Esophageal Cancer
- Author: Fernando AM Herbella, MD, PhD, TCBC; Chief Editor: Jules E Harris, MD more...
Background
Esophageal cancer (EC) is a devastating disease. Although some patients can be cured, the treatment for esophageal cancer is protracted, decreases quality of life, and is lethal in a significant number of cases. The ideal treatment is debatable. Defendants of surgical treatment argue that resection is the only treatment modality to offer curative intent; whereas defendants of nonsurgical approach claim that esophagectomy has a prohibitive index of mortality and that esophageal cancer is an incurable disease.
Adenocarcinoma of the esophagus, different from squamous cell carcinoma, affects the distal esophagus of young patients and is usually detected in an early stages. These facts changed the natural history of surgical treatment in this population, making cure a reality.
Historically, esophageal carcinoma has been well described since the beginning of the 19th century. The first successful resection was performed in 1913 by Frank Torek.[1] In the 1930s, Ohsawa in Japan and Marshall in the United States were the first to perform successful 1-stage transthoracic esophagectomies with continent reconstruction.[2, 3]
See the image below.
Endoscopy demonstrating intraluminal esophageal cancer. Pathophysiology
The etiology of esophageal carcinoma is thought to be related to exposure of the esophageal mucosa to noxious or toxic stimuli, resulting in a sequence of dysplasia to carcinoma in situ to carcinoma.
Vitamin and nutritional deficiencies have been recognized as contributing factors. In a high-risk country such as China, deficiencies in vitamin or microelement levels may play a role in causation. Riboflavin deficiency in China may contribute to a high incidence of esophageal cancer.
A genome-wide association study by Wu et al identified 7 susceptibility loci on chromosomes 5q11, 6p21, 10q23, 12q24, and 21q22. The findings suggest the involvement of multiple genetic loci and gene-environment interaction in the development of esophageal cancer.[4]
Risk factors
In Western cultures, retrospective evidence has implicated cigarette smoking and chronic alcohol exposure as the most common etiological factors for squamous cell carcinoma.
In the Netherlands Cohort Study, Steevens et al prospectively explored this association in 120,852 participants.[5] Among participants who drank 30 g or more of ethanol daily, the multivariable adjusted incidence rate ratio (RR) for esophageal squamous cell carcinoma was 4.61 (95% confidence interval [CI], 2.24-9.50) compared with abstainers. The RR for current smokers who consumed more than 15 g/d of ethanol was 8.05 (95% CI, 3.89-16.60) when compared with nonsmokers who consumed less than 5 g/d of ethanol. No associations were found between alcohol consumption and esophageal adenocarcinoma.
In contrast, the risk of esophageal squamous cell carcinoma and esophageal adenocarcinoma was increased among current smokers. Human papillomavirus infection has been recognized as a contributing factor. Helicobacter pylori infection has not been found to be associated with esophageal cancer.
Tylosis palmaris et plantaris is also implicated in esophageal cancer.
Gastroesophageal reflux disease (GERD) is the most common predisposing factor for adenocarcinoma of the esophagus.
As a consequence of the irritation caused by the reflux of acid and bile, 10-15% of patients who undergo endoscopy for evaluation of GERD symptoms are found to have Barrett epithelium.
Adenocarcinoma may develop in these patients, representing the last event of a sequence that starts with the development of GERD and progresses to (Barrett) metaplasia, low-grade dysplasia, high-grade dysplasia, and adenocarcinoma (see the image below).
Cascade of events that lead from gastroesophageal reflux disease to adenocarcinoma. In 1952, Morson and Belcher first described a patient with adenocarcinoma of the esophagus arising in a columnar epithelium with goblet cells.[6] In 1975, Naef et al emphasized the malignant potential of Barrett esophagus.[7] With the premalignant nature of Barrett esophagus well established, many investigators have searched for markers of esophageal carcinoma that could facilitate earlier diagnosis and follow-up of tumor recurrence.
The risk of adenocarcinoma among patients with Barrett metaplasia has been estimated to be 30-60 times that of the general population.
The prognosis of esophageal cancer is still poor, as these cancers are found late. However, a better understanding of the molecular progression of Barrett metaplasia to dysplasia to adenocarcinoma sequence may improve the prognosis. Tilanus et al reviewed data from the published literature to address the molecular changes in the pathogenesis of Barrett esophagus-associated neoplastic lesions. He found that the progression of Barrett metaplasia to adenocarcinoma is associated with several changes in gene structure, gene expression, and protein structure.[8] The oncosuppressor gene TP53 and various oncogenes, particularly erb -b2, have been studied as potential markers.
Casson and colleagues identified mutations in the TP53 gene in patients with Barrett epithelium associated with adenocarcinoma.[9] In addition, alterations in p16 genes and cell cycle abnormalities or aneuploidy appear to be some of the most important and well-characterized molecular changes. However, the exact sequence of events in the progression of Barrett esophagus to adenocarcinoma is not known. Probably multiple molecular pathways interact and are involved.
Bhat et al examined the incidence of esophageal adenocarcinoma in patients with Barrett esophagus using data from the Northern Ireland Barrett Esophagus Register, which is one of the largest population-based registries in the world. The study found that the malignant progression among patients with Barret esophagus was lower than previously reported at 0.22% per year. This suggests that current surveillance approaches may not be cost effective.[10]
A nationwide population-based case-control study performed in Sweden found an odds ratio of 7.7 (95% confidence interval, 5.3-11.4) for adenocarcinoma among persons with recurrent symptoms of reflux, as compared with persons without such symptoms, and an odds ratio of 43.5 (95% confidence interval, 18.3-103.5) among patients with long-standing and severe symptoms of reflux.
A large cohort study examined whether use of oral bisphosphonates was associated with an increased risk of esophageal or gastric cancers. No significant difference was observed for increased risk of esophageal or gastric cancers between the bisphosphonate cohort and the control group.[11]
Epidemiology
Frequency
United States
In the United States in 2008, the American Cancer Society estimated 16,470 new cases of esophageal cancer (12,970 men and 3,500 women); 14,280 persons (11,250 men and 3,030 women) were expected to die of the disease, resulting in a mortality rate of 87%. Adenocarcinoma of the esophagus has the fastest growing incidence rate of all cancers in the United States. The incidence of esophageal carcinoma is approximately 3-6 cases per 100,000 persons, although certain endemic areas appear to have higher per-capita rates. The age-adjusted incidence is 5.8 cases per 100,000 persons.
The epidemiology of esophageal carcinoma has changed markedly over the past several decades in the United States. Until the 1970s, squamous cell carcinoma was the most common type of esophageal cancer (90-95%). It was located in the thoracic esophagus and affected mostly African American men who had a long history of smoking and alcohol consumption. Over the last 2 decades, the incidence of adenocarcinoma of the distal esophagus and gastroesophageal junction has progressively increased. Currently, it accounts for more than 50% of all new cases of esophageal cancer. Unlike squamous cell carcinoma, it affects mostly white men, and its pathogenesis is linked to gastroesophageal reflux disease (GERD) and the development of Barrett epithelium (see the image below).
Cascade of events that lead from gastroesophageal reflux disease to adenocarcinoma. International
Esophageal cancer is the seventh leading cause of cancer death worldwide. Incidence of esophageal carcinoma can be as high as 30-800 cases per 100,000 persons in particular areas of northern Iran, some areas of southern Russia, and northern China. Unlike in the United States, squamous cell carcinoma is responsible for 95% of all esophageal cancers worldwide.
Race
In the United States, African-Americans have a higher incidence of esophageal cancer than whites.
Sex
Esophageal cancer is generally more common in men than in women, with a male-to-female ratio of 3-4:1.
Age
Esophageal cancer occurs most commonly during the sixth and seventh decades of life. The disease becomes more common with advancing age; it is about 20 times more common in those older than 65 years than in persons younger than 65 years.
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| Stage IA | T1 | N0 | M0 |
| Stage IB | T2 | N0 | M0 |
| Stage IIA | T3 | N0 | M0 |
| Stage IIB | T1,T2 | N1 | M0 |
| Stage IIIA | T4a | N0 | M0 |
| T3 | N1 | M0 | |
| T1,T2 | N2 | M0 | |
| Stage IIIB | T3 | N2 | M0 |
| Stage IIIC | T4a | N1,N2 | M0 |
| T4b | Any N | M0 | |
| Any T | N3 | M0 | |
| Stage IV | Any T | Any N | M1 |
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