosa is lifted and grasped with forceps, trapping and strangulating the lesion with a snare, and then resected by electrocautery.

A fourth method of endoscopic mucosal resection employs the use of a clear cap and prelooped snare inside the cap. After insertion, the cap is placed on the lesion and the mucosa containing the lesion is drawn up inside the cap by aspiration. The mucosa is caught by the snare and strangulated, and finally resected by electrocautery. This is called the "band and snare" or "suck and cut" technique. The resected specimen is retrieved and submitted for microscopic examination for determination of tumor invasion depth, resection margin, and possible vascular involvement. The resulting "ulcer" heals within 3 weeks.

Although most lesions treated in the esophagus have been early squamous cell cancers, endoscopic snare resection can also be used to debulk or completely treat polypoid dysplastic or malignant lesions in Barrett’s esophagus. In a preliminary report from Germany, EMR was performed as primary treatment or adjunctive therapy following photodynamic therapy for early adenocarcinomas in Barrett's esophagus. The "suck and cut" technique (with and without prior saline injection) was used as well as the "band and cut" technique. Although all tumors were resected without difficulty, 12.5% developed bleeding (which was managed successfully by endoscopic therapy). Eighty-one percent of the lesions were completely resected. The other lesions were also treated with other endoscopic techniques. While this report suggests it is feasible to completely resect local, circumscribed, early adenocarcinomas arising in Barrett's esophagus, the relative safety and efficacy of EMR in conjunction with photodynamic therapy is unknown.

The major complications of endoscopic mucosal resection include postoperative bleeding and perforation and stricture formation. During the procedure, an injection of 100,000 times diluted epinephrine into the muscular wall, along with high frequency coagulation or clipping can be applied to the bleeding point for hemostasis. It is important to administer acid-reducing medications to prevent postoperative hemorrhage. Perforation may be prevented with sufficient saline injection to raise the mucosa containing the lesion. The "non-lifting sign" and complaints of pain when the snare strangulates the lesion are contrainidications of EMR. When perforation is recognized immediately after a procedure, the perforation should be closed by clips. Surgery should be considered in cases of endoscopic closure failure. The incidence of complication range from 0–50% and squamous cell recurrence rates range from 0–8%.

Laser therapy is the use of high-intensity light to destroy tumor cells; it affects only the treated area. This is typically done if the cancer cannot be removed by surgery. The relief of a blockage can help to reduce dysphagia and pain. Photodynamic therapy (PDT), a type of laser therapy, involves the use of drugs that are absorbed by cancer cells; when exposed to a special light, the drugs become active and destroy the cancer cells.

Chemotherapy depends on the tumor type, but tends to be cisplatin-based (or carboplatin or oxaliplatin) every three weeks with fluorouracil (5-FU) either continuously or every three weeks. In more recent studies, addition of epirubicin (ECF) was better than other comparable regimens in advanced nonresectable cancer. Chemotherapy may be given after surgery (adjuvant, i.e. to reduce risk of recurrence), before surgery (neoadjuvant) or if surgery is not possible; in this case, cisplatin and 5-FU are used. Ongoing trials compare various combinations of chemotherapy; the phase II/III REAL-2 trial – for example – compares four regimens containing epirubicin and either cisplatin or oxaliplatin and either continuously infused fluorouracil or capecitabine.

Radiotherapy is given before, during or after chemotherapy or surgery, and sometimes on its own to control symptoms. In patients with localised disease but contraindications to surgery, "radical radiotherapy" may be used with curative intent.

Follow-up

Patients are followed up frequently after a treatment regimen has been completed. Frequently, other treatments are necessary to improve symptoms and maximize nutrition.

Prognosis

In general, the prognosis of esophageal cancer is quite poor, because so many patients present with advanced disease: The overall five-year survival rate (5YSR) is less than 5%. Individualized prognosis depends largely on stage. Those with cancer restricted entirely to the esophageal mucosa have about an 80% 5YSR, but submucosal involvement brings this down to less than 50%. Extension into the muscularis propria (muscular layer of the esophageus) has meant a 20% 5YSR and extension to the structures adjacent to the esophagus results in a 7% 5YSR. Patients with distant metastases (who are not candidates for curative surgery) have a less than 3% 5YSR. Of all patients undergoing surgery with curative intent, the 5YSR is only about 25%.But these statistics are getting better, as more patients are getting diagnosis earlier because of the awareness of Barrett's Esophagus.

Epidemiology

[[Image:Oesophagus cancer world map - Death - WHO2004.svg|thumb|Age-standardized death from esophagus cancer per 100,000 inhabitants in 2004.


]]Esophageal cancer is a relatively rare form of cancer, but some world areas have a markedly higher incidence than others: Chinamarker, Icelandmarker, Indiamarker and Japanmarker, as well as the United Kingdommarker, appear to have a higher incidence, as well as the region around the Caspian Seamarker.

The American Cancer Society estimates that during 2007, approximately 15,560 new esophageal cancer cases will be diagnosed in the United States.

The esophageal cancer incidence and mortality rates for people of African-American descent have been higher than the rate for Caucasians. According to the NCI, incidence of adenocarcinoma of the esophagus, which is associated with Barrett's esophagus, is rising in the United States. This type is more common in Caucasian men over the age of 60.

Multiple reports indicate that esophageal adenocarcinoma incidence has increased during the past 20 years, especially in non-Hispanic white men. Esophageal adenocarcinoma age-adjusted incidence increased in New Mexico from 1973 to 1997. This increase was found in non-Hispanic whites and Hispanics and became predominant in non-Hispanic whites.

References

  1. Esophageal cancer at Mount Sinai Hospital
  2. Corley DA, Kerlikowske K, Verma R, Buffler P. Protective association of aspirin/NSAIDs and esophageal cancer: a systematic review and meta-analysis. Gastroenterology 2003;124:47–56. PMID 12512029. See also NCI - "Esophageal Cancer (PDQ): Prevention".
  3. NCI Prevention: Dietary Factors, based on Chainani-Wu N. Diet and oral, pharyngeal, and esophageal cancer. Nutr Cancer 2002;44:104–26. PMID 12734057.
  4. Gallus S, Bosetti C, Negri E, Talamini R, Montella M, Conti E, Franceschi S, La Vecchia C. Does pizza protect against cancer? Int J Cancer 2003;107:283–4. PMID 12949808. Cited and qtd. by WebMD and BBC News.
  5. Ross P, Nicolson M, Cunningham D, Valle J, Seymour M, Harper P, Price T, Anderson H, Iveson T, Hickish T, Lofts F, Norman A. Prospective randomized trial comparing mitomycin, cisplatin, and protracted venous-infusion fluorouracil (PVI 5-FU) with epirubicin, cisplatin, and PVI 5-FU in advanced esophagogastric cancer. J Clin Oncol 2002;20:1996–2004. PMID 11956258.
  6. Stewart BW, Kleihues P (editors). World cancer report. Lyon: IARC, 2003. ISBN 92-832-0411-5.


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