Endoscopic Management of Early Adenocarcinoma and Squamous Cell Carcinoma of the Esophagus: Screening, Diagnosis, and Therapy

Because the esophagus is easily accessible with endoscopy, early diagnosis and curative treatment of esophageal cancer is possible. However, diagnosis is often delayed because symptoms are not specific during early stages of tumor development. The onset of dysphagia is associated with advanced disease, which has a survival at 5 years lower than 15%. Population screening by endoscopy is not cost-effective, but a number of alternative imaging and cell analysis technologies are under investigation. The ideal screening test should be inexpensive, well tolerated, and applicable to primary care. Over the past 10 years, significant progress has been made in endoscopic diagnosis and treatment of dysplasia (squamous and Barrett’s), and early esophageal cancer using resection and ablation technologies supported by evidence from randomized controlled trials. We review the state-of-the-art technologies for early diagnosis and minimally invasive treatment, which together could reduce the burden of disease. Because the esophagus is easily accessible with endoscopy, early diagnosis and curative treatment of esophageal cancer is possible. However, diagnosis is often delayed because symptoms are not specific during early stages of tumor development. The onset of dysphagia is associated with advanced disease, which has a survival at 5 years lower than 15%. Population screening by endoscopy is not cost-effective, but a number of alternative imaging and cell analysis technologies are under investigation. The ideal screening test should be inexpensive, well tolerated, and applicable to primary care. Over the past 10 years, significant progress has been made in endoscopic diagnosis and treatment of dysplasia (squamous and Barrett’s), and early esophageal cancer using resection and ablation technologies supported by evidence from randomized controlled trials. We review the state-of-the-art technologies for early diagnosis and minimally invasive treatment, which together could reduce the burden of disease. Marcia I. CantoView Large Image Figure ViewerDownload Hi-res image Download (PPT)Rebecca C. FitzgeraldView Large Image Figure ViewerDownload Hi-res image Download (PPT) Screening means a program in which individuals are invited by a health care professional or system to undergo a test for a medical condition. The target may be the general population, or subsets of the population, selected, for example, by age or sex, to increase the prevalence of the disorder in those tested. Alternatively, systematic testing might target a group of individuals with specific symptoms who might not otherwise have been investigated. In the context of esophageal cancer, screening would aim to detect Barrett’s esophagus (BE) and dysplasia in squamous epithelium, which are precursor lesions to esophageal adenocarcinoma (EA) and esophageal squamous cell carcinoma (ESCC), respectively. To fulfill the updated Junger criteria1Andermann A. Blancquaert I. Beauchamp S. et al.Revisiting Wilson and Jungner in the genomic age: a review of screening criteria over the past 40 years.Bull World Health Organ. 2008; 86: 317-319Crossref PubMed Scopus (253) Google Scholar for screening, any test would need to be conducted in an enriched population in view of the low prevalence of the disease and the low conversion rate. The target population can be defined according to known risk factors for BE and squamous cell dysplasia, which have high geographical variation (see article by Abnet et al in this Special Issue).2Vaughan T.L. Fitzgerald R.C. Precision prevention of oesophageal adenocarcinoma.Nat Rev Gastroenterol Hepatol. 2015; 12: 243-248Crossref PubMed Scopus (29) Google Scholar However, given the high prevalence of some risk factors, for example reflux in the context of BE, and the need for confirmatory investigations to reach a definitive diagnosis, it is essential that the screening test has a high level of specificity, to avoid false-positive results and resulting unnecessary invasive procedures. The characteristics of different screening tests for esophageal cancer are summarized in Table 1.Table 1Characteristics of Screening Tests for Esophageal CancerAccuracyCost-effectivenessSuitable for primary careScientific evidenceEsophago-gastro duodenoscopy (EGD)Standard:•Good image quality•Histologic diagnosis with sampling biasVery low:•High direct and indirect costsNo:•Not portable•Sedation requiredYes:•High diagnostic yield in selected groupsTrans-nasal endoscopy (TNE)Good:•Acceptable image quality•Small or no biopsy samplingUnknown:•Low direct and indirect costsYes:•For office-based system•Expertise required to perform testYes:•Generally preferred over endoscopy•Feasible in community-based studiesCapsule endoscopy (CE)Good:•High frame rate for new generation•No tissue samplingLow:•Comparative studies show EGD is preferred to CEYes:•Expertise required for image analysisLimited:•Lack of community-based studiesCytospongeGood:•Tissue based diagnosis with pan-esophageal sampling•Molecular diagnosis possibleYes:•ICER for Cytosponge followed by EGD ≈$30,000Yes:•Nurse-led clinic•Central laboratoryYes:•Feasible and well tolerated in community-based studies•Large studies in secondary careCirculating or stool markersUnknownUnknown:•Low direct and indirect costsYes:•Nurse-led clinic•Central laboratoryLimited:•Small pilot studies onlyVolatile compounds in breathUnknownUnknown:•Low indirect costs•Limited data on direct costsYes:•Nurse-led clinic•Central laboratoryLimited:•Small pilot studies only Open table in a new tab Esophago-gastro duodenoscopy (EGD) is the standard used to detect esophageal cancer and the precursor lesions. For patients who consult their general practitioner with upper gastrointestinal symptoms, referral rates for endoscopy vary significantly among practices; this is likely to be the case worldwide, depending on the level of awareness and nature of the reimbursement systems for endoscopic procedures.3Nandurkar S. Locke 3rd, G.R. Murray J.A. et al.Rates of endoscopy and endoscopic findings among people with frequent symptoms of gastroesophageal reflux in the community.Am J Gastroenterol. 2005; 100: 1459-1465Crossref PubMed Scopus (0) Google Scholar, 4Shawihdi M. Thompson E. Kapoor N. et al.Variation in gastroscopy rate in English general practice and outcome for oesophagogastric cancer: retrospective analysis of Hospital Episode Statistics.Gut. 2014; 63: 250-261Crossref PubMed Scopus (23) Google Scholar Furthermore, because there is effective over-the-counter medication available to relieve gastroesophageal reflux symptoms, most individuals will not seek medical advice.5Boardman H.F. Delaney B.C. Haag S. Partnership in optimizing management of reflux symptoms: a treatment algorithm for over-the-counter proton-pump inhibitors.Curr Med Res Opin. 2015; 31: 1309-1318Crossref PubMed Scopus (7) Google Scholar In a region of exceptionally high ESCC incidence in China, endoscopic screening is performed for asymptomatic adults using a mobile van to reach rural areas. Lugol’s iodine is sprayed at endoscopy to identify nonstaining areas more likely to contain dysplasia (Figure 1F), which can be treated endoscopically. This strategy has proven effective in reducing the incidence and mortality from ESCC.6Wei W.Q. Chen Z.F. He Y.T. et al.Long-term follow-up of a community assignment, one-time endoscopic screening study of esophageal cancer in China.J Clin Oncol. 2015; 33: 1951-1957Crossref PubMed Google Scholar The optimal stratification criteria to increase efficiency of these programs are not yet clearly defined. For individuals referred for investigation of gastroesophageal reflux symptoms, most society guidelines recommend endoscopy, and biopsy for cases of endoscopically visible BE.7Shaheen N.J. Falk G.W. Iyer P.G. et al.ACG clinical guideline: diagnosis and management of Barrett's esophagus.Am J Gastroenterol. 2016; 111 (quiz 51): 30-50Crossref PubMed Scopus (164) Google Scholar, 8Fitzgerald R.C. di Pietro M. Ragunath K. et al.British Society of Gastroenterology guidelines on the diagnosis and management of Barrett's oesophagus.Gut. 2014; 63: 7-42Crossref PubMed Scopus (338) Google Scholar, 9Whiteman D.C. Appleyard M. Bahin F.F. et al.Australian clinical practice guidelines for the diagnosis and management of Barrett's esophagus and early esophageal adenocarcinoma.J Gastroenterol Hepatol. 2015; 30: 804-820Crossref PubMed Scopus (20) Google Scholar, 10Weusten B. Bisschops R. Coron E. et al.Endoscopic management of Barrett's esophagus: European Society of Gastrointestinal Endoscopy (ESGE) Position Statement.Endoscopy. 2017; 49: 191-198Crossref PubMed Scopus (0) Google Scholar However, screening for BE is recommended only for patients with multiple risk factors (age older than 50, white race, male sex, chronic reflux symptoms, obesity).7Shaheen N.J. Falk G.W. Iyer P.G. et al.ACG clinical guideline: diagnosis and management of Barrett's esophagus.Am J Gastroenterol. 2016; 111 (quiz 51): 30-50Crossref PubMed Scopus (164) Google Scholar, 8Fitzgerald R.C. di Pietro M. Ragunath K. et al.British Society of Gastroenterology guidelines on the diagnosis and management of Barrett's oesophagus.Gut. 2014; 63: 7-42Crossref PubMed Scopus (338) Google Scholar The British Society of Gastroenterology guidelines suggest that the threshold for screening should be lowered when there is a family history of EA. Overall mass endoscopic screening to detect and remove dysplastic lesions in squamous esophageal epithelium or BE would present a substantial challenge even in a high-resource environment and is not tenable, even in regions of high incidence. Transnasal endoscopy (TNE) is better tolerated than EGD, because small-caliber endoscopes (less than 6 mm), inserted transnasally, do not touch the root of the tongue; this reduces the gagging reflex and dispenses with the need for sedation. New disposable and more compact designs are compatible with office-based practice or mobile units.11Sami S.S. Dunagan K.T. Johnson M.L. et al.A randomized comparative effectiveness trial of novel endoscopic techniques and approaches for Barrett's esophagus screening in the community.Am J Gastroenterol. 2015; 110: 148-158Crossref PubMed Google Scholar, 12Peery A.F. Hoppo T. Garman K.S. et al.Feasibility, safety, acceptability, and yield of office-based, screening transnasal esophagoscopy (with video).Gastrointest Endosc. 2012; 75: 945-953.e2Abstract Full Text Full Text PDF PubMed Scopus (42) Google Scholar In the context of screening for squamous cell carcinoma, unsedated TNE has been shown to be safe and feasible. TNE detected esophageal neoplasia with similar rates as Lugol’s chromoendoscopy in some series studies, which were enriched for patients at high risk.13Wang C.H. Lee Y.C. Wang C.P. et al.Use of transnasal endoscopy for screening of esophageal squamous cell carcinoma in high-risk patients: yield rate, completion rate, and safety.Dig Endosc. 2014; 26: 24-31Crossref PubMed Scopus (12) Google Scholar, 14Arantes V. Albuquerque W. Salles J.M. et al.Effectiveness of unsedated transnasal endoscopy with white-light, flexible spectral imaging color enhancement, and lugol staining for esophageal cancer screening in high-risk patients.J Clin Gastroenterol. 2013; 47: 314-321Crossref PubMed Scopus (0) Google Scholar The American College of Gastroenterology is the only society that suggests the use of unsedated TNE for patients undergoing screening for BE.7Shaheen N.J. Falk G.W. Iyer P.G. et al.ACG clinical guideline: diagnosis and management of Barrett's esophagus.Am J Gastroenterol. 2016; 111 (quiz 51): 30-50Crossref PubMed Scopus (164) Google Scholar Three randomized, crossover studies of TNE in populations of patients with reflux, enriched for known BE cases, reported that TNE detected BE with 84% to 98% sensitivity.15Jobe B.A. Hunter J.G. Chang E.Y. et al.Office-based unsedated small-caliber endoscopy is equivalent to conventional sedated endoscopy in screening and surveillance for Barrett's esophagus: a randomized and blinded comparison.Am J Gastroenterol. 2006; 101: 2693-2703Crossref PubMed Scopus (0) Google Scholar, 16Shariff M.K. Bird-Lieberman E.L. O'Donovan M. et al.Randomized crossover study comparing efficacy of transnasal endoscopy with that of standard endoscopy to detect Barrett's esophagus.Gastrointest Endosc. 2012; 75: 954-961Abstract Full Text Full Text PDF PubMed Scopus (43) Google Scholar However, due to the small TNE biopsy forceps, there is a lower sensitivity (66.7%) for histologic diagnosis. A recent meta-analysis of 10 studies found that nonsedated TNE was preferred over conventional endoscopy by 63% of patients, with high rates of acceptability.11Sami S.S. Dunagan K.T. Johnson M.L. et al.A randomized comparative effectiveness trial of novel endoscopic techniques and approaches for Barrett's esophagus screening in the community.Am J Gastroenterol. 2015; 110: 148-158Crossref PubMed Google Scholar However, a community-based randomized controlled trial of more than 400 individuals did not find higher participation rates when patients were offered TNE in a mobile unit vs standard endoscopy in a hospital outpatient unit.15Jobe B.A. Hunter J.G. Chang E.Y. et al.Office-based unsedated small-caliber endoscopy is equivalent to conventional sedated endoscopy in screening and surveillance for Barrett's esophagus: a randomized and blinded comparison.Am J Gastroenterol. 2006; 101: 2693-2703Crossref PubMed Scopus (0) Google Scholar However, physicians may be reluctant to perform TNE when it requires similar time and expertise as conventional endoscopy, with the intrinsic caveats of small biopsy size and reduced field of view.17Shariff M.K. Varghese S. O'Donovan M. et al.Pilot randomized crossover study comparing the efficacy of transnasal disposable endosheath with standard endoscopy to detect Barrett's esophagus.Endoscopy. 2016; 48: 110-116PubMed Google Scholar, 18Iyer P.G. Chak A. Can endosheath technology open primary care doors to Barrett's esophagus screening by transnasal endoscopy?.Endoscopy. 2016; 48: 105-106Crossref PubMed Scopus (0) Google Scholar Furthermore, the cost of ultrathin devices may not allow widespread distribution in primary care. Large community-based cohort studies are required to assess fully the suitability of TNE for esophageal cancer screening. Imaging capsules have generally been tested in the context of BE, but not squamous cell dysplasia. Most studies have been carried out using untethered dual-camera wireless capsule endoscope.19Sharma V.K. Coppola Jr., A.G. Raufman J.P. A survey of credentialing practices of gastrointestinal endoscopy centers in the United States.J Clin Gastroenterol. 2005; 39: 501-507Crossref PubMed Scopus (19) Google Scholar However, to obviate to rapid esophageal transit, tethered cameras have been developed. A meta-analysis of 9 studies (618 patients) found that video capsules detect BE with a pooled sensitivity of 77%, ranging from 73% to 90%, depending on whether the histologic or endoscopic diagnosis was used as standard, respectively.20Bhardwaj A. Hollenbeak C.S. Pooran N. et al.A meta-analysis of the diagnostic accuracy of esophageal capsule endoscopy for Barrett's esophagus in patients with gastroesophageal reflux disease.Am J Gastroenterol. 2009; 104: 1533-1599Crossref PubMed Scopus (0) Google Scholar However 2 studies in an unenriched screening population reported that capsule-based analysis detects BE with sensitivity values of 60% and 78%, respectively.21Ramirez F.C. Akins R. Shaukat M. Screening of Barrett's esophagus with string-capsule endoscopy: a prospective blinded study of 100 consecutive patients using histology as the criterion standard.Gastrointest Endosc. 2008; 68: 25-31Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar, 22Galmiche J.P. Sacher-Huvelin S. Coron E. et al.Screening for esophagitis and Barrett's esophagus with wireless esophageal capsule endoscopy: a multicenter prospective trial in patients with reflux symptoms.Am J Gastroenterol. 2008; 103: 538-545Crossref PubMed Scopus (0) Google Scholar Further large-scale studies, in relevant populations, are required to assess the suitability of capsules for screening. However, despite their high levels of safety and acceptability, the cost might be prohibitive.23Rubenstein J.H. Inadomi J.M. Brill J.V. et al.Cost utility of screening for Barrett's esophagus with esophageal capsule endoscopy versus conventional upper endoscopy.Clin Gastroenterol Hepatol. 2007; 5: 312-318Abstract Full Text Full Text PDF PubMed Scopus (55) Google Scholar Volumetric laser endomicroscopy (VLE) is a new-generation optical coherence tomography that produces high-resolution, 3-dimensional cross-sectional images of the esophagus. VLE has also been produced as a tethered capsule endomicroscopy. In a proof-of-principle study, tethered VLE could distinguish patients with vs without BE. Subsequently, an automated segmentation and characterization algorithm has been developed to make this technology more clinically applicable.24Gora M.J. Sauk J.S. Carruth R.W. et al.Tethered capsule endomicroscopy enables less invasive imaging of gastrointestinal tract microstructure.Nat Med. 2013; 19: 238-240Crossref PubMed Scopus (103) Google Scholar, 25Ughi G.J. Gora M.J. Swager A.F. et al.Automated segmentation and characterization of esophageal wall in vivo by tethered capsule optical coherence tomography endomicroscopy.Biomed Opt Express. 2016; 7: 409-419Crossref PubMed Scopus (47) Google Scholar Once the capsule is withdrawn, it can be disinfected for reuse, making it potentially inexpensive and feasible to be used for population screening. Similar to capsule endoscopy, the question remains whether an optical technology is sufficient to detect BE, without a tissue sample, given that identification of cellular atypia is required for optimal patient management. Over many years, investigators have explored the use of esophageal cell collection devices that can be deployed via a catheter or swallowed by the patient.26Pan Q.J. Roth M.J. Guo H.Q. et al.Cytologic detection of esophageal squamous cell carcinoma and its precursor lesions using balloon samplers and liquid-based cytology in asymptomatic adults in Llinxian, China.Acta Cytol. 2008; 52: 14-23Crossref PubMed Scopus (39) Google Scholar, 27Roth M.J. Liu S.F. Dawsey S.M. et al.Cytologic detection of esophageal squamous cell carcinoma and precursor lesions using balloon and sponge samplers in asymptomatic adults in Linxian, China.Cancer. 1997; 80: 2047-2059Crossref PubMed Scopus (0) Google Scholar, 28Fennerty M.B. DiTomasso J. Morales T.G. et al.Screening for Barrett's esophagus by balloon cytology.Am J Gastroenterol. 1995; 90 (-2)Google Scholar, 29Rader A.E. Faigel D.O. Ditomasso J. et al.Cytological screening for Barrett's esophagus using a prototype flexible mesh catheter.Dig Dis Sci. 2001; 46 (2681–266)Crossref PubMed Scopus (15) Google Scholar, 30Falk G.W. Chittajallu R. Goldblum J.R. et al.Surveillance of patients with Barrett's esophagus for dysplasia and cancer with balloon cytology.Gastroenterology. 1997; 112: 1787-1797Abstract Full Text Full Text PDF PubMed Scopus (110) Google Scholar, 31Lao-Sirieix P. Boussioutas A. Kadri S.R. et al.Non-endoscopic screening biomarkers for Barrett's oesophagus: from microarray analysis to the clinic.Gut. 2009; 58: 1451-1459Crossref PubMed Scopus (61) Google Scholar Unfortunately, the accuracy for BE detection was too low to be clinically useful, due to a low cell yield and the reliance on standard cytology to identify cell atypia. The Cytosponge is a small mesh sponge on a string within a soluble gelatin capsule that can safely be administered, orally, by a nurse in primary care settings to collect esophageal cells for analysis. The device can collect cells from the entire esophagus with a with a large cellular sample size. The Cytosponge has been reported as an accurate method of sample collection for BE screening.32Kadri S.R. Lao-Sirieix P. O'Donovan M. et al.Acceptability and accuracy of a non-endoscopic screening test for Barrett's oesophagus in primary care: cohort study.BMJ. 2010; 341c4372Crossref PubMed Scopus (149) Google Scholar, 33Ross-Innes C.S. Debiram-Beecham I. O'Donovan M. et al.Evaluation of a minimally invasive cell sampling device coupled with assessment of trefoil factor 3 expression for diagnosing Barrett's esophagus: a multi-center case-control study.PLoS Med. 2015; 12e1001780Crossref PubMed Scopus (0) Google Scholar It might also be used in primary detection of squamous dysplasia.34Roshandel G. Merat S. Sotoudeh M. et al.Pilot study of cytological testing for oesophageal squamous cell dysplasia in a high-risk area in Northern Iran.Br J Cancer. 2014; 111: 2235-2241Crossref PubMed Google Scholar Once Cytosponge material is collected, an immunohistochemical assay is performed to detect trefoil factor 3 (TFF3), a highly specific biomarker of intestinal metaplasia.31Lao-Sirieix P. Boussioutas A. Kadri S.R. et al.Non-endoscopic screening biomarkers for Barrett's oesophagus: from microarray analysis to the clinic.Gut. 2009; 58: 1451-1459Crossref PubMed Scopus (61) Google Scholar Collection of samples by Cytosponge and detection of TFF3 identified patients with BE with 73.3% sensitivity in a primary care–based study of 500 patients; the technique identified patients with BE with 79.9% sensitivity in a secondary care case-control study of more than 1000 patients, with levels of specificity ranging from 92% to 94%.32Kadri S.R. Lao-Sirieix P. O'Donovan M. et al.Acceptability and accuracy of a non-endoscopic screening test for Barrett's oesophagus in primary care: cohort study.BMJ. 2010; 341c4372Crossref PubMed Scopus (149) Google Scholar, 33Ross-Innes C.S. Debiram-Beecham I. O'Donovan M. et al.Evaluation of a minimally invasive cell sampling device coupled with assessment of trefoil factor 3 expression for diagnosing Barrett's esophagus: a multi-center case-control study.PLoS Med. 2015; 12e1001780Crossref PubMed Scopus (0) Google Scholar The Cytosponge has high levels of acceptability, with 82% of participants reporting low levels of anxiety before the test. Patients significantly preferred it vs conventional endoscopy.32Kadri S.R. Lao-Sirieix P. O'Donovan M. et al.Acceptability and accuracy of a non-endoscopic screening test for Barrett's oesophagus in primary care: cohort study.BMJ. 2010; 341c4372Crossref PubMed Scopus (149) Google Scholar, 33Ross-Innes C.S. Debiram-Beecham I. O'Donovan M. et al.Evaluation of a minimally invasive cell sampling device coupled with assessment of trefoil factor 3 expression for diagnosing Barrett's esophagus: a multi-center case-control study.PLoS Med. 2015; 12e1001780Crossref PubMed Scopus (0) Google Scholar, 35Freeman M. Offman J. Walter F.M. et al.Acceptability of the Cytosponge procedure for detecting Barrett's oesophagus: a qualitative study.BMJ Open. 2017; 7e013901Crossref PubMed Scopus (1) Google Scholar Finally, cytology samples can be analyzed by additional tests, such as DNA methylation assays and DNA sequencing, to increase diagnostic accuracy and allow risk stratification.36Ross-Innes C.S. Chettouh H. Achilleos A. et al.Risk stratification of Barrett's oesophagus using a non-endoscopic sampling method coupled with a biomarker panel: a cohort study.Lancet Gastroenterol Hepatol. 2017; 2: 23-31Abstract Full Text Full Text PDF PubMed Scopus (5) Google Scholar, 37Yu M. O'Leary R.M. Kaz A.M. et al.Methylated B3GAT2 and ZNF793 Are Potential Detection Biomarkers for Barrett's Esophagus.Cancer Epidemiol Biomarkers Prev. 2015; 24: 1890-1897Crossref PubMed Scopus (0) Google Scholar A microsimulation study compared the cost-effectiveness of BE screening by either Cytosponge or endoscopy vs no systematic diagnostic test and found that the Cytosponge-based test was cost-effective in detection of BE when combined with endoscopic therapy.38Benaglia T. Sharples L.D. Fitzgerald R.C. et al.Health benefits and cost effectiveness of endoscopic and nonendoscopic cytosponge screening for Barrett's esophagus.Gastroenterology. 2013; 144: 62-73.e6Abstract Full Text Full Text PDF PubMed Scopus (62) Google Scholar An additional microsimulation study demonstrated that Cytosponge screening, followed by endoscopic confirmation, is a cost-effective strategy for detection of BE, with incremental cost-effectiveness ratios ranging from $28,791 to $33,307.39Heberle C.R. Omidvari A.H. Ali A. et al.Cost effectiveness of screening patients with gastroesophageal reflux disease for Barrett's Esophagus With a Minimally Invasive Cell Sampling Device.Clin Gastroenterol Hepatol. 2017; (1`5:1397–1404.7)Abstract Full Text Full Text PDF Scopus (0) Google Scholar A large primary care study of more than 9000 primary care patients with reflux symptoms is under way (Trial ID ISRCTN68382401) to provide definitive evidence that collection of cells with the Cytosponge, followed by TFF3 analysis, increases detection of BE. A blood-based test would be an ideal screening platform to be carried out in a primary care setting. Five peptides have been identified in blood that distinguish patients with ESCC from healthy volunteers; this peptide panel has been validated in an independent cohort.40Fan N.J. Gao C.F. Zhao G. et al.Serum peptidome patterns for early screening of esophageal squamous cell carcinoma.Biotechnol Appl Biochem. 2012; 59: 276-282Crossref PubMed Scopus (0) Google Scholar A number of studies have shown that microRNAs can distinguish patients with BE from controls (including patients with esophagitis),41Mallick R. Patnaik S.K. Wani S. et al.A systematic review of esophageal microRNA markers for diagnosis and monitoring of Barrett's esophagus.Dig Dis Sci. 2016; 61: 1039-1050Crossref PubMed Scopus (11) Google Scholar but validation is needed in a larger population. Circulating tumor DNA can be detected, at high allele fractions, from blood samples of patients with advanced esophageal cancer. It is not clear how sensitive this method is in detection of early-stage disease.42Wan J.C. Massie C. Garcia-Corbacho J. et al.Liquid biopsies come of age: towards implementation of circulating tumour DNA.Nat Rev Cancer. 2017; 17: 223-238Crossref PubMed Scopus (70) Google Scholar Synchronous cancers can affect the specificity of detection of esophageal cancer by circulating markers; studies are needed to address this issue. There are also potential stool markers of esophageal cancer, but their sensitivity of detection for early lesions is not known. Positive results from studies of stool markers would have to include evaluation of the entire gastrointestinal tract, unless the biomarker is highly specific for esophageal cancer.43Zou H. Molina J.R. Harrington J.J. et al.Aberrant methylation of secreted frizzled-related protein genes in esophageal adenocarcinoma and Barrett's esophagus.Int J Cancer. 2005; 116: 584-591Crossref PubMed Scopus (116) Google Scholar, 44Jin Z. Cheng Y. Gu W. et al.A multicenter, double-blinded validation study of methylation biomarkers for progression prediction in Barrett's esophagus.Cancer Res. 2009; 69: 4112-4115Crossref PubMed Scopus (0) Google Scholar, 45Schulmann K. Sterian A. Berki A. et al.Inactivation of p16, RUNX3, and HPP1 occurs early in Barrett's-associated neoplastic progression and predicts progression risk.Oncogene. 2005; 24: 4138-4148Crossref PubMed Scopus (0) Google Scholar, 46Alvi M.A. Liu X. O'Donovan M. et al.DNA methylation as an adjunct to histopathology to detect prevalent, inconspicuous dysplasia and early-stage neoplasia in Barrett's esophagus.Clin Cancer Res. 2013; 19: 878-888Crossref PubMed Scopus (0) Google Scholar Further studies are needed because few tests have been investigated in the context of screening. Biomarkers in breath samples are an attractive method for cancer screening, because tests to detect them would be noninvasive, applicable to the primary care setting, and probably cost-effective. A panel of breath volatile organic compounds (VOCs) was reported to distinguish patients with esophagogastric cancer from noncancer controls with an area under the receiver operating characteristic curve value of 0.87 in a validation set. However, it is not clear if a test for VOCs can identify patients with BE.47Kumar S. Huang J. Abbassi-Ghadi N. et al.Mass spectrometric analysis of exhaled breath for the identification of volatile organic compound biomarkers in esophageal and gastric adenocarcinoma.Ann Surg. 2015; 262: 981-990Crossref PubMed Scopus (24) Google Scholar An e-nose device differentiated VOCs from patients with BE from controls (without BE) with an area under the receiver operating characteristic curve value of 0.79.48Chan D.K. Zakko L. Visrodia K.H. et al.Breath testing for Barrett's esophagus using exhaled volatile organic compound profiling with an electronic nose device.Gastroenterology. 2017; 152: 24-26Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar These results are promising but require validation in a screening setting. Endoscopic diagnosis of early esophageal cancer refers to the detection of early malignant lesions, which are curable and associated with high rates of survival, and preinvasive neoplasia, also known as dysplasia. BE-related dysplasia is often inconspicuous, so the mainstay of endoscopic surveillance for BE is random sampling, according to the Seattle protocol (quadrantic biopsies every 1 or 2 cm).7Shaheen N.J. Falk G.W. Iyer P.G. et al.ACG clinical guideline: diagnosis and management of Barrett's esophagus.A