This document provides an overview of Barrett's esophagus, including its history, definitions, diagnosis, carcinogenesis process, biomarkers, and new diagnostic and treatment methods. It discusses how Barrett's esophagus is defined as abnormal columnar epithelium in the esophagus above the esophagogastric junction, can be classified as short or long segment, and must show intestinal metaplasia for a definitive diagnosis. The document also summarizes that dysplasia is a precursor to adenocarcinoma in Barrett's esophagus and reviews biomarkers like p53 that show promise but are not yet used routinely in practice.

1. Barrett’s oesophagus : definitions and diagnosis An update in 2011Jean-François FléjouDept of Pathology, Hôpital Saint-Antoine,Faculté de Médecine Pierre et Marie Curie, Paris, France

2. Covering the literature on Barrett’s oesophagusA difficult task! Medline 1985-2010 « Barrett and esophagus »

3. Barrett - Summary Some words on history Definition Barrett’s carcinogenesis Dysplasia Carcinogenetic process Alternative markers Novel therapeutic possibilities A consequence, the importance of double muscularis mucosae New diagnostic methods

4. Some words on the history of Barrett’s oesophagus Lyall, Br J Surg 1937 : “ulcers occur in the oesophagus, and are surrounded by heterotopic gastric mucosa” Barrett NR, Br J Surg 1950 : “chronic peptic ulcer of the oesophagus and oesophagitis” 2 distinct lesions : Reflux oesophagitis Peptic ulcer of the oesophagus, that correspond to congenital short oesophagus with gastric ulcer in the mediastinal stomach Morson & Belcher, Br J Cancer 1952: “Adenocarcinoma of the oesophagus and ectopic gastric mucosa” Allison & Johnstone, Thorax 1953 : reflux oesophagitis, with stomach drawn up to the mediastinum by the contracting scar tissue in the stricture

5. A short history of Barrett’s oesophagus Some may be worried because I have changed my opinion The lesion should be called “the lower esophagus lined by columnar epithelium” It is probably the result of a failure of the embryonic lining of the gullet to achieve maturity. Lord RV. Norman Barrett, “Doyen of esophageal surgery”. Ann Surg 1999;229:428.

6. Barrett’s oesophagus : acronyms

7. Which kind of epithelium lines Barrett’s esophagus? Initial descriptions : “ectopic gastric mucosa”. Accurate reading : “columnar cells, mucus secreting units, tubular glands, no oxyntic cells” (Barrett 1957) Morson & Belcher 1952 : Intestinal metaplasia Paull et al 1976 Classical description of 3 types of metaplastic epithelium “Modern” period : Intestinal metaplasia (goblet cells) is mandatory for the diagnosis ? “Post-modern” period : No need for IM in all cases

8. BE: practical diagnostic definitionsendoscopical and histological Zonal? “Classical”: circumferential columnar epithelium > 30 mm above the oesophago-gastric junction (OGJ) 3 types of columnar epithelium (Paull 1976) “Specialized” or intestinal Cardiac (junctionnal) Fundic (gastric) Now considered as “long segment BE”. Can also be present as tongues Endoscopic Prague C and M system Mosaic? Chatelain et al Virchows Archiv 2003

11. You may also have pancreatic metaplasia, Paneth cells, endocrine cells…

14. Normal GOJ Long segmt BO squamous Cardiac and oxynto-cardiac Fundic Fundic with gastritis (H pylori) Intestinal metaplasia Gastric folds cm Ultrashort BO Carditis + IM cm

17. Barrett type IM CK20 CK7 CK20 Gastric type IM CK7

18. Features that help differentiate IM From Odze, Am J Gastro 2005

19. and for the moment, the problem is not supposed to exist… Riddell and Odze, 2009 … « it is probably wise to avoid biopsying the GEJ region in patients without endoscopic evidence of BE »…

20. Guidelines USA, Germany: goblet cells UK, Japan: no goblet cells Classical arguments for goblet cells They are always present when sampling is adequate Cancer develops from IM New arguments against the definition based on goblet cells They can be absent Due to insufficient sampling Really absent (children, but also adults) They can be difficult to diagnose (false neg, false pos) Non goblet cells have the same genetic alterations Small cancers often develops from non IM mucosa (Takubo)

22. What about the cardiac mucosa? A highly controversial issue. Always short, metaplastic?

23. Carcinogenesis of Barrett’s mucosa 10% of patients with GERD have Barrett’s esophagus (and 1-2% of the general population). Almost all esophageal adenocarcinomas develop in Barrett’s esophagus. The frequency of esophageal adenocarcinoma is increasing (including in France). Adenocarcinoma is preceded by intraepithelial neoplasia (dysplasia) in all prospective surveillance studies. The molecular mechanisms involved in the transformation of Barrett’s mucosa are still incompletely established.

25. Classification : revised Vienna, new WHO

26. Problems: sampling (« Seattle protocol », or > 8 biopsies), reproducibility, natural history

28. Riddell and Vienna classifications

31. Diagnostic algorithm of dysplasia in Barrett’s oesophagus (Montgomery et al, Hum Pathol 2001) Four features 1- surface maturation in comparison with the underlying glands 2 - architecture of the glands 3 - cytologic pattern of the proliferating cells 4 - inflammation and erosions / ulcers Reparation Transformation (dysplasia) 1 presentabsent 2 nal or mild alteration mild (LG) or marked (HG) 3 nal or atypia mild or focally LG: mild diffuse, marked focal marked (with inflammation) HG: marked diffuse 4 « cases with abundant inflammation and the other features of LGD are usually best classified in the indefinite category »

32. Dysplasia in Barrett’s oesophagusDiagnostic reproducibilityMontgomery et al, Hum Pathol 2001 Diagnosis k 1rst set k 2nd set Non dysplastic 0.44 0.58 Indefinite 0.13 0.15 Low grade 0.23 0.31 High grade – cancer 0.63 0.64

33. Low grade dyspasia in Barrett has to be confirmed before decision

34. But all these descriptions and studies feature « classical » dysplasia Adenomatous – intestinal (ressembles adenomas of the colon) Recent description of new forms Polypoid (do not use the term adenoma) Cryptic with surface maturation Non adenomatous - foveolar Serrated

36. Biomarkers in Barrett’s oesophagus Any biologic measurement that can predict with reliability which individuals will develop cancer and which will not* Practically, three types : histopathology : dysplasia other tests using endoscopical bioptic sampling, mainly molecular alternative endoscopical or non endoscopical techniques, under development As the current practice is histopathology, any new markers need increased reproducibility, sensitivity, and specificity as compared with histology Spechler SJ “please, not another marker of Barrett’s oesophagus!” *Reid et al, Gastrointest Endoscopy Clin N Am 2003

40. Invasion and metastasisE-cadherinb-catenin From Morales et al, Lancet 2002

41. Biomarkers in Barrett’s mucosa An incomplete list of recently published biomarkers : RANK, SPARC, cdx-2, villin, Bcl-XL, c-Src, IGF1R, Kras, BRAF, HMGI(Y), HSP27, PLA2, DAF, Neuropilin-1, RXR, Telomerase, p16, p53, DNA damage, CGH array, VEGF, CK7/20, COX2, COX1, HCA, Hep-par1, MMR, polymorphisms of cytokines, CD1a, ERK, CDK1, c-Met, CDX1, CDX2, survivin, MUC2, PITX1, MTAP, CD105, Rab11a, Claudin, CD10, MUC5AC, Defensine 5, cyclin D1, TFF1, CES2, nfKb, 7q, RUNX3, HPP1, microRNAs, Slug, racemase, GATA4, GRP78, REG1a, Ski/SnoN, AKAP12, leptin, WIF-1, SS, E2F-1, HER-2… In routine practice, in 2010, only p53 and Ki67 can be used, with still limited value +++. The diagnosis remains on H&E.

43. LOH

44. gene mutation

45. protein expression

46. Numerous phase 1-2 studies show frequent alterations, increasing with the severity of histological lesions

48. Progressive increase of LOH, similar to protein overexpression

54. Kaye PV, et al. Novel staining pattern of p53 in Barrett’s dysplasia. The absent pattern. Histopathology 2010 ;57 :933-40.

55. A critical review of the diagnosis and management of Barrett’s esophagus: The AGA Chicago workshop Statement number 28 “The use of flow cytometry or biomarkers (such as p53 and p16 mutations) is promising and merits further clinical research” Nature of evidence : II (obtained from well-designed cohort or case-controlled studies) Subgroup support : A (good evidence to support the statement) Accept completely : 72% Sharma et al, Gastroenterology 2004

58. autofluorescence

59. Pillcam

60. Laser confocal endoscopy

61. Optical coherence tomography

62. Raman Spectroscopy

63. …New endoscopical and non endoscopical methods to explore Barrett’s mucosa

65. Double MM in BO Constant May be triple External is original Implications for cancer staging: Between two, it is still mucosa External can look as muscularis propria Very important on mucosectomy specimens (Offerhaus, Virchow Archiv)

66. « Messages » Diagnose short segment BE with goblet cells (changing soon?) What about ultrashort BE ?? H&E is enough in most cases, p53 (and Ki67) can be of help Use international classifications for dysplasia and cancer staging Be very careful with mucosectomy specimens Accompany the development of new diagnostic methods