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  • Review Article
  • Published:

Progression of Barrett oesophagus: role of endoscopic and histological predictors

Key Points

  • The currently used dysplasia grading system for risk stratification of Barrett oesophagus has its limitations

  • The lack of standardization, variability in methodology, requirement for special collection media and need for validation in large prospective studies currently precludes the use of biomarkers in routine clinical practice

  • Knowledge of easily available endoscopic and histological factors could serve an adjunctive role in risk stratification of patients in both pre-treatment and postendoscopic eradication settings

  • Prediction models incorporating clinical–demographic factors in conjunction with biomarkers hold promise for risk stratification of Barrett oesophagus

Abstract

Barrett oesophagus is an important precursor lesion for the development of oesophageal adenocarcinoma (OAC). Upper gastrointestinal endoscopy is the modality most widely used to visualize and biopsy the oesophagus to establish a diagnosis. Additional clues are available at the time of endoscopy that can identify high-risk features known to increase the risk of progression to OAC, such as the length of the Barrett oesophagus segment, length of hiatal hernia and the presence of nodularity or visible endoscopic lesions in this segment. Until molecular biomarkers are identified and validated as adjunctive tools for risk stratification, knowledge of endoscopic features could complement dysplasia grading for risk stratification of patients with Barrett oesophagus and identify subgroups at risk of progression to OAC. This approach would, in turn, facilitate more rational tailoring of endoscopic surveillance. This Review summarizes the current role of endoscopic and histological factors involved in neoplastic progression of Barrett oesophagus to OAC, and provides an overview of the risk-prediction models that have utilized endoscopic and histological factors for risk stratification in patients with Barrett oesophagus.

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Figure 1: A schematic representation of the stages involved in progression of Barrett oesophagus to OAC.

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References

  1. Pohl, H. & Welch, H. G. The role of overdiagnosis and reclassification in the marked increase of esophageal adenocarcinoma incidence. J. Natl Cancer Inst. 97, 142–146 (2005).

    Article  PubMed  Google Scholar 

  2. Siegel, R., Ma, J., Zou, Z. & Jemal, A. Cancer statistics, 2013. CA Cancer J. Clin. 64, 9–29 (2014).

    PubMed  Google Scholar 

  3. Hur, C. et al. Trends in esophageal adenocarcinoma incidence and mortality. Cancer 119, 1149–1158 (2013).

    Article  PubMed  Google Scholar 

  4. Reid, B. J., Blount, P. L. & Rabinovitch, P. S. Biomarkers in Barrett's esophagus. Gastrointest. Endosc. Clin. N. Am. 13, 369–397 (2003).

    Article  PubMed  Google Scholar 

  5. Tischoff, I. & Tannapfel, A. Barrett's esophagus: can biomarkers predict progression to malignancy? Expert Rev. Gastroenterol. Hepatol. 2, 653–663 (2008).

    Article  CAS  PubMed  Google Scholar 

  6. Prasad, G. A. et al. Utility of biomarkers in prediction of response to ablative therapy in Barrett's esophagus. Gastroenterology 135, 370–379 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Bansal, A. et al. Feasibility of microRNAs as biomarkers for Barrett's esophagus progression: a pilot cross-sectional, phase 2 biomarker study. Am. J. Gastroenterol. 106, 1055–1063 (2011).

    Article  CAS  PubMed  Google Scholar 

  8. Varghese, S., Lao-Sirieix, P. & Fitzgerald, R. C. Identification and clinical implementation of biomarkers for Barrett's esophagus. Gastroenterology 142, 435–441 (2012).

    Article  PubMed  Google Scholar 

  9. Paterson, A. L. & Fitzgerald, R. C. Biomarkers in Barrett's oesophagus and oesophageal adenocarcinoma. Expert Opin. Med. Diagn. 1, 363–376 (2007).

    Article  CAS  PubMed  Google Scholar 

  10. Prasad, G. A., Bansal, A., Sharma, P. & Wang, K. K. Predictors of progression in Barrett's esophagus: current knowledge and future directions. Am. J. Gastroenterol. 105, 1490–1502 (2010).

    Article  PubMed  PubMed Central  Google Scholar 

  11. Theisen, J. et al. Preoperative chemotherapy unmasks underlying Barrett's mucosa in patients with adenocarcinoma of the distal esophagus. Surg. Endosc. 16, 671–673 (2002).

    Article  CAS  PubMed  Google Scholar 

  12. Sharma, P. Clinical practice. Barrett's esophagus. N. Engl. J. Med. 361, 2548–2556 (2009).

    Article  CAS  PubMed  Google Scholar 

  13. Lagergren, J., Bergstrom, R., Lindgren, A. & Nyren, O. Symptomatic gastroesophageal reflux as a risk factor for esophageal adenocarcinoma. N. Engl. J. Med. 340, 825–831 (1999).

    Article  CAS  PubMed  Google Scholar 

  14. Eloubeidi, M. A., Mason, A. C., Desmond, R. A. & El-Serag, H. B. Temporal trends (1973–1997) in survival of patients with esophageal adenocarcinoma in the United States: a glimmer of hope? Am. J. Gastroenterol. 98, 1627–1633 (2003).

    PubMed  Google Scholar 

  15. Wang, K. K. & Sampliner, R. E. Updated guidelines 2008 for the diagnosis, surveillance and therapy of Barrett's esophagus. Am. J. Gastroenterol. 103, 788–797 (2008).

    Article  PubMed  Google Scholar 

  16. Corley, D. A., Levin, T. R., Habel, L. A., Weiss, N. S. & Buffler, P. A. Surveillance and survival in Barrett's adenocarcinomas: a population-based study. Gastroenterology 122, 633–640 (2002).

    Article  PubMed  Google Scholar 

  17. Ferguson, M. K. & Durkin, A. Long-term survival after esophagectomy for Barrett's adenocarcinoma in endoscopically surveyed and nonsurveyed patients. J. Gastrointest. Surg. 6, 29–35 (2002).

    Article  PubMed  Google Scholar 

  18. Spechler, S. J., Sharma, P., Souza, R. F., Inadomi, J. M. & Shaheen, N. J. American Gastroenterological Association medical position statement on the management of Barrett's esophagus. Gastroenterology 140, 1084–1091 (2011).

    Article  PubMed  Google Scholar 

  19. Sikkema, M., de Jonge, P. J., Steyerberg, E. W. & Kuipers, E. J. Risk of esophageal adenocarcinoma and mortality in patients with Barrett's esophagus: a systematic review and meta-analysis. Clin. Gastroenterol. Hepatol. 8, 235–244 (2010).

    Article  PubMed  Google Scholar 

  20. Jung, K. W. et al. Epidemiology and natural history of intestinal metaplasia of the gastroesophageal junction and Barrett's esophagus: a population-based study. Am. J. Gastroenterol. 106, 1447–1455 (2011).

    Article  PubMed  PubMed Central  Google Scholar 

  21. Anderson, L. A. et al. Mortality in Barrett's oesophagus: results from a population based study. Gut 52, 1081–1084 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Schouten, L. J. et al. Total cancer incidence and overall mortality are not increased among patients with Barrett's esophagus. Clin. Gastroenterol. Hepatol. 9, 754–761 (2011).

    Article  PubMed  Google Scholar 

  23. Bedi, A. O. et al. A survey of expert follow-up practices after successful endoscopic eradication therapy for Barrett's esophagus with high-grade dysplasia and intramucosal adenocarcinoma. Gastrointest. Endosc. 78, 696–701 (2013).

    Article  PubMed  PubMed Central  Google Scholar 

  24. Cameron, A. J. Barrett's esophagus: prevalence and size of hiatal hernia. Am. J. Gastroenterol. 94, 2054–2059 (1999).

    Article  CAS  PubMed  Google Scholar 

  25. Avidan, B. et al. Hiatal hernia size, Barrett's length, and severity of acid reflux are all risk factors for esophageal adenocarcinoma. Am. J. Gastroenterol. 97, 1930–1936 (2002).

    Article  PubMed  Google Scholar 

  26. Weston, A. P. et al. Risk stratification of Barrett's esophagus: updated prospective multivariate analysis. Am. J. Gastroenterol. 99, 1657–1666 (2004).

    Article  PubMed  Google Scholar 

  27. Patti, M. G. et al. Hiatal hernia size affects lower esophageal sphincter function, esophageal acid exposure, and the degree of mucosal injury. Am. J. Surg. 171, 182–186 (1996).

    Article  CAS  PubMed  Google Scholar 

  28. Ouatu-Lascar, R., Fitzgerald, R. C. & Triadafilopoulos, G. Differentiation and proliferation in Barrett's esophagus and the effects of acid suppression. Gastroenterology 117, 327–335 (1999).

    Article  CAS  PubMed  Google Scholar 

  29. Fitzgerald, R. C., Omary, M. B. & Triadafilopoulos, G. Dynamic effects of acid on Barrett's esophagus. An ex vivo proliferation and differentiation model. J. Clin. Investig. 98, 2120–2128 (1996).

    Article  CAS  PubMed  Google Scholar 

  30. Pohl, H. et al. Risk factors in the development of esophageal adenocarcinoma. Am. J. Gastroenterol. 108, 200–207 (2013).

    Article  PubMed  Google Scholar 

  31. Sikkema, M. et al. Predictors for neoplastic progression in patients with Barrett's esophagus: a prospective cohort study. Am. J. Gastroenterol. 106, 1231–1238 (2011).

    Article  CAS  PubMed  Google Scholar 

  32. Menke-Pluymers, M. B., Hop, W. C., Dees, J., van Blankenstein, M. & Tilanus, H. W. Risk factors for the development of an adenocarcinoma in columnar-lined (Barrett) esophagus. The Rotterdam Esophageal Tumor Study Group. Cancer 72, 1155–1158 (1993).

    Article  CAS  PubMed  Google Scholar 

  33. Weston, A. P., Badr, A. S. & Hassanein, R. S. Prospective multivariate analysis of clinical, endoscopic, and histological factors predictive of the development of Barrett's multifocal high-grade dysplasia or adenocarcinoma. Am. J. Gastroenterol. 94, 3413–3419 (1999).

    Article  CAS  PubMed  Google Scholar 

  34. Wong, T., Tian, J. & Nagar, A. B. Barrett's surveillance identifies patients with early esophageal adenocarcinoma. Am. J. Med. 123, 462–467 (2010).

    Article  PubMed  Google Scholar 

  35. Wani, S. et al. Patients with nondysplastic Barrett's esophagus have low risks for developing dysplasia or esophageal adenocarcinoma. Clin. Gastroenterol. Hepatol. 9, 220–227 (2011).

    Article  PubMed  Google Scholar 

  36. Thomas, T., Abrams, K. R., De Caestecker, J. S. & Robinson, R. J. Meta analysis: cancer risk in Barrett's oesophagus. Aliment. Pharmacol. Ther. 26, 1465–1477 (2007).

    Article  CAS  PubMed  Google Scholar 

  37. Rudolph, R. E. et al. Effect of segment length on risk for neoplastic progression in patients with Barrett esophagus. Ann. Int. Med. 132, 612–620 (2000).

    Article  CAS  PubMed  Google Scholar 

  38. Yousef, F. et al. The incidence of esophageal cancer and high-grade dysplasia in Barrett's esophagus: a systematic review and meta-analysis. Am. J. Epidemiol. 168, 237–249 (2008).

    Article  PubMed  Google Scholar 

  39. Bhat, S. et al. Risk of malignant progression in Barrett's esophagus patients: results from a large population-based study. J. Natl Cancer Inst. 103, 1049–1057 (2011).

    Article  PubMed  PubMed Central  Google Scholar 

  40. Anaparthy, R. et al. Association between length of Barrett's esophagus and risk of high-grade dysplasia or adenocarcinoma in patients without dysplasia. Clin. Gastroenterol. Hepatol. 11, 1430–1436 (2013).

    Article  PubMed  Google Scholar 

  41. Buttar, N. S. et al. Extent of high-grade dysplasia in Barrett's esophagus correlates with risk of adenocarcinoma. Gastroenterology 120, 1630–1639 (2001).

    Article  CAS  PubMed  Google Scholar 

  42. Tharavej, C. et al. Predictive factors of coexisting cancer in Barrett's high-grade dysplasia. Surg. Endosc. 20, 439–443 (2006).

    Article  CAS  PubMed  Google Scholar 

  43. Peters, F. P. et al. Histologic evaluation of resection specimens obtained at 293 endoscopic resections in Barrett's esophagus. Gastrointest. Endosc. 67, 604–609 (2008).

    Article  PubMed  Google Scholar 

  44. Montgomery, E. et al. Are ulcers a marker for invasive carcinoma in Barrett's esophagus? Data from a diagnostic variability study with clinical follow-up. Am. J. Gastroenterol. 97, 27–31 (2002).

    Article  PubMed  Google Scholar 

  45. Giacchino, M. A clinical prediction model to risk-stratify patients with Barrett's esophagus (BE): Results from a large, multicenter cohort [abstract 342]. Gastroenterology 144 (Suppl. 1), S71–S72 (2013).

    Article  Google Scholar 

  46. Hull, M. J. et al. Endoscopic mucosal resection: an improved diagnostic procedure for early gastroesophageal epithelial neoplasms. Am. J. Surg. Pathol. 30, 114–118 (2006).

    Article  PubMed  Google Scholar 

  47. Chennat, J. et al. Complete Barrett's eradication endoscopic mucosal resection: an effective treatment modality for high-grade dysplasia and intramucosal carcinoma—an American single-center experience. Am. J. Gastroenterol. 104, 2684–2692 (2009).

    Article  PubMed  Google Scholar 

  48. Lee, M. H., Buterbaugh, K., Richards-Kortum, R. & Anandasabapathy, S. Advanced endoscopic imaging for Barrett's esophagus: current options and future directions. Curr. Gastroenterol. Rep. 14, 216–225 (2012).

    Article  PubMed  Google Scholar 

  49. Spechler, S. J., Sharma, P., Souza, R. F., Inadomi, J. M. & Shaheen, N. J. American Gastroenterological Association technical review on the management of Barrett's esophagus. Gastroenterology 140, e18–e52 (2011).

    Article  PubMed  PubMed Central  Google Scholar 

  50. Srivastava, A. et al. Extent of low-grade dysplasia is a risk factor for the development of esophageal adenocarcinoma in Barrett's esophagus. Am. J. Gastroenterol. 102, 483–493 (2007).

    Article  PubMed  Google Scholar 

  51. Wani, S. et al. Risk factors for progression of low-grade dysplasia in patients with Barrett's esophagus. Gastroenterology 141, 1179–1186 (2011).

    Article  PubMed  Google Scholar 

  52. Dar, M. S., Goldblum, J. R., Rice, T. W. & Falk, G. W. Can extent of high grade dysplasia in Barrett's oesophagus predict the presence of adenocarcinoma at oesophagectomy? Gut 52, 486–489 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Hvid-Jensen, F., Pedersen, L., Drewes, A. M., Sorensen, H. T. & Funch-Jensen, P. Incidence of adenocarcinoma among patients with Barrett's esophagus. N. Engl. J. Med. 365, 1375–1383 (2011).

    Article  CAS  PubMed  Google Scholar 

  54. Sharma, P. et al. Dysplasia and cancer in a large multicenter cohort of patients with Barrett's esophagus. Clin. Gastroenterol. Hepatol. 4, 566–572 (2006).

    Article  PubMed  Google Scholar 

  55. Wani, S., Choi, W. & Sharma, P. Low-grade dysplasia in Barrett's esophagus—an innocent bystander? Pro. Endoscopy 39, 643–646 (2007).

    Article  CAS  PubMed  Google Scholar 

  56. Wani, S., Mathur, S. & Sharma, P. How to manage a Barrett's esophagus patient with low-grade dysplasia. Clin. Gastroenterol. Hepatol. 7, 27–32 (2009).

    Article  PubMed  Google Scholar 

  57. Downs-Kelly, E. et al. Poor interobserver agreement in the distinction of high-grade dysplasia and adenocarcinoma in pretreatment Barrett's esophagus biopsies. Am. J. Gastroenterol. 103, 2333–2340 (2008).

    Article  PubMed  Google Scholar 

  58. Montgomery, E. et al. Reproducibility of the diagnosis of dysplasia in Barrett esophagus: a reaffirmation. Hum. Pathol. 32, 368–378 (2001).

    Article  CAS  PubMed  Google Scholar 

  59. Alikhan, M. et al. Variable pathologic interpretation of columnar lined esophagus by general pathologists in community practice. Gastrointest. Endosc. 50, 23–26 (1999).

    Article  CAS  PubMed  Google Scholar 

  60. Curvers, W. L. et al. Low-grade dysplasia in Barrett's esophagus: overdiagnosed and underestimated. Am. J. Gastroenterol. 105, 1523–1530 (2010).

    Article  PubMed  Google Scholar 

  61. Schnell, T. G. et al. Long-term nonsurgical management of Barrett's esophagus with high-grade dysplasia. Gastroenterology 120, 1607–1619 (2001).

    Article  CAS  PubMed  Google Scholar 

  62. Reid, B. J., Levine, D. S., Longton, G., Blount, P. L. & Rabinovitch, P. S. Predictors of progression to cancer in Barrett's esophagus: baseline histology and flow cytometry identify low- and high-risk patient subsets. Am. J. Gastroenterol. 95, 1669–1676 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  63. Rastogi, A. et al. Incidence of esophageal adenocarcinoma in patients with Barrett's esophagus and high-grade dysplasia: a meta-analysis. Gastrointest. Endosc. 67, 394–398 (2008).

    Article  PubMed  Google Scholar 

  64. Gaddam, S. et al. Persistence of non-dysplastic Barrett's esophagus identifies patients at lower risk for esophageal adenocarcinoma-results from a large multicenter cohort. Gastroenterology 145, 548–553 (2013).

    Article  PubMed  Google Scholar 

  65. Thrift, A. P., Kendall, B. J., Pandeya, N., Vaughan, T. L. & Whiteman, D. C. A clinical risk prediction model for Barrett esophagus. Cancer Prev. Res. (Phila.) 5, 1115–1123 (2012).

    Article  Google Scholar 

  66. Rubenstein, J. H. et al. Prediction of Barrett's esophagus among men. Am. J. Gastroenterol. 108, 353–362 (2013).

    Article  PubMed  PubMed Central  Google Scholar 

  67. Bird-Lieberman, E. L. et al. Population-based study reveals new risk-stratification biomarker panel for Barrett's esophagus. Gastroenterology 143, 927–935 (2012).

    Article  CAS  PubMed  Google Scholar 

  68. Sato, F. et al. Three-tiered risk stratification model to predict progression in Barrett's esophagus using epigenetic and clinical features. PLoS ONE 3, e1890 (2008).

    Article  PubMed  PubMed Central  Google Scholar 

  69. Evans, J. A. et al. The role of endoscopy in Barrett's esophagus and other premalignant conditions of the esophagus. Gastrointest. Endosc. 76, 1087–1094 (2012).

    Article  PubMed  Google Scholar 

  70. Pech, O. et al. Long-term results and risk factor analysis for recurrence after curative endoscopic therapy in 349 patients with high-grade intraepithelial neoplasia and mucosal adenocarcinoma in Barrett's oesophagus. Gut 57, 1200–1206 (2008).

    Article  CAS  PubMed  Google Scholar 

  71. Bulsiewicz, W. J. et al. Predictors of recurrent Barrett's esophagus after successful radiofrequency ablation in a nationwide, multicenter cohort: results from the U.S. RFA Registry [abstract 3]. Gastroenterology 144 (Suppl. 1), S1 (2013).

    Article  Google Scholar 

  72. Haidry, R. J. et al. Radiofrequency ablation and endoscopic mucosal resection for dysplastic barrett's esophagus and early esophageal adenocarcinoma: outcomes of the UK National Halo RFA Registry. Gastroenterology 145, 87–95 (2013).

    Article  PubMed  Google Scholar 

  73. Badreddine, R. J. et al. Prevalence and predictors of recurrent neoplasia after ablation of Barrett's esophagus. Gastrointest. Endosc. 71, 697–703 (2010).

    Article  PubMed  Google Scholar 

  74. Gupta, M. et al. Recurrence of esophageal intestinal metaplasia after endoscopic mucosal resection and radiofrequency ablation of Barrett's esophagus: results from a US Multicenter Consortium. Gastroenterology 145, 79–86 (2013).

    Article  PubMed  PubMed Central  Google Scholar 

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R.A. researched data for and wrote the article. Both authors made equal contributions to discussion of content and reviewing/editing the manuscript before submission.

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Correspondence to Rajeswari Anaparthy.

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Anaparthy, R., Sharma, P. Progression of Barrett oesophagus: role of endoscopic and histological predictors. Nat Rev Gastroenterol Hepatol 11, 525–534 (2014). https://doi.org/10.1038/nrgastro.2014.69

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