Abstract
Due to its increasing incidence, esophageal adenocarcinoma and its precursor lesions have received increasing attention in recent years. The histopathologic steps in the process of malignant progression in Barrett’s esophagus are well described and include the following: (a) metaplasia of the normal esophageal squamous epithelium to a specialized intestinal glandular epithelium, (b) development of dysplasia (classified histologically as low and high grade), and (c) development of adenocarcinoma characterized by invasive and metastatic potential. Intestinal metaplasia can be identified by the presence of goblet cells, the detection of which can be aided by finding mucin stained by Alcian blue at low pH. Despite this well-characterized sequence, the timing of the development of dysplasia and the subsequent transition to carcinoma and the risk of development of carcinoma in low-and high-grade dysplasia are not precisely known. In addition, there are problems in the identification of dysplasia, including sampling error and interobserver discrepancies among pathologists. A better understanding of the mechanisms of these events would allow early identification and elimination of high-risk lesions before adenocarcinoma with its attendant poor prognosis were able to develop. In order to better understand this process and to potentially identify early markers of malignant transformation, a variety of molecular studies have been carried out in recent years on adenocarcinoma and its precursor lesions in Barrett’s esophagus. On the phenotypic level, increased expression and changes in pattern of expression of proliferation marker (Mib-1) Ki-67 antigen, overexpression of p53 protein, overexpression of growth factors such as epidermal growth factor (EGF), c-erbB2, and transforming growth factor (TGF)-a, decreased and abnormal expression of the cell adhesion molecule E-cadherin, and, in carcinomas, increased expression of serine proteases have all been described. A new area of interest is the family of rab proteins, which play an important role in maintaining cell polarity in the gastrointestinal tract. Increased expression of one of these proteins, rab ll, has been described in low-grade, but not high-grade dysplasia. In cytogenetic studies, an increased S-phase fraction, followed by an increased tetraploid (4N) fraction and then aneuploidy, has been described. So far, the specific genes which have been most thoroughly investigated have been p53, APC, p16, and the sites of probable tumor suppressor genes, including 3p (FHIT), 13q, and 18q. With only a few exceptions (i.e., rabll expression, and possibly mutations of FHIT), the numerous molecular abnormalities which have been described occur late in malignant progression, which means that the best marker which presently exists to identify high-risk lesions in Barrett’s esophagus is the histologic identification of dysplasia in endoscopic biopsies, especially high-grade dysplasia. We are presently beginning studies using laser microdissection and competitive genomic hybridization (CGH), which could help to identify new chromosomal areas that might contain genes that are crucial in the early phases of malignant progression in Barrett’s esophagus. In the future, identification of such early molecular events which predispose to carcinoma development will allow more precise and earlier risk assessment for individual patients, therefore enabling more effective therapy.
This is a preview of subscription content, log in via an institution.
Buying options
Tax calculation will be finalised at checkout
Purchases are for personal use only
Learn about institutional subscriptionsPreview
Unable to display preview. Download preview PDF.
References
al-Kasspooles M, Moore JH, Orringer MB, Beer DG (1993) Amplification and over-expression of the EGFR and erbB-2 genes in human esophageal adenocarcinomas. Int J Cancer 54: 213–219
Altorki NK, Oliveria S, Schrump DS (1997) Epidemiology and molecular biology of Barrett’s adenocarcinoma. Semin Surg Oncol 13: 270–280
Audrezet MP, Robaszkiewicz M, Mercier B, Nousbaum JB, Hardy E, Bail JP, Volant A, Lozac’h P, Gouerou H, Ferec C (1996) Molecular analysis of the TP53 gene in Barrett’s adenocarcinoma. Hum Mutat 7: 109–113
Barrett MT, Galipeau PC, Sanchez CA, Emond MJ, Reid BJ (1996) Determination of the frequency of loss of heterozygosity in esophageal adenocarcinoma by cell sorting, whole genome amplification and microsatellite polymorphisms. Oncogene 12: 1873–1878
Barrett MT, Sanchez CA, Galipeau PC, Neshat K, Emond M, Reid BJ (1996) Allelic loss of 9p21 and mutation of the CDKN2/p16 gene develop as early lesions during neoplastic progression in Barrett’s esophagus. Oncogene 13: 1867–1873
Barrett MT, Schutte M, Kern SE, Reid BJ (1996) Allelic loss and mutational analysis of the DPC4 gene in esophageal adenocarcinoma. Cancer Res 56: 4351–4353
Becker KF, Atkinson MJ, Reich U, Becker I, Nekarda H, Siewert JR, Hofler H (1994) Ecadherin gene mutations provide clues to diffuse type gastric carcinomas. Cancer Res 54: 3845–3852
Behrens J (1994) Cadherins as determinants of tissue morphology and suppressors of invasion. Acta Anat (Basel) 149: 165–169
Blot WJ, Devesa SS, Kneller RW, Fraumeni JF Jr (1991) Rising incidence of adenocarcinoma of the esophagus and gastric cardia. JAMA 265: 1287–1289
Blount PL, Meltzer SJ, Yin J, Huang Y, Krasna MJ, Reid BJ (1993) Clonal ordering of l7p and 5q allelic losses in Barrett dysplasia and adenocarcinoma. Proc Natl Acad Sci USA 90: 3221–3225
Breen E, Clarke A, Steele G Jr, Mercurio AM (1993) Poorly differentiated colon carcinoma cell lines deficient in alpha-catenin expression express high levels of surface E-cadherin but lack Ca(2+)-dependent cell-cell adhesion. Cell Adhes Commun 1: 239–250
Casson AG, Manolopoulos B, Troster M, Kerkvliet N, O’Malley F, Inculet R, Finley R, Roth JA (1994) Clinical implications of p53 gene mutation in the progression of Barrett’s epithelium to invasive esophageal cancer. Am J Surg 167: 52–57
Chen MY, Ott DJ, Gelfand DW (1995) More evidence for the increasing prevalence of adenocarcinoma of the esophagus over an 18-year period. J Clin Gastroenterol 21: 254–255
Chen YJ, Chen PH, Lee MD, Chang JG (1997) Aberrant FHIT transcripts in cancerous and corresponding non-cancerous lesions of the digestive tract. Int J Cancer 72: 955–958
Fearon ER, Vogelstein B (1990) A genetic model for colorectal tumorigenesis. Cell 61: 759–767
Giaretti W (1997) Aneuploidy mechanisms in human colorectal preneoplastic lesions and Barrett’s esophagus. Is there a role for K-ras and p53 mutations? Anal Cell Pathol 15: 99–117
Gleeson CM, Sloan JM, McGuigan JA (1995) Multiple gene alterations in esophageal adenocarcinoma. Proc Ann Meet Am Assoc Cancer Res 6: 3251A
Gleeson CM, Sloan JM, McGuigan JA, Ritchie AJ, Russell SE (1995) Base transitions at CpG dinucleotides in the p53 gene are common in esophageal adenocarcinoma. Cancer Res 55: 3406–3411
Goldenring JR, Shen KR, Vaughan HD, Modlin IM (1993) Identification of a small GTPbinding protein, Rab25, expressed in the gastrointestinal mucosa, kidney, and lung. J Biol Chem 268: 18419–18422
Gonzalez MV, Artimez ML, Rodrigo L, Lopez-Larrea C, Menendez MJ, Alvarez V, Perez R, Fresno MF, Perez MJ, Sampedro A, Coto E (1997) Mutation analysis of the p53, APC, and p16 genes in the Barrett’s oesophagus, dysplasia, and adenocarcinoma. J Clin Pathol 50: 212–217
Haggitt RC (1994) Barrett’s esophagus, dysplasia, and adenocarcinoma. Hum Pathol 25: 982–993
Hahn SA, Schutte M, Hogue AT, Moskaluk CA, da Costa LT, Rozenblum E, Weinstein CL, Fischer A, Yeo CJ, Hruban RH, Kern SE (1996) DPC4, a candidate tumor suppressor gene at human chromosome 18q21.1. Science 271: 350–353
Hamelin R, Flejou JF, Muzeau F, Potet F, Laurent-Puig P, Fekete F, Thomas G (1994) TP53 gene mutations and p53 protein immunoreactivity in malignant and premalignant Barrett’s esophagus. Gastroenterology 107: 1012–1018
Hartwell L (1992) Defects in a cell cycle checkpoint may be responsible for the genomic instability of cancer cells. Cell 71: 543–546
Hollstein M, Shomer B, Greenblatt M, Soussi T, Hovig E, Montesano R, Harris CC (1996) Somatic point mutations in the p53 gene of human tumors and cell lines: updated compilation. Nucleic Acids Res 24: 141–146
Hong MK, Laskin WB, Herman BE, Johnston MH, Vargo JJ, Steinberg SM, Allegra CJ, Johnston PG (1995) Expansion of the Ki-67 proliferative compartment correlates with degree of dysplasia in Barrett’s esophagus. Cancer 75: 423–429
Hughes SJ, Nambu Y, Soldes OS, Hamstra D, Rehemtulla A, Iannettoni MD, Orringer MB, Beer DG (1997) Fas/APO-1 (CD95) is not translocated to the cell membrane in esophageal adenocarcinoma. Cancer Res 57: 5571–5578
Ireland AP, Clark GW, DeMeester TR (1997) Barrett’s esophagus. The significance of p53 in clinical practice. Ann Surg 225: 17–30
Jones DR, Davidson AG, Summers CL, Murray GF, Quinlan DC (1994) Potential application of p53 as an intermediate biomarker in Barrett’s esophagus. Ann Thorac Surg 57: 598–603
Krishnadath KK, Tilanus HW, van Blankenstein M, Bosman FT, Mulder AH (1995) Accumulation of p53 protein in normal, dysplastic, and neoplastic Barrett’s oesophagus. J Pathol 175: 175–180
Krishnadath KK, Tilanus HW, van Blankenstein M, Hop WC, Kremers ED, Dinjens WN, Bosman FT (1997) Reduced expression of the cadherin-catenin complex in oesophageal adenocarcinoma correlates with poor prognosis. J Pathol 182: 331–338
Levine AJ (1992) The p53 tumor-suppressor gene. N Engl J Med 326: 1350–1352
Levine DS, Haggitt RC, Blount PL, Rabinovitch PS, Rusch VW, Reid BJ (1993) An endoscopic biopsy protocol can differentiate high-grade dysplasia from early adenocarcinoma in Barrett’s esophagus. Gastroenterology 105: 40–50
Lewin KJ, Appelman HD (1996) Tumors of the esophagus and stomach. Atlas of tumor pathology, 3rd series, 3rd edn. Armed Forces Institute of Pathology, Washington DC
Lukas J, Parry D, Aagaard L, Mann DJ, Bartkova J, Strauss M, Peters G, Bartek J (1995) Retinoblastoma-protein-dependent cell-cycle inhibition by the tumour suppressor p16. Nature 375: 503–506
McArdle JE, Lewin KJ, Randall G, Weinstein W (1992) Distribution of dysplasias and early invasive carcinoma in Barrett’s esophagus. Hum Pathol 23: 479–482
Menke-Pluymers MB, van Drunen E, Vissers KJ, Mulder AH, Tilanus HW, Hagemeijer A (1996) Cytogenetic analysis of Barrett’s mucosa and adenocarcinoma of the distal esophagus and cardia. Cancer Genet Cytogenet 90: 109–117
Michael D, Beer DG, Wilke CW, Miller DE, Glover TW (1997) Frequent deletions of FHIT and FRA3B in Barrett’s metaplasia and esophageal adenocarcinomas. Oncogene 15: 1653–1659
Montesano R, Hollstein M, Hainaut P (1996) Genetic alterations in esophageal cancer and their relevance to etiology and pathogenesis: a review. Int J Cancer 69: 225–235
Montgomery EA, Hartmann DP, Carr NJ, Holterman DA, Sobin LH, Azumi N (1996) Barrett esophagus with dysplasia. Flow cytometric DNA analysis of routine, paraffin-embedded mucosal biopsies. Am J Clin Pathol 106: 298–304
Mori T, Aoki T, Matsubara T, Jida F, Du X, Nishihira T, Mori S, Nakamura Y (1994) Frequent loss of heterozygosity in the region including BRCA1 on chromosome 17q in squamous cell carcinomas of the esophagus. Cancer Res 54: 1638–1640
Moskaluk CA, Heitmiller R, Zahurak M, Schwab D, Sidransky D, Hamilton SR (1996) p53 and p21(WAF1/CIP1/SDI1) gene products in Barrett esophagus and adenocarcinoma of the esophagus and esophagogastric junction. Hum Pathol 27: 1211–1220
Nagata S, Goldstein P (1995) The Fas death factor. Science 267: 1449–1456
Nekarda H, Schmitt M, Schlegel P, Stark M, Becker K, Mueller J, Siewert JR (1998) Strong prognostic impact of tumor-associated urokinase-type plasminogen activator (uPA) in completely resected adenocarcinoma of the esophagus. Clin Cancer Res 4: 1755–1763
Neshat K, Sanchez CA, Galipeau PC, Blount PL, Levine DS, Joslyn G, Reid BJ (1994) p53 mutations in Barrett’s adenocarcinoma and high-grade dysplasia. Gastroenterology 106: 1589–1595
Ohta M, Inoue H, Cotticelli MG, Kastury K, Baffa R, Palazzo J, Siprashvili Z, Mori M, McCue P, Druck T (1996) The FHIT gene, spanning the chromosome 3p14.2 fragile site and renal carcinoma-associated t(3;8) breakpoint, is abnormal in digestive tract cancers. Cell 84: 587–597
Pera M, Trastek VF, Carpenter HA, Allen MS, Deschamps C, Pairolero PC (1992) Barrett’s esophagus with high-grade dysplasia: an indication for esophagectomy? Ann Thor-ac Surg 54: 199–204
Petty EM, Kalikin LM, Orringer MB, Beer DG (1998) Distal chromosome 17q loss in Barrett’s esophageal and gastric cardia adenocarcinomas: implications for tumorigenesis. Mol Carcinog 22: 222–228
Polkowski W, Baak JPA, Van Lanshot JJB, Meijer GA, Schuurmans LT, Ten Kate FJW, Obertrop H, Offerhaus GJA (1998) Clinical decision making in Barrett’s oesophagus can be supported by computerized immunoquantitation and morphometry of features associated with proliferation and differentiation. J Pathol 184: 161–168
Rabinovitch PS, Reid BJ, Haggitt RC, Norwood TH, Rubin CE (1989) Progression to cancer in Barrett’s esophagus is associated with genomic instability. Lab Invest 60: 65–71
Ray GS, Lee JR, Nwokeji K, Mills LR, Goldenring JR (1997) Increased immunoreactivity for Rabll, a small GTP-binding protein, in low-grade dysplastic Barrett’s epithelia. Lab Invest 77: 503–511
Reid BJ, Barrett MT, Galipeau PC, Sanchez CA, Neshat K, Cowan DS, Levine DS (1996) Barrett’s esophagus: ordering the events that lead to cancer. Eur J Cancer Prey 5 [Suppl 2]: 57–65
Reid BJ, Blount PL, Rubin CE, Levine DS, Haggitt RC, Rabinovitch PS (1992) Flow-cytometric and histological progression to malignancy in Barrett’s esophagus: prospective endoscopic surveillance of a cohort. Gastroenterology 102: 1212–1219
Reid BJ, Haggitt RC, Rubin CE, Roth G, Surawicz CM, Van Belle G, Lewin K, Weinstein WM, Antonioli DA, Goldman H (1988) Observer variation in the diagnosis of dysplasia in Barrett’s esophagus. Hum Pathol 19: 166–178
Rusch VW, Levine DS, Haggitt R, Reid BJ (1994) The management of high grade dysplasia and early cancer in Barrett’s esophagus. A multidisciplinary problem. Cancer 74: 1225–1229
Schmitt M, Wilhelm O, Janicke F, Magdolen V, Reuning U, Ohi H, Moniwa N, Kobayashi H, Weidle U, Graeff H (1995) Urokinase-type plasminogen activator (uPA) and its receptor (CD87): a new target in tumor invasion and metastasis. J Obstet Gynaecol 21: 151–165
Schneider PM, Casson AG, Levin B, Garewal HS, Hoelscher AH, Becker K, Dittler HJ, Cleary KR, Troster M, Siewert JR, Roth JA (1996) Mutations of p53 in Barrett’s esophagus and Barrett’s cancer: a prospective study of ninety-eight cases. J Thorac Cardiovasc Surg 111: 323–331
Sciallero S, Giaretti W, Bonelli L, Geido E, Rapallo A, Conio M, Ravelli P, Lombardo L, Briglia R, Lapertosa G (1993) DNA content analysis of Barrett’s esophagus by flow cytometry. Endoscopy 25: 648–651
Serrano M, Hannon GJ, Beach D (1993) A new regulatory motif in cell-cycle control causing specific inhibition of cyclin D/CDK4. Nature 366: 704–707
Shibata H, Toyama K, Shioya H, Ito M, Hirota M, Hasegawa S, Matsumoto H, Takano H, Akiyama T, Toyoshima K, Kanamaru R, Kanegae Y, Saito I, Nakamura Y, Shiba K, Noda T (1997) Rapid colorectal adenoma formation initiated by conditional targeting of the Apc gene. Science 278: 120–123
Soslow RA, Ying L, Altorki NK (1997) Expression of acidic fibroblast growth factor in Barrett’s esophagus and associated esophageal adenocarcinoma. J Thorac Cardiovasc Surg 114: 838–843
Spechler SJ, Goyal RK (1986) Barrett’s esophagus. N Engl J Med 315: 362–371
Spechler SJ, Goyal RK (1986) Barrett’s esophagus. N Engl J Med 315: 362–371
Sutherland GR (1991) Chromosomal fragile sites. Genet Anal Tech Appl 8: 161–166
Swift A, Risk JM, Kingsnorth AN, Wright TA, Myskow M, Field JK (1995) Frequent loss of heterozygosity on chromosome 17 at 17g11.2-q12 in Barrett’s adenocarcinoma. Br J Cancer 71: 995–998
Washington K, Chiappori A, Hamilton K, Shyr Y, Blanke C, Johnson D, Sawyers J, Beauchamp D (1998) Expression of beta-catenin, alpha-catenin, and E-cadherin in Barrett’s esophagus and esophageal adenocarcinomas. Mod Pathol 11: 805–813
Williamson WA, Ellis FH Jr, Gibb SP, Shahian DM, Aretz HT, Heatley GJ, Watkins E Jr (1991) Barrett’s esophagus. Prevalence and incidence of adenocarcinoma. Arch Intern Med 151: 2212–2216
Wong DJ, Barrett MT, Stoger R, Emond MJ, Reid BJ (1997) p16INK4a promoter is hypermethylated at a high frequency in esophageal adenocarcinomas. Cancer Res 57: 2619–2622
Yacoub L, Goldman H, Odze RD (1997) Transforming growth factor-alpha, epidermal growth factor receptor, and MiB-1 expression in Barrett’s-associated neoplasia: correlation with prognosis. Mod Pathol 10: 105–112
Zhuang Z, Vortmeyer AO, Mark EJ, Odze R, Emmert-Buck MR, Merino MJ, Moon H, Liotta LA, Duray PH (1996) Barrett’s esophagus: metaplastic cells with loss of heterozygosity at the APC gene locus are clonal precursors to invasive adenocarcinoma. Cancer Res 56: 1961–1964
Zou TT, Lei J, Shi YQ, Yin J, Wang S, Souza RF, Kong D, Shimada Y, Smolinski KN, Greenwald BD, Abraham JM, Harpaz N, Meltzer SJ (1997) FHIT gene alterations in esophageal cancer and ulcerative colitis ( UC ). Oncogene 15: 101–105
Author information
Authors and Affiliations
Editor information
Editors and Affiliations
Rights and permissions
Copyright information
© 2000 Springer-Verlag Berlin Heidelberg
About this paper
Cite this paper
Mueller, J., Werner, M., Siewert, J.R. (2000). Malignant Progression in Barrett’s Esophagus: Pathology and Molecular Biology. In: Lange, J., Siewert, J.R. (eds) Esophageal Carcinoma. Recent Results in Cancer Research, vol 155. Springer, Berlin, Heidelberg. https://doi.org/10.1007/978-3-642-59600-1_3
Download citation
DOI: https://doi.org/10.1007/978-3-642-59600-1_3
Publisher Name: Springer, Berlin, Heidelberg
Print ISBN: 978-3-642-64044-5
Online ISBN: 978-3-642-59600-1
eBook Packages: Springer Book Archive