Esophageal cancer

The two major risk factors for esophageal squamous-cell carcinoma are tobacco (smoking or chewing) and alcohol.[2] The combination of tobacco and alcohol has a strong synergistic effect.[21] 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.[2] Risks associated with alcohol appear to be linked to its aldehyde metabolite and to mutations in certain related enzymes.[16] Such metabolic variants are relatively common in Asia.[2]

Other relevant risk factors include regular consumption of very hot drinks (over 65 °C or 149 °F)[22][23] and ingestion of caustic substances.[2] High levels of dietary exposure to nitrosamines (chemical compounds found both in tobacco smoke and certain foodstuffs) also appear to be a relevant risk factor.[16] Unfavorable dietary patterns seem to involve exposure to nitrosamines through processed and barbecued meats, pickled vegetables, etc., and a low intake of fresh foods.[2] Other associated factors include nutritional deficiencies, low socioeconomic status, and poor oral hygiene.[16] Chewing betel nut (areca) is an important risk factor in Asia.[4]

Physical trauma may increase the risk.[24] This may include the drinking of very hot drinks.[3]

Esophageal cancer (lower part) as a result of Barrettʼs esophagus

Male predominance is particularly strong in this type of esophageal cancer, which occurs about 7 to 10 times more frequently in men.[25] This imbalance may be related to the characteristics and interactions of other known risk factors, including acid reflux and obesity.[25]

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.[26] Longstanding GERD can induce a change of cell type in the lower portion of the esophagus in response to erosion of its squamous lining.[26] This phenomenon, known as Barrett's esophagus, seems to appear about 20 years later in women than in men, possibly due to hormonal factors.[26] At a mechanistic level, in the esophagus there is a small HOXA13 expressing compartment that is more resistant to bile and acids as the normal squamous epithelium and that is prone to both intestinal differentiation as well as oncogenic transformation. Following GERD this HOXA13-expressing compartment outcompetes the normal squamous compartment, leading to the intestinal aspect of the esophagus and increased propensity to the development of esophageal cancer.[27] 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.[16] Bile reflux containing unconjugated bile acids, including deoxycholic acid and chenodeoxycholic acid, appears to contribute to esophageal adenocarcinoma carcinogenesis by inducing oxidative stress and DNA damage[28].The risk of developing adenocarcinoma in the presence of Barrett's esophagus is unclear, and may in the past have been overestimated.[2]

Being obese or overweight both appear to be associated with increased risk.[29] The association with obesity seems to be the strongest of any type of obesity-related cancer, though the reasons for this remain unclear.[30] 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.[30] This type of obesity is characteristic of men.[30] Physiologically, it stimulates GERD and also has other chronic inflammatory effects.[26]

Helicobacter pylori infection (a common occurrence thought to have affected over half of the world's population) is not a risk factor for esophageal adenocarcinoma and actually appears to be protective. Despite being a cause of GERD and a risk factor for gastric cancer, the infection seems to be associated with a reduced risk of esophageal adenocarcinoma of as much as 50%.[31][32] The biological explanation for a protective effect is somewhat unclear.[32] One explanation is that some strains of H. pylori reduce stomach acid, thereby reducing damage by GERD.[33] Decreasing rates of H. pylori infection in Western populations over recent decades, which have been linked to less overcrowding in households, could be a factor in the concurrent increase in esophageal adenocarcinoma.[31]

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.[31]

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.[31]

• 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).[34][35]
• History of radiation therapy for other conditions in the chest is a risk factor for esophageal adenocarcinoma.[16]
• Corrosive injury to the esophagus by accidentally or intentionally swallowing caustic substances is a risk factor for squamous cell carcinoma.[2]
• Tylosis with esophageal cancer is a rare familial disease with autosomal dominant inheritance that has been linked to a mutation in the RHBDF2 gene, present on chromosome 17: it involves thickening of the skin of the palms and soles and a high lifetime risk of squamous cell carcinoma.[2][36]
• 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.[37]
• Plummer–Vinson syndrome (a rare disease that involves esophageal webs) is also a risk factor.[2]
• There is some evidence suggesting a possible causal association between human papillomavirus (HPV) and esophageal squamous-cell carcinoma.[38] The relationship is unclear.[39] Possible relevance of HPV could be greater in places that have a particularly high incidence of this form of the disease,[40] as in some Asian countries, including China.[41]
• There is an association between celiac disease and esophageal cancer. People with untreated celiac disease have a higher risk, but this risk decreases with time after diagnosis, probably due to the adoption of a gluten-free diet, which seems to have a protective role against development of malignancy in people with celiac disease. However, the delay in diagnosis and initiation of a gluten-free diet seems to increase the risk of malignancy. Moreover, in some cases the detection of celiac disease is due to the development of cancer, whose early symptoms are similar to some that may appear in celiac disease.[42]

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.[43][44] Positron emission tomography is also used to estimate the extent of the disease and is regarded as more precise than CT alone.[45] PET/MR as a novel modality has shown promising results in preoperative staging with fair feasibility and good correlation in comparison to PET/CT. It can enhance tissue differentiation with lowering the radiation dose to the patient.[46] 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.

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

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 and lymphoma, among others.[47][48]

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).[16] The currently preferred classification is the 2010 AJCC staging system for cancer of the esophagus and the esophagogastric junction.[16] 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[49]).[50]

• 
  T1, T2, and T3 stages of esophageal cancer
• 
  Stage T4 esophageal cancer
• 
  Esophageal cancer with spread to lymph nodes

People with Barrett's esophagus (a change in the cells lining the lower esophagus) are at much higher risk,[54] and may receive regular endoscopic screening for the early signs of cancer.[55] Because the benefit of screening for adenocarcinoma in people without symptoms is unclear,[2] it is not recommended in the United States.[1] Some areas of the world with high rates of squamous-carcinoma have screening programs.[2]

If the cancer has been diagnosed while still in an early stage, surgical treatment with a curative intention may be possible. Some small tumors that only involve the mucosa or lining of the esophagus may be removed by endoscopic mucosal resection (EMR).[58][59] Otherwise, curative surgery of early-stage lesions may entail 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 in early-stage ESCC than EAC. There are a number of surgical options, and the best choices for particular situations remain the subject of research and discussion.[56][60][61] 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.[62] Surgical outcomes are likely better in large centers where the procedures are frequently performed.[60] If the cancer has spread to other parts of the body, esophagectomy is nowadays not normally performed.[60][63]

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.[60]

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.[60] 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.[60]

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.[60]

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 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.[64] 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.

Forms of endoscopic therapy have been used for stage 0 and I disease: endoscopic mucosal resection (EMR)[65] 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.

• 
  Internal radiotherapy for esophageal cancer
• 
  Self-expandable metallic stents are sometimes used for palliative care

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

In the United States, esophageal cancer is the seventh-leading cause of cancer death among males (making up 4% of the total).[73] 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).[70][73]

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 2002. This increase was found in non-Hispanic whites and Hispanics and became predominant in non-Hispanic whites.[74] 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.[75] Between 1975 and 2004, incidence of the adenocarcinoma type increased among white American males by over 460% and among white American females by 335%.[70]

The incidence of esophageal adenocarcinoma has risen considerably in the UK in recent decades.[16] 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).[76]

Humphrey Bogart, actor, died of esophageal cancer in 1957, aged 57.

Christopher Hitchens, author and journalist, died of esophageal cancer in 2011, aged 62.[77]

Morrissey in October 2015 stated he has the disease and describes his experience when he first heard he had it.[78]

Mako Iwamatsu, voice actor for Avatar: The Last Airbender as General Iroh and Samurai Jack as Aku, died of esophageal cancer in 2006, aged 72.

Robert Kardashian, attorney and businessman, died of esophageal cancer in 2003, aged 59.

Traci Braxton, singer and reality TV star died of esophageal cancer in 2022, aged 50.