Esophageal cancer

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Esophageal cancer
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
Classification and external resources
Specialty Oncology, general surgery
ICD-10 C15
ICD-9-CM 150
OMIM 133239
DiseasesDB 9150
MedlinePlus 000283
eMedicine article/277930 article/368206
Patient UK Esophageal cancer
MeSH D004938
[[[d:Lua error in Module:Wikidata at line 863: attempt to index field 'wikibase' (a nil value).|edit on Wikidata]]]

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

The two main sub-types of the disease are esophageal squamous-cell carcinoma (often abbreviated to ESCC),[3] which is more common in the developing world, and esophageal adenocarcinoma (EAC), which is more common in the developed world.[1] A number of less common types also occur.[1] Squamous-cell carcinoma arises from the epithelial cells that line the esophagus.[4] 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][5] The most common causes of the squamous-cell type are: tobacco, alcohol, very hot drinks, and a poor diet.[6] The most common causes of the adenocarcinoma type are smoking tobacco, obesity, and acid reflux.[6]

The disease is diagnosed by biopsy done by an endoscope (a fiberoptic camera).[7] Prevention includes stopping smoking and eating 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.[7] 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.[7] 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][8] Five-year survival rates are around 13% to 18%.[2][9]

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][10] Rates vary widely among 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

Prominent symptoms usually do not appear until the cancer has infiltrated over 60% of the circumference of the esophageal tube, by which time the tumor is already in an advanced stage.[11] Onset of symptoms is usually caused by narrowing of the tube due to the physical presence of the tumor.[12]

The first and the most common symptom is usually difficulty in swallowing, which is often experienced first with solid foods and later with softer foods and liquids.[2] Pain when swallowing is less usual at first.[2] Weight loss is often an initial symptom in cases of squamous-cell carcinoma, though not usually in cases of adenocarcinoma.[13] Eventual weight loss due to reduced appetite and undernutrition is common.[14] Pain behind the breastbone or in the 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 when swallowing. This can lead to nausea and vomiting, regurgitation of food and coughing.[11] There is also an increased risk of aspiration pneumonia[11] due to food entering the airways through the abnormal connections (fistulas) that may develop between the esophagus and the trachea (windpipe).[8] Early signs of this serious complication may be coughing on drinking or eating.[15] 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. Hypercalcemia (excess calcium in the blood) may occur.[11]

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.[11] Liver metastasis can cause jaundice and abdominal swelling (ascites). Lung metastasis can cause, among other symptoms, impaired breathing due to excess fluid around the lungs (pleural effusion), and dyspnea (the feelings often associated with impaired breathing).

Causes

The two main types (i.e. squamous-cell carcinoma and adenocarcinoma) have distinct sets of risk factors.[13] Squamous-cell carcinoma is linked to lifestyle factors such as smoking and alcohol.[16] Adenocarcinoma has been linked to effects of long-term acid reflux.[16] Tobacco is a risk factor for both types.[13] Both types are more common in men and in the over-60s.[17]

Squamous-cell carcinoma

The two major risk factors for esophageal squamous-cell carcinoma are tobacco (smoking or chewing) and alcohol.[1] The combination of tobacco and alcohol has a strong synergistic effect.[18] 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] Risks associated with alcohol appear to be linked to its aldehyde metabolite and to mutations in certain related enzymes.[13] 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.[13] 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.[13] Chewing betel nut (areca) is an important risk factor in Asia.[19]

Physical trauma may increase the risk.[20] This may include the drinking of very hot drinks.[6]

Adenocarcinoma

Male predominance is particularly strong in this type of esophageal cancer, which occurs about 7 to 10 times more frequently in men.[21] This imbalance may be related to the characteristics and interactions of other known risk factors, including acid reflux and obesity.[21]

The long-term erosive effects of acid reflux (an extremely common condition, also known as gastroesophageal reflux disease or GERD) have been strongly linked to this type of cancer.[22] Longstanding GERD can induce a change of cell type in the lower portion of the esophagus in response to erosion of its squamous lining.[22] This phenomenon, known as Barrett's esophagus, seems to appear about 20 years later in women than in men, maybe due to hormonal factors.[22] Having symptomatic GERD or bile reflux makes Barrett's esophagus more likely, which in turn raises the risk of further changes that can ultimately lead to adenocarcinoma.[13] The risk of developing adenocarcinoma in the presence of Barrett's esophagus is unclear, and may in the past have been overestimated.[1]

Being obese or overweight both appear to be associated with increased risk.[23] The association with obesity seems to be the strongest of any type of obesity-related cancer, though the reasons for this remain unclear.[24] Abdominal obesity seems to be of particular relevance, given the closeness of its association with this type of cancer, as well as with both GERD and Barrett's esophagus.[24] This type of obesity is characteristic of men.[24] Physiologically, it stimulates GERD and also has other chronic inflammatory effects.[22]

EAC has one significant protective factor reducing risk for both sexes.[medical citation needed] Although Helicobacter pylori infection, which has affected over half of the world's population, is a cause of GERD and a risk factor for gastric cancer, it seems to be associated with a reduced risk of esophageal adenocarcinoma of as much as 50%.[25][26] The biological explanation for a protective effect is somewhat unclear.[26] One explanation is that some strains of H. pylori reduce stomach acid, thereby reducing damage by GERD.[27] The decreasing rates of H. pylori infection in Western populations in recent decades have been suggested as a factor in the great increase in oesophageal adenocarcinoma over the same period. The decrease is caused by better hygiene, for example through increased refrigeration of food and less crowded households, and has also been associated with an increase in stomach cancer.[25]

Female hormones may also have a protective effect, as EAC is not only much less common in women but develops later in life, by an average of 20 years. Although studies of many reproductive factors have not produced a clear picture, risk seems to decline for the mother in line with prolonged periods of breastfeeding.[25]

Tobacco smoking increases risk, but the effect in esophageal adenocarcinoma is slight compared to that in squamous cell carcinoma, and alcohol has not been demonstrated to be a cause.[25]

Related conditions

  • 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).[28][29]
  • History of radiation therapy for other conditions in the chest is a risk factor for esophageal adenocarcinoma.[13]
  • Corrosive injury to the esophagus by accidentally or intentionally swallowing caustic substances is a risk factor for squamous cell carcinoma.[1]
  • 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 squamous cell carcinoma.[1][30]
  • 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.[31]
  • 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.[32] The relationship is unclear.[33] Possible relevance of HPV could be greater in places that have a particularly high incidence of this form of the disease,[34] as in some Asian countries, including China.[35]
  • There is limited evidence to support an association between celiac disease and esophageal cancer.[31]

Diagnosis

Clinical evaluation

Although an occlusive tumor may be suspected on a barium swallow or barium meal, the diagnosis is best made with an examination using an endoscope. This involves the passing of a flexible tube with a light and camera down the esophagus and examining the wall, and is called an esophagogastroduodenoscopy. Biopsies taken of suspicious lesions are then examined histologically for signs of malignancy.

Additional testing is needed to assess how much the cancer has spread (see #Staging, below). 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 nearer the stomach and squamous cell carcinomas nearer the throat, but either may arise anywhere in the esophagus.

Types

Esophageal cancers are typically carcinomas that arise from the epithelium, or surface lining, of the esophagus. Most esophageal cancers fall into one of two classes: esophageal squamous-cell carcinomas (ESCC), which are similar to head and neck cancer in their appearance and association with tobacco and alcohol consumption—and esophageal adenocarcinomas (EAC), which are often associated with a history of GERD and Barrett's esophagus. A rule of thumb is that a cancer in the upper two-thirds is likely to be ESCC and one in the lower one-third EAC.

Rare histologic types of esophageal cancer include different variants of squamous-cell carcinoma, and non-epithelial tumors, such as leiomyosarcoma, malignant melanoma, rhabdomyosarcoma, lymphoma, among others.[36][37]

Staging

Staging is based on the TNM staging system, which classifies the amount of tumor invasion (T), involvement of lymph nodes (N), and distant metastasis (M).[13] The currently preferred classification is the 2010 AJCC staging system for cancer of the esophagus and the esophagogastric junction.[13] To help guide clinical decision making, this system also incorporates information on cell type (ESCC, EAC, etc.), grade (degree of differentiation – an indication of the biological aggressiveness of the cancer cells), and tumor location (upper, middle, lower, or junctional[38]).[39]

  • Endoscopic image of an esophageal adenocarcinoma

  • Endoscopic image of Barrett esophagus – a frequent precursor of esophageal adenocarcinoma

  • Mid esophageal mass.jpg

    Endoscopy and radial endoscopic ultrasound images of a submucosal tumor in the central portion of the esophagus

  • Contrast CT scan showing an esophageal tumor (axial view)

  • Contrast CT scan showing an esophageal tumor (coronal view)

  • Micrograph showing histopathological appearance of an esophageal adenocarcinoma (dark blue – upper-left of image) and normal squamous epithelium (upper-right of image) at H&E staining

Prevention

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.[19]

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."[40] Dietary fiber is thought to be protective, especially against esophageal adenocarcinoma.[41]

Screening

People with Barrett esophagus (a change in the cells lining the lower esophagus) are at much higher risk,[42] and may receive regular endoscopic screening for the early signs of cancer.[43] 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

Before and after a total esophagectomy
Typical scar lines after the two main methods of surgery

Treatment is best managed by a multidisciplinary team covering the various specialties involved.[44][45] Adequate nutrition must be assured, and appropriate dental care is essential. Factors that influence treatment decisions include the stage and cellular type of cancer (EAC, ESCC, and other types), along with the person's general condition and any other diseases that are present.[13]

In general, treatment with a curative intention is restricted to localized disease, without distant metastasis: in such cases a combined approach that includes surgery may be considered. Disease that is widespread, metastatic or recurrent is managed palliatively: in this case, chemotherapy may be used to lengthen survival, while treatments such as radiotherapy or stenting may be used to relieve symptoms and make it easier to swallow.[13]

Surgery

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Further information: Esophagectomy

Early-stage EAC may be treated by surgical removal of all or part of the esophagus (esophagectomy), although this is a difficult operation with a relatively high risk of mortality or post-operative difficulties. The benefits of surgery are less clear for early-stage ESCC. There are a number of surgical options, and the best choices for particular situations remain the subject of research and discussion.[44][46][47] As well as characteristics and location of the tumor, other factors include the patient's condition, and the type of operation the surgical team is most experienced with.

The likely quality of life after treatment is a relevant factor when considering surgery.[48] Surgical outcomes are likely better in large centers where the procedures are frequently performed.[46] If the cancer has spread to other parts of the body, esophagectomy is nowadays not normally performed.[46][49]

Endoscopic mucosal resection (EMR) is the removal of small tumors that only involve the mucosa or lining of the esophagus.[50]

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 is pulled up through the chest cavity and interposed. This is usually the stomach or part of the large intestine (colon) or jejunum. Reconnection of the stomach to a shortened esophagus is called an esophagogastric anastomosis.[46]

Esophagectomy can be performed using several methods. The choice of the surgical approach depends on the characteristics and location of the tumor, and the preference of the surgeon. Clear evidence from clinical trials for which approaches give the best outcomes in different circumstances is lacking.[46] A first decision, regarding the point of entry, is between a transhiatial and a transthoracic procedure. The more recent transhiatial approach avoids the need to open the chest; instead the surgeon enters the body through an incision in the lower abdomen and another in the neck. The lower part of the esophagus is freed from the surrounding tissues and cut away as necessary. The stomach is then pushed through the esophageal hiatus (the hole where the esophagus passes through the diaphragm) and is joined to the remaining upper part of the esophagus at the neck.[46]

The traditional transthoracic approach enters the body through the chest, and has a number of variations. 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. Recent approaches by some surgeons use what is called extended esophagectomy, where more surrounding tissue, including lymph nodes, is removed en bloc.[46]

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.

Chemotherapy and radiotherapy

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[clarification needed] than other comparable regimens in advanced nonresectable cancer.[51][medical citation needed] 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.

Other approaches

Forms of endoscopic therapy have been used for stage 0 and I disease: endoscopic mucosal resection (EMR) [50] and mucosal ablation using radiofrequency ablation, photodynamic therapy, Nd-YAG laser, or argon plasma coagulation.

Laser therapy is the use of high-intensity light to destroy tumor cells while affecting only the treated area. This is typically done if the cancer cannot be removed by surgery. The relief of a blockage can help with pain and difficulty swallowing. 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.

Follow-up

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

Prognosis

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 difficulty swallowing) appear, 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.[52] The latest survival data for England and Wales (patients diagnosed during 2007) show that only one in ten people survive esophageal cancer for at least ten years.[53]

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 (muscle layer of the esophagus) suggests a 20% 5YSR, and extension to the structures adjacent to the esophagus predict a 7% 5YSR. Patients with distant metastases (who are not candidates for curative surgery) have a less than 3% 5YSR.[citation needed]

  • T1, T2, and T3 stages of esophageal cancer

  • Stage T4 esophageal cancer

  • Esophageal cancer in the lymph nodes

Epidemiology

Age-standardized death from esophagus cancer per 100,000 inhabitants in 2004[54]
  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,[1] and because of its poor prognosis it is the sixth most common cause of cancer-related death.[42] It caused about 400,000 deaths in 2012, accounting for about 5% of all cancer deaths (about 456,000 new cases were diagnosed, representing about 3% of all cancers).[1]

ESCC comprises 60–70% of all cases of esophageal cancer worldwide, while EAC accounts for a further 20–30% (melanomas, leiomyosarcomas, carcinoids and lymphomas are less common types).[55] The incidence of the two main types of esophageal cancer varies greatly between different geographical areas.[56] In general, ESCC is more common in the developing world, and EAC is more common in the developed world.[1]

The worldwide incidence rate of ESCC in 2012 was 5.2 new cases per 100,000 person-years, with a male predominance (7.7 per 100,000 in men vs. 2.8 in women).[57] It was the common type in 90% of the countries studied.[57] ESCC 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.[55] In 2012, about 80% of ESCC cases worldwide occurred in central and south-eastern Asia, and over half (53%) of all cases were in China.[57] The countries with the highest estimated national incidence rates were (in Asia) Mongolia and Turkmenistan and (in Africa) Malawi, Kenya and Uganda.[57] The problem of esophageal cancer has long been recognized in the eastern and southern parts of Sub-Saharan Africa, where ESCC appears to predominate.[58]

In Western countries, EAC has become the dominant form of the disease, following an increase in incidence over recent decades (in contrast to the incidence of ESCC, which has remained largely stable).[7][25] In 2012, the global incidence rate for EAC was 0.7 per 100,000 with a strong male predominance (1.1 per 100,000 in men vs. 0.3 in women) Areas with particularly high incidence rates include northern and western Europe, North America and Oceania. The countries with highest recorded rates were the UK, Netherlands, Ireland, Iceland and New Zealand.[57]

USA

In the United States, esophageal cancer is the seventh-leading cause of cancer death among males (making up 4% of the total).[59] 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 would be diagnosed, resulting in 15,450 deaths).[56][59] 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.[60] 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 continued to increase.[61] Between 1975 and 2004, incidence of the adenocarcinoma type increased among white American males by over 460% and among white American females by 335%.[56]

UK

The incidence of esophageal adenocarcinoma has risen considerably in the UK in recent decades.[13] Overall, esophageal cancer is the thirteenth most common cancer in the UK (around 8,300 people were diagnosed with the disease in 2011), and it is the sixth most common cause of cancer death (around 7,700 people died in 2012).[62]

Society and culture

Notable cases

Christopher Hitchens, an author who is well known for the book "God is Not Great," also wrote about his life with esophageal cancer.[63]

Morrissey in October 2015 stated he has the disease and describes his experience when he first heard he had it.[64]

Research directions

Lua error in package.lua at line 80: module 'strict' not found. The risk of esophageal squamous-cell carcinoma may be reduced in people using aspirin or related NSAIDs,[65] but in the absence of randomized controlled trials the current evidence is inconclusive.[1][25]

See also

References

  1. ↑ 1.00 1.01 1.02 1.03 1.04 1.05 1.06 1.07 1.08 1.09 1.10 1.11 1.12 1.13 1.14 1.15 1.16 1.17 1.18 1.19 1.20 1.21 1.22 1.23 1.24 Lua error in package.lua at line 80: module 'strict' not found.
  2. ↑ 2.0 2.1 2.2 2.3 2.4 2.5 Lua error in package.lua at line 80: module 'strict' not found.
  3. ↑ Even by those using the British English spelling "oesophagus"
  4. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  5. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  6. ↑ 6.0 6.1 6.2 Lua error in package.lua at line 80: module 'strict' not found.
  7. ↑ 7.0 7.1 7.2 7.3 Lua error in package.lua at line 80: module 'strict' not found.
  8. ↑ 8.0 8.1 Lua error in package.lua at line 80: module 'strict' not found.
  9. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  10. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  11. ↑ 11.0 11.1 11.2 11.3 11.4 Lua error in package.lua at line 80: module 'strict' not found.
  12. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  13. ↑ 13.00 13.01 13.02 13.03 13.04 13.05 13.06 13.07 13.08 13.09 13.10 13.11 13.12 Lua error in package.lua at line 80: module 'strict' not found.
  14. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  15. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  16. ↑ 16.0 16.1 Lua error in package.lua at line 80: module 'strict' not found.
  17. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  18. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  19. ↑ 19.0 19.1 Lua error in package.lua at line 80: module 'strict' not found.
  20. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  21. ↑ 21.0 21.1 Lua error in package.lua at line 80: module 'strict' not found.
  22. ↑ 22.0 22.1 22.2 22.3 Lua error in package.lua at line 80: module 'strict' not found.
  23. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  24. ↑ 24.0 24.1 24.2 Lua error in package.lua at line 80: module 'strict' not found.
  25. ↑ 25.0 25.1 25.2 25.3 25.4 25.5 Lua error in package.lua at line 80: module 'strict' not found.
  26. ↑ 26.0 26.1 Lua error in package.lua at line 80: module 'strict' not found.
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  30. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  31. ↑ 31.0 31.1 Lua error in package.lua at line 80: module 'strict' not found.
  32. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  33. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  34. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  35. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  36. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  37. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  38. ↑ Cancer arising at the junction between the esophagus and stomach is often classified as stomach cancer, as in ICD-10. See: Lua error in package.lua at line 80: module 'strict' not found.
  39. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  40. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  41. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  42. ↑ 42.0 42.1 Lua error in package.lua at line 80: module 'strict' not found.
  43. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  44. ↑ 44.0 44.1 Lua error in package.lua at line 80: module 'strict' not found.
  45. ↑ Berry 2014, p. S292
  46. ↑ 46.0 46.1 46.2 46.3 46.4 46.5 46.6 Lua error in package.lua at line 80: module 'strict' not found. Online edition, with updates to 2014
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  48. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  49. ↑ Berry 2014, p. S293
  50. ↑ 50.0 50.1 Lua error in package.lua at line 80: module 'strict' not found.
  51. ↑ Lua error in package.lua at line 80: module 'strict' not found.
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  53. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  54. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  55. ↑ 55.0 55.1 Lua error in package.lua at line 80: module 'strict' not found.
  56. ↑ 56.0 56.1 56.2 Lua error in package.lua at line 80: module 'strict' not found.
  57. ↑ 57.0 57.1 57.2 57.3 57.4 Lua error in package.lua at line 80: module 'strict' not found.
  58. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  59. ↑ 59.0 59.1 Lua error in package.lua at line 80: module 'strict' not found.
  60. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  61. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  62. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  63. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  64. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  65. ↑ Lua error in package.lua at line 80: module 'strict' not found.

External links

Lua error in package.lua at line 80: module 'strict' not found.

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