Esophageal cancer

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Esophageal cancer
Classification and external resources
Diagram showing oesophageal cancer that has spread (M staging) CRUK 175.svg
Diagram showing esophageal cancer in an advanced stage with spread to the liver
ICD-10 C15
ICD-9 150
OMIM 133239
DiseasesDB 9150
MedlinePlus 000283
eMedicine article/277930 article/368206
NCI Esophageal cancer
MeSH D004938

Esophageal cancer (or oesophageal cancer) is cancer arising from the esophagus—the foodpipe that runs between the throat and the stomach.[1] Symptoms often include trouble swallowing and weight loss. Other symptoms may include pain with swallowing, a hoarse voice, enlarged lymph nodes (glands) around the clavicle (collarbone), a dry cough, and possibly coughing up or vomiting blood.[2]

The two main sub-types of esophageal cancer are squamous-cell carcinoma, which is more common in the developing world, and adenocarcinoma, which is more common in the developed world.[1] A number of less common types also occur.[1] Squamous-cell carcinoma arises from the skin cells that line the esophagus.[3] Adenocarcinoma arises from glandular cells present in the lower third of the esophagus, often where they have already transformed to intestinal cell type (a condition known as Barrett's esophagus).[1][4] The most common causes of the squamous-cell type are: tobacco, alcohol, very hot drinks, and a poor diet.[5] The most common causes of the adenocarcinoma type are smoking tobacco, obesity, and acid reflux.[5]

The disease is diagnosed by biopsy done by an endoscope (a fiberoptic camera).[6] Prevention includes stopping smoking and a healthy diet.[1][2] Treatment is based on the cancer's stage and location, together with the person's general condition and individual preferences. Small localized squamous-cell cancers may be treated with surgery alone with the hope of a cure. In most other cases, chemotherapy with or without radiation therapy is used along with surgery.[6] Larger tumors may have their growth slowed with chemotherapy and radiation therapy.[1] In the presence of extensive disease or if the affected person is not fit enough to undergo surgery, palliative care is often recommended.[6] Outcomes are related to the extent of the disease and other medical conditions, but generally tend to be fairly poor, as diagnosis is often late.[1][7] Five-year survival rates are around 13% to 18%.[2][8]

As of 2012, esophageal cancer is the eighth-most common cancer globally with 456,000 new cases during the year.[1] It caused about 400,000 deaths that year, up from 345,000 in 1990.[1][9] Rates vary widely between countries, with about half of all cases occurring in China. It is around three times more common in men than in women.[1]

Signs and symptoms[edit]

Prominent symptoms usually do not appear until the cancer has infiltrated over 60% of the tube's circumference, by which time the tumor is already in an advanced stage.[10] Onset of symptoms is usually caused by stenosis (i.e. narrowing of the tube due to the physical presence of the tumor).[11]

The first and the most common symptom is usually difficulty in swallowing (dysphagia), often initially experienced with solid foods and later with softer foods and liquids.[2] Pain when swallowing is less usual initially.[2] Weight loss is often an initial symptom in cases of squamous-cell carcinoma, though not usually in cases of adenocarcinoma.[12] Eventual weight loss due to reduced appetite and malnutrition is common.[13] Pain behind the sternum (breastbone) or in the epigastric region around the stomach often feels like heartburn. The pain can frequently be severe, worsening when food of any sort is swallowed. Another sign may be an unusually husky, raspy, or hoarse-sounding cough, a result of the tumor affecting the recurrent laryngeal nerve.

The presence of the tumor may disrupt the normal contractions of the esophagus on swallowing. This can lead to nausea and vomiting, regurgitation of food, coughing, and an increased risk of aspiration pneumonia.[10] Abnormal connections (fistulas) occasionally develop between the esophagus and the trachea (windpipe).[7] Early signs of this serious complication may be coughing on drinking or eating.[14] Fistulas often lead to pneumonia, which is usually heralded by cough, fever, or aspiration.[7] The tumor surface may be fragile and bleed, causing vomiting of blood. Compression of local structures occurs in advanced disease, leading to such problems as upper airway obstruction and superior vena cava syndrome. Symptoms of hypercalcemia (excess calcium in the blood) may occur.[10]

If the cancer has spread elsewhere, symptoms related to metastatic disease may appear. Common sites of spread include nearby lymph nodes, the liver, lungs and bone.[10] Liver metastasis can cause jaundice and abdominal swelling (ascites). Lung metastasis can cause shortness of breath, pleural effusions, etc.

Causes[edit]

The two main types (i.e. squamous-cell carcinoma and adenocarcinoma) have distinct risk factors, but both types are generally more common in men, and are most common in the over-60s.[15] Esophageal squamous-cell carcinoma is strongly associated with life-style factors such as smoking and alcohol, whereas the adenocarcinoma type is linked to long-term acid reflux.[16] Tobacco is a risk factor for both types.[12]

Squamous-cell carcinoma[edit]

The two major risk factors for esophageal squamous-cell carcinoma are tobacco (smoking or chewing) and alcohol.[1] The combination of these two exposures seems to exert a strong additive effect.[17] Some data suggest that about half of all cases are due to tobacco and about one-third to alcohol, while over three-quarters of the cases in men are due to the combination of smoking and heavy drinking.[1] The risks associated with alcohol appear to be linked to its aldehyde metabolite and to mutations in certain related enzymes.[12] Such metabolic variants are relatively common in Asia.[1]

High levels of dietary exposure to nitrosamines (chemical compounds found both in tobacco smoke and certain foodstuffs) appear to be a relevant risk factor.[12] Unfavorable dietary patterns seem to involve exposure to nitrosamines through processed and barbecued meats, pickled vegetables, etc., and a low intake of fresh foods.[1] Other associated factors include nutritional deficiencies, low socioeconomic status, and poor oral hygiene.[12] Chewing betel nut (areca) is an important risk factor in Asia.[18]

Adenocarcinoma[edit]

Risk of esophageal adenocarcinoma has been linked to the long-term effects of acid reflux, an extremely common condition also known as gastroesophageal reflux disease (GERD).[19] Longstanding GERD can induce a change of cell type in the lower portion of the esophagus in response to erosion of its squamous lining.[19] Having symptomatic GERD or bile reflux makes Barrett's esophagus more likely, which in turn raises the risk of further changes that in certain cases may ultimately lead to adenocarcinoma.[12] The risk of developing adenocarcinoma in the presence of Barrett's esophagus is unclear, and may in the past have been overestimated.[1] Obesity is also associated with increased risk of adenocarcinoma.[20] Abdominal obesity encourages GERD and may also exert other relevant biological effects.[19]

Corrosive injury to the esophagus by accidentally or intentionally swallowing caustic substances is also a risk factor,[1] as is radiation therapy for other conditions in the chest.[12]

Related conditions[edit]

  • Head and neck cancer is associated with second primary tumors in the region, including esophageal squamous-cell carcinomas, due to field cancerization (i.e. a regional reaction to long-term carcinogenic exposure).[21][22]
  • Tylosis with esophageal cancer is a rare familial disease that has been linked to a mutation in the RHBDF2 gene. It involves thickening of the skin of the palms and soles and a high lifetime risk of esophageal cancer.[23]
  • Achalasia (i.e. lack of the involuntary reflex in the esophagus after swallowing) appears to be a risk factor for both main types of esophageal cancer, at least in men, due to stagnation of trapped food and drink.[24]
  • Plummer–Vinson syndrome (a rare disease that involves esophageal webs) is also a risk factor.[1]
  • There is some evidence suggesting a possible causal association between human papillomavirus (HPV) and esophageal squamous-cell carcinoma.[25] The relationship is unclear.[26] Possible relevance of HPV could be greater in places that have a particularly high incidence of this form of the disease,[27] as in some Asian countries, including China.[28]
  • There is limited evidence to support an association between celiac disease and esophageal cancer.[24]
  • Although the Helicobacter pylori bacterium is a cause of GERD and a risk factor for gastric cancer, it seems to be associated with reduced risk of esophageal adenocarcinoma.[29] The biological explanation for a protective effect is somewhat unclear.[29] One explanation is that some strains of H. pylori reduce stomach acid, thereby reducing damage by GERD.[30] Acid reduction due to gastric atrophy induced by H. pylori may be a relevant factor.[29][31]

Diagnosis[edit]

Clinical evaluation[edit]

Although an occlusive tumor may be suspected on a barium swallow or barium meal, the diagnosis is best made with esophagogastroduodenoscopy (endoscopy); this involves the passing of a flexible tube down the esophagus and examining 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 a CT scan is limited by its ability to detect masses (e.g. enlarged lymph nodes or involved organs) generally larger than 1 cm. Positron emission tomography is also used to estimate the extent of the disease and is regarded as more precise than CT alone. Esophageal endoscopic ultrasound 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 in 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.

Classification[edit]

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 GERD and Barrett's esophagus. A general rule of thumb is that a cancer in the upper two-thirds is a squamous-cell carcinoma and one in the lower one-third is an adenocarcinoma.

Rare histologic types of esophageal cancer are different variants of the squamous-cell carcinoma, and nonepithelial tumors, such as leiomyosarcoma, malignant melanoma, rhabdomyosarcoma, lymphoma, and others.[32][33]

Prevention[edit]

Prevention includes stopping smoking or chewing tobacco.[1] Overcoming addiction to areca chewing in Asia is another promising strategy for the prevention of esophageal squamous-cell carcinoma.[18]

According to the National Cancer Institute, "diets high in cruciferous (cabbage, broccoli/broccolini, cauliflower, Brussels sprouts) and green and yellow vegetables and fruits are associated with a decreased risk of esophageal cancer."[34] Dietary fiber is thought to be protective, especially against esophageal adenocarcinoma.[35]


Screening[edit]

People with Barrett esophagus (a change in the cells lining the lower esophagus) are at much higher risk,[36] and may receive regular endoscopic screening for the early signs of cancer.[37] Because the benefit of screening for adenocarcinoma in people without symptoms is unclear,[1] it is not recommended in the United States.[2] Some areas of the world with high rates of squamous-carcinoma have screening programs.[1]

Management[edit]

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 person cannot swallow at all, an esophageal stent may be inserted to keep the esophagus open; 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.

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 or jejunum) is pulled up to the chest cavity and interposed.[38] If the tumor is not resectable or the patient is not fit for surgery, palliative esophageal stenting can allow the patient to tolerate a soft diet.

Types of esophagectomy:

  • The thoracoabdominal approach opens the abdominal and thoracic cavities together.
  • The two-stage Ivor Lewis (also called Lewis–Tanner) approach involves an initial laparotomy and construction of a gastric tube, followed by a right thoracotomy to excise the tumor and create an esophagogastric anastomosis.
  • The three-stage McKeown approach adds a third incision in the neck to complete the cervical anastomosis.

Data are accumulating to indicate 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) who do not have regional or distant metastasis. Patients with carcinoma ''in situ'' or high-grade dysplasia can also be treated with endoscopic therapy. Submucosal cancers with increased risk of nodal metastases may not be as amenable to curative therapy.

Endoscopic resection[edit]

Forms of endoscopic therapy have been used for stage 0 and I disease: endoscopic mucosal resection (EMR) and mucosal ablation using radiofrequency ablation, photodynamic therapy, Nd-YAG laser, or argon plasma coagulation.

EMR 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 carcinoma. It has also been shown to have be safe and effective for early adenocarcinoma arising in Barrett’s esophagus. The prognosis after treatment with EMR 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 EMR 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.

Another method of EMR 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 three weeks.

EMR can also be used to debulk or completely treat polypoid dysplastic or malignant lesions in Barrett’s esophagus, the known precursor lesion to esophageal adenocarcinoma. 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.

The major complications of endoscopic mucosal resection include postoperative bleeding, 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 "nonlifting 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 complications ranges from 0–50% and recurrence of esophageal squamous-cell carcinoma range from 0–8%.

Other approaches[edit]

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, 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 was better than other comparable regimens in advanced nonresectable cancer.[39] 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.

Radiofrequency ablation is a new treatment modality for the treatment of Barrett's esophagus and dysplasia, and has been the subject of numerous published clinical trials. The findings demonstrate radiofrequency ablation has an efficacy of 80–90% or greater with respect to complete clearance of Barrett's esophagus and dysplasia with durability up to five years and a favorable safety profile.[40][41][42][43] Recent clinical trials have shown that endoscopic resection of esophageal mucosal irregularities and nodules which contain dysplasia or carcinoma combined with subsequent radiofrequency ablation of the remaining flat Barrett's esophagus and dysplasia can effectively and safely eradicate the disease.[44] Further, a recent multicenter randomized control trial found that in patients with Barrett's esophagus containing nodules or mucosal irregularities which contained high grade dysplasia or cancer, subsequent radiofrequency ablation resulted not only in eradication of Barrett's esophagus and dysplasia, but also had significantly less esophageal stricture versus patients who had circumferential endoscopic mucosal resection for their disease.[45]

Follow-up[edit]

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

Prognosis[edit]

In general, the prognosis of esophageal cancer is quite poor, because most patients present with advanced disease. By the time the first symptoms such as dysphagia start manifesting themselves, the cancer has already well progressed. The overall five-year survival rate (5YSR) in the United States is around 15%, with most people dying within the first year of diagnosis.[46]

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 esophagus) 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.[citation needed]

Epidemiology[edit]

Age-standardized death from esophagus cancer per 100,000 inhabitants in 2004[47]
  no data
  less than 3
  3–6
  6–9
  9–12
  12–15
  15–18
  18–21
  21–24
  24–27
  27–30
  30–35
  more than 35

Esophageal cancer is the eighth most frequently diagnosed cancer worldwide,[48] and because of its poor prognosis it is the sixth most common cause of cancer-related death.[36] It caused about 395,000 deaths in 2010, up from 345,000 in 1990.[9] Its incidence varies greatly among different geographical areas, as does the relative preponderance of the two main types.[49] The cancer is particularly frequent in the so-called "Asian esophageal cancer belt", an area that passes through northern China, southern Russia, north-eastern Iran, northern Afghanistan and eastern Turkey.[48] In Sub-Saharan Africa, where the problem has long been recognized, incidence is much higher in countries in the eastern and southern parts of the region.[50]

Squamous-cell carcinoma is the most common type of esophageal cancer worldwide, comprising 60-70% of all cases, while adenocarcinomas account for a further 20-30% (melanomas, leiomyosarcomas, carcinoids and lymphomas being rarely diagnosed).[48] In the Asian esophageal cancer belt that stretches from northeast China to the Middle East, incidence rates of esophageal squamous-cell carcinoma have been reported to be as high as 100 new cases per 100,000 person-years.[49]

In Western countries, esophageal adenocarcinoma has become the dominant form of the disease, following an increase in incidence over recent decades (in contrast to the incidence of the squamous-cell type, which has remained largely stable).[6][31]

In the United States, esophageal cancer is the seventh-leading cause of cancer death among males (making up 4% of the total).[51] The National Cancer Institute estimated there were about 18,000 new cases and more than 15,000 deaths from esophageal cancer in 2013 (the American Cancer Society estimated that during 2014, about 18,170 new esophageal cancer cases will be diagnosed, resulting in 15,450 deaths).[49][51] The squamous-cell carcinoma type is more common among African American males with a history of heavy smoking or alcohol use. Until the 1970s, squamous-cell carcinoma accounted for the vast majority of esophageal cancers in the United States. In recent decades, incidence of adenocarcinoma of the esophagus (which is associated with Barrett's esophagus) steadily rose in the United States to the point that it has now surpassed squamous-cell carcinoma. In contrast to squamous-cell carcinoma, esophageal adenocarcinoma is more common in Caucasian men (over the age of 60) than it is in African Americans. Multiple reports indicate 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.[52] Esophageal cancer incidence and mortality rates for African Americans continue to be higher than the rate for Causasians. However, incidence and mortality of esophageal cancer has significantly decreased among African Americans since the early 1980s, whereas with Caucasians, it has slightly increased.[53] Between 1975 and 2004, incidence of the adenocarcinoma type increased among white American males by over 460% and among white American females by 335%.[49]

Research directions[edit]

References[edit]

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