Primary Motility  Disorders of the  Esophagus
 The Esophageal
 Esophagogastric  Junction

  Browse by Author
  Browse by Movies
Volume: Barrett's Esophagus
Chapter: Dysplasia

Does high-grade dysplasia always lead to invasive adenocarcinoma?

S.R. Hamilton (Houston)

The natural history of high-grade columnar epithelial dysplasia has important implications for the management of patients with dysplasia [1-3]. The more commonly that progression to adenocarcinoma occurs, the greater the potential benefit of prophylactic esophagectomy, endoscopic mucosal resection or ablation procedures to eliminate high-grade dysplasia (HGD) from patients with this premalignant lesion because the risk of harms from these interventions must be considered relative to the possible prevention of malignancy and cancer-related mortality. Two different topographical relationships between HGD and adenocarcinorna are noteworthy in regard to this potential benefit: adenocarcinoma arising in the identified lesion with HGD, and, secondly, HGD as a manifestation and indicator of a field defect in Barrett mucosa that can give rise to synchronous or metachronous adenocarcinoma in locations in the patient's columnar-lined segment discontinuous with the identified HGD.

Determining the ultimate cumulative frequency of adenocarcinoma in patients with HGD poses several challenges. Biopsy sampling, even with rigourous protocols, leaves a very substantial portion of the Barrett mucosa unexamined [1]. The histopathologic appearances of HGD are variable, and intra and inter-observer variation in diagnosis does occur [4-6]. The agreement about classification of HGD among pathologists in subspecialty practice of gastrointestinal pathology and among community pathologists, however, is high, especially as compared to the weak agreement in the diagnosis of low-grade dysplasia and changes indefinite for dysplasia in Barrett mucosa. Extent of HGD is difficult to quantitate and may have stochastic impact on cumulative incidence rates of adenocarcinoma. It is reasonable to propose that more surface area of Barrett mucosa with HGD translates to higher risk of adenocarcinoma [7, 8], although some studies show no relationship between extent of Barrett mucosa and occurrence of cancer [9]. In addition, ascertainment of the endpoint of the natural history may be difficult. antireflux therapy in patients with the diagnosis of Barrett esophagus is almost universal and has at least some theoretical potential to influence the natural history [3, 10]. Furthermore, patients who are suitable candidates for therapy directed at HGD when it is recognized are usually treated [11-14]. Ascertainment of Barrett patients with symptomatic adenocarcinoma is high but may be reduced if the primary site is not investigated so that origin of adenocircinoma in Barrett esophagus is missed. Finally, various prophylactic interventions such as esophagectomy interrupt the natural history.

Despite these obstacles to understanding the natural history of HGD, the high frequency of invasive adenocarcinoma is well-documented in several series of patients who have undergone prophylactic esophagectomy [3, 11, 12, 15, 16]. Many of the patients with HGD in such series are prevalent cases in whom HGD was already present at the time of the initial diagnosis of Barrett esophagus. As a consequence, the duration of the HGD prior to its discovery cannot be known. The incidence rate of adenocarcinoma based on prospective follow-up of patients with Barrett esophagus beginning at the time when no dysplasia was detected has not yet been established in a large number of prospective studies. Only a few papers have addressed the timeline of the metaplasia-dysplasia-adenocarcinoma sequence [6, 8, 11, 12, 15, 17]. Some of the available data suggest that adenocarcinoma can develop rapidly from high-grade columnar epithelial dysplasia, but other studies indicate that HGD can remain stable for long periods of time.

The answer to the posed question (Does HGD always lead to invasive adenocarcinoma?) is that it is highly unlikely, even if the natural history is permitted to run its course. The general principle never to say "never" or "always" is applicable in this situation. The basis of the heterogeneity of biological behavior or progression of HGD is poorly understood [5, 6, 18, 19]. Molecular biology genomics and proteomics have the potential to produce new insights and complement histopathology, which remains as the mainstay in classification of dysplasia [5]. The identification, validation and clinical application of markers for high-risk HGD characterized by strong propensity to progress to adenocarcinoma would be helpful in tailoring management to the biology of each patient's dysplasia [17].


1. De Looze D. Endoscopic follow-up of Barett's esophagus:protocol and implications. Acta Gastroenterol BeIg 2000;63:29-35.

2. Pellegrini CA, Pohl D. High-grade dysplasia in Barrett's esophagus:surveillance or operation? J Gastrointest Surg 2000;4:131-134.

3. DeMeester SR, DeMeester TR. Columnar mucosa and intestinal metaplasia of the esophagus:fifty years of controversy. Ann Surg 2000;231:303-321.

4. Reid BJ, Haggitt RC, Rubin CE, Roth G, Surawicz CM, Van Belle G, Lewin KJ, Weinstein WM, Antonioli DA, Goldman H, et al. Observer variation in the diagnosis of dysplasia in Barrett's esophagus. Hum Pathol 1988;19:166-178.

5. Mueller J, Werner M, Siewert JR. Malignant progression in Barrett's esophagus: pathology and molecular biology. Rec Res Cancer Res 2000;155:29-41.

6. Geboes K. Barrett's esophagus: the metaplasia-dysplasia-carcinoma sequence: morphological aspects. Acta Gastroenterol Belg 2000;63:13-17.

7. Aldulaimi D, Jankowski J. Barrett's esophagus: an overview of the molecular biology. Dis Esophagus 1999;12:177-180.

8. Sharma P, Weston AP, Morales T, Topalovski M, Mayo MS, Sampliner RE. Relative risk of dysplasia for patients with intestinal metaplasia in the distal oesophagus and in the gastric cardia. Gut 2000;46:9-13.

9. Rudolph RE, Vaughn TL, Storer BE, Haggitt RC, Rabinovitch PS, Levine DS, Reid BJ. Effect of segment length on risk for neoplastic progression in patients with Barrett esophagus. Ann Intern Med 2000;18:612-620.

10. Stein HJ, Feith M, Siewert JR. Malignant degeneration of Barrett's esophagus: clinical point of view. Rec Res Cancer Res 2000;55:42-53.

11. Weston AP, Sharma P, Topalovski M, Richards R, Cherian R, Dixon A. Long-term follow-up of Barrett's high-grade dysplasia. Am J Gastroenterol 2000;95:1888-1893.

12. Zaninotto G, Parenti AR, Ruol A, Costantini M, Merigliano S, Ancona E. Oesophageal resection for high-grade dysplasia in Barrett's oesophagus. Br J Surg 2000;87:1102-1105.

13. van Sandick JW, Bartelsman JF, van Lanschott JJ, Tytgat GN, Obertop H. Surveillance of Barrett's oesophagus: physician's practices and review of current guidelines. Eur J Gastroenterol Hepatol 2000;12:111-117.

14. Levine DS, Haggitt RC, Blount PL, Rabinovitch PS, Rusch VW, Reid BJ. An endoscopic biopsy protocol can differentiate high-grade dysplasia from early adenocarcinoma in Barrett's esophagus. Gastroenterology 1993;105:40-50.

15. Hameeteman W, Tytgat GJ, Houthoff HJ, van den Tweel JG. Barrett's esophagus: development of dysplasia and adenocarcinoma. Gastroenterology 1989;96:1249-1256.

16. Heitmiller RF, Redmond M, Hamilton SR. Barrett's esophagus with high-grade dysplasia. An indication for prophylactic esophagectomy. Ann Surg 1996;224:66-71.

17. Reid BJ, Levine DS, Longton G, Blount PL, Rabinovitch PS. Predictors of progression to cancer in Barrett's esophagus: baseline histology and flow cytometry identify low- and high-risk patient subsets. Am J Gastroenterol 2000;95:16691676.

18. Ransford RA, Jankowski JA. Genetic versus environmemental interactions in the oesophagitis-metaplasia-dysplasiaadenocarcinoma sequence (MCS) of Barrett's oesophagus. Acta Gastroenterol Belg 2000;63:18-21.

19. Tselepis C, Perry I, Jankowski JA. Barrett's esophagus: disregulation of cell cycling and intercellular adhesion in the metaplasia-dysplasia-carcinoma sequence. Digestion 2000;61:1-5.

Publication date: August 2003 OESO©2015