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Summary of Evidence
Note: Separate PDQ summaries on Esophageal Cancer Prevention, Esophageal Cancer Treatment, and Levels of Evidence for Cancer Screening and Prevention Studies are also available.
Based on fair evidence, screening would result in no (or minimal) decrease in mortality from esophageal cancer in the U.S. population.
Description of the Evidence
- Study Design: Evidence from cohort or case-control studies.
- Internal Validity: Fair.
- Consistency: Multiple studies.
- Magnitude of Effects on Health Outcomes: Small positive.
- External Validity: Poor.
Based on solid evidence, screening would result in uncommon but serious side effects associated with endoscopy which may include perforation, cardiopulmonary events and aspiration, and bleeding requiring hospitalization. Potential psychological harms may occur in those identified as having Barrett esophagus who may consider themselves to be ill even though their risk of developing cancer is low.
Description of the Evidence
- Study Design: Evidence obtained from cohort or case-control studies.
- Internal Validity: Fair.
- Consistency: Multiple studies, large number of participants.
- Magnitude of Effects on Health Outcomes: Fair evidence for no reduction in mortality; good evidence for uncommon but serious harms.
- External Validity: Poor.
Natural History, Incidence, and Mortality
In 2017, it is estimated that 16,940 Americans will be diagnosed with esophageal cancer, and 15,690 will die of this malignancy. Of the new cases, it is estimated that 13,360 will occur in men and 3,580 will occur in women.[1 ]
Two histologic types account for the majority of malignant esophageal neoplasms: adenocarcinoma and squamous carcinoma. The epidemiology of these types varies markedly. In the 1960s, squamous cell cancers comprised more than 90% of all esophageal tumors. The incidence of esophageal adenocarcinomas has risen considerably for the past 2 decades, such that it is now more prevalent than squamous cell cancer in the United States and Western Europe, with most tumors located in the distal esophagus.[2 ] Although the overall incidence of squamous cell carcinoma of the esophagus is declining, this histologic type remains six times more likely to occur in black males than in white males.[3 ] Incidence rates generally increase with age in all racial/ethnic groups but squamous cell cancer is consistently more common in blacks than in whites. Among black men, the incidence rate for those aged 55 to 69 years is close to that of white men aged 70 years and older. In black women aged 55 to 69 years, the incidence rate is slightly higher than white women aged 70 years and older.
While risk factors for squamous cell carcinoma of the esophagus have been identified (such as tobacco, alcoholism, malnutrition, and infection with human papillomavirus),[4 ] the risk factors associated with esophageal adenocarcinoma are less defined. The most important epidemiological difference between squamous cell cancer and adenocarcinoma, however, is the strong association between gastroesophageal reflux disease (GERD) and adenocarcinoma. The results of a population-based case-controlled study suggest that symptomatic gastroesophageal reflux is a risk factor for esophageal adenocarcinoma. The frequency, severity, and duration of reflux symptoms were positively associated with increased risk of esophageal adenocarcinoma.[5 ,6 ,7 ]
Long-standing GERD predisposes to Barrett esophagus, the condition in which an abnormal intestinal epithelium replaces the stratified squamous epithelium that normally lines the distal esophagus.[8 ] The intestinal-type epithelium of Barrett esophagus has a characteristic endoscopic appearance that differs from squamous epithelium.[9 ] Dysplasia in Barrett epithelium represents an alteration of the columnar epithelium that may progress to invasive adenocarcinoma.[10 ]
An interesting hypothesis relates the rise in incidence of esophageal adenocarcinoma to a declining prevalence of Helicobacter pylori infection in Western countries. Reports have suggested that gastric infection with H. pylori may protect the esophagus from GERD and its complications.[11 ] According to this theory, H. pylori infections that cause pangastritis also cause a decrease in gastric acid production that protects against GERD.[12 ] Patients whose duodenal ulcers were treated successfully with antibiotics developed reflux esophagitis twice as often as those in whom infection persisted.[13 ]
Past use of lower esophageal sphincter (LES)-relaxing drugs was positively associated with risk of esophageal adenocarcinoma. Among daily, long-term users (>5 years) of LES-relaxing drugs, the estimated incidence rate ratio was 3.8 (95% confidence interval [CI], 2.2-6.4) compared with persons who had never used these drugs. Gastric cardia adenocarcinoma and esophageal squamous cell carcinoma were not associated with use of LES-relaxing drugs.[14 ]
There exists a strong relationship between body mass index (BMI) and esophageal adenocarcinoma. The adjusted odds ratio (OR) was 7.6 (95% CI, 3.8-15.2) among persons in the highest BMI quartile compared with persons in the lowest. Obese persons (those with BMI >30 kg/m2) had an OR of 16.2 (95% CI, 6.3-41.4) compared with the leanest persons (BMI <22 kg/m2). Esophageal squamous cell carcinoma was not associated with BMI.[15 ]
- American Cancer Society: Cancer Facts and Figures 2017. Atlanta, Ga: American Cancer Society, 2017. Available online. Last accessed October 13, 2017.
- Blot WJ, McLaughlin JK: The changing epidemiology of esophageal cancer. Semin Oncol 26 (5 Suppl 15): 2-8, 1999.
- Devesa SS, Blot WJ, Fraumeni JF Jr: Changing patterns in the incidence of esophageal and gastric carcinoma in the United States. Cancer 83 (10): 2049-53, 1998.
- Oesophagus. In: World Cancer Research Fund, American Institute for Cancer Research: Food, Nutrition and the Prevention of Cancer: A Global Perspective. Washington, DC: The Institute, 1997, pp 118-129.
- Lagergren J, Bergström R, Lindgren A, et al.: Symptomatic gastroesophageal reflux as a risk factor for esophageal adenocarcinoma. N Engl J Med 340 (11): 825-31, 1999.
- Wijnhoven BP, Tilanus HW, Dinjens WN: Molecular biology of Barrett's adenocarcinoma. Ann Surg 233 (3): 322-37, 2001.
- Skacel M, Petras RE, Gramlich TL, et al.: The diagnosis of low-grade dysplasia in Barrett's esophagus and its implications for disease progression. Am J Gastroenterol 95 (12): 3383-7, 2000.
- Spechler SJ, Goyal RK: The columnar-lined esophagus, intestinal metaplasia, and Norman Barrett. Gastroenterology 110 (2): 614-21, 1996.
- Van Dam J, Brugge WR: Endoscopy of the upper gastrointestinal tract. N Engl J Med 341 (23): 1738-48, 1999.
- Reid BJ, Blount PL, Rubin CE, et al.: Flow-cytometric and histological progression to malignancy in Barrett's esophagus: prospective endoscopic surveillance of a cohort. Gastroenterology 102 (4 Pt 1): 1212-9, 1992.
- O'Connor HJ: Review article: Helicobacter pylori and gastro-oesophageal reflux disease-clinical implications and management. Aliment Pharmacol Ther 13 (2): 117-27, 1999.
- Graham DY, Yamaoka Y: H. pylori and cagA: relationships with gastric cancer, duodenal ulcer, and reflux esophagitis and its complications. Helicobacter 3 (3): 145-51, 1998.
- Labenz J, Blum AL, Bayerdörffer E, et al.: Curing Helicobacter pylori infection in patients with duodenal ulcer may provoke reflux esophagitis. Gastroenterology 112 (5): 1442-7, 1997.
- Lagergren J, Bergström R, Adami HO, et al.: Association between medications that relax the lower esophageal sphincter and risk for esophageal adenocarcinoma. Ann Intern Med 133 (3): 165-75, 2000.
- Lagergren J, Bergström R, Nyrén O: Association between body mass and adenocarcinoma of the esophagus and gastric cardia. Ann Intern Med 130 (11): 883-90, 1999.
Evidence of Benefit
Squamous Cell Cancer
Squamous cell carcinoma of the esophagus does not have a highly prevalent predisposing condition, although the incidence increases in persons who have had long-standing exposure to tobacco and alcohol,[1 ] achalasia,[2 ] head and neck squamous cell cancer attributable most likely to long-standing alcohol and/or tobacco exposure,[3 ] tylosis,[4 ,5 ] history of lye ingestion,[6 ] celiac sprue,[7 ] and, in South America and China, hot liquid ingestion.[8 ] The etiological role of human papillomavirus infection in squamous cell cancer is under study.[9 ,10 ]
Efforts at early detection of squamous cell cancer of the esophagus have concentrated on cytological or endoscopic screening of populations in countries where there is a high incidence. While these programs have demonstrated that it is possible to detect squamous cell cancers in an early asymptomatic stage, a study from China assessed one-time endoscopic screening on the outcome of patients with esophageal cancer. In this study, communities were chosen nonrandomly in Cixian County, Hibei Province; 14 villages in the north were intervention communities and ten villages in the south were control communities. The intervention was one-time endoscopy, completed by experts, using Lugol's iodine staining to identify dysplasia or occult cancer. After biopsy was obtained and read, dysplasia and occult cancers were treated by endoscopic mucosal resection or argon plasma coagulation. Among the 6,827 participants aged 40 to 69 years in the intervention group, 3,319 volunteers were screened. Among the 6,200 participants aged 40 to 69 years in the control group, 797 individuals were interviewed. Outcome in each group was monitored to assess incidence and mortality of esophageal squamous cancer. In a 10-year follow-up, there were 542 cases of fatal esophageal squamous cell carcinoma (ESCC), a reduction in cumulative mortality from 5.05% in the control group to 3.35% in the intervention group (P < .001), and lower incidence of ESCC in the intervention group (5.92% vs. 4.17%, P < .001). Potential weaknesses of the study include the following:[11 ]
- Participants were not randomly assigned but rather came from different villages, in which underlying rates may have differed geographically (northern vs. southern villages), and it was not clear what the baseline cancer rates were.
- It was not clear whether cause of death (e.g., ESCC) or cancer incidence was assessed in a blinded manner, which might have been important for assignment of what is a subjective assessment.
Esophageal cytological screening studies have been reported from China,[12 ,13 ] Iran,[14 ] South Africa,[15 ,16 ] Italy,[17 ] and Japan.[18 ] In the United States, such efforts have been focused on individuals perceived to be at higher risk.[19 ,20 ] Studies of primary endoscopic screening have been reported from France [21 ] and Japan.[22 ]
Comparisons of both Chinese and U.S. cytological diagnoses with concurrent histological findings showed low (14% to 36%) sensitivities for the cytological detection of biopsy-proven cancers. Specificity ranged from 90% to 99% with a positive predictive value of 23% to 94%.[23 ] The development of uniform and accurate cytological criteria will require formal cytological-histological correlation studies of esophageal lesions. Such studies should become more feasible with the increasing availability of endoscopy in high-risk populations.
The efficacy of surveillance cytology or endoscopy for high-risk patients with tylosis or long-standing achalasia is not known.
Adenocarcinoma of the Esophagus
Considerable debate has ensued concerning the risk of cancer in patients with Barrett esophagus. Prospective studies have reported annual esophageal cancer incidence rates ranging from 0.2% to 1.9%.[24 ] Concern over publication bias has led some authors to suggest that the risk may be lower than the literature suggests.[25 ] A risk of 0.5% per year for development of adenocarcinoma is now thought to be a reasonable estimate for Barrett esophagus.[26 ]
Barrett esophagus is strongly associated with gastroesophageal reflux disease (GERD), and the changes of Barrett esophagus can be found in approximately 10% of patients who have GERD. However, GERD is very common; surveys have found that approximately 20% of adult Americans experience symptoms of GERD, such as heartburn, at least once each week.[27 ] The likelihood of finding Barrett esophagus on endoscopy is related to the duration of symptoms of gastroesophageal reflux. In a series of 701 individuals, 4% of those with symptoms for less than 1 year had Barrett esophagus on endoscopy, whereas Barrett esophagus was found in 21% of those with more than 10 years of symptoms of GERD. It has been estimated that physicians identify only approximately 5% of the population who have Barrett esophagus.[28 ] There is insufficient evidence that population screening for Barrett esophagus reduces cancer mortality.[29 ,30 ]
Surveillance of Barrett esophagus involves the use of tests to identify preneoplastic changes or curable neoplasms in patients who are known to have Barrett esophagus. Certain factors are essential in the implementation of an effective surveillance protocol, including low risk of the surveillance method, correct histological diagnosis of dysplasia, proof that surgical resection for high-grade dysplasia will decrease the risk of cancer, and successful resection of cancer. The interval between endoscopic evaluations is typically determined by histologic findings, in accordance with published guidelines by gastroenterological committees.[31 ] GERD should be treated prior to surveillance endoscopy to minimize confusion caused by inflammation in the interpretation of biopsy specimens. The technique of random, four-quadrant biopsies taken every 2 cm in the columnar-lined esophagus for standard histological evaluation has been recommended by some clinicians. For patients with no dysplasia, surveillance endoscopy at an interval of every 2 to 3 years has been recommended.[31 ] For patients with low-grade dysplasia, surveillance every 6 months for the first year has been recommended, followed by annual endoscopy if the dysplasia has not progressed in severity. For patients with high-grade dysplasia, two options have been recommended: surgical resection or repeated endoscopic evaluation until the diagnosis of intramucosal carcinoma is made. Although widely adopted in clinical practice, these practices are based on uncontrolled series and the opinion of expert gastrointestinal endoscopists and pathologists.
Evidence of Harm
Screening for esophageal cancer by the use of blind nonendoscopically directed balloon cytological sampling for squamous cell carcinoma is minimally inconvenient and uncomfortable. Endoscopic screening for esophageal adenocarcinoma is expensive, inconvenient, and usually requires sedation.
Complications such as perforation and bleeding can occur. The incidence of complications including perforation, respiratory arrest, and myocardial infarction, has been estimated to be 0 to 13 per 10,000 procedures with an associated mortality of 0 to 0.8 per 10,000 procedures.[34 ,35 ]
Individuals who are informed they have Barrett esophagus may consider themselves to be ill even though their risk of developing cancer is very low.
- Bollschweiler E, Schröder W, Hölscher AH, et al.: Preoperative risk analysis in patients with adenocarcinoma or squamous cell carcinoma of the oesophagus. Br J Surg 87 (8): 1106-10, 2000.
- Aggestrup S, Holm JC, Sørensen HR: Does achalasia predispose to cancer of the esophagus? Chest 102 (4): 1013-6, 1992.
- Abemayor E, Moore DM, Hanson DG: Identification of synchronous esophageal tumors in patients with head and neck cancer. J Surg Oncol 38 (2): 94-6, 1988.
- Ellis A, Field JK, Field EA, et al.: Tylosis associated with carcinoma of the oesophagus and oral leukoplakia in a large Liverpool family--a review of six generations. Eur J Cancer B Oral Oncol 30B (2): 102-12, 1994.
- Risk JM, Mills HS, Garde J, et al.: The tylosis esophageal cancer (TOC) locus: more than just a familial cancer gene. Dis Esophagus 12 (3): 173-6, 1999.
- Isolauri J, Markkula H: Lye ingestion and carcinoma of the esophagus. Acta Chir Scand 155 (4-5): 269-71, 1989 Apr-May.
- Ferguson A, Kingstone K: Coeliac disease and malignancies. Acta Paediatr Suppl 412: 78-81, 1996.
- Rolón PA, Castellsagué X, Benz M, et al.: Hot and cold mate drinking and esophageal cancer in Paraguay. Cancer Epidemiol Biomarkers Prev 4 (6): 595-605, 1995.
- Lagergren J, Wang Z, Bergström R, et al.: Human papillomavirus infection and esophageal cancer: a nationwide seroepidemiologic case-control study in Sweden. J Natl Cancer Inst 91 (2): 156-62, 1999.
- Sur M, Cooper K: The role of the human papilloma virus in esophageal cancer. Pathology 30 (4): 348-54, 1998.
- Wei WQ, Chen ZF, He YT, et al.: Long-Term Follow-Up of a Community Assignment, One-Time Endoscopic Screening Study of Esophageal Cancer in China. J Clin Oncol 33 (17): 1951-7, 2015.
- Shen O, Liu SF, Dawsey SM, et al.: Cytologic screening for esophageal cancer: results from 12,877 subjects from a high-risk population in China. Int J Cancer 54 (2): 185-8, 1993.
- Dawsey SM, Lewin KJ, Wang GQ, et al.: Squamous esophageal histology and subsequent risk of squamous cell carcinoma of the esophagus. A prospective follow-up study from Linxian, China. Cancer 74 (6): 1686-92, 1994.
- Dowlatshahi K, Daneshbod A, Mobarhan S: Early detection of cancer of oesophagus along Caspian Littoral. Report of a pilot project. Lancet 1 (8056): 125-6, 1978.
- Jaskiewicz K, Venter FS, Marasas WF: Cytopathology of the esophagus in Transkei. J Natl Cancer Inst 79 (5): 961-7, 1987.
- Tim LO, Leiman G, Segal I, et al.: A suction-abrasive cytology tube for the diagnosis of esophageal carcinoma. Cancer 50 (4): 782-4, 1982.
- Aste H, Saccomanno S, Munizzi F: Blind pan-esophageal brush cytology. Diagnostic accuracy. Endoscopy 16 (5): 165-7, 1984.
- Nabeya K: Markers of cancer risk in the esophagus and surveillance of high-risk groups. In: Sherlock P, Morson BC, Barbara L, et al., eds.: Precancerous Lesions of the Gastrointestinal Tract. New York, NY: Raven Press, 1983, pp 71-86.
- Dowlatshahi K, Skinner DB, DeMeester TR, et al.: Evaluation of brush cytology as an independent technique for detection of esophageal carcinoma. J Thorac Cardiovasc Surg 89 (6): 848-51, 1985.
- Jacob P, Kahrilas PJ, Desai T, et al.: Natural history and significance of esophageal squamous cell dysplasia. Cancer 65 (12): 2731-9, 1990.
- Meyer V, Burtin P, Bour B, et al.: Endoscopic detection of early esophageal cancer in a high-risk population: does Lugol staining improve videoendoscopy? Gastrointest Endosc 45 (6): 480-4, 1997.
- Yokoyama A, Ohmori T, Makuuchi H, et al.: Successful screening for early esophageal cancer in alcoholics using endoscopy and mucosa iodine staining. Cancer 76 (6): 928-34, 1995.
- Dawsey SM, Shen Q, Nieberg RK, et al.: Studies of esophageal balloon cytology in Linxian, China. Cancer Epidemiol Biomarkers Prev 6 (2): 121-30, 1997.
- Drewitz DJ, Sampliner RE, Garewal HS: The incidence of adenocarcinoma in Barrett's esophagus: a prospective study of 170 patients followed 4.8 years. Am J Gastroenterol 92 (2): 212-5, 1997.
- Shaheen NJ, Crosby MA, Bozymski EM, et al.: Is there publication bias in the reporting of cancer risk in Barrett's esophagus? Gastroenterology 119 (2): 333-8, 2000.
- Spechler SJ: Barrett's esophagus: an overrated cancer risk factor. Gastroenterology 119 (2): 587-9, 2000.
- Locke GR 3rd, Talley NJ, Fett SL, et al.: Prevalence and clinical spectrum of gastroesophageal reflux: a population-based study in Olmsted County, Minnesota. Gastroenterology 112 (5): 1448-56, 1997.
- Spechler SJ: Barrett's esophagus: should we brush off this ballooning problem? Gastroenterology 112 (6): 2138-42, 1997.
- Gerson LB, Triadafilopoulos G: Screening for esophageal adenocarcinoma: an evidence-based approach. Am J Med 113 (6): 499-505, 2002.
- Wang KK, Wongkeesong M, Buttar NS: American Gastroenterological Association technical review on the role of the gastroenterologist in the management of esophageal carcinoma. Gastroenterology 128 (5): 1471-505, 2005.
- DeVault KR, Castell DO: Updated guidelines for the diagnosis and treatment of gastroesophageal reflux disease. The Practice Parameters Committee of the American College of Gastroenterology. Am J Gastroenterol 94 (6): 1434-42, 1999.
- Canto MI, Setrakian S, Petras RE, et al.: Methylene blue selectively stains intestinal metaplasia in Barrett's esophagus. Gastrointest Endosc 44 (1): 1-7, 1996.
- Panjehpour M, Overholt BF, Vo-Dinh T, et al.: Endoscopic fluorescence detection of high-grade dysplasia in Barrett's esophagus. Gastroenterology 111 (1): 93-101, 1996.
- Clarke GA, Jacobson BC, Hammett RJ, et al.: The indications, utilization and safety of gastrointestinal endoscopy in an extremely elderly patient cohort. Endoscopy 33 (7): 580-4, 2001.
- Sieg A, Hachmoeller-Eisenbach U, Eisenbach T: Prospective evaluation of complications in outpatient GI endoscopy: a survey among German gastroenterologists. Gastrointest Endosc 53 (6): 620-7, 2001.
Changes to This Summary (03 / 17 / 2017)
The PDQ cancer information summaries are reviewed regularly and updated as new information becomes available. This section describes the latest changes made to this summary as of the date above.
Updated statistics with estimated new cases and deaths for 2017 (cited American Cancer Society as reference 1).
This summary is written and maintained by the PDQ Screening and Prevention Editorial Board, which is editorially independent of NCI. The summary reflects an independent review of the literature and does not represent a policy statement of NCI or NIH. More information about summary policies and the role of the PDQ Editorial Boards in maintaining the PDQ summaries can be found on the About This PDQ Summary and PDQ® - NCI's Comprehensive Cancer Database pages.
About This PDQ Summary
Purpose of This Summary
This PDQ cancer information summary for health professionals provides comprehensive, peer-reviewed, evidence-based information about esophageal cancer screening. It is intended as a resource to inform and assist clinicians who care for cancer patients. It does not provide formal guidelines or recommendations for making health care decisions.
Reviewers and Updates
This summary is reviewed regularly and updated as necessary by the PDQ Screening and Prevention Editorial Board, which is editorially independent of the National Cancer Institute (NCI). The summary reflects an independent review of the literature and does not represent a policy statement of NCI or the National Institutes of Health (NIH).
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Levels of Evidence
Some of the reference citations in this summary are accompanied by a level-of-evidence designation. These designations are intended to help readers assess the strength of the evidence supporting the use of specific interventions or approaches. The PDQ Screening and Prevention Editorial Board uses a formal evidence ranking system in developing its level-of-evidence designations.
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PDQ® Screening and Prevention Editorial Board. PDQ Esophageal Cancer Screening. Bethesda, MD: National Cancer Institute. Updated <MM/DD/YYYY>. Available at: https://www.cancer.gov/types/esophageal/hp/esophageal-screening-pdq. Accessed <MM/DD/YYYY>. [PMID: 26389241]
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Last Revised: 2017-03-17