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The contribution of intraepithelial inflammatory cells to the histological diagnosis of microscopic esophagitis

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Abstract

Background

Diagnosis of gastro-esophageal reflux disease (GERD) is mainly based on symptom evaluation, possibly coupled with various invasive investigations (endoscopy, pH-metry, and impedance). New input has recently come from histology: in this context, the diagnostic role of inflammatory cells other than eosinophils and neutrophils is still debated. Aim of the study is to evaluate the diagnostic relevance of intraepithelial lymphocytes, mast cells, and Langerhans cells in GERD-associated microscopic esophagitis (GAME).

Methods

Twenty healthy volunteers and 119 patients with GERD symptoms were prospectively recruited and subdivided, on the basis of endoscopy and pH-metry, in erosive (ERD, 48) and non-erosive disease (NERD, 71). Biopsy samples at 2 cm above the Z-line and at Z-line were evaluated for GERD-associated histological lesions (basal cell hyperplasia, papillae elongation, intercellular space dilatation, intraepithelial eosinophils, and neutrophils). Immunohistochemistry for T lymphocytes (CD3, CD4, CD8), B lymphocytes (CD20), NK cells (CD56), macrophages (CD68), mast cells (c-Kit), and Langerhans cells (S100) was performed.

Results

Among inflammatory cells, only intraepithelial T lymphocytes (ITLs) showed statistical correlation with the other histological lesions both in ERD and NERD. ITLs distinguished GERD patients from controls with good sensitivity and specificity (85.5 and 85 % at 2 cm above Z-line; 89.5 and 75 % at Z-line) when a cut-off of 20 cells was applied. An analysis of the T subpopulations found a CD4+/CD8+ ratio close to 1:1; B cells, mast cells, Langerhans cells, NK cells, and macrophages showed a limited role in GERD.

Conclusions

ITL evaluation represents an additional useful parameter in the histological evaluation of GAME.

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References

  1. Dent J, Vakil N, Jones R, et al. Accuracy of the diagnosis of GORD by questionnaire, physicians and a trial of proton pump inhibitor treatment: the Diamond Study. Gut. 2010;59:714–21.

    Article  PubMed  Google Scholar 

  2. Vakil N, van Zanten SV, Kahrilas P, et al. The Montreal definition and classification of gastroesophageal reflux disease: a global evidence-based consensus. Am J Gastroenterol. 2006;101:1900–20.

    Article  PubMed  Google Scholar 

  3. Dent J, El-Serag HB, Wallander MA, Johansson S. Epidemiology of gastro-oesophageal reflux disease: a systematic review. Gut. 2005;54:710–7.

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  4. El-Serag HB. Time trends of gastroesophageal reflux disease: a systematic review. Clin Gastroenterol Hepatol. 2007;5:17–26.

    Article  PubMed  Google Scholar 

  5. Li YM, Du J, Zhang H, et al. Epidemiological investigation in outpatients with symptomatic gastroesophageal reflux from the Department of Medicine in Zhejiang Province, east China. J Gastroenterol Hepatol. 2008;23:283–9.

    Article  PubMed  Google Scholar 

  6. Shaheen NJ, Hansen RA, Morgan DR, et al. The burden of gastrointestinal and liver diseases, 2006. Am J Gastroenterol. 2006;101:2128–38.

    Article  PubMed  Google Scholar 

  7. Calabrese C, Fabbri A, Bortolotti M, et al. Dilated intercellular spaces as a marker of oesophageal damage: comparative results in gastro-oesophageal reflux disease with or without bile reflux. Aliment Pharmacol Ther. 2003;18:525–32.

    Article  PubMed  CAS  Google Scholar 

  8. Solcia E, Villani L, Luinetti O, et al. Altered intercellular glycoconjugates and dilated intercellular spaces of esophageal epithelium in reflux disease. Virchows Arch. 2000;436:207–16.

    Article  PubMed  CAS  Google Scholar 

  9. Villanacci V, Grigolato PG, Cestari R, et al. Dilated intercellular spaces as markers of reflux disease: histology, semiquantitative score and morphometry upon light microscopy. Digestion. 2001;64:1–8.

    Article  PubMed  CAS  Google Scholar 

  10. Mastracci L, Spaggiari P, Grillo F, et al. Microscopic esophagitis in gastro-esophageal reflux disease: individual lesions, biopsy sampling, and clinical correlations. Virchows Arch. 2009;454:31–9.

    Article  PubMed  Google Scholar 

  11. Zentilin P, Savarino V, Mastracci L, et al. Reassessment of the diagnostic value of histology in patients with GERD, using multiple biopsy sites and an appropriate control group. Am J Gastroenterol. 2005;100:2299–306.

    Article  PubMed  Google Scholar 

  12. Fiocca R, Mastracci L, Riddell R, et al. Development of consensus guidelines for the histologic recognition of microscopic esophagitis in patients with gastroesophageal reflux disease: the Esohisto project. Hum Pathol. 2010;41:223–31.

    Article  PubMed  Google Scholar 

  13. Yerian L, Fiocca R, Mastracci L, et al. Refinement and reproducibility of histologic criteria for the assessment of microscopic lesions in patients with gastroesophageal reflux disease: the Esohisto project. Dig Dis Sci. 2011;56:2656–65.

    Article  PubMed  Google Scholar 

  14. Palmer ED. Subacute erosive (“peptic”) esophagitis: clinical study of one hundred cases. AMA Arch Intern Med. 1954;94:364–74.

    Article  PubMed  CAS  Google Scholar 

  15. Lodge KV. The pathology of non-specific oesophagitis. J Pathol Bacteriol. 1955;69:17–24.

    Article  PubMed  CAS  Google Scholar 

  16. Peters PM. The pathology of severe digestion oesophagitis. Thorax. 1955;10:270–86.

    PubMed  CAS  Google Scholar 

  17. Ismail-Beigi F, Horton PF, Pope CE. Histological consequences of gastroesophageal reflux in man. Gastroenterology. 1970;58:163–74.

    PubMed  CAS  Google Scholar 

  18. Seefeld U, Krejs GJ, Siebenmann RE, Blum AL. Esophageal histology in gastroesophageal reflux. Morphometric findings in suction biopsies. Am J Dig Dis. 1977;22:956–64.

    Article  PubMed  CAS  Google Scholar 

  19. Schindlbeck NE, Wiebecke B, Klauser AG, Voderholzer WA, Müller-Lissner SA. Diagnostic value of histology in non-erosive gastro-oesophageal reflux disease. Gut. 1996;39:151–4.

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  20. Collins BJ, Elliott H, Sloan JM, McFarland RJ, Love AH. Oesophageal histology in reflux oesophagitis. J Clin Pathol. 1985;38:1265–72.

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  21. Mangano MM, Antonioli DA, Schnitt SJ, Wang HH. Nature and significance of cells with irregular nuclear contours in esophageal mucosal biopsies. Mod Pathol. 1992;5:191–6.

    PubMed  CAS  Google Scholar 

  22. Wang HH, Mangano MM, Antonioli DA. Evaluation of T-lymphocytes in esophageal mucosal biopsies. Mod Pathol. 1994;7:55–8.

    PubMed  CAS  Google Scholar 

  23. Geboes K, De Wolf-Peeters C, Rutgeerts P, Janssens J, Vantrappen G, Desmet V. Lymphocytes and Langerhans cells in the human oesophageal epithelium. Virchows Arch A Pathol Anat Histopathol. 1983;401:45–55.

    Article  PubMed  CAS  Google Scholar 

  24. Barclay RL, Dinda PK, Morris GP, Paterson WG. Morphological evidence of mast cell degranulation in an animal model of acid-induced esophageal mucosal injury. Dig Dis Sci. 1995;40:1651–8.

    Article  PubMed  CAS  Google Scholar 

  25. Morganstern JA, Wang MY, Wershil BK. Direct evidence of mast cell participation in acute acid-induced esophageal inflammation in mice. J Pediatr Gastroenterol Nutr. 2008;46:134–8.

    Article  PubMed  Google Scholar 

  26. Martinelli F, Odze R, Furuta GT, et al. Mast cell numbers in the esophagus are increased in association with specialized intestinal metaplasia. Gastroenterology. 1995;108:A159.

    Article  Google Scholar 

  27. Justinich CJ, Kafalus D, Esposito P, et al. Mucosal mast cells distinguish allergic from gastresophageal reflux-induced esophagitis. J Pediatr Gastroenterol Nutr. 1996;23:342.

    Article  Google Scholar 

  28. Mastracci L, Grillo F, Zentilin P, et al. Cell proliferation of squamous epithelium in gastro-oesophageal reflux disease: correlations with clinical, endoscopic and morphological data. Aliment Pharmacol Ther. 2007;25:637–45.

    Article  PubMed  CAS  Google Scholar 

  29. Carlsson R, Dent J, Bolling-Sternevald E, et al. The usefulness of a structured questionnaire in the assessment of symptomatic gastroesophageal reflux disease. Scand J Gastroenterol. 1998;33:1023–9.

    Article  PubMed  CAS  Google Scholar 

  30. Ballem CM, Fletcher HW, McKenna RD. The diagnosis of esophagitis. Am J Dig Dis. 1960;5:88–93.

    Article  PubMed  CAS  Google Scholar 

  31. Brown LF, Goldman H, Antonioli DA. Intraepithelial eosinophils in endoscopic biopsies of adults with reflux esophagitis. Am J Surg Pathol. 1984;8:899–905.

    Article  PubMed  CAS  Google Scholar 

  32. Winter HS, Madara JL, Stafford RJ, Grand RJ, Quinlan JE, Goldman H. Intraepithelial eosinophils: a new diagnostic criterion for reflux esophagitis. Gastroenterology. 1982;83:818–23.

    PubMed  CAS  Google Scholar 

  33. Moons LM, Kusters JG, Bultman E, et al. Barrett’s oesophagus is characterized by a predominantly humoral inflammatory response. J Pathol. 2005;207:269–76.

    Article  PubMed  CAS  Google Scholar 

  34. Kirsch R, Bokhary R, Margaret A, Cutz E. Activated mucosal mast cells differentiate eosinophilic (allergic) esophagitis from gastroesophageal reflux disease. J Pediatr Gastroenterol Nutr. 2007;44:20–6.

    Article  PubMed  Google Scholar 

  35. Yassin TM, Toner PG. Langerhans cells in the human oesophagus. J Anat. 1976;122:435–45.

    PubMed  CAS  PubMed Central  Google Scholar 

  36. Black DD, Haggitt RC, Orenstein SR, Whitington PF. Esophagitis in infants. Morphometric histological diagnosis and correlation with measures of gastroesophageal reflux. Gastroenterology. 1990;98:1408–14.

    PubMed  CAS  Google Scholar 

  37. Vieth M, Peitz U, Labenz J, et al. What parameters are relevant for the histological diagnosis of gastroesophageal reflux disease without Barrett’s mucosa? Dig Dis. 2004;22:196–201.

    Article  PubMed  CAS  Google Scholar 

  38. Schneider NI, Plieschnegger W, Geppert M, et al. Validation study of the Esohisto consensus guidelines for the recognition of microscopic esophagitis (histoGERD trial). Hum Pathol. 2014;45:994–1002.

    Article  PubMed  Google Scholar 

  39. Savarino E, Zentilin P, Mastracci L, et al. Microscopic esophagitis distinguishes patients with non-erosive reflux disease from those with functional heartburn. J Gastroenterol. 2013;48:473–82.

    Article  PubMed  Google Scholar 

  40. Resnick MB, Finkelstein Y, Weissler A, et al. Assessment and diagnostic utility of the cytotoxic T-lymphocyte phenotype using the specific markers granzyme-B and TIA-1 in esophageal mucosal biopsies. Hum Pathol. 1999;30:397–402.

    Article  PubMed  CAS  Google Scholar 

  41. Rubio CA, Sjodahl K, Lagergren J. Lymphocytic esophagitis. A histologic subset of chronic esophagitis. Am J Clin Pathol. 2006;125:432–7.

    Article  PubMed  Google Scholar 

  42. Tantibhaedhyangkul U, Tatevian N, Gilger MA, et al. Increased esophageal regulatory T cells and eosinophils characteristics in children with eosinophilic esophagitis and gastroesophageal reflux disease. Ann Clin Lab Sci. 2009;39:99–107.

    PubMed  CAS  Google Scholar 

  43. Haque S, Genta RM. Lymphocytic oesophagitis: clinicopathological aspects of an emerging condition. Gut. 2012;61:1108–14.

    Article  PubMed  Google Scholar 

  44. Ronkainen J, Walker MM, Aro P, et al. Lymphocytic oesophagitis, a condition in search of a disease? Gut. 2012;61:1776.

    Article  PubMed  Google Scholar 

Download references

Acknowledgments

We thank Simona Pigozzi and Silvia Bonadio for technical support and Sonia Massa and Margherita Colombara for secretarial support.

Statement of Human Rights

All procedures followed were in accordance with the ethical standards of the responsible committee on human experimentation (institutional and national) and with the Helsinki Declaration of 1975, as revised in 2008. Informed consent was obtained from all patients for being included in the study.

Conflict of interest

Luca Mastracci, Martina Bruzzone, Elena Pacella, Carmine Tinelli, Patrizia Zentilin, Edoardo Savarino, Annalisa De Silvestri, Roberto Fiocca, and Federica Grillo declare that they have no conflict of interest.

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Mastracci, L., Bruzzone, M., Pacella, E. et al. The contribution of intraepithelial inflammatory cells to the histological diagnosis of microscopic esophagitis. Esophagus 13, 80–87 (2016). https://doi.org/10.1007/s10388-015-0501-9

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  • DOI: https://doi.org/10.1007/s10388-015-0501-9

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