Digestive Diseases and Sciences

, Volume 58, Issue 1, pp 115–122 | Cite as

Increase of Epidermal Growth Factor Receptor Expression in Progression of GERD, Barrett, and Adenocarcinoma of Esophagus

  • Guilherme PrettoEmail author
  • Richard Ricachenevsky Gurski
  • Marcelo Binato
  • Daniel Navarini
  • Wolfgan William Schmidt Aguiar
  • Luise Meurer
Original Article



Gastroesophageal reflux disease (GERD) is a pathology with a wide range of clinical and endoscopic manifestations. Epidermal growth factor receptor (EGFR), found in the epithelium of the digestive tract, plays an important role in epithelial repair and shows increased expression in different neoplasms, including esophageal tumors.


The purpose of this study was to evaluate EGFR expression using immunohistochemistry in esophageal biopsies obtained from patients with GERD, Barrett’s esophagus, and adenocarcinoma of the esophagus.


EGFR expression was immunohistochemically determined in biopsies from 194 patients with symptoms suggestive of GERD or adenocarcinoma of the esophagus, seen at two Brazilian university hospitals between January 2003 and December 2008. Based on histopathological analysis, patients were divided into three groups: GERD, Barrett’s esophagus and adenocarcinoma of the esophagus. EGFR expression was considered positive when staining was detected in the membrane.


Mean age was 55.25 years (range 30–90). Patients with GERD (n = 127) accounted for 65.5 % of the sample, compared with 12.4 % (n = 24) of patients with Barrett’s esophagus and 22.2 % (n = 43) of patients with esophageal adenocarcinoma. Immunohistochemical analysis was positive for EGFR in 19.1 % of the patients (37/194), divided as follows: 8.7 % (11/127) in the GERD group, 25 % (6/24) in the Barrett’s esophagus group, and 46.5 % (20/43) in the esophageal adenocarcinoma group. Statistical analysis revealed significant differences between the three groups (p = 0.0001).


GERD patients showed lower levels of EGFR expression than patients with Barrett’s esophagus or patients with adenocarcinoma of the esophagus, suggesting a direct relationship between EGFR expression and disease progression.


EGFR GERD Adenocarcinoma of the esophagus Barrett’s esophagus 


Conflict of interest



  1. 1.
    Moraes-Filho JP, Navarro-Rodriguez T, Barbuti R, Eisig J, Chinzon D, Bernardo W. Guidelines for the diagnosis and management of gastroesophageal reflux disease: an evidence-based consensus. Arq Gastroenterol. 2010;47:99–115.PubMedCrossRefGoogle Scholar
  2. 2.
    Locke GR 3rd, Talley NJ, Fett SL, Zinsmeister AR, Melton LJ 3rd. Prevalence and clinical spectrum of gastroesophageal reflux: a population-based study in Olmsted County, Minnesota. Gastroenterology. 1997;112:1448–1456.PubMedCrossRefGoogle Scholar
  3. 3.
    Jones RH, Lydeard SE, Hobbs FD, et al. Dyspepsia in England and Scotland. Gut. 1990;31:401–405.PubMedCrossRefGoogle Scholar
  4. 4.
    Moraes-Filho JP, Chinzon D, Eisig JN, Hashimoto CL, Zaterka S. Prevalence of heartburn and gastroesophageal reflux disease in the urban Brazilian population. Arq Gastroenterol. 2005;42:122–127.PubMedCrossRefGoogle Scholar
  5. 5.
    Gurski RR, da Rosa AR, do Valle E, de Borba MA, Valiati AA. Extraesophageal manifestations of gastroesophageal reflux disease. J Bras Pneumol. 2006;32:150–160.PubMedGoogle Scholar
  6. 6.
    Kahrilas PJ, Shaheen NJ, Vaezi MF. American Gastroenterological Association Institute technical review on the management of gastroesophageal reflux disease. Gastroenterology. 2008;135:1392–1413.PubMedCrossRefGoogle Scholar
  7. 7.
    Kahrilas PJ. Clinical practice. Gastroesophageal reflux disease. N Engl J Med. 2008;359:1700–1707.PubMedCrossRefGoogle Scholar
  8. 8.
    Kongara K, Varilek G, Soffer EE. Salivary growth factors and cytokines are not deficient in patients with gastroesophageal reflux disease or Barrett’s esophagus. Dig Dis Sci. 2001;46:606–609.PubMedCrossRefGoogle Scholar
  9. 9.
    Campos GM, Peters JH, DeMeester TR, Oberg S, Crookes PF, Mason RJ. The pattern of esophageal acid exposure in gastroesophageal reflux disease influences the severity of the disease. Arch Surg. 1999;134:882–887.PubMedCrossRefGoogle Scholar
  10. 10.
    Demeester TR, Johnson LF, Joseph GJ, Toscano MS, Hall AW, Skinner DB. Patterns of gastroesophageal reflux in health and disease. Ann Surg. 1976;184:459–470.PubMedCrossRefGoogle Scholar
  11. 11.
    DeMeester TR, Johnson LF. The evaluation of objective measurements of gastroesophageal reflux and their contribution to patient management. Surg Clin North Am. 1976;56:39–53.PubMedGoogle Scholar
  12. 12.
    Wang C, Hunt RH. Precise role of acid in non-erosive reflux disease. Digestion. 2008;78:31–41.PubMedCrossRefGoogle Scholar
  13. 13.
    Orlando RC. Esophageal epithelial defense against acid injury. J Clin Gastroenterol. 1991;13:S1–S5.PubMedCrossRefGoogle Scholar
  14. 14.
    Marcinkiewicz M, Han K, Zbroch T, et al. The potential role of the esophageal pre-epithelial barrier components in the maintenance of integrity of the esophageal mucosa in patients with endoscopically negative gastroesophageal reflux disease. Am J Gastroenterol. 2000;95:1652–1660.PubMedCrossRefGoogle Scholar
  15. 15.
    Barlow WJ, Orlando RC. The pathogenesis of heartburn in nonerosive reflux disease: a unifying hypothesis. Gastroenterology. 2005;128:771–778.PubMedCrossRefGoogle Scholar
  16. 16.
    Okuyama M, Fujiwara Y, Tanigawa T, et al. Roles of ZO-1 and epidermal growth factor in esophageal epithelial defense against acid. Digestion. 2007;75:135–141.PubMedGoogle Scholar
  17. 17.
    Jankowski J, Murphy S, Coghill G, et al. Epidermal growth factor receptors in the oesophagus. Gut. 1992;33:439–443.PubMedCrossRefGoogle Scholar
  18. 18.
    Jankowski J, Coghill G, Tregaskis B, Hopwood D, Wormsley KG. Epidermal growth factor in the oesophagus. Gut. 1992;33:1448–1453.PubMedCrossRefGoogle Scholar
  19. 19.
    Reindel JF, Gough AW, Pilcher GD, Bobrowski WF, Sobocinski GP, de la Iglesia FA. Systemic proliferative changes and clinical signs in cynomolgus monkeys administered a recombinant derivative of human epidermal growth factor. Toxicol Pathol. 2001;29:159–173.PubMedCrossRefGoogle Scholar
  20. 20.
    Playford RJ, Hanby AM, Gschmeissner S, Peiffer LP, Wright NA, McGarrity T. The epidermal growth factor receptor (EGF-R) is present on the basolateral, but not the apical, surface of enterocytes in the human gastrointestinal tract. Gut. 1996;39:262–266.PubMedCrossRefGoogle Scholar
  21. 21.
    Alroy I, Yarden Y. The ErbB signaling network in embryogenesis and oncogenesis: signal diversification through combinatorial ligand-receptor interactions. FEBS Lett. 1997;410:83–86.PubMedCrossRefGoogle Scholar
  22. 22.
    Koppert LB, Wijnhoven BP, van Dekken H, Tilanus HW, Dinjens WN. The molecular biology of esophageal adenocarcinoma. J Surg Oncol. 2005;92:169–190.PubMedCrossRefGoogle Scholar
  23. 23.
    Morgan S, Grandis JR. ErbB receptors in the biology and pathology of the aerodigestive tract. Exp Cell Res. 2009;315:572–582.PubMedCrossRefGoogle Scholar
  24. 24.
    Ciardiello F, Tortora G. EGFR antagonists in cancer treatment. N Engl J Med. 2008;358:1160–1174.PubMedCrossRefGoogle Scholar
  25. 25.
    Wilkinson NW, Black JD, Roukhadze E, et al. Epidermal growth factor receptor expression correlates with histologic grade in resected esophageal adenocarcinoma. J Gastrointest Surg. 2004;8:448–453.PubMedCrossRefGoogle Scholar
  26. 26.
    Jankowski J, Hopwood D, Pringle R, Wormsley KG. Increased expression of epidermal growth factor receptors in Barrett’s esophagus associated with alkaline reflux: a putative model for carcinogenesis. Am J Gastroenterol. 1993;88:402–408.PubMedGoogle Scholar
  27. 27.
    Li Y, Wo JM, Ray MB, et al. Cyclooxygenase-2 and epithelial growth factor receptor up-regulation during progression of Barrett’s esophagus to adenocarcinoma. World J Gastroenterol. 2006;12:928–934.PubMedGoogle Scholar
  28. 28.
    Wang KL, Wu TT, Choi IS, et al. Expression of epidermal growth factor receptor in esophageal and esophagogastric junction adenocarcinomas: association with poor outcome. Cancer. 2007;109:658–667.PubMedCrossRefGoogle Scholar
  29. 29.
    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.PubMedGoogle Scholar
  30. 30.
    Flora-Filho R, Camara-Lopes LH. Histological criteria of esophagitis in the gastroesophageal reflux disease. Reevaluation of the sensitivity of the esophageal 24-hours pHmetry. Arq Gastroenterol. 2000;37:197–202.PubMedCrossRefGoogle Scholar
  31. 31.
    Lundell LR, Dent J, Bennett JR, et al. Endoscopic assessment of oesophagitis: clinical and functional correlates and further validation of the Los Angeles classification. Gut. 1999;45:172–180.PubMedCrossRefGoogle Scholar
  32. 32.
    Riddell RH. The biopsy diagnosis of gastroesophageal reflux disease, “carditis,” and Barrett’s esophagus, and sequelae of therapy. Am J Surg Pathol. 1996;20:S31–S50.PubMedCrossRefGoogle Scholar
  33. 33.
    Pera M, Cameron AJ, Trastek VF, Carpenter HA, Zinsmeister AR. Increasing incidence of adenocarcinoma of the esophagus and esophagogastric junction. Gastroenterology. 1993;104:510–513.PubMedGoogle Scholar
  34. 34.
    Altorki NK, Oliveria S, Schrump DS. Epidemiology and molecular biology of Barrett’s adenocarcinoma. Semin Surg Oncol. 1997;13:270–280.PubMedCrossRefGoogle Scholar
  35. 35.
    Sakai Y, Nelson KG, Snedeker S, et al. Expression of epidermal growth factor in suprabasal cells of stratified squamous epithelia: implications for a role in differentiation. Cell Growth Differ. 1994;5:527–535.PubMedGoogle Scholar
  36. 36.
    Qureshi FG, Tchorzewski MT, Duncan MD, Harmon JW. EGF and IGF-I synergistically stimulate proliferation of human esophageal epithelial cells. J Surg Res. 1997;69:354–358.PubMedCrossRefGoogle Scholar
  37. 37.
    Breider MA, Bleavins MR, Reindel JF, Gough AW, de la Iglesia FA. Cellular hyperplasia in rats following continuous intravenous infusion of recombinant human epidermal growth factor. Vet Pathol. 1996;33:184–194.PubMedCrossRefGoogle Scholar
  38. 38.
    Juhl CO, Vinter-Jensen L, Poulsen SS, Orntoft TF, Dajani EZ. Chronic treatment with epidermal growth factor causes esophageal epithelial hyperplasia in pigs and rats. Dig Dis Sci. 1995;40:2717–2723.PubMedCrossRefGoogle Scholar
  39. 39.
    Zhao J, Yang J, Vinter-Jensen L, Zhuang F, Gregersen H. Biomechanical properties of esophagus during systemic treatment with epidermal growth factor in rats. Ann Biomed Eng. 2003;31:700–709.PubMedCrossRefGoogle Scholar
  40. 40.
    Jimenez P, Lanas A, Piazuelo E, Esteva F. Effect of growth factors and prostaglandin E2 on restitution and proliferation of rabbit esophageal epithelial cells. Dig Dis Sci. 1998;43:2309–2316.PubMedCrossRefGoogle Scholar
  41. 41.
    Fujiwara Y, Higuchi K, Takashima T, et al. Roles of epidermal growth factor and Na +/H + exchanger-1 in esophageal epithelial defense against acid-induced injury. Am J Physiol Gastrointest Liver Physiol. 2006;290:G665–G673.PubMedCrossRefGoogle Scholar
  42. 42.
    Fujiwara Y, Higuchi K, Hamaguchi M, et al. Increased expression of transforming growth factor-alpha and epidermal growth factor receptors in rat chronic reflux esophagitis. J Gastroenterol Hepatol. 2004;19:521–527.PubMedCrossRefGoogle Scholar
  43. 43.
    Jankowski J, Hopwood D, Wormsley KG. Expression of epidermal growth factor, transforming growth factor alpha and their receptor in gastro-oesophageal diseases. Dig Dis. 1993;11:1–11.PubMedCrossRefGoogle Scholar
  44. 44.
    Poller DN, Steele RJ, Morrell K. Epidermal growth factor receptor expression in Barrett’s esophagus. Arch Pathol Lab Med. 1992;116:1226–1227.PubMedGoogle Scholar
  45. 45.
    Mukaida H, Yamamoto T, Hirai T, et al. Expression of human epidermal growth factor and its receptor in esophageal cancer. Jpn J Surg. 1990;20:275–282.PubMedCrossRefGoogle Scholar
  46. 46.
    Scagliotti GV, Selvaggi G, Novello S, Hirsch FR. The biology of epidermal growth factor receptor in lung cancer. Clin Cancer Res. 2004;10:4227s–4232s.PubMedCrossRefGoogle Scholar
  47. 47.
    Mansour EG, Ravdin PM, Dressler L. Prognostic factors in early breast carcinoma. Cancer. 1994;74:381–400.PubMedCrossRefGoogle Scholar
  48. 48.
    Vet JA, Debruyne FM, Schalken JA. Molecular prognostic factors in bladder cancer. World J Urol. 1994;12:84–88.PubMedCrossRefGoogle Scholar
  49. 49.
    O’Dwyer PJ, Benson AB III. Epidermal growth factor receptor-targeted therapy in colorectal cancer. Semin Oncol. 2002;29:10–17.PubMedGoogle Scholar
  50. 50.
    Yacoub L, Goldman H, Odze RD. Transforming growth factor-alpha, epidermal growth factor receptor, and MiB-1 expression in Barrett’s-associated neoplasia: correlation with prognosis. Mod Pathol. 1997;10:105–112.PubMedGoogle Scholar
  51. 51.
    Lazebnik Y. What are the hallmarks of cancer? Nat Rev Cancer. 2010;10:232–233.PubMedCrossRefGoogle Scholar
  52. 52.
    Yarden Y. The EGFR family and its ligands in human cancer. Signalling mechanisms and therapeutic opportunities. Eur J Cancer Engl. 2001;37:S3–S8.CrossRefGoogle Scholar
  53. 53.
    Voldborg BR, Damstrup L, Spang-Thomsen M, Poulsen HS. Epidermal growth factor receptor (EGFR) and EGFR mutations, function and possible role in clinical trials. Ann Oncol. 1997;8:1197–1206.PubMedCrossRefGoogle Scholar
  54. 54.
    Hanahan D, Weinberg RA. The hallmarks of cancer. Cell. 2000;100:57–70.PubMedCrossRefGoogle Scholar
  55. 55.
    Okawa T, Michaylira CZ, Kalabis J, et al. The functional interplay between EGFR overexpression, hTERT activation, and p53 mutation in esophageal epithelial cells with activation of stromal fibroblasts induces tumor development, invasion, and differentiation. Genes Dev. 2007;21:2788–2803.PubMedCrossRefGoogle Scholar
  56. 56.
    Logan A. Intracrine regulation at the nucleus–a further mechanism of growth factor activity? J Endocrinol. 1990;125:339–343.PubMedCrossRefGoogle Scholar
  57. 57.
    Aaronson SA. Growth factors and cancer. Science. 1991;254:1146–1153.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2012

Authors and Affiliations

  • Guilherme Pretto
    • 1
    Email author
  • Richard Ricachenevsky Gurski
    • 1
  • Marcelo Binato
    • 2
  • Daniel Navarini
    • 1
  • Wolfgan William Schmidt Aguiar
    • 1
  • Luise Meurer
    • 3
  1. 1.Department of Surgery, Post Graduation Program in Digestive SurgeryHospital de Clínicas de Porto AlegrePorto AlegreBrazil
  2. 2.Department of Surgery, Post Graduation Program in Digestive SurgeryFederal University of Santa MariaSanta MariaBrazil
  3. 3.Department of Pathology Hospital de Clínicas de Porto AlegrePorto AlegreBrazil

Personalised recommendations